BAT Notes

BAT Notes
2017 A/L Repeat Campaign

Term 1
Anatomy – Term 1
VERTEBRAL COLUMN
33 vertebrae. 7 – Cervical, 12 – Thoracic, 5 – Lumbar, 5 – Sacral, 4 – Coccygeal
Flexibility of column 24 movable vertebrae

Vertebrae and many intervertebral joints close together
curvatures / sinuous bends in the column
• 1ry curvatures - concave forward

thoracic curve & sacral curve
• 2ry curvature - convex forward

 cervical curvature (4-5 months) - infant starts supporting its head
 lumbar curve (12- 18 months ) - Child assumes upright position
typical vertebra body pedicles

neural arch laminae
processes transverse processes - 2

spinous process sup. articular processes - 2 &
inf. articular processes – 2
• related ligaments
01. Anterior longitudinal ligament - attached to body and intervertebral disc. More strongly to body.
Extend from base of skull to anterior of sacrum
02. Posterior longitudinal ligament - attached to body and intervertebral disc. More strongly to disc.
Starts from axis. Lines part of anterior surface of vertebral canal
03. ligamentum flavum - connects laminae. Lines the posterior surface of vertebral canal
04. Interspinous ligament - unites spinous processes along adjacent borders. Well developed in
lumbar region
05. Supraspinous ligament - joins tips of spinous processes up to spine of C7
06. Intertansverse ligament - joins transverse processes along adjacent borders
07. ligamentum nuchae – extends from C7 spine to the external occipital protuberance.
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Vertebra Body Vertebral foramen Transverse process Spine
Cervical presence of foramina transeversaria
sup.surface ●Larger than body, ●ant.root/tubercle ●short
●Kidney shaped ●triangular ●costotransverse bar ●bifid
●concave ●pos.root/tubercle ●filled with
transversely ●foramen ligamentum
●lips/uncus - transversarium nuchae
Typical C3-C6
laterally transmits vertebral.
Inferior surface artery, venous plexus,
●saddle shaped sympathetic fibres
●C6 ant.tubercle-large
carotid tubercle
Atlas C1 ●no body, no spine, ring shaped
●median anterior tubercle → post. side oval facet for dens
●median posterior tubercle
●groove in superior surface → vertebral artery
●superior articular facet → concave atlanto-occipital joint condyle
●inferior articular facet → flat atlantoaxial joint
Atypical
Axis C2. ●dens from the superior surface of the body
●only posterior tubercle present
●massive spinous process
Vertebra ●thick long nearly horizontal spine, not bifid, ends in tubercle
Prominens C7 ●only posterior tubercle present
Foramen transversarium doesn't transmit vertebral artery, only the vein
Thoracic vertebra costal facets on body and transverse processes

Typical T2- T8 ●heart shaped ●small, circular costal facets ●long
●Costal [demi] ●downward &
facets: upper 6 lower 6 backward
superior-larger
inferior-smaller concave flat
Atypical T1 ●cervical type
●superior costal nearly horizontal
facet complete
T9 ●inferior costal
facet missing
T10 ●superior costal
facet complete
T11 ●superior costal no facet

facet complete
T12 ●superior costal ●3 tubercles horizontal

facet complete superior, inferior, lateral

Lumbar vertebrae *No costal facet or foramina transeversaria
Typical L1 - L4 ● thin, tapering
●postero-superior root→
● Large Quadrilateral
● Triangular (medium) mammillary process
● Kidney shape plate
●postero-inferior root→
accessory process
Atypical L5 ●Transverse process a ached to whole thickness of pedicle & also the body
●thick, short, pyramidal in shape.
●Distance between inferior articular processes equal or more than between sup. art.
processes
●Spine- rounded at tip
Sacrum  Base ●sacral promontory – anteriorly
●sacral canal – triangular
●transverse process + costal elements – Ala
 apex - oval facet for coccyx
 Pelvic surface - concave

▪ 4 transverse ridges
▪ 4 anterior sacral foramina
 Dorsal surface - median sacral crest – spines

- Sacral hiatus
- articular processes - sup. of S1 – free
- inf. of S5 - sacral cornua
- 4 dorsal sacral foramina
- lateral sacral crest – fusion of transverse processes
- intermediate sacral crest – fusion of articular facets
Thoracic spines
T1, T2—horizontal
T3, T4—oblique
T5-T8—vertical
T9, T10—oblique
T11, T12 – horizontal

Atlas Axis
Typical Cervical Typical Thoracic Typical Lumbar

JOINTS OF THE VERTEBRAL COLUMN
I. Intervertebral joints
a) Zygapophyseal joints - between superior & inferior articular facets
Synovial joint
Cervical region: articular facets lie obliquely
Thoracic region: articular facets lie in an arc
In lumbar region: articular facets interlock
b) intervertebral discs -
between vertebral bodies
secondary cartilaginous
thickest in lumbar region
outer: annulus fibrosus - fine meshwork of collagen & fibrocartilage
- Weak posterolaterally
inner: nucleus pulposus – semiliquid gelatinous substance
- Remnant of notochord
II. Atlanto – occipital joint
• Type : synovial joint of ellipsoid variety
• Articular surfaces : above - occipital condyles

below - superior articular facet of atlas
• Ligaments : Capsular ligament - thick posterolaterally, thin anteromedially
Anterior atlanto-occipital membrane - from foramen magnum above
to anterior arch of atlas
Posterior atlanto-occipital membrane - from foramen magnum
above to posterior arch of atlas
o Movements. : flexion & extension around a transverse axis
Slight lateral flexion around anteroposterior axis
o Arterial supply : vertebral artery
o Nerve supply : first cervical nerve
III. Atlanto – axial joint

▪ Pair of lateral atlanto-axial joints between inferior facets of the atlas &
superior facet of the axis – PLANE JOINTS
▪ Median atlanto-axial joint between anterior arch of atlas, transverse
ligament & dens – PIVOT JOINT
 4 Ligaments: Capsular ligament , anterior longitudinal ligament , ligamentum flavum

 Movements : rotatory movements at all 3 joints
Transverse ligament
 a broad, strong band which arches across the atlantal ring behind the dens
 attached on each side to the medial surface of the lateral mass of the atlas
 in the median plane prolonged upwards to basiocciput and downwards to body of
axis forming cruciform ligament
 prevent dislocation of dens
apical ligament – from tip of dens to foramen magnum
apical ligament – from sides of dens to sides of foramen magnum. Resists rotation.
Clinicals
 Death in execution is due to the rupture of the transverse ligament of dens, which then
compress the medulla oblongata & spinal cord
 Cervical spondylosis
 Due to the horizontal position of articular facets, dislocation occurs without fracture
Intervertebral foramen – spinal nerve emerges through
Superior & inferior margins – pedicles of vertebra above & below
Posterior margin - articular processes of vertebral arches & zygapophyseal joint
Anterior margin - intervertebral disc & adjacent bodies of vertebra above & below
Vertebral canal
Formed by continuation of vertebral foramina
Boundaries - anterior wall: vertebral bodies, intervertebral discs & posterior longitudinal
ligament
-posterior wall: ligamentum flavum & vertebral arches.
Contents – spinal cord
Meninges
Internal vertebral venous plexus
Epidural/extradural space – a potential space containing extradural fat, connective tissue & internal
vertebral venous plexus

Movements of vertebral column
 Lumbar – articular facets lie in anteroposterior plane, limits rotation greatly

Flexion and extension possible
Lateral flexion possible
 Thoracic – rotation possible

Flexion, extension and lateral flexion possible
 Cervical- flexion and extension free

pure rotation impossible
Lateral flexion is not a pure movement
Clinical
• 1/5 of height of vertebral column – Intervertebral disc
01. Disc prolapse [slip disc]
Trauma Degenerative disease Sudden stress
Rupture of annulus fibrosus in its weak posterolateral portion
protrusion of nucleus pulposus mostly posterolateral

[sometimes directly backwards, can compress all the nerves below the level. Ex: When cauda equina is compressed- paraplegia]
pressure on the spinal nerve below
Irritation of the nerve root 01.pain 02 .muscle weakness

03.stiffness 04. Paresthesia
** Affected nerve roots,
 most commonly - lower lumbar L4/L5, L5/S1 sciatic nerve is affected
 less commonly - lower cervical C5/C6, C6/C7
02. Spina bifida

• 2 halves of the neural arch fail to fuse. Causes spinal canal infection & ultimately, death.
** No protrusion, but spina bifida is present spina bifida occulta (commonest type)
** spina bifida cystica with,
•herniated meninges meningocele
•herniated meninges + spinal cord meningomyelocele
** posteriorly opened spinal cord myelocele

03. Spondylosis
• Degenerating changes with ageing
• If causes spinal cord compressions back pain
04. Spondylolysis
• Inf. articular processes, spine & laminae vertebra separate from rest of body due to
fracture of pars interarticularis (loss of scotty dog appearance)
Common in L5
05. Spondylolisthesis
• Forward slippage of vertebral body
06. Abnormalities of curves
• Normal vertebral column is a straight line in A/P view.

I. Postural curvature
• Because of muscle abnormalities [ not due to abnormalities in vertebral column]
II. Anterior- posterior curvature abnormalities
A. Kyphosis - Increased concavity anteriorly [thoracic]

[humpback/ hunchback]
• Due to erosion of ant. part of one or more vertebrae.
• Overall reduction of height
B. Lordosis - Increased convexity anteriorly [lumbar]
III. Lateral curvature abnormalities
C. Scoliosis - Accompanied by rotation of the vertebrae

• Asymmetric weakness of intrinsic back muscle Myopathic scoliosis
• Failure of half of vertebra to develop hemivertebra
• Difference in length of lower limbs [disappears when seated down]
• Habitual standing, sitting or improper position Habit scoliosis
[if entirely postural - disappears with max. flexion]
 Common in Klinefelter syndrome
07. Lumbar Puncture
• Done to - obtain CSF

- inject local anaesthetic drugs
• At the level of L4/L5 vertebra Highest point of iliac crest
(spinal cord finishes at lower border of L1)
• Spine is flexed to maximise the gap between 2 vertebral arches
•Structures pierced
- Skin
- Superficial fascia
- Supraspinous ligament

- Interspinous ligament
- Ligamentum flavum
- Dura mater, Arachnoid mater
08. Epidural anaesthesia – anaesthetics can be injected into epidural space for surgical
requirements
09. Spread of cancers – prostatic, breast & cervical cancers can spread into external vertebral
venous plexus via valveless connections & then into any part in the body
Stability of the spine

3 column concept
Ant. column Middle column post. Column

- body - body - facets
annulus fibrosus ant. annulus fibrosus pos. - everything posterior to
nucleus pulposus nucleus pulposus post. lon. lig.
- ant. lon. lig. - pos. lon. lig.
- fractures stable - unstable - unstable

Bones of Upper Limb
Clavicle
 Long bone – shaft, medial & lateral ends

 Transmits weight from upper limb to sternum .
 Side determination
- Lat. End – flat
Med. End – large, quadrilateral
- Med. 2/3 of shaft – convex forwards
Lat. 1/3 of shaft – concave forwards
- Inf. Surface – middle 1/3 – presence of a longitudinal groove (Groove for Subclavius)
- Conoid tubercle and trapezoid ridge- for 2 parts of coracoclavicular ligament
 Special features
- Only long bone which lies horizontally
- Subcutaneous throughout
- 1st bone to start ossifying
- Only long bone which has a membranous ossification
- Only long bone which has 2 primary centers of
ossification
- Generally, has no medullary cavity
- The supraclavicular nerves crossing it can be rolled
against the bone
Shaft
o Lateral 1/3
 Flattened from above downwards
 Anterior border concave forwards, posterior
border convex backwards
 Superior surface is subcutaneous, inferior
surface has an elevation – conoid tubercle, and
a ridge- trapezoid ridge
o Medial 2/3
 Rounded
 Anterior surface convex forwards
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 Posterior surface smooth
 Superior surface rough in the medial part
 Inferior surface has a rough oval impression at the medial end for costoclavicular
ligament
 Lateral half of the inferior surface has a longitudinal subclavian groove. The nutrient
foramen lies in the lateral part of the groove
The ends
o Medial
 Sternal end
 Quadrangular
 Articulates with the clavicular notch of the manubrium to form the sternoclavicular
joint
 Articular surface extends up to the inferior aspect to articulate with the 1 st costal
cartilage
o Lateral
 Acromial end
 Flatten from above downwards
 Has a facet for the acromion and forms the acromioclavicular joint
Attachments
 Margins of the lateral and medial articular surfaces give attachment to the joint capsules

 In the medial 2/3s of the shaft the subclavian vessels and cords of brachial plexus lie
between the inferior surface of the clavicle and upper surface of the first rib. Subclavius
muscle acts as a cushion.
Clinical
 Fracture
- Commonest site – junction between medial 2/3 & lat. 1/3 (weakest point) between
costoclavicular and coracoclavicular ligament
- Caused by falling on the outstretched hand
- Lat. fragment – displaces downwards by the weight of the upper limb
- Med. fragment – displaces upwards by the action of sternocleidomastoid
- Adductor muscles spasm – adduction of the arm
Dislocation
 Can be from either end

 Medial end
- Usually dislocates forwards - presence of costoclavicular ligament posteriorly
-The articular disc of the sternoclavicular joint is attached to the clavicle above and to
manubrium below- prevents the medial end from tilting upwards
 lateral end
-the clavicle dislocates upwards because the clavicle overrides the acromion
 Weight transmission
1. Scapula
2. Coracoclavicular ligament
3. Clavicle
4. Sternoclavicular joint to sternum or
5. Costoclavicular ligament to first rib
Therefore, the clavicle usually fractures between the two ligaments

SCAPULA
Triangular-shaped, thin bone. from 2nd to 7th rib level
Side determination
 Glenoid cavity- lies laterally and superiorly

 Dorsal surface -convex and divided into two fossae by the spine
2 surfaces
1. Costal – subscapular fossa. Directed medially and forwards. Have three longitudinal ridges.
2. Dorsal – spine of scapula is present. It divides the surface into supraspinous and infraspinous
fossae. Two fossae connected through spinoglenoid notch laterally.
3 borders
1. Superior- thin and short. Suprascapular notch present at the root of coracoid process
2. Lateral- thick. At the upper end the infraglenoid tubercle is present
3. Medial- thin.

3 angles
1. Superior- covered by trapezius

2. Inferior- covered by latissimus dorsi. Moves forwards when the arm is abducted.
3. Lateral/glenoid- bears the glenoid fossa which is directed forwards, laterally and slightly
upwards. It’s somewhat comma-shaped
3 processes
1. Spine- triangular. Has 3 borders and 2 surfaces. The posterior border is called the crest of
spine which has upper and lower lips.
2. Acromion- has medial and lateral borders. Has superior and inferior surfaces. Has an oval
facet for clavicle.
3. Coracoid- directed forwards and slightly laterally. Directly inferior to lateral part of the
clavicle. Bent. Has an atavistic type of epiphysis.
Muscle attachments
Clinical
 Winging of scapula
 Due to paralysis of serratus anterior
 Medial border becomes unduly prominent.
 Arm cannot be abducted beyond 90 degrees.
 Scaphoid scapula
 Development anomaly.
 Medial border is concave.
 Fracture
 Rare.
 Strong thick covering of muscles protects it.
 Only by direct and severe violence.
 Suprascapular nerve and vessels
Navy under the bridge (superior transverse scapular ligament), Army over the bridge
Movements
Humerus

The Humerus
Upper End Shaft Lower End
1) Head of humerus Rounded in the upper half and triangular Articular

in lower half
Directed medially backwards and upwards Capitulum- head of the radius
Forms about 1/3rd of sphere larger than 3 borders- Anterior, Medial, Lateral lateral
glenoid cavity (1:4) hemispherical
3 surfaces – Anterolateral Projects anteriorly and somewhat inferiorly
2) Anatomical neck-conscriction immeadiate Not visible on posterior aspect of humerus
distal to head Anteromedial Trochlea- trochlear notch of ulnar
Medial
3) Lesser tubercle (anterior aspect) Posterior Pulley shaped
subscapularis attachment Medial edge projects down more than
Deltoid tuberosity in anterolateral surface lateral edge
4) Greater tubercle marked by 3 impressions behind runs downwards the radial groove Extends onto posterior surface of Humerus
Upper-supraspinatus Nutrient foramen in anteromedial surface

Non-articular part consists of epicondyles
Middle- infraspinatus and fossae
Posterior aspect bears radial groove
Lower -Teres minor Lateral epicondyle - less pronounced
demarcating medial and lateral heads of
gives attachment to posterior compartment
5) Intertubercular sulcus has medial and triceps
muscles of forearm
lateral lips, accommodates upper part of biceps Medial epicondyle - major palpable
tendon landmark
gives attachment to the anterior
Floor-latissimus dorsi compartment muscles of forearm
3 fossae – radial, coronoid and olecranon
Lateral lip-pecroralis major Radial- Least distinct
Immediately superior to the capitulum
Medial lip-Teres major Accommodates head of radius when flexed
Coronoid-Adjacent to radial fossa
Lateral lip continues inferiorly as deltoid
Superior to trochlea
tuberosity
Accommodates coronoid process of ulna
when flexed
6) Surgical neck-Between expanded upper end
Olecranon
and the shaft
Larges
Immediately superior to trochlea In
related to axillary nerve and posterior
Posterior surface
circumflex humeral artery posteriorly
accommodates olecranon process of ulna
when extended

Related nerves Related arteries
- Surgical neck - Axillary nerve - Posterior circumflex humeral

- Radial groove - Radial nerve - Profunda Brachii
- Posterior to the medial - Ulnar nerve - Superior Ulnar collateral
epicondyle
Common sites of FRACTURE
- Surgical neck – axillary nerve more prone to damage

- Shaft – radial nerve liable to injury
- Supracondylar region
- Elbow is unduly prominent. But 3 bony points are in usual equilateral triangle
- May cause damage to median nerve
- Volkmann’s ischemic contracture
- Lower end of the proximal fragment, damages the brachial artery Ischemia of the
forearm muscles fibrosis & contraction of long flexors & extensors
flexors are bulkier than extensors wrist – flexed
M/P – extend
I/P – flexed
Radius & Ulna

Radius
 The radius consists of a head, neck, shaft

and an expanded lower end
Side determination:
 Upper end has a disc shaped head and

lower end is expanded with a styloid
process on the lateral side
 Lower end presents a tubercle of Lister
on the posterior aspect
 Sharpest border is the medial border and
it presents the radial tuberosity close to
the neck
Upper end
 Head – superior concave surface which

articulates with the capitulum of humerus
at the elbow joint
 Circumference of head is also articular. It
fits into the socket formed by the radial notch of ulna and the annular ligament
Shaft
 Has 3 borders of which medial border is sharpest

 Anterior border- extends from anterior margin of radial tuberosity to the styloid process
 Posterior border- is a mirror image of anterior border
 Medial- extends from the radial tuberosity to the posterior margin of ulnar notch below
Lower end
 Radial artery is palpated on the anterior surface

 Posterior surface- 4 grooves for the extensor tendons
-dorsal tubercle of lister lies lateral to an oblique groove
 Medial surface- occupied by ulna notch for head of ulna
 Lateral surface- styloid process
Inferior surface- area for scaphoid and lunate which take part in forming the wrist joint
Clinical – Radius
 Commonly fractured 1” proximal to the wrist

 Colles’ fracture
- More common
- Distal fragment dislocates backwards & upwards
- Radial styloid process becomes proximal to the ulnar styloid process
 Smith’s fracture
- Reverse of Colles’ fracture
 Subluxation of head of the radius
- Common in children
- Head is dislodged from the grip of annular ligament (reason)
Ulna
Side determination
 The upper end is hook like with its concavity directed forwards
 Lateral border is sharp and crest like
 Pointed styloid process lies posteromedial to the rounded head of ulna at its lower end
Upper end
 Presents :
Olecranon process- projects up from the shaft
Coronoid process- just below olecranon process
Trochlear notch-articular surface for trochlear of humerus to form the elbow joint
Radial notch- for head of radius
Shaft
 3 borders
 Lateral border is the sharpest
 Posterior border is subcutaneous and is not crossed and therefore can be exposed surgically
 Anterior border terminates at the medial side of styloid process

Lower end
 Head and styloid process are present

 Head articulates with ulna notch of radius- inferior radioulnar joint
 Separated from joint by articular disc
 Ulnar nerve and artery lie anterior aspect of head of ulna
Clinical-
Dislocation of the elbow by a fall on the outstretched hand with the elbow slightly flexed. -
 The olecranon shifts posteriorly

 The elbow is slight flexion.
 Normally
 in an extended elbow, tip of the olecranon lies in un a horizontal line with the two
epicondyles of the humerus
 flexed elbow, the 3 bony points form an equilateral triangle.
These relations are disturbed in dislocation of the elbow
 Fracture of the olecranon is common and is caused by fall on the point of the elbow
 Miner’s elbow / Student’s elbow
- Subcutaneous bursa over the olecranon

- Inflamed when exposed to repeated trauma
- Olecranon bursitis
 Green stick fractures (common in children)-one side of bone is broken &other side only bent

Muscles of Upper Limb
Muscles of shoulder
Muscle Origin Insertion Innervation Function

Trapezius Superior nuchal line, Superior edge of the Motor: spinal Upper fibres: Powerful
* external occipital crest of the spine of part of elevator of the scapula
protuberance, the scapula, accessory during abduction of
medial margin of the medial margin of nerve (XI) humerus above horizontal
ligamentum nuchae, acromion, Sensory level
spinous process of C7 to posterior border of (proprioceptio middle fibres: retract
T12 and the related lateral one third of n): scapula
supraspinous ligaments clavicle anterior rami lower fibres: depress
of C3 and C4 scapula
Deltoid* Posterior fibers- Inferior Deltoid tuberosity of Axillary nerve Major abductor of arm
edge of the crest of the humerus (C5, C6) (abducts arm beyond
spine of the scapula initial 15 done by
Middle fibers- lateral supraspinatus)
margin of the acromion clavicular fibres: assist in
Anterior fibers- anterior flexing the arm
border of lateral one third posterior fibres: assist in
of clavicle extending the arm
Levator Transverse process of C1 Posterior surface of Branches Elevates the scapula
Scapulae and C2 vertebrae and medial border of directly from
posterior surface of scapula from anterior rami
transverse processes of superior angle to of C3 and C4
C3 and C4 vertebrae root of spine of the spinal nerves
scapula and by
branches (C5)
from dorsal
scapular nerve
Rhomboid Lower end of the Posterior surface of Dorsal Elevates and retracts the
minor ligamentum nuchae and medial border of scapular nerve scapula
spinous process of C7 and scapula at the root (C4, C5)
T1 vertebrae of the spine of the
scapula
Rhomboid Spinous process of T2-T5 Posterior surface of Dorsal Elevates and retracts the
major vertebrae and intervening medial border of scapular nerve scapula
supraspinous ligaments scapula from the (C4, C5)
root of the spine of
the scapula to the
inferior angle

Muscles of posterior scapular region

Supraspinatus Medial 2/3 of the Most superior Suprascapular Rotator cuff muscle;
* supraspinous fossa of the facet on the nerve (C5, C6) initiation of abduction of
scapula and the deep fascia greater tubercle arm to 15 at
that covers the muscle of the humerus glenohumeral joint
Infraspinatus Medial 2/3 of the Middle facet on Suprascapular Rotator cuff muscle;
* infraspinous fossa of the posterior nerve (C5, C6) Lateral rotation of arm at
scapula and the deep fascia surface of the the glenohumeral joint
that covers the muscle great tubercle
of the humerus
Teres minor* Upper 2/3 of a flattened Inferior facet on Axillary nerve Rotator cuff muscle;
strip of bone on the the posterior (C5, C6) lateral rotation of arm at
posterior surface of the surface of the the glenohumeral joint
scapula immediately greater tubercle
adjacent to the lateral of the humerus
border of the scapula
Teres major* Elongate oval area on the Medial lip of Inferior Medial rotation and
posterior surface of the the subscapular extension of the arm at
inferior angle of the intertubercular nerve (C5, C6, the glenohumeral joint
scapula sulcus on the C7)
anterior surface
of the humerus
Muscles of anterior wall

Pectoralis Clavicular head-anterior Lateral lip of Medial and lateral Flexion, adduction
major* surface of medial half of intertubercular pectoral nerves; and medial rotation of
clavicle sulcus of clavicular head (C5, C6) arm at the
sternocostal head- humerus sternocostal head (C6, glenohumeral joint
anterior surface of C7, C8, T1) clavicular head-
sternum, flexion of extended
first seven costal arm
cartilages, sternocostal head-
sternal end of sixth rib, extension of flexed
aponeurosis of external arm
oblique
Subclavius First rib at junction Groove on Nerve to subclavius (C5, Pulls tip of shoulder
between rib and costal inferior surface C6) down
cartilage of middle one Pulls clavicle medially
third of clavicle to stabilize
sternoclavicular joint

Pectoralis Anterior surface and Coracoid Medial pectoral nerve Pulls tip of shoulder
minor* superior borders of ribs 3 process of (C5, C6, C7, C8, T1) down
to 5, scapula (medial Protracts the scapula
deep fascia overlying the border and
related intercostals space upper surface)
Muscles of medial wall of scapula

Serratus Lateral surface of upper 8 Costal surface Long Protraction and rotation of the
anterior* ribs and deep fascia of medial thoracic scapula keeps medial border
overlying the related border of nerve (C5, and inferior angle of scapula
intercostals spaces scapula C6, C7) opposed to thoracic wall
Muscles of the lateral and posterior wall of the axilla

Subscapularis Medial two thirds of Lesser tubercle Upper and lower Rotator cuff muscle;
* subscapular fossa of humerus subscapular medial rotation of the
nerves (C5, C6, arm at the
C7) glenohumeral joint
Teres major* Elongate oval area on the Medial lip of Lower Medial rotation,
posterior surface of the intertubercular subscapular extension of the arm at
inferior angle of the scapulasulcus on the nerve (C5, C6, the glenohumeral joint
anterior C7)
surface of the
humerus
Latissimus Spinous processes of lower 6 Floor of Thoracodorsal Adduction,
dorsi* thoracic vertebrae and intertubercular nerve (C6, C7, medial rotation,
related interspinous sulcus C8) extension of the arm at
ligaments; the glenohumeral joint
via the thoracolumbar fascia
to the spinous processes of
the lumbar vertebrae;
related interspinous
ligaments,
iliac crest
lower 3-4 ribs

Arm
Flexor Compartment

Coracobrachialis Apex of coracoid Linear roughening Flexor of the arm at the
process on mid shaft of glenohumeral joint
humerus on medial
side Musculocutaneous
Biceps brachii Long head- Radial tuberosity nerve Powerful flexor of the
supraglenoid (posterior border) forearm at the elbow
tubercle of joint the supinator of the
scapula forearm
short head-apex Accessory flexor of the
of coracoid arm at the glenohumeral
process joint
Brachialis Anterior aspect Tuberosity of the Musculocutaneous Powerful flexor of the
of humerus ulna nerve (C5, C6) forearm at the elbow
(medial and small contribution joint
lateral surfaces) by the radial nerve
and adjacent (C7) to lateral part
intermuscular of muscle
septae
Extensor compartment

Triceps Long head- infraglenoid Common Radial nerve Extension of the forearm at the
brachii tubercle of scapula tendon of (C6, C7,C8) elbow joint; long head can also
Medial head-posterior surface insertion on extend and adduct the arm at
of humerus the olecranon the shoulder joint
Lateral head-posterior surface process of
of humerus ulna Also a
few fibers to
capsule of
elbow joint
Long Infraglenoid tubercle on scapula Radial nerve Extension of the forearm at the
head of (C6, C7, C8) elbow joint; accessory abductor
triceps and extensor of the arm at the
brachii glenohumeral joint

Forearm
Flexor compartment
Superficial layer
Flexor Humeral head-medial Pisiform bone and then Ulnar nerve (C7, Flexes and adducts the
carpi epicondyle of via pisohamate and C8, T1) wrist joint
ulnaris humerus; pisometacarpal
ulnar head-olecranon ligaments into the
and posterior border hamate and base of
of ulna metacarpal 5
Palmaris Medial epicondyle of Palmar aponeurosis of Flexes wrist joint;
longus humerus hand because the palmar
aponeurosis anchors skin
of the hand, contraction
of the muscle resists
shearing forces when
gripping
Flexor Medial epicondyle of Base of metacarpals 2 Flexes and abducts the
carpi humerus and 3 Median nerve wrist
radialis
Pronator Humeral head-medial Roughening on lateral Pronation
teres epicondyle and surface, midshaft of
adjacent supra- radius
epicondylar ridge;
ulnar head-medial
side of coronoid
process
Intermediate layer

Flexor Humero-ulnar head- Four tendons which Median Flexes proximal interphalangeal
digitorum medial epicondyle of attach to the palmar nerve (C8, joints of the index, middle, ring
superficialis humerus and adjacent surfaces of the T1) and little finger
margin of coronoid middle phalanges of Can also flex metacarpo-
process the index, middle, phalangeal joints of the same
radial head-oblique ring and little finger fingers and the wrist joint
line of radius

Deep layer

Flexor Anterior and medial Four tendons which Lateral half by Flexes distal interphalangeal
digitorum surfaces of ulna and attach to the palmar median nerve joints f the index, middle,
profundus anterior medial half surfaces of the distal (anterior ring and little fingers
of interosseous phalanges of the index, interosseous Can also flex metacarpo-
membrane middle, ring and little nerve) medial phalangeal joints of the same
finger half by ulnar fingers and the wrist joint
nerve(C8,T1)
Flexor Anterior surface of Palmar surface of base Flexes interphalangeal joint
pollicis radius and radial of distal phalanx of of the thumb
longus half of interosseous thumb Median nerve Can also flex metacarpo-
membrane (anterior phalangeal joint of the
interosseous thumb
Pronator Linear ridge on Distal anterior surface nerve) Pronation
quadratus distal anterior of radius
surface of ulna
Extensor compartment
Superficial layer
Brachioradial Proximal part of Lateral surface of Radial nerve (C5, Accessory flexor of elbow
is lateral supra- distal end of C6) before division joint when forearm is
epicondylar ridge of radius into superficial and midpronated
humerus and deep branches
adjacent
intermuscular septum
Extensor Distal part of lateral Dorsal surface of Radial nerve (C6, Extends and abducts the
carpi radialis supra-epicondylar base of C7) before division wrist
longus ridge of humerus and metacarpal 2 into superficial and
adjacent deep branches
Extensor Lateral epicondyle of Dorsal surface of Deep branch of Extends and abducts the
carpi radialis humerus and base of radial nerve (C7, wrist
brevis adjacent metacarpals 2 C8) before
intermuscular septum and 3 penetrating
supinator muscle
Extensor Lateral epicondyle of Four tendons Extends the index, middle,
digitorum humerus and which insert via ring and little fingers
adjacent extensor hoods Can also extend the wrist
intermuscular septum into the dorsal Posterior
and deep fascia aspects of the interosseous nerve
bases of the (C7, C8)
middle and distal
phalanges of the
index, middle,

ring and little
fingers
Extensor Lateral epicondyle of Extensor hood of Extends the little finger
digiti minimi humerus and the little finger
adjacent
together with
extensor digitorum
Extensor Lateral epicondyle of Tubercle on the Posterior Extends and adducts the
carpi ulnaris humerus and base of the interosseous nerve wrist
posterior border of medial side of (C7, C8)
ulna metacarpal 5
Anconeus Lateral epicondyle of Olecranon and Radial nerve (C6, Abduction of the ulna in
humerus proximal C7, C8) (via branch pronation
posterior surface to medial head of Accessory extensor of the
of ulna triceps brachii) elbow joint
Deep layer
Muscle Insertion Innervation Function

Supinator Lateral surface of radius Supination
superior to the anterior
oblique line
Abductor pollicis longus Lateral side of base of Abducts carpometacarpal
metacarpal 1 joint of thumb
Accessory extensor of the
Posterior thumb
Extensor pollicis brevis Dorsal surface of base of interosseous Extends metacarpophalangeal
proximal phalanx of the nerve (C6, joint of the thumb
thumb C7) Can also extend the
carpometacarpal joint of the
thumb
Extensor pollicis longus Dorsal surface of base of Extends interphalangeal joint
proximal phalanx of the of the thumb
thumb Can also extend
carpometacarpal and
metacarpophalangeal joints of
the thumb
Extensor indicis Extensor hood of index Extends index finger
finger

Muscles testing of the upper limb
A. Muscles of pectoral girdle
1) Pectoralis Major-
clavicular head - the arm is abducted to 90
degrees or more
The patient pushes the arm forwards against
resistance.
sternocostal head- the arm is abducted to 60
degrees
Adduct against resistance.
The contracting heads can be seen and felt.
2) Trapezius- The shoulder is shrugged against

resistance and the upper border of the muscle
is seen and felt.
3) Latissimus Dorsi-
 The arm is abducted to a right angle
 Adducted, extended and medially rotated
against resistance
 The lateral part of the muscle below the
posterior axillary fold can be seen and felt
contracting.
 The muscle can also be felt to contract here when the patient coughs.

4) Serratus Anterior- With the arm flexed and the elbow extended the
outstretched hand is pushed against a wall. Paralysis results in ‘winged
scapula’, where the vertebral border becomes prominently raised off the
posterior chest wall.
B. Muscles of shoulder
1) Supraspinatus- The arm is abducted against resistance and the muscle

palpated (deep to trapezius) above the scapular spine.
2) Deltoid- The arm is abducted against resistance and the muscle is seen and
felt.
C. Anterior compartment of the arm
1) Biceps Brachii- With the forearm supinated the elbow is flexed against
resistance. The contracted muscle in the arm, and the tendon and
aponeurosis at the elbow are easily palpable.
D. Posterior compartment of the arm
1) Triceps- The flexed forearm is extended against resistance and the muscle
seen and felt.
E. Anterior compartment of the forearm
1) Pronator Teres- From the supine position the forearm is pronated against
resistance and the muscle palpated at the medial margin of the cubital fossa.
2) Flexor Carpi Radialis- The wrist is flexed and abducted against resistance and
the tendon is easily seen and felt.
3) Flexor Digitorum Superficialis- The fingers are flexed at the proximal

interphalangeal joints against resistance applied to the middle phalanges,
while the distal interphalangeal joints are kept extended.
4) Flexor Carpi Ulnaris- The wrist is flexed and adducted against resistance and
the tendon palpated.

F. Deep muscles of the forearm
1) Flexor Digitorum Profundus- With the fingers extended and the hand lying
supine on the table, the distal interphalangeal joints are flexed against
resistance with the middle phalanx held in extension.
2) Flexor Pollicis Longus- With the proximal phalanx of the thumb held steady,
the distal phalanx is flexed against resistance.
G. Posterior compartment of the forearm
1) Brachioradialis- With the forearm in the midprone position the elbow is flexed
against resistance; the muscle can be seen and felt
Transverse section of the arm at the level of insertion of coracobrachialis
Transverse section of the forearm

Changes happening at the level of insertion of Coracobrachialis
1. Bone: The circular shaft becomes triangular below this level
2. Fascial septa: The medial and lateral intermuscular septa become better
defined from this level down
3. Muscles
i. Deltoid and Coracobrachialis are inserted at this level
ii. Upper end of origin of brachialis
iii. Upper end of origin of the medial head of triceps brachii
4. Arteries
i. The brachial artery passes from the medial side of the arm to its
anterior aspect
ii. The profunda brachii artery runs in the spiral groove and divides into its
anterior descending/anterior collateral artery and posterior
descending/middle collateral branches
iii. The superior ulnar collateral artery originates from the brachial artery,
and pierces the medial intermuscular septum along with the ulnar
nerve
iv. The nutrient artery of the humerus enters the bone
5. Veins
i. The basilic vein pierces the deep fascia
ii. Two venae comitantes of the brachial artery may unite to form one
brachial vein
6. Nerves
i. The median nerve crosses the brachial artery from the lateral to the
medial side
ii. The ulnar nerve pierces the medial intermuscular septum with the
superior ulnar collateral artery and goes to the posterior compartment
iii. The radial nerve pierces the lateral intermuscular septum with the
anterior descending/radial collateral branch of profunda brachii artery
and passes from the posterior to the anterior compartment
iv. The medial cutaneous nerve of the arm pierces the deep fascia
v. The medial cutaneous nerve of the forearm pierce

Joints
Fibrous Cartilaginous Synovial

 Articular surfaces joined by
 Joint capsule
fibrous tissue
 Synovial membrane (lines
 Limited movement
the
Eg: skull sutures,
capsule, but does not cover
interosseus membrane
articular surfaces)
Primary Secondary
Synovial joints
 Articular surfaces
 Plane- inter metatarsal
 Hinge- humero-ulnar, interphalangeal
 Pivot- atlanto-axial
 Bicondylar- knee, TM joint
 Ellipsoid- metacarpo-phalangeal
 Saddle- thumb carpo-metacarpal
 Ball and socket- shoulder

Joints of Upper limb
Shoulder Joint / Glenohumeral Joint

 Type - Synovial, ball & socket, multiaxial
 Articular surfaces – Shallow, too small glenoid fossa (deepened by glenoidal labrum)
Head of humerus (1/3 of a sphere) covered by hyaline cartilage
 Capsule – Collagen
Pain sensitive
Strong but lax (doesn’t strengthen the joint enough)
Attachment
Proximal – proximal margins of glenoidal labrum (margin of the glenoid fossa)
Distal – anatomical neck of humerus except inferiorly upto surgical neck
Superiorly allows the passage of biceps tendon
Supported by rotator cuff muscles SITS (least supported inferiorly – anteroinferior
dislocation is common)
 Synovial membrane – Lines the capsule

Not pain sensitive
Continued to surgical neck along with tendon of long head of biceps
Doesn’t cover articular surfaces
 Bursae – 1. Subacromial (Subdeltoid)

Situated Below-- coracoacromial arch & deltoid
Separates the supraspinatus tendon
Largest bursa in the body- Doesn’t communicate in normal conditions
2. Subscapular bursa- Communicates with joint cavity through an aperture between
superior and middle glenohumeral ligaments.
3. Infraspinatus bursa - Sometimes communicates with shoulder joint capsule.
 Ligaments Extracapsular
*Transverse humeral ligament (bridges bicipital groove)
*Coracoacromial ligament
Superior
Intracapsular
*Glenohumeral lig. Middle
Inferior

 Blood supply - Anterior & posterior circumflex humeral
- Suprascapular
- Subscapular
 Nerve supply - Axillary nerve, Musculocutaneous nerve, Suprascapular nerve

 Highly mobile joint at the expense of stability.
 Stability-
Muscular factors
1.Rotator cuff - Tendons of Supraspinatus, Infraspinatus, Subscapularis, Teres minor
blends with each other & joint capsule (doesn’t cover inferiorly)
2. Long heads of biceps and triceps- Only support inferiorly is tendon of long head of triceps
Ligamentous factors
3. coracoacromial arch- superiorly secondary socket for the head of the humerus
4. Glenoid labrum Deepning the glenoid cavity
Bony stability is less.
 Mobility -
1. 4:1 disproportion between head of humerus and glenoid fossa
2. Strong yet lax capsule
 Movements - Abduction
*initiated by Supraspinatus (1st 15o)
*up to 90o - Deltoid
*up to 180o - Serratus anterior & Trapezius
After 30° of abduction, Scapula starts to rotate (Humerus : Scapula = 2 : 1 ) SITS also plays
a role here by providing stability to head of humerus
 Muscles acting on shoulder joint

o Abductors - Supraspinatus, Deltoid (middle fibers), Serratus anterior, Trapezius
o Adductors - Lady between 2 Majors
Latissimus dorsi, Teres major, Pectoralis major
o Flexors - Pectoralis major (clavicular), Deltoid (anterior fibers), Coracobrachialis, Short head of

biceps
o Extensors - Deltoid (posterior fibers), Teres major, Latissimus dorsi, Pectoralis Major
(sternocostal fibers)
o Medial rotators - Pectoralis major, Latissimus dorsi, Teres major, Deltoid (anterior fibers),
Subscapularis
o Lateral rotation - Infraspinatus, Teres minor, Deltoid (posterior fibers)
Clinicals
 More prone to dislocation than any other joint
 Dislocation – inferiorly (usually occurs in abducted
position)
No rotator cuff inferiorly therefore less
supported.
 Reduced by Kocher’s method
 Axillary nerve can be damaged,
o Deltoid is paralyzed loss of abduction
o Sensory loss over badge area
o Rounded contour is lost. Acromion becomes
prominent
 Supra spinatus tendinitis - Painful arch – 60° - 120°
 Subacromial bursitis - Tenderness over greater tuberosity beneath the Deltoid, disappears when
the arm is abducted
 Shoulder tip pain – due to irritation of respective dome of diaphragm (phrenic nerve carrying
impulses from peritoneum and supraclavicular nerves from skin above shoulder have common
C3 and C4 roots)
 Osteomyelitis of upper end of humerus can spread to shoulder joint by direct spread due to the
capsule attachment
 Frozen shoulder – Common occurrence
 Two layers of synovial membrane adhere together
 Usually in patients aged 40-60
 Complaints: Stiffness of SJ/Increasing pain/restriction of movement
 Spontaneous healing or physiotherapy done
Elbow Joint
 Type - Synovial, compound.

 3 articulations.
1. humero-ulnar (hinge) – trochlea trochlear notch of ulna
2. humero-radial (ball & socket) – capitulum radial head
3. Superior radio-ulnar (pivot)- head of radius radial notch of ulna
 Capsule – round articular arrangement.

Lateral & medial epicondyles are extracapsular.
Thin and loose anteriorly and posteriorly.
Reinforced medially & laterally by medial & lateral collateral ligaments.
Lateral ligament expands to form annular ligament.
Annular ligament is attached to the anterior and posterior margins of radial notch of ulna.
Capsule doesn’t attach to radius but attaches to annular ligament instead (capsule includes the
coronoid, radial and olecranon fossae)
Ulnar collateral ligament is triangular shaped and crossed by ulnar nerve
Radial collateral ligament is fan shaped
 Blood supply – Anastomoses around the elbow joint.

 Nerve supply – Ulnar, Radial, Median, Musculocutaneous.
 Movements – Flexion – brachialis, biceps brachii, brachioradialis.
Extension – triceps brachi, anconeus.
 Carrying angle – Disappear in full flexion. (Normally 5 - 15 away from the body, more in females.)
Factors forming the carrying angle is,
Medial flange of trochlea is 6mm deeper than the lateral flange
The superior articular surface of the coronoid process of ulna is placed
oblique to the long axis of the bone
Clinicals
 Dislocation – posteriorly triangular relationship (between 2 epicondyles and olecranon process) is

lost and coronoid may fracture
Posterior dislocation is common because capsule is weak and deep fascia is thin
 Subluxation - pulled elbow (radial head subluxate through the annular ligament)
Common in children
 Minors elbow (student’s elbow) – bursitis over the olecranon process.
 Tennis elbow- pain and tenderness over lateral epicondyle due to sprain of radial collateral, tearing
of fibers of extensor carpi radialis brevis, degenerative condition
 Golfers elbow - pain and tenderness over medial epicondyle. Microtrauma to medial epicondyle
 Cubital valgus: carrying angle more than 13o
 Cubital varus: carrying angle less than 13o
Proximal Radioulnar Joint
 Type: Pivot type, Synovial joint

 Articular surface: Circumference of head of radius
 Osseofibrous ring formed by radial notch of ulna & annular ligament
 Ligaments:
o Annular ligament forms four-fifth of the ring
o Head of radius rotates within it
o Attached to margins of radial notch of ulna
o Continuous with the capsule of the elbow joint
o Quadrate ligament extends from neck of the radius to lower margin of radial notch of ulna
 Blood supply: Elbow anastomoses
 Nerve supply: Median, radial and musculocutaneous
 Movements: Supination & Pronation
Distal Radioulnar Joint

 Type: Pivot type, Synovial joint
 Articular surface: Head of ulna
Ulna notch of radius
 Ligaments:
o Capsule surrounds joint
o Has a fibrocartilaginous articular disc attached to the base of styloid process of ulnar
 Blood supply: Anterior & Posterior interosseous arteries
 Nerve supply: Anterior & Posterior interosseous nerves
 Movements: Supination & Pronation
Interrosseus membrane
 Interrosseus membrane – downwards and medially from radius to ulnar
 Superior aperture- posterior interosseous vessels
 Inferior aperture- anterior interosseous vessels
 Other than providing attachments for muscles and binding bones, transmits forces from radius to
ulna.
Pronation & Supination

 During pronation head of the radius rotates within the annular ligament.
 Distal radius rotates in front and around the ulna.
 Axis of pronation and supination passes through head of radius above & the ulna attachment of
articular disk below
 However, this axis isn’t stationary because lower end of ulnar isn’t fixed: It moves backwards &
laterally during pronation & vice versa in supination by anconeus
 Supination is more powerful
 Supination : Chiefly by biceps when flexed elbow
Associated by supinator
 Pronation : Chiefly by pronator quadratus
Pronator teres
Anconeus
Wrist Joint
Biaxial, synovial, ellipsoid
Between lower end of radius (+articular disc
of inferior radioulnar joint), scaphoid,
lunate,
triquetral (SLT)

Clinical
Common site for rheumatoid arthritis
Back of wrist is common site for ganglion
Intercarpal joints - Has a common joint space

2nd to 4th Carpo-Metacarpal Joints - Has a common joint space
1st Carpo–Metacarpal Joint - Has a separated cavity (saddle)
Metacarpo- Phalangeal Joint – synovial ellipsoid variety
Interphalangeal Joint –Synovial Hinge variety
Acromio Clavicular Joint
 Type - Plane, Atypical synovial

 Between lateral end of clavicle & acromion process of scapular
 Articular facets are covered by fibrocartilage
 Has incomplete articular disc
 Coracoclavicular ligament (conoid and trapezoid parts)
 Stability of the joint is provided by coracoclavicular ligament. It transmits the weight of scapula to
clavicle.
Sternoclavicular Joint
 Type - Atypical Synovial, ball and socket
 Articular facets – covered by fibrocartilage
 Has complete articular disc
 Ligaments
1) Costoclavicular ligament
- Main stabilising factor
- It transmits the weight from clavicle to axial skeleton
2) Anterior and posterior sternoclavicular ligaments
3) Interclavicular ligament
01. The short (cuff) muscles of the shoulder joint

a. comprise subscapularis, supraspinatus, infraspinatus and teres major
b. provide the greatest stabilizing foresees at the shoulder joint
c. provide maximal support to the inferior aspect of the shoulder joint
d. are all attached to the greater tuberosity of the humerus
e. are all supplied by the branches of the posterior cord of the brachial plexus
02. The biceps muscle

a. is attached to the scapula
b. has an intra-articular tendon
c. is attached to the humerus
d. has an aponeurosis passing to the dorsal surface of the radius
e. is a powerful pronator of the forearm
f. distal attachment is to radial tuberosity and by the bicipital aponeurosis to the deep facia of the
medial side of the forearm
03. The triceps muscle
a. is attached to the infraglenoid tubercle of the scapula
b. is attached to the boards of the radial groove of the humerus
c. is attached to the ulna olecranon
d. act mainly to the shoulder joint
e. is supplied by the median nerve
04. The anterior superficial group of forearm muscles

a. all arise from the anterior surface of the lateral epicondyle of humerus
b. includes pronator teres
c. all are supplied by the branches of the median nerve
d. may affect flexion of at the elbow
e. has attachment to the anterior surface of both the radius and the ulna
05. The supinator muscle

a. forms part of the floor of the cubital fossa
b. is attached to the medial epicondyle of the humerus
c. is attached to the proximal end of ulna
d. is attached to the proximal end of the radius
e. is supplied by the ulnar nerve
06. The interossei muscles

a. are 8 in total
b. all arise by two heads from adjacent metacarpal bones
c. all are attached distally to the base of the corresponding proximal phalanx and the dorsal extensor
expansion
d. may flex the metacarpophalangeal joints
e. may extend the middle and distal phalanges
f. these muscles are attached to the bodies of the metacarpal bones, the palmar by a single head and
dorsal by two heads, from adjacent sides of the metacarpal bones
07. The elbow joint

a. is lined by synovial membrane which is continuous with that of the superior radio ulnar joint
b. is strengthened by radial colateral ligement
c. is strengthened by an ulnar colateral ligament
d. owes most of its stability to the close proximity of brachialis and triceps
e is supplied by posterior interosseous nerve
d. the most important factors in stabilising the joint are the shape of the bones and strong capsule
e. it is also supplied by the branches of radial, median, ulnar and musculocutaneous nerves
08. The proximal radio ulnar joint

a. is of condyloid variety
b. occurs between the heads of the radius and the radial notch of the ulanr
c. is stabilized mainly by the surrounding capsular ligement of the elbow joint
d. owes its stability mainly to the annular ligament
e. is separated from the elbow joint by a fibrocartilaginous disc

09. The wrist joint
a. comprises the lower articular surfaces of the radius and ulnar and the proximal row of carpal bones
b. usually coomunicates with the distal radio-ulanr joint
c. owes its sability to the neighbouring tendons
d. is an ellipsoid joint
e. contributes to the major degree of flexion at the wrist

Pectoral Region, Breast and Scapular region
Pectoral region
Muscle Origin Insertion Nerve supply Action
Pectoralis  Clavicle – ant. Surface Bicipital groove – Medial & lateral Adduction, med.
major medial part lateral lip pectoral nerves rotation & flexion of
 Manubrium (bilaminar tendon) shoulder joint
Sternum ant.
Upper 6 costal surface clavicular head-
Cartilage flexion of arm at
 External oblique shoulder
aponeurosis
Pectoralis 3,4,5 ribs Coracoid process Medial pectoral Protraction,
minor (Medial side) nerve depression and lateral
rotation of the
scapula
Serratus Upper 8 ribs Scapula medial Long thoracic Entire muscle
anterior border – entire nerve protracts scapula &
length holds it against ribs.
Rotates scapula
laterally
Muscle origin Insertion innervation Action

Deltoid Anterior border Deltoid tuberosity Axillary nerve  Abduction
(has a of lateral 1/3rd of  Flexion and medial
multipennate clavicle rotation- Anterior fibers
part) Acromion  Extension and lateral
Spine of scapula rotation of pos. fibers
Clinical
 Paralysis of Serratus anterior causes ‘winging’ of the Scapula
- Medial border of scapula – unduly prominent
- Arm can’t be abducted beyond 90
 Pec. Major testing (Pec. Major is the only muscle of the upper limb to be supplied by all 5 segments
of brachial plexus)
- Clavicular head - attempt to lift a heavy table
- flex arm to a 90 against resistance
- sternocostal head – try to depress a heavy table
- extend the flexed arm against resistance
press fists against each other

Pectoral fascia- deep fascia
 Covers the pectoralis major muscle
 Passes septa into the muscle fasciculi
 Attaches superiorly - clavicle
Anteriorly – sternum
Inferolaterally – continuous with axillary fascia
Superolaterally – continuous with deltoid fascia
 Connected to clavipectoral fascia by septum passing deep
to deltopectoral groove
Clavipectoral fascia- deep fascia

 Lies deep to pectoral fascia
 Encloses subclavius & pectoralis minor
 Can be seen on the floor of deltopectoral triangle
 Superiorly attaches to the clavicle and inferiorly to the axillary fascia
 The part of this, below pectoralis minor is called the suspensory ligament of axilla. It pulls the floor
of axilla upwards.
Pierced by, (CALL)

 Cephalic vein
 Acromiothoracic artery
 Lymphatics draining the posterior part of the breast to apical nodes
 Lateral pectoral nerve

Breast
 Modified apocrine sweat gland of compound tubuloalveolar type
 Rudimentary in males. Well developed in females
 Extent
2nd rib
Midaxillary line lateral border of

sternum
6th rib
- Lies within superficial fascia--------- EXCEPT – small

axillary tail of Spence which pierces the deep
fascia & lies in the axilla.
 Medial 2/3 – on Pectoralis major muscle

 Lateral 1/3 – on Serratus anterior muscle
 Small anterior part – over the aponeurosis of external oblique muscle
Retromammary space – loose areolar tissue layer separating

breast from pectoral fascia.

Structure
Skin Parenchyma Stroma
 Covers the gland  Glandular tissue.  Supporting framework
 Nipple  Secretes milk
- Level – 4th ICS just medial to the  15-20 lobes
midclavicular line (in males)  Components Fibrous Fatty
- Pierce by 15-20 lactiferous ducts -alveoli  Septa –  Main bulk
- Circular & longitudinal muscle fibers -lactiferous duct suspensory  Absent beneath
– can make stiff/flatten it -lactiferous sinus ligaments of nipple & areola
- Rich nerve supply cooper
- Few modified sweat & sebaceous  Anchor the
glands skin & gland to
 Areola pectoral fascia
- Pigmented circular area around the Piercing
nipple retromammary
- Rich in modified sebaceous glands space
During Pregnancy &  Alveolar epithelium
Lactation, become - Resting phase – cuboidal
Enlarged, modified. - Lactation – columnar
Tubercles of Montgomery
- Some sweat glands  Along the ducts –
- Accessory mammary glands myoepitheliocytes
 Smaller ducts- columnar
The skin of nipple & areola is devoid of epithelium
hair & no fat subjacent to it.  Larger ducts- stratified
squamous keratinized
 Lobuloalveolar development
occurs at puberty
Blood Supply
Arterial supply
1) Branches of axillary artery
I. Superior thoracic
II. Acromiothoracic - Pectoral branch
III. Lateral thoracic- Main
2) Branches of internal thoracic artery – Those of 2nd & 3rd
spaces are the largest
3) Branches of posterior intercostal arteries
 Posterior side of the breast is relatively avascular.

 Blood vessels reflect back from anterior

Veins follow arteries
Posterior intercostal V. communicate with external vertebral venous plexus

Nerve supply
- Ant. & lat. Cutaneous branches of 4, 5, 6 intercostal nerves
- Nerves DO NOT control the secretion of milk. Controlled by hormone, Prolactin
LYMPHATIC DRAINAGE
Lymph nodes Lymphatic vessels
1. Axillary (75%) Anterior(Pectoral) Superficial Deep

(Lateral thoracic vessels) lymphatics lymphatics
Posterior - Skin except - Parenchyma of

(Subscapular vessels) nipple & areola nipple & areola
Axillary tail of breast
Lateral (medial to the
Axillary vein)
Apical Central (In the fat of axilla)

(Axillary vessels) receive lymph from ant,post,lat. groups
Receive lymph from central and upper part of Breast
2. Internal mammary nodes (20%) – internal thoracic vessels
3. Posterior intercostal nodes (5%)
4. Other – Supraclavicular nodes

Cephalic (Deltopectoral)
Subdiaphragmatic & subperitoneal lymph plexus

Milk line – axilla to groin
By invagination of surface ectoderm
Developmental abnormalities
 Amastia
 Athelia
 Polymastia
 Polythelia
 Gynecomastia (XXY- Klinefelter)
Clinical
-Frequent site of carcinoma

-Incision – radially – to avoid cutting lactiferous ducts
-Dimpling / retraction (folding) of the skin – # infiltration of suspensory ligament- fibrous contraction
# Breast becomes fixed
-Retraction of nipple - infiltration of lactiferous ducts- fibrous contraction
-Peau d’ orange appearance - Obstruction of superficial lymph vessels Oedema
-Superficial lymphatics communicate across the midline Cancer can spread from one breast
to another
-Communication of lymphatics * Spread to abdominal organs.

* secondaries in the pelvis.
Spread through veins

Valveless communication

Veins of breast vertebral venous plexus # vertebrae # brain
Commonest nerves that can be damaged in complete mastectomy – long thoracic,

intercostobrachial, thoracodorsal
SCAPULAR REGION
Muscle Origin (Scapula) Insertion Nerve Supply Action
(Humerus)
Supraspinatus Supraspinous Greater tubercle Suprascapular  Initiate abduction (up

fossa – upper nerve to 15)
impression  Steadies head of
Humerus
Infraspinatus Infraspinous Greater tubercle Suprascapular Lateral rotator of arm

fossa – middle nerve
impression
Teres Minor Upper 2/3 of Greater tubercle Axillary nerve
dorsal surface- – lower
lateral border impression
Subscapularis Subscapular Lesser tubercle Upper & lower  Medial rotator of arm
(Multipennate) fossa subscapular nerves  Adduction of arm
Teres major Lower 1/3 of Bicipital groove – Lower subscapular

dorsal surface- medial lip nerve
lateral border
CLINICALS
Intramuscular injections -- to lower part of the deltoid muscle (avoid injury to axillary nerve)
Muscle testing --- ask to abduct against resistance
INTERMUSCULAR SPACES
Quadrangular space
TERES MINOR # Axillary nerve
# Post. Circumflex humeral
vessels
TERES MAJOR (Surgical neck)
Upper triangular space

# Circumflex Scapular
vessel vvevessels
HUMERUS
(shaft)
M Lower triangular space L
# Radial nerve
7 # Profunda Brachii vessels © 2017 A/L Repeat Campaign
TRICEPS-LONG HEAD
Scapular movements
 Protraction- Serratus anterior
 Retraction- Rhomboids, Trapezius middle fibers
 Medial rotation- Weight of upper limb, Levator scapulae, Rhomboids
 Lateral rotation- Serratus anterior, Trapezius
 Elevation- Trapezius, Levator scapulae
 Depression- Weight of upper limb, Pec. Minor, Latissimus dorsi, Trapezius
Scapular Anastomosis
Around body of Scapula Over the Acromion process

Acromial branches of
- Suprascapular - thoracoacromial artery
branches of
- Deep branch of - Suprascapular artery
Thyrocervical trunk of
transverse cervical Subclavian A. - Posterior circumflex humeral
artery artery
-Circumflex scapular artery- branch of
subscapular A. of Axillary A.

Clinicals
These are anastomosis between -1st part of Subclavian artery

-3rd part of Axillary Artery
They provide a collateral circulation when distal part of subclavian A. or proximal part of Axillary A. is blocked
Important in coarctation of the Aorta
01. Regarding the mammary gland

a) Secretory cells do not develop until puberty.
b) Major lymph drainage is to the parasternal lymph nodes.
c) Pectoral lymph nodes lie along the lateral thoracic artery.
d) The axillary tail lies along the superficial fascia and the skin.
e) Ducts are lined by stratified cuboidal epithelium.
f) Venous drainage is to the vertebral venous plexus.
g) The whole breast lies in the superficial fascia.
h) Most of the lymphatic drainage of the breast into the parasternal nodes.
i) Pectoral nodes lie along the subscapular artery.
j) During surgical removal of the breast the long thoracic nerve may get damaged.
k) Myoepitheliocytes are found around alveoli and ducts.
02. T/F regarding the breast

a) It is a compound tubuloalveolar gland.
b) The nipple has smooth muscles.
c) It receives its main blood supply from subscapular artery.
d) The axillary tail lies in relation to pectoral lymph nodes.
e) Gynecomastia is seen in XYY.

HAND
Bones of the hand
Carpal bones
 Arranged in two rows She Looks Too Pretty

Proximal row - scaphoid, lunate, triquetral, pisiform Try To Catch Her
Distal row - trapezium, trapezoid, capitate, hamate
Pisiform on the anterior surface of triquetral where FCU is inserted
Scaphoid - tubercle (palpable)
Crest of trapezium
Hook of the hamate
Carpus is arched transversely, the palmar aspect being concave

The concavity is maintained by,
 Shapes of Individual bones - broader posteriorly than anteriorly except lunate (Lunate is broader
posteriorly)
 The tough flexor retinaculum passing from the scaphoid and the ridge of the trapezium laterally
to the pisiform and the hook of the hamate medially
 Arrangement of metacarpals relative to carpal bones
 Fracture of Scaphoid
- Caused by falling on the palm with the hand abducted
(There the scaphoid lies directly facing the radius)
- May cause tenderness of anatomical snuff box (floor is
formed by scaphoid)
- 1/3 of cases – blood supply enters distally along waist

- If fracture is proximal to the wrist
Avascular necrosis of proximal segment
 Dislocation of Lunate carpal tunnel syndrome

- Carpal bones are broader posteriorly than anteriorly except lunate
- Therefore, fall on the hand may dislocate carpal arch backwards from lunate (perilunate
dislocation of the carpus)
- Dislocated carpus may then reduce spontaneously and tilt it over; its distal surface facing
forwards (dislocation of the lunate)
- Increased pressure in the carpal tunnel

- Leading to Carpal tunnel syndrome
WRIST AND HAND

 Skin
 Thick
 Immobile
 Creased
 Superficial fascia
 Dense fibrous bands
 Bind skin to palmar aponeurosis
 Contains a subcutaneous muscle, Palmaris brevis
 Deep fascia
 Wrist - flexor retinaculum
 Palm - palmar aponeurosis
Palmar aponeurosis
 The deep fascia in the central region of the palm, reinforced by a superficial layer of longitudinal
fibers continuous with the tendon of the palmaris longus muscle and by deeper transverse fibers
 Triangular in shape
 Proximal apex blends with flexor retinaculum & continuous with the tendon of palmaris longus
 Distally divides into 4 strips; 1 for each finger
 Distally divides into 2 layers
 Superficial layer – blends with skin
 Deep layer – 4 slips- blends with fibrous flexor sheaths
 No slip for thumb – more mobile (but plantar aponeurosis has)
 Fingers fibrous flexor sheaths (see grants pic)
Forms a blind fibro-osseous tunnel – tendons of FDS and
FDP and synovial sheath lie there.

Clinical:
1) Dupuytren’s contracture
 Inflammation involving the ulnar side of palmar aponeurosis

 Thickening & contraction of aponeurosis
 Results - longitudinal thickening in the palm together with flexion of the metacarpophalangeal and
proximal interphalangeal joints - proximal and distal phalanges become flexed, can’t be
straightened
 Distal interphalangeal joints - not involved
* Ring finger most commonly involved
2) Volkmann’s contracture
 Follows ischemia and subsequent fibrosis and contraction of the long flexor and extensor muscles of
the forearm
 Deformities
 Flexion at the wrist - since the flexors of the wrist are bulkier than the extensors,
their fibrous contraction is greater
 Extension at the metacarpophalangeal joints - due to the contracture of the long
flexors inserted into the proximal phalanges
 Flexion at the interphalangeal joints - due to the contracture of long flexors;
inserted into the distal and middle phalanges

Muscles of the Hand
 Extrinsic muscles
 Intrinsic muscles
Intrinsic muscles of hand - 20

Muscles of thenar eminence - 3
1) Opponens pollicis
2) Flexor pollicis brevis
3) Abductor pollicis brevis
 One adductor for thumb – Adductor pollicis
 Hypothenar muscles - 4
1) Opponens digiti minimi
2) Flexor digiti minimi brevis
3) Opponens digiti minimi
4) Palmaris brevis
 4 lumbricals
 4 palmar interossei
 4 dorsal interossei
Thenar muscles
Muscle Nerve Action
Abductor pollicis median nerve (recurrent abduction of thumb C/M & M/P joints
brevis branch) [associated with medial rotation]
Flexor pollicis superficial - median flexion of thumb
brevis nerve deep head may be
by ulnar nerve
Opponens pollicis median nerve (recurrent opposition - thumb [flexion, medial rotation]
branch)
Hypothenar muscles
Muscle Nerve Action
Opponens digiti minimi ulnar nerve deep branch opposition with thumb,
lat. rotation
Flexor digiti minimi flexion of M/P joints
brevis
Abductor digiti minimi abduction of M/P joints

- Other intrinsic muscles
Muscle Nerve Action
adductor pollicis Deep branch of ulnar adduction of thumb
nerve
palmaris brevis superficial branch of helps gripping [makes
ulnar nerve hypothenar more prominent]
lumbricals origin 1, 2 -median flexion of M/P joints,
from the tendons 3,4 – deep branch of extension of I/P joints
of FDP ulnar nerve
dorsal interossei ulnar nerve deep Insertion via Abduction of fingers
extensor expansion
palmar interossei ulnar nerve deep Adduction of finger
Movements of the Thumb
1) Flexion at the metacarpophalangeal and interphalangeal joints - by flexor pollicis longus and
brevis
2) Extension at the metacarpophalangeal and interphalangeal joints - by extensor pollicis
longus and brevis
3) Palmar abduction (abduction) - by abductor pollicis brevis; thumb moves away from the
index finger in a plane perpendicular to the palm
4) Radial abduction (extension) - by abductor pollicis longus and extensor pollicis brevis
5) Adduction - by adductor pollicis; further transpalmar adduction is by flexor pollicis brevis
6) Opposition - a composite movement making the thumbnail lie parallel with the nail of the
opposed finger

Testing of Some Intrinsic Muscles
1) Pen test for abductor pollicis brevis - Lay the

hand flat on a table with the palm directed
upwards. The patient is unable to touch
2) Test for opponens pollicis – Request the

patient to touch the proximal phalanx of 2nd
to 5th digits with the tip of the thumb
3) The dorsal interossei are tested by asking

the subject to spread out the fingers against
resistance. As index finger is abducted one
feels 1st dorsal interosseous (hand must lay
flat on the table to avoid the tricky
movements of long flexors)
4) The palmar interossei and

adductor pollicis are tested
by placing a piece of paper
between the fingers,
between thumb and index
finger and seeing how
firmly it can be held
Test for palmar interossei Testing adductor pollicis
5) Froment’s test or book test for adductor

pollicis muscle - When the patient is
asked to grasp a book firmly between the
thumb and the other fingers of both the
hands, the terminal phalanx of the thumb
on the paralyzed side becomes flexed at
the interphalangeal joint (by the flexor
pollicis longus which is supplied by the
median nerve)
6) The lumbricals and interossei are tested by asking the subject to flex the fingers at the
metacarpophalangeal joints against resistance

Dorsal digital/Extensor expansion
 Triangular aponeurosis, covering

dorsum of proximal phalanx and
metacarpophalangeal joint
 Base is proximal and the apex is
distal.
 Separated from M/P joint by a
bursa
 Tendons of interossei and
lumbrical muscles attaches to
posterolateral corners
 Deep transverse metacarpal ligaments are attached to the corners
 Tendon of extensor digitorum occupies the central part
 Near the proximal IP joint, the extensor tendon divides into a central slip and two collaterals
 Central slip is inserted on the dorsum of the base of the middle phalanx
 Two collaterals are inserted on the dorsum of the base of the distal phalanx
 Extensor expansion forms the dorsal part of the fibrous capsule of the MP and IP joints
 There is no extensor hood in thumb, but the extensor pollicis longus tendon receives a fibrous expansion
from both abductor pollicis brevis and adductor pollicis
Fibrous flexor sheaths
 After exiting the carpal tunnel, the tendons of the flexor digitorum superficialis & profundus cross the
palm & enter fibrous sheaths on the palmar aspect of the digits.
 These fibrous sheaths
 Begin proximally, anterior to the MP joints, and extend to the distal phalanges
 Are formed by annular ligaments & cruciate ligaments, which are attached posteriorly to the
margins of the phalanges and to the palmar ligaments associated with the MP & IP joints
 Hold the tendons to the bony plane & prevent the tendons from bowing when the digits are flexed

SEQ – Describe the arrangement of tendons of the middle finger. (70)
Synovial sheaths of flexor tendons
ULNAR BURSA RADIAL BURSA
1. Ulnar bursa (common flexor synovial sheath)
 is a common synovial sheath, enclosing the flexor tendons of fingers (FDS& FDP)
 pass deep to flexor retinaculum
 extent upwards -2”-3” into forearm
Downwards –upto middle of shafts of metacarpal bones into palm
Lower medial end- continuous with digital synovial sheath of the little finger
 Seems like tendons have invaginated the bursa laterally.
Clinical:
Infection of little finger infection of ulnar bursa forearm space of parona Hour glass swelling
2. Radial bursa
 Synovial sheath of flexor pollicis longus tendon
 Extent – Upwards – 2”-3” into forearm
Downwards – up to distal phalanx of thumb
3. Digital synovial sheath

 enclose flexor tendons in fingers
 line the fibrous flexor sheaths
 Digital synovial sheaths of index, middle & ring fingers are separate & independent
 Terminate proximally at the levels of the heads of the metacarpals
 Synovial sheath of the little finger continues proximally with the ulnar bursa and that of the thumb
with the radial bursa

SPACES OF THE HAND
 Palmar spaces Hypothenar space

Midpalmar space
Thenar space
 The forearm space of parona
 Pulp space
 Web spaces
(01) Pulp spaces of the fingers
-in the tips of fingers

-subcutaneous fat arranged in tight compartments formed by fibrous septa
-septa pass from skin to periosteum of terminal phalanx
Cinical:
Whitlow
 infection of the pulp space rising pressure in space (not much space) severe pain
If neglected
Occlusion of vessels by pressure
Avascular necrosis of distal 4/5th of terminal phalanx

(proximal 1/5 escapes because its artery doesn’t traverse the compact space which is traversed by fibrous septa)
 At each of the skin crease of the fingers, the skin is bound down to the underlying
flexor sheath so that the pulp over each phalanx is in a separate compartment cut off
from its neighbors. So usually infection doesn’t spread much. Infection may however track from one space to another
along the neurovascular digital bundles if the infection is not treated well.

02)
Midpalmar space
Tenosynovitis of middle & ring fingers Web infection
(spread proximally
through lumbrical canal)
Midpalmar space infection

 Normal concavity of palm is obliterated
 Swelling extends to dorsum of the hand
(03) Thenar space
Thenar space infection (usually the infection in the web of thumb or untreated infection in the
pulp space of thumb or index finger)
Swelling of web of thumb & thenar region

(04) Forearm space of parona
 Rectangular
 Just above the wrist
 In front of pronator quadratus deep to long flexor tendons
 Extent
 Proximal - oblique origin of flexor digitorum superficialis
 Distal - Flexor retinaculum
 communicates with
- Midpalmar space
- Thenar space
 proximal part of ulnar & radial bursae protrudes into forearm space
(05) Web spaces
 3 web spaces lie in the distal part of the palm between the bases of proximal phalanges of four fingers
 Bounded by superficial transverse metacarpal ligament above & deep transverse metacarpal ligament
below.
 Extend proximally up to the metacarpophalangeal joint.
 Contents from superficial to deep
- Superficial transverse metacarpal ligament
- Proper palmar digital nerves
- Proper palmar digital arteries
- Digital slips of palmar aponeurosis
- Lumbricals
- Deep transverse metacarpal ligament
 Incised to drain palmar space infections
Web of thumb
- Lacks both superficial & deep transverse metacarpal ligaments
- Contain the heads of adductor pollicis & 1st dorsal interosseous
- Princeps pollicis & radialis indicis arteries
- Sensory loss over the skin in radial nerve palsy
Clinical:
 Infections of Synovial sheaths (especially ulnar bursa)
 Forearm space maybe infected
 Pus points at margins of distal part of forearm, swelling and pain

 It may be drained by an incision along the lateral margin of the forearm

01)T/F
a) Ulnar bursa encloses all flexor tendons
b) Infections of little finger and thumb can spread upto the forearm
c) Thick, creased skin in palmar surface increases grasping ability of hand
02)T/F
a) In whitlow distal 1/5th may get necrosed
b) In infections of mid palmar spaces swelling can be seen in the dorsal surface
c) Severe throbbing pain in pulp space infections is due to tight compartments formed by
subcutaneous fat
03)T/F in carpal tunnel syndrome

a) Sensory loss over thenar eminence present
b) The flexor retinaculum is cut to release pressure
c) Guyon’s canal transmits ulnar neurovasscular bundle

Nerves – Upper Limb
Brachial plexus
 Plexus of nerves formed by the ant. Primary rami of the C 5, C6, C7, C8, T1 nerve roots with
contributions from the C4 and T2 nerve roots.
Roots – ant. Primary rami of C5 to T1

Trunks – upper, middle, lower
Divisions – ventral and dorsal divisions of each trunk
Cords – lateral, medial, posterior
Prefixed plexus -contribution by C4 is large

- T₁ is reduced in size
-T2 is often absent
post fixed plexus -contribution by T1 is large
-T2 is always present
-C4 is absent
-C5 is reduced in size
ROOTS between ant. & middle scaleni
TRUNKS Posterior triangle of neck
DIVISIONS behind middle 1/3 of clavicle
CORDS & BRANCHES axilla (within the axillary sheath so UL anesthesia)

Erb’s Duchenne Klumpke’s Paralysis
Paralysis
Site Erb’s point – upper trunk – lower trunk
Cause Undue separation of head from - undue abduction of arm due

shoulders to- birth injury (breech delivery)
Due to –birth injury -clutching something after fall
fall on shoulder from a height
a anaesthesia
-cervical rib
Nerve roots  C5, C6  T1, C8

Muscles paralyzed Biceps,
Supinator  Intrinsic muscles of the
Deltoid, hand (T1)
Brachialis, -interosseus
Brachioradialis -thenar
-hypothenar
Supraspinatus,  ulnar flexors of wrist
Infraspinatus, and fingers (C8)
Supinator -flexor carpi ulnaris
Medial half of flexor
digitorum profundus
Deformity Arm- adducted, medially rotated complete claw hand
Forearm- extended, pronated
Appearance Porters Tip Hand
Disability Lost movements,

1. Abduction, lat. Rotation of 1. Cutaneous anaesthesia-
arm ulnar border of forearm
2. Flexion, supination of and hand(C8), lower medial
forearm arm(T1)
3. Biceps and supinator jerks 2. Horner’s syndrome- ptosis,
lost miosis, anhidrosis,
4. Sensation lost of lower part
enophthalmos
of deltoid & lateral side of
arm & forearm(C5)(C6)
Injury to nerve to Serratus Ant. (Long thoracic nerve / Nerve of Bell)
Causes - sudden pressure on shoulder from above

- carrying heavy loads on shoulder
Deformity winging of scapula – inferior angle and medial

border of scapula are unduly prominent
Deformity -Pushing and punching actions absent, when trying

– winging of scapula
-Arm can’t be raised beyond 90° (overhead
abduction)
Musculocutaneous Nerve
 Root values are C5, C6, C7 anterior primary rami.
 Main nerve of the front of the arm & cutaneous supply to lateral side of forearm.
 Originates from the lateral cord of the brachial plexus at the lower border of Pect Minor.
 In the axilla lies lateral to the 3rd part of the axillary artery & lateral root of median nerve.
 It supplies the Coracobrachialis.
 Then pierces the Coracobrachialis and leaves the axilla.
 Enters the anterior compartment of the arm, runs between Brachialis & Biceps brachii.
 Gives motor branches to Biceps brachii & Brachialis.
 At the level of the elbow, becomes superficial by piercing the deep fascia lateral to the tendon of
biceps and continues as the lateral cutaneous nerve of forearm.
 Gives articular branches to the elbow joint through the motor branch to brachialis.
 It also gives articular branches to shoulder joint.
Axillary Nerve
 Root values are C5, C6 anterior primary rami.
 Origin in axilla from posterior cord of brachial plexus, posterior to the axillary artery.
 Leaves axilla through the quadrangular space. (supplies no structure within axilla)
 Below the capsule of shoulder joint.
 Gives articular branches to shoulder joint.
 Accompanied by posterior circumflex humeral vessels.
 Passes behind the surgical neck of humerus.
 Divides into anterior and posterior divisions.
 Anterior division – Winds around the surgical neck of humerus with posterior circumflex
humeral vessels.
Supplies Deltoid.
 Posterior division – Supplies Teres Minor.
Cutaneous supply to skin over lower half of deltoid via Upper lateral cutaneous nerve of arm.

Clinical
Damaged in inferior dislocation of shoulder, Fracture of the surgical neck of the humerus & Misplaced
injection into deltoid.
 Paralysis of deltoid.
 Arm can’t be abducted beyond 15 degrees.
 Sensory loss over lower half of deltoid. (regimental badge sign)
 Greater tubercle becomes prominent. (atrophy of the deltoid) - flattened contour of shoulder.
Median Nerve (labourer’s nerve)

 Root values are C5, C6, C7, C8, T1 anterior primary rami.
 Origin by the union of medial root from medial cord & lateral root from lateral cord in axilla lateral to
the axillary artery, where medial root crosses 3rd part of axillary artery from medial to lateral and join
with lateral root to form the median nerve.
 Nerve runs lateral to the 3rd part of the axillary artery.
 In the upper part of arm, runs lateral to the brachial artery.
 At the level of insertion of corachobrachialis, crosses brachial artery from lateral to medial anteriorly.
 In the lower part of the arm, runs medial to brachial artery.
 Supplies Brachial artery.
 Gives a motor branch to Pronator teres before leaving the arm.
 Runs anterior to elbow joint supplying it with an articular branch.
 In the cubital fossa, runs medial to brachial artery. (RTAN)
 Gives motor branches to Flexor carpi radialis, Palmaris longus, Flexor digitorum superficialis.
 Passes between two heads of pronator teres. (here ulnar artery lies deep to the deep head of pronator
teres)
 Passes deep to the fibrous arch of flexor digitorum superficialis, on flexor digitorum profundus.

 In the forearm gives Anterior interosseous branch supplying lateral half of Flexor digitorum
profundus, Flexor policis longus, Pronator quadratus.
 Continuation descends deep to flexor digitorum superficialis and adheres to it.
 In the middle of the forearm it gives branch to index finger part of flexor digitorum superficialis.
 At the lower border of forearm, gives Palmar cutaneous branch which goes superficial to flexor
retinaculum supplying lateral 2/3rd of palm.
 At wrist lies deep and lateral to the palmaris longus tendon.
 Enters the Carpal tunnel just deep to the flexor retinaculum.
 Lies between tendons of flexor digitorum superficialis and tendon of flexor carpi radialis.
 Lies medial to the muscles of thenar eminence.
 Gives off recurrent branch to thenar muscles. (Abductor pollicis brevis, Flexor pollicis brevis,
Opponens pollicis)
 Divide into medial and lateral branches.
 Gives Digital branches to 1st & 2nd lumbricals.
 Cutaneous supply to Palmar surface of lateral 3 ½ digits with their nail beds & distal dorsal skin.
Arm Cubital fossa Forearm
Brachial artery Flexor carpi radialis (Anterior interosseous)

Pronator teres Flexor digitorum superficialis Lateral half of Flexor digitorum
Palmaris longus profundus
Flexor pollicis longus
Pronator quadratus
Clinical
If damage is above the elbow. (Supracondylar fracture)
 Motor loss - 4 ½ flexors and 2 pronators of forearm - pointing index finger

while making fist due to unopposed action of extensors / supinated
forearm / ulna deviation of wrist.
 Thenar eminence muscles - wasting, mainly loss of abduction.
 1st and 2nd lumbricals paralysed.
 Gross movements of fingers are lost - labourer’s nerve.
Cutaneous loss-
 Lateral 2/3rd of palm.

 Palmar surface of lateral 3 ½ distal phalanges & their nail beds.
Vasomotor changes-
 Oedema
 Pigmentation of skin
 Friable nails
 Dryness of skin

Trophic changes –
 Flattening - lat. side forearm muscles.

- Thenar eminence flattened.
- Ape like thumb – thumb adducted laterally rotated.
 Ulcers - lateral 3 ½ digits
 Commonly injured at wrist lies beneath Palmaris longus tendon
Carpal Tunnel Syndrome
 Caused by compression of median nerve within carpal tunnel.

 Causes - Dislocation of lunate.
- Bursitis of ulnar and radial bursae.
 Paralysis of thenar eminence leading to ape like hand.
 No cutaneous loss of lateral 2/3rd of palm but of palmar surface of lateral 3 ½ digits with their nail
beds is lost.
Clinical testing – median nerve
1) Unable to pick a pin with thumb & index finger. (Due to inability to oppose thumb)
2) Pen test for abductor pollicis brevis.
Lay the hand flat on a table, palm directed upwards. Patient is unable to touch a pen held in
front of the palm by a thumb.
3) Ape like hand. (adducted & laterally rotated thumb)

4) Sensory loss.
Ulnar Nerve (Musician’s nerve)

 Root values are (C7), C8, T1 anterior primary rami.
 Originates from medial cord, medial to the 3 rd part of the axillary artery.
 In the axilla, between the axillary vein and axillary artery on a deeper plane.
 In the arm, medial to brachial artery, runs downwards with it in its proximal part.
 Pierces the medial inter-muscular septum at the level of insertion of coracobrachialis.
 Passes into the posterior compartment with superior ulnar collateral artery.
 Passes behind the medial epicondyle (here it could be palpated, causes tingling sensations so humerus
is called funny bone)
 Enters forearm between two heads of flexor carpi ulnaris.
 Runs between flexor carpi ulnaris and flexor digitorum profundus medial to the ulnar artery at lower
two thirds of forearm.
 Supplies Flexor carpi ulnaris and medial ½ of Flexor digitorum profundus.
 Gives Palmar cutaneous branch for medial 1/3rd of palm and Dorsal cutaneous branch for medial
1/3rd of dorsum of hand.

 At wrist lies between flexor carpi ulnaris and flexor digitorum superficialis.
 Passes superficial to the flexor retinaculum within Guyon’s canal alongside the radial border of the
pisiform bone and medial to the ulnar artery.
 Divides into superficial and deep branches just distal to pisiform
 Superficial branch palpated on hook of hamate, supplies Palmaris brevis and cutaneous supply to
ulnar 1 ½ fingers.
 Deep branch passes between the heads of origin of flexor digiti minimi and abductor digiti minimi and
through the origin of opponens digiti minimi accompanying deep branch of ulnar artery
 Passing down to the interossei, grooves the distal border of the hook of hamate and arches in the palm
within the concavity of the deep palmar arch.
 Gives motor branches to three hypothenar muscles, two lumbricals on ulnar side, interossei and end
by supplying Adductor pollicis.
Clinical
Damage at wrist
 Commonest.
 Produces Ulnar claw hand. (Claw hand - Hyperextension at m/p
joints due to paralysis of interossei & lumbricals, Flexion at I/p
joints)
 Sensory loss – medial 1/3rd of palm & medial 1 ½ fingers including
nail beds.
 Vasomotor & trophic changes.
Cubital tunnel syndrome
 Ulnar nerve gets entrapped between two heads of FCU leading to ulnar claw
hand, loss of hypothenar eminence and muscle paralysis.
Ulnar paradox
 If injured @elbow, clawing of fingers is less, because medial half of FDP is also paralysed.
 If injured @wrist, clawing is more, because intact FDP flexes digits more.
 Distal more clawing; Proximal less clawing.
Control fine movements of fingers - musician’s nerve.
Complete claw hand – both ulnar and median nerves get paralysed.
Dorsal guttering - wasting of interossei
Clinical Testing
1) Place the hand on a flat surface.

2) Place a paper between two fingers.
3) See how firmly it can be held.

Radial Nerve
 Root values are C5, C6, C7, C8, T1 anterior primary rami.
 Originates from the posterior cord posterior to the 3 rd part of the axillary artery.
 In the axilla gives motor branches to long head & medial head of Triceps and Posterior cutaneous
nerve of arm.
 Passes through the lower triangular space along with the profunda brachii vessels.
 Enters the posterior compartment of arm.
 In the upper part of the arm, runs posterior to brachial artery.
 Then enters the radial groove between medial and lateral head of triceps along with profunda brachii
vessels running downwards medial to lateral.
 Gives motor branches to lateral & medial heads of Triceps brachii and Anconeus.
 Cutaneous branches Lower lateral cutaneous nerve of arm and Posterior cutaneous nerve of forearm.
 At the level of insertion of coracobrachialis, pierces the lateral intermuscular septum with radial
collateral branch of profunda brachii artery and enters the anterior compartment of arm.
 Descends on lower lateral front of arm deep in interval between brachialis on medial side and
brachioradialis and ECRL on lateral side to reach capitulum of humerus.
 Small lateral part of brachialis is supplied by radial nerve.
 Supplies Brachioradialis, lateral part of Brachialis, Extensor carpi radialis longus and articular
branches to elbow joint.
 Most laterally at cubital fossa. (RTAN)
 Divides into superficial and deep branches at the level of the lateral epicondyle.
 Superficial branch runs deep to brachioradialis (middle 1/3rd is accompanied by radial artery), winds
around the radius deep to tendon of brachioradialis.
 Enters the anatomical snuff box and divides into cutaneous branches supplying posterior aspect of
lateral 3 ½ digits except their nail beds and lateral 2/3rd of dorsum of hand.
 Deep branch gives branches to Extensor carpi radialis brevis, passes between the two heads of
supinator and winds around the radius and sprays out as the Posterior interosseous nerve
accompanying posterior interosseous artery.
 Supplies all muscles of posterior compartment of forearm except Anconeus, Brachioradialis and
Extensor carpi radialis longus.
Axilla Radial groove Just above lateral Deep branch

epicondyle
Posterior cutaneous Lateral head of triceps Proprioceptive fibres ECRB
nerve of arm Lower lateral cutaneous to brachialis Supinator
Long head of Triceps nerve of arm Brachioradialis Deep branch for supply
Medial head of Triceps Posterior cutaneous ECRL of muscles of back of
nerve of forearm forearm
Medial head of triceps
Anconeus

Clinical
 In the axilla - Crutch palsy
 Saturday night palsy
 Fracture of the shaft of the humerus
 Damage to the radial nerve causes,
 Wrist drop
 No or weak extension of elbow
 Weak extension of wrist, MP and IP joints
 Sensory loss in the 1st dorsal web space
Damage to posterior interosseous nerve does not produce wrist drop. (ECRL is very powerful which
is supplied before division of radial nerve)
Long Thoracic Nerve

 Root values are C5, C6, C7.
 Origin at the roots of brachial plexus.
 Supplies Serratus anterior.
 Damage results in winging of scapula.
Cutaneous Innervation of Upper Limb

Intercostobrachial nerve
 This nerve is the lateral
cutaneous branch of the
second intercostal nerve.
 Emerges from the second
intercostal space anterior to
the long thoracic nerve and
crosses the axilla.
 Supplies the skin of the axilla
and over a variable extent on
the medial side of the upper
arm, often communicating with
the medial cutaneous nerve of
the arm.
 It may be in contact with level I
lymph nodes and be at risk
during node excision.
 The thoracoepigastric vein
crosses the nerve vertically on
its posterior aspect and aids
identification.

Dermatomes of upper limb
Myotomes of upper limb
C6, C7, C8
C7, C8

ARTERIAL SUPPLY OF THE UPPER LIMB
1) Axillary artery
 Continuation of Subclavian artery.
 Extends from outer border of 1st rib to lower border of Teres major.
 Continues as Brachial artery.
 Enclosed within axillary sheath with cords of brachial plexus.
2nd part

 3 parts – divided by Pec. Minor – 1st part above, 2nd part behind and 3rd part below Pec. Minor
Branches
SALSAP
 1st part -Superior Thoracic Artery
 2nd part- Acromiothoracic Artery Acromial APCD

(Also thoracoacromial Artery) Pectoral
Clavicular
Deltoid
-Lateral Thoracic Artery
 3rd part -Subscapular (largest branch)

 Circumflex scapular Lower triangular space Scapular anastomosis
 Continuation - thoracodorsal artery Latissimus dorsi (mainly)
-Anterior circumflex humeral Artery 1 or 2 branches to serratus anterior
 Ascending branch (Anastomose with posterior intercostal
-Posterior circumflex humeral artery artery)
 Descending branch
Anteriorly Posteriorly Laterally Medially
1st part -skin -serratus ant. -lateral & pos. -Axillary vein
-superf. fascia -medial cord of cords of brachial
-deep fascia brachial plexus plexus
-pec major with medial
- clavipectoral pectoral nerve
fascia -1st intercostal sp.
2nd part -skin -post. Cord of -lateral cord of -Axillary vein
-superf. fascia brachial plexus brachial plexus -medial cord of
-deep fascia -subscapularis -coracobrachialis brachial plexus
-pec major -medial pectoral
-pec minor nerve
3rd part -skin -radial nerve -median nerve -Axillary vein

-superf. fascia -Axillary nerve -musculocut.n. -ulnar nerve
-deep fascia -subscapularis -coracobrachialis -medial cutane.
-pec major -tendons of lat nerves of arm &
-medial root of dorsi & teres forearm
median nerve major

Scapular Anastomosis
Around body of Scapula Over the Acromion process

Acromial branches of
- Suprascapular - Thoracoacromial artery
Branches of
- Deep branch of - Suprascapular artery
Thyrocervical trunk of
transverse cervical - Posterior circumflex humeral artery
Subclavian A.
artery --
-Circumflex scapular artery- branch of
subscapular A. of Axillary A.
Clinicals
These are anastomosis between -1st part of Subclavian artery
-3rd part of Axillary Artery
They provide a collateral circulation when distal part of subclavian A. or proximal part of Axillary A. is blocked
Important in coarctation of the Aorta
2) Brachial Artery
 Continuation of the Axillary Artery.
 Extends from the lower border of Teres Major to neck of the radius.
 In the proximal arm, lies on medial side.
 In the distal arm, it moves laterally to assume a position midway between lateral epicondyle and the
medial epicondyle of the humerus.
 It crosses anteriorly to the elbow joint, lies immediately medial to the tendon of biceps brachii muscle.
Surface marking – Arm abducted to eight angle, line from middle of clavicle to the midpoint between
the humeral epicondyle. Readily palpable.
Relations of important structures to Brachial Artery

 Median Nerve -lies laterally in the upper part; Crosses in front of the of the artery from lateral to
medial side (at level of insertion of Coracobrachialis)
 Ulnar nerve -lies medially in the upper part
 Radial nerve -lies posteriorly in the upper part
 Basilic vein -lies medial to the upper part

Branches
-profunda Brachii artery -Superior Ulnar collateral artery

-Inferior ulnar collateral artery -Terminal branches – radial, ulnar (in cubital fossa)
3) Profunda Brachii Artery
 Arises just below Teres major.

 Accompanies radial nerve in lower triangular space and
radial groove.
 Pass along the radial groove on the posterior surface of the
humerus deep to the lateral head of triceps brachii.
Branches -Ascending branch

-Anterior descending branch (radial collateral)
-Posterior descending branch (middle collateral)
-(Nutrient branch to humerus)
4) Ulnar Artery
 Main artery of forearm.
 Starts at the level of neck of Radius.
 Oblique in upper 1/3 & vertical in lower 2/3.
 Runs on medial side of forearm with ulnar nerve (in lower
part) under flexor carpi ulnaris muscle upon flexor
digitorum profundus.
 Median nerve crosses superficially to ulnar artery
seperated by deep head of Pronator teres.
 Leaves forearm superficial to flexor retinaculum deep to
volar capal ligament
Branches -Common interosseous branch (below radial tuberosity)

 Anterior interosseous (passes posterior through interosseous
membrane at the level of upper border of pronator quadratus)
o Gives median artery /nutrient artery to Radius
 Posterior interosseous (passes backwards through gap above upper
end of interosseous membrane)
o Gives interosseous recurrent branch
-Anterior ulnar recurrent

-posterior ulnar recurrent
-Muscular branches
-palmar and dorsal carpal branches
-Deep palmar branch (completes deep palmar arch)
 It ends by dividing into superficial palmar branch, which is the main continuation of the artery, and
deep palmar branch
 Superficial branch continues as superficial palmar arch in the hand.

Superficial palmar arch
 Formed by direct continuation of ulnar
artery
 Convexity towards fingers
 Most distal point- level of distal border
of fully extended thumb web
 Goes beyond flexor retinaculum
 Often not a complete arch
 Lateral side can be completed by one of superficial palmar branch

Branches of Radial artery radialis indicis
Princeps pollicis
Superficial
Deep to palmar Superficial
arch
- Palmaris brevis - Flexor digiti minimi
- Palmar - Flexor tendons of fingers
aponeurosis - Lumbricals
- Median nerve- digital branches
Branches – - to medial 3 ½ finger
3 common digital branches –joined to palmer metacarpal arteries from deep palmer arch
1 proper digital branch
Surface marking_1. Just lateral & distal to pisiform.

2. Medial to hook of hamate.
3. on the distal border of the thenar eminence in line with the 2 nd cleft
5) Radial Artery
 Main artery of hand.

 Starts at the level of neck of Radius.
 Lies laterally on muscles forming radial bed with superficial branch of radial nerve. (only in middle 1/3
of forearm)
 Medially related to brachioradialis in its whole length.
 Gives off a branch to assist in forming superficial palmar arch.
 Leave forearm by turning posteriorly then passes deep to the tendon of abductor pollicis longus and
extensor pollicis brevis to enter the anatomical snuffbox. (pulsation can be felt)
 Runs between two heads of the first dorsal interosseous muscle
 Lie deep to oblique head of adductor pollicis and then pass through two heads of adductor pollicis.
 Form the deep palmar arch, with the deep branch of ulnar artery.

Branches
 in forarm -radial recurrent artery
-muscular branches
-palmar carpal branch
-dorsal carpal branch – form dorsal carpal arch
-Superficial palmar branch-arise just before winding backward

Pass through thenar muscles
Join superficial branch of Ulnar artery to complete the superficial palmer arch
 Dorsum of hand
 -
 In the palm (deep to the oblique head of the adductor pollicis)
- Princeps pollicis artery-divides at the base of the proximal phalanx of the thumb into 2
branches for the palmar surface of the thumb
- Radialis indicis artery- descends between the 1st dorsal interosseous muscle and the
transverse head of the adductor pollicis to supply the lateral side of the index finger
Deep palmar arch

Surface marking - 1.2cm Proximal to superficial
arch
 Formed by direct continuation of radial

artery
 Goes between the 2 heads of the 1st dorsal
interossei and deep to the tendons of the
abductor pollicis longus, extensor pollicis
longus & extensor pollicis brevis and
superficial to the lateral ligament of the wrist
joint
 Completed medially at base of 5th
metacarpal bone by deep palmar branch of
ulnar artery
 Marked by a more or less horizontal line
(4cm)
 Just distal to hook of hamate
 Immediately superficial to bases of
metacarpal bones
 Deep to long flexor tendons
 Slight convexity towards fingers
DEEP
PALMAR
Deep to Superficial to
ARCH
-Metacarpals-shafts-proximal parts
-adductor pollicis- oblique head -interossei
-long flexor tendons of fingers
-lumbricals
 Deep branch of ulnar nerve lies within the concavity of arch
Branches
1. 3 palmar metacarpal arteries – join with lateral 3 digital branches to form
common digital branches,
Each common digital branch divides into proper digital branches & supply digits

2. 3 perforating digital arteries –pass through medial 3 interosseous spaces
Anastomose with dorsal metacarpal arteries
3. recurrent branch –runs proximally to supply the carpal bones
Clinical
Allen’s test
 To test the patency of each ulnar & radial arteries, related to blood supply of the hand
Clench fist occlude radial & ulnar arteries fist is released skin of palm pale release one artery
Elbow Anastomosis
Surface marking of arteries

Midpoint of clavicle
Axillary artery
Junction of Ant. 1/3 & posterior 2/3 of lateral wall of axilla
(At lower limit where pulsations are felt)
Brachial artery
Level of neck of radius
Medial to biceps tendon
Radial artery ulnar artery
Wrist – radius (ant. Border) laterally Junction – upper 1/3 & lower 2/3 of
Flexor carpi radialis tendon medially forearm medial border
(Radial pulse felt) Lateral to pisiform

Upper limb - venous drainage
Venous Drainage of hand

 Mainly drainage by dorsal venous arch
 It lies on the dorsum of the hand
 Its afferents are
1. 3 dorsal metacarpal veins
2. Dorsal digital veins from thumb, little & index finger
 Medial side of dorsal venous arch is drained by basilic vein
 Lateral side is drained by cephalic vein
Dorsal venous arch
Medial end
Basilic vein Lateral end
(Post axial) Cephalic vein
(preaxial)
-runs along medial side of arm & forearm -lies in the roof of anatomical snuff box
-Pierces deep fascia at the middle of arm -Lateral border of upper limb
-continues as axillary Vein at the lower -Most of the blood drains into basilic vein via
border of teres major median cubital vein
-Can be used for emergency venous cut
down at the deltopectoral groove.
-It pierces clavipectoral fascia and drains
into axillary vein
 There's a constant valve where cephalic vein drains into axillary vein.
Median Cubital vein

-shunts blood from cephalic to basilic
 Cardiac catheterization
 Withdrawal of blood
 Suitable for intravenous injections- WHY?
1) Separated from brachial artery by bicipital aponeurosis
2) Perforator vein, piercing the aponeurosis fixes the MCV
Lateral thoracic Superficial epigastric vein

Thoracoepigastic vein
vein

Upper Limb- Lymphatic drainage
Two groups of one or two lymph nodes each.
 Infraclavicular group
 Lie along the cephalic vein in the upper part of the deltopectoral groove.
 Drain through the clavipectoral fascia into the apical axillary nodes.
 Receive afferents from the superficial tissues of the thumb and lateral side of forearm and arm.
 Supratrochlear group/superficial cubital
 Lie in the subcutaneous fat just above the medial epicondyle.

 Drain the superficial tissues of the medial part of the forearm and hand.
 Afferent lymphatics running with the basilic vein and its tributaries.
 Efferent vessels pass to the lateral group of axillary nodes.
 Superficial lymphatics follow veins.-to axillary nodes

 Deep lymphatics follow arteries.-to infraclavicular /supratrochlear
 Lymph shed line - back of arm & forearm

Axilla
Definition
 Pyramidal shaped region situated between the upper part of arm and side of chest wall.
Boundaries
 Apex - truncated & bounded by,

Clavicle-upper border
Scapula-superior border
1st rib-outer border
- directed towards root of neck
- Also known as cervicoaxillary canal
 Base - directed downwards

- Skin, axillary fascia
 Anterior wall - Pec. major

- clavipectoral fascia enclosing subclavius
and pec. minor
 Pos. wall - Subscapularis

- Teres Major
- Lat. Dorsi
 Ant & post walls converge laterally.

 Lat. Wall - upper part of the shaft of the humerus
- coracobrachialis, short head of biceps
 Med. Wall - upper 4 ribs, their intercostal muscles
- Serratus ant.
Contents of the Axilla

 Axillary artery and its branches
 Axillary vein and its tributaries
 Infraclavicular part of the brachial plexus
 5 groups of axillary lymph nodes and
associated lymphatics

Axillary Lymph nodes
Group Location Drainage area
1)Anterior (Pectoral) group •Along the lateral thoracic •Upper ½ of the anterior wall
vessels of the trunk
•Along lower border of pec •Major part of the breast
minor
2)Posterior (Scapular) group •Along subscapular vessels •upper ½ of the posterior
•On the posterior fold of wall of the trunk
Axilla •Axillary tail of the breast
3)Lateral group •Along the upper part of the •Upper limb
humerus
•Medial to axillary vein
4)Central group •Lie in the fat of the upper •Anterior, posterior & lateral
Axilla groups
•Floor of axilla
5)Apical (infraclavicular) •Lie deep to clavipectoral •Central group
group fascia •Upper part of the breast
•along the axillary vessels •The thumb and its web
Anterior, posterior, lateral groups drain into the central group which in turn drains
into the apical group.
 Long thoracic and intercostobrachial (supplies skin of upper medial side of arm and axilla) nerves
(These two nerves and thoracodorsal nerve can get damaged in surgeries of the axilla)
*T2 dermatome
 Axillary fat and areolar tissue
Levels of axillary lymph nodes (surgical classification)
 Level 1 – lateral to lower border of pec. minor

 Level 2 – behind pec. minor
 Level 3 – medial to upper border of pec. minor
Clavipectoral fascia
Fibrous sheet situated deep to the clavicular portion of the Pectoralis Major muscle.
Extends- From clavicle (above) to the axillary fascia (below)
Upper part- Encloses subclavius
Lower part- Encloses pec.minor
Below pec minor->suspensory ligament

Structures piercing clavipectoral fascia
 C- Cephalic vein
 A- Acromiothoracic artery
 L- Lateral pectoral nerve
 L- Lymphatics
Axillary Sheath
Continuation of prevertebral fascia
Encloses brachial plexus, axillary artery. But NOT axillary vein.
Clinical
Nerves that can be damaged during mastectomy

1. Long thoracic nerve
2. Intercostobrachial nerve – supplies floor of axilla
3. Thoracodorsal nerve
CUBITAL FOSSA
-Triangular, hollow space
-in front of elbow
Boundaries
- Laterally-medial border of brachioradialis

- Medially-lateral border of pronator teres
- Base-imaginary line joining 2 epicondyles
- Apex-downwards
- Roof-skin
 superficial fascia containing
median cubital vein, lateral
cutaneous nerve of forearm,
medial cutaneous nerve of
forearm
 Deep fascia
 Bicipital aponeurosis
-Floor-brachialis & supinator
Content (MBBS)
M to L-Median nerve N
-Brachial artery & its branches A
-Bicipital tendon T
-Superficial branch of radial nerve R
Median nerve- Supply flexor carpi radialis, palmaris longus, flexor digitorum superficialis
Leaves fossa between the two heads of pronator teres
Brachial artery (divides at the level of the neck of the radius)
Radial artery ulnar artery
(Smaller, superficial) (goes deep to both heads of pronator teres)
- Radial recurrent -anterior ulnar recurrent
-posterior ulnar recurrent
-common interosseous artery and branches
Radial Nerve
Deep branch Superficial Branch
-Ext.carpi radialis brevis
-Supinator
•leaves the fossa by piercing supinator
Clinicals
Median cubital vein is chosen for intravenous injections
Brachial artery is used to record blood pressure
Venipuncture -1. Stability-fixed by perforator
2.most superficial
3.seperated from brachial artery by bicipital aponeurosis

CARPAL TUNNEL
 a fibro-osseous tunnel at the wrist

 formed by concavity of carpal bones - posteriorly
flexor retinaculum - anteriorly
Carpal bones – L to M, proximal row
Scaphoid, Lunate, Triquetral, Pisiform
Distal row
Trapezium, Trapezoid, Capitate, Hamate
Flexor Retinaculum
 A strong fibrous band, 2-3cm transversely and longitudinally

 Lies across the carpus at the proximal part of the hand
 Proximal limit- the level of the distal, dominant skin crease on the front of the wrist
 Attachments of the flexor retinaculum
- Laterally-tubercle of scaphoid & crest of trapezium
- Medially-hook of hamate & pisiform bone
 Surface marking of flexor retinaculum
Structures passing through the carpal tunnel
1. Median nerve lies most superficially within the canal

2. Flexor pollicis longus
3. Flexor digitorum profundus tendons
4. Flexor digitorum superficialis
5. Flexor carpi radialis (within a separate tunnel)
6. Radial bursa enclosing flexor pollicis tendon
7. Ulnar bursa enclosing long flexor tendons (laterally opens, containing superficialis and
profundus tendons)
•tendons of flexor digitorum superficialis - Above -tendons of middle & ring fingers
Below -tendons of index & little fingers
Structures superficial to the flexor retinaculum
1. Palmaris longus tendon

2. Ulnar artery & nerve (in Guyon’s canal which is closed by the slender band of fascia called
volar carpal ligament)
3. Palmar cutaneous branch of median nerve and ulnar nerve
Clinical
Carpal tunnel syndrome
Symptoms caused by compression of the median nerve within the carpal tunnel due to any lesion
diminishing the size of the compartment
- dislocation of the lunate

- arthritis
- Edematous synovial sheaths
Dislocation of Lunate Carpal tunnel syndrome
 Carpal bones are broader posteriorly than anteriorly except Lunate.

Therefore, fall on the hand may dislocate carpal arch backwards from lunate
Increased pressure in the carpal tunnel
Carpal tunnel syndrome
 Symptoms
1. Motor changes - ape like thumb deformity/wasting of thenar eminence
loss of opposition
2. Sensory changes – loss of sensation in lateral 3 ½ digits

No sensory loss over thenar eminence
(because it is supplied by a branch of the median nerve which arises at the forearm)
3. Vasomotor changes - warm, reddish, dry & scaly

4. Trophic changes – nails get cracked with atrophy of pulp spaces
Extensor Retinaculum
Attachment – Laterally – Lower part of sharp anterior border of the radius
Medially – Styloid process of Ulna
Triquetral
Pisiform
Anatomical Snuffbox
Triangular depression on the posterolateral side of the wrist

Seen best when the thumb is extended
Boundaries
Anteriorly- Abductor pollicis longus

Extensor pollicis brevis
Posteriorly- Extensor pollicis longus
Limited above by the styloid process of the radius
Floor- Scaphoid & Trapezium
Contents
Radial artery
Superficial branch of radial nerve
Cephalic vein

Clinicals
Fracture of scaphoid - Tenderness

- Avascular necrosis
Radial artery – Arterial blood gas analysis
01. Regarding axillary region,

a) Divisions of the brachial plexus lie beneath the lateral 1/3 of the clavicle.
b) Damage to axillary nerve affects abduction.
c) Subclavian artery does not give any branches to scapular anastomoses.
d) All the lymph nodes which drain the mammary glands are palpable.
e) Apex of the axilla communicates with the posterior triangle of the neck.
02. In the axilla

a) Pectoral nodes lie along the subscapular artery.
b) Axillary fascia is a continuation of the prevertebral fascia.
c) Medial cord of the brachial plexus lies medial to the third part of the axillary artery.
d) Complete destruction of the brachial plexus will not affect sensation over the shoulder region.
e) Damage to axillary nerve results in the adduction of arm as seen in Erb’s palsy.
03. Regarding the axilla

a) The pectoral lymph nodes are closely related to the lateral thoracic artery.
b) During surgical removal of the breast the long thoracic nerve may get damaged.
c) The intercostobrachial nerve is sensory to the floor of the axilla.
d) The axillary vein receives the brachial vein inferiorly.
04. T/F in carpel tunnel syndrome
a) Sensory loss over thenar eminence present

b) The flexor retinaculum is cut to release pressure
c) Guyon’s cannel transmit ulnar neurovascular bundle

Hip bone
 The innominate or hip bone is formed of three bones, which fuse in a Y-shape, in the
acetabulum.
 The anterior two-thirds of the ilium forms the iliac fossa, part of the posterior abdominal wall.
 The posterior one-third carries the auricular surface for the sacrum
 The outer surface of the ilium gives attachment to buttock muscles.
 In the anatomical position of the bone, the pubic tubercle and anterior superior iliac spine lie in
the same vertical plane, and the upper border of the symphysis pubis and the ischial spine lie in
the same horizontal plane.
Lateral surface of the hip bone

 The acetabulum is a concave hemisphere which is directed downwards and slightly backwards
along the axis of the femoral neck.
 There is a deficiency at its inferior margin, the acetabular notch.
 The hyaline cartilage lining the inside of the acetabulum over the iliac part of the fossa overlies
the weight-bearing area.
 Pubis and ilium meet at the iliopubic eminence on the anterior margin of the acetabulum
 The convex upper margin of the ilium, the iliac crest, extends from the anterior superior iliac
spine to the posterior superior iliac spine.
 The tubercle of the iliac crest lies 5cm behind the anterior superior spine and forms the most
lateral part of the bony pelvis, but not the highest part.
 The line between the highest points of the two iliac crests, the supracrestal plane – L4
 The tubercle -L5
 The posterior superior iliac spine makes a characteristic dimple (Venus dimple) in the skin of the
buttock - S2

 The gluteal surface of the ilium shows three curved gluteal lines. (ant., pos., inf.)
 The fascia lata is attached along the whole length of the external lip of the iliac crest
Pubis
 The body of the pubis projects laterally as a superior ramus which joins the ilium and ischium at
the acetabulum
 Inferior ramus fuses with the ischial ramus medial to the obturator foramen.
 The symphyseal surface of the body forms the secondary cartilaginous joint that constitutes the
pubic symphysis
 The upper border of the body is the pubic crest.
 It is marked laterally by a prominence – the pubic tubercle.
 From the pubic tubercle two ridges diverge laterally onto the superior ramus.
 The upper ridge, sharp, is the pectineal line; it forms part of the pelvic brim and joins the arcuate
line of the ilium.
 Pectineus arises from the pectineal line and the adjacent surface of the superior ramus.
 The lower ridge, more rounded, is the obturator crest.
 Below the obturator crest on the pubic ramus is the obturator groove, which lodges the
obturator nerve.
 The pubic tubercle receives the attachment of the inguinal ligament,
Ischium
 The ischium is an L-shaped bone
 The body joins with pubis and ilium at the acetabulum and extends down to the ischial
tuberosity; it supports the sitting weight.
 The obturator membrane is attached to the margin of the foramen.
 Outer surface - obturator externus inner surface – obturator internus
 The spine of the ischium projects medially to divide the greater from the lesser sciatic notch
below it.
 The sacrospinous ligament is attached to it, contributing to conversion of the greater sciatic
notch into the greater sciatic foramen
 The lesser sciatic notch lies between the spine and the ischial tuberosity.
 It is bridged by the sacrotuberous ligament, which with the sacrospinous ligament converts the
notch into the lesser sciatic foramen
 Obturator internus emerges through this foramen into the buttock, and the internal pudendal
vessels and nerve pass forward into the perineum.
 The ischial tuberosity

Medial surface of hip bone
 The auricular area extends from the pelvic brim to the posterior inferior iliac spine
 It articulates with the ala of the sacrum.
 Iliacus arises from the upper two thirds of this area down to the level of the anterior inferior iliac
spine.
 The lower one-third of the fossa is separated by a large bursa from the overlying iliacus.
 Muscle attachments
Sex determination

Femur
 Longest and strongest bone of the body
 Growth direction of long bones of lower limb– away from knee
 Ossifies from 1 primary center and 4 secondary centers
 Upper end
 Consists of head, neck, greater and lesser trochanters
 Head
 More than half a sphere
 Articulates with acetabulum to form hip
joint
 Contains a roughened pit behind and
below the center of the head called
fovea
 Neck
 Connects head with shaft
 Upper border is concave, horizontal and
meets shaft at greater trochanter
 Lower border is straight, oblique and
meets shaft near lesser trochanter
 Anterior surface is flat and meets shaft
at intertrochanteric line and is entirely
intracapsular
 Posterior surface is convex vertically
and concave horizontally and meets
shaft at intertrochanteric crest. Medial half is intracapsular
 Makes an angle with the shaft (125° in adults)
 Angle larger in males
 Angle facilitates movement of hip joint
 Calcar femorale is a thickening of bone present along its concavity which strengthens it
 Greater trochanter – Quadrangular prominence

 Lesser trochanter - Conical eminence
 Intertrochanteric line
 Prominent roughened ridge
 Continuous below with spiral line
 Intertrochanteric crest
 Smooth rounded ridge
 Ends at lesser trochanter
 Rounded elevation present a little above the crest’s middle – quadrate tubercle
 Shaft
 Cylindrical (middle part triangular)
 Directed obliquely downwards and medially – therefore brings knees closer to center of gravity

Upper 1/3 Middle 1/3 Lower 1/3
Borders 4 -Medial border, 3 -Medial and lateral borders 4- medial,
lateral border, are ill-defined, rounded and lateral,
spiral line and directed more backwards, medial supracondylar line,
lateral lip of gluteal lateral supracondylar line.
tuberosity posterior border is a broad (Medial border and medial
roughened ridge forming linea supracondylar line meet inferiorly
aspera which has distinct to obliterate the medial surface
medial and lateral lips
Surfaces 4 -Anterior, 3 4 -Anterior,
medial, medial,
lateral, lateral,
posterior (2 lips of linea Popliteal
aspera diverge to (2 lips of linea aspera diverge as
enclose posterior supracondylar lines to enclose the
surface) popliteal surface)
 Lower end
 Widely expanded to form 2 large condyles
 Anteriorly the 2 condyles are united and are in line with the front of the shaft
 Posteriorly separated by a deep gap – Intercondylar fossa
 Walls of intercondylar fossa
 Lateral surface of medial condyle – large oval facet for posterior cruciate ligament
 Medial surface of lateral condyle – small oval facet for anterior cruciate ligament
 Articular surface partially covers 2 condyles
 Articular surface for patella
 Covers the anterior surface of both condyles
 Extends more on the lateral condyle than the medial condyle
 Tibial surface
 Covers the inferior and posterior surfaces of the 2 condyles
 Merge anteriorly with patellar surface
Lateral condyle Medial condyle
 Laterally flat  Medially convex

 More in line with shaft  Most prominent point – medial
 Therefore, takes greater part in the transmission of epicondyle
body weight to tibia  Posterosuperior to the epicondyle –
 Less prominent than medial condyle adductor tubercle
 Lateral aspect presents
 Lateral epicondyle
 Popliteal groove
 Muscular impression
 Surfaces of the medial and lateral condyles that articulate with the patella form a V-shaped trench
which faces anteriorly. Lateral surface of trench is larger and steeper

Clinicals
1. Fractures of the neck of the femur
Pertrochanteric – Extracapsular
Basal
Cervical. Intracapsular
Subcapital
2.Midshaft fractures
 Considerable shortening occurs
 Due to longitudinal contracture of surrounding muscles
 Proximal segment flexed by iliacus and psoas and
abducted by gluteus medius and minimus
 Distal segment pulled medially by adductors
3.Fracture of femur-distal shaft

 Damage to popliteal artery
 Due to contracture of gastrocnemius

*** Bones that are prone to avascular necrosis.
1. Scaphoid
2. Head of Femur
3. Talus
4. Distal Phalanx
Patella (Kneecap)
 Triangular in shape with its apex downwards
 Posterior surface is divided by a vertical ridge
 Largest sesamoid bone of the body
 Lies in the tendon of quadriceps tendon. Continues as ligamentum patellae
from apex
 When set on a table it rests on the larger lateral surface (side
 determination)
 Posterior surface is articular in its upper three-fourths and covered with
hyaline cartilage
 Separated from the skin by prepatellar bursa
Clinical
 Has a natural tendency to dislocate laterally
(Patellar ligament vertical, but pull of quadriceps is oblique)
But it is prevented by,
1. Bony factors: prominent articular surface of the lateral femoral condyle
2. Muscular factors: medial pull of the lower most fibres of vastus medialis which
insert almost horizontally along medial margin
3. Ligamentous factors: tension of medial patella retinaculum
 Lateral condyle underdeveloped Genu valgum (Knock knee deformity)

 Recurrent patellar dislocations
 Bipartite patella
 Fracture by direct blow/Strong contraction of quadriceps

Tibia
Side determination
 Upper end much larger than lower end – Vertical shaft

 Medially projected medial malleolus – Subcutaneous and palpable
 Crest like anterior border
UPPER END
Expanded side to side by 2 massive condyles
1)Medial condyle
 Larger
 Superior articular surface is oval, longer anteroposteriorly, concave
 with medial femoral condyle(central) and medial meniscus(peripheral)
 Lateral margin of articular surface is raised to cover the medial intercondylar tubercle
 Groove on back Semimembranosus tendon
2)Lateral condyle
 Superior articular surface is nearly circular
 With lateral femoral condyle(centre) and lateral meniscus(peripheral)
 Medial margin of articular surface is raised to cover the lateral Intercondylar tubercle
 Postero-inferior aspect articulates with the fibula. Fibula facet is flat, circular
 Superior to fibular facet groove for popliteus
tendon
 Anterior aspect Smooth ‘Gerdy’s tubercle’
ITT
3)Intercondylar area
 Tibial plateau rough and elevated between
condylar surfaces Intercondylar eminence
 Intercondylar eminence grooved antero-

posteriorly Medial and Lateral Intercondylar tubercle
 Horns of meniscus and cruciate ligaments attached
4)Tuberosity
 Upper Smooth Quadrate tubercle via patella ligament
 Lower Rough Subcutaneous Subcutaneous infrapatellar bursa
 Inferior Continuous with anterior border of shaft
SHAFT
Triangular in Cross section
1)Borders
Anterior Sharp, crest-like, subcutaneous & forms shin
Tibial tubercle anterior border of medial malleolus
Medial convexity above behind it Tibialis anterior on upper 2/3 of ext/lateral
surface
Lower smooth deep fascia of leg
Medial Medial condyle Posterior border of medial malleolus

Upper part Tibial collateral ligament, popliteus
Middle 1/3 Soleus
Interosseous/Lateral Lateral condyle Fibular notch

Split into 2 at lower end
Interosseous membrane attached Oblique Slope down to fibula
Deep fascia attached along border and fused with periosteum of medial
surface
2)Surfaces
Medial Subcutaneous, smooth
Lateral Upper 2/3 Tibialis anterior

Lower 1/3 Tendon of tibialis anterior, EHL, EDL (M L)
Posterior Oblique line in upper part Soleal line run to lateral border
Soleus Soleal line and mid 1/3 of posterior surface
Above soleal line Popliteus(medial)
Below soleal line Divided by vertical ridge into lateral and medial parts
Lateral Tibialis Posterior Medial FDL
Upper end of ridge Nutrient foramen Branch of Posterior tibial artery
LOWER END
Rectangular in cross section
Medially elongated Medial malleolus GSV and Saphenous nerve in front
Anterior bare Crossed by TA, EHL, Anterior tibial artery, Deep peroneal nerve, EDL, PT
Lateral Fibular notch(triangular) Inter tibiofibular ligament
Posterior Tibialis Posterior (which lies in a groove), FDL, FHL
Inferior Saddle shape articular surface from talus up to medial malleolus
Medial malleolus posterior sup and deep deltoid ligament

 Ossification Primary 8th week IUL
 10 years Tuberosity
Epiphysis fusion 18-20 years
 Upper end of the shaft most common site for acute osteomyelitis.
(upper extremity of the tibial diaphysis is extracapsular; involvement of the knee
joint therefore only occurs in the late and neglected case.)
 Tibia-mostly fractured at - junction of upper 2/3 and lower 1/3
- poor blood supply Union is slow / nonunion
 commonest long bone to be fractured and to suffer compound injury. (Ellis)
 anteromedial surface- subcutaneous therefore a donor site for bone graft
Fibula
 Fibula is shorter than tibia.
 Head
-has a styloid process
-Tendon of biceps femoris insertion and fibular collateral ligament attachment
 Neck- Common peroneal nerve can be rolled against the neck
of the fibula, where it is commonly damaged (Foot drop)
 Shaft
 Lower end
-The fibula is subcutaneous for its terminal
above the lateral malleolus, which extends
more distally than the stumpier medial
malleolus of the tibia.
-Groove for peroneus longus and brevis on
posterior aspect of malleolus
 side determination - by the position of malleolar fossa behind triangular articular area
1.T/F
a) The common peroneal nerve turns around the medial surface of the
neck of the fibula.
b) The shaft of the tibia unprotected posterolaterally
c) Patella has a tendency to dislocate laterally
d) Patella is developed in the tendon of quadratus femoris.
e) The posterior surface of patella contains a large medial surface.
2.T/F
a) Subcapital fractures are known to cause avascular
necrosis of femur head.
b) Fractures of femoral shaft are accompanied by

considerable shortening
c) Upper end of tibia is a common site of acute
osteomyelitis
d) A fracture of the trochanteric neck of femur leads to
avascular necrosis.
e) Acetabulum has both articular and non-articular fibres
3.What stabilizes patella

a) Intermediate fibres of vastus medialis
b) Medial condyle of femur
c) Lateral retinacular fibres
d) Ligamentum patellae
e) Medial retinacular fibre

Muscles of Lower Limb
Gluteal region
Superficial
Deep
Gluteus Maximus Origin

o Fascia covering gluteus medius
o External surface of ilium behind posterior gluteal line
o Fascia of erector spinae
o Dorsal surface of lower sacrum
Insertion
o Lateral margin of coccyx
o Iliotibial tract
o External surface of sacrotuberous ligament
o Gluteal tuberosity

Gluteus medius and minimus
Clinical – Trendelenburg’s sign
Fascia lata
 Deep fascia of thigh

 Tough fibrous sheath
 Attachments
 Superiorly anterior – inguinal ligament
Lateral – iliac crest
Posterior (through gluteal fascia) – Sacrum, Coccyx, Sacrotuberous lig.
Medial – pubis. Pubic arch, Ischial tuberosity
 Inferiorly front & sides – subcutaneous bony prominences
Knee joint capsule
Posteriorly – becomes roof of popliteal fossa
Modifications of fascia lata
1. Iliotibial tract
 Thigh – lateral side
 Thickened band of fascia lata
 Attachments
 Superiorly 2 slips superficial lamina iliac crest – tubercle
Deep lamina hip joint – capsule

 Inferiorly tibia – lateral condyle
 Importance
 Insertion of - Gluteus maximus
- Tensor fascia latae
 Stabilize knee (in extension & partial flexion)
 Leaning forward with slightly flexed knees tract is the main antigravity support
2. Saphenous openings
3. Lateral intermuscular septum

5.T/F
a) Fascia lata stabilizes the knee joint in the extended position
b) Most parts of the gluteus maximus are attached to the gluteal tuberosity
c) Gluteus maximus is supplied by inferior gluteal nerve
d) Gluteus maximus has an origin from the sacrospinous ligament
e) Tensor fascia lata extends the knee.
Thigh - anterior compartment
 4 muscles from other regions

01. iliacus 03. pectineus
Iliac region Adductor compartment
02. Psoas major 04. adductorlongus
& Medial Rotator

 In fractures of femoral neck, psoas acts as a lateral rotator.
 If the fracture is intracapsular  partial lateral rotation
 2 major muscles Sartorius, quadriceps femoris
- Extends Knee joint
knee joint
Thigh - Medial compartment
or ant. Division

Back of thigh
 Hamstrings are 01.Semitendinosus 02.Semimembranosus

03.Biceps femoris-long head 04.Adductor magnus-hamstring part
 All hamstrings,
- originate from ischial tuberosity
- inserted into leg bones (except adductor magnus)
- supplied by  sciatic nerve - tibial part
 Long head of biceps femoris & semitendinosus have a common origin in medial facet of
ischial tuberosity
 Semimembranosus originates from the lateral facet of ischial tuberosity
6.T/F
a) Semimembranosus is inserted into posteromedial surface of
medial condyle of tibia
b) Reflected head of rectus femoris arises from a groove immediately
below the acetabulum
c) Semimembranosus is inserted posterior to gracilis & Sartorius into
the medial surface of tibia
d) Sciatic nerve innervates only the hamstring muscles
e) Hamstring muscles all arise from ischial tuberosity
Leg muscles are inserted to the bones of the leg
f) All hamstring
g) All the hamstrings are innervated by the tibial nerve
*pes anserinus

Leg - anterior compartment

Clinical
1.Footdrop 2.Compartment Syndrome
Damage to common peroneal n. Involved most commonly compartments of the leg

Especially anterior compartment
Paralysis of ant.comp. muscles Treated by performing fasciotomy
Loss of dorsifexion
Foot drop
*Can occur due to damage of sciatic nerve as well
Leg - lateral compartment
Peroneus longus – insertion
Passes deep to peroneal retinacula

Runs through the tunnel in cuboid
Inserts into lateral side of base of 1st metatarsal

Back of leg
Muscle Insertion Nerve Supply Action
Superficial
01. Gastrocnemius 2 Tendons fuse to
form Achilles
02. Soleus tendon and inserts Flexor of the knee
into posterior Tibial Nerve Strong plantar flexors
surface of
calcaneus
03. Plantaris
Soleus More powerful, postural (bottom gear)
Gastrocnemius Faster acting (top gear)
Deep
01. Popliteus Tibia – medial side of  Unlocks the knee
posterior aspect joint
 Flexes knee
 Retracts and hence
protects lat
meniscus
02. Flexor digitorum Distal phalanges of  Flexion of lat 4 toes
longus lateral 4 toes (plantar  Plantar flexion at
surface) Tibial Nerve ankle
03. Flexor Hallucis Distal phalanx of big  Flexion of big toe
toe  Plantar flexion at
ankle
04. Tibialis posterior Navicular bone  Plantar flexion
tuberosity (gives slips  Inversion
to all tarsal bones
except talus and 2, 3,
4 metatarsals)

Joints of the lower limb
Hip joint
1) Type – synovial, multi axial, ball and socket
2) Articular surface- acetabulum & head of femur (2/3rd of a sphere)

- Acetabulum- horse shoe/crescent shaped articular surface
- covered by hyaline cartilage
- Deepened by acetabular labrum.
-Transverse acetabular ligament bridge the acetabular notch.
Gives origin to Ligamentum teres
-Acetabular fossa filled with haversian fat pad
3) Capsule – attachment:
proximal – margin of acetabulum, transverse acetabular ligament
Distal- ant- intertrochanteric line, base of 2 trochanters
Post. - neck of femur – 0.5” proximal to intertrochanteric crest
From the distal attachment fibers are reflected into the capsule as the retinacular fibers
Provide pathway for the blood supply of femur!
4) Synovial membrane- covers only non-articular surface. Lines the capsule.

Joint cavity communicates with a bursa lying deep to the tendon of iliopsoas.
(By synovium bulging out between Iliofemoral ligament and Ischiofemoral
ligament)
5) Ligaments-
* iliofemoral ligament (strongest, anteriorly) – limits extension
Inverted “Y” shape, arise from anterior inferior iliac spine, inserted to each end of
trochanteric line
*pubofemoral ligament (inferiorly)
Arise from iliopubic junction
blend with capsule
*ischiofemoral ligament(posteriorly)(weakest)
Arise from ischium inserted onto the greater trochanter
*round ligament (ligamentum teres)
Attached to the fovea capitis.

Tendon of obturator
6) Relations - internus
ant: iliopsoas, pectineus, femoral artery, vein and

nerve.
Pos: obturator internus tendon, gemelli,

quadratus femoris, gluteus maximus, piriformis,
sciatic nerve (injured in posterior dislocation)
Sup: reflected head of rectus femoris, gluteus

minimus & medius.
Inf: obturator externus, adductors, hamstrings,

gracilis
Lat: tensor fasciae latae, gluteus min and medius
7) Movements- high stability and mobility
Movement Muscles Involved

Flexion Iliacus, Psoas, Rectus Femoris, Sartorius, Pectineus
Extension Gluteus Maximus, Hamstrings
Abduction Gluteus Medius, Gluteus Minimus, Tensor fascia lata, Sartorius
Adduction Adductor longus, brevis & magnus, Gracilis, Pectineus
Medial Rotation Tensor fascia lata, Gluteus Medius & Minimus
Lateral Rotation Gluteus Maximus, Gemelli, Obturators int. & ext, Quadratus Femoris
Medial & lateral rotation – vertical axis passes through head of femur and condyle
Shaft doesn’t rotate around its own axis
8) Blood supply:
 Through ligamentum teres of femur- from obturator artery
 Retinacular arteries- from trochanteric anastomosis (main in adults)
 Trochanteric anastomosis – medial & lateral circumflex femoral arteries, inferior gluteal &
ascending branch of 1st perforating artery
 Nutrient artery of femur
9) Nerve supply (by the nerves that pass the joint)

 Femoral
 Obturator (anterior division)
 Sciatic
 Nerve to quadrates femoris
 Superior gluteal nerve
10) Clinical:
*Dislocation-
# head of femur slips upwards onto the gluteal surface---lead to lurching gait (positive
Trendelenburg test)

 Usually dislocated backwards- which is produced by force applied along femoral shaft
when hip is flexed
leads to damage of sciatic nerve. Due to its close
relationship. (Foot drop)
 When hip is in adducted position- backward dislocation without acetabular fracture
 When hip is in abducted position- backward dislocation with fracture of posterior
acetabular lip
 # safe area (eg for injections) --- upper outer quadrant of gluteal region
 Sciatic nerve which is related inferiorly to hip joint can be damaged in hip dislocations
 Disease of the hip joint may cause referred pain in knee joint & vice versa, due to
common nerve supply of two joints.
*coxa vara -‹ 125°

*coxa valga- ›125° (angle in children: 150°)
*pain in the hip joint is referred to knee
*Congenital dislocation of the hip is more common than

any other joint. This occurs when the upper margin of the
acetabulum is developmentally deficient
*Shenton’s line will be disturbed during

hip dislocation
Hip diseases have an age pattern

 Below 5 years – congenital dislocation & tuberculosis
 5-10 years – Perthes disease
 10-20 years – Coxa Vera
 Above 40 years – Osteoarthritis
Trendelenburg’s test-
positive when abductors (gluteus medius & minimus) of opposite side are paralyzed (eg:- in
poliomyelitis) , dislocation, fracture of head of femur
Normally when body weight is supported on one limb, the glutei of the supported side rise the
opposite unsupported side of the pelvis.
1. T/F
a) Axis of gravity passes anterior to the hip joint.
b) Tensor fascia lata stabilizes the knee joint in the extended position
c) Acetabulum has both articular and non-articular surfaces
d) Trendelenburg test is positive when the normal side is raised
e) Capsule of the hip joint extends up to the trochanteric crest.
f) A fracture of the trochanteric neck of the femur leads to avascular necrosis
g) A disease of the hip joint may cause pain in the knee because of their common
nerve supply by the femoral nerve.

Knee joint
1) Type: complex synovial joint (2 condylar joints femur tibia)

(modified hinge joint) ( Saddle joint patella femur)
The joint cavity is divided into upper (flexion, extension) &
lower(rotation) compartments by the menisci.
2) Articular surface: main joint-

between femoral and tibial condyles
Patella joint-between patella and patellar surface of femur
(Fibula doesn’t contribute)
3) Capsule: attached little beyond the margin of articular surface of tibia & femur. Attached to
the sides of patella and anteriorly deficient and replaced by
patella
quadriceps femoris
ligament of patella
2 constant gaps- suprapatellar bursa, popliteal tendon

Attached to periphery of menisci
Capsule strengthened by - පැෙකා ISSO – patella retinacula, quadratus femoris, iliotibial
tract, sartorius, semimembranosus, oblique
popliteal ligament (this is an expansion of
semimembranosus
4) Synovial membrane:
lines the non-articular surface of the joint cavity
Cruciate ligaments are not covered,
covers deep surface of the infra patella fat pad (ala fold)
infrapatellar fat pad- deep to ligamentum patellae
5) Relations:
Ant- prepatellar, subpatellar, infra patellar bursae and patellar plexus
Pos- muscle forming borders of popliteal fossa and contents of popliteal fossa
Medial- semitendinosus, tendon of Sartorius and gracilis, great saphenous vein
with saphenous nerve
Laterally- biceps femoris, common peroneal nerve, tendon of origin of popliteus
Bursae: 12 bursae.
capsule communicates –
above suprapatellar bursa

(between the lower femoral shaft and quadriceps)
posteriorly bursa under the

medial head of gastrocnemius
also communicate with bursa under the
semimembranosus
Anteriorly Prepatellar bursa

Inferiorly Infrapatellar bursa

6) Mobility:
flexion – hamstrings, Sartorius and gracilis, popliteus, gastrocnemius, plantaris
Extension- quadriceps femoris, tensor fascia lata
Medial rot.- popliteus
Lat rot.- piriformis, obturator int, gemelli
Flexion and extension take place between the femoral condyle and the menisci
Rotation takes place between menisci and tibial condyle
7) Stability–
Locking andstraighten
Factors----- unlocking the
mechanism
knee joint
Locking of the knee joint – result of medial rotation of femur at
the last stage of extension
Knee remains in full extension. ligaments are taut. Not much
muscular effort against gravity.
Unlocking of the knee joint-lat rotation produced by popliteus
Menisci
 Crescent shaped (semilunar)

 Intra-capsular intra-synovial
 fibro-cartilaginous discs
 Thick peripherally and thin centrally
 Peripheral part is vascular.
 2 ends attached to tibia
 2 borders Outer border –Thick, convex, fixed to the capsule

Inner border – Thin, concave, free
 2 surfaces upper surface

Concave
articulates with femur
lower surface
Flat
rest on tibial condyles

 Function:
 deepens articular surface of  Softens movements
tibial condyles  Proprioception
 Shock absorber  Divides joint cavity
 Increased mobility
Medial meniscus # semi circular - larger

# peripherally adherent to tibial collateral ligament
# more prone to damage due to its more fixity.
Lateral meniscus # circular - smaller

# separated from the fibular collateral lig. By capsule & popliteal
tendon
# 2 meniscofemoral ligaments (join post. End to the femur)
# Popliteal tendon attached to it thus the mobility is controlled by

pulling backwards-less prone to injury
Ligaments
1. Intracapsular
Cruciate Ligament
 Strong fibrous connection between femur and tibia
 Determines Antero-posterior stability
 Intra-capsular extra-synovial
Ant. Cruciate ligament

- Ant. part of inter condylar space pos. part of medial surface of lat condyle of femur
- runs upwards, backwards and laterally
- taut during extension
- prevents forward displacement of tibia on femur
Pos. Cruciate Ligament
- pos. part of inter condylar space ant. part of lateral surface of medial condyle of
femur
- runs upwards forwards and medially
- taut during flexion
- prevents backward displacement of femur on tibia
2. Extracapsular ligaments
 tibial collateral ligament – blends with capsule & medial meniscus

 fibular collateral ligament - separated from capsule and lat.
Meniscus By popliteal tendon
Embraced by biceps tendon
Stability continued…
 Cruciate ligaments maintain anteroposterior stability
 Collateral ligaments maintain side to side stability
 Factors strengthening the capsule

 Iliotibial tract-plays an important role.
 Knee joint can work efficiently with a ligamentous damage
 Due to presence of powerful Quadriceps femoris muscle
 For the stability muscular factors are more important
Patella is stabilized by:
 Forward prominence of the lateral condyle of femur (the lateral edge of the patellar
articular surface is deeper than the medial edge)
 Tension exerted medially by the pull of the patellar ligament
 Lowest fibers of the Vastus medialis.
8) Blood supply:
*From thigh- descending genicular branch of femoral,
popliteal and lateral circumflex femoral
* From leg- circumflex fibular artery
recurrent branch of ant. Tibial artery
9) Nerve supply:
* obturator *Femoral *Tibial *Common Peroneal
Clinical: C1- Collateral ligaments- Taut in full extension Medial C.L- Damaged
so liable to injury in in violent abduction
this position(less common) Lateral C.L- Damaged
in violent adduction
Anterior Cruciate- in hyperextension (more commonly

Soft tissue C2-Cruciate ligaments- damaged)
injuries in knee Posterior Cruciate- in hyperflexion
(3 Cs)
 Both can be damaged in violent adduction or
abduction
C3- Cartilages (Menisci)- Only damaged in Medial- In abduction

flexed position
Lateral- In adduction
Baker’s cyst: central swelling

Occurrence due to osteoarthritis of knee joint
Synovial membrane protrudes through a hole in the posterior part of capsule of knee
Joint
Semimembranosus bursitis is quite common. It causes a swelling in popliteal fossa region.
In diseases of knee joint vastus medialis is first to atrophy and last to recover
 Medial menisci more vulnerable to damage than lateral due to its fixed position
 Genu valgum (knock knee) abnormally abducted knee
 Genu varum (bow knee) abnormally adducted knee Due to rickets, posture, congenital
diseases & osteogenesis imperfecta

2. T/F
a) (Patella) It has a tendency to dislocate laterally.
b) House maid’s knee involves prepatellar bursa.
c) Clergyman’s knee involves infrapatellar bursa.
d) (Patella) It is developed in the tendon of quadratus femoris.
e) (Patella) The posterior articular surface contains a large medial surface.
f) Foot baller is likely to injure his knee when his flexed knee twists while running.
g) Tendon of popliteus is intracapsular
Ankle joint
-A Hinge joint formed between mortise formed by two malleoli and between lower end of tibia and
body of talus.
01. Type ---uniaxial, hinge, synovial
02.Articular surface --- concavity convexity
# lower end of tibia # body of talus (trochlear surface,

comma, triangular)
# lateral malleolus
# medial malleolus [convex anteropost.
# tibiofibular ligament concave side to side]
03. Capsule --- * thin anteriorly & post.

* strengthened on side by medial & lateral lig.
* attached to articular margin but anterioinferiorly to the neck of the talus &
posterosuperiorly to inf. Transverse tibiofib. Lig.
04. Synovial membrane --- * line the capsule
05. Ligaments --- medial lig. (deltoid) & lateral lig.
1. superficial part --- Ant. talofibular lig.

Tibionavicular Post. talofibular lig.
Tibiocalcaneal Calcaneofibular lig.
posterior tibiotalar
2. deep part--- ant. tibiotalar
06. Mobility --- only dorsiflexion, plantarflexion

inversion & eversion take place at subtalar and midtarsal joint not at ankle joint
Dorsiflexors-anterior & lateral compartment

Plantar flexors-Posterior compartment

07. Stability --- unstable during plantar flexion
bony factors
* downward projection of malleoli on to the sides of the talus
* wedge shape of talus-being wider anteriorly
muscular factors
* tendon of long flexors & extensors
ligaments
* collateral ligaments
* inferior transverse tibiofibular lig. –bridges the gap between
the tibia and the fibula behind the talus.
08. Blood supply --- peroneal artery

ant.tibial artery
post. tibial artery
09. Nerve supply --- deep peroneal, tibial nerves
Clinical
01. Pott’s fracture
Pott’s fracture
 Most common ankle fracture.

 Tibia internally rotates with the foot rigidly held
01. spiral fracture of the lateral malleolus 1 st degree
02. avulsion of the medial malleolus 2 nd degree
03. posterior margin of the lower end of the tibia shears of against
the talus 3 rd degree
02. Sprains of the ankle are almost always abduction sprains of subtalar joints. True sprains are
caused by forced plantarflexion
 Collateral ligaments of ankle joint can be sprained or completely torn by forcible abduction
or adduction
 Lateral collateral ligament is the most affected, because medial collateral ligament is
stronger.
**Avascular necrosis of the Talus- Occur due to forced dorsiflexion causing fracture of the neck of
talus. If arteries to body of talus go through neck only as in some cases, the body will get avascular
necrosis.
03. Dislocation of ankle joint is rare. Most stable when foot is dorsiflexed

3. T/F
a) Club foot is due to the shortening of plantar calcaneonavicular ligament.
b) A “Bunion” is an inflamed adventitious bursa.
c) Dorsiflexion of the foot is limited than the plantarflexion.
d) Transverse arch is more prominent at the base of metatarsals.
e) Medial ligament of the ankle is attached to both calcaneus & cuboid.
f) Cuneonavicular joint cavity is continuous with that between the 2nd & 3rd intermetatarsal
joints.
g) Movements of the foot occurs around an axis that goes through the subtalar joint & the
head of the talus.
h) 2nd cuneiform is the shortest among the cuneiforms.
i) Subtalar joint is the only movable joint in the foot.
j) Calcaneocuboid articulation allows dorsomedial movement.
k) Talocalcaneonavicular joint complex is supported superiorly by the talonavicular ligament.
l) Spring ligament aids in the maintenance of the medial arch of the foot.
m) Inversion and eversion both take place at ankle joint

Arteries of Lower Limb
FEMORAL ARTERY
- Chief artery of L.L
- Continuation of external iliac artery as the vessel passes under the inguinal
ligament
Surface marking
Thigh-slightly flexed, abducted & laterally rotated
Upper 2/3rd of the line joining midinguinal point to adductor tubercle
Course
 Enters the thigh behind inguinal ligament at midinguinal point (Pubic symphysis & ASIS)
 Just below the inguinal ligament artery is lateral to vein
 Lies in lateral compartment of the femoral sheath
 Passes downwards & medially
-femoral triangle
-adductor canal (deep to Sartorius)
 Vein gradually crosses medial to lateral deep to artery
 Saphenous nerve crosses to medial superficially
 through adductor hiatus (at junction of upper 2/3rd & lower 1/3rd of thigh)
 continues as popliteal artery

Branches
In femoral triangle – 4 superficial –
1. Superficial epigastric
 emerges through the saphenous opening.
 runs towards the umbilicus.
2. Superficial circumflex iliac
 pierces the fascia lata
 to the anastomosis at the anterior superior iliac spine.
3. Deep external pudendal
 pierces the fascia lata
 behind the spermatic cord (round ligament)
 to supply the skin of the scrotum (labium majus).
4. Superficial external pudendal
 emerges from the saphenous opening
 in front of the spermatic cord (round ligament)
 to the penis and scrotum (labium majus).
-2 deep-
1. Profunda femoris
2. Muscular branches
In adductor canal -
1. Muscular
2. Descending genicular
Profunda femoris artery
 chief artery of the thigh (to all 3 compartments)

 largest branch of femoral artery which arises from the lateral side at apex of femoral
triangle posterior to femoral artery
 Leave femoral triangle deep to adductor longus
 Descends 1st between – adductor longus & adductor brevis
 2nd between – adductor longus & adductor magnus

Branches Descending
 Medial circumflex femoral artery

Transverse
pass posteriorly
• between psoas major & pectineus

• between obturator externus and adductor brevis
• between quadratus femoris and
adductor magnus and supplies
adductor muscles Ascending: Hip joint, greater trochanter, Trochanteric anastomosis
 Lateral circumflex femoral artery Transverse: Cruciate anastomosis, pierce Vastus lateralis
Descending: Anastomosis around knee
runs laterally between ant. & pos. divisions of femoral Nerve
 4 perforating arteries
• 2nd branch = (diaphyseal artery) terminates as 4th perforating branch

• 1st perforating branch – above the adductor brevis
• 2nd perforating branch – through the adductor brevis
• 3rd and 4th perforating branches – below the adductor brevis
• Ascending and descending branches of these arteries form a vertical channel
• Upper end – to cruciate anastomoses
• Lower end – anastomoses with popliteal artery
Clinical:
- Compress femoral artery -at midinguinal point

- Against head of femur
- To control bleeding from distal L.L
- Femoral artery pulsations – at the mid inguinal point (against the head of femur/ psoas
tendon)
- Femoral artery is superficial in the femoral triangle
- Easy exposure for ligature
- Cannulation(2nd only to radial artery)

Trochanteric anastomosis
- Main supply to head of femur retinacular arteries
- In trochanteric fossa
- Communication between internal iliac A femoral A
- supplies the head of femur
Cruciate anastomosis
at the level of lesser trochanter
Internal iliac artery Femoral artery
Deep circumflex iliac

artery Ascending branch
External iliac ASIS
artery
Superficial circumflex
iliac artery
Deep branch of Superior

gluteal artery
Ascending branch
Ascending branch
Trochanteric
Inferior gluteal artery
Medial circumflex Transverse branch Transverse branch Lateral circumflex

femoral artery
Cruciate femoral artery
1st perforating branch of

profunda femoris

Genicular Anastomosis
 Around the patella and the femoral and tibial

condyles
 Lateral superior genicular
 Lateral inferior genicular Popliteal
 Medial inferior genicular artery
 Medial superior genicular
 Anterior tibial recurrent Anterior tibial artery
 Posterior tibial recurrent
 Circumflex fibular → Posterior Tibial Artery
 Descending genicular → Femoral Artery
 Lateral circumflex femoral – descending branch
OBTURATOR ARTERY
 Anterior division of internal iliac artery
 Emerge through obturator foramen with the nerve
 divides into anterior and posterior branches that encircle the foramen.
 anastomose with each other and with the medial circumflex artery
 posterior branch - articular branch to hip joint
-enters the acetabular notch in ligament of head of femur
 Abnormal obturator artery replaces the pubic branch of inferior epigastric artery

POPLITEAL ARTERY
 continuation of femoral artery

 begins at adductor hiatus (hand’s breadth above the knee joint)
 descends downwards & laterally
 terminates at the fibrous arch of soleus. (hands
breadth below the knee joint)+lower border of
the popliteus
 deepest of the large neurovascular structures
 It enters the fossa medial to the sciatic nerve and
lies medial to the tibial nerve
 Then passes downwards and convex laterally to
lie lateral to the tibial nerve
 Below the fibrous arch in soleus as the
posterior tibial artery – returns medial side of
the nerve
 At all levels the popliteal vein lies between the artery and the nerve.
 It passes under the fibrous arch in soleus and divides into
1. Anterior tibial arteries
2. Posterior tibial arteries
Branches –
 Muscular branches - 2 large sural arteries for heads of gastrocnemius
 5 genicular branches
1. Medial superior genicular artery
2. Lateral superior genicular artery
3. Medial inferior genicular artery
4. Lateral inferior genicular artery
These four contribute to genicular anastomoses
5. Middle genicular artery

 pierces oblique popliteal ligament
 supply cruciate ligaments
 accompanied by
1. genicular branch of post division of Obturator Nerve
2. genicular branch of tibial nerve

Clinical:
-most prone to aneurysms
-used to record B.P in L.L
-Palpation against the popliteal surface of femur
ANTERIOR TIBIAL ARTERY
- main artery of the anterior compartment of leg

- begins at the lower border of popliteus
- comes to anterior compartment through an opening of upper part of
interosseus membrane (do not pierce)
- continues to the dorsum of foot as dorsalis pedis artery
Course
o Runs vertically downwards on the interosseous membrane

o deep peroneal nerve reaches from the lateral side, runs in front of it in
middle of the leg, returns its lateral side again below
o Accompanied by two venae comitantes on each side – Anterior Tibial Veins
o crosses the lower end of the tibia at the front of the ankle joint, midway
between the 2 malleoli.
Branches
1. Anterior recurrent Branch - genicular anastomoses

2. Posterior recurrent Branch - genicular anastomoses
3. Lateral malleolar branch
4. Medial malleolar branch
POSTERIOR TIBIAL ARTERY
o Laterally related to the tibial nerve

o Begins at the lower border of popliteus
o Runs through fibrous soleal arch
o Deep to flexor retinaculum divides into
1. Lateral planter artery
2. Medial planter artery

Course
o runs down on tibialis posterior

o between flexor digitorum longus and flexor hallucis longus.
o descends deep to soleus
o accompanied by a pair of venae comitantes
Branches
 Peroneal artery – Deep part of posterior compartment

- descends in a fibrous canal between flexor hallucis longus and tibialis
posterior
- nutrient artery to fibula
- perforating branches pierces posterior intermuscular
septum and supplies lateral compartment
- gives lateral calcanean branch may replace or supplement the dorsalis pedis
artery.
 Nutrient artery – to tibia
 Circumflex fibular – laterally around the fibular neck to genicular anastomosis
 Muscular Branches – soleus, deep flexors
Anastomosis
* 4th perforating artery popliteal artery (upper muscular branch)
Arteries of foot
 Posterior tibial artery is the artery of foot

 Lie between 1st and 2nd layers inferior to long tendons
Posterior tibial
Medial plantar lateral plantar
*No plantar arch *crosses the sole obliquely

*Digital supply to big toe *Plantar arch
*Across the bases of 2,3,4 metatarsals
*Joined in 1st intermetatarsal space by dorsalis pedis artery
*Lies between 3rd & 4th layers

Dorsalis Pedis
 Runs to 1st intermetatarsal space & passes down into the sole where it joins the lateral
plantar artery to complete plantar arch
 Palpated between tendons of extensor digitorum longus & extensor hallucis longus
 3 branches
- 1st dorsal metatarsal artery
- Arcuate artery- 2, 3, 4 dorsal metatarsal arteries
- Lateral tarsal artery
Radio femoral delay in coarctation of aorta Most distal pulse point

Felt on underlying navicular and intermediate cuneiform
01.WOTF true regarding the arteries of the back of the leg
a) The popliteal artery divides into anterior & posterior tibial arteries at the distal
border of popliteus.
b) The anterior tibial artery passes to the anterior compartment of the leg by piercing
the interosseous membrane.
c) The posterior tibial artery is the main artery of the foot.
d) The main blood supply of both tibia & fibula is from posterior tibial artery.

Venous Drainage of Lower Limb
 Veins of lower limb are more muscular than any other veins
3 types deep
veins Superficial Veins
Perforating veins
Deep veins
 Ant. Tibial
 Post. Tibial
 Peroneal
 Popliteal
 Femoral
 Valves-more numerous
 Supported by surrounding
powerful muscles
 Accompany major arteries
 More efficient
 Most of the venous return
happens through the deep
vein system.
Superficial veins
 Great (long) saphenous vein
 Small (short) saphenous vein
- Drains into deep veins via
perforating veins
 Less valves
Great Saphenous vein

Longest vein in the body.
Course
 Starts by union of medial marginal vein & the medial end of dorsal
venous arch
 Runs upwards in front of medial malleolus (constant position)
 Crosses the lower third of the medial surface of the tibia obliquely along
with the saphenous nerve (In varicose surgery sensory loss in medial
side of leg)
 Along medial side of leg
 To Posteromedial aspect of knee (hand’s breadth behind the medial border
of the patella)
 Spirals forwards around the medial convexity of the thigh

 Ends by passing through the Cribriform Fascia covering the saphenous
opening. (About 3 cm below and lateral to the pubic tubercle) Constant
valve is present here
 Receive 3 tributaries
1. Superficial circumflex iliac
2. Superficial epigastric
3. Superficial external pudendal
 Pierces cribriform fascia
After piercing
 Receives deep external pudendal
 Opens into femoral vein (constant valve) (saphenofemoral junction)
 Up to 20 valves
 Incompetence of valves is a cause of varicosity of the vein.
 Unusually thick wall
 Accompanied by saphenous nerve (anterior to the vein)
 Thoracoepigastric vein - connects
o Lateral thoracic vein of axillary vein Obstruction of inferior vena cava
o Superficial epigastric vein
Small saphenous vein
Course
 Starts – drains the lateral side of the dorsal venous arch of the foot and lateral margin of the foot.
 Ascends behind the lateral malleolus, accompanied by the Sural nerve. (lateral to the vein)
 Ascends in the subcutaneous fat along post. Aspect of leg up to midcalf level
 Pierces deep fascia (anywhere between midcalf to roof of the popliteal fossa)
 Drains into popliteal vein.
 It communicates by several channels with the great saphenous vein.
Perforating veins
Indirect direct
Through muscles 1) Hand’s breath above knee
Superficial veins deep veins  Great saphenous vein femoral vein
2) Hand’s breath below knee
 Great saphenous vein post. Tibial v.
3) Hand’s breath above ankle
 Medially- great saphenous post. Tibial v.
 Laterally- small saphenous peroneal v.

 valves – permit blood flow only
Superficial to deep
Factors helping venous drainage of lower limb
General factors
1. Negative intrathoracic pressure

2. Arterial pressure – overflow from capillary bed
3. Compression of veins accompanying arteries by arterial pulsation
4. Presence of valves – divide blood into short columns
Local factors
1. Venous – More muscular veins in lower limb

Great number of valves, perforating veins
2. Muscular – muscular contraction

3. Fascial – Deep fascia makes muscular compression of veins effective
By limiting outward bulging of muscles
Clinicals
 Muscle pump
 Soleus (peripheral heart)
 Varicose veins & ulcers
 incompetence of
o valves of perforators or deep veins
o valves at termination of superficial
veins
become high pressure leaks
high pressure transmitted to superficial veins
dilation & gradual degeneration of superficial veins
varicose veins & varicose ulcers
 Deep vein thrombosis – may occur in deep veins of lower limb and pelvic veins
Valves of Lower limb may be destroyed leading to varicose veins

 Great saphenous vein in front of medial malleolus-
 Constant position for immediate blood transfusion
 For reperfusion in heart surgery
 Related to saphenous nerve

Lymph Drainage of Lower Limb
01) Lymph nodes
Superficial Deep
 Superficial inguinal lymph nodes
1.Deep inguinal lymph nodes
 About 10 nodes, T shaped arrangement
 Proximal group – Just distal to the  ¾ nodes
inguinal ligament
 Medial to femoral vein
 Distal group – Lies vertically along the
 eg:- lymph nodes of
terminal great saphenous vein
Cloquet/Rosenmuller
 Efferent – Pierce cribriform fascia and
terminate in deep inguinal nodes - afferents from
* Superficial inguinal nodes
* Popliteal nodes
* Glans penis / clitoris (→Cloquet)
 Upper medial – Umbilicus and anterior
abdominal wall. * deep lymphatics – L.L.
Below it, - efferent to
External genitalia, lower anal * external iliac nodes
canal and perineum, uterus
 Upper lateral – buttock, flanking back 2. Popliteal lymph nodes
below the waist - near small saphenous vein termination
 Lower vertical (distal group) – Superficial - afferents from
lymphatics of the lower limb except * territory of small saphenous vein
posterolateral calf * leg – deep parts
* heel of foot
* knee joint
-efferents to
 Lower part of anterior abdominal wall *deep inguinal nodes
below the level of umbilicus
Superficial
Deep External iliac nodes
Popliteal

5. WOTF regarding venous drainage of lower limb
a. Superficial & deep lymphatics systems communicate with each other only at the restricted regions
b. Deep vessels are much more numerous than the superficial vessels.
c. Superficial nodes in the virtually restricted to the inguinal region.
d. There is a lymph shed along the back of the lower limb.
e. Some efferents of the superficial inguinal nodes enter into deep nodes on the same region

Nerves of Lower Limb
Lumbar plexus (posterior abdominal wall)
Femoral nerve
Nerve of the extensor compartment of thigh
Root value - Posterior Divisions of Ant. Primary rami L2, L3, L4
Course
 Starts from the lumbar plexus
 Emerges at the lateral border of psoas major in abdomen then lies in the iliac fossa
between psoas and iliacus.
 Enters thigh by passing deep to inguinal ligament, at the lateral edge of the femoral
sheath, which separates it from the femoral artery. (Lies behind iliacus fascia)
 Lies between iliacus and psoas tendons in the femoral triangle
 Not a content of the femoral sheath
 Divides into branches immediately (~4cm distal to the inguinal lig)
Branches
 Iliacus is supplied by the nerve in the abdomen.
 As it enters the femoral triangle, it gives off the branch to Pectineus, which passes behind
the femoral sheath to reach the muscle.
Femoral nerve supplying quadriceps femoris is tested by patellar jerk (L3, L4)

Femoral nerve
(Separated by
Anterior division lateral circumflex artery) Posterior division
Anterior division Posterior division
Muscular  2 nerves to Sartorius  Rectus femoris
(usually double)
 Intermediate, medial,
lateral vasti
(medial – lat side of femoral
artery enter the adductor
canal)
(lateral- with descending
branch of lat circumflex
femoral)
Largest branch – Vastus medialis
Cutaneous  Intermediate  Saphenous nerve – leaves
cutaneous nerve (one femoral triangle at its apex
of Sartorius) and enters the adductor canal
 medial cutaneous then run across the femoral
nerve artery. leaves the canal
between Sartorius and
gracilis)
Largest branch. Accompany
great saphenous vein, anterior
to the vein.
Hip joint (nerve to rectus
Articular femoris)
Knee joint (nerves to all 3 vasti )

Obturator nerve
Nerve of the adductor compartment
Root values - Anterior Divisions of Ant.
primary Rami of L2, L3, L4 nerves.
Course
 Emerges on the medial border of psoas major within the abdomen
 Crosses the pelvic brim
 Runs forwards on the lateral wall of pelvis
 Enters thigh by passing through the obturator canal
 Divides into anterior and posterior divisions in the obturator canal
 Articular branches to hip joint
Anterior Division
 Passes above and anterior to the obturator externus
 Then behind pectineus and adductor longus
 Over the ant. surface of adductor brevis
 After supplying gracilis, enters the subsartorial plexus ends by
supplying femoral artery (supplies skin over the medial side of thigh)
Posterior division
 Enters thigh, piercing obturator externus
 Passes vertically downwards on adductor magnus, deep to the other
adductor muscles.
* Adductor brevis separates 2 divisions from each other.

Branches
Anterior Posterior
Muscular Pectineus Adductor magnus(adductor part) Obturator
Adductor externus
longus
Gracilis Sometimes adductor brevis
Adductor brevis
Articular Hip joint Genicular(supplies knee joint capsule and cruciate
ligaments, it passes along with the middle
genicular artery)
Clinical
 Both femoral and obturator nerves supply knee joint and hip joint. Pain in the knee can be
referred to hip joint
 Due to deep position, damage due to trauma is rare, but may be involved in obstetrics processes and
pelvic disease. (Ovarian tumour causes pain referred to medial side of thigh)
Subsartorial plexus
 Medial cutaneous nerve of thigh
 Saphenous nerve
 Obturator nerve- anterior division
Supplies the overlying fascia lata and an area of skin above the medial side of the knee

Patellar plexus
 Lateral cutaneous nerve of thigh
 Intermediate cutaneous nerve of thigh
 Medial cutaneous nerve of thigh
 Saphenous nerve
Sciatic Nerve
 Nerve of the flexor compartment
 Thickest nerve in the body.
 Main Branch of sacral plexus
Root values - ventral divisions of anterior primary rami L4, L5, S1, S2, S3 (tibial Part),
- dorsal divisions of anterior primary rami L4, L5, S1, S2 (common peroneal part)
Surface Marking in the gluteal region

 Exits the pelvis and enters the gluteal
region at a point 1/3rd of the way up
from ischial tuberosity to the PSIS.
 Enters the thigh midpoint between ischial
tuberosity and greater trochanter.
Course
 In the pelvis
 Lies in front of piriformis
 Undercover of fascia
 In the gluteal region
 Enters through the greater sciatic foramen below piriformis (more laterally than the
inferior gluteal and pudendal nerves and vessels)
 Posteriorly related to the capsule of hip joint
 Passes vertically downwards on the posterior surface of Superior Gemellus, Obturator
Internus, Inferior Gemellus, Quadratus femoris.
Pass midway between the ischial tuberosity and greater trochanter. No branches given in
this region
Enters back of thigh at the lower border of gluteus maximus.
 Nerve to quadratus femoris is deep to the sciatic nerve.
 Superficially lies the posterior cutaneous nerve of thigh.
 In the thigh
 Lies under cover of the Gluteus Maximus, crossed posteriorly by
the long head of Biceps Femoris.
 Runs vertically downwards up to the superior angle of popliteal
fossa on the posterior surface of the adductor magnus, where it

 Terminates by dividing into tibial and common peroneal nerves
above the knee. (variable point)
Branches -Articular branch to hip joint
-muscular branches
Tibial part Common Peroneal part

- Semitendinosus
- Short head of biceps femoris
- Semimembranosus
Hamstrings
- Long head of biceps femoris
- Ischial head of adductor magnus
Clinical
Sciatica
- Shooting pain over cutaneous distributions of sciatic nerve and its terminal branches
- Due to compression and irritation of nerve roots forming sciatic nerve (osteoarthritis, lumbar disc
prolapse, spondylolisthesis
Foot drop
-Penetrating wounds Loss of all

-Dislocation of the hip Injury to movements Foot drop
-Fractures of pelvis sciatic nerve below the
(gravity)
Injury to sciatic nerve knee
 Sensory loss
o Whole of leg and foot
o except the area supplied by the saphenous nerve (branch of femoral nerve)
 Sciatic nerve is accompanied by a small artery (branch of inf. gluteal artery)
 In above knee amputation companion artery must be carefully isolated and ligated separately
-ligation of the nerve fibres with the artery causes severe pain in the stump.
Intramuscular injections
Gluteal region is a typical site for intramuscular injections. Sciatic nerve passes through this
region and it needs to be avoided. Safest place to inject is the upper outer region of the gluteal
region.
Sleeping foot
- Compression of sciatic nerve (Since sciatic nerve lies on femur between quadratus femoris
and adductor magnus)
- Unusual stretching after sitting for a long time

01. Sciatic nerve
a) Is formed by the ventral and dorsal divisions of
sacral ventral rami
b) Emerges from the pelvis through the lesser sciatic
foramen
c) divides at a constant level
d) When the nerve is completely damaged plantar
flexion is diminished
e) Is related to the upper lateral quadrant of gluteal
region
Tibial Nerve
Nerve of the flexor compartment of the leg
Larger subdivision of sciatic nerve
Root values - ventral division of ventral rami L4 ,
L5 , S1 , S2, S 3
Course
 Descends vertically in the popliteal fossa
 Crosses popliteal vessels from lateral to medial side superficially
 Descends as the neurovascular bundle with post. tibial vessels (Post. Tibial artery first lies lateral
to it then passes ant. to it and continues down on its medial side.
 Lies superficial to tibialis posterior and deep to flexor digitorum longus
 Passes deep to the middle of the flexor retinaculum and
 terminates by dividing into medial and lateral plantar nerves
Popliteal fossa Back of leg

Muscular Gastrocnemius Soleus
Soleus Popliteus Flexor digitorum longus
Plantaris Flexor hallucis longus
Tibialis posterior
Cutaneous Sural
articular 3 genicular branches-
sup. Med, Ankle joint
middle, inf. Med

Common Peroneal nerve
Smaller terminal branch of sciatic nerve
Root values - Dorsal division of anterior primary rami L4, L5, S1, S2
Course
- Crosses the popliteal fossa from medial to lateral side along the medial border of biceps
femoris
- Winds around neck of fibula
- Enter substance of the peroneus longus muscle and
Branches - terminates by dividing into superficial and deep peroneal nerves
Cutaneous -lateral cutaneous nerve of calf
-Sural communicating nerve joins the sural nerve below the gastrocnemius heads
Articular - sup. Lat genicular
inf. Lat genicular
recurrent genicular
Clinical  Commonest nerve to be damaged in the lower limb. (fracture of neck of fibula, compression of
the nerve by a plaster on the leg)
- Site- as it winds around the neck of the fibula
 Effects of injury (talipes equinovarus)
o Paralysis of dorsiflexors of the foot ------- foot drop (unopposed action of plantar flexors)
o Paralysis of evertors -------- inversion of the foot
Sensory loss
Back of leg
Lateral side of leg
Most of dorsum of foot

Deep peroneal nerve
Nerve of the anterior compartment of leg
(like posterior interosseus nerve of forearm)
Course
- Arises within PL, over the neck of the fibula at the bifurcation of the common peroneal nerve.
- Spirals around the neck of the fibula, under cover of peroneus longus muscle, pierces anterior
intermuscular septum then pierces fibres of the extensor digitorum longus and reaches the
interosseous membrane.
- Runs down lateral to the anterior tibial vessels
- Upper part lies between the EDL and Tibialis Anterior, in the middle lies between the
Extensor Hallucis Longus and Tibialis Anterior. (EHL crosses in front of the neurovascular
bundle to lie on its medial side)
- Ends by dividing into medial and lateral branches
Branches
Muscular -Tibialis Anterior (Muscles of the extensor compartment of leg)
-Extensor Hallucis longus
-Peroneus tertius
-Extensor digitorum brevis & longus
Cutaneous -dorsal digital nerves for the adjacent sides of the big toe and second toe
Articular - ankle joint

-Tarsal joints
-Tarsometatarsal joints
-Metatarsophalangeal joint of big toe
Superficial peroneal nerve

Smaller terminal branch of the common peroneal nerve, formed in the substance of PL.
 Descends in the lateral compartment of leg deep to peroneus longus.
 First lies between peroneus longus and peroneus brevis
 Then between peronei and extensor digitorum longus
 Pierces deep fascia in distal third of leg and descends to the dorsum of foot
Branches
Muscular -Peroneus longus

-Peroneus brevis
Cutaneous
- Anterolateral aspect of the lower leg.
- to most of the dorsum of foot

FOOT
Lateral plantar nerve & Medial plantar nerve
Terminal branches of tibial nerve
Begin deep to the flexor retinaculum
Medial plantar nerve Lateral plantar nerve

(=Median nerve in hand) (=Ulnar nerve in hand)
SUPPLY
4 muscles main trunk- 2 muscles (Runs between 1 &2)
1) Abductor hallucis 1) Abductor digiti minimi
2) Flexor digitorum brevis 2) Flexor digitorum accessorius
3) Flexor hallucis brevis
4) 1st lumbrical
Cutaneous branches
Nail beds of medial 3 ½ nail beds
superficial branch -3 muscles deep branch
1) flexor digiti minimi all other intrinsic muscles of
2) palmar interosseous sole
3) dorsal interosseous lateral most

Gluteal region
Lies behind pelvis
Extends from Iliac crest to gluteal fold of buttock
Relations to piriformis
Pass from the pelvis into the gluteal

Above piriformis
 Superior gluteal vessels
 Superior gluteal nerve
Greater sciatic foramen
Below piriformis pudendal nerve
region
 Internal pudendal vessels
PIN  Nerve to obturator internus
 Inferior gluteal vessels
 Inferior gluteal nerve
 Posterior cutaneous nerve of thigh
 Nerve to quadratus femoris
 Sciatic nerve
Lesser sciatic foramen
 Obturator internus muscle tendon
 Pudendal nerve
 Internal pudendal vessels Pass into perineum from gluteal region
Relations of the sciatic nerve

 Nerve to quadratus femoris
 Posterior cutaneous nerve of the thigh

Cutaneous innervation
Nerves
Superior gluteal nerve (L4, L5, S1)

 Runs between gluteus medius and minimus
 Supplies
o Gluteus medius
o Gluteus minimus
o Tensor fascia latae
o (No cutaneous distribution)
Inferior gluteal nerve (L5, S1, S2)

 Enters deep surface of gluteus maximus
 Supplies
o Only gluteus maximus
o (No cutaneous distribution)
Nerve to obturator internus (L5, S1, S2)

 Loops around the (base) of the ischial spine
 Supplies
o Obturator internus
o Superior gemellus
Nerve to quadratus femoris (L4, L5, S1)

 Passes posterior to the hip joint
 Continues downwards deep to obturator internus and gemelli
 Enters the anterior surface of quadratus femoris
 Supplies
o Quadratus femoris
o Inferior gemellus
Posterior femoral cutaneous nerve / posterior cutaneous nerve of the thigh (S1, S2, S3)
 Runs medial or posterior to sciatic nerve
 Immediately deep to the deep fascia
 Branches
 Perineal branch
o Crosses the ischial tuberosity
o Enters the urogenital triangle
 Gluteal branches
o Supplies skin of posteroinferior quadrant of gluteal region
Arteries
Superior gluteal artery

 Branch of posterior division of internal iliac artery
 Above piriformis
Inferior gluteal artery

 Branch of anterior division of internal iliac artery
 Below piriformis
Internal pudendal artery

 Branch of anterior division of internal iliac artery
 Crosses the ischial spine
 Enters ischioanal fossa through lesser sciatic foramen
Muscles
 Gluteus maximus
 Gluteus medius
 Gluteus minimus
Ligaments
Sacrotuberous ligament
 Between ischial tuberosity and posterior iliac spines
Sacrospinous ligament
 Deep to sacrotuberous ligament
 Attached to, laterally – ischial spine
Medially – sacrococcygeal junction
Clinical
Intramuscular injection- upper outer quadrant of buttock

Femoral Triangle
Definition - Triangular space, on the front of upper 1/3 of the thigh immediately below inguinal ligament
Boundaries -
Superior/base – Inguinal ligament
Lateral – Medial border of Sartorius
Medial – Medial border of Adductor Longus
Apex –Point where the medial & lateral boundaries

meet directed downwards
Continuous below with adductor canal
Floor – [Medial to Lateral]

Adductor Longus =>Pectineus => Psoas major
[tendon] =>Iliacus
Roof –
● Deep fascia [Fascia Lata] - Saphenous opening
with cribriform fascia
● Superficial fascia
- Upper part of Great saphenous vein
- Superficial inguinal nodes
- Genitofemoral nerve - femoral branch
- Ilioinguinal nerve - branches
- Femoral artery- 3 superficial branches & accompanying 3 superficial veins
(superficial circumflex iliac, superficial epigastric, superficial external pudendal)
● Skin
Contents - 01. Femoral artery and branches [midinguinal point to the apex -6 Branches-3 superficial and 3 deep
-superficial branches-superficial external pudendal
-superficial epigastric
-superficial circumflex iliac
-deep branches -profunda femoris
-deep external pudendal
-muscular branches]
02. Femoral vein and tributaries
[At base - medial to artery] Great saphenous vein
[At apex - post. to artery] Veins corresponding to branches of artery
(Receives greater saphenous vein, circumflex veins and corresponding branches of femoral artery)
03. Femoral sheath
04. Nerves
A) Femoral nerve (in the groove between iliacus & psoas muscles outside the femoral sheath)
B)Nerve to the pectineus (branch of femoral nerve)
C) Femoral branch of genitofemoral nerve
D) Lateral cutaneous nerve of the thigh
05. Deep inguinal lymph nodes
 Femoral artery lies in front of psoas major tendon
 Femoral vein lies in front of pectineus
 Femoral nerve lies in the groove between iliacus and psoas muscles
Femoral sheath
● Funnel shape sleeve of fascia
● It is asymmetrical
● Enclose upper 4cm of femoral vessels
 Prolongation of
o Fascia transversalis=>Ant. wall
o Iliacus fascia=>Pos. wall
 Inferiorly merges with adventitia of femoral vessels
Lateral Compartment Intermediate Compartment Medial Compartment

(arterial) (venous) (lymphatic/femoral canal)
Femoral branch of the
genitofemoral nerve
Femoral artery Femoral lymph node
Femoral vein
Lateral septum Medial Septum
Nerve to pectineus
 Femoral lymph node of Cloquet/ Rosenmuller in the medial compartment
Femoral Canal
-Medial compartment of femoral sheath
-Conical
-wide above at the base and narrow below
-Base is also known as Femoral ring
Boundaries Anteriorly - Inguinal lig.

Posteriorly - Pectineal ligament
Medially - Lacunar ligament
Laterally - septum separating from femoral vein
Closed by - Femoral septum [condensation of extraperitoneal tissue]
Contents - Deep Inguinal lymph nodes [of Cloquet/Rosenmuller]

Lymphatics (This Lymph node drains glans penis in males
and clitoris in female)
Areolar tissue

Functions ●dead space for expansion of the femoral vein
●lymphatic pathway from the lower limb to the external iliac nodes
Clinical
Femoral Hernia
➢ Abdominal contents bulge out through femoral canal
➢ More common in female
 Wider pelvis
 Smaller size of femoral vessels
In strangulation, have to enlarge femoral ring => By incising lacunar ligament
 Normally => No Danger
 Abnormal(accessory) obturator artery => Alarming hemorrhage
Abnormal obturator artery

 Normal obturator artery is a branch of internal iliac artery
 Its pubic branch anastomoses with pubic branch of inferior epigastric artery.
(Abnormal ob. artery- when ob. artery is replaced by this branch from inferior epigastric artery)
Abnormal obturator artery
usually sometimes
Passes lateral to lies along the medial
femoral canal border of femoral ring
Differentiating inguinal hernia from femoral hernia??

Neck of the Femoral hernial sac protrudes below and lateral to the pubic tubercle and neck of the inguinal hernial sack
protrudes above and medial to the pubic tubercle.
Femoral hernia is never found in the newborn (not congenital)
Lump in the femoral triangle can be due to

 Skin & soft tissue --lipoma, sebaceous cyst, sarcoma
 Artery--- aneurysm of the femoral artery
 Vein--- varices of the great saphenous vein
 Nerve--- neuroma of femoral nerve / its branches
 Femoral canal--- femoral hernia
 Psoas fascia--- psoas abscess
 Lymph nodes--- Enlargement by any of the causes of
lymphadenopathy
Stab wounds at apex of triangle
Cut all large vessels of lower limb
Because 01 Femoral artery
02 Femoral vein
03 Profunda femoris artery
04 Profunda femoris vein are arranged in an anteroposterior line.

Adductor Canal
[Hunter’s / Subsartorial canal]
Definition - Intermuscular space, triangular in cross section, on medial side of middle 1/3 of thigh
Extent - From - Apex of femoral triangle above
To - Tendinous opening in adductor magnus below
Boundaries - Ant.lateral wall – Vastus medialis
Post.medial wall - Adductor longus[above]
- Adductor magnus [below]
Medial wall - Fibrous sheath joining ant. & pos. wall
Overlapped by Sartorius [Subsartorial plexus --between fibrous sheath & Sartorius, Formed by
saphenous nerve, medial cutaneous nerve of thigh Anterior division of obturator nerve]
Contents=>01. Femoral artery & branches
o Muscular
o Descending genicular
Femoral artery leaves the adductor canal through the opening in adductor magnus
At all levels in the thigh, the femoral artery lies between saphenous nerve and femoral vein
02. Femoral vein => Upper - posterior to artery
Lower - lateral to artery
03. Saphenous nerve=>pierces roof to leave canal (Crosses anterior to femoral artery from lateral to medial side)
04. Obturator nerve =>Ant.& Pos. divisions
05.Nerve to vastus medialis
Clinical
Exposure and ligature of femoral artery in this canal for aneurysm of the popliteal artery
T/F
Saphenous nerve crosses femoral artery medial to lateral in the adductor canal

Popliteal fossa
Definition=> Diamond/Rhomboid shaped
depression behind the knee joint, lower
part of femur and upper part of tibia
Boundaries=>
Superomedial
* Semitendinosus
* Semimembranosus (supplemented
by Gracilis, Sartorius, Adductor
Magnus)
Superolateral
*Biceps femoris
Inferomedial
*Gastrocnemius medial head
Inferolateral
* Gastrocnemius lateral head
* Plantains
Roof
Skin, superficial fascia
Contains
01. Short saphenous vein
02. Cutaneous nerves – 3
Medial cutaneous N. of thigh
Posterior cutaneous N. of thigh
Sural communicating N.
Floor
Above
01.Femur popliteal surface
02. Knee joint – capsule & oblique popliteal ligament below
03.Popliteal fascia covering popliteus
Contents
01. Popliteal artery &branches 05. Pos.cutaneous nerve of thigh
02. Popliteal vein & tributaries 06. Obturator nerve - genicular branch
03. Tibial nerve & branches [Sural N.] 07. Popliteal lymph nodes
04. Common peroneal nerve & branches 08. Fat
 Superficial to deep- N, V, A
 Medial to lateral- above- A, V, N
below- N, V, A
(popliteal vessels cross the tibial nerve anteriorly in the middle of fossa. Arrangement @ middle is N, V, A
behind forwards)
 Tibial nerve crosses fossa vertically downwards.
 Popliteal artery runs downwards and slightly laterally, divides at the lower border of popliteus
 Common peroneal nerve crosses the fossa obliquely along the medial border of biceps femoris.
Clinical
Pulsation of popliteal artery – in aneurysms

Regarding the contents of the popliteal fossa.
a) The Tibial nerve lies anterior to the popliteal vessels.
b) Lymph nodes of the fossa drain superficial tissues form the medial side of the foot.
c) The Sural nerve lies in a groove between the heads of gastrocnemius.
d) The common peroneal nerve can be palpated against the posterior surface of the lateral condyle of femur
immediately medial to the biceps tendon.
e) The roof is pierced by the small saphenous vein.

Foot
Comma shaped medial
Bones of the foot articular surface
Fan shaped lateral articular

surface

 Talus has no muscle attachments.
 When it is fractured can undergo avascular necrosis
 side determination- (medial surface-comma shaped impression/lateral surface-fan
shaped)
Bony prominences of the foot
1. tuberosity of the navicular- stands out as a bony prominence in front of the

medial malleolus; it is the principal point of insertion of tibialis posterior.
2. base of the 5th metatarsal - easily felt on the lateral side of the foot and is
the site of insertion of peroneus brevis.
3. If the calcaneus carefully palpated→ the peroneal tubercle can be felt below
the tip of the lateral malleolus
4. Sustentaculum tali below the medial malleolus.

Peroneal tubercle and sustentaculum tali represent pulleys respectively for
peroneus longus and for flexor hallucis longus
Joints of the foot
 Subtalar joint (Talocalcaneal joint) - Multiaxial, synovial joint

Gliding & inversion eversion movements
associated with talo-calcaneo-navicular joint.
 Talo-calcaneo-navicular joint - Ball & socket synovial joint.

Talus, calcaneus, navicular
Inferiorly supported by spring ligament (plantar
calcaneonavicular ligament)
Inversion and eversion take place (supported by
subtalar joint)
Talonavicular & calcaneocuboid joints lie in one line and together called “Transverse
tarsal joint” (mid tarsal joint) here pronation and supination take place as hidden
movements for plantigrade contact (gripping) – reinforced by the bifurcate ligament
 Cuboideonavicular joint - Fibrous joint. No movement (All other joints are synovial)
 Cuneonavicular joint - Continue with 2nd and 3rd intermetatarsal joints
 Calcaneocuboid joint - long and short plantar ligaments on its plantar surface
 Tarso-metatarsal joints - Gliding and aid in pronation and supination. Synovial
 Metatarso-phalangeal joints - Condyloid joints, Synovial

1st metatarso-phalangeal joint is the site of hallux valgus. Oblique attachment
of tendons of flexor hallucis longus and flexor hallucis brevis increase the
deformity
 Inter pharyngeal joints- Hinge type
Long plantar ligament

Attached between plantar surface of the calcaneus and base of middle 3 metatarsals
It covers the short plantar ligament
It also covers the peroneus longus tendon
Short plantar ligament (plantar calcaneocuboid ligament)

Attached between plantar surface of the calcaneus and cuboid
Muscles of the foot
Dorsum of the foot
Muscles Nerve Action

Extensor digitorum brevis Deep peroneal nerve Extend the medial 4 toes
**The tendon to the great toe is different from others and is named extensor hallucis brevis
Sole of the foot

Muscle Nerve Action
1st layer
01) Abductor hallucis -abduction of great toe

medial plantar
02) Flexor digitorum nerve -flexion of toe
brevis
03) Abductor digiti -abdution of little toe

minimi
2nd layer
01) Flexor digitorum -tibial nerve ref.

longus
02) Flexor digitorum -lateral plantar nerve -straigthens the pull of long flexor
accessorius main trunk tendons
03) Lumbaricals 4 1st -med. Plantar nerve -I/P joints -- extension

lat. 3- lat. Planter n.--deep bra.
04) Flexor hallucis tibial nerve ref.
3rd layer
01)Flexor hallucis brevis -medial plantar nerve -flexion of great toe
02) Adductor hallucis -lat. plantar nerve-deep branch -adduction-- great toe
03) Flexor digiti minimi lat. Plantar nerve-superf. Bran. -flexion of little toe
4th layer
01) Plantar interossei 3 -lat. Plantar nerve -adduction of toes

-most lat - superficial branch -PAD
-rest -deep branch
02) Dorsal interossei 4 -lat. Plantar nerve -abduction of toes

-most lat - superficial branch -DAB
-rest -deep branch

Posture
Line of gravity
passes anterior to the
 atlanto-occipital joint
 knee joint
 ankle joint
 four vertebral curvatures
Except the hip joint – posterior to the hip joint. Tendency to extend is
prevented by iliofemoral ligament
Postural/Anti gravity muscles:
*Erector Spinae
*Gluteus maximus
*Soleus
*Quadriceps femoris
Standing
 There are series of forward and backward movements

 During forward movement
 line of gravity moves forwards in front of hip joint
 prevented by Gluteus Maximus
 During backward movements
 line of gravity moves backwards
 knee joint tends to flex
 prevented by Quadriceps Femoris
Clinical: In wearing high heels the spine is pushed forward, knees excessively bent, soleus & gluteus
maximus in contraction, toes in extreme flexion, forward tilting of pelvis, cervical extension, lumbar
lordosis

Arches of the Foot
medial longitudinal arch Lateral longitudinal transverse arch

(More prominent) arch J.
(Less prominent)
Bones Calcaneus Calcaneus Metatarsals
Talus Cuboid Cuboid
Navicular Lateral 2 metatarsals Three cuneiforms
3 Cuneiforms
1st three metatarsals
Ends (pillars) Anterior – 1st three Anterior – heads of 4th
metatarsals (the and 5th metatarsals
phalanges do not take
part) Posterior – medial
tubercle of calcaneus
Posterior – Medial
tubercle of calcaneus
Summit Body of Talus Superior surface of

calcaneus
Key Stone Talus Cuboid

Slip Plantarcalcaneonavicular Long plantar ligament Dorsal interossei
ligament Short plantar ligament Transverse head of
(Spring ligament) Short muscles of foot adductor hallucis
Tie beam Plantar aponeurosis Plantar aponeurosis Peroneus longus

Flexor digitorum brevis Abductor digiti minimi
Flexor digitorum longus Flexor digitorum longus
Flexor hallucis longus Flexor digitorum brevis
Flexor hallucis brevis
Suspension Tibialis anterior Peroneus longus Peroneus longus

Tibialis posterior Peroneus brevis Peroneus brevis
Medial ligament of ankle
joint
Main stabilizing factor Muscles Ligaments Peroneus longus
tendon
Function of the arches
 To distribute body weight

 Acts as a spring during running and walking
 Acts as a shock absorber in jumping
 Concavity protects the soft tissues of the sole

Clinicals
 Pes cavus - high arch

 Pes planus – flat foot
1.Regarding the arches of the foot

a) Transverse arch is maintained by the peroneus longus tendon.
b) Plantar muscles play an active role in maintaining the arches even when the
arches are not subjected to stress.
c) Tibialis posterior tendon sends slip to talus.
d) Transverse arch is more prominent at the base of metatarsals.
Gait
 The gait cycle consists of one cycle of swing and stance by one limb.
Stance phase (60%)
o Begins with heel strike, when the heel strikes the ground and begins to assume the
body’s full weight
o Ends with push off, from the forefoot – a result of plantar flexion
o Occupy 60% of walking cycle
o Contains two periods
 Double stance period -- when both feet are on the ground
 Single stance period – when one foot is on the ground
 In running there is no period of double stance
o After the heel strikes, the forefoot must be lowered to the ground via plantar flexion

Swing phase (40%)
o Begins after push off, when the toes leave the ground
o Ends when the heel strikes the ground
o Plantar flexors (soleus, gastrocnemius) contract to raise the heel
o The long flexors of the digits flex the toes – leads to toe off
o The Foot is raised off the ground by flexion of the hip and knee
As one foot is raised from the ground, pelvis of the unsupported side drops
This is corrected by the gluteus medius and minimus of the opposite side
When these muscles are paralyzed
In one side – lurching gait
Both sides – waddling gait
(+ve Trendelenburg test)
 Rising up
o Hip extension
o Knee extension
 Walking up stairs
o Extension of the hip & knee joint in the leading limb to pull up the trunk to the
Step above

Physiology – Term 1
HOMEOSTASIS
Homeostasis
Maintaining the conditions of the internal environment nearly constant relative to the external
environment.
Internal Environment
In a multicellular organism, it is the interstitial fluid or tissue fluid.
What should be kept constant?

 Volume
 Osmolality
 Temperature
 Chemical composition
All the systems of the body help to maintain the homeostasis.

Eg: Supply of nutrients & waste products – Respiratory sys, GI sys
Protection of the body – Immune sys, Skin & surface membranes
There are various physiological arrangements which serve to restore the normal state once it is
disturbed.
Eg: Plasma [H+]
Buffers Respiration Renal mechanisms
Plasma [H+]
There are various Control Systems to make this happen. They maintain a variable at a particular set
point.
-Gets inputs from set point & feedback
from the sensor. If the set point changes with
Set point
-Detects the error
time of the system is called
-Output to effector.
a “servo mechanism”.
Controller
Inputs Set point-
Output
Feedback
Feedback =error
signals
Sensor
Effector
-Continuous
monitoring of the -Receives output of the
variable controller
-Detects disturbance -Applies necessary correction
-Sends feedback to
controller Response
Controlled
variable
Correction
Disturbance(s)

Negative feedback mechanisms Positive feedback mechanisms
Keeps a physiological level of a substance Accelerates a process which has already started
constant to reach an end point
Effects are negative to initiating stimulus Effects are positive to initiating stimulus
“Vicious cycle”
Vomiting, Childbirth, Blood clotting, Nerve
impulse transmission
 In each case positive feedback is useful, the positive feedback itself is part of an overall
negative feedback process.
Effectiveness of a control system
Measured by GAIN 𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑖𝑜𝑛

𝐺𝑎𝑖𝑛 =
𝐸𝑟𝑟𝑜𝑟
Not 100% effective.
If the gain is higher, system is better.
Variable Set Disturbance Hypothetical Actual Correction Error Gain

point change change
Systolic BP 120 Blood loss 60 100 100-60=40 120- 40/20=2
mmHg 100=20
Temperature 37 cold 17 36.5 36.5- 37- 18.5/0.5=
C 17=18.5 36.5=0.5 37
1. T/F regarding homeostasis

a) Disturbances in variables are detected by sensor.
b) Controller is responsible for calculating the error.
c) In negative feedback it facilitates the initial stimulus.
d) Efficient systems have a higher gain.
2. T/F regarding physiologic regulatory system

a) They are negative feedback systems.
b) The essential inputs of the controller are the set point and current value of the variable.
c) If the set point changes with time of the system is called a “servo mechanisms”.
3. Regarding a physiological regulatory system

a) Error is calculated by the controller
b) Efficient systems have a higher correction / error ratio
4. A 25-year-old person was admitted to the hospital after a road traffic accident. He has lost blood.
His systolic pressure was 90mmHg at the time of admission (normal systolic point is 120mmHg).
Deviation of blood pressure from the set point would,
A) Be due to decreased volume in the intra vascular compartment
B) Larger in the absence of a regulatory system
C) Be detected by the sensors in the circulatory system
D) Blood pressure can be normal by positive feedback
E) Can be normal 100% by negative feedback

Fluid and electrolyte balance
Body fluid and compartments
Total Body Water

(TBW)
60% of Body
weight(BW)
ECF ICF
1/3 of TBW or 20% of 2/3 of TBW or 40% of
BW BW
Interstital Fluid/ Tissue

Plasma
Fluid Transcellular Fluid
5% of BW
15% of BW (negligible)
(1/4 of ECF)
(3/4 of ECF)
Transcellular fluid belongs to ECF & includes CSF, secretions in gut, fluids in joints and eye.
Blood-8% of the BW
? Calculate approximate values for a 70 kg young adult male. (1kg=1L)
Factors affecting TBW
1) Age - age TBW(Infants – 70%, Young adults – 60%, Old – 50%)

2) Gender - F – 50% < M – 60% (low percentage of fat)
3) Fat content - Fat TBW
Water Balance
In a healthy person,
Water gain = water output
3L/day = 3L/day
Over hydration - gain > loss

Dehydration - gain < loss

Types of Dehydrations and Over hydrations
Isotonic over hydration Isotonic dehydration

ECF volume ↑ ECF volume ↓
ECF osmolarity not changed ECF osmolarity not changed
ICF volume not changed ICF volume not changed
ICF osmolarity not changed ICF osmolarity not changed
Net fluid shift 0 Net fluid shift 0
BP ↑ BP ↓
Hematocrit ↓ Hematocrit ↑
Hypertonic over hydration Hypertonic dehydration

ECF osmolarity ↑ ECF osmolarity ↑
ICF volume ↓ ICF volume ↓
ICF osmolarity ↑ ICF osmolarity ↑
Net fluid shift ICF to ECF Net fluid shift ICF to ECF
BP ↑ BP ↓
Hematocrit ↓↓ Hematocrit not changed
Hypertonic over hydration Hypotonic dehydration

ECF osmolarity ↓ ECF osmolarity ↓
ICF volume ↑ ICF volume ↑
ICF osmolarity ↓ ICF osmolarity ↓
Net fluid shift ECF to ICF Net fluid shift ECF to ICF
BP ↑ BP ↓
Hematocrit not changed Hematocrit ↑↑
Distribution of electrolytes
ICF ECF Serum Intracellular
Major Cation (+) K+ Na+ Na+ 135-145 mmol/L 15 mmol/L
Major anion (-) PO43- Cl- K+ 3.5-5 mmol/L 150 mmol/L

Prot -
Proteins - [ICF]>>[plasma]> [interstitial fluid]
Measurement of electrolytes
SI unit - mmol/L
Traditional unit- mEq/L

Infants & children more prone to dehydration
 TBW : infants (70%) > adult (60%)

 ECF/ ICF : Infants & Children > adults
 ECF volume : Infants & Children < adults
 Possibility of H2O loss : ECF > ICF
 Dehydration develops
1) More rapidly
2) Frequently more severe in children than adults as ECF/ICF ratio is
higher in children
 Severe Vomiting : HCO3- ↓

 Cation concentration: Plasma > ICF
 Anion concentration: ICF > ECF
 ICF cation exchange > ICF anion exchange
 pH : ICF < ECF (due to metabolism)
2+
 50% of the Ca in the plasma are bound to protein.
Dilution principle Known amount of

1. A known amount of substances (x) introduced to substance injected (x)
the concerned body of fluid compartment & Volume (v)
allowed to equilibrate.
2. After equilibrium is reached concentration in the
sample is measured (C) volume of body fluid
Body fluid
compartment (V) is calculated
compartment
𝑥 sample
𝑉=
𝐶
Characteristics of the substances used

1. non-toxic
2. easily measured
3. distribution limited to the compartment
4. mix evenly throughout the compartment
5. not changed or lost in time taken for equilibrium to reach or amount changed or lost is known
6. compartment should be accessible for sample collection
7. must not have an effect on its own on body fluid distribution.

Measurement of volumes of body fluid compartments
 TBW - D2O, T2O, aminopyrine
 ICF - not measured, calculated using TBW - ECF
 ECF - radioactive inulin (most accurate)
Mannitol
Sucrose
Radioactive Cl- / Br-
 Plasma - dyes which bind to plasma proteins
Serum albumin labeled with radioactive iodine
100
 TBV -
100−𝐻𝑎𝑒𝑚𝑜𝑡𝑜𝑐𝑟𝑖𝑡
× 𝑝𝑙𝑎𝑠𝑚𝑎 𝑣𝑜𝑙𝑢𝑚𝑒
 Interstitial fluid - ECF - plasma
1. In a normal healthy adult

a) the ratio ECF/ ICF is less than one
b) interstitial fluid has a higher osmotic pressure than plasma
c) the quantity of total body water is directly proportional to the fat content of the body
d) increase Na+ loss causes a reduction in ECF
e) the percentage of total body water is higher in children
2. In health the proportion of the water in the body is higher

a) in infants than in adults
b) in young adults than in the old
c) in thin people than in fat people
d) in women than in men
e) than in an edematous person

Movement of substances across biological barriers
Mechanisms
Filtration
Glomerular Solvent Drag
filtration 1.Transport of
nutrients
2.RBCs in blood
Diffusion
1. Simple :
Gases-O2, CO2
Lipid Soluble Substances Active Transport
2.Facilitated : Glucose 1. Primary : Na+ /K+ ATPase
Mechanisms 2. Secandary :
Na+/glucose (SGLT)
Na+ /bile salt co-transporters
Exocytosis
Nerve Impulse Endocytosis
Transmission Osmosis
Phagocytocis
Pinocytosis
1) Diffusion
 The process by which
-a gas or
-a substance in solution
-expands
-because of the continuous random movements of particles
-to fill all of the available volume
 Net flux of
-solute particles
-from areas of high
-to areas of low concentrations

Factors affecting diffusion
1. Fick’s Law of diffusion

∆
Magnitude of Tendency to diffuse α
√
A- Cross sectional area available for diffusion

d- distance
M- molecular weight
∆𝐶-concentration gradient
2. Electrical charge of the ion
3. Membrane permeability
i. thickness of membrane (d)
ii. lipid solubility
iii. no. of protein channels per unit area
iv. Temperature
v. Molecular weight of substance
4. Donnan Effect
Presence of a non-diffusible ion
-on one side of a membrane
-affects the
-distribution of
-diffusible ion
-across that membrane
In a predictable manner.
Effects of Donnan’s phenomenon

1. Rupture of cells
Normal cell volume & pressure depends on Na+ - K+ ATPase
2. inside of cell membrane is (-) charged
3. (plasma proteins) ion movement across the capillary wall
Types of diffusion
a. Simple Diffusion
b. Facilitated Diffusion

c. Nonionic diffusion
HA H+ + A-
H+ X
A- X
Net movement of undissociated substance (in GIT & kidney)
2) Active transport uphill movement

Energy required
Іry Active IIry Active

Energy Source ATP (directly) Derived from
concentration gradients
by Iry Active transport
Eg: - Na+-K + ATPase pump Na+ /glucose transporter
2ry active transport

 Symport Eg: – SGLT 1 (driving ion Na+ : driven Glu)
 Antiport Eg: – Na+ - H+ antiporter

Exocytosis Endocytosis
 Energy dependent  Energy dependent

 Ca2+ dependent (in nerves)  Reverse of exocytosis
Types
1. Phagocytosis
Polymorphonuclear leukocytes engulf
bacteria, dead tissue
2. Pinocytosis
“Cell drinking”- engulf substances in a
solution
3) Filtration
Movement of fluid due to difference in pressure on two sides
Amount of fluid filtered depends on
1. pressure difference on either side (∆P)

2. membrane permeability
3. surface area of membrane
Eg: - Across capillary wall. (But across cell membrane no filtration)
4) Osmosis
Diffusion of solvent from a region of low solute [conc.]/ low osmotic pressure to a region of high
solute [conc.]/ high osmotic pressure across a semi permeable membrane.
Occurs from low osmotic pressure to high osmotic pressure
Osmotic pressure (OP)
Pressure necessary to be applied to a solution to prevent the inward flow of solvent across a
semipermeable membrane by osmosis
Depends on no. of dissolved particles
Osmole = amount of solute that dissociates in solution to form 1 mole
Glucose 1 mol/L =1osmol / L
NaCl 1mol/L = 2 osmol/L
Osmolarity - no. of osmoles per litre of solution

Osmolality - no. of osmoles per kilogram of solvent
Plasma osmolality - 290 mOsm/kg

Measured by - freezing point depression (By osmometer)
Calculated by -
Osmolarity 2 [ Na + ] + 0.055[Glucose] + 0.36[BUN]
(mOsm/L) = mEq/L (mg/dL) (mg/dL)
BUN- Blood Urea Nitrogen
Osmolarity measured is higher than calculated value

Why??
Osmolarity must have been increased due to a substance other than Na+, glucose, BUN like ethanol,
mannitol or poisons.
Tonicity
Osmolality of a solution relative to plasma
Isotonic - same as plasma
{0.9% Saline, 5% Dextrose, king coconut water}
Hypertonic - greater than plasma
Hypotonic - lesser than plasma
1. The osmolality of a solution

a) is the number of osmoles per kg of solvent
b) is independent of the volume of the solutes
c) varies with temperature
d) containing 180 g of glucose per kg of distilled water is about the same as that of normal human
plasma
e) containing 58.5 g of NaCl in 500 g of distilled water is one osmole
2. Assuming complete dissociation into Na+ & Cl- a solution of 5.85 g NaCl in litre of water
a) will have an osmolality of 0.1 osmole
b) will contain 0.1 mole of Na+ per litre
c) would be more concentrated than ECF
d) would have higher H+ concentration than ECF
e) will cause hemolysis of a normal red cells added to the solution in a few seconds

Interstitial fluid formation
Diffusion through the capillary membrane
1. Lipid soluble - diffuse directly

2. Water soluble - through the capillary pores (Na+, Cl-, Glu)
3. Protein & large substances - Transcytosis
This suggests capillary walls acts like semi permeable membranes. Impermeable to colloids.
So, COP develops. COP due to plasma colloids is called the oncotic pressure.
Factors contributing to the formation of interstitial fluid
 Starling forces –Filtration (depends on hydrostatic pressure gradient)

Osmosis (depends on colloid osmotic pressure gradient)
 Capillary permeability
 Available surface area
Hydrostatic pressure - Pressure exerted by fluid (e.g.: - blood in the capillary)

Colloid osmotic pressure - Pressure exerted by colloidal substances (e.g.: - mainly albumin)
Hydrostatic P =
Net Pressure = ↓( 37 – 1) – 25 mmHg ↑(1-17) + 25 mmHg

↓ 11 mmHg ↑9 mmHg
∆P = ↓(11-9) mmHg
= ↓ 2 mmHg
Balance carried by lymphatics

Odema
Abnormal accumulation of fluid in interstitial spaces.
Odema
Generalized Localized
1. ↑ venous pressure 1. ↑ venous pressure in local obstruction
In right heart failure -Late pregnancy (IVC)
↑ R atrial pressure.
2. lymphatic obstruction (lymphoedema)
2. hypoalbuminemia -cancers
+ protein malnutrition -filariasis
+liver disease
+nephrotic syndrome 3. ↑ capillary permeability
+Hypoproteinemia -insect bites
-Inflammation & allergy
-Substance P, histamine, kinins
Odema first seen in most dependent parts of the body.

Eg- Ankle odema.
Oedema causes weight gain.
Oedema (except lymphedema) ex – Filariasis; leads to pit formation.
1. Ankle oedema is known to be caused by

a) Nephrotic syndrome
b) Severe protein energy malnutrition
c) Chronic renal failure
d) Deep vein thrombosis in legs
e) Systemic hypertension in the absence of heart failure
2. Capillary filtration
a) decreases if interstitial oncotic pressure increases
b) is normally smaller in magnitude than capillary reabsorption
c) is the main mechanism of cerebro-spinal fluid formation
d) will decrease if the capillary hydrostatic pressure decreases
e) is increased in protein malnutrition

EXCITABLE TISSUES
Neurones Muscles
Neurones
Structural Classification
1. Unipolar
2. Bipolar – retina
3. Pseudounipolar – Sensory
neurone
4. Multipolar – motor
Functional components of a
neurone
 A receptor zone - Dendrites or
the cell body integration of
multiple local potentials
generated by synaptic
connections
 Cell body
 Generator of propagated
impulse - Initial segment or the
1st node of Ranvier
 Pathway to transmit the
impulse - axon
 Nerve endings to release the
neurotransmitters – axon
terminal
Glial cells
Microglia – Derived from macrophages Removes debris resulting from infection + diseases
Macroglia
1. Oligodendrocytes – Forms myelin sheath in CNS. A single cell can form myelin sheaths of multiple neurones
by emitting branches.
2. Schwann cells – forms myelin sheath in PNS. A single cell contributes only to one neurone.
3. Astrocytes
a. Only found in blood brain barrier
b. Trophic to nerves (produce neutrophins)
c. Take up K+ and neurotransmitters
Macroglia also secrete nerve growth factors.
Multiple sclerosis – Myelin destruction in CNS
Guillain barre syndrome – Myelin destruction in PNS

Axonal Transport
Orthograde – from cell body to axon ending – transport of polypeptides
Retrograde – from axon ending to cell body – growth factors, some viruses
RESTING MEMBRANE POTENTIAL
 Membrane potential is the electrical potential energy difference between the inside and outside of a cell
 Resting membrane potential (RMP) is the membrane potential when not transmitting an impulse
 In neurons its value is usually -70 mV (inside the cell membrane compared to outside)
– Due to different concentrations of ions across the membrane
– Different permeability for different ions
 The bulk solution inside and outside is electrically neutral
 The potential difference exists only across the cell membrane
 Main determinant of RMP is the movement of K+ through K+ leak channels
 Therefore, changes in extracellular [K+] have major effects on RMP
 Negativity inside is maintained by Na+/K+ ATPase pump Ion concentrations when R.M.P is -70 mV
– An electrogenic pump
– Inhibited by Ouabain and Digitalis Extracellular Intracellular
 At rest the membrane is impermeable to proteins Na + - 150 Na+ - 15
 Due to leak channels, the membrane is K - 5.5
+ K+ - 150
– Slightly permeable to Na+ Cl- - 125 Cl- - 9
– Highly permeable to K+ (impermeable
to proteins)
– Freely permeable to Cl- (No net movement as Electrical responses of nerve to a
its equilibrium potential is -70 mV) stimulus
 +
K diffuses “out” of the cell along its
concentration gradient Propagated action Local, non-propagated
potential potential
 Na+ diffuses “in” to the cell along its
concentration gradient
Receptor potential
 If ion leakage across the membrane continues unopposed, it would proceed
until concentration gradients are balanced by the electrical gradient
 But, Na+/K+ ATPase pumps 3Na+ out & brings 2K+ in, per turn End plate potential
(Na+/K+ ATPase pump act as an electrogenic pump because it generates
electronegative potential Synaptic potential
 +
This maintains the concentration gradients of K and Na +
(but contribution of Na+/K+ ATPase pump for RMP is a very small value of -5mV)
 Therefore, the membrane potential is maintained at RMP
 Changes in membrane potential that reach the threshold level can be propagated along a nerve fibre
 Threshold is usually 15 to 20 mV above RMP (about -55 mV)
3 major factors determining for maintenance of RMP

1. Unequal distribution of one for more ion species across the membrane
2. Selective permeability of membrane to one or more of these ions
3. Na+/K+ ATPase pump

How extracellular ion concentrations affect excitability of a neurone:
 [Na+] – not much effect on excitability
 Increased [K+] – more excitable (hypopolarization) Causes amplitude of action potential
to decrease + have a little effect on
 Decreased [K+] – less excitable (hyperpolarization)
RMP
 Increased [Ca2+] – less excitable
 Decreased [Ca2+] – more excitable
Action Potential
 Is generated in response to a stimulus

 Is a rapidly spreading change in membrane potential
 Membrane needs to be depolarized to the firing level (-55mV) for its generation
 Self-propagating
 Nerve impulses are transmitted as action potentials.
 Site of generation of action potentials
In spinal motor nerve  Initial segment

In cutaneous sensory nerve  First node of
Ranvier
RMP Depolarization  Repolarization  HyperpolarizationRMP

Ionic basis of an Action Potential
←---ARP------→ ←---→
RRP
A. Depolarization
 Stimulus generates a graded ARP-Absolute Refractory Period
potential in the nerve fibre
 Some voltage gated Na+ RRP-Relative Refractory Period
channels open.
 Na+ INFLUX
 Membrane potential rises to
threshold level (-55mV)
 More voltage gated Na+
channels open
 Rapid influx of Na+ makes the
membrane potential more
positive.
 Membrane potential
overshoots zero potential.
 This is a positive feedback
cycle Hyperpolarization
B. Repolarization
 Resistance for Na+ influx
increases as membrane
potential becomes more positive, reversing the electrical gradient for Na+.
 Voltage gated Na+ channels close 1/104 s after they open.
 Na+ INFLUX stops.
 When MP rises from -70mV to 0mV, voltage gated K+ channels open.
– They are slow to open and slow to close.
 Opening of K+ channels coincide with the closure of Na+ channels.
 Resulting K+ EFFLUX makes the membrane potential negative again.
 After depolarization, K+ voltage gated channels close via a negative feedback mechanism
C. Hyperpolarization
 K+ efflux lasts longer than needed to restore membrane potential to RMP.
 Therefore, the membrane is hyperpolarized.
 When K+ channels close, K+ EFFLUX stops.
 Membrane stops becoming more negative.
 RMP is restored. But a large amount of Na+ remains within the cell & a large amount of K+ has escaped.
 Na+ / K+ ATPase corrects the ionic distribution.
Effects of ECF ion concentration
Ion Increased Decreased

Na+ RMP unchanged RMP unchanged
Action potential (AP) amplitude increased AP amplitude decreased
K+ RMP decreased (RMP closer to threshold potential) RMP increased
Ca2+ Excitability↓ (more depolarization to generate AP) Excitability↑ (less depolarization for AP)

 How do changes in Ca2+ concentration affect the excitability?
Ca2+ can affect the membrane potential through both channel movements and membrane interactions, A
decrease in extracellular [Ca2+] increases the excitability of the nerve and muscle cells by decreasing the
amount of depolarization necessary to initiate the changes in Na+ & K+ conductance that produce AP
All or None Principle

 Once the threshold potential is reached, a full-sized action potential is created.
 Further increase in intensity of the stimulus does not produce any changes in the amplitude of the AP.
 Subthreshold stimuli fail to produce an AP.
 Threshold & supra-threshold stimuli produce APs of constant amplitude.
Refractory Period of the membrane
Absolute Relative
• Time period from reaching the firing level to the first • Time period from the last 2/3 of repolarization to
1/3 of repolarization the beginning of after-depolarization
• Does not respond to any stimuli • Only suprathreshold stimuli can evoke an AP
1. In a nerve cell
a) K+ efflux contributes to repolarization.
b) Initial rapid depolarization is due to opening of Na+ channels.
c) High Na+ concentration in ECF increases the magnitude of action potential.
d) Conductance of fibre type A is faster than type C.
e) Slightly higher cation concentration in the interstitial space affects the RMP of the cell.

Strength Duration Curve
 Strength-duration curves are drawn to test the nerve
function
 Graph is drawn with the duration of stimulus against
the strength of the stimulus
A - Rheobase – minimum strength to

elicit response
B - Chronaxie – Duration of stimuli at
twice rheobasic strength.
 Longer the time of application of the stimulus Smaller the required minimum strength of the stimulus
 Shorter the time of application of the stimulus Greater the required minimum strength of the stimulus
 Very slowly increasing current  No AP
o Slow opening of voltage gated Na+ channels and slow opening of voltage gated K+ channels coincide.
Na+ influx is balanced by K+ efflux.
Action Potential Propagation
 Active, self-propagating process

 Impulses move with constant magnitude (mV), amplitude & constant velocity (ms -1).
 Spreads away from a stimulus.
 An action potential creates a “current sink” (an area to which current, i.e. “positive” charges flow)
 Positive charges move in to the current sink, depolarizing the adjacent membrane to firing level.
 Therefore, action potentials are generated in the adjacent membrane.
 These too act as current sinks and the process repeats.
 Action potentials are thus generated sequentially further and further away from the point of application of
the stimulus.
 APs that reach a synapse from the wrong side (along a dendrite) die out because synapses permit
conduction in one direction only.
 The strength of the AP is not diminished as it travels along the axon
 AP doesn’t reverse; Because once the axon has (+) charge, reversing also has a slight refractory period

Propagation along unmyelinated nerve fibre Propagation along myelinated nerve fibre
(Simple Conduction) (Saltatory Conduction)

Nerve fibre types
1. Erlanger & Gasser classification 2. Numerical classification of sensory nerves

- Down the list, diameter increases; velocity increases
3. Relative susceptibility of A, B, C fibres to conduction block by various agents
Susceptibility To: Most Susceptible Intermediate Least Susceptible

Hypoxia B A C
Pressure A B C
Local anesthetics C B A
Clinical relevance
 Demyelination (Eg: Multiple sclerosis) – Conduction velocity is decreased
 Axonopathy – Reduction of amplitude. Later the velocity also reduced.
 Injury to nerves – PNS likely to regenerate, CNS mostly degenerated.
 Local anaesthesia – Blocks only C fibres
Neutrophins
Nerve growth factor (NGF)
 Necessary for the growth & maintenance of sympathetic and other sensory neurones
 Reduce apoptosis of neurons
 Produced in structures innervated by them. Eg: muscles. In the CNS, produced by astrocytes
 Transported retrogradely to the nerve cell body
Local potentials
Can be subdivided into,
1. Receptor potential
2. End-plate potential
3. Synaptic potential

Receptor potential
 When stimulus act on the unmyelinated nerve end or receptor changes occur in
receptor membrane
 Opening of Na+/Ca2+ channels, inhibition of K+ channels or inhibition of Na+/K+
ATPase pump leads to produce non-propagated receptor potential
 When this receptor potential reaches the threshold, An AP is generated in the 1st
node of Ranvier
End Plate Potential
 Ach binds to the muscle type nicotinic-cholinergic receptors in the motor end
Local plate
 This opens a gate within the ligand gated channels which are equally permeable
Potentials to Na+ & K+
 Depolarization & causes a local graded potential on the end plate
Synaptic potential
 EPSP (Excitatory Post Synaptic Potential)

– Temporary partial depolarization of post synaptic membrane
 IPSP (Inhibitory Post Synaptic Potential)
– Hyperpolarization of post synaptic membrane

Synapse
 Impulses are transmitted from nerve cell to

other cells at synapses
 Permit conduction of impulses in one
direction only
 Transmission in most synapses are chemical
but, in a few cases, electrical (in brain-faster
than chemical)
 Voltage gated Ca2+ channels are found in

the active zone.
 When an AP reaches an axonal terminal,
Ca2+ diffuses in. Junction between 2
 Triggers exocytosis of neurotransmitters into the synaptic excitable cells
cleft.
 Three types of vesicles
o Small clear vesicles- Ach, glycine, glutamate, GABA Nerve - Nerve Nerve - Muscle
o Small vesicles with dense core – catacholamine - Axodendritic
o Large vesicle with dense core- neuropeptide
 Vesicles are synthesised in cell body & are transported
- Axoaxonal
along the axon - Axosomatic
 Synaptic delay is usually 0.5ms
 Synaptic transmission of Ach??
Synaptic Potentials
Single stimulus does not produce an action potential in postsynaptic membrane, instead it produces a transient
depolarization or transient hyperpolarization
•Temporary, partial depolarization of post synaptic membrane, due to

EPSP
•Closure of K+ channels
(Excitatory Post •Opening of Na+ channels/Ca2+ channels
Synaptic Potential) •Acetylcholine, Glutamate produce EPSPs in post synaptic membrane
•Hyperpolarization of post synaptic membrane, due to

•Opening of Cl- channels
IPSP (Inhibitory Post •Opening of K+ channels
Synaptic Potential) •Closure of Na+ channels
•Closure of Ca2+ channels
•GABA & glycine produces IPSPs in postsynaptic membrane

Events at synapses
1. Summation
Summation of synaptic
potentials
Spatial Temporal
Many presynaptic terminals are stimulated at the same Successive discharges from a single presynaptic
time. terminal,
The depolarization induced at several points on the neuron If they occur rapidly enough, can add to one-
spread to trigger zone before decaying out another and summate
The potentials summate to elicit an AP
2. Convergence 3. Divergence e.g.: - Preganglionic & post

ganglionic neurones in ANS
4. Inhibition
a. Presynaptic b. Postsynaptic
Inhibitory interneuron-GABA
Reduce transmitter release from the excitatory

neurone by, Inhibitory interneuron-
1. Opening of K+ channels → K+ efflux GABA, Glycine etc.
2. Increase in Cl- conductance
Decrease the size of the AP reaching the nerve
ending
Reduce Ca2+ influx
Reduce neurotransmitter release
5. Facilitation
6. Negative feedback inhibition
Renshaw cell → ankle clonus
Motor neurone

Clinical
 Tetanus (medical condition) – Tetanus toxin blocks the release of inhibitory neurotransmitters (glycine,
GABA) from inhibitory interneuron cell
marked rise in motor neuron activity in the CNS causing spastic paralysis
 Botulism – Botulinum toxin blocks acetylcholine release into the NMJ causing flaccid paralysis
Synaptic Plasticity
Changes in the function of synapses due to past experience
Basis of learning and memory
1. T/F
a) Decrease in ECF [K+] hyperpolarize the nerve axons
b) Chronaxie is a time measurement
c) Rheobase the minimum strength of a stimulus to initiate an action potential
d) A slight increase in extracellular Na+ is enough to depolarize the membrane
e) Increased extra cellular Ca2+ increases the excitability of the nerve membrane
2. In a myelinated nerve fibre

a) APs are mostly generated in axon hillock
b) Synaptic potentials are integrated in receptor zone
c) Node of Ranvier is rich in voltage gated Na + channels
d) Conduction velocity progressively increases along the length
e) Local pressure around nerve fibres inhibit conduction of impulses
3. Factors that affect the velocity of conduction in nerves include

a) Diameter of the nerve.
b) Myelination of the nerve.
c) Compression of the nerve fibre.
d) Length of the nerve fibre.
e) Local anaesthetic infiltration around the nerve.
4. Saltatory conduction
a) Occurs only in myelinated fibres.
b) Does not depend on depolarization of the nerve cell membrane.
c) Velocity decreases as the temperature rises.
d) Transmits impulses with a velocity proportionate to fibre diameter.
e) Produces a great voltage change in the membrane than in non-saltatory conduction

Neuromuscular transmission
 Impulse arrives at the terminal bouton.
 Opening of voltage gated Ca2+ channels, permeability to Ca2+ is
increased, Ca2+ influx.
 Triggers exocytosis of Acetylcholine (Ach) vesicles
 Ach. diffuse across the synaptic cleft
 Ach. binds with muscle type nicotinic cholinergic receptors.
Receptors are in the motor end plate (M.E.P)
 Opens a gate within the channel, equally permeable to Na+ and
K+ (ligand-gated ion channels).
 Increased Na+ and K+ conductance & Na+ influx greater than K+
efflux as electrochemical gradient is higher for Na+
 Depolarization (End plate potential) - local graded potential
 Acts as a current sink
 Depolarizing adjacent muscle fiber (Rapid Na+ channels are not
present in motor end plate)
 Firing level  action potential spreads in both directions into T
tubules
 Initiates muscle contraction
 Spatial summation is not possible at an NMJ, as a single NMJ is
synapsed with one terminal bouton.
 Temporal summation is possible, but the earlier impulse usually
generates an AP in the muscle so that it doesn’t last until the
next impulse to be transmitted through the NMJ to cause
temporal summation.
 Removal of Ach. from the synaptic cleft is by Ach. esterase
 (Neostigmine is a competitive inhibitor of Ach. esterase.)
Acetylcholine receptors
1. Muscarinic (M1-5) 2. Nicotinic – NMJ and synapses

G-protein coupled receptor Ligand gated ion channel
Blocked by - atropine Blocked by
 NMJ and synapses both - alpha bungarotoxin
(found in snake venom)
 NMJ type - curare
 Synapses type - hexamethonium
Events at motor end plate at rest
 At rest continuous release of Ach occurs from the nerve terminal

 This produces minute changes in polarity of the MEP. These changes in voltage are called Miniature end-
plate potentials.
 Important for the integrity of the muscle. Otherwise muscle wasting occurs.

SKELETAL MUSCLE
Heads of Myosin have Actin-binding sites and ATP-
 Contractile unit of muscle fibre – sarcomere hydrolyzing sites
Troponin
 C – binds Ca2+
 T – binds to tropomyosin
 I – Inhibits actin-myosin interaction
Tropomyosin
 Block myosin-binding sites of actin
 Z lines move closer. ‘A’ band remain constant. All others get shorter.
 Functional unit of muscle – motor unit (=single motor neurone and all the muscle fibers innervated by it)
Neurone All the muscle fibers in one motor unit are innervated by one
motor neuron.
Contraction of skeletal muscles
 Discharge of motor neuron

 Release of acetylcholine at motor end plate
 Binding of acetylcholine to muscle type nicotinic cholinergic receptors
 Increased Na+ & K+ conduction at motor end plate
 Generation of end plate potential (local non-propagated)
 Generation of action potential in muscle fiber
 Inward spread of depolarization along T tubules

E-C Coupling
 Depolarization leads to conformational change in voltage sensitive dihydropyridine receptors, opening

ryanodine Ca 2+ channels of terminal cistern, causing release of Ca2+ into cytoplasm
 Binding of Ca2+ to troponin C
 Conformational change exposes myosin binding sites of actin.
 Myosin binds to the newly uncovered binding sites on the thin filament (cross bridge formation)
 Upon formation of cross bridge ADP is released.
 This causes a conformational change in myosin head that moves the thin filament relative to the thick
filament, causing the “power stroke”.
 This will pull the Z-lines towards each other, thus shortening the sarcomere and the I-band.
 ATP quickly binds to free site on myosin, allowing it to release from actin and return to the weak binding
state.
 ATP is then hydrolyzed, and the energy released is used to move into the "cocked back" conformation (“re-
cocking” of myosin head) completing the cycle.
 Steps mentioned above repeat as long as ATP is available and Ca2+ level remains elevated.
 Many myosin heads cycle at or near the same time, and they cycle repeatedly, producing gross muscle
contraction.
T-Tubule System
Sarcolemma of a muscle fiber

invaginates into the cell so that
ECF comes into close contact with
each and every myofibril of the
muscle cell.
Its purpose is to transmit Ca2+ to

myofibrils rapidly and
simultaneously.
T-tubules can be seen at the

junction between A and I bands of
skeletal muscles (but in cardiac
muscles, they are seen at Z lines).
Relaxation
 Ca2+ pumped in to SR by Ca2+ - Mg2+ ATPase pump (SERCA) (this pump needs ATP, therefore ATP dependent
process)
 Release of Ca2+ from troponin C
 Interaction between actin-myosin stops.
If Ca2+ transport into reticulum is inhibited, relaxation does not occur, resulting in sustained contraction called
contracture.

Skeletal muscles - Rapid excitation and contraction coupling
Electrical response
Mechanical response-
Starts 2ms after the onset of depolarization
before repolarization is complete
Isotonic contraction Isometric contraction

Work = negative or positive Work = 0
Has a change in the fiber length No change in fiber length
Muscle twitch – a single action potential causes a brief contraction followed by relaxation
Summation of Contraction
a) Tetanus - when there are repeated stimulations with a high frequency, individual responses fuse into a
single continuous contraction.
Twitch Summation Unfused incomplete tetanus Tetanus
b) Treppe (Staircase phenomenon) – Maximal stimuli given at a frequency just below the tetanizing frequency
Increase in tension develop in each twitch. After a few contractions uniform tension per contraction is
reached (due to progressive increase in Ca2+ in the sarcoplasm)
E.g.- when muscle begins to contract after a long period of rest initial strength is little, after strength of
contraction increase to a plateau.
Tension
Time

Length tension relationship
Resting length of muscle Length of the muscle at which

fiber the active tension is maximal
In isometric contraction,
Tension α cross linkages between actin & myosin
Too shortened – distance thin filaments can more reduced
Too stretched – overlap of thin & 2 thick filaments reduced
MUSCLE FIBER TYPES
Results of denervation
 Muscle atrophy
 Fibrillation – Fine irregular contractions of individual fibers, cannot be seen by naked eye but can be
observed by electromyography
 Denervation hypersensitivity – due to increased sensitivity to circulating Ach
Fasciculations – Jerky, visible contractions of groups of muscle fibers that occur as a result of pathological discharge
of spinal motor neurones

T/F
1. Regarding skeletal muscles

a) Tension that can be produced during contraction is maximal at resting length.
b) In treppe uniform strength per contraction can be produced.
c) Actin & myosin filaments shorten when muscle contracts.
d) Become more excitable as its RMP falls.
e) During isometric contraction length is constant.
2. In the neuromuscular junction of skeletal muscle,

a) Neurexin facilitates the close proximity of the pre & pro synaptic membrane
b) Exocytosis of Ca2+ is a passive process
c) Analogues of acetylcholine blocks the receptors of the synapse
d) Acetylcholine esterase is needed to terminate transmission of impulses
CARDIAC MUSCLE
 Does have 5 Phases
0 - Initial rapid depolarization Opening of voltage gated Na+ channels
1 - Initial rapid repolarization Closure of voltage gated Na+ channels &opening of

one type of K+ channels (also Cl- influx)
2 - Plateau phase Slower but prolonged opening of voltage gated Ca2+

channels
3 - Final repolarization Closure of voltage gated Ca2+ channels and efflux

of K+ ions through K+ channels
4 - RMP (-90 mv) Slow delayed efflux of K+ channels
 Depolarization (2ms) is followed by a prolonged plateau (200ms)

 Mechanical response starts 2 msec after the onset of depolarization and lasts 1.5 times longer than the
action potential.
 Cell is refractive to excitation during contraction (during Phase 0 – 2 and half of Phase 3) - Prevents tetany
Excitation contraction coupling Method of Ca2+ influx – Initially Ca2+ enters through DHPR. Triggers Ca2+
induced Ca2+ release by RyR receptors from SR.

SMOOTH MUSCLE
TYPES
Visceral smooth muscle/ Single unit smooth muscles Multi-unit smooth muscle
Large sheets Individual units
Low resistance bridges {gap junctions) between cells No interconnecting bridges
Functions in a syncytial fashion Functional similarities to skeletal muscles
Contracts when stretched, stretch causes decline in

membrane potential,
increase in frequency of spikes, general increase in tone.
 E.g.- walls of hollow viscera  E.g. – iris of eye
Tunica media of blood vessels has both visceral and multi-unit smooth muscle types.
 Lacks visible cross striations as actin and myosin filaments are not arranged in regular arrays.
 Troponin is absent, but tropomyosin is present
 Poorly developed sarcoplasmic reticulum
 Few mitochondria
 Depends mostly on glycolysis
Spikes
Ionic fluxes
 Binding of Ach. muscarinic receptor
 Increased influx of Ca2+ into cells from ECF through voltage gated Ca2+ channels
 Activation of calmodulin dependent myosin light chain kinase
 Phosphorylation of myosin light chains
 Binding of myosin to actin and increased myosin ATPase activity
 Contraction
 Dephosphorylation of myosin by various phosphatases
 Relaxation or sustained contraction due to latch bridge mechanism
E.g.: - vascular smooth muscles

Smooth muscles have no constant RMP. Very slow excitation contraction coupling(200ms) compared to skeletal &
cardiac muscles(10ms). Ca2+ release is mostly from the ECF.
Varicosities - Dilated areas of nerve fibers innervating smooth muscles that release neurotransmitters.
Latch bridge mechanism
Dephosphorylated myosin cross-bridges remain attached to actin for some time after the cytoplasmic Ca 2+
concentration falls. This produces sustained contraction with little expenditure of energy.
Important in vascular smooth muscle.
Action of catecholamines and acetylcholine on smooth muscle (Reverse happens in some smooth
muscles.)
Catecholamines Acetylcholine
Membrane potential become more negative Membrane potential becomes less negative
Spikes decrease in frequency Spikes more frequent
Muscle relaxes Muscle tone increases
α action – increased Ca2+ efflux from cells By phospholipase C and IP3, increase intracellular Ca2+
β action – via cAMP increased intracellular binding of Ca2+ concentration
 Function of the nerve supply to smooth muscle is not to initiate activity but to modify it.
Smooth muscles also can undergo summation of contractions.
Mysthenia gravis – Autoimmune disorder that destroys muscle type nicotinic Ach receptors. What happens?
Lambert-Eaton syndrome – Autoimmune disease. Patients develop antibodies against voltage gated Ca 2+
channels in the nerve endings.
SKELETAL MUSCLE CARDIAC MUSCLE SMOOTH MUSCLE

Innervated by myelinated nerves ANS and pacemaker cells ANS
No absolute refractory period in Long absolute refractory period
contraction
Can be tetanized Can’t be tetanized Not tetanized but prolonged
contraction by latch-bridge
mechanism
Have a fixed RMP = -90mV Have a fixed RMP = -90mV Unstable membrane potential
(average about -50mV)
Metabolism is aerobic, can be Metabolism is aerobic Mostly by glycolysis
anaerobic
Rapid excitation-contraction Slow excitation – contraction Very slow excitation – contraction
coupling coupling coupling (200 ms after onset of
spike)
Ca2+ influx intracellular Initially from ECF and then extracellular
intracellular Ca2+
cAMP increases force of cAMP relaxes smooth muscles
contraction

1. T/F
a) Visceral smooth muscle – well developed sarcoplasmic reticulum
b) Multi-unit smooth muscle – low resistance junctions
c) Cardiac muscle – high myoglobin content
d) Type I (slow) skeletal muscle – high oxidative capacity
e) Type II (fast) skeletal muscle – high number of Ca2+ channels

Autonomic Nervous System
Regulates most of the involuntary activities of the body
Visceral afferents with endocrine system maintain body homeostasis
General Organization (reflex arc)

Cell bodies of peripheral & visceral
afferents are in dorsal root ganglia
OsmoR
& cranial nerve ganglia (follow the
ChemoR Central
same pathway as somatic afferents)
BaroR integrating
Receptor
Pain and
Afferents modulating
Temperature
area (Spinal
cord, brain)
Effector
Postganglionic Preganglionic neuron
 Cell bodies are outside  Cell bodies are in intermediolateral

CNS –ganglia grey column of the spinal cord and
the cranial nuclei (Brain stem)
 Unmyelinated C fibers
 Myelinated B fibers
Two neurons between CNS & effector system unlike in the

somatic nervous system
ANS
SYMPATHETIC NS PARASYMPATHETIC NS ENTERIC NS
Sympathetic Nervous System
Myelinated type B Unmyelinated type C

fibers fibers
Receptors – alpha, beta
Transmitter – Noradrenaline, adrenaline
Nicotinic Ach Ach in few
receptors
Parasympathetic Nervous System
Myelinated type B Unmyelinated type C

fibers fibers
Receptors – Muscarinic (no nicotinic receptors)
Transmitter - Acetylcholine

Sympathetic Nervous System Parasympathetic Nervous System
Mostly generalized effects Most responses are specific
1st thoracic to 3rd/4th lumbar spinal nerves
To head arise in superior, middle and stellate To Head - cranial nerves III, VII, IX
ganglion & travel with blood vessels
To Thorax and upper abdomen - Cranial nerve X
Parts of uterus and male genital tract from
To sacral region S2-S4 spinal nerves
collateral ganglia
Short preganglionic and long postganglionic fibers Long preganglionic and short postganglionic fibers
Ganglion in sympathetic chain and superior, middle Near the viscera/ inside the viscera
& stellate ganglion
Some preganglionic fibers pass through

sympathetic chain and end on post ganglionic
neurons located in collateral ganglia (close to
viscera)
some preganglionic neurons terminate directly on
the effector organ, the adrenal gland
Preganglionic synaptic transmitter - ACH Preganglionic synaptic transmitter – ACH
Post ganglionic synaptic transmitter Post ganglionic synaptic transmitter
 Acetylcholine - blood vessels in  Acetylcholine

skeletal muscles, uterus, sweat glands,
pilomotor muscle
 Noradrenaline - except above
Receptors Receptors
 Ach - muscarinic  Ach - muscarinic

 α - α1, α2
 β - β1, β2
ACETYLCOLINE NOADRENALINE
No systemic circulation Noradrenaline, adrenaline, dopamine found in

plasma
Effects are localized and short term Spread further than Ach more prolonged &
(Acetylcholinesterase) diffuse action
Receptors Receptors
Nicotinic Alpha receptors-α1, α2
muscarinic Beta receptors-β1, β2

 Catecholamines are removed by,
o Reuptake into adrenergic nerve endings
o Diffuse away from site (To blood)
o Inactivated by, MAO (Mono Amine Oxide), COMT (Catecholamine O-Methyl
Transferase)
Receptors
Cholinergic receptors Adrenoreceptors

(all are GPCR)
Nicotinic (Ligand gated channels) Muscarinic (GPCR)- α1

Blocked by atropine
α2
NN-Autonomic ganglia M1
Blocked by hexamethonium M2-HEART β1 (mostly in heart)
M3-SMOOTH MUSCLES & GLANDS
M4 β2
NM-NMJ (Blocked by curare) M5
β3
Most of the organs are supplied by both divisions of The ANS but few organs are supplied only by
one division of ANS
 Exclusively by sympathetic-blood vessels, sweat glands, pilomotor muscles
 Exclusively by parasympathetic-lacrimal glands, ciliary muscles, sublingual glands
 The axons of some of the

postganglionic neurons leave the
chain ganglia and reenter the
spinal nerves via the grey rami
communications
 Other post ganglionic fibers leave
the chain ganglia to reenter the
thoracic cavity terminate in
visceral organ
Parasympathetic action
Acetylcholine - Muscarinic receptor
01. Decrease heart rate
02. Bronchoconstriction and increase
mucous secretion
03. Increase motility and secretion and decrease sphincter tone in GIT
04. Increase gastric acid secretion (M3)

Sympathetic action
Norepinephrine α1 1. Vasoconstriction.
(More affinity to α ®) 2. Inhibit mucous secretion in respiratory tract.
Epinephrine β1 1. Increase heart rate.
(More affinity to β ®) 2. Increase myocardial contractility
β2 1. Bronchodilation
2. Increase mucous secretion in respiratory tract.
3. Vasodilation in liver and skeletal muscles.
Effect of Sympathetic stimulation

1.GIT a) Decrease motility
b) Decrease secretions
c) Increase sphincter tone
2.Eyes a) Pupillary dilation
b) Relaxation of ciliary muscle (far vision)
Sympathetic cholinergic system

1. Generalized sweating.
2. vasodilation in skeletal muscles.
Propranolol inhibits β1 and β2 receptors
Problem Component of ANS Treatment

activated
Anxiety Sympathetic β blocker (propranolol)

Salivation Parasympathetic Ach Receptor blocker
Atropine
To cause pupillary dilation Sympathetic (oppose Ach Receptor blocker

parasympathetic) (Atropine)
High blood pressure Sympathetic α blocker (Prazosin)

-vasoconstriction β blocker (atenolol)
-↓cardiac output
Narrowing of airways Reduced sympathetic β stimulant

(Bronchoconstriction) (salbutamol)

Enteric nervous system
 Sometimes referred to as mini brain

 Situated with in the walls of digestive tract (esophagus to anus)
 Comprised of 2 organized neural plexuses
1. Myenteric plexus
 Situated between longitudinal & circular muscle layers of GIT
 Control the motility of GIT
2. Submucosal plexus
 Located between circular & luminal mucosa
 Regulate the blood flow & epithelial cell functions
Although the enteric NS can function autonomously, normal digestive function often requires
communication between the CNS & the enteric NS

Biochemistry – Term 1
Functions of the cell
Prokaryotic vs. Eukaryotic cell
Prokaryotic Eukaryotic
High S/V ratio Low S/V ratio
Unicellular Uni or multicellular
Single membrane surrounded by rigid cell Lipid bilayer membrane with proteins.
wall.
(Membrane - phospholipid
Cell wall - heteropolysaccharides )
No membrane bound organelles Contains membrane bound organelles
No well-defined nucleus, Nucleus well-defined.

no nucleolus Nucleolus rich in RNA
Circular DNA, plasmids present DNA linear. No plasmids
Ribosomes are 70S with 50S and 30S subunits Ribosomes are 80S with 60S and 40S
subunits
Reproduce by binary fission Divide by mitosis
Cytoskeleton absent Cytoskeleton present
A Prokaryotic cell

Eukaryotic animal cell
Functions of the cellular organelles
1. Lysosomes
 Contains hydrolytic enzymes for intracellular digestion.
2. Peroxisomes
 β oxidation of excess fatty acids.
 Removal of H2O2. Catalase converts to H2O and O2.
 Participate in synthesis of cholesterol, bile acids.
 Breakdown of excess purine nucleotides to uric acid.
 Synthesis of lipids used to make myelin.
 Detoxify toxic molecules.
3. Mitochondria
 Aerobic respiration and ATP production.
 Certain heme synthesis reactions, urea cycle.
 β-Oxidation of fatty acids.

4. RER
 Synthesis of membrane lipids and secretory proteins
5. SER
 Synthesis of lipids and steroids
 Detoxification of drugs and chemicals
 Stores Ca2+ ions
6. Golgi
 Receive, modify, sorts and package of proteins (secretory)
 Creation of lysosomes.
7. Cell membrane
 Permeable to water, carbon dioxide, and oxygen
 Acts as a gate for different substances/semipermeable
 Forms vesicles and participate in exocytosis and endocytosis.
Importance of cell specialization division of labor (Tissue differentiation by

regulation of gene Expression)
Mechanisms of intercellular communication;
1) Direct communication – gap junctions

2) Paracrine communication
3) Endocrine communication
4) Synaptic communication

CARBOHYDRATES
Isomerism
Isomer
 Same molecular formula but
different structure
Eg: glucose, fructose, mannose,
galactose(C6H12O6)
Epimer
 Different configuration around 1
specific ‘C’ except Carbonyl C
Eg: D-glu & D-gal - C-4

D-glu & D-mann - C-2
(mann & gal - not epimers)
Anomer - Different stereoisomers after cyclization, aldehyde/ketone called anomeric C
Mutarotation
OH
OH
α anomer β anomer
(Mutarotation – α & β anomers spontaneously interconvert in solution)
Enantiomer - mirror images. differ in configuration at every chiral center

Eg: D & L forms
(D form is more abundant)
Medical importance of carbohydrates

a) Heparin
 Prevention & treatment of venous thrombosis, pulmonary embolism
 Treatment of ischemic heart diseases
 Prevention of clotting in arterial & cardiac surgery
 Stroke after cerebral venous sinus thrombosis, potential cardiogenic re-embolization
 Symptomatic dissection of arteries supplying brain
b) Inulin
 polymer of fructose furanose
 to measure GFR by inulin clearance test

c) Dextran
 polysaccharide of bacterial origin
 branched polymer of D-glucapyranose
 High molecular weight dextran is a plasma volume expander
 Restores blood plasma lost through severe bleeding
 To treat hypovolemia (as a result of surgery, trauma, injury, burns etc.)
 Used in certain IV fluids (intravenous fluids) to solubilize other factors such as iron (iron
dextran) – imferon
 treatment of iron deficiency anaemia
 Used in some eye drops
d) Glycoproteins
 Used in blood group analysis (in ABO system)
e) D-glucose
 Used as a parenteral source of calories & water for parenteral nutrition & hydration
 Hypertonic dextrose injections (>5%) are used to provide adequate calories in minimal
volume of water
 10-25% dextrose injections are used to restore blood glucose concentration in treatment of
acute symptomatic hypoglycemia
 Reviving unconscious patients who have consumed too much alcohol
 May be admixed with amino acid injections or other compatible IV fluids to provide
parenteral nutrition
f) Cellulose Carbohydrates - (CH2O) n

 Wound dressing
 Energy - 4 kcal/g
 Tissue engineering
 Roles;
 Controllable drug delivery system
 Energy
g) Hyaluronic acid  DNA & RNA framework
 Treat osteoarthritis by injecting into joint  Structure
 Treat dry, scaly skin caused by dermatitis  Linked to proteins and lipids
Classification of carbohydrates

Simple carbohydrates
Monosaccharides Disaccharides
 Cannot hydrolyze
 Can be hydrolyzed.
 reducing sugars (Benedict’s Test)  reducing sugars (except sucrose)
 cyclization (become stable) sugars prefer  contains glycosidic bonds
cyclic structures to linear structures
 6-member ring- pyranoses (Eg: glu & gal) E.g.
 5-member ring- furanoses (Eg: fructose) Maltose (from hydrolysis of starch)
 derivatives;  Glu+Glu
Eg:  α-1-4 glycosidic bond
1. Phosphate esters (Eg: - glu. 6. Phosphate, Sucrose
glu. 1. Phosphate)  Glu+fru
2. Sugar amines (Eg: - D- glucosamine,  α-1-2 glycosidic bond
N-acetyl glucosamine) Lactose
3. Sugar sulphates - biological tissues  Glu+ gal
4. Deoxy Sugars - component of nucleic acids  β-1-4 glycosidic -galactosidic type
5. Sugar alcohols (Eg: - sorbitol)
6. Sugar acids (Eg: - glucuronic acid – in urine  N- glycosidic(nucleotides)
Simplest carb. & bile; proteoglycans)  O- Glycosidic(sugar)
Glycosidic Bond
(Classified according to carbonyl C)
1)No.: Designate C atom that forms the bond.
2) α / β: Bond up or down
3)Type;
 Digestible
Eg: Lactose - β-1-4 galactosidic type of glycosidic
 Indigestible
Eg: cellulose - β-1-4 glucosidic type of glycosidic
 Salivary α amylase catalyzes the hydrolysis of
α-1-4 glycosidic bond
Complex carbohydrates
Oligosaccharides Polysaccharides
 3-10 mono. (>10 mono.)
 components of cell membrane
and human milk
Eg: Raffinose, Stachyose

Common features of mono, di & oligosaccharides;
 forms crystals
 readily soluble in water
 sweet taste
Polysaccharides
Homo polysaccharides Hetero Polysaccharides

(1 type of monomer) (different type of monomers)
Unbranched Branched
1.Cellulose 1.Glycogen
 Group of plant  Animal polysaccharide for
polysaccharides glucose storage
 β-1-4 glucosidic type of  Highly branched – rapid
glycosidic bond breakdown (more branched
 not hydrolyzed in humans than amylopectin)
 α-1-4 & α-1-6 glycosidic Bond
2.Amylose 2.Amylopectin
 20% in starch  α-1-4 & α-1-6 glycosidic bonds
 α-1-4 glycosidic bond  Difficult to digest.
 Blue-black colour with iodine  Most abundant in Starch
 Easy to digest.
Starch types
(Plant polysaccharide
for glucose storage)
Conjugated
Pure
 GAGs
 Pectin
With Lipids With Proteins  Gums
 glycolipids  proteoglycans
 glycoproteins

Heteropolysaccharides
Pure
01.Glycosaminoglycans (GAGs)
 Most abundant heteropolysaccharides in body

 Long, unbranched
 Composed of repeating disaccharide units
-acid sugar (uronic acid eg: D-glucuronic, L-Iduronic)
-amino sugar (N-acetyl glucosamine/ N-acetyl galactosamine)
 Negatively charged – due to SO42-, COO-
 (-) charge attracts cations which leads to sucks water in and create pressure. It enables ECM
to withstand compressive forces.
 Contain sulphate group (except hyaluronic acid.) in one or both sugars
 Low compressibility & rigidity
 Form matrix to hold protein component of skin, CT and ECM.
02.Hyaluronic acid
 Doesn't contain any sulphate.

 Synovial fluid (shock absorber, lubricator), ECM of loose connective tissue
 Vitreous humor of eye, embryo, umbilical cord
 Not covalently bound to protein, forms noncovalently linked complexes with proteoglycans
to form proteoglycan aggregates in ECM.
 Degradation by hyaluronidase.
 Polymers are very large and can displace a large amount of water.
03.Keratan sulphate
 For corneal transparency, bone, cartilage

 Aggregate with chondroitin sulphate
 Galactose instead of acidic sugar
 Most heterogeneous of GAGs.
 Critical role in corneal transparency.
04.Chondroitin sulphate
 Cartilage, bone, heart valves, certain neurons (maintain their shape)

 Most abundant GAG in ECM

05.Dermatan sulphate:
 Skin, blood vessels, cornea, heart valves.

 Binds LDL
06.Heparin & Heparan sulphate:
 Heparan sulphate - Basement membrane of kidney-determine charge selectiveness,

Component of cell surface receptors.
 Heparin - anti coagulant in blood. Cell lining of arteries of lungs, liver, skin.
 Heparans - less sulphate groups than heparins.
Conjugated (Glycoconjugates)
Lipids - (01) Glycolipids

Eg-
 Glycoglycerolipids,
 Glycophosphatidylinositol
 Glycosphingolipids (major glycolipid In animal)- occur as ceramide with one / more sugars
Functions-
 receptor molecules
 Cell to cell interactions Simplest ones-
 provides energy
 Galactosyl ceramide-
 blood group antigens
nervous tissue
 Glucosyl ceramide- extra
Proteins- (01) Proteoglycans (protein content low)
neural tissue
 GAG covalently bound to core Protein
 In all CT, ECM, surface of many cell types.
 Function derives from physiochemical characteristics of GAG components.
 Functions
 Secreted proteases and antiproteases-GAG
Eg: antithrombin III - binds tightly to heparin and certain Heparan sulfates - they control the
blood coagulation
 Polypeptide growth factors-GAG
Several growth factors- bind to heparin or Heparan sulfate. Binding can alter the
conformation, proteolytic susceptibility and biological activity of some of these proteins
 Cell surface proteoglycans
anchor cells to matrix fibers; act as receptors; participate in the mediation of cell growth &
cell communication
 Large aggregating proteoglycan aggrecan in cartilage
GAG chains on each of the monomers generates a large osmotic swelling pressure - important
in the ability of cartilage to resist compressive forces

 Heparan sulfate proteoglycan in the
glomerular basement membrane
act as the major anionic site
responsible for the charge selectivity in
glomerular filtration.
Proteins- (02) Glycoproteins (carbohydrate

content low)
 Predominant sugars - glucose,

galactose, mannose, fucose, GalNAc,
NANA
 Nearly all proteins on the outer surface
 abundant in plasma
 Contain short oligosaccharide chains
(2-10). Longer chains often breakdown.
 Functions
 Structural molecules – cell wall,
collagen, elastin, fibrins, bone matrix
 Lubricant / protective agents – mucins, mucus secretions
 Transport molecule – Vitamins, lipids, minerals & trace elements
 Immunologic molecule – Immunoglobins, histocompatibility antigens, interferon
 Hormones – Chorionic gonadotropin, Thyrotropin (TSH)
 Enzymes – Proteases, nucleases, glycosidases, hydrolases, clotting factor
 Cell attachment / recognition – Cell-cell; virus-cell; bacterium-cell; hormone receptors
Glycoproteins
O linked N linked
O linked Glycoproteins
Eg-
 Glycophorin, a protein in erythrocyte cell membranes
 Mucin, a protein in saliva involved in formation of dental plaque
 Notch, a transmembrane receptor involved in development and cell fate decisions
 Thrombospondin
 Factor VII, Factor IX
 Urinary type Plasminogen Activator
Functions- recognition, interaction and enzyme regulation

N linked Glycoproteins
Eg-
 cell-surface receptors
 extracellular matrix proteins
 intracellular organellar proteins
 plasma proteins (except albumin)
 luminal lysosomal proteins.
Functions-
 Conferring resistance to proteolysis
 Conferring solubility
 Facilitating correct folding and oligomerization
 Being a recognition marker in molecular interactions
 Being a recognition marker in cell targeting
 Being important for the activity of the glycoprotein.
 N-linked glycosylation is essential for cellular and organismal viability.
Glycoproteins Proteoglycans
Length of CHO chain relatively shorter. Relatively longer
CHO do not have serial repeats GAGs present. Have repeating disaccharides.
CHO chain often branched. Unbranched
CHO may/may not be negatively charged. Negatively charged.
Less CHO More CHO
 Dextrin – Intermediate of starch hydrolysis. Varying MW.

(With iodine- Erythrodextrin- red, Achiodextrin- NO colour)
 Dextrose (D-glucose)– Similar to glucose. Use 5% dextrose drip
 Dextran – Polysaccharides of bacterial origin. Use as a plasma substitute
Tests
Benedict’s test Test for reducing Brick red Here anomeric C form enediols
sugars precipitate (intermediate) in alkaline medium
Barfoed test Specific for Red precipitate Oxidation of monosaccharides
monosaccharides (carbonyl group to carboxylic group)
Iodine Test For starch Blue black I2 + I- -------- I2-
colour
Diseases
 Diabetes mellitus
 GAGs – mucopolysaccharidosis

 Hyaluronic acid, Chondroitin sulphate – Osteoarthritis
Mucopolysaccharidosis
 Hereditary disease caused by a deficiency of any one of the lysosomal hydrolases normally
involved in degradation of Heparan sulphate or dermatan sulphate.
 Characterized by lysosomal accumulation of GAGs in various tissues.
 All are autosomal recessive. (except Hunter syndrome- x linked)
 Incomplete lysosomal degradation of GAG- presence of oligosaccharides in urine.

LIPIDS
 Major stored form of energy

 Enzyme cofactors
 In bio membranes
 Electron carriers
Eg: Co Q
 Emulsifying agents
 Hormones/ signaling molecules
Building blocks of lipids
Lipid = Fatty acid + Alcohol or amino alcohol
E.g. = Palmitic + glycerol or sphingosine

CH2-OH H
CH3-R-COOH + CH-OH or R-C-CH2OH
CH2-OH NH3
Saturated Unsaturated
 No / bonds  Has 1 / many / bonds
 Strong interactions between FA chains  Monounsaturated (only 1 = bond)
 Abundant in animals  Poly unsaturated (more than 1 / bond)
Eg: palmitic, stearic Eg: linoleic (sunflower/olive/gingerly)
( except palmitic and stearic all other examples α- linoleic
given for FAs on lecture note are unsaturated ) Lauric (coconut)
Arachidonic
 If there is more than 1 double bond, they
are separated by a methylene (-CH2) group
 Week attractions between FA chains, chain length, presence, number, position and
confirmation of double bonds affect the melting point. (length melting point - due to
number of vanderwaals interactions)
 Most naturally occurring unsaturated fatty acids have cis double bonds. Nearly all the FA s in
mammals have even number of carbon atoms
 Trans double bonds increase the melting point of unsaturated fatty acids.
Eg: margarine, elaidic acid (natural trans unsaturated)
 αLinolenic & Linoleic acids are essential fatty acids.

Fatty acid saturation/ unsaturation indication method
Position of double bond
(from last carbon)
16:0 ← saturated ω carbon = last carbon
16:1ω9 first carbon with double e.g. –C-C-C=C-C=C-COOH in this example it is a ω-3 FA
bond 1 2 3 4
(counting from the end) ω carbon doesn’t change in metabolism so can trace.
No. of double bonds
No. of carbons e.g. Arachidonic ω-6 (20:2ω6)
Linoleic ω-6 (18:2ω6) Sounds the same
α Linolenic ω-3 (18:3ω3) but different
 Parental FA
 α Linolenic - ω 3 series
 Linoleic - ω 6 series

LIPIDS
Storage lipids Membrane lipids – complex lipids

(all amphipathic)
TAG
(triglycerides) Sphingolipids Steroid Phosphoglycerolipids
(glycerophopholipds)
sphingosine
Glycerol
FA X
Cholesterol
Sphingosine + FA = ceramide FA FA phosphoric
alcohol
 Lecithin
Phosphosphingolipids Glycosphingolipids  Choline alcohol - neural
transmission
sphingosine sphingosine  Most abundant phospho lipid
in cell membrane
FA phosphoric FA Sugar (one or more)  Lung surfactant - dipalmytoyl
lecithin
alcohol  Blood group antigens  Cardiliopin
 Cerebrosides  Only in mitochondria
 Galactosyl ceramide - brain  Inositol
 Sphingomyaline  Precursor of 2nd messengers
 Glucosyl ceramide - extra
 Myaline sheath in
neural tissue
brain and nervous
 Gangliosides - receptor
system (no glycerol)
 Cell surface receptors for
cholera and tetanus
 Major glycolipids in animal
tissue
 Common in cell membrane
(outer leaflet)

Phospholipids
 Polar & ionic

 Form micelles, bilayers & liposomes
 Micelles - important in lipid absorption
 Liposomes - important in oral delivery of certain dietary and supplementary drugs/ gene
transfer
 Emulsions - non-polar in an aqueous medium stabilized by emulsifying agent
Storage lipids
1) TAG
 storage lipids
 neutral fat
 hydrophobic / non polar
 not components of bio membranes
 high energy molecule
 anhydrous
 C1 & C2 of glycerol is not identical & they are enzyme specific
 Presence of unsaturated FAs reduce melting T of lipids

2) Steroids
 Animal origin, not in plants or bacteria

 Steroid hormones
Eg: cortisol, aldosterone,
testosterone, estradiol, progesterone
 Weekly amphipathic
 Maintains the fluidity of cell membrane
3) Cholesteryl ester
 Hydrophobic
Cholesterol FA
Eicosanoids
 Physiologically and pharmacologically active compounds derived from:

C20 (eicosanoid) PUFA – arachidonate & other C 20 physiologically active PUFA
 Act as local hormones, mostly through G-protein linked receptors (intercellular signaling)
 Are rapidly degraded, so not transported to distal sites within the body (very short half-life)
 Made in almost all tissues
 Not usually stored up
Eicosanoids
Prostanoids Leukotrienes Lipoxins
Prostacyclin Prostaglandin Thromboxane

Linoleic acid (ω6 precursor)
Phospholipase A2
Arachidonic acid
NSAIDs - - Inhibited in
COX 1 lipoxygenase asthma
Ex: - aspirin COX 2 treatment
Prostanoids Hydroperoxy acid
Prostaglandins Thromboxane prostacyclin

 Mediate;  Platelet
 Pain aggregations
 Fever  Constriction of
 Inflammation & arteries
swelling  Has 6 membered
 Has cyclopentane ring/cyclopentane
ring ring with an
oxygen atom
Hydroxy FA Lipoxins Leukotrienes

 Attract WBC
 Involve in
inflammatory
diseases
 Has 3 conjugated
= & 1 more
unconjugated
 No ring structure

PROTEINS
 Most abundant macromolecule in human body.
hydrolysis
Proteins Amino acids
Amino acids
 Building blocks of proteins

 More than 300 A.A. found in proteins
 All amino acids are α amino acids
 But proline is not α amino acid, it’s an imino acid.
 Amino acids are classified according the properties of the side chain (R group)
 Glutamine is the most abundant AA in plasma

 Histidine acts as a buffer in its biological pH and is the only AA DO YOU KNOW?
with R chain that can be ionized within physiological pH range. Normal urine contains – Gly,
(mostly uncharged) Glu, Ala, His, Ser, MetHis
 Isoleucine AA are charged in nature.
 S containing AA – Methionine (Essential), Cysteine (Non-essential)
 Some AA are not found in proteins but found in the free state in cells or as derivatives.
Eg: - epinephrine, norepinephrine
 Ketogenic AA
 Amino acids that only yield acetyl CoA & they can’t be used for gluconeogenesis.
 But can be used for ketogenesis
Eg: - Lysine & Leucine
 Ketogenic & Gluconeogenic AA
 Amino acids that yield both acetyl CoA & TCA cycle intermediates
Eg: - trypsine, tyronine, Phe, Ile

 Gluconeogenic AA
 Yields TCA cycle intermediates

 Can be used for gluconeogenesis
Eg: - Ala, Asp, Asn, Cys, Glu, Gln, Gly, Pro, Ser, Arg, His, Met, Thr, Val
Reactions about non essential AA s
 They can be derived from essential AA s

Phenylalanine hydroxylase
Phenylalanine tyrosine
By 3 stages
Methionine homocysteine
Cystathione synthase Cystathione γ lyase
Homocystein cystathione Cystine
 Metabolism of all AA except branched chain AA (Val, Leu, Ile) takes place in Liver
Isoelectric pH (pI)
 pH at which zwitter ion predominates with equal but very small amounts of cationic &
anionic forms.
 A zwitter ion is a dipolar ion with two or more functional groups one is (+) charged and
other one is (-) charged. (At pI - no net charge)
 not move in an electric field
 solubility is least
Cystinuria
Proteins  An inherited abnormality in
reabsorption of Cystine, Orn, Arg,
Ninhydrin reaction
Lys (COAL) in kidney tubule.
T
AA + Ninhydrin Bluish Purple  It leads to increased excretion of
these AA in urine.
 But Pro & OH-Pro gives a yellow colour  Clinical features due to precipitation
 Useful in detecting and qualifying amount of of Cystein in renal tracts
AA in plasma and urine

Peptide bond
 Rigid
 Planar
 Trans configuration
 Partially double bond (it prevents free rotation)
 Uncharged but polar
 Proteins are not hydrolyzed by normal handling or denaturation.

 They are hydrolyzed by
 Enzymes – proteases
 Non enzymatic hydrolysis required strong acid (6M HCL) or bases at high temperature.
Biologically important peptides
1) Glutathione
 Antioxidant
 AA transporter
 Glutamine, Cysteine, Glycine
2GSH Glutathione peroxidase GS-GS

(Reduced) (oxidized)
2) Insulin
 1 Intrachain disulphide bond bridge A chain
 2 interchain disulphide bonds A & B chains
3) Oxytocin & Vasopressin (ADH)

 Peptides with 9 AA
Protein structure

1) Primary
 Nature & sequence of AAs in polypeptide chains that a protein is comprised of

 Each protein has a unique primary structure determined by gene code
 Proteins have a common backbone, different R group sequence
 3D arrangement depends in this
2) Secondary
 Structure that arises as a result of interactions between backbone groups that are close to one
another in protein
 Helix and alpha chain are not same
α Helix β pleated sheet

 Intra chain H bonds (CO of one AA to NH of AA  Inter Chain or different segments of same
4 residues ahead  chain - H bonds
 H bonds parallel to imaginary axis  Perpendicular to the axis
 Disrupt α helix  Favored by AAs having small R groups
 Pro, OH-Pro (by secondary NH2 group)
 Gly (its R group has high flexibility)
 Destabilize α helix
 Glu, Asp, His, Lys, Arg (by charged / bulky
R groups)
 Trp, Val, Ile ( branched β carbon )
 Found in -> α keratin, Myoglobin, Haemoglobin  In both fibrous & globular proteins
 Spiral, Extensible right handed, 3.66AA per turn  Cannot be extended further
 Other secondary structures α keratin

 β bend - Pro-Gly at the bend
 non repetitive structures - loops and coils  Has a high content of
histidine
 super secondary structures – motifs (globular proteins)  Does not contain
Eg; - β barrel, Greek key, β meandex hydroxylysine residues
3) Tertiary
 structure due to interactions of R group in protein with

 aqueous environment
 other R groups far apart
such as
 H bonds
 Hydrophobic interactions
 Ionic interactions
 Disulphide linkage

 When proteins fold
Nonpolar in polar, charged out
 Proline kinks protein
Fibrous Globular
 Structural
proteins  functional
 Insoluble  compact, tight
 Long half life packing in core
 Secondary structure  Secondary, tertiary &
quaternary structure
Intermediate structure
Eg: - α keratin,  Soluble in water
collagen, elastin Eg: - Hb, myoglobin,
lysosome,
Eg: - fibrinogen ribonuclease
 Some globular proteins have both α helical and B pleated sheet (higher amount of B
pleated sheet) structures in the same molecule
Myoglobin  The haem group of the myoglobin is

lined with non-polar amino acids
 Haem protein - heart & skeletal muscles (exception- 2 His residues).
 O2 storing & O2 transfer within muscle cells  Myoglobin creates a special
 Single polypeptide chain & single haem unit microenvironment for the hem that
 Eight α helical segments (80% of polypeptide permits the reversible binding of one O2
chain) molecule
 Haem unit stabilized by ‘His’ & hydrophobic
interactions.
 Globular functional protein
Lysozyme
 some globular proteins have both α helical &

β pleated sheet structures in the same
molecule
Domains
 Distinct 3-dimensional structural units of a polypeptide chain which may have separate
functions.
 Often encoded by different exons
 A chain with a domain folds independently of others
 Each domain has a characteristic of a small compact globular protein structurally
independent of the others.
 Core of domain is composed of super secondary structures(motifs).

Protein folding
 Governed mainly by interactions between side chains

 Primary driving force for protein folding is hydrophobic interactions
 Not all proteins fold spontaneously as they are synthesized
 Usually supported by action of molecular chaperones (most of the molecular chaperons
are Heat Shock Proteins
 Complex trial and error process Molecular chaperons
 Protein misfolding - usually degraded
 Specialized proteins
 Spontaneously
 Facilitate correct folding
 Mutation of a particular gene
 Other stimuli pathway
 Reversible interact with
partially or improperly
folded polypeptides
4) Quaternary
 In functional molecule
 2 types
a) Monomeric
b) Oligomeric
 Individual polypeptide chain – protomers / monomers / sub units
 Quaternary structure; characteristic manner in which individual polypeptide chains held
together by weak non covalent
 H bonds
 Ionic linkage
 Hydrophobic interactions
 One type of subunit; - homo multimer

 Several different subunits; - hetero multimer
Eg: - Hb
 α2 β2 –tetramer
 2 chains within each dimer held tightly by hydrophobic interactions. primarily
dimers are held by polar bond
 Sub units may function independently of each other or may work cooperatively as in Hb
Prion diseases
 Natural non infectious form is alpha helical found in human brain cells
 Prion protein is a causative agent of transmissible spongiform encephalopathies
 Infectious beta pleated sheet act as a template and convert naturally occurring non infectious
prion protein alpha helical structure to beta pleated sheet
 Insoluble aggregates of fibrils

Eg: - Creutzfeldt Jakob disease in human
Mad cow disease in cattle (bovine spongiform
encephalopathy)
Scrapie in sheep
Amyloidosis
 Apparently normal protein undergoes abnormal proteolytic

cleavage
 Form long fibrillar assemblies of pleated sheets (Amyloids)
aggregates spontaneously which are toxic
 Deposit in tissues
 Degenerative disease
Eg: - Alzheimer’s disease- deposited in brain
Collagen
 High amount in supporting structures

 Most abundant protein (25% of proteins in mammals)
 Rigid
 insoluble
 Several types depend on structural role
 Usual amino acid composition
 33% Glyicine – enables easy packing
 25% Proline /Hydroxy Proline
 Also contain Lysine, Hydroxy Lysine
 Low aromatic amino acids (Try, Tyr)
 Gly – X-Y repeating sequence
 X= Pro or other, Y= OH-Pro, OH-Lys or other
 Pro α chain forms a left handed kinked helix with 3 AA per turn
 Triple helical structure with 3 α chains (not
α helixes) intertwined in right handed Organisation of collagen
manner to form pro collagen
 Opposite twist gives added strength  Bone cartilage & teeth – highly mineralized
 Tendons – parallel bundles
 Type 1 is the most common  Skin, connective tissues - network
 Cornea – laminated sheets

 Types;
 Type 1 – skin, bone, tendon, blood vessels, cornea
 Type 2 – cartilage, intervertebral disc mineralized
 Type 3 – blood vessels, foetal skin
 Type 4 – basement membrane
Synthesis of collagen
1. Genes for pro α 1 / proα 2 are transcribed in to mRNA

2. mRNA translated in to pre-pro α polypeptide chains and extruded into RER lumen
3. removal of signal sequence from the N terminal
4. hydroxylation
Prolyl hydroxylase O2 Fe2+
Proline hydroxyl Proline
Lysyl hydroxylase
Lysine hydroxyl Lysine
 hydroxylation facilitates interchain H bond formation to stabilize triple helix
5. Glycosylation
 Hydroxyl lysine by glucose & galactose
6. 3 pro α chains assemble triple helical structure (by interchain H bonds)
7. Inter & intra chain disulphide bonds formed at C terminal & N terminal extensions which
have no helical structure
8. Secretion
9. Removal of C & N terminal ends by C & N terminal procollagen peptidase and producing
tropocollagen molecules
10. Triple helical structures arranged with ¼ length displacement
 Levels of organization of collagen fibrils

Amino acid sequence α chain triple helix molecule fibril
 Cross linking between side chains, mainly by Lys

 Denaturation converted into gelatin (on boiling with water or acid)
 Degradation - collagen molecules are highly stable. Degrade during connective tissue
remodelling by collagenases producing amino acids
 OH Pro not reused and excreted in urine so reflects - ↑ collagen turnover
Collagen diseases
 Caused by defects in collagen synthesis or structure
1) Vit. C deficiency - defective hydroxylation causes

Scurvy – increased fragility of blood vessels, delayed wound healing, gum decay
2) Ehlers danlos syndrome - defects in collagen processing enzymes. (Lysyl hydroxylase or

procollagen peptidase) type 2 and type 2
Or mutation in collagen genes - alteration of AA sequence and those degraded.

3) Osteogenesis imperfect - mutations in genes for pro α 1 or pro α 2 genes of type 1 collagen.
Gly replaced by AA with bulky R groups.
4) Brittle bones, twisted spine
Properties of Proteins
1. Charged nature
 Mainly from charged R groups and to a lesser extent COOH or NH2, can exist as cations,
anions or zwitter ions, depending on pH
 IpH depending on nature of R groups
 At IpH solubility and osmotic pressure are minimum
Alkaline medium negative ions react with Zn2+/Ba2+ deproteinising body fluid
Acidic medium positive ions react with complex ions precipitate
Eg; - sulphosalicylic test
2. Buffering action
 pH = pK buffering is maximum
 Imidazole of His important in buffering action of Hb (Globin is rich in His, pka = 7)
3. MW is very high 5000-5X106, not dialyzable, can separated by ultra centrifugation
4. Solubility
 Most need small amount of salt to solubilisation
Eg: globulins in plasma
5. participates in specific interactions

 antigen - antibody
 hormone - receptor
 enzyme - substrate
6. Denaturation Denaturants
 II, III, IVry structures altered  Heat
 Iry structure unchanged  Organic solvents
 Loss of biological activity  Mechanical mixing
 Solubility decreased  Strong acids/bases
Eg: heat coagulation test  Detergents
 Digestibility increased  Heavy metal ions
 Irreversible (refolding uncommon)  Urea 8M

Plasma protein
 Fibrinogen present Serum Protein

 Most have pI < 7 (negatively charged in physiological pH)  No clotting factors
 total plasma serum protein -70-80g/L (Fibrinogen)
 concentration affected by posture, venous stasis
 Albumin (main)
 Globulins
 fibrinogen
 Functions
1. Control of fluid distribution - albumin maintains colloid osmotic pressure
2. Transport (albumin, others) - bilirubin, free FA, Ca2+, Zn2+, fat soluble vitamins &
hormones (others - thyroid hormones, lipids, irons)
3. Haemostasis (enzymatic activity)
4. Defense - Immunoglobulins (γ globulins), acute phase proteins (inflammatory
responses in severe conditions)
Proteins Simple
Conjugated = Apo protein + non protein
 Chromo protein = protein +coloured compound (Eg; haemoglobin =

globin + haem)
 Glycoprotein & proteoglycan = protein + carbohydrates (Eg; mucin of
saliva)
 Lipoprotein - protein + lipid (Eg; cell membrane, plasma lipoprotein)
 Nucleoprotein - protein + nucleic acid (Eg; chromosome, ribosome)
 Phosphoprotein - protein + phosphate (Eg; casein linked via Ser, Thr)
Electrophoresis
 Separation of proteins based on charge & MW

 pH of medium charge of protein
<pI positive
>pI negative
 Proteins migrate to anode or cathode when an electric field applied

 Carried out in;
 Constant pH 8.6 barbiturate buffer
 Constant temp. & DC voltage
 Plasma proteins move towards anode (+) pH > pI negative charged
Rate of movement α magnitude of - ve charge

Shape
Charged: size ratio
 Albumin is the fastest protein in electrophoresis
 Apply electric current for given period of time and stain paper or gel for protein in normal
serum

Electrophoresis can also be used to separate
 Different Hbs
Eg: - sickle cell Hb(Hbs), Hbc
HbA HbS HbC
β globin chain 6th AA Glu Val Lys
Electrophoretic mobility HbA HbS HbC
 Plasma lipoprotein
 Separate as for serum proteins but stain for lipids (Eg: - Sudan red)

THE CYTOSKELETON
 It is a 3 dimensional meshwork of protein filaments that extend throughout the cytoplasm.
 Dynamic
 Highly organized
 Adaptable
 Made of proteins - 3 types

1. Microfilaments
2. Intermediate filaments
3. Microtubules
 Most cytoskeleton proteins are encoded by multi gene family.
Microfilaments (/Actin filaments )
 Thinnest (7 nm)
 Helical polymer
 Has polarity
 Dynamic structure
 Flexible
 G actin self-assemble into F actin

+ end / barbed end Higher order
organization
F actin
(Filamentous)
G actin
(Globular)
- end / pointed end
 Reversible Polymerization at both ends of Actin Filaments. Faster at (+) end.

 Accessory proteins regulate polymerization / depolimerization
 Even at steady state, there is polymerization & depolymerization at both ends. - A dynamic
equilibrium exists.
Functions
 Mechanical strength
 Maintains cell shape
 Cell Motility
 Pseudopodia - actin reorganizes/ weakens to form a pseudopodium
 Cell streaming - cytoplasm cycles over a carpet of actin filaments within the cell.
 Myosin also contributes
 Cell division - cytokinesis (Division of cytoplasm by forming Cleavage furrow)
 Contractile structures (with Myosin)
1
© 2017 A/L Repeat Campaign
 Involvement in cell adhesion - Tight junctions, Adherent junctions
 Any process which involves a change in the shape of the cell needs microfilaments.
Eg: -
 platelet aggregation, phagocytosis, development of embryo, immune response, cell crawling,
angiogenesis, extension of neurons, muscle contraction, cell division
 RBC Cytoskeleton has no Microtubules or intermediate filaments. Structural support.
Biconcave Shape
Hereditary Spherocytosis
 Defective Cytoskeleton (Ankyrin, Spectrin)
 Production of Sphere shaped RBCs.
 Leads to breakdown of RBCs. Haemolysis in spleen.
Duchenne’s muscular dystrophy (DMD)/Becker’s muscular dystrophy (BMD)

 Dystrophin is required for anchoring muscle cells
 Absence or the expression of abnormal Dystrophin leads to DMD
Microtubules
 Hollow tube-like structures 25nm

 Composed of tubulin dimer (α β subunit)
 Requires GTP
 Show polarity. Dynamic.
 Reversible polymerization. Faster at (+) end
 (-) end anchored at the centrosome
 Growth and shrinkage depend on cellular signals
 Slow growth, rapid shrinkage
Functions
 Structural support of cilia / flagella
 Forms mitotic spindle (moves chromosomes during mitosis)
 Determines position of organelles
 Provide “tracks” for movement of organelles / vesicles (Dynein, Kinesin)
 Polarize cells. Eg: cell division, T-cells (positioning of Golgi apparatus)
 Centrioles
 Microtubules provide “tracks” for movement of organelles / Motor proteins

vesicles
 Transport is driven by motor proteins ATP
 Motor proteins are proteins that use energy to do
mechanical work
Eg: Kinesin - towards the (+) end away from the centrosome Microtubules
Dynein - towards the (-) end
2
 Motor proteins interact with & move along microtubules
 Energy dependent process
Cilia & flagella
 (9+2) microtubule structure

 Responsible for cellular movements (unicellular) or move fluid over a surface
 Associated with Dynein (motor protein)
 Dynein causes bending of cross linked micro tubules resulting in flagella movement
Cilia
Motile Non motile/Primary- Acts

 lungs as a sensory antenna to
 respiratory tract cells
 middle ear  kidney
 eye - photoreceptors
Clinical
Cancer treatment by targeting microtubules
 Drugs bind with Microtubules and stabilize them.
 Mitotic Spindles cannot form.
 Taxol - binds & stabilizes microtubules
Drug Name Target component Effect Clinical application

Vinblastine Microtubules Prevents Chemotherapy
polymerization
Colchicine Microtubules Prevents Used to treat gout
polymerization
Paclitaxel(Taxol) Microtubules Stabilizes Chemotherapy
microtubules and
prevents mitosis
Immotile cilia syndrome (Kartagener’s syndrome)

 Occurs due to an inherited defect that leads to the absence or production of abnormal
dynein arms, radial spokes and central microtubules.
 This causes complications such as; chronic / recurrent infections of the bronchial and
nasal sinuses, situs inverses, infertility/ subfertility/ miscarriages/ ectopic pregnancy.
3
Intermediate filaments
 Apolar
 More stable. Not involved in movement
 Different subunits
 8 tetramers twisted into a rope-like filament
 Various globular protein subunits are incorporated into IF filaments
 Heterogeneous group of proteins
 Assembly & disassembly is controlled by phosphorylation.
Functions
 Maintains cell shape (specialized for tension bearing)
 Anchorage of nucleus and other organelles
 Formation of nuclear laminar
 Involvement in cell adhesion - Desmosomes (cell-cell), Hemi desmosomes(cell-BM)
Type Proteins Site of expression

I and II Keratins epithelial cells
III Vimentins
Eg: Vimentin Variety of cell types
(fibroblasts, WBC, Smooth muscle cells)
Eg: Desmin muscle cells
IV Neurofilaments mature neurons
V Nuclear Lamins nuclear lamina of all cells
VI Nestin Stem cells of the CNS
Disorders
Keratin - Epidermolysis bullosa simplex.

 Skin blistering in response to mild mechanical trauma in skin and mucous membranes
 Defective keratins in basal layer of epidermis due to mutation in certain keratin genes.
 Lysis of cells in Basal Layer of Epidermis
Neurofilaments - Parkinson’s disease

Amyotrophic lateral sclerosis
tooth disease
*Microvilli - Microfilaments anchored to a network of Intermediate filaments
4
Overall Functions
1) Structural support
 acts as scaffolding (stabilize cell shape)
 provides shape to sub-structures of cells
 anchorage for cells / organelles
2) Movement
 movement of whole cells
 provides “tracks” for movement of cellular components
 cell division
3) Regulation
 organizers structures and activities of the cell
 regulation of cytoskeleton dynamics
EXTRA CELLULAR MATRIX
 Acellular material around cells (ground substance + protein network)

 Dynamic
 Filled with complex network of macromolecules secreted by cells
 Degradation controlled by proteases
 Highly organized, complex structure
 Proportion and composition of ECM varies between tissues. (Reflects functional role)
Key Functions
 Anchorage for cells
 Structural support for tissues
 Barrier functions for segregation of tissues from one another
 Lubrication of joints
 Regulates cell migration and intercellular communication
 Local store for growth factors
 Important for growth, wound healing and fibrosis.
5
Composition of ECM
 Components are locally produced
1) Polysaccharide GAGs (often found as Proteoglycans) - ground substance
Structural proteins (fibrous proteins)

2) Protein - Collagen, Elastin, Fibrin
Adhesive proteins
- Fibronectin, Laminin, Fibrillin
3) Water
1) Polysaccharides
Properties of GAGs
 Highly polar and attracts water.

 Highly negatively charged, with extended conformation that gives high viscosity to the
solution.
 Low compressibility - makes these molecules ideal for a lubricating fluid in the joints
 At the same time their rigidity provides structural integrity to cells and provides passage
ways between cells allowing cell migration.
Proteoglycans
 Aggrecan - cartilage
 Syndecan - cell surface Na+
High negative charge

Na+ Hyaluronic acid
Location and function

Osmotically  Synovial fluid - Biological lubricant
Hydrophilic
Active
and shock absorber
 ECM of cartilage and tendons -
provides strength and elasticity
 Vitreous of the eye - Clear gel
H 2O H 2O  Umbilical cord
Matrix  Embryos - Cell migration
Selective barriers
H 2O H 2O
Masks pain
6 Swell (Hydrated)
 When compressed,
 the water is 'squeezed out'. Molecules ‘slip' past each other due to repulsion.
 When compression is released,

 returns to original hydrated volume.
Mucopolysaccharidosis (Lysosomal storage disease)

 Lysosomes degrade proteoglycans.
 Proteases - protein components
 Acid hydrolases / Glycosidase - GAG
 Deficiency of glycosidase → Defects in GAG degrada on
 Leads to accumulation of partially degraded GAGs in tissues Urine
Ehler-Danlos Syndrome
 Defects in collagen processing enzymes and mutations in collagen genes.
 Abnormally stretchy skin.
Osteogenesis Imperfecta
 Defect in synthesis of collagen. Often type I collagen.
 Defective ∝ chains. Inadequate bone mineralization
 Brittle bones - High frequency of fractures
2) Proteins
Fibrous proteins
 Bone Matrix
 Proteins (Organic matrix) are synthesized first and then the minerals are added.
 The vast majority of the organic matrix is collagen which provides tensile strength.
 Type of mineralized ECM embedded with bone cells, blood vessels and nerves.
ECM↑, Cells ↓
Protein ↑ (type I collagen)
7
Polysaccharide ↓
 Mineralization gives mechanical strength & rigidity. (Hydroxyapatite)
Elastin
 Rich in Pro & Gly, little OH-Pro Emphysema due to α 1 - antitrypsin deficiency
 hydrophobic  Neutrophils secrete elastase
 Non-glycosylated
 Elastase breakdown Elastin in lung tissue
 Permits deformability and
passive recoil  α 1 - antitrypsin inhibits Elastase
 Smoking – oxidize Methionine of active site
of Antitrypsin
Marphan’s syndrome  Leading to Emphysema (Chronic obstructive
 Mutations in fibrillin gene pulmonary disease)
 Elongated bones in fingers and
arms
Adhesive proteins
Fibronectin Laminin
(widespread) (In Basal Laminar)
Attach cells to ECM
 Maintain tissue / organ structure

 Cell - ECM communication
 Cell migration
Epidermolysis Bullosa
Types Defects Lysis Region
EB simplex Keratins (Cytoskeletal proteins) Epidermis

Junctional EB Laminin Dermal Epidermal junction
Dystrophic EB Collagen type VII Dermis
 Cartilage
 Semi rigid connective tissue

 Tough and yet flexible
8
 ECM
 Proteoglycan aggregates (Chondroitin sulphate, Keratin sulphate)
 Collagen (Type II), Elastin
 Hyaline Cartilage in joint - Cushions bones at joints

 Protects bones by preventing rubbing
 Helps movements allowing bones to glide over each other
 Near-frictionless articulation at joints
 Synovial fluid in joints (High amount of hyaluronic acid)

 Prevents cartilage from grinding against each other
 Allows diffusion of nutrients to cartilage
Osteoarthritis
 Proteoglycans autoantigens
 Destruction of the cartilage
 Replacement by bones
 Synovial fluid & Osteoarthritis

 Reduction in Synovial fluid volume (Reduction of Hyaluronic acid in synovial fluid)
 Loss of elasticity & fluidity
 Affects shock absorbing power of the joint
 Prone to injury
Fibrosis
 Excessive collagen production - over expression of collagen gene
 Decreased activity of removing enzymes - decreased ECM degradation
Cancer
 ECM barrier to cancer metastasis
 Invasion requires cell adhesion, migration and protease activity
Development of atherosclerotic plaque

 DS binds plasma LDL / atherosclerotic lesion Arterial smooth muscle cell
proliferation
Function of ECM
 Wound healing
 Mechanical support for cells and tissues
9
 Integration of cells into tissues. Provide framework for cell adhesion
 Binds tissue to each other
 Influence cell shape and movements.
 Influence growth, proliferation and migration of cells
 Influences cell development and differentiation. (Embryogenesis)
 Serving as a medium for exchange
 Aiding in defense and protection
 Coordinates cellular functions through signaling with cellular adhesion receptors
 Reservoir for extracellular signaling molecules
 Regulation of filtration (Kidney glomerulus)
 Regulation of blood clotting
 (Damage to blood vessels Exposure of ECM Interaction of platelets with ECM)
 Scaffolding for tissue renewal
 ECM binding many growth factors and hormones
 Migratory cells bind to ECM via - focal adhesions
 Stationary cells bind to ECM via - hemi desmosomes
10
BIO MEMBRANES
 The composition of the membrane is dynamic
Structure
Lipid bilayer
Held together by non-covalent interactions
Components proteins
Carbohydrates covalently linked to proteins (glycoproteins)
Lipids (glycolipids)
Only in outer leaflet.
 Relative proportion of lipid and proteins depend on membrane function

Eg: - myelin sheath of certain neurons is primarily composed of lipids.
Inner mitochondrial membrane consists of more proteins
 Structure is described in Fluid mosaic model by Singer and Nicolson.
 Membrane function depends on Lipid ratio.
Protein
1. Lipids
Choline phospholipids (PC, SM-contain serine)

Glycerophospholipids
Amino phospholipids (PE, PS)
Types Sphingolipids
Cholesterol
Hydrophilic head →
 PI - minor phospholipid critical for signaling
 Cardiolipin - a constituent of MC membrane exposed to water
Hydrophobic tails →
Lipids are amphipathic in interior
Unsaturated tail → cis double

When mixed with bond → forms kinks
water
Saturated tail
Micelles /emulsions Lipid bilayers Liposomes → can be made from

solutions of pure phospholipids.
Enzymes
Used in DNA to target
delivery of Anticancer tissues.
drugs

Micelles
 stabilized by emulsifying agents such as amphipathic lipids (Eg: - lecithin)
Absorption of lipids from intestine
Aggregation of bile salts into lipids and liposomes
Formation of mixed micelles with the products of fat digestion
Facilitates lipid absorption
2. Membrane proteins.
 Determine most of the specific function of membranes.
Peripheral proteins → Not embedded (loosely bound to the surface of

proteins)
Two classes
Integral proteins → Penetrate the hydrophobic core of the bilayer
→ Transmembrane proteins.
(completely spanning the membrane)
 Protein asymmetry → func onal difference.
Functions of membrane proteins
 Transporter
 Enzyme binding site Outside
 Cell surface receptor
 Cell surface identity marker
 Cell adhesion Inside
 Attachment to cytoskeleton Glycophorin
Properties of bio membranes
1) Asymmetry
2) Fluidity
3) Flexibility
4) Dynamic
5) Self-sealing
6) Selectively permeable

1) Asymmetry
Asymmetry
Lateral Asymmetry Transverse Asymmetry
Regional Heterogeneities - Some Asymmetry between inner &

proteins are localized in different outer leaflets of bilayer
parts of cell
 Flippase actively maintains the concentrations of PS and PE in inner membrane. Cell damage
leads to loss of membrane asymmetry
 Carbohydrates mainly in outer leaflet
 Phosphatidylserine
 Anionic-Gives negative charge to cytoplasmic side of the membrane.
 Their polar heads are small and hydrocarbons are more spread out and more suited for the
curvature
 Cofactor for membrane bound enzymes
Eg: - Protein Kinase C, Na+/K+ ATPase
2) Fluidity
Temperature → fluidity is men oned over a wide range.

Depends on
Membrane composition Types of phospholipids
Amount of cholesterol
(Fluidity Buffer)
 Type of phospholipids
a) Saturation
 Unsaturated - high fluidity

Eg: - Animals during hibernation, synthesize more unsaturated FA to cope with low body
temperature
b) Chain length
 shorter the length-more fluid
 Amount of cholesterol
Q. Briefly explain the role of cholesterol in maintaining the fluidity of the bio membranes.
 The steroid cholesterol is wedged between phospholipid molecules in plasma membrane of
animal cells.
 - OH groups of cholesterol are aligned with the polar head of phospholipids in the
membrane
 It acts as fluidity buffer
 At warm temperatures it controls the movement of phospholipids and reduces fluidity
 At cool temperatures it maintains fluidity by preventing tight packing
3) Flexibility
 Permits shape change without loss of integrity
4) Dynamic
 movement in lipid bilayer

1. Lateral diffusion → fast
2. rotation → very fast
3. Transverse diffusion (flip flop) → slow
→ need flippase to make it fast.
 Flippases catalyzes rapid phospholipid

movement from one monolayer to the
other ATP-dependent process

Protein mobility
1. Rotational mobility
2. Lateral diffusion
 Protein mobility can vary greatly.

 Some proteins are free to move
 Some adhered to structures in the cytoplasm or extracellular spaces
Biochemical basis of snake venom on RBCs
 Snake venom contains phospholipases.

 Phospholipase A2 acts on C2 of phospholipids and produce arachidonic acid and lysolecithin
 Lysolecithin acts as a detergent.
 So destroy the glycolipid bilayer
 Lead to rupture of RBCs
MEMBRANE TRANSPORT
Simple diffusion → small uncharged molecules.

Passive transport
(Substrates move down Facilitated diffusion
the concentration gradient)
Transporters Ion channels (Very selective)

Eg: - erythrocyte glucose channel mediated Non-gated
transporter -GLUT 1
Gated
{Ligand, Voltage, Mechanical}

1) Passive mediated transport (facilitated diffusion)
 Transporters bind to substrate through

weak non-covalent bonds and binding
induces conformational change
 Faster than simple diffusion
 Show saturation kinetics
 Susceptible to competitive inhibition (like
enzymes)
 Chemical and stereo chemical specificity for transported molecules
Eg: - glucose transporters (GLUT1, 2...)
Passive mediated transport - protein channels
 Highly selective for

specific molecules
 Very fast
 Cannot be saturated
 Do not bind molecules
and ions to be
transported.
 Do not require ATP
Gated channels - opened

and closed in response to
stimulus
Ion channels - allow passage of ions which are associated with water
Gap junctions
 Transport ions connect the cytoplasm of two cells by 2 CONNEXONS
 A connexon is made by 6 connexin proteins
 Opening of gap junctions is inhibited by intracellular Ca2+.
Aquaporin
 Transport water (too narrow for ion transportation)
 Tetrameric transmembrane protein

Categories of assisted transport
 Uniport
 Transport single solute
 Eg- GLUT 1 glucose carrier
 Symport / cotransport
 Two different solutes to be
transported
 Gradient of one substrate drive
uphill transport of co-substance
 Eg: - Glucose-Na+ symport
 Antiport
 Exchange one solute for another
Eg: -
Na+- H+ exchanger,
Cl-/HCO- exchanger
bands protein in RBC membrane
 Symport and antiport are secondary active
transport methods
2) Active transport
 Requires energy as it is against concentration gradient

 Different forms of energy can be used
 ATP
 Gradient (co-transporters)
 Light (e.g. bacteriorhodopsin)
 two types
a) primary active (Eg: - Na+ / K+ ATPase, H+ / K+ ATPase)
b) secondary active
a) Primary active transport
Na+ / K+ ATPase
 Na+/K+ ATPase binds 3 intracellular Na+
 ATP phosphorylates protein with bound sodium
 Phosphorylation causes conformational changes reducing its affinity to Na+, then 3 Na+
diffuses out
 New conformation has higher affinity to extracellular K+
 Binding of 2 K+ facilitates dephosphorylation of protein
 Required to maintain osmotic balance and cell volume
 Cell contain high concentration of solutes

 This create large osmotic gradient which pulls water in
 Counteracted by opposite osmotic gradient due to high concentration of inorganic ions
 Digitalis inhibits this pump, Careful use as a therapeutic benefit for heart patients
Q. Explain the molecular mechanism of acidification of the stomach lumen by parietal cells in the
gastric lining
 Omeprazole inhibits the H+/K+
ATPase pump and used for gastric
ulcers
b) Secondary active transport
Glucose transport by SGLT

 As concentration of glucose is
higher inside the cells compared to
the intestine, Glucose needed to
be pumped into cells against the
concentration gradient.
 Energy required for this comes
from the electrochemical gradient
maintained by Na+/K+ ATPase.
 Na+ within intestinal cell < lumen
 So SGLT (Sodium glucose
symporter) which is located at the
apical membrane of intestinal cells
pumps glucose in to cells against
its concentration gradient while
taking Na+ down its concentration gradient.
Q. Explain why glucose is a component of oral rehydration fluid
 In the healthy state there are glucose-dependent and glucose independent methods of
absorbing Na+ in the gut
 In diarrhoea glucose independent method is inactivated

 The Na+ in the intestinal lumen is transported into the enterocytes via the Sodium Glucose
Cotransporter (SGLT-1) which is a symport
 Therefore, glucose must be present (along with Na+) in the ORT fluid
 Na+ that enters the cell is then pumped into the blood using ATP by the Na+/K+ ATPase
pump
 Glucose enters the blood from the enterocytes via the GLUT-2 transporter
 Since both Na+ and glucose are osmotically active substances, water will also move in from
the lumen to the enterocytes and then to the blood
 Therefore, both lost water and electrolytes (Na+) are replaced due to ORT
Multidrug-resistance (MDR) transport protein or ABC transporters
 Energy derived from ATP hydrolysis

 Export drugs, various natural and metabolic toxins from the cytosol to the extracellular
medium
 Tumors produce MDR Makes resistant to chemotherapeutic agents
Molecular mechanisms in Cystic Fibrosis
 The gene defective in cystic fibrosis codes for CFTR (cystic fibrosis transmembrane conductance
regulator)
Mobile Carriers(Ionophores)
 Ions may be carried across by ionophores, small molecules that mask the charge of the ions and
allow them to diffuse through the lipid bilayer.
 They transport ions down the concentration gradient to equilibrium,
 Number of antibiotics function as ionophores
Eg: - Valinomycin
Bulk transport - ENERGY REQUIRING
 Two types
1) endocytosis
2) exocytosis

1) Endocytosis
 Plasma membrane envelope particulate matter and liquids
 Phagocytosis (cellular eating)

 Ingest solid particles
 Pinocytosis (cellular Drinking)

 Ingest liquid and matter dissolved in liquid
 Receptor mediated endocytosis, specific molecules are taken in
2) Exocytosis
 Form vesicles that transport to the membrane

 Vesicles fuse with the membrane releasing substance out

VITAMINS
 Vitamins are unrelated organic compounds that cannot be synthesized in adequate amounts by
humans. Therefore, they must be supplied by the diet.
 They are organic compounds.

 Essential to human health
 Involved in fundamental functions of the body
 Some are not dietary essential.
E.g. Vitamin D
Niacin containing coenzymes are derived from tryptophan
 Micronutrients.
 Absence is usually manifested as deficiency diseases.
Water soluble vitamins Fat soluble vitamins

Readily excreted in urine. (after exceeding the Not readily excreted in urine.
renal threshold)
Not stored, except vitamin B12. Stored in liver & adipose tissue.
Toxicity is rare, except vitamin B6. Excess amounts of vitamin A & D are toxic.
Deficiency can occur quickly. Deficiencies are rare.
Absorbed and transported in chylomicrons
with dietary fat.
Most vitamins are precursors of coenzymes. Only vitamin K has coenzyme function.
Should be given in frequent doses, (in daily Large doses are given at once.
basis) except vitamin C. E.g. vitamin A mega dose.

WATER SOLUBLE VITAMINS
1) Folic acid (pteroyl glutamate)
Structure
Pteridine - PABA - glutamate

(-)
Sulphonamide is a competitive inhibitor
Active form - tetrahydrofolate (THF)
DHF reductase
Dietary folate (DHF) THF
2H+ + NADPH (-) 2NADP+
Methotrexate is a competitive inhibitor.

Function
(Transfer one C segment)
Donors intermediates in the synthesis of;
 Amino acids
Eg: Serine, Glycine,
 Purines
Histidine  Thymidine monophosphate
N10 formyl THF Purine synthesis
THF N5, N10 Methylene THF TMP synthesis
Homocysteine
N5 Methyl THF
Vit. B12
Methionine
Deficiency
 Causes for inadequate serum levels of folate,

 Increased demand (pregnancy, lactation).
 Poor absorption caused by;
 Pathologies of SI
 Alcoholism
 Drugs (methotrexate)
 Folate free diets.

 Effects of deficiencies,
 Macrocytic megaloblastic anaemia.
Synthesis of TMP ↓ DNA ↓ cell division ↓
 Neural tube defects.
E.g. Spina bifida, anencephaly (common among pregnant women & alcoholics)
2) Vitamin B12 (Cobalamin)
Structure - contains Cobalt
Active form
1. Methyl Cobalamin (methionine production)

2. Deoxy adenosyl cobalamin (succinyl CoA production)
Function
1. Methylation
Homocysteine Methyl cobalamin THF
Methionine Cobalamin N5Methyl THF
2. Isomerization
Vit. B12
Methyl malonyl CoA Succinyl CoA
Bioavailability
 Only from microorganisms, not present in plants and animals.
Absorption, transportation and storage
 Vit. B12 in diet is released in acidic environment
Bind Intrinsic factor Absorption

Free B12 B12+IF Mucosal cells of ileum
Binding protein
In blood
Stored in liver B12+B12 binding protein
 Released to bile and efficiently restored.

Deficiency
 Causes,
 Decreased intake (take several years to develop).
 Impaired absorption (quicker).
 Reduced secretion of gastric acid.
 Reduced secretion of IF (autoimmune destruction of parietal cells).
 Effects of deficiencies,
 Pernicious anaemia;
 Neuropsychiatric
symptoms
 Need to give folic acid
throughout the life

 N5 methyl THF can’t be translated into other active forms of THF regeneration.
 The only reaction, occurs when Vit. B12 is present.
 If Vit. B12 is deficient, THF will accumulate in methyl form.
 Thus, other forms, needed for purine and TMP production will be reduced. Cell division
impaired, anemic conditions occur.
Folic acid can partially reverse the haematological abnormalities of B12 deficiency, and therefore
Folic acid can partially reverse the hematological abnormalities of B12 deficiency, and therefore can
can mask the B12 deficiency. So treatment initiated with both folic acid and B12 until the cause of
mask the B12 deficiency. So treatment initiated with both folic acid and B12 until the cause of the
the anaemia is diagnosed
anaemia is diagnosed.
3) Vitamin C (Ascorbic acid)
Active form - Ascorbic acid
Functions
 As a cofactor for reactions requiring a reduced metal ion (Fe2+, Cu2+).

 Copper-containing hydroxylases
Cu2+ Ascorbic acid (Vit. C) Cu+

Reduced
 Iron-containing hydroxylases.
 Hydroxylases - modification of proteins.
E.g. Hydroxylation of proline in collagen synthesis.
Cofactor for proline and lysine hydroxylases - stabilizes the structure & enhance H
bonding.
 Non-enzymatic reducing agent.

 can readily donate electrons to reactive free radicals and oxygen species to reduce,
 molecular oxygen
 nitrate
 cytochrome a, c
 Other biological antioxidants to regenerate active reduced form (Vitamin E).
 Reduces lipid peroxidation by regenerating active form of vitamin E (antioxidant).

 In iron metabolism
 Reduction of Fe3+ to Fe2+ by ascorbic acid, which is required in iron transfer and storage
pathways. Thereby enhance iron absorption in the gut.
Other functions
 Carnitine biosynthesis
 Degradation of tyrosine
Tyrosine epinephrine, synthesis
 Bile acid formation
 Inhibit nitrosamine formation during digestion
Deficiency
 Microcytic anaemia (due to decreased absorption of dietary iron)

 Scurvy (due to deficiency in hydroxylation of collagen)
4) Vitamin B1 (Thiamine)
Active form - Thiamine pyrophosphate (TPP)
Functions
 coenzyme in energy metabolism

 oxidative decarboxylation reactions
Pyruvate Dehydrogenase
E.g. Pyruvate Acetyl CoA + CO2
TPP
α keto glutarate Dehydrogenase

α keto glutarate Succinyl CoA + CO2
TPP
 Transketolase reactions in HMP

Deficiency
 Decreased production of ATP, increase in plasma lactate and pyruvate

 Beri beri
5) Vitamin B2 (Riboflavin)
Active form
 Flavin mono nucleotide (FMN)

 Flavin adenine dinucleotide (FAD)
 Derived from Tryptophan
Functions
 Reduced substrate Oxidized substrate
FAD/FMN FADH2/FMNH2
 Temporarily hold electrons

 Serve as cofactors to flavoenzyme
6) Vitamin B3 (Niacin)
Active forms
 Nicotinamide adenine dinucleotide (NAD)

 Nicotinamide adenine dinucleotide phosphate (NADP)
Functions
 Serves as coenzymes in redox reactions.
NAD+/NADP++ H + NADH/NADPH
Reduced substrate Oxidized substrate
E.g. coenzyme for lactate dehydrogenase and malate dehydrogenase
 Source of ADP ribose in DNA repair mechanism.

Deficiency
 Pellagra
7) Vitamin B5 (Pantothenic Acid)
Active form - Coenzyme A
Function - transferring acyl groups, thiol group carries acyl component
CoA (acetyl CoA, fatty acyl CoA, succinyl CoA)

Metabolized into two
Main cofactors
Acyl Carrier Protein (ACP)
8) Vitamin B6 (Pyridoxine)
Active form
 Pyridoxal phosphate (PLP)

 Pyridoxamine phosphate
 Only water soluble vitamin with toxicity and neurological symptoms.
Function
 Catalyzes reaction involving amino acids.
Reaction Type Example

Transaminase AST
OAA + Glu Asp + αKG
Deamination Glu Dehydrogenase
Glu αKG + NH3
Decarboxylation Histidine Histamine + CO2
Condensation Glycine + Succynyl CoA S amino levulinic acid
 Glycogen metabolism → Glycogen phosphorylase

 Important in steroid hormone reactions

9) Biotin (Vitamin H/B7)
 Vitamin Biotin required by human is produced by intestinal bacteria.
Function
 Act as a co-enzyme in carboxylation reactions, carrier of active CO2
Carboxylation reactions
Substrate product
Carboxylase-biotin-COO-
E.g. Pyruvate Pyruvate carboxylase Oxaloacetate

Acetyl CoA Carboxylase
FAT SOLUBLE VITAMINS
1) Vitamin A (retinoid)
Structure
Retinol
Retinal
Retinoic Acid
Visual Cycle
all trans retinol
11 - cis retinol all trans retinal
11- cis retinal
opsin
Rhodopsin
 Retinol → Retinal → β-carotene (conversion of β-carotene to retinal is inefficient)
Active Form - Retinoic Acid and 11 - cis retinal

 Retinoic acid can't be reduced 6μg β carotene = 1μg retinol
in the body back to retinol or
retinal
Importance of carotenoids
 some carotenoids have pro vitamin A activity

 carotenoids show antioxidant properties
 Help to scavenge oxygen free radicals at low oxygen tensions
 Thus protect against many chronic degenerative diseases esp. cancer, cardiovascular disease
Absorption, Transportation and Storing

Function
Dim light - rods
 Vision Visual cycle Only by 11-cis retinal
Colour - cones retinoic acid doesn't
contribute to these
 Reproduction spermatogenesis functions
Fetal resorption prevention (making placenta)
 Growth and maturation

 maintenance of epithelia l cells (integrity) and mucus secretion (glycoprotein synthesis), carries
oligosaccharides across membranes
 against anaemia - promotes red cell proliferation, better utilization of iron
 involved in immune response
 modulate protein synthesis, gene expression and tissue differentiation
 acts as a steroid hormone
 act on intra nuclear receptors
Deficiency To prevent retinol and carotenoid precursor are used as dietary supplement
Conjunctival xerosis
Night blindness is the earliest sign
Large bitot spot
Toxicity excessive intake hypervitaminosis A
Congenital malformation of the developing fetus
2) Vitamin D
 A group of sterols in human body is produced from 7-dehydrocholesterol

Active form - calcitriol 1, 25-dihydrocholecalciferol
Vitamin D2 - ergocalciferol: found in plants
Vitamin D3 - cholecalciferol: found in animals
 group of sterols (hormone like function)
 stimulates or represses gene transcription
 regulates plasma levels of calcium and phosphorus

Regulation of hydroxylation of vitamin D
Functions of vitamin D
 Functions as a hormone
 Main function - Ca absorption and homeostasis
 Maintains adequate plasma levels of calcium
 When necessary, calcitriol can:
 increase uptake of calcium by the intestine: by increasing the gene expression of calcium-
binding proteins
 minimize loss of calcium by the kidney by increasing reabsorption
 stimulate bone resorption (demineralization), synthesis and secretion of parathyroid and
thyroid hormone
 Act like a steroid hormone - binds to nuclear receptor protein

1, 25-dihydroxycholecalciferol
(Calcitriol) -active form
Calcium Target organs homeostasis
intestine bone kidney

Ca & PO4 absorption Essential for bone Ca & PO 4 reabsorption
mineralization & resorption
Deficiency
 Nutritional rickets and osteomalacia

 Renal osteodystrophy
 Hyperphosphatemia and hypocalcemia
Toxicity
 Hyper vitaminosis D
 enhanced calcium absorption and bone resorption → hypercalcemia
3) Vitamin E (Tocopherol)
Active form - D-α-tocopherol
Functions - Major lipid soluble antioxidant in prevention of non-enzymatic oxidation of cell

membranes and plasma lipoproteins (E.g. LDL) & peroxidation of PUFA by O2 & free radicals
 Vitamin E (D-α-tocopherol) as an antioxidant

 first line of defense against membrane phospholipid peroxidation
 effective at high PO2: RBC membrane
Respiratory tree
 β-Carotene as an antioxidant
 Traps peroxy free radicals formed in tissues
 Functions at low PO2
 Complements vitamin E function in the body
 vitamin E and β carotene compete with each other for antioxidant properties
 Toxicity and Deficiency both low

 Vitamin E deficiency is almost entirely restricted to premature infants
4) Vitamin K (Phylloquinone)
Active form
 Phylloquinone (in green vegetables)

 Menaquinone (synthesized by intestinal bacteria)
 Menadione (synthetic)
Functions
 Post translational modification of proteins

 Coenzyme in the gamma carboxylation of glutamic residues in clotting factors and calcium
binding proteins.
Precursors of clotting factor Polypeptide
II, VII, IX, X Glu glutamate residue
COO- Vitamin K hydroquinone
O2 ϒ carboxylase epoxidase reductase
CO2 Vitamin epoxide
mature clotting factors Glu
ϒ carboxy glutamate
COO- COO- Warfarin
 inhibit the cycle

 inhibit clotting in
strokes, MI
 Anticoagulant
(2-) attract Ca2+
help blood clot formation
Carboxylation = addition of COO-

NUCLEIC ACIDS & DNA PACKAGING
Components of nucleic acids

 Pentose (C5) Sugar
 Nitrogenous Base
 Purines (bicyclic)
 Adenine (A)
 Guanine (G)
 Pyrimidines (monocyclic)
 Cytosine (C)
 Thymine (T) - only in DNA
 Uracil (U) - only in RNA
 Phosphate group
 Nucleoside = Pentose sugar(1C) + Nitrogenous Base

(N-linked β Glycosidic bond)
Eg: - Adenosine, Guanosine, Cytidine, Thymidine, Uridine
 Nucleotide = Nucleoside (2C, 3C, 5C or phosphate)
+ Phosphate group (one or more) (Ester bond)
Eg: - Deoxyadenosine triphosphate - dATP
Adenosine triphosphate - ATP
Features of the polynucleotide chain

 Backbone – repeating sugar phosphate groups
 (-) vely charged
 Bases directed away from backbone.
 Two distinct ends
 5’ end (phosphate group)
 3’ end (free hydroxyl group)
Results in Polarity
DNA
Structure of DNA (Watson & Crick Model)

 Two polynucleotide chains coiled around a common axis
 Double helical (for replication, transcription)
 Antiparallel
5’ 3’
3’ 5’

 Complementary (not identical)
 Right-handed coiling
 10 bp/turn, 20' A diameter
 Sugar phosphate backbone outside
 Hydrophilic
 Polar sugar molecules
 Negatively charged phosphate groups
 Polyanionic backbone
 Make railing
 Bases inside
 Hydrophobic
 Plane of bases perpendicular to the axis of backbone
 Make steps with H bonds
Base pairing in the double helix;(Chargaff's rule)
 A=T & G= C
 A+G= T+C (number of purines=number of pyrimidines)
 A+T/G+C=k
 Complementary base pairing sequence of basses in a single chain will automatically
determine the sequence of the other chain.
Stability
 Base stacking interactions

 H-bonds between bases
 Ionic interactions
 Strong acid & high temp. - completely hydrolysed
 pH 3-4: apurinic nucleic acids (weak acids)
 High pH has a small effect on DNA structure, but can change the tautomeric state of the
bases which can result in instability & denaturation
 When viewed from outside 2 grooves can be observed. Due to base pair stacking and
phosphate sugar backbone twisting. (Important for binding of drugs & proteins)
 Additional DNA strand can form a triplet stranded DNA at the groove.
 RNA is unstable at higher pH as 2’OH group in RNA hydrolyses
Denaturation
H bonding of the duplex DNA can be broken, and the two strands can be separated by
 increasing the temperature
 increasing the pH
 specific enzymes.
Denaturation is a reversible process.
Melting temperature (Tm)
The temperature where half the duplex DNA is unwound is called melting point.

Renaturation
Process where the denatured complementary strands of DNA forms the duplex DNA.
Slow cooling of denatured DNA allows renaturation.
Hybridization
 Denatured DNA when cooled in the presence of exogenous DNA, strand of DNA forms the
duplex DNA.
 Depends on
 Favourable temperature of the solution
 Salt-ion concentration
Even if two sequences do not match perfectly, they can be hybridized. Used in disease diagnosis
(DNA annealing)
RNA (Ribonucleic acid)
 Chemically similar to DNA, but linear & single stranded

 Shows 5’ to 3’ polarity
 Have modified bases (specially in tRNA)
E.g. Methylated
Acetylated
Deaminated
 Some have secondary structures→ intra-molecular base pairing
E.g. Hair pin (stem-loop) structure
Cruciform structure
Non-Coding minor RNA
 Regulate Transcription, translation and protein translocation

 RNA processing, modifying and editing.
 RNA stability and degradation
 DNA replication

Other nucleotides
1. Energy carriers - ATP, GTP
2. Phosphate donors - ATP
3. Physiological mediators in regulation - cAMP, cGMP
4. Activated mediators in reactions. - UDP glucose
5. Enzyme cofactors - NAD, FAD, FMN, NADP
DNA PACKAGING
Supercoiling of DNA
 Bending, twisting of the DNA helix(coil)
 DNA ------- coil of DNA ----------- supercoil
How DNA is supercoiled

Negative supercoiling
In cells, DNA is normally underwound
Strand separation.
Important during replication and transcription.
Topoisomerases
 Increase or decrease the extent of DNA supercoiling by,

 Cleaving DNA (nuclease activity)
 Rotating DNA strands
 Rejoining DNA strands (ligase activity)
 Important in DNA packaging, replication, transcription and DNA repair.
Topoisomerase I Topoisomerase II
1) Cleaves one DNA strand 1) Cleaves both DNA strands
2) No energy required 2) Energy required (ATP)
3) Present in both prokaryotes and 3) Present in both prokaryotes and Eukaryotes
Eukaryotes 4) DNA gyrase (bacterial) - introduce (-ve) supercoils
 Prokaryotes: Relaxes (-ve) supercoils Remove (+ve) supercoils
only 5) Eukaryotic topo 2 cannot introduce supercoils. It
 Eukaryotes: can work on both (-ve) can only relax them.
and (+ve) supercoils 6) Linear daughter chromatids are separated by
Type II topoisomerases following replication.
DNA Gyrase
 Responsible for maintaining (-) ve supercoiling of bacterial chromosomes.

 Inhibited by: Novobiocin - blocks ATP binding do not inhibit eukaryotic
Nalidixic acid - blocks the breakage and rejoining mechanism topoisomerases
 Doxorubicin, etoposide – eukaryotic topo 2 inhibitor. Used as chemotherapeutic agents.

(anticancer drugs)
DNA packaging in eukaryotes
DNA + Proteins Chromatin

1 : 2
Euchromatin Heterochromatin
Poorly stained Darkly stained
Loosely packed Densely packed
Transcriptionally active Transcriptionally inactive

DNA Binding Protein
Histones Non-Histone proteins

4 major types. Not involved in packaging
Highly conserved in eukaryotes Eg: - topoisomerases, gene regulatory proteins,
H1, H2A, H2B, H3, H4 scaffold proteins
Rich in lysine & arginine Highly species/ organ specific
(+ve) charge
Nucleosomal histones H1 histones

H2A, H2B, H3, H4 Less conserved
Help fold DNA into nucleosomes Help pack nucleosomes to higher order structure
Form ‘’Histone core’’ (histone octamer) Histone H1 binds to linker DNA; act as ‘hinge’
Most highly conserved
ds-DNA (2nm)
Nucleosomes - Unit of packaging (11nm)

“Beads on a string appearance”
DNA (2DNA superhelical
form) +Histone octamer
30nm fibre - H1 binds to linker DNA &

‘pulls’ the nucleosomes
together
Looped domains (120-300 nm)
Chromosomes(700nm)
 Packaging alter in replication & transcription
 To make DNA sequences accessible, DNA has to

separate from the histones.
 Histones undergo reversible covalent modifications
By; Histone acetyltransferases
Histone methyltransferases
Protein kinases

Eg: Selected lysine side chains – acetylated
Selected serine side chains – phosphorylated
 Those modifications regulate transcription, DNA repair, apoptosis, replication
Histone acetylation/deacetylation
In bacteria
 “Nucleoid” is the packaging structure

 Don’t have Histone proteins.
 Have several types of chromatin proteins; e.g. HU proteins (Histone like proteins)

DNA REPLICATION
Importance of DNA replication,
 Provide a (accurate) copy of the genome for the cells in cell division.
 Occurs in the ‘S’ phase of the cell cycle.
Key features of DNA Replication, (DNA – only molecule that can duplicate itself)
 Semi-conservative - new strand built on parent strand, so, each DNA molecule consists of
one old (parental) strand and one new (daughter) strand. (Advantage – Replication errors
can be repaired)
 Bi-directional - The two replication forks move in opposite directions.
 Semi-discontinuous
Concept of Template
 If the sequence on one strand is given, then the sequence of the other strand is
automatically determined. (complementary base pairing)
Replication Fork (ϴ structure)
Machinery for DNA replication
Enzymes Other proteins

Single stranded binding proteins(SSB),
Brace and clamp proteins (β subunits
of pol III)

DNA Polymerase
 Uses DNA as a template to synthesize new DNA by catalyzing chain growth (phosphodiester
bonds) in 5´ to 3´direction.
 This requires,
 A template
 A primer with a free 3´ OH
 Deoxynucleotides in the form of tri-Phosphates (PP released in reaction)
DNA polymerase has nuclease activity too.
1. 3´ to 5éxonuclease activity
 Proofreading activity replication fidelity
(Removing wrong nucleotides & replace)
2. 5´ to 3éxonuclease activity
 Removes nucleotides from 5énd.
 This is used in removal of RNA primer and DNA repair.
Only DNA Polymerase-I, has 5´ to 3´ exonuclease activity.
Differences between 3’ to 5’ and 5’ to 3’ exonuclease activity
3’ to 5’ exonuclease 5’ to 3’ exonuclease
 Important for proof reading function  Important for removal of “RNA
of DNA polymerase I primers”
 Can remove wrong nucleotides and  Removes nucleotides from 5’ end
replace
 Removes only mismatching points  Removes matching pairs also
 Removes only one nucleotide  Can remove a large part
 Only remove deoxyribonucleotides  Remove both deoxyribo and
ribonucleotides
Activity Pol I Pol II Pol III

Polymerization 5´ to 3´ Yes Yes Yes
3´ to 5´ exonuclease activity Yes Yes Yes
5´ to 3´ exonuclease activity Yes No No
Primase
 Initiate the DNA replication.
 DNA polymerases require a free 3 OH group, so, DNA polymerases can’t initiate the
replication.
 Primase is a RNA polymerase, that synthesize a short sequence of RNA in a template
dependent manner known as the primer.
 Then DNA polymerases, extends from the 3’ OH of that short RNA strand to form DNA.

Helicase
 DNA polymerases cannot use double stranded DNA as template.

 Helicase unwind duplex DNA providing single stranded DNA to act as a template, by
breaking the H bonds between the complementary bases.
 Require ATP.
Topoisomerases
 DNA supercoils are removed by reversibly cleaving one or two strands.

 Separation of DNA strands causes topological strain on the rest of the DNA strand.
 Topoisomerases relieve this strain.
 Type 1 topoisomerase cleaves only one strand and it is ATP independent. (one → indepen.)
 Type 2 topoisomerases can cleave both strands and it is ATP dependent.
 DNA gyrase is a special type two topoisomerase enzyme which found in E-coli. It can
introduce negative supercoils.
 Quinoline drug is a topoisomerase inhibitor.
DNA ligase
 Seals nicks(gaps)between DNA fragments by catalyzing formation of 3´ to 5´

phosphodiester bonds in an ATP dependent reaction.

Replication Process
 Replication occurs in 3 stages,

1) Initiation
2) Elongation
3) Termination
1) Initiation
 Occurs at a single specific site called ‘origin of replication’ (oriC). It is a highly conserved A:T
rich repeat sequence.
a) DnaA (Initiation factor) binds to ‘oriC’ and induces melting of DNA strands.
b) DnaB (Helicase) binds and begins further unwinding of DNA strands – requires ATP.
c) SSB binds and stabilize ssDNA. Also protect ss from inappropriate attacks from nucleases.
d) Primase binds and synthesizes RNA primer. Separate two single strands.
e) Topoisomerases relieve topological strain.
f) DNA pol III binds and begins to add dNTPs – deoxy nucleotide triphosphates, to the
primer.
2) Elongation
 Mainly done by DNA polymerase - III,
 Reads the template from 3´ to 5´ end.

 Synthesize new DNA strand in 5´ to 3´ end. (Polymerase activity)
 Has proofreading activity. (3´ to 5´ exonuclease activity)

 Synthesizes DNA from both strands simultaneously.
 High processivity / high fidelity.
 Two DNA strands grow in opposite directions.
 Helicase continues to unwind the DNA.

 SSB proteins stabilize the SS-DNA.
 Topoisomerase relieves the strain.
 Replication of one strand is discontinuous, because DNA polymerase activity is in 5’ to 3’

direction only.
Leading strand
 Continuous synthesis
 Chain elongation in the same direction as replication fork movement.
Lagging strand
 Synthesized in the opposite direction to the fork movement.

 Discontinuous synthesis.
 Synthesized short fragments – Okazaki fragments.
 Each Okazaki fragment has its own RNA primer.
DNA polymerase - I,
 5´ to 3´ exonuclease activity – Digest RNA primer.

 5´ to 3´ polymerase activity – extends strand up to adjacent Okazaki fragment and
replaces RNA primer with DNA, because new lagging strand consists with RNA-DNA
unjoined pieces of RNA-DNA combinations.
 3´ to 5´ exonuclease activity – proofreading
DNA Ligase
 Joins adjacent Okazaki fragments. ATP dependent.
3) Termination
 Replication forks from bi-directional replication run into each other and terminates Or One fork
STOPS and WAITS for the other.
 Events that occur at the terminus that result in separation of daughter strands.

Eukaryotic DNA replication
 Slow compared to prokaryotes. (1/10 of rate of bacterial DNA synthesis)

 More complex, but similar to prokaryotic replication process.
 Has multiple origins of replication.
 This ensures, replication can be completed during ‘S’ phase of cell cycle.
 At least 5 DNA polymerases identified,

 Pol α – Synthesis of DNA primer (Multi subunit along with Primase activity), No
proofreading
 Pol β – Base excision repair (Gap filling)
 Pol γ – Replication of mt.DNA – mitochondrial DNA
 Pol δ – Synthesis of leading and lagging strands, proofreading activity (Lagging strand only
complete DNA synthesis in leading strand)
 Pol ε – DNA repair, proofreading activity
Overcoming the end replication problem
 In the lagging strand, synthesis at the 5’ end cannot be completely done because the
primer cannot be laid down at the very end of the chromosome.
 Therefore, each time cell divides, a small part of the 5’ end will be lost from the
chromosome end, making the chromosome shorter.
 This end replication problem is overcome by addition of G+T nucleotides at the 3’ end of
parental strand
 These added sequences are known as “Telomeres”, which are special DNA sequences
found at the ends of eukaryotic chromosomes. They are essential for genome stability.
 Telomeres are several thousand bases of tandem repeats. The G T rich region at the
3’end of one strand extends as a single stranded G rich overhang (G tail) and fold back
on itself.
 Addition of the bases at the 3´ end is done by the “Telomerase”

Telomerase,
 Ribonucleoprotein complex
 Has an RNA template
 Has Reverse Transcriptase activity.
 Has other proteins for binding of DNA.
 Telomerase recognizes the G rich single stranded 3´ end of the parent strand and elongates it by
copying its RNA template. It contains both template and enzyme activity.
 Telomerase maintains appropriate length of telomere.

 Telomerase activity is absent in most somatic cells; therefore, telomere length
gradually decreases with aging due to repeated cell division.
 Loss of telomeres lead to chromosomal instability and cell senescence (cell aging).
 Telomerase activity is found in tissues associated with reproduction and abnormal (cancer)
cells.
 Telomerases make cancer cells immortal and is a potential drug target.
Retroviruses
 RNA genome containing viruses

 Synthesize DNA using RNA by Reverse Transcriptase activity
During replication
Faster rate of evolution
 HIV Reverse transcriptase is 10 times less accurate than other reverse transcriptase
enzymes, therefore they have very high rate of evolution

DNA TRANSCRIPTION
Central Dogma
RNA
1. RNA – Translated into proteins
 mRNA 5%
2. Structural / Functional RNA - Not translated
 rRNA - An integral component of ribosome 80% [Some rRNAs functions as catalysts
(rybozymes)]
 tRNA - Involve in translation 15%
 snRNA - Involve in RNA splicing
 scRNA - Involve in protein trafficking
Transcription
The synthesis of RNA molecules using DNA strands as templates so that the genetic information
is transferred from DNA to RNA.
 Promoter - The nucleotide sequence upstream of a gene, that acts as a signal for RNA
Polymerase binding
 Exons - coding DNA segments of eukaryotic genes.
 Introns - non-coding DNA segments of eukaryotic genes. (intervening sequences)
(Transcripted but not translated. They are removed to produce mature mRNA)
Prokaryotic RNA polymerase
 The enzyme responsible for the RNA synthesis is DNA dependent RNA polymerase.
 But RNA polymerase is 100% processive.
 Multiple subunit protein.

Subunit Role
α Determines the DNA to be transcribed
β Catalyzes polymerization
β’ Binds and open DNA template
σ Recognizes promoter for synthesis initiation
sigma factor (σ)
 Act as initiation factor

 Ensure that RNA polymerase binds stably to DNA only at Promoters.
 Stabilize specific binding to promotor of DNA.
 Destabilizes non-specific binding to non-promoter DNA.
 σ – sigma factor releases after initiation and rebind to other core enzymes.
 Accelerates the search for relevant promoter DNA.
 Core enzyme - Has 4 subunits → 2α, 1β and 1β’

 Cannot recognize the promoter region
 Holo enzyme - Core enzyme + σ-factor

 Can recognize the promoter region
 Termination factor - Termination of transcription needs termination factors.
Functions of RNA polymerase
1) Searches for initiation site

2) Selects correct NTP for base pairing for initiation & elongation
3) Detects terminal signals
4) Interacts with activator or repressor proteins- control transcriptional levels
5) Unwinds DNA template by local melting

 But no error correcting ability (error rate very low 10 -4- 10-5) & needs no primer to initiate.
 Binding of several transcription factors into distinct sites of the promoter, or some
distance away from it, is needed for initiation of transcription of eukaryotic genes.
 Binding of different factors determine which gene to be transcribed.
Eukaryotic RNA Polymerases
 3 types
Enzyme Transcription
RNA Polymerase I rRNA
RNA Polymerase II mRNA, some SnRNAs
RNA Polymerase III tRNA, SnRNA, ScRNA
 Unlike prokaryotic RNA polymerases eukaryotic RNA polymerase 2 can’t recognize the
promoter.
 Therefore, transcription factors do it
Eg: TF II D
Steps of DNA transcription
1) Initiation
2) Elongation
3) Termination
Transcription – A Brief Overview
Transcription starts with RNA polymerase binding

to the promoter
(When the gene is on, transcription factors help
RNA polymerase bind to the promoter) - Closed
promoter complex
↓
Once it binds, RNA polymerase unwinds a small
section of the DNA & uses it as a template -
Open promoter complex with localized
melting of DNA
↓
The complementary RNA copy is made from 5’ end to 3’
end
↓

DNA-RNA base pairing occurs in the open
complex bubble (When the bubble is moved,
supercoils are generated. It is relieved by
topoisomerases)
↓
Recognize the termination sequence & then complex dissociates
↓
Termination
 Bubble moves forwards by unwinding in front & rewinding behind the DNA strand.
 DNA-RNA base pairing CG GC TA AU
 Transcription unit - extends from the promoter to the terminator region

 Primary transcript - mRNA coming straight off the DNA template
Promoters
 Transcription begins with binding of RNA polymerase holoenzyme to the

promoter region on the DNA.
Eg;
 In prokaryotes - Pribnow box, -35 sequence
 In eukaryotes - TATA or Hogness box, CAAT box, GC rich regions
Transcription elements (Regulatory elements)
 regulates efficiency & frequency of transcription

 located upstream, downstream or within genes
 can be very close to or thousands of base pairs away from a gene
 Transcription elements,
1) Enhancers (increase transcription rate)

2) Silencers (decrease transcription rate)
Prokaryotic Promoter regions

Eukaryotic Promoter regions
Transcription Bubble
Termination of prokaryotic transcription
Rho- independent(direct) Rho- dependent(indirect)
 mRNA transcript has a termination  mRNA transcript has a termination

sequence sequence
 Hairpin(stem) loop structure is formed due  Stem loop structure is formed
to inverted repeats of G & C
 Long tail of Uracil is transcribed immediately  No poly uracil tail after stem loop
after stem loop
 Long tail (hairpin loop) acts as a signal  The ATP dependent RNA – DNA helicase activity of
to release RNA polymerase rho, separates the RNA –DNA hybrid helix

RNA polymerase pauses at the stem loop &
rho protein denatures the hybrid helix, close
enough to RNA pol. To cause enzyme to
dissociate
 No clear evidence for a discrete termination in eukaryotes
Differences between prokaryotic transcription and eukaryotic transcription
PROKARYOTES EUKARYOTES
 Transcription & Translation occurs  Transcription in the Nucleus
simultaneously Translation in the cytosol
 One type of RNA polymerase  3 types of RNA polymerase
 Polycistronic - mRNA codes for more  Monocistronic - mRNA codes only for one
than one gene gene
 Most part of DNA is accessible to  Only small amounts are accessible
transcription
 mRNA doesn’t show post  All mRNA, tRNA, rRNA undergo post
transcriptional modification transcriptional modification
 Eukaryotic transcription more complex.

 Need transcriptional factors for initiation of eukaryotic transcription.
 In eukaryotes organelle DNA is transcribed & translated within the organelle.

Inhibitors of Transcription
INHIBITOR EFFECT
 Rifampicin(on prokaryotes)  Inhibit transcription by binding to
RNA polymerase (prevent chain
extension beyond 8 nucleotides)
 Blocks initiation
 Actinomycin D (on both  Intercalate between DNA base pairs.
prokaryotes and eukaryotes) –  Stop movement of RNA polymerase.
Cancer drugs  RNA elongation inhibitor.
 Both prokaryotes & eukaryotes
 α amanitin (on eukaryotes) – poisonous  Eukaryotic RNA polymerase II inhibitor
mushrooms
Post transcriptional modifications of eukaryotes

 occur in the nucleus
1) mRNA
Modification Function
1) Addition of the 7-methylguanosinecap at the  Prevent nucleases from destroying the
5’position (5’capping) transcript
 Occur at the beginning of transcription  Ribosome recognition
 Enzyme - Guanylyl transferase  Transfer of the transcript to the cytoplasm
2) Adding the poly A tail to the 3’ position  Stability
 At the end of transcription  Transfer of RNA to the cytoplasm
 Enzyme - Poly A polymerase
3) Splicing – Removal of Introns & joining  Make exon intron boundaries recognizable by
together off exons by SNURP SNURP
 Catalyze the removal of introns, based on
conserved sequences
2) tRNA
 Remove introns
 3’ end is cut off and replaces by a CCA sequence
 Removal of the leader sequence
 Some base modifications

3) rRNA
 Large pre-RNA in to 3 mature rRNA

(endonuclease & exonuclease cleavages, base modifications, removal of introns in some rRNAs)
Prokaryotic post transcriptional modifications
 Primary transcript is processed into mature rRNA & tRNA,

 Endonuclease & exonuclease cleavages
 Base modifications
 3’ end replacement by CCA is also present in prokaryotic tRNAs Prokaryotic mRNA
doesn’t undergo post transcriptional modifications
Similarities between DNA transcription & replication
 Occur in the 5’ to3’direction

 Use DNA strands as templates
 Catalyzed by polymerases
 Substrate is nucleoside triphosphate
 Phosphodiester bonds are formed in both cases.
Differences between replication and transcription
Replication Transcription
 Template Both strands Single strand
 Substrate dNTP NTP
 Primer Yes No
 Enzyme DNA Polymerase RN Polymerase
 Product dsDNA ssRNA
 Base Pairs A-T, G-C A-U, T-A, G-C
Differences between DNA polymerase and RNA polymerase
DNA polymerase RNA polymerase

 Involved in DNA replication and repair  Involved in transcription
 Requires a primer  Needs no primer to initiate.
 Have proofreading activity  No proofreading activity

TRANSLATION
Central dogma of life
DNA transcription translation

mRNA Protein
- Flow of information from DNA to RNA to Protein –
THE GENE
 Genetic code-information in the cell is stored in the form of linear sequence of nucleotides in
DNA
 The code has 4 different letters- A, C, G & T (4 bases)
 The code is composed of triplet codes/codons. eg - AGC, CTC, TGG
 Each codon codes for one amino acid.
 There are 64 different codons. ( 𝟒𝟑 = 𝟔𝟒 )
 But only 61 of them code for amino acids. (rest of them are stop codons) (61 codons-->20 AAs)
 A series of codons in DNA that coding for a protein is a GENE.
Characteristics of the genetic code

 Unambiguous (specific) - The code occurs as codons. Each codon code for only one amino acid.
 Degenerate - But an amino acid may have more than one codon.
e.g. - Alanine - 4 codons
 Non-overlapping - Code is read, Each nucleotide is part of
1. From a fixed starting point. (AUG) 5’ to 3’
only one Codon
2. 3 bases at a time
3. No punctuation – comma less
 Universal (almost) - The code is almost the same for all the living organisms.
Why “almost”? Because there are minor variations

1. The amino acid for start codon (AUG)
 In eukaryotes - Methionine
 In prokaryotes - Formyl Methionine
2. Variations in mitochondrial genome, chloroplast & some ciliated protozoa.

 Human UAG – ‘stop’  Human AUA - Ile
 Mitochondrial UAG - Trp  Mitochondrial AUA - Met
 Mitochondrial AGA - ‘stop’

Translation
Converting the coded message in the mRNA into the amino acid sequence of the protein.
Translation requires,
 mRNA
 tRNA
 Ribosomes
 free ribosomes - synthesize proteins required in cytosol, nucleus, mitochondria,
peroxisomes.
 RER bound ribosomes – synthesize secretory proteins, SER, Golgi, plasma & lysosomes
 Translation factors – Initiation, Elongation & Termination factors
 AAs
 Aminoacyl tRNA synthetase
 Energy
ATP GTP
 For removal of PPi  Binding of aminoacyl
 Hydrolysis of PPi tRNA to A site
 Additional ATP is needed  translocation
for initiation in  termination
eukaryotes for initiation in
tRNA
 Has 2 sites (AA attachment site & Anticodon site)
 Large number of modified bases.
 3’ end carries AA from cytoplasm to ribosomes.
 Cloverleaf structure (because of unusual bases folds into three
dimensional shape)
 Has duel specificity - translate language of nucleic acid to
language of proteins, because it recognizes the codon in mRNA &
carries the correct AA.
(Adaptor molecule/ bilingual translation molecule)
 Base pairing is antiparallel & complementary.
(3rd base of codon pair with 1st base of anticodon)
 Bases read always 5’ to 3’ direction
wobble hypothesis
 Pairing of 3rd base in codon (wobble base) with 1st base of anticodon isn’t strong, but
other 2 base pairs follow strong Watson & crick pairs.
 Genetic Code 61 codons Coding for 20 amino acids
 All 61 codons do not have individual tRNA to pair.
 Therefore, more than one tRNA can bring one amino acid, because non tradition base pair
can occur.
e.g. - anticodon- (3’) XYU (5’)
codon - (5’) YXA (3’) or (5’) YXG (3’)
 So the 1 base of the anticodon determines the number of codons read by a given tRNA
st

Preparatory steps for Translation
1) Formation of amino acyl tRNA (Charging of tRNA & activation of AAs)
 Occurs in cytosol
 Catalyzed by Aminoacyl tRNA synthetase – In addition to their synthetic activity
 It has a 3’-5’ proof reading activity to ensure that the correct amino acid is bound to the
tRNA.
 There are 20 ‘aminoacyl tRNA synthetases, each specific for one AA, but there
are several tRNAs. (more than 20)
 Aminoacyl tRNA synthetase has dual specificity that it can identify both its AA
& corresponding tRNAs.
 So, these tRNAs can bind with same amino acids which recognized by the same enzyme.
 Specific nucleotides on tRNAs are involved in this recognition by the enzyme.
(second genetic code – interaction between tRNA & aminoacyl tRNA synthetase)
tRNA
AA + ATP Aminoacyl AMP Aminoacyl tRNA

+
+ PPi AMP
1st Step 2nd Step
(AA attaches to enzyme) (Transfers AA to tRNA)
- If wrong amino acyl AMP is bound - If wrong AA is bound to tRNA,

to the enzyme, it’s hydrolyzed the ester linkage of amino
to AA & AMP. acyl tRNA is hydrolyzed.
2) Dissociation of subunits of ribosome

 ribosomes must dissociate into subunits at the end of each round of translation to initiate the
next one.
Ribosomes
Factory site for the protein synthesis

Translate mRNA to build polypeptide chains using AAs delivered by tRNA.
Consists with 2 subunits & each composed of rRNA &
ribosomal proteins
(rRNA + ribosomal protein Ribonucleo protein)
Small subunit
 mRNA binding site
Large subunit
 A site (Aminoacyl tRNA binding site)
 P site (Peptidyl tRNA binding site)
 E site (tRNA exit site)

Small, large eukaryotic - 80S 40S + 60S
Prokaryotic - 70S 30S + 50S
Prokaryotic DNA translation.
Three steps: - Initiation Elongation Termination

Recruitment of aminoacyl tRNA
Peptide bond formation
Translocation
1) Initiation
 Ribosome binds to mRNA and 1st AA, attach to its tRNA
 Involves the assembly of 2 ribosomal subunits, Aminoacyl tRNA, GTP & initiation factors
 2 subunits of ribosome separate
 30S subunit joins mRNA near 5’ end, the P site opposite the initiation codon.
Shine-Delgano sequence
 Shine Delgano sequence is a ribosomal binding site which located, just upstream of the start
codon (AUG) in the prokaryotic mRNA. It base pairs with the end of rRNA of 30s small subunit
& helps to position & recruit the ribosome.
 But eukaryotic mRNA doesn’t contain a ‘shine delgano sequence’, so in eukaryotes 40 s
small subunit binds to the 5’cap region of the mRNA & scan for the start codon (AUG).
This process requires ATP.
 fMet-tRNA binds to AUG forming 30S initiation complex (fMet-tRNA is the only tRNA which
goes into the P site)
 50S subunit binds to 30S initiation complex forming 70S initiation complex.
2) Elongation (From N terminal to C terminal)
 Ribosomes add 1 AA at a time to carboxylic end of growing polypeptide chain, GTP required
 Ribosome translocates by 3 bases after peptide bond formed.
 New charged tRNA aligns in the A site.
 Peptide bond between amino acids in A and P sites is formed by peptidyl-transferase.
 Ribosome translocates by three more bases.
 The uncharged tRNA in the P site is moved to the E site.
 Translocation: translocation of the new peptidyl t-RNA with its mRNA codon in the A site
into the free P site occurs.
 Now the A site is free for another cycle of Aminoacyl tRNA codon recognition and
elongation. Each translocation event moves mRNA one codon length through the
ribosomes.

 Translocation requires
 in prokaryotes: EF-G-GTP
 in eukaryotes: EF-2-GTP
3) Termination
 The ribosome releases the mRNA and the polypeptide

 Requires specific protein factors identified as releasing
factors. RFs in E. coli and eRFs in eukaryotes.
 Signals for termination
 3 termination codes, UAG, UAA and UGA.
 Same in both prokaryotes and
eukaryotes.
 Nonsense codon = termination codon of
mRNA appears in the A site.
 Recognize as a terminal signal by eukaryotic
releasing factor which cause the release of
the newly synthesized protein from
ribosomal complex releasing requires GTP.
 Polyribosome/ Polysome- several
ribosomes attached to one mRNA.
 Can be free in cytosol or attached to ER (RER)
Differences between Prokaryotic & Eukaryotic Translation
Prokaryotes Eukaryotes
 70s ribosomes  80s ribosome
 Prokaryotic mRNA is polycistronic.  Eukaryotic mRNA is monocistronic.
 Initiator Met-tRNAi or Met-tRNAf  Initiating tRNA carries methionine
carries formyl- methionine
 Prokaryotic mRNA has specific purine rich  No specific purine-rich sequence.40s subunit
‘Shine Delgano sequence’ on the mRNA. binds to 5’ cap region and scan for the first AUG
 Fewer translation factors  Many translation factors
 Elongation GTP driven translocation  Similar to prokaryotes but specific elongation
factors
 Termination carries out by 2 release  Termination in eukaryotes is carried out by a
factors single released factor eRF 1

Antibiotics that inhibit ribosomal protein synthesis
Drug subunit Target organism Effect

Streptomycin 30S Prokaryotes Stop initiation & misread mRNA
Aurintricarbocyl 30S Prokaryotes & Inhibit formation of initiation complex
ic 40S Eukaryotes
acid
Tetracycline 30S Prokaryotes & Stop aminoacyl tRNA binding to the A site,
Eukaryotes so elongation is inhibited
Chloramphenic 50S Prokaryotes Inhibit peptidyl transferase activity of 50s
ol Subunit. May also inhibit mitochondrial
protein synthesis.
Colicin E3 30S Prokaryotes Interfere with function of small subunit.
Erythromycin 50S prokaryotes Inhibit translocation
Puromycin 50S prokaryotes Structural analogue of aminoacyl-tRNA
60S & incorporated at c-terminal & stop
eukaryotes elongation, causes premature chain
termination.
Cycloheximide 60S eukaryotes Inhibit peptidyl transferase, activity of 60s
subunit laboratory tool in blocking
protein synthesis.
Effect of diphtheria toxin on protein synthesis
 Produced by Corynebacterium diphtheriae, a bacterium

 The toxin bind to receptors on mucosal cell surface & is
proteolytically cleaved.
 One fragment enters the cell & inactivate EF-2 which is
equivalent to prokaryotic EF-G.
 EF-2 is required for the GTP driven translocation of
ribosome along mRNA.
 Stop protein synthesis & kills the cell.
 Act as an enzyme & small amount is sufficient for a great
damage.

Translation Process

POST TRANSLATIONAL MODIFICATION OF PROTEINS
PTMs are,
 Removal of part of translational sequence or covalent addition of one or more chemical groups
required for protein activity after translation is initiated.
 This is also a key mechanism to increase proteomic diversity.
 PTMs are found in both Prokaryotic & Eukaryotic.
 PTM can be a single or a combination of events such as cleavage & addition of functional
groups.
 PTMs can be reversible or irreversible.
Native proteins – inactive

Undergo post-translational
modifications
Active protein
They’re done after,

 Shortly after translation is completed;
 Gives;
 proper protein folding
 Stability
 directs the nascent protein to distinct cellular compartments (e.g. nucleus,
membrane)
 After folding and localization are completed, To;

 activate or inactivate catalytic activity.
 influence the biological activity.
 target a protein for degradation.
Chaperones
 Proteins in the cell which assist the covalent folding or unfolding
 They guide folding of proteins present in cytosol, lumen of RER, mitochondria, etc.
 Chaperones promote the assembly of protein complexes from subunits.
 Prevent the aggregation of unfolded proteins.
Example: Heat shock proteins,

 A set of proteins induced by a brief exposure of cells to Elevated temperature (420C).
 Many molecular chaperones are HSPs.
 The heat shock causes many proteins to unfold or misfold and the HSPs are induced to
help refold these proteins correctly.
 HSPs bind to exposed hydrophobic regions of proteins to achieve proper folding.
 ATP required for action.

Eg:
 hsp 70
in cytosol
 hsp 60
 BiP (binding proteins) → in lumen of RER
 Mitochondrial hsp (mhsp 60 & mhsp 70)
Protein folding
 BiP (hsp) helps to fold protein correctly.
ATP
Open state confirmation, BiP-ATP
BiP weakly binds to target protein
hsp 40;
helps to hydrolyze ATP to ADP
conformational changes that causes BiP-ADP
BiP to clamp tightly to hydrophobic
region of the protein
This process is repeated over and over until protein is folded into its final form.
PTMs in Prokaryotes,
 Protein folding
 Removal of the Signal Peptide
 Removal of Formyl – Methionine from the N terminal
PTMs in Eukaryotes,
 Protein folding
 Removal of the Signal Peptide
 Removal of Methionine from the N terminal (initial Amino Acid)
In eukaryotes, PTMs helps to direct proteins in to,

 Lysosomes
 Mitochondria
 Nucleus

Protein folding by Chaperones
Types of Post Translational Modifications
1) Proteolytic cleavage
2) Disulphide bond formation
3) Glycosylation
4) Methylation
5) Phosphorylation
6) Lysosomal targeting of enzymes
7) Ubiquitination
8) S-Nitrosylation
9) Acylation
10) Sulfation
11) Vitamin C- dependent modification (Hydroxylation)
12) Vitamin K dependent modifications
1) Trimming – proteolytic cleavage
 Proproteins – synthesized as inactive precursors (e.g. pancreatic enzymes, enzymes

involved in clotting)
 Preproteins – proteins that contains a signal peptide. preproteins are cleaved in ER
 Preproproteins – proproteins having a signal peptide destined for secretion &
proteolytic cleavage prior to activation.

Eg:
a) Insulin Removal of signal peptide (Preproinsulin Proinsulin)
Removal of the C peptide (Proinsulin Insulin) in secretory granules of βcell
b) Collagen Removal of signal peptide (Prepro α chains Pro α chains)

Extracellular cleavage of N & C terminal propeptides
(Procollagen Tropocollagen)
c) Trypsinogen Trypsin (active enzyme)

(Proenzyme) Removal of a hexapeptide
d) Pepsinogen Pepsin (active)

Removal of 44 AAs from amino terminal
2) Covalent attachments
a) Hydroxylation
Eg: In collagen synthesis; hydroxylation of selected proline and lysine residues of pro α chains.
Prolyl hydroxylase
Proline Hydroxy proline
Vit C= Ascorbic acid
Lysyl hydroxylase
Lysine Hydroxy Lysine
Vit.C = Ascorbic acid
 Ascorbic acid is required for this process. So, Vit.C deficiency leads to scurvy.
b) Glycosylation
 Enzymatic addition of oligosaccharide molecules into the peptide chain about 50% of
eukaryotic proteins are glycosylated
 Attached glycosyl residue determines the function of the glycoprotein
 predominated by mannose, glucose, galactose, GALNAC, GLCNAC, NANA
N linked glycoproteins O linked glycoproteins

 CHO chains attached to amide N of  CHO chain is attached to OH group of
Asparagine Ser, Thr, OH Lys
 Occurs in ER  Occurs in Golgi
Blood group antigens - O linked

Functions of glycosylation;
 Aids in proper protein folding

 Provide protection against proteases (e.g. lysosomal membrane proteins)
 Employed for signaling
 Targeting of proteins
Eg:
 In collagen synthesis
 glycosylation of selected hydroxylysine residues by glucose or galactose.
 Glycation of Hb
 Non-enzymatic addition of a sugar residue to amino groups of protein.

 97% of Hb are HbA (α2β2). Different types of glycation products are formed from the
HbA, depending on the carbohydrate moiety.
 Carbohydrate moieties attached to amino terminal of the Valine in beta chain.
 HbA1C; Glycated by glucose.
 Glycosylation of HbA1C depends on prevailing glucose concentration in blood.
 Once a HB molecule is glycated, it remains in the RBC for the rest of its life span (120
days).
 Useful to check long term glycemic control.
[HbA1C] α Average blood glucose concentration over the previous 3 months.
 Glycosylation of serum albumin
 Useful to check midterm glycemic control

 Generally, not tested. But together with HbA1C it will give a better estimation.
[Fructosamine] α Average blood glucose concentration over the previous 1-2 weeks
Albumin-NH2 + Glucose Glucosamine

Rearrangement
Fructosamine
c) Phosphorylation
 Selected serine side chains of Histone proteins are phosphorylated  DNA packaging is
altered.
Glycogen synthase Glycogen synthase
(Active) (Inactive)

d) γ – carboxylation
 Clotting factors II, VII, IX, X
3) Formation of disulphide bonds between cysteine residues
Eg:
 Insulin – 2 interchain S-S bonds
1 intrachain S-S bonds
 Oxytocin – 1 intrachain S-S bond

 Vasopressin (ADH) – 1 intrachain S-S bond
Post Translational Modifications of Insulin

 N-terminal signal peptide direct preproinsulin into secretory pathway
 Signal peptide cleaved off in the ER, leaving proinsulin.
 Proinsulin falls into specific tertiary structure to form correct disulphide bonds in secretory
granules of β cells.
 Elevated blood glucose trigger insulin secretion.
 Proinsulin converted into active insulin by proteolytic cleavage of the connecting peptide C.
4) Ubiquitination; Addition of ubiquitin to a protein.
This can affect proteins in many ways,

 Signal for degradation via proteasomes
 Alter the cellular location of protein
 Affect their activity and promote or prevent interactions

5) Others
S-Nitrosylation
NO is a chemical messenger. It reacts with free cysteine residues to form
S-nitro thiols (SNOs).
S-Nitrosylation is a critical PTM used by cells to;
 stabilize proteins
 regulate gene expression
 provide NO donors
Methylation – Different methylases modify specific proteins including

Ribosomal proteins.
Acylation – Includes acetylation, formylation, other acyl groups.

Helps to stabilize proteins. (~80% eukaryotic cytosolic proteins are
acetylated at their N-termini.
Lysosomal targeting of enzymes
 Lysosomal enzymes are synthesized in RER and modified in the Golgi apparatus.
 A carbohydrate moiety, mannose-6-phosphate label (man 6-PO4) is tagged to direct these
hydrolytic enzymes to lysosomes.
 Man 6-PO4 is bound by a specific glycosyltransferase or phosphotransferase.
 Man 6-PO4 acts as a Targeting signal that is identified by receptor that target the protein into
lysosomes.

I- cell disease
Defective phosphotransferase in the Golgi → cannot add PO43-to the mannose residue.
Enzymes are not targeted to direct it to lysosome but excreted outside the cell.
Lysosomes cannot function without enzymes.
Partly digested materials (oligosaccharides, lipids, GAGs, etc.) accumulated within lysosomes.
Lysosomes accumulate partly digested materials that manifest as Inclusion bodies.
Causes disease called ‘’I cell disease’’ or ‘’inclusion cells’’.
 Defective lysosomal enzymes are found in high concentrations in the blood and urine.
(lysosomal enzymes are normally found only within lysosomes.)
Signal hypothesis
 This explains how proteins destined for secretion are synthesized.
 Free ribosomes in the cytosol are directed to the ER by the presence of a signal peptide in the
protein being synthesized.
 Signal peptide; ~18-36 AAs near the N-terminal of the chain
Absent in the mature protein
Direct the ribosome to ER
 ER membrane bound ribosomes make 3 classes of proteins;

 Secretary proteins – expel from cells
 Lysosomal proteins
 Proteins spanning the plasma membrane
Protein synthesis in ER
 ER synthesize proteins which are to be exported out of the cell (Eg: Insulin, Collagen)
 Signal hypothesis  Explains how proteins destined for secretion, are synthesized
 Signal sequence,
 Free ribosomes in the cytosol are directed to the ER by the presence of a signal
peptide in the protein being synthesized.
 Absent in the mature protein.

Steps involved in secretory protein synthesis
 mRNA attached to the free ribosome makes the signal peptide.

 Signal Recognition Particle (SRP) in the cytosol recognizes the signal peptide and binds to it.
 The elongation of the peptide is arrested.
 The ribosome diffuses to the ER and the SRP binds to the SRP binding protein (docking
protein).
 The signal peptide opens special channels in the ER (by a complex mechanism).
 When the SRP is released the protein synthesis starts again.
 The signal peptide is cleaved by a signal peptidase in the lumen side of the ER.
Secretory protein synthesis

DNA DAMAGE, MUTATION AND REPAIR
DNA
Exogenous Sources Endogenous cellular processes
DNA Damage
Different types of DNA Damages
Repair mechanisms Damaged DNA that escaped

repair mechanisms
Repaired DNA
DNA replication
Normal DNA DNA mutations
Different types of mutations
DNA damage
 DNA damages can occur due to various reasons, but they can be mainly categorized into,
1) Endogenous damages
2) Exogenous damages
 If these damages occur in germ cells, they are inherited by offspring if not repaired, but
unrepaired damages in somatic cells affects individual only.
1) Endogenous DNA damage
a) Base damage
 Modification of bases
 Deamination - can cause base conversions.

Eg:
1. Cytosine Uracil
 Deaminated C pairs with A
2. Adenine Hypoxanthine
 Deaminated A pairs with C

 Tautomerization - rare condition which can convert bases into their isoforms.
Eg:
1. Guanine
 Keto form Enol form
 Tautomerized G pairs with T
2. Cytosine
 Amino form Imino form
 Tautomerized C pairs with A
 Loss of bases
 Depurination - creates an apurinic site (AP gap) due to breakage of n - glycosidic

bond between the base & the pentose sugar. Spontaneous reaction which can be due
to heat (heat induced). Depurination is more common than depyrimidination.
 Depyrimidination - creates an apyrimidinic site.
 Both apurinic & apyrimidinic sites are known as ‘Abasic sites’, during replication DNA
polymerase will incorporate a random base, opposite (daughter strand) to the abasic
site.
b) Replication errors
 Replication errors are the main source of mutations because DNA polymerase is not
perfect.
 Replication errors can be due to,
 Base pair mismatch - a wrong base can be added by DNA polymerase during replication.
 Insertions or deletions - repeat sequence regions are more prone due to strand slippage
by DNA polymerase
Eg: - Single nucleotide repeat
c) Recombination errors
 Unequal cross overs
d) By products of metabolism
 Oxygen radicals (O2, H2O2, OH*) g

 Guanine convert into ‘8 – hydroxyguanine’ by oxygen free radicals, it can lead to,
G:C to T:A transversion

 because 8 - hydroxyguanine can base pairs with A.
e) Alkylation
 reaction of S- Adenosyl Methionine (SAM) with DNA bases.

2) Exogenous DNA damage (Induced DNA damages)
a) Chemicals (mutagens)
 Natural
 in food - (Aflatoxin)
 Food preservatives
 Nitrites/ Nitrates/ Nitrosamines HNO2(Deaminating agent)

 Causes base conversions,
 Adenine Hypoxanthine
 Guanine Xanthine
 Cytosine Uracil
 CH 3- Cytosine Thymine
 Benzopyrene
 Polycyclic aromatic hydrocarbons, which alters the DNA structure, from coal, cigars & etc.
Causes mutations that Forms DNA adducts Conversion of G to T

inactivate p53 gene (Transversion)
Error prone repair pathways
Bulky lesions
Substitutions/ Deletions/ Chromosomal rearrangements
 Intercalating agents
 Planar/ aromatic molecules which are inserted between base pairs

 Causes stretching of the DNA duplex
 Leads to insertion of an extra base during replication
 Alkylating agents
 largest group of mutagens

Eg: -  Methyl bromide
 Ethylene oxide
 Nitrogen mustard (Nerve gas)
 Dimethyl sulphate
Guanine Methyl-Guanine (base pairs with T)

b) Radiation
Radiation
Depending on source Depending on type of particle

1. Natural 1. UV radiation
2. Artificial 2. Ionizing radiation
 UV radiation
 cannot penetrate beyond the outer layer of the skin, so it mainly leads to
formation of pyrimidine (Thymine - Thymine) dimers.
 Ionizing radiation
 penetrate the whole body, so they can cause both somatic & germ line mutations.
Eg: -
 α, β, γ particles
 X rays
There are 2 types of damages caused by ionizing radiation,

1) Direct damage
 Cleavage of one or both DNA (can leads to rearrangements, deletions & chromosomal loss)
 Damage or loss of bases
 Cross linking of DNA to itself or proteins
2) Indirect damage
 water dissociates to H* & OH* (radiolysis of water) under α radiation
 free radicals cause DNA / RNA damage
DNA damage response
Process which enables the link between DNA damages & the relevant Damage repair mechanisms.
 Activation of a cell cycle checkpoint
 Carrying out DNA repair mechanisms
 Initiation of cell apoptosis when the damage is severe
DNA damage repair

 Reduce potential mutations for acceptable levels
 Several systems
 Specific for different types

Damage Repair Mechanisms
Damage Reversal Damage Removal Damage Tolerance
Damage Reversal
Ligation of single stranded breaks Photo-reactivation

 Simple breaks rapidly repaired by ligase  By Photolyase enzyme
 Damages caused by X-rays & peroxidases  Not found in humans
 Breaks covalent bond in the presence
 Bloom syndrome when DNA ligase is
of light
deficient
Damage Removal
1. Base excision repair 2. Nucleotide excision 3. Mismatch repair

 Recognize damage repair  Recognizes which base to
 Base removed by N- excise
 Carried by multi-
glycosylases  Follows replication fork
protein complex
 Excise the part of  Repairs mismatched
 Damaged DNA
strand (backbone) by bases
recognition
endonucleases  Incision followed by  Final spellcheck
 DNA polymerase I fills excision (removes  Conserved through
the gap using oligonucleotides) evolution
complementary strand  DNA pol makes new
 Ligase seals nick  Mut proteins identify &
DNA bind mismatched
Uracil N-glycosylase  DNA ligase seals methylated parental
Cytosine Uracil+ NH3 nick
strand on GATC
E.g. TT dimers
sequence
Uracil removed by above Adducts
enzyme, leaving an apurinic  Exonuclease cleaves
Aflatoxins daughter strand in
site.
E.g. Methylated bases Cisplatin region of mismatch
Deaminated bases  DNA pol fills the gap
 Ligase seals the nick
Abasic sites
 Multiprotein complexes
Oxidized bases
99.9% efficiency

Nucleotide excision repair

Mismatch repair Base excision repair

Damage tolerance
 Repair double strand breaks caused by high energy radiation and oxygen free radicals
End-joining repair (mutagenic) Recombination repair
repair proteins bind to ends of the double  Damage not repaired

stranded break  DNA polymerase uses DNA sequence in
other strands to complete replication
nucleases remove few bases from the ends
ends joined by ligase Two daughter molecules, one complete,

other with a gap
 Few bases lost, if wrong ends are joined, Crossing over/strand exchange
mutations can happen
Resulting gap in sister chromatid filled by
polymerase
Diseases due to defects in DNA repair pathways
 Mismatch repair defects

 caused by loss of function mutations in genes
 E.g. HNPCC (hereditary non-polyposis colorectal cancer)
Autosomal dominant, multi-genic
 Nucleotide excision repair pathway defects

 Xeroderma pigmentosum
 ↑ Skin cancers
 Recombination repair defects

 defects in homologous recombination
 E.g.: Defects in BRCA1, BRCA2 which are tumor suppressor genes, Predisposed
to breast and ovarian cancers
 End joining repair defects

 predisposition to cancers and immuno-deficiency syndrome

Mutations
Stable & heritable changes in nucleotide sequence
Gross mutations Fine scale mutations

 Observed cytogenetically  Involve less than 100 base pairs
 Include deletions,  Often point mutations
duplications, inversions, and
translocations
Substitutions Deletions Insertions

1. Transversion
Purine Pyrimidine
Silent Frame shift mutations
 Nucleotide change 2. Transitions
 But no phenotypic change Purine Purine  Change in the reading frame
 Mostly occur in wobble Pyrimidine Pyrimidine  Out of frame translocation of
base all downstream codons
 Causing different AA sequences
Eg:
Reading through  α thalassemia
 Stop Read  β thalassemia
Triplet expansion
Missense Nonsense
 Base pair substitutions  Net change result in stop codon  Increasing the number of
Eg: β globin gene –  Forms truncated proteins triplets in sequence
substitution of  Premature termination Eg:
Valine in 6th place of translocation of  Huntingdon’s disease
instead of Glutamate proteins  accumulation of protein
 Causing change of cell Eg: aggregates
shape  Cystic fibrosis  neuro-degenerative disease
 Leads to sickle cell  Duchene muscular dystrophy  Fragile X syndrome
anaemia  β thalassemia

REGULATION OF GENE EXPRESSION
 Every cell in an organism contains thousands of genes (same Genome) which code for proteins
 But every gene is not actively producing proteins always in the cells, because of the regulation
of gene expression.
Importance of regulation of gene expression
Prokaryotes
 are unicellular or colonial
 evolved to quickly exploit transient resources
 gene regulation is to allow cells to adjust to changing conditions
 different genes are active in the same cell at different times
Eukaryotes
 are multicellular organisms
 evolved the ability to maintain a stable internal environment -Homeostasis
 gene regulation is to allow specialization / differentiation & division of labor among the cells
 different genes are active in different cells at the same time
Types of Genes depending on the expression rate
a) Constitutive genes / House Keeping genes - non-methylated, found in euchromatic regions

 genes that are actively transcribed & translated at essentially all development stages in
virtually all cells because their protein products are required for basic cellular functions
 normally these types of genes are not regulated & expressed all the time at a low level

b) Facultative genes - methylated
 genes that are expressed only when needed compared to constitutive genes
c) Inducible genes
 genes that are transcribed & translated at higher levels in response to an inducible factor
d) Repressible genes
 genes whose transcription & translation decreases in response to a repressing signal
 Induction or repression can be due to,
1. environmental change
2. position of the cell cycle
Levels of Regulation of Gene Expression in Eukaryotes

Regulation at Epigenetics level (Chromatin Modifications)
Chromatin Structure
 Two forms of Chromatin

1) Euchromatin
 lesser coiled regions which contain the transcriptionally active genes
 easily accessed by RNA Polymerase
2) Heterochromatin
 highly condensed regions which contain the transcriptionally inactive genes
 difficult to access by RNA Polymerase
 two forms of Heterochromatin,
1. Constitutive Heterochromatin
 permanent organization
 contain no genes
Eg: Centromeric & Telomeric regions of human Y chromosome
2. Facultative Heterochromatin
 not permanent
 contain genes that are inactive in some cells or at some periods of the cell cycle
Eg: Barr body formation in females (X inactivation)
Chromatin Modifications
 These can affect the genes in 2 ways,

1) Activating the gene
 Histone modifications
 Histone acetylation
 Nucleosome remodeling
 modification or repositioning of nucleosomes within a short region of the genome, so that
DNA binding proteins can gain access to their attachment sites.
2) Silencing the gene

 histone deacetylation
 DNA methylation
 Histone proteins in a nucleosome should move (rearrange) to express or depress a gene, but
this movement is dependent on signals found on both the histone proteins & on the DNA.

 These signals are tags added to histone proteins & DNA, that tell the histones, if a
chromosomal region should be condensed or loosened.
 Condensed chromatin structures are transcriptionally inactive & loosened
 chromatin structures are transcriptionally active, because RNA polymerases cannot gain
access to bind with DNA, if DNA is condensed.
 Condensed chromatin can be loosened (remodeled) by adding of acetyl groups to the lysine
amino acid residues on histone tails of nucleosomes by Histone
 Acetyl Transferase (HAT) enzyme – Histone Acetylation. This reduces the positive charge of
histones so that negatively charged DNA can be loosened
 Also loosened chromatin can decondensed by removing the acetyl groups from lysine
residues by Histone Deacetylase (HDAC) – Histone Deacetylation. It restores the positive
charge of histone proteins.
 Other than the Acetylation, histones can be modified by

a. Methylation - Condensation
b. Phosphorylation - Loosen
(Histones also have attachment sites for Ubiquitin)
 These tags do not alter the DNA base sequence, but they alter the gene expression by changing
the arrangement of histone proteins
 DNA Methylation
 Methylation occurs within very specific regions called CpG islands. These are stretches with
a high frequency of Cytosine (C) & Guanine (G) dinucleotide DNA pairs found in the
Promoter regions of genes (~ 56 % of human genes).

 Methylation of Cytosine in CpG islands results in Transcriptional inactivation of the genes
(Gene silenced). So active genes are located in the unmethylated regions.
 The amount of methylation affects the level of gene transcription.
1) Hyper methylation
Eg: Barr body formation in females (X inactivation)
Fragile X Syndrome
Tumor suppressor genes leads to cancer
2) Hypo methylation
Eg: Proto oncogenes leads to cancer
Diseases related with modifications in Epigenetic level
Non-communicable diseases
 epigenetic modifications occur in response to cellular environment, such modifications
occurring at key stages in fetal development are now thought to play a role in subsequent
development of Obesity, Diabetes & etc. later in life.
Eg: Exposure of fetus to high glucose environment in mother with Gestational Diabetes
Mellitus (GDM).
Genomic imprinting
 epigenetic mechanism, where one allele of a gene is silenced by methylation, in a parent of
origin specific manner.
 Mutations to unimprinted (expressed) allele, may lead to diseases.
Eg: Prader-Willi Syndrome
Angelman Syndrome
Regulation at transcriptional level
Enhancers/silencers
Cis acting sequences
 Distal control element act on more than one
promotor
 Regulatory DNA sequences that
increase/decrease transcription of genes in
vicinity
 15-25 bp
promoters  Upstream/downstream or within the gene
 Bind with transcription factors
 Found upstream
 Enhancers/silencers for regulatory proteins or
 Proximal control element
specific transcription factor s are called as
 Determines the strength of the promoter
response elements

Transcription factors/DNA binding proteins
Trans acting proteins a) Basal TFs

 for all genes
b) Specific TFs
 For high level of transcription of specific genes
 Contribute to
 tissue specific gene expression
 Embryogenesis
 Cell growth & differentiation
Activators Co-activators
 Bind to enhancers & stimulate transcription  Proteins, which serve as a physical bridge
 2 domains between the activator & the RNA
 DNA binding domain polymerase.
Eg: Zn finger motif  They consist of 2 types of binding sites
leucine zipper 1) polymerase binding sites
homeodomain, 2) Activator binding sites
basic helix-turn-helix Eg: Histone Acetyl Transferases(HATs)
 Transcription factor binding domain
 Binding sites for Coactivators
 Variable
 Increase transcription by 100-fold

Hormone Response Elements (HREs)
 HRE is a common cis acting regulatory element present in genes, which need to coordinate their
expression, to affect a particular response.
 HREs bound by particular trans-acting factors under particular conditions to effect gene
expression.
Eg: lipid soluble hormones bind to specific soluble intracellular receptors, which functions as
trans-acting factors to a particular HRE.
 Steroid hormones, thyroid hormones, retinoic acid, calcitriol
Thyroid & steroid hormones Peptide hormones/Catecholamines

 Hormone bind to intracellular/nuclear  Hormones bind to cell surface
receptor receptors
 Conformational change in the  Activation of adenylyl cyclase
receptor  Formation of cAMP
 Dimerization  Activation of PK-A
 Bind via a Zn finger motif to DNA (with  cAMP response element binding
association of co-activators) at a HRE protein gets phosphorylated(CREBP)
 active CREBP bind via a leucine zipper
to cAMP response element(CRE)
Eg. PEP-CK, G6Pase

Regulation at Post-Transcriptional level
 Post transcriptional regulation, allow a cell to fine-tune gene expression. There are various
regulatory mechanisms of gene expression at this level.
 Alternative splicing of RNA

 different mRNA molecules are produced from the same primary transcript & these different
spliced products often expressed in a tissue specific manner (~60% of genes are alternatively
spliced).
Eg: α - Tropomyosin gene
 RNA editing
 modification of nucleotide sequence after transcription.
Eg:
 mRNA stability
 length of time an mRNA remains in the cytosol before it is degraded, influences how much
proteins are produced from that mRNA.
 binding of proteins called RNA binding proteins (RBPs) to the regions of the RNA just
upstream or downstream of the protein coding region, can influence its’ stability.
 These regions in the RNA that are not translated into proteins, are called the Untranslated
regions (UTRs).
 They are not introns, but these are the regions that regulate,
 mRNA localization
 stability
 protein translation
Eg: Regulation of cellular Iron status

Gene silencing by RNA interference

Regulation of cellular Iron status
 Excess free Iron (Fe) in cell causes cell damage, so cellular iron uptake & storage must be
tightly regulated, because there is no proper excretory method of Iron, in humans.
 Transferrin - plasma protein that transports Iron

 Transferrin Receptor (TfR) - receptor for Transferrin
 Apoferritin - cellular Iron storage protein
 IRE (Iron Response Elements) - present on,
 3’ UTR of Transferrin Receptor
 mRNA 5’ UTR of Apoferritin mRNA
 IRP (Iron Response Protein) - binds with Iron & Iron Response Elements
 Gene silencing by RNA interference
 Mechanism of gene silencing mediated by short non-coding micro RNAs. They decrease
expression of mRNA by,
 Repression of translation
 Increased degradation
 Micro RNAs (miRNA)
 Micro RNAs are derived from longer dsRNAs, which are cleaved by an endonuclease (Dicer) &
associate with cytosolic protein complex (RISC).
 They bind to complementary sequences in target mRNAs to exert their silencing effect.
 The use of short regulatory RNAs to block the translation appears to be important for
developmental regulation.
 Increase or decrease in miRNAs play a role in diseases by altering gene expression.

Regulation at Translation & Post Translational level
 Regulation of initiation of Translation

 Phosphorylation of eukaryotic translation initiation factor (eIF2), inhibits its’ function.
 Post Translational Modifications (PTMs)
Regulation at Protein level
 Protein degradation control

 Ubiquitin Proteasomal pathway
Prokaryotic regulation of gene expression
 In prokaryotes, regulation of gene expression mainly done via operons, but eukaryotes lack
operons.
 Operon is a functioning unit of DNA containing a cluster of genes which are acting together &
expressed under the control of a single promoter.
Eg: Lac Operon - contains 3 genes
Try Operon - contains 5 genes

DNA BASED TECHNOLOGY
(BASIC DNA-BASED TECHNIQUES IN MOLECULAR MEDICINE)
Some basic concepts: These concepts are used for:

 Recombinant DNA  DNA Cloning
 Restriction Enzymes  DNA Libraries
 DNA Ligation  DNA Fingerprinting
 Hybridization (DNA Typing/DNA Profiling)
 Agarose Gel Electrophoresis
 Southern Blotting
 DNA Sequencing
 Polymerase Chain Reaction (PCR)
Definitions:
 Recombinant DNA – Creation of a new combination of DNA not found naturally
 DNA Cloning – making genetically identical copies of DNA/genes using a cellular process
 Amplification – making lots of copies of a selected fragment of a genome using either DNA
cloning or PCR
Restriction Enzymes
 Isolated from bacteria (bacteria uses to kill viruses)
 Not affect to bacterial DNA, their DNA has methylated sequences
 Recognize specific DNA sequences (palindromes)
 Does not cleave RNA, only dsDNA
 Cleave at specific sites, within/close to recognition sequence.
 Cleave both strands at a specific site – Endonuclease activity
 produce Blunt Ends (Hae III) or Sticky Ends (Eco RI/TAQI)
Blunt ends/ Flush ends Sticky ends/ Cohesive ends
5’
5’
CCGG3’ 5’
CC3’ 5’
GG3’ 5’
GAATTC3’ 5’
G3’ AATTC3’
3’GGCC5’ 3’GG5’ 3’CC5’ 3’CTTAAG5’ 3’CTTAA5’ 3’G5’
Do not easily form H bonds Easily form H bonds

Can be ligated easily
DNA Ligation
 Joins DNA fragments of compatible termini via phosphodiester bonds (ATP needed)
 Enzyme – DNA Ligase

DNA Cloning (Biological cloning)
 Same restriction enzyme is used
Above techniques are used in DNA Cloning. to cleave both DNA fragment and
1. Obtain DNA fragments vector
 Cleave DNA (Restriction Enzyme digestion)
 Reverse transcribe mRNA (by Reverse Transcriptase)
2. Insert into Cloning Vector - Plasmid/ Bacteriophages (see below)
 By DNA Ligase Recombinant plasmid
3. Introduce into host cell - Transformation/Transfection
 Transformation: into Bacteria or Yeast cells
 Transfection: into higher eukaryotic cells in culture
4. Screen for Transforments/Recombinants
 Transformant - Host cells which have taken up plasmid vector
 Recombinant - Hybrid plasmid
5. Choose cells which are resistance to antibiotics
6. Amplification of DNA of interest as the host cell multiplies
Cloning Vector
 Transports foreign DNA into host cells

 Used to amplify a DNA fragments
→ Plasmids
→ Bacteriophages (virus)

Properties of a Cloning Vector;
 Self-replicating - contain an origin of replication

 Small - can incorporate large portions of foreign DNA
 High copy number - exist in large numbers within the cell
 Multiple cloning site - Polylinker
→ Restriction enzyme cleavage sites
→ Polylinker is a DNA fragment with many such sites (many palindromes)
 Selection markers - Antibiotic resistance genes
→ Enables the identification of transformed bacteria
 Contain universal primer binding sites and strong/inducible promoters
 Exo-chromosomal
 Circular
Applications of DNA Cloning
 Production of recombinant proteins

→ human insulin (see below) → human growth hormone
→ tissue plasminogen activator → clotting factor VIII
→ interferons
 Production of recombinant Vaccines (e.g. Hepatitis B- Hep B surface antigen produced in
yeast)
 Gene therapy (SCID – Severe Combined Immunodeficiency Disease)
 Diagnostics – species specific DNA probe based diagnosis of disease (e.g. Dengue,
Tuberculosis, Filariasis)
 Enhanced nutrition – e.g. Golden rice (increased Vit. A content by incorporating β-
carotene gene)
 Edible vaccines (e.g. Hepatitis B, Diarrhoea, Measles), Plant based oral vaccines (tomato,
potato, banana)
 Medical research (Transgenic mice)
Production of recombinant human insulin:
Reverse Cloning Transformation

Insertion
Isolate Transcriptase cDNA Bacteria/
Vector Culture
mRNA (Plasmid) Yeast
Extraction and
Purification of Insulin protein

DNA Libraries
 DNA Library / Genomic Library
 Collection of DNA Clones (transformed bacteria) that together represents the entire genome
of an organism
Genomic Restriction DNA Insertion Cloning Transformation Bacterial

DNA Endonuclease Fragments Vector Host
 cDNA Library
 Collection of DNA clones (transformed bacteria) that represents the expressed genes in an
organism
Reverse cDNA Insertion Cloning Transformation Bacterial

mRNA
Transcriptase fragments Vector Host
cDNA libraries,
 Are smaller than a genomic library
 May vary according to
 Particular tissue
 Particular developmental stage
 Particular conditions (e.g. disease states)
 Can be used to synthesize eukaryotic proteins as cDNA has no intervening sequences (i.e.
no introns, only the expressed exons)
Library Screening – Finding the gene of interest in a DNA Library. Can use the following
techniques:
 Extraction of plasmid DNA
 Restriction enzyme digestion
 Agarose gel electrophoresis
 Southern blotting
 Hybridization
 DNA sequencing
Denaturation
Separating DNA in to single strands by heat and alkali. (dsDNA ssDNA)

Annealing
Forming double stranded DNA using single strands.

Renaturation
Annealing
Hybridization
Renaturation
Annealing of DNA of same origin
Hybridization (Nitrocellulose membrane)
 Hybridization is the annealing of DNA (nucleic acids) from different origins.

 The sequences of the strands do not need to be 100% complementary (as long as they are
similar enough, hybridization can occur).
 Used for identification of complementary or homologous molecules
 Types – DNA to DNA, DNA to RNA, RNA to RNA
1. Using a hybridization probe - a radio-labelled nucleic acid fragment

2. Forms a base paired stable hybrid (Probe is hybridized to immobilized DNA forming a
double stranded DNA)
3. Wash-out ssDNAs
4. Autoradiography - radiation from the radio-labelled probe is detected using an X-ray film
5. Black marks - positive hybridization
 Probe: A short piece of ssDNA or RNA labeled with radio isotope (eg: - 32 P) or a non-
radioactive molecule (eg: - Biotin, Fluorescent dye)
Factors affecting hybridization
 Temperature
 Salt concentration
 Denaturing agents (urea, formamide)
 High molecular weight polymers (dextran sulphate)
 Shear forces

Gel Electrophoresis
 Electrophoresis in polyacrylamide or agarose gel

 Separation according to size of fragment
 DNA negatively charged – moves to positive electrode
 Smaller fragments – higher mobility
 Results can be visualized by ethidium bromide stain
 Fluoresces pink under UV light when bound to DNA
 Only used if a small number of fragments present
Southern Blotting
 The transfer of DNA from agarose gel to a nitrocellulose or nylon membrane

 Used to locate and identify genes on DNA fragments
 Can be used with large number of fragments because only specific fragments are
visualized
1. After gel electrophoresis DNA fragments are denatured to give ssDNA

(Gel soak I- HCl, Gel soak II- Alkaline medium, Gel soak III- neutral medium)
2. ssDNA fragments are blotted to nitrocellulose paper
 DNA binds permanently to the membrane (DNA fragments are immobilized on the
membrane) An exact copy of the pattern on the gel is obtained (Replica)
3. Target fragments are visualized by hybridization with radio-labelled probes
4. Excess probes are washed out and obtain an auto-radiograph
Northern Blotting - For RNA
DNA Sequencing
 Sanger’s method – use dideoxynucleotides
 Used to identify the nucleotide sequence in a DNA fragment
Steps involved
1. Denaturation of dsDNA
2. Annealing ssDNA with a primer
3. Extension by a DNA polymerase and 4 types of deoxynucleotides
4. Termination due to ddNTP
 ddNTP lacks a 3’-OH, therefore chain elongation stops
 4 different types of dideoxynucleotides are added to 4 different samples
5. So bands with same terminal nucleotide can be separated and the sequence can be read by
 Agarose gel electrophoresis
 Autoradiography
(Refer page 487, Lippincott)
PCR - Polymerase Chain Reaction
Amplification of specific DNA fragments in vitro (i.e. a cell-free DNA amplification system)
Requirements:
 Template DNA
 DNA primers (×2) – specify target DNA fragment (3’OH end should be pointed towards
target sequence)
 DNA polymerase – Thermostable DNA polymerase (e.g. Taq polymerase)
 Deoxynucleotide triphosphates (dATP, dGTP, dCTP, dTTP)
 Buffer

The reaction takes place in three repetitive steps that are automated
Step 1: Denaturation at 94°C (1 min)
Step 2: Annealing at 54°C (45 sec)
The forward and reverse primers anneal to the specific DNA sequence
Step 3: Extension at 72°C (2 min)
The Taq polymerase synthesizes the DNA fragments.
Important features of PCR:

 Highly sensitive and very fast, while being technically easy to operate
 Just 30 cycles of the 3 steps can amplify the selected target DNA fragment 10 9 times! (x2
per each cycle)
 The polymerase used must be able to stand repetitive heating and cooling cycles → Hence
the need for thermostable DNA polymerases such as Taq polymerase
 For PCR, it is not necessary to know the target DNA sequence (the sequence which will be
amplified), BUT it is required to know the base sequence of the flanking sequences (the
sequences on either side of the target sequence to which the primers bind) – since proper
primers must be chosen
 Only small fragments are amplified
 Taq Polymerase lacks proofreading action
Applications of PCR:
1. Genetic disease diagnosis
2. Detection of infectious diseases – Dengue, Malaria, Tuberculosis
(Using primers specific to pathogen’s DNA)
3. DNA fingerprinting (DNA typing/ DNA profiling)
DNA Fingerprinting
Determination of an individual’s unique collection of DNA fragments (restriction fragments)

 No two people, except identical twins, have the exact same DNA sequence
 Most of the human genome (≈99.9%) is similar from one person to the next
 BUT, there are small regions (≈0.1%) which are highly variable – “Polymorphic Regions”
 If we focus on such regions, although only a limited portion of DNA of a person is analyzed
in this procedure, those segments are proven to be statistically unique to identify that
person
 Has applications in:
→ Forensics (criminal investigations)
→ Paternity testing
→ Diagnosis of presence/carriers of genetic diseases (Sickle cell anaemia, DMD, cancers)

REMINDER: Two main types of variations: -
1. Variation in single nucleotide bases scattered along the chromosomes → Single
Nucleotide Polymorphisms (SNPs)
2. Variations in copy number of tandem repeats → Variable Number of Tandem Repeats
(VNTRs) & Simple Sequence Repeats/Simple Tandem Repeats (SSRs/STRs)
Minisatellites Microsatellites
DNA fingerprinting is based on three main methods:
1. RFLP (Restriction Fragment Length Polymorphism) → based on either SNPs or VNTRs

2. RAPD (Random Amplified Polymorphic DNA)
3. AFLP (Amplified Fragment Length Polymorphism)
RFLP (Restriction Fragment Length Polymorphism)
 The variability of the size of fragments obtained from the same restriction
enzyme digestion
Digest DNA with restriction enzymes
↓
Gel electrophoresis
(Separate DNA fragments by size)
↓
Southern blotting
(Obtain ssDNA copy in nitrocellulose)
↓
Hybridize with a radio-labelled probe & Wash the blot to remove excess probes
↓
Autoradiography (Expose to X-ray film and develop)
Specific examples are given later on in this note (see below).
RAPD (Random Amplified Polymorphic DNA)
 The variability of the size of the PCR products obtained with the same random primers
(Use of PCR on the genomic DNA with an arbitrary oligonucleotide primer results in
amplification of several discreet DNA products)
 RAPD technique is not used that much. Instead, we use the AFLP technique given below.
AFLP (Amplified Fragment Length Polymorphism)
 AFLP uses a combination of features of RFLP and RAPD for the amplification of a set of
fragments using selective primers.
 Since PCR is efficient at amplifying only small fragments,

 AFLP is usually used for analyzing SSRs/STRs. AFLP is not used for analyzing VNTRs.
Example for use of AFLP for analyzing SSRs/STRs to identify two people:
A B
Rohini
CACACACACA
A B
Rohan
CACACACACACACACACACAC
 A and B are the primers for PCR – by using 2 primers the selected region can be
specifically amplified (microsatellite marker – PCR primers designed from unique
flanking DNA)
 PCR products differ in length, depending on the number of repeat units (copy number)
 Since the PCR product is a single amplified segment, the use of Southern blotting and
hybridization is not needed
Rohini (-) (+)
Rohan
Examples for use of RFLP technique: (No PCR is needed)
1) In analysis of SNPs
Features of SNPs:
 A single base pair is changed
 Leads to creation or removal of a restriction endonuclease site
Examples:
 In sickle cell anaemia → single base pair subs tu ons in β-globin gene removes an
existing site
 DMD (deletions in dystrophin gene)
 Cancers (various mutations)

Consider the restriction fragments:
Using a radio-labelled probe that binds to sequence in the larger fragment in a normal person, after
gel electrophoresis:
1 2 3
2) In analysis of VNTRs
 Select restriction sites on either side of VNTR sequences

 As the repeat number changes, the size of the restriction fragment change
 Probes can be homologous with repeat unit, or with the unique sequence adjacent to the
repeat units
3) In Paternity Testing
 Paternity testing using RFLP uses analysis of VNTRs of the child, mother and the suspected
fathers
 The corresponding alleles of a child come from the father and the mother

 When comparing the patterns of RFLP, each line in the child’s analysis should correspond
to a line of the father or to a line of the mother
A couple complained to the police that their male infant war lost from the maternity ward. The
police investigations detected a suspected woman with a male infant. Outline a DNA typing
method to prove beyond a reasonable doubt that the complainant couple is the true parents of
the infant. (50)
 Method used here is (VNTR analysis) using RFLP
 DNA is extracted from infant, couple and suspected woman
 All four DNA samples are cleaved using same restriction endonuclease enzyme
 Restriction fragments are subjected to gel electrophoresis on an agarose gel/
polyacrylamide gel
 Restriction fragment pattern is transferred from gel into a nitro cellulose paper by southern
blotting
 In that procedure dsDNA is made single strand DNA and immobilized
 A suitable radiolabeled probe is added to the filter paper and hybridization is allowed
 Excess probes are washed out
 Autoradiography is performed using X-ray film
 X-ray film is developed
 Each DNA band of the infant must correspond to either the mother’s or father’s DNA bands.
 If such correspondence is found when comparing the infant’s DNA band pattern and if such
correspondence is not found with the suspect woman, the couple’s DNA band pattern then
the complainant couple are the true parents of the infant
CELL CYCLE
Features,
 Composed of orderly sequence of biochemical events.
 Directional
 Leads to the production of two daughter cells containing chromosomes that identical to
parental cells.
Eukaryotic cell cycle take place in a highly coordinated fashion. It consists of several phases &
gaps.
 S phase - DNA synthesis

 M phase - Mitosis
 Two gaps (G1 & G2) separate the two processes.
 G0 (gap 0) - The cells that are not subjected to cell division after maturity, reside in this
resting state.
 Frequency of cell division varies depending on the cell type.

 Embryo < 20 minutes
 Skin cells - divide frequently throughout the life. (12-24 cycle)
 Liver cells - retain ability to divide, but keep it in reserve. Divide once every year or two.
 Mature nerve cells & muscle cells - do not divide at all after maturity. Permanently in G 0

Initiation of cell cycle
 Should receive positive signals.
 Molecular signals present on cytoplasm;
 Polypeptide hormones
 Growth factors (e.g. PDGFs)
 Cytokines - interleukins
Cell cycle control proteins

 Cyclin dependent kinases (CDKs)
 Cyclins
 Cyclin-dependent kinase inhibitors (CKIs) – (inhibit CDK activity)
 Ubiquitin ligases
The cell-cycle control system is based on 2 key families of protein
Cyclin-dependent Cyclins;
Protein kinases (CDK) - the regulatory subunits
- catalytic subunits of CDK
Association of these 2 subunits is

necessary for the phosphorylation of proteins
to regulate cell cycle
Cyclin dependent kinases (CDKs)
 Serine /Threonine kinases.

 Activation /inhibition of these kinases regulate the progression of the cell cycle
 CDK modulate the metabolic activities of the cell at precisely timed intervals to produce
orderly cell division
Cyclins
 Serves as regulatory subunits of CDKs. It binds and activates its specific CDK.
 Important in cell cycle control & that depends on their concentration. Concentrations
fluctuate with the phases of the cycle, due to changes in synthesis & degradation.
 Cyclin-CDK complex phosphorylates other proteins to control cell activities.

 Activity of a cyclin-CDK complex is changed during cell cycle by
Differential synthesis of CDKs & cyclins → The levels of kinases present are constant. Levels of
cyclin proteins fluctuate cyclically. So activity of one
cyclin-CDK complex is proportional to corresponding
cyclin concentration.
Specific degradation of cyclin by ubiquitination.

Growth factor signals - regulate cycle
Check points (cell cycle control systems)
 Sense problems that may occur during DNA synthesis & chromosomal segregation.
 Minimize the occurrence of mistakes in cell cycle events.
 Ensures that;
 chromosomes are intact
 each stages of the cell cycle are completed before the following stage is initiated.
 If conditions fail, cell cannot move onto next phase.

Eg: G1 checkpoint - external factors
G2 checkpoint - chromosomes have replicated, DNA damage
M checkpoint - chromatids attached to spindle

Cell cycle regulation by p53 proteins
DNA damage/cell cycle abnormalities/hypoxia
Mdm2-p53 p53
Cell cycle arrest Apoptosis (cell death)

↓
DNA repair
↓
Cell cycle events

CANCER
 Cancer usually arises from the mutation of a normal gene.
 Mutated genes that cause cancer → Oncogenes
Causes of cancer
Exogenous carcinogens Endogenous carcinogens
 Chemicals – Nickel, Nitrosamines  Chronic inflammation

(smoked & pickled foods) Metabolic intermediates (free
 Physical – UV, X rays & etc. radicals)
 Biological – Viruses (DNA & retro Alternations of DNA replication &
viruses, HPV, Hepatitis B) repair
Molecular basis of cancer
 Cells become cancerous after several mutations are accumulated.

 Cancer involves uncontrolled cell division.
 Growth regulation is lost.
 Caused by;
 Mutations in genes during cell division
 External agents
 Random events resulting in altered proteins
Some traits of Cancer cells
1) Independent of GROW signals from other cells

Eg: RAS gene Upregulation of growth factors &
insensitivity to antigrowth signals
2) Ignores STOP signal
 defective damage control, so problems are not corrected.
3) No cell suicide (apoptosis)

 self-generation of factors that promote growth
4) No limit to cell divisions

 cancer cells express telomeres to prevent shortening of chromosomes, which
lead to limitless replicative potential.
5) Angiogenesis
 Formation of new blood vessels

Steps in angiogenesis;
 Cancer cells secrete angiogenic factors - VEGF (Vascular Endothelial Growth Factor)
 VEGF stimulate endothelial cells to grow, divide, proliferate & survival
 Bind to receptors on endothelial tissue
 Endothelial cells become activated
 Release enzymes for proteolytic degradation (Metalloproteinases & Plasminogen
activators)
 Metalloproteinases digest the ECM
 Plasminogen system is activated &
 Break down basal lamina
 Cells migrate through basal lamina into surrounding tissue
 Express integrins to attach to new locations
 Divide and develop into a mature blood vessel network
6) Metastasis & tissue invasion

 Ability to move to other tissues.
 Benign tumors - do not move from tumor site.
 Malignant tumors - invasive cells, can travel in blood & lymph system.
Steps in metastasis,
 tumor cell secretes plasminogen activator (a serine protease - urokinase type)

 convert serum plasminogen to active protease plasmin
 plasmin digests basal lamina & release from contacts
 allows cells to migrate through basal lamina
 invade surrounding host tissue
 penetrate lymphatic or blood capillaries - intravasation
 release cells or clumps of cells into circulation
 arrest in capillary beds in distant tissue
 penetrate the vessel wall and enter tissue - extravasation
 colonization
 Normal cells obey the following,
 Dependence on growth factors.

 Cell and tissue specific signals.
 Loss of these signals leads to apoptosis
 Anchorage dependent proliferation.

 Requires interaction of trans-membrane proteins (integrins) with components of the ECM
 Contact inhibition
 Contact with the cells inhibits cell proliferation and movement.
 Limited proliferation capacity
 Normal somatic cells have a limited number of divisions they can do. (telomeres wear out)
 Loss of telomeres which occurs normally during DNA replication limits the number of cell
divisions.

 Telomerase is abundant in stem and germ line cells but not in somatic cells. The length of
the telomere is a measure of replicative capacity.
Normal tissues
Rate of new cell growth = Old cell death rate
 The balance between cell apoptosis & survival signals, allow the controlled homeostasis of
the tissue
 But in cancer cells survival signals triggered by oncogenic transformation favors
uncontrolled growth
Modifications leading to cancer
Genomic Non genomic
Epigenetic Genetic
Occurs outside the coding sequence Occurs inside the coding sequence
Eg: Promoter/enhancer silencing
Mutations of DNA
Viral infection Chromosomal Gene amplification Point mutation

translocation

Proteins that lead to cancer when mutated
1. Growth factors and other signaling molecules
2. Receptors for growth factors or other signaling molecules.
3. Signal transduction proteins
4. Transcription factors
5. Pro - or anti - apoptotic proteins
6. Cell - cycle control proteins
7. DNA repair proteins
8. Cell adhesion molecules
 Certain viral proteins can activate signal receptors.
 Alterations that lead to the unregulated cell growth

1) Gaining an unlimited proliferation capacity
2) Loss of contact inhibition.
3) Loss of anchorage dependent growth.
4) Failure to respond to substances that signal to stop proliferation.
5) Self-generation of factors that promote growth.
6) Evasion of apoptosis.
7) Motility and invasiveness.
8) Facilitated angiogenesis.

 These mutations lead to production of abnormal proteins, which lead to uncontrolled and
random cell growth and division, which lead to tumor growth or cancer.
Genes that could mutate to cause cancer

 are divided into 2 groups,
1) Proto-oncogene (Normal genes contributing to cell proliferation & survival)
Proto-oncogene oncogene (genetically dominant)
 Proto oncogene become oncogene by a gain of function mutation.

 Results in increased action of the gene.
 Oncogenes act dominantly, so even if only one gene of the pair is mutated, it can
cause cancer.
Eg: RAS gene.
 An Intracellular signal transduction protein
 Normally remain bound to GDP - off state
 Activated by growth factors to bind to GTP - on state
 Once protein is mutated, it remains bound to GTP and stimulate cell
division without the ligand binding to the receptor.
 RAS activated by gene amplification

point mutation
chromosomal translocation
 Proto-oncogene converted to oncogene by;

1) Point mutation making an overactive protein
Eg: Proto-oncogene receptor proteins
2) Amplification
 resulting in many copies of same gene in the genome which lead to
overproduction of the same normal protein.
3) Chromosomal translocation where gene comes under a stronger promoter/ enhancer

 leading to excess production of normal protein
 Lead to production of abnormal proteins
4) Chromosomal translocation where 2 genes fuse to make a hyperactive protein
5) Recombination of a retroviral and host gene

Eg: Effects of a Retrovirus - (c-myc gene)
 Insertion of viral DNA changes host DNA to make oncogenes by promoter or
enhancer insertion

 Viral proteins can activate host receptors for growth factors
 Host genes can be truncated to code for a hyperactive gene
 Long terminal repeats can act as promoters or enhancers, cause over
expression of a normal gene
2) Tumor Suppressor genes
 Normal function - inhibit cell proliferation when necessary & regulates the cell cycle.
 Eg: P53 gene, Rb gene
 They become oncogenes by loss of function mutations
 Mutated gene acts recessively
 So both gene copies should be defective for the action to be lost.
 Absence/ inhibition of inhibitor uncontrolled cell proliferation
 Classes of tumor suppresser genes,

 Genes that control cell divisions
 Genes that repair DNA
 Cell suicide genes
 Genes for cell adhesion molecules
 Tumor suppressor genes,

 RB → encodes a protein that interact with transcription factors & indirectly control gene
expression & cell division process
 APC → Regular (suppress) cell growth
 DNA repair genes → BRCA 1
 P53 → can halt cell division, induce abnormal cells to apoptosis, DNA repair
Role of P53 protein as a tumor suppress,
P53 is a key enzyme of cell cycle regulation & most frequently mutated gene
P53 exists in a normal cell at low concentrations
During stress conditions it accumulates and the concentration increases (DNA damage,
Hypoxia & etc.)
 Protein kinases and acetyl-transferases are activated
 Results in stabilization and activation of P53 within nucleus
 Phosphorylated or acetylated P53 interacts with DNA at P53 response elements of target genes
 Induce transcription of genes involved in DNA repair
 Arrests cell cycle till repair is complete
 Once complete P53 is degraded and cell cycle restarts
 If damage is extensive, cell apoptosis is started
 If P53 is Inactive, a damaged or mutated cell will continue to proliferate instead of
starting to apoptosis & mutated P53 is often associated with resistance to anti-cancer
drugs.

Rb protein
Function of retinoblastoma protein
 Retinoblastoma protein exists in phosphorylated and dephosphorylated states

 Its normally in Dephosphorylated form
 Which attaches to E2F transcription factor and inhibits it.
 When cell is stimulated by a growth factor
 Signal is carried from receptor to nucleus via intra cellular signaling pathway
 G1 phase Cyclin-CDK complex is activated
 G1 CDK kinase phosphorylates Rb protein
 Which prevents it from attaching to E2F transcription factor
 Inhibition of E2F is removed
 E2F activates transcription of genes needed to enter S phase
 Once needed proteins are made cell moves into S phase
 If RB is inactive or constantly phosphorylated, E2F will be always active and cell will enter
S phase without any regulation. Lead to uncontrolled cell division.
 Late G1 cyclins can phosphorylate Rb further & S cyclin, M cyclin maintains Rb in
phosphorylated state.
Cancers caused by epigenetic changes
 Some cancers are caused by epigenetic changes. This refers to heritable changes in gene
expression that occur without alteration in DNA sequence.
2 mechanisms
DNA methylation covalent modifications of histones
 Changes in methylation pattern;

 Hyper methylation can silence nearby tumor suppressor genes
Eg: Hyper methylation of CpG islands in the promoter region of tumor suppressor genes is
a major event in the origin of many cancers
 Hypo methylation can permit activation of silenced proto-oncogenes

Eg: Hypo methylation of CpG

 Epigenetic mediated gene regulation is affected by several factors.
 base analogs
 radiation
 smoke - toxins
 stress
 hormones
 undernutrition
 reactive oxygen species.
 other agents (such as nickel, arsenic, cadmium)
 Cancer can be treated by halting cell division.
 Microtubules targeted drugs,
 Taxol - binds and stabilizes microtubules

 Colchicine
 Vinblastine
bind to the tubulin subunits prevent polymerization
 Vincristine
 Nocodazole

THE HUMAN GENOME
 1 base pair(bp) → Single A=T or G≡C pairing

Types of sequences in the human
 1000bp = 1kb
genome
 1000kb = 1Mb5
 Genes code for proteins (2%)
 3.1 billion bases → But, only<25,000 genes
 Non coding
Gene density  Introns (25%)
 Transposable Elements (45%)
 Gene density of human genome is VERY LOW  Repeated sequences (long,
(avg - 10genes/Mb) compared to others. simple)
 Gene density varies between chromosomes.  Other intergenic (22%)
1. Highest gene density - chromosome
19(17,22)
2. Lowest gene density - chromosome 13 and
Y [mostly pseudo chromosomes. (Not
working now) inherited through evolution]
Arrangement of genes
 Gene dense areas → G, C rich → light bands

 Gene poor areas → A, T rich → dark bands
 Genes are concentrated in random areas with vast expanses of non-coding DNA
 CG repeating sequences (CpG islands)
 Occur near gene rich areas.
 Form barrier between genes & junk DNA
Repeat sequences
 Repeat sequences differ in their,

 Position in the genome
 Sequence
 Size
 Number of copies
 A presence or absence of
coding regions
 There are 2 types of repeats

1) Interspersed repeats
2) Tandem repeats

1) Interspersed repeats
Interspersed Repeats
Transposable Elements Others

 Mobile jumping
 Retrotransposoms
 SINEs
 LINEs
 LTRs
2) Tandem repeats
Tandem Repeats
Satellites Mini satellites Micro satellites
 Highly repetitive  Moderately repetitive.  Moderately repetitive

 Very large array  Large array (30kbp)  Small array (200bp)
(100Mbp)  Found in euchromatic  Found in euchromatic
 In heterochromatic regions regions
regions near
centromeres, telomeres
Transposable elements (Transposons)
 Derived from parasitic DNA

 Propagate by replicating & inserting a new copy. (jumping elements)
 Tandemly repeated sequences show exceptional variability among individuals in terms of copy
number. (used to study polymorphisms)
Variations in the Human Genome
 99.9% of the sequences is similar among individuals. 0.1% may vary.
 Mutation - differences in DNA sequence in an individual that are rare, may be unique to the
individual or family line, occur in coding/ regulatory region. (<1% in population)

 Polymorphism - differences in DNA sequences found in 1% or greater in the population. Has a
higher frequency than mutations (mainly in non-coding regions)
 Two types of variations.

1) SNP → Single Nucleotide Polymorphism-variation in single nucleotide bases scattered
along the chromosomes
Variations in copy
2) VNTR → Variable Number of Tandem Repeats
number of tandem
SSR/STR → Simple Sequence Repeats/Simple Tandem Repeats
repeats
Importance of SNPs
 Genetic markers for disease

 Development of personalized drugs
 Mapping migration of population
 Information about evolution
 Gene therapy

ENZYMES
Localized in specific organelles in the cell
Enzymes Selectively channel substrates into lower energy pathways
Catalyze the reaction (x103-108) (Biocatalyst)

 Catalyze one or few reactions
 Act on one type of bond or linkage
Enzyme turnover time = No. of molecules of Substrate converted to product per

enzyme per second
Proteins Certain RNA (Ribozymes)
Increase the velocity of reaction

Enzymes
Not consumed
Specific for substrate
Enzyme Active Site
 Special pocket formed by folding of protein.

 Contains amino acid side chains
𝐸 + 𝑆 → 𝐸 − 𝑆 𝐶𝑜𝑚𝑝𝑙𝑒𝑥 → 𝐸 − 𝑃 𝐶𝑜𝑚𝑝𝑙𝑒𝑥 → 𝐸 + 𝑃

1) Lock and Key hypothesis - Enzyme specificity
2) Induced Fit hypothesis - Flexibility
Enzyme Classification
 Oxidoreductase - Catalyze oxidation reduction reactions

 Transferase - Catalyze transfer of C-, N- or P containing groups
 Hydrolases - Catalyze cleavage of bonds by addition of water
 Lyases - Catalyze cleavage of C-C, C-S and certain C-N bonds
 Isomerases - Catalyze racemization of optical or geometric Isomers
 Ligases - Catalyze formation of bonds between C and O, S and N
coupled to hydrolysis of high energy phosphates
 How do enzymes increase reaction rate? By binding with substrate &

reducing activation energy.

 Enzymes provide an alternate energetically favorable reaction pathway.
 They do not change the
 Energies of reactant and products
 Equilibrium point
Cosubstrate
Only transiently
associated with enzyme.
Dissociate in an altered
state.
Coenzyme
Eg: - NAD+
Small Organic
molecules Derived from
Vitamins
Prosthetic Group
Non protein moiety
Permanently associate
Cofactor with the Enzyme.
Metal Ion Eg: - FAD+
Eg: - Zn2+/Fe2+
Cu2+/Mn2+

Isoenzyme
 Catalyze same reaction, but has different primary structures, therefore different
kinetic properties.
Eg: Creatine kinase CK-1, CK-2, CK-3
LDH
→ (Refer Medical Diagnostics)
Creatine kinase ;
Lactate Dehydrogenase (LDH);
Subunits Major source

LD1 HHHH Heart, RBC, Renal cortex
LD2 HHHM Heart, RBC, Renal cortex
LD3 HHMM Lung, Lymphoid tissue, Pancreas
LD4 HMMM Liver, Skeletal Muscle
LD5 MMMM Liver, Skeletal Muscle

 Lactate Dehydrogenase in MI,
Michaelis - Menten Kinetics
𝑉𝑚𝑎𝑥 [𝑆]
𝑉𝑜 =
𝐾𝑚 + [𝑆]
V0 = Initial Velocity
[S] = Substrate Concentration
Km = Substrate Concentration at half Vmax
Vmax = Maximum Velocity
What is Km? (Michaelis constant)
 Reflects the affinity of an enzyme for its

substrate
 Numerically,
 Km = [S] at which reaction velocity is equal
to 1/2Vmax

Low Km = High affinity
High Km = Low affinity
 Km changes with
1. Temperature
2. pH
3. Structure of Substrate
 Km does NOT change with concentration of enzyme
 When Vo is plotted against [S] → hyperbolic curve

 It’s not always possible to determine when Vmax has been achieved.
 If plotting 1/Vo vs 1/[S] → Lineweaver Burk Plot (Straight line)

 can calculate Km & Vmax
Km = Rate of breakdown [E][S]

Rate of formation [E][S]
Lineweaver Burk plot
Factors that affect enzyme catalyzed reactions
1) Substrate Concentration.
 Vo increases with the substrate concentration, as it becomes higher, V o

becomes constant.
Velocity = No. of substrate molecules converted to product per unit time (μmol/min)
 At saturation, all binding sites are filled.

 Most enzymes show this hyperbolic shape due to Michaelis Kinetics
 But allosteric enzymes show sigmoidal curve

2) pH of the reaction medium
 For each enzyme there is an optimum pH.

 pH affects the charge of the amino acid of
the active site which changes its
properties.
 Extremely high or low pH denatures
the enzyme
Eg: - Pepsin 1.5-2.5, Trypsin 8-9
 H+ affects reaction velocity
 E and S require specific chemical groups (ionized or unionizes)
3) Effects of Temperature
0oC <--------------------------------------------------------(35o-40o)-------------------------------------------> 70oC

Rate is close to zero Optimum Temperature Completely Destroyed
(But thermophilic bacteria have optimum temperature of 70 C) o
Increase of velocity with temperature
 Increases no. of molecules with

sufficient energy to pass over
the barrier and form products
 Increase until peak velocity is
reached

4) Effect of electrolytes
5) Enzyme Concentration
 Rate of the reaction increases with the enzyme concentration
vo
Enzyme Concentration
6) Enzyme inhibitors and activators
Enzyme inhibitors
Any substrate that can diminish the velocity of an enzyme catalyzed reaction is called “inhibitor”.
Enzyme
inhibitor
Competitive Noncompetitive Uncompetitive Special type of

inhibitor inhibitor inhibitor inhibitor(irreversible)
Suicide Proteinase Organoposphate

inhibitors inhibitors poisoning
 Equilibrium exits between enzyme and inhibitor
E+I EI
 Equilibrium constant for dissociation of EI is called the inhibitor constant. (Ki)

[E] [ I ]
Ki =
[E I]
Ki affinity of I
Ki affinity of I

Competitive and Non-Competitive Inhibitors
Competitive Non-Competitive
Active Site Active on active site Not on Active site
Structure of inhibitor Structural analogues. Unrelated molecules
Substrate and inhibitor are
chemically similar and have
similar shapes
Effect on Active site Inhibitor does not change Inhibitor changes the
active site shape of the active site
Inhibition Reversible Generally irreversible
Excess of Substrate Inhibition relieved No effect
E+S ⇌ ES ⇌ E+P E+S ⇌ ES ⇌ E+P
+I +I +I
EI EI ESI
Inhibitor binds with Enzyme Enzyme or ES complex
Km ↑ Unchanged
Affinity ↓ Unchanged
Vmax Unchanged ↓
Examples 1. Succinate Dehydrogenase 1. Pyruvate Kinase is

is inhibited by Malonate inhibited by Alanine
2. Statins inhibit HMG CoA 2. Heavy Metals (Arsenic,
Reductase Silver, Mercury and Lead)

Competitive Inhibitors
1) Statins
 Statins such as Atorvastatin and Pravastatin are

structural analogues of natural substrate for HMG CoA
Reductase.
 Inhibit De novo Cholesterol synthesis, thereby lowering
plasma cholesterol levels.
2) Sulfa drugs
3) Methanol Poisoning is treated by Ethanol.
Alcohol dehydrogenase
Methanol Formic acid → Metabolic acidosis and tissue injury
-
Ethanol
Uncompetitive Inhibitors
 Uncompetitive inhibitors bind only to ES complex.

 Inhibition can’t be reversed by increasing substrate concentration.
E+S ⇌ ES+I ⇌ E+P
ESI

Summary
Special Types of Inhibitors.
1. Suicide inhibitors
 A special group of irreversible inhibitors.

 Inhibitor is a relatively inert molecule.
 Binds with the active site of enzyme.
 Transformed into a reactive compound. (intermediate)
 The intermediate forms a covalent linkage with active site.
 Inactivates the enzyme.
 Enzyme loses its original form.
Eg: - Aspirin which inhibits cyclooxygenase-1(COX-1)

 Mechanism based enzyme inactivation
E.g.: - Use of allopurinol in gout
 Allopurinol- blocks the actions of Xanthine Oxidase by substrate competition and is also
metabolized by it to form Alloxanthine. (Suicide Inhibition)
 Alloxanthine – A non-competitive Xanthine Oxidase inhibitor
2. Proteinase inhibitors
 These inhibitors are analogues of the

substrates that proteases would normally
recognize
Proteinase inhibitors + Proteinase enzyme

↓
Non-dissociable complex
Examples for proteinase inhibitors: -

a) α1 proteinase inhibitors (α1 trypsin)
 This inhibits proteinases with serine in
active site such as elastase, trypsin,
and chymotrypsin.

 Genetic deficiency of α1 proteinase inhibitor predisposes to pulmonary emphysema and
liver diseases
b) Many proteinase inhibitors are present in plasma.

 They control
 Blood coagulation
 Dissolution if blood clots
 Activation of complement cascades
 Formation and destruction of some peptide hormones
c) Proteinases and their inhibitors play a major role in cancer metastasis. (E.g.: Genetic
deficiency of α1 proteinase inhibitors)
 Suicide inhibitors
 Substrate inactive
 Product is the inhibitor non-dissociable complex with the enzyme
 Protease inhibitors
 Inhibitor analogue of substrate and forms a non-dissociable complex with the enzyme
3. Organophosphate poisoning (OP)
 OP is an irreversible inhibitor of serum cholinesterase. Forms covalent bonds with serine.

Regulation of enzyme activity.
 Some enzymes are specialized for regulatory function.

 Regulatory enzymes are enzymes whose activity is changes due to molecular signals
Allosteric
Enzymes
Short Term
Covalent
Regulatory Modification
Enzymes
Regulation of
Long Term
Enzyme Synthesis
A. Allosteric enzymes
Enzymes
Effectors
bind with Have active and
modulatory modulatory site
site non
covalently
Frequently
catalyze Activated by
the Substrate
committed and other
step in a positive
pathway Allosteric modulators
Enzymes
Do not
obey
Michaelis Inhibited by
end products
Menten
Kinetics
Normally
composed of
Catalyse an multiple
irreversible
subunits
reaction
(Identical/
different)

 Binding modulators (effectors) to the allosteric site leads to change of conformation of the
active site
Negative Effector->
Inhibits enzyme
(Km↑ Vmax↓)
Effectors of By Activity
Allosteric Positive Effector->
(Km↓ Vmax↑)
Enzymes
Changes
 Km Homotropic Effector->
 Vmax Effector = Substrate
By Type of
 Both Substance
Heterotropic Effector->
Effector ≠ Substrate
I. Homotropic effectors
 Substrate = effector = activator

 Mostly positive effectors
 Bind to active site →activate other
binding sites
 Presence of substrate molecule at one
site enhances the catalytic properties of
other substrate binding sites.
(Cooperativity)
 Sigmoidal curve
II. Heterotropic effector
 Effector ≠ substrate
 i.e. feedback inhibition
𝐻𝑀𝐺 𝐶𝑜𝐴 𝑅𝑒𝑑𝑢𝑐𝑡𝑎𝑠𝑒

Eg: Acetyl CoA → HMG CoA Mevalonate → Cholesterol
 Glycogen phosphorylase
 Pi is a positive homotropic effector

 Pyridoxal phosphate is needed as a cofactor.
 ATP is a feedback inhibitor

 Glucose-6-P is a negative heterotropic effector (inhibitor)
 AMP is a positive heterotropic effector (activator)
 Activated by phosphorylation and deactivated by dephosphorylation
B. Covalent modification
 Addition/removal of groups
 Phosphorylation and dephosphorylation
 Phosphorylation by protein kinases
 Dephosphorylation by phosphoprotein Phosphatases
 Some Enzymes are active when phosphorylated
 Some are inactive
C. Induction and repression of enzyme synthesis
 Cells can regulate not just the activity of an enzyme, but the synthesis or degradation
 Increase in synthesis -> Induction
 Decrease in synthesis -> repression
Eg – Effect of Insulin Glucagon on enzyme activity during fasting
Clinical applications of enzymes
1) As therapeutic reagents
2) Enzyme activity in body fluids (serum and urine) in diagnosis and prognosis
3) As analytical reagents in measurements of non-enzyme substances (Drugs, Proteins)
1) As therapeutic reagents

a) Use of Asparaginase in leukemia
 Asparagine is an amino acid which is incorporates into proteins and helps in cell growth.
 It is important for healthy cells and lymphoblasts (lymphoblasts show malignant growth in
leukemia)
 Lymphoblasts do not have L-asparagine synthetase. Therefore, asparagine is required for
lymphocytes.
 In leukemia, Asparaginase is given to reduce malignant cell growth
b) Fibrolytic enzymes
 Streptokinase, Tissue type plasminogen activator(tPA)

 Converts Plasminogen to Plasmin
 Fibrin clot is dissolved by Plasmin
c) Digestive enzymes
 Oral administration in cystic fibrosis.

 Capsule contains pancreatic enzymes (varying amounts of lipase, protease and amylase
 Granules coated with a pH sensitive material that protects the enzyme from destruction by
acid in the stomach
 Coating dissolves in alkaline medium of duodenum, releasing enzyme.

d) Rhodonase
 Given in Cyanide poisoning
Rhodonase
2- 2-
S2O3 + CN --------------------------> SO3 + SCN-
2) Enzymes in Plasma
a) Constituent enzymes
 Plasma specific Enzymes

 Functional Enzymes
 Present in high concentrations
Eg: -Thrombin, Plasmin, Lipoprotein lipase
b) Non-constituent enzymes
 Non-plasma enzymes
 No functional role
 Generally present in low concentration
 Present in bile
 ALP
 Increase in non-constituent enzymes in

serum indicates tissue damage or
change in metabolism
 May or may not indicate disease
Eg: - Transient hyperphosphatemia in infancy.

 ALP levels in serum are 20x normal in children 2-38 months’ old
 Metabolism in most tissues is similar
 Specific enzymes are selected to indicate certain tissues
 Mild inflammatory conditions release cytoplasmic enzymes.

 Examples – Enzyme levels in
Enzyme Assays
 Serum is used
 Hemolyzed samples cannot be used
 Unit of enzyme activity:
 μ moles of substrate converted/min at a given pH and temperature
 Unit - μ moles/min
 Measured by termination of reaction or pH/temperature changes

Measurement of product formation
 Photometric methods
Eg: –
1. ALT activity
ALT
α – KG + Alanine Pyruvate + Glutamate
Colour Indicator NADH LDH
NAD+
Lactate
 The rate of NADH consumption is determined photometrically and is

directly proportional to the ALT activity in the sample
2. ELISA
 Antibody is added
 Antigen in the blood sample binds with

specific antibody
 Adding the enzyme linked specific

antibody (A2). This antibody binds only
with the antigen-antibody complex
 The final complex converts

specific substrates into
products.
 Products are fluorescent and
can be measured by
photometry
 Product α Concentration of antigen

BIOENERGETICS, OXIDATIVE PHOSPHORYLATION AND
ELECTRON TRANSPORT CHAIN
 There are two major sources of high energy phosphate for formation of ATP synthesis:
Substrate Level Phosphorylation Oxidative Phosphorylation

 Substrate-P (or Pi) + ADP → Product + ATP  Electrons stored in the form of
reduced coenzymes (NADH & FADH2)
Examples:  These electrons are passed to oxygen,
1) In Glycolysis - cytosol through a highly organized chain of
Phosphoglycerokinase proteins and coenzymes called Electron
1,3-bisphosphoglycerate → 3-bisphosphoglycerate Transport Chain (ETC).
PK  A proton gradient is established
PEP Pyruvate
across the inner mitochondrial
2) In TCA Cycle - mitochondria
membrane - cristae
Succinate thiokinase
 It is the energy that drives ATP synthesis.
Succinyl CoA + Pi → Succinate + ATP
(erythrocytes do not have
mitochondria to generate ATP by ETC)
 Standard free energy change (ΔG) for aerobic respiration is negative. The standard free energy
change for phosphorylation of ATP is positive. The energy released in respiration (in ETC) is
coupled to phosphorylation of ATP.
 Aerobic respiration uses an ETC to break the fall of the electrons to oxygen into several
energy - releasing steps. (If electrons were transferred directly to oxygen, a large
proportion of the energy would be lost.)
Mitochondria
 Mitochondria Outer Membrane: (channels by proton porin) → permeable to most

ions and small molecules.
 Mitochondria Inner Membrane → Impermeable to most (H+, ATP, ADP, Pyruvate)
 Need specialized carriers / transport systems
 Highly convoluted (increase surface area)
 Rich in proteins (involved in Oxidative Phosphorylation)
 Complex I − − → V and CO Q are located
 Inter membranous Space (cytochrome C is here)
 Mitochondria Matrix (50% protein)
Electron Transport Chain

 Coupling reactions with a common intermediate.
 Coupling concept is provided by dehydrogenation reactions.
 The ETC is a multi-compartmental system with four large proteins – Complex I, II, III, IV –
and two mobile carriers present in cristae – Coenzyme Q and Cytochrome C – which
contains electron carriers.

Complex Name Electron exchanger
Complex I NADH Dehydrogenase FMN Fe-S
(NADH Co Q Oxidoreductase)
Complex II Succinate dehydrogenase FAD Fe-S
Complex III Cytochrome bc1 Haem (Fe2+) Fe-S
Complex IV Cytochrome c oxidase Haem (Fe2+) Cu
(cytochrome a+a3)
[Only electron carrier with
coordination site that reacts
directly with O2 ]
 All complexes and Cytochrome C are proteins. (CoQ is not)

 Electron Carriers in ETC:
 NAD+/NADH
 FAD+/FADH2
 FMN/FMNH2
 Coenzyme Q
 Cytochrome C
 Coenzyme Q (CoQ or ubiquinone)

 located in the lipid core of the membrane and very hydrophobic.
 The only non-protein electron carrier – Quinone derivative (lipid)
 Cytochrome C
 A small water-soluble mobile protein.
 Shuttles electrons from complex III to IV.
 Cytochromes use the ability of metal atoms to accept and release electrons.
 Iron is most commonly used.
 Copper and iron (as haem) are used in the Complex IV – Cytochrome c oxidase.
Pathways from which electrons are donated to Coenzyme Q
NADH+ H+ Succinate
Complex I Complex II
(NADH) (Succinate DH)
NAD+ Fumarate
FMNH2 FADH2
Co. Q
FADH2 FADH2
β Oxidation Glycerol-P shuttle

Fatty Acyl CoA Glycerol-3P (Glycerol
(Acyl CoA DH) phosphate DH)

 The energy released by electrons (as they move down the ETC) is used to pump H+ ions
(protons) from the matrix to the intermembrane space of the mitochondria. Only complex I,
III and IV pump H+ this way. Complex II does not.
 Oxygen (O2 molecule) is the final electron acceptor. O2 accepts the electrons to form H2O,
catalysed by complex IV (cytochrome c oxidase).
 (Transport of a pair of electrons from NADH to O2 through ETC releases 52.58kcal)
ATP synthase (Complex V) (F1/FO ATPase)
 Synthesizes ATP using the energy of proton gradient

 2 domains
 F0 – spans inner mitochondrial membrane
 F1 – protrudes into the mitochondrial matrix
 F0 rotation causes conformational changes in β
subunit of F1.
 These changes allow,
 Binding of ADP + Pi
 Phosphorylation of ADP → ATP Flow of 3 H+
 Release of ATP
 Oligomycin binds to F0 → Close protein channel.
 pH and electrical gradients cannot be dissipated in
the presence of this drug, electron transport stops
because of the difficulty of pumping anymore protons against the steep gradient.
 Couples ETC with ATP synthesis
Chemiosmotic Theory of ATP Production/ Mitchell hypothesis
 A proton concentration gradient formed as a result of electron transfer serves as the energy
reservoir for driving ATP formation.
Electrons release energy as they flow down the ETC

↓
+
This energy is used to pump H ions (protons) from the matrix to the intermembrane space
(by complex I, III and IV only – NOT complex II) This pump is vectorial (specific direction)
↓
This creates an electro-chemical gradient and a pH gradient (due to H+ concentration
difference)
+ charge outer ↓ lower pH outside
membrane
ATP synthase (Complex V) on the inner membrane provides a way for the H+ to flow back into the
matrix down the gradient
↓

This releases energy (stored in the electro-chemical and pH gradients)
↓
This causes a conformational change in ATP synthase which uses the energy released to
produce ATP
 (Flow of three H+ ions through ATP synthase complex causes a conformational change which
causes ATP synthase to synthesise ATP using ADP and Pi – this is oxidative phosphorylation)
 NADH results in more net H+ movement than FADH2 because complex I pump protons but
complex II does not.
 One NADH  3 ATP P: O Ratio
 One FADH  2 ATP ATP count for 1 O atom (H2O) → NADH 3:1
FAD 2:1
 Extra energy releases as heat
Transporters on the Inner Membrane
 Once ATP is formed, the ATP is transported out of the matrix, in exchange for ADP,
by adenine nucleotide translocase (an antiport). The most abundant inner
membrane protein
 Phosphate (as H2PO4-) is brought to the matrix by phosphate translocase which is a
symport that transports H2PO4- and H+ ions into the matrix through the inner
membrane.
 Together, adenine nucleotide translocase and phosphate translocase provide substrates
and remove the product of ATP synthase. (multi-subunit enzyme)

Uncoupling
 Normally, ETC and oxidative phosphorylation are tightly coupled for ATP synthesis
 Certain substances can uncouple the ETC from oxidative phosphorylation
 This causes the collapse of the electro-chemical H+ gradient
 The energy stored in the gradient is dissipated as heat
 This leads to Non-shivering thermogenesis.
1) Natural uncouplers (Eg: UCP1, UCP2, UCP3)
 Natural uncoupling protein ‘thermogenin’ (UCP1) is found in brown adipose tissue in the
newborn. Brown adipose tissue contains many mitochondria and helps maintain body
temperature. Thermogenin (UCP1) is an important factor in heat production and in lipid
turnover.
 Decrease H+ gradient by proton leakage without ATP synthesis
[Brown fat containing natural uncouplers is also important in animals – e.g. adapting to
the cold & during hibernation]
2) Synthetic uncouplers
 Synthetic uncouplers such as 2,4-DNP and FCCP are hydrophobic and contain a dissociable
proton (i.e. they are hydrophobic weak acids). In their uncharged form, they can pass into
the mitochondrial matrix and release H+ in the matrix – dissipating the H+ gradient.
 Drugs such as aspirin (and other salycilates) which are weak acids at high doses can act as
uncouplers.
Inhibitors/Uncouplers/Drugs Affecting ETC and Oxidative Phosphorylation
Name Function Site of Action

Rotenone, Amytal Electron transport inhibitor Complex I
Suppress in
Antimycin A Electron transport inhibitor Complex III reduced forms
CN-, CO, Azide Electron transport inhibitor Complex IV
2,4-DNP, FCCP Uncoupling agents Act as transmembrane H+ carriers
Oligomycin Inhibits ATP synthase ATP synthase (F0)
(pH in outside, ETC equilibrium)
Atractyloside Inhibits ATP/ADP translocase ATP/ADP translocase (adenine
(adenine nucleotide translocase) nucleotide translocase)
Shuttles for NADH
 NADH made in the cytosol (in glycolysis) cannot move into the matrix of the mitochondria.
 Two mechanisms are present in cells to shuttle the cytosolic NADH to the mitochondrial
matrix:

1. Glycerol phosphate shuttle (in muscle, brain)
2. Malate/Aspartate shuttle (in liver, heart)
Glycerol Phosphate Shuttle Malate/Aspartate Shuttle
Glycerol 3-
DHAP
phosphate
Glycerol 3-
DHAP
phosphate
Synthesize 2 ATPs for each cytosolic NADH Yields 3 ATPs for each cytosolic NADH oxidized.
oxidized
Cyanide Poisoning
CN- binds with the Fe3+ of haem in complex IV (cytochrome c oxidase)

↓
This prevents binding of O2 to complex IV (cytochrome c oxidase), where O2 is the final electron
acceptor
↓
-
CN causes a rapid and extensive inhibition of ETC
↓
So aerobic respiration stops, no ATP synthesis by ETC
↓
Leads to anaerobic metabolism and concomitant lactic acidosis and cell death

Antidotes to Cyanide Poisoning
1) Administration of nitrite (as sodium nitrite)
Oxyhaemoglobin (Fe2+) nitrate Methaemoglobin (Fe3+)
 Cyanide preferentially binds with Fe3+ of methHb (producing cyanomethaemoglobin)

as compared to Fe3+ of complex IV (cytochrome C oxidase).
 So administering nitrite restores inhibition of complex IV (cytochrome c oxidase).
2) Administration of thiosulphate
 This convert the cyanide to non- toxic thiocyanate

2-
 CN- + S2O3 → CNS
Inherited Defects in ETC and Oxidative Phosphorylation
 Inherited diseases of mitochondrion respiratory chain can cause lactic acidosis. Fatal
infantile mitochondrial myopathy, leber hereditary optic neuropathy (vision loss) and
renal dysfunction involves in severe deficiency/absence of most oxidoreductases of the
respiratory chain.
 Also, absence of ATP/ADP translocase can cause lactic acidosis. WHY?
 13/120 polypeptides needed for Oxidative phosphorylation are coded

by mit.DNA (37) and synthesized in the mitochondria (>rate for
mutation) (~ 10 times more than chromosomal DNA)
 Alterations in mitochondrial DNA → Defects in Oxidative Phosphorylation
 Remainder coded by nuclear DNA, synthesized in the cytosol
 Tissues with greatest ATP requirement (CNS, skeletal muscles, liver etc.)
are affected by defects in Oxidative phosphorylation.
Mitochondria and Apoptosis
 Apoptosis (programmed cell death)

 Initiated through the intrinsic pathway by formation of pores in the outer
mitochondrial membrane.
 These pores allow cytochrome C to leave the inter-membranous space and enter cytosol.
 Cytochrome C binds to preapoptotic factors, which activates proteolytic enzymes → cause
cleavage of key proteins → cell apoptosis.
Eg: Caspases (proteolytic enzymes)

Term 2
Anatomy – Term 2
THORAX
Thoracic cage
Borders
  Anterior-sternum 
 Posterior-12 thoracic vertebrae &
 intervening intervertebral discs 
 On each side- 12 ribs with their costal
cartilages+ intercostal muscles 
Shape
 Adult
Transverse section - kidney shape
Transverse diameter> antero-posterior diameter
Ribs - oblique ribs
Thoracic & abdominal respiration
 Infant
Transverse section – circular
Transverse diameter< antero-posterior diameter
Ribs - horizontal ribs
Purely abdominal respiration
Superior Thoracic Aperture

 Anterior- upper border of manubrium sterni
 Posterior- superior surface of body of 1st
thoracic vertebra (T1)
 On each side- 1st rib & cartilage
Inclined at an angle of 45 degrees
*Suprapleural membrane=”Sibson’s fascia”

 Triangular
 Separates thorax from the neck
 Attachments
o apex-tip of the transverse process of C7
o Base-inner border of the 1st rib & cartilage
Inferior Thoracic Aperture

 Anterior-infrasternal angle
 Posterior-inferior surface of body of T12
 On each side-costal margin
*Diaphragm separates thorax from abdomen.

Bones of thorax
A) Ribs
12 pairs of ribs
1-7 True ribs 8-12 False ribs

Vertebrosternal
Vertebrochondral Vertebral(floating ribs)

8-10 11-12
Atypical -1, 2, 10, 11, 12
Typical -3-9
Longest -7th rib
Most angular -9th rib
Typical rib
 Anterior end
 concave depression
 attach with costal
cartilages
 Posterior end
Head – 2 facets & a crest in between
  Upper facet – body of the higher vertebra 
  Crest – intra articular ligament 
 Lower facet – body of the numerically corresponding vertebra 
Neck – 2 surfaces
 Anterior – smooth related to costal pleura 
 Posterior – rough inferior costotransverse ligament
 Superior border or crest superior costotransverse ligament 
Tubercle – at the junction of the neck & shaft

2 parts
 Medial articular – costotransverse joint with the transverse process
 Lateral non-articular – lateral costotransverse ligament
Shaft
 Convex outwards
 Bent & twisted at the angle (weakest point)
 Has two surfaces
 Inner surface – covered by pleura
- Grooved inferiorly (subcostal groove)
Contains from superior to inferiorly
V- Posterior intercostal Vein
A- Posterior intercostal Artery
N- Intercostal Nerve
 Outer surface – rough up to the angle
Attachment of Erector spinae

Atypical ribs
1st rib
 Shortest, broadest, most curved, flattest 
 Shaft has no twist 
 Flattened from above downwards 
 Upper surface – 2 shallow grooves for the subclavian artery and vein.
 Separated by scalene tubercle near the inner border
 Lower surface – no subcostal groove 
Relations of the 1st rib
 Superior surface
 In between insertion of scalenus anterior to
the scalene tubercle

 Subclavian vein - anteriorly
 Subclavian artery & the lowest trunk of
 the brachial plexus - posteriorly
 Medially
 Apex of the lung & cervical pleura 
 Suprapleural membrane is attached 

 Neck 
From Medial to Lateral 
S – Sympathetic trunk 
V – 1st posterior intercostal Vein
 – Superior intercostal Artery 
A
N – T1 Nerve (Larger portion of T1 nerve to form inferior trunk of brachial plexus) 
2nd rib 10th rib 11th rib 12th rib

Much less curved Only 1 articular Short
than 1st rib Twice facet on the No tubercles, No neck
as long as 1st rib head Only 1 facet on the head
Tapering ends
11th have a slight angle a 12th have neither
shallow subcostal groove
CLINICALS
 Rib fractures 
Children – rare - Chest wall is highly elastic 
Adult – common

By Direct or indirect violence
Indirect weakest point (at the angle) but, upper 2 ribs – protected by the clavicle
Lower 2 ribs – floating, are least commonly fractured

 Cervical rib 
Attached– C7 transverse process
 Articulates with 1st rib or if short the free distal extremity attached to the 1st
rib by a fibrous band
 Can be unilateral or bilateral
Pressure on
1) Lowest trunk of brachial plexus (T1) -
Parasthesia along the ulnar border of forearm -
Wasting of intrinsic muscles of the hand
2) Subclavian artery (less likely due to thickness of

the wall)
-Vascular changes -Gangrene
3) Subclavian vein -Oedema
 Thoracic inlet syndrome

 -cervical rib 
-Variation of the insertion of scalenus anterior
-above structures compressed
1. Lowest trunk of brachial plexus (T1)
2. Subclavian artery
3. Subclavian vein

 Coarctation of the aorta 
 Constriction of aorta beyond the origin of left subclavian artery
 If collaterals open up,
 Posterior intercostal arteries enlarged - notching of ribs
 thyrocervical trunk, internal thoracic artery are also enlarged
B) COSTAL CARTILAGES
  Hyaline cartilage 
  In old age – progressive ossification 
 Add resilience to the thoracic cage - Protects sternum & ribs 

C) STERNUM
3 parts- manubrium, body, xiphoid process
Clavicle
1st costal cartilage
2nd costal cartilage
Manubriosternal joint

 Manubrium opposite toT3/T4
 Body – opposite to T5 - T8
4 sternebrae - fused between puberty & 25 years Lateral border – notched
Articulate with part of 2nd, 3rd- 7th costal cartilages
Lower end – secondary cartilaginous xiphisternal joint
 Xiphoid - Cartilage
May ossify at adult life (40)
Overlies the Epigastric fossa
*bone marrow – manubriosternal puncture
JOINTS OF THE THORAX

1) Manubriosternal joint – secondary cartilaginous
Act as a hinge joint
2) Costovertebral
Articular surfaces – 1. head of the rib
2. Body of the vertebra above & numerically corresponding
vertebra
Ligaments – 1. capsular
2. Intra-articular
3. Radial ligament (Triradiate)
3) Costotransverse joint - synovial

Articular surfaces – 1. medial part of tubercle of rib
2.Transverse process of numerically corresponding vertebra
Ligaments
1. capsular
2. Superior, Inferior, lateral costotransverse
 superior – crest on the neck of the rib 

Transverse process of the vertebra
above
 inferior – posterior surface of the neck of the rib 
Transverse process of the
corresponding vertebra
 lateral – lateral part of the tubercle of the rib 
tip of the transverse process of the
corresponding vertebra
4) Costochondral – primary cartilaginous

Immovable
5) Chondrosternal – 1st primary cartilaginous
2nd-7th - synovial
th th
6) Interchondral - 5 -9 – synovial (among hyaline cartilages of those ribs)
Between 9 & 10 - fibrous

RESPIRATORY MOVEMENTS
Vertical diameter
 Contraction of the diaphragm (losing its convexity)
 Piston movement
Transverse diameter
 Mainly ribs 7-10 (partly 2-6) 
 Bucket handle movement
 Replacement of a shorter rib with a longer rib
 Axis of rotation- costovertebral joints
 Chondrosternal joints
Antero-posterior diameter
 Mainly ribs 2-6 (partly 7-10) 
 Pump handle movement 
 Forward movement of manubrio-sternum 
 Axis of rotation – costovertebral joints 
-Costotransverse joints
Muscles
Quiet inspiration – diaphragm
External intercostals muscles
Quiet expiration – passive
Forced inspiration – scalene muscles

Sternocleidomastoid
Pectoralis major
Pectoralis minor
Levator scapulae
Trapezius

Rhomboidus
Serratus anterior
Serratus posterior superior
Forced expiration –Lattisimus dorsi

Anterior abdominal wall muscles
Internal & innermost intercostals
Serratus posterior inferior
IMPORTANT SURFACE LANDMARKS OF THORAX

1. Superior angle of scapula – T2
2. Suprasternal notch or jugular notch (T2/T3) trachea is palpable in this notch
3. Spine of the scapula – T3
4. Sternal angle of Louis
 (T4/T5) 2nd costal cartilage
 Ascending aorta ends
 Descending aorta begins
 Arch of the aorta begins & ends
 Trachea divides into 2 principal
bronchi
 Azygos vein arches over right lung root & drains into SVC
 Thoracic duct crosses from right to left side
 Pulmonary trunk divides into right & left pulmonary arteries
 Intervertebral disc between T4 & T5
 Tracheobronchial lymph nodes
 Cardiac plexus
 Upper limit of the back of the heart
5. Inferior angle of scapula – T8
6. Xiphisternal joint – T9
7. Longest part of the costal margin – 10th rib
8. Sternum – T5/T8
Overlies heart
9. C7 – vertebral prominence, 1st palpable
10. All thoracic spines in the posterior midline
11. Nipple – in a male – 4th intercostals space, 10cm from the midsternal line
Female – it varies
12. Apex beat
Left 5th intercostal space 9cm from the midline
Just below & medial to nipple

THE WALLS OF THORAX
Intercostal spaces
 Intercostal muscles
3 layers – external intercostals Subcostalis
Internal intercostals
Tranversus thoracis Sternocostalis
Innermost intercostals
Muscle Fibre direction Origin Insertion Extent Nerve supply Action
External Forwards Lower Outer lip of Elevate
Downwards border of the upper b From the the ribs
Medially the rib order of the tubercle to the during
above the rib below Costochondral inspiration
space Junction.
Then muscle is
replaced by
anterior
intercostals
membrane.
Internal Backwards Floor of the Inner lip of Lateral border
Downwards costal the upper of the sternum Intercostal
groove of border of the to the angle of nerves
the rib rib below the rib. depress
above the ribs in
After the angle forced
of the rib expiration
continue as post
intercostals
membrane.
Innermost Backwards Middle 2/4 Inner lip of Middle 2/4th of
Downwards of the ridge upper the rib
above border of
costal the rib
groove below
Intercostal nerves
 Intercostal nerves – anterior primary rami of T1-T11 spinal nerves, after the dorsal primary rami has
been given
 Subcostal nerve – anterior primary rami of T12
 Typical intercostal nerve – T3-T6
 Branches – lateral cutaneous, anterior cutaneous, and collateral muscular

CLINICALS
Pus from the vertebral column tends to track around the thorax along the course of the
neurovascular bundle,
  Dorsal primary ramus 
 2 cutaneous branches 
Intercostal arteries
Each intercostal space contains
  1 posterior intercostal artery 
 2 anterior intercostal arteries 
 posterior intercostal artery (gives a collateral branch)

 11 in number
- 1, 2 – superior intercostal artery, branch of the costocervical trunk
- 3-11 – descending thoracic aorta
 anterior intercostal artery
 9 intercostal spaces anteriorly
- 2 in each space
- 1-6 – internal thoracic artery
- 7-9 – musculophrenic artery (branch of internal thoracic)
Intercostal vein
Anterior intercostal veins
- Upper 6 spaces internal thoracic vein
- Lower 3 spaces musculophrenic vein

Posterior intercostal veins Right side Left side
1st Right brachiocephalic Left brachiocephalic
Join to form the right superior Join to form the left superior
intercostal vein intercostal vein
2-4th Azygos vein Left brachiocephalic vein

5-8th Azygos vein Accessory hemiazygos vein
9-11th Azygos vein Hemiazygos vein
Posterior intercostal veins communicate with vertebral venous plexus
Lymphatic drainage
Anterior aspect Posterior aspect
Internal mammary nodes Posterior intercostal nodes

(along internal thoracic artery)
Tracheobronchial nodes
Lower 4 spaces upper spaces
Brachiocephalic nodes
Cisterna chyli Right Left
Bronchomediastinal trunk right lymphatic duct thoracic duct
Right Left
Subclavian trunk Thoracic duct
Neurovascular bundle
From above downwards - V A N
Between: internal intercostal & innermost intercostal muscle layers (neurovascular plane)
Lying in the subcostal groove
 intercostal nerve block – upper border of the space/ just below the rib 
INTERNAL THORACIC ARTERY

st
  branch of the 1 part of the subclavian artery opposite the thyrocervical trunk 
 at the 6th space divide in to –superior epigastric 
musculophrenic
Branches
i. anterior intercostal arteries for upper 6 spaces
ii. pericardiophrenic
iii. perforating branches
iv. superior epigastric artery
v. musculophrenic artery
vi. mediastinal artery

AZYGOS VEIN

















 drains the thoracic wall & upper lumbar region 
 forms an important channel connecting SVC & IVC 
 lies anterior to the vertebral column to the right of the thoracic duct & aorta 

Formation
 Formed by right subcostal vein, ascending lumbar vein 
 Drains right superior intercostal vein (2-4 posterior intercostal veins) 
 5-11 right posterior intercostal veins 
 Hemiazygos, accessory hemiazygos – T8 level 
CLINICALS
SVC obstruction – azygos vein transmits blood from the upper half of the body to
unobstructed part of the SVC or to the IVC.
Thoracoepigastric vein (Superficial vein formed by anastomoses between lateral
thoracic vein of axillary vein and superficial epigastric vein of greater saphenous vein)
opens up.
HEMIAZYGOS VEIN
  Formed by the left ascending lumbar & left subcostal 
 9-11 left posterior intercostal veins 
ACCESSORY HEMIAZYGOS VEIN

 5-8 left posterior intercostal veins 

THORACIC SYMPATHETIC TRUNK
  Descending from the cervical chain It crosses 
- Neck of the 1st rib
- Heads of the 2nd-10th ribs
- Bodies of 11th & 12th thoracic vertebrae
- Passes behind the medial arcuate ligament of diaphragm
st
 1 thoracic ganglion + inferior cervical ganglion = stellate ganglion
 Post ganglionic fibres T1-T5 heart, great vessels, oesophagus
 Splanchnic nerves formed by T5-T12 preganglionic fibers Supply to
abdominal viscera via -coeliac 
-Inferior mesenteric
-Superior mesenteric
-Renal plexus
 Greater splanchnic (T5-T10)
 Lesser splanchnic (T10-T11)
 Least splanchnic (T12)
DIAPHRAGM
- dome shaped fibromuscular septum
- partition between the thorax & abdomen
- chief muscle of respiration
- 2 parts: peripheral muscular
Central tendon (aponeurosis)
- Normal - Right dome upper border of the 5th rib
- left dome lower border of the 5th rib
- In forced expiration - Right dome 4th intercostal space
- Left dome 5th rib
- In forced inspiration – Right dome 6th rib
Muscular fibers (origin)
- Sternal – 2 small slips from the back of the xiphisternum
- Costal – inner aspect of lower 6 ribs & costal cartilages
- Vertebral/ lumbar – from the crura & arcuate ligaments
Right crus: anterolateral aspect of bodies of upper 3 lumbar vertebrae & intervening inter-
vertebral discs
Fibers forms a sling around esophagus.
Left crus: corresponding parts of upper 2 lumbar vertebrae
Median arcuate ligament: medial margins of 2 cruratendinous arch in front of the Aorta
Medial arcuate ligament: thickening of psoas fascia

Medially- side of body of L1
Laterally- transverse process of L1
Lateral arcuate ligament: thickening of fascia covering quadratus lumborum medially-

transverse process of L1
Laterally- 12th rib

Central tendon (insertion)
- Trefoil shaped
- Partially fused with pericardium
*right dome of the diaphragm is higher than the left dome (due to liver)
Nerve supply
Entire motor supply: phrenic nerves (C3, C4, C5)
Sensory: central- phrenic
Peripheral (including crura) - lower 6 intercostal nerves
Blood supply
CLINICAL
*paradoxical movements
*referred pain
Position
- Highest in supine position
- Lowest while sitting
- Intermediate while standing
OPENINGS OF THE DIAPHRAGM

Large
1. aortic-T12
(osseoaponeurotic)
- abdominal aorta
- azygos vein
- thoracic duct
2. oesophageal – T10 (muscular- It lies in
fibers of the left crus but a sling of fibers
from the right crus loop around it)
- oesophagus
- 2 vagi
- Oesophageal branches of left gastric
artery
3. venacaval - T8 (central tendon)
- IVC
- Branches of the right
phren
ic
nerve
4. Under lateral arcuate ligament- subcostal neurovascular bundle

5. Under medial arcuate ligament- sympathetic chain
6. Through the right crus- greater & lesser splanchnic nerves
7. Through the left crus – greater & lesser splanchnic nerves and hemiazygos vein

CLINICALS
Diaphragmatic hernia
Congenital hernia– unusual to occur
1. Anteriorly – through foramen of Morgagni (retrosternal); between xiphoid & costal margin
2. Posteriorly – through the foramen of Bochdalek (pleuroperitoneal canals) - posterolateral
hernia
3. through a deficiency of the whole central tendon (central hernia)
4. congenitally large oesophageal hiatus
Acquired hernia- common

- traumatic
- hiatal – sliding hernia
- upper stomach and lower esophagus slide upwards
- competence of cardia disturbed
- gastro-esophageal reflux take place
-rolling hernia
- gastro-esophageal junction remains constant
- fundus rolls up
- no gastro-esophageal reflux
Irritation of diaphragm can cause referred pain in the shoulder tip (via root values C3, C4 and C5

Mediastinum
**Space between the two pleural cavities situated at the center of the thorax
Boundaries of mediastinum.
 Anterior – Sternum
 Posterior – 12 thoracic vertebrae
 Superior – Superior thoracic aperture
 Inferior – Inferior thoracic aperture
 On each side - mediastinal pleurae
Divisions
Imaginary plane through sternal angle of Louis &
lower border of T4 divides mediastinum into
Mediastinum
Superior Inferior
Anterior Middle Posterior
What is the anatomical significance of the plane through sternal angle?
Superior mediastinum
 Boundaries
- anterior - manubrium sterni
- posterior- upper 4 thoracic vertebrae
- superior- superior thoracic aperture
- inferior- imaginary plane through sternal angle and lower border of T4
- on each side- mediastinal pleura
Contents:
- Trachea, oesophagus, thymus, thoracic duct
- Nerves - Vagi, phrenic, left recurrent laryngeal, cardiac nerves
- Veins - Left & right brachiocephalic, SVC, left superior intercostal veins
- Arteries - Left common carotid, left subclavian, brachiocephalic artery & arch of aorta
- Muscles - Sternothyroid, sternohyoid
- Lymph nodes – paratracheal, brachiocephalic, tracheobronchial

CLINICALS
Superior mediastinal syndrome
Cause: enlargement of mediastinal lymph nodes, aortic aneurysm, bronchogenic carcinoma

Compression of mediastinal structures results in:
- Oesophagus– dysphagia (difficulty in swallowing)

- Trachea – dyspnea (difficulty in breathing)
- Phrenic nerves – paralysis of diaphragm (paralyzed diaphragm is raised,
paradoxical movements), shoulder tip pain (C4 – pain referred from
diaphragmatic peritoneum)
- Left recurrent laryngeal nerve – hoarseness of voice(dysphonia)
- SVC – dilatation of neck & facial veins *thoracoepigastric vein
- Stellate ganglion (sympathetic trunk) – Horner’s syndrome
- Vertebral bodies – erosion
- Intercostal nerves - intercostal neuralgia
Mediastinitis
 Little loose connective tissue
 Lots of dead space – expand veins, more on the right side
 Easy spread of infection
 Large surface area
 Toxins get absorbed
 Attachment of prevertebral fascia to T4 – infections spread from the neck to the sup
mediastinum
 Attachment of pretracheal fascia with arch of aorta – neck infections
spread to sup mediastinum & through it to posterior mediastinum

Inferior mediastinum
Anterior Mediastinum Middle Mediastinum Posterior Mediastinum

Boundaries anterior – Body of anterior – sternum & anterior - pericardium,
sternum Sternopericardial ligaments bifurcation of trachea,
posterior – Pericardium posterior - oesophagus, thoracic pulmonary vessels, posterior
superior – imaginary duct, descending thoracic aorta, part of upper surface of
plane azygos vein diaphragm
inferior – Diaphragm On each side – mediastinal posterior– lower 8 thoracic
On each side – pleura vertebrae
mediastinal pleura On each side – mediastinal
pleura
Contents Thymus Heart & pericardium Esophagus, Thoracic duct
Areolar tissue Ascending aorta, pulmonary Descending thoracic aorta &
Lymph nodes trunk, 2 pulmonary arteries branches
&lymphatics Phrenic, deep cardiac plexuses Azygos, hemiazygos& accessory
Sternopericardial Tracheobronchial nodes hemiazygos veins
ligaments Bifurcation of trachea, principal Vagi, splanchnic nerves
Mediastinal branches of bronchi Posterior mediastinal
internal thoracic artery SVC, azygos vein (terminal part), lymph nodes along aorta
pulmonary veins

Great vessels
SVC
- Internal jugular vein + subclavian vein = Brachiocephalic (behind the

sternoclavicular joint)
- Right + left brachiocephalic vein = SVC (behind the sternal end of the right fist
costal cartilage)
- Pierces pericardium – second right costal cartilage
- Opens in to upper part of RA – third right costal cartilage
- *no valves
- Tributaries:
 Azygos - second right costal cartilage
- Before SVC enters pericardium

 Mediastinal, pericardial veins
CLINICALS
Obstruction of SVC
Above azygos opening – through azygos
Below azygos opening – through IVC

Aorta
1.Ascending aorta
 Lower border of 3rd costal cartilage
 Forwards, upwards to the right
 Ends at sternal angle (upper border of 2nd right costal cartilage)

 Branches: right & left coronary arteries
 Relations:
o Anterior
 Sternum
 Left lung & pleura
 Infundibulum
 Root of pulmonary trunk
 Right auricle
o posterior
 Transverse sinus
 Left atrium
 Right pulmonary artery
 Right principal bronchus
o To the right – SVC, right atrium
o To the left – pulmonary trunk, left atrium
2.Arch of aorta
nd
 Begins at upper border of right 2 sternochondral joint
 Upwards, backwards to the left across the bifurcation of trachea
 Downwards behind left bronchus- reach the body of T4 just left of midline
 Arches over root of left lung(Left primary bronchus)
 Ends at the sternal angle
 The convexity reaches as high as midpoint of manubrium
Relations:
anteriorly to the left
 Left phrenic nerve, cardiac nerves, vagus
 Left superior intercostals vein-deep to phrenic nerve & superficial to
vagus
 Left lung & pleura
 Remains of thymus
posteriorly to the right

 Trachea with deep cardiac plexus & tracheobronchial lymph nodes
 Oesophagus
 Left recurrent laryngeal nerve
 Vertebral column
 Thoracic duct

Superiorly
- 3 branches of aorta – brachiocephalic, left common carotid, left subclavian
- All of these crossed by the left brachiocephalic vein close to origin
Inferiorly
- Bifurcation of pulmonary trunk
- Left bronchus
- Ligamentum arteriosum with superior cardiac plexus on it
- Left recurrent laryngeal nerve

Descending thoracic aorta
 Begins on the left side of the lower border of T4
 Descends with an inclination to right
 Terminates at lower border of T12
Relations:
Anterior - root of left lung
-pericardium & heart
-esophagus in the lower part
-diaphragm
Posterior - vertebral column
-hemiazygous veins
-accessory hemiazygous vein
Right - oesophagus in the upper part
-Azygous vein
-Thoracic duct
-Right lung & pleura
Left – left lung & pleura
Branches
O 9 posterior intercostals arteries
o Subcostal artery
o 2 left bronchial arteries
o Oesophageal branches
o Pericardial branches
o Mediastinal branches
o Superior phrenic arteries
CLINICALS
 Aortic aneurysm
 Ductus arteriosus, ligamentum arteriosum, patent ductus arteriosus
 Coarctation of aorta
 Pre ductal– patent ductus arteriosus
 Post ductal – collateral circulation between branches of subclavian & descending

thoracic aorta
- anastomoses between anterior & posterior intercostals – notching of ribs

- anastomoses between inferior epigastric & internal thoracic arteries

- Scapular anastomoses – pulsating scapula
RADIOGRAPHY
 The diaphragm is higher on the Dome of right side (due to the liver)
 Mediastinal shadow – heart & great vessels
 Right border –
o Right brachiocephalic vein
o SVC
o Right atrium
o IVC
 Left border – 
o Aortic knuckles (arch of the aorta)
o Pulmonary trunk
o Left auricle
o Left ventricle
 Inferior border – 
o Centrally merge with diaphragm
o Either side forms cardiophrenic angles
Oesophagus
 25cm long muscular tube
 Begins – C6 – lower border of the cricoid cartilage
 Traverses the superior & posterior mediastina
 Curvatures-2 side to side curvatures ( to the left)
-anteroposterior curvature corresponding to the curvature of

cervicothoracic spine
 Pierces the diaphragm – T10
 Ends at the cardiac orifice of the stomach (T11)
Constrictions:
o C6 : at the beginning (cricopharyngeal sphincter) – 15cm (6’’) from upper incisor teeth `
(narrowest-commencement)
o T4 : Crossed by aortic arch – 22.5 cm (9’’)
o T5 : Crossed by left bronchus – 27.5cm (11’’)
o T10 : Pierces diaphragm – 37.5cm (15’’)

Relations:
Cervical
 Anterior – trachea, thyroid gland
 Posterior – C6,C7,prevertebral fascia
 On each side- Common carotid arteries
Recurrent laryngeal nerves
Left subclavian artery
Terminal part of thoracic duct
Thoracic
 Anterior : -Trachea
-Just below bifurcation of trachea crossed anteriorly by Left bronchus &
Right Pulmonary artery
-Pericardium with left atrium
-Diaphragm

Posterior–
 Vertebral column
 Thoracic duct(first on its right, At T5 crosses to left behind oesophagus)
More
posterior
 Azygos vein &its tributaries
plane  Right posterior intercostal arteries
 Level of T7 – descending thoracic aorta pass behind to it
 To the right –
o right lung & pleura
o Azygos vein – arches over Right primary bronchus
o Right vagus
 To the left

o in the superior mediastinum,
o Left subclavian artery
o Aortic arch
o Left recurrent laryngeal nerve
o Thoracic duct
o Left pleura & lung
-In the posterior mediastinum
 Descending thoracic aorta
 The left lung & pleura
Abdominal
 Passes through an opening in the right crus of the diaphragm
 Behind it, lies the left crus
 Comes to lie in the oesophageal groove on posterior surface of left lobe of liver
 Covered by peritoneum anteriorly & left
Blood supply
Arterial supply:
 Cervical - inferior thyroid arteries
 Thoracic - oesophageal branches of aorta
 Abdominal - oesophageal branches of left gastric artery
Venous drainage:
 Cervical – inf. thyroid vein/brachiocephalic veins
 Thoracic – azygos vein
 Abdominal – partly azygos, partly left gastric
Lymphatic drainage:
 Perioesophageal lymphatic plexus
 Cervical – deep cervical nodes supraclavicular
 Thoracic – post. mediastinal nodes & tracheobronchial nodes
 Abdominal – left gastric nodes & coeliac nodes
Nerve supply:
 Parasympathetic - below the root of the lung vagi form a plexus on it
 Sympathetic – middle cervical & thoracic ganglia
CLINICALS
 Barium swallow

 Indentations – aortic arch, left bronchus, Left atrium
 Oesophageal varices in portal hypertension
 Left atrial enlargement – mitral stenosis
 Achalasia cardia – lower esophageal sphincter fails to open up during swallowing
 Dysphagia -difficulty in swallowing (can be caused by mediastinal syndrome)
Thoracic duct
 45cm long (L2 to root of neck)
 Beaded appearance - presence of valves
 Continuation of cisterna chyli
 Ascends through the aortic opening of the diaphragm (T12)
 Runs through posterior mediastinum behind oesophagus in front of vertebral bodies
 Crosses from right to left (T5)
 Arches laterally – C7 transverse process
 Descends over – left subclavian artery
 Drains – commencement of left brachiocephalic vein (confluence of internal jugular and
subclavian veins)
 Drains the whole lymphatic field below the diaphragm & left half of the body above it
 Right side – right subclavian + jugular trunks = right lymphatic duct
 Together with mediastinal trunk drains into the origin of right brachiocephalic vein
At the aortic opening:

A T A
(R) (L)
Azygous Aorta

Heart & Pericardium
Pericardium
**Fibroserous sac which encloses heart and the roots of great vessels
Pericardium
Fibrous pericardium Serous pericardium

Apex fuses with adventitia of great vessels
Parietal layer
Visceral layer
Base blends with central tendon. (E
Fused with fibrous (Epicardium)

pericardium Adherent to heart
(except along cardiac grooves)
Nerve supply → Phrenic nerve autonomic nerves

Pain sensitivity → sensitive Insensitive
Blood supply → 1) Internal thoracic Artery coronary vessels

2) Musculophrenic Artery
3) Descending aorta
 Angina / cardiac pain originates in the cardiac muscle.
 The pain of pericarditis originates in the parietal pericardium.
Embryological origin→ pleuropericardial membrane - mesothelium of septum transversum
• Parietal and visceral (epicardium) layers of pericardium

• Continuous at the root of great vessels Encloses
•
pericardial cavity → a potential space

Sinuses of pericardium
 Serous pericardium forms an arterial tube
around ascending aorta and pulmonary trunk.
 &
 A venous tube around vena cavae and
pulmonary veins.
Transverse sinus More

posteriorly
 Horizontal gap related to
 Lies between arterial and venous tubes oesophagus
 Bounded,
o Anteriorly → arterial tube
o Posteriorly → superior vena cava
o Inferiorly → left atrium
 When the pericardium is opened anteriorly
during a surgery, a finger placed in the
transverse sinus separates arteries from veins.
 A hand placed under the apex and moved
superiorly, slips into the oblique sinus.
Oblique sinus
Bounded,
O Anteriorly – left atrium
O Posteriorly – parietal pericardium
o On right & left-reflections of the pericardium
 A recess between left atrium and

parietal pericardium
Clinical
Pericardial effusion Collection of fluid in the
(cardiac tamponade) pericardial cavity
• Drained by puncturing -
o Left 5th or 6thintercostals space just lateral to
sternum
o Left xiphicostal space
o Needle directed upward, backward and to the left
• Structures pierced by,
 skin
 superficial fascia
 deep fascia
 external intercostal muscle
 internal intercostals
 innermost intercostals
 fibrous pericardium
 parietal layer of serous pericardium
Pericarditis inflammatory condition of the pericardium.
2
Heart
Position → behind the body of

the sternum,
In the middle mediastinum,
In front of the T5 –
T8 vertebral bodies,
2/3 of the heart- to the
left of the midline
External features
a) Apex → entirely by left ventricle

Left 5th intercostal space, 9 cm lateral to
midline Just medial to midclavicular line
Pulsation can be felt (apex beat)
b) Surfaces→
• Anterior / sternocostal surface
mainly right ventricle & right
atrium (left ventricle, left auricle)
• Posterior/base left atrium
(mainly) & small part of
right atrium
• Inferior/ diaphragmatic right
1/3 of right ventricle, left 2/3
of left ventricle, on central
tendon of diaphragm
• Left surface mainly left
ventricle, Upper end by left
auricle
c) Borders
• Right → right atrium only (acute border)
• Left → left ventricle, partly by left auricle (obtuse border)
Grooves
• Atrioventricular/ coronary sulcus→ separate atria and ventricle

• Interventricular sulcus →Anterior -separate apex from rest of inferior border
Posterior- situated in inferior surface
• Interatrial groove faintly visible posteriorly, anteriorly hidden by
aorta & pulmonary trunk

Surface marking
1) 2nd left costal cartilage

2) 3rd right costal cartilage 0.5 inch from sternal angle
3) 6th right costal cartilage
4) 5th left intercostal space 3.5 inches(9cm) from midline
Chambers of Heart
Right Atrium
Right upper chamber
External features
• Sulcus terminalis→ groove from SVC to IVC along the right border
(Produced by internal muscular ridge- Crista terminalis)
• Upper part of the sulcus contains SA node
• Right atrioventricular groove → separates right atrium from right ventricle
• Right auricle → prolonged upper end
Openings to the right atrium

• SVC • Coronary sinus • Venae cordis minimi
• IVC • Anterior cardiac veins
Smooth post. Part Rough ant. Part Interatrial septum
Derived from right horn of sinus venosus Derived from primitive atrial Derived from septum
chamber primum & septum secundum
Contains muscular ridges Fossa ovalis present in the
Openings arising from crista terminalis lower part
SVC-upper end (musculi pectinati) Limbus fossa ovalis
IVC-lower end Forms posterolateral wall of
Coronary sinus- between the IVC and the right atrium
right atrioventricular orifice
 Venae cordis minimi through
small foramina

Right ventricle
2 parts interior (separated by infundibuloventricular crest)
o In flowing part rough
shows trabeculae carneae/ muscular ridges (proximal part of bulbus cordis)
o out flowing part (infundibulum) smooth (mid portion of bulbus cordis)
2 orifices
• right atrioventricular orifice/tricuspid valve
• pulmonary orifice/semilunar valve
Papillary muscle→3 muscles: Anterior, Posterior, Septal
• Attached to cusps of tricuspid valve via chordae tendinae
• Moderator band contains right branch of AV bundle
(septomarginal trabecula)
-Cavity of the right ventricle is crescentic in shape
Left atrium
• Posterior surface forms the anterior wall of
the oblique sinus
• Greater part of interior is smooth walled
• Fossa lunata on the septal wall
• Two pairs of pulmonary veins open on each
side of posterior wall
• Musculi pectinati are present only in auricle
Left ventricle
2 parts interior
• Upper smooth part →aortic vestibule
gives origin to ascending aorta
• Derived from mid part of bulbus cordis
• Lower rough part with trabeculae carneae
derived from primitive ventricle
• Contains 2 well developed papillary
muscles (anterior & posterior)
• 2 orifices Left atrioventricular orifice/bicuspid (mitral) valve
Aortic orifice/semilunar valve
• Interventricular septum upper part is thin & membranous
Lower part is thick and muscular
Valves of the heart
1) Atrioventricular valves
• Fibrous ring to which the cusps are attached
• Cusps → Smooth atrial surface, Rough ventricular surface
• Rough margins to which chordae tendineae are attached
• Papillary muscles attached to the cusps
• Blood vessels only in fibrous ring
a) Tricuspid valve - between right atrium and right ventricle
b) Bicuspid valve/ -between left atrium and left ventricle
Mitral valve
5 © 2017 A/L Repeat
Campaign
 The mitral valve is more prone to valvular disease
2) Semilunar valves
• 3 semilunar cusps, no chordae tendinae attached
• Nodule in the free margin & lunule extends up to the base of the cusp
• Opposite cusps vessel walls are slightly dilated to form sinuses
a) Aortic valve between left ventricle and ascending aorta
b) Pulmonary valve between right ventricle and pulmonary trunk
-Valves prevent back flow of blood -Chordae tendinae prevent eversion of cusps
-Normal heart sounds are produced by closure of heart valves
Auscultation
Valve Auscultatory area
Pulmonary Second left intercostals space near the sternum
Aortic Second right intercostal space near the sternum
Mitral Cardiac apex- left 5th intercostal space at midclavicular line
Tricuspid Just to the left of the lower part of the sternum near the 5th intercostal space
Conducting system
*Composed of specialized cardiac muscle fibres
SA node
Pacemaker of the heart, Horse shoe shaped
Situated at the atrio-caval junction in the upper
part ofthe sulcus terminalis
Supplied by right coronary artery (60%)
AV node
Situated lower posterior part of interatrial
septumJust above the opening of coronary
sinus
AV bundle of His only muscular connection
between atrial and ventricular musculatures
Right branch A large part enters moderator band (septomarginal trabecula)
Left branch
Purkinje fibres form a subendocardial plexus, pale fibres striated only at margins
Due to defects or damages to this system cardiac arrhythmias
Coronary circulation

Arterial supply
• Heart is supplied by right and left coronary arteries.
Right coronary artery
Arises from anterior coronary sinus ascending aorta. SA nodal artery
Emerges between pulmonary trunk and right auricle. Right atrial
Infundibular branches (right conus artery)
It runs in the right anterior coronary sulcus/right anterior atrioventricular groove.
Winds around the inferior border of the heart right marginal artery
Enters diaphragmatic surface. AV nodal artery
posterior interventricular (IV) artery
runs in the posterior IV groove and ends

by anastomosing with the posterior
interventricular artery
Terminates by anastomosing with the terminal part of the left coronary artery.
• Distribution –
o Right atrium
o Right ventricle except a small area near the anterior IV groove.
o Left ventricle near posterior ventricular groove.
o Posterior 1/3 of the intervent. Septum.
o Whole conducting system except a part of left bundle branch.
Left coronary artery

Arises from the left posterior coronary sinus of ascending aorta.
Emerges between the pulmonary trunk and the left auricle. Left atrial artery
After a short course (sometimes) Diagonal artery
circumflex artery anterior IV artery.
Runs in the anterior IV sulcus

Runs in the left anterior coronary sulcus
Winds around the left border of the heart and Anastomose with the post. inter. Artery at the
gives off the left marginal artery. apex.
Runs in the left posterior coronary sulcus Gives off a conus branch
Gives off several ventricular branches. Largest
branch is called ‘Diagonal artery’
Ends by anastomosing with terminal branches of right. coro. Artery

• Distribution –
o Left atrium
o Left ventricle except for a small area near posterior IV grove.
o Right ventricle – small area near anterior IV groove
o A part of the bundle branch of the AV node
o Anterior 2/3 of IV septum.
 The right and left conus arteries form an anastomotic

ring around the base of the pulmonary trunk.
Veins of the heart
A) Coronary sinus→ largest vein

Situated In left posterior coronary sulcus
Opens into posterior wall of R/atrium
It receives;
Accompanies
Great cardiac vein - first anterior interventricular artery then left coronary artery
Middle cardiac vein- posterior interventricular artery
Small cardiac vein - right coronary artery

(Right marginal vein may drain into this)
Posterior vein of left ventricle
Right marginal vein - marginal artery of right coronary artery
Oblique vein of left atrium derived from left common cardinal vein
B) Anterior cardiac veins directly to right atrium

C) Venae cordis minimi numerous small veins (more in right side)
Present in all four chambers which open
directly into the cardiac cavity

Clinicals
Cardiac pain
 Ischaemic pain- Angina Pectoris

 Incomplete obstruction of a coronary artery, Spasm occurs
 Pain sensations from the heart are carried by sympathetic
fibres which relay on T1 -T5 of the spinal cord
 Sensations from the medial side of the arm, forearm
upper part of front of the chest are carried by somatic
fibres which relay on T2 –T5.
Pain is referred to those areas.
Coronary bypass is done using

  Great saphenous vein OR
 Internal thoracic artery
 Though the pain is usually referred to the left side, it may even be referred to the right
arm, jaw, epigastrium or the back.
Nerve supply of heart

• Parasympathetic – via vagus - Cardioinhibitory
• Sympathetic – from upper 2 to 5 thoracic segments of spinal cord - Cardioacceleratory, Dilate coronary arteries
• Both parasympathetic and sympathetic nerves form superficial and deep cardiac plexuses.
• Superficial plexus - Below arch of aorta, in front of right pulmonary artery
• Deep plexus - In front of bifurcation of trachea, behind arch of aorta

Cardiac Outline
 The right border of the mediastinal shadow is formed from above downwards by the
right brachiocephalic vein, SVC & right atrium.
 The left border of the mediastinal shadow presents a well-marked projection, the aortic
knuckle which represents the aortic arch.
 Beneath this are the shadows due to the pulmonary trunk (infundibulum of LV), left
auricle & left ventricle successively.
 The shadow of the inferior border of the heart blends centrally with the diaphragm but
are separated on either side by well-defined cardiacophrenic angles.
Cardiothoracic ratio
 It is a useful index of cardiac size evaluation, and a value of 50% is generally

considered to indicate the upper limit of normal.
 It is measured by taking the sum of the measurements from the midline to the furthest
point on the right side of the heart & from the midline to the furthest point on the left
side of the heart, and dividing by the transverse diameter of the thoracic wall.

Pleura and Lung
Pleura Lungs
Cervical pleura Apex

I. Curved line I. A line convex upwards
II. Over medial 1/3 of clavicle II. Rising 2.5cm above the junction
III. 2.5cm above the junction between between medial 1/3rd & middle
medial 1/3 & middle 1/3 of clavicle 1/3rd of clavicle
IV. 5cm above the 1st rib
Anterior margin Anterior border
I. From sternoclavicular joint I. From sternoclavicular joint
II. Downwards and medially to the II. Downwards medially to the
midpoint of sternal angle midpoint of the sternal angle
Right Vertically downwards to the midpoint Right Vertically downwards just above the
of sternal angle xiphisternal joint
Left Same course up to level of the 4th Left Up to the 4th costal cartilage, curves
costal cartilage laterally and forms the cardiac notch,
Arches laterally reaches 6th costal cartilage
Descends along the lateral boarder of
sternum up to 6th costal cartilage
Inferior margin Inferior(lower) border

I. Laterally downwards I. Crosses the,
II. Crosses the,  6th rib – midclavicular line
 8th rib – midclavicular line  8th rib – midaxillary line
 10th rib – midaxillary line  10th rib – lateral border of the
 12th rib – lateral border of erector erector spinae & ends 2cm
spine laterally to T10 vertebral spine
Posterior margin Posterior border
I. 2cm lateral to the midline T12 & C7 spine I. 2cm lateral to midline from T10 – C7

Pleura
 Serous membrane lined by single layered mesothelium.
 2 layers
Parietal
Visceral
 2 layers are continuous with each other around the hilum of the lung.
 In between a potential space - the pleural cavity – pleural fluid volume (10-20ml)
Pulmonary/Visceral Pleura
 From splanchnopleuric mesoderm.
 Firmly adherent to the lung.
 Covers the surfaces & fissures of lungs except along the pulmonary ligament & hilum of
the lung.
 Pain insensitive – autonomic supply (T2-T5 sympathetic,
Vagus parasympathetic)
 Supplied by – bronchial arteries

 Drained by – Bronchial veins
 Lymphatic drainage - Broncho pulmonary lymph nodes/tracheobronchial lymph nodes
Parietal Pleura
1. Cervical – covered by suprapleural membrane
2. costal - loosely attached to ribs of int.spaces by endothorasic fascia
3. mediastinal
4. diaphragmatic – covers base of lung
 Pain sensitive Intercostal and phrenic nerves

 Blood Supply Intercostal, Internal thoracic & musculophrenic
Arteries/pericardiophrenic
 Drained by Azygos & internal thoracic veins
 Lymphatics Intercostal nodes
Internal mammary nodes
Posterior mediastinal nodes
Diaphragmatic nodes
Recesses of pleura - Obvious only in expiration
1. Costomediastinal recess
 Between costal & mediastinal pleurae.
 obvious in regions of cardiac notch of the
Left lung.
 Filled by anterior margins of the lungs
even during quiet breathing.
2. Costodiaphragmatic Recess
 Vertically 5 cm.
 extends from 8-10 ribs along the
midaxillary line.
 between costal & diaphragmatic pleura.
3. Pulmonary Ligament
 Parietal Pleura extend downwards beyond the
root.
 Provide a dead space for pulmonary veins and lung roots.
Root of lung-structures that connect lung to
mediastinum.
Hilum-site where structures enter & leave the lung

 Pleura descends below the costal margin at 3 places.
 Right xiphicostal angle.
 Right & left costo vertebral angles below the 12th rib – related to the upper pole of the
kidney.
Clinicals
 Paracentesis thoracis
Tube thoracostomy-chest tube insertion into plural cavity to drain air, blood, bile,
pus or other fluids.
Ex: pneumothorax
Done at safe triangle
Boundaries of safe triangle:
1…………………………………………..........................……..
…………………….……………………………………………………
2…………………………………………………………………………
..…………………………………………………………………………
3………..………………………………………………………………
………………..………………………………………………………..
Structures pierced at this procedure:

1. Skin
2. Superficial fascia
3. Serratus anterior
4. External intercostal
5. Internal intercostal
6. Innermost intercostal
7. Endothoracic fascia
8. Parietal pleura
 Using safe triangle is safer in emergency procedure.
Needle/Syringe insertion

Thoracentesis
Traditionally done
 between 7th and 9th spaces and
 between posterior axillary line and the midline
*Paracentesis thoracis
During any of these procedure needle or tube pass above upper border of the rib. (lower part of the
intercostal space)
Why?
……………………………………………………………………………………………………………………………………………..……………
………………………………………………………………………………………………………………………………………………..…………
Some clinical conditions associate with pleura
Pleurisy – inflammation of pleura

Pneumothorax – air in the pleural cavity
Haemothorax – blood in the pleural cavity
Hydropneumothorax – both fluid & air in the pleural cavity
Empyema – pus in the pleura cavity
Referred pain
Diaphragmatic pleura
 costal and peripheral part - intercostal nerve

 mediastinal and central part – phrenic nerve (C4)
 Irritation of mediastinal and central part is referred to tip of the shoulder.

Pain on
 Right shoulder occurs inflammation of gall bladder

 Left shoulder occurs splenic rupture

Lungs
 Conical shape
 Spongy
 Apex – blunt
 Base – rests on the diaphragm , semilunar , concave
 Anterior border – thin
 Posterior border – ill defined
 Inferior border
 Costal & mediastinal surfaces
Anterior view Posterior view
Fissures
Oblique fissure – Cuts into whole thickness of lung, except at hilum
Due to; lower lobe more posterior than others
o 2cm lateral to the T3 spine
o 5th rib in the mid axillary line
o 6th costal cartilage 3 inches (7.5cm) from midline
OR
Full abduction of the shoulder
o Oblique fissure corresponds to the position of the medial border of the scapula

Transverse Fissure (horizontal) – On right lung only
o Line drawn horizontally along the 4th cc
o Meet the oblique fissure on the 5th rib
Lingula – Tongue shaped projection of left lung below the cardiac notch.
Root of the lung
 short , broad pedicle that connect mediastinal surface into mediastinum.
Contents
1. Principal bronchus on the left, eparterial and hyparterial bronchi on the right.
2. One pulmonary artery.
3. Two pulmonary veins; superior and inferior.
4. Bronchial arteries; one on the right and two on the left.
5. Bronchial veins.
6. Anterior and posterior pulmonary plexuses of nerves.
7. Lymphatics of the lungs.
8. Bronchopulmonary lymph nodes.
9. Areolar tissue.

Arrangement
From before backwards-
- Superior pulmonary vein
- Pulmonary Artery
- Bronchus
From above downwards-

Right Left
- Eparterial bronchus - Pulmonary artery
- Pulmonary Artery - Bronchus
- Hypartrerial bronchus - Inferior pulmonary vein
- Inferior pulmonary vein
Anterior
- phrenic nerve
- pericardiophrenic vessels on both sides
- anterior pulmonary plexuses
*on the right – svc, right atrium
Posterior
- Vagus nerve
- posterior pulmonary plexus on both sides
*on the left – descending thoracic aorta
Superior
On the right – terminal part of the azygos vein
On the left – arch of aorta
Inferior
Pulmonary ligament
Hilum
Lies opposite the bodies of T5, T6, T7 vertebrae
Behind 3rd and 4th costal cartilages
Contents;
 bronchial vessels
A – Right 1, left 2
V
 lymphatics
 bronchopulmonary lymph nodes

Relations of the mediastinal surface
Right Left
- Right atrium and auricle - left ventricle, auricle, infundibulum
- Right ventricle - pulmonary trunk
- SVC, IVC - arch of aorta, descending thoracic aorta
- Azygos vein - left brachiocephalic vein
- Esophagus, trachea - thoracic duct, esophagus
- Right vagus & phrenic - left recurrent laryngeal nerve, left vagus and phrenic

Arterial supply
Bronchial arteries
R – 1 artery from 3rd post. Intercostal
L – 2 arteries from descending aorta upper one – opposite to T5 vertebrae
Lower one – just below left bronchus
Venous drainage 2 bronchial veins on each side

R – Azygos vein
L – Left superior intercostal vein
Greater part - pulmonary veins
Lymphatic drainage
Superficial lymphatics (sub pleural) Deep lymphatics
Pulmonary nodes
Bronchopulmonary nodes
Inferior & superior tracheobronchial nodes (bifurcation of the trachea)
Paratracheal nodes
R & L bronchomediastinal trunks
Directly to the brachiocephalic veins

Indirectly via thoracic or right lymphatic duct
Nerve supply
Parasympathetic – vagus anterior & posterior pulmonary plexuses
Sympathetic – T2, T5 situated in front and behind the lung root
Clinicals
Auscultation of lung
1. Upper lobe – 4th rib on both sides
2. Lower lobe – back
3. Middle lobe – between 4th & 6th ribs on both sides

Bronchial tree
Trachea (C6-T4)
Lower border of T4
Primary/principal bronchi
Secondary/lobar bronchi
One for each lung lobe (2 for left & 3 for right)
Tertiary /segmental bronchi
10 for each side one for each segment
Divide repeatedly
Terminal bronchioles
Respiratory bronchioles
Alveolar ducts
Components of pulmonary unit
Atria
Air saccules
Alveoli
Bronchi Eparterial
Right principal bronchus – divides before enter lungs
Hyparterial
 Wider
 Shorter
 More in line with trachea (More vertical) than left
 2.5cm long

 Angle with tracheal bifurcation – 250
 Infections are common in right side (right lower lobe apical segment/sometimes in middle
lobe at erect position and upper lobe apical segment at supine position)
 Before entering the lung gives superior lobar bronchus
 Superiorly – right – terminal part of the azygos vein
Left principal bronchus
 Nearly 5 cm
 Downwards & outwards below the arch of aorta
 Pulmonary artery anteriorly & above
 Esophagus posteriorly
 Narrower, longer, more oblique
 Angle with tracheal bifurcation - 45°
Bronchopulmonary segments
Definition - a segment of lung supplied by a single segmental (IIIry) bronchus
Features
• 10 in each lung.
• Independent respiratory unit. (surgical, functional, structural)
• Each segment has its own separate artery.
• Veins lie in the intersegmental planes, can isolate a particular segment along the veins
• Bronchopulmonary segment is not a bronchovascular segment (as it doesn’t have its
own vein).
● Pyramidal, apex directs towards root.
Clinicals
 Bronchoscopy
 Widening and distortion of the angle between the primary bronchi
- Carina
- Carcinoma of tracheobronchial lymph nodes around the bifurcation of the trachea.
- Bronchial infections are restricted to specific bronchopulmonary segment.
Trachea

 10-15cm long
 Commencement - lower border of cricoid cartilage. (C6)
 Bifurcation - lower border of T4. (sternal angle)
 In a living subject-varies during respiration--T6-deep inspiration & T4-expiration
 Felt in the jugular notch **displacement
 Blood supply –inferior thyroid arteries
- left brachiocephalic veins
 Lymphatics -pretracheal and paratracheal nodes
 Nerve supply-sympathetic-middle cervical ganglion
-parasympathetic - vagus
 Radiology - translucent as it contains air
 Tracheostomy
 Tracheal tug
Relations
Cervical
Anterior
• Isthmus of thyroid gland
• Inf. Thyroid veins
• Sternothyroid
• Sternohyoid
Posterior
• Esophagus
• Recurrent laryngeal nerve
Laterally
• Lobes of the Thyroid gland
• Common carotid artery {carotid sheath & its contents}

Thoracic
Anterior
• Brachiocephalic artery
• Left carotid artery
• Left brachiocephalic vein
• Thymus
Posterior
• Esophagus
• Recurrent laryngeal nerve
To the left
• Arch of aorta
• Left common carotid artery
• Left subclavian artery
• Left recurrent laryngeal nerve
• Left lung and pleura
To the right
• Right vagus
• Azygos vein
• Right lung and pleura

Physiology of Blood
Composition of Blood
Plasma (55%)
Buffy Coat (WBC and Platelets)(1%)
Red Blood Cells(44%)
(Packed Cell Volume/Haematocrit)
Measurement of Haematocrit- Macrohaematocrit method, Microhaematocrit method
• Total Circulating Blood Volume - 8% of body weight

• Total Plasma Volume - 5% of Body weight
Composition of Plasma
• Water - 90%
• Proteins - 8%
albumin
globulin (α,β,γ - From lymphatic tissues)
fibrinogen
• Inorganic Ions - 1% (Na+, K+, HCO3-, Cl-, Mg+, Ca+)
• Others - 1% (Hormones, gases, waste products)
Functions of Plasma Proteins

1) Binding and Career Proteins (albumin - hormones, fatty acids )
2) Osmotic Regulators (albumin)
3) Buffering action of Blood(15% of buffering action of blood)
4) Producing the viscosity of blood (with RBC)
5) Immunity (γ globulin )
6) Blood coagulation/clotting factors
7) Anti-coagulation
8) Inflammatory responses
• SERUM is the plasma without
• Clotting factors
• Has a higher Serotonin content- Due to breakdown of platelets during clotting
(fluid left behind after a clot is formed)
Haemopoesis ( formation of blood cells)

Haemopoesis
Medullary Extramedullary

First few weeks → yolk sac produces primitive blood cells
6 week- 6-7 of fetal months→ liver, spleen
5-9 months bone marrow (medullary haemopoesis)
Long bones Membranous bones

Eg: femur, humerus Eg: sternum, ribs,
↓ vertebrae, pelvis, cranium
Stop at 30 years ↓
Continuous
Extra medullary hematopoiesis occurs when bone marrow becomes destroyed / fibrosed-liver and
spleen can resume.
In the bone marrow
Pluripotent Haemopoietic stem cell (PHSC) (Multipotent uncommitted stem cell)
IL-1, GM-CSF, IL-6, G-CSF, IL-3, SCF
Committed stem cell (Progenitor cell)
Erythroid Megakaryocyte progenitor CFUGM CFUEO CFUBaso

progenitors (CFUM) GM-CSF  GM-CSF, IL-5  IL-4, IL-3
(CFUE )  GM-CSF, Thrombopoietin Eosinophil Basophil
GM-CSF, Megakaryocyte
Erythropoietin 
Red cells Platelets
CFUM CFUG
 M-CSF  G-CSF
2 Monocyte Neutrophil © 2017 A/L Repeat Campaign
Myelocytic pathway- RBC, platelets, Neutrophils, basophils, monocytes
Lymphocyte pathway-T&B Lymphocytes & NKCells
Growth factors
Formation of growth factors and
differentiation inducers is itself controlled by
factors outside the bone marrow
Ex; RBC production is increased
By exposure to low O2 levels
Growth factor actions
1. cell proliferation
2. differentiation
3. suppression of apoptosis
4. maturation
5. functional activation
Growth Factors -sources of growth factors-
2nd messenger
systems
Gene Activation
Red Blood Cells
Less
basophilic

Normoblast Reticulocyte Mature RBC
Nuclear DNA Yes No No
RNA in cytoplasm Yes Yes No
In marrow Yes Yes Yes
In blood No Yes Yes
• No Nucleus
• Life span-120 days
• Higher concentration in males than females - sex hormones affect the rate of haemopoiesis
• Contains Hemoglobin
34% i.e. 1/3 from the weight of a RBC
• As RBCs carries the maximum amount of Hb at normal circumstances it can never become
hyperchromic
• Daily; only 25% of Pluripotent Haemopoietic stem cell (PHSC) differentiate into RBCs but high
amount of RBCs seen in blood because of its long life time
• Mature RBC - Biconcave disc shaped - High surface area: Volume ratio
Functions of RBC
• Transport of O2 and CO2
• Buffering action by Hb and proteins
• Contains Carbonic Anhydrase enzyme
Functions of RBC membrane

• Maintain the shape of the cell
• Helps in the transportation of essential cellular ions and gases
• supporting system for surface antigens
Reticulocytosis (normal <1% of RBC)
Reticulocyte count is more than 2 % from RBC count
1. To compensate for hemolysis

2. Following treatment for deficiency anemia
Requirements for normal erythropoiesis

1) Erythropoietin- Specific growth factor
(85%-kidney, 15%- liver) = glycoprotein
2) Iron for Hb synthesis
3) Vit B12 & Folic acid (for DNA synthesis)
4) B6, A, C, E, Riboflavin(B2)
5) Trace metals- Zn, Cu, Co
6) Hormones - androgens & thyroxine

Erythropoietin
Glycoprotein Hormone, having following functions
1) Proliferation of Progenitor cells committed to erythropoiesis

2) Differentiation of stem cells committed to erythropoiesis
3) Suppresion of apoptosis - maintain cells of erythroid series
4) Release of reticulocytes to the circulation
5) Promoting Transferrin receptor synthesis
6) Hb synthesis
Kidney and liver has O2 sensors, when there is hypoxia, erythropoietin synthesis is stimulated.
If both kidneys are affected , non- renal production of erythropoietin can compensate the RBC production
up to 33%-50% (1/3-1/2)
Hemoglobin
HbA (adult ) = 2α 2β HbF (fetal) = 2α 2γ
HbS (sickle cell) = 2α 2𝛽 ′ (β chain is affected)
HbA2 = 2α 2𝛿
Glycated haemoglobin = HbAIC (increased in patients with Diabetes mellitus.So it used as clinical marker
for Diabetes mellitus )
oxygenation
Hb + 402 Hb (O2)4 oxyhaemoglobin
RBC Abnormalities
• Due to a defect in the membrane - Hereditary spherocytosis
• Due to a defect in hemoglobin production - Thalassemia , sickle cell disease
• Due to the deficiency of enzyme G6PD-Haemolysis
Red cell destruction
➢ Intravascular hemolysis - Hb is released into the plasma due to

1. RBC enzyme defects (G6PD deficiency)
2. Incompatible blood transfusions
➢ Extravascular hemolysis - Reticulo-endothelial system(Tissue macrophage system)

1. Membrane defects (Hereditary spherocytosis)
2. Hb abnormal

Bilirubin Metabolism
(Jaundice GIT)
Anaemia
Reduction in concentration Of Hb below accepted normal range (which depends on sex, age, ethnic
group, altitude)
Features - Tachycardia, palpitations, heart murmur, dyspnea, pallor
Causes of Anaemia
↓ Production
↑ Loss ↑ Destruction
*nutritional deficiency
Haemorrhages Eg: hemolytic
anaemia *↓ bone marrow erythroid cells
*renal disease

Examples of anemia
1. Blood loss anemia
After rapid blood loss
Body replaces fluid portion in about 3 days
But cells are not replaced so quickly
PCV and Hb concentration Reduced
Normocytic normochromic anemia
In a chronic blood loss
Loss iron is not compensated from absorbed iron
Microcytic hypochromic anemia
2. Megaloblastic anemia
Pernicious anemia Gastrectomy Absorption defects in small intestine
Reduction of Folic acid and Vit B 12
RBC proliferation is hindered
Macrocytic megaloblastic anemia
3. Hemolytic anemia
a) Hereditary spherocytosis
Defects in RBC plasma membrane(Defects in spectrin protein)
Cells become spherical rather than being biconcave disks
Can not withstand compression forces
Hemolyse (when passing through spleen ,through vascular beds)

b) Sickle cell anemia
Abnormal haemoglobin (HbS with faulty 𝛽 chain)
Form crystals and precipitate when exposed to low O2 conditions
Elongate the cell
Cell become sickle shaped
Haemolyse easily
Reduction of RBC for O2 transport
Further low O2 conditions
Enter a vicious cycle that may even lead to death in some cases
c) Erythroblastosis fetalis(Haemolytic disease of New born)
Rh+ RBC in the fetus are attacked by Rh- antibodies from mother
Child born with severe anemia and Jaundice
d) G6PD Deficiency
Hinder HMP pathway
Reduction of NADPH which is needed to maintain RBC membrane
Fragile RBC membrane
Haemolysis
4. Normocytic normochromic anemia

Renal failure, Aplastic anemia , Leukemia
5. Microcytic hypochromic anemia
Fe deficiency , Thalassemia
MCV = Mean corpuscular volume = Average volume of a RBC = 76- 96 fL
Microcyte < 76normocyte Macrocyte>96 (Values not needed )
MCH = Average amount of Hb in RBC 27-33 pg
MCHC = amount of Hb in a dL of RBC 32-36 g/dL Hypochromic<25 g/dL

RBC being Hyperchromic is impossible since RBCs normally carry the maximum amount of Hb they can
carry
Polycythemia (erythrocytosis)
Polycythemia (erythrocytosis)
Primary Secondary
pathological Physiological
-cancer ↑ erythropoiesis
*polycythemia rubra vera Hypoxic
Renal disease
❖ Comparison between Fe deficiency anemia Vit B12 deficiency anemia and physiological
anemia in pregnancy
Fe deficiency anemia Vit B12 deficiency Pregnancy

anemia
RBC count Normal/Reduced Reduced Raised
[Hb] Reduced Reduced Reduced
PCV Reduced Reduced Reduced
MCV Reduced Raised Normal
MCH Reduced Raised
MCHC Normal/Reduced Normal
Serum iron Reduced Normal
Serum ferritin Reduced Normal
Total Fe binding Raised Normal

capacity
ESR – Erythrocyte Sedimentation Rate
Increased in Decreased in
Severe anemia Polycythemia
Malignancies Sickle cell anemia
Pregnancy Protein abnormalities
Rheumatic fever
TB

Blood groups
Agglutinogens (Antigens) : complex oligosaccharide substances found only on RBC membrane
Agglutinins: antibodies against Agglutinogens , present in plasma after birth
Phenotype Agglutinogens Agglutinins genotype

H antigen + N acetyl
( on RBC ) (in plasma) A antigen
galactosamine
A B antigen H antigen + Galactose

A Anti-B AA,AO
B
B Anti-A BB,BO
O antigen H antigen
AB
A,B None AB
O Bombay blood group do not have H antigen
None Anti-A ,Anti-B OO
in their RBC, have both anti A and anti B
antibodies in blood.
Rh system
Antigens present only on RBC
C , D , E - three types of antigens, D is most antigenic
• Unlike ABO antibodies Anti D antibodies do not develop without exposure of D- RBC to D+ RBC by
transfusion or pregnancy
• Cross matching Donor RBC + Recipients plasma
Complications of blood transfusion
1. Incompatibility reactions
Antigens on Donor RBC + Antibodies in recipients plasma
RBC Agglutination
Clumps
IV Hemolysis
May block blood
Release Hb
vessels
Jaundice
Renal failure
2. Fever, allergic reaction, circulatory overload, Iron overload, Air embolism, diseases (ex:- malaria,
AIDS)

Hemolytic disease of newborn
Rh+ incompatibility
↓
When mother Rh-, first baby Rh+
↓
Fetal blood can leak into maternal circulation at the time of the delivery
↓
Mother is sensitized
↓
Formation of Anti D antibodies in mother’s circulation
↓
These antibodies can cross the placenta in subsequent pregnancies
↓
Hemolysis of fetal RBCs
↓
Hemolytic disease of the new born (erythroblastosis fetalis)
• At first IgM antibodies which are pentamers are formed, they cannot cross placenta
• Secondly IgG antibodies which are monomeric are formed, so they can cross the placenta in
subsequent pregnancies
• Rhogam is administered within 72 hours after delivery, it consist of synthetic anti D antibodies,
prevent sensitization of mother to D antigen
Complications
o Death,
o severe anaemia
o jaundice
o oedema(hydrops fetalis)
o Kernicterus = destruction of neuronal cells due to deposition of bilirubin (as fetal blood brain barrier
is still underdeveloped and may be permeable to certain substances)
White Blood Cells

• Opsonization is done by antibodies that coating of material to be phagocyted like “making it tasty”
Neutrophils secrete
• Metalloproteinases -Facilitate the movements of other
• Elastase neutrophils by digesting collagen in the ECM
• Defensins - Antimicrobial peptide
• Thrombaxanes - Vasoconstriction
• Leukotrines - Increases vascular permeability and attraction of other
neutrophils
• Prostaglandins - Inflammatory mediator
• PAF - platelet aggregation
• Lactoferrin -Binds to iron required for bacterial growth
❖ WHY MACROPHAGE ACTION IS MORE POTENT THAN NEUTROPHILS?
• Neutrophils can only ingest 3-20 bacteria whereas macrophages can about 100.
• Macrophages have the ability to ingest large particles as RBC/malaria parasites.
• Macrophages can extrude the residual products after digesting particles and can survive for
more months whereas neutrophils cannot.
• Macrophage lysosomes have large amount of lipases which can digest the thick lipid
membranes of bacteria. (specially Tuberculosis bacillus)

WBC in order of abundance in health- Neutrophils>Lymphocytes>Monocytes>Eosinophils>Basophils
• WBC count- Differential count, Absolute count
• leucopenia, leukocytosis, –Decrease, increase in no. of WBC
• leukemia- increase in no. of abnormal WBC in blood
• Pancytopenia, - Decrease of RBC,WBC and platelet count
• Bicytopenia- decrease in any two of above

Immunity
Ability to resist almost all

Immunity types of organisms or toxins
that tend to damage tissues
and organs
Acquired
Innate
1. Phagocytosis- WBC, tissue

macrophage Humoral Cell mediated
2. Acid & enzymes in GIT • Antibody mediated • Involves T
3. Skin • Involves B lymphocytes, antigen
4. Blood- lysozyme ,basic lymphocytes, presenting cells and
polypeptides plasma cells and MHC (major
Complement complex antibodies histocompatibility
Natural killer lymphocytes complex) molecules
5. Sneezing, coughing reflex
Innate immunity Acquired immunity

Non-specific Specific to antigen
First response Second response
Immediate Delayed
Cell structure is not modified (no memory) Memory acquired, so ability to produce
accelerated response to the second infection
Persist for a long time
Immune tolerance – deactivation of lymphocyte
precursors that react to self-antigens
Clonal section – stimulate division of effector
cells that respond to particular antigen
Innate Immunity
Acquired Immunity
Complement system
• Plasma proteins 4th LINE OF DEFENCE

• Act via a cascade
• Bridge between innate and acquired immune systems
• 3 pathways to activate
o Classic pathway – activated by immune complexes
o Mannose binding lectin pathway – triggered when lectin binds to mannose groups in bacteria
o Alternative pathway – triggered by contact with virus, bacteria, fungi and tumor cells

Functions of Complements
• Opsonization and facilitate phagocytosis (acts over bacteria to make them tasty)
• Chemotaxis (attract neutrophils to infected areas)
• Lyses of the cells (destruction of the cells)
• Activation of B lymphocytes
MHC (major histocompatibility complex)
• Glycoproteins
• Present on the surface of the cells
o MHC I – PresentAll nucleated cells
o MHC II – Macrophages, dendritic cells and natural killer cells
• Polypeptide products of digested antigens are coupled to MHC on surface of cells.
Immunoglobulin
• Ig G = Monomer; complement activation, can cross placenta
• Ig A = localized protection in external secretion , Monomer/Dimer/Trimer
• Ig M = Complement activation, can't cross placenta, Pentamer
• Ig D = Antigen recognition by B cells, Monomer
• Ig E = Binds to basophiles & mast cells, Monomer
Functions of Immunoglobulin
1) Binds and neutralize protein toxins

2) Blocks attachment of organisms to cell
3) Opsonization of bacteria
4) Activate compliment system by classic pathway

Acquired Immunity Pathway
Antigen (pathogen)
Invaded by macrophages, dendritic cells, natural killer cells and other nucleated cells
Polypeptide products of antigens are digested and coupled to MHC
Products of viruses Products of

& pathogens within extracellular
infected cell or APC organisms
MHC I, In APC (antigen

presenting cell) and all MHC II only in APC
nucleated cells
Present it to CD8 of cytotoxic T cells Present it to CD4 of T helper cells
Directly destroy the cells Secrete lymphokines (GM-CSF, IL 2-6,Interferon γ)

containing the antigen that activate other lymphocytes
Suppressor T cells
(virus, fungi, tubercle
GM-CSF acts on Memory T cells
bacillus) by initiating Cytotoxic T cells
apoptosis via perforins bone marrow to
increase WBC
Stimulation of B
cell growth and
B cell
differentiation
Memory B cells Plasma cells
Important in Produce antibodies

secondary infection
Antibodies=Immunoglobin
s
Direct Actions
Agglutination
Complement
Precipitation system activation
(classic pathway)
Neutralization of protein toxin
Lysis by enzymes

Clonal selection & clonal expansion - In a pre existing group of lymphocytes, a specific antigen only
activates (i.e. Selects) its counter specific cell so that particular cell is induced to multiply (producing
its clones i.e. Expansion) for antibody production.
Active Immunity - Person's own body develops either antibodies or activated T cells in
response to invasion of the body by a foreign antigen
Passive Immunity - By infusing antibodies, activated T cells or both, obtained from the blood
of someone else or from some other animal that has been actively
immunized against the antigen
Immune Tolerance - Process by which the immune system does not attack an antigen.
Auto Immunity - The failure of an organism in recognizing its own constituent parts as self, which,
b allows an immune response against its own cells and tissues.
Primary Immune response : Slow, Lower level, shorter duration, IgM Main type
Secondary Immune Response : Rapid, Potent, Longer duration, IgG main type
Electron dense Platelet

Platelets granules Membrane
Ca, ADP, ATPm Binding sites for

• Small Granulated bodies collagen,
Serotonin(5- HT)
• No Nuclei fibrinogen VWF,
• 2-4 µm in diameter ADP
Cytoplasm
• Life span 7-10 days α Granules
• 60-75% in circulation, others in spleen Lysosomes-hydrolytic
• 150-400 x 109 per liter enzymes PDGF
Peroxisome -catalase β thromboglobulin,
Actin , myosin heparin antagonist
Contractile
thrombosthenin fibrinogen clotting factors
Protein
VWF & Other
✓ Thrombocytopenia - Decrease in platelet count below normal e.g.: HIV AIDS, dengue, Portal
hypertension (Blood is diverted to spleen → Splenomegaly →Sequestration of platelets → Reduction
of platelets → Thrombocytopenia) Leads to failure of clot retraction
✓ Thrombocytosis - Increase in platelet count above normal e.g.: splenectomy, bone marrow cancer
Thrombocytopenia
Purpura - Low count
(Purplish discolouration due to small
Haemorrhages) Thrombosthenic
- Loss of function
Von WILLEBRAND Factor (VWF)
• Forms adhesive bridges between endothelial cells and platelets as well as in between platelets
• Extends the half-life of factor VIII (factor VIII regulation)
Haemostasis
Haemostasis is the process of forming clots in the walls of the damaged blood vessel and preventing blood
loss while maintaining blood in fluid state within vascular system
Injury to a vessel
Anticoagulants
Bleeding
Breakdown the clot once the
damage is repaired
procoagulants
Prevent intravascular
Formation of clot
coagulation or Thrombus
formation (thrombosis)
Stop bleeding
Vessel injury
Vasoconstriction Exposure of collagen Tissue thromboplastin
Vascular response
Clotting response
Platelet response
(Formation of a definitive
(Formation of a temporary clot)
clot)
Vascular response
Obliteration of lumen of the damaged blood vessel Stop bleeding
• Nervous reflexes - pain

• Initiated by direct damage to vessel wall
• Local humoral factors - 5 HT (Serotonin/5 Hydroxy Triptamine), thromboxane A2
• Local myogenic contractions of blood vessel
Platelet Response
• Can plug up small perforations

Vessel injury
Collagen & endothelial cells

exposed VWF needed
Platelet adhesion Produced by endothelial cells
Intraplatelet Ca2+ 
- Change shape
Platelet Activation - Put up pseudopodia
- Contract using contractile
protein
Platelet release reaction Discharge granular contents
PAF (Platelet Aggregating Factor), ADP, Neutrophils

Thromboxane A2 Monocytes
Platelets
Platelet aggregation
Platelet Plug
(Prostacyclin)
• Aspirin is a non-selective irreversible inhibitor of Cyclooxygenase enzyme.

• Once Cyclooxygenase enzyme is inhibited endothelial cells can readily produce it as endothelial cells
have a nucleus. Platelets do not have nucleus. So, they cannot produce Cyclooxygenase enzyme.
So, concentration of prostacyclin increases with time. So that aspirin act as vasodilator.
Clotting response
Loose aggregation of platelets Definitive clot in the temporary plug
01. Formation of activated factor X (Xa) Intrinsic &

[Rate limiting step in the clotting process]
Extrinsic pathways
02. Conversion of Prothrombin to Thrombin
03. Conversion of Fibrinogen To Fibrin [ fundamental reaction in the clotting of blood ]
Intrinsic pathway (6-10 mins)
Exposure of blood to collagen fibers underlying endothelium – in vivo

[Exposure of blood to electronegatively charged water wettable surface e.g. glass – in vitro]
(High molecular weight Kininogen)

Prevented by coating glass
with Wax
(Not Essential)
(Platelet Phospholipids)
Extrinsic Pathway (12-20S)

From damaged tissues
Xa
Common Pathway
Once blood clot has formed, clot

retraction occurs expelling most of
the fluid (serum) in it.
Formation of fibrous tissue +

+
- if the clot is too small OR Dissolution
of the clot
- if the clot is too large

(Fibrin Stabilization Factor)
❖ all reactions are Enzymatic
❖ All steps except 1st two steps in intrinsic pathway requires Ca2+ but it won’t be a rate limiting factor
since such low levels of Ca2+ causes death
By foaming Cross links Between Fibrin monomers
Anti-clotting mechanisms
In order to prevent clotting inside the blood vessels and to break down any clots formed
1. Endothelial surface factors

- Smoothness of endothelium
- Glycocalyx layer- repels clotting factors and platelets
- Thrombomodulin-thrombin binding protein
Thrombomodulin-thrombin complex
Protein C Activated protein C

- Thrombomodulin-thrombin complex isn’t present in the cerebral microcirculation. This
increases the tendency of getting strokes.
2. Antithrombin III (circulating protease inhibitor)

Antithrombin III Binds to thrombin
This binding is facilitated by Heparin.
Heparin-Antithrombin III complex inhibits activated Factors IIa, IXa, Xa, XIa, XIIa
3. Tissue Factor pathway inhibitor (makes complex with Va, VIIa, Xa)
4. Interaction between TXA2 & Prostacyclin
5. Fibrinolytic system (Plasminogen System)
Plasminogen plasmin
t-PA, u-PA
Streptokinase -bacterial enzyme -fibrinolytic - Function like t-PA

Fibrinolytic agents
Streptokinase & Human recombinant t-PA are used in treatment of myocardial infarction
Streptokinase cannot cross blood brain barrier, so recombinant t-PA is given in stroke medication
Anti-coagulants
A. In vivo
1. Low molecular Heparin weight -Facilitates the action of antithrombin ш
2. Coumarin derivatives -Dicoumarol, Warfarin
Inhibit the action of Vitamin K (by inhibiting vit K reductase enzyme) , vitamin K is necessary for
the production of Factors II (Prothrombin), VII, IX and X, protein C and protein S
Glutamic acid residues -Carboxy-glutamic acid residues

Cofactor – Vit K
* -Carboxy-glutamic acid residues increases (-) charge in the clotting factors which can then adhered to
platelet membrane phospholipids through Ca2+
B. In Vitro
1. Heparin
2. Oxalate - E.g.-Na Oxalate, K Oxalate
From insoluble salts with Ca2+
3. Citrates -E.g.- Na Citrate ACD CPD

4. EDTA - Chelating agent- bind Ca 2+
Abnormalities of hemostasis
1. Vessel wall abnormalities (e.g. – Weakening of collagen in Vit. C deficiency)

2. Platelet disorders - platelet number & quality
3. VIII deficiency - Hemophilia A(classic hemophilia)
4. IX deficiency -Hemophilia B(Christmas disease)
5. Congenital deficiency of VWF
6. Liver disease - production of clotting factors is decreased
Clearance of plasminogen activator is reduced
Reduced production of Thrombopoietin and hence platelets
7. Bile duct obstruction - Vit K absorption is reduced

8. Excess of clot formation & excessive activation of the fibrinolytic system- DIC (Disseminated
intravascular coagulation) – in infections, extensive tissue injury
9. Renal failure
Test for Haemostasis
1. Bleeding time test - for vascular response & platelet response( minor/superficial wounds)
2. Platelet count
3. Hess Test - for vascular integrity (capillary integrity) ; Checking progression of Dengue
4. Prothrombin time test/INR - For extrinsic pathway and common pathway of clotting
5. Whole blood clotting time test - for intrinsic pathway and common pathway of clotting
6. Activated Partial Thromboplastin Time Test(APTT) -For Intrinsic + common pathway of clotting
7. Thrombin time

White Blood Cells
 Opsonization is done by antibodies that coating of material to be phagocyted like “making it tasty”
Neutrophils secrete
 Metalloproteinases -Facilitate the movements of other
 Elastase neutrophils by digesting collagen in the ECM
 Defensins - Antimicrobial peptide
 Thromboxanes - Vasoconstriction
 Leukotrienes - Increases vascular permeability and attraction of other
neutrophils
 Prostaglandins - Inflammatory mediator
 PAF - platelet aggregation
 Lactoferrin - Binds to iron required for bacterial growth
 WHY MACROPHAGE ACTION IS MORE POTENT THAN NEUTROPHILS?
 Neutrophils can only ingest 3-20 bacteria whereas macrophages can about 100.
 Macrophages have the ability to ingest large particles as RBC/malaria parasites.
 Macrophages can extrude the residual products after digesting particles and can survive for
more months whereas neutrophils cannot.
 Macrophage lysosomes have large amount of lipases which can digest the thick lipid
membranes of bacteria. (specially Tuberculosis bacillus)

WBC in order of abundance in health- Neutrophils>Lymphocytes>Monocytes>Eosinophils>Basophils
 WBC count- Differential count, Absolute count
 leucopenia, leukocytosis, –Decrease, increase in no. of WBC
 leukemia- increase in no. of abnormal WBC in blood
 Pancytopenia, - Decrease of RBC,WBC and platelet count
 Bicytopenia- decrease in any two of above

Immunity
Ability to resist almost all

Immunity types of organisms or toxins
that tend to damage tissues
and organs
Acquired
Innate
1. Phagocytosis- WBC, tissue

macrophage Humoral Cell mediated
2. Acid & enzymes in GIT  Antibody mediated  Involves T
3. Skin  Involves B lymphocytes, antigen
4. Blood- lysozyme ,basic lymphocytes, presenting cells and
polypeptides plasma cells and MHC (major
Complement complex antibodies histocompatibility
Natural killer lymphocytes complex) molecules
5. Sneezing, coughing reflex
Innate immunity Acquired immunity

Non-specific Specific to antigen
First response Second response
Immediate Delayed
Cell structure is not modified (no memory) Memory acquired, so ability to produce
accelerated response to the second infection
Persist for a long time
Immune tolerance – deactivation of lymphocyte
precursors that react to self-antigens
Clonal section – stimulate division of effector
cells that respond to particular antigen
Innate Immunity
Acquired Immunity
Complement system
 Plasma proteins 4th LINE OF DEFENCE

 Act via a cascade
 Bridge between innate and acquired immune systems
 3 pathways to activate
o Classic pathway – activated by immune complexes
o Mannose binding lectin pathway – triggered when lectin binds to mannose groups in bacteria
o Alternative pathway – triggered by contact with virus, bacteria, fungi and tumor cells

Functions of Complements
 Opsonization and facilitate phagocytosis (acts over bacteria to make them tasty)
 Chemotaxis (attract neutrophils to infected areas)
 Lyses of the cells (destruction of the cells)
 Activation of B lymphocytes
MHC (major histocompatibility complex)
 Glycoproteins
 Present on the surface of the cells
o MHC I – Present in all nucleated cells
o MHC II – Macrophages, dendritic cells and natural killer cells
 Polypeptide products of digested antigens are coupled to MHC on surface of cells.
Immunoglobulin
 Ig G = Monomer; complement activation, can cross placenta
 Ig A = localized protection in external secretion , Monomer/Dimer/Trimer
 Ig M = Complement activation, can't cross placenta, Pentamer
 Ig D = Antigen recognition by B cells, Monomer
 Ig E = Binds to basophiles & mast cells, Monomer
Functions of Immunoglobulin
1) Binds and neutralize protein toxins

2) Blocks attachment of organisms to cell
3) Opsonization of bacteria
4) Activate compliment system by classic pathway

Acquired Immunity Pathway
Antigen (pathogen)
Invaded by macrophages, dendritic cells, natural killer cells and other nucleated cells
Polypeptide products of antigens are digested and coupled to MHC
Products of viruses Products of

& pathogens within extracellular
infected cell or APC organisms
MHC I, In APC (antigen

presenting cell) and all MHC II only in APC
nucleated cells
Present it to CD8 of cytotoxic T cells Present it to CD4 of T helper cells
Directly destroy the cells Secrete lymphokines (GM-CSF, IL 2-6,Interferon γ)

containing the antigen that activate other lymphocytes
Suppressor T cells
(virus, fungi, tubercle
GM-CSF acts on Memory T cells
bacillus) by initiating Cytotoxic T cells
apoptosis via perforins bone marrow to
increase WBC
production
Stimulation of B
cell growth and
B cell
differentiation
Memory B cells Plasma cells
Important in Produce antibodies

secondary infection
Antibodies=Immunoglobin
Direct Actions
Agglutination
Complement
Precipitation system activation
(classic pathway)
Neutralization of protein toxin
Lysis by enzymes

Clonal selection & clonal expansion - In a preexisting group of lymphocytes, a specific antigen only
activates (i.e. Selects) its counter specific cell so that particular cell is induced to multiply (producing
its clones i.e. Expansion) for antibody production.
Active Immunity - Person's own body develops either antibodies or activated T cells in
response to invasion of the body by a foreign antigen
Passive Immunity - By infusing antibodies, activated T cells or both, obtained from the blood
of someone else or from some other animal that has been actively
immunized against the antigen
Immune Tolerance - Process by which the immune system does not attack an antigen.
Auto Immunity - The failure of an organism in recognizing its own constituent parts as self, which,
b allows an immune response against its own cells and tissues.
Primary Immune response : Slow, Lower level, shorter duration, IgM Main type
Secondary Immune Response : Rapid, Potent, Longer duration, IgG main type
Electron dense Platelet

Platelets granules Membrane
Ca, ADP, ATPm Binding sites for

 Small Granulated bodies collagen,
Serotonin(5- HT)
 No Nuclei fibrinogen VWF,
 2-4 µm in diameter ADP
Cytoplasm
 Life span 7-10 days α Granules
 60-75% in circulation, others in spleen Lysosomes-hydrolytic
 150-400 x 109 per liter enzymes PDGF
Peroxisome -catalase β thromboglobulin,
Actin , myosin heparin antagonist
Contractile
thrombosthenin fibrinogen clotting factors
Protein
VWF & Other
 Thrombocytopenia - Decrease in platelet count below normal e.g.: HIV AIDS, dengue, Portal
hypertension (Blood is diverted to spleen → Splenomegaly →Sequestration of platelets → Reduction
of platelets → Thrombocytopenia) Leads to failure of clot retraction
 Thrombocytosis - Increase in platelet count above normal e.g.: splenectomy, bone marrow cancer
Thrombocytopenia
Purpura - Low count
(Purplish discolouration due to small
Haemorrhages) Thrombosthenic
- Loss of function
Von Willerbrand Factor (VWF)
 Forms adhesive bridges between endothelial cells and platelets as well as in between platelets
 Extends the half-life of factor VIII (factor VIII regulation)
Haemostasis
Haemostasis is the process of forming clots in the walls of the damaged blood vessel and preventing blood
loss while maintaining blood in fluid state within vascular system
Injury to a vessel
Anticoagulants
Bleeding
Breakdown the clot once the
damage is repaired
procoagulants
Prevent intravascular
Formation of clot
coagulation or Thrombus
formation (thrombosis)
Stop bleeding
Vessel injury
Vasoconstriction Exposure of collagen Tissue thromboplastin
Vascular response
Clotting response
Platelet response
(Formation of a definitive
(Formation of a temporary clot)
clot)
Vascular response
Obliteration of lumen of the damaged blood vessel Stop bleeding
 Nervous reflexes - pain

 Initiated by direct damage to vessel wall
 Local humoral factors - 5 HT (Serotonin/5 Hydroxytriptamine), thromboxane A2
 Local myogenic contractions of blood vessel
Platelet Response
 Can plug up small perforations

Vessel injury
Collagen & endothelial cells

exposed VWF needed
Platelet adhesion Produced by endothelial cells
Intraplatelet Ca2+ 
- Change shape
Platelet Activation - Put up pseudopodia
- Contract using contractile
protein
Neutrophils
Platelet release reaction Discharge granular contents Monocytes
Platelets
PAF (Platelet Aggregating Factor), ADP,

Thromboxane A2
Platelet aggregation
Platelet Plug
(Prostaglandins)
 Aspirin is a non-selective irreversible inhibitor of Cyclooxygenase enzyme.

 Once Cyclooxygenase enzyme is inhibited endothelial cells can readily produce it as endothelial cells
have a nucleus. Platelets do not have nucleus. So, they cannot produce Cyclooxygenase enzyme.
So, concentration of prostacyclin increases with time. So that aspirin act as vasodilator.
Clotting response
Loose aggregation of platelets Definitive clot in the temporary plug
01. Formation of activated factor X (Xa) Intrinsic &

[Rate limiting step in the clotting process]
Extrinsic pathways
02. Conversion of Prothrombin to Thrombin
03. Conversion of Fibrinogen To Fibrin [ fundamental reaction in the clotting of blood ]
Intrinsic pathway (6-10 mins)
Exposure of blood to collagen fibers underlying endothelium – in vivo

[Exposure of blood to electronegatively charged water wettable surface e.g. glass – in vitro]
(High molecular weight Kininogen)

Prevented by coating glass
with Wax
(Not Essential)
(Platelet Phospholipids)
Extrinsic Pathway (12-20S)

From damaged tissues
Xa
Common Pathway
Once blood clot has formed, clot

retraction occurs expelling most of
the fluid (serum) in it.
Formation of fibrous tissue +

+
- if the clot is too small OR Dissolution
of the clot
- if the clot is too large

(Fibrin Stabilization Factor)
 all reactions are Enzymatic
 All steps except 1st two steps in intrinsic pathway requires Ca2+ but it won’t be a rate limiting factor
since such low levels of Ca2+ causes death
By foaming Cross links Between Fibrin monomers
Anti-clotting mechanisms
In order to prevent clotting inside the blood vessels and to break down any clots formed
1. Endothelial surface factors

- Smoothness of endothelium
- Glycocalyx layer- repels clotting factors and platelets
- Thrombomodulin-thrombin binding protein
Thrombomodulin-thrombin complex
Protein C Activated protein C

- Thrombomodulin-thrombin complex isn’t present in the cerebral microcirculation. This
increases the tendency of getting strokes.
2. Antithrombin III (circulating protease inhibitor)

Antithrombin III Binds to thrombin
This binding is facilitated by Heparin.
Heparin-Antithrombin III complex inhibits activated Factors IIa, IXa, Xa, XIa, XIIa
3. Tissue Factor pathway inhibitor (makes complex with Va, VIIa, Xa)
4. Interaction between TXA2 & Prostacyclin
5. Fibrinolytic system (Plasminogen System)
Plasminogen plasmin
t-PA, u-PA
Streptokinase -bacterial enzyme -fibrinolytic - Function like t-PA

Fibrinolytic agents
Streptokinase & Human recombinant t-PA are used in treatment of myocardial infarction
Streptokinase cannot cross blood brain barrier, so recombinant t-PA is given in stroke medication
Anti-coagulants
A. In vivo
1. Low molecular Heparin weight -Facilitates the action of antithrombin ш
2. Coumarin derivatives -Dicoumarol, Warfarin
Inhibit the action of Vitamin K (by inhibiting vit K reductase enzyme) , vitamin K is necessary for
the production of Factors II (Prothrombin), VII, IX and X, protein C and protein S
Glutamic acid residues -Carboxy-glutamic acid residues

Cofactor – Vit K
* -Carboxy-glutamic acid residues increases (-) charge in the clotting factors which can then adhered to
platelet membrane phospholipids through Ca2+
B. In Vitro
1. Heparin
2. Oxalate - E.g.-Na Oxalate, K Oxalate
Form insoluble salts with Ca2+
3. Citrates -E.g.- Na Citrate ACD CPD

4. EDTA - Chelating agent- bind Ca 2+
Abnormalities of hemostasis
1. Vessel wall abnormalities (e.g. – Weakening of collagen in Vit. C deficiency)

2. Platelet disorders - platelet number & quality
3. VIII deficiency - Hemophilia A(classic hemophilia)
4. IX deficiency - Hemophilia B(Christmas disease)
5. Congenital deficiency of VWF
6. Liver disease - production of clotting factors is decreased
Clearance of plasminogen activator is reduced
Reduced production of Thrombopoietin and hence platelets
7. Bile duct obstruction - Vit K absorption is reduced

8. Excess of clot formation & excessive activation of the fibrinolytic system- DIC (Disseminated
intravascular coagulation) – in infections, extensive tissue injury
9. Renal failure
Test for Haemostasis
1. Bleeding time test - for vascular response & platelet response( minor/superficial wounds)
2. Platelet count
3. Hess Test - for vascular integrity (capillary integrity) ; Checking progression of Dengue
4. Prothrombin time test/INR - For extrinsic pathway and common pathway of clotting
5. Whole blood clotting time test - for intrinsic pathway and common pathway of clotting
6. Activated Partial Thromboplastin Time Test(APTT) -For Intrinsic + common pathway of clotting
7. Thrombin time

Cardio-vascular Physiology
Electrical Properties of the Heart
 Nomenclature
1) Chronotropic = related to heart rate
2) Inotropic = Related to contractility of heart muscle
3) Dromotropic = Related to conductivity of AV node
Heart muscle
Contractile tissue Excitatory / conducting tissue
Pacemakers Latent pacemakers
Pacemaker tissue/cells
 Rhythmically spontaneously discharging cells

 Show prepotentials/pacemaker potentials
Membrane potential declines to firing

level after each impulse triggers the next
impulse
 IK brings repolarization (K+ reflux)

 When IK decreases (K+ efflux
decreases)
 A channel permeable to both Na+
and K is activated – Called the ‘h’ channel
+
(funny Na+ channel)

 h channel (Ih) – Forms 1st part of the prepotential
 Transient Ca2+ channels (ICa2+ T ) open & complete the prepotential
 L channel opening produces the rapid depolarization (ICa2+ L)

No contribution from Na+ for rapid depolarization
Other features
1. RMP varies from -50 to -60 mv

2. Prepotentials are only prominent in SA & AV nodes
3. Latent pacemakers (other portions of conducting system) discharge only when SA & AV
nodes are depressed or blocked
4. Atrial & ventricular muscle cells discharge spontaneously only when injured or abnormal.

Effect of ANS
Parasympathetic Sympathetic
 Membrane hyperpolarized  Slope of prepotential is
& slope of prepotential is increased
decreased  By ANS+ Catecholamines
 By vagi (Left-AV Right-SA)
 β1 adrenaline receptor
 M2 receptor-mainly in SA
present in every cell of
& AV
myocardium
 Lies in atrial tissue & not in
ventricle
 So Ach’s influence is to
decrease mainly
chronotropic action not
inotropic action
A
c
h
Noradrenalin
R ↓
Ach M2 muscarinic
β1 R
cAMP in the cell ↓ ↓

↓ cAMP in the cell ↑
↓
G ↓
Open K+ channels Slows the opening of Facilitates opening of
↓ Ca2+ channels Ca2+L channels
Stimulate K ↓
conductance ↓
ICa2+ ↑
↓ ↓
Counters IK decay Membrane hyperpolarized Speeds up depolarization
(Slows the depolarizing
effect of Ih)
Other factors
Rate of discharge of SA & other nodal tissue
Increased Decreased
- Temp. ↑ (tachycardia in fever) - Drugs – Digitalis (ve inotrope)
- Drugs (Depresses nodal tissue &exerts vagal
effects)
Mainly to AV node

 Only SA & AV
nodes have
prepotentials
Heart rate control
ANS
Sympathetic Parasympathetic (Vagus)

(Noradrenergic) (Cholinergic)
Resting
(-)45
(+)5
Resting, recumbent,  Temperature

SA NODE  pH
young adult
Intrinsic  Circulating substances
discharge rate
100 –110 / min. Local factors
Rate= 70/min High
cholinesterase
Heart rate - variation
Wide variation—rate of 80-90 seen in healthy persons

Muscular training reduces the rate (Trained athletes- rate 50-60)
Age: at birth ---- 130/min- decreases till adolescence. Increases slightly with old age
Physiological Pathological
Increase During muscular exercise Fever ( 10 beats / 1
Emotional excitement deg F )
 Increased action of
High environmental temperature Haemorrhage
baroreceptors
During digestion (mild increase) Hyperthyroidism
 Increased action of atrial
stretch receptors (Brain
bridge reflex)
 Inspiration
 Anger
 Most painful stimuli
 Hypoxia
Decrease Sleep (55 – 60) Hypothyroidism
 Increased action of In trained athletes Increased ICP (Cushing
baroreceptors reflex)
 Expiration
 Fear
 Grief
 Stimulation of pain fibers of
trigeminal nerve
Conducting system of the heart
Tissue Location Rate of discharge Conduction Rate Importance
SA node Junction of SVC & 70 /min 0.05 Referred to as the

R atrium “pacemaker” of
the heart
AV node Right posterior 60 /min 0.05 Responsible for
interatrial the AV nodal delay
septum
Bundle of His IV septum 50 /min 1 Sole connection
(subendocardial between atrial &
tissue) ventricular
2 branches syncytia
Purkinje fibers Ventricular 40 /min 4
myocardium
Spread of cardiac excitation
SA node

 Spread of cardiac excitation from endocardial to epicardial direction (Easy to remember
‘n’ before ‘p’)
 Depolarization moves from left to right of the interventricular septum.
 The last portions of the heart to become depolarized are
1. Posterobasal portion of the left ventricle
2. Pulmonary conus
3. Uppermost part of the septum
Contractile tissue
Phase
0 - Initial rapid depolarization Opening of voltage gated Na + channels
1 - Initial rapid repolarization Closure of voltage gated Na+ channels &

opening of one type of K+ channels (Cl- influx)
2 - Plateau phase Slower but prolonged opening of voltage

gated Ca+ channels
3 - Final repolarization Closure of voltage gated Ca+ channels and

efflux of K+ ions through K+ channels
4 - RMP (-90mv) Slow delayed efflux of K+ channels

 Depolarization (2ms) is followed by a prolonged plateau (200ms)
 Mechanical response starts 2 msec after the onset of depolarization and lasts 1.5
times longer than the action potential.
 Cell is refractive to excitation during contraction (during Phase 0 – 2 and half
of Phase 3) - prevents tetany
Electrocardiogram (ECG)
 Body fluids are good conductors – Changes in potential that measure the
algebraic sum of action potentials can be recorded.
 Record of these changes are known as an electrocardiogram.
ECG wave patterns and their genesis
 The electrocardiogram is a recording of electrical activity of the heart.

 Depolarization moving towards the active electrode is recorded as a positive
deflection. +ve
 Depolarization moving away from the active electrode is recorded as a negative
deflection.
ECG leads
-ve
 Record the electrical potential differences between electrodes placed on the body.
Standard 12 lead ECG
Chest leads (unipolar) Limb leads

V1, V2, V3, V4, V5, V6
Standard limb Augmented limb leads

Leads (Unipolar)
(Bipolar) aVR, aVL, aVF
I, II, III
Unipolar leads (Chest)

 Measure heart’s electrical activity in the antero-posterior plane
 Unipolar chest leads do not require any augmentation unlike bipolar leads (since
they are placed close to the heart)
 6 chest leads are used
1. V1 - Placed in 4th intercostal space just right to the sternum
2. V2 - Placed in 4th intercostal space just left to the sternum
3. V3 - Placed between V2 and V4
4. V4 - Placed in 5th intercostal space along the midclavicular line
5. V5 - Placed in anterior axillary line 5th intercostal space
6. V6 - Placed in mid axillary line 5th intercostal space
Unipolar leads (Limb)

 Measure electrical activity of the heart in coronal plane
 Augmented leads (aVR, aVL and aVF) increase the size of
the potential by 50% without any change in the
configuration
 aVR – Augmented right arm lead
 aVL – Augmented left arm lead
 aVF – Augmented left foot lead
Relating ECG leads to heart chambers
View of hea rt Leads
Inferior II, III, aVF
Lateral I, aVL, V5, V6
Anterior V3, V4
Septal V1, V2
Bipolar leads/Standard limb leads
 Measure electrical activity of the heart in the coronal plane

 Consists of a single positive and a negative electrode
 Location of lead doesn’t depend on location of leads on arm and leg
(NOTE: Leads are placed on RA and LA avoiding thick muscle and on the left lateral calf muscle)
 When placed, these leads form an equilateral triangle – Einthoven’s triangle with heart in center
 3 bipolar leads are used
1. Lead I – Right arm/Left arm
2. Lead II – Right arm/Left leg
3. Lead III – Left arm/ Left leg

() (+)
LI
(+) (+)
LIII LII
I + III = II
ECG Paper
 ECG waves are recorded on special graph paper with 1mm2 grid-like boxes
 Horizontal – duration
 Vertical – wave amplitude
Horizontal
 Paper speed usually 25 mm/s
 Each 1mm (small square) = 0.04 s (40ms)
 Each 5mm (large square) = 0.2 s (200ms)
Vertical
 10mm (10 small squares) = 1mV
0.1 s
0.04
0.04 s
0.2 s

 Lead II – Usually used in measuring HR (cardiac axis is almost parallel with lead II axis)
 P wave – atrial depolarization
 QRS interval –
- Reflects ventricular depolarization
- From beginning of Q to end of S wave (when Q is absent, measured from R/R’ to S)
- Normal duration 0.08– 0.1 S → (2-3 boxes small)
- Atrial repolarization is not detected as its magnitude is too small.
 Important  In QRS complex waves represent septal, ventricular and last

part of depolarization is different from lead to lead. (But; 1st (+)ve
deflection is always a ‘R’ wave)
 T wave – Ventricular repolarization (from bottom to top)

 U wave – May be present due to slow repolarization of papillary muscles In children is normal
but pathologic in adults
- PR interval – Atrio-ventricular conduction,

- From beginning of ‘P’ wave to beginning of QRS
- atrial depolarization +AV nodal delay (0.12-0.20s) Number of boxes (3-5)
- QT interval - Ventricular action potential

- From beginning of ‘QRS’ to beginning of ‘T’
- Ventricular depolarization + Ventricular repolarization
- ST segment – From end of ‘QRS’ to beginning of ‘T’ ventricular repolarization

(NOTE: In myocardial infarction electrical activity is seen here, known as ST segment
elevation)
Normal rhythm of heart – 60-100 bpm

Electrical impulses are initiated in the SA node and conducted to
the AV node,
Heart rate is increased - >100 bpm

RR intervals are constant and regular and all wave forms are
present
Heart rate is decreased - <60 bpm

RR intervals are constant and regular and all waveforms are
present
Occurs during sleep and is seen in athletes
RR intervals change according to a pattern which typically follows

the respiratory rate which has become irregular

RR interval decreases when patient inhales and increases when he exhales. Why???
Tachycardia is seen during inspiration. Bradycardia is seen during expiration. Intra-thoracic pressure
decreases during inspiration. So venous return to the atria increases. Atrial stretch receptors are
stimulated which results in vasodilation and hypotension. These receptors in turn signal the medullary
control centers to increase the heart rate. This is called the Bainbridge reflex.
Cardiac Axis
 The direction of the largest dipole in the frontal plane is called the Cardiac axis of the heart.
 The Cardiac axis has a very wide, normal range, from −30° to +90 °.
 The Cardiac axis depends partly on an individual’s anatomy; the heart.
 Cardiac axis are more vertical in a tall, thin person than in a short, broad-chested individual.
 The axis also becomes more vertical during each inspiration because the descending diaphragm tugs
on the pericardium and drags down the apex
 The axis depends also on the relative thickness of the right and left ventricle walls
 Hypertrophy of the left ventricle (e.g. due to exercise training, hypertension or hypertrophic
cardiomyopathy) shifts the electrical axis to the left (left axis deviation)
 Hypertrophy of the right ventricle (often due to pulmonary disease) produces right axis deviation

Efficiency of heart as a pump
 Substantial AV nodal delay.
 Sustained action potential maintaining contraction until the entire
myocardium has had time to depolarize and contract.
 Absence of tetany.
 Coordinated contraction of ventricular cells. Depolarization through
cardiac muscle rapid with ventricular cells contracting nearly
simultaneously.
 Ventricular contraction begins at the apex & progress upwards: squeezes blood towards exit.

Protodiastole Mid stage of diastole in which the
passive filling has slowed down, but
before atrial contraction.
Cardiac
cycle
Series of events
that occurs
during a single
heart beat
.
Mechanical events of the cardiac cycle
1) late diastole
2) atrial systole VD VS
3) ventricular systole
AD AS AD
a. isovolumetric ventricular contraction
b. ventricular ejection (0.8 – 1s)
4) early diastole a) Protodiastole
b) Isovolumetric relaxation
c) Rapid ventricular filling
Late diastole
 Atrio-ventricular valves opened; aortic & pulmonary valves are closed

 Blood flows into the heart through SVC, IVC & pulmonary veins; filling atria and ventricles.
 The rate of filling ↓ when ventricles become distended
(Especially when HR ↓)
 Cusps of AV valves drift towards closing position
 70% filling occurs (passively)
 Pressure remains low
Atrial systole
 Coincides with late ventricular diastole
 About 30% of ventricular filling occurs
 Atrial musculature contracts & propels additional blood to ventricles
 Orifices of SVC, IVC & pulmonary veins narrow
But some regurgitation occurs

Ventricular systole
At the start AV valves close.
Isovolumetric contraction (0.05 s) Ventricular ejection
 AV & semilunar valves closed  Ventricular pressure exceeds aortic &

 Ventricular muscle initially shortens Pulmonary arterial pressure
relatively little (Volume remains more or  Semilunar valves open & ejection begins
less same)  Rapid at first ; slows down later
 But IV pressure ↑ sharply (myocardium  The IV pressure rises to a maximum
presses the blood of the ventricle)  (LVP =120mmHg, RVP = 25mmHg) & declines
 This lasts until the pressure of L & R somewhat before the ventricular systole ends
ventricles exceed the pressure of aorta (80  (the pressure in aorta can exceed that of left
mmHg) & pulmonary artery (10 mmHg) ventricle but for a short period the
 AV valves bulge towards atria (↑ atrial momentum keeps the blood moving)
pressure, 120mmHg<) but they remain  AV valves pulled down due to the contraction
closed of papillary muscles (atrial Pressure↓)
 Amount of blood ejected  70 - 90 ml (rest)
Early diastole
1) Protodiastole (0.04 s)
 Ventricular muscle is fully contracted
 Already falling ventricular pressure drops more rapidly
 It ends when the momentum of ejected blood is overcome and
 Aortic & pulmonary valves closed.
2) Isovolumetric relaxation
 Both AV & semilunar valves are closed
 Ventricular pressure continues to drop rapidly
 Atria in diastole are filling and atrial pressure increases
 Ends when ventricular pressure falls below atrial pressure & AV valves open; permitting ventricles to
fill
3) Rapid ventricular filling
 Once AV valves open, blood accumulated in atria fill rapidly into ventricles
 Rate ↓ as ventricles filled
 End diastolic volume – Final volume in each ventricle at the end of diastole just before the systole. (130ml)
 Stroke volume – Amount of blood ejected by each ventricle in each heartbeat. In a resting supine man of
average size, (it is 70 - 90ml)
 End systolic volume – Amount of blood left in each ventricle at the end of ventricular systole. (around 50 ml)
𝑆𝑉
𝐸𝑗𝑒𝑐𝑡𝑖𝑜𝑛 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 = = 65%
𝐸𝐷𝑉
 da – ventricular filling

 ab – isovolumetric contraction
 bc – ventricular ejection
 cd – isovolumetric relaxation
Timing of events in cardiac cycle
Similar in 2 sides but take place at different times (asynchronous)

 RA systole precedes LA systole (Because electrical activity of RA finishes before LA, as SA & AV nodes are in RA)
 L ventricular systole precedes right ventricular systole
(Because in RV impulses have to travel through moderate band to purkinje; but not in LV)
 R ventricular ejection begins before L ventricular ejection, in other words pulmonary valve opens before aortic valve
[ pulmonary arterial pressure (10 mmHg) < aortic pressure (80mmHg)]
 Aortic valve closes before pulmonary valve (in inspiration) - Reduced impedance of pulmonary vasculature and
increased venous return to the right side (which prolongs ejection).
(Resistance of pulmonary vascular tree becomes lower in inspiration)
 Pulmonary & aortic valves close almost at the same time during expiration.
 But during inspiration physiological splitting of 2nd heart sound occurs due to asynchronous closure of semilunar
valves.
When measured over a period of time, outputs of 2 ventricles are equal
Length of Systole and Diastole Passive filling

Systole is more fixed than diastole
Diastole is more affected when heart rate is increased.
 Compromised filling (70% of ventricular filling occurs in rapid inflow and diastasis phases of diastole)
 Marked decrease of blood to subendocardial portions of left ventricle
 It is during diastole that the heart muscle rests.
 Increased vulnerability of left ventricle (sub endocardial) to ischaemia.
Heart sounds
Name Character Reason Timing Specialities
S1 Low pitched- slightly Vibrations set up by At the start of Loud in tachycardia

prolonged closure of mitral ventricular systole (poor filling)
(Lub) valve
S2 Shorter - high pitched Vibrations set up by End of ventricular Loud when diastole
(Dub) closure of aortic & systole P. is elevated in
pulmonary valves aorta
S3 near the end of the rapid filling phase of the ventricle

(Sometimes normal-healthy young people)
S4 due to ventricular filling (when atrial pressure is high, when there is ventricular hypertrophy or when
ventricular wall is stiff)
Abnormal– immediately before S1 (during atrial systole)
Events that occur simultaneously with S 2
Closure of aortic and pulmonary valves

Commencement of isovolumetric relaxation
Atrial diastole
V wave of JVP curve
End of protodiastole

Murmur
 Abnormal sound within heart
 When the velocity of blood surpasses the critical velocity, flow becomes turbulent and creates sound
 Stenosis – The narrowing of the opening of a valve

 Regurgitation – The leaking of blood through a closed valve (in the reverse direction)
Type of Murmur Timing

Mitral stenosis Diastole
Mitral regurgitation Systole  Pan systolic
Aortic stenosis Systole  Ejection systolic
Aortic regurgitation Diastole
 Systolic murmur seen in anaemia. (As a result of low viscosity of blood & associated rapid flow)
(NOTE- Systole and diastole of the cardiac cycle are named regarding to ventricles)
Bruits – abnormal sounds in blood vessels

E.g. 1. Aneurysmal dilatation of one of the large arteries
2. An arteriovenous fistula
3. Patent ductus arteriosus
4. Narrowing of a blood vessel (e.g. – atherosclerosis)
Pulse
Characteristics of pulse
 Rate
 Rhythm
 Character – feeling of pulse (e.g. :- thready in shock)
 Volume – normal / high / low (e.g.:- strong pulse during exercise ↑SV)
 Presence or absence of femoral pulse in relation to radial pulse (e.g. Post ductal coarctation)
 Vessel wall [e.g. Adults – vessel wall is calcified, so pulse is strong
Children – vessel wall is elastic, so pulse is weak]
Arterial pulse
 Blood forced into aorta during systole sets up a pressure wave that travels around arteries
 This pressure wave expands arterial wall which is palpable as pulse
 The pulse has no relationship with the flow of blood within the vessel.
 The speed of the pulse increases with the decrease of elasticity. (e.g. – old age, in peripheral regions)
Due to the
closure of the
aortic valve

Venous pulse
 Seen, not felt
JVP
 Measurement
1. Right internal jugular vein
2. Patient at 450 and head turned slightly to the left (at 450 so that jugular venous pressure is seen at
the neck. If kept supine, position where JVP is seen moves up)
3. Vertical distance between angle of Louise & highest level of jugular vein pulsation
4. Add 5cm (since R. atrium is 5cm below the angle)
Central Venous Pressure (CVP) – pressure in the SVC near the right atrium (= R. atrial P)
 Important determinant of Preload
Normal CVP=8 cm H2O (6mmHg during expiration, 2mmHg during inspiration)
 Venous pressure falls during inspiration as a result of the increased negative intrathoracic pressure &
rises again during expiration.
The changes in right atrial pulse pressure are transmitted to the great veins producing 3 characteristic waves
Diastole Ventricular Diastole

Systole
Name Timing Reason Thr
a wave Atrial systole Regurgitation of blood through ee
narrowed orifice des
c wave Isovolumetric ventricular Bulging of tricuspid valve into R cent
contraction atrium s
v wave Diastole (before tricuspid valve Rise in atrial pressure and
opens) reas
ons for them.
Three descents and reasons for them.

X1 descent- right atrium relaxes
X2 descent-tricuspid valves move downwards due to papillary muscle contraction
Y descent –filling of left ventricle after tricuspid valve opens

Cardiac output
Cardiac output (CO) = SV × HR
The volume of blood

The volume of blood pumped by each No. of beats per unit
pumped by each ventricle per beat in a time
ventricle per unit time. resting, supine man of ~72 / min
5.5 L/minute (from average size.
each ventricle) ~70 mL
Stroke Volume
Preload Afterload Myocardial contractility
The degree to which Resistance against which The intrinsic ability of heart
myocardium is stretched blood is expelled muscle to generate force and to contract
before it contracts at a given degree of stretch
( TPR)
( EDV)
Factors affecting EDV
Venous Return Ventricular filling time Ventricular filling pressure Ventricular compliance
Depends on Depends on Depends on  compliance by;
1. Total blood Heart Rate 1. Blood volume 1. Ventricular wall stiffness

Volume in tachycardia 2. Atrial contraction 2. Pericardial thickening
2. Venous tone in bradycardia (constructive pericarditis)
3. Thoracic pump 3. Pericardial collection of
4. Muscle pump fluid (pericardial effusion)

Increased resistance in (1) Hypertension
arterial tree (2) Obstruction of LV outflow tract (aortic stenosis)
Factors affecting (3) Vasoconstriction
afterload Anaphylaxis
Decreased resistance in (1) Hypotension  Severe allergic condition
arterial tree (2) Vasodilation   BP due to histamine
 Treat with adrenaline
Frank starling law of heart
 Describes the ability of the heart to change its force of contraction (& stroke volume) in response to changes
in venous return.
 Force of contraction α initial muscle fibre length
SV α EDV
Special.......
SV  Chronotropy  Heart rate
 Inotropy  Force of contraction
 Dromotropy  Transmission in cardiac conductive tissue
EDV
Changes in contractility
 Sympathetic 1adrenergic stimulation + activation
SV  Catecholamines of adenylyl cyclase cAMP
 Inotropic agents (Dopamine)
 Digitalis (Na+/K+ ATPase inhibitor)
Increased contractility
 Xanthine – (Caffeine, theophylline) – Inhibit breakdown of cAMP
 Force frequency relationship
Decreased contractility
Digitalis inhibits Na+/K+ ATPase and thus
activates Na+/Ca2+ ATPase which transports
Na+ out of myocyte and Ca2+ into myocyte.
 Parasympathetic Thus, increases intracellular [Ca2+] in
 Hypoxia , hypercapnia myocyte, increasing power of contraction.
 Acidosis
 Pharmacological agents (barbiturates, quinidine, procainamide)
EDV  Loss of myocardium
 (Intrinsic depression) Heart failure
Downregulation of 1receptor
Impaired Ca2+ release from SR
Ejection fraction = SV 60-65%
EDV
Cardiac index = CO
Surface area of the body

Measuring CO
1) direct Fick method
CO = O2consumption (ml/min)
Theoretical Amount of O2 in  Amount of O2in
arterial blood (ml/L) venous blood (ml/L)
2) Indicator Dilution method

3) Doppler combined with echo - cardiography- non-invasive
Practical 4) Electromagnetic flow meter on aorta - ventricular function, velocity &
Volume of flow can be assessed
Factors affecting CO
Increase Decrease No change
Exercise Standing/sitting from Sleep

Environmental temp. (High) lying position Moderate changes in
Eating Arrhythmias environmental temp.
Epinephrine Heart disease
Emotions (Anxiety, Excitement)
Pregnancy
Oxygen consumption by heart
 Heart muscle is supplied by coronary arteries

 When O2 consumption increases, an organ may; 1.  O2extraction from arteries
2.  Its blood supply
 But heart muscles can only  its blood supply because it extracts almost maximum O2
from arteries.
O2 consumption by heart determined primarily by
Intramyocardial tension Contractile state Heart rate

EDV R T to  O2 number & strength of contraction
maintain P consumption
Stroke work / Ventricular work = SV x MAP Cardiac work = CO x MAP
 Stroke work of LV is higher than RV (Because LV has to pump blood against a higher pressure in aorta)
  in stroke work due to an  in MAP causes a greater O2 consumption than  in stroke volume.
 Aortic Stenosis is considered to cause an increase in pressure work as a higher pressure must be given from
within the chamber.
 Aortic regurgitation is considered to cause an increase in volume work as some amount of blood flows back,
needing a larger volume to be pumped.
 An  in afterload causes greater O2 consumption than an  in preload.
 Angina pectoris is more common in aortic stenosis than aortic regurgitation.

WHY?
1. In aortic stenosis pressure work increases. (O 2 consumption for a given amount of pressure work is
higher than that for the same amount of volume work)
2. In stenosis ventricular hypertrophy occurs. This causes the intramyocardial blood vessels to be
compressed and occluded, increasing the pressure needed to perfuse the ventricular myocardium.
3. In aortic stenosis the pressure in the aorta is reduced, thus reducing pressure in the left coronary
artery. So the perfusion pressure of this artery is insufficient to perfuse the myocardium.
Dynamics of blood and Lymph Flow
Structural features of circulation
2 major cell types
Endothelium Vascular smooth muscle (VSM)

Respond to * Flow changes * Contains K+, Ca2+, Cl channels
* Stretch * Determines vascular tone
* Circulatory substances * Has different and opposite effects in response
* Inflammatory mediators to high and low levels of cytosolic Ca2+
Secrete Growth regulators

Vasoactive substances
 Endothelium is an endocrine organ

(Because it is active & has a regulatory function

Arteries and arterioles
 Elastic tissue % aorta > large arteries > small arteries > arterioles
 Smooth muscle % aorta < large arteries < small arteries < arterioles
 Muscle is innervated by noradrenergic fibres
(But in some instances, by cholinergic fibres. E.g. - Cutaneous blood vessels have muscarinic cholinergic )
 Arterioles are the major site of resistance to blood flow
(As R  1/r4; small change in calibre causes large change in TPR)
Capillaries
 Surrounded on upstream side by ‘precapillary sphincters’

Not innervated
Can respond to local stimulating substances
 Diameter  - Just sufficient to permit RBC to squeeze through in a single file
- Large in venular end than arteriolar end.
Lymphatics
Following features differ a lymphatic from a capillary
1. No fenestrations in endothelium
2. Very little if any basal laminar under endothelium
3. Junctions between endothelial cells are open
4. No tight intracellular connections
5. Contain valves
 Lymph flow occurs mainly due to contractions and not due to valvular action.
Venules & veins

1. Wall is thin and easily distended
2. Relatively little SM
(But considerable venoconstriction is produced by noradrenergic nerves & vasoconstrictors)
3. Variations in venous tone are important in circulatory adjustment
4. Contain valves (Except in; small veins, great veins, & veins from brain & viscera)
Biophysical considerations of circulatory physiology
Flow
Q = MAP - MVP
Flow = Effective Perfusion Pressure (P) R
(Q) Resistance (R)
P = MAP  MVP
Streamline Flow * When the vessel is obstructed flow
Parallel to long axis beyond that become turbulent.
Laminar Occurs in layers * Turbulent flow produces a noise
Flow Layer close to the wall doesn’t flow due to vibration.
Centremost layer has highest velocity * Results in bruits and murmurs
Flow is silent * This is being used as the principle of
Occurs in normal blood vessels auscultation method of BP measurement
Re – Reynolds number * Higher the Re, higher the turbulence
Re = vD v – velocity
 D – diameter
If Re<2000, flow is usually not
 – density
turbulent
 – viscosity
If Re> 3000, turbulence is almost
always present.
 Turbulence increases at branching points
Resistance
Poiseuille – Hagen Formula
Q=P  R= 8l
Q= r4P
R r4
8l
 Resistance to blood flow  Vascular hindrance
Radius (R  1/r4)
Determined by
Viscosity (R   )
Determined largely upon haematocrit
Viscosity
Conditions  Conditions 
Polycythaemia Anaemia
 Temperature Pregnancy
 Flow rate THINK… why can murmurs be heard
 Plasma volume in pregnant women even though they
 Plasma proteins (mostly immunoglobulins) do not have any disease?
Hereditary spherocytosis
 Increased viscosity of the blood, causing increased peripheral resistance leads to hypertension.
Shear stress
 Shear stress  force created on the endothelium parallel to the long axis of vessel
Shear stress = viscosity x shear rate

11 () () (dy/dr) © 2017 A/L Repeat Campaign
Average velocity
Q = AV A1/V  V  - Higher in aorta

- Declines steadily in small vessels
Flow area of average - lowest in capillaries
conduit velocity
Diagrams of the changes in pressure and

velocity as blood flows through the systemic
circulation.
TA – Total surface area of circulation
Application of Bernoulli’s theory in circulation
 During standing MAP is 100mmHg in proximal aorta and 180mmHg in foot

 Yet blood flows from heart to foot
 Explanation: proximal aortic blood has 90 mmHg more gravitational potential energy so total energy of
aortic blood is 190 mmHg.
 When a blood vessel narrows, the velocity increases, increasing the kinetic energy. Therefore the vessel
tends to close due to a decrease of distending pressure.

THINK… what are the events
occurring in a person who stands
Critical closing pressure (CCP)
up from supine position?
 Tissue surrounds the vessel exerts a pressure on them.
 When intraluminal pressure < tissue pressure ; vessel collapse
 At this time as the intraluminal pressure is not ‘0’ no blood flows from vessel
 The pressure at which flow ceases is called the CCP
Law of Laplace Transmural Pressure is the

 Tension (T)  Transmural pressure (P) T = Pr ∆𝑃 across the blood vessel
T  Radius (r) w wall.
T  1/wall thickness (w)
 Importance of T  r – 1. Tension becomes low from arteries to capillaries

2. In dilated heart  r  T  to produce given P
Resistance vs capacitance vessels

Resistance Capacitance
 Principle site of peripheral resistance Have large capacity to accommodate extra
 Only 2 % of cardiac output volume of blood
is contained. e.g. 1. Veins (50% of blood)
e.g. 1. Small arteries & arterioles 2. Low pressure system
2. High pressure system
Percentages of blood contained
 Systemic veins 50%

 Pulmonary circulation 18%
 Heart 12%
 Arteries 8%
 Capillaries 5%
13  Aorta 2% © 2017 A/L Repeat Campaign
 Arterioles 1%
Arterial Pressure
Flow through systemic circulation = CO
Q = MAP  CVP CO = MAP  CVP * CVP is close to  MAP = CO x TPR

TPR TPR atmospheric pressure  0
Systolic pressure: - Peak pressure in aorta and other large arteries during cardiac cycle
Depends on CO
 120 mmHg
Diastolic pressure:- Minimum pressure in aorta and other arteries during cardiac cycle
Depends on TPR
 70 mmHg
 Recorded as SBP/DBP = 120 mmHg
70
Measurement of arterial blood pressure (Korotkoff sounds)
Snapping sound onset marks SYSTOLIC phase I
Becomes soft murmur (bruit) phase II
Sounds louder clearer phase III
Muffling of sounds phase IV
Sounds disappear phase V
Factors affecting arterial BP

1. Gravity 6. Sleep Pulse pressure (PP) = SBP – DBP
2. Emotions 7. Posture
3. Aging 8. Exercise
Mean Arterial pressure (MAP) = DBP + 1/3 PP
4. Gender 9. Body size
5. Digestion
 1/3 PP is taken due to the time difference and the pressure difference between the two
 Systolic pressure increases with age.
 Diastolic pressure, 1st increases then decreases.
 Therefore, pulse pressure increases.

Venous Pressure
 In head Sub-atmospheric in Dural sinuses (important to know in neurosurgery)

 In neck  close to ‘0’
 Venules  12 – 18 mmHg
 Great veins outside thorax  5.5 mmHg
 Great veins at entrance to RA (CVP)  4.6 mmHg (fluctuate with respiration & heart beat)
Above
 Peripheral veins 
RA
Below
Thoracic pump
Venous Pressure is affected by Muscle pump
Variations in RA pressure

Shunt
 Communication that deviate from the normal circulatory circuit

 Cardiac shunts  between chambers of heart
 Extracardiac shunts  In systemic & pulmonary circulations
 Clinical consequences will depend on direction of the blood flow
Physiological E.g. Venae Cordis Minimi

Bronchial veins draining into Pulmonary veins
Types of
Shunts
Pathological E.g. ASD

CVS regulation
Regulation – 1. Long term – RAAM
2. Short term
1) Local Mechanisms (SEQ)
2) Systemic mechanisms
 Circulating hormones
 Neural regulation
Local regulatory mechanisms
1. Autoregulation / reflex constriction

2. Vasoactive metabolites
3. Substances secreted by endothelium
1) Auto Regulation
Capacity of tissues to control their own blood flow.
 Partly as an intrinsic contractile response of smooth muscle to stretch (myogenic

theory)
 Partly as accumulation of vasodilator metabolites in active tissues. (Metabolic
theory)
 Localized vasoconstriction
Injured arteries and arterioles constrict strongly (also veins) (partly due to serotonin
from activated platelets)
Cold causes vasoconstriction (MCQ)
Places where autoregulation takes place – Kidney, Brain, Skeletal muscles, Liver,
Myocardium, Mesentery etc.
Myogenic Theory Metabolic Theory
Increased Blood Flow Decreased flow
Dilation of arterioles Increase accumulation of

vasodilator metabolites
Smooth muscles of tunica
media are stretched Dilation of arteriole
Muscle contraction Increase flow
Constriction of arteriole
Decrease flow

2) Localized vasodilation by vasoactive metabolites – relax arterioles &
precapillary sphincters
Increase in decrease in
PCO2 PO2
T pH
K+
Lactate (Mainly in skeletal Muscles)
Histamine (Increases vascular Permeability)
Adenosine (only in cardiac muscle)
 In generalized/ systemic hypercapnia vasodilation takes place only in Brain and Skin.
3) Substances secreted by endothelium (MCQ)
Dilators - NO, Prostaglandins

Constrictors - Endothelin (most potent vasoconstrictor)
NOS 1 – Nervous system
NOS 2 – macrophages
NOS 3 – endothelium
NOS 1 & NOS 3 activated

by Ach & bradykinin
NOS 2 is activated by Ca2+
Nitroglycerin – treatment
in angina
Mimics the action of NO

Endothelins
 Most potent vasoconstrictor identified Family of ET (ET-1, ET-2, ET-3)

 Release stimulated by
o Stretching of blood vessels
o Thrombin
o Epinephrine
o Angiotensin – II
o Oxidized LDL

Functions
 Constricts vascular smooth muscle (veins & arteries)
 Endothelin in brain play a role in regulating transport across BBB
 Positive chrono /inotropic effects on heart
 Increases plasma ANP, renin, aldosterone, catecholamines
Systemic Regulatory Mechanisms

1) Hormonal regulation
Vasodilators
VIP (act via NO)
Kinins (via NO)
Natriuretic hormones
ANP, BNP found in blood
CNP not found in blood (MCQ)
ANP
 Increases when atria are stretched and central venous P is increased.
 Natriuresis (increased excretion of sodium and water in urine) (MCQ)
 Vasodilation
BNP- secreted when ventricles are stretched
- Also from brain
CNP- c type natriuretic peptide
Paracrine action
From brain, kidneys, pituitary
Vasoconstrictors
Epinephrine, Norepinephrine, Vasopressin, Angiotensin II, Thromboxane A2
Receptor Place Function Neurotransmitter

α1 Blood Vessels Vasoconstriction Norepinephrine
𝛽1 Heart Increase HR & myocardial Norepinephrine
contractility Epinephrine
β2 Skeletal Muscles Vasodilation Epinephrine
Bronchi, Liver Bronchodilation

2) Neural Regulation
 Stretch of walls of heart and blood vessels

Stimulus  Both pulse pressure and mean arterial pressure
 Blood volume
Receptor Baroreceptors
Afferent Buffer Nerve
Centers IN Medulla
Sympathetic and parasympathetic fibers to heart

Efferent and sympathetic fibers to blood vessels, adrenal
medulla, JGA
Effector
Buffer nerve – Both Vagus and glossopharyngeal nerves together known as buffer nerve. Vagus nerve carries
impulses from aortic sinus. Glossopharyngeal nerve carries impulses from carotid sinus.
Centers
 Group of neurons in the rostral  Neurons in

ventrolateral medulla(RVLM)  dorsal motor nucleus of
 The vasomotor center Vagus(DMN)
 Stimulate sympathetic activation  nucleus ambiguous
 stimulate parasympathetic activation
nucleus of tractus solitarius(NTS)

receives afferents from baroreceptors
excitatory neurotransmitter is glutamate
 stimulate vagal motor neurons via  project to caudal ventrolateral

dorsal motor nucleus of vagus medulla (glutamate)
(DMN)
 nucleus ambiguus  inhibit RVLM (by GABA)

Hypercapnia Chemoreceptors (cardiac, aortic)
Hypoxia
emotions, sexual excitement
Pain pathways
Juxtaglomerular
apparatus Stretching of lungs
(Pulmonary receptors)
 HR
 TPR
RVLM/VMA
Sympathetic ±
stimulate From cortex via hypothalamus
Adrenal GABA ()
Medulla
CVLM
Myocardial
Contractility Glutamate (+)
Glutamate (+) Dorsal
NTS Nucleus Vagal parasympathetic
ambiguus nucleus
Glutamate (+)
 HR Myocardial
contractility
Buffer nerve
Baroreceptors
High pressure (Arterial) Low pressure (cardiopulmonary)
 Aortic arch  R and L atria

 Carotid sinus  Entrance of SVC, IVC,
 pulmonary veins
 Pulmonary circulation
RVLM – Rostral ventrolateral medulla

CVLM – Caudal ventrolateral medulla
NTS – Nucleus of Tractus Solitarius
VMA – Vasomotor Area (presently this VMA is known as RVLM)

Cushing reflex - if bradycardia & hypertension is present together one should always
suspect for cranial damage
Raised intracranial pressure Impairs blood supply to vasomotor area Local

hypoxia & hypercapnia Stimulates vasomotor center directly Increases
sympathetic discharge increases systemic BP Restores blood supply to VMA and
stimulates baroreceptors Inhibits VMA Bradycardia with hypertension
Valsalva Manuever
 To check baroreceptors, occur during coughing, defecation, heavy lifting
Occurs during coughing, defecation, heavy coughing
Take a deep breath → exhale against closed glo s → blood pressure goes up (due to the
compression of aorta at onset) → Venous return decreases (due to compression of great
veins) → CO decreases → blood pressure decreases → baroreceptor discharge decreases →
parasympathetic inactivate, sympathetic activate → HR increases, Contractility increases, CO
increase, vasoconstriction → BP increase with tachycardia → exhale → venous return come
to normal → blood pressure increases → baroreceptor discharge increases → sympathetic
inactivates parasympathetic Activates→ HR decreases, contractility decreases → s ll vessels
compressed → Hypertension with bradycardia

Blood Pressure (BP)
CO TPR Sympathetic
(No parasympathetic)
SV HR Circulatory substances Diameter

Sympathetic Viscosity
Parasympathetic Elasticity
Temperature
pH
Preload  EDV Venous Return  TBV, Posture

Venous tone
Thoracic Pump
Muscle pump
Filling time  HR
Filling pressure  atrial contraction
Blood volume
Ventricular compliance  Stiffness

High intrapericardial pressure
Afterload  BP
TPR (Total peripheral resistance)
Size of ventricle  Sympathetic
Viscosity  Catecholamines
 Digitalis
 Xanthines
SV  Positive Inotropes-
Myocardial contractility  Dopamine
 Force frequency relation
 Parasympathetic
 Hypoxia
 Hypercapnia
 barbiturates, quinidine, procainamide
Frank Starling Law
 Heart failure
EDV

Circulation Through Special Regions
Resting blood flow and arteriovenous O2 difference in organs in health
 Carotid body has the highest blood flow per 100g per minute
Cerebral blood flow

• 750-900 ml per min
 Average brain mass – 1400 g
• Gray matter - high O2 demand
• Both large and small arteries contribute to vascular resistance
• Perfusion pressure P= PA-PV (depend on ICP & CVP whichever is high)
Depends on
1. CPP - MAP, ICP
2. Viscosity
 Vessel diameter
 Auto Regulation
 Neural factors
 Metabolic factors – CO2, Acidosis, Hypoxia

Cerebral blood flow needs to be kept constant
 Too much blood flow – hyperemia

o Increases ICP
o Compresses & damages brain tissue
 Too little blood flow – ischemia
o Damages to brain & cell death
o Neurons totally depend on O2 to produce ATP

 Neural regulation is not clear
Important in Hypertension
-Vasoconstriction protects the brain.

-noradrenergic discharge increase the auto regulation raise by extending the plateau phase
So, auto regulation of cerebral blood flow occurs at higher arterial pressure.
 250ml/min (5% of CO)
 Supplies myocardium (no supply from blood within chambers)
 Myocardium
–High O2 consumption and high O2 extraction (70-80%)
–Requires regular uninterrupted coronary blood flow to function
 Left & right coronary arteries are end arteries.
 If need to increase O2 supply - blood supply is increased. (Flow is coupled to O 2 demand)
 Considerable auto regulation present
Coronary flow to
 Left ventricle – mostly in diastole
 Other chambers – throughout cardiac cycle
 Most superficial part of LV is supplied throughout cardiac cycle
 Subendocardium of LV is supplied exclusively in diastole
Effect of autonomic nerve system

o SNS alpha 1 adrenoceptors – vasoconstriction
o Metabolites (mainly adenosine) - vasodilation
o SNS activity – Transient vasoconstriction followed by vasodilation. (Metabolites from
increased mechanical & metabolic activity of the heart due to β1 adrenoceptor stim.
cause vasodilation)
 pure action of sympathetic activity is vasoconstriction. (primarily mediated by α receptors)

but β Action additionally increases the rate & force of contraction of heart resulting in
accumulation of vasodilator metabolites. Therefore, there is vasodilation secondarily to
increase activity of the heart. But if we block the β receptors, vasoconstriction is seen with
norepinephrine accumulation.
α β
Constriction Dilation
Increase activity of heart

o Metabolites (mainly adenosine) - vasodilation
o SNS activity – Transient vasoconstriction followed by vasodilation. (Metabolites from
increased mechanical & metabolic activity of the heart due to β1 adrenergic receptor
stimulation cause vasodilation.
 Most important single factor determining the coronary blood

flow is the requirement of the heart for oxygen. Metabolic
regulation of coronary vascular resistance is major determinant
 Reactive Hyperemia: transient increase in blood flow following an occlusion of an artery

and its subsequent release. Hypoxia is seen in the region ahead of occlusion causing
dilation. This occurs in the heart due to adenosine.

Systolic compression
• Left ventricular wall- Generate a large
force
during contraction within myocardium.
• Due to intra myocardial forces,
pressure inside
becomes greater(121mmHg) than aortic
pressure(120mmHg). So coronary
vessels get collapsed increasing the
coronary
vascular resistance.
• In systole, blood supply is interrupted
to the area
close to the cavity (sub endocardium).
Blood flows only during diastole. (But
more superficial areas of the L ventricle
get blood supply throughout the
cardiac cycle.)
• When HR is increased diastole becomes
shorter.
reduced blood supply to sub
endocardium of the L ventricle.
• More prone to IHD
• But pressure difference between aorta
& R ventricle or atria is greater during
systole.
(Aortic Pressure) So coronary flow to these regions is not much reduced during systole.
• Anterior interventricular artery- more prone to atherosclerosis
Splanchnic circulation
 30% (250ml/min) of cardiac output.

 Reservoir function (Important in moderate arterial blood loss).
 Active hyperemia caused by food ingestion.
 High responsiveness to vasoconstrictors
 Reciprocal blood flow between liver and other organs
 Portal vein 75% hepatic artery 25%

Cutaneous circulation
 Varies with the temperature of the body

 Vasoconstriction by noradrenergic nerve fibers &
catecholamines
 Only vasoconstrictors no dilators (By sympathetic)
 Dilation is done by reduction of vasoconstrictor tone and
bradykinin
 Reactive hyperemia seen on skin
Reduction in core temperature of body
Sensed by posterior hypothalamus
Reduced skin blood flow (by low resistance AV anastomoses)
Reduce heat loss

Special features of cutanous circulation
 Reactive hypermia
 White reaction
 Triple response
o Reddening
o Swelling
o Flare
Applied CVS
Hypertension
 Sustained elevation of systemic blood pressure above 140/90 mmHg

 BP determined by Cardiac output & Peripheral resistance
 Hypertension usually caused by increased peripheral resistance
Causes;
 Essential hypertension – multi factorial
 Renal disease – increased secretion of renin
 Hormonal overactivity – aldosterone, glucocorticoids,
catecholamine, GH
 Coarctation of aorta
 Drugs – oral contraceptives, cocaine
 Pregnancy induced hypertension
 Increased blood viscosity – polycythemia
 Baroreceptor resetting at a higher BP in chronic HT
Hypertension – principles of management
 Vasodilators
 Ca2+ channel blockers
 Angiotensin Converting Enzyme Inhibitors (ACEI)
 Angiotensin II Receptor Blockers (ARB)
 α blockers
 Drugs decreasing heart rate
 β blockers
 Diuretics (drugs reducing blood volume by increasing urine output)
 Others….
Angina pectoris
 Heart is supplied by T1-T5 spinal segments

 Due to ischemia produced by increased O2 consumption
 Pain originated in the heart is referred to skin of neck & upper medial part of left arm
 Angina pectoris is more common in aortic stenosis than aortic regurgitation.
IHD (Ischemic Heart Disease)
 Inadequate blood supply to heart muscle to satisfy oxygen requirements
o Mechanical obstruction - Atheroma

Thrombosis
o Non mechanical destruction - Anaemia
Hypotension
o Increased demand for O2 by the myocardium
Angina unstable angina Myocardial Infarction
Effects of IHD
 ECG Abnormalities (ST segment elevation)

 Release of enzymes and proteins from damaged cells (troponin T & I)
 Heart failure
 Arrhythmias
 T wave inversion, Q wave become prominent

Management
o Vasodilatation - nitrates
o Fibrinolytics- streptokinase
o Antiplatelet therapy-aspirin
o Anti-thrombotic- heparin
o Reducing myocardial O2 demand-β
blockers
o Reducing cholesterol deposition-statins
o Increasing O2 supply
o Reperfusion - fibrinolytic, angioplastin,
bypass grafting
o Pain relief- Morphine
Heart failure
 Inability of the heart to maintain an enough cardiac output to meet tissue needs
 Types
o acute or chronic
o LV (commonly), RV or both ventricles
o Systolic or diastolic
o High-output or low-output

Heart failure -Types
LV failure RV failure
 Pathophysiology  Reduced LV output  Reduced RV output
 Tissue perfusion  Reduced (apathy, faintness)  Reduced (apathy, faintness)
 Congested (Pulmonary
oedema, breathlessness on
exertion & lying down,
cough, blood stained
sputum)
 Pulmonary blood vessels
Due to accumulation of
blood in the Left ventricle.
The back flow of blood to the
lungs causes to increase
pulmonary pressure. Causing
pulmonary oedema.
 JVP  Elevated
 Lower Limb  Oedema
Systolic failure Diastolic failure

 Pathophysiology  Impaired  Impaired diastolic
contractility filling
 Ventricles  Dilated  Stiff
 Heart size  Enlarged  Normal
 SV & CO  Reduced  Reduced
 EF  Reduced  Initially normal

Heart failure –Manifestation
Management –
 ↓preload and a erload
Note lowering preload is only for systolic failures
Lowering afterload is for both types
 Decrease venous congestion-diuretics, venodilators, aldosterone antagonist
 Decrease peripheral resistance-ACE inhibitors, Angiotensin receptor blockers
 Improving contractility-Digitalis, ACEI
 Improving symptoms
Reducing mortality- beta blockers
Shock
 Definition;
Inadequate tissue perfusion with a relative or absolute inadequacy in cardiac output.
Classification
o Hypovolemic
o Haemorrhage, trauma, severe diarrhoea
o Cardiogenic
o Myocardial infarction, heart failure, arrhythmia
o Obstructive
o Tension pneumothorax, cardiac tamponade, pulmonary embolism
o Distributive
o Neurogenic shock (major brain or spinal injury)
o Anaphylaxis (triggered by allergens)
o Septic shock
 Cardiac tamponade - fluid collects between myocardium and pericardium. pressure within
the pericardium prevents heart chambers from expanding fully. It reduces the preload.
 Pulmonary embolism – blockage of a main artery of the lung or one of its branches
 Neurogenic- due to disruption of autonomic pathways in spinal cord. lack of sympathetic

supply for arterioles causes hypotension. Unopposed vagal action causes bradycardia
 Anaphylactic shock- triggered by allergens, results in widespread vasodilation

 Septic shock- due to an infection
Eg: Haemorrhagic shock
Haemorrhagic shock
•Blood volume is reduced.
• So, the venous return to the right atrium is reduced. It causes reduced preload and
stroke volume resulting in reduced cardiac output. It results in decrease in blood
pressure.
• Low blood volume causes reduction of discharge rate and stimulation of volume
receptors on atrial wall at the opening of the SVC, IVC and pulmonary vessels. low blood
pressure causes reduction of discharge rate and stimulation of carotid sinus and aortic
arch baroreceptors.
• This reduces the neural discharge of buffer nerves to the nucleus tractus solitarius
which in turn causes the stimulation of the vasomotor Centre and inhibition of the
cardiac inhibitory Centre resulting in an overall sympathetic stimulation and reduction
of parasympathetic activity.
• Sympathetic stimulation via norepinephrine on α1 receptors constricts arterioles in

the circulation which increases the arterial pressure and thus the perfusion pressure of
vital organs which helps maintain perfusion.
• Furthermore, sympathetic stimulation also causes constriction of veins displacing

blood towards the heart, thus increasing venous return. Decreased vagal activity
increases heart rate. Also, sympathetic stimulation via both norepinephrine and
epinephrine on β1 receptors increase heart rate and contractility of heart muscle. Both
these factors increase cardiac output and hence blood supply to vital organs.
• Increased heart rate causes rapid but thready pulse because the blood volume is
reduced.
• Another part of the mechanism to maintain perfusion to vital organs is autoregulation.

This is the dilation of vessels in brain and heart due to local metabolites which maintains
a normal blood flow despite the reduction in volume.
• Sympathetic stimulation causes increased secretion of catecholamines from adrenal

medulla and sympathetic nerve endings secrete catecholamine. These act on
Juxtaglomerular cells.
• In addition, a decrease in the stimulation of intra renal baroreceptors would cause

renin to be secreted by juxta glomerular cells which converts Angiotensinogen to

Angiotensin I which is in turn converted to Angiotensin II by ACE which is produced by
the endothelium of pulmonary vessels.
• Angiotensin II causes the secretion of aldosterone and ADH which increase renal Na+
reabsorption from tubules and water reabsorption from collecting ducts respectively.
•Angiotensin II constricts renal afferent and efferent arterioles; efferent arterioles are
Constricted more and angiotensin II causes constriction of mesangial cells. In both these
ways it will reduce UFR resulting in oliguria and thus increasing blood volume in turn
increases the blood pressure to supply vital organs.
• In addition, Angiotensin II and ADH can act as a vasoconstrictor and cause an increase
in venous return.
• Haemorrhage causes decreased blood flow through aortic and carotid body chemo
receptors resulting stagnant hypoxia which stimulate the peripheral chemoreceptors.
• And due to the blood loss amount of RBC is reduced. Resulting anemia causes
Inadequate tissue perfusion.so the cells generate energy from anaerobic glycolysis.
Lactic Acid is produced. Lactic acid reduces blood pH and stimulate peripheral
chemoreceptors.
• The impulses from these via afferent nerves modulate the respiratory center to
increase discharge in the efferent nerves supplying respiratory muscles which would
increase respiratory rate and depth resulting in adequate O2 supply to vital organs.
• In addition, the release of epinephrine as a stress reaction in shock could be having

the same effects of a sympathetic stimulation.
●It is in the wake of these physiological adapta ons inside the body that you would see
a rapid thready pulse, increased respiratory rate, oliguria and cold clammy hands in a
person with shock.

Respiratory Physiology
Functions of the RS
1. Main function is gas exchange to supply tissues with O2 and remove CO2.
2. Defense 3. Metabolic & Endocrine
Humidify air and control its temperature Secrete surfactant (DPPC)

Epithelium secretes IgA, collectins, Pulmonary circulation contributes to
defensins, Proteases, peptides and Fibrinolytic system
reactive O & N species.
Prevent foreign matter from entering Pulmonary endothelium has ACE,
alveoli (hairs, mucous membrane and Therefore, converts AT-I to AT-II and
curvature with Waldeyer’s ring) Inactivates bradykinin
Reflex bronchial constriction & coughing

Mucociliary escalator
Pulmonary alveolar macrophages/ PAM

(phagocytosis, antigen processing)
External/ Pulmonary respiration Internal/ cellular respiration

Occurs at respiratory membrane in alveoli, Occurs at cellular level where O2 is consumed, CO2 is
exchange produced, and gases are exchanged with ECF then with
Gas between blood and air, excretory function blood across the endothelium
Gas exchange organ = lungs
Conducting System = from nasal openings to terminal bronchi

Respiratory System
Structural = respiratory muscles, chest wall
CNS
Pumping
mechanism
Regulatory
Nerves = motor & sensory
(phrenic, vagus etc.)
The collective activity of all above results in the main function of gas exchange to supply O2 and remove CO2. This task of
delivering gases between atmosphere and cells is staged into the following processes.
1. 2. 3. 4.
VENTILATION GAS EXCHANGE GAS TRANSPORT REGULATION

VENTILATION
It is the process by which air is transferred between the lungs and the atmosphere, so that O 2 and CO2 can
be exchanged in alveoli.
Mechanism of Airways & Compliance & Alveolar

Breathing Airflow Surface Tension
Lung Volumes, Capacities & Alveolar Ventilation Equation & Work of

Lung Function Tests Breathing
Mechanism of Breathing
The movement of air between the lungs &
atmosphere depends on;
1. Total pressure gradient (mass movement)
2. Partial pressure gradient of individual gases
 Pressures aiding ventilation;
Atmospheric pressure – The pressure of the outside air at sea level
Intra-alveolar pressure – The pressure inside the alveoli; Approx. to atmospheric pressure
at rest = 0mmHg
Intra-pleural pressure - Always negative except maybe in forced expiration
Transpulmonary pressure = [Intra-alveolar pressure (Palv)] – [Intra-pleural pressure (Ppl)]

o This force operates across the walls of the lungs and causes the lungs to expand
 Lung & chest wall are elastic (elasticity-resistance

to deformation) and are held together by the
adhering parietal & viscera pleura
 Recoil forces of the lung & chest wall pull in opposite
directions
 At rest these forces just balance each other.
 Negative P in the intrapleural space (Intra-pleural pressure)
 Lymphatic channels are more abundant in the lungs than any
other organ; They absorb excess fluid and maintain a slight
suction (Also to absorb surfactant in the first inspiration in an
infant)
 Therefore, at rest there is a slight IPP= - 2.5 mmHg (relative to
atmospheric pressure)
Lungs expand & contract in 2 ways
1. Upward & downward movement of the diaphragm (this is sufficient
for normal quiet breathing) – almost entirely this method accounts
for 75% of the change in ITP. (Vertical diameter)
2. Elevation & depression of ribs by pump handle and bucket handle
movements. (Transverse & anteroposterior diameters)

Pneumothorax
o Air entry to the pleural cavity results in Pneumothorax

o The lung on that side collapses and the chest wall bulge out
o If the lungs lose their elasticity, the lungs do not pull the chest
wall inwards and therefore the chest expands to spring out and
takes a BARREL SHAPE CHEST
Inspiration
 Active process
 Contraction of inspiratory muscles increase thoracic
volume
 Main muscle of inspiration – diaphragm
 Other/ accessory muscles – external intercostals,
sternocleidomastoid, scaleni, serratus anterior
 Chest wall expands, lungs begin to expand because
visceral pleura is in contact with parietal pleura,
expansion of lungs leads to increased elastic recoil
 Intrapulmonary volume increases
 Negative IPP transmitted to alveoli becomes -6 mmHg
 Intrapulmonary pressure drops
 Air flows into lungs

Expiration
 Passive process during rest.
 Inspiratory muscles stop contracting
 Thorax & lung come back to their original positions because the lung & chest wall are elastic (passive
process)
 Intrathoracic volume decreases.
 Alveolar pressure becomes positive relative to the atmosphere
 Air flows out until the pressure equalize
 Negative intrapleural pressure returns to previous value (-2.5 mmHg) but does not become positive.
Quite Inspiration Quite Expiration

 Diaphragm accounts for 75% P/V change  Elastic recoil account for P/V change
Strong inspiration Forced expiration

 IPP more negative, up to - 30mmHg  Active process (cough & sneeze, exercise,
 Accessory muscles become more voluntary hyperventilation)
active- sternocleidomastoid, scaleni,  Contraction of expiratory muscles –int.
intercostals & anterior abdominal
serratus anterior
 IPP can be positive
 Negative pressure breathing - Patm is held constant. Palv lowered
 Positive pressure breathing - Patm is increased than the normal atmospheric
Airways & Airflow
 Nose
 Pharynx Upper R>L
 Larynx Airway
 Trachea
 RL main bronchi Lower
 Lobar bronchi Airways
 Segmental bronchi
 Terminal bronchioles
Anatomical dead space (150 mL)
 Respiratory bronchioles Gas

 Alveolar ducts Exchange
 Alveoli area/Respiratory
Zone
Volume of alveolar region 2.5-3L
A1V1 = A2V2
Total cross section area increases along the tract
∴Velocity decreases along the tract
 Nose to terminal bronchioles  Respiratory bronchioles to alveoli

↓ ↓
Conducting zone Respiratory/ gas exchange zone
↓ ↓
Air moves via bulk flow Air moves via diffusion
 Respiratory bronchioles, alveolar ducts and alveoli together is called an acinus
 Collectively form most of the lung volume (2.5 – 3 L at rest)
 Air flows by bulk flow up to the terminal bronchioles, thereafter the volume / total cross area
greatly increases causing velocity of air to rapidly decrease.
 Therefore, there is a high chance of unfiltered inhaled dust particles depositing in the respiratory zone

Blood Supply of Lungs
Lungs have a dual blood supply:

 Pulmonary circulation (to respiratory zone)
 Bronchial circulation (to conducting zone & pleura. Physiological shunts occur between bronchial veins
and pulmonary veins)
Bronchial Tone – Status of Contraction of bronchial smooth muscle
Dilatation Constriction
Inspiration Expiration
Sympathetic Parasympathetic
Circadian rhythm (max 6 pm) Circadian rhythm (max 6 am)
Thus, asthma attacks are more prone in the morning

Factors Affecting Airflow (Resistance & Compliance)
∆𝑃×𝜋×𝑟4 8𝜂𝑙
Poiseuille equation: 𝐹 = 𝑅=
8𝜂𝑙 𝜋𝑟4
η = viscosity
𝜂
r= radius of the tube Thus, 𝑅 ∝ 𝑟4
∆𝑃
𝐹 =
𝑅
1. Resistance - “Pressure difference required for a unit air flow (R = ΔP/Flow Rate)”
Depends on:
 Pressure gradient between the mouth and alveoli (determines the volume of air coming in)
 Caliber of the airways
o Tone of bronchial smooth muscle
 Neural: Parasympathetic (Ach mediated) – constrict
Sympathetic (β2 adrenergic) – dilate
Chemical: NO, VIP – dilate
Histamine, substance P - constrict
o Patent bronchi
 Density & viscosity of the inhaled gas (O2 mixed with He is given in hospitals)
 Direction of flow
 Nature of flow
 Lung volume (this is why obstructive respiratory disease patients breathe at high lung volumes;
radial traction on bronchioles during inflation pulls them open.)
 Large bronchi Medium size bronchioles  Increase resistance
Medium size bronchi Small bronchioles  Decrease resistance
Bronchoconstriction is precipitated (increased) by

1. Cool air
2. Exercise -> Sympathetic↑->Respir. Rate↑
Reduced warming & humidifying inflowing air
3. Irritants
4. Inflammatory agents (bacteria, virus,
allergens)
5. Cytokines
6. Adenosine
7. Leukotrienes
8. Histamines
9. Substance P
10. Epinephrine/ Norepinephrine
Dilators
1. VIP – Relaxes smooth muscles
2. Salbutamol – β2 agonist
3. Atropine – Parasympathetic antagonist

Disorders due to increased airway resistance
Reversible Draw the graph for vital capacity against time in an

asthma patient and comment on the ratio FEV1/VC
Asthma
Chronic OPD
 Main issue in asthma is the decrease of airway

diameter due to,
1. Increased smooth muscle tone
 Due to irritants; histamine, cytokines
2. Inflammation
 Oedema & inflammation of
submucosal layer
 Obstruction of the lumen by excess
secretions
 Vascular congestion
3. Smooth muscle proliferation
 Allergens of asthma
o infectious viruses, exercise, environmental and air pollution, occupational factors,
pharmacological agents.
Is asthma an obstructive or restrictive lung disease?
Difficulty higher in expiration, why?
 Basis of treatment
1. Dilate airways – bronchodilators. Ex: Salbutamol (2 receptor agonist)

Block bronchoconstrictors Ex: muscarinic receptor antagonist
2. Reduce density of gas – He & O2 mixtures
3. Increase the pressure gradient – Mechanical ventilators & accessory muscles of inspiration
4. Prevent or reverse inflammation – glucocorticoids, mast cell stabilizers, inhibitors of

leukotriene synthesis/ action.
5. Eliminate causative agents – avoid exposure to allergens.
6. Desensitization – reduce reactivity

Elastic Properties of Lungs
1. Compliance/ Stretchability /Distensibility
“Change in lung volume per unit change in transpulmonary pressure (ΔV/ΔP)” 200 mL/cm H2O
Depends on:
 Lung volume
 Surface tension
 Structural properties
Compliance during,
 Supine position  Pulmonary congestion
 Pneumothorax  Removal of one lung
 Pulmonary oedema  Rigid chest wall
 Old age  Acute respiratory distress
*Reason – saline reduces the surface tension to

nearly zero.
So, assess only the tissue elasticity
very ↑ or ↓  The P-V curves are different for inspiration &

volumes have expiration. “Hysteresis”. Due to the presence of
↓ P/V surface tension
∴  Stiff lung at very high and very low volumes
↓ compliance  Gradient (∆V/∆P); AKA compliance
 Nature depends on,
o Elastic tissue of lung
o Surface tension
High Compliance Low Compliance

Greater change in V per unit change in P Smaller change in V per unit change in P
Expiration is difficult Inspiration is difficult
Lungs are expanded Lungs are stiff
Causes: Causes:
Old age, Emphysema, Reduced elastin Lung fibrosis, pulmonary
Content oedema, atelectasis
Emphysema
 As the walls of the airways are weaker and less supported they tend to collapse when the
pressure outside increases in expiration.

Draw the graph for vital capacity against time in a lung
fibrosis patient and comment on the ratio FEV1/VC
Alveolar Surface Tension

1/3rd of this nature, due to elasticity of lung tissue.
Lung tissue tends to recoil
2/3rd of this nature, due to surface tension
“Surface tension is the force acting perpendicular on an imaginary line 1cm long on the surface of a liquid”
This occurs due to the intrinsic property of a liquid to assume the minimum surface: volume ratio (the
attractive forces between liquid molecules is greater than their attraction to other surrounding molecules.
𝐿𝑎𝑝𝑙𝑎𝑐𝑒′𝑠 𝐿𝑎𝑤 ∶ 𝑃 = 2T/R 𝑆𝑢𝑟𝑓𝑎𝑐𝑒 𝑡𝑒𝑛𝑠𝑖𝑜𝑛 𝛂 𝑒𝑙𝑎𝑠𝑡𝑖𝑐 𝑟𝑒𝑐𝑜𝑖𝑙

Surfactant
 A lipid surface tension lowering agent present in the fluid lining the alveoli
 Secreted by type II alveolar epithelial cells, in response to β adrenergic stimulation.
 Rapid rate of turnover
 Recycled by type II pneumocytes & pulmonary alveolar macrophages (PAMs)
 DPPC (dipalmitoyl phosphatidylcholine) [ 90% lipids, 10% proteins]
 Formed 32 / 34 weeks in fetal life.
 Maturation of surfactant at this time is by glucocorticoid hormones
 Smoking decreases surfactant
How does surfactant  ST?

 DPPC molecules are hydrophobic at
one end and hydrophilic at the other.
 Align on surface
 Intermolecular repulsive forces
oppose normal attractive forces
between liquid molecules on the
surface
Functions & Advantages of Surfactant (Explain how each is achieved by surfactant)
1. Reduce surface tension – increase compliance, decrease work of expansion

2. Increases alveolar stability –
- Prevent smaller alveoli from collapsing and large alveoli from bursting
- Prevents atelectasis. *Infant respiratory distress syndrome (IRDS)
3. Keeps the alveoli dry – ST forces suck fluid into the alveoli.
Disadvantages of loss of Surfactant,

1. Stiff lung 2. Pulmonary Edema 3. Atelectasis
Write the relationship of DPPC to ST What is the function of type I alveolar

epithelial cells?
1 Primary Lining of the Alveoli (40%)
𝑆𝑢𝑟𝑓𝑎𝑐𝑒 𝑇𝑒𝑛𝑠𝑖𝑜𝑛 𝛼
[𝑠𝑢𝑟𝑓𝑎𝑐𝑡𝑎𝑛𝑡]/𝑎𝑟𝑒𝑎 Which cell type is more numerous?
1 Type II Pneumocyte (60%)
𝛼
𝑚𝑜𝑙𝑑𝑚−3 Which cells occupy a greater surface area of
( )
𝑚2 the alveoli?
Type I Pneumocyte (90-95%)
Surfactant and alveolar stability

If T1=T2, P1>P2 P1 = 2T1/R1 P2=2T2/R2
But as [surfactant] per unit area is R1<R2
high in the small alveoli, the surface ∴P1>P2
tension is greatly reduced than the
large alveoli. T1<T2; this prevents the collapsing of the small alveoli
Work of Breathing
Work done by respiratory muscles.
 To move inelastic tissue7% (viscous resistance)

 To move elastic tissues in lung and chest wall 65% (elastic work)
 To move air through respiratory passage 28% (airway resistance)
Work = Pressure × Volume
In asthma the resistance work is greatly increased.

In Emphysema elastic work is increased.

Lung Volumes, Capacities & Lung Function Tests
4 volumes and 4 capacities are identified.

Volumes are measured. Capacities are additions of volumes.
Measurement Typical Definition

value (mL)
TV The volume of air inspired or expired with each normal breath

IRV The maximum extra volume of air that can be inspired over and above
the normal TV when the person inspires with full force
ERV The maximum extra volume of air that can be expired by forceful
expiration after the end of a normal tidal expiration
RV The volume of air remaining in the lungs after the most forceful
expiration
VC The maximum amount of air that can be expelled IRV+TV+ERV
after first filling the lungs to their maximum extent
and then expiring to the maximum extent
IC The amount of air that can be inspired, beginning at TV+IRV
the normal expiratory level and distending the lungs
to the maximum amount
FRC (relaxation The amount of air that remains in the lungs at the ERV+RV
volume) end of normal expiration
TLC The maximum volume to which the lungs can be VC+RV
expanded with the greatest possible effort
 Exhalable air measured by; spirometry
 Non exhalable air by; (RV, FRC, TLC)
o He dilution method
o Total body plethysmography
o N2 washout method
FEV1 – Fraction(volume) of FVC expelled during first second of forced expiration (Normally 75% of VC)
FVC – Forced Vital Capacity
Respiratory rate – breaths per minute (12-16 per min: healthy adult)
Dead Space
The volume of gas, which occupies that region of the respiratory system, which does not take part in gas
exchange.
 Anatomical dead space (150 mL)

o The volume of all the airways proximal to the respiratory bronchioles
o Increases in deep breathing. WHY? – Due to involvement of accessory muscles, more
negative Intra Pleural Pressure & high increase in lung tissue leading to increasing of caliber
of conducting system.
o Depends on the body size and posture
 Physiologic dead space

o The total volume of air that is not equilibrating with blood (wasted ventilation), simply, the
volume of alveoli, which are ventilated but not perfused.
o Un-perfused alveoli
o In diseases, un-perfused and over-ventilated alveoli increases.
o In a healthy adult, Physiological DS = Anatomical DS
Respiratory minute volume = RR × TV
VA – Alveolar ventilation. To increase ventilation, increasing TV is better

Volume of air than increasing RR.
that reach the alveoli. Because of the dead space, rapid shallow
breathing produces much less alveolar
Tidal volume
ventilation than slow deep breathing at the
Respiratory rate VA same respiratory minute volume.
Dead space
Calculation of Ventilation
Tidal volume = Anatomic dead space + alveolar compartment
= 150 mL + 350 mL
= 500 mL
Respiratory rate = 15 cycles/min (12 – 20) Alveolar ventilation equation

Total ventilation/ = TV × RR VA = (TV – DSV) × RR
RMV = 500 mL × 15 min-1 = (500-150) × 15
= 7500 mL/min (RMV) = 5250 mL/min

Lung Volumes and Capacities in Disease States
Obstructive Restrictive
Caused by airway obstruction Caused by stiff lungs
Difficulty in expiration Difficulty in inflating lungs
FEV1 decreases FEV1 decreases
VC unchanged VC decreases
FEV1/VC ratio less than 75% FEV1/VC ratio normal or higher than 75%
Ex: Asthma, COPD, Emphysema Ex: Lung Fibrosis, pneumothorax, pulmonary oedema

Lung Function Tests
1.Maximum/ Peak Expiratory Flowmetry
 Peak flow is the volume of air that can be expired in a unit time in a maximum expiratory effort.
 This ranges from 400 – 750 L/min
 Peak flow meter is used
 Measurement of PEF- select best of the 3 blows, not the average.
 Peak flow is reduced in
o Restrictive diseases
 Fibrotic diseases
 Tuberculosis, Lung fibrosis, Silicosis
 Abnormal chest walls
 Kyphosis, Scoliosis
o Obstructive diseases
 Asthma
 Emphysema
Other Methods
i. Peak expiratory Flow
ii. Pulse oximetry – measure O2 saturation
iii. ABG testing

GAS EXCHANGE
Partial pressure Oxygen Diffusion Pulmonary Ventilation – Perfusion
Cascade Circulation Relationships
Partial Pressure
o Pressure exerted in any one gas in a mixture of

gases.
o Dissolved gases also exert partial pressure
o Partial pressure of a dissolved gas in the liquid is
proportional to its concentration
o Net diffusion between alveolar air and pulmonary
blood depends on difference of partial pressures
Oxygen Cascade
PIO2 = PB%
PAO2
PaO2
PIO2 = O2 PP of inspired air

PA – Alveolar partial pressure
Pa – Arterial partial pressure
Gas exchange occurs at blood gas interface – Made of alveolar & capillary walls + fused basement
membrane/ Alveolar capillary membrane/ Respiratory membrane
Diffusion
Factors effecting the rate of diffusion across the membrane (V/t)
 Thickness of the membrane (T)
 Surface area of the membrane (A)
 Pressure difference of the gas across the membrane (P1-P2)
 Diffusion coefficient (D) – Depend on solubility (sol) & square root of the gas’s molecular weight (MW)
𝐕 𝐀
∝ × 𝐃 × (𝐏𝟏 − 𝐏𝟐)
𝐭 𝐓 In emphysema surface area
𝐬𝐨𝐥 decreases as alveoli coalesce
𝐃∝
√𝐌𝐖

Diffusion Capacity (DL)
𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑔𝑎𝑠 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑒𝑑 𝑖𝑛 𝑢𝑛𝑖𝑡 𝑡𝑖𝑚𝑒

𝐷𝐿 =
∆𝑃
 “Volume of gas that will diffuse through the respiratory membrane each minute for a partial pressure
difference of 1 mmHg”
 It is a measure of the ability of the lung to transfer gas across the respiratory membrane. (High surface
area, adequate perfusion with haemoglobin)
Diffusion capacity depends on

- Surface area
- Capillary blood flow
DLCO = VCO / Alveolar-Arterial pressure difference of CO
- Haemoglobin available
* Arterial pressure is taken as Zero, except in
 Diffusion capacity of lungs is measured using
DLCO method. habitual smokers VCO = Volume of CO inspired
 CO is used because its diffusion limited. by the patient
Procedure
1. Inhale a gas mixture with 0.3% CO. Condition DLCO
2. Hold breath for 10s. Exercise ↑
(CO diluted by gas already present and also Emphysema ↓
taken up by Hb.) Lung Fibrosis ↓
3. Exhale 1st to wash out the dead space Lung Lobe resection ↓
4. Next exhaled alveolar sample Anaemia ↓
collected. 5.CO concentration measured. Alveolar Hematoma ↑
6. Should make corrections for Hb concentration
and lung volume.
 Diffusing capacity markedly increased in – exercise (because of capillary dilation and distension)
 Diffusing capacity decreased in – emphysema, lung fibrosis, lung lobe resection, anaemia
 Diffusing capacity CO2 >>O2 → CO2 retention is rarely a problem in patients with lung fibrosis
 O2 diffusing capacity reduction severe
Diffusion and Perfusion limitations

 N2O is perfusion limited. WHY?
- Rapidly crosses blood-gas barrier.
- Doesn’t bind with HB, ∴ partial pressure rises rapidly
- I.e.: it equilibrates with alveolar N2O rapidly, ∴ no gas is
thereafter transferred
-
 CO is diffusion limited. WHY?
- CO moves rapidly across blood brain barrier.
- Binds to Hb. ∴ large amount can be taken up by RBC
o with no ↑ in par al pressure.
- Amount of CO that diffuses into blood depends not on
amount of blood, but on properties of lung.

 O2 is perfusion limited. WHY?
 Why does O2 transfer become

diffusion limited during severe
exercise?
- Blood spends about 0.75s in capillary
around alveolus at rest. During exercise
that time is 0.25s.
∴ time for oxygenation is less.
 Why is it not so for mild exercise?
Pulmonary Circulation
2 main supplies
o Bronchial arteries – oxygenated blood from aorta, supply nutrients to the pulmonary tree.
o Pulmonary arteries – deoxygenated blood from r. ventricle for gas exchange.
After exchange, oxygenated blood is carried to the heart by pulmonary veins. There it is mixed with
deoxygenated blood draining the lungs. Thus, a physiological shunt is seen here.
Differences from systemic circulation

 Much less smooth muscle
 Walls thinner
 Larger diameters
 Large numerous capillaries
 Multiple anastomoses
Shunts Deoxygenated blood entering the arterial side of the circulation without undergoing gas exchange within
ventilated regions of the lung for oxygenation.
Hypoxemia caused by shunts

Right to left Left to right
can never be abolished by
Bronchial veins  Pulmonary veins ASD
breathing 100% O2 because
Coronary veins  Left atrium
(Venae Cordis Minimi)
shunted blood is never
Under ventilated but perfused alveoli ventilated. But PaO2 slightly
increases with 100% O2.
Physiological Pathological (useful in diagnostic tests)
shunts
When enlarged to cause pathological Most added O2 is dissolved form, because blood that
conditions, ‘pathological shunts’ is perfusing, ventilated alveoli are hardly saturated.
Pressures in the Pulmonary System
Mean pressure
15 mmHg
 Alveolar Pulmonary Exposed to pressure of

vessels capillaries alveoli. Compressed if
alveolar pressure >
capillary pressure
 Extra alveolar Pulmonary arteries Pulled open by radial
vessels & veins traction of surrounding
elastic lung
tissue
Pulmonary Vascular Resistance – PVR

 Very low
 1/10 of systemic vascular resistance
 Due to absence of muscular arterioles.
 Compatible with distributing blood in a thin film over a vast area.
 When pressure within the system rises, PVR become smaller by;
o Recruitment – previously closed capillaries open
o Distension – vessels increase in caliber
 Serotonin, histamine, norepinephrine increases PVR
 Acetylcholine decreases PVR
 PVR↑ with alveolar hypoxia due to, hypoxic pulmonary
vasoconstriction. “Critical Opening Pressure”
Effect of Lung Volume on PVR
Inspiration PVR
 Extra alveolar vessels are opened by radial traction from
surrounding lung tissue.
Other functions of pulmonary circulation.

 Pulmonary Reservoir
 Due to distensibility
 Lying down position –
Blood volume  vital capacity 
* During hemorrhage blood can be directed to the systemic circulation

Uneven Ventilation
Upright
 Lower regions ventilated better than upper
zones.
Supine
 Apical ventilation = basal ventilation.
 Lowermost (posterior) > Uppermost (anterior)
 Increase in perfusion down an upright lung is more rapid

than the increase in ventilation.
 ∴ V/Q abnormally high at the top and lower at the bottom.
 Dependent lung is best ventilated
 Dead spaces more prevalent in apical lung. Lower at bottom.
 Regional differences alveolar Po2, Pco2, imply differently in end-capillary gas concentrations.
 Intra-pleural pressure more negative

State the sizes of alveoli & state of perfusion at  Larger alveoli (Compliance low)
the lung apex and base. Explain why there is a  Lower intravascular pressure
difference. Based on your answer, what factor is  Less blood flows
the main reason for this variation?  Less ventilation
 At the lung apex, alveoli size is large, but  But V/Q is high
the lung compliance is low. Size is due to
 So low O2 extraction
more negative intrapleural pressure.
Compliance is due to reduced elastic tissue.
 Dead spaces are high
 At the apex, perfusion is low than the base
due to the effect of gravity
 At the apex the ventilation is low as the
compliance is low
Which part of this lung is susceptible to

tuberculosis?  Intra-pleural pressure less negative
 Lung Apices. More oxygenated; PAO2 is  Smaller alveoli (Compliance high)
higher than the bases, and the apices are  Higher intravascular pressure
relatively unperfused due to the  Better blood flow
collapsing of capillaries leading to  Better ventilation
reduced O2 diffusion. Therefore, the  But V/Q is low
PAO2 is similar to inspired air  So O2 Extraction is high
 Shunts are high

Uneven perfusion of lungs
Effect of Gravity on Regional Blood Flow
 Can be explained by hydrostatic pressure difference. Nice to know -
Waterfall effect
 Bases are better perfused than the apex in the upright position
(Blood flow is greater in the most dependent part)
 Affected by exercise and change of posture (on mild exercise, regional differences become less)
Zone 1: Upper-most part

 Pulmonary capillary pressure is very low
 Alveolar pressure at the apices cause capillary collapse at apices
 Therefore, ventilated but un-perfused. More “Alveolar dead space”
Zone 2: Middle part

 Pulmonary capillary pressure overcomes alveolar pressure
 Flow rate depends on the difference of PA and Pa
 Perfusion occurs to a limited extent, only during systole
 Therefore, not a dead space
Zone 3: Lower part

 Pulmonary venous pressure is also high
 Therefore, PA is overcome easily
 Flow rate depends on Pa – Pv
 More “Shunting” prevalent in lower lung.
Ventilation Perfusion Relationships

 Diffusion of gases is not enough to achieve the best gas exchange; there must be a matching
between ventilation (V) and perfusion (Q).
 This matching is expressed as a ration V/Q
 Ideal alveoli must have V/Q = 1
 However, in reality V/Q = 0.8
The V/Q Scatter Spectrum of Alveoli
Shunts Dead space
Mixed venous blood

 Thus, as V/Q ratio is altered, its gas composition
approaches
Inspired gas
Variation of V & Q Along the Lung
L/min
Q
V
Q
Bottom Top
Q>V V>Q
∴ V/Q is ∴ V/Q is
low high
Effect of inequality on overall gas exchange

 Lung with V/Q inequality can’t transfer O2 & CO2 as much as a uniformly ventilated & perfused lung.
 Reason: Po2 at lung apex > base, but major share of blood comes from lower zones of lung where
Po2↓, ∴ Pao2 is suppressed.
 By some reasoning Pco2 will be elevated.
 ∴ V/Q inequalities can cause hypoxia, even hypercapnia due to CO2 retention. But it doesn’t manifest
because CO2 can be removes by ↑ ven la on unlike O2. (due to different dissociation curves)
Eg: 1.
2. Ventilatory drive ↑
Draw a graph showing the variation of V, Q & V/Q from the dependent part to non-
dependent part of a lung
 V/Q abnormalities
o Do not commonly lead to CO2 retention, if ventilation can be increased.
o Hypoxemia cannot be eliminated by increasing ventilation
 Different behavior of the 2 gases result from the different shapes of their dissociation curves.
 V/Q mismatch is an important & common cause of hypoxemia. It can also cause hypercapnia BUT it
does not manifest! WHY? CO2 can be excreted by increasing ventilation but not O2 diffusion. CO2 is
highly water soluble than O2
 V/Q ratio increase in emphysema, decrease in fibrosis.
Autonomic supply – (sympathetic - ↓blood flow)
Active
- O2
Local factors (Hypoxic pulmonary vasoconstriction)
- CO2 (→ pH↓ → vasoconstriction)
- NO
Systemic factors (eg- systemic hypoxia → constrict arterioles, P↑)

Regulation
Of Blood Flow
Gravity
Passive The main controllers under normal conditions

Dominate Cardiac output
under  PVR
normal  Distribution of
conditions
flow
Hypoxic pulmonary vasoconstriction – HPV

o Occurs when PAO2 is reduced. NOT PaO2 Relevance of HPV
o Does NOT depend on CNS High altitude  PVR 
o Due to decreased production of NO (EDRF) At birth  PVR 
o Contraction of smooth muscle in small arterioles. (when alveoli get
o Directs blood away from the under ventilated regions.
Water Balance of Lungs

 Inward directed pressure gradient of -15 mmHg
 Numerous lymphatic channels
 Keeps alveoli dry
25 mmHg 10mmHg
Oncotic Pressure Hydrostatic Pressure

Gas Transport
O2 Transport
O2 delivery system = CVS + RS

O2 delivery to a particular tissue depends on
 Amount of O2 entering the lungs
 Adequate gas exchange
 Blood flow to the tissues (degree of constriction of the vascular bed, Cardiac Output)
 Capacity of blood to carry O2

Dissolved O2 follows Henry’s Law
Transported in 2 ways
o Bound to Hb 97%
𝐴𝑚𝑜𝑢𝑛𝑡 𝑑𝑖𝑠𝑠𝑜𝑙𝑣𝑒𝑑 𝛼 𝑃𝑎𝑟𝑡𝑖𝑎𝑙 𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒
o Dissolved 3%
Amount of O2 in blood depends on

 Hb – Amount
Affinity for O2
 Dissolved O2
O2 & Hb
 Hb has Globin (2α + 2β), Fe2+, Porphyrin

 Each Fe2+ binds reversibly to 1 O2 molecule
 Oxygenation – Iron remains Fe2+
 Hb4O8
1st O2 molecule is bound

DeoxyHb (less affinity) Relaxed configuration – R
Tense configuration – T cooperativity Affinity greatly increased
Saturation = % of O2 binding sites which have O2 attached.

At 100% saturation, in vivo bound O2 is less than in vitro
Reason – minor structural differences of Hb & small amounts of inactive Hb derivatives
 Systemic arterial blood - Why 97%, not 100% O2 saturation?

 Due to Physiological shunts
1. Pulmonary veins (pulmonary capillaries bypassed by bronchial veins)
2. Thebesian veins (Venae Cordis Minimi)
3. Poor V/Q matching
1. O2 capacity – Maximum amount of O2 that can be combined with Hb

(1.39 mL/g in vitro, 1.34 mL/ g in vivo)
1.39mL/g ×15 g/100 mL = 20.8 mL/100 mL
2. O2 saturation
𝑂2 𝑐𝑜𝑚𝑏𝑖𝑛𝑒𝑑 𝑤𝑖𝑡ℎ 𝐻𝑏
× 100%
𝑂2 𝑐𝑎𝑝𝑎𝑐𝑖𝑡𝑦
Arterial blood = 97%
Venous blood = 75 %
≈30mmHg → 50%
50mmHg → 85%

O2 – Hb Dissociation Curve  Shape- sigmoid (due to tense-relax
configuration)
 Steep lower part
o At low PaO2, low affinity of
Hb to bind with O2
o O2 unloading is maximum for
small change in PaO2
o Capillary PO2 > Tissue PO2,
therefore diffusion is high
 Flat upper part
o At high PaO2, high affinity of
Hb to bind with O2
o Even if PAO2 is less, O2
loading is not affected
o Saturation % changes very
little
o PAO2 > PaO2, therefore
diffusion is high
 Dissolved O2 has linear relationship
with PaCO2
P50 = the PO2 at which Hb is 50% saturated
with O2.
Left shift – P50 decrease Right shift – P50 increase
1) ↓ 2,3 BPG (during acidosis it inhibits glycolysis by ↑ 2,3 BPG

↓ 3-phosphoglyceraldehyde)
2) ↓ temperature ↑ temperature
3) ↑pH ↓pH Exercise
4) ↓Pco2 ↑Pco2
5) ↑CO
6) After blood transfusion due to depressed metabolic activity

that reduced 2,3 BPG
Fetal Hb
HbF affinity for O2  than HbA.
Mother to baby O2 movement is
facilitated.
Reason:  chains in HbF have poor affinity for
2,3, BPG than in  chains in HbA.

2,3 - BPG in RBC
↑ ↓
Thyroid hormones, androgens, Acidosis - pH   2,3, BPG 

growth hormones
Exercise In exercise, temp, pH
Anemia P5o  2,3 BPG
Chronic hypoxia
CO2 Transport
 Solubility of CO2 in blood is about 20 times that of O2
 Mainly 3 ways. - In
o RBC
o Plasma
1. Dissolved - 7 - 10%
2. Carbamino compounds - 23 - 30% -
(bound to amino groups of Hb, plasma proteins)
3. Hydration – HCO3- - 60 -70%
Haldane effect
 Occurs at lung level
 Deoxy Hb
o binds more H+ than HbO2 (Better buffer) Plasma
o forms carbamino compounds more readily RBC
than HbO2 CO2 CO2+ H2O
Binding of O2 to Hb affinity for CO2. Carbonic
anhydrase
H2CO3
Bohr effect
 H+
Occur at tissue level Band 3 HCO3- HHb
 Rise in Pco2 causes rise in H+ (AE1)
 in O2 affinity of Hb when  pH Cl- Hb

 Deoxy Hb binds H+ more actively than HbO2 HbO2
 Curve shift to the right.
O2 O2
 P50 , thus affinity decreases

Chloride Shift
 70% of HCO3- formed in RBC enters the plasma in exchange for Cl-.
 By Anion Exchanger 1 (AE1/ Band 3)
 Cl- of RBC in venous blood >>> arterial blood
 For each CO2 molecule added to an RBC −−−→ ↑of 1 osmo cally ac ve par cle in the RBC
 HCO3- or
 Cl-
RBC takes up water → increase in size Small amount of arterial

blood return via lymphatics
Haematocrit of venous blood 3% greater than arterial blood
in the lungs, Cl- moves out of the lungs →RBC shrinks
Lungs
RBC
CO2 CO2+ H2O
Carbonic
anhydrase
H2CO3
HCO3- H+ HHb
Band 3
(AE1)
Cl- Hb
HbO2
O2 O2

RS REGULATION
Neural
Chemical Regulation Non-chemical
Negative feedback mechanism
Respiration is mainly controlled

by chemical receptors Central controller Descending tracts,
Buffer nerves – IX, X Medulla, pons, other motor neurons
areas of the brain
Effectors
Sensors Respiratory muscles
Chemoreceptors –  Reciprocal innervation-
 Central excite agonists, inhibit
 Peripheral antagonists
PaCO2
PaO2
H+
Response
Change ventilation
Rate & depth

Chemical (via chemoreceptors)
Central-medullary Peripheral
Carotid Bodies-IX Buffer nerves
Monitor [H+] in CSF and brain ECF Aortic bodies-X
Stimulated by –
↑ PaCO2, ↑ H+ in CSF and ECF  Has a rich blood supply for a unit mass. – because the blood
flow per unit of tissue is so enormous, the O2 needs of cells
can be met largely by dissolved O2 alone. Therefore, the
 H+ in blood cannot pass through BBB receptors are not stimulated in conditions such as Anemia or
 CO2 diffuses CO poisoning
CO2 + H2O H2CO3 H+ +HCO3-  respond to changes in dissolved O2, CO2 and pH
 Not stimulated in
o Anemia (PaO2 is normal)
o CO poisoning
Receptors for H+  Receptors stimulated
o pH
 Main stimulation PaCO2 o PCO2(above 40mmHg)
o PO2  (below 60mmHg) Discharge rate 
 When PaCO2  cerebral vasodilatation ↓
o Vascular stasis
 More CO2 diffuses to CSF and brain ECF -
o CN poisoning Respiratory center
 Stimulate respiration +
o K Infusion ↓
o Exercise  Ventilation
o Nicotine & Lobeline
 If peripheral chemoreceptors are denervated response to
hypoxia is abolished
 Response to H+ is affected significantly
 Morphine depresses respiration
Mechanism of peripheral chemoreceptors
 Carotid Body consists of two types of cells:

 Type I cells (glomus cells) of these receptors have O2 sensitive K+ channels.
 Type II cells surround type I cells (glia like)
 Its conductance is reduced proportional to the degree of hypoxemia.
 So, when the PaO2 drops K+ efflux reduces, and the cell get depolarized. This triggers influx of Ca 2+
 Neurotransmitter dopamine released by exocytosis & an action potential is generated.
 [Hypoxic pulmonary vasoconstriction also happens via O2 sensitive K+ channels. In systemic circulation, ATP
dependent K+ channels cause vasodilation]

Innervation
Unmyelinated
Myelinated
fibers
Juxta Capillary
Slowly Adapting Rapidly Adapting
Receptors
Stretch Receptors
(Hering-Breurer Irritant Receptors
reflex)
Stretch receptors/ irritant

Neural receptors airways, lungs
Arterial
baroreceptors Inspiration
Voluntary Autonomic
Vagal afferents
Cortex Medullary respiratory center Inhibitory effect (does not
Pre-Botzinger complex affect the respiratory rate)
Pacemaker cells
Damage: - depth 
Override the activity of
medulla within limits Rhythmic
discharge  Pneumotaxic centre - pons
(RAMP action  Groups of neurons active
Potential) during inspiration,
expiration
 Role in switching between
inspiration & expiration
 Phrenic nerve- Damaged: -tidal volume, rate ↓
diaphragm Not essential.
 other motor nerves to
other respiratory
muscles
 glossopharyngeal Apneutic centre
nerve-tongue-air way  In the pons
resistance  Maintains inspiration
 If damaged inspiratory
gasps occur
 Impulses from proprioceptors of joints can increase the ventilation.
 Baroreceptors inhibit respiration. (little effect)
 Substance P stimulates respiration
Response to changes in acid base status
 Metabolic acidosis – chief site of action – peripheral chemoreceptors

Pronounced respiratory stimulation → PCO2 ↓
Diabetic ketoacidosis – Kussmaul’s breathing
 Metabolic alkalosis – ventilation depressed. PCO2 ↑
Most important factor in controlling ventilation under normal conditions is PaCO2

o Reduction in PaO2 increase the sensitivity of peripheral chemoreceptors to PaCO2
Response to hypoxia
 PO2 must fall below 60mmHg for a marked response
Hb less saturated
PaO2 
More H+
Peripheral
Peripheral
 Ventilation Chemoreceptor
Chemoreceptor
trigger
trigger HHb
Buffering of H+
Central  PCO2
Chemoreceptor
[H+]  in plasma
Triggered Respiration inhibited
 Hypoxemia should be severe enough to overcome above inhibitions.

o Sensitive to  plasma [K+]
o  discharge in - hypoxic hypoxia
- vascular stasis
- cyanide poisoning
Other sensors & non-chemical control
 airway and lung receptors

 proprioceptors
 Baroreceptors
 afferents from pons, hypothalamus, limbic system

Voluntary Hyperventilation
Changes is RS, CNS, CVS and skin.
Increased rate and depth of ventilation
RS Changes
 PaO2 PaCO2  ,
 Periodic breathing - apnoea →few shallow breaths → apnoea (During apnoea, the alveolar pO 2
falls and pCO2 rises. Breathing resumes because of hypoxic stimulation of carotid and aortic
chemoreceptors before the CO2 levels have returned to normal. Another few breaths eliminate
the hypoxic stimulus, then again apnoea occurs until the alveolar pO 2 falls again)
 CO2+ H2O H2CO3H++ HCO3-
CNS Changes
 When CO2 is washed out, H+

 Minus charges in proteins exposes
 Binds with plasma Ca+ and precipitate.
 Plasma [Ca+] 
 Excitability of nerve fibres 
 Synaptic transmission 
 Net effect is  excitability  Chvostek’s sign-on face
 Trousseau’s sign - carpopedal spasms
 Hypocapnia  Cerebral vasoconstriction-paresthesia, dizziness, light headedness

CVS Changes
 HR - ↑
 BP - ↑
Before During Hyperventilation After 5 min

HR 75 80 70
BP (mmHg) 130/70 135/86 125/75
Skin changes
 Hypocapnia  Cutaneous vasoconstriction-cold extremities
High altitude
 Total barometric P. But, composition - constant

 Acclimatization – variety of compensatory mechanisms
Initial changes Delayed changes

1. Involuntary hyperventilation to hypoxemia
stimulation. Initial increase in ventilation is small Active transport of H+ into CSF / lactic acidosis in brain →
due to respiratory alkalosis due to elimination of ↑ven latory response to hypoxia
CO2
2. Respiratory alkalosis Erythropoietin ↑ → RBC ↑ → polycythemia
3. Increased 2,3 –DPG in RBC
2,3 –net effect on HB-O2 Dissociation curve. Tissue changes
 Increase P50  mitochondria ↑
 Right Shift  cytochrome oxidase ↑
 myoglobin ↑
 Increased tissue capillarity
 Natives at high altitudes-barrel chested, polycythemia
 At 3000m above the sea level PAO2 is about 60mmHg. And there is enough hypoxic stimulation
of chemoreceptors under normal breathing to cause hyperventilation.
Effects of rapid ascent
 Cerebral oedema
o Local vasodilation of cerebral vessels due to hypoxia

o Increased blood flow – Increased permeability
o More fluid leaks into the cerebral tissue causing cerebral oedema

Raptures in deep
 Increased barometric P
 P on the body rises
 Pushes N2 into blood
 N2 is very lipid soluble (nervous system, bone marrow, fat)
 If ascent rapid, PN2 ↓ abruptly, N2 ‘boils’ out of tissuesair bubbles → bends and chokes
 N2 narcosis is seen
Hypoxia
 O2 deficiency at tissue level
Anaemic hypoxia
Hypoxia PaO2 normal
Hb ↓
O2 content of arterial blood is
low
Hypoxic Stagnant / Ischaemic Histotoxic hypoxia
hypoxia hypoxia O2 delivery normal Respiratory symptoms not
↓PaO2 O2 delivery inadequate Tissue O2 utilization severe at rest unless Hb is
Normal PaO2, Hb impaired very low
Impaired circulation (Dissolved O2 is normal →
 Local E.g.- CN- poisoning Chemoreceptors not
 Generalized Inhibit cytochrome stimulated)
oxidase
CO poisoning
Irreversible
Causes of hypoxemia −−−−−−−−→ COHb
Cherry red
1. Hypoventilation Cannot take up O2
Curve of remaining Hb → left
1.1. Restrictive diseases
 Depression of the respiratory center by drugs (morphine & barbiturates)
 Diseases of the medulla (encephalitis, hemorrhage)
 Diseases of conduction pathways (spinal cord, nerves)
 Diseases in neuromuscular junction (myasthenia gravis)
 Diseases of respiratory muscles (Duchenne muscular dystrophy)
 thoracic cage abnormalities (crushed ribs)
 diseases of the pleura (pleural effusion, pneumothorax)
1.2. obstructive diseases

 bronchitis
 emphysema
 asthma

2. diffusion impairment
 low barometric pressure
 thickened blood gas barrier due to
o asbestosis
o fibrosis
o lung oedema
3. shunts
 patent ductus arteriosus (PDA)
 ventricular septal defects (VSD)
 atrial septal defects (ASD)
4. V/Q imbalance
 COPD
 Pulmonary embolism
Effects – Hypoxemia Compensatory - increased ventilation

-increased CO
-polycythemia as erythropoietin 
Non compensatory -cellular changes-2,3 BPG 
-other
Cyanosis
Dusky, bluish discoloration of tissues due to increase of deoxygenated Hb concentration (above
5g/dL)
Depends on;
o Total Hb level in blood(polycythemia)
o Degree of saturation
o State of capillary circulation
Central peripheral
e.g.: - VSD e.g.: - impaired local circulation
Conjunctiva nail beds
tongue
 Cyanosis more prominent in polycythemia

 Cyanosis - not seen –
o CO poisoning / CN- poisoning – cherry red
o Histotoxic hypoxia

 Difficult to see in –
o Anaemia
o Dark skinned people
In methhemoglobinemia (higher than normal level of methhemoglobin - metHb, [Fe 3+] rather than [Fe2+])
in the blood) discolouration is seen. Caused by nitrite, thiosulphate like drugs.
Effects of hypoxia on brain
 Sudden severe drop in PIO2 → death

 Less sever changes →
 Impaired judgment, drowsiness, dulled pain sensibility, excitability, disorientation, headache,
vomiting, tachycardia, hypertension
Management of hypoxia
 Hypoxic hypoxia – O2 therapy very valuable except in R→L shunts & V/Q imbalance
 Anaemic, stagnant, histotoxic hypoxia – O2 of limited value. Primary cause should be treated
 O2 therapy in chronically hypercapnic patients – dangerous. WHY??
 If the patient is severely hypoxemic & his [CO2] is above 7%

 Hypoxia drives respiration.
 High CO2 depresses central drive.
 If the patient is treated with 100% O2, hypoxia is improved.
 But respiratory drive is still depressed by high CO2
 Could be lethal
CO2 narcosis
 If CO2 concentration exceed 7%
o Depression of CNS
o Confusion
o diminished sensorium
o coma
o respiratory depression
o Severe acidosis
o death

Hypocapnia
 Constriction of cerebral vessels

 Respiratory alkalosis
 Hypocalcemia
Pneumothorax - the presence of air or gas in the pleural cavity
Peak Expiratory Flow Meter (PEFM)
Used to monitor the progress of obstructive lung diseases. Ex: Asthma
Unit: L/min
Normal rate: 400L/min (varies with age, gender, height and ethnicity)
Method
1. Should hold the peak flow meter horizontally.
2. Do not block the indicator with your fingers.
3. Mouthpiece and lips should be sealed.
4. Inhale deeply then blow as fast as possible.
Do this three times and take the highest reading as the result.

EXERCISE PHYSIOLOGY
Muscle Fiber Types
Fast Twitch Slow twitch

Diameter Larger diameter Smaller diameter
Energy Phosphagen & anaerobic systems Aerobic system more active
source more active
Action For extreme amounts of power for For endurance eg: Soleus
sec-mins eg: gastrocnemius
Fast twitch to slow twitch fiber proportions differ in individuals.

• Marathoners – Fast twitch < Slow twitch
• Sprinters - Fast twitch > Slowtwitch
• Weight lifters - Fast twitch > Slow twitch Average
• Males - Fast twitch > Slow twitch
Integrated CVS & RS mechanisms operate to supply

O2 & nutrients and remove CO2, metabolites & heat.
How is energy provided for exercise
o Primarily our muscles use ATP as its source of energy

o ATP has 2 high energy (7300cal) bonds and one low energy bond but only the 2 high
energy bonds are utilized. (????? not sure)
Adenosine----PO4-----PO4----PO4
o To generate ATP, we use different substrates at different levels of physical activity.

o In resting state, we use fatty acids as our primary substrate for ATP generation.
o As soon as we start exercising, we initially use the available ATP in the muscle (3s- one
half of a 50m dash), and then ATP energy stored as Phosphocreatine.
o Phosphocreatine Creatine+ PO43- [8-10s:100m sprint]

(only enough for 3 seconds of maximal muscle power)

As we have run out of ATP, we have to generate ATP; so now we use Glucose, Gycogen
(stored in the Muscle), Fatty acids, Amino acids to generate ATP
o Anaerobic respiration (2min) → Lac c accumula on
o Aerobic respiration → Glucose, glycogen (short term) If not enough,
Fat (long term) Again, aerobic
Protein (excessive exercise) respiration starts.
CVS in exercise
Types of contraction
# Isometric contraction (iso=same, metric=measurements/length) – no appreciable

muscle shortening; no work done.
(e.g. Weight lifter trying to lift a weight but not being able to lift it, a person
trying to push a heavy load but not moving it)
# Isotonic contraction (same muscle tone/tension) - contraction against a constant

load; work done. (climbing a staircase, slow running)
Systemic circulatory changes

Isometric Isotonic
A prompt
increase in HR
a result of psychic stimuli on medulla oblongata. [due to a decrease in vagal tone (mainly)
+ increase in sympathetic activity]
Increased total peripheral resistance due to Net fall in PR due to vasodilation in muscles
compression of vessels (increased intra- (initially neural, then local vasodilation due to
muscular pressure due to sustained accumulation of metabolites-CO2, K+,
contraction) vasoactive substances)
Decreased or zero muscle BF (>70% of max Increased muscle blood flow
muscle tension)
Low increase in venous return (lack of muscle Marked increase in venous return
pump)
Stroke volume relatively unchanged (due to very Marked increase in stroke volume
less increase of venous return)
CO increased (CO=HR*SV; HR has ) CO markedly increased (both ,SV )
Sharp increase in systolic & diastolic pressure Moderate increase in systolic
(increased CO and PR) pressure. (increased CO)
Diastolic pressure decreased/unchanged (due
to the fall in PR)

Sympathetic
Exercise Discharge(psychic) Accounts mostly for in
CO
Contractility (of HR (270%)
Max HR decreases
with age (Max
(Frank- Starling)
HR=220-age)
EDV SV (50%) Cardiac
Output
Increase due to,
×6
(5.5→20-35)
Muscle pump
Venous return Thoracic pump
(Not the main Mobilization from viscera
cause of CO) Noradrenergic
venoconstriction
(shunting blood from
reservoirs
:skin, GUT)
Increased pressure
transmitted from dilated
arterioles to veins.
©2017 A/L Repeat Campaign

 Trained athletes have lower heart rates, greater end-diastolicvolumes,greater ventricular
capacity, greater cardiac mass and greater stroke volumes at rest than untrained people.(since both
generate equal CO at rest)
 Therefore they can achieve a given increase in Cardiac Output by further increases in Stroke
volume without increasing their HR as much as an untrained individual does.
 After exercise BP may fall transiently due to vasodilation by accumulated metabolites.
RS in exercise
Changes occur in:
 O2 consumption (cellular respiration)
 Pulmonary ventilation
 Diffusing capacity External and pulmonary respiration
O2 consumption:
O2 Consumption
VO2 max
Exercise intensity
VO2 max: Rate of oxygen usage under maximal aerobic metabolism.

VO2 max: the maximum amount of O2consumed by a unit weight of muscle per
unit time.
VO2 max = CO max (ml/min)* Max O2 extraction(ml/g)
 Above the exercise intensity corresponding to VO2 max oxygen consumption levels off.
 Stored 2L of O2 → Enough for 1min of heavy exercise.
 Rate of utilization of E stores > Rate of aerobic resynthesis of E stores
 Therefore, anaerobic metabolism begins Lactate is produced
O2 debt incurred

Pulmonary Ventilation:
Gradual increase due to
 increased body T,
 increased plasma K.
 increased sensitivity of neurons controlling the

response to CO2
 (O2) also plays a role
The respiratory rate

does not reach basal
level until O2 debt is
repaid to reconstitute
phosphagen and lactate
systems
90 min
Abrupt increase due to psychic stimuli +

impulses from proprioceptors in muscles.
tendons &
 During moderate exercise Arterial pH, PCO2 & PO2 remain constant.
 When exercise becomes more vigorous buffering of lactic acid liberates more CO2.
This further increases ventilation.
 Increases ventilation (CO2 washout) & CO2 production remain proportionate. So,
alveolar and arterial CO2 change relatively little – isocapnic buffering
 Further accumulation of lactic acid (stimulates Carotid body) causes increased ventilation
which outstrips CO2 production. Thus alveolar & arterial PCO2 fall.
 The decline in arterial PCO2 provides respiratory compensation for the metabolic acidosis
caused by lactic acid.
 Moderate exercise: depth of breathing increase.
 Strenuous exercise: depth and rate of breathing increases.

Respiratory rate does not reach basal levels until O2 debt
is repaid!
The stimulus for respiration is elevated arterial H+

concentration due to lactic acidemia.
During repayment (9L of O2 for repayment)
O2 concentration in muscle myoglobin rises.
ATP & phosphorylcreatine resynthesized.
Lactic acid removed. (80% converted to glycogen &
20% oxidized to CO2 & H2O)
Diffusing capacity:
Rate at which O2 diffuses from alveoli to blood
 PO2 in pulmonary capillaries fall from 40 to 25mmHg. (increased alveolar-capillary gradient)

 Pulmonary blood flow increases (recruitment of under-perfused alveoli) (increased surface area)
CO2 excretion also increase from 200ml to 8000ml

O2 entering: 250ml to 4000ml
Changes in muscle
• ↑ Muscle blood flow (×30)
×100
• ↑ O2 extraction (×3)
Muscle Blood Flow

When muscle contracts vessels are compressed (> 70% of max tension blood flow
is completely stopped- zero perfusion)

 Between contractions blood flow is increased.
 Rise in blood flow at the onset of exercise neutrally mediated
(Sympathetic vasodilator system- β2 )
 Once exercise has started local mechanisms maintain high blood
flow.
- Fall in tissue PO2
- Increase in tissue PCO2
- Accumulation of K+ & other
vasodilators
- Rise in temperature
Dilation of arterioles and precapillary sphincters increases number of open
capillaries.
Distance between blood and cells reduced.
(the distance O2 & metabolic products must diffuse
reduced)
Increased cross sectional area leads to a fall in velocity

of blood flow.
 Fluid transudation into interstitial spaces is increased.

- Capillary hydrostatic pressure rises until it increases oncotic
pressure throughout the length of the capillaries.
- Osmotically active metabolites accumulate in the interstitium.
- Therefore, the lymph flow is increased limiting the accumulation of
interstitial fluid.
- Increase in muscle diameter due to accumulated interstitial fluid.
O2 extraction
More O2 used by muscles muscle PO2 falls O2 gradient from blood
to muscle increased
More O2 removed Blood pO2 drops More O2 diffuses

from Hb from blood
Mean distance from blood to cells is decreased, therefore facilitates

movement of O2.
 High Temperature/ High 2,3BPG & acidosis (due to accumulation of CO2) shift the
O2-Hb dissociation curve to right. Reduces affinity of Hb for O2
 Ergo increased CO2 and a decreased O2 level is maintained around an active

muscle

Changes in temperature during exercise
Muscle work (eff:20-25%)

Nutrient energy
Heat (75-80%)
When body T Hypothalamus centres controlling heat dissipation

activated.
- Sweat secretion –vaporization causes heat loss
- Cutaneous vasodilation (due to inhibition of
vasoconstrictor tone + locally acting vasodilators)
- Ventilation – heat loss in expired air
- Heat loss by radiation
I
N
C
R
E
A
Myofibrils S
Mitochondrial Ez E
Glycogen stores
Stored triglycerides
- Metabolic systems (aerobic + anaerobic)
Male & Female athletes…….

 Maximal force of contraction almost similar.
 But muscle bulk is lesser in females
 Other values for females are 2/3- 3/4 of those of males.
(CO, ventilation)
 Due to testosterone.
Ageing & Exercise……..

 Sedentary (disuse) muscle atrophy
 Decrease of max breathing capacity
 Max CO & HR decrease
 But muscle training results 100% increase in muscle strength.

Exercise tolerance depends on,
 O2 delivering rate to tissues
 O2 entering rate to lungs
 Fatigue
o Neural signals (muscles → brain)
o Temp ↑
o Dyspnea
o pH ↓ (lac c acidosis)
o stimulation of J receptors of lungs.

HAEM METABOLISM
Important haemoproteins
 Haemoglobin, Myoglobin
 Cytochromes (heam + protein)
 cytochrome c – involves in ETC
 cytochrome P450 – hydroxylation of xenobiotics
 Chlorophyll (Mg containing porphyrin) – photosynthesis
 Vitamin B12
 Tryptophan pyrrolase – oxidation of tryptophan
 Catalase
 Peroxidases
 Nitric oxide synthase
Heam
Protoporphyrin Fe2+
(Porphyrin)
Porphyrins
 4 pyrrole rings joined together.

Methenyl bridge
 Cyclic compounds
 Coloured Fe2+
 Bind with metal ion
Pyrrole rings (4)
Porphyrinogens
E.g. uroporphyrinogen, coproporphyrinogen
 Porphyrin precursors / intermediates of haem synthesis

 Colorless
 Chemically reduced
 Unstable  auto oxidize to porphyrins
Haem
 Haem is an iron containing porphyrin & most common porphyrin in human.
 In Erythroid – Haemoglobin (6g-7g of Hb is synthesized per day)

 In Nonerythroid – Myoglobin, Cytochromes, Catalase, Tryptophan pyrrolase,
Vitamin B12, Cytochrome p450

HAEM BIOSYNTHESIS
 Occurs in most cells (not in RBC)
 In Liver (e.g. cytochrome p450) main site (15%)
 Bone marrow (hemoglobin) (85%)
 1st and last 3 reactions take place in Mitochondria. Other reactions occur in cytosol.
 Mature RBCs lack mitochondria, so they can’t synthesize Heam.
 All C & N atoms of the porphyrin molecule are provided by Glycine (non-essential AA)
&Succinyl CoA (Intermediate in TCA, Origin from acetate)

Regulation
 In the liver – Rate is variable, responds to alterations in cellular haem pool
 In erythroid – Rate is constant, matched to the rate of Globin synthesis
ALA Synthase
 This reaction is the committed and rate-controlling step in hepatic porphyrin (heam)
biosynthesis.
 Co enzyme for ALA Synthase is pyridoxal phosphate (Vit. B6)

Regulation of Haem synthesis in the Liver
1) Haem / Haemin control
 Feedback Allosteric inhibitor and negative regulator.

 Decrease ALAS1 enzyme synthesis
(Repression derepression) ALAS 1 – rapid turnover (t1/2- 1hr)
 Control transcription, translation and translocation.
 Decrease transcription at gene level
 Decrease stability of mRNA, therefore decreases translation
 Decrease transport of enzyme from cytosol to mitochondria
Done by ATP
dependent
chaperon I. ALAS I only unfolded form can cross
proteins II. N terminal signal sequence, cleaved by
III. To active refolding by oligomeric folding protein.
Metal Proteins
2) Glucose – repression
3) Substrate availability – Fe2+ (in Fe2+ deficiency, Zn can be incorporated into haem)
4) Drugs – derepression (Eg- barbiturate)
5) Certain steroids induce
Effect of drugs on ALA synthase activity
Some drugs are detoxified/metabolized by Cyt. P450 in liver (Microsomal monooxygenase system)
↑synthesis of Cyt. P450
consumption of haem
↓[Haem] in liver cells
Derepression of ALAS 1
↑Synthesis of ALAS 1

Effect of Pb2+
 Inhibits,
a) ALA dehydratase - Impairs PBG formation, Elevated porphyrin levels in RBC,
Elevated ALA & coproporphyrin in urine
b) Ferrochelatase - Decreases Haem formation, Causes sideroblastic anaemia
Regulation of erythroid heam biosynthesis
 Bone marrow ALAS II

 not induced by drugs
 no feedback inhibition by haem
 So, erythroid heam bio-synthesis depend on,
1) erythropoietin – stimulates synthesis of ALAS II
2) availability of intracellular iron
3) (Availability of globin)
Porphyrias
 Inherited porphyrias are autosomal dominant with few exceptions.

 Heterogeneous group of rare inborn errors of metabolism
 Due to defect in 7 enzymes (2nd step – 8th step)
 Accumulation and increase excretion of metabolic intermediates; Porphyrins
 Chemicals and drugs can predispose the disease
Mutations in various genes
Abnormalities of enzymes of haem synthesis
Accumulation of ALA & Accumulation of

PBG and/or decrease in porphyrinogens in skin
haem in cells and body and tissues
Neuropsychiatric signs and symptoms Spontaneous oxidation or

porphyrinogens to porphyrins
Photosensitivity
(Skin itches, blisters)

 Porphyrias can be classified into hepatic and erythropoietic, and subdivided into acute and
non-acute.
1) Acute
 Accumulation of ALA & PBG
 Neurological, psychiatric & acute GI disturbances
2) Non-acute
 Increased ALAS & defect in uroporphyrinogen
carboxylase
 Specific uro & coproporphyrins accumulate
 Urinary uroporphyrin excretion increase (Urine turns red on standing)
 Congenital erythropoetic porphyria recessive.
Nutritional and environmental factors precipitate symptoms
 Low carbohydrate diet - decreased succynyl CoA

 Drugs /alcohol/ smoking
 Some porphyrias are water soluble – red urine
 Some porphyrias are water insoluble – accumulation in liver
Managing
1. Avoid Cyt. P450 inducing dugs

2. Carbohydrate diet??
3. Administration of hematin-
4. Administration of β carotin to detoxify free radicals (to ↓ photosensivity)
 Cancer phototherapy (additional)
 Tumors take up more porphyrins

 Haematoporphyrin is administered to the patient
 Tumor is exposed to argon laser
 Cytotoxic effects to cells

HAEM CATABOLISM
 Occurs in microsomal haem oxygenase system (substrate inducible) in
reticuloendothelial cells of liver, spleen and bone marrow.

Bilirubin
 Two binding sites in albumin for bilirubin,

 High affinity - 25mg bilirubin (displaced by drugs)
 Low affinity - excess, loosely binds and easily detached & diffuses to tissues
 Uptake by liver - Not rate limiting, facilitated transport, carrier mediated, saturable
 Conjugation - Drug inducible (Phenobarbital)
 Secretion by liver
 Rate limiting
 active transport
 drug inducible (Phenobarbital)
 Secretion of Bilirubin glucuronide into bile canaliculi is the rate limiting step.
Clinicals
1. Jaundice (Icterus)
 Definition – Yellowish discoloration of skin, sclera and nail beds due to increased levels of
conjugated or unconjugated bilirubin or both in blood.
 Clinically detectable when serum bilirubin > 2-2.5 mg/dl
Types of jaundice
Pre-hepatic (before uptake)
Jaundice Hepatocellular (Uptake to secretion)
Post-hepatic (from bile canaliculi to small intestine)
a) Prehepatic jaundice (Hemolytic jaundice)
 Can be seen in sickle cell anemia, G-6-PDH deficiency, pyruvate kinase

deficiency, in malaria treatment.
 RBC lysis at high rate bilirubin production > conjugation.
 Unconjugated bilirubin level increases.
 ↑Heme breakdown ↑conjugation ↑bile secretion ↑urobilinogen.
Therefore, high levels of urobilinogen in urine - dark colour urine.
 ALT, AST, ALP levels normal. LDH increases. Albumin increases.
 Bilirubin isn’t present in urine, but conjugated form is present.

b) Hepatocellular jaundice
 Due to liver damage (cirrhosis/ hepatitis)

 ↓Uptake
 ↓Conjugation ↑unconjugated bilirubin in blood
 Impaired secretion pale stools (low stercobilin) and low urobilinogen
regurgitation of conjugated bilirubin in blood
Dark urine
 Enterohepatic circulation of urobilinogen → more enter into blood → filtered into the urine
 Plasma AST, ALT levels due to liver damage but no increase in ALP or slightly increased
 GGT increased in severe conditions
c) Post-hepatic jaundice (Obstructive jaundice) cholestatic / acholuric
 Retention and regurgitation of bile due to bile duct obstruction (extrahepatic cholestasis ).
Palpable gall bladder suggestive of pancreatic cancer/ gall stones
 Conjugated bilirubin in blood tea color urine

 Unconjugated bilirubin normal.
 No urobilinogen → pale, clay colored stools
 Increased ALP in plasma
 AST and ALT level normal
 Increased GGT
 Prolonged obstruction can lead to liver damage leading to increase in unconjugated

bilirubin in blood. (ALT and AST increased)
2. Displacement of bilirubin from albumin by drugs – Salicylates, Sulfonamides
 permitting bilirubin to enter the CNS
3. UDP glucuronide transferase deficiency
 Bilirubin - Uridine glucuronyl transferase (UGT) activity can be induced by drugs

E.g. Phenobarbital
4. Jaundice in new born (Pre mature jaundice of newborn)
 Due to,
I. Activity of hepatic glucuronyl transferase is low at birth (Immature hepatic system)

 late onset of expression of bilirubin glucuronyl transferse

II. Conversion of HbF  HbA
 So, catabolism is increased Unconjugated bilirubin ↑
5. Haemolytic disease of the newborn (HDN)
 Feto-maternal incompatibility for red cell antigens (ABO/ Rh)

 Maternal antibodies against fetal RBC antigens
 Transfer from mother to fetus through placenta
 Destroy fetal RBCs
 Severe jaundice in the newborn baby,
 BBB is immature Increased bilirubin can pass through

deposits in basal ganglia
kernicterus - Toxic encephalopathy – brain damage
 Treated with
 blue fluorescent light. Converts bilirubin to more polar compound (more water
soluble). Can be extracted with bile without conjugation.
 Administration of phenobarbital
 Exchange transfusion in severe cases
6. Congenital disorders
 Deficiency of bilirubin glucuronyl transferase - Crigler-Najjar I & II, Gilbert syndrome

 Deficiency in transport protein – Dublin Johnson syndrome
Tests for bilirubin
1) Van den Bergh test
 bilirubin in plasma.
 Conjugated bilirubin level  direct test (without methanol)
 Unconjugated bilirubin level  indirect test (by measuring total bilirubin level using
methanol)
Unconjugated bilirubin = Total bilirubin – Conjugated bilirubin
2) Ehrlich’s test
 bilirubin in urine
 Ehrlich’s diazo reagent + bilirubin  reddish purple

MINERALS
 Categorized into 2 classes,
1) Major minerals
(Required intake > 100mg/day)
2) Trace minerals
(Required intake < 100mg/day)
1) Major Minerals
 Ca and P are the minerals present in the highest amount in the body.
 All major minerals (Eg: -Na+, K+, Cl-) influence the fluid balance
Na+ K+
 A major cation in ECF  Major cation in ICF
 Water balance  Water and acid base balance
 Regulate the acid base balance  Muscle activity
 Cell permeability  CHO metabolism
 Muscle action and nerve impulse  Protein synthesis
transmission  Control of blood pressure
 “Trace Elements” - Inorganic metals which occur in biological fluids at a very low concentration
(less than 1μg/g of wet weight). Most essential, others may be required.
 Deficiency common for Iron, Iodine, Fluorine.

 Deficiency identified for Manganese, Chromium, Cobalt, Molybdenum, Zinc, Selenium, Copper
Deficiency of trace elements may occur due to: BUT, trace elements may be toxic,
 Inadequate intake  If taken excessively
 Due to malnutrition (→ “food faddism”)  If taken in the wrong chemical form
 Due to malabsorption (Eg: Cr3+ is the normal active form while
 Due to alcoholism Cr6+ is toxic)
 Low bio-availability  Depending on rate of excretion
 Antagonistic interactions
 Increased loss
 As a consequence of disease
 As a consequence of therapy (e.g.
dialysis, total parenteral nutrition/TPN)

IRON
 Dietary sources: Meat, fish, poultry, dark green leafy vegetables, pulses
Deficiency Functions Symptoms/Consequences of

(Requirement- 15mg/day) Deficiency
 Inadequate intake  Active form: Fe2+  Compromised development
 Malnutrition  Component of: in young children (iron
 food faddism  Hb & myoglobin enzymes in
 malabsorption  Cytochromes neurotransmitter systems
 Low bio-availability  Haem enzymes → affect motor & cogni ve
 Antagonistic interactions (peroxidises) development)
(Ca2+ and Zn2+ compete  Non-haem enzymes  Impairs work performance
with Fe2+ during (NADH dehydrogenase, & exercise capacity
absorption) phenylalanine  ↓Cytochromes →
 Due to disease hydroxylase) ↓Oxida on reac ons in
 Due to therapy  Iron-Sulphur clusters muscles→ ↓Energy
production
 ↓Hb → ↓O2 transport
 Risk groups; infants, pre-schoolers, adolescent females, pregnant females

 Body prioritizes the use of iron in deficiencies
Progresses
Mild deficiency Anaemia
 Iron is never found in free form (Fe2+) in cells because Fe2+ can generate oxygen free radicals.
 Always converted to Fe3+ and bound to proteins:
 During transport - bound to apotransferrin (to form transferrin)
 During storage - bound to apoferritin (to form ferritin)
Iron Absorption
HT = Haem Transporter, DMT1 = Divalent Metal Transporter 1,

Hp = Hephaestin, FP = Ferroportin, TF = Transferrin
 Iron is ingested in diet either as non-haem or haem iron
 Haem iron absorption
 Haem carrier protein/haem transporter present on microvillus surface of absorptive
enterocyte
 Non-haem iron absorption
 via divalent metal transporter
 Ferropotin: - A transmembrane segment protein present in the macrophages, duodenum,

hepatocytes and placenta
Factors influencing iron absorption

 Inhibitors: - phytates, tanins, soil clay, Laundry starch, iron overload, Antacids
 Competitors: - lead, cadmium, cobalt, Strontium, manganese, Zinc, Calcium
 Facilitators: - ascorbate, citrate, amino acids, iron deficiency
NOTE: There is no specialised route for excretion of iron. Iron absorption is controlled so that the
amount absorbed is just sufficient to replace losses.
 Regulation of absorption at intestines:

1) Dietary Regulator (Recently consumed iron-ferritin in intestinal cells affects absorption)
2) Stores regulator (total body iron affects levels of apical transporter) in deficiency Fe
absorption increases 2 - 3
3) Erythropoietic regulator (erythropoiesis requirements change iron absorption irrespective
of current iron levels → a soluble signal from bone marrow to intes ne)
Iron Transport & Uptake by Tissues

 Transported bound to apotransferrin (apotransferrin + Fe3+ = transferrin)
 Transferrin binds to Transferrin receptors (TfRs) on cells
 Iron taken into cells is stored in ferritin and haemosiderin
Old RBCs Phagocytosed by macrophages Haemoglobin in RBCs
Haem oxygenase
Biliverdin + Fe2+
Released to blood via ferroportin

Regulation of iron absorption and uptake by tissues:
Whole body iron status is regulated through a combination of:

 Hepcidin and Ferro protein mediated iron released from hepatocytes, enterocytes and
macrophages
 Regulation of iron absorption at gut level
1) Iron deficiency and hypoxia stimulate

 ↑ Expression of DMT-1, Ferric reductase, Ferroportin → ↑ Increased iron absorption &
uptake
2) Cellular iron status is regulated at cellular level through reciprocal regulation of transferrin
receptors and ferritin expression
 Translation of mRNA coding for ferritin and transferrin receptors (TfRs) is reciprocally
regulated.
 When intracellular iron level is high, ↑ ferritin ↓ TfR
 When intracellular iron level is low, ↓ ferritin ↑ TfR
 Discussed in detail under “Regulation of Gene Expression” lesson
3) Systemic iron levels controlled by hepcidin

 Hepcidin - Protein produced by liver and secreted to blood
 Hepcidin binds to ferroportin and triggers its internalization & degradation
 Hepcidin inhibits:
 Transfer of iron to blood by intestinal cells
 Release of iron by macrophages
 Hepcidin production is regulated by:

 Iron availability (in deficiency, ↓ hepcidin release)
 Erythropoiesis
 Inflammation/Chronic diseases (↑ hepcidin release) - “anaemia of inflammation”

Excretion of Iron
 Iron is one-way element and very little of it is excreted. Any type of bleeding will cause loss
of iron.
 Almost no iron is excreted through urine.
 Considerable faecal loss.
 Some amount from skin.
Assessment of Iron Status

 Hb & peripheral blood film
 Erythrocyte protoporphyrin (ZincPP measured)
 Serum Iron (SI)

 Transferrin - bound iron
[NOTE: Only 1/3 of transferrin’s binding sites are used]
 Total Iron Binding Capacity (TIBC)

 Total capacity of serum transferrin to bind iron
 Percentage of Transferrin Saturation (TS) = × 100%
 Serum ferritin indicates amount of stored iron.
Iron overload
1. Excessive absorption → Hereditary haemochromatosis
2. Excessive intake
3. Transfusional haemosiderosis - multiple blood transfusions
4. Inappropriate administration of iron

CALCIUM
 Mineral present in largest amount in the body.

 99% in bones and teeth.
 <10g found in soft tissue and ECF (part in ionized form)
Absorption
 Intestine most rapid in duodenum (pH <7)
 2 mechanisms,
a) Active transcellular absorption
 Duodenum and proximal jejunum, at low luminal Ca concentration, controlled by
Vit. D through the protein calbindin.
b) Passive para cellular absorption (between cells)
 At high luminal Ca2+ conc. and is bidirectional.
Increased absorption Decreased absorption

 Vit. D adequacy  Vit. D deficiency
 Increased mucosal mass  Decreased mucosal mass
 Ca deficiency  Decreased gastric acid
 Phosphate deficiency  High fat diet
 Pregnancy  Diets rich in oxalates, phytates, fibre
 Lactation  Menopause / old age
 Mucosal permeability  Rapid intestinal transit time

1. Entry across brush border - by Ca transporter 1(CaT1)
2. Intracellular diffusion - calbindin
3. Extrusion – Ca2+ ATPase
Effects of Hormones
Parathyroid Hormone 1,25-dihydroxycholecalciferol

Calcitonin
(PTH) (Calcitriol)
 Increase plasma Ca2+  In intestine:  ↓ Plasma Ca2+ level
 In bone:  ↑ Ca2+ absorption (By:  minor effect
 ↑ Ca2+ mobilisation from  ↑ calbindin,  [By ↓ Ca2+ mobilisation
bone (↑ osteoclastic  ↑ membrane transporters) from bones]
resorption)
 In bone:
 In kidney:  ↑ Ca2+ mobilisation from
 ↑ Ca2+ reabsorption bone (in presence of PTH)
 ↓ Ca2+ excretion
 ↓ PO43- reabsorption  In kidney:
 ↑ Calcitriol production  ↑ Ca2+ reabsorption
 (↑ 1-hydroxylase activity)  ↓ Ca2+ excretion

Functions
1) Structural - Supporting material in bones and teeth
2) Neuromuscular - control of excitability
- Release of neurotransmitters
- Initiation of muscle contraction
3) Signalling - 2nd messenger
4) Enzymatic - co enzyme for clotting factors

Cellular proteins binding or activated by Calcium
1) Calmodulin - modulator/regulator of several protein kinases
2) Troponin C - modulator of muscle contraction
3) Protein kinase C - protein kinase
4) Calbindin - Ca storage
Ca transport in plasma
Non diffusible (protein bound) (40%)
Total Ca
Free ionic Ca physiolo. Active (50%)
Diffusible (60%)
Complexed [with citrate, Phosphate] (10%)
Associated disorders
Hypocalcaemia Hypercalcaemia
 With low PTH  Hyperparathyroidism
 Hypoparathyroidism  high serum Ca2+
 With high PTH  ↑ Ca excretion & renal calculi can occur
 Deficient intake/absorption of Vit. D or Ca 2+  Malignant diseases
 Inadequate exposure to sunlight  Excessive Vit. D and Ca intake
 Disordered Vit. D metabolism
 CRF failure to form 1,25 dihydroxyD3
Measurement of plasma Ca2+

 Only ionized Ca is phys. active & its concentration maintained by homeostatic mechanisms
 Total Ca commonly measured
 Changes in plasma albumin affect total Ca independently of ionized Ca - measure Alb &
correct
 Venous stasis during blood sampling common cause of hyperalbuminaemia & hypercalcaemia
Avoid use of tourniquet

IODINE
 Importance: As a component of thyroid hormones

 Active form: I- (iodide ion)
 Sources: Iodised salt, sea food, drinking water
 Rapidly absorbed in small intestine and transported in plasma loosely attached to proteins
 Nearly 1/3rd taken up by thyroid gland (by Na+/I- symporter), remainder excreted in urine
 Thiocyanate & perchlorate: Inhibit the Na+/I- symporter in thyroid follicle cells
 Propyl thiouracil, carbimazole, methimazole: Inhibit iodination & coupling
Movement of Iodine between Compartments
 T4 - most abundant form synthesized in the thyroid gland.

 Most T3 is derived by deiodination of T4 in peripheral tissues.
 T3 - more active but less amount
Thyroid hormone synthesis

1) Follicular cells synthesise enzymes and thyroglobulin for colloid.
2) I- is co transported into cell with Na+ (Na-I symporter) and then into colloid.
3) Oxidation of iodine.
4) Iodination of tyrosine portion of the thyroglobulin.
5) Coupling of MIT & DIT/DIT & DIT to form T3/T4
6) Product is taken back into cells.
7) Intracellular enzymes separate T3 & T4 from proteins.
8) Free T3 & T4 enter circulation.

Regulation of Thyroid hormone
Transport of thyroid hormones in plasma

 99% protein-bound → Mainly Thyroxin Binding Globulin (TBG) and a smaller amount bound to
prealbumin & albumin also
 Only the free (unbound) form is physiologically active
Free T4 concentration is 2 to 3 times higher than free T3 concentration
 Bound hormone acts as a reservoir which helps maintain free T3 and T4 levels in plasma
Actions of Thyroid Hormones

 Promote normal differentiation & growth. Essential for normal foetal & neonatal
development.
 Overall effect is to speed up metabolic reactions and BMR:
 ↑ Oxida ve phosphoryla on
 ↑ Carbohydrate metabolism
 ↑ Lipid metabolism
 Increase sensitivity of cardiovascular and nervous systems to catecholamines
Tests of Thyroid Function

 Free T4 (fT4) and free T3 (fT3) → methodological problems if binding proteins grossly
altered (plasma total T3 and T4 affected by binding proteins)
 TSH - increased in hypothyroidism.
 TRH test - TSH measured before and after IV administration of TRH
 Thyroid antibodies - Thyroperoxidase antibodies, thyroglobulin antibodies
 Thyroid imaging
 Uptake tests

Iodine Deficiency
Iodine Deficiency
↓
↓Thyroid hormone produc on
↓
↑TSH (due to less negative feedback)
↓
↑Blood flow to thyroid
↓
Stimulates follicular cells
↓
↑colloid produc on
 Iodine deficiency will produce hypothyroidism and then it will lead to goitre. Goitre is not
always iodine deficiency. (Selenium deficiency)
Disorders of Thyroid Function

 Hypothyroidism - Due to iodine deficiency, Hashimoto’s thyroiditis, Congenital thyroiditis,
Idiopathic, Secondary
 Hyperthyroidism - Grave’s disease, Toxic multinodular goitre, Solitary toxic adenoma,
Exogenous iodine containing drugs
PHOSPHORUS
85% bones
Total body P 600g
15% soft tissues and blood
Absorption of phosphorus
 Absorbed very effectively from the small intestine
Functions of phosphorus
 Part of a major buffer system in body cells (as phosphoric acid and its salts)
 Component of DNA and RNA. Hence essential for growth and function of cells.
 Assist in energy metabolism: - many enzymes and substrates activated by phosphorylation
ATP as energy currency.
 Phospholipids: - membranes and phosphoproteins in milk.

FATTY ACID BIOSYNTHESIS
 Contributing Tissues - Liver, Lactating mammary glands, Adipose tissue (lesser extent)
 Sub cellular location - cytoplasm (on the FA synthase complex)
 FA beta oxidation takes place in mitochondria, so it’s compartmentalized doesn’t occur at
the same time.
 Substrates - Acetyl CoA, NADPH, CO2
Amino acid degradation
(cytosolic ACoA)
glycolysis
Dietary CHO glucose Acetyl CoA Fatty acids oxidation
HMP (Mitochondrial)
Malic enzyme NADPH LIPOGENESIS
ATP Citrate-Malate-Pyruvate shuttle

 Transfer acetate from
mitochondrial Acetyl CoA to
cytosol
The main regulatory step
 Occurs when mitochondrial
Citrate levels are high
 1st step = committed step = irreversible = regulation point
 High ATP and Citrate enhance FA
synthesis
Acetyl CoA Malonyl CoA  Isocitrate DH decreases FA
(initial substrate) Acetyl CoA carboxylase synthesis
CO2(HCO3-), Biotin(VitB7), ATP
 CoA of Acetyl CoA

cannot cross the
mitochondrial
membrane.
 So it converts to
Citrate which can
cross the
membrane &
produces the
cytosolic ‘Acetyl
CoA’ by using
‘ATP-Citrate lyase’
enzyme.

Regulation mechanisms short term Allosteric
Covalent modification
Long term gene expression
1) Long term regulation
Acetyl CoA Carboxylase gene

+
CHO
-
Fat
+
Insulin Transcription
Prolonged consumption of a diet containing excess

calories
increased ACC synthesis
increased FA synthesis
2) Short term regulation
a) Allosteric regulation
Citrate L.C.F.A(end product inhibition)

_
+
Acetyl CoA Acetyl CoA
carboxylase carboxylase
(polymer) (protomer)
Active Inactive
b) Covalent modification
 Regulation of acetyl CoA carboxylase by phosphorylation and dephosphorylation

Insulin
+
protein phosphatase
Acetyl CoA carboxylase Acetyl CoA carboxylase

P
Inactive Active
cAMP dependent
ADP protein kinase ATP
+
+ Metformin
 Used in the treatment of type
Glucagon + AMPK 2 diabetes
Epinephrine Kinases  Lowers plasma TAG through
(covalent) (covalent) activation of AMPK
 Resulting in inhibition of ACC
AMP
+ activity, inhibition of ACC & FA
(allosteric)
synthase expression
LCFA
Net reaction
Reused for Acetyl CoA carboxylase
Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+ C16:0 fatty acid + 8 CoA + 7CO2 + 14 NADP+
O
||
O- —C—CH2 —CH2–CH2 - - - - - - - - CH2–CH2
Malonyl CoA Acetyl CoA
Fatty acid synthase
 Multi-functional
 7 enzyme functions
 Cytosolic
 Contains Vit.B5 ----> Acyl carrier protein
 Contains ‘Phospho-pantatheine’ residue derived from B5, which contains -SH group at the
active site and cysteine residue
 Primary end product is palmitate

Questions
01. Describe 2 effects of Vit.B5 deficiency
02. Role of Acetyl CoA in fatty acid synthesis
03. How do long chain fatty acids inhibit FA synthesis?
Sources of NADPH
 HMP Pathway
 Cytosolic conversion of malate to pyruvate
Fatty acid synthesis process
 Major7 steps for one cycle. 4 carbons, saturated fatty acyl –ACP)
 Repetition of cycle of reactions producing palmitate (16carbon) as the primary end product.
 For the initial step Acetyl CoA is utilized but for further elongation 2C donor is Malonyl CoA.
 Shorter length fatty acids are produced in the lactating mammary gland.
 Elongation
Further elongation
Primary end product (Palmitate) In SER and mitochondria
Separate enzymic processes
 Elongated with addition of 2 “C” units. (separate enzymic processes)

 Brain also has this capacity (Very long chain FA)
 Required for synthesis of brain lipids.
 Desaturation
 In SER Add cis bond

 Require NADH & oxygen, cytochrome B5 and its FAD linked reductase in eukaryotes
 (Prokaryotes use an O2 independent process) PUFA can be made.
 Mammals cannot synthesize double bonds from C10 to ω end but mammals require poly
unsaturated FAs.
 Humans have C 9,6,5,4 desaturases, but they lack the ability to introduce double bonds
from C10 to ω end. (but plants have that ability)
 Location of first double bond in unsaturated fatty acids determines the naming &
characteristics of unsaturated fatty acids.
a) Omega-3-fatty acid
Ex – alpha-linolenic acid (ALA)
b) Omega-6-fatty acid
Ex – linoleic acid
 Best ratio of ω3: ω6 = 1:5

Role of L.C.F.A
Reduction of substrate
Inhibition of the
Citrate Transporter citrate↓ [ cytosol]
+
Acetyl CoA [ dimer] Acetyl CoA [ polymer]
-
L.C.F.A AMPKK AMPK Acetyl CoA carboxylase

(active) (active) (inactive)
-
- Transcription of Acetyl CoA carboxylase gene
PDH
Effect of Insulin on lipogenesis – stimulates lipogenesis
Glucose mobilization
Insulin +
Glut 4 [Adipose muscle]
Activation of PDH [Adipose tissue only]
cAMP
ATP cAMP 5’ AMP

Adenylate phosphodiesterase
+ +
Glucagon Insulin
ROLE OF INSULIN
Less activation of cAMP

Kinase
Less inactivation of lipolysis Free FA

Acetyl CoA carboxylase
+ Less inhibition (by
P Fatty Acyl CoA)
Protein phosphatase
Acetyl CoA carboxylase Acetyl CoA carboxylase (active)
+
Transcription
+
Acetyl CoA carboxylase gene Acetyl CoA carboxylase enzyme
+
F.A. Synthase gene F.A. Synthase enzyme

Role of citrate
 Transport Acetyl CoA

 Produce NADPH Via Malic enzyme
 Regulates Acetyl CoA carboxylases
TAG synthesis
 Cannot form stable micelles by themselves.

 Coalesce to form only droplets within adipocytes.
 Major energy reserve in the body.
 Synthesis in liver & adipose tissue.
 No storage in liver but stored in adipocytes.
 Made in to VLDL for transport.
 Glycerol 3-phosphate is the initial acceptor of fatty acids.
 Only liver has glycerol kinase. (primary site) So in Adipose tissue, glycerol-3-phosphate is
supplied only by glycolysis.
 Stored TAG – enough to support basal energy for 12 weeks.
 Esterified through carboxyl group.
Synthesis of Glycerol phosphate
 Liver
 Can synthesize glycerol 3 phosphate from glycolysis and by glycerol kinase activity.
 Adipose tissue
 Glycerol kinase is absent in adipose tissue.

 Adipocytes can take up Glucose only in the presence of Insulin.
 When Glucose (and Insulin) levels are low adipocytes have limited ability to produce TAG.
 Adipocytes contain GLUT-4 transporters which is Insulin dependent.
Synthesis of TAG molecule from Glycerol Phosphate
 FA should be activated by attaching it to CoA by Fatty Acyl CoA synthatase

 Addition of 2FAs from fatty acyl CoA by Acyl transferase
 Removal of phosphate by phosphatase
 Addition of 3rd FA by Acyl transferase

Importance of glycolysis in adipose tissue and Liver in TAG synthesis
HS-Lipase →
Hormone sensitive
Glycolysis
lipase
Glucose
FA CoA
synthatase
Cholesterol Biosynthesis
peripheral tissues HDL VLDL
GIT CM LIVER Free cholesterol(bile)
De novo synthesis synthesis of bile acids/salts
 Cholesterol – structural component of cell membrane (maintain fluidity)

 Precursor of bile salts, steroid hormones & Vit D
 Major role in cholesterol metabolism
 Major sources of cholesterol

 diet
 Cholesterol synthesized in extra hepatic tissues
 De novo synthesis in liver

 Tissue – mainly in liver & intestine, adrenal cortex, reproductive tissues. (testis, ovaries,
placenta)
 Site – cytosol
 Substrates – Acetyl CoA using NADPH
 Regulating enzyme – 3 hydroxy-3 methyl-glutaryl CoA Reductase enzyme or HMG CoA

reductase
 Two forms of HMG CoA synthase isoenzyme
 Cytosolic -- cholesterol biosynthesis
 Mitochondrial matrix – ketone bodies synthesis
 Enzymes in cytosole, SER, peroxisome used in this.
Acetyl CoA + Acetyl CoA
CoA
Acetoacetic CoA
CoA Acetyl CoA
HMG CoA ( - hydroxy  Methyl Glutaryl CoA)

NADPH
HMG CoA Reductase (Rate limiting)
NADP+
free cholesterol
Mevalonate [C6] Cholesterol VLDL
Conversion of bile
 HMG CoA reductase is an integral membrane protein of the SER, with its catalytic domain
projecting into cytosol.

Cholesterol biosynthesis regulation
Sterol dependent regulation of gene expression

SREBP-2 proteolytic cleavage
In Golgi
SREBP2- sterol
regulating Element
binding protein2
Binds DNA at SRE SREBP2
SRE- sterol of the reductase gene SCAP
regulatory element
SCAP- SREBP
cleavage activating ↑ transcription
protein SREBP2-SCAP-inactive
(integral proteins
[-] of SER membrane)
↑ translation Cholesterol
Short term regulation Mevalonate

inhibition by drugs
P Protein kinase
(AMPK) Structural Simvastatin
HMG CoA [+] AMP [-] analogues of
HMG CoA reductase lovastatin
reductase (active) HMG CoA atorvastatin
(inactive) (competitive
mevastatin
Phosphoprotein inhibitors)
HMG CoA
phosphatase
Sterol accelerated enzyme degradation
1) ubiquitination [+] Cholesterol,

2) proteosomal oxidized forms
degradation of cholesterol
Low concentration of
HMG CoA reductase
Long term regulation

 Insulin and thyroxine favours up regulation of gene expression
 Glucagon down regulates.

Glucose Glucose
DHAP DHAP
Glycerol 3 Glycerol 3
phosphate phosphate
dehydrogenase dehydrogenase
Routes by which cholesterol leaves the liver
 Free cholesterol secreted in bile

 Secretion of VLDL
 Conversion to bile acids/salts
 Balance between influx & efflux is not precise.

 Excessive cholesterol leads to ATHEROSCLEROSIS.
 Plant sterols appear to block absorption of dietary cholesterol – useful in the treatment of
hypercholesterolemia.
Q. Explain how Lovastatin reduces plasma LDL level?

TRIGLYCERIDES AND FATTY ACID CATABOLISM
 TAG storage in adipocytes as globules in muscles (lesser amount)

 TAG is broken down to free fatty acids and glycerol by Hormone sensitive lipase (HSL) in
adipose tissue – Mobilization of stored fat
 Initiated by ‘HSL’ or ‘Adipose triglyceride lipase’.
 HSL removes a FA from C1 and/or C3 of TAG and additional lipases remove the remainder.
Hormonal regulation of TAG degradation in adipose tissue

Adrenaline glucagon
and ACTH
Hormone
Receptor (β- adrenergic)
Phosphorylation of
Adenyl cyclase Perilipin that coats
lipid droplets
ATP cAMP
Translocation
of Perilipin
Protein kinase A Protein kinase A
(Inactive) (Active) Facilitates binding
of HSL to TAG
P
TAG
HSL Inactive ATP ADP HSL Active
High level of
insulin and glucose Free FA
+
DAG
Protein
Pi phosphatase H2O
 Glycerol is delivered to liver for glycolysis or gluconeogenesis

 Free fatty acids are bound to albumin and delivered to tissues
 Free fatty acids are not used in RBCs.

Stages of FA Oxidation
1. Activation
2. Transport into mitochondria
3. Removal of C2 fragments as acetyl CoA (β Oxidation)
Introduction,
 Source – from diet & adipose tissue (because enzymes are here)
 Occurs in the mitochondrial matrix
 Products – Acetyl CoA, NADH, FADH2
 The products of oxidation will further be oxidized through the electron transport chain in
the mitochondria, to form ATP
Activation Step – 1st step
Fatty Acyl CoA Synthatase

(Thiokinase)
R—COO- R—CO—S—CoA
Fatty Acid Fatty Acyl CoA -
Thioesters Phosphatase
CoA—SH
ATP AMP + PPi PPi + H2O  2Pi
(Hydrolysis)
 Easily reversible, however phosphatase based hydrolysis shifts equilibrium to right & makes
it irreversible.
 ATP dependent (only energy dependent step)
 Short and Medium Chain (12C) Fatty Acids (SCFA & MCFA)- can cross the inner
mitochondrial membrane directly (Without transporters) - activation occurs inside
mitochondria
 Long Chain(>14C) Fatty Acids – cannot cross inner membrane – activation occurs at outer
mitochondrial membrane (ER/peroxisome)
 Acetyl CoA/CoA regulates FA oxidation.
Transport into mitochondria – 2nd step
 Long Chain Fatty Acyl CoA are transported into the mitochondria through
Carnitine Acyl-Transferase System. (Because inner membrane impermeable to CoA)

So the carrier is ‘Carnitine’ – it’s the rate limiting step.
-Carnitine Shuttle
Carnitine Shuttle
 Outer membrane has – Carnitine Acyl Transferase-1 (CAT-1)/ Carnitine Palmitoyl

Transferase- 1 (CPT-1) enzyme
 This transfers the fatty acid part from CoA to Carnitine, forming Acyl Carnitine
 Malonyl-CoA inhibits CAT-1 (product of FA biosynthesis)
 Hence prevents the degradation of newly formed palmitate/ FA.
 This is the regulation point of β – oxidation by regulating entry of Long Chain Fatty Acids
into mitochondria. (rate limiting step)
 In muscles, though they do not synthesize FAs, has mitochondrial isoform of ACC to regulate
β - oxidation
 Inner membrane has Carnitine Acyl Transferase-2 (CAT-2) enzyme
 It transfers the Fatty acid part again to CoA, forming Fatty Acyl CoA and releasing Carnitine
 Carnitine-Acyl Carnitine Translocase – inner mitochondrial membrane antiport
 This sends Acyl Carnitine into the mitochondrial matrix, taking free Carnitine out of it.
 Also this process is regulated by,
[ 𝐴𝑐𝑒𝑡𝑦𝑙 𝐶𝑜𝐴
𝐶𝑜𝐴 ] Ratio ------ Leads to inhibition
Clinical conditions related with FA oxidation,
Genetic CPT 1 / CAT 1 deficiency
 Affect the liver

 No/Less ATP from FA oxidation in fasting for gluconeogenesis
 Severe hypoglycemia, coma & death
Carnitine deficiency
 Sources of Carnitine
 Primarily in meat
 Synthesized from AAs → Lysine & methionine → Liver & Kidney
 Most of the carnitine in the body present in skeletal muscles (97%)

1. Primary Carnitine Deficiency - Congenital deficiency in components of CAT system -
genetic mutations
a. Decreased renal tubular reabsorption
Defects in the membrane transporter
b. Poor uptake of Carnitine by cells
2. Secondary Carnitine Deficiency - Defects in fatty acid oxidation leading to acylcarnitine

accumulation
a. Liver disease – decreased synthesis
b. Malnutrition / Strict vegetarian diets (main source of Carnitine is meat)
c. Increased requirement for Carnitine in pregnancy, severe infections, trauma, burns
d. Patients undergoing hemodialysis
e. Organic acidurias - inhibit renal tubular reabsorption of carnitine
(Eg: - Lactic acidosis due to Von Gierke’s disease)
β Oxidation – 3rd step
 A cyclic process [one cycle -> 4 reactions]

 Occurs inside the mitochondrial matrix
Palmitoyl CoA + 7CoA + 7FAD + 7NAD + 7H2O 

8 Acetyl CoA + 7FADH2 + 7NADH +
 Each Cycle produces one acetyl CoA and a Fatty Acyl CoA with 2
carbons reduced.
 Also each cycle produces 1 NADH and 1 FADH2 → they enter ETC to
yield ATP
 The Acyl CoA dehydrogenases vary according to the no. of carbons in
the Acyl CoA (very long chain/medium chain/short chain Acyl CoA
Dehydrogenase). As three isoenzymes are favo proteins.
 Acetyl CoA can,
- Enter TCA and form ATP
- Be used as a substrate for Amino Acid biosynthesis. But CANNOT
be used as a substrate for gluconeogenesis.
7FADH2 + 7 NADH 31 ATP

But 2 ATP for
activation step
29 ATP
 Deficiencies of medium chain acyl CoA dehydrogenase results

for inability to gluconeogenesis during fasting (MCAD
deficiencies). It’s an autosomal recessive genetic disorder.
Eg: - SIDS, Reye Syndrome

β oxidation of odd number C FAs.
 Rare in mammals, but rather common in marine organisms.

 Initial steps are same until final 3C are reached. (Propionyl CoA)
 Propionyl CoA is metabolized into succinyl CoA
Propionyl Carboxylation Methyl Vit.B12 Succinyl CoA (Utilized in

CoA Biotin Malonyl CoA Gluconeogenesis)
Very Long Chain Fatty Acids oxidized in peroxisomes
 Preliminary oxidation of VLCFAs (20 - 22C)

 Initial dehydrogenation is catalyzed by FAD-containing acyl CoA oxidase.
 Forms acetyl CoA & H2O2 by using FADH2 (No ATP production in this step)
 Catalase detoxify the H2O2.
 These enzymes induced by high fat diets.
 Shortened FAs diffuse to mitochondria for further oxidation
 Unsaturated FA oxidation yields lower amount of energy contrast to saturated FA of same

length.
Other types of oxidations

1. α oxidation – branched chain (20C) Phytanic acid
1st C – CO2 , rest – β oxidation
2. ω oxidation (ER) – increased in MCAD
Effect of oxygen supply & energy status on β – oxidation
 β – oxidation only produces the reducing equivalents NADH and FADH2. But ATP is made in
the e-transport chain.
 Oxygen is necessary for the electron transport chain
 When oxygen is deficient  e-transport chain inhibited  Accumulation of NADH and
FADH2  inhibit β – oxidation
 When energy status is high  ATP will accumulate  ADP low

e – transport chain inhibited  NADH & FADH2 high  inhibit β – oxidation
 When energy status is low  ADP is high  e – transport chain activated
 NADH & FADH2 low  NAD+ & FAD high  stimulate β – oxidation
 Low Insulin/Glucagon ratio will stimulate β- oxidation

Low Insulin / Glucagon ratio
Acetyl CoA carboxylase inhibited (FA synthesis inhibited)

Low Malonyl CoA (it is an intermediate in FA synthesis)
Activate carnitine shuttle
More fatty acyl CoA enter mitochondria
Increased β – oxidation
Facilitate ATP production for use in gluconeogenesis under fasting conditions
KETOGENESIS
 Ketone bodies are water soluble, transportable forms of acetyl units

 3 substances : -  - hydroxybutyrate
Acetoacetate
Acetone
 Produced in liver mitochondria
 When FA oxidation rate is high (insulin/glucagon ratio is low)
 In response to prolonged starvation, uncontrolled diabetes and severe exercise
 If produced in large amounts  acetoacetate and  - hydroxybutyrate are acidic  lowers
body pH ketoacidosis
 Why produce ketone bodies?
 Can be lysed to form acetyl CoA, which produces ATP through entering the TCA cycle
 Heart muscle and renal cortex use acetoacetate in preference to glucose
 Brain utilizes ketone bodies when glucose is deficient
 As it is water soluble, it is easily transported via blood
 Under conditions for ketogenesis,
 OAA is utilized for gluconeogenesis
 It cannot condense with Acetyl CoA
 Acetyl CoA cannot enter TCA cycle
 This excess Acetyl CoA is channelled towards ketogenesis.
Formation of ketone bodies
Since equilibrium depends on NADH/NAD+

ratio & increased oxidation causes
3-hydroxybutyrate
NADH/NAD+ equilibrium to shift to the right.
NAD+
3-hydroxybutyrate
dehydrogenase
Thiolase HMG CoA synthase HMG CoA lyase NADH
2AcetytlCoA Acetoacytyl CoA HMG CoA Acetoacetate
Mitochondrial + Acetyl CoA
CoA Acetyl matrix
CoA blood
CoA
CO2
Acetone
Utilization of Ketone bodies
 - hydroxybutyrate
 - hydroxybutyrate dehydrogenase Acetoacetate
Succinyl CoA
NAD+ NADH + H+
Acetoacetate – Succinyl CoA
transferase
Succinate
Acetoacetyl CoA
2 Acetyl CoA
TCA
 Liver lacks the “Thiophorase” enzyme which is need for metabolize Acetoacetate, hence liver
doesn’t utilize KBs, but export them into other tissues.
Excessive ketone body production in Diabetes Mellitus

LIPID TRANSPORT
Plasma lipids
Cholesterol esters (36%) Phospholipids (30%)

Triacylglycerol (16%) Cholesterol (14%)
Free fatty acids (4%) – metabolically most active
Lipid transport
Majority
FFA + albumin Lipoprotein

Why?
 Lipids are water insoluble.
 Only SCFA are soluble in aqueous medium of blood plasma
 Therefore, cannot be transported in the Free State.
Lipoproteins
 Macromolecules
 Have week covalent bonds
 Spherical particles
 Contents : TAG, CE, PL, Cholesterol, Proteins
Lipids Proteins
Hydrophobic Hydrophilic (Polar)

TAG, CE PL, Cholesterol
(Core) (Surface)
Classes of LP
 CM highest % of TG lowest % of proteins

 VLDL high % of TG
 LDL high % of CE
 HDL highest % of proteins & PL
 And CM remnants, IDL (VLDL remnants), LPa Can be proatharogenic and antiatharogenic

Lipoprotein separation
Ultracentrifugation – by density Electrophoresis - by size
Density CM
Origin
CM
VLDL LDL (β lipoprotein)
LDL protein content & density VLDL (pre β
HDL Mobility
lipoprotein)
HDL
(α lipoprotein)
CM Transport exogenous TG synthesized in intestine, to peripheral tissues [adipose,

skeletal & Cardiac (80%) and liver (20%)]. Formation fluctuates with load of TG
absorbed. Give turbidity after a fatty meal, rapidly catabolized and cleaved from
circulation (1-2 hrs)
C I II III, B48,E,AI, AII
Transport endogenous TG synthesized in liver to extra hepatic tissue.
VLDL CI II III, B100, E, A
Less affected by dietary TG. Precursor for LDL
Forward transport of cholesterol produced in plasma during intra vascular
LDL metabolism of VLDL.
B100
Reverse transport of cholesterol produced in liver and intestine.
HDL A1, AII, CI CIII, D, E
Functions of Apoliporotein (Apoprotein)
 Solubilizing and transport of hydrophobic lipids.

 Structural components of lipoprotein
 Co-factors inhibitors and recognition sites for LP metabolism.
1. Co. factors- CII for LPL, AI for LCAT
2. Inhibitors-AII & CIII for LPL, CI for CETP
3. Regulation sites – act as ligand for receptors

Functions of major Apolipoproteins
Apo LP LP Function
AI HDL Structural protein. Activates LCAT (PCAT). Interacts
with ABC AI transporter.
AII HDL Structural protein
B48 CM Structural protein required for synthesis and
CM remnants secretion of CM.
B100 VLDL , LDL, IDL Structural protein required for synthesis and
secretion of VLDL
Recognition and binding of LDL to LDL receptors.
( reduced due to autosomal dominant disease)
CII CM, VLDL, HDL Activates LPL.
Apo E CM, VLDL & Triggers clearance of remnants of VLDL (IDL) & CM
remnants remnants. Is recognized by remnant receptors.
Nonsense modification
Apo B gene m-RNA m-RNA R-RNA RER Apo B48 SER
(For Apo B100) (For Apo B48)
Lipids
CM Golgi Microsomal TAG
transfer protein (MTP)
CM Metabolism
 Transport of exogenous lipids.

 Nascent CM synthesized in the intestinal mucosal cells contain Apo B 48.
 Enter to the blood stream via lacteal.
 It receives Apo C2 and E from HDL in the blood plasma.
 Apo C2 activates LPL
 LPL degrades TAGs in the CM and FFAs are released to peripheral tissues
 C2 is returned to HDL & CM remnants binds to Apo E to receptors on the liver.

VLDL Metabolism
 VLDLs are secreted directly in to the blood by the liver as nascent VLDL.
 Nascent VLDL contain Apo B100.
 They obtain Apo C2 & E from HDL in the blood plasma.
 Apo C2 activates LPL
 LPL hydrolyzes TAG into FFA & glycerol.
 Remnants of VLDLs, (IDL) now take part in the formation of LDLs.
 VLDL remnants return the Apo C & E to HDL but retain Apo B100.

 If there is some failure to produce B100 or MTP there will be accumulation of lipid within the
liver called fatty liver. (hepatic steatosis)
Lipoprotein lipase
 Insulin induces synthesis and transfer of LPL to the luminal surface of capillaries
 And on the surface of capillaries (outside the tissues) or on the surface of the hepatocyte
(liver cells)
 Hydrolyzing TG to release fatty acids near the tissue. High local concentration of fatty acids
leads to their uptake by tissues.
 Apo CII activates LPL and Apo CIII inactivates LPL.
 LPL has different Km values depending on the tissue.
 Ex: Km in heart muscle cells < Km in adipose tissue
 So adipose tissue only takes up TAG when there is excessive amount.
LDL metabolism
LDLs are produced in the intravascular metabolism of VLDLs.

 Some TAG are transferred from VLDL to HDL in exchange of some CEs from HDL to LDL by
cholesteryl ester transfer protein.
 This modifies circulating VLDLs to LDLs.
Uptake of LDLs
 Uptake of LDL by tissue is mediated through specific cellular LDL receptors. It’s a negatively
charged glycoprotein.
 LDL binding domain of the receptor is in the N terminal end. (rich in Glu, Asp) (-)
 Cytosolic domain controls interaction with clathrin coated pits & participates in endocytosis.
 Uptake is controlled by intra cellular free cholesterol concentration.
 Adrenals, gonads, etc. has more LDL receptors.
DEFECTIVE UPTAKE →LDL accumulates in plasma → hypercholesterolemia

 Decrease LDL uptake due to receptor defects
 reduced membrane LDL receptors
 decreased synthesis
 defects in transport to cell surface
 defective binding to LDL
 defective internalization
 Familial defective apoprotien B 100
FORMATION OF ATHEROSCLEROTIC PLAQUE
 Excessive LDL converted in to oxidized LDL by ROS.

 Vitamin C, E beta carotene and other antioxidants inhibit this reaction.
 Since Oxidized LDL are more active they bind with both scavenger receptors (have low
affinity) and specific LDL receptors(high affinity)
 Step 1 – in response to endothelial injury-caused by oxidized LDL.Monocytes adhere to
endothelial cells, move to sub endothelium, and are transformed into macrophages.
 Step 2 –Macrophages consume excess modified (oxidized lipoprotein, becoming foam
cells.
 Step 3 – foam cells accumulate releasing growth factors and cytokines that stimulate the
migration of smooth muscle cells from media to intima. There they proliferate produce
collagen and take up lipid potentially becoming foam cells.

HDL functions
 Produced in liver & intestine. Apo C& E synthesized in liver- transferred to intestinal form in
plasma
 Acts as a repository of Apo C & E required for CM & VLDL metabolism
 Uptake of unesterified cholesterol
 Esterifies Chol & transfer to other LPs
 Reverse transport of Chol (from tissues to liver)
HDL metabolism
1. Nascent HDL are disc shaped particles that contain PL and Apoproteins A, C and E.
2. They rapidly accumulate cholesterol via ATP binding cassette transporter-1
(ABC-A1).
3. Cholesterol is esterified within HDL by LCAT/PCAT (lecithin cholesterol acyl transferase)
4. LCAT is activated by Apo AI.
5. As the nascent HDL accumulates CE, it 1st becomes a relatively CE-poor HDL3 and eventually
CE-rich HDL2.
6. CEs are transferred to VLDLs via cholesterol ester transfer protein (CETP).
Live contains HDL2 receptor.
Free fatty acids
 Extracellular transport via albumin because they are water insoluble.

 Uptake via membrane FA transport protein (MFTP), which is a cotransporter with Na + .
 After enter to the cell bind with intracellular FA binding protein (FABP) for intracellular
transport of FFA.
More Clinical Aspects

1. Imbalance in the rate of TAG formation and export causes fatty liver.
2. Accumulation of lipid as TAG in the causes cirrhosis and impaired liver function.
Fatty liver considers in to two categories.
A. Free fatty acid amounts that taken up by liver can be raised due to
1. Mobilization of fat from adipose tissue
2. Hydrolysis of LP TAG by LPL in extra hepatic tissue
 Increase amounts of free fatty acids are taken by liver and esterified. The production of
VLDL does not keep pace with the influx of the FFA, allowing TAG to accumulate causing
fatty liver.
 During starvation, quantity of TAG in the liver is increased, and ability to secret VLDL is
impaired. Tis may be due to low level of insulin.
B. Due to metabolic block in the production of plasma lipoproteins, thus allowing TAG to
accumulate. lesion could be due to:
1. A block in apolipoprotein synthesis
2. A block in synthesis of lipoprotein from lipid and apolipoprotein.
3. A failure in the secretary mechanism itself.
Ethanol causes fatty liver.
 Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately

cirrhosis.
Ethanol Acetaldehyde
Alcohol
Dehydrogenase/microsomal
ethanol oxidizing system
A. Increased NADH/NAD+ ratio causes

 Shift in the malate OAA, which may reduce activity of the TCA cycle.
 Net effect of inhibiting fatty acid oxidation is to causes increased esterification of fatty
acids in TAG, which may be the cause of fatty liver.
B. Also causes increase in Lactate/pyruvate ratio that results in Hyperlacticacidemia, which in
turn decreases the capacity of the kidney to excrete uric acid.
C. Increase in acetyl CoA causes increased lipogenesis and cholesterol.

Hyperlipidemic Disorders
1. Corneal arcus & xanthelasma
2. Xanthomata
3. Frozen plasma

Term 3
Anatomy – Term 3
ABDOMEN
Surface Anatomy
 T9 – Xiphoid 
 L1 – Transpyloric plane {passes through tips of 9th costal cartilage (bears a distinctive step)
anteriorly and lower border of L1 posteriorly)}
*Lies halfway between the suprasternal notch & the top of the pubis /a hand’s breadth below the
xiphoid
*transpyloric plane passes through,
1. Pylorus of stomach 5. Termination of spinal cord
2. Hila of the kidneys 6. Duodenojejunal flexure
3. Fundus of gall bladder 7. Origin of superior mesenteric artery
4. Neck of pancreas 8. Tip of 9th costal cartilage
9. Splenic vein → portal vein
Mnemonic-
Please - pylorus
Feed – fundus of gall bladder
Him – hilum of the kidney
Some – origin of superior mesenteric artery
Love – lower end of spinal cord
 L3 – Subcostal plane (inferior margin of 10 rib)

1. Origin of Inferior Mesenteric artery 

 L4 – Plane of highest point of iliac crest (supracristal plane)
1. Bifurcation of aorta
2. Lumbar puncture 

 L3-L4 (Inter vertebral disc) 
1. Umbilicus

 L5-Transtubercular plane (passes through tubercles of iliac crest)
Bifurcation of common iliac artery
Liver (Points)
1. Tip of right 10th rib in midaxillary line
2. Left 5th intercostal space in midclavicular line
3. Right 5th intercostal space in mid axillary line
*Not palpable in normal subjects
Spleen (Points)–Left side

1. Axis – 10th rib directed downwards, forwards and laterally
2. Upper border – upper border of 9th rib
3. Lower border – lower border of 11th rib
4. Medial end – 2 inches from midline *Must be enlarged 3 times than normal to be
5. Lateral end – Mid axillary line palpated
Fundus of Gallbladder (Right side)

1. Tip of 9th costal cartilage (at the intersection of9th costal cartilage & lateral border of rectus abdominis)

Kidney
Hilum-on the transpyloric plane 4 fingers’ breadth from the midline
*This plane passes through the upper part of the hilum of the right kidney & through the lower part of
the left kidney
* Two horizontal lines
1. Level of upper border of T12
2. Level of center of L3
*Right kidney is 1 inch lower than the left
*Left kidney is nearer to the median plane
Anterior Abdominal wall
Midclavicular line
Transpyloric plane
Transtubercular plane
Layers of the wall

a. Skin
b. Superficial fascia
c. Muscles - External Oblique, Internal Oblique, Transversus abdominis
d. Fascia Transversalis
e. Extra peritoneal fat
f. Parietal peritoneum
 Abdomen has no deep fascia**
▬Superficial
9 fascia
2 layers below Umbilicus Camper’s Fascia/ superficial fatty layer
Penis – Devoid of fat
Scrotum – Replaced by Dartos muscle
Scarpa’s fascia/ deep membranous layer
Scarpa’s fascia
Goes to corona of penis Over scrotum Over perineum Goes over the inguinal
(junction between neck and ligament and blends with
shaft of the penis fascia lata (Holden’s line)
Dartos fascia Colles’ fascia
Buck’s fascia
Line of attachment of membranous layer
o Holden’s line-a horizontal line extending laterally
from the pubic tubercle where the membranous
layer is firmly attached to the deep fascia of the
thigh
**Importance of this line- when the urethra is injured in
the perineum, it prevents extravasated urine from
descending into the thigh beyond this line
o Pubic tubercle
o Body of pubis & margins of the pubic arch
o The posterior border of the perineal membrane

 RECTUS SHEATH
▪ Definition–Aponeurotic sheath covering the rectus abdominis muscle
▪ 2 walls-Anterior wall- continues throughout
Adherent to the rectus muscle at tendinous intersections
- Posterior wall - free
Above costal margin – ant wall: external oblique
Post wall: deficient (muscle rests on 5, 6, 7 costal cartilages)
Between costal margin- ant wall: ext. oblique, ant. Layer of int. oblique
& arcuate line
post wall: transverses abdominis, post. Layer of int. oblique
(arcuate line=halfway between umbilicus and pubic symphysis)
Below arcuate line – ant wall: aponeurosis of all 3 muscles
Post wall: deficient, muscle rests on fascia transversalis
Contents- muscles = rectus abdominis & pyramidalis

Superior & inferior epigastric vessels
Lower five intercostal nerves (T7 -T11) and subcostal nerves(T12)
Splitting of internal oblique aponeurosis along the lateral border of rectus sheath forms the semilunar line.
**Two rectus sheaths fuse in the midline to form the linea alba

**Functions: increases the efficiency of the muscle, gives strength to the ant. abd. wall
Sup. Epigastric artery enters sheath

by passing through highest costal
fibers of diaphragm.
Inf. Epigastric artery enters sheath by

slipping over arcuate line

Blood supply
Flanks – intercostal, lumbar, subcostal arteries
Ventral structures – Superior epigastric- internal thoracic
Inferior epigastric – external iliac
Venous drainage
Above umbilicus – Lateral thoracic vein, Internal thoracic vein
Below umbilicus – Great saphenous vein
In obstruction, superficial abdominal veins are dilated & provide a collateral circulation.
In vena caval obs: Thoracoepigastric veins open up, connecting the great saphenous vein with the axillary
vein
Inferior vena caval obstruction – blood flow upwards watershed barrier broken
Superior vena caval obstruction- blood flow downwards
Few para-umbilical veins accompany ligamentum teres. In portal vein obs: dilated veins cause
caput medusae at the umbilicus
▬ Lymph drainage
Above umbilicus – Axillary nodes
Below umbilicus – Superficial inguinal nodes
 Water-shed line – lymph and venous blood flow upwards above the plane of umbilicus &
downwards below the plane
- Innervation -lower 5 intercostal and subcostal (between internal oblique & transverse
abdominis) T7- xiphoid process, T10- umbilicus level
- Iliohypogastric L1
- Ilioingunal L1
- Subcostal and iliohypogastric supply the gluteal region as well

Anterolateral abdominal muscles
External oblique Internal oblique Transversus abdominis

Fiber Downward, forward, Upward, forward, medially Horizontal
direction medially
Nerve Lower 6 thoracic nerves Lower 6 thoracic & L1 Lower 6 thoracic nerves &
supply L1
-between the anterior superior iliac spine & the pubic tubercle the external oblique
aponeurosis folds on itself to form the inguinal ligament
-internal oblique muscle arises from its lateral 2/3 -transversus abdominis arises from its lateral 1/3
-Conjoint tendon: fused lowest aponeurotic fibers of the internal oblique & transversus abd.
muscles. Is attached to the pubic crest
INGUINAL CANAL
▪Definition–Oblique musculo-aponeurotic passage in lower anterior abdominal wall just above the medial
half of inguinal ligament, extending from deep ring to superficial ring(4cm)
▪Rings -Superficial inguinal ring
*Is a V shaped gap in the external oblique aponeurosis, above the pubic crest
- Deep inguinal ring
*Is an opening in the fascia transversalis, situated ½ inch above the midpoint of the inguinal
ligament and immediately lateral to the stem of the inferior epigastric artery
▪Walls–
Anterior wall
 Whole extent – skin, superficial fascia, external oblique aponeurosis
 Lateral 1/3 – Internal oblique muscle fibers
Posterior wall
 Whole extent – Fascia transversalis, extraperitoneal tissue, parietal peritoneum
 Medial 2/3 – Conjoint tendon, at the medial end by the reflected part of the inguinal ligament
 Lateral 1/3 -interfoveolar ligament
Roof
 Arching fibers of internal oblique & transversus abdominis (arching in front of the cord laterally to
behind the cord medially)
Floor
 Grooved upper surface of Inguinal ligament
 Medial end by Lacunar ligament
▪Contents–Male
1. Spermatic cord (male reproductive system)
• three layers of fascia – the external spermatic, from the external oblique aponeurosis; the cremasteric,
from the internal oblique aponeurosis (containing muscle fibres termed the cremaster muscle); the
internal spermatic, from the transversalis fascia;
• three arteries – the testicular (from the aorta); the cremasteric (from the inferior epigastric artery); the
artery of the vas (from the inferior vesical artery);
• three veins – the pampiniform plexus of veins (draining the right testis into the inferior vena cava and the
left into the left renal vein), and the cremasteric vein and vein of the vas, which accompany their
corresponding arteries;

• three nerves – the nerve to the cremaster (from the genitofemoral nerve); sympathetic fibres from the T10
and T11 spinal segments; the ilioinguinal nerve (strictly, on and not in the cord);
• three other structures – the vas deferens; lymphatics of the testis, which pass to the para-aortic lymph
nodes; and, pathologically present as the third structure, a patent processus vaginalis in patients with an
indirect inguinal hernia!
2. Ilioinguinal nerve (doesn’t enter through the deep ring, enters the canal through the interval between
external & internal oblique muscles & passes out through the superficial ring) supplying inguinal region,
upper part of thigh, anterior third of scrotum, root of penis
Female
1. Round ligament of uterus 2. Ilioinguinal nerve
MECHANISM OF INGUINAL CANAL

 Obliquity of the inguinal canal 
 Sup. ring guarded from behind by conjoint tendon& by reflected part of inguinal ligament 
 Deep ring guarded from in front by muscle fibers of transverse abdominis

▪Clinical–Hernia-> abnormal protrusion of abdominal contents through any of its walls
▫Hasselbach’s triangle
Boundaries
A-inguinal ligament
B B-inferior epigastric artery
C C-lateral border of rectus abdominis
Deep inguinal ring
medial lateral
A
Surface marking of inferior epigastric artery
0.5in just above the femoral pulse (midinguinal point=halfway between pubic symphysis and anterior
superior iliac spine)
Indirect inguinal hernia Direct inguinal hernia

 Passes through the deep inguinal ring  Passes through the posterior wall of inguinal
 Passes lateral to the inferior epigastric artery canal, occurs through Hasselbach triangle
 Can descend into the scrotum  Passes medial to the inferior epigastric artery
 Corrected by digital pressure  Mainly in adults
Coverings  Uncommon
 Can’t be corrected by digital pressure
• Coverings
Skin, external spermatic fascia, conjoint tendon,
Skin, external spermatic fascia, cremasteric fascia, fascia transversalis, extra peritoneal tissue,
internal spermatic fascia, extra peritoneal tissue, bowel bowel
Inguinal hernia – neck of the sac lies above & medial
to pubic tubercle
Femoral hernia – neck of the sac lies below & lateral
to pubic tubercle
Referred pain from gut-derived structures,
Pain of foregut- T8 – epigastric area
Pain of midgut- T10 – periumbilical area
Pain of hindgut- T12 – suprapubic area
Abdominal incisions
 McBurney’s incision – for appendicectomy
(Iliohypogastric and ilioinguinal nerves should be
preserved)
 Kocher’s incision
 Midline incision
 Paramedian incision

Peritoneum
 Peritoneum is a serous membrane which lines the abdominal cavity. 
 2 Layers – Parietal
Visceral

Various folds or reflections of the peritoneum connect viscera to abdominal wall or to one
 another. 
Some are properly called folds, others are called mesentery, omentum or ligament.

Peritoneal folds of anterior abdominal wall
Falciform ligament - connects liver to anterior abdominal wall & diaphragm, sickle shaped
Ligamentum teres - from umbilicus to the inferior margin of Falciform lig. (remnant of
left umbilical vein)(left is left)
Median umbilical fold - containing median umbilical lig. (remnant of urachus), from apex
of bladder to umbilicus
Medial umbilical fold - containing medial umbilical lig. (remnant of umbilical artery)
Lateral umbilical fold - containing inferior epigastric vessels (only up to arcuate line)
Median umbilical fold
Arcuate line Medial umbilical fold
Lateral umbilical fold



 Ligaments
Left triangular lig. – formed from the left leaf of the Falciform lig.
Superior layer of coronary lig. – formed from the right leaf of the Falciform lig.
Right triangular lig. – formed where the superior & inferior layers of the Coronary lig. meet.
Ligament Extend Contents

4.Gastrosplenic Greater curvature of the stomach Short gastric vessels
to Hilum of spleen L. Gastro-epiploic vessels
5. Lienorenal Hilum of spleen Tail of pancreas

to anterior surface of kidney Splenic vessels
Pancreaticosplenic lymph nodes
1.
6. Phrenicocolic ligament – From left colic flexure (Splenic flexure) to Diaphragm.

Separates left paracolic gutter from Lienorenal space & spleen
7. Gastrophrenic ligament

Mesentery
Contents Attachment of root
 
Jejunal & ileal branches of Begins at duodenojejunal flexure
1. Mesentery
proper superior mesenteric vessels.
Ends at right sacroiliac joint

Autonomic nerve plexuses 
Crosses =>
[Mesentery of
 rd
Small intestine]  Lymph nodes & lymphatics 3 part of duodenum
 Fat  Abdominal aorta
 IVC
 Right Psoas Major
 Right ureter

2. Mesoappendix  Appendicular vessels From - Posterior surface of the mesentery of the
terminal ileum

To - Tip of the appendix
 
3. Transverse Middle colic vessels Anterior surface of neck &

Mesocolon Lymph nodes anterior border of body of pancreas
 
Lymphatics Crosses 2nd part of duodenum

ANS
4. Sigmoid 
Sigmoid & superior rectal vessels 
Inverted V shape
Mesocolon 
ANS 
Apex - at bifurcation of common iliac vessels on
pelvic brim at left sacroiliac jnt.

Medial limb - slopes down to front of S3 (rectum
begins here)

Lateral limb - along pelvic brim
Omentum
Contents Attachment
1. Greater omentum 
R & L gastro epiploic vessels 
Double layer of peritoneum folded on itself to form four

Fat layers

Lymph nodes & lymphatics 
Anterior two layers descend from greater curvature

Curves back on itself & ascends

Blend with – peritoneum on anterior surface of transverse
colon & transverse mesocolon
 Bile duct
 Hepatic artery
 Portal vein
2. Lesser omentum  Right gastric vessels  Superior - liver (inverted L shaped attachment to porta

Hepatogastric lig.  Left gastric vessels hepatis & Ligamentum venosum)

Hepatoduodenal lig.  Lymph nodes  Inferior - lesser curvature of stomach, 1st part of duodenum
(Extends from abdominal oesophagus → lesser


 Gastric nerves curvature → duodenum )

Peritoneal cavity
 divided – Greater sac 
Lesser sac (omental bursa / Left subhepatic space)
 2 sacs communicate via epiploic foramen 
 Male - totally enclosed, 9

Female - perforated by openings of uterine tubes
1. Lesser sac – Part of Peritoneal cavity behind the stomach
Anterior wall - Caudate lobe

Lesser omentum
Posterior surface of Stomach
Anterior two layers of greater omentum
Posterior wall - Posterior two layers of greater omentum

Anterior surface of transverse colon & transverse mesocolon
Peritoneum covering the stomach bed
Left wall - Gastrosplenic ligament

Lienorenal ligament
 On the right opens up to greater sac via epiploic foramen
2. Greater sac - Rest of the space among the serous coated organs

9

Epiploic foramen - a slit at the right border of lesser sac through which it communicates with greater sac
Boundaries Anterior – Right free margin of lesser omentum
Containing – Common bile duct (R)
Hepatic artery proper (L)
Portal vein (P)
Posterior – IVC, T12 vertebra, right suprarenal gland.
Inferior – 1st part of duodenum
Superior – Caudate process of liver
 
Peritoneal compartments
1. Right sub-phrenic space (closed above by – superior layer of coronary lig.)
2. Left sub-phrenic space (closed above by – left triangular lig.)
3. Right sub-hepatic space(closed above by – inferior layer of coronary lig. & right triangular lig.)
4. Right para colic gutter (lateral to ascending colon)
5. Left para colic gutter (lateral to descending colon)
 Hepato-renal / Morrison’s pouch/ Right sub-hepatic –

 Behind the right lobe of liver & in front of right kidney.
 On the left – it communicates with lesser sac via epiploic foramen
 Inferiorly – continuous with right paracolic gutter
 When lying down - the most dependent part of the peritoneal cavity
**So, area where intra peritoneal fluid tends
to accumulate

Recto-vesical pouch – a peritoneal
 pouch between
rectum & bladder in males



Recto-uterine pouch (pouch of Douglas) - a peritoneal
 pouch between rectum & uterus in females -most
dependent part of the peritoneal cavity.
-pus which are collected here can be drained through
the rectum or pos. fornix of the vagina


Vesico-uterine pouch - a peritoneal pouch between uterus
 & bladder in females 


  Clinical

Peritonitis – Inflammation of peritoneum o Caused by

=>
 Ascites – Fluid in peritoneal cavity 
▪Fluid Collects

in the Lesser sac => Fluid may pass through epiploic foramen to hepatorenal
pouch
1. By Posterior Gastric ulcer 2. By Pancreatitis - Pancreatic pseudocyst


Fluid Collects in the Hepatorenal pouch of Douglas =>Subphrenic abscess (Commonest site) 

Most dependent part in the supine position 
By spread of infection from GB, Appendix
▪Treatment =>
 
Paracentesis – Removal of fluid in abdomen by puncturing the abdominal wall 

Posterior Colpotomy – Drain pus from the  Hepatorenal pouch of Douglas through
Rectum or Posterior fornix of the vagina


Pneumoperitoneum
 – Air in peritoneal cavity


Haemoperitoneum – Blood in peritoneum 
o Inflammation of Parietal Peritoneum => localized severe pain & tenderness
o Delay the onset of peritonitis =>

By Greater omentum – limits the spread of infection by sealing off the site.
2. Laparoscopy – Examine the peritoneal cavity under direct vision

o Instrument used =>Laparoscope
o Opening up abdominal cavity (Small incisions to insert Laparoscope) =>Laparotomy
3. Peritoneal dialysis – is done in renal failure
4. Internal Hernia –
o Through epiploic foramen into the lesser sac (Strangulated)
Surgically approached through the greater omentum =>
Epiploic foramen cannot be enlarged because there are important structures
o Paraduodenal fossa => between the duodenojejunal flexure and the Inf. Mesenteric V.
o Intersigmoid fossa => formed by the inverted V attachment of the meso sigmoid
5. Palpation of abdominal viscera– When the patient is in

supine position & hip, knee are flexed

Blood Supply of GIT
Supplied by ,
1. Coeliac Trunk – derivatives of foregut
2. Superior Mesenteric Artery - derivatives of midgut
3. Inferior Mesenteric Artery - derivatives of hindgut
Coeliac Trunk (T12)

– between crura of diaphragm just below median arcuate ligament @the upper border of pancreas
divided in to,
Cystic artery
Left gastric artery

 Runs towards the oesophageal opening
 Gives off oesophageal branches
 Runs along lesser curvature
 Anastomose with right gastric artery
Splenic artery
Coeliac Trunk
 Tortuous
 Runs behind upper pancreatic border
 Gives off posterior gastric artery
 Runs towards the hilum of left kidney
 Runs in splenorenal ligament
left gastroepiploic artery 6 short gastric arteries

 anastomose with right
7 gastroepiploic artery © 2017 A/L Repeat Campaign
Right Gastric Artery
Common Hepatic
Gastroduodenal artery
 Pass behind the 1st part of the
duodenum
Right gastro epiploic artery Superior pancreaticoduodenal

 Enters the greater artery
omentum  Anastomose with
inferior pancreatico
duodenal artery
Anterior Posterior
Hepatic artery proper Left
(runs upwards between 2

layers of lesser omentum)
Right Cystic Artery
Clinicals
Foregut - Posterior gastric ulcer or cancer may erode the pancreas giving pain referred to back.
Ulceration into splenic artery (direct posterior relation to stomach) may cause torrential hemorrhage.
posterior duodenal ulcer can erode gastroduodenal artery resulting a severe hemorrhage.
Midgut - Acute infection in appendix may result in thrombosis of appendicular artery, which is an end
artery thus leading to gangrene of appendix.
Hindgut – Hemorrhoids in the anal canal.

Superior Mesenteric Artery (L1)
Inferior pancreaticoduodenal artery
 Anastomoses with superior
pancreaticoduodenal artery
Left branch
Anastomose with a branch
of left colic artery at splenic
flexure
Middle colic artery

(descends in the transverse
mesocolon)
Superior mesenteric artery
 Runs downwards behind Right branch
splenic vein and body of Anastomose with
pancreas with superior ascending branch of right
mesenteric vein on right Jejunal and Ileal branches colic artery at hepatic
 Lies anterior to left renal (from main trunk, to the left) flexure
vein, uncinate process of (runs in the mesentery proper)
pancreas and 3rd part of
duodenum Ascending branch
Anastomose with right
branch of middle colic
artery
Right colic artery
(runs to the right across right psoas
major, gonadal vessels, ureter, and
Ileal branch genito-femoral nerve and Descending branch
Anastomose with terminal quadratus lumborum) Anastomose with superior
branch of superior branch of ileocolic artery
mesenteric artery
Ileocolic artery
Superior branch
Inferior branch Anastomose with right colic
artery
Appendicular artery
Anterior caecal artery Posterior caecal artery
 End artery
 1st runs in the free margin of
the mesoappendix, then
close to appendicular wall
Ascending branch
 Cross left psoas, gonadal
Inferior mesenteric artery (L3) vessels, ureter, genitofemoral
nerve, quadratus lumborum
 Crossed anteriorly by inferior
Left colic artery mesenteric vein
Descending branch
 Anastomoses with highest
Sigmoid arteries (2-4) sigmoid artery
 Runs in the sigmoid
mesocolon
At the apex of Ʌ (inverted V)

attachment of sigmoid colon,
bifurcation of left common iliac
vessels over sacroiliac joint;
Inferior mesenteric artery
Continues as Superior rectal artery
 Inferior border of 3rd part
of duodenum
Left branch
Superior rectal artery

 Descend in the medial limb
of sigmoid colon reach
rectum at S3 level
Right branch
Clinicals
 Anastomotic branches near inner margin colon forms marginal artery of Drummond.
 Avascular window lies between middle colic and left colic arteries around the splenic flexure where
surgeons use to enter the lesser sac.

Venous Drainage of GIT Paraumbilical vein
Right Branch Left Branch Ligamentum venosum
Ligamentum Teres
Portal Vein
 Runs in the free
Right Gastric Vein margin of the lesser Left Gastric vein
omentum short Gastric
Vein
Behind the neck of Splenic vein

the Pancreas
Prepyloric vein of mayo
(not accompanied by an
artery) Left Gastroepiploic vein
Superior
Pancreaticoduodenal vein Passes behind the lower border of the body
of the pancreas in front of left renal vein and
joins splenic vein
Crosses the third
part of the
duodenum and
uncinate process Left colic vein Sigmoid veins
of pancreas.
Right Gastroepiploic vein

Inferior Mesenteric vein
Middle Colic vein
Superior mesenteric vein Superior Rectal vein
Right colic vein
Jejunal and Ileal Ileocolic vein

tributaries
Gastro-intestinal tract
1. Stomach
External features
 J shaped muscular bag

 Two orifices
o Cardiac orifice - Lies behind the left 7th costal cartilage (T11).
 Has a physiological sphincter (not anatomical)
o Pyloric orifice -Lies at the level of transpyloric plane (L1).
Its position is indicated by,
 A circular groove produced by underlying pyloric sphincter
 The prepyloric vein/ vein of Mayo lying in front
 Anatomical, physiological sphincter
 In epigastric, umbilical and left hypochondrial regions
 Widest and most distensible part of GI tract
Fundus-filled with air
Parts of the stomach Cardiac part Body
Pyloric part Pyloric antrum

Pyloric canal
▪Relations –
-Peritoneal,
Ventral mesogastrium (dorsal part) - lesser omentum
Dorsal mesogastrium 1.along the greater curvature- greater omentum
2. near the fundus- gastrosplenic ligament
3. near the cardiac end- gastrophrenic ligament
1 ©2017 A/LRepeat Campaign
-Visceral,
Anterior – Anterior abdominal wall
Left costal margin
Diaphragm
Left lobe of liver
Posterior (Stomach bed) –
Pancreas
Transverse colon
Left kidney
Left suprarenal gland
Spleen
Splenic artery
▫Are separated from stomach by the lesser sac
Superior – left dome of diaphragm
Inferior – coils of intestine
Functions
 Storage of food
 Mechanical grinding and digestion
 Prevent reflux
 Prevent digestion and damage of its wall
 Controlled release of food at pylorus
 Absorption (H2O, Ethanol)
 Intrinsic factor
Mechanisms to prevent gastroesophageal reflux
 Physiological sphincter at the gastroesophageal junction

o Transverse mucosal folds of gastroesophageal junction
o Sphincteric action of right crus of diaphragm
 Acute angle of entrance of esophagus into the stomach
 The positive intra-abdominal pressure compresses the abdominal part of esophagus.
Blood Supply of Stomach

Lymph Drainage of Stomach
Nerve supply
Sympathetic greater splanchnic nerves
Parasympathetic ant & post vagal trunks
Hepatic branch
Anterior vagal trunk Gastric branches – Fundus & body
Anterior nerve of Latarjet – pyloric antrum & sphincter

Coeliac branch (bulk)
Posterior vagal trunk Gastric branches – Fundus & body
Posterior nerve of Latarjet – Pyloric antrum
Not to sphincter
 Anterior & posterior vagi give secretary & motor supply

 Gastric divisions of both vagi reach stomach at cardia
 Then descend along lesser curvature in the lesser omentum
 Terminal part of this nerve innervates pylorus –nerve of Latarjet
Complete vagotomy
Selective vagotomy
Highly selective vagotomy
-divide branches which supply acid secreting body of stomach
-preserving nerve of Latarjet
-function of pylorus remain intact

Clinical
 posterior ulceration of stomach, damaging the pancreas & splenic artery
o common in lesser curvature because rugae are longitudinal (gastric canal)
 gastric carcinoma- commoner along greater curvature
 “signal nodes” (Virchow’s nodes) – left supraclavicular node is enlarged (Troisier’s sign) ,mostly due
to gastric carcinoma
 pyloric stenosis – causes vomiting after meals
1. Regarding stomach
a. Prepyloric vein marks the pyloric sphincter
b. Cardiac orifice lies deep to the left seventh costal cartilage
c. Part of lesser sac lies within gastrocolic ligament
d. Left supraclavicular nodes enlarges in gastric carcinoma
e. Lymph from upper part of greater curvature drains into pancreaticosplenic nodes
2. The stomach
a) Is supplied in part by arteries arising from the splenic artery
b) Is supplied by arteries which each arise from branches of the coeliac trunk
c) Has a venous drainage passing equally to the portal and systemic venous systems
d) Is lined by columnar and squamous epithelium
e) Is totally covered by serosa (peritoneum)
2) DUODENUM
 C shaped loop around head of pancreas
 Secondarily retroperitoneal except duodenal cap.
 Forms lower most boundary of epiploic foramen of Winslow.
1st part – L1 level (2 inches) – the shortest, widest

and most fixed part of SI
2nd part – to the right of L2 (3 inches)
3rd part – crosses in front of L3 (4 inches)
4th part – to the left of L2 (1 inch)

Relations of Duodenum
Parts of Anterior Posterior Medial Superior Inferior

duodenum
Peritoneum Portal vein Neck of gall bladder Neck of
Superior Gall bladder Gastroduodenal pancreas
Quadrate lobe artery
(1st part)
Bile duct
IVC
Transverse colon Hilum of right Head of
Transverse kidney pancreas
Descending mesocolon Renal vessels Pancreatic
(2nd part) Coils of SI Ureter duct
Fundus of gall Aorta Bile duct
bladder Right ureter
Head & uncinate
Superior
Right psoas major process
mesenteric
IVC of pancreas
Horizontal(3rd vessels
Aorta Superior mesenteric
part) Coils of SI Right ureter vessels
Root of Gonadal vessels
mesentery
Ascending(4th Beginning of root Left psoas major Head of Body of pancreas
part) of mesentery Left margin of pancreas
Coils of jejunum aorta
 Two papillae: Major – hepatopancreatic ampulla (ampulla of Vater). 8-10cm distal to pylorus
Minor – accessory pancreatic duct opens 2cm above the major papilla
 Duodenal cap: Seen after a barium meal. 1st part of duodenum is seen as a shadow.
o Reason: absence of plicae circularis.
 Suspensory ligament of Treitz
 between DJ junction and right crus of diaphragm
 marks DJ junction
 Inferior mesenteric artery lies immediately to the left of the DJ junction.
Clinical
o peptic ulcer – common site – 1st part
o obstruction
o Annular pancreas
o Pressure by the superior mesenteric artery
o Contraction of suspensory ligament of duodenum
o Ulceration of gall stones into duodenum & obstruct the lower ileum-gall stone ileus
o Posterior duodenal ulcer
o Damages the gastroduodenal artery & pancreas
1. Duodenum
a) Is almost completely covered by peritoneum
b) Lies behind the portal vein
c) Lies anterior to the hilum of the right kidney
d) Is crossed anteriorly by the superior mesenteric vessels

3) JEJUNUM & ILEUM
Jejunum Ileum
1.Wall Thicker & more vascular Thinner & less vascular
2.Lumen Wider & often empty Narrow & often loaded
3.mesentery • Less fat • More fat
• Windows present • No windows
• 1/2 arcades(few) • 3/5 arcades(numerous)
• Vasa recta long & few • Vasa recta short & numerous
4.Plicae Large & closely placed throughout Small & sparse, only in proximal part
circularis
5.Villi Large, thick & more Short, thin & few
6.Payers Present
patches Absent
7. solitary
Fewer More
lymph follicles
8.Location Upper left part of abdomen Lower right part

9.length 2/5 3/5

4. LARGE INTESTINE
▪Caecum
▪Ascending colon
▪Transverse colon
▪Descending
colon
▪Sigmoid colon
▪Appendix
●Caecum – intraperitoneal, in right iliac fossa

▪large blind sac
▪form commencement of large
intestine
▪width is greater than length
▪Distensible
▪appendix opens in to posteromedial wall, 2cm below ileocecal valve
Relations of the Caecum
Anterior – Coils of intestine

Anterior abdominal wall
Posterior – Muscle – right psoas & iliacus
– Nerves – Genitofemoral
Femoral (in iliopsoas groove)
Lateral cutaneous nerve of thigh
– Vessels – Right gonadal
External iliac
 Colon, caecum - taeniae coli

 Colon - appendices epiploicae
1. The caecum
a) Is completely invested in peritoneum
b) Possesses a longitudinal muscle coat but no taeniae coli
c) Lies on the right psoas muscle
d) Has an ileocecal orifice opening inferiorly
e) Lies adjacent to the right femoral nerve
●Appendix
o Vermiform blind ended tube ,situated in right iliac fossa, larger in children & base is fixed
o Opens into posteromedial wall of caecum
o Tip of the appendix has no anatomy, it can be anywhere within abdominal cavity
o Position - Retrocaecal – 65%
 Pelvic – 30% Retroileal
o Base - McBurney’s point (gridiron incision)
 Junction between lateral 1/3 & medial 2/3rd of line joining the
umbilicus & the right anterior superior iliac spine
o Taeniae coli meet at the base
o Blood supply – Lower division of ileocolic artery
Appendicular artery (It is an end artery)
Pass behind terminal ileum & enters mesoappendix
Runs first in free margin of mesoappendix and then along the appendicular wall.
Clinical
Inflammation: Appendicitis
Pain initially referred to umbilicus (T10)
Later when parietal peritoneum irritates – pain in right iliac fossa
Thrombosis of appendicular artery causes gangrene as it is the
sole blood supply to the appendix.
McBurney’s point- site of maximum tenderness in appendicitis
Inflamed pelvic appendix Inflamed Retrocaecal appendix

• Lies on obturator internus, • Lies between caecum & right psoas
More pain when seated(medially More pain when standing(extended
rotated thigh) thigh)
Appendix of
 Children – larger
 Adults – obliterated
 So appendicitis occurs more in teenagers.
1. The appendix
a) Arises from the inferior aspect of the caecum
b) Has a mesentery
c) Is commonly absent
d) Usually lies retrocaecally.
e) Is clothed in peritoneum

Colon
Feature Small intestine Large intestine

1.Caliber Smaller Larger
2. Sacculation Absent Present
3. Taeniae coli Absent Present
4.Transverse mucosal folds Permanent Obliterated when longitudinal
muscle coat relaxes
5.Appendices epiploicae Absent Present
6.Fixity Greatly mobile Greater part fixed
7.Villi Present Absent
8.Common infection Intestinal worms E.hystolytica
Typhoid Dysenteric organisms
Tuberculosis Carcinoma
9.Effects of infection Diarrhoea Dysentery
10. X ray identification 1.Complete transverse lines across Incomplete septa projecting into
bowel shadow due to transverse gas shadow due to sacculation
folds of plicae circularis
2.shadow – centrally Periphery
 Descending colon is also supplied by pelvic splanchnic nerves which arise from anterior
primary rami of S2, S3, S4 sacral nerves. These supply parasympathetic function including
transmitting the sensation of pain.

Liver
Surface marking
1. Tip of right 10th rib in mid axillary line
2. Left 5th intercostal space in mid clavicular line
3. Right 5th intercostal space in mid axillary line
*Not palpable in normal subject
Tuber Omentale
Papillary Process
Caudate Process

Peritoneal Attachments –
o Liver is enclosed in peritoneum (Ventral mesogastrium), except at the bare area
Ventral part
i. Falciform lig. – Attached to liver & anterior abdominal wall
o Inferior margin – Ligamentum teres hepatis (Remnant of L. Umbilical V.)
ii. Right & left triangular ligaments
iii. Coronary ligament – Superior & Inferior layers
Dorsal part
 
 Lesser omentum – arise from inverted ‘L’ attachment
o Vertical limb – Ligamentum venosum (Remnant of Ductus Venosus)

 o Horizontal limb - margins of porta hepatis

Lobes – Right & Left
Anatomical Division
Divided into Left and larger Right lobes :

Diaphragmatic surface – Falciform ligament
Visceral surface – ‘H’ shaped arrangement

Right Lobe
 
Caudate lobe
-Between groove for IVC & Fissure for Ligamentum venosum
-Caudate process – Inferior to the right, connecting to the right lobe
- Papillary process – Inferior to the left
 
Quadrate lobe
-Between GB fossa & Fissure for Ligamentum Teres
 
Porta hepatis
-Arrangement
Portal Vein – posteriorly
Bile duct – anteriorly to the right
Hepatic artery – anteriorly to the left
o Left Lobe

Tuber Omentale (omental tuberosity) – near the
fissure for Ligamentum
 venosum, right to gastric
impression
Functional Division
 According to distribution of Bile duct, Hepatic artery, Portal vein. Oblique plane through the GB
Fossa & IVC groove divides it into left and right halves.
 8 lobes
 Caudate lobe is supplied by both hepatic arteries, both portal veins, both hepatic
ducts, but it has an independent venous drainage
 Stability – Ligaments, Hepatic veins, Abdominal muscle tone
 Relations-5 Surfaces 
Anterior Surface
●Diaphragm 

●Pleura
●Anterior Abdominal Wall
●Xiphoid Process 

Posterior Surface-Right Lobe

(Bare Area – Area that grows in to the Septum Transversum) 
●Diaphragm
●IVC+ Hepatic V.
●Suprarenal Impression - R. Suprarenal Gland
Left Lobe
●Oesophageal Impression- Oesophagus
●2 Crura
●Aortic Opening
●Celiac Trunk

Inferior Surface (visceral surface)
Right Lobe
●Gall Bladder
●Colic Impression - Hepatic Flexure
●R. Kidney - Renal Impression
Left Lobe
●Gastric Impression -Stomach
●Fissure for LigmentumTeres
Quadrate Lobe
●Pylorus of Stomach
●Duodenal Impression -1st Part of Duodenum
Superior Surface ●Right & Left Domes of Diaphragm
Right Surface - ●Upper 1/3-Lung, Pleura, Diaphragm

(In Midaxillary line) ●Middle 1/3-, Diaphragm
●Lower 1/3-Diaphragm
Blood supply Right hepatic artery cystic artery

1. Hepatic artery proper
Left hepatic artery
Right
2. Portal vein
Left
Left In the plane

3. Hepatic veins IVC
Middle
between
functional 2 lobes
Right
4
 [Small accessory hepatic veins drain directly to the IVC]
 
Clinical 
1. Liver biopsy – Needle passes through right 8th intercostal space
2. Cirrhosis – Liver Fibrosis, causes Caput medusae
3. Malignant growths – Tumors
Can send an embolus to destroy tumors (contain end-arteries)
Secondary tumors – from colon cancers
4. Hepatomegaly – Liver enlargement
5. Pringle’s Maneuver – Liver bleeding stopped by = compressing right free margin of lesser omentum
6. Liver resection & transplantation

Important Facts
O Can regrow
O Occupies R.Hypochondrium, Epigastrium, L.Hypochondrium,Under the Costal margin
Normally not palpated in the infrasternal angle
Due to - tone of the recti muscles & the softness of the liver

EXTRA HEPATIC BILIARY SYSTEM
`

 
Apparatus consists of –
i. Right & left hepatic ducts
ii. Common hepatic duct
iii. Gall bladder
iv. Cystic duct
v. Bile duct
  Calot’s triangle – 
i. Cystic duct
ii. common hepatic duct
iii. inferior surface of liver
Cystic artery and cystic lymph nodes can be located here.
i. Gall bladder
 Pear shaped fibromuscular sac for storage and concentration of bile.
 Lying in gall bladder fossa
 Plastered onto the visceral surface of right lobe of liver, adjacent to quadrate lobe.
 Capacity:- 30-50 ml
 Relations
Neck – Superior - Attached to liver, by areolar tissue
Inferior - 1st part of duodenum
Body – Anterior –Adherent to liver, not covered by peritoneum

Posterior – Transverse colon,1st & 2nd parts of duodenum
Inferior – Covered by peritoneum
Fundus – Anterior – Anterior abdominal wall = 9th costal cartilage tip (transpyloric plane)
Posterior – Transverse colon
Blood Supply
It has a Dual blood supply from:
-Cystic artery (cystic veins do not accompany the cystic artery. Venous drainage is via multiple
veins in gall bladder bed to Liver
-From liver bed, So gangrene is rare.
Clinical
Gall Stones
 In gall bladder-Cholelithiasis
Spasmodic pain occurs
Murphy’s sign – Pain felt when pressing at 9 th costal cartilage tip in
 Hartmann’s pouch. -Posteromedial wall of the neck is dilated (Gall stones lodge here)
Inflammation of gall bladder
Referred pain -in the lower border of the scapula via sympathetics
- Stomach via vagal fibers
-Shoulder tip via phrenic nerve
4. Courvoisier’s Law
 Extrinsic obstruction (Carcinoma of head of the pancreas) – Dilation of GB
 Intrinsic obstruction (Stones) – Fibrosis, no dilation of GB

2. Bile duct
Common hepatic duct is joined by the cystic duct at an acute angle to form the common bile duct.
(commences approximately 2.5 cm above the duodenum )
▪Diameter-6mm (not more than 8mm)

▪Relations
▫Supraduodenal part (Lie in free edge of lesser omentum)
- Anterior-liver
-Posterior-portal vein, epiploic foramen (more posteriorly IVC)
-Left-hepatic artery
▫Retro duodenal part(most accessible part of surgery)
-Anterior-1st part of
duodenum
-Posterior- IVC
-Left –gastroduodenal artery
▫Infraduodenal part
-Anterior-head of pancreas (neoplasm of duct may obstruct here)
-Posterior-IVC, Left renal
vein
 Join main pancreatic duct of Wirsung at angle of 600 degrees, to form Ampulla of Vater guarded by sphincter
of Oddi.
 Open to posteromedial wall of middle of second part of duodenum.

 8-10 cm from pylorus.
 Small bile ducts from liver enter to the GB bed

Pancreas
Compound gland with a major exocrine (98%) and smaller endocrine part
retroperitoneal
Surface marking
The transpyloric plane defines the level of the neck of the pancreas which overlies the vertebral Column. From
this land mark head passes downward & to the right, the body & tail pass upward
& to the left
Head Superior 1st part of duodenum

Broadest part Anterior
Right to midline Gastroduodenal artery
Transverse colon+ transverse mesocolon
In C shaped Loops of small intestine
concavity of Posterior
IVC
duodenum Right renal vessels+ left renal vessels
Right crus of diaphragm
Bile duct
Inferior Third part of duodenum
Uncinate process Anterior Superior mesenteric vein and artery

Posterior Aorta
Inferior Third part of duodenum
Neck Anterior Pylorus (at transpyloric plane – L1 )

Peritoneum of lesser sac
Posterior Termination of superior mesenteric vein
Beginning of portal vein
Aorta
Body Anterior Lesser sac & Stomach
Anterior surface
covered by
peritoneum, reflected
Slightly triangular in anteroinferiorly from
the surface
cross section Posterior Left renal vein
Has superior and Aorta
inferior border. Origin of superior mesenteric artery
L crus
Ant superior, ant L Psoas
inferior and Hilum of left kidney
Posterior surfaces Left suprarenal gland
Inferior Duodenojejunal flexure
Superior mesenteric vessels
Splenic flexure
Superior Splenic artery runs along superior border
Coeliac artery and branches
Tail Lies in the lienorenal lig
Contact with visceral surface of spleen

Ducts – Main Pancreatic duct of Wirsung– Begins at the tail =>lies near posterior surface
Joins with bile duct =>Hepatopancreatic ampulla of Vater =>Major duodenal papilla Accessory Pancreatic duct
of Santorini – Begins at the uncinate process => Minor D. P.
Blood supply
 From Coeliac trunk and Superior mesenteric artery

 Mainly from splenic artery.
 Head, uncinate process - superior and inferior pancreaticoduodenal arteries.
 Anterior branches of pancreaticoduodenal arteries (superior and inferior) anastomose forming anterior
pancreaticoduodenal arcade, posterior branches- posterior pancreaticoduodenal arcade
 Branches of splenic artery – Dorsal pancreatic artery (mainly), Great Pancreatic artery, Artery to the tail
 Dorsal pancreatic artery gives anterior and posterior branches which anastomose with
pancreaticoduodenal arcades and supply head
 Venous drainage – accompany arteries.
 Body and Tail Splenic vein
 Head Superior pancreatico duodenal veins portal vein
Inferior pancreatico duodenal veins Superior mesenteric vein
Lymph drainage
Coeliac
Head Neck Pancreaticosplenic nodes Pre aortic nodes
Superior mesenteric
Tail and Body Nodes along splenic artery

Clinical –
1. Carcinoma of head of the pancreas - may cause obstruction of the bile duct
2. Pancreatitis – fluid collect in the lesser sac = Pseudocyst(or by posterior gastric ulcerations)
3. Annular pancreas
4. Neoplasm of the head of pancreas – obstructive jaundice
Of the body – portal or IVC obstruction
Referred pain to
Epigastrium => T6 to T10
Posterior paravertebral region =>inflamed soft tissues of retro-peritoneum
Histology
Encapsulated and lobulated gland
 Exocrine pancreas –
compound branched acinar gland
Individual acini consists of pyramidal cells which secrete digestive enzymes
Acinar cells have abundant RER, secretory zymogen granules
Ducts systems eventually drain to large interlobular ducts lined by tall cuboidal/columnar epithelium
 Endocrine pancreas –
Pancreatic islets / islets of Langerhans
Most numerous in the tail
Highly vascularized
Contain Alpha(secrete Glucagon), Beta, and Delta cells(secrete somatostatin)
Beta cells secreting insulin is most abundant
Spleen
Surface anatomy
In Left hypochondrium
(Points) – Left side
1. Axis – 10th rib directed downwards forwards and laterally
2. Upper pole – upper border of 9th rib
3. Lower pole – lower border of 11th rib
4. Medial end – 2 inches from midline
5. Lateral end – Mid axillary line
*Must be enlarged 3 times than normal to be palpated


Important Facts 
1) Tetrahedral in shape
2) Lies deep to the left 9th to 11th ribs
obliquely along the long axis of 10th rib
3) 2 surfaces – diaphragmatic (smooth,
convex) and visceral.
4) Borders –
 Anterior/Superior – notched
 Posterior/Inferior
 Intermediate – separating gastric
and renal impressions
5) Wedged between fundus of stomach
and diaphragm
6) Impressions on visceral surface

i. Gastric (largest) - Fundus of Stomach
ii. Renal – L. Kidney
iii. Colic – Splenic Flexure
Pancreatic – Tail of pancreas

Ligament Extend Contents
1.Gastrosplenic Greater curvature of the stomach to Short gastric vessels
Hilum of spleen L. Gastro-epiploic vessels
2. Lienorenal Hilum of spleen to Tail of pancreas

anterior surface of left kidney Splenic vessels
Pancreaticosplenic lymph nodes
Forms the left lateral extremity of the lesser sac

  Clinical – 
1. Stab injuries to posterior left chest can tear the spleen.
2. Thin tense capsule - Commonest intra-abdominal structure to rupture
3. Normal spleen is not palpable
Splenomegaly- Spleen enlarge along the axis of the 10th rib =>Right iliac fossa
Notch on its anterior border felt under the left costal margin
3. Splenectomy – Tail of the pancreas & contents of the lig. should be preserved Only
one segment can be removed, due to segmental blood supply
Can be cut into small pieces & implanted within the greater omentum
4. Splenic puncture – through 8th or 9th intercostal space in midaxillary line, using L. Puncture needle
5. Splenic Infarction – since splenic A. are end-arteries, can be obstructed
Referred Pain
Referred pain is a term used to describe the phenomenon of pain perceived at a site adjacent to or at a distance
from the site of an injury's origin.
1. Biliary tract – stretch of GB or CBD

• Epigastrium & R. hypochondrium => T7 to T9
• R. shoulder tip => C4 via R. phrenic N.
• Inferior angle of R. Scapula
2. Spleen – Splenic Infarction

•Epigastrium => T7
•L. Shoulder tip (Kehr’s sign) => C4 via L. phrenic N.
3. Appendix - appendicitis
•Umbilical region – 1st felt => T10
•Right iliac fossa - increased inflammation =>Inflamed appendix touches the parietal peritoneum
4. Pancreas - Pancreatitis
•Epigastrium => T6 to T10
•Posterior paravertebral region =>inflamed soft tissues of retro-peritoneum
5. Kidney
• Lumbar region of back
• External genitalia of Anterior abdominal wall
=>T12 to L1 via sympathetic fibers
6. Ureter
• Renal colic – severe pain due to a ureteric stone
• Pain starts in the loin & radiates down the groin, the scrotum or labium majus & the
inner thigh [Pain is referred to the cutaneous areas innervated by segments,
mainly T11 & L2 which also supply the ureter]
7. Uterus.
• corresponding dermatomes =>T10-L1 via sympathetic fibers
8. Ovary.
• Loin & groin =>T10-T11 via Aortic plexus
POSTERIOR ABDOMINAL WALL
 Made up of 3 bony & 4 muscular structures
 Bones- Bodies of lumbar vertebrae
Sacrum
Wings of ilium
(11th & 12th ribs)
 Muscles - Diaphragm
Quadratus lumborum
Psoas major & minor
Iliacus
Psoas major
 Origin - transverse process of all lumbar vertebrae
Side of the bodies (T12-L5 )
Intervening discs (T12-L5 )
 Insertion - lesser trochanter of femur
 Action – flexion of the hip joint
 Roots of lumbar plexus lie within the substance of the muscle.
 Genitofemoral nerve - front of psoas
 Femoral, Iliohypogastric, ilioinguinal, lateral femoral cutaneous
nerves, femoral nerve - lateral border
 Obturator & lumbosacral trunk - medial border
 Nerve supply - first 3 lumbar nerves
 Psoas fascia - invests the surface of psoas major

- Attached to vertebral bodies, fibrous arches & transverse processes
- Thickening, curving from body of L1
(or L2) to transverse process of L2 - medial arcuate ligament
Clinical
 Psoas abscess
 enclosed in sheath
 pus from tubercular infection may tract down through the sheath in to the thigh
 soft swelling in the femoral triangle
Iliacus
 Origin - Upper 2/3 of iliac fossa, anterior sacroiliac and iliolumbar ligament.
 Insertion - lesser trochanter of femur along with the psoas tendon
 Nerve supply - femoral nerve (L2-L4)
 Iliac fascia - covers iliacus muscle

Attached to the margins of the muscle & to the inguinal ligament
Quadratus lumborum
 Origin - transverse process of vertebra LV, the iliolumbar ligament, and the adjoining
part of the iliac crest
 Insertion - attach superiorly to the transverse processes of the first four lumbar
vertebrae and the medial half of the inferior border of rib XII.
 Nerve supply - anterior rami of T12 and L1 to L4 spinal nerves.

Thoraco lumbar fascia
 enclose deep muscles of the back
 3 layers, enclose 2 muscle compartments as anterior & posterior
 anterior layer → forms lateral arcuate ligament Only the lumbar region
 middle layer
 posterior layer → extends above, to the lower part of the neck and below the dorsal
surface of the sacrum
 Anterior muscle compartment - quadratus lumborum

 posterior muscle compartment - erector spinae

Abdominal aorta
 The surface marking of the abdominal aorta is from a point 2.5 cm above the
transpyloric plane in the midline to a point 1 to 2 cm below and to the left of a
normally situated umbilicus, level with the highest points of the iliac crest.
 Enters the abdomen behind the median arcuate ligament behind peritoneum
slightly inclining to left.
 The main branches of the abdominal aorta fall into 3 main categories.
1. Single ventral arteries to the gut and its derivatives

Eg – Coeliac, superior mesenteric and inferior mesenteric
2. Paired branches to other viscera

Eg – Suprarenal, renal and gonadal
3. Paired branches to the abdominal wall

Eg – Inferior phrenic and lumbar arteries
 A small posterior branch, the median sacral artery leaves the aorta a little above its
bifurcation.

Inferior phrenic arteries Supra renal branches
(slights upwards over th crus of the diaphrgm)
T12 Coeliac trunk Left

(Behind posterior wall
of lesser sac)
Supra renal arteries
Right
(Behind IVC)
Crossed by the splenic vein and
body of pancreas
L1 Superior mesenteric artery Left

 Short
 Crosses left crus & psoas behind
left renal vein
 Covered by tail of pancreas &
splenic vessels
L2 Renal arteries
(At right angle)
Right
 Long
Crossed by left renal vein
 Crosses right crus & psoas
behind IVC & right renal vein
Crossed by uncinate process
Crossed by 3rd part of duodenum

Testicular artery – enters deep
inguinal ring, runs in
Gonadal arteries the spermatic cord
Ovarian artery – enters the
suspensory ligament
L3 Inferior mesenteric artery
Lumbar arteries 4
(Leave the aorta opposite the
bodies of L1-L4)
Divide in to common iliac arteries

L4 (Pass in front of sacroiliac joint, ureter Median sacral artery-Posteriorly arises
lies in systemic
Porto front) anastomosi

Site Systemic vein Portal vein In portal
hypertension
Lower end of Oesophageal branches of the Oesophageal Hematemesis
oesophagus azygos system branches of left (vomiting of blood)
gastric vein
Anal canal Inferior rectal branch- Superior rectal Hemorrhoids
internal iliac vein branch- inferior
mesenteric vein
Around Veins of abdominal wall Portal branches of the Caput medusae
umbilicus liver
Bare area of Veins of diaphragm Portal branches of
liver liver
Posterior Renal, lumbar & phrenic Portal tributaries in
abdominal veins mesenteric &
wall mesocolon
Portal vein
 Formed by draining of the splenic vein into the superior mesenteric vein
 Behind the neck of the pancreas
 At the L2 vertebral level
 Relations
 Infraduodenal part
Anteriorly – neck of pancreas
Posteriorly – IVC
 Retroduodenal part
Ant. - 1st part of duodenum
Common bile duct
Pancreas
Gastroduodenal artery
Post. – IVC
 Supraduodenal part - between the 2 layers of the free edge of lesser omentum
Ant. – Hepatic artery
Bile duct
Post. - Epiploic foramen
 Tributaries
 Splenic vein
 Superior mesenteric vein
 Left gastric vein
 Right gastric vein
 Superior pancreaticoduodenal vein
 Paraumbilical vein (running with the ligamentum teres)
 Cystic vein (if present)
 Branches
Right – shorter & wider
Receive cystic vein & enters the right lobe of the liver
Left - longer & narrower
Receive paraumbilical vein
Ligamentum teres
Ligamentum venosum

Inferior Vena Cava
Right common iliac vein Left common iliac vein
Iliolumbar vein
Median sacral vein
Lateral sacral vein
Inferior Vena Cava (L5) -runs right to midline
3rd & 4th lumbar veins The 3rd and 4th lumbar veins
(1st & 2nd lumbar veins join ascending drain directly into the IVC
lumbar vein while the 1st and 2nd veins
do not.
2 Right gonadal veins 2 venae
commitantes unite on psoas
Right gonadal vein
2 left gonadal veins unite on psoas

Left renal vein
Left gonadal vein
(3 times long as right, crosses
aorta)
Left suprarenal vein
Right renal vein
Right supra renal

vein
Inferior phrenic veins

Below liver
Left hepatic vein Middle hepatic Right hepatic vein

vein
T8 (Pierce the central tendon of the diaphragm)
Drain to6the right atrium ©2017 A/L Repeat Campaign

Sympathetic trunk (lumbar part)
 Ganglionated chain situated on either side of lumbar vertebrae.

 Continuous with thoracic part of sympathetic trunk deep to medial arcuate ligament.
 Runs vertically downwards along medial margin of psoas major and across lumbar
vessels.
 On the right side it is overlapped by inferior vena cava and on left side by the aortic
lymph nodes.
 Chain ends by becoming continuous with the sacral part behind common iliac
vessels.
 Lumbar ganglia are usually 4.
 White rami communicantes from first 2 lumbar nerves, join the trunk and relay in
lumbar and sacral ganglia.
 Gray rami communicantes from lumbar ganglia accompany the lumbar arteries,
around the sides of the vertebral bodies, medial to the fibrous arches to join the
anterior rami of lumbar nerves, for distribution to the body wall and lower limb,
through the branches of lumbar plexus.

Autonomic plexuses
 Coeliac Situated anterior to the aorta

 Superior mesenteric containing sympathetic and
 Inferior mesenteric parasympathetic which supplies
 Superior hypogastric abdominal viscera.
 Fibers pass downwards into pelvis from superior hypogastric plexus as the
hypogastric nerves to form the inferior hypogastric plexus with pelvic splanchnic
nerves.
Somatic nerves
Lumbar plexus
Formed by anterior rami of upper 4 lumbar nerves.
 L1 - Iliohypogastric & ilioinguinal
 Skin over the inguinal region & front of the scrotum
 Motor supply for the internal oblique & transversus abdominis (conjoint
tendon)
 L1,L2 - genitofemoral
Genital branch - Sensory to tunica vaginalis & spermatic fascia
Motor to cremaster muscle
Femoral branch – supplies an area of skin below the middle of the inguinal ligament
 L2,L3 (posterior division) - lateral femoral cutaneous
 Wholly sensory to the iliac fascia & peritoneum of the iliac fossa &
 To the lateral side of the thigh down to the knee.
 L2,L3,L4 (posterior division) - femoral
 L2,L3,L4 (anterior division) - obturator

KIDNEY
Location
 Retroperitoneal– in the paravertebral gutters
 Occupies epigastric, hypochondriac, lumbar and umbilical regions
 Long Axis – Parallel with the lateral border of the Psoas major
 Vertically – (Approximately) From Upper border of T12 Body of L3 vertebra
 Hilum – directed anteromedially
Left hilum
Transpyloric plane
Right hilum
 Side differences –
o R. kidney little lower => Liver superiorly located
o R. kidney little away from the mid-line => IVC medially located
o R. kidney lies anterior to 12th rib, while L. kidney lies anterior to 11th& 12th ribs
Relations
-Posterior – similar to both kidneys
 Diaphragm & quadratus lumborum muscles
 Behind the diaphragm – costodiaphragmatic recess
 Medially overlaps (hilum) – Psoas major
 Laterally overlaps – Transversus abdominis
 Upper pole – Medial & lateral arcuate ligaments
 Emerging beneath the lateral arcuate ligament – Subcostal vein, artery and
nerve
 Emerging from the lateral border of psoas major – Iliohypogastric & ilioinguinal nerves
1
Right Left
- Anterior
Superior R. Suprarenal gland L. Suprarenal gland
Liver Stomach & Spleen
Peritoneum of hepatorenal Peritoneum of lesser sac medially
pouch (greater sac) Peritoneum of greater sac laterally
Middle 2nd part of Duodenum Body of the pancreas
Splenic A. & V.
Lateral Hepatic flexure Splenic flexure of colon
Inferior Beginning of Descending colon
Medial Small intestine Jejunum
Medial
Above the hilum - Suprarenal glands
Below the hilum - Ureter
Lateral
Right kidney Left kidney
Right lobe of the Liver Spleen
Hepatic flexure of the colon Descending colon
Relations of the hilum (Ant to pos-VAP)

Renal vein (V)
Renal artery (A)
Renal pelvis (P)
2
Coverings (inside to outside)
1. Fibrous/true capsule- easily stripped off in normal, but becomes adherent in disease conditions
2. Perinephric fat (fatty capsule)- fills up extra space in renal sinus
3. Renal fascia/false capsule –

Condensation of the Areolar tissue between parietal peritoneum & posterior abdominal wall
2 Layers–Anterior & Posterior
Superiorly
Enclose Suprarenal gland – A fascial septum forms a separate compartment for it
Then fuse with each other
Inferiorly
Two layers remain separately
Enclose ureters (fading into extraperitoneal tissue around them)
Laterally
2 layers fuse
Continues with Fascia transversalis
Medially
Anterior layer-fuse with aorta & IVC
Posterior layer-fuse with fascia covering Psoas & Quadratus lumborum
Forms a septum
4. Paranephric fat
Variable amount of fat lying outside the renal fascia
Fills up the paravertebral gutter, forming a cushion for the kidney
3
▪Structure
Renal pyramids – Conical masses in the medulla
Apices of the pyramids form the renal Papillae which indent into minor calyces
Cortical Arches– Form the caps over the pyramids
Renal columns – Dip in between the pyramids
A lobe of the kidney– Each pyramid along with the overlying cortical arch
Renal sinus – Space extending into kidney from the Hilum, containing
 Renal artery – branches
 Renal vein – tributaries
 Renal pelvis ( Major calyces Minor calyces Papillae)
Hilum – A deep vertical slip on the medial aspect of the kidneys extending to the renal sinus
Level – L1 lower border [Transpyloric plane]
Renal V, A, P and Lymphatics and Nerves travel through this
 Blood supply
Supply each vascular segment
Venous drainage Arterial supply [END ARTERIES]
But their corresponding veins
IVC Aorta communicate with each other
RENAL
Segmental SEGMENTAL A. (5)

lobar
LOBAR A.
INTERLOBAR
Arches over pyramid bases
ARCUATE At right angles to interlobar A
At corticomedullary junction
INTERLOBULAR
AFFERENT ARTERIOLES Ascends in cortex radially

at right angles to Arcuate A
GLOMERULUS [END ARTERIES]
EFFERENT ARTERIOLES
PERITUBULAR CAPILLARIES
 Renal arteries leave the abdominal aorta at right angles to it at L2 level

 They lie behind the pancreas and renal veins
Posterior division Posterior segment
 Renal artery
Apical segment
Upper segment
Anterior division
Middle segment
4 Lower segments
Lymphatic Drainage
Into para aortic nodes- L2 level
Nerve Supply
 Sympathetic – from T12 to L1
 Pain may be referred to back and lumbar region which may radiate to anterior abdominal wall and down to
the external genitalia
▪Clinical
1. Kidney exposure from behind

Skin
Superficial fascia
Posterior layer of TLF [Thoraco-Lumbar fascia] with
Latissimus dorsi
Erector spinae
Middle layer of TLF
Quadratus lumborum
Anterior layer of TLF
 Costodiaphragmatic recess –
 an important posterior relation
 Risk of entering it during lumbar approach to kidney
2. Renal angle – Angle between 12th rib-lower border & erector spinae-outer border
▪Enlarged kidney – Lower pole bimanually palpated, on deep inspiration
3. Perinephric Abscess – Blood from ruptured kidney or pus

▪ Can’t cross to opposite side – prevented by the fascial septum
▪ Can descend in to the pelvis – along the covering of ureter
4. In Renal Failure –
o Kidney Transplantation – In recipient’s pelvis
o Peritoneal dialysis or hemodialysis
5. Polycystic kidney – Leads to hypertension

o In children => Autosomal Recessive – Form from collecting ducts
o In Adults => Autosomal Dominant – Form from all segments of the nephron
6. Nephroptosis
5
Ureter
 Extraperitoneal throughout
 25cm
 Whitish non pulsatile cord which shows peristaltic
activity when gently pinched with forceps.
Constrictions
1. Pelvi-ureteric junction
2. Pelvic brim
3. Point of crossing of the ureters by the
ductus deferens/ ligamentum teres.
4. Passage through the bladder wall
5. At its opening at the latera angle of
the trigone.
▪ Course
1) Abdominal part
 Begins within renal sinus=renal pelvis
 Renal pelvis lies along medial border of kidney behind it
 At lower pole it becomes ureter proper
 Lies on psoas major, underneath the peritoneum
 Crosses in front of the genitofemoral nerve
 It descends in front of tips of transverse processes of L2-L5
Crossed By [Anteriorly]
Right Both Sides Left
rd
3 part of Duodenum Gonadal vessels Left colic
Right colic Genitofemoral N. [Posteriorly]
Ileocolic
Root of the mesentery of small intestine
2) Pelvic part
 Passes anterior to the bifurcation of the common Iliac A.
o At pelvic brim + In front of Sacroiliac jnt. + Level of lumbosacral disk
o Left side – In the Intersigmoid recess [Under the apex of sigmoid mesocolon]
 Goes along the curvature of greater sciatic notch & anterior to internal Iliac A.
 Reaches ischial spine & turns forwards & medially
6
MALE FEMALE
Crossed By - [Superiorly from lateral to medial]
Ductus deferens Uterine artery
Lies - [Superior to]
Seminal vesicles Lateral fornix of vagina
o Posterior –
 Sacroiliac joint
 Lumbosacral trunk
 Internal iliac vessels
o Lateral –
 Obturator internus and fascia
 Obturator nerves and vessels
 Superior vesical arteries
 Inferior vesical veins
 Posterior border of ovarian fossa
3) Intravesical part
 Enters the bladder at an acute angle
 Obliquity of the course produces a sphincteric function
4) Nerve supply
- Sympathetic => T10 to L1 Parasympathetic => S2 to S4 (pelvic splanchnic)
5) Blood Supply
 Segmental blood supply
 Upper end – ureteric branch of renal artery
 Middle – abdominal aorta, gonadal, common iliac, internal iliac
 Lower end – superior and inferior vesical, uterine artery
Clinical
1. Ureteric Stones [Calculus]
- Lodge in constricted sites of ureter
- Renal [Ureteric] Colic => Due to spasm of the ureter
Severe pain – radiates from loin to groin, referred to testis
- In X-rays =>
 Postero-Anterior View - Ureteric stones – At the tip of transverse processes of lumbar vertebra
 Lateral view - Ureteric + Kidney stones – On the body of vertebra
GB stones – Anterior to the body of vertebra
7
Supra renal gland
 Lies antero-superiorly to each kidney

 Lies within its own compartment formed by renal fascia
 Shape –
 Right – pyramidal
 Left - crescentic
Two parts
- Cortex -- mesodermal origin
- Medulla (1/10 of gland)-- neural crest origin
 Right supra renal gland apex related to bare area of liver. It is overlapped medially by the inferior vena cava.
 Blood supply
o Arterial supply
 Superior suprarenal artery– from inferior phrenic artery
 Middle suprarenal artery – abdominal aorta
 Inferior suprarenal artery- renal artery
o Venous drainage
 Right suprarenal vein– to IVC
 Left suprarenal vein – left renal vein
 Lymph Drainage
To para aortic lymph nodes
 Nerve Supply
Preganglionic sympathetic fibers from splanchnic nerves via coeliac plexus
8
PELVIS
1. Bony Pelvis formed by 4 bones united by 4 joints
 2 hip bones anteriorly by pubic symphysis (2ry cartilaginous joint)
 Sacrum & coccyx by sacrococcygeal joint
 Sacrum & 2 hip bones each side by 2 sacroiliac joints
2. Bony pelvis is divided into true pelvis & false pelvis by,
Pelvic brim (pubic crest, pectinate line of pubis, arcuate line of ilium, ala & promontory of sacrum)
3. The plane of the pelvic brim is oblique, lying at 600 with the horizontal plane (the vagina lies in the same plane)
4. Pelvic floor slopes downwards and faces forwards (so that the anterior superior iliac spine (ASIS) and the upper
border of the pubic symphysis lies in the same coronal plane)
True pelvis
Superior ASIS
aperture
Pelvis False pelvis Head of Ischial spine
the femur
Inferior Perineum
aperture
Upper border of
pubic symphysis Apex of Tip of the
greater coccyx
Boundaries of true pelvis trochanter
1. Upper border of pubic symphysis
2. Pubic crest
3. Pubic tubercle
Pelvic
4. Pectineal line
inlet
5. Arcuate line
6. Sacroiliac joint
7. Sacral promontory
1. Lower border of pubic symphysis

Pelvic 2. Ischio-pubic rami
outlet 3. Ischial tuberosity
4. Sacrotuberous ligament
5. Coccyx

Stability
Joint Bony factors Ligamentous factors

1.Lumbosacral Widely spaced inferior Strong iliolumbar ligament (prevents forward
Articular disc is very thick; articular processes of L5 movement of sacroiliac joint)
thickest anteriorly  From – transverses process of L5 to iliac crest
Lumbosacral ligament
 From – transverse process of L5 to ala
2. Sacroiliac joint Interlocking articular Thick & strong interosseous ligament
Anterior, interosseous, surfaces Vertebro pelvic ligaments (Iliolumbar, sacrotuberous,
posterior sacroiliac ligaments sacrospinous ligaments)
Sex differences
 Due to easier passage of fetal head in labor
 female bones are more slender than male bones
Identify the sex from a X –ray by the shadow of the penis

Obstetrical Pelvic measurements
1. Transverse diameter of the outlet- distance between the ischial tuberosities along a plane of the anus
2. Anteroposterior outlet diameter-distance from the pubis to the sacrococcygeal joint.
3. Diagonal conjugate—from the lower border of the pubic symphysis to the promontory of the sacrum.
4. Finger of the examiner should not reach sacral promontory in vaginal examination
Clinical
Caudal anesthesia
The sacral hiatus, between the last piece of sacrum and coccyx - entered by a needle which pierces skin, fascia
and the tough posterior sacrococcygeal ligament to enter the sacral canal.
Pelvic fascia
 Parietal pelvic fascia on the pelvic surface

on Obturator Internus with periosteum at
the upper margin of the muscle.
 The sacral anterior primary rami emerging
from the anterior sacral foramina lie
behind the Piriformis fascia.
 Internal iliac vessels, are in front of the
fascia over the Piriformis; but large
(presacral) lateral sacral veins lie initially
behind this fascia as they emerge from the
anterior sacral foramina.
Pelvic muscles
Piriformis
 Origin – front of the middle 3 pieces of its own half of the sacrum
 Sacral plexus and sacral nerves lie on the muscle
 Pelvic surface of the muscle and sacral plexus are covered by pelvic fascia.
Obturator Internus
 Origin – from the whole Obturator membrane and from the bony margins of the foramen
 Leaves the pelvis through the lesser sciatic foramen; makes a 90° bend around the ischium between the
ischial spine and ischial tuberosity.
Postanal plate/anococcygeal ligament/median fibrous raphe

 Layered musculotendinous structure between the anal canal and the caudal part of the vertebral column, on
which the terminal rectum sits.

Pelvic diaphragm
Levator ani
 Nerve supply from the S4 sacral nerve & inferior rectal nerve
 Arises from the posterior aspect of the body of the pubic bone, the fascia of the side wall of the pelvis
(thickening of obturator internus fascia/white line) and the spine of the ischium.
 Contain 2 parts
1. Pubococcygeus
 Levator prostate/Sphincter vaginae
o Anterior fibers
o form a sling around the prostate/vagina
o In both sexes, fibers also attach to the perineal body
 Puborectalis
o Middle fibers
o form a sling around the rectum and also insert into deep part of the longitudinal muscle
coat of the anal sphincter at the anorectal ring
 Pubococcygeus proper
o Posterior fibers
o Attached to the sides of the coccyx and to the median fibrous raphe, which stretches
between the apex of the coccyx and the anorectal junction.
2. Iliococcygeus
o posterior half of the white line & ischial spine
Coccygeus (3. Ischiococcygeus part of pelvic diaphragm)

 Arises from ischial spine & sacrospinous ligament and insert to the side of the coccyx and the lowest piece of
the sacrum.
 Nerve supply from S3 & S4 sacral nerves
Actions
1. Acts as the principal support of the pelvic floor
2. Has a sphincter action on the rectum and vagina.
3. Assists in increasing intra-abdominal pressure during defecation, micturition and parturition.

Pelvic vessel Superior vesicle artery
 Remnant of Umbilical artery (medial umbilical ligament)
 Adjacent ureter, vas deferens
Obturator artery
 Periosteum of back of pelvis
 Accessory/abnormal obturator artery can arise from the
inferior epigastric artery*
 Crossed by ureter (in the ovarian fossa in females)
Uterine artery
 Uterus, cervix, uterine tube
Anterior  Crossed by ureter 1cm lateral to supra vaginal fornix
Uterine
division
Vaginal
 Upper part of vagina
Inferior vesical
 Trigone, lower bladder, vas deferens
Internal iliac Middle rectal (frequently absent)
Internal pudendal
 Leaves the pelvis through the greater sciatic foramen below the piriformis
 Anal region, external genitalia
Inferior gluteal
 Leaves the pelvis first through S1 & S2 ventral rami & then
through the greater sciatic foramen below the piriformis
Anterior (lateral)
 Psoas, Quadratus lumborum
Lumber branch (5th
lumbar segmental
artery) Posterior
 Erector spinae
Iliolumbar Spinal branch
Iliac branch
 Iliac fossa, iliacus, iliac
bone
Posterior Anastomosis
Lateral sacral around ASIS
division
 Piriformis
Spinal branches
Superior gluteal
5  Leaves the pelvis first through lumbosacral trunk ©2017 A/L Repeat Campaign
& S1 ventral rami & then through the greater
sciatic foramen above the piriformis
Bladder
 Pelvic organ; as the bladder fills, it
domes into the abdominal cavity.
 Trigone of the bladder
o Least mobile part of the bladder
o Mucous layer tightly adhered
Relations
 Empty bladder is tetrahedral (three
sided pyramid) in shape.
 Has an apex, base, neck, superior
surface and 2 inferolateral surfaces.

o Retropubic space (of Retzius) seperates apex from the pubic symphysis – urachus is attached to the
apex.
o Base lies posteriorly
o Superior surface is covered by the peritoneum (distending bladder strips the peritoneum from
behind rectus abdominis, leaving transversalis fascia on the back of the muscle)
o Neck
 In the male; lies against the upper surface or the base of the prostate
 In the female; lies above the urethra in the connective tissue of the anterior abdominal wall
1. Anteriorly - the pubic symphysis, puboprostatic & pubovesical ligaments in the retropubic space
2. Superiorly - the bladder is covered by peritoneum with coils of small intestine and sigmoid colon In the
rectovesical pouch in male. In the female; the body of the uterus flops against its posterosuperior aspect forming
the vesicouterine pouch.
3. Posteriorly - in the male; the rectum, the termination of the vas deferens and the seminal vesicles; separated
from the rectum by denonvilliers’ fascia
in the female; the vagina and the supravaginal part of the cervix (with no peritoneum
intervening)
4. Laterally - the levator ani and obturator internus
 Blood supply; mainly by superior and inferior vesical arteries. Veins do not follow the arteries; instead forms
the vesicoprostatic plexus in the groove between the bladder and prostate, which drain into internal iliac
vein.
 Lymph drainage is mainly into external iliac nodes.
 Nerve supply;
o Sympathetic (vasomotor & inhibitory to Detrusor muscle) – superior and inferior hypogastric plexus
(L1,L2)
o Parasympathetic (motor and sensory) – Pelvic splanchnic nerves
o Trigone is supplied exclusively by sympathetic nerves
Supports of the bladder

1) Lateral true ligament
True ligaments 2) Lateral puboprostatic ligament
(condensation 3) Medial puboprostatic ligament
of pelvic fascia) 4) Urachus
5) Posterior ligament
Ligaments
False 1) Median umbilical fold
ligaments 2) Medial umbilical fold
(condensation 3) Lateral false ligament
of peritoneum)

Perineum
Diamond shaped region positioned inferior to the pelvic diaphragm between thighs at lower
end of the trunk
Inferior border of pubic symphysis
Urethral opening Urogenital Hiatus
Ischiopubic ramus
Vaginal opening Urogenital triangle
Ischial tuberosity
Anal aperture
Sacrotuberous ligament,
covered by inferior border
Anal triangle of gluteus maximus
Perineum boundaries: - Peripheral – Pelvic outlet

Roof – Pelvic diaphragm
Lateral walls – Pelvic cavity walls below the origin of levator ani
Anterior point – inferior border of pubic symphysis

Posterior point – tip of the coccyx
Lateral points – ischial tuberosity
Lateral borders – Anterior – ischiopubic rami
Posterior – sacrotuberous ligament
Anal tringle Urogenital triangle

 Anal canal  External genitalia
 Ischioanal fossae
Cutaneous supply
1. Inferior rectal nerve 1. Ilioinguinal nerve (L1) - anterior third of the
2. Perineal branch of S4 scrotum (labium majus)
3. Twigs from coccygeal plexus 2. Dorsal nerve of penis (clitoris) (S2) – branch of
pudendal nerve
3. Posterior 2/3rd of scrotum
a. Medially – scrotal branches of the perineal
branches of pudendal neve
b. Laterally – perineal branches of the posterior
cutaneous nerve of thigh

Anal triangle
Ischio-anal fossa (Ischio-rectal fossa)
wedge shaped space filled with fat either side of anal canal Below the pelvic diaphragm.
 Base- skin over the anal triangle of perineum

 medial wall – external anal sphincter and levator ani
 lateral wall- Obturator Internus and its fascia below the attachment of levator ani
muscle and ischial tuberosity
 Apex- medial and lateral wall meeting
 Base
 Anterior- posterior border of perineal membrane
 posterior- Sacro tuberous ligament overlapped by lower border of gluteus
maximus
Anterior recesses of Ischioanal fossa
Arrangement of fat lobules Lies above the perineal membrane as far as the
upper part - large lobules perineal surface of body of the pubis
lower part -small lobules
(adjacent to skin)
Clinical
1. Abscesses can be ruptured internally or externally into the anal canal or to the surface of perineum –
anorectal fistula.
2. Ischiorectal fossa acts as a cushion giving support to rectum & anal canal.
3. Anteriorly infection of one space can't communicate across the midline, but posteriorly communicates
through horseshoe shaped path
Pudendal canal
connective tissue tunnel on the lower lateral wall of the ischioanal fossa
splitting of the obturator fascia (fascia

posterior border of the
lesser sciatic foramen lunata) above the falciform process
perineal membrane.
Contents – 1. Pudendal nerve 2. internal Pudendal vessels
arches convexly upwards through ischioanal fossa towards anal canal
inferior rectal branch

Perineal body (Central Tendon of Perineum)
Midline fibromuscular mass attached to the posterior border of perineal membrane

between anal canal and Vagina / bulb of the penis
Attachments: -
 external anal sphincter – unpaired
 pubovaginalis / puboprostaticus of levator Ani.
 Bulbospongiosus Paired
 Superficial transverse perineal muscle
 deep transverse perineal muscle
action: -
stabilizing influence for pelvic and perineal structures
Weakness causes prolapse of the vagina and uterus.
Urogenital Region
Superior fascia of urogenital diaphragm
Deep perineal space (pouch)
Deep transverse perineal muscles

Urogenital diaphragm Sphincter urethrae
+
Membranous part of urethra
pudendal vessels
Inferior fascia of urogenital diaphragm
Perineal Membrane
Anteriorly – anterior free border

 Base of penis and penile musculature are fixed
 transverse perineal ligament
 Horizontal when standing upright
Laterally attached to
 Membrane is pierced by urethra ducts of
 ischiopubic ramus
bulbourethral glands, nerves and vessels
Posteriorly attached to
 centrally perineal body
Pubic arcuate ligament
deep dorsal vein of penis Vasicoprostatic venous plexus
Transverse perineal ligament

Deep perineal space
Boundaries Male Female
Superficial Perineal membrane Same
Deep Superior fascial layer of urogenital diaphragm Same
Laterally Ischiopubic rami Same
Posteriorly Closed by fusion of superior & inferior fascia Same
of urogenital diaphragm
Anteriorly Closed by fusion of superior & inferior fascia Same
of urogenital diaphragm
contents ●membranous Urethra ●Urethra, vagina
●Deep perineal muscles ●Same
●Bulbourethral glands ●no glands
●Nerves( branches of pudendal nerve) ●Same
Superficial perineal space

Boundaries Male Female
Superficial Colles fascia Same
Deep Perineal membrane Same
Laterally Ischiopubic rami Same
Posteriorly Closed by fusion of the colles fascia Same
& the perineal membrane
Anteriorly Continuous with spaces of scrotum, Continuous with spaces of clitoris,
penis, anterior abdominal wall anterior abdominal wall
contents ●Root of penis with urethra ●Clitoris, urethra & vagina
●Superficial perineal muscles ●bulbospongiosus unfused
●No glands ●Greater vestibular glands
●Nerves (branches of perineal bran ●Same
ch of pudendal nerve)
Superficial perineal fascia of Colles

Continuation of the Scarpa’s fascia of anterior abdomen wall
attached → ischiopubic rami and post margin of the perineal membrane
 encloses superficial perineal space
bulbous scrotal expansion (dartos fascia) cylindrical penile expansion (buck’s fascia)
attached round the corona of the glans penis

Pudendal nerve Branches –
Pudendal nerve 1. Inferior rectal nerve
2. Perineal nerve
Origin -anterior primary rami of S2,3,4
3. Dorsal nerve of penis or clitoris
Course –
o 3 parts- pelvic region, gluteal region, ischiorectal
fossa
3
o leaves pelvis through greater sciatic foramen
below piriformis
o to enter gluteal region 2
o crosses dorsum of ischial spine
o relations in gluteal region - PIN
o through the lesser sciatic foramen, enters into
pudendal canal 1
o travels along lateral wall of ischiorectal fossa
o accompanied by internal pudendal vessels
Clinical
Pudendal nerve block Inferior rectal nerve
Needle passes through
vaginal wall to ischial
spine guided by finger
OR
Just medial to ischial
tuberosities

Internal Pudendal Artery
In the pudendal canal
Inferior Rectal artery

Enters the deep perineal pouch and
runs along the ischiopubic ramus.
Pierce the perineal membrane

at the posterior angle.
Perineal Artery Artery to the bulb

Corpus spongiosus
Anterior Anastomose at
Transverse Posterior
margin of
scrotal artery Glans penis
perineal artery perineal
membrane
Deep artery of the penis Dorsal artery of the penis
Enter the crus Between crus and pubic

symphysis to pierce
suspensory ligament
Helicine arteries
Skin, fascia of penis
Supply cavernous
 Inferior Rectal Artery-

At the pudendal canal arches over in the ischiorectal fossae.

Female reproductive system
1. Uterus
▪ Peritoneal attachments
1. Anterior ligament or uterovesical fold
2. Posterior ligament or rectovaginal fold
3. Two broad ligaments
Mesovarium-ovary to posterior layer
Mesosalpinx - part between ovarian ligament & uterine tube
Mesometrium- part below ovarian ligament
4. Suspensory ligament of ovary
▪Supports of the uterus
1. Broad ligament
Primary Secondary 2. Uterovesical fold
3. Rectovaginal fold
Fibromuscular Muscular
1. Uterine axis 1. Pelvic diaphragm

2. Pubocervical ligament 2. Perineal body
Cervix to pubis 3. Distal urethral sphincter
3. Round ligament of uterus mechanism
4. Transverse cervical ligament
Cervix to lateral
pelvic wall

 angle of anteversion Is kept by round ligament & uterosacral ligament
 sphincter vaginae of pubococcygeus is partially inserted into perineal body

so it supports as well as forms a sphincter.
Structure
 Muscular organ responsible for the protection & nourishment of fertilized ovum so
that it can develop into a full-term fetus.
 Pear shaped
 Possess 3 parts
o Fundus o Body o Cervix
FUNDUS
 convex upper end of uterus

 Above the entrance of uterine tubes
 Covered by peritoneum

BODY
Consists of anterior & posterior surfaces & lateral borders

Anterior surface
 Flat
 Related to superior surface of bladder
 Covered by peritoneum
 Forms posterior & superior walls of vesicouterine pouch
Posterior surface
 Directed upwards
 Related to coils of terminal ileum & sigmoid colon
 Covered with peritoneum & forms rectouterine pouch posterior to it
Lateral borders
 Provide attachment of uterus to the side walls of the pelvis
 Uterine tubes open into the uterus at the upper end of this border
 Anteroinferior to the opening of uterine tubes is the round ligaments
 Posteroinferior to the opening is the ligament of the ovary
 Uterine cavity occupies the body & is triangular shaped
 Apex is directed downwards & is continuous with the cervical canal via the internal
os.
CERVIX
 Lower cylindrical part of the uterus
 Projects into the vault of the vagina
 Contains two parts
1. Supravaginal part
 Related anterior to bladder
 Posteriorly to rectouterine pouch
 Lateral to it are the ureters
 Uterine artery between layers of the broad ligament
2. Vaginal part
 Projects into vagina
 A deep sulcus is formed around (fornices of the vagina)
 Cervical canal opens to the vagina through the external os

▪ Site of implantation posterior wall of fundus
Ureter runs forwards slightly above the lateral fornix of vagina and is 2cm lateral to
supravaginal part of cervix
Uterine artery crosses ureter superiorly at right angles from lateral to medial
▪ Clinical
- In hysterectomy ureter can be divided in the process of clamping uterine artery
- The only site where a ureteric stone can be palpated is where the ureter relates to
supravaginal cervix
2. Ovaries
 Situated in ovarian fossa of lateral pelvic wall
 Has 2 poles; upper and lower.
 Has 2 borders; anterior or mesovarian border and posterior border.
 Has 2 surfaces; medial and lateral.

 Relations
Boundaries of ovarian fossa
Ant – obliterated umbilical artery, external iliac vessels
Pos - Internal iliac vessels, ureter
Obturator nerve lies laterally
Peritoneal relations
 Mesovarium – attaches anterior border of ovary to broad ligament
 Suspensory ligament of ovary – from ovary to lateral pelvic wall
 Ligament of ovary – lower pole of ovary to lateral angle of uterus
3. Uterine tubes
- form a connection between abdominal & uterine cavities
Infundibulum – mouth is fimbriated
Ampulla (lateral 2/3rd) – widest
Isthmus (medial 1/3rd)
Intrauterine/ Interstitial part – narrowest
 Only the lower pole and the lateral surface of the ovary are not related to the
uterine tube. The remaining 2 borders, upper pole and medial surface are related
to the tube.
- Clinical
Blockage of uterine tubes – commonest cause for female sterility
Rubin’s test
Hysterosalpingography
4. Vagina
 Fibromuscular tube
 Extends from vaginal orifice within vestibule
 Upward & backwards towards uterus
 Passes through pubovaginalis, deep perineal pouch & the perineal membrane
 Expanded upper end has uterine cervix projected into it
 Circular groove in the vagina around uterine cervix is fornices
 4 fornices
 Anterior –shallowest, posterior-deepest & 2 lateral
 Below the cervix anterior & posterior walls of vagina lie within contact with each
other to form a H shaped slit
 Lower end of vagina is covered by a thin fold called hymen in virgins, in married
women replaced by tags called hymen caruncles
▪Relations
Ant 1. Base of bladder (upper half)
2. Urethra embedded in anterior wall (lower half)
Post (above downwards)
▪ant wall of vagina >1.Pouch
pos wallof Douglas (in upper 1/4th)
th
▪ ant wall of vagina >2.pos
Rectum
wal (in middle 2/4 )th
3. Anal canal (in lower 1/4 ) [separated by perineal body]
Lat 1. Transverse cervical ligament (upper 1/3rd)
2. pubovaginalis muscle (middle 1/3rd)
3. Bulb of vestibule, bulbospongiosus & ducts of greater vestibular
gland (lower 1/3rd – after piercing perineal membrane)
▪ per vaginal examination
1. Anterior & posterior relations are palpable
2. Ureteric stones
3. Ovary, uterine tubes, side of pelvis is felt laterally
4. Collection of fluid, prolapsed uterine tubes, ovaries & distended bowel in pouch of Douglas
Arterial Supply
1. Ovarian Artery
 Arises from the abdominal aorta, just below the renal artery.
 Descends over the posterior abdominal wall & enters the suspensory
ligament of the ovary.
 Supplies the ovary through the mesovarium & continues medially through
the broad ligament to anastomose with the ovarian artery.
 Also supplies the lateral 1/3rd of the uterine tube, the side of the uterus &
ureter.
2. Uterine artery
 Branch of the anterior division of the internal iliac artery.
 First passes medially across the pelvic floor in the base of the broad
ligament to reach the cervix.
 Crosses the ureter above the lateral fornix of the vagina, 2cm lateral to the
fornix.
 Ascends along the side of the uterus, with a tortuous course.
 Runs laterally towards the ovary & ends by anastomosing with the ovarian
artery.
 Also supplies the medial 2/3rd of the uterine tube, vagina, ovary, ureter &
structures in the broad ligament.
 The vagina is supplied mainly by the vaginal branch of the internal iliac artery. In
addition,
 Upper part - Uterine artery
 Lower part - Middle rectal & uterine artery

Venous Drainage
Nerve Supply
 Lower 1/3rd of the vagina is pain sensitive & supplied by the pudendal nerve
through the inferior rectal & posterior labial branches of the perineal nerve.
 The rest has a sympathetic & parasympathetic supply
 Parasympathetic supply for the ovaries, medial half of the uterine tubes, uterine
tubes and vagina is by the nerve rots S2 – S4
 Lateral halves of the uterine tubes are supplied by the vagus nerve.
1. Ovary
 Supplied by the ovarian plexus
 Sympathetic supply is by T10/ T11
2. Uterine tubes
 Supplied by the hypogastric plexuses
 Sympathetic supply is by T10 – L2
3. Uterus
 Supplied by the inferior hypogastric plexus & the ovarian plexus.
 Sympathetic supply is by T12 – L1

 Pain in the body of the uterus is transmitted along the sympathetic
nerves.
 Pain in the cervix is transmitted along the parasympathetic nerves.
4. Vagina (upper 2/3rd)

 Supplied by the inferior hypogastric & uterovaginal plexuses.
 Sympathetic supply is by L1/L2
 Pain insensitive
Lymph Drainage
 The lateral 2/3rd of the uterine tubes drain into the lateral & preaortic nodes.
 The medial 1/3rd of the uterine tubes drain into the superficial inguinal nodes
following the course of the round ligament.
Vagina
 Upper 1/3rd - External iliac nodes
 Middle 1/3rd - Internal iliac nodes
 Lower 1/3rd - Superficial inguinal nodes

External Genitalia
1. Regarding the vagina

a) Anterior wall is related to the base of the bladder.
b) Lymph from upper part drains into the internal iliac nodes.
c) Internal surface is lined by pseudostratified columnar epithelium
d) has no glands in lamina propria
e) posterior fornix is shallow
2. Cervix of the uterus

a) Triangular in shape.
b) Directly overlies the superior surface of the bladder without in between peritoneum.
c) Uterine arteries are laterally related.
d) Supported by transverse ligament.
e) Supplied by the vaginal artery.

Male reproductive system
External genitalia Internal genitalia
▪ Scrotum ▪ Epididymis
▪ Testis ▪ Ductus deferens
▪ Penis ▪ seminal vesicle
▪ Prostate
▪ Ejaculatory duct
External genitalia
1. Scrotum- a cutaneous bag containing testes, epididymis, and lower part of vas deferens layers
 Skin
 Superficial fascia/Dartos muscle
 External spermatic fascia - from external oblique muscle
 Cremasteric fascia - from internal oblique
 Internal spermatic fascia - from fascia transversalis
Clinical
Scrotum is supplied by widely separated dermatomes (L1 & S3)
So whole scrotum is difficult to anesthetize
2. Testis –male gonad

Suspended by the spermatic cord obliquely, upper end tilted forward and laterally
Oval shaped
Epididymis lies along the lateral part of posterior border
Medial surface of epididymis is separated from testis by sinus of epididymis (extension of tunica
vaginalis)
Coverings: - Covered by the layers of the scrotum and in addition by;
Tunica vaginalis (parietal & visceral layers)
Tunica albuginea
Tunica vasculosa
 Tunica Vaginalis –lower persistent portion of the processus vaginalis

Has a parietal & a visceral layer with a cavity in between
Covers the whole testis except for its posterior border

 Tunica Albuginea- Dense white fibrous coat
Cover testis all around
Posterior border is thickened to form mediastinum testis
Septa from mediastinum to inner divide the testis into lobules
 Tunica Vasculosa- Innermost vascular coat of the testis

Line the lobules
The glandular part of the testis consists of lobules which contains seminiferous tubules.
 Seminiferous tubules Rete testis Efferent ductules Epididymis
 Arterial supply - testicular artery
 venous drainage - pampiniform plexus of veins
Clinical
1. Referred pain: - loin
2. Varicocele: - dilation of veins in pampiniform plexus
mostly left side. Why??
 Left testicular vein drains in to left renal vein at right angle 
 Tumour of the left kidney can invade left renal vein & block the drainage of left testicular vein 
 Left renal vein put into spasm by adrenalin rich blood by suprarenal vein 
 Pressure of the superior mesenteric artery 

3. Undescended testis fails to descend into scrotum
 May rest anywhere along its course to scrotum intra abdominally
 Inguinal canal
 External ring
 Malignancies are more prone to occur in undescended testis
4. Ectopic testis
 Testis remain in a site other than its normal course
 Abdomen
 Perineum
 Upper thigh
 Femoral canal
 Penis
 The testis is fully developed. Usually accompanied by indirect inguinal hernia
5. Hydrocele
 Condition where fluid accumulates in the processus vaginalis of peritoneum
3. Penis
Made up of
 A root (attached portion)
 Body (free portion)
▪ Root
Made up of 3 masses of erectile tissue:
 two crura – covered by ischiocavernosus muscle
 bulb - covered by bulbospongiosus muscle. The deep surface is pierced by the urethra.
▪ Body
Composed of three elongated masses of erectile tissue;
 Right and left corpora cavernosa- Forward continuation of the crura. They terminate
under the cover of the glans penis.
 Corpus spongiosum- This is the forward continuation of the bulb of the penis. Its terminal part
enlarges to form the glans penis. Traversed by the urethra throughout the whole length.

Supports of penis
Fundiform ligament Suspensory ligament of penis

(Continuation of linea alba) (Formed by Scarpa’s fascia & attached to the pubic symphysis)
 Arterial Supply

Male urethra
▪20cm long
▪3 parts
1. Prostatic urethra [3cm]
Posterior wall contains
o Urethral crest
o Colliculus seminalis (verumontanum) – prostatic utricle opens here
o Prostatic sinus- openings of prostatic glands
2. Membranous urethra [2cm]

Surrounded by external urethral sphincter
3. Penile urethra [15cm]

Dilated at commencement- Intrabulbar fossa
Within glans penis – Navicular fossa
Clinical
1. Catheterization – catheter should be introduced into the urethra beak downwards???
Roof of navicular fossa bears a mucosal fold called lacuna magna. It is directed forwards and can
catch the tip of catheter.
2. Urethral rupture- In damage to spongy part of urethra, urine does not extravasate into;
a) Thigh
b) Ischiorectal fossa
Urine passes into;
a) Scrotum
b) Penis
c) Lower part of abdomen
Because the attachment of membranous layer of superficial fascia.
 Holden’s line (just below the inguinal ligament, Scarpa’s fascia joins the inguinal ligament,
preventing urine leakage into the thigh)
 Pubic tubercle
 Body of pubis
 Pubic arch
 Posterior border of perineal membrane

Membranous layer of abdomen continuous in to the perineum as the Colle’s fascia
Internal genitalia
1. Epididymis
 Organ made of a highly coiled tube
 Three parts
o Head
o Body
o Tail (inferiorly)
 Lies on the lateral part of posterior border of testis
 Supplied by branches of the testicular artery
2. Ductus deferens
 45cm long thick-walled muscular tube
 Originates from the tail of epididymis
 Ascends along posterior border of testis medial to epididymis
 Enters the spermatic cord.
 Traverses the inguinal canal within spermatic cord
 At deep inguinal ring winds around inferior epigastric artery
 Along its course in the pelvic wall it is crossed by the obturator vein, artery, nerve and
obliterated umbilical artery and the ureter
 Crosses the ureter and approaches its opposite from the other side
 Turns medially to base of bladder
 Medial to seminal vesicles and dilate to form ampulla
 Ampulla is joined by duct of seminal vesicle to form the ejaculatory duct and
 Open in to the prostatic urethra at the verumontanum on either side of utricle

3. Seminal vesicles
 Lies on each side extra peritoneally at the bladder base, between the bladder and the rectum
at termination of ductus deferens.
4. Prostate gland
 Pyramidal shape fibromuscular gland
 Apex lies inferiorly
 Five lobed
 The prostatic urethra emerges just in front of the apex. Base directed upwards and fused
with the neck of the bladder.
 Relations
 Superiorly- neck of bladder
 Inferior – apex rests on urogenital diaphragm
 Anterior – pubic symphysis separated by retropubic fat
Prostatic venous plexus
Puboprostatic ligament
 Posterior – Rectum (Separated by Denonvillier’s fascia)
 Lateral – Levator ani
 Capsules
 TRUE capsule :- condensation of peripheral part of gland
 FALSE capsule :- endopelvic fascia
o Prostatic venous plexus lies between two capsules
 Zones
- Peripheral zone - 70% of glandular tissue. Located behind the central zone.
- Central Zone – 20% glandular tissue. Forms the base of the gland. Surrounds the ejaculatory
ducts.
- Transistional zone - 5% of glandular tissue. Lies around the distal part of the pre- prostatic
urethra.
 Blood supply:
Supplied by the artery to the ductus deferens.
Venous drainage is to the venous plexus situated between the false and the true capsules.
Clinical
1. Pathological capsule
Benign prostatic hypertrophy
Normal peripheral part of the gland become compressed into the capsule.
2. Prostatic venous plexus has valve-less communications with vertebral venous plexus
Carcinoma of prostate may spread to pelvic bones, vertebrae & to skull
● deep dorsal vein of penis also drains in to the prostatic venous plexus
3. Denonvillier’s fascia
In excising rectum, the plane passes through this without damaging prostate &
urethra and acts as a barrier to prevent spread of carcinoma of prostate into
the rectum.
4. Prostatectomy
Both true & false capsules are left with venous plexus

5. Prostatic cancer
o Occurs mainly in the peripheral zone.
o The cancer may spread to the vertebral column through the vertebral venous plexus due to
the valve-less communications between the prostatic venous plexus and the internal
vertebral venous plexus.
6. Benign prostatic hyperplasia

Occurs due to enlargement of the transitional zone. Causes obstruction of the prostatic
urethra and inability of passing urine. Trans-urethral resection of the prostate is performed
Lymphatic drainage of male reproductive system

Penis (skin)
Superficial Inguinal nodes
Scrotum
Deep inguinal nodes

Glans penis
Vas deferens &

seminal vesicles
External & internal illiac nodes
Prostate
Preaortic & Para-aortic

Testis

RECTUM AND ANAL CANAL
Rectum
 Continuation of sigmoid colon at the level of S3

 from the rectosigmoid junction to the anorectal
junction
 12cm long
 In front of lower 3 pieces of sacrum and coccyx
 No taenia coli, sacculations, appendices
epiploicae
 Lower part is dilated to form the rectal ampulla
 Direction of the rectum
 Downwards & backwards → Downwards →
 Downwards & forwards
 Shows lateral and antero-posterior curvatures
 3 lateral curvatures which are convex to,
 Right
 Left Due to mucosal folds
 Right
 2 Antero-posterior curvatures
a) Sacral flexure - due to concavity of
sacrum and coccyx.
b) Perineal flexure - due to backward bend
at the anorectal junction.
Relations
 Peritoneal relations
 upper 1/3rd front and side
 middle 1/3rd only the front
 lower 1/3rd below the level of peritoneum
 visceral relations
 Posterior - [female, male similar]
 Waldeyer’s fascia
 Sacrum, coccyx
 Median sacral, superior rectal vessels
 Sympathetic trunk
 Anterior - [Male]
 Denonvilliers’ fascia
 Upper 2/3 - recto vesical pouch
 Lower 1/3 - base of bladder
Ductus deferens
Seminal vesicles
1
 Anterior - [Female]
 Denonvilliers’ fascia
 Upper 2/3 - rectouterine pouch
 Lower 1/3 - lower part of vagina
 Supports
1) Pelvic floor by levator ani
2) Waldeyer’s fascia
 Condensation of pelvic fascia behind the rectum.
 Attaches the lower part of the rectal ampulla to the sacrum.
 Encloses superior rectal vessels and lymphatics.
3) Lateral ligaments of rectum
4) Rectovaginal fascia of Denonvilliers’
5) Perineal body
Anal Canal
 Terminal part of the GI tract.

 Below the level of the pelvic diaphragm.
 Lies in the anal triangle of the perineum between the right and left Ischio-anal fossae.
 Length 4cm
 From anorectal junction to anus.
 Anorectal junction is marked by the forward convexity of the perineal flexure.
Relations
 Anteriorly
 In both sexes → Perineal body
 In males → Membranous urethra & bulb of the penis
 In females → Lower end of vagina
 Posteriorly
 Anococcygeal ligament
 Tip of the coccyx
 Laterally
 Ischio-anal fossae
 All around
 Sphincter muscles
2
Musculature of the Anal canal
1) External anal sphincter

 Voluntary
 3 parts -
 Subcutaneous
 Superficial
 Deep
 extends throughout the anal canal

(surrounds the whole length of the
anal canal)
 nerve supply - Perineal branch of S4
2) Internal anal sphincter

 Extends from upper end of anal
canal to white line of Hilton.
 Formed by the thickened muscular coat of this part of gut.
 Surrounds the upper ¾ of the anal canal.
 Involuntary
Anorectal ring
Muscular ring formed by puborectalis, deep external sphincter & internal sphincter
Main support of rectum.
3
Blood supply of the rectum and anal canal
Arterial supply
a) Superior rectal artery

 Divide into right and left branches opposite S3
 Runs on each sides of rectum
 Pierce the muscular coat and runs in the anal columns up to anal valves
 Form looped anastomoses
b) Middle rectal artery
c) Inferior rectal artery
Venous drainage
 Major site for

portosystemic
anastomoses
Clinical
Hemorrhoids
 Hemorrhoids (piles) are dilatations of

the superior rectal veins.
a) 1st degree - contained within the
anal canal
b) 2nd degree - prolapse on defecation
c) 3rd degree - remain prolapsed
through the anal orifice
4
Per rectal examination
 Finger directed towards umbilicus
Normal
 both sexes - the anorectal ring, coccyx and sacrum, ischiorectal fossae, ischial spines
 male - prostate, rarely the healthy seminal vesicles
 female - perineal body, cervix, the ovaries.
Abnormalities which can be detected

 within the lumen - fecal impaction, foreign bodies
 in the wall - rectal growths, strictures, granulomata
 outside the rectal wall - pelvic bony tumors, abnormalities of the prostate or seminal
vesicle, distended bladder, uterine or ovarian enlargement, collections of fluid or neoplastic
masses in the pouch of Douglas.
HEMORRHOIDS CAN’T BE DETECTED UNLESS THEY ARE THROMBOSED
Anal fissure
 Caused by the rupture of one of the anal
valves by passage of dry hard stool.
Anal fistula
 Fistula is an abnormal epithelialized track
connecting two cavities or one cavity with
the exterior.
 Anorectal abscess tends to track in
various directions and may open
 medially into the anal sinus
 laterally into the ischio-anal fossa
 inferiorly at the surface
 superiorly into the rectum
5
GIT
Mouth
Saliva - Composition
A. Water
Lingual lipase # FA + 1,2 DAG #glands of the tongue
B. Enzyme # Active in stomach
# can digest up to 30% of dietary TAG
Salivary α amylase (optimal pH 6.7) #salivary glands
Function stops in the stomach
C. Mucin – lubricates food, protects oral mucosa

D. Immunological factors - IgA ---
defense against bacteria and virus
Lysozyme ---
destroy bacterial cell wall
Lactoferrin ---
bind Fe (bacteriostatic)
Proline rich proteins ---
Bind toxic tannins Salivary glands
Protect enamel
Parotid 20%
E. Blood group antigens (only ABO)
Submandibular 70%
Gland to gland
Sublingual 5%
F. Inorganic ions Vary from
Rest/active period
*1500ml per day
*HCO3- neutralizes acid regurgitated into oesophagus When active Parotid
is highest
Salivary secretion
Active Rest
K+, HCO3- NaCl Rate ↑ Rate ↓
Never become
Tonicity ↑ Tonicity ↓
Iso/hypertonic Iso. Hypo. (since
reabsorption is
less)
* As the ducts are relatively impermeable to H2O NaCl ↑ NaCl ↓
K+ ↓ K+ ↑
pH ↓ pH ↑
**Aldosterone increases K+ and decreases Na+ in saliva
 Control of salivary secretion
Nausea Conditional
Sight, smell & thought of food.
Reflex Food in mouth/ chewing
Secretion
Vagal afferents from gastric end of
esophagus
Neural control
Fear +
Sleep Sympathetic Parasympathetic
(VII, IX cranial nerves)
Fatigue
vasoconstriction Vasodilatation
Dehydration ↓ amount ↑ amount
↑ organic ↓ organic
Fear
 Problems related to impaired salivary secretion
(1) Dry mouth
(2) Difficulty in swallowing
(3) Bad smell (Halitosis)
(4) Dental caries
(5) Speech difficulty
Oesophagus
Two sphincters
1. upper - Functionally less important (normally closed by continuous contraction of
cricopharyngeus) 1.Oesophageal smooth muscles
2. lower – tonically active, Relaxes upon swallowing, made of 2.Crural fibers of the diaphragm
Prevent regurgitation (heart burn, strictures) 3.Oblique muscle fibres of stomach
Tone -↑ Ach, ↓ NO, VIP
Resting pressure is approximately 15mmHg; higher than the intragastric pressure
*One of the very few instances where

Ach contracts sphincters.
Clinicals,
 GERD
o Permits reflux of gastric contents into esophagus, making symptoms such as heartburn and
esophagitis.
 NG tube insertion
 Achalasia – LES is always tight – Results in food accumulation and oesodilation
Swallowing
 Is a reflex
Stimulus Food in the mouth 3 phases

1.oral (voluntary)
Receptors Pharyngeal receptors 2.pharyngeal (Principally a reflex)
3.oesophageal
Afferents Vth, IXth, Xth cranial nerves
Centre NTS/ NA
Efferent Vth, VIIth, IXth, Xth, XIIth cranial nerves.
Effectors Pharyngeal muscles, tongue.
Effect Swallowing
 Anti-reflux mechanism
Tonic constriction of LES
Lower end of oesophagus has a higher pressure than stomach
Flap valve is formed by oblique angle of LES
Fold of the mucus barrier

 Act of swallowing – Initiated voluntary & continued involuntarily
Voluntary collection of food on the tongue and pushing them back into the pharynx
Involuntary contraction of pharyngeal muscles, pushes food in to oesophagus
Inhibition of respiration and glottis closure (By a reflex)
Relaxation of UES
Peristalsis Liquids are swept ahead of the

peristaltic wave due to gravity
Relaxation of LES
Food in the stomach

Peristalsis
 A reflex which is initiated when gut wall is stretched by the contents of the lumen.
 Occurs in all parts of GI tract.
 Independent of extrinsic innervation but can be regulated.
 Peristalsis does not stop if a part of gut is removed and resutured in its original
In front of,
position, but will stop if it is reversed and resutured.
Stimulus 6. Relax smooth muscles ahead
,
Behind, 1. Local stretch due to the pressure of a food bolus of the bolus
9. Contraction of smooth
muscles behind the bolus
5. Activate neurons to .
release NO, VIP
8. Activates neurons to release

substance P and Acetylcholine
4. Cholinergic neurons passing in
an anterograde direction
7. Cholinergic neuron 2. Release serotonin
in retrograde direction
3. Activates sensory neuron which activate the

myenteric plexus
10. This results in the bolus to move in oral to caudal direction.
Secondary peristalsis
 Peristalsis wave stimulated by distention of oesophagus by retained food
 Continues in waves till the oesophagus is cleared

Stomach
Functions
 Storage of food
HCl: - Parietal cells
 Digestive function Pepsinogen: - chief cells / peptic cells
Gastric lipase: - chief cells
Mixing
Gastric mucosal barrier

 Protective function HCl
Prostaglandin
 Controlled release of food into duodenum

 Production of Intrinsic Factor: - Parietal cells
Hormones (Motilin/Glucagon)
 Absorptive Ethanol / water
Gastric secretion
Gastric secretions – 2.5 L/day
Pepsinogen 1→in high [HCl]

HCl
Chief cells Pepsinogen 1 & 2 Pepsin
Proteins and large

Small peptides
peptides
Gastric lipase
TAG FA + Glycerol
Parietal cells Intrinsic factor (a glycoprotein)

Intrinsic factor + cyanocobalamin (vitamin B12) (binding occurs at SI)
Ileal receptors
Absorbed by endocytosis
HCL Aids protein digestion

Makes the necessary pH for the action of pepsin to start protein
digestion
Kills ingested bacteria
Stimulate the flow of bile & pancreatic juice

 Mechanism of secretion
Postprandial Alkaline Tide

Increase HCl secreted after a meal
Increase HCO3- absorbed to blood
Alkaline urine
Stimulated by COX Pathway

(Inhibited by
NSAIDs)
On stimulation tubulovesicular structures with

H+/K+ ATPase move to apical membrane and fuse
with it, increasing surface area available for H+/K+
exchange
M3 receptors
 Regulation of HCl secretion H2 receptors
1. Cephalic Gastrin
 Food in mouth, sight/ smell/ thought of food Receptors CCK-B
 Stimulation of hypothalamus/ frontal cortex
 Emotional responses – anger/hostility increase
 Fear/ depression decrease
 1/3 – ½ of acid secretion in response to a normal meal in this phase
 Due to vagal outflow →causes ↑ of Ach and GRP
 Activation of one receptor type potentiates the response of another for stimulation synergistic
action
 Ach is direct effector while GRP (Gastrin Releasing Peptide) acts through Gastrin release
 Atropin (anti-muscarinic) doesn’t affect Gastrin secretion as GRP is involved (not Ach)
2.Gastric
 a local reflex arcs
Stimulus: -
- Stretch
Gastrin↑ - Products of digestion Receptors in stomach wall
- Amino acids & ↑pH
ECL Meissner’s plexus From vagus

(Intrinsic innervation) (Extrinsic innervation)
Parietal cells
Histamine
Acid secretion

3.Intestinal
Neural effects
Hormonal effects (somatostatin, GIP,
Gastric acid and pepsin
Fats, carbohydrates and
secretion
acids in duodenum
Gastric motility
Others - Stimulants
Hypoglycemia – acts via brain and vagal afferents
Alcohol – acts directly on the mucosa
Caffeine – Stimulate CCK / gastrin
Mucus
 Forms a flexible gel coating the mucosa  Secretion stimulated by prostaglandins
 Made up of glycoproteins(mucins)  Function – “Gastric mucosal barrier”
 Secreted by neck and surface mucosal
cells
 Gastric mucosal barrier

A. Surface mucous layer B. Mucous cells C. Trefoil peptides
-thick -surface membrane -acid resistant
-Trapped HCO3 (Neutralize HCl) -tight junctions between cells
-
- channels for HCl -fast turnover of cell
Disrupted by,
-ethanol NSAIDS Inhibits cyclooxygenase
-Vinegar
-Bile salts Prostaglandin secretion is inhibited
-NSAIDS e.g.-Aspirin
-Helicobacter pylori infections Mucus secretion Acid secretion ↑
Gastric motility & emptying
1. Food enters the stomach

2. Fundus & upper part of body relaxes
(receptive relaxation)
-vagally mediated
-triggered by movement of pharynx and
oesophagus
3. Peristalsis in the lower part
-Controlled by BER (Basal Electrical
Rhythm)
-sweeps towards pylorus
4. Mixing & grinding of food
5. Gastric emptying
-Antrum, pylorus, upper part of the
duodenum function as one unit
-contraction of pylorus persists slightly longer than that of duodenum, preventing regurgitation (Due
to CCK and Secretin)
Clinical implications
1. Gastric by-pass surgery Leads to dumping syndrome
Effects of dumping syndrome,
o Hyperinsulinemia and consequent hypoglycemia
o Diarrhoea
o Transient hypovolemia
o Inadequate food intake
o Malabsorption of nutrients
o These patients are advised to have small
infrequent meals throughout the day
2. Anorexia due to Ghrelin deficiency
3. After total gastrectomy,
o Fe absorption impaired due to poor conversion of
Fe3+ to Fe2+. Due to loss of production of gastric
acid
o B12 absorption impaired due to loss of Intrinsic
Factor
o anaemia due to Vitamin B12 deficiency and
anaemia due to Fe deficiency occurs, BUT Vitamin
B12 deficiency predominates and macrocytic
anaemia results.
Liver
Functions
1. Nutrient metabolism
2. Inactivation of substances (toxins, ammonia, steroids and other hormones)
3. Storage (blood, vitamins A, D, B12, iron)
4. Synthesis of Plasma proteins (clotting factors, binding proteins, albumin,) But liver does not
5. Immunity (Kupffer cells) synthesize
6. Formation and secretion of Bile Immunoglobulins
Liver Enzymes Within hepatocytes

 Cytochrome P450 – metabolize many substances
 ALT / AST: -  in blood in hepatocellular damage
Within cells lining the bile ducts

 ALP: -  in blood in bile duct obstruction
 -glutamyl transferase: -  in bile duct obstruction
Induction of hepatic metabolic enzymes
Bile
 Daily secretion = 500mL

 Synthesized in the liver and concentrated and acidified in the gall bladder
 Composition - water, inorganic salts, bile salts and pigments, Cholesterol, Fatty acids, Lecithin
fat, ALP mainly HC03 
 Functions – Emulsification, assisting in lipid absorption
 Cholesterol and ALP excreted in bile

 Bilirubin Metabolism
RBC HB
Haem Globin
Porphyrin Fe2+
Prehepatic
Biliverdin
Circulation Bilirubin reductase
Bilirubin + Albumin Bilirubin
uptake
Bilirubin + 2UDPGA
Conjugation Glucuronyl Transferase Hepatocellular
Bilirubin Diglucuronide [BDG]
Excretion
Excrete
In Rate limiting step
Bile EHC Post
BDG Urobilinogen Hepatic
Fecal excretion
Unconjugated bilirubin (Indirect) Conjugated bilirubin (Direct)
Poor water solubility More water soluble
Not excreted in urine Excreted in Urine
High lipid affinity Low lipid affinity
High albumin binding Low albumin binding
 JAUNDICE(Icterus)
When total plasma bilirubin (free and conjugated bilirubin) level is greater than 2mg/dL or 34µmol/L it is
known as Jaundice.
Yellowish tint to the body tissues (skin, sclera, deep tissues)
Classification of Jaundice
Prehepatic Hepatocellular Post-hepatic
excess production of bilirubin  decreased uptake of bilirubin extrahepatic bile duct obstruction
into hepatic cells
 disturbed intracellular protein
binding or conjugation
 disturbed secretion of
conjugated bilirubin into bile
canaliculi.
 intrahepatic bile duct
obstruction
unconjugated bilirubin conjugated or unconjugated conjugated bilirubin
bilirubin
hemolytic anemia Cirrhosis bile duct obstruction (cholestasis)
Inflammation of hepatocytes, Ex: Carcinoma in bile duct
tumors, drugs, hepatocytes (bilirubin enters circulation
(Functions of the hepatocytes are through hepatic vein)
impaired)
 Bile Salts
 Synthesis and Circulation
Cholesterol HEPATOCYTE
↓
I bile acids (0.2 g/d)
ry
↓conj: with glycine and taurine

Glycocholic/Taurocholic acid
↓ Na+/K+
Na ,K salts of glycocholate and
+ +
Taurocholate/Bile salts (3.5 g/d)
At the terminal ileum 90% - 95% reabsorbed by

Excreted in bile Na+ - bile salt cotransporter via enterohepatic
circulation
Secondary bile salts are produced by action of bacteria on Iry bile salts in the colon.
Functions of Gall Bladder

1. Reservoir for bile
2. Concentration of bile
 By the absorption of water, Cl-,& HCO3-.
 But bile remains isotonic.
3. Acidification of bile
4. Release of stored bile-mediated by CCK
 Regulation of Biliary Secretion

1. Hormones - Secretin -↑production of HCO3- rich watery bile
CCK - causes contraction of gall bladder
2. Autonomic Nerves - Vagal stimulation-↑production of bile
3. Bile salts *most important physiological stimulus
Choleretics - Substances that increase secretion of bile

-Vagus nerve stimulation
-Secretin
-Bile salts
Cholagogues – Substances that cause gall bladder contraction

-CCK
- Ach
Gall stones
Calcium bilirubinate stones
1. 2 types Cholesterol stones
2. Causes: -
 Due to increased hemolysis increased bile pigments
 Disturbance of cholesterol: Bile salt: lecithin (1 :10: 3)
 Inflammation of epithelium.

Pancreas
Pancreatic juice
 pH of pancreatic juice ~ 8
 ↑ Duodenal pH to 6-7
 Secreted by exocrine pancreas (compound alveolar gland)
 Composition – Na+, K+, Ca2+, Mg2+, HCO3-, Cl-, SO42-,HPO4- ,proteins
 Enzymes- Proteins - (Trypsin, Chymotrypsin, Elastase, Carboxypeptidase A & B)
Fat - (Colipase, Pancreatic lipase, Cholesterol ester hydrolase)
Starch - (pancreatic α amylase)
Nucleic acid - (Ribonuclease, Deoxyribonuclease)
Phospholipids - (Phospholipase A2)
Found in the brush border.
Protein in lumen Has higher carbohydrate percentage
to prevent it from hydrolysing itself.
Pro enzyme Enzyme

Enteropeptidase Trypsin inhibitor
(Inside the pancreas)
Trypsinogen Trypsin
Chymotrypsinogen Chymotrypsin
Proelastase Elastase
Procarboxypeptidase Carboxypeptidase
Procolipase Colipase
Prophospholipase A2 Phospholipase A2
In acute pancreatitis, intra pancreatic activation of pancreatic enzymes like trypsin and auto digestion of
pancreatic issue.
 Pancreatic secretion regulation
primarily done by hormones, but also done neutrally.
Watery secretion of alkaline juice,

Secretin Pancreatic duct cells cAMP↑
↑in HCO3- ,↓ in Enzymes
Hormonal
CCK Acinar Cells Phospholipase C Juice rich in enzymes
Vagus Ach
Neural
Small Intestine
Adaptations for absorption
1. ↑ Surface area – valvular connivantes, villi, microvilli

2. ↑ Contact time of products of digestion – segmentation contraction, tonic contraction
3. Brush border with microvilli – rich in enzymes

Intestinal secretion
Isotonic fluid
3L/d pH=7.8-8
Enzyme ↑ stimulated by hormones e.g.: - VIP
Contents – water & mineral salts, digestive enzymes, mucus
Digestion done in lumen, brush border, intracytoplasmic

Enzymes  Enteropeptidase
 Amino/Carboxy/Di peptidase
 Maltase/Lactase/Sucrase
 Α-dextrinase/Nuclease
Carbohydrate absorption
Luminal Enterocyte Basolateral
3Na+
+
2Na
SGLT 1 & 2
2K+
Glucose(&Galactose)
GLUT 2
GLUT 5
Glucose
Fructose
[Independent of Na+
facilitated diffusion] Some fructose is converted to glucose in
the mucosal cell.
Pentose
Simple Diffusion
Lactose Intolerance
Deficiency of intestinal lactase causes abdominal cramps & diarrhoea after consumption of
food that contains lactose.
Amino acid absorption
↑absorption in duodenum and jejunum
 Na+/AA Co transporter
AA
 Na+ independent transport
 H+/di or tri peptide co transport (hydrolysis release AA in muscle cells)
Clinical implications
 Congenital transport system Hartnup’s disease: - neutral AA Absorption
defects Cystinuria: - Basic AA impaired
 Infants IgA in colostrum
 Food allergy absorb small quantities of proteins / small peptides

Fat absorption
Finally emulsified in SI
(Detergent action of bile salts, lecithin, monoglycerides)
Bile salt concentration LUMEN
Spontaneously aggregate in to micelles
Take up lipids
Move down concentration gradient to unstirred layer of brush border
Lipids diffuse out of micelles
Enter Enterocyte
FA > 10 - 12 C & Re-esterified Tri Glycerides Chylomicrons
Cholesterol
Fat & cholesterol
Lacteals
SCFA (FA < 10 - 12 C)
Actively transported in to capillaries Lymph

SCFA are water soluble, no
need to esterify for absorption.
Free fatty acids
Long Chain Fatty Acids Mostly absorbed in upper S.I
In infants, fat absorption mechanisms are not well developed by birth and malabsorption of fat soluble
vitamins may occur.
 Steatorrhoea Fatty
Bulky
Clay coloured
Stools Pale
Foul smelling
Greasy
Hard to flush
Pancreatic Lipase
deficiency Chronic liver ↓ Alkaline secre on from
disease pancreas
Acidity
Fat ↑ Gastric Acid
Bile duct
Malabsorption
obstruction
Defective reabsorption of Due to ileal resection

bile salts Or disease in distal ileum
Pancreatic disease Defective lipase secretion
Fat soluble A, D, E, K (“kade”)
Vitamins Mostly absorbed in upper SI
Others - Na dependent
Water Soluble B12,
Na independent Terminal ileum
Folate
Fe2+
Gastric acid and ascorbic acid
Fe3+ Fe2+
Fe2+ via DMT1 in duodenum

Almost all the iron absorption occurs in the duodenum.
Heme is transported into the Transport of Fe2+ into the

enterocyte by a separate enterocytes occurs via DMT1
heme transporter.
(heme carrier protein)
A protein called hephaestin (Hp)

facilitates basolateral transport.
Fe2+ is transported out of the

enterocytes by basolateral
transporter names
ferroportin-1
In the plasma Fe2+ is converted into Fe3+
and bound to the iron transport protein
Ca2+ transferrin.
30 – 80 % active transported facilitated by Vit. D
Water - mainly (98%) in small intestine.

Absorbed via TRPV6 (Transient Receptor Potential Vanilloid type 6)
Mg2+ - facilitated by proteins.
Vitamin B12
Binds to Intrinsic Factor in the small intestine
The complex is absorbed predominantly in the Ileum
Small Intestine Colon

Absorption of
Upper Middle Lower
Sugars    0
AA    0
LCFA    0
Bile salts    
Vitamin B12 0   0
Other vitamins   0 0
Na    
K 
   secrete
Protective function
Mucus
Solitary
Protection Lymph
Aggregated (Peyer’s patches)
Defensins Paneth cells
Fatty Fat mal Prevents reabsorption of bile salts & enters

infiltration of hepatic circulation is interrupted.
absorption
the liver. Protein Body wasting
Vit B12 deficiency oedema
deficiency
Vit A, D, E, K
Resection Resection
or disease Vit A, D, E, K or disease Ca2
of ileum Diarrhoea of upper SI +
PT
PT Fat malabsorption
Ca2+
Motility of Small Intestine
 MMC (Migrating motor complexes)

 Peristaltic waves
 Segmentation contraction
o Ring like contractions which appear at regular intervals, which are replaced by another set of
contractions in the segments between the previous contractions
 Tonic contraction
o Relatively prolonged contractions that in effect isolate one segment from another
Large Intestine
Functions K+, HCO31-
1. Absorption of water (1 – 2 L) and electrolytes
K+ - component of mucus, Na+, Cl-, H2O
along an electrochemical gradient
HCO3- - to neutralize the acidic substances
Produced by microbial activation.
Na+ - active transport (ENaC) Desquamated mucosal
Cl- in exchange for HCO3- cells/mucus
2. Formation and excretion of faeces Cellulose
Water 75% Solids 25% Bacteria (30%)
Inorganic material
mostly Ca2+, PO43-, fat
and fat derivatives.
Non-dietary in origin (unaffected by diet & starvation
4. Microbial activity LI colonized in early life.
Effects of intestinal bacteria Very few in jejunum
But sterile at birth
High in colon
Harmful effects to Host (Pathogens) Beneficial effects to host No effect to host

(Symbions) (commensals)
1. Utilization of nutritionally important 1. Synthesis of useful 1. Deconjugation of bile

substances. substances. pigments
Ex: Vit B12 Ex: Vit. K / B complex
Folic acid, SCFA
2. Cause UTI/ septicaemia 2. Anti-inflammatory effects 2. Odour
By E. coli Ex: probiotics
3. Synthesis of potentially toxic amines. 3. Digestion of cellulose in 3. Production of some gases

Ex: Histamine, Tyramine herbivores in flatus
4. Conversion of AA NH3
 Harmful in liver disease
 Associated with hepatic
encephalopathy
Vit B12 ↓ Macrocytic anemia
Vit ADEK ↓
Overgrowth of bacteria
Steatorrhoea Ca2+↓
E.g. blind 100p Unconjugated
syndrome PT ↑
bile salts
Irritates
Colon Diarrhoea
 Gastroileal reflex
Food leaving stomach Relaxation of caecum Passage of chyme through ileocecal valve
 Ileocecal valve
Usually closed. Opens when ileal pressure ↑ & closes when colonic pressure ↑
Movements of colon
 Peristalsis
 Segmentation contraction
 Mass action contraction
o Only in colon. Simultaneous contraction of smooth muscle over a large confluent area.

Defecation
Spinal reflex which can be modified voluntarily.
In infants no voluntary control
Resting,
 rectum empty
 External anal sphincter in a state of tonic contraction
 Internal anal sphincter tone - ↑ by sympathetic stimulation
↓ by parasympathetic stimulation
Distension of rectum with faeces
Increased rectal pressure (18mmHg)
Reflex relaxation of internal anal sphincter
Reflex contraction of external anal sphincter
Urge to defecate
Inappropriate Appropriate
Urge temporarily subsided External sphincter voluntarily open
Sphincter tone becomes normal Ab. Contraction + diaphragm
Voluntary defecation Intra-abdominal pressure increased

Straining Rectal pressure up to 55mmHg
Contracts abdominal muscles Evacuation
Increased intra ab. Pressure

Gastrocolic Reflex
Pelvic floor lowered
Distension of stomach with food
Puborectalis relaxed ↓
Decreased anorectal angle Contraction of rectum (due to gastrin on colon, not neural)
↓
Relaxation of ext. sphincter Desire to defecate
Defecation
Constipation  70% of undigested food  recovered 72 hours

Tonic Contractions
 100% recovery  1 week
 ↓ Water
 ↓ Fiber
 ↓ Colon motility
 ↑ Ca2+
 ↑ Sympathetic action
 ↓ Parasympathetic action
 Intestinal obstruction

Vomiting
3 phases Vomiting reflex
1) Nausea – hypersalivation/ pallor/ Salivation and sensation of nausea

sweating
2) Retching – strong involuntary effort Reverse peristalsis
to vomit (Upper part of SI to stomach)
3) Vomiting – expulsion of gastric
contents through mouth
Glottis closure
Breath held in mid inspiration
Contraction of abdominal muscles. (Increase intra-abdominal pressure)
Relaxation of LES & then UES
Reverse peristalsis
Ejecting gastric content
Stimulation of vomiting

Motility of GIT
1. Peristalsis Oesophagus to rectum A reflex response to stretch
2. BER All part of the GIT except Spontaneous rhythmic fluctuations in RMP
oesophagus and proximal of GIT smooth muscles
part of the stomach
3. MMC Stomach to distal ileum Cycles of motor activity during fasting
period
4. Segmentation Small intestine Ring like contractions appear at regular
contraction Large intestine intervals, then disappear and are replaced
by another between the previous two
5. Tonic Small intestine Prolonged contraction of isolated
contractions segments at a time
6. Mass action Large intestine Simultaneous contraction of smooth
contractions muscles
over a large confluent area
Patterns of GI motility
General patterns Segment specific patterns

 Basic electrical activity  Mastication = chewing
 Fasting pattern  Swallowing
o Migrating motor complexes  Gastric motility and emptying
 Fed patterns  Vomiting
o Peristalsis  Small intestinal motility
o Segmentation and mixing  Colonic motility
 Defecation
Basic electrical rhythm (Slow waves)
 Spontaneous rhythmic fluctuations in the membrane potential of GI smooth muscle.((-45) - (-65)mV)

 All parts except esophagus & the proximal part of the stomach.
 This BER is initiated by the intestinal cells of Cajal.
 BER rarely cause muscle contractions.
 If the membrane potential drifts up to the threshold, spike potentials appear.

 Spike Potentials excite muscle contraction.
 Many neurotransmitters & polypeptides affect the BER

o Excitability neurotransmitters
 Ach- Increase the number of spikes & the tension of the smooth muscle
o Inhibitory neurotransmitters
 NE- Decreases the number of spikes and the tension.
Migrating Motor Complexes
 Associate with increase in gut secretions and helps to clean the left overs (Housekeeping Waves)
 In the stomach and SI up to distal ileum.
 During periods of fasting and abolished by eating.
Each cycle
Phase I - Quiescent period (resting/ inactive)
Phase II – irregular electrical and mechanical activity.
Phase III – burst of regular activity.
 Mediated by motilin which increases in blood of intervals of 90- 120 min between meals.
 Causes gastric secretion, bile flow, pancreatic secretion.
 Clear the stomach & small intestine to avoid bacterial growth.
Segmentation
 A segment of bowel contracts at both ends and forces chyme backwards and forwards.
 Slows down movement of intestinal contents along intestine allowing time for digestion &
absorption.
 Carried out by enteric nervous system.

GI regulatory mechanisms
Hormonal act in paracrine fashion, also enters blood stream
Regulation
Neural Extrinsic
Intrinsic (enteric nervous system)
 Neural regulation
CNS Sympathetic Enteric nervous system

/parasym.
GI function
Intestinal smooth muscles
Sympathetic post ganglionic fibers End on blood vessels (vasoconstriction)

(Noradrenergic neurons)
Cholinergic neurons
(Inhibit release of Ach)
Result in - constriction of sphincters

Reduced activity of smooth muscles
Parasympathetic pre-ganglionic fibers end on cholinergic nerve cells in

(Post ganglionic parasympathetic system)
Result in - relaxation of sphincters
Increased activity of smooth muscle
Intrinsic innervation
Myenteric/ Auerbach’s Submucous/ Meissner’s

plexus plexus
Circular and longitudinal Glandular epithelium

smooth muscle Intestinal endocrine cell
Submucosal blood vessels
Primarily motor Primarily secretomotor
 Hormonal regulation
Gastrin family Gastrin

CCK
Secretin family Secretin
VIP
GIP

Others
Hormone Produced Increased by Action Decreased by
by
Gastrin G cells in Luminal  ↑Acid secretion Luminal
gastric Peptides, AA.  ↑ Pepsin secretion Acid
antral distension  ↑ Insulin after protein meal Somatostatin
mucosa  ↑ Motility
Neural  Growth of stomach/ SI/ LI/ Blood borne
↑ Vagal discharge via Mucosa Calcitonin
GRP Glucagon
Secretin family
Blood borne
↑ [Ca2+]
Epinephrine
CCK- PZ I cells in  Inhibit gastric emptying, When chyme moves
upper SI  GB contraction down from upper SI
 Pancreatic juice rich in

(CCK) FA > 10 C atoms in enzymes
duodenum  trophic action on pancreas
 augments action of
(PZ) Contact of products secretin
of digestion
(peptides, aa) with
intestinal mucosa
Secretin S cells in Products of protein  ↓Gastric acid secretion

mucosa of digestion  ↑Secretion of HCO3- by
upper SI Acid bathing mucosa biliary tract and pancreas
of SI  ↑ Secretion of watery
pancreatic juice
 Augments action of CCK
to produce digestive
enzymes
 Contraction of pyloric
(CCK augments sphincter
action of Secretin)  ↑ Insulin
GIP K cells Glucose and fats in ↑ Insulin secretion

duodenal/ duodenum ↓ acid secretion
jejunal
mucosa
VIP  marked stimulation of
(rem. secretion of electrolytes
VIPoma) and water
 relaxation of intestinal
smooth muscles (including
sphincters)
 dilation of peripheral blood
vessels
 gastric acid secretion

(A) Volume of secretions of GI tract per day
o Salivary glands 1500ml
o Stomach 2500ml
o Bile 500ml
o Pancreas 1500ml
o Intestine 3000ml
(B) Hormones in GI tract
Hormone Action
(1) Motilin Contraction of intestinal smooth muscles. Enterochromaffin cells
(Stomach/SI/colon) M6 cells in stomach/ SI/ LI
(2) Ghrelin (stomach) Central control of food intake
(3) Somatostatin  secretion of gastrin, VIP, GIP, secretin and D cells in pancreas
(Pancreas/GI motilin SI mucosa
mucosa)
(4) Peptide YY(Jejunum) Inhibits food intake  acid secretion & motility
(C) Chemical digestion in GI tract
Site Enzyme Action

Mouth Lingual lipase (act in stomach) TG  FA + DAG
Salivary -amylase Starch   dextrins + maltose
Stomach Pepsinogen
HCl Proteins + Large peptides  small
Pepsin peptides
Gastric lipase TAG  FA + monoglycerides
Exocrine pancreas Trypsin Proteins + PP  Small PP

Chymotrypsin Proteins + PP  Small PP + AA
Carboxypeptidase Proteins + PP  Dipeptide + AA
Pancreatic -amylase Starch   dextrins + maltose
Pancreatic lipase TAG  FA + monoglycerides
Ribonuclease RNA  ribonucleotides
Deoxyribonuclease DNA  Deoxyribonucleotides
Phospholipase A2 Phospholipids  FA + lysophospholipids
Intestinal Mucosa Enteropeptidase Trypsinogen  Trypsin
Aminopeptidase Polypeptides  Dipeptide + AA
Carboxypeptidase PP  DP + AA
Dipeptidase DP  AA
Amylase Starch  maltose
Sucrase Sucrose Glucose + Fructose
Maltase Maltose  Glucose
Lactase Lactose  Glucose + Galactose
Nucleotidase Nucleotide  Nucleoside + PO43
Nucleoside  Nitrogenous bases +
pentose sugar

Renal Physiology
Excretory
Urea,
creatinine
Regulatory Metabolic
Functions of Kidney
Fluid, electrolyte, pH Gluconeogenesis
Endocrine
renin, erythropoietin,
25(OH)D3
Urine Formation
 Site – Nephron (functional unit)
 3 steps
1. glomerular filtration
2. tubular reabsorption
3. tubular secretion
1) Glomerular Filtration
I. Filtration Membrane (contains negatively charged heparin sulphate. Therefore, repels albumin
preventing filtration)
These are stellate cells located
Afferent between the basal lamina and the
arteriole endothelium
Efferent arteriole
Capillary
endothelium
Mesangial
cells
Basal lamina
Epithelium
of capsule Podocytes
Filtration slit
II. Filtrate
 Isotonic to plasma
 Contain plasma except – plasma proteins (albumin)/ fat/ blood cells/protein bound
calcium ion
III. GFR Determinant-Effect on GFR
 The amount of plasma ultrafiltrate formed by
Net filtration pressure
two kidneys per minute - 125 ml/min in a
healthy adult male - Hydrostatic pressures
 Depends on - Osmotic pressures
 Age – with age ↓ Glomerular ultrafiltration coefficient -Kf
 Gender – (F) < (M)
- Surface area of filtration
 Body surface area – with body surface area ↓
Mesangial cells regulate this by
contraction (reduces surface area)
Glomerular filtration - Permeability of membrane
Permeability of the
𝐺𝐹𝑅 = 𝐾 [𝑃 − 𝑃 − (𝜋 − 𝜋 )] membrane depends on the
charge & size of the
molecules.
Neutral molecules of up to
4nm can pass
Filtration Almost no particles greater
Glomerular Glomerular colloid than 8 nm are able to pass
hydrostatic pressure - osmotic pressure –
PGC (45) πGC (20)
Bowmann’s capsule Bowmann’s capsule

colloid osmotic hydrostatic
pressure - πB(0) pressure - PB (10)
(no proteins)
Capillary length
 GFR may vary due to changes in the above quantities
 Changes in PGC
 Changes in mean arterial pressure (eg - shock)
 Constriction of afferent/efferent arterioles
 Changes in PB
 Obstruction of the ureter, bladder, urethra
 Oedema of the kidney within the capsule
 Changes in πGC
 Changes in plasma protein levels
 Changes in πB
 Changes in the permeability of Glomerular capillaries

Uses of eGFR or GFR to categorize the severity of Chronic Kidney Disease
 Stage 1 GFR ≥90 mL/min →Normal kidney Function

 Stage 2 GFR ≥(60-90) mL/min →Mild decline in kidney Function
 Stage 3 GFR ≥(30-59) mL/min →Moderate decline in kidney Function
 Stage 4 GFR ≥(15-29) mL/min →Severe decline in kidney Function
 Stage 5 GFR ≤15 mL/min →Kidney Failure, require dialysis
Why glomerular capillary oncotic pressure is higher than plasma??
 Glomerular capillaries have high concentrated plasma proteins as plasma filters through the membrane.
𝐺𝐹𝑅
𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 = = 0.16 − 0.20
𝑅𝑒𝑛𝑎𝑙 𝑃𝑙𝑎𝑠𝑚𝑎 𝐹𝑙𝑜𝑤
(Note: When blood pressure drops GFR and Renal Plasma Flow both reduced. But Renal Plasma Flow reduced
more than GFR. So filtration fraction increases.)
Renal blood flow
25% of the cardiac output
High blood flow for a gram of tissue
RBF & RPF measured using the Fick principle.
Significant auto-regulation can be seen in the range 90 mL/min – 220 mL/min.
Renal vascular resistant varies with blood pressure.
Keep RBF and GFR constant
Renal blood flow
(mL/min)
Arterial pressure
(mmHg)
90 220

Renal clearance –
The volume of plasma that is completely cleared or removed of substance by the kidneys in unit time.
Renal Clearance
Complete
Zero Partial
Eg:- PAH (para amino hippuric
Eg:- glucose acid) Eg:- creatinine
All substances filtered is Almost completely removed By filtration & tubular secretion
completely absorbed (90%)in a single circulation, by Inuline
filtration and tubular secretion
Only by filtration.
 Clearance of inulin – no tubular reabsorption or secretion

o CInulin = GFR
 Inulin is the standard substance used to measure GFR but in clinical practice creatinine is used.
Advantages Disadvantages
Inulin  Free filtered  Not an endogenous substance

 Neither reabsorbed nor  Has to be administered
secreted intravenously
 Not metabolized in the kidney  Need to keep arterial plasma
 Not toxic level of inulin constant
Creatinine  Endogenous substance  Secreted by tubules
 Daily production – constant  UCr V high
 Plasma level – constant  Inaccurate at low levels
 Clearance of creatinine easy to  PCr – high
measure  Need accurate UFR
measurement

Measuring GFR
The amount of a substance ‘y’ filtered = amount excreted in urine.
Plasma[y] mg/ml × Plasma volume filtered ml/min = Urine[y] mg/ml × Urine volume excreted ml/min
GFR = Volume of plasma cleared of substance ‘y’ by the kidneys per minute
GFR = Uymg/ml × V ml/min Uy – Urine concentration of ‘y’
Pymg/ml Py – Plasma concentration of ‘y’
V – Urine volume
 CCr< Serum creatinine level
Serum creatinine (μmol/L)

 No linear relationship
 Indicator of renal function
SCR
 Not much change in CCr seen until unit
renal function decreases up to 50-60%.
 Based on Scr, GFR can be estimated.
CCr (mL/min)
0 60
 Creatinine clearance over-estimates GFR by 10-20% (due to the secretion)

Good measure of GFR
 Serum Urea
 influenced by many factors. not constant.
 95% of urea excretion is by the kidneys.

Calculate Renal Blood Flow – By Fick principle
ERPF = Amount of substance excreted in urine/min
Renal arterial – Venous concentration of substance
 PAH completely removed by the kidney. So venous concentration approximately = 0

 Plasma flow to kidney = Effective renal plasma flow
 Renal extraction ratio of PAH = 90 %
 Actual renal plasma flow = × 100 mL/min
 𝑅𝑒𝑛𝑎𝑙 𝑏𝑙𝑜𝑜𝑑 𝑓𝑙𝑜𝑤 = × 100 𝑚𝐿/𝑚𝑖𝑛 = × 100𝑚𝐿/𝑚𝑖𝑛
 Renal Blood Flow = 1200 ml/min ≈ 25% of cardiac output
 Extraction ratio of PAH = Arterial concentration – venous concentration

Arterial concentration
Features of a substance that can be used to measure RPF
 Excreted by the kidney

 Renal arterial and venous levels of that substance can be measured
 Not stored
 Not metabolized
 Not produced
 Should not affect the renal blood flow
Physiological control of
GFR & RBF
Autoregulation Reflex activation of

Hormones
Sympathetic N.S.
Mesangial cells
 Contractile – Play a role in regulating glomerular

filtration.
 Take up immune complexes
 Secrete Extracellular matrix
6  Contraction by –Angiotensin II, Vasopressin, Endothelin
 Relaxation by – ANP, PGE2
1. Autoregulation
 Intrinsic renal mechanism
 Change of arterial pressure between 90-220 mmHg → Renal vascular resistance varies →Keeps
RBF and GFR relatively constant
 When pressure is high →Constriction of AA as a response to stretch and dilatation of arterioles
by NO
 At low perfusion pressure, angiotensin II → constrict EA to maintain GFR
 Therefore, renal failure may occur in hypertensive patients who are given ACE blockers.
A. Tubulo-Glomerular feedback– Relate this to regulation of renin secretion when learned
Increased flow through the ascending limb of LOH cause decreased GFR in the
same nephron.
Maintain the consistency of load delivered to DCT.
Mechanism
 Increased Na+ reabsorption via Na+/K+/2Cl- co-transporter
 Na+ and Cl- in DCT sensed by macula densa
 Increased Na+/K+ ATPase activity
 More adenosine formed by ATP hydrolysis
 Act on receptors of macula densa cells
 Release of Ca2+
 Cause afferent arteriolar constriction

 Decrease GFR and RPF

B. Myogenic contractions of vessels to stretch
 Due to stretch, Ca2+ moves to muscle cells from ECF.
C. Glomerulotubular balance
 GFR increases → reabsorp on of solutes increases →reabsorp on of water
increases in PCT → % of the solute reabsorbed is held constant.
2. Reflex activation of Sympathetic nervous system

Symp  renal vasoconstriction  reduced RBF & GFR (Indirectly by RAAM)
3. Hormones and other factors
Norepinephrine Reduce GRF NO Increase GFR and renal
Epinephrine and Dopamine plasma flow
Angiotensin II Renal plasma Ach
Endothelin flow
Exercise Prostaglandin Increase blood flow in Renal cortex
Decrease blood flow in Renal medulla
(H) norepinephrine/ epinephrine – released from adrenal medulla
(A) endothelin – released by damaged vascular endothelial cells of kidney
(H/A) angiotensin II – constricts EA>AA
 Help prevent decrease in PGC (pressure in glomerular capillaries) and GFR

 ↓ RBF by EA constriction causes ↓flow through peritubular capillaries which in turn ↑ reabsorption
of Na+ and H2O

Tubular Function
Early part of DCT Late part of DCT
Collecting Tubule
PCT
Collecting Duct
Thin Limb of LOH
Thick Ascending Limb of LOH

REABSORPTION GFR/Day-180L
 From renal tubule to blood
Urine/Day-1.5L
 Solutes are reabsorbed via transcellular and paracellular pathways.
 Paracellular pathway is the major pathway for reabsorption of water.

 Most absorption occurs in PCT.
SECRETION
 From blood to renal tubule.
 More secretion make substance less dependent on GFR

 PCT is the main site except for K+ (main site is PCT & CD)
 Penicillin, Urea, Uric acid etc

 Control blood pH
01.PCT(Proximal Convoluted Tubule)

REABSORBED SECRETED
 Glucose  +
H
 Amino Acids
 Na+
 Water
 HCO3-
 Cl-
 K+
 Ca2+
 K+
 Uric acid (later secreted)
 Urea
 small proteins like insulin(via pinocytosis)
 The fluid which filter from glomerular membrane remain isotonic when passing through PCT.
02.Thin Limb of LOH
 Water is reabsorbed mainly along the osmotic gradient which is produced by medullary
hyperosmolality.
03.Thick Ascending Limb of LOH
 Renal Tubule is impermeable to water.

 At the end of LOH fluid becomes hypotonic.
04.Early part of DCT

05. Late part of DCT & Collecting Tubules
Intercalated Cells
Principal cells
 In late part of DCT, Principal cells involve in water reabsorption by the actions of ADH &
Aldosterone. Intercalated cells involve in Acid Base Balance.
 Collecting tubules act same as late part of DCT.
 Early part DCT– Na+ is reabsorbed by Na+/Cl- Cotransporters

 Late part DCT – Na+ is reabsorbed by ENaC channels facilitated by Aldosterone.
 K+, H+ secreted.
06. Collecting Ducts

 Collecting ducts mainly have principal cells instead of intercalated cells.
 Urea Reabsorption occurs mainly at late part of collecting ducts.( Thick loop of Henle, DCT &
cortical CD are relatively impermeable to urea)
Urea Reabsorption
 Required to maintain the medullary hyper osmolality

 Reabsorption is increased by vasopressin
 Urea reabsorption increases after a high protein diet as urea excretion increases.
Summary for absorption of few important substances

01. GLUCOSE
 Glucose reabsorbed most in early portion of PCT.
 Reabsorbed by IIry active transport.
Amount reabsorbed α amount filtered α PG × GFR (PG =Glucose concentration in plasma)

 In a healthy adult, all of glucose in glomerular filtrate is reabsorbed
So, renal clearance of glucose is zero in a healthy person.
 Upto TmG,(Transport maximum)
 TmG is 375 mg/min in men & 300mg/min in Women.
 When PG exceeds TmG, as in uncontrolled Diabetes Mellitus, the amount of glucose in urine rises
proportional to the rise in plasma concentration.
 The renal threshold for glucose is the plasma level at which the glucose 1 st appears in urine.
 It is about 200 mg/dL of arterial plasma & 180 mg/dL of venous level.
 Actual renal threshold is less than predicted.
 Because - all nephrons don’t have same TmG
- some nephrons excrete glucose before others reached their Tm G
02.Na+
7% cotransporter
99% reabsorbed
Na+/ Cl-
ENaC channels - Na+
3%
65% mainly at PCT
1. Na+ /H+
Aldosterone
exchanger (Main) + + -
Na / K /2Cl
2. Na+/glu Bind with receptors of
Cotransporter Cotranspor Principle cells →
3. Na+/AA ter Increase ENaC synthesis
and insertion
→Increased Na+/K+
Not permeable to solutes

03.K+
Freely filtered in glomeruli.
Mostly reabsorbed in PCT
Secreted in DCT & CD
 Faster flow in tubules cause more secretion

 Amount approximately equal to the intake
 Increased H+ secretion reduces excretion of K+
 Decreased when K+ reaching the DCT is less
Reabsorbed in DCT in exchange for H+ via H+/K+ ATPase
The ability to eliminate unwanted K+ is less dependent on GFR than urea and creatinine
04.H2O
PCT – passively along osmotic gradient 65%-70% reabsorbed.
Aquaporin 1(not sensitive to ADH), simple diffusion
LOH-thin descending limb of LOH → 15% reabsorbed
Thick ascending limb of LOH → not permeable
DCT-5% (with solutes) (early part)
CD- predominantly Na+ independent.
 Depends on ADH (vasopressin) → Bind with V2 receptors of P cells → insert aquaporin 2
channels→ ↑ Permeability of CD to H2O
In cortical collecting duct - 10% when there is vasopressin
In medullary collecting duct – 5% (4.7%)
But when there is no vasopressin only 2% of water reabsorbed from both

cortical & medullary collecting ducts
In that case,if there s no ADH, Only 2% of filtrate is reabsorbed.
13% of filtrate is excreted

Diabetes Insipidus
ADH deficiency (Central Diabetics Insipidus)
CD fails to respond to ADH (Nephrogenic DI)-unresponsive v 2 receptors, non-functional water

channels
Formation of Concentrated urine depends on two factors

1. ADH
2. Hyperosmolarity of medullary interstitium
Kidneys maintain the osmolality of body fluid approximately 290mosm/kg
Humans have the concentrating ability of urine according to the needs of the body. Osmolality of urine
varies in a vast range according to the body water need. (30-1400 mOsm/kg)
This is maintained by counter current mechanism.
Counter current mechanism

Inflow runs, parallel, counter, in close proximity to outflow.
Depends on
Maintenance of a Gradient of increasing osmolality along the medullary pyramids
Produced by Maintained by
(1) Counter current multiplier (2) counter current exchanger
01.Counter current multiplier
1. Active process (Active transport of Na+/Cl- out of thick ascending LOH)

2. High permeability of thick descending LOH to H2O
3. Inflow of tubular fluid from PCT/out flow into the DCT
Produce a gradient of hyperosmolarity in medullary interstitium
02. Counter current exchanger
 Solutes recirculate in medulla while water get absorbed to the vasa recta.
 This maintain the medullary hyperosmolality

 Vasa recta do not create the medullary hyperosmolarity, but they do prevent it from
being dissipated.
↓ Gradient of
Osmolality
Isotonic
Hypotonic
Isotonic Cortex
Isotonic
Medulla
Hypertonic (If ADH is

available)
Hypertonic
Regulation of renal functions
Renin-Angiotensin-Aldosterone mechanism
 Renin is a glycoprotein
 Secreted by juxtaglomerular cells in the juxtaglomerular apparatus
 Converts angiotensin to angiotensin I
 Lead to formation of Angiotensin II from angiotensin I by ACE
 ACE found in vascular endothelium
 Specially lungs
Factors affecting the renin secretion
 Increased sympathetic Increased Na+ and Cl- reabsorption

activity via renal nerves via macula densa
 Catecholamine
Increased afferent arteriolar
 prostaglandins
pressure
 Hypotension
 Haemorrhage Angiotensin II
 Dehydration Vasopressin
 Cardiac failure
Decrease in plasma K+ level
Diuretics
Cirrhosis
Intra renal baroreceptor mechanism – Renin is secreted when the blood pressure falls.
1 ©2017 A/L Repeat Capmaign

Acts on brain and increase Stimulate vasopressin secretion
ACTH secretion
Stimulate thirst Vasoconstriction
Angiotensin II
Constrict glomerular PCT direct – Na+

vessels reabsorption
Mesangial cell contraction Increase sympathetic nerve

activity
Stimulate aldosterone
secretion(indirect effect
Increase the number & activity of Increases the activity of

Na+/K+ ATPase pumps of DCT & CD Na+/K+ exchanger
Increase the number & activity

Increases the production of
of ENAcs in the P cells Increases the activity of TCA ATP
cycle enzymes
*Angiotensin II stimulate aldosterone secretion but main stimulus for Aldosterone secretion is
increasing the Plasma K+ concentration
 Mesangial cell contraction – Reduce GRF

 Constrict glomerular vessels – Angiotensin II constrict Reduce the renal
both plasma flow
 afferent and efferent arterioles.
 But the efferent arteriole is constricted comparatively
more.

Explain how Angiotensin II reduces the GFR, but increase the filtration fraction.
 Angiotensin II constrict both afferent and efferent arterioles

 Renal Plasma Flow reduced
 But efferent arterioles constrict more
 Due to the pressure effect caused by more constriction of efferent arteriole GFR is not
reduced as much as Renal Plasma Flow
 So the filtration fraction increases
Natriuretic peptides
ANP, BNP and CNP
Actions – counter the actions of angiotensin-II
 Dilate arterioles Decrease RPF and GFR

 Relax mesangial cells
 Inhibit Na+ reabsorption
 Increase capillary permeability
 Decrease blood pressure
 Inhibit renin secretion
Regulation of ECF osmolality and volume
ECF osmolality – 280-296 mosm/kg (285 normal)
NaCl is the main contributor for the ECF osmolality.
ECF osmolality is regulated mainly by changing the blood volume.
Thirst Aldosterone is not involved in

Two main mechanisms regulating the osmolality
Vasopressin secretion

Thirst and vasopressin secretion
Both occur concurrently
Receptors
 Osmoreceptors – In hypothalamus
 Baroreceptors – In blood vessels
Vasopressin
 Cause vasoconstriction.
 Increase water reabsorption. How??
Regulation of vasopressin secretion
 Decrease in plasma osmotic

 Increase in plasma osmotic
pressure
pressure
 Increase in ECF volume
 Reduction in plasma volume
 Alcohol
 Pain, Emotions
 Stress, exercise, standing
 Nausea, vomiting
 Angiotensin II

Stimulation for vasopressin secretion
Pain Nausea Stress Angiotensin II
Hypothalamic osmoreceptors CVLM

Hypothalamus
NTS
Vasopressin
Increased plasma
osmolality
Low pressure baroreceptors
V2 Receptors in Principle
cells Decreased blood
volume
Aquaporin 2 channels insert
Increased water permeability
Increased water reabsorption
Decreased plasma osmolality and

increased plasma volume

Stimulation of thirst
Plasma hypertonicity Hypovolemia
Baroreceptors
Osmoreceptors in
hypothalamus Angiotensin II
Hypothalamus
Dryness in
pharyngeal mucosa Thirst
Drinking
Increase blood volume

Decrease plasma osmolality
 What stimulate vasopressin secretion in an acute haemorrhage??
Acute hemorrhage Blood volume reduced
Baroreceptor discharge Blood pressure reduced

Specially (low pressure rate) reduced
Nucleus of tractus solitarius CVLM
vasopressin hypothalamus

 Explain the autoregulation of GFR combining the effect of renin and tubulo-glomerular
feedback
When flow through ascending loop of Increased reabsorption

Henle is iecreased via Na+/K+/Cl- transporter
More adenosine formed by ATP Increased Na+ concentration sensed

hydrolysis via macula densa cells
Adenosine act on receptors in macula densa Release of Ca2+
GFR reduced Cause afferent arteriole constriction
When arterial blood pressure is reduced Renal blood flow is reduced
By renin angiotensin reactions

GFR is reduced
angiotensin II is produced
Juxtaglomerular cells are stimulated

Angiotensin II preferentially constricts EA
to release renin
GFR is increased

 Explain the responses of kidney to hypovolemia and hypotension.
Hypotension & Hypovolemia
Activation of aortic and

Renal Hypoperfusion carotid baroreceptors
Low afferent Decreased Na+ , Cl- Increased

arteriolar pressure delivery to Macula Densa sympathetic Tone
Renin release from Juxtaglomerular cells of nephron
Converted by Renin
Angiotensin I Angiotensinogen
How GFR is maintained

Angiotensin II
 Due to Hypotension, RPF & GFR is

Binds to AT1 Receptors reduced
 Released Angiotensin II act on
both afferent and efferent
arterioles and constrict
both(efferent arteriole constrict
 Generalized vasoconstriction of renal more)
and systemic arteries  So Renal blood pressure & PGC
↑Blood
 Output of sympathetic nervous system increased
Pressure
to heart and vasculature is increased by  GFR increased up to normal value
activation of AT2 receptors in brain
If GFR increased more than normal
Macula densa mechanism is activated
 Act on adrenal Cortex to release and GFR decreases again
Aldosterone
↑Blood  Increased Na+ reabsorption both directly &
Volume indirectly via Aldosterone by Angiotensin II Decreased urine output and more
with Na+ , H2O is also reabsorbed in great concentrated urine is produced
amounts
Regulation of Na+ concentration
Variations in Na+ concentration is brought about by changes in GFR & tubular reabsorption
 Natriuresis  Na+ retention

- ANP - Reduction of dietary intake of salt
- PGE2 - Aldosterone
- Endothelin - Angiotensin II
- Interleukin 1
- Ouabain
- Dopamine
Regulation of K+ concentration
 Filtered K+ is absorbed by active reabsorption in PCT

 Secreted in DCT & CD coupled to Na+ reabsorption.
 Rate of secretion is proportional to rate of flow
 Aldosterone induces K+ excretion
 K+ secretion is decreased when tubular Na+ concentration is reduced
 Increased H+ secretion in acidosis leads to decreased K+ excretion(hyperkalemia)

Diuresis
Increased urine output
WATER DIURESIS OSMOTIC DIURESIS

CAUSE Drinking large amounts of hypotonic Administration of filtered but
fluids unabsorbed osmotically active particles
(mannitol etc.)
Infusion of large amounts of NaCl, urea
In diabetes mellitus
WATER REABSORPTION AT PCT Normal decreased→ due to↑ osmo cally

active particles
ADH SECRETION Inhibited Maximum
o By act of drinking But less effect

o Due to↓ plasma osmolality
URINE OSMOLALITY Reduced(hypotonic) isotonic
URINE FLOW Increased Increased + ↑excre on of Na⁺ and

other electrolytes
GFR Normal/Increased Decreased
Plasma osmolality Decreased *if pathological Increased *if pathological
Water Diuresis –
Begins 15 mins. After drinking water (40 mins maximum)
Small decrease in vasopressin secretion even before water is absorbed from the gut.
 Ethanol → inhibit vasopressin secretion
 Antagonists of V2 receptors → inhibit action of vasopressin on CD
Osmotic Diuresis –
Increase in urine volume due to presence of large quantities of unabsorbed solutes in the renal tubules
 In diabetes mellitus filtered glucose is not completely reabsorbed. Remaining glucose cause
osmotic diuresis leading to polyuria and polydipsia
Process-
1.↑concentra on of osmo cally ac ve par cles in PCT lumen hold water in the tubules, not
allowing reabsorption
2.↑water volume in lumen→↓[Na⁺] concentra on in spite of high Na⁺ amount→ limi ng

concentration gradient reached (at DCT) →Na⁺ reabsorp on down the concentration gradient
prevented→↑Na⁺ reducing further water reabsorp on

3.↓[Na⁺] →↓Na⁺ reabsorp on by Na⁺K⁺2Cl⁻ co transporter→↓medullary hypertonicity→↓water
reabsorption
4. maximum ADH secretion but less influence due to osmotically active particles in lumen
SEQ) Explain presence of polydipsia in a patient with uncontrolled diabetes mellitus.??
Class of Diuretic Mechanism of Action Tubular Site

of Action
Osmotic diuretics (mannitol, Inhibit water and solute reabsorption Mainly
sucrose, glucose) by increasing osmolality of tubular proximal
fluid tubules
Loop diuretics (furosemide, Inhibit Na+-K+-Cl- co-transport in Thick
bumetanide) luminal membrane ascending loop
Hypokalemi
of Henle
a occurs as
a result of Thiazide diuretics Inhibit Na+-Cl- co-transport in Early distal
these drugs (hydrochlorothiazide, luminal membrane tubules
chlorthalidone)
Carbonic anhydrase Inhibit H+ secretion and HCO3- Proximal
inhibitors (acetazolamide) reabsorption, which reduces Na+ tubules
reabsorption
Aldosterone antagonists Inhibit action of aldosterone on Collecting
(spironolactone) tubular receptor, decrease Na+ tubules
Hyperkal
reabsorption, and decrease K+
emia secretion
occurs as
a result Sodium channel blockers Block entry of Na+ into Na+ channels Collecting
(amiloride) of luminal membrane, decrease Na+ tubules
of these
reabsorption, and decrease K+
secretion
Water Inhibit ADH secretion
Ethanol Inhibit ADH secretion
Antagonists for V2 Inhibit ADH secretion Collecting
vasopressin receptors Duct
Xanthines (Caffeine) Reduce reabsorption of Na+
Increase GFR
 Aldosterone antagonists and Sodium channel blockers are K + sparring natriuretics.

Acid Base Balance
[H+] normal range= 37-45 nmol/l Daily production rate >12500 mEq /L
Arterial blood 7.4 (7.38-7.42) no significant effect between 7.35-7.45

Venous blood /Interstitial fluid 7.35(venous blood CO2 > arterial blood CO2)
Limiting pH of urine-4.5
Intracellular pH 6.8
If pH is more than normal - alkalemia.
If pH is lower than normal - acidemia ECF survival range 6.8-7.7
Defense mechanisms
1. Buffer systems in body fluid (Act immediately)
2. Respiratory system (within minutes)
3. Renal system (hours, days) – Most effective
1.) Buffer systems

act immediately
 Body’s 1st line of defense.
 Cannot remove or add H+ by themselves.
 Only keep H+ ions tied up temporary.
 Replace a strong acid or base with a weak acid or base respectively.
I. HCO-3 III NH3
II. Phosphate IV Proteins
Buffer systems in the body

A] Plasma
 Bicarbonate buffer D] Intracellular fluid
 Protein buffer: HPr→H⁺ + Pr⁻  Protein
B] RBC  Phosphate buffer: H₂PO₄→H⁺ + H PO₄⁻
 Protein E] Cerebrospinal fluid
 Deoxyhaemoglobin: HHb→H⁺ + Hb⁻  Bicarbonate buffer
C] Tissue fluid  Phosphate buffer
 Bicarbonate buffer F] Urine
 Bicarbonate buffer
 Phosphate buffer
*Phosphate buffer is important at

HCO₃⁻ buffer system renal tubules.
Largest quantity
When a strong base is added
When a strong acid is added
H2CO3 + OH- HCO-3 + H2O
H+ +HCO-3 H2CO3 H2O + CO2 Weak base [HCO₃⁻] replaces strong base
CO₂ is formed H₂CO₃ ↓ so more CO₂ and H₂O forms H₂CO₃
CO2 stimulates respiration CO2 level↓
CO2 is eliminated Depresses respiration
CO2 level ↑
Non-bicarbonate buffer systems
1. Phosphate buffer system
 Important at the DCT and CD of the renal tubules
 Major intracellular buffer
2. Proteins
 Including Hb
 Work in blood and ICF
 Carboxyl group gives H+
 Amino group buffers H+
3. Ammonia
 Renal buffer ONLY
2.) Respiratory system

 2nd line of defense
 Controls ECF [CO2] – Remove volatile acids
 Not 100% effective[effectiveness-50%-75%]
↑H+ in ECF ↓ H+ in ECF

↓ ↓
↑ Stimulation of chemoreceptors ↓Stimulation of chemoreceptors&
↓ the respiratory center
↑ Stimulation of respiratory center ↓
↓ Depression of respiration
↑ Respiratory rate & depth ↓
↓ DecreaseCO2 eliminated
CO2 eliminated ↓
↓ ↑ Pco2
↓Pco2 ↓
↓ ↑ H+
↓ H+
3.) Renal Contribution

 Most powerful regulatory system
 Excrete acidic or alkaline urine
 Remove non-volatile acids
 Buffer systems and RS keep [H+] from changing too
until the kidneys takeover
H+ in ECF H+ in ECF
H+ Secretion HCO-3 HCO-3 H+ HCO-3 HCO-3

reabsorption production & Secretion reabsorption excretion
NH3
production
Production of acidic Production of alkaline

urine urine
Arterial Blood Gas Report Analysis
pH
<7.4 >7.4
↓ ↓
Acidemia Alkalemia
HCO-3 < 24meq/L Pa co 2>40mmHg HCO-3>24meq/L Pa co 2 <40mmHg
Metabolic Respiratory Metabolic Respiratory

acidemia acidemia alkalemia alkalemia
Respiratory Metabolic Respiratory Metabolic

Compensation Compensation Compensation Compensation
Pa co 2 <40mmHg HCO-3>24meq/L Pa co 2 >40mmHg HCO-3< 24meq/L
 Compensation is not perfect

 Respiratory acidosis Respiratory Metabolic acidosis Metabolic alkalosis
alkalosis
Primary ↑Pᴄᴏ₂ ↓Pᴄᴏ₂ ↓plasma H₂CO₃ ↑plasma H₂CO₃
cause
reasons Any respiratory disorder 01. Voluntary 01. Kidney fails to 01. Diuretics (due to ↑H+ loss; part
producing ↑H₂CO₃ hyperventilation excrete normally of loss of K+ and H+ by loop &
VA=RR(TV-DS) 02. High formed acids thiazide diuretics results from
01. Fibrosis, oedema, stiff altitudes 02. ↑Metabolic acid activation of RAAM that occurs
lung [↓ TV] formation (keto because of ↓blood volume and
02. Pump defects acidosis from arterial pressure)
(denervation of respiratory diabetes mellitus or 02.↑Aldosterone→↑Na+
muscles) [↓ TV] lactic acidosis etc) reabsorption→
- -
03. Depression of the 03. ↑Loss of HCO3 ↑Secre on→↑HCO3 reabsorption
respiratory center [↓ RR] [diarrhoea] 03. Increased ingestion of
04. Airway obstruction 04. Ingestion of alkaline drugs
metabolic acids 04. Vomiting of gastric contents
compensation ↑HCO₃⁻ in plasma ↑HCO₃⁻ ↑ven la on ↓ven la on
excretion
How to ↓pH ↑pH ↓pH ↑pH
identify? ↑Pᴄᴏ₂ ↓Pᴄᴏ₂ ↓HCO₃⁻ ↑HCO₃⁻
↑HCO₃⁻ due to par al ↓HCO₃⁻ due to ↓Pᴄᴏ₂ due to ↑Pᴄᴏ₂ due to respiratory
renal compensation partial renal respiratory compensation
compensation compensation

Renal Contribution Towards H+ Homeostasis
Plasma [H+] = 40 nmol /dL

Very high amount of H+ added to the circulation daily.
Fate of H+ in the body

 1st line of buffering – Plasma & intracellular
 2nd line of defense – Removal of volatile acids as CO2 from lungs
 3rd line of defense – removal of non-volatile acids by kidney
Kidney regulates ECF [H+] by

 Secreting acids
 Reclaiming filtered HCO3-
 Regenerating HCO3-
Urine pH may vary from 4.5 - 8
Mechanisms of H+ secretion
1. Na+/H+ exchange – PCT, Thick ascending limb of LOH and early DCT
2. ATP-driven proton pump – Intercalated cells in late DCT
and CD (Increased by aldosterone)
3. H+/K+ ATPase – In DCT and CD
Main buffers in urine that buffer the secreted acid –

 HCO3-
- Mainly in PCT
 NH3/NH4
- In PCT, DCT and CD
 Phosphate
- In DCT and CD
HCO3- buffer
Rapidly removes H+ from urine. But no excretion of H+ in urine.
Prevents decrease in pH of filtrate
For each HCO3- absorbed from filtrate one HCO3- is added to blood – “Reclaiming HCO3- “

NH3 buffer
Buffer about 50% of the acid excreted. Buffering
action increases in chronic acidosis.
Only method of passing acids over the normal level.
Phosphate buffer
Generates new HCO3-.
Buffer about 50% of the acid excreted. For each NH4+ or phosphate excreted, one
Mostly in DCT and CD as the concentration increases. HCO3- added to the blood
Excreted as titratable acidity.
Metabolism of proteins
↓
Non-volatile acids
-
H+ secretion HCO3
PCT 85% PCT

Thick limb of the LOH
DCT, CD
 No H+ secretion or HCO3- reabsorption happen at the level of LOH
H+ secretion at the level of PCT
 Brush Border of the luminal

surface is rich in Carbonic
Anhydrase

 H+ secretion coupled with Na+ reabsorption IIry active transport
 For each H+ added one Na+ and HCO3- added to the blood.
 Most of the HCO3- (over 80%) absorbed by this process.
 Secreted H+ is buffered by HCO3- buffer system and NH3 buffer system
H+ secretion at the level of late DCT & CD
H+ secretion
 Independent of Na+ reabsorption
 Secreted by ATPase driven proton pump – I cells of CD
 Iry active transport
 Aldosterone increases its activity.
 In acidosis many tubulo-vesicular structures are inserted to the apical membrane to
increase H+ secretion.
 Limiting pH is achieved. (4.5pH)
 For each H+ secreted, HCO3- enters the interstitial fluid
 Secreted H+ buffered by
o Phosphate buffer in the filtrate
o NH3 made in the cells

NH3 buffer in DCT & CD
 Mainly in I cell
 Amino acid metabolism  Glutamine ( in liver )
 Glutamine glutamate + NH4+
Glutaminase
 Glutamate -KG + NH4+

Glutamate DH
NH4+ NH3 + H+
-KG + 2 H+ 2HCO3-
 NH3 lipid soluble  diffuses across cell membranes
 chronic acidosis  ↑ NH3 buffer system activity
 ↑ NH4+ excretion in urine in acidosis

 HCO3- buffer system is mainly important at the level of PCT
 Prevent reaching the limiting pH
 Phosphate buffer system is important at the level of DCT & CD where it reaches the limiting pH = 4.5
Most of the acid is excreted in PCT. In the PCT pH drops slowly as secreted H+
binds with HCO3- and form H2CO3 and then
- But only little as × 4 increase in urine [H+]
CO2 and H2O. The apical membrane is
- Lower limit pH 6.7 permeable to CO2 and it is removed from
Only 5% of the acid secreted in DCT the tubular cells by Carbonic Anhydrase.
- But as × 900 increase in [H+] But,
In DCT, secreted H+ is buffered by many
- Lower pH limit 4.5
HPO4- or NH3
Factors increasing / decreasing H+ secretion & HCO3- reabsorption
Increase Decrease
 PCO2 ↑
 H+ ↑ , HCO3- ↓
 ECF volume ↓ Opposite
 angiotensin II ↑
 aldosterone ↑
 Hypokalemia

 The following observations were made in a 45-year-old man
RR=40min
Arterial blood gas analysis report
Ph=7.2(normal range 7.35-7.45
Pᴄᴏ₂=28mmHg (normal range 38-40mmHg)
HCO₃⁻=12mmol/L (normal range 24-26mmol/L)
Explain the above findings?
 Write the observations

 Decision
 Compensation
• Respiratory rate is higher than normal

• pH is reduced
• Pᴄᴏ₂ is reduced
• HCO₃⁻ is reduced
• Actions is due to reduced HCO₃⁻
• So, this person is having metabolic acidosis
• Acidosis stimulates the peripheral chemoreceptors
• They stimulate the respiratory center in the medulla
• Via buffer nerves
• Increasing the respiratory rate
• Which decreases Pᴄᴏ₂
• pH α HCO₃⁻/Pᴄᴏ₂
• so, there is partial respiratory compensation

REPRODUCTION
Sex determination (Testis or Ovaries) - by SRY region of Y chromosome.
 SRY is a DNA-binding regulatory protein.
 It initiates transcription of other downstream genes required for testicular development. Eg. MIS gene
Sexual differentiation (male or female phenotype) - Hormonal.
Male Female
Genetic Sex (Genotype) XY XX

Gonadal Sex Testes Ovaries
Genital Sex (Phenotype) Penis, Scrotum Vulva
SEXUAL DIFFERENTIATION
Embryonic
ovary does
not produce
or excrete any
hormone in
considerable
amounts
AND
X
(From 8th -
13th week)
X - 5α Reductase type 2
 MIS is also known as Mullerian Regression Factor(MRF).
1  2017 A/L Repeat Campaign

 Sex chromatin (Barr body) – inactive, condensed X chromosome(s) seen in the nucleus
 The inactivated chromosome is selected randomly and may not be the same chromosome in different
cells.
 If more than 2 X chromosomes are present (Klinefelter’s syndrome), only one remains active.
• Hormonal treatment of the mother has no effect on gonadal differentiation. But affects internal and
external genitalia development
• Bipotential stages of the embryo:
o Bipotential gonads – up to the 6th week of gestation

o Bipotential genital ducts – up to the 7th week of gestation
o Bipotential external genitalia - up to the 8th week of gestation
 At the 13th week development of genitalia is complete. So exposure to hormones after this period will not
affect development of any genitalia.
 Both DHT and testosterone bind with the same receptors. But DHT has higher affinity to the receptor.
MIS Levels
 MIS levels are high in male foetuses and through infancy.

 It is believed to be involved in germ cell maturation
 MIS levels slowly drop and reach a constant level after puberty.
 In females, MIS is secreted in very low (undetectable) amounts by granulosa cells in the fetal and pre
pubertal stage.
 Levels increase at puberty and acquire a constant value.
 After puberty plasma MIS level is equal in both male and female. (2ng/mL)

Aberrant sexual differentiation
Chromosomal Hormonal
Results in Pseudohermaphroditism
1. Transposition of parts to other  Male pseudohermaphroditism (XY,Testis +

chromosomes Female external genitalia)
 Deletion of SRY - XY female 1. Absent /Defective androgen synthesis/action
 Translocation of SRY to X
chromosome or an autosome - I. Defective testicular development
 Absence of MIS and Testosterone
XX male
II. Enzyme defects in androgen synthetic pathway
 protein mutation (StAR protien)
 cholesterol desmolase
2. Chromosomal abnormality (Non-  17  hydroxylase, 17,20 lyase 2.
disjunction) 2. Testicular feminization syndrome (Androgen
resistance)
 Turners Syndrome - XO
 Both MIS and testosterone are present. MIS causes
 streaky ovaries
regression of Mullerian duct. Testosterone cannot act
 female external genitalia since receptors are defective
 lack of secondary sexual  Mutation in androgen receptor gene -complete loss

development of receptor function (Testicular feminization
syndrome)
 Klinefelter’s Syndrome - XXY
 Testes, Female external genitalia
 Testis - seminiferous tubule
dysgenesis  Presence of MIS - Female internal genitalia not
properly formed.
 Male external genitalia
 Blind ending vagina
 Defective spermatogenesis +
azoospermia *mcq  Breast development
 True Hermaphroditism - XX,  Primary amenorrhea
XY mosaicism (Nondisjunction
in mitosis)  Defects in post receptor events
 both ovaries and testes 3. Deficiency of 5-alpha reductase type 2

 DHT is not formed
 ambiguous external genitalia  At birth; testis and female genitalia
 At puberty; penile enlargement due to increase
testosterone secretion (Penis at 12 syndrome)
Female pseudohermaphroditism  Often request a sex change
(XX,Ovaries + Male external genitalia)
 Exposure of fetus to androgens during 8th
to 13th weeks of gestation
 Congenital virilizing adrenal hyperplasia in fetus Pseudo hermaphroditism – Individuals have gonads
(genetic constitution) of one sex and the genitals of
 Androgen treatment to mothers the other
 Androgen secreting tumors in fetus
 Exposure of the female foetus to androgens
 Defects in steroids synthetic pathway leading to
accumulation of androgens.(That is deficiency after week 13, may cause hypertrophy of the
of 3β HSD, 11βHSD, 21βHSD ) clitoris.

Androgen Synthetic Pathway
 Androgen synthesis occurs both in adrenal cortex and testis
Cholesterol
17 hydroxylase 17,20 lyase

Cholesterol
desmolase
pregnenolone 17-OH pregnenolone DHEA
3 HSD
Progesterone 17-OH Progesterone Androstenedione
21 HSD
11 – deoxycorticosterone 11 – deoxy cortisol Testosterone
11 HSD
Corticosterone Cortisol Oestrogens
Deficiency leads to male pseudohermaphroditism
Deficiency leads to female pseudohermaphroditism

PUBERTY
 Puberty is the period when endocrine and gametogenic functions of the gonads have first developed to
the point where reproduction is possible.
 Age of onset
o Girls: 8 – 13 years
o Boys: 9 – 14 years
BOTH SEXES
1. Increased physical growth
 Increased GH pulse amplitude

 Increased Insulin like Growth Factor (IGF) – From liver – induced by Growth hormone
 Increased Thyroid activity (not important for pubertal growth but for infancy)
 Effects of androgens and oestrogen
 Female androgens- from adrenal glands.
Androgens - Protein anabolic (Increase muscle mass)
Oestrogens – fusion of epiphysis (in both sexes, stops growth in long bones)
 Peak height velocity; Peak of Growth Spurt
o Girls: 12 years
o Boys: 14 years

Pubertal Growth spurt
25.4 Infantile growth spurt

H Mainly due to thyroid
activity
ei
gh 20.3
t
Pubertal growth spurt
ga 15.2
in
(c Pubertal growth spurt
10.2 occurs earlier in females
Girls
Boys
5.1
2 4 6 8 10 12 14 16 18 18
Age in years
Though both DHT and Testosterone play huge roles in the changes which occur in males at puberty, these 2
hormones also have functions which are exclusive to each of them
1. Dihydrotestosterone (DHT)
 Enlargement of the prostate
 Enlargement of the penis
 Temporal recession
 Facial hair
 Acne
2. Testosterone
 Increase in muscle mass
 Increase in male sex drive and libido

2. Appearance of Secondary sexual characteristics
Boys Girls
 Axillary and Pubic hair  Axillary and Pubic hair
 Growth and enlargement of internal  Growth and enlargement of internal
and external genitalia and external genitalia
 Increased facial + body hair  Breast development
 Decreased scalp hair (hair line goes  Subcutaneous fat deposition
above)  Menarche
 Increased muscle mass
 Low pitched voice
3. Behavioural and emotional changes

 Libido (attraction to opposite sex)
 Aggressiveness in boys
 Concerned about appearance
 Withdrawn/ Apprehension / Emotional instability
4. Adrenarche
 Increase in adrenal androgenswithout a simultaneous increase in ACTH.
 Due to increased activity of enzymes in androgen producing pathway
 Principal adrenal androgen – DHEA (Dehydroepiandrosterone)
 Promotes;
 physical growth,
 axillary and pubic hair growth,
 sebaceous gland development,
 body odour and acne.
Note; Growth of pubic and axillary hair in both sexes is due to androgens,rather than oestrogen
GIRLS-Order-
Breast budding (Thelarche)
1. Thelarche
Pubic hair begins (Pubarche)
 Development of breast followed by development of pubic and axillary hair
 Ovarian oestrogen stimulates growth of lactiferous ducts Peak height spurt
 Progesterone – Alveolar lobule development
Menarche
2. Menarche Pubic hair adult

 First menstrual bleeding
 Often anovulatory. Next 1-2 years can be anovulatory Breast adult
 Irregular cycles follow. Takes about 1 year for regularity of cycles.

 Due to maturation of H-P-O axis

BOYS
-Order-
1. Nocturnal Emissions
 Emission of seminal fluid during sleep (wet dreams) Genital development begins
 LH pulse first appear during nocturnal sleep 
2. Spermarche (1st ejaculation) Pubic hair begins

Peak height spurt

Genitalia adult
Tanners classification 
Pubic hair adult
 Reproductive maturity was staged by Prof. Martin A Tanner
 Development of the breast, external genitalia, pubic hair are staged by this classification
 5 stages, stage 1 (pre-pubertal) to stage 5 (adult)
Factors affecting age of menarche
1. Nutrition – Well-nourished  early

Undernourished  delayed
“Critical body fat” (~ 17% of body weight)- leptin secreted by adipocytes
2. Constitutional - some families, ethnic groups…. early or late
3. Secular trend – age of menarche decreased over the years, due to increased nutritional status.
Endocrine changes seen in puberty
 Pulsatile secretion of GnRH brings on puberty (Hypothalamo-pituitary-gonadal axis)

 GnRH (hence LH) pulse first appears in nocturnal sleep and later spreads to daytime awake periods
 GnRH pulse FSH, LH pulse Maturation of gonads
 Removal of gonads from birth to puberty causes only a slight increase in gonadotrophin secretion.

Control of the onset of puberty
Reduced intrinsic CNS inhibition Reduced sensitivity of the Gonadostat

Intrinsic CNS inhibition prevents Extremely low levels of sex hormones in pre-
GnRH pulsatility in pre pubertal pubertal years keep the Hypothalamus and
period, may be due to Pituitary inhibited. This mechanism is known
inhibition of, some gene products as gonadostat.
which stimulate GnRH secretion
At puberty: Sensitivity of the gonadostat ↓
Inhibition of those genes during
prepubertal period prevents puberty GnRH, LH, FSH levels ↑
occurring
Gonads stimulate to increase activity.
When conditions are appropriate for puberty
Intrinsic CNS inhibition reduced Body’s sensitivity to gonadostat

reduced
GnRH pulsatility is stimulated Increased levels of GnRH, LH,

and FSH
Onset of PUBERTY
Precocious puberty
 Early development of secondary sexual characteristics with or without gametogenesis
True-precocious Pseudo-precocious
- Maturation of H-P-G axis - H-P-G axis is immature
- GnRH, FSH, LH increased - GnRH, FSH, LH levels are low
- True gametogenesis - No gametogenesis
- Early, but normal pubertal pattern of - Excess oestrogen in girls and Androgens
pituitary gonadotrophin secretion. in boys

Causes Causes
- Idiopathic - Androgen/Oestrogen secreting tumours
- CNS lesions In adrenals or gonads
 Only true precocious will have fertility.
Delayed puberty
Boys Girls
- No genital growth by 20 years - No menarche by 17 years (primary
amenorrhoea)
Causes Causes
- Klinefelter Syndrome - Turner’s Syndrome
- Anorexia Nervosa
Transport of Hormones
CBG – Corticosteroid binding Globulin GBG – Gonadal Steroid binding Globulin

1
Male Reproductive System

Blood-testis Barrier
 Formed by tight junctions between Sertoli cells.
Functions of blood-testis barrier

 Allows testosterone (steroids) and also some paracrine proteins to enter seminiferous tubules.
 Allows maturing germ cells to pass through and move to the lumen, without disrupting the barrier.
 Won’t let sperms leak into blood.
 Protects germ cells from blood-borne noxious agents.
 Establish an osmotic gradient that facilitate movement of fluid into tubular lumen.
 Prevents antigenic products of germ cell division and maturation, from entering the circulation
and generating an autoimmune response.
 Luminal fluid contains androgens, estrogens, K+, inositol, Glutamate, Aspartate. Very little protein
or glucose.
Hormone secreting cells in the testis
Leydig cells Sertoli Cells
Synthesize;  Helps in nourishment of germ cells.

 Formation of blood-testis barrier.
 Testosterone
 Ensures a high concentration of
 Estrogen
androgens in tubular fluid.
 Contains glycogen granules.
 synthesize
Effects of Testosterone  Inhibin (-FSH)
 Estrogen
 Male secondary characteristics  MIS
 Protein anabolic effect  Androgen Binding Protein(ABP)
 Growth promoting effect  Cannot synthesize testosterone but
 Maintain spermatogenesis (along with FSH) contains aromatase. Aromatase
  Sebum & acne convert androgens to oestrogens.
 Development of male internal genitalia  Maintains high concentration of
 Hypothalamus Pituitary (LH) regulation androgen in tubular fluid via ABP.
Effects of DHT MIS
 Reaches peak at 1-2 years

 In fetal life development of male external
 Decreases at puberty
genitalia
 Secreted in very small amounts in
 After puberty temporal recession of hair line
girls
 At puberty growth of facial hair and acne
1 Note; Increase muscle mass, sex drive, libido depends on testosterone. NOT on DHT
 2017 A/L Repeat Campaign
2
 Spermatic arteries are tortuous

 Therefore, a countercurrent system is formed by it & the Pampiniform plexus to facilitate heat
& testosterone exchange
Spermatogenesis
Spermatogenesis [Spermatogonia  spermatid] Spermiogenesis

- Androgen independent [spermatid sperm (morphological changes)]
- In deep folds of the cytoplasm of theSertoli cells
- Androgen (hence LH) and FSH dependant
 Begins during Puberty
 Requires
 FSH
 Acts on Sertoli cells to facilitate late stage of spermatid development.
 Stimulate androgen-binding protein production.
 With testosterone, promote spermatogenesis.
 Testosterone
 LH indirectly
 Acts on G-Protein Coupling receptors on Leydig cells to stimulate testosterone synthesis.
 Trophic effects on Leydig cells.
 Locally produced oestrogen.
 Low Temperature 34C
Temperature is maintained by counter-current mechanism.
 Takes about 74 days.
 1 spermatogonium gives rise to 512 spermatids.
2
3
Further Maturation of Sperm
 Acquire progressive motility (the ability to move forward) by activating CatSper proteins in principal piece
of the sperm within epididymis.
 The CatSper protein forms an alkaline sensitive Ca2+ channel that becomes more active when the sperm
travels from the acidic vagina to the more basic cervical mucus.
 At rete testes, fluid is absorbed, and spermatozoa are concentrated.
 This is carried out by the activity of oestrogen on receptors in this region.
 Failure of this process leads to infertility.
 Spermatozoa contain olfactory receptors required for chemotaxis
Capacitation–
 Functional changes which make sperms able to fertilize.
 Occurs in isthmus of uterine tubes
 Increase motility
 Preparation for acrosome reaction
 Capacitation is facilitatory, not obligatory, because fertilization can be produced in vitro without it.
Acrosome Reaction
Breakdown of acrosome and release of enzymes- proteases
Proteolytic enzymes help in penetrating zona pellucida
Acrosomal reaction can occur in many sperms. But only one acrosome reacted sperm fuses with the oocyte.
3
4
Seminal Fluid
Testicular products Products of accessory glands

Sperms Fluid of Eg- Seminal vesicles (60% of seminal volume)
epididymis Seminal vesicle fluid contains Fructose, Ascorbic
acid & prostaglandins.
Prostate
“Fertile” Seminal Fluid

Chemical disrupters of Reproductive
Sperm count - 60-100million/ml
function
Volume - 2.5 to 3.5 ml/ ejaculate
pH – 7.35-7.5  Alcohol
Sperm motility - >40% actively motile  Smoking
Sperm morphology - <20% abnormal  Narcotics
Liquefication time - 5 to 30 mins  Pesticides/ Weedicides
Azoospermia – absence of sperms
Oligospermia – count <20 million
Asthenospermia – active motility <40%
4
5
Neuroendocrine regulation of male reproductive system
Hypothalamus
GnRH
Stimulation
Negative feedback
Anterior pituitary
LH FSH Male gonadotrophin secretion is
noncyclical
Leydig cells Sertoli cells

In both sexes main regulator of FSH is
inhibin
Testosterone Inhibin B
Estrogen Estrogen
 Castration causes increased levels of FSH & LH.

5
6
 Administered testosterone decreases sperm count due to negative feed back of FSH and LH.
 Testosterone doesn’t inhibit FSH at physiological concentrations but may do so in large doses.
 Inhibin is used as a male contraceptive. (Testosterone can also be used)
 Inhibins are produced in Sertoli cells in males and granulose cells in females.
 Testosterone mainly bound to GBG/SHBG.
 Androstenedione, estradiol and progesterone bound to albumin.
 Late spermatids & spermatozoa contain a germinal Angiotensin-converting enzyme.
6
Female Reproductive System
Menstruation
Periodic vaginal bleeding with shedding of uterine mucosa, from menarche to menopause which is absent during
pregnancy & sometimes during lactation. Most common cause for secondary amenorrhoea is pregnancy.
 Menorrhagia is excess bleeding during menstruation.
 Dysmenorrhoea is painful menstruation.
 Average - 3 to 5 days [normal – 1 to 8 days]

- 30 ml [normal – 0 to 80 ml]
28 days (range 21 to 35 days) < 21 d short cycle

>35 d long cycle
Note; Oogenesis begins during fetal life. No new ova formed after birth.
 Formation of an antrum around the oocyte causes the development of several antral
follicles
Development of
Recruitment of dominant follicle Formation & maintenance
follicles (1-5 d) Rest – become atretic. of corpus luteum
1 6 14 24 28
Dominant follicle; has the highest Ovulation Corpus luteum
capacity to secrete estragon regression begins
Follicular (proliferative) phase/Preovulatory Luteal (secretory) phase/Post-ovulatory

Phase – more variable Phase – less variable
Cyclical changes in reproductive organs
Ovarian Changes
Follicular phase Luteal phase

Recruitment of follicles Formation & maintenance of the corpus luteum
Emergence of dominant follicle Synthesis of estrogen, progesterone, inhibin
Synthesis of estrogen & inhibition

Ovary with different stages of ovum development
Pattern of secretion of reproductive hormones during the normal menstrual cycle
 FSH levels high in early follicular phase to stimulate granulosa cells to produce estragon. Decrease in
follicular phase and luteal phase due to negative feedback.
 LH levels initially low due to negative feedback. Peak happens at mid-cycle due to positive feedback from
high levels of oestrogen.
 LH surge occurs 9 hours before ovulation.
 Corpus luteum secretes oestrogen and progesterone in luteal phase and maintains FSH and LH at low
levels.
 Inhibin levels reach the peak at mid luteal phase. Then decrease allowing FSH levels to rise.
 Progesterone and oestrogen levels then decrease in late luteal phase due to formation of corpus albicans.
Endometrium is shed because high levels of oestrogen and progesterone are needed to maintain it in
secretory phase.
 Ovum lives for 72 hours after ovulation but fertilizable for 24 hours.
 Oestrogen levels show 2 peaks. Just before ovulation mid luteal phase.
Pattern of secretion of reproductive hormones during the normal menstrual cycle

Oogenesis
•2 million at birth --> 50% are atretic follicles

- 400 used for ovulation (300 000 at puberty)
- rest - undergo atresia at various stages of development
Primodial •primary oocyte (arrested in prophase of meiosis I)
follicles •Basement membrane
•1 layer of granulosa cells
•primary oocyte (Formed at puberty)
Primary •zona pellucida
follicles •additional layers of granulosa cells
•primary oocyte
•granulosa cells
Secondary
(Pre-Antral) •theca cells (interna + externa)
follicles •Theca interna- Andogen producing Theca externa-Protective capsule
•primary oocyte - eccentrically placed

•granulosa cells
•theca cells Many for
Antral
follicle •antrum formation each cycle
•produces oestrogen
•secondary oocyte (meiosis I- completed, meiosis II begun) 1 for each cycle

•granulosa cells
- for final maturation
•theca cells
Dominant - may be selected by
follicle •antrum
•becomes the Graffian follicle ability of follicle to
secrete oestrogen
•oocyte arrested in metaphase of meiosis II

•caused by pre-ovulatory LH surge.
Ovulation •weakening of follicular wall, rupture
•release of ovum & follicular fluid
•when graffian follicle ruptures, it fills with blood.

Corpus •fat cells get accumulated
haemorrha • bleeding from the folicle into the abdominal cavity may cause peritoneal
gicus irritation & abdominal pain.
•granulosa lutein cells

- secretes oestrogen, progesterone and inhibin
Corpus •theca lutein cells
Luteum - secretes androgens and progesterone
Corpus •regressed corpus luteum (4 days before the next menstruation)

Albicans

Uterine Cycle/Changes
Menstruation
•due to regression of Corpus Proliferative phase
luteum (5th - 14th day)
•endometrium - becomes thinner •rapid increase in
•spasm & degeneration of walls of thickness. (proliferation)
arteries due to locally produced •Straight uterine glands
prostaglandins --> ischemia and lengthen
necrosis of superficial layers -->
spotty haemorrhages --> •Maintained by estrogen
confluence --> menstrual flow
Secretory phase
•highly vascularised
•stroma oedematous
•coiled glands
•spiraling of the arteries
increased
Length of the secretory •secretes clear fluid
phase is more constant than •changes in cell adhesion
the length of the proliferative molecules etc Note Menstrual blood is
•later --> Prolactin mainly arterial and does
phase. production
not clot due to the
•Maintained by estrogen
& progesterone presence of fibrinolysin
Stratum functionale – Superficial 2/3rd Stratum basale – Deep 1/3rd

Long, coiled, spiral arteries Short, straight, basilar arteries
Shed. Not shed.
Uterine cervix does not undergo cyclical desquamation

Basal body temperature rises 1-2 days after ovulation due to progesterone.
Cervical mucus
Follicular phase Mid cycle Luteal phase

Volume Highest
Viscosity Lowest
Stretchability/Spinnbarkeit Highest
Ferning begins Well developed Disappears
Vaginal Epithelium changes
Oestrogen – Epithelium is cornified. (Fern pattern)

Note: Vagina does not
Progesterone – Thick mucus secreted (From cervix) have mucus glands
Epithelium proliferates and becomes
infiltrated with leukocytes.

6
Effects on breast
 Estrogen & progesterone act on the breast during the luteal phase.
 Swelling, tenderness, and pain during the 10 days preceding menstruation due to distension
of ducts and hyperaemia.
Anovular menstruation
 Can occur during the,
a. 1st 12 – 18 months after menarche
b. Before the onset of menopause
 Duration of the cycle is variable, but is always less than 28 days.
Follicle development fails to reach no ovulation & corpus

ovulatory maturity luteum is not formed
Estrogen synthesized
Endometrium develops absence of progesterone
Follicular atresia
Estrogen endometrium breaks
Oestrogen Synthesis
C LH FSH
Cholesterol
i
r Cholesterol Androstenedione
c A
u n
Androstenedione aromatase
l t
a r
Estrone Estrone Estradiol
t u
i Estradiol Granulosa m
Theca interna
o cells/theca lutein
cells/theca lutein
n in corpus luteum
in corpus luteum
Note;
 Both LH and FSH act by increasing cAMP levels
 Granulosa cells produce inhibin too
 LH also stimulate mature granulosa cells
Progesterone Synthesis by follicular cells
 Cholesterol → Pregnenolone in theca cells

 Pregnenolone → Progesterone in Granulosa cells
6
7
Neuro-endocrine regulation of the Menstrual Cycle
Hypothalamus Stimulate
GnRH Negative
Follicular
feedback
Ant. pituitary
LH FSH
Ovarian follicles
Oestrogen Inhibin
Hypothalamus Positive
Mid Cycle GnRH feedback
GnRH Ant pituitary
Stimulates secretion of FSH and LH. LH and FSH

Secreted in episodic bursts. Frequency
increases in late follicular phase resulting Dominant follicle
in LH surge. At mid cycle sensitivity to
normal GnRH levels is increased. (Self-
priming effect of GnRH). Catecholamines
Oestrogen++
increase pulse frequency of GnRH
GnRH
Luteal phase
Ant pituitary
LH stimulate progesterone LH and FSH
production. FSH and LH both
stimulate estrogen
production.
Corpus Luteum
Oestrogen Inhibin
Progesterone
7
8
Detection of ovulation
Menstrual history – regularity, Dysmenorrhoea (pain in menstruation),
Mid cycle pain (indicate the ovulation)
During second half of cycle – Serum hormones (progesterone day 21 to 24)
Changes in cervical mucus (watery change to viscid)
Rise in basal body temperature (1-2 days after ovulation)
Secretory endometrium
Visualization by ultrasound and laparoscopy (corpus luteum or Graafian follicle)
Oestrogen Progesterone
3 forms,  Thermogenic
 Regulation of hypothalamus and
 17β estradiol-Normal menstrual cycle
 Estrone-After menopause pituitary
 Estriol-Pregnancy  Breast-lobular, alveolar growth
Reproductive effects of Oestrogen  Endometrium-secretory changes

 Myometrium- ↓frequency and
 Secondary sexual characteristics
 Regulation of hypothalamus and pituitary intensity of uterine contractions
 Proliferation of endometrium  ↑Sebum/acne
 Myometrium - ↑contrac le proteins,
 cervical mucus thick & viscid and
excitability, gap junctions.
 Breast – duct growth, fat deposition & cellular
pigmentation of areola  Natriuresis
 Cervical mucus – thin, watery & alkaline  Stimulate respiration
 Oviduct motility
 (oppose most of the actions of
 Growth of ovarian follicles & reproductive
organs oestrogen)
 Increased ferning  Decrease of oestrogen receptors
 Increased libido
 No anabolic effect
Non-reproductive effects of Oestrogen
 Na+ and water retention

↓Sebum/acne
 Prevents osteoporosis
 Lipid metabolism – LDL  HDL 
 Glucose tolerance 
 Mitogen activity– tumour formation
 Bone epiphyseal closure (in both sexes)
 Vasodilation by increase of local NO
 Increased secretion of angiotensinogen &
8 Thyroid-binding globulin.
9
Menopause
Last menstrual period (45-55 yrs.)

Identified retrospectively. After menopause main product of oestrogen is estrone.
Climacteric: Period during which reproductive function diminishes.
Q. Why FSH, LH found in the urine of women after menopause in considerable amounts?
 Decrease of oestrogen & progesterone levels will reduce their negative feedback on FSH &
LH.
 No significant change in the progesterone levels as
it is produced by the corpus luteum.
Transitional period (4th decade) -
↓Reduc on in gonadotrophin- ↓Estradiol ↑FSH (Progesterone and LH no
responsive follicles Inhibin significant change)
After menopause -
↓Absent gonadotrophin- ↓Estradiol ↑ FSH, LH (Excreted in urine)
responsive follicles Inhibin Progesterone
Oestrogen synthesis after menopause

 Adipose tissue, Liver, Brain, Hair, Muscle
Adrenal cortex, ovarian stroma
Androstenedione Estrone (major product)
Testosterone Aromatase Estradiol
Adipose tissue, liver, brain, hair, muscle
Estrogen deficiency
 Hot flushes
 Atrophy of breast & reproductive tract
 Reduced vaginal acidity (reduced glycogen in cells – prone to infections)
 Dyspareunia (pain during sexual intercourse)
 Prone to IHD. Why?
 Behavioural & emotional changes
 Osteoporosis
Hot flashes (flushes)

 Set point of the central thermostat lowered
 Heat dissipating mechanisms are activated
9
10
 Wave of heat passing over the chest & spreading to neck, face, upper arms followed by
sweating
 Marked vasodilatation followed by vasoconstriction
 Oestrogen therapy brings relief
10
Fertilization & Implantation
Millions of sperms deposited in vagina
Chemoattraction by substances secreted by ovum (50 -100 sperms)
Penetration of corona radiata
Sperm head adheres to zona pellucida
Acrosomal reaction and penetration of zona pellucida
One sperm fuse with ovum, mediated by fertilin in sperm head, nucleus released, and fusion of
nuclei
 Sperms move up due to their own motility and due to propulsion of uterus and oviducts,
produced by oxytocin.
 Sperms fertile up to 72 hours in female genital tract
 Ovum fertilizable up to 24 hours after ovulation
 Most fertile period is 48 hours before ovulation
Fertilization usually occurs in the ampulla of the uterine tube
Events after fertilization
 Reduction in membrane potential of the ovum (Prevent polyspermy)

 Triggers development of the blastocyst
 Growth of corpus luteum
 Endometrium prepared for implantation
 Fertilized ovum transported to uterine cavity in 3-5 days
 Fertilized ovum divides continuously and forms a blastocyst
Blastocysts
Inner cell mass Outer cell mass
Along with endometrium

Forms foetus
Forms placenta

Implantation
 Usually, upper posterior part of uterine cavity.
 Endometrium→decidua
 Blastocyst lies in a cavity of endometrial glands.
 Maternal vessels eroded by trophoblast; blood extravasates around blastocyst
Corpus luteum of pregnancy

 Starts enlarging after fertilization in response to HCG secreted by placenta.
 Secretes oestrogen, progesterone, and relaxin.
 After 6wks function is taken over by the placenta.
 Therefore, removal of ovaries before the 6th week causes abortion.
 Though the functions of the corpus luteum declines after the 8th week, it persists
throughout pregnancy.
Placenta
 Exchange of O2,CO2, nutrients, waste products

 Hormone production (hCG, hPL, Oestrogen, Progesterone)- almost all the body hormones
 Barrier function
 Placental circulation: no direct mixing of maternal and foetal blood occurs.
Oestrogen synthesis during pregnancy 37th week of gestation is called the Term
Source - Corpus luteum of pregnancy-2/3months
Feto placental unit
Main type-estriol
Functions- Enlargement of uterus, genitalia
Enlargement & ductal proliferation of breast
Relaxation of pelvic ligaments
Placenta Fetal adrenal
Cholesterol
Pregnenolone DHEAS 16OHDHEAS
Progesterone Cortisol, Corticosterone Urinary estriol excretion by

mother is an index of the state
of the foetus.
Estradiol DHEAS
Estriol 16OHDHEAS
(Principal)
 Urinary excretion of estriol is considered to be an index of the state of the fetus.
Progesterone synthesis during pregnancy

Sources - Corpus luteum -2/3months
- Placenta

Functions -Development of decidual cells
-Prevents uterine contraction
-Nutrition and cleavage of the early embryo  hCG, LH, FSH & TSH have the same α
- Prepares breasts for lactation subunit
 hCG has the same receptor as LH
 The structures of hCS, GH & Prolactin
Endocrine changes during pregnancy are similar as they are derived from a
common precursor.
hCS
hCG: - (glycoprotein)
 Secreted by the syncytiotrophoblast(also; Fetal liver ,kidney or even by GIT tumours)
 Primarily luteinizing effect. (prevent degeneration of CL)
 Acts on the same receptors as LH.
 Present in blood  6 days after conception/fertilization Basis of
present in urine  14 days after conception/fertilization pregnancy test
 Peak-10th week
 Detectable even before missing menstruation.→Sensitive method to detect pregnancy
Human Chorionic Somatomammotropin(hCS) / hPL

 Secreted by syncytiotrophoblast
 Lactogenic
 Structure similar to GH & Prolactin
 progressive increase throughout the pregnancy
 (Maternal Lipolysis ↑ & glucose utilization↓) Glucose for the fetus.
 Pregnancy induced diabetes mellitus.
 K+, Ca2+, Na+ retention
 Amount secreted is proportionate to size of the placenta.
low hCS placental insufficiency.
Relaxin
 Polypeptide
 Found in prostate gland in men (involved in sperm motility & penetration)
 Found in the secretory phase, not proliferative phase
 Secreted by
 Corpus luteum  Uterus
 Placenta
Actions
 Relaxes pubic symphysis & other pelvic joints
 Softens and dilates uterine cervix
 Inhibits uterine contraction
o hCG and relaxin – peak in first trimester
o oestrogen,progesterone,hCS – peak at term
Amniotic fluid
o 300-800 ml term
o Similar to ECF. Contains waste products, foetal cells
o Allows free movement, diffusion of external trauma, provides constant environment
o Amniocentesis for pre-natal diagnosis
Diagnosis of pregnancy
Clinical: Amenorrhoea Foetal heart sounds
Uterine enlargement Breast, skin changes
Nausea, vomiting Frequency of micturition
Investigations: Biological,immunological assays Ultrasound scanning
Period of gestation-280days from the 1st day of the last regular period
37thweek→term
conception
1st 2nd 3rd trimesters
12 28 40 weeks
Last regular menstrual period
 GnRH & inhibin are sereted by the placenta.

 GnRH stimulates & inhibin inhibits hCG secretion.
 Therefore, hCG secretion is regulated.
 The placenta also secretes prolactin.
Changes in other systems during pregnancy
General -
o Weight gain
o Increased BMR (5-25%)

o Uterus
o Decidual reaction-endometrial changes during pregnancy
o Hypertrophy - the enlargement of the uterus by the increase in size of its cells
o Hyperplasia - the enlargement of the uterus by an increase in the number of its cells
o ↑vascularity
o Changes in connective tissue and contractile proteins
Cervix,Vagina, Vulva
o Cervix softens, ↑vascularity and secretions
Skin
o Linear nigra
o Striae gravidarum
Breast
o Enlarge to almost double size

o Dilated veins become visible
o Nipples, areola enlarge & get pigmented
Blood & cardiovascular system
o Blood volume↑↑with haemodilution Physiological anaemia
o Plasma volume (40-50%) RBC mass(20-30%)
o Relatively hypercoagulable(prevent excess bleeding at delivery)
o Albumin, globulin& fibrinogen ↑ESR↑
o HR,SV Cardiac output↑
o ↓Diastolic blood pressure. Lowest in 2nd trimester and then rises to non-pregnant level. Why?
o No change in pulmonary BP
o Ankle oedema due to
 venous stasis (reduction in venous tone compression of pelvic veins by uterus)
 Fluid retention (about 5L)
 Decreased colloid osmotic pressure
Urinary tract
o ↑RBF, GFR (↓serum creatinine, urea)
o ↓Tubular reabsorption – renal glycosuria
o ↑ frequency of micturition
o ↑renal size, hydronephrosis,hydroureter
Respiratory system
o ↑minute ventilation&respiratory rate.
o ↑IRV, Tidal volume
o ↓RV, FRC(Uterus exert pressure on diaphragm; more thoracic muscles used)
o ↑oxygen consumption
o ↓arterial / alveolar PCO2
Gastro-intestinal system
o Nausea, vomiting (morning sickness, hyperemesis gravidarum)
o Alteration of appetite
o Tone, motility↓,gastric emptying time prolonged
o Constipation
o Gastro-oesophageal reflux- heart burn in pregnancy (↓sphincter tone)
Locomotor system- Softening of ligaments and joints
Metabolic changes
o ↑Fat mobilization and tendency of ↑ketoacidosis

Parturition
Changes during the last 2 to 3 weeks of pregnancy culminating in child birth
Final maturation Ripening and

of fetal organs Activation of myometrial
softening of the
contractile apparatus
(lung, liver etc) cervix
Oestrogen
 Increase gap junctions between myometrial cells (function as syncytium)
 ↑prostaglandin synthesis
 Increase uterine contraction by ↑ contractile proteins
 Increase no. of oxytocin receptors
Prostaglandins
 Ripening of cervix
 Myometrial contractions (↑Ca2+ ions for actin myosin interactions)
Ripening - Events happening in the cervix during parturition
 dilate
 Softens
Increase in oxytocin receptors distension of uterus

Oestrogen
Oxytocin
Endometrium
Myometrium Prostaglandin synthesis

Positive
feedback Uterine contraction
mechanism
Dilation of cervix &Distension of vagina
Nerve endings stretched
Neural impulses to hypothalamus
Oxytocin release
 In early labour, maternal plasma concentration of oxytocin, is not elevated from the pre-
labour value. There is only a marked rise in receptors.
 It is considered that the signal for birth to occur is given by the fetus.

Increase of
CRH produced
 Surfactant in the lungs matures at around 32- 34 weeks
by fetal of fetal life.
hypothalamus  Therefore, premature babies who lack functioning
surfactant may experience Infant Respiratory Distress
& placental Syndrome
CRH  This may result in death due to collapse of alveoli.
Increase of ACTH
Increase of Cortisol
Maturation of
Respiratory system

Labour
Painful uterine contractions aided by voluntary contractions of, maternal abdominal muscles for
expulsion of uterine contents
Beginning of painful uterine contractions
Full cervical dilation
Birth of baby
Delivery of placenta
Puerperium
Changes in pregnancy revert approximately to the non-pregnant state during the 6 weeks from
child birth
Lactation is established.
Systems come to non-pregnant levels
Lactation
 During puberty
Oestrogen Progesterone
Developments of ducts development of lobules & alveoli
 During pregnancy
 [Oestrogen]&[ progesterone] are high
 Prolactin levels increase steadily in term  Full lobulo-alveolar development of breast
 Milk secretion is inhibited by oestrogens.
 Ejection of milk
 Expulsion of placenta initiates lactation.

Prolactin – Regulation of Secretion
Hypothalamus
 Suckling
Dopamine Pregnancy
(-) Sleep
 L – Dopa Stress
(+) Pituitary
 Apomorphine Exercise
(+) Nipple stimulation
 Bromocriptine
(Dopamine agonists) Prolactin Sexual intercourse in women
Hypothyroidism (TRH)
Phenothiazine
VIP and other polypeptides
Suckling
Sensory nerve endings in nipples stimulated
Hypothalamus
Oxytocin ↓Dopamine
Contraction of myoepithelial cells ↑ Prolactin
Milk ejection/ let down ↑Milk production
(↑mRNA of milk proteins-
Lactalbumin, casein
↑mRNA of UDP-galactosyltransferase
Oestrogen – prevents lactation
 Binding of PRL to receptors
 Milk volume
Progesterone – prevents initiation
No effect once established
Prolactin
From anterior pituitary
Secretion inhibited/regulated by dopamine (prolactin inhibiting hormone)
A peptide, structurally similar to GH &hCS.
Receptors resemble GH receptors
1) InhibitsGnRH secretion and action of it on pituitary
2) Antagonizes the gonadotrophins' actions in ovary
So, women who nurse regularly have amenorrhea for 25 – 30 weeks (who do not - up to 6 weeks)

-Lactational amenorrhoea-
Hypothalamus
GnRH
-
Prevent
↑ Breast ↑ Prolactin - Anterior
pituitary
menstruation
feeding & ovulation
- FSH/LH
Contraceptive
Ovary effect
Oestrogen& Progesterone
After resumption, there are anovulatory cycles in the first 6 months

If no lactation, menstruation returns 6/52 postpartum.
Lactation has a high influence by the brain centre .

Reproduction
Contraceptive methods
Contraception; The practise followed by individuals or couples to prevent women becoming

pregnant as a result of sexual intercourse
Contraceptive methods
Natural methods Artifeticial methods
Periodic Coitus Lactational

Temporary Permanent
Abstinence Interruptus Amenorrehoea
Basal Body Temperature

Method
Male Female Male Female
Barrier
Ryhthm/calander method Condoms
Methods Hormonal IUCD Vasectomy LRT
Subdermal
Cervical Mucus method Condoms OCP DMPA
Implants
Symto-thermal Method Diaphragm COC
Spermicidal
POP
Creams
Emergency CP

Natural methods
Contraceptive Mechanism of action Advantages Disadvantages
Periodic Abstaining from sexual  User controlled  Require skill &

Abstinence intercourse during women’s  Readily available motivation
fertile period  Low cost  Signs of fertility may not
The fertile phase can be  Safe and free of side be reliable
estimated by calendar effects  Requires partners
method*, cervical mucus cooperation to abstain
method**  No protection from STDs
,basal body temperature
method,*** or sympto
thermal method****
Coitus Removal of the penis from  Not reliable
interruptus the vagina immediately
(Withdrawal before ejaculation takes
method) place
Lactational Nursing→Stimulates  Not reliable

Amenorrhoea Prolactin→Inhibit  No protection from STDs
(For breast GnRH→Reduce LH &
feeding women) FSH→Inhibit ovulation
*calendar method
Record the length of at least six menstrual cycles
 Subtract 18 from the shortest cycle (Gives the probable 1st day of fertile
period)
 Subtract 10 from the shortest cycle (Gives the probable last day of fertile
period)
Avoid sexual intercourse during fertile period
**Cervical mucus method

Avoid sexual intercourse 1st sensation or observation of watery thin mucus until 4th days
after slippery wet sensation has gone (Dry days are infertile)

***Basal body temperature method
Measure temperature daily, immediately after waking up, before getting out of bed or
drinking tea. Use the same thermometer. Sexual intercourse can take place on the 3rd day
where the consecutive daily temperature has been above the level of previous six days. It is
safe to have intercourse from this day until the next menstrual cycle begins
**** sympto thermal method
Combination of Basal body temperature, calendar and cervical mucus method
Barrier methods
Contraceptive Mechanism Advantages Disadvantages
of action
Male condom Prevent entry  Prevent sexually  Some may find it difficult to
of sperms to transmitted use correctly (correct
vagina diseases technique)
 Safe to use  less effective if not used
 No systemic correctly
effects  Require partner corporation
 Easy to initiate  May interrupt sexual
and discontinue activity
 Do not require  Cultural barriers may
Female clinic visits prevent use
condom/Diaphragm  Immediate return  Need proper storage and a
to fertility after continuous supply
discontinuation

Hormonal methods
Contracept Mechanism of action Advantages Disadvantages

ive
Combined  Inhibition of ovulation  Reduce menstrual  Side effects

oral and follicular irregularities  Increased risk
contraceptiv development  Users of COC generally of thrombo-
e pill (COCP) (Negative feedback have light pain free regular embolism
effect of oestrogen periods  Drug
and progesterone )  Improve premenstrual interactions
 Make endometrium syndrome  No protection
hostile and atrophic to  Reduce risk of pelvic against STDs
an implanting embryo inflammatory diseases  Adverse effects
(Progesterone)  Protection against ovarian on lactation
 Thicken cervical mucus and endometrial cancers  So, should not
to prevent sperms  Rapid return to fertility be used if
ascending to the when discontinued lactating
uterine cavity  Highly effective
(Progesterone)
Progesterone  Thickens cervical  Suitable for women who  No protection
only pills mucus cannot use COCP due to against STDs
(POP)  Inhibition of ovulation breast feeding, with
 Makes endometrium diabetics, with
thin & atrophic cardiovascular risk factors
and at times of low
fertility.
Injectable  Suppression of  Highly effective  Weight gain
hormonal ovulation  Safe, can be used at any  Persistence
contraceptives  Change of cervical age menstrual
(Depot mucus  Need to be taken only once irregularities
Medroxy  Atrophy of in every three  Delay in return
Progesterone endometrium months(Lasts 12-13 weeks) of fertility
acetate  Alteration of tubal
DMPA) motility

Subdermal  Increase viscosity of  Return to fertility  Weight gain
implants cervical mucus immediately after removal  Menstrual
which release  Suppression of  Provide protection for 5 irregularities
levonorgestrel endometrium years  No protection
(Jadelle,  Inhibition of ovulation over STDs
Norplant,
Implanon)
Hormone  Induce an  Effective for 10 years  Increased
releasing inflammatory  Immediate return of menstrual
Intra uterine response in the fertility after removal blood loss
contraceptiv endometrium that  Increased
e device prevents ovulation dysmenorrhoea
(IUCD)*  Local hormone effects  Risk of pelvic
on cervical mucus and inflammatory
endometrium. disease
 Expulsion of
IUCD
 Clinic visit is
needed for
inserting
* IUCDs are Small flexible device usually made of plastic. They are three types
 Inert
 Copper bearing – Most efficient emergency contraceptive method available
 Hormone releasing-Release progesterone
Permanent contraceptive methods (sterilization)

 Voluntary surgical contraception
 Permanent method

Contraceptive Mechanism of Advantages Disadvantages
action
Female sterilization  Mechanical  No need of  High cost
(LRT) blockage of constant use of  Invasive
both fallopian contraceptives  Although
tubes to  Useful with there are
prevent sperm people who have surgeries to
reaching and completed obtain
fertilizing the families, and fertility again,
ovum people with their
Male sterilization  Division of both health issues effectiveness
(Vasectomy) vas deference where pregnancy is very low
to prevent is contraindicated
release of
sperms during
ejaculation
Emergency contraceptives
 Not recommended for regular use

 Following unprotected intercourse to prevent unplanned pregnancies
 Can prevent pregnancies but unable to interrupt an established pregnancy
 Effective only if administered in the first few days following intercourse
 Levonorgastrel (Progesterone only method) & Copper bearing intra uterine
contraceptive devices Cu-IUCD) are commonly used

Contraceptive Mechanism of Timing of the Advice to the user
action tablets
Levonorgestrel  Prevent or  First pill within 72  Has to be taken within
0.75mg (Prostinor delay hours of 5 days of unprotected
2) ovulation unprotected intercourse
Two tablets  Thicken intercourse  Nausea and vomiting
cervical  Second pill 12 are side effects
mucosa hours after taking  If vomited within 2
first pill hours of intake
further dose should
be taken ASAP
Note; Though 4 low dose COC pill within first 72 hours and then another 4 COC pills
after 12 hours can be taken Instead of Prostinor , they are intolerance due to severe
side effects
Cu-IUCDs Copper prevents Should be inserted  If a woman is
fertilization by within 5 days (120 pregnant should not
causing a hours) of be used
chemical change unprotected  Most effective form of
that damages intercourse emergency
ovum & sperm Most efficient contraception
emergency available
contraceptive  Safe method-Risk of
method available infections, expulsion,
& perforations are
less

pH and Buffers
pH
𝐩𝐇= −𝐥𝐨𝐠𝟏𝟎[𝐇+] (where [H+] is in moles/dm3 or moles/litre)
 Unit change in pH changes [H+] by ten-fold (e.g. when pH increases by 1, [H+] decreases
by 10 times)
 Biological systems (e.g. enzymes) are extremely sensitive to changes in pH.
pH < 7.2 → acidosis pH > 7.6 → alkalosis
 Conjugate Acid-Base pair: A proton donor and its corresponding proton acceptor
Dissociation of Weak Acids and the Henderson-Hasselbalch Equation
HA ⇌H+ + A−
Acid dissociation constant = Ka
𝐾𝑎 =[𝐻+][𝐴−]
[𝐻𝐴]
(Higher the Ka, better the dissociation of the acid)
[𝐻+ ]=𝐾𝑎[𝐻𝐴]
[𝐴−]
−log10[𝐻+] = −log10𝐾𝑎−log10[𝐻𝐴]
[𝐴−]
𝐩𝐇=𝐩𝐊𝐚+𝐥𝐨𝐠𝟏𝟎[𝐀−]
[𝐇𝐀]
The pKa of any acid is equal to the pH when [A-] = [HA]
Drug absorption – an application of the Henderson-Hassel Bach equation:
 Weak acids (e.g. aspirin, pKa ≈ 3.5) are in the unionized form in the stomach
(due to its highly acidic pH)
 Unionized form of a drug (i.e. HA) is more soluble in phospholipid bilayer
 Therefore, will cross the cell membranes more rapidly and move into blood

 In the blood, at physiological pH, they are in the ionized form (i.e. A–) and do not flow back
into the stomach
Buffers
 Substances that resist pH changes
 Combinations of H+ donors and H+ acceptors (weak acids or weak bases)
 Mixture of weak acid/base and its conjugate base/acid
 Buffers work by accepting H+ when they are in excess and donating H+ to the solution
when they are depleted
 Buffering capacity depends on the type of buffer and the molarity of the solution
 Optimum activity of buffer occurs when pH = pKa (i.e. when [A-] = [HA])
 Maximum buffering capacity in the pH range (pKa ± 1)
 Conjugate acid-base pairs act as buffer when pH = pKa
 Buffering systems in the body: (controlled by lungs/kidney)
In plasma: H2CO3 ⇌ H+ + CO32−
In RBCs: HHb ⇌ H+ + Hb (Hb = deoxygenated haemoglobin)
In body cells: protein∙H ⇌ H+ + protein
In urine: NH4+ ⇌ H+ + NH3

H2PO4− ⇌ H+ + HPO42−
H2CO3 ⇌ H+ + CO32−

MEDICAL DIAGNOSTICS
Biochemical diagnostic tests
Diagnosis of any disease is first done by considering the medical history and physical examination &
can be confirmed by lab diagnostic tests. Also, they are important in determination of,
 severity of the disease
 Assess patient response to specific treatments
Common biochemical tests in medicine,
 Testing for glycemic levels

 (Diabetes mellitus)
 Cardiac biomarkers
 Lipid profile
 Liver function tests
 Renal profile
 Urine testing
Types of samples that are commonly used,
 Body fluids - blood, serum, plasma, urine, cerebrospinal fluid (CSF), feces.
 Body tissues (Biopsy) - tumors.
Preparation of blood samples
Blood collection or Phlebotomy - drawing blood from a vessel for laboratory analysis. Different
specimens may be used,
 Whole blood
 Serum
 Plasma

Whole-blood specimen
 It must be analyzed within limited time because,

 Over time, cells lyse in whole-blood which changes the concentration of some analytes.
Eg - ↑ K+, Phosphate & Lactate Dehydrogenase (LDH)
 Some cellular metabolic processes continue which alters the concentration of some
analytes.
Eg - ↓ Glucose & ↑ Lactate
(NaF coated test tubes are used for Blood glucose level tests, because F -
ions inhibit the Enolase enzyme, thereby preventing Glycolysis)
Plasma and serum
 Serum is same as plasma except that it does not contain clotting factors, but plasma
contains all clotting factors.
Eg - Fibrinogen.
 Anyway, serum and plasma contain the same contents of electrolytes, enzymes,
proteins & hormones.
Enzymes in serum / plasma
1) Constituent enzymes
 has a functional role in serum

 present in ↑ concentrations in serum
Eg - Thrombin, Plasmin, Lipoprotein Lipase.
2) Non-constituent enzymes
 No functional role in serum

 generally present in ↓ concentrations
 present in ↑concentrations in plasma, by leakage from tissues, due to,
 ↑ Cell permeability (Toxins)
 ↑ Cell death (necrosis)
 ↑ Cell turnover (neoplastic tissue)
 ↑ Synthesis
Eg - Gamma Glutamyl transferase in response to alcohol
 ↑ Obstruction to route of secretion
Eg - ALP in cholestasis
 life time in plasma - 10 h to 5 days

 secreted (excreted) in,
 Urine - Amylase (related with Pancreatitis)
 Bile - ALP (related with Liver diseases)
 Increment of these enzymes may indicate tissue damages or changes in

metabolism, but also, it may not indicate a disease.
Eg - Transient Hyper-phosphatasemia in infancy

 ALP level may increase in serum 20 times than normal, can observed in
children 2-38 months old, without any diseases.

Changes in the serum color may indicate,
 Haemolysed - serum appears pink to red due to rupture of RBCs. (haemoglobin)

 Icteric - serum appears yellow due to high bilirubin.
 Lipemic - serum appears milky or turbid due to high lipid.
Heamolysis
 In heamolysis plasma or serum appears pink to red in colour because of liberation of Hb

due to rupture of RBCs. When phlebotomy heamolysis must be avoided.
 Because it causes elevation in K+, Ca2+, Phosphate, SGOT (Serum Glutamic Oxaloacetatic
Transaminase/AST), LDH & Acid phosphatases.
Temperature effect on Heamolysis,
↓ Temperature ↑ Stability
 Denaturing of enzymes & Sun-light damage to cell membranes, can leads to heamolysis.
Blood glucose levels (Diabetes Mellitus)
Investigations for glycaemic level
 Fasting plasma glucose

 Random plasma glucose
 Oral Glucose Tolerance Test (OGTT) - 2h plasma glucose test.
 HbA1c test
 Capillary blood glucose test – GLUCOMETER (for home monitoring)
 Urine glucose tests
WHO diagnostic criteria for the diagnosis of Diabetes Mellitus
 Diabetes Mellitus
Fasting plasma glucose - ≥ 7.0 mmol/l [126 mg/dl] or
2h plasma glucose - ≥ 11.1 mmol/l [200 mg/dl]
 Impaired Glucose Tolerance (IGT)

Fasting plasma glucose - < 7.0 mmol/l (126mg)
2-h plasma glucose - 7.8 and - 11.1 mmol/l
[140 mg/dl – 200 mg/dl]
 Impaired Fasting Glucose (IFG)

Fasting plasma glucose - 6.1 - 6.9 mmol/l [110 mg/dl - 125 mg/dl]
2-h plasma glucose - <7.8 mmol/l [140 mg/dl] (if measured)

WHO criteria for interpreting 2h OGTT
ADA (American Diabetes association) Criteria for the diagnosis of Diabetes Mellitus.
 HbA1c ≥ 6.5% (OR) up to 6.5 is normal (OR)

 FPG ≥ 126 mg/dl (7.0 mmol/l) (OR)
Same as WHO
 2 - h plasma glucose ≥ 200 mg/dl (11.1mmol/l) (OR)
 In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
plasma glucose ≥ 200 mg/dl [11.1 mmol/l]
Tests for analysis of plasma glucose level
1) Glucose oxidase method (GOD - POD method / Glucose Oxidase - Peroxidase)
GOD
Glucose + O2 + H2O ------------------> Gluconolactone + H2O2
Peroxidase
2H2O2 + 4 NH3-phenazone + Phenol----------------------> 4 Phenazone (Quinonimine) + 4H20
 Quinonimine is a pink colored compound & its' concentration can be measured by

colorimetry.
 Hexokinase method
 Glucose Dehydrogenase method
 Orthotoluidine method
 not commonly utilized nowadays, because Orthotoluidine is carcinogenic
2) Oral Glucose Tolerance Test (OGTT)
 OGTT is not recommended for routine diagnosis of type 1 or type 2 diabetes.

 Recommended for establishing the diagnosis of GDM - Gestational Diabetes Mellitus.
 When Fasting Plasma Glucose (FPG), in the Impaired Fasting Glucose (IFG) range, 100 - 126
mg/dl, an OGTT is recommended.

 Procedure;
 3 days unrestricted carbohydrate diet
 Overnight fast
 Oral ingestion of 75 g glucose, in 250 - 300 ml of water over 5 min
 Collect blood samples - just before (fasting) & 2h after glucose load.
3) Glycated Hemoglobin Test (HbA1c)
 Measurement of glycated hemoglobin (also called HbA1c, glycohemoglobin & glycosylated

hemoglobin)
 Average amount of HbA1c reflects the mean blood glucose concentration over the previous
6 to 8 weeks.
 Estimation of mean blood glucose by HbA1c
 labile A1c formation is directly proportional to the blood glucose concentration
 Glucose can attach to many proteins via a non-enzymatic process.
 A reversible reaction leads to the formation of an unstable aldimine (labile 2) Followed by
an Amadori rearrangement to form an irreversible stable ketoamine.
Factors causing misleading results in HbA1c test (A1c values are influenced by red cell survival)
 Falsely high values

 low red cell turnover / disproportionate number of older red cells in circulation
Eg: Iron, Vitamin B12 or Folate deficiency anemia
 Falsely low values

 rapid red cell turnover / greater younger red cells in circulation
Eg: Haemolysis, Haemoglobinopathies
Cardiac biomarkers
(MI - Myocardial Infarction)
Characteristics of Cardiac biomarkers
 Are myocardial proteins

 Are markers of myocardial damage
 They differ with other proteins in,
 location within the myocyte
 release after damage (depends on location & molecular weight)
 clearance from the serum
 Characteristic rise and fall pattern
 Ruling out a Ml requires;

a) A test with high diagnostic sensitivity
b) A test with high diagnostic specificity
 Cardiac biomarkers should be measured in all patients who present with chest
discomfort consistent with Acute Coronary Syndrome (ACS).

 Some important markers of myocardial ischemia / necrosis,
1) Cardiac troponins
2) Creatine kinase (isoenzymes)
3) Lactate dehydrogenase (isoenzymes)
4) Myoglobin
5) Heart fatty acid binding protein (h-FABP)
6) Natriuretic peptides (BNP & NT-pro BNP)
Troponin
 Troponin is a protein released from myocytes, when irreversible myocardial damage occurs.
 It is highly specific to cardiac tissue
 Accurately diagnoses myocardial infarction with a history of ischemic pain or ECG changes
reflecting ischemia.
 Considered as the “gold standard” for the diagnosis of acute myocardial infarction (AMI).
Cardiac troponins l & T
 Specific cardiac isoforms of TnT & Tnl are possible to detect, & they are located in the thin
filaments of myofibrils. They are consisting of 3 isoforms.
 cTnT, cTnl (specific to heart) released early, peak at 12-24 hours and remain
elevated for 7-10 days.
 TnT is also released in small amounts by skeletal muscles. But clinical assays
do not detect skeletal TnT.
 TnC is similar in cardiac and skeletal muscle. So it is not cardiac specific.
 Fewer false positive results in the presence of skeletal muscle injury.
 Discriminates myocardial injury even when CK-MB is minimally increased.
Creatine kinase (CK)
 CK - 1 (CK - BB)
 Brain fraction
 CK - 2 (CK - MB)
 specific to myocardium (greater concentrations in cardiac muscle)
 10 - 20 % of total CK activity
 Following AMI, it rises within 3 - 8 hrs & peaks in 10-24 hrs
 Plasma t1/2, is about 12 hrs
 Returns to normal in 48-72 hrs, in contrast to troponins
 CK - 3 (CK - MM)
 in skeletal & heart muscle

Lactate Dehydrogenase (LDH)
 LDH is a cytosolic enzyme, which is found in all tissues.

 Consists with five isoenzymes, which are LD 1,2,3,4 & 5.
 Anyway LD -1 & LD - 2 are found in heart muscle, kidney cortex & RBCs.
 But LD-1 is normally found in heart muscle & LD-2 is predominantly found in blood serum.
 So plasma LD may reflect a normal leakage.
 But in post Ml - LD activity rises 5-fold & comprises LD - 1 & LD - 2 with LD - 1 > LD - 2.
Myoglobin
 It’s an Oxygen binding protein in cardiac & skeletal muscles.

 It is smaller in size & located in cytoplasm, hence early appearance in
circulation.
 Released earlier than CK (about 1 hr after MI). So it's useful for early detection, but
non-specific because it increases in serum after trauma to skeletal or cardiac
muscle.
Change in cardiac biomarkers over 6 days
Lipid Profile - Blood Cholesterol Level (Hypercholesteremia)
Precautions
 9 - 12 hours of fasting to avoid Chylomicrons.

 Person should be seated for at least 5 minutes, prior to phlebotomy to avoid
haemoconcentration.
 Blood should be collected in tubes / bottles, without anticoagulant for serum.
 Blood should be collected in tubes with EDTA for plasma.

Friedwald formula
 Direct measurement of LDL is time consuming, expensive & requires specialized equipment.
 So, LDL is most commonly estimated from quantitative measurements of Total Cholesterol (TC),
HDL & plasma Triglycerides (TG) using the Friedwald Formula.
 If concentrations measured by,
 mg/dl, [LDL-c] = [TC] - [HDL-c] - [TG/5]
 mmoI/L, [LDL-c] = [TC] - [HDL-c] - [TG/2.2]
 The quotient - TG/5 is used as an estimate of VLDL concentration. It assumes, that all the
plasma TG is carried on VLDL & the TG: VLDL ratio is constant at about 5: 1
 Limitations of the Friedwald formula,

 Not valid, if TG > 4.6 mmol/L (400 mg/dl)
 Cannot use under the presence of Chylomicrons
 Cannot use for patients with Dysbetalipoproteinemia
Classification of total & HDL cholesterol

Total cholesterol
< 200 mg/dl - desirable
200 - 239 mg/dl - borderline high
≥ 240 mg/dl - high
HDL cholesterol
< 40 mg/dl - low
≥ 60 mg/dl - high
Serum triglycerides
< 150 mg/dl - desirable
Three categories of risk that modify LDL goals in adults
Risk category LDL goal (mg/dl)

 CHD & CHD risk eq. (CHD - Coronary Heart Diseases) <100
 Multiple (2+) risk factors <130
 0 - 1 risk factors <160

Serum Creatinine - GFR
 Glomerular Filtration Rate (GFR), is measured by using Cockcroft – Gault formula.

(overestimated results with Cr cl)
Cr cl = (140 - age) x Mass (kg) x (0.85 if female)

72 x Serum creatinine (mg/dl)
Urine Testing
Microalbuminuria
 It’s a clinical condition, which moderate increase in the level of urine Albumin.
 It's a marker of vascular endothelial dysfunction & important marker for kidney diseases
in Diabetes Mellitus, Hypertension.
 During this phase
 It's associated with retinopathy, peripheral vascular disease and neuropathy.
 Blood pressure increases and lipid abnormalities develop in this phase, so, strongly predictive
of death from a cardiovascular disease.
 Also, Glomerular filtration rate (GFR) starts to decline during the phase of Microalbuminuria.
Diagnosis;
 Excretion of 30 - 300 mg of Albumin / 24 h urine collection.
 ACR (Albumin / Creatinine Ratio) 30 - 300 mg/g.

Term 4
Anatomy – Term 4
SKULL
 Skull is the skeleton of the head. Skull also includes the mandible
Brain case (calvaria) Facial skeleton

 Paired  Paired
1. Parietal 2. Temporal 1. Maxilla 2. Zygomatic 3. Nasal 4. Lacrimal 5.Palatine
 Unpaired 6.Inferior nasal concha
1. Frontal 2. Occipital 3. Sphenoid 4. Ethmoid
 Unpaired
1. Mandible 2. Vomer
SKULL JOINTS
1. Fibrous joints – immovable
2. Few primary cartilaginous joints
3. Pair of synovial joints – temporomandibular joints
 Sutures start ossifying from INSIDE between 30 – 40 years

 Sutures complete ossification on the outside at about 50 years
EXTERIOR OF THE SKULL
1. Superior view (norma verticalis)

Clinicals
Fontanelle: sites of growth of skull – permits growth

Anterior fontanelle: Lies between four bones. Bounded by
Two parietal bones from behind, the two halves of the
frontal bone lie in front.
Overlies the superior sagittal dural venous sinus.
Closed by 18 months bregma
Posterior fontanelle: Lies between apex of squamous part

of occipital bone & posterior edges of the two parietal
bones.
Closed by 3 months lambda
Sphenoidal & mastoid: Smaller fontanelles at lateral

sides; sphenoidal more anteriorly & mastoid posteriorly
During vaginal delivery, helps to reduce the size of the

skull.
Coronal suture: between frontal & parietal bones

 Sagittal suture: between the parietal bones
 Lambdoid suture: between occipital & 2 parietal bones
 Metopic suture: between 2 frontal bones
 Vertex: highest point of sagittal suture
 Bregma: coronal & sagittal sutures meet – anterior fontanelle in the foetal skull, closed by 18 months
 Lambda: sagittal &lambdoid sutures meet – posterior fontanelle in foetal skull, closed by 3rd month
 Parietal eminence- most prominent part of the parietal bone – commonly fractured
 Parietal foramina – transmits emissary veins in front of the lambda
 Temporal lines begin from zygomatic process of frontal bone and then divide into superior & inferior lines over
parietal bone. Superior line lost over posterior part.

2. Posterior view
(norma occipitalis)
 External occipital protuberance – junction of head & neck, most prominent point – INION
 Superior nuchal line – junction of head & neck – pass from the protuberance
 Highest nuchal line – begin from upper part of the protuberance
 Occipital point – above inion farthest from glabella
 Occasionally interparietal bone present
Lateral view
(temporal view)
 Zygomatic arch – temporal process of zygomatic bone + zygomatic process of temporal bone
 Jugular point – anterior end of zygomatic arch
 PTERION: point where frontal, parietal, temporal, sphenoid bones meet
- Deeply lies middle meningeal vein, anterior of middle meningeal artery & stem of the lateral sulcus of the
brain (7.17 C) grants
- 4cm above zygoma, 2.5cm behind frontozygomatic suture
3. Norma basalis
*attachments
 Pharyngeal tubercle: raphe of superior constrictor
 Medial pterygoid: pharyngobasilar fascia, superior constrictor, pterygomandibular raphe
 Lateral pterygoid plate: lateral pterygoid and medial pterygoid
 Foramen magnum: anterior, posterior Atlanto-occipital membrane, alar ligament
 External occipital protuberance: ligamentum nuchae
*relations: spine of sphenoid medial – chorda tympani

Lateral –auriculotemporal
: foramen spinosum posterolateral to foramen ovale
4. Norma frontalis
 Nerves come out, which have

the same names as their
foramina.

Structures passing through foramina
Anterior view
Supra-orbital foramen – supra-orbital nerve and vessels
Infra-orbital foramen – infra-orbital nerve and vessels
Mental foramen – mental nerve and vessels
Lateral view
Zygomaticofacial foramen – Zygomaticofacial nerve
Superior view
Parietal foramen – emissary veins
Inferior view
Incisive foramen – nasopalatine nerve, greater palatine vessels
Greater palatine foramen – greater palatine nerve
Lesser palatine foramen – lesser palatine nerve
Pterygoid canal – pterygoid nerve and vessels
Foramen ovale – Mandibular nerve
Accessory meningeal artery
Lesser petrosal nerve
Emissary vein
Foramen spinosum – middle meningeal artery, meningeal branch of mandibular nerve
Foramen lacerum – filled with cartilage
Foramen magnum – continuation of brain and spinal cord, vertebral arteries and nerve plexus
Anterior spinal artery
Posterior spinal arteries
Roots of accessory nerve
Meninges
Carotid canal – internal carotid artery and nerve plexus
Condylar canal – emissary veins
Hypoglossal canal – hypoglossal nerve (XII) and vessels
Jugular foramen – Internal jugular vein
Glossopharyngeal nerve (IX)
Inferior petrosal sinus
Vagus nerve (XII)
Accessory nerve (XI)
Stylomastoid foramen – Facial nerve (VII)
INTERNAL FORAMINA
Anterior cranial fossa

Foramen cecum – emissary veins to nasal cavity
Olfactory foramen in cribriform plate – olfactory nerve (I)
Middle cranial fossa

Optic canal – Optic nerve (I)
Ophthalmic artery
Superior orbital fissure – Oculomotor nerve (III)
Trochlear nerve (IV)
Ophthalmic division of trigeminal nerve (V1)
Abducent nerve (VI)
Ophthalmic veins
Foramen rotundum – Maxillary division of trigeminal nerve (V2)
Foramen spinosum – middle meningeal artery
Hiatus for greater petrosal nerve – greater petrosal nerve
Hiatus for lesser petrosal nerve – lesser petrosal nerve
Posterior cranial fossa
Foramen magnum – End of brain stem/beginning of spinal cord, vertebral arteries, spinal roots of accessory nerve,
meninges
Internal acoustic meatus – Facial nerve (VII)
Vestibular-cochlear nerve (VIII)
Hypoglossal canal – Hypoglossal nerve (XII)
Meningeal branch of ascending pharyngeal artery
Condylar canal – Emissary vein

05) Interior of skull Cranial fossa
fossa Boundaries features
Anterior Anteriorly & Frontal Bone Foramen caecum
cranial On the sides Cribriform plate
Fossa Posteriorly -- Posterior border of lesser wing of
Sphenoid, ant. clinoid process,
Anterior margin of sulcus chiasmaticus
Middle cranial Anteriorly—posterior boundary of ant.cranial fossa Foramen spinosum

Fossa Posteriorly—sup.border of petrous temporal bone & Foramen ovale
Dorsum sellae of sphenoid Hiatus for greater petrosal
Laterally—greater wing of sphenoid, anteroinferior nerve
angle of parietal bone, squamous temporal Hiatus for lesser petrosal
bone. nerve
Posterior Anteriorly—post.boundary of middle crn.fossa Internal acoustic meatus
cranial Posteriorly—squamous part of occipital bone Jugular foramen
Fossa Laterally—mastoid part of temporal &mastoid angle of Hypoglossal canal
parietal Foramen magnum
Clinicals
Anterior cranial fossa fracture:
  bleeding or CSF leakage through nose-CSF rhinorrhoea 
  Black eye
Middle cranial fossa fracture: -
commonly fractured 
  Bleeding & leakage of CSF through ear 
 Bleeding through nose & mouth 
 Vertigo 
 Damage to the VII & VIII nerves 
Posterior fossa fracture: Bruise extends over mastoid region to sternocleidomastoid
Cranial fossa contents

Anterior
Frontal lobe
Olfactory nerves
Anterior ethmoidal artery and nerve
Sphenoparietal sinus (along the edge of lesser wing of
sphenoid)
Middle
Pituitary
Optic chiasma
Cavernous sinus
III to VI cranial nerves
Trigeminal ganglion
Internal carotid artery and ophthalmic artery
Middle and accessory meningeal vessels
Greater and lesser petrosal nerves
Temporal lobes
Posterior communicating artery
Posterior
Cerebellum
Pons
V to XII cranial nerves
Spinal root of accessory nerve
Vertebral arteries
Basilar artery

*principles governing fractures of skull
I. Prevented by: elasticity, rounded shape, muscles
II. Passes through lines of resistance
III. Bas more fragile
IV. Inner table more brittle
V. Common sites : parietal area, middle fossa
VI. Commonly fractured facial bones: nasal bone, mandible

Meninges
1. Pia mater
Closely invests brain and spinal cord
Contains blood vessels.
No structure in between brain tissue and pia
2. Arachnoid mater
Delicate impermeable membrane
Deep to inner layer of dura
From the inner surface, thin processes or trabeculae extend downwards, crossing the subarachnoid space and
continuous with pia mater.
Subdural space – between dura and arachnoid
Vessels penetrate the space
Arachnoid villi – arachnoid herniate into venous sinuses through dura
CSF enters venous sinuses
More numerous in superior sagittal sinus
Subarachnoid space – between pia and arachnoid
Traversed by trabeculae running from arachnoid to pia
3. Dura mater
Dense
Inner (meningeal) and outer (endosteal) layers
Inner layer – prolonged into vertebral canal as the dura of spinal cord
Outer layer – periosteum of the bone
Not prolonged into vertebral canal
2 layers fuse except where the 2 layers are separated by venous sinuses
Folds of dura project into the cranial cavity as – tentorium cerebelli, falx cerebri, falx cerebelli.

MANDIBLE
 Horizontal U-shaped body anteriorly
 Vertical ramus posteriorly is quadrangular in shape
 Body arbitrarily divided into base of mandible inferiorly and superior alveolar part
 The alveolar part contains teeth and is reabsorbed when teeth are
removed
 Mental protuberance on anterior surface where the two sides meet
marked by a midline swelling in the base
 Slightly pronounced bumps on either side of the protuberance are
mental tubercles
 Laterally a mental foramen is visible halfway between upper border of
the alveolar part and the lower border of base
 Behind the foramen is an oblique line passing in front of ramus to the
body of mandible
 Superior part of the ramus extends as a condylar and a coronoid
process
 Condylar process for articulation with temporal bone (temporo-
mandibular joint)
 Coronoid process is the point of attachment for temporalis muscle
 Ramus join the body to form the angle
 Pterygoid fovea, a shallow depression on neck of mandible for
attachment of lateral pterygoid muscle
 Medial surface of ramus of mandible is the lateral wall of infratemporal
fossa
 Mandibular foramen opens up the mandibular canal carrying inferior alveolar nerves and vessels
 Immediately anterosuperior to the mandibular foramen is a triangular elevation, lingula for attachment of
sphenomandibular ligament
 Mylohyoid groove runs antero-inferiorly from the foramen carrying nerve to mylohyoid
 Medial to mylohyoid groove is a roughened area for attachment of medial pterygoid muscle
 Body composed of left and right parts fused each other in midline at mandibular symphysis
 2 halves fuse at symphysis menti at 2 years
 Posterior to mandibular symphysis is superior and inferior mental spines, they are muscle attachment of tongue muscles
and to connect to hyoid bone
 Above the anterior 1/3rd of mylohyoid line is sublingual fossa while below posterior 2/3rd is submandibular fossa
 Between last molar tooth and mylohyoid line is a shallow groove for lingual nerve
Children Adult Old age

Angle of jaw > 1400 0 0
110 -120 > 1400
Mental foramen lower border middle alveolar border

Venous sinuses
 Lie between the inner meningeal and outer endosteal layers of dura mater – except inferior sagittal &
straight sinuses (between inner layers)
 Receives all the blood from the Brain,
Meninges,
Bones of skull
 Communicates with veins outside the skull via emissary veins
 Lined interiorly by endothelium
 Do not contain valves
1. Superior sagittal sinus
Commence just above the foramen cecum

Ends turns at the internal occipital protuberance, generally to the right and becomes transverse sinus
Course lies between the two layers of the falx cerebri along the convexity of its attached margin
Drains from superior cerebral veins
 Upper and posterior parts
 Lateral and medial parts of both hemispheres
 Does not drain frontal pole of hemispheres.
Drains into Right transverse sinus

 3/4 lakes of blood project laterally from it.
 Into these lakes, arachnoid granulations project to return CSF into blood.

2. Inferior sagittal sinus
Commence little distance above the crista galli

Ends as the straight sinus at the attachment of falx cerebri and tentorium cerebelli
Course along the free margin of falx cerebri
Drains from lower parts of medial surface of each hemisphere
Drains into straight sinus
3. Straight sinus
Commence continuation of inferior sagittal sinus with receiving the great cerebral vein of Galen
Ends turning into the transverse sinus generally to the left at the internal occipital protuberance
Course slopes down steeply in the attachment of the falx cerebri into the tentorium cerebelli
Drains from inferior sagittal sinus, great cerebral vein, adjacent occipital lobes, upper surface of cerebellum
Drains into left transverse sinus

4. Transverse sinus
Commence at the internal occipital protuberance
Ends as the sigmoid sinus
Course runs laterally from the internal occipital protuberance,

Horizontally forwards, grooving the occipital bone and the mastoid angle of the parietal bone.
Drains from Right sup sagittal sinus Left inf sagittal sinus
Nearby surfaces of cerebral and cerebellar hemispheres
 One sinus is larger – which receives the sup sagittal sinus (right)
 Communicate with each other at confluence of sinuses
5. Sigmoid Sinus
Commence as the termination of transverse sinus

Ends expands into the superior jugular bulb of the internal jugular vein
Course Deeply grooving the inner surface of the mastoid part of the petrous bone
Curves downwards and forwards to the post margin of the jugular foramen through which it passes
Drains from transverse sinus at superior end - sup petrosal sinus
Inferior end – occipital sinus
Cerebellar veins
Veins from mastoid air cells
Drains into internal jugular vein
 Mastoid emissary vein sigmoid sinus with post auricular vein (mastoid foramen)
 Emissary vein through post condylar foramen sigmoid sinus with suboccipital plexus of veins
6. Occipital sinus
Commence confluence of sinuses (the commencement of the transverse sinus)

Ends inferior ends of the sigmoid sinuses
Course runs downwards towards the foramen magnum as a single trunk and becomes a pair of sinuses and
runs around the margins of the foramen magnum
Drains from receives tributaries from cerebellum and medulla and drains choroid plexus of the 4 th ventricle
Drains into sigmoid sinuses
 Communicates with the internal vertebral plexus (veins outside the spinal dura) at the foramen magnum
7. Basilar plexus
 On the clivus
 Connects the two inferior petrosal sinuses
 Drains from the lower part of medulla and pons
 No veins accompany the vertebral and basilar arteries
 Vertebral vein itself commences outside the skull below the occipital bone.
8. Cavernous sinus
Commence medial end of the superior orbital fissure (apex of the orbit)
Ends apex of the petrous bone
Course alongside the body of the sphenoid bone in the middle cranial fossa

Relations
 Outside the sinus
a. Superiorly – Optic tract
Internal carotid artery
Anterior perforated substance
b. Inferiorly – Foramen lacerum
Junction of body and greater wing of sphenoid
c. Medially – Pituitary gland
Sphenoidal air sinus
d. Laterally – Temporal lobe with uncus
e. Anteriorly – Superior orbital fissure
Apex of orbit
f. Posteriorly – Apex of petrous temporal bone
Crus cerebri of midbrain
 In the lateral wall of sinus (from above downwards)

-Oculomotor nerve (divides in to superior and inferior divisions in the anterior part of sinus)
-Trochlear nerve
-Ophthalmic nerve (divides in to lacrimal, frontal and nasociliary nerves in the anterior part)
-Maxillary nerve
-Trigeminal ganglion
 Passing through the center of sinus
-Internal carotid artery + venous and sympathetic plexuses around it
-Abducent nerve (inferolateral to internal carotid artery)
 Structures in the center and lateral wall of sinus are separated from blood by the endothelial lining.
Tributaries – a. From orbit – Superior ophthalmic vein

Inferior ophthalmic vein
Central vein of retina
b. From brain – Superficial middle cerebral vein
Inferior cerebral veins
c. From meninges – Sphenoparietal sinus
Frontal trunk of middle meningeal vein
Communications (valve-less)
 Transverse sinus (through superior petrosal sinus)

 Internal jugular vein (through inferior petrosal sinus and plexus around internal carotid)
 Pterygoid plexus of veins (through emissary veins)
 Facial vein (through superior ophthalmic vein)
 Cavernous sinus of opposite side (through anterior and posterior intercavernous sinuses
and basilar plexus of veins)

Clinical
 Thrombosis of cavernous sinus

- Caused by sepsis in danger area of face, nasal cavities, paranasal air sinuses
- Nervous symptoms – Severe pain in eye and forehead (ophthalmic nerve)
Paralysis of ocular muscles (3rd, 4th and 6th cranial nerves)
- Venous symptoms – Oedema of eyelids, cornea, root of nose
Exophthalmos
 Pulsating exophthalmos
- In head injury, a communication between cavernous sinus and internal carotid artery may
occur.
- Eyeball protrudes and pulsates with each heartbeat.
Extradural hemorrhage
 Fractures of the side of the skull may rupture the middle meningeal artery (especially the frontal
branch)
 Hematoma between the bone of the skull and the dura
 In x-rays, it has a lens shaped whitish area as it is attached to the sutures.
Subdural hemorrhage
 Venous blood escapes into the (potential) space between the dura and arachnoid
 Venous blood is involved (so it is slower to develop and less severe)
 In x-rays, they are shown in a crescent shape (falx cerebri)
Subarachnoid hemorrhage
 Rupture of arteries that lie within the space, such as aneurysms of arterial circle at the base of
brain.
 Causes blood to contaminate CSF
Appear in whitish (accumulation of blood in fissure)
 Blood accumulates along fissures

SCALP, TEMPLE & FACE
Scalp
 Extent
 Anteriorly - supraorbital margin
 On each sides - superior temporal line
 Posteriorly - superior nuchal line, external occipital protuberance
 5 layers
 S - Skin
 C - Connective tissue
 A – Aponeurosis
(Epicranial/deep fascial galea)
 L - Loose connective tissue
 P - Pericranium
 The 1st 3 layers are called the
surgical layers of the scalp /
scalp proper.
 Skin
 Thick (thickest in occipital region)
 High concentration of sebaceous glands
 Connective tissue (superficial fascia)

 dense in the center
 Contains many blood vessels and nerves
 Aponeurosis
 Epicranial aponeurosis is movable on
Pericranium
 on each side attached to superior temporal
line – blends with temporoparietal fascia
 Occipitofrontalis
 Occipitalis arises from the lateral 2/3rd
of superior nuchal line
 Occipital muscle bellies are separated
across the midline by the aponeurosis
 Occipitalis is innervated by posterior
auricular branch of facial nerve
 Frontalis arises from the front of the aponeurosis/skin of forehead and is inserted to the upper part of
orbicularis oculi and overlying skin of the eyebrow. (Frontalis part has no attachment to the skull).
 The subaponeurotic space extends down beneath the orbicularis oculi into the eyelids.
 Bleeding anywhere beneath the aponeurosis may appear as a ‘black eye’ due to the blood tracking through
the space.
 Frontalis muscle bellies are partially united in the midline and innervated by the temporal branch of the
facial nerve
 Function of the frontalis muscle is to raise eyebrows & cause horizontal wrinkles in the forehead.
1 2017 A/L Repeat Campaign

 Loose connective tissue
 extends anteriorly to eyelid because- no bony attachment to frontalis, posteriorly to highest and superior nuchal
line & on each side to superior temporal lines
 This layer is called the dangerous area of the scalp because the emissary veins which course here may transmit
infections from the scalp to the venous sinuses.
 Pericranium
 Loosely attached to surface of the bones but adherent to the sutures
 Therefore, a collection of fluid deep to the pericranium (cephalohematoma) takes the shape of the bone
concerned.
 Blood Supply
 External carotid – occipital, posterior auricular, superficial temporal
 Internal carotid – supraorbital and supratrochlear (via ophthalmic artery)
 There is an external and internal carotid anastomosis around the vertex.
 Veins receive diploic veins from vault bones and emissary veins from intra cranial sinuses.
 Superficial temporal vein retromandibular vein
 Posterior auricular vein external jugular vein
 Occipital vein vertebral vein
 Supratrochlear & supraorbital veins angular vein facial vein
 Lymph drainage
 Anterior – pre auricular
 Posterior – mastoid
 Ultimately drain into deep cervical chain
 No lymph nodes within the scalp.
 Nerve supply
 Occipital region – greater occipital & 3rd occipital nerves
 Skin behind the ear – lesser occipital
 Temple – auriculotemporal & zygomaticotemporal
 Forehead & front of head – supratrochlear & supraorbital

 Clinical
 S - Common site for sebaceous cysts – abundant sebaceous glands
 C - Rich blood supply – wounds bleed profusely because the dense superficial fascia prevents the vessels
from retracting (arterial walls are attached to fibrous septa); therefore can be arrested by pressing
against the bone.
● A - Wounds of the scalp do not gape unless aponeurosis is divided transversely
 L - Loose areolar tissue is the danger area of the scalp because emissary veins open here
 Blood in loose connective tissue extends to eye lids causing black eye
 P - Collection of fluid deep to pericranium – cephalohematoma; take the shape of the bone concerned
because, pericranium is attached to the sutures.
Scalping – evulsion of the layers of the scalp above the loose areolar tissue that doesn't cause necrosis of
underlying bones
Face
 Extends from adolescence position of hairline (superiorly) base of mandible (inferiorly) & auricles (on either side)
 Forehead common both to face & scalp
 Skin – very vascular (wounds heal rapidly)
 rich in sebaceous & sweat glands
 Lax
 Boils in nose & ear causes pain because of fixity of skin to cartilage
 Superficial fascia
 facial muscle inserted into skin – injuries tend to gape
 Fat absent in eyelids but well developed in cheeks
 Deep fascia – absent except over parotid gland & buccinator muscle
 Facial muscles (muscles of facial expression)
Fissure Sphincter Dilator

Levator palpebrae superioris
Orbit Orbicularis oculi
Occipitofrontalis
Mouth Orbicularis oris Other muscles around mouth
Nostrils Compressor naris Dilator naris
Orbicularis oculi
 2 parts
 palpebral part (close eye lids gently)
 Orbital part (both parts – close eye lids forcibly)
 Nerve supply – temporal & zygomatic branches of facial nerve
Orbicularis oris
 Bulk is formed by buccinator
 Nerve supply – buccal and marginal mandibular branches of facial nerve
Buccinator
 Origin – alveolar processes of maxilla & mandible, pterygomaxillary ligament, pterygomandibular raphe
 Insertion – orbicularis oris (fibers from the raphe decussate; maxillary & mandibular fibers do not
decussate)
 Nerve supply – buccal branch of facial nerve
 Action – prevent distention of cheeks when intraoral pressure rises
 Pierced by the parotid duct opposite the 3rd upper molar teeth.

Lymph drainage
 Submental (chin, tip of tongue)
 Submandibular
 Preauricular/parotid nodes (forehead, temple, orbital contents, cheek)
 Ultimately drains into deep cervical nodes
 Arterial Supply
1. Facial artery External carotid
2. Transverse facial artery – superior temporal
3. Supraorbital and supratrochlear – from ophthalmic artery – Internal carotid
Facial course of Facial Artery

 Grooves the posterior part of submandibular gland.
 Winds around the base of mandible,
 Pierces deep fascia at anteroinferior angle of masseter – can be palpated
 Tortuous course – room for facial expressions
 Lying on buccinator, deep to the dilator muscles of the mouth,
 Passes upwards to lateral part of mouth

 Reaches medial part of eye
 Ends up supplying lacrimal sac
 Anastomoses with dorsal nasal branch of ophthalmic artery
 Branches; inferior labial, superior labial (anastomose with the corresponding artery of opposite side) &
lateral nasal
Transverse Facial Artery

 Branch of superficial temporal artery.
 Emerges from within the parotid gland behind the neck of mandible
 Runs over the masseter accompanied by the upper buccal nerve between the parotid duct & zygomatic
arch
Venous drainage
 Entirely superficial
 Forehead – supraorbital & supratrochlear veins unite at medial canthus to form the angular vein
 CLINICALS
 Facial vein communications

 Supra orbital vein superior ophthalmic vein
 Deep facial vein pterygoid plexus
 hence the cavernous sinus is connected to the facial vein
 Infections can spread via valveless communications
 infections in the face can cause thrombosis of cavernous sinus
 When the buccal nerve is damaged- food accumulates in the vestibule @ 2

 Bell’s palsy (LMN lesion in Facial Nerve)
 Black eye: blood in loose areolar tissue seeps into the eyelids
 Subdural & extradural hemorrhages
 Dangerous area of the face – area lying between angular and deep fascial veins
 Angular vein – continues as facial vein (straight)

 Facial vein – just below the lower border of mandible pierces the deep fascia and joins retromandibular
vein;
Facial vein Retromandibular vein
Anterior division Posterior division Occipital

Vein
Common External
facial vein jugular vein
Internal
jugular vein

 Parotid Gland
 largest salivary gland
 Serous gland / more water secretion
 situated below the external acoustic meatus
Location
 between the ramus of the mandible & sternocleidomastoid
 gland overlaps these structures
 anteriorly it overlaps the masseter
Parotid capsule
 deep cervical fascia splits to form the capsule (between angle of mandible and mastoid process)
 superficial lamina thick & adherent to gland
 attached to zygomatic arch superiorly
 deep lamina thin & attached to styloid process & angle of mandible
 part of the deep lamina forms stylomandibular ligament which separates the gland from the submandibular
gland
 thickened anteroinferiorly
Surface marking
1. upper border of the head of the mandible
2. center of the masseter muscle
3. posteroinferior to the angle of the mandible
4. upper part of the anterior border of the mastoid process
Relations
 pyramid shaped: base, superficial surface, anteromedial & posteromedial surfaces
 Apex
a) Overlaps posterior belly of digastric
b) Cervical branch of facial nerve & 2 divisions of retromandibular vein
 Base
a) Cartilaginous part of external acoustic meatus
b) Posterior part of TM joint
c) Superficial temporal vessels
d) Auriculotemporal nerve
 Superficial surface
a) Skin
b) Parotid fascia
c) Lymph nodes
d) Anterior branch of great auricular nerve
 Anteromedial surface
a) Grooved by ramus of mandible
b) Masseter
c) Lateral part of TM joint
d) Medial pterygoid
e) Emerging branches of facial nerve
f) Maxillary artery emerges
 Posteromedial surface
a) External carotid artery enters through
this surface
b) Mastoid process
c) Styloid process & structures related to it

Structures within the gland
1) External carotid artery, maxillary artery, superficial temporal
artery , transverse facial artery
2) Retromandibular vein formed by union of superficial temporal
& maxillary vein
3) Facial nerve
4) Parotid lymph nodes
Parotid duct (of Stensen)

 from the anterior surface runs forward on the masseter
 surface marking; middle 1/3rd of the line joining the lower
border of the tragus to point between ala of nose & red
margin of lip (midpoint of philtrum)
 Relations
 Superior: accessory parotid gland
Upper buccal nerve
Transverse facial artery
 Inferior: lower buccal branch
 At the anterior border of masseter turns medially & pierce the

Buccal fat pad, Buccopharyngeal fascia and Buccinator (obliquely)
 The duct runs forward for a short distance between the buccinator
and the oral mucosa.
 & opens above the crown of the 2nd upper molar tooth
Blood supply
 Arterial supply - external carotid artery
 Venous drainage – Retromandibular vein
Nerve supply:
 Secretomotor (reach the gland by hitch-hiking along the auriculotemporal nerve)
Inferior salivatory ganglion Glossopharyngeal nerve Tympanic branch Tympanic plexus
Auriculotemporal nerve Otic ganglion Lesser petrosal nerve
 Sympathetic plexus  Sensory

 Vasomotor from the plexus around  Parotid gland – Auriculotemporal nerve
external carotid artery  Parotid fascia – Greater auricular nerve
Lymphatic drainage
 Parotid nodes upper deep cervical nodes

CLINICALS
 Parotid swellings are painful due to the unyielding nature of fascia
 Can be infected by infections spread from mouth
 Horizontal incisions
 Facial nerve divides the gland into superficial & deep parts
 Nerve is preserved in parotidectomy
 Parotid tumor painless – malignant changes are indicated by pain
 Frays syndrome -> parotidectomy -> division of peripheral nerve fibers of auriculotemporal nerve ->
regeneration of secretomotor fibers -> joins great auricular nerve -> stimulation of sweat gland during
salivation (gustatory sweating)
 Calculi formation and deposition is more commonly seen in the duct of the submandibular gland than in
the parotid gland. This is because,
a) The parotid produces serous secretions while the submandibular gland produces mucus secretions
b) The duct of the submandibular gland is longer
c) The duct of the submandibular gland courses upwards while that of the parotid gland is more
horizontal
 Facial Nerve
 Extra-cranial course
 Crosses the lateral side of the styloid process after emerging through stylomastoid foramen
 Enters the posteromedial surface of the parotid gland
 Crosses the retromandibular & external carotid artery
 Behind the neck of mandible divides into terminal branches
 Branches & distribution
A. Within Facial Canal:

a) Greater petrosal nerve
b) Nerve to stapedius
 Arises opposite pyramid of middle ear
 Causes hyperacusis if paralyzed
c) Chorda tympani
 Vertical part of facial nerve, arises 6mm above the Stylomastoid Foramen
 Closely related to tympanic membrane
 Leaves middle ear through petrotympanic fissure
 Medial to the spine of sphenoid
 Joins the lingual nerve
 Carries,
1. Preganglionic secretomotor fibers to submandibular & sublingual glands
2. Taste fibers from tongue
B. Exit from Stylomastoid Foramen

a) Posterior auricular:
1. auricularis posterior
2. occipitalis
3. Intrinsic muscles on the back of the auricle
b) Digastric
c) Stylohyoid
 Enters the parotid gland & divides into a temporofacial and a cervicofacial branch. These divide into
branches which rejoin to form the pes anserines
C. Terminal branches
 The branches leave the gland through its anteromedial surface & appear on the surface at the
anterior border.
a) Temporal
1. auricularis anterior & superior
2. Intrinsic muscles on lateral side of ear
3. Frontalis
4. Orbicularis oculi
5. Corrugator supercili
b) Zygomatic
1. orbicularis oculi
c) Buccal
1. Orbicularis oris
2. Buccinator
3. Muscles of nostrils & upper lip
d) Marginal mandibular
1. Platysma
2. Muscles of lower lip & chin
e) Cervical
1. platysma

TEMPORAL AND INFRATEMPORAL REGIONS
Temporal Fossa
 Boundaries
1. Superiorly – temporal lines
2. Inferiorly – zygomatic arch
3. Roof – temporalis fascia(deep temporal fascia)
4. Floor – side of skull including Pterion
5. Anterior wall – zygomatic processes of frontal bone, zygomatic bone , maxilla
 Contents
1. temporalis muscle
2. Deep temporal arteries
3. Deep temporal branches of mandibular nerve
4. Middle temporal artery – a branch of superficial temporal artery
7 layers through temporal region of scalp

1. Skin
2. Subcutaneous connective tissue
3. Temporoparietal fascia- extending from zygomatic arch to Aponeurotic layer
4. Temporoparietal fat pad – continuous with loose C.T. layer
5. Temporal fascia
6. Temporalis
7. Pericranium
Muscle Origin Insertion Innervation Action

Temporalis Floor of temporal Coronoid process Mandibular nerve Elevation and
fossa, below of Mandible and – deep temporal retraction of mandible
inferior temporal anterior border of branches of Side to side movement
line ramus anterior division
Masseter Lower border of Angle and Lateral Masseteric branch Elevation and
Zygomatic Arch surface of Ramus of Anterior division protrusion
3 layers of the Mandible of mandibular
nerve

Infratemporal Fossa
 Walls of Infratemporal Fossa
 Medial – lateral pterygoid plate, tensor palatini , superior constrictor muscle
 Lateral – ramus and coronoid process of mandible
 Anterior – posterior surface of maxilla, inferior orbital fissure
 Posterior – styloid process, carotid sheath
 Roof – infratemporal surface of greater wing of sphenoid , squamous temporal bone
Contents
1. Pterygoids – medial and lateral
2. Mandibular nerve
3. Maxillary artery
4. Pterygoid venous plexus
5. Otic ganglion and lesser petrosal nerve
6. Maxillary nerve
7. Chorda Tympani nerve
 Communications of Infratemporal Fossa
Fissure/Foramen Communicates with Structures going through

1. Inferior Orbital Fissure Orbit Infraorbital Artery, Nerve and
Zygomatic nerve
2. Pterygomaxillary Fissure Pterygopalatine Fossa Maxillary Artery

3. Petrotympanic Fissure Middle Ear Chorda Tympani
Anterior Tympanic Artery
4. Foramen Ovale Middle Cranial Fossa Mandibular Nerve
Accessory Meningeal Artery
Lesser Petrosal Nerve
Emissary Veins
(Nervus Spinosus)
5. Foramen Spinosum Middle Cranial Fossa Middle Meningeal Artery
Nervus Spinosus
6. Mandibular Foramen Mandibular Canal Inferior alveolar vessels and nerves
7. Foramina in posterior surface of Posterior superior alveolar artery
maxilla – Alveolar foramen and nerve
 Muscles of infratemporal fossa
Muscle Origin Insertion Innervation Action

1. Medial Superficial head Medial aspect of angle Medial  Protrusion
pterygoid tuberosity of maxilla , pyramidal of mandible pterygoid  Elevation
process of palatine bone branch-  Deviation to
Main trunk opposite side
Deep head(larger) of
medial side of lateral pterygoid Mandibular
plate nerve
2. Lateral Upper head  Neck of Anterior  Depression
pterygoid roof of infratemporal fossa mandible division of  Protraction
 Articular disc of Mandibular  Deviation to
Lower head the nerve oppsite side
lateral side of lateral pterygoid temporomandibular  Pulls articular
plate joint disc forwards
 Pterygoid fovea
on the front of the
neck of the
mandible
 Relations of Lateral pterygoid – Key muscle of infratemporal surface
Upper border – Temporal, Masseteric branches of mandibular nerve
Lower border – lingual and inferior alveolar nerves

Buccal and maxillary artery pass between the 2 heads of the muscle
Superficial – mandibular ramus, maxillary artery, superficial head of medial pterygoid
Deep- Deep head of medial pterygoid, sphenomandibular ligament, middle meningeal artery, mandibular nerve
 Maxillary artery
 Larger terminal branch of
external carotid.
 Enters infratemporal fossa
by passing forwards between
the neck of mandible and
sphenomandibular ligament.
 Above – auriculotemporal
Nerve N
 Below – maxillary Vein A
 Runs forwards deep to the V
lower head of lateral
pterygoid and then between
the 2 heads.
 Enters pterygopalatine fossa
through pterygomaxillary
fissure .
 Then enters infraorbital canal through inferior orbital fissure and continues as the infraorbital artery.
 3 parts- Sphenomandibular ligament
 1st part – before lateral pterygoid muscle Derived from Meckel’s cartilage
5 branches
 2nd part – on the lateral pterygoid muscle
each  arises from the spine of
 3rd part – beyond the lateral pterygoid
sphenoid and inserts into the
muscle
lingula and inferior margin of
mandibular foramen.
1st part  It runs deep to
auriculotemporal nerve,
maxillary artery & vein
 It is pierced by
2nd part mylohyoid nerve, which is
Deep auricular artery accompanied by mylohyoid
vessels.
Anterior tympanic artery
3rd part
pterygoid
Middle meningeal artery Infraorbital artery
Masseteric
Accessory meningeal artery Sphenopalatine
2 Deep temporal  main supply to nasal cavity
Inferior alveolar artery
Buccal Posterior superior alveolar
Greater palatine
 Pterygoid plexus
 Lie around and within the lateral pterygoid muscle Pharyngeal
Artery of Pterygoid Canal
 Plexus is valved, and acts as a peripheral heart
 Receives inferior ophthalmic vein, deep facial vein
 Drains into Short Maxillary Vein
 Connect with cavernous sinus via emissary veins through Foramen Ovale and Foramen Lacerum
 Mandibular Division of the

Trigeminal Nerve
 Enters fossa through
foramen ovale.
 Larger sensory root and
smaller motor root from
trigeminal ganglion
eventually join and
 Lies between upper
head of lateral pterygoid
and tensor veli palatini.
 Otic ganglion lies
between upper head of
lateral pterygoid and
tensor palatine muscles.
 Otic ganglion lies on
deep surface of the
nerve.
 After a short course
divides into a small
anterior division and a large posterior division.

Main trunk
Meningeal branch
(nervus spinosus) Via otic ganglion Nerve to Medial Pterygoid
supplies dura
Nerve to Tensor Tympani

Anterior division Posterior division
Motor (sensory) Sensory (Motor)
Nerve to Tensor veli
palatini
Auriculotemporal nerve
 Forms a loop around the middle meningeal
deep temporal branches
artery
Motor Masseteric Inferior alveolar nerve

 before entering the mandibular
Nerve to Lateral Pterygoid foramen, gives off the nerve to mylohyoid.
*inferior alveolar artery is posterior to
Buccal nerve - sensory nerve
Motor
Nerve to mylohyoid
Lingual nerve  Pierces Sphenomandibular
Ligament
Mental nerve  supplies mylohyoid and
anterior belly of digastric.
Chorda tympani nerve

 emerges from the Petrotympanic Fissure
 joins lingual nerve at an acute angle
 supplies taste sensation to anterior 2/3 of the tongue, floor of mouth
 carries parasympathetic fibres to Submandibular Ganglion.
 Pterygopalatine fossa
 Narrow space communicating with infratemporal fossa through
pterygomaxillary fissure.
 Boundaries
 Anterior wall – posterior surface of maxilla
 Posterior wall – sphenoid bone
 Medial wall – perpendicular plate of palatine bone
 Roof – body of sphenoid
 Floor – articulation of pyramidal process of palatine bone with
lateral pterygoid plate.
 Contents
 maxillary vessels (3rd part – 5 branches)
 Maxillary nerve
 Pterygopalatine ganglion & fat
Maxillary nerve
 enters fossa through Foramen Rotundum and runs through inferior orbital fissure into Infraorbital Canal as
Infraorbital Nerve.
 Completely sensory
 Branches
From main trunk –
meningeal, zygomatic,
superior alveolar nerves
(anterior, middle and
posterior), infraorbital nerve
Via pterygopalatine ganglion

– orbital, nasopalatine,
posterior superior nasal,
greater and lesser palatine,
pharyngeal nerves
o Zygomatic nerve
o Zygomaticofacial
o Zygomaticotemporal
o Posterior Superior
Alveolar Nerve
 Foramina which opens into

pterygopalatine fossa
1. Foramen rotundum – maxillary nerve
2. Pterygoid canal – nerve and artery of pterygoid canal
3. Palatovaginal canal – pharyngeal artery and nerve
4. Inferior orbital fissure – infraorbital artery and nerve
5. Pterygomaxillary fissure – 3rd part of maxillary artery
6. Sphenopalatine foramen – sphenopalatine artery, nasopalatine nerve
7. Palatine canal – greater palatine nerve and artery

 Temporomandibular Joint
 Atypical synovial joint.

 Articular surfaces
 Head of mandible
 Mandibular fossa of the squamous part of temporal bone
 Covered by fibrocartilage. No hyaline cartilage.
 Joint cavity is separated into 2 compartments as upper and lower by a fobrocartilaginous disc.
 The periphery of the articular disc is attached to the capsule.
 Articualr disc is anteroposteriorly concavoconvex (to fit the articular eminence and fossa)
 Inferior surface is concave.
 Joint capsule
Lax above the articular disk while taut below

 Mandible – Anteriorly to the Neck of mandible; Posteriorly Lower down in the neck
 Skull – Anteriorly, Just in front of the articular eminence.
 Posteriorly – to the Squamotympanic fissure
 Medially and laterally – Articular margins.
 Synovial membrane lines the capsule.

 Ligaments
 Lateral ligament - Zygomatic arch to neck of mandible
 Sphenomandibular ligament – From spine of sphenoid to lingula of mandible
 Stability
 Most stable when teeth in occlusion.
 Forward displacement is more common.
 Relations
Superiorly – glenoid fossa, middle cranial fossa
Medially- maxillary artery & proximal branches (middle meningeal), auriculotemporal nerve
Laterally- parotid capsule, facial nerve
Anteriorly – lateral pterygoid, articular eminence
Posteriorly – tympanic plate, tegmen tympani, superficial temporal artery (Lat)
 Movements
1. Depression and elevation
a. Lower compartment – hinge movement
b. Upper compartment – gliding movement
c. Axis – horizontal
2. Side to side movements – Medial and lateral pterygoids of the same side contract together.
3. Protraction – All 4 pterygoids contract.
Retraction – Elastic recoil (Temporalis, Masseter)
Depression – digastric, mylohyoid, geniohyoid
Elevation – masseter, medial pterygoid,
temporalis
 Nerve Supply
 Auriculotemporal Nerve
 Nerve to Masseter
 Middle meningeal artery

 Branch of 1st part of maxillary artery (in
Infratemporal Fossa)
 Enters Middle Cranial Fossa through Foramen
Spinosum
 Runs forwards and laterally grooving the
squamous temporal bone following an
extradural course
 Ends by dividing into frontal (anterior) and parietal (posterior) branches
 Frontal branch crosses the Pterion and is closely related to motor area of cerebral cortex, 1cm posterior to
coronal suture, little in front of central sulcus
 Posterior branch closely related to superior temporal sulcus
 Predominantly a periosteal artery supplying bone and red bone marrow in diploe (gives small branches to dura
mater)
 Relations
 In infratemporal fossa
o Deep to lateral pterygoid muscle
o Superficial to sphenomandibular ligament
o Passes through a loop formed by 2 roots of auricotemporal nerve
 In middle cranial fossa – Middle meningeal veins are closer to the bone than artery
 Branches – ganglionic, petrosal, superior tympanic, temporal, anastomotic
Clinical
Lesion of:
Anterior branch – Contralateral hemiplegia
Posterior branch – Contralateral deafness

DEEP NECK
Root of the Neck (Thoracic Outlet)
• Is bounded by the
1. T1 vertebra
2. 1st pair of ribs & costal cartilages
3. Manubrium of the sternum
• It’s the junction of structures and tissue spaces passing to and

from the neck thorax and upper limb. An arbitrary area above the apex of the lungs.
• Structures pass through it between the apices of the lungs.
• The key to the root of the neck is the Scalenus Anterior & its relations.
 Scalenus Anterior
 Origin – Anterior tubercles of the transverse processes of typical vertebrae (C3-C6)
 Insertion – Scalene tubercle & adjacent ridge on 1st rib
 Nerve supply – Anterior rami of C4-C6
Anterior relations
1) The Phrenic Nerve,
 passes vertically down across the obliquity of the muscle. (plastered to the prevertebral fascia).
 The nerve leaves the medial border of the muscle low down.
 Crosses in front of the Subclavian Artery and its internal thoracic branch, behind the Subclavian Vein.
 Lying on the supra pleural membrane it passes medial to the apex of the lung, in front of the Vagus Nerve,
to enter the superior mediastinum.
2) The Ascending Cervical Artery,

 a branch of the inferior thyroid artery of the thyrocervical trunk, runs up medial to the phrenic nerve. (on
the prevertebral fascia)
3) Transverse Cervical & Suprascapular,

 In front of the prevertebral fascia, these arteries lie between the scalenus anterior and the carotid sheath
(internal jugular vein).
4) The Vagus Nerve

 (in the carotid sheath) passes down in front of the subclavian artery, on the right side giving off its
recurrent laryngeal branch. It hooks around the artery and passes upwards.
 The vagus nerve inclines posteriorly and runs on the medial surface of the apex of the lung to enter the
superior mediastinum.
5) The Internal Jugular Vein

 is surrounded by the inferior deep cervical lymph nodes.
6) The Subclavian Vein

 lies in a groove on the 1st rib; in a lower level than the Scalenus Anterior.
 It runs below the clavicle and subclavius and joins the internal jugular vein at the medial border of scalenus
anterior.
 The thoracic duct (left) and the right lymphatic duct (right) enter the angle of confluence of the two veins.

Medial relations
• Pyramidal Space,
 The medial edge of scalenus anterior muscle makes a pyramidal space/ ∆ with the lateral border of the lower
part of longus colli.
 There’s no fascial roof across the pyramidal space between the muscles.
o Base - is formed by the subclavian artery lying on the suprapleural membrane.
o Apex - is the Carotid (Chassaignac's) Tubercle on the transverse process of C6 vertebra. (Common carotid
artery can be compressed against it.)
1) The common carotid artery, medial to the internal jugular vein, lies deep to sternocleidomastoid
immediately in front of the pyramidal space.
2) The space contains the stellate ganglion & vertebral artery and vein(s).
3) The inferior thyroid artery arches medially in a bold curve whose upper convexity lies in from of the apex of
the pyramidal space (C6 level).
4) At a lower level, and further forward, the Thoracic Duct (or right lymphatic duct) makes a similar convexity
as it arches over the lung apex and subclavian artery enter the confluence of the subclavian and internal
jugular veins.
5) The 1st Part of The Subclavian Artery,

1. is medial to the muscle. It arches over the suprapleural membrane and impresses a groove upon the apex of
the lung.
6) The Vertebral Vein,

1. emerges from the foramen in Transverse Process of C7 & runs forwards in front of vertebral & subclavian
arteries to empty into the brachiocephalic vein.
Posterior relations
 2nd part of the Subclavian artery.
 Cervical pleura covered by supra pleural membrane.
 Scalenus Medius
 Anterior rami of lower cervical & 1st thoracic nerves.
Lateral relations
 3rd part of the Subclavian artery.
 Trunks of the brachial plexus.
Cervical pleura:
 Covers the apex of the lung.
 It rises into the root of the neck.
 The pleural dome is strengthened on its outer surface by the supra pleural membrane (Sibson’s Fascia) so that
the root of the neck is not puffed up and down during respiration.

Pressure on
Existence of a cervical rib
Subclavian artery
Thoracic inlet/outlet syndrome
Elevation of 1st rib by scalenus anterior & lowest root of
brachial plexus
 Contents of the root of the neck

1. Glands - Thyroid & Parathyroid
2. Arteries - Subclavian & Carotid
3. Veins - Subclavian, Internal jugular & Brachiocephalic
4. Nerves - IX, X, XI, XII, Sympathetic chain, Cervical plexus
5. Lymph nodes & Thoracic duct
6. Viscera - Trachea & Oesophagus
7. Scalene muscles (Anterior, Middle & Posterior)
1) Glands
Thyroid Gland
Introduction
• Butterfly shaped/ shield like endocrine gland.
• The gland has 2 conical lobes each joined by an isthmus in its lower part.
• An inconstant pyramidal lobe may project upwards form the isthmus.
Extent & Location

• In the lower part of the front & side of the neck.
• Gland lies against C5, C6, C7 & T1 vertebrae / each lobe extends from the oblique line of the thyroid cartilage
to the 6th tracheal rings.
• Isthmus overlies 2nd to 4th tracheal rings.
Capsules & ligaments

• Has 2 capsules.
• True capsule – derived from peripheral condensation of the connective tissue.
• False capsule – derived from the pretracheal fascia which encloses it.
• Dense capillary plexus present deep to the true capsule.
• In the prostate gland, the venous plexus lies between the 2 capsules
• Inner surface of the gland connected to the Cricoid Cartilage by thickened pretracheal fascial layer -
Suspensory ligament (of Berry) to which the recurrent laryngeal nerve is closely associated.
Arterial supply
1. Superior Thyroid Artery
 The 1st anterior branch of external carotid artery
 Close relation to external laryngeal nerve away from gland.
 At the upper pole divides into anterior and posterior branches.
 Divides into branches after piercing false capsule
 External laryngeal nerve deviates at the apex of a lobe of the gland. Therefore, during thyroidectomy superior
thyroid artery is ligated near the gland
2. Inferior Thyroid Artery –

 A branch of thyrocervical trunk
 Passes behind the carotid sheath & in front of the vertebral vessels.
 Close relation to recurrent laryngeal nerve near the gland. Individual branches are ligated to maintain the
blood supply to parathyroid gland
 Divides into branches before piercing false capsule.

3. Additional supply
 Thyroidea ima artery (brachiocephalic or arch of aorta)
 Oesophageal and tracheal branches.
• Superior thyroid artery reaches the upper pole of the gland and anastomosis with the opposite artery along
the upper border of the isthmus.
• Inferior thyroid artery reaches the lower pole.
Venous drainage
• Superior thyroid vein emerges from the upper pole of the gland drains into internal jugular vein.
• Middle thyroid vein also drains into internal jugular vein.
• Inferior thyroid vein emerges from the lower border of the isthmus, to be eventually drained into the left
brachiocephalic vein.
• Dense capillary plexus present deep to the true capsule.
Lymphatic drainage
 Lymph from the upper part of the gland drains into upper deep cervical lymph nodes.
Nerve supply
 Sympathetic fibres are mainly derived from the middle cervical ganglia / cervical sympathetic trunk.
Relations
• Superficially/Anterolateral
 skin, superficial fascia and investing deep fascia
 strap muscle of the neck (sternohyoid, sternothyroid, superior belly of omohyoid) overlapped by
sternocleidomastoid.
 Anterior jugular vein courses over the isthmus.
• Medially
 On the deep aspect lie the larynx (Cricothyroid) and trachea, pharynx (Inferior constrictor) and
oesophagus
 Recurrent laryngeal nerve coursing on the tracheoesophageal groove is closely related to the inferior
thyroid artery.
 External laryngeal nerve is closely related to the superior thyroid artery.
• Behind/Posterolaterally
 the carotid sheath (common carotid artery) lies on either side.
Clinical Anatomy
1. Swellings (goitre) move with deglutition (gland is adhered to the trachea)
2. Flex head when palpating
3. Cancer recurrent laryngeal nerve damage hoarseness of voice.
4. In thyroidectomy Superior thyroid ligated near gland to save the external laryngeal nerve. Inferior thyroid
ligated away from gland to spare the recurrent laryngeal nerve
Parathyroid gland
• 2 pairs Superior and inferior. (1 pair on each lateral lobe).
• Lies on the posterior surface of the thyroid gland, within the false capsule
• Size of split pea
• Brownish yellow colour
• Lie close to anastomosis between superior & inferior thyroid arteries.
• Superior parathyroid more constant in position
• Inferior parathyroid inconsistent position
 Within capsule
 Outside capsule
 Within substance of lobe
 Within thymus (due to the same embryological origin )
 Behind trachea
 Behind great vessels
• Blood supply – mainly from Inferior Thyroid Artery (both inferior & superior glands)
• Easily subject to subscapular haematoma formation on handling

2) Arteries
Subclavian Artery
 Left subclavian arises from arch of aorta.
(Immediately behind commencement of Left
common carotid.)
 It ascends laterally, against the mediastinal surface of
left lung & pleura, with the trachea & oesophagus
medially, to lie behind sternoclavicular joint.
 Right subclavian artery arises behind right
sternoclavicular joint from the brachiocephalic trunk.
 It is divided by the scalenus anterior into 3 parts.
Relations
1st part 2nd part 3rd part

Anterior • Sternocleidomastoid  Scalenus anterior  External jugular vein
• Strap muscles
• Phrenic nerve
• Vagus nerve
• Vertebral vein
• Carotid sheath
• Thoracic duct (left side)
Posterior • Right recurrent  Scalenus medius  Scalenus medius

laryngeal nerve (right  Anterior rami of lower  lower trunk of brachial
side) cervical & 1st thoracic plexus
nerves
Inferior  1st rib
Branches (Mnemonic: VIT C D)
1st PART 1. Vertebral Artery

• Arises from the upper convexity of the artery.
• Passes up to disappear at the apex of the pyramidal space into the foramen
of the transverse process of C6.
• Ascends through transverse foramina of C6 to C1.
• Turns posteriorly and medially over posterior arch of atlas to enter cranial cavity at
foramen magnum (pierces dura).
• Runs anteromedially to ascend over the medulla oblongata.
• Two arteries join at pons to form the basilar artery.
• Branches
1. Anterior & Posterior spinal A.
2. Posterior inferior cerebellar A.
2. Internal thoracic artery

• Arises from the lower surface of the artery.
• Passes downwards over the lung apex.
• Crossed usually anteriorly by the phrenic nerve.
3. Thyrocervical Trunk (Lateral to the Vertebral Artery)

1. Transverse cervical (Deep & Superficial)
2. Suprascapular
3. Inferior thyroid

2nd PART
3rd PART
Costocervical trunk Axillary artery
• Passes back across the suprapleural membrane
towards the neck of the 1st rib & divides into. Dorsal scapular
1. Superior/Supreme intercostal (runs downwards) – • Runs laterally through the brachial
into the thorax. plexus in front of scalenus medius &
2. Deep cervical (runs upwards) – Passes backwards then deep to the levator scapulae to
between the transverse process of C7 & the neck take part in the scapular
of the 1st rib and then ascends. anastomosis.
Common Carotid Artery

 Enclosed in carotid sheath medial to the internal jugular vein with the vagus nerve intervening.
 Terminates at the neck by dividing into External & Internal carotids at the level of the upper border of the
thyroid cartilage/ Upper border of C4.
 At the termination point, shows a slight dilatation – Carotid sinus
Relations
Anterolateral Posterior Medial Lateral

• Sternocleidomastoid  Transverse process of  Larynx  Internal jugular
• Sternohyoid lower 4 cervical vertebrae  Pharynx vein
• Sternothyroid  Prevertebral muscles  Trachea  Vagus nerve
• Superior belly of  Sympathetic trunk  Oesophagus
Omohyoid  Inferior Thyroid artery  Thyroid
• Superior thyroid vein Vertebral artery  Recurrent laryngeal nerve
1. Internal carotid artery

 One of the two terminal branches of the Common
Carotid Artery.
 Begins at the upper border of thyroid cartilage (C4)
 Supplies the brain, eyes, forehead and part of nose
 Ascend within the Carotid Sheath
 First lies lateral to the external carotid at its origin,
but soon passes up posteriorly to a medial & deeper
level.
 Passes into the cranial cavity through Carotid Canal in
petrous part of temporal bone.
 Course of the artery is divided into 4 parts.
 Cervical part, in the neck
 Petrous part, within the petrous temporal bone.
 Cavernous part, within the cavernous sinus
 Cerebral part related to the base of the brain.
 No branches of the internal carotid artery in the neck.

2. External carotid artery
 Supplies the neck, face, scalp, tongue,
maxilla
 Terminates in substance of parotid
gland behind neck of mandible by
dividing into maxillary & superficial
temporal branches.
 Emerges from undercover of
sternocleidomastoid where pulsations
can be felt
 First it is medial to internal carotid
but then comes to lie lateral to it
(generally lying more anteriorly)
Branches (Mnemonic * :p)
1) She - Superior Thyroid

2) Always - Ascending Pharyngeal
3) Like - Lingual
4) Friends - Facial
5) Over - Occipital
6) PApa - Posterior Auricular
7) Mama - Maxillary
8) Sis - Superficial temporal
3) Veins
1. Subclavian Vein
 Continuation of the axillary vein at
the outer border of 1st rib. Joins
internal jugular vein to form
brachiocephalic vein.
 Receives External jugular vein.
 Receives the thoracic duct (left) or
right lymphatic duct (right) at its
confluence with the internal jugular
vein.
 Relations
 Anterior - Clavicle
 Posterior - Subclavian artery,
Scalenus anterior & Phrenic nerve
 Inferior - Upper surface of 1st rib
 Tributaries are:
 External Jugular vein
 Dorsal scapular vein
2. Internal Jugular Vein

 Direct continuation of the Sigmoid Sinus.
 Drains the brain, face & neck.
 Leaves skull through Jugular Foramen (Posterior Compartment) and descends through neck in carotid
sheath.
 Joins Subclavian to form Brachiocephalic Vein
 Related to deep cervical nodes.

 Has 2 dilatations; Superior &
Inferior bulbs
 Between the two heads of the
sternocleidomastoid JVP
 Tributaries:
 Inferior Petrosal Sinus – 1st
tributary
 Common facial vein
 Lingual vein
 Pharyngeal veins
 Superior thyroid vein
 Middle thyroid vein
3. Brachiocephalic vein
 The left is longer than the right.
 Formed behind the Sternoclavicular
Joint
 Right – Vertical
 Left – Oblique
 The two unite at lower border of right 1st coastal cartilage to form SVC
 Tributaries
 Branches of 1st part of subclavian artery
 1st posterior intercostal vein
Clinical Anatomy
1. Cardiac failure - Internal jugular vein dilated.
2. Closely associated lymph nodes mean that the vein should also be resected in removing malignancy.
4) Nerves
1. Phrenic nerve
 Origin - C3, C4 (main), C5
 Mixed nerve
 The sole motor supply of diaphragm.
 Sensory to Central Tendon of Diaphragm, Pleura, Pericardium & part of Peritoneum.
 Formed at lateral border of scalenus anterior at the level of upper border of Thyroid Cartilage.
 Runs vertically downwards on Scalenus Anterior from lateral to medial.
 Leaves scalenus anterior & runs downwards on cervical pleura & enters thorax behind 1st costal cartilage.
 Descends anterior to the lung root & then on the surface of the pericardium.
 In the left side, the nerve leaves the medial margin of the Scalenus Anterior at a higher level and crosses in
front of the first part of the Subclavian Artery.
Cervical sympathetic chain

 Continues upwards crossing neck of the 1st rib (SVAN relation)
 Ascends attached to posterior wall of carotid sheath to base of skull in front of prevertebral fascia.

Ganglia – theoretically there should be 8, but due to fusion only 3 present.
 Superior cervical ganglion – largest, located at C2/C3 level, fusion of upper 4, forms plexus
around ECA and ICA
 Middle cervical ganglion – very small, situated at C6 level, fusion of 5 and 6
Connected to the inferior cervical ganglion via ansa subclavia
which hooks under the 1st part of the subclavian artery.
 Inferior cervical ganglion (stellate ganglion) – between C7 and neck of the 1st rib and
extends in front of neck of 1st rib, form plexus around vertebral artery
The ICG often unites with 1st thoracic ganglion to form the stellate ganglion
o No white rami from cervical nerves.

o Grey rami communicans are present (sympathetic – thoracolumbar outflow)
o Gives carotid branches and vascular plexus along carotid, subclavian and
vertebral vessels
o Grey rami pass from superior cervical ganglion to cranial nerves IX, X and XII

THE SUPERFICIAL NECK
 SURFACE MARKING

 Notch of thyroid cartilage
 Hyoid bone – C3
  Cricothyroid ligament (important - cricothyroid puncture) 
 Isthmus of thyroid gland – 2-4 tracheal rings (sometimes palpable) 
 Lower border of Cricoid cartilage - C6 
Also, at the lower border of the cricoid cartilage (C6) lies the,
1. junction of larynx with trachea
2. junction of pharynx with oesophagus
3. inferior thyroid artery enters & middle thyroid vein leaves the thyroid gland
4. vertebral artery enters foramen transversarium of C6 vertebra
5. superior belly of omohyoid crosses carotid sheath
6. middle cervical sympathetic ganglion
7. carotid artery can be compressed against anterior tubercle of the transverse process (carotid tubercle) of 6 th
cervical vertebra
 carotid sheath – join the following points 

i. a point midway between tip of mastoid process & angle of the jaw
ii. sternoclavicular joint
 bifurcation of common carotid artery – upper border of thyroid cartilage 
 Cutaneous innervation
 C2, C3, C4
 anterolateral part – anterior primary rami through
  lesser occipital 
  great auricular 
  Transverse cervical 
 supraclavicular 
 posterior part – posterior primary rami
*C1 – no cutaneous innervation
C4 – through supraclavicular nerves supply pectoral region
Clinical – diaphragmatic irritation causes referred pain

in shoulder tip via supra clavicular nerve which is a
branch of cervical plexus.
 SUPERFICIAL FASCIA
 platysma 
 cervical branch of facial nerve 
 lymph nodes & vessels.

 external jugular vein 
 deep to platysma
 posterior auricular + posterior division of
retromandibular vein
External jugular vein

 begins within lower part of parotid gland
 crosses the sternocleidomastoid obliquely
 pierces the anteroinferior angle of the roof of the posterior triangle
 opens into subclavian vein
 used to assess venous pressure * air embolism when cut
Clinical:
Division of the external Jugular vein in the supraclavicular space may cause air embolism and death because the cut
ends of the vein are prevented from retraction and closure by the fascia, attached firmly to the vein.


 Anterior Jugular vein 
 begins in submental region
 Descends in the superficial fascia
 Above the sternum it pierces the
investing layer of deep fascia
 Enters suprasternal space
 Connected to opposite vein by
jugular venous arch
 Turns laterally and runs deep to
sternocleidomastoid just above the
clavicle
 Ends in the external jugular vein.
 DEEP CERVICAL FASCIA

The deep fascia of the neck is condensed to
form the following parts:
1. investing layer
 surrounds the neck like a collar 
 Forms the roof of anterior & posterior
triangle.
 attachments 
A) superiorly – external occipital
protuberance,
Superior nuchal line, 
Mastoid, 
Lower border of mandible 
 between angle of mandible &
mastoid process, the fascia
splits to enclose the parotid gland 
 superficial lamina is thick – attached to zygomatic arch 
 deep lamina is thin – attached to styloid process, mandible,
tympanic plate 
o deep lamina forms stylomandibular ligament – separates parotid & submandibular glands
o pierced by external carotid artery

B) inferiorly – spine of scapula
Acromion process, Clavicle, Manubrium
C) posteriorly – ligamentum nuchae, Spine of C7
D) anteriorly – hyoid bone
 encloses 2 muscles, salivary gland, 2 spaces 
sternocleidomastoid Parotid Suprasternal

trapezius supraclavicular
 forms pulleys for digastric & omohyoid
Suprasternal
 space of Burns 
 jugular venous arch and
the anastomotic arch
between them
 sternal heads of
sternocleidomastoid
 lymph node
 interclavicular ligament
supraclavicular space
 external jugular vein
 supraclavicular nerves
 lymphatics
2. Pretracheal layer
 forms the false capsule
of thyroid gland 
 The posterior layer of
the Thyroid capsule is thick. On either side it makes the suspensory ligament of Berry which is attached to the cricoid.
 attachments 
 superiorly – hyoid bone
Oblique line of thyroid cartilage Cricoid cartilage
 inferiorly – encloses inferior thyroid veins
Passes behind brachiocephalic veins & blend with arch of aorta
 laterally – fuses with carotid sheath
Clinical:
Thyroid gland and all thyroid swellings move with deglutition because the thyroid is attached to
cartilage of the larynx by the suspensory ligament of Berry.
Swellings due to lymph node enlargement do not move with deglutition.
3. Prevertebral layer
 in front of prevertebral muscles 
 forms floor of posterior triangle 
 attachments 
 superiorly – base of skull
 inferiorly – anterior longitudinal ligament & body of T4
 anteriorly – separated from pharynx & buccopharyngeal fascia by retropharyngeal space (areolar tissue)
anterior surfaces of transverse processes and bodies of vertebrae C1 – C3
 Laterally – thins out deep to trapezius
 cervical & brachial plexuses lie behind the fascia 
 forms the axillary sheath – does not contain axillary vein 
 Posteriorly – ligamentum nuchae

4. Carotid sheath
 condensation of fibroareolar tissue around vessels of neck 
 Attachments 
 Superiorly – base of the skull
 Inferiorly – adventitia of the arch of the aorta
 anteriorly embedded in the carotid sheath lies the ansa cervicalis 
 posteriorly between the carotid sheath and the prevertebral fascia lies the sympathetic chain 
 fuses with pretracheal and investing layers of deep fascia

5. Buccopharyngeal layer
covers superior constrictor externally & extends on to the superficial surface of buccinator.
So that parotid duct has to pierce it
6. Pharyngobasilar layer
Thick between upper border of superior constrictor & base of skull
Clinicals
 parotid swellings are painful due to the unyielding nature of parotid fascia 
 while excising submandibular gland external carotid artery should be secured 
 thyroid gland & all swellings move with deglutition due to fascial attachments 
 pus due to tuberculosis of vertebrae may pass forward forming a chronic retropharyngeal abscess in
the median plane 
o it may extend laterally through axillary sheath; it may descend as far as superior
mediastinum
 pus collected from neck infections
In front of prevertebral fascia extend in a paramedian position as far as the posterior
mediastinum
 neck infections
In front of pretracheal fascia extend into the anterior mediastinum
 Muscles of the neck

Muscles of the Neck
Sternocleidomastoid Suprahyoid Infrahyoid (strap muscles)
STERNOCLEIDOMASTOID MUSCLE
 origin 
- sternal head – (tendinous) manubrium sterni
- clavicular head – (musculotendinous) medial 1/3rd of superior surface of clavicle *deep to the interval between the 2
heads lie the internal jugular vein
 insertion 
- mastoid process
- lateral half of superior nuchal line
  nerve supply 
 motor – spinal accessory nerve proprioceptive – ventral rami of C2 
  blood supply 
occipital artery (2 branches), superior thyroid & suprascapular arteries 
 actions 
contraction of 1 muscle – 1. Turns chin to opposite side
2. Tilts head towards shoulder
contraction of both muscles – 1. Draw head forwards
2. Flex neck against resistance
3. Forced inspiration

 relations 
  superficial 
  skin 
  superficial fascia 
  platysma 
  external jugular vein 
  superficial layer of investing fascia 
  lymph nodes 
  parotid gland 
 great auricular, transverse cutaneous, medial supraclavicular 
nerves
(The muscle is crossed superficially form above downwards by the great auricular nerve, external jugular vein and the
transverse cervical nerve)
 deep
 bones & joints – mastoid process, sternoclavicular joint 
 carotid sheath 
 muscles – sternohyoid, sternothyroid, omohyoid, 3 scaleni. Levator scapulae, longissimus capitis,
posterior belly of digastric 
 arteries – common, internal & external carotids, arteries to muscles, occipital, subclavian,
suprascapular, transverse cervical 
 veins – internal jugular, anterior jugular, facial & lingual 
 nerves – X, XI, cervical plexus, upper part of brachial plexus, phrenic, ansa cervicalis 
 lymph nodes deep cervical.
CLINICALS
 most common cause for swelling in the posterior triangle is due to – enlargement of supraclavicular lymph nodes 

 left supraclavicular nodes – signal nodes (malignancies in stomach & testis) 
 wry neck – head bends to 1 side & chin points to other side: spasm of muscles supplied by spinal accessory nerve 
Muscle Innervation Action

Suprahyoid muscles
1. Digastric Posterior belly – Facial nerve
Anterior belly – Nerve to mylohyoid
2. Stylohyoid Facial nerve
3. Mylohyoid Own nerve from inferior alveolar
4. Geniohyoid Branch from hypoglossal nerve
Infrahyoid muscles
1. Sternohyoid Ansa cervicalis
2. Omohyoid Superior belly – superior root of
ansa cervicalis
All depressors of larynx
Inferior belly – ansa cervicalis
3. Thyrohyoid Branch from hypoglossal nerve
4. Sternothyroid Ansa cervicalis
 Triangles of the neck
Posterior triangle Anterior triangle

 Submental triangle
 Digastric/ Submandibular triangle
 Muscular triangle
 Carotid triangle

POSTERIOR TRIANGLE OF NECK
It’s a space on the side of the neck situated behind the sternocleidomastoid muscle
Boundaries
o anteriorly – posterior border of sternocleidomastoid 
o posteriorly – anterior border of trapezius 
o base – middle 1/3rd of clavicle 
o apex – superior nuchal line where the 2 muscles meet 
o roof – investing layer of deep cervical fascia 
o floor – prevertebral layer of deep cervical fascia covering splenius capitis, levator scapulae, scalenus medius 
 Divisions – divided by inferior belly of omohyoid into larger upper part (occipital triangle) & smaller lower
part (subclavian triangle)
ANTERIOR TRIANGLE OF NECK

Boundaries
 medially – anterior medial plane
 laterally – anterior border of the sternocleidomastoid
 superiorly – base of mandible & a line joining the angle of mandible to mastoid process

Borders Contents
submental lymph nodes
submental on each side - anterior belly of digastric formation of anterior jugular vein
triangle base – body of hyoid bone apex – chin
floor – mylohyoid muscle
The triangle crosses the midline
Submandibular salivary gland and lymph nodes
digastric Anteroinferiorly-anterior belly of digastrics Facial, submental and mylohyoid vessels
triangle Posteroinferiorly-posterior belly of digastrics Hypoglossal and mylohyoid nerves
Base-the lower border of the mandible and
line joining the angle of mandible to mastoid
process
Roof – skin, superficial fascia, deep fascia
Floor – anteriorly – mylohyoid: posteriorly –
hyoglossus
 Arteries
carotid Antero-superiorly – posterior belly of Common, internal & external carotid
triangle digastric Carotid sinus & body
Antero-inferiorly – superior belly of All branches of external carotid except posterior auricular
omohyoid  Veins
Posteriorly – sternocleidomastoid Internal jugular
Roof – skin, superficial fascia, deep fascia Common facial
Floor – thyrohyoid, hyoglossus, middle & Lingual
inferior constrictors Pharyngeal
 Nerves
Vagus
Superior laryngeal
Spinal accessory
Hypoglossal
Sympathetic chain
 Carotid sheath
 Lymph nodes
Anteriorly – median plane
Muscular
Postero-superiorly – superior belly of omohyoid The Infra hyoid strap muscles
triangle
Postero-inferiorly – sternocleidomastoid
Clinicals
Common anterior midline swellings of the neck are

o Enlarged submental lymph nodes
o Sublingual dermoids
o Thyroglossal cyst
o Subhyoid bursitis
o Goitre
o Carcinoma of the larynx
o Enlarged supra sternal lymph nodes
Cervical plexus
Formed by ventral rami of upper cervical nerves. (C1 gives no cutaneous branches)
Branches:
Superficial branches-
1. Lesser Occipital (C2)
2. Great auricular (C2, C3)
3. Transverse cutaneous nerve of the neck (C2, C3)
4. Supraclavicular (C3, C4)
Deep branches –
Muscular branches to:
1. Rectus capitis anterior (C1)
2. Rectus capitis lateralis (C1, C2)
3. Longus capitis (C1-C3)
4. Lower root of Ansa cervicalis
Communication branches:
1. Grey rami from the superior cervical ganglion to C1-C4 nerves.
2. Branch from C1 joins the hypoglossal nerve
3. Branch from C2 to sternocleidomastoid & branches from C3 & C4 to the Trapezius
communicate with accessory nerve.

Ansa Cervicalis
 This is a thin nerve loop that lies embedded in the anterior wall of carotid sheath over the lower part of larynx.
 It supplies the infrahyoid muscles.
 Formed by a superior and inferior root.
 Superior root is the continuation of the descending branch of the hypoglossal nerve derived from C1.
 Inferior root derived from C2, C3. This root winds around the internal jugular vein and continues anteroinferiorly to join
the superior root in front of the common carotid artery.
Distribution:
 superior root to the superior belly of omohyoid
 Ansa cervicalis to the sternohyoid, the sternothyroid and the inferior belly of omohyoid
 Thyrohyoid and geniohyoid are supplied by separate branches from the first cervical nerve through the hypoglossal
nerve.
1) Cervical fascia splits

a) and embraces the infrahyoid muscles
b) and partially encloses submandibular salivary gland
c) inferiorly enclosing jugular venous arch
d) posteriorly around the scapula
e) to enclose sternocleidomastoid muscle

2) Prevertebral fascia
a) encloses the thyroid gland
b) extends laterally into the upper limb as the axillary sheath
c) has the cervical sympathetic chain embedded in it
d) blends inferiorly with anterior longitudinal ligament infront of body of C6 vertebra
e) splits around the hyoid bone
3) Carotid sheath
a) is attached superiorly to the base of the skull
b) fuses with the pericardium inferiorly
c) lies deep to the prevertebral fascia
d) encloses the jugular vein and vagus nerves
e) encloses the external carotid artery
4) Posterior triangle of the neck

a) is floored by the prevertebral fascia
b) is bordered posteriorly by the rhomboideus major muscle
c) has the spine of the scapula as its inferior border
d) is bordered anteriorly by the sternocleidomastoid muscle
e) is crossed by the internal jugular vein
Lymph drainage of the neck
 Horizontally arranged nodes –
 At the junction between head and neck there is a circular arrangement of lymph nodes.
 Submental nodes – submental triangle Drain superficial tissues
 Submandibular nodes – digastric triangle of head & neck
 Preauricular(parotid) nodes – within the gland / deep or superficial to capsule
 Mastoid nodes – on the mastoid process
 Occipital nodes – apex of posterior triangle of the neck
 Mandibular and buccal nodes

 Vertically arranged nodes –
 Superficial cervical nodes – along external jugular vein

 Anterior cervical nodes – along anterior jugular vein. Drain trachea
 Deep to investing deep fascia of front of neck - infrahyoid nodes – on thyrohyoid membrane larynx
Prelaryngeal nodes – on cricothyroid membrane esophagus
Pretracheal nodes – on trachea thyroid
Paratracheal nodes – either side of trachea and part of pharynx
Esophagus
● Deep cervical nodes
Vertical group along the internal jugular vein.
Within or outside the carotid sheath.
All the structures in the head and neck pass ultimately to this group directly or indirectly.
Efferents form jugular trunk.
Left trunk thoracic duct

Right trunk right lymphatic duct
Retropharyngeal nodes – behind the pharynx – back of nose, pharynx, auditory tube
All lymph from horizontal and vertical groups drain into deep cervical nodes.
o Stylomandibular ligament
o Stylohyoid ligament
o Sphenomandibular ligament
o Pterygomandibular raphe
o Pterygomaxillary ligament
o Petrosphenoid ligament

Root
NOSE & PARANASAL SINUSES Bridge
Nose
Consists of external nose and nasal cavity, Skin is abundant in
sebaceous glands Dorsum
External nosebony & cartilage framework
Bones
 2 nasal bones
 frontal process of maxilla Tip
Cartilages
 lateral Processes of septal cartilages
Base
 major alar cartilages
 minor alar cartilages
 Alasolely of fatty tissue at its free lower border
Nasal cavityAnterior nares to posterior choanae

Communicate with nasopharynx
divided by medial nasal septum (medial wall)
Medial wall
  perpendicular plate of ethmoid bone 
 vomer bone 
 septal cartilage 
 Small contribution from maxillary bone and palatine
bone
Lateral wall
 frontal process of maxilla (mainly)
 perpendicular plate of the palatine bone
 medial pterygoid plate
 ethmoid labyrinth with superior and middle conchae
 inferior nasal conchae
 nasal bone
 lacrimal bone
 Cartilaginous part
Conchae and Meatus

Conchae
 curved bony projections directed downwards and
medially
1. Superior conchae Projections from
2. Middle conchae ethmoid bone
3. Inferior conchae – independent bone
Meatus
 Passages beneath the
overhanging conchae
 Paranasal sinuses
open into meatus
1. Superior meatusposterior ethmoidal air cells
2. Middle meatus● Ethmoidal bulla middle ethmoidal air cells
 hiatus semilunaris (A deep semicircular sulcus below bulla)Frontal sinus (anteriorly)
Anterior ethmoidal air cells (middle)
 Maxillary air sinus (posteriorly)
3. Inferior meatusnasolacrimal duct
 Spheno-ethmoidal recess (just above the superior conchae) sphenoidal air cells
* Roof
 horizontal – made by cribriform plate
 anteriorly – frontal bone
 posteriorly – sphenoid bone
* Floor
Hard palate = Palatine process of maxilla + horizontal plate of palatine bone
Soft palate
Mucous membrane
 Olfactory epithelium - thin 
 confined to superior conchae and adjacent upper part of septum
 Respiratory epithelium - thick (mucous secretions) 
Blood supply & nerve supply

Nerve supply

Blood supply
Little’s area
 Anterior inferior part of the septum
 Has rich arterial supply
 Anastomoses between
 Superior labial branch of facial artery
 Greater palatine artery
 Branch of sphenopalatine artery
Forms the Kiseselbach’s plexus
 A common site for nosebleed
(epistaxis)
Blood supply of the nasal cavity
 Include vessels that originate from both
the internal and external carotid arteries
 Vessels that originate from branches of
external carotid artery
 Sphenopalatine(major blood
supply),greater palatine, superior labial
and lateral nasal arteries
 Vessels that originate from branches of

internal carotid artery
 Anterior and posterior ethmoidal arteries
 Veins draining the nasal cavities generally follow the arteries
 veins that pass with branches that ultimately originate from the maxillary artery drain into the pterygoid
plexus of veins in the infratemporal fossa
 veins from anterior regions of the nasal cavities join the facial vein.
Nerve supply of the nasal cavity
 the olfactory nerve [I] for olfaction; and branches of the ophthalmic [V1] and maxillary [V2] nerves for general
sensation
 Secretomotor innervation of mucous glands in the nasal cavities and paranasal sinuses is by parasympathetic
fibers from the facial nerve [VII], which mainly join branches of the maxillary nerve [V2] in the pterygopalatine
fossa.
Paranasal sinuses
 air containing sacs lined by ciliated epithelium
 function of the sinuses resonators to the voice; reduce the weight of the skull 
 at birthmaxillary, sphenoid present but rudimentary 
 all become fully formed only in adolescence
 Innervated by branches of the trigeminal nerve [V]

1. Frontal sinus
 related to anterior cranial fossa and orbit
 only sinus not present at birth
 sizes vary greatly, one or both occasionally absent
 Clinicals

1. closely related to frontal lobe infections may result in frontal lobe abscess

2. C.S.F rhinorrhea contralateral due to inter communication

-trickling of CSF through nostrils

-due to tearing of meningeal layers → subarachnoid space communicates with nasal cavity

(due to fracture of anterior cranial fossa involving frontal sinus)
2. Maxillary sinus (largest)

 pyramidal shaped, within the body of the maxilla
 opening is inefficient, superiorly placed drains the apex 
 infraorbital nerve in the groove bulges down into the roof 
 Relations
o Base - lateral wall of nose
o Apex - zygomatic process
o Superior - floor of orbit
o Floor - alveolar part of maxilla
o Posteriorly - infratemporal fossa
 o Anterior - cheek 
 Floor separated from upper premolar, molar teeth by only a thin layer of bone.  Relations of the
Dental roots project into the sinus 
 Floor corresponds to the level of alveolus (not to the floor of nasal cavity) floor


 Clinicals
  symptoms in carcinoma of maxillary sinus 
 1) Medial – epistaxis, obstruction of nares

 epiphorea (blocked nasolacrimal duct)
 2) Orbit - diplopia + exophthalmos
 infraorbital nerve facial pain, anesthesia of skin over the maxilla
 3) Floor – bulging/ulceration in the palatal roof
 4) Lateral - swelling of face
 5) Posterior - palatine nerves referred severe pain to teeth of upper jaw
 2. Infections of the maxillary sinus

 From nasal cavity

  From caries of upper molar teeth
3. Ethmoidal sinus
 Numerous, small, intercommunicating spaces (8-10)
 Lie within the labyrinth of ethmoid bone
 Divided in to anterior, middle and posterior groups
Clinicals
 related to frontal lobe - frontal lobe abscess 
 C.S.F rhinorrhea 
4. Sphenoid sinus
 Either side of midline, in body of sphenoid 
 Drain above superior conchae (spheno-ethmoidal recess) 
Clinicals
In pituitary tumor, Pituitary gland may be excised through fibre-optic trans-nasal trans-sphenoidal approach
(endoscopically)
LARYNX
 Musculofibrous structure with a cartilaginous

framework.
 Extent
 In the anterior midline of neck, from root of tongue to
trachea. 
 In adult male C3 – C6
 Constitution
 Cartilage
 Paired- Arytenoid, Corniculate, Cuneiform
 Unpaired- Thyroid, Cricoid, Epiglottic.
 Ligaments
 Membranes
 Cartilage
 Thyroid
 Cricoid. Hyaline cartilages
 Arytenoid
 Epiglottis
 Cuneiform. elastic fibrocartilages
 Corniculate

Thyroid (largest)
 Right & left laminae 
 The angle between the two laminae is more acute Corniculate
in men (90°) than in women (120°) so the  Lie in posterior parts of aryepiglottic fold
laryngeal prominence is more apparent in men
than women. Cuneiform
 
 Just superior to the laryngeal prominence, the  Lie in aryepiglottic fold, anteriorly to corniculate
superior thyroid notch separates the two laminae
 Anterior borders fuse at laryngeal prominence Arytenoid
anteriorly  Pyramidal shaped
 Superior horn connected hyoid bone by thyrohyoid  Apex articulates with corniculate cartilages
membrane  
 Prolonged anteriorly to form vocal process&
 Oblique line muscles (extrinsic)
laterally to form muscular process
 medial surface of the inferior horn has a facet for
articulation with the cricoid cartilage
Histology
 Thyroid, hyoid & arytenoids (basal part) – hyaline
 Others – elastic
Cricoid
 Signet-ring shaped
 Only complete cartilaginous ring in the whole air
passage
 facets on superolateral surface of the lamina
articulates with the base of arytenoid cartilages
 In posterior surface esophagus is attached to a vertical
ridge & depression on either side are for attachment
of posterior cricoarytenoid muscles


Epiglottis
 Placed in anterior wall of laryngopharynx
 Aryepiglottic fold
 Hyoepiglottic ligament 
 Glossoepiglottic fold
 leaf-shaped cartilage
 Attached to posterior surface of thyroid cartilage at
angle via Thyroepiglottic ligament.



 Ligaments/Membranes
Extrinsic membranes/ligaments
 Thyrohyoid membrane
 Has an aperture for,
o Superior laryngeal artery
o Superior laryngeal vein
o Internal laryngeal branch of superior
laryngeal nerve
 Form the lateral wall of piriform recess
 Hyoepiglottic ligament
 Cricotracheal ligament
Intrinsic membranes/ligaments
 Quadrangular membrane
 Thin fibro elastic membrane
 Between arytenoid cartilage & epiglottis
 Lower border is a free margin, thickened to
form the Vestibular ligament (false vocal
cords)
 Cricothyroid ligament/membrane
 Mainly elastic tissue
 Anteriorly in the midline, thick band called
Median Cricothyroid ligament
 Free upper margin forms the Vocal Ligament
(True vocal cords) inserting to the vocal
process of arytenoid cartilage
 Cavity of Larynx
 From laryngeal inlet extends up to lower border of

cricoid cartilage 
 inlet is bounded anteriorly by epiglottis, posteriorly by
inter arytenoids folds & the sides by aryepiglottic fold 
 vestibular fold superiorly (opening - “rima vestibuli”)
 vocal fold inferiorly (opening – “rima glottidis”) 
 Ventricle between the vestibular folds above and the
vocal folds below.

 Mucous membrane
 anterior surface & upper half of posterior surface of
epiglottis, the upper part of epiglottic folds & vocal folds
– stratified squamous
 others – ciliated columnar 
 mucous glands absent over vocal folds 
 Above vocal fold
1. superior laryngeal artery
2. superior laryngeal vein

3. internal laryngeal nerve (sensory)
4. Antero-superior (deep cervical) lymph drainage
 Below vocal fold

1. inferior laryngeal artery
2. inferior laryngeal vein
3. recurrent laryngeal nerve (sensory)
4. Postero-inferior (deep cervical) lymph drainage
 Muscles
Muscles Nerves Action

External
Cricothyroid Tensor of vocal cords
laryngeal
Posterior cricoarytenoid Abduct vocal cords

Lateral cricoarytenoid Adduct vocal cords
Transverse arytenoids Adduct vocal cords
Oblique arytenoids Recurrent Adducts vocal cords
Aryepiglottic laryngeal Close laryngeal inlet
Thyroarytenoid Relax vocal cords
Vocalis Relax vocal cords
Thyroepiglotticus Open inlet
Clinicals
1. Bilateral complete damage to Recurrent Laryngeal Nerves
 Vocal cords in cadaveric position 
 Phonation lost 
 Breathing difficult 

2. Bilateral partial damage of Recurrent Laryngeal Nerves
 Vocal folds completely adducted 
 Breathing lost (Outer fibres supply abductors)

3.Laryngotomy: The needle is inserted in the midline of cricothyroid membrane,below the thyroid prominence.This
is done as an emergency procedure.

ORAL CAVITY
 Oral cavity can be divided into oral cavity proper (Inner larger)
and vestibule (outer smaller )
PALATE
Separates the oral cavity from the nasal cavity
1.Hard palate:
Palatine plate of maxilla- anterior 2/3
Horizontal plate of palatine bone- posterior 1/3
2.Soft palate:
Divide naso & oro pharynx
Anterior surface marked by median
raphe uvula at posterior edge
* Muscles
 tensor veli palatini (tenses soft palate)  Framework by the aponeurosis
  levator palatine (elevation) 
  palatoglossus
  palatopharyngeus inserted to the aponeurosis
 muscular uvulae 
Nerve supply - Motor

Passavant’s ridge
All palatine musclesX, XI Some fibres of palatopharyngeus, Closes
(vagoaccessory complex) pharyngeal isthmus with soft palate
during swallowing.
except tensor vali palatine (by
V3)
if paralyzed nasal regurgitation

impaired voice
flat palatal arch
 If one side of the palate is paralysed it

deviate to non-affected side
(Face, palate opposite side
Rest same side )

Pillars of fauces
From each side of base of uvula two curved folds of mucous

membrane extend laterally and downwards.
 Anterior fold – palatoglossus arch (contain palatoglossus

muscle)
 Posterior fold – palatopharyngeal arch (contain

palatopharyngeus muscle)

TONGUE
Muscles
External (extrinsic) Internal (intrinsic)
 genioglossus (protrudes tongue) ● Ver cal
 hyoglossus (depresses tongue) ● inferior longitudinal
styloglossus(pulls upward & backwards) - retracts ● transverse
palatoglossus (pulls upwards &backwards) – elevates ● superior longitudinal
(thus narrows oropharyngeal isthmus)
* Under aspect median frenulum linguae

either side of the frenulum deep lingual veins
* Main blood supply: lingual artery (from external carotid artery )
* Lymph drainage
 tip bilaterally submental nodes
 remaining anterior 2/3 unilateral Submandibular Jugulo-omohyoid
 posterior 1/3 bilateral jugulo-digastric

* Nerve supply
Sensory Supply
General sensation Taste sensation

Anterior 2/3 Lingual(V) chorda tympani(VII)
Posterior 1/3(also the palate) IX IX
Posterior most X X
Motor supply: XII(hypoglossal nerve)

except palatoglossus  cranial root of accessory nerve
Openings of salivary glands

 Parotid ductopposite crown of 2nd upper molar tooth into vestibule of mouth
 Submandibular ductson either side of the base of frenulum of tongue
 Sublingual ductssublingual fold

PHARYNX
Introduction
 Fibromuscular tube
 Anteriorly incomplete open into nasal cavity, oral cavity and larynx, posteriorly in front of prevertebral muscle.
 Acts as a common entrance for RS & GIT
Base of the skull=> => Soft palate=> => Tip of Epiglottis => =>Esophagus
1.Nasopharynx 2. Oropharynx 3. Laryngopharynx
[Pharyngeal isthmus][C6]
Extent
Superiorly => Base of the skull –pterygomandibular raphe, mandible, hamulus

Medial pterygoid plate
Pharyngotympanic tube
Petrous temporal
Basal part of Occipital
Inferiorly => Esophagus
Anteriorly => From above downwards – Posterior nasal apertures [Choanae]
Oropharyngeal isthmus
Laryngeal inlet
Posteriorly =>Vertebral column
On either side => styloid process and muscles attached to it
Common carotid, internal and external carotid arteries
Waldeyer’s Lymphatic ring
Several aggregations of lymphoid tissues in relation to naso-oropharyngeal isthmus

 Most important, right and left palatine tonsils (Between palatoglossus and palatopharyngeal arches)
 Nasopharyngeal tonsils (posteriorly and above)
 Tubal tonsils (laterally and above on tubal elevation)
 Lingual tonsils (inferiorly at dorsum of tongue)
All lymphatics ultimately drain into deep

cervical lymph nodes
Pharyngeal wall
From inside to outside

• Mucosa
• Submucosa
• Pharyngobasilar fascia: Thickest in upper part
From pharyngeal raphe posteriorly, Deficient below superior
constrictor
1 ©2017 A/L Repeat campaign

• Muscular coat: Outer circular - 3 constrictors
Inner longitudinal
• Pharyngeal plexus of veins & nerves
• Buccopharyngeal fascia: extend forward across pterygomandibular
raphe to cover Buccinators
Muscles
 3 pairs of Constrictors =>Constrict the pharyngeal cavity
From => Posterior Opening of => Nose + Mouth+ Larynx

 Superior – Pterygoid Hamulus + Pterygomandibular raphe
 Middle – Stylohyoid lig. + Lesser & greater horns of hyoid
 Inferior – Oblique line of thyroid =>Thyropharyngeus
Cricoid => Cricopharyngeus
Gap between 2 parts => Killian’s Dehiscence
To=>Pharyngeal Raphe [From pharyngeal tubercle to C6]
 Covers the above muscle by the below (Telescope-like)
 3 pairs of Longitudinal =>Elevate the pharyngeal wall
From=> Styloid process - Stylopharyngeus

Palate - Palatopharyngeus
Auditory tube - Salphingopharyngeus
To => Inner aspect of constrictor
Gaps among constrictors
Above superior constrictor- Auditory tube + Levator palatini + Ascending palatine A.

Closed by Pharyngobasilar fascia
Bw Sup & Mid constrictors - Stylopharyngeus + CN9
Bw Mid &Inf constrictors - Internal laryngeal N. + Sup laryngeal Vessels Piercing Thyrohyoid membrane
Below Inf constrictor - Recurrent laryngeal N. + Inf. Laryngeal Vessels
1. Nasopharynx

 base of the skull to upper surface of soft palate
 Contents
o pharyngeal tonsil- at the junction of roof and post. wall

Pathological enlargement – Adenoids - prominent in children, when chronically inflamed, mouth
breathing & cause deafness
o Opening of auditory tube just behind the inferior nasal concha
 Posterior lip of the opening elevated [Tubal elevation] – contains tubal tonsil
 Posterior to the tubal elevation - Pharyngeal recess – related to internal carotid.
 Salpingopharyngeal fold descends downwards from tubal elevation – Overlies Salpingopharyngeus muscle
2. Oropharynx
 from lower surface of soft palate to upper border of epiglottis.

 Anterior boundary - Palatoglossal arch + Sulcus terminalis
 Contents
o Palatine Tonsils
In the lateral wall=>Tonsillar fossa
- between Palatoglossal arch – Overlies Palatoglossus
& Palatopharyngeal arch – Overlies Palatopharyngeus
- Floor[Bed] = i. Tonsillar hemicapsule.=> Condensation of pharyngobasilar fascia

ii. Loose Areolar tissue
iii. Superior constrictor
b/w capsule and sup. constrictor – paratonsillar vein – bleeding after tonsillectomy
- Posteriorly = Carotid sheath
- Contain=>lymphoid tissue covered by squamous epithelium Pitted by crypts
Bears a deep intratonsillar cleft [2nd pharyngeal pouch]
o- Blood supply=>Tonsillar branch of facial artery, twigs from lingual, ascending palatine,
ascending pharyngeal arteries
Veins drain into pharyngeal plexus and a constant vein - paratonsillar vein
- Lymph drainage => to Jugulodigastric nodes - piercing the superior constrictor, in tonsillitis,
most commonly undergo pathological enlargement
 When holding liquid in the oral cavity =>Oropharyngeal isthmus is closed by
 Depression of the soft palate
 Elevation of the back of the tongue
 Movement toward the midline of the palatoglossal and palatopharyngeal fold
Lingual Tonsils
In the mucosa covering the posterior 1/3 of the tongue
3. Laryngopharynx
 From upper border of epiglottis to cricoid cartilage(c6)

 Valleculae => Mucosal pouches on each side of the midline bw the base of the tongue
 Piriform fossae => Mucosal recess, anterolaterally on either side
- bw aryepiglottic fold & Lamina of the thyroid c.
- Internal laryngeal nerve lies beneath the mucosa
- Ingested sharp foreign bodies may lodge (eg: fish bones)

- Internal laryngeal nerve lies beneath the mucosa
- ingested sharp foreign bodies may lodge (eg: fish bones)
Nerve supply
From Pharyngeal Plexus =>Chiefly lying on middle constrictor
I.Pharyngeal branch of Vagus with cranial accessory nerve fibres

II.Pharyngeal branch of glossopharyngeal
III.Pharyngeal branch of superior cervical sympathetic ganglion
 Motor
All muscles by =>CN10 - Vagus
Except Stylopharyngeus by =>CN9
 Sensory
Nasopharynx – V2
Oropharynx – CN 9
Laryngopharynx – CN 10
Deglutition - Occurs in 3 stages
1st stage = Voluntary from oral cavity into Oropharynx

I. Tongue pushes bolus into posterior part of oral cavity
II. Oropharyngeal isthmus is closed by Soft Palate => helps to form the Bolus
III. Hyoid moves upwards & forwards – by Suprahyoid muscles
IV. Posterior tongue elevated – by Styloglossus
V. Palatoglossal arches approximated – by Palatoglossus =>push the bolus to oropharynx
2nd stage= Involuntary from oropharynx to laryngopharynx

I. Nasopharyngeal isthmus closed by soft palate & Palatopharyngeal sphincter
II. Laryngeal inlet closed
III. Larynx & pharynx elevated
IV. Epiglottis closes
3rd stage= Involuntary from laryngopharynx to oesophagus by inferior constrictor of pharynx
Clinicals
1) Pharyngeal Pouch [Zenkers Diverticulum] – Killian’s dehiscence

Due to neuromuscular incoordination in the 2 parts of Inferior
Constrictors
If Cricopharyngeus [by recurrent pharyngeal] fails to relax,
When Thyropharyngeus [by pharyngeal plexus] contracts
=> Food bolus is pushed backwards and produces a diverticulum
Backward extension is prevented by the Prevertebral fascia
=> Project to one side of the pharynx [usually more exposed left]
With further enlargement
=> Pouch pushes the esophagus aside & lies in line with pharynx
Resulting
Food passes to the pouch => Dysphagia
Spillage of the pouch contents into the larynx => Respiratory infections & Lung abscess
2) In Palatine tonsillitis

Referred pain in the ear
3) Tonsillectomy
- Lymphoid tissue is removed with the capsule - Paratonsillar V. may be damaged
- Structures preserved
Superior constrictor => as it is separated from the capsule by loose areolar tissue Internal Carotid A. =>as it lies within Carotid sheath
covered by fatty tissue
4) Quinsy - suppuration in the peritonsillar tissue secondary to tonsillitis
Submandibular region
 Area between mandible & hyoid bone including floor of mouth & root of the tongue
 includes the suprahyoid muscles (digastric, stylohyoid, mylohyoid, geniohyoid), submandibular & sublingual gland &
submandibular ganglion
SUBMANDIBULAR SALIVARY GLAND
• Large salivary gland; not the largest

• Anterior part of the digastric triangle
• J shaped, indented by the posterior border of the mylohyoid
• Large superficial part, smaller deep part
* Superficial part
 Situated in the digastric triangle
 Enclosed between 2 layers of deep cervical fascia
Relations
 Inferior surface is covered by

- Skin
- Platysma
- Cervical branch of facial nerve
-Deep fascia
- Facial vein
- Submandibular lymph nodes
 lateral surface
- Submandibular fossa
- Insertion of medial pterygoid - Facial artery
 Medial surface
- Lies against the mylohyoid muscle.
- Behind it hyoglossus, lingual nerve, hypoglossal nerve
* deep part
 Continuous with superficial part round the
 Lies deep to mylohyoid
 Superficial to hyoglossus & styloglossus
 posterior border of mylohyoid Anteriorly
extends up to posterior end of sublingual
gland
*Submandibular duct
 Emerges from anterior end of deep part
 Runs forward on hyoglossus between hypoglossal & lingual nerves
 Lingual nerve crosses at anterior border of hyoglossus
 Lingual nerve double crosses at the duct. 1. medial to lateral 2.lateral to medial
 Opens lateral to the base of the frenulum of the tongue
* Blood supply
- facial artery
- drains to common facial / lingual vein
* Lymph drainage- To submandibular lymph node
* Innervation
Secretomotor
Superior salivatory nucleus
Sensory root of facial nerve
Geniculate ganglion
Facial nerve
Chorda tympani nerve
Lingual nerve
Submandibular ganglion (Relay)
Post ganglionic fibers
Submandibular gland and sublingual gland
Clinical
In excision of submandibular gland incision is carried out 2.5 cm below the base of the mandible to preserve marginal mandibular
nerve
Injury to spine of sphenoid may impair secretions from salivary glands
Bimanual method.
SUBLINGUAL SALIVARY GLAND

 Beneath the mucosa of the floor of the mouth medial to the
sublingual fossa of mandible
 Ducts open on the floor of mouth
 Blood supply – lingual, submental artery
SUBMANDIBULAR GANGLION
 Parasympathetic peripheral ganglion
 Relay station for secretomotor fibers to submandibular &
 sublingual salivary gland
 Topographically related to lingual nerve
 Functionally related to chorda tympani nerve
 Lies on hyoglossus muscle
 Sensory fibers reach the ganglion through lingual nerve
1. The hyoglossus muscle

a) Lies lateral to the styloglossus.
b) Has a different nerve supply from palatoglossus.
c) Has the hypoglossal nerve on its lateral surface.
d) Has the submandibular duct on its medial surface.
e) Has the submandibular gland wrapped around its posterior border.
2. The submandibular gland

a) Like the sublingual receives, its parasympathetic innervation from the facial nerve.
b) Is grooved superiorly by the loop of the lingual artery.
c) Overlies the glossopharyngeal nerve.
d) Is a mixed salivary gland.
e) Develops from 2nd pharyngeal arch mesoderm.
3. The submandibular duct

a) Lies deep to mylohyoid.
b) Opens at the base of the frenulum.
c) Passes deep to the lingual nerve.
d) Passes superficial to the lingual nerve.
e) Receives all the sublingual gland secretion.
4. The pharynx
a) Extend from the base of the skull to the 4th cervical vertebra. b) Is supported superiorly by the pharyngobasilar fascia.
c) Is related posteriorly to the prevertebral fascia.
d) Is related anteriorly to the pretracheal fascia.
e) Has a muscular attachment to the pterygomandibular raphe.
5. The middle constrictor muscle

a) Lies medial to the superior constrictor.
b) Is attached anteriorly to the stylomandibular ligament.
c) Is attached ed anteriorly to the stylohyoid ligament.
d) Has the superior laryngeal artery between it and the inferior constrictor. e) Is innervated by the glossopharyngeal nerve.
6. The interior of the pharynx

a) Is ridged by the salpingopharyngeus muscle.
b) Receives a sensory innervation from the accessory nerve.
c) Has the palatine tonsil in the lateral wall.
d) Receives a sensory innervation from the mandibular nerve.
e) Has an anterior extension on each side of the larynx known as the vallecula.

Ear
External ear
3 parts Middle ear
Inner ear
External ear
 Comprises of auricle/pinna and the external
acoustic meatus
 Auricle-mostly cartilaginous with skin closely
applied
 External acoustic meatus-
i. S shaped canal
ii. 1.5 inches long
iii. Directed medially upwards forwards then
medially backwards,finally medially forwards downwards
iv. Conduct sound waves from the concha to tympanic membrane
v. Medial 2/3 is bony and lateral 1/3 is cartilaginous
vi. Bony part – narrower, formed by tympanic plate of temporal bone and the squamous
temporal bone, lined by thin skin firmly adherent to the periosteum
vii. Cartilaginous part – Lined by skin containing
hair, sebaceous glands and wax glands
(modified sweat glands - ceruminous)
viii. Nervous supply –
Anterior ½ by auriculotemporal nerve
Posterior ½ by auricular branch of Vagus nerve
Tympanic membrane
 Separates external acoustic meatus from middle ear
 Derived from all 3 dermal layers
 Oval shaped, faces downwards, forwards and
laterally
 Translucent except at margins
 Placed obliquely at an angle of 55 with the floor of
the meatus
 Has outer and inner surfaces
 Thickened circumferentially which is attached to the tympanic sulcus of the temporal bone and
superiorly attached to the tympanic notch where the sulcus is deficient
 Outer surface– concave, lined by skin
 Inner surface – convex, provide attachment to the handle of the malleus
 Point of maximum convexity – umbo, lies at the tip of the handle of the malleus
 Greater part of the membrane tightly stretched –pars tensa
 Loose part between the two malleolar folds, thin and lax – pars flaccida
 Pars flaccida – crossed internally by chorda tympani and more likely to rupture than pars tensa

 external acoustic meatus is straightened for introduction of an otoscope in adults by
pulling the auricleupwards, backwards and slightly laterally
 In infants – auricle drawn downwards and backwards
Clinical-
 in a healthy ear a Cone of light visible on pars tensa anteroinferior to umbo.
cone of light- over the anterior inferior quadrant,apex at umbo
Nerve supply
Outer surface– anteroinferior part – auriculotemporal nerve

Posterosuperior part – auricular branch of Vagus with a communicating
branch of facial nerve
Inner surface – tympanic branch of glossopharyngeal nerve through tympanic plexus
Blood supply
Outer surface- Deep auricular branch of maxillary artery
Inner surface – anterior tympanic branch of maxillary artery
posterior tympanic branch of maxillary artery
stylomastoid branch of posterior auricular artery
Middle ear/tympanic cavity
 Narrow, air filled space located in the petrous temporal bone
 Cube shaped with six walls
 Roof/tegmental wall – formed by tegmen tympani, separates middle ear from middle cranial
fossa and temporal lobe of the brain
 Floor/jugular wall – formed by a part of temporal bone, separates middle ear from the superior
bulb of the internal jugular vein
Tympanic canaliculus transmit tympanic branch of glossopharyngeal nerve
 Anterior/carotid wall –
i. superior part has the opening of the canal for tensor tympani muscle
ii. Middle part has the opening for the auditory tube
iii. Inferior part-formed by a thin plate of bone which forms the posterior wall of carotid
canal, separates middle ear from internal carotid artery.

 Posterior/mastoid wall –
i. has an opening through which middle ear communicate with mastoid/tympanic antrum
and mastoid air cells,
ii. posterior canaliculus for chorda tympani through which the nerve enter middle ear
iii. Has an opening for passage of the tendon of stapedius muscle.
iv. Has a canal for facial nerve
 Lateral/membranous wall –
i. Separates middle ear from external acoustic meatus
ii. Formed mainly by tympanic membrane and partly by squamous temporal bone
iii. Petrotympanic fissure lodge anterior process of malleus and transmit tympanic branch
of maxillary artery
iv. Contain anterior canaliculus for chorda tympani nerve
 Medial/labyrinthine wall –
i. Separates middle ear from internal ear
ii. Presents – promontory : formed by first turn of cochlea, fenestra cochleae (round
window), fenestra vestibule (oval of lateral window), prominence of facial canal &
prominance of
lateral semicircular canal

Ossicles of the middle ear
01. Malleus –
 Largest
 Most laterally placed
 Rounded head articulates
posteriorly with body of
incus
 Neck lies against pars flaccida crossed by chorda tympani
 Handle attached to upper half of tympanic membrane
 Anterior and lateral processes present, lateral processes form
malleolar folds
02. Incus –
 Anvil shaped
 body present – articulate with malleus
 two processes
 short process – attach to posterior wall of middle
ear
 long process - articulates with head
of stapes.
03. Stapes –
 Stirrup shaped
 small and most medially placed
 head articulates with incus
 neck provide attachment to tendon of
stapedius posteriorly
 footplate is oval shaped and fits in to fenestra vestibuli.
Muscles of middle ear
01. Tensor tympani – lies in a bony canal

above auditory tube,
Origin-walls of the canal
Insertion – handle of malleus,
Nerve supply- mandibular nerve.
02. Stapedius – Lies in a bony canal,
Origin- walls of the canal
Insertion- posterior surface of neck of
stapes
Nerve supply- facial nerve
 Both serve to damp high frequency
vibrations

Epitympanic recess
 Lateral wall of the middle ear cavity is formed by the tympanic membrane mainly and a part above it
is formed by the squamous temporal bone.
 The part of the middle ear cavity above tympanic membrane is known as epitympanic recess.
 It contains head of malleus and incus.
Mastoid Antrum
 In petrous temporal bone

 Connected to the epitympanic recess by narrow aditus
 Communicate with mastoid air cells and posteriorly related to sigmoid sinus and cerebellum
CLINICAL ANATOMY
Otitis media (middle ear infection)
 Throat infections commonly spread through auditory tube to the middle ear and cause otitis
media.
 Pus from the middle ear can take one of the following courses.
01. May discharge into external ear following rupture of tympanic membrane.
02. May erode the roof and spread upwards causing meningitis and brain abscess.
03. May erode the floor and spread downwards causing thrombosis of sigmoid sinus and internal
jugular vein.
Tympanic04. May spread
nervous plexusbackwards causing mastoid abscess.
 Lies over the promontory.

 Formed by, tympanic branch of glossopharyngeal nerve + superior and inferior caroticotympanic
nerves which arise from the sympathetic plexus around the internal carotid artery.
 Supply mucous membrane of the middle ear.

Inner ear
 Lies in the petrous temporal bone.
 Consist of bony labyrinth within which there is the
membranous labyrinth.
 Membranous labyrinth is filled with endolymph and
is separated from the bony labyrinth by perilymph.
 Bony labyrinth – consist of 3 parts.

a. Cochlea(anteriorly)
b. vestibule(in the middle)
c. semicircular canals(posteriorly)
 Membranous labyrinth –
i. Epithelium is specialized to form receptors for
sound(organ of corti), receptors for static
balance (maculae), receptors for kinetic balance
(cristae)
ii. Contains 3 parts
a. organ of corti (anteriorly)
b. Utricle and saccule with maculae (within vestibule)
c. Semicircular ducts with cristae (posteriorly)
 Blood supply – Mainly from labyrinthine branch of basilar artery and partly from stylomastoid
branch of posterior auricular artery.

Auditory tube/Eustachian tube
 Trumpet shaped channel connecting middle ear cavity with nasopharynx thus ensuring equal air
pressures on both sides of tympanic membrane.
 Usually closed. Opens during swallowing, yawning and sneezing.
 Is about 4cm long, directed downwards, forwards and medially.
 Divided into bony and cartilaginous parts.
Bony part –
i. Forms posterior 1/3 of the tube, 12mm long.
ii. Lie in petrous temporal bone near tympanic plate.
iii. Lateral end open on the anterior wall of middle ear and the medial end is narrow and jagged.
iv. Relations – superior: canal for tensor tympani, medial: carotid canal, lateral: chorda tympani,
auriculotemporal nerve, spine of sphenoid and temporomandibular joint.
Cartilaginous part –
i. Forms anteromedial 2/3 of the tube and 25mm long
ii. Lies in sulcus tubae (a groove between greater wing of sphenoid and apex of petrous temporal)
iii. Made up of a triangular plate of cartilage which forms the superior and medial walls. Lateral wall
and floor are completed by a fibrous membrane.
 Blood supply – Arterial supply by ascending pharyngeal artery, middle meningeal artery and
artery of pterygoid canal.
 Veins drain into pharyngeal and pterygoid plexuses of veins.
 Nerve supply –
 at the ostium : by pharyngeal branch of pterygopalatine
ganglion
 cartilaginous part: by nervus spinosus branch of mandibular
nerve,
 bony part: by tympanic plexus.

Clinical
Dental causes (impacted wisdom tooth, caries, tooth abscess)
Lesions of anterior Temporomandibular joint

Mandibular nerve lesions
2/3 of the tongue
Great auricular Pharyngeal and

EAR ACHE Vagus nerve
nerve and facial laryngeal lesions
nerve
Glossopharyngeal nerve
Cervical spine lesions, Tongue –
other neck lesions and posterior 1/3 lesions
geniculate herpes.
Tonsillar lesions Nasopharynx lesions
Clinical- Ramsay hunts syndrome (herpes zoster oticus)
 After chickenpox clears, the virus lies dormant in the nerves. If they reactivate and effect the facial nerve.
 A painful red rash (fluid filled blisters) in, on and around the ear.
 Facial weakness/ paralysis on same side

Orbit & Eye
Orbit
Orbital Skeleton
 Orbital margin
 Above – frontal bone 
 Lateral – frontal & zygomatic 
 Inferior – zygomatic & maxilla 
 Medial – maxilla & frontal 
 Walls
 Roof – orbital plate of frontal bone & lesser wing of sphenoid
 Lateral – zygomatic & greater wing of sphenoid
 Floor – orbital plate of maxilla, zygomatic, palatine bone 
 Medial – anterior lacrimal crest on frontal process of maxilla, posterior lacrimal crest on lacrimal, orbital plate
of ethmoid, body of sphenoid 
 Clinicals
1. In blow out fracture, orbital floor or medial wall may be damaged.
2. Fracture of floor causes herniation of orbital fat into maxillary sinus
3. Entrapment of an extra-ocular muscle causing diplopia
4. Injury to infra-orbital nerve
 Openings

Supra orbital notch - supraorbital nerve & vessels 

Infraorbital groove - infraorbital nerve & vessels. Lodges the orbitalis muscle 

Nasolacrimal canal - nasolacrimal duct 

Inferior orbital fissure - maxillary & zygomatic nerves, branch of inferior ophthalmic vein, sympathetics
(gap between lateral wall and floor) 


Superior orbital fissure - L, F, T, S, O, N, I, A
(gap between lateral wall and roof)
 Optic canal - optic nerve & ophthalmic artery
 Anterior & posterior ethmoidal foramina – at the junction of roof and medial wall. Transmits the anterior & posterior
ethmoidal nerves & vessels 
 
Orbital Fascia
 Periosteum of orbital skeleton 

 Continuous with dura & sheath for optic nerve 
 Orbitalis - sympathetic supply 
 Orbital septum- extension of orbital fascia 
 Holds the fibrous pulley of tendon of superior oblique 
 Lacrimal fascia
Eye lids
 Covered in front with loose skin and behind with
conjunctiva.
 Eye lids meets at medial and lateral canthi.
 Fibrous framework is orbital septum, thickened at the
margins of lids to form tarsal plates.
 Upper & lower eye lids
 Layers (from superficial to deep)
1. Skin
2. Loose connective tissue
3. Orbicularis oculi – palpebral part
4. Tarsal plates
5. Tarsal glands
 6. Conjunctiva

 Eye lashes arise along mucocutaneous junction 

 Immediately behind lashes – openings of Meibomian
glands/Tarsal glands
 Upper tarsus receives 2 tendinous slips from levator
palpebrae superioris 

 Tarsal glands
o large sebaceous glands
o secretions help to see the palpebral fissure when eyelids are closed.
o Forms a thin layer over the exposed surface of the open eye
 Clinicals 

 Meibomian cysts – distention of the meibomian glands due to the blockage 
 Chalazion – inflammation of tarsal glands which causes swelling. 
 Stye – inflammation of sebaceous & sweat glands

Conjunctiva 
 Delicate mucous membrane lining the inner surface of lids
 Attached to sclera at the margins of cornea.
 Reflected to inner surfaces of eye lids.
o Over the eye lids – palpebral conjunctiva/thicker and highly vascular
o Over the sclera – bulbar conjunctiva/thinner
o Over the cornea – reduced to a single layer
 Superior conjunctival fornix receives opening of lacrimal glands
Conjunctival fornix – line of reflection from lid to the sclera
Orbital septum
 Attached to margins of orbit forming palpebral fissure between eye lids.
 Above and below the fissure form superior and inferior Tarsal plates.
 At the medial end – medial palpebral ligament
 At the lateral end – lateral palpebral ligament
 Levator palpebral superioris is attached to superior tarsal plate.
 Tarsal/meibomian glands embedded within tarsal plates
Lacrimal apparatus
 Concerned
 with secretion & drainage of tear fluid 
 Components-lacrimal gland & ducts, lacrimal canaliculi, lacrimal sac, nasolacrimal duct 
Lacrimal gland
 A serous gland situated in the lacrimal fossa
 (in the upper lateral part of the orbit)
 J shaped 
 Indented by the tendon of levator palpebrae
 superioris 
 Has orbital part & palpebral part 
 Orbital part - large & deeper 
 Palpebral part - smaller & superficial 
 8-12small ducts drain the gland
 Ducts open into superior Conjunctival fornix 
 secretions spread over the surface of the eye
 lacrimal canaliculi drain tears to the lacrimal
sac via lacrimal papillae
 Lacrimal sac lies in lacrimal groove formed by
 the maxilla and lacrimal bone.
 Nasolacrimal duct begins at lower end of
lacrimal sac 
 Naso-lacrimal duct opens into inferior Meatus
of nose. 
 Small accessory lacrimal glands are found in the conjunctival fornices 
 Supplied by lacrimal branch of ophthalmic artery& lacrimal nerve 
secretomotor fibres from superior salivary nucleus which travel in greater petrosal nerve
pterygopalatine ganglion
zygomatic branch of maxillary nerve

Lacrimal nerve
Extra-ocular muscles  Superior rectus
Muscles of the eye  Inferior rectus
Intra-ocular muscles  Medial rectus
 Lateral rectus
 Superior oblique
Mnemonic - LR6SO4  Inferior oblique
Extra-ocular muscles
Muscle Origin course insertion Innervations
Annular tendon
Lateral rectus -
(tendinous ring around To the sclera, anterior to
abducent (LR6)
4 recti the optic canal and the the equator of the
Other recti –
medial part of the eyeball
Oculomotor (CN3)
superior orbital fissure)
Tendon runs through
pulley in trochlear Sclera behind
Body of sphenoid
fossa. Then Equator. Below Trochlear (CN4)
Superior oblique (just above the
down, back, left superior, (SO4)
tendinous ring)
below & lateral recti
superior. rectus
Maxilla, lateral to Up, back, left, below Sclera behind equator,
Inferior oblique lacrimal groove Inferior rectus, deep between inferior and Oculomotor (CN3)
(medial side of orbit) to lateral rectus lateral rectus
Levator palpebrae
Superioris
Lesser wing of Anterior Surface of
superior tarsus, skin of
Lower – smooth Sphenoid Oculomotor (CN3)
eyelid, Upper margin of
muscles supplied by (apex of the orbit)
superior tarsus
internal carotid
venous plexus

Movements
 Superior rectus - elevation, adduction, medial rotation
 Inferior rectus - depression, adduction, lateral rotation
 Medial rectus - adduction
 Lateral rectus - abduction
 Superior oblique - abduction, depression
 Inferior oblique - abduction, elevation
 superior rectus (turns up and in) +inferior oblique (up and out) = vertical upward movement
 inferior rectus (down and in) + superior oblique (down and out) = vertical downward movement
 Superior rectus + superior oblique = intortion
 Inferior rectus + inferior oblique = extortion

Nerves of the orbit
1. Optic nerve
2. Oculomotor nerve with ciliary ganglion
3. Trochlear nerve
4. Branches of maxillary and ophthalmic divisions of trigeminal nerve
5. Abducent nerve
6. Sympathetic nerves
 II – optic nerve
 Nerve of sight 
 Made up of axons of ganglionic layer of retina 
 Passes through optic canal to enter the middle cranial fossa 
 Enclosed in 3 meningeal sheaths 
 Relations: 
1. Ciliary ganglion is between optic nerve & lateral rectus
2. Pierced by central artery of retina, inferomedially
3. Crossed inferiorly by the nerve to medial rectus
4. Crossed superiorly by ophthalmic artery, nasociliary nerve & superior ophthalmic vein
 III – Oculomotor nerve

 Arise medial to the cerebral peduncle 
 Passes forwards between superior cerebellar & posterior cerebellar artery 
 Runs lateral to posterior communicating artery 
 Pierces dura & runs in lateral wall of cavernous sinus 
 Divides into superior & inferior branches & enters superior orbital fissure 
 Superior division runs above optic nerve and supply superior rectus and levator palpebrae muscles.
 It carries sympathetic fibers from internal carotid plexus to smooth muscle part of levator palpebrae muscle.
 Inferior division passes below optic nerve and supply medial, inferior rectus and inferior oblique.
 Gives off parasympathetic root to Ciliary ganglion.
Ciliary ganglion
 Lies at the apex of the orbit just lateral to optic nerve bet nerve and lateral rectus.
 Has 3 roots.
 Motor root – from nerve to inferior oblique (inferior branch of oculomotor)
 They are Preganglionic parasympathetic fibers from Edinger Westphal nucleus
 Supplies sphincter pupillae & ciliary muscle
 Sensory root – branches of nasociliary nerve; supply eye but not conjunctiva.
 Sympathetic root – from internal carotid plexus; vaso-constrictor fibers to vessels of eye.
 Branches – short ciliary nerves which contain fibers from all 3 roots.
 Supplies blood vessels & dilator pupillae

 IV – trochlear nerve
 Arise dorsally from inferior colliculus 
 Passes between superior cerebellar & posterior cerebellar arteries 
 Runs forwards in lateral wall of cavernous sinus 
 Enters superior orbital fissure
 supply superior oblique (SO4)
 VI – abducent nerve
 Arises from between pons & medulla 
 Passes forwards to enter cavernous sinus 
 Lies inferolaterally to internal carotid artery 
 Enters superior orbital fissure 
 Supply Lateral rectus (LR6)
 Trigeminal nerve
Ophthalmic division
Lacrimal Frontal Nasociliary

 Passes on upper surface of
 Joined by branch of  crosses above optic nerve
levator palpebrae superioris
zygomatico-temporal  Divides into supra-orbital and from lateral to medial
nerve containing supra-trochlear branches  ends by dividing in to
parasympathetic fibers to  Supra-trochlear anterior ethmoidal and
lacrimal gland  Conjunctiva infra-trochlear nerves
 upper eyelid
 Supplies conjunctiva and  skin over the root of nose  branches
upper eye lid - To ciliary ganglion
 Supra-orbital - Long ciliary nerves
 Conjunctiva - Posterior ethmoidal
 central part of upper eyelid
 frontal air sinus
 skin over the forehead and
scalp up to vertex.
Zygomatic
Maxillary division
Infra-orbital
Vessels of the orbit
 Ophthalmic artery
 Branch of internal carotid artery 
 Runs through optic canal inferolaterally to optic nerve within its Dural sheath.
 In orbit the artery pierces the dura mater & crosses above the optic nerve from lateral to medial along with
 nasociliary nerve anterior to it.
 Terminates by dividing into supratrochlear & dorsal nasal branches 
 Branches 
 Central artery of retina - supply optic nerve and retina (Posterior ciliary capillaries supply the choroid coat of
eye, they also supply outer layers of retina but there is no anastomosis bet central artery and them)
 Lacrimal artery
 from main trunk (branches accompany all the branches of nasocilliary, lacrimal and frontal nerves)
i. Ciliary branches
ii. Supraorbital & supratrochlear
iii. Anterior & posterior ethmoidal
iv. Medial palpebral branches
v. Dorsal nasal
 Establish connections between external and internal carotid systems.
 Ophthalmic veins
Superior ophthalmic vein
 Commences above the med palpebral ligament
 Passes back above optic nerve
 Drain to cavernous sinus via superior orbital fissure
 Communicate with angular vein at its commencement.
Inferior ophthalmic veins

 Drains to pterygoid plexus via inferior orbital fissure or to cavernous sinus via superior orbital fissure

Eye
 Bulbar fascia (Tenon’s Capsule)
 Facial sheath of the eye
 Attached anteriorly to sclera just behind limbus
 Extends from optic nerve to limbus
 Pierced by extra-ocular muscles and ciliary vessels and nerves.
 Reflected back around those muscles forming ligaments
 Medial Check ligament - from medial rectus to lacrimal bone
 Lateral Check ligament - from lateral rectus to zygomatic bone.
 Sleeve of inferior rectus blends with check ligaments and form - Suspensory ligament (of Lockwood)
 Eye ball
 Formed by segments of 2 spheres of different size – sclera-corneal junction 
 Anterior – transparent 1/6th – cornea
 Posterior – opaque 5/6th – sclera
 Optic nerve enters 3mm nasal to posterior pole
 3 coats 
1. Fibrous coat
 anteriorly transparent cornea & posteriorly opaque sclera – sclerocorneal junction
Sclera
 is tough
 outer surface is covered by Tenon’s capsule
 deep part of limbus contains canal of Schlemm
 maintains shape of eyeball
 receives insertion of extraocular muscles
 posteriorly pierced by optic nerve
 dura sheath continues
Cornea
 avascular
 layers
 Epithelium
 Basement membrane
 Connective tissue
 Descemet membrane
 Endothelium
 Cornea is supplied by
 Short ciliary nerves
 Long ciliary nerves
2. Vascular coat
 consists of choroid, ciliary body and iris
Choroid
 thin
 pigmented
 highly vascular
 pierced by optic nerve
 lines the inner surface of the sclera
 anteriorly connected to iris by ciliary body


Ciliary Body
 ciliary ring & ciliary process continuous with iris and choroid 
 suspensory ligament (zonular fibers)
 ciliary muscle changes convexity of lens (accommodation) 
Iris
 4 layers 
i. anterior mesothelial lining
ii. connective tissue with pigment cells (few melanin granules)
iii. smooth muscle
iv. posterior pigmental cell layer (packed with melanin granules)
3. Neural coat
Retina
 outer pigmented 
 Inner neural
 Continuous with optic nerve
 anterior pole is called ora serrata
 posterior pole is called macula lutea
macula lutea fovea centralis 3mm nasally Blind spot

Optic disc
(site of central vision) (only cones) (no rods or cones)
Central artery
Temporal Temporal
Upper Lower
Nasal Nasal
 no blood vessels over macula lutea

 maximum visual acuity is in fovea centralis (fovea centralis is the thinnest part of the retina)
 Outer Receptor Layer
 The rods and cones, synapse with bipolar cells
 bipolar cells synapse with ganglion cells.
 Horizontal cells connect photoreceptor cells to the other photoreceptor cells in the outer plexiform layer.
 Amacrine cells connect ganglion cells to one another in the inner plexiform layer via processes of varying
length and patterns.
Lens
 Biconvex obliteration of iridocorneal angle
 Enveloped by lens capsule; an elastic membrane 
 between vitreous body & aqueous humor  impaired reabsorption
 more curved posteriorly
 Anterior surface is kept flattened by the tension of suspensory ligament increased intra-ocular tension

Aqueous Humor  GLUCOMA
 filtered plasma
 secreted into posterior chamber from vessels of iris & ciliary body
 reabsorbed through canal of Schlemm

Vitreous Humor
 thin transparent gel within hyaloid membrane
 pierced by lymph filled hyaloid canal
 occupies the posterior 4/5th of the eye ball
Clinicals
 Oculomotor nerve paralysis
 Ptosis – paralysis of levator palpebrae superioris
 When the lid manually lifted up, eye is looking down and out - unopposed action of lateral rectus and superior
oblique
 Diplopia (double vision)
 When looking out diplopia disappears - lateral rectus intact
 Pupil is dilated and doesn’t react to direct light reflex or accommodation - interruption of parasympathetic fibres
 Consensual light reflex of opposite eye works.
 Abducens nerve paralysis
 Can’t look outwards - paralysis of lateral rectus
 diplopia
 Trochlear nerve paralysis
 Can’t look downwards - superior oblique paralysis (patient complain of diplopia when reading or difficulty in
going downstairs
 Extortion effect due to inferior oblique (to compensate extortion, patient tilts the head towards the opposite
shoulder)

Neuroanatomy
Neuroanatomy
Spinal cord
 Extent
o Fetus – occupies the entire length of the vertebral canal
o at birth – upper border of L3
o Adult – lower border of L1
 Nearly cylindrical in shape & approximately circular in cross section
 Diameter varies in different levels
 Two enlargements – cervical (C3-T2) and lumbar ( L1-S3) (where the
brachial and lumbar plexus start)
 Surrounded by 3 meninges
o Dura mater
o Arachnoid mater
o Pia mater
 End of the spinal cord is cone shaped – conus medullaris
 Dura matter ends at S2
 Filum terminale (Prolongation of pia mater) pierces the dura at S2
and ends at its attachment to the dorsum of coccyx
 As the spinal cord is shorter than the vertebral column, lower spinal
nerves have a long downward course –cauda equina
 Spinal cord is a segmented structure
Spinal segments
- Area of spinal cord that gives origin to single spinal nerve

- Spinal nerve arises from spinal cord by number of rootlets
- Spinal cord is shorter than vertebral canal so spinal segments do not align with vertebral segments
Vertebral level Spinal level

Cervical +1
T1 – T6 +2
T7 – T9 +3
T10 L1/L2
T11 L3/L4
T12 L5
L1 Sacral/Coccygeal
Spinal meninges
 3 coverings
 Dura mater, Arachnoid mater, Pia mater

1.Dura mater
 Dense, strong, outermost, fibrous membrane
 Inferiorly extends up to S2 vertebral level
 Extends along spinal nerves
 Attaches to epineurium of nerve
2.Arachnoid mater
 Delicate and impermeable
 Extends along spinal nerves
 Subarachnoid space extends along spinal nerves up to intervertebral foramen
 Ends on filum terminale at S2 level
3.Pia mater
 Vascular membrane
 Extends laterally to form tooth like extensions which attach to inner surface of
dura mater – “Ligamenta denticulata” 22 pairs, hold spinal cord in position
Spinal nerves
 31 paired spinal nerves

 Dorsal root – afferent nerve fibres
 Ventral root – efferent nerve fibres
 Dorsal/ventral rootlets cross the sub arachnoid space and unite to form mixed nerve as coming
through Intervertebral foramina
 Dorsal root bears dorsal root ganglia
 C1- C7 nerves run superior to corresponding vertebrae
 C8 runs between C7 and T1 vertebrae
 Other nerves run inferior to vertebrae of same number
 C1 nerve has only motor fibers
 S5 and Coccygeal nerve have only sensory fibers
Clinicals-
 Lumbar Puncture
 To obtain CSF
 Spinal cord ends at lower border of L1
 Subarachnoid space extends to the lower border of S2
 Below 1st lumbar vertebrae can be used to do a lumbar puncture. Usually done between
4th/5th
 Flexed position – open the space between adjoining laminae
 Structures that are pierced,
o Skin
o Superficial fascia
o Supraspinous ligament
o Interspinous ligament
o Ligamentum flavum
o Areolar tissue with the internal vertebral venous plexus
o Dura mater
o Arachnoid mater sub arachnoid space

Blood Supply
 The spinal cord acquires its blood supply from two sources mainly
1. longitudinal vessels
2. Segmental vessels
1) Longitudinal vessels
a) ONE anterior spinal artery

 2 anterior spinal branches of the vertebral artery fuse above foramen magnum to form ‘Anterior
spinal artery’
 Midline vessel and lies on the anterior median fissure
 Supplies anterior 2/3rd of the spinal cord (anterior to the posterior grey columns)
 Runs the whole length of the spinal cord but variable in size (negligibly small in the thoracic region)
b) TWO posterior spinal arteries

 Derived from PICA or vertebral artery
 Runs the whole length of the spinal cord
 Supplies posterior grey and white columns of its respective side
 Some anastomoses between the two and scanty anastomoses between ASA
2) Segmental arteries/Radicular arteries
 Two for each spinal segment in embryonic stage (one from each side)
 Derived from various parent vessels depending on level
 Vertebral
 Costocervical
 Posterior intercostal
 Lumbar
 Lateral sacral
 In adult many segmental arteries are absent and the remaining ones
form anastomoses with ASA &PSA
 Variable in number & position
 Eg: Lower cervical
 Lower thoracic
 Upper lumbar
 Arteria radicularis magna of Adamkiewicz - largest, arise from lower intercostal or upper
lumbar aortic branch on left side, unilateral, major supply to lower 2/3
 Anastomotic connection deep to pia mater between ASA, PSA and radicular arteries are capable of
supplying peripheral areas of the spinal cord, hence the sparing of sacral regions of anterolateral
tracts and lateral corticospinal tracts in ASA interference.

Venous drainage
Anterior & Posterior midline longitudinal veins and pair of longitudinal veins behind anterior and
posterior nerve roots
Drain to internal vertebral venous plexus
Basivertebral veins
External vertebral venous plexus
Segmental veins
Internal structure
 Outer white matter, inner gray matter

 Amount of gray matter α amount of muscles that innervate skin, viscera
 Larger in cervical and lumbar
 The absolute amount of white matter is greater in cervical levels
 Decrease progressively at lower levels because descending fibres shed as they descend and
ascending fibres accumulate as they ascend
Spinal gray matter

 Dorsal gray horn / ventral gray horn
 Gray communicants connect dorsal – ventral horns
 H shaped - “butterfly” shaped
 Dorsal horn – termination of primary afferent fibers
 Ventral horn –alpha efferent and gamma efferent nerves
 A small intermediate lateral horn is present at the thoracic and lumbar levels
Dorsal gray horn

 The dorsal horn is a major receptive zone of primary afferent fibers
 4 nerve cell groups
o Substantia gelatinosa
o Nucleus proprius
o Nucleus dorsalis (Clarke’s column)
o Visceral afferent nucleus
Lateral gray horn

 First thoracic to 2nd / 3rd lumbar segments
 Preganglionic sympathetic fibers
 Similar group of cells found in 2nd, 3rd, 4th sacral segments for parasympathetic fibers

Ventral gray horn
 Most nerves are large and multipolar
 Alpha efferent – innervates skeletal muscles
 Gamma efferent – innervates intrafusal muscle fibers of neuromuscular spindles
 3 nerve cell groups
o Medial o Central o Lateral
Substantia gelatinosa (C1-L1)
Nucleus proprius (C1-L1)
Nucleus dorsalis
Clark’s column (C8-L3)
Cell group Position in gray matter Extend Action

Substantia gelatinosa Apex of dorsal column Throughout its Pain, temperature, touch, pressure
Nucleus proprius Anterior to s.gelatinosa length Proprioception, vibration
Base of dorsal Proprioception from
LAT DORSAL
Nucleus dorsalis C8-L3/L4

root, medially neuromuscular spindles
Visceral Base of dorsal Visceral afferents
T1-L3
afferent nucleus root, laterally
Sympathetic Lateral gray column T1-L3/L2 Preganglionic sympathetic
Parasympathetic Lateral gray column S2, S3, S4 Preganglionic parasympathetic
Medial part of Most of Skeletal muscles of trunk
Medial
ventral column segments
Central Phrenic Central part of C3-C5 Diaphragm
VENTRAL
Accessory ventral column C1-C5/6 Trapezius, sternocleidomastoid

lumbosacral L2-S1 Unknown
Lateral part of Cervical and Skeletal muscles of upper and
lateral
ventral column lumbar segments lower limb

Spinal White matter
 Surrounds the central gray matter

 Contains nerve fibers, neuroglia, blood vessels
 Most nerve fibers arranged longitudinally
 Arranged in 3 large masses on either side of spinal cord - dorsal, lateral and ventral columns
 Fibers of common function, common origin, destination are grouped as ascending and descending tracts
within columns
 Narrow dorsal and ventral white commissure run between two halves of the spinal cord
 Fibers may vary in caliber, size, myelination
 Significant overlap between adjacent tracts occur
 Ascending tracts –
o Afferent fibers
o Dorsal root
o Carry afferent to supra spinal levels
 Descending tracts –
o Long fibers
o Descends from supra spinal levels to synapse with spinal nerves
 Intersegmental tracts –
o Short ascending and descending tracts that originate and end within the spinal
cord
 Tract – Group of fibers in CNS that have common origin, course and termination
 Nucleus – Group of nerve cells that have common cellular features and giving rise to fibers
that have common path, termination and function
 Decussation – Fibers from right cross to left side and fibers from left cross to right
 Ipsilateral – Fibers that enter spinal cord pass on the same side
 Contralateral – Those who cross to opposite side
Ascending tracts
 Dorsal column
o Fasciculus gracilis - Tract of Goll
o Fasciculus cuneatus – Tract of Burdach
 Lateral column
o Lateral spinothalamic
o Anterior and posterior spinocerebellar
o Spinoreticular
 Ventral column
o Anterior spinothalamic
o Spinotectal
o Spino-olivary
Lateral spinothalamic tract

First order neuron
o Pain and temperature sensation
o Free nerve endings as receptors
o Aδ fibers – fast conducting; sharp pain
o c fibers – slow conducting; prolonged, burning pain
o Enter the spinal cord through dorsal root
o Cell bodies – dorsal root ganglion
o Terminates by synapsing with the cells in the dorsal gray column, substantia gelatinosa

Second order neuron
o 2nd order neurons cross obliquely to the opposite side in the anterior gray and white
commissure
o Within one spinal segment
o Ascend up to thalamus
o Somatotopic organization can be seen - fibers crossing at any level join the deep aspect of those that
already crossed
o Tracts are segmentally laminated
o In medulla oblongata spinothalamic tract lies near the lateral surface
and between the inferior olivary nucleus and spinal nucleus of
trigeminal
o Then it is accompanied by anterior spinothalamic tract and spinotectal
tract to form spinal lemniscus
o In the mid brain it lies in the tegmentum lateral to medial leminiscus
o Fibers of the lateral spinothalamic tract end by synapsing with the third
order neurons in the ventral posterolateral (VPL) nucleus of the
thalamus
In the thalamus
 Crude pain and temperature sensation
 Localization is poor and dull
 Emotional reaction initiated
Third order neuron

o Passes from thalamus to post central gyrus of cerebral cortex
o Fibers pass through the posterior limb of internal capsule and the corona radiata
o Interpretation of sensory information at the level of consciousness
o The contralateral half of the body is represented as inverted
Anterior spinothalamic tract
First order neuron

 Enter the spinal cord through dorsal root
 Terminated by synapsing with the cells in the dorsal gray
column, substantia gelatinosa
Second order neuron
 2nd order neurons cross very obliquely (across several
segments) to the opposite side in the anterior gray and
white commissure
 Then it is accompanied by lateral spinothalamic tract and
spinotectal tract to form spinal lemniscus
 Synapse - ventral posterolateral (VPL) nucleus of the
thalamus
Third order neuron
 Passes from thalamus to post central gyrus of cerebral cortex
Through the posterior limb of internal capsule and the corona
radiata
 Interpretation of sensory information (touch and pressure) at
the level of consciousness
 The contralateral half of the body is represented as inverted

Dorsal columns
Has 2 large ascending tracts
o Fasciculus gracilis
− Throughout cord (lumbar-Sacral)
o Fasciculus cuneatus
− Only from midportion
Discriminative touch, proprioception and vibration sensation,
Stereognosis, graphesthesia
High portion of myelinated fibers
First order neurons

 Dorsal root ganglion and passes directly to the dorsal white
column of the same side
 Many fibers ascend upward as fasciculus gracilis and fasciculus cuneatus
 fasciculus gracilis – throughout the length of spinal cord and fibers from
sacral to lower 6 thoracic spinal nerves
 fasciculus cuneatus – starts from 6 thoracic spinal nerve and fibers from
upper 6 thoracic and cervical spinal nerves
 fibers ascend in the same side
 arranged in a somatotopical manner
 lower fibers are more medial and upper fibers are more lateral
 1st order neurons terminate by synapsing with nucleus gracilis and
 nucleus cuneatus of medulla oblongata
 Contains ascending and descending fibers (intersegmental fibers/tract)
Second order neuron

 Internal arcuate fibers cross anteromedially around the central gray matter and cross the median
plane
 decussate with the corresponding fibers of the opposite side – the sensory decussation
 fibers then ascend as a simple single compact bundle – the medial lemniscus, throughout the medulla,
pons and mid brain
 synapse with 3rd order neurons in the ventral posterolateral nucleus in the VPL nucleus of the
thalamus
Third order neuron

 Leave the thalamus and pass through the posterior limb of the internal capsule and corona radiata
 To the somatosensory area in the post central gyrus of cerebral cortex
 The contra lateral half of the body is represented inversely
Other ascending pathways
1. Anterior/posterior spinocerebellar tract

 First order neuron - Receives unconscious proprioception
- Posterior root fibers pass to Clarke’s column
 Second order neuron
- Ascend on the same side up to medulla as Posterior spinocerebellar tract
- Enter cerebellum via inferior cerebellar peduncle
- majority cross to the opposite side and ascend as Anterior spinocerebellar
tract
- Enter cerebellum through superior cerebellar peduncle
- Fibers cross back within cerebellum

2. Spinotectal tract - Cross to opposite side
- Afferent information for visual reflexes and bringing about movements
of eye and head towards the source of stimulation
3. Spinoreticular tract - Uncrossed tract

- Afferent pathway for reticular formation, important in influencing level of
consciousness
4. Spino-olivary tract - Cross midline

- Enter cerebellum through inferior cerebellar peduncle
Tract Lateral Anterior spinothalamic Fasciculus gracilis/ Fasciculus
spinothalamic cuneatus
1st order neuron Dorsal root ganglion
2nd order neuron Substantia gelatinosa Nucleus gracilis & Nucleus cuneatus
Point of decussation Cross obliquely Cross obliquely across Medulla (sensory decussation)
within same spinal spinal segments
segment
Lemniscus Ant + Lat spinothalamic + spinotectal =spinal Medial lemniscus
lemniscus
3rd order neuron VPL nucleus of thalamus
3rd order neuron
Posterior central gyrus
termination
Action Pain and Touch and pressure 2-point discrimination, vibration,
temperature proprioception
Descending Tracts
General arrangement
First order neuron (UMN) – Has cell body in the cerebral cortex. Axon descends to spinal
cord.
Second order neuron – Internuncial neuron situated in anterior gray column.
Third order neuron (LMN) - In anterior gray column. Innervates skeletal muscles.
- Originate primarily in the cerebral cortex and numerous sites within the brain
stem
- Control of the movements, muscle tone, posture, modulation of spinal reflexes
 Lateral column
o Lateral corticospinal tract
o Rubrospinal tract
 Ventral column
o Anterior corticospinal tract
o Vestibulospinal tract
o Tectospinal tract
o Reticulospinal tract
o Olivospinal tract

Corticospinal tract (pyramidal tract)
Corticospinal fibers facilitate α motor neurons

 Responsible for rapid skilled movements
 Arise as axons of neurons of the cerebral cortex
 About one-third of the fibers originate from the primary
motor cortex (area 4), one-third originate from the
secondary motor cortex (area 6), and one-third originate
from the parietal lobe (areas 3, 1, and 2)
 Descend down – corona radiata, posterior limb of internal
capsule, ventral part of the midbrain in the cerebral
peduncle (middle 3/5)
 As they continue through the pons the are separated from
its ventral surface by transversely running pontocerebellar fibers
 In medulla they form a discrete bundle, the pyramids,
longitudinal elevation on the ventral surface of medulla
 Just superior to the spino-medullary junction 90% of the
fibers in the pyramids cross the median plane – motor decussation
 Continue caudally as lateral corticospinal tract
 10% of uncrossed fibers descend as anterior corticospinal
tracts
 Somatotopic organization –cervical fibers medially; sacral
fibers laterally
 As it descends progressively diminish in size
 Terminate in the anterior gray column of all the spinal cord
segments
 Most corticospinal fibers synapse with internuncial neurons, which, in turn, synapse with α
motor neurons and some γ motor neurons
 Only the largest corticospinal fibers synapse directly with the motor neurons.
Other descending pathways

o Reticulospinal tract
o Rubrospinal tract
o Descending autonomic fibers
o Vestibulospinal tract
o Tectospinal tract

Clinical
Upper motor neuron lesion
UMN lesion
Pyramidal tracts Extrapyramidal tracts

 When skin of the sole scratched  Spastic paralysis
(Loss of inhibition)
Babinski sign present  No muscle atrophy
(normal - plantar flexion of big toe) (LMN intact)→
 Exaggerated deep muscle reflexes &
 Corticospinal tract lesion clonus
- Dorsiflexion due to the influence of other descending tracts (Loss of inhibition)
- Loss of performance of voluntary fine skilled movements  Clasp knife reaction
- Superficial abdominal reflexes absent
- Cremasteric reflex absent
Lower motor neuron lesion

 Flaccid paralysis
 Muscle atrophy
 Loss of reflexes
 Muscular fasciculation
Types of paralysis
 Hemiplegia- paralysis of one side of the body
 Monoplegia- paralysis of one limb
 Diplegia- paralysis of 2 corresponding limbs
 Paraplegia- paralysis of both legs
 Quadriplegia- paralysis of all 4 limbs
Spinal shock syndrome

 Clinical condition following acute severe damage to the spinal cord
 All the cord functions below
 level of the lesions become depressed /lost
o Sensory impairment
o Flaccid paralysis

Syndrome Cause At the level of the lesion Below the level of the lesion
Sensory Motor Sensory Motor
Complete Bullet hole All gone LMN type All lost bilaterally UMN type lesion
cord Stab wound bilaterally lesion (pain & temp- from the -descending tracts
transaction -post. -Ant. Gray level
Grey column Touch & pressure- 2 to
column 3 segments below) -asc.
tracts
Brown Fracture Ipsilateral LMN type Pain & temp- UMN type lesion
Sequard dislocation band of lesion contralateral from the Ipsilateral
syndrome Bullet cutaneous Ipsilateral level
Stab wound loss Touch & pressure –
contralateral 2 to 3
segments below
Proprioception / 2point
discrimination/
vibration – ipsilateral
from the level
Anterior cord Fracture UMN lesion Pain temp. touch & UMN type lesion
syndrome dislocation bilateral press. -Ant corticospinal
Injury to ant (ant grey Bilateral -Extrapyramidal
spinal column) Ant/lateral tracts
artery spinothalamic
Proprio/2point
discrimination
preserved
Central cord Hyperextension Bilateral loss of pain Bilateral spastic
syndrome of temperature, paralysis with
the cervical light touch and pressure characteristic
region sacral sparing,
of spinal cord because of
lamination
Syringomyelia Development LMN Loss of pain and temp. – Bilateral spastic
abnormality in weakness bilateral paralysis with
the spasms in the -crossing fibres positive Babinski
formation of small muscles damaged reflex
central canal of hand Vibration and
-ant grey proprioception normal Horner’s syndrome
column Descending
autonomic fibres
Poliomyelitis Viral infection LMN type
of the paralysis,
neurons of the mostly in
ant. lower limb,
Grey column respiration is
affected due to
paralysis of
intercostal
muscles and
diaphragm

Brain stem
It consists of 3 parts
 Medulla oblongata
 Pons
 midbrain 
 In the posterior cranial fossa of the skull 
 Pathway for ascending & descending tracts
 Reflex center (CVS, RS) Are located in the brainstem
 Cranial nerve nuclei
Cranial nerve nuclei
Mid CN 3
brain CN 4 Mesencephalic
Pons CN 6
CN 7 Motor
CN 5
Main sensory
Medulla CN 8
CN 9
Spinal nucleus
CN 10 (NA, NTS, DNV)
CN 11
CN 12
Medulla oblongata
Gross appearance
  Connects superiorly with the pons and inferiorly spinal cord 

  Conical in shape, its broad extremity being directed superiorly 
  In the upper part of medulla, the central canal expands as cavity of the 4 th ventricle 
  Each side of the anterior median fissure is the pyramid 
  The pyramids taper inferiorly at the level of motor decussation (decussation of the pyramids) 
  Posterolateral to pyramids – olives 
  Posterior to olives – inferior cerebellar peduncle 
 The roots of the glossopharyngeal and vagus nerves and the cranial roots of accessory nerve emerge between
olives & inferior cerebellar peduncle 

 The posterior surface of the superior half of the medulla forms the lower part of the floor of the fourth
ventricle 

 On each side of posterior median sulcus, there is an elongated swelling – the gracilis tubercle, and lateral to
that is the cuneate tubercle 

Internal structure
Internal structure of the medulla oblongata is considered at 4 transverse levels
1. Level of decussation of pyramids

2. Level of sensory decussation (level of decussation of lemnisci)
3. Level of the olive
4. Just inferior to pons
Level of decussation of pyramids
 Decussation of pyramids – corticospinal tract 

 The decussation displaces the central canal dorsally 
 The fasciculus gracilis and fasciculus cuneatus continue to ascend superiorly posterior to the central gray matter 
 Substantia gelatinosa –spinal nucleus of trigeminal nerve 

Level of sensory decussation
  Dorsal columns decussate at this level 

  Anteriorly to the central gray matter and posterior to pyramids 
  Lemnisci have been formed from the internal arcuate fibers 
  Which have emerged from the anterior aspect of the nucleus gracilis and nucleus cuneatus 
 The anterior and lateral spinothalamic tracts and spinotectal tracts unite and form spinal lemniscus 
Levels of olives
th
  Section through the inferior part of 4 ventricle 
  Increased amount of gray matter is present at this level 
 Olivary nuclei complex 
 Nuclei of vestibulocochlear, glossopharyngeal, vagus, accessory, and hypoglossal nerves and the arcuate
nuclei


Olivary nuclei complex
 Largest nucleus – inferior olivary nucleus 
  Smaller dorsal and medial accessory olivary nuclei also are present 
 Afferent fibers to inferior olivary nucleus from spinal cord (spino-olivary tract) and from the cerebrum and
 cerebral cortex 
  Inferior olivary nucleus sends fibers to cerebellum through inferior cerebellar peduncle 
 Function – associated with voluntary muscle movements 
Vestibulocochlear nuclei
 4 vestibular nuclei 
o Medial vestibular nucleus o Lateral vestibular nucleus
o Inferior vestibular nucleus o Superior vestibular nucleus
 2 cochlear nuclei 
o Anterior cochlear nucleus
o Posterior cochlear nucleus
Nucleus ambiguus
  The nucleus ambiguus consists of large motor neurons 

  Situated deep within the reticular formation 
  Motor nucleus of glossopharyngeal, vagus and cranial part of the accessory nerve 
 Distributed to voluntary muscles 
Central gray matter

 Central gray matter lies beneath the floor of the 4th ventricle at this level 
 From medial to lateral 
o Hypoglossal nucleus
o Dorsal nucleus of vagus
o Nucleus of tractus solitarius
o Medial and inferior vestibular nuclei
 Anteriorly - pyramids 
 Medial lemniscus forms a flattened tract on each side of the midline posterior to the pyramids 
 Medial longitudinal fasciculus situated on each side of midline posterior to the medial lemniscus 
 It’s a small tract of nerve fibers with ascending and descending fibers 
 It connects 3, 4, 6, 8 cranial nerves 
 The inferior cerebellar peduncle is situated posterolaterally 
 Spinal tract of trigeminal nerve/nucleus are situated anteromedial aspect of inferior cerebellar peduncle 
 Reticular formation consists of a diffused mixture of nerve fibers and small group of nerve cells 
 It is deeply placed posterior to the olivary nucleus 
 The glossopharyngeal, vagus and cranial part of accessory nerves can be seen running forward and laterally
through the reticular formation 
 The nerves emerge between the olives and inferior cerebellar peduncle 
 The hypoglossal nerve also run anteriorly and laterally through the reticular formation and emerge between
pyramids and the olives 
Level just inferior to the pons

 No major changes 
  The lateral vestibular nucleus has replaced the inferior vestibular nucleus 
 Cochlear nuclei are visible on the anterior and posterior surface of the inferior cerebellar peduncle 

Clinicals
 Vascular disorders
Blood supply
 Posterior inferior cerebellar artery (from vertebral artery)
 Medullary artery (from vertebral artery)
 Anterior inferior cerebellar artery (from basilar artery)
Lateral medullary syndrome

Cause: Thrombosis in PICA or vertebral artery
1. Analgesia & thermoanesthesia on ipsilateral face Spinal nucleus of trigeminal (CN 5)
2. Vertigo, nausea, vomiting, nystagmus Vestibular nuclei (CN 8)
3. Dysphagia & dysarthria Paralysis of ipsilateral palatal & laryngeal muscles
(Nucleus Ambiguus) (CN 9,10,11)
4. Loss of pain & temperature (contralateral body) Spinal lemniscus (spinothalamic tracts)
5. Ìpsilateral Horner’s syndrome Descending sympathetic fibers
6. Ipsilateral cerebellar signs(ataxia) Inferior cerebellar peduncle

Medial medullary syndrome
Cause: thrombosis of medullary branch of vertebral artery
1. Contralateral hemiparesis Pyramidal tract
2. Contralateral loss of proprioception & 2point discrimination Medial lemniscus
3. Ipsilateral tongue paralysis (deviate to paralyzed side when protruded) Hypoglossal nerve
Pons
Gross appearance
 Connects the medulla oblongata and midbrain 
  Anterior to cerebrum 
  Pons – “bridge” that connect right and left hemispheres 
 The anterior surface is convex from side to side 
 Shows many transverse fibers that converge on each side to form the middle cerebral peduncle 
 Shallow groove in midline – basilar groove, basilar artery is lodged there 
 Trigeminal nerve emerges from the anterolateral surface of pons 
  In the groove between medulla and pons the abducent, facial and vestibulocochlear nerves emerge 
 Posterior surface is covered from cerebellum 
  It forms the upper half of the floor of the fourth ventricle and is triangular in shape 
 The posterior surface is limited laterally by the superior cerebellar peduncles and is divided into symmetrical
halves by a median sulcus 
Internal structure

 Pons is commonly divided in to 
1. Tegmentum – posteriorly
2. Basal part – anteriorly

 Internal structure of the pons is considered at 2 transverse levels 
1. Transverse section through the caudal part, passing through the facial colliculus
2. Transverse section through the cranial part, passing through the trigeminal nuclei
Transverse section through the caudal part, passing through the facial colliculus
 Medial lemniscus rotates as it passes from medulla to pons to the most anterior part of the tegmentum with
its long axis running transversely 
 The medial lemniscus is accompanied by spinal and lateral lemnisci 

 Laterally and posteriorly to the medial lemniscus is the facial nucleus 
 Medial and posterior to the facial nucleus is the abducent nucleus 
 Fibers of the facial nerve wind around the abducent nucleus and produce facial colliculus 
 The medial longitudinal fasciculus is situated beneath the floor of the fourth ventricle on either side of the
midline 
 The medial vestibular nucleus is situated lateral to the abducent nucleus 
 The posterior and anterior cochlear nuclei are also found at this level 
 The trapezoid body is made up of fibers derived from the cochlear nuclei and the nuclei of the trapezoid body 
 The corticopontine fibers of the crus cerebri of the midbrain terminate in the pontine nuclei, which are small
masses of nerve cells situated in the basilar part of the pons 
 The axons of these cells give origin to the transverse fibers of the pons, forms the main pathway linking the
cerebral cortex to the cerebellum 
Transverse section through the cranial part, passing through the trigeminal nuclei
 Similar to the caudal part 

 Contains the motor and main sensory nucleus of the trigeminal nerve 
 The motor nucleus of the trigeminal nerve is situated beneath the lateral part of the fourth ventricle within the
 reticular formation 
 The principal sensory nucleus of the trigeminal nerve is situated on the lateral side of the motor nucleus 
 The superior cerebellar peduncle is situated posterolateral to the motor nucleus of the trigeminal nerve 
 It is joined by the anterior spinocerebellar tract 
 The trapezoid body and the medial lemniscus are situated in the same position as they were in the previous
 section 
 The lateral and spinal lemnisci lie at the lateral extremity of the medial lemniscus 

Clinicals
Tumor of pons
1. Weakness of jaw muscles Motor nucleus of trigeminal nerve (CN5)
2. Weakness of ipsilateral facial muscles Facial nerve (CN 7)
3. Paresis of lateral rectus Abducent nucleus (CN 6)
4. Nystagmus, vertigo Vestibular nuclei (CN 8)
5. Impairment of hearing Cochlear nuclei (CN 8)
6. Contralateral hemiparesis, quadriparesis Pyramidal tracts
7. Anesthesia to light touch in face (pain & Main sensory nucleus of CN 5 (spinal nucleus intact)
temperature preserved)
8. Contralateral sensory defects in trunk Medial & spinal lemnisci
9. Ipsilateral cerebellar signs Cerebellar peduncle/corticopontocerebellar fibers
Pontine hemorrhage
The pons is supplied by the basilar artery and the anterior, inferior, and superior cerebellar arteries
1. facial paralysis on the side of the lesion facial nerve nucleus

2. paralysis of the limbs on the opposite side corticospinal fibers as they pass through the pons
unilateral
3. paralysis of conjugate ocular deviation the abducent nerve nucleus and the medial
longitudinal fasciculus
1. the pupils may be “pinpoint” ocular sympathetic fibers
2. bilateral paralysis of the face and the limbs corticospinal fibers and facial nerve nucleus
Bilateral
severe damage to the pons has cut off

3. poikilothermic (body temperature varies the body from the heat-regulating centers in the
with the environment) hypothalamus
Midbrain
Gross appearance
 Connect the pons and the cerebellum with the forebrain 
 The midbrain is traversed by a narrow channel, the cerebral aqueduct 
 On the posterior surface are four colliculi, rounded eminences that are divided into superior and inferior pairs
 by a vertical and a transverse groove 
o Superior colliculus - centers for visual reflexes
 o Inferior colliculus - lower auditory centers 
 The trochlear nerves emerge from the posterior surface of midbrain, below the inferior colliculi 
 The superior brachium passes from the superior colliculus to the lateral geniculate body and the optic tract 
 The inferior brachium connects the inferior colliculus to the medial geniculate body 
 Interpeduncular fossa - deep depression in the midline 
  It is bounded on either side by the crus cerebri 
  Many small blood vessels perforate the floor of the interpeduncular fossa - the posterior perforated substance 
 The oculomotor nerve emerges from a groove on the medial side of the crus cerebri 

Internal structure
  Midbrain comprise 2 lateral halves – cerebral peduncles 

 Midbrain is divided in to 3 parts 
1. Crus cerebri
2. Tegmentum
3. Tectum
  Crus cerebri is the most anterior 
  Tegmentum is posterior to crus cerebri and it is divided by a pigmented band of gray matter, substantia nigra 
  Narrow cavity of the midbrain is the cerebral aqueduct which connect the 3rd and 4th ventricles 
 Tectum is posterior to cerebral aqueduct 
 Internal structure of the pons is considered at 2 transverse levels 
1. Transverse section at the level of inferior colliculus
2. Transverse section at the level of superior colliculus

Transverse section at the level of inferior colliculus
 Consisting of a large nucleus of gray matter 

 Inferior colliculus receives many of the terminal fibers of the lateral lemniscus 
 The pathway then continues through the inferior brachium to the medial geniculate body 
 The trochlear nucleus is situated in the central gray matter close to the median plane just posterior to the
medial longitudinal fasciculus 
 Fibers of the trochlear nucleus pass laterally and posteriorly around the central gray matter and leave the
midbrain just below the inferior colliculi. 
 The mesencephalic nuclei of the trigeminal nerve are lateral to the cerebral aqueduct 
 The decussation of the superior cerebellar peduncles occupies the central part of the tegmentum 
 The medial lemniscus ascends posterior to the substantia nigra 
 The spinal and trigeminal lemnisci are situated lateral to the medial lemniscus and the lateral lemniscus is
posterior to the trigeminal lemniscus. 
 The crus cerebri contains important descending tracts and is separated from the tegmentum by the substantia
nigra 
 The corticospinal and corticobulbar fibers occupy the middle 2/3 of the crus. 
 The frontopontine fibers occupy the medial part of the crus 
 The temporopontine fibers occupy the lateral part of the crus 
Transverse section at the level of superior colliculus


 Superior colliculus forms part of the visual reflexes. It is connected to the lateral geniculate body by the superior
brachium. 
 It receives afferent fibers from the optic nerve, the visual cortex, and the spinotectal tract 
 The oculomotor nucleus is situated in the central gray matter close to the median plane, just posterior to the
medial longitudinal fasciculus 
 The fibers of the oculomotor nucleus pass anteriorly through the red nucleus to emerge on the medial side of the
crus cerebri in the interpeduncular fossa. 
 The medial, spinal, and trigeminal lemnisci form a curved band posterior to the substantia nigra 
 But the lateral lemniscus does not extend superiorly to this level 
 The red nucleus is a rounded mass of gray matter situated between cerebral aqueduct and substantia nigra 
 Afferent fibers reach the red nucleus from 
o The cerebral cortex through the corticospinal fibers
o The cerebellum through the superior cerebellar peduncle
o The lentiform nucleus, subthalamic and hypothalamic nuclei, substantia nigra, and spinal cord
 Efferent fibers leave the red nucleus and pass to 
 The spinal cord through the rubrospinal tract (as this tract descends, it decussates)
o The reticular formation through the rubroreticular tract
o The thalamus
o The substantia nigra
 Descending tract arrangement in the crus is same as the inferior colliculus level 
o The corticospinal and corticobulbar fibers - middle 2/3
o The frontopontine fibers - medial part of the crus
o The temporopontine fibers - lateral part of the crus
Midbrain
Vascular lesions of midbrain
Weber syndrome
  Cause: Occlusion of a branch of a posterior cerebral artery 
 There is ipsilateral ophthalmoplegia – damaged medal
 longitudinal fasciculus 
 Contralateral paralysis of the lower part of the face, the
 tongue, and the arm and leg 
  The eyeball is deviated laterally 
 There is drooping (ptosis) of the upper lid and the pupil is
dilated and fixed to light and accommodation. 
Benedikt’s syndrome
 Similar to Weber syndrome 
 But the necrosis involves the medial lemniscus and red
nucleus 
 Contralateral hemianesthesia and involuntary movements
of the limbs of the opposite side 



Lemnisci
 anterior spinothalamic
Spinal lemniscus  lateral spinothalamic
 spinotectal
→ VPL nucleus (thalamus)
 nucleus cuneatus
Medial lemniscus
 nucleus gracilis
Trigeminal lemniscus  sensory nuclei of CN 5 →VPM nucleus (thalamus)
Lateral lemniscus  superior olivary & trapezoid body →medial geniculate body
Note
Medial longitudinal fasciculus→ connect CN 3, 4, 6, 8
Applied neuroanatomy
Brainstem lesions
 ipsilateral cranial nerve damage
 contralateral hemiparesis
 contralateral sensory loss in the body

Brainstem lesions
Medulla oblongata Pons Mid brain
 Vascular disorders   Pontine hemorrhage   Vascular disorders 

- Medial medullary syndrome  Tumors of pons  - Weber syndrome
- Lateral medullary syndrome  Infections of pons  - Benedikt’s syndrome
 Raised pressure   Trauma to midbrain 

- Downward herniation of the  Blockage of cerebral
medulla and cerebellar aqueduct 
tonsils through the foramen
magnum

1.Explain the term decussation. (10)
a) Describe the motor & sensory decussations in the medulla. (60)
b) State briefly the changes in sensory & motor functions in lesions above and below each decussation. (30)
(AL2002 main)
2. Sixty-year-old hypertensive female patient complains of imbalance& difficulty in speaking. She also complains of
nausea & vertigo. On examination she was found to have right sided palatal paralysis, loss of pain & temperature
sensation over the right side of the face. There were also positive cerebellar signs on the right side.
a) Where is the most possible site of the lesion?
b) What is the most possible cause?
c) Explain the above signs & symptoms
d) What other clinical features would you expect to find in this patient?
3. Draw & label a cross section at the trigeminal level of the pons to show the position of the ascending &
descending tracts (50 marks)
Give the commencement & the termination of these tracts (50 marks)
4. Draw a labeled diagram of the transverse section through the pons at the level of the facial nucleus (40)
On what anatomical basis would you differentiate between UMN lesion & LMN lesion of the facial nerve (20)
5. Draw & label a diagram of the midbrain at the level of inferior colliculus (30)
Describe the trochlear nerve from its origin to its termination (70)
T/F
1. Facial colliculus is formed by facial nucleus.
2. Facial nerve curves over the 6th cranial nerve to form facial colliculus.
3. Spinal lemnisci are most posterior in the lower part of the mid brain.
4. Trochlear nerve leaves the brainstem on its dorsal aspect.
5. Hypoglossal nerve leaves the brainstem between olives & inferior cerebellar peduncles.

Cranial Nerves
 12 pairs
 For head & neck (vagus-also thorax & abdomen)
sensory motor Mixed
I III V
II IV VII
VIII VI IX
XI X
XII
component function Letter symbols
Afferent fibers Sensory
General somatic afferent General sensations GSA
Special somatic afferent Hearing, balance, vision SSA
General visceral afferent Viscera GVA
Special visceral afferent Smell, taste SVA
Efferent fibers
General somatic efferent Somatic striated muscle GSE
General visceral efferent Glands & smooth muscle GVE
(parasympathetic innervation)
Special visceral efferent Branchial arch muscles SVE
Nerve sensory motor Parasympathetic Opening in the skull

(GVE)
I Olfactory(SVA) smell - - Cribriform plate
II Optic(SSA) vision - - Optic canal
III Oculomotor - Eye muscles – MR, Ciliary body Superior orbital fissure
(GSE,GVE) SR, IR, IO, levator Constrictor pupillae
palpebrae superioris
IV Trochlear(GSE) - Superior oblique - Superior orbital fissure

(LR6SO4)
V Trigeminal Face Muscles of - V1 – superior orbital fissure
(GSA,SVE) Scalp mastication
Cornea Mylohyoid V2 – foramen rotundum
Paranasal sinuses Anterior belly of
Nasal cavity digastric V3 – foramen ovale
Anterior 2/3 of tongue Tensor palatine
Oral cavity tensor tympani
VI Abducent(GSE) - Lateral rectus - Superior orbital fissure
(LR6SO4)
VII Facial(SVE,SVA,GVE) Anterior 2/3 of tongue Stapedius Submandibular Internal acoustic meatus
Mouth floor Muscles of facial Sublingual Facial canal
taste expression Lacrimal Stylomastoid foramen
Palate Posterior belly of Nasal and palatine glands
digastric
Stylohyoid
Scalp muscles
VIII Vestibulocochlear(SSA) Inner ear - - Internal acoustic meatus
IX Glossopharyngeal Posterior 1/3rd of the tongue stylopharyngeus Parotid gland Jugular foramen
(SVE, GVE) Carotid sinus
(GVA,SVA, GSA) Carotid body
X Vagus (GVE, SVE) viscera viscera Blood vessels Jugular foramen
(GSA,GVA,SVA viscera
XI Accessory - Jugular foramen
~Cranial(SVE) Muscles of larynx,
pharynx, soft palate
~Spinal(SVE) Trapezius,
sternocleidomastoid
XII Hypoglossal(GSE) - Tongue muscles - Hypoglossal canal

Cranial nerve
Motor part Sensory part
Alar plates – sensory root

Basal plate – motor root
Therefore, motor roots and nuclei are medial to the sensory root and nuclei
Motor part arrangement

Axons whose cell bodies are in the brainstem.
Cell bodies (LMN) = motor nucleus
Motor nucleus receives impulses from cerebral cortex via corticonuclear tracts.
Corticonuclear tract
Pyramidal cells (precentral gyrus) corona radiata genu of the internal capsule CN nucleus
Bilateral connections are present for all the motor nuclei except,
1. Part of the facial nucleus that supply the muscles of the lower part of the face
2. Part of the hypoglossal nerve that supply the genioglossus muscle
Therefore, unilateral corticonuclear lesions will not produce symptoms except in the above nerves.
Sensory part arrangement

First order neuron -Axons whose cells are outside the brain
Cell bodies are situated in the ganglion on the nerve trunks (= posterior root ganglion of spinal nerves)
or in the sensory organ- nose, eye, ear
Second order neuron – Cells and axons of the cranial nerve nucleus
Axons cross the midline and synapse with the thalamus/nuclei of termination/another sensory nuclei
Third order neuron – Terminates in the cerebral cortex

CN 1 - OLFACTORY NERVE
Central processes of olfactory hair cells in the olfactory mucosa pass through the cribriform
plate to synapse with mitral cells in olfactory bulb.
Axons of mitral cells pass as olfactory tract to uncus (1ry olfactory cortex)
Fibers do NOT relay in thalamus
Bilateral anosmia – due to fracture of anterior cranial fossa associated with CSF rhinorrhea.
CN 2 - OPTIC NERVE
 Fibers=axons of the ganglionic cells
 Leave the eye at the optic disc (medial to the center- blind spot)
 Fibers are myelinated. BUT by oligodendrocytes (comparable to CNS- a tract not a nerve)
 Optic chiasma→ fibers of the nasal half of the re na decussate

 Optic chiasma is situated at the junction of anterior wall and floor of the 3 rd ventricle
 Posterolateral angles of optic chiasma are continuous with optic tracts.
 Most of the fibers terminate by synapsing in Lateral Geniculate Body (LGB)
o Directed via optic radiation to the visual cortex (area 17)
 Fibers related to light reflex leave the optic tract →join pretectal nucleus in the superior
colliculus of the mid brain

CN 3 - OCULOMOTOR NERVE
Nuclei
Main motor nucleus - anterior part of the grey matter surrounding cerebral aqueduct
-at the level of superior colliculus
Edinger-Westphal nucleus (parasympathetic) - posterior to main motor nucleus
- Connect with pretectal nuclei of both sides
Connections
→ Corticonuclear fibers from both hemispheres
→Via medial longitudinal fasciculus connect with CN 4, 6, 8
→Visual cortex
Course
Intraneural
Courses anteriorly Through red nucleus
Exit from Anterior surface of mid brain
Intracranial
Exit between the 2 cerebral peduncles in the Inter peduncular fossa,
Between superior cerebellar & posterior cerebral arteries
Crossed by posterior communicating artery
Runs along the free edge of tentorium cerebelli
Enters the Middle cranial fossa
Runs in the Lateral wall of the cavernous sinus (above CN 4)
Divides into superior & inferior divisions
Enters the Orbit through middle part of the superior orbital fissure (SONIA)
Distribution
 Motor –superior division (+sympathetic)
1. superior rectus
2.levator palpebrae superioris
Superior cervical ganglion → Postganglionic sympathetic fibers → Internal carotid cavernous plexus →
Superior division of oculomotor nerve → Smooth muscle part of the LPS (Muller muscle)
-inferior division 1. medial rectus

2. Inferior rectus
3. Inferior oblique (gives off the branch to ciliary ganglion)
 Parasympathetic (ciliary ganglion→ short ciliary nerves) 1. ciliary muscle
2. constrictor pupillae of iris
Parasympathetic fibers
motor fibers

Clinicals
*Surgical oculomotor nerve division

 Oculomotor nerve is crossed by posterior communicating artery
 PCOM is a common site for cerebral aneurysms
 In PCOM aneurysm oculomotor nerve can be compressed in the interpeduncular
fossa
Ptosis Levator palpebrae superioris

Lateral squint Paralysis- medial rectus
Unopposed action of lateral rectus
Dilatation of pupil Paralysis-constrictor papillae
Loss of accommodation Paralysis-ciliary muscle
Slight proptosis (forward projection of eye) Loss of integrity of muscle cone
Diplopia(double vision)
Trochlear nerve (CN 4)
 Most slender CN
 Only CN to leave the posterior surface of the brain stem
Nuclei- Trochlear nucleus
 Anterior part of the grey matter around cerebral aqueduct
 At the level of the inferior colliculus
Connections → Cor conuclear fibers from both hemispheres
→medial longitudinal fasciculus
→visual cortex
Course
Intraneural
1. Posteriorly around grey matter
Intracranial
1. Exit from Dorsal aspect of the mid brain
2. Decussate (attached to superior
medullary velum)
3. Courses Ventrally around the superior
cerebellar & cerebral peduncles
4. Between superior cerebellar &
posterior cerebral arteries
5. Runs in the Lateral wall of the
cavernous sinus (b/w CN3 & CN51)
6. Crosses over CN 3
Extracranial
1. Orbit through lateral part of the superior
orbital fissure (LFT) Distribution -Superior oblique
muscle (turns eye downwards & laterally)
2. in the orbit lies medial to the frontal nerve on
Superior oblique
Clinical
Diplopia on looking downwards
Extortion effect

TRIGEMINAL NERVE CN-5
 Largest cranial nerve
 Both motor & sensory
 4 nuclei
o main sensory
o spinal
o mesencephalic
o motor- only for mandibular division
 Main sensory-
-posterior part of pons
-lateral to the motor nucleus
-continues with spinal nucleus
touch & pressure
 Spinal-
-continues -superiorly with main sensory nucleus
-inferiorly with substantia gelatinosa of the spinal cord
-extent: whole length of medulla oblongata and inferiorly to the C2 segment of spinal cord
-pain & temperature
 Mesencephalic—
midbrain –proprioception from
1)Muscles of mastication
2) Facial muscles
3) Extraocular muscles
These fibres bypass trigeminal nucleus (They are dendrites of unipolar cells)
 Motor-
-pons, medial to main sensory
nucleus -Supply: - muscles of
mastication
-anterior belly of Digastric
-mylohyoid
-tensor veli palatini & tensor tympani
Course-
Leaves the anterior aspect of the pons as a small motor root & a large sensory root
Pass forward out of the posterior cranial fossa
Upper surface of the apex of the petrous temporal bone
In the middle cranial fossa
Sensory root expands to form a trigeminal ganglion in Meckel’s cave

(a pouch of dura mater)
Ophthalmic maxillary mandibular

Ophthalmic
Trigeminal ganglion
Lateral wall of cavernous sinus, inferior to Trochlear nerve & superior to maxillary nerve
Lacrimal frontal nasociliary
Lateral part of superior lateral part of SOF middle part of SOF

orbital fissure(SOF) between 2 divisions
parasym. sensory of oculomotor nerve
zygomatico lacrimal gland supratrochlear supraorbital sensory root to

temporal ciliary ganglion
Upper eye lid frontal air sinus long ciliary nerves -

upper eye lid sensory-cornea, iris -
skin up to vertex sym-dilator papillae
post.ethmoidal
infratrochlear ant.ethmoidal

Maxillary
Lateral wall of cavernous sinus most inferiorly
foramen rotundum
pterygopalatine fossa zygomaticofacial
post.sup.alveolar zygomatic IOF
zygomaticotemporal
inf. orbital fissure(IOF)
infraorbital nerve ant.sup.alveolar
infraorbital foramen
face
sensory root to
pterygopalatine ganglion
greater palatine pharyngeal branches orbital branches

lesser palatine nasal branches
greater palatine palatovaginal canal inferior orbital
fissure
canal lesser palatine sphenopalatine foramen
canal
hard palate nasopharynx orbit
lateral wall of soft palate lateral wall & septum of nose
nose

Mandibular
Nerve of 1st branchial arch.
Motor & sensory roots pass through foramen ovale
Fuse to form main trunk which lies in infratemporal fossa on the tensor veli palatini,
Sensory to deep to lateral pterygoid
buccinator Meningeal (nervus spinosus) medial pterygoid
(only sensory branch)
nerve to medial pterygoid Tensor veli
Buccal
otic ganglion palatine &
Tensor tympani
masseteric
ANTERIOR (mainly motor) Otic POSTERIOR (mainly sensory)

Inf.alveolar
ganglion
Deep
temporal Lateral Auriculo
temporal Lingual Chorda
Pterygoid Mandibular
branch tympani foramen
TMJ temporalis
2 roots Superficial to
hyoglossus,deep
Mental
Encircle MM to myelohyoid
nerve
artery
winds around the Nerve to Mylohyoid

Sensory to parotid submandibular (only motor branch)
pinna, Ext. duct
AcousticMeatus
& tympanic Secretomotor
membrane Mylohyoid &
& sensory
Sensory& post.belly of
gustatory to digastric
ant.2/3 of
tongue,
Secretomotor
to the
sublingual &
submandibular
glands

Trigeminal Ganglion
Motor root (small & medial) and sensory root(large & lateral) emerge from pons
Present in Meckel’s cave
Contains axons from main sensory and spinal nuclei
Motor root lies below it
Three nerves arise from the ganglion
V1 & V2- sensory only
V3- mixed (both sensory and motor)
CLINICALS
Clinical testing-Sensory div. by using a cotton & pin
Very little overlap of dermatomes
Motor div. –by asking the patient to clench his teeth & feeling for the contracting masseter.
& asking the patient to move the jaw from side to side
TRIGEMINAL NEURALGIA
Severe stabbing pain of unknown cause involving mainly of V2 & V3
Sensory root is divided preserving fibres of the ophthalmic div. to avoid damage to the cornea.
Lingual nerve can be damaged in extracting the malplaced wisdom tooth as the nerve lies in
contact with the medial surface of the 3rd molar tooth.

Abducent nerve (CN 6)
Nucleus
 Floor of the 4th ventricle
 Beneath facial colliculus - pons
Connections → Cor conuclear fibers from both hemispheres
→ medial longitudinal fasciculus
Course
Intraneural
1. Pass anteriorly through the pons
2. Leave it through the groove b/w pons & medulla (above pyramids)
Intracranial
1. Longest intracranial course
2. Ascend on the clivus in the pontine cistern
3. Sharp bend over the superior surface of the petrous temporal bone(crosses apex of petrous
temporal bone
4. Runs anteriorly Through cavernous sinus (inferolateral to internal
carotid artery)
Extracranial
1. Orbit →middle part of the superior orbital fissure (inferolateral to CN 3 & nasociliary) (SONIA)
2. Enter the ocular surface of the lateral rectus muscle
Clinical
Complete paralysis
1. Medial (convergent) squint
2. Diplopia
False localizing sign in raised intra cranial pressure
Due to
1. long course
2. Sharp bend over petrous temporal bone
-Downward shift of brainstem due to raised intracranial pressure

Visual reflex
Direct & consensual light reflex
If a light is shown in to an eye, pupils of both eyes constrict
● Same eye- direct
● Opposite eye- consensual
1. Optic nerve
2. Optic chiasma
3. Optic tract
4. Pretectal nucleus
5. Edinger-Westphal nucleus of both sides
6. CN 3
7. Ciliary ganglion
8. Short ciliary nerves
9. Constrictor pupillae muscle
Accommodation reflex
When eyes are directed from a distant to near objects
1. Medial recti contract -Occular axis converge
2. Ciliary muscle contract -Lens thickens & refractive power increases
-direct light waves to the thickest central part of the lens
3.Pupils constrict 1. Optic nerve
2. Optic chiasma
3. Optic tract
4. Lateral geniculate body
5. Optic radiation
6. Visual cortex
7. Eye field of the frontal cortex
● CN 3 nucleus →medial rec
● Edinger-Westphal nucleus of both sides
CN 3
Ciliary ganglion
Short cilliary nerves
Constrictor pupillae & ciliary muscle
Corneal reflex
Light touching of cornea results in blinking of the eye (V1→MLF→VII)

The 3rd cranial nerve
a) Is related to the 4th and the 6th in the cavernous sinus.

b) Closely related to the posterior communicating artery.
c) Supplies the lateral rectus muscle
d) Leaves the brain stem through the interpeduncular fossa
e) Enters the inferior rectus muscle on its ocular aspect
Trochlear nerve
a) Leaves the brainstem on its dorsal aspect

b) Is exclusively a motor nerve
c) Pass between the superior cerebellar & posterior cerebellar arteries
d) crosses over the CN 3 in the anterior part of the cavernous sinus
e) Is important in light leflex
Regarding optic nerve
a) when damaged to optic chiasma bitemporal hemianopia results

b) is covered by dura upto eyeball
c) cannot regenerate after destruction
d) is connected to the CN 3 via pretectal nucleus
e) is connected to CN 3,4,,8 via the medial longitudinal fasciculus
Regarding abducent nerve
a) winds over the superior border of the petrous temporal bone

b) gives rise to false localizing sign
c) when damaged lateral squint results
d) lies inferomedial to the internal carotid artery in the cavernous sinus
e) travels on the superior border of the lateral rectus muscle

FACIAL NERVE CN-7
 Nerve of the 2nd branchial arch.

 Both motor & sensory, facial colliculus level
Components-
•SVE - muscles of face & scalp
Stapedius, posterior belly of digastric & stylohyoid
•SVA - taste from anterior 2/3 of tongue
•GVE - submandibular & sublingual salivary glands.
•GVE - lacrimal gland
nuclei-
3. Main motor
lacrimatory
2. Parasympathetic in pons
sup. Salivatory
3. Sensory - NTS
Main motor
–lower part of the pons (at the level of facial colliculus)
•Part of nucleus that controls the muscles of lower half of the face receive corticonuclear fibres only
from contralateral cerebral hemisphere.
•Upper part from both cerebral hemispheres.
Lesion 1
– No paralysis of ipsilateral face
– Paralysis of lower part of the contralateral face
Lesion 2
– paralysis of ipsilateral face
Parasympathetic--
same level
-fibers from hypothalamus
Sensory-
Taste- anterior 2/3 of tongue
Floor of mouth
Palate
 Taste sensation travels through axons of cells situated in geniculate ganglion. (1st order)
 Central processes synapse on cell bodies of NTS.
 Efferents (2nd order neurons) from NTS cross the medial plane and ascend to VPM nucleus to
thalamus.
 From the thalamus fibers (3rd order neurons) pass through internal capsule, corona radiata
to taste area of cortex.
NTS VPM of
Lingual Chorda Facial thalamus
nerve tympani nerve
Tongue Geniculate cortex
Course- ganglion
Intracranial-
-Consists of motor & sensory root
-motor fibers travel posteriorly around the medial side of the abducent nucleus. (facial colliculus)
-sensory root + parasympathetic root-Nervus intermedius
Emerges through Ponto medullary junction (CP angle)
Laterally in the posterior cranial fossa

Secretomotor supply
to lacrimal gland, nasal enters the internal acoustic meatus above 8th nerve
mucosa, oral mucosa
enters the facial canal at the bottom of IAM
courses laterally on the vestibule anterior Secretomotor to sublingual &

to semicircular canals & posterior to cochlea submandibular gland,
Pterygopalatine ganglion gustatory to anterior 2/3 of
motor root & nervus intermedius fuse
tongue
sharp bend(genu) posteriorly To submandibular ganglion
joined by lingual nerve
Greater petrosal nerve geniculate ganglion
Through petrotympanic
turns posteriorly runs above the promontory fissure to infratemporal fossa
below the canal for lateral semicircular canal Crosses the neck of the
malleus & pars flaccida of
bend downwards at the posterior wall of tympanic cavity tympanic membrane in the
middle ear
vertically downwards medial to aditus
nerve to stapedius Corda tympani(6mm above
exit from the stylomastoid foramen styomastoid foramen)
posterior auricular, occipitalis
Muscular branch Nerve to stylohyoid

crosses styloid process laterally Nerve to posterior belly of digastric
enters the posteromedial surface of the parotid
crosses external carotid artery & retromandibular vein superficially
temporofacial cervicofacial
temporal zygomatic buccal marginal mandibular cervical
orbicularis oculi orbicularis oris platysma
Clinical notes
SYMPTOMS SITE OF LESION
Internal strabismus Pons
Hearing loss IAM
Loss of lacrimation Facial canal before geniculate ganglion
Hyperacusis Facial canal before giving nerve to stapedius
Loss of taste in ant. 2/3 of tongue + lack of salivation Facial canal before giving corda tympani
Paralysis of muscles of facial expression extracranial

VESTIBULOCOCHLEAR NERVE CN-8
Emerges from CP angle
VESTIBULAR
SSA- from utricle,saccule & semicirucular canals- Balance
Nerve fibres-central processes of nerve cells located in the vestibular ganglion.
Enter through CP angle lateral to 7th nerve
ICP Vestibular nuclei(sup,inf,lat,med) - medulla
MLF
Cerebellum nuclei of 3,4,6 cranial nerves cortex
COCHLEAR
SSA-organ of Corti –hearing
Nerve fibres-central processes of nerve cells in the spiral ganglion
CP angle
Cochlear nuclei-in medulla,on the surface of ICP
Trapezoid body sup. olivary nucleus
Inferior colliculus + medial geniculate body
Internal capsule-acoustic radiation
Auditory cortex (areas 41,42) (Sup.temporal gyrus)

Glossopharyngeal nerve (CN IX)
Nuclei
 Nucleus ambiguus- motor to stylopharyngeus muscle

 Inferior salivatory nucleus- parasympathetic supply to parotid gland via otic ganglion
 Nucleus of Tractus Solitarius- taste from post. 1/3 of the tongue, carotid sinus afferents
Course
Leave medulla -between the olives & inferior cerebellar peduncle
Parotid gland
Anterior part of the jugular foramen otic ganglion
Superior ganglion (no branches) tympanic plexus (middle ear,

auditory tube, mastoid antrum & air cells)
Inferior ganglion tympanic branch tympanic canaliculus
Between the internal jugular vein & the internal carotid artery carotid branch (carotid sinus)
Deep to the styloid process & muscles attached to it
Turn forward winds around the stylopharyngeus supplies stylopharyngeus
Between internal & external carotid arteries pharyngeal branches pharyngeal plexus
Pass deep to hyoglossus (sensory to mucous membrane of the pharynx)
submandibular region tonsillar branch tonsil, soft palate
Lingual branch taste & general sensation

for posterior 1/3 of the
tongue & circumvallate
papillae

Tympanic nerve→tympanic canaliculus→ tympanic plexus on the promontory of the middle
ear→lesser petrosal nerve→ penetrate the tegmen tympani→ middle cranial fossa→ foramen
ovale→ otic ganglion→ auriculotemporal nerve→ parotid gland
Clinicals
Clinical testing
 gag reflex - on tickling the posterior wall of the pharynx there is reflex contraction of
pharyngeal muscles
 testing the taste sensibility of the posterior 1/3 of the tongue

Vagus nerve (CN X)
Nuclei
Nucleus ambiguus- motor to pharynx & larynx
Dorsal nucleus of vagus- parasympathetic
Nucleus of tractus solitaries- taste
Course
 Between olives & inferior cerebellar peduncles
 Through the middle part of the jugular
foramen anterior to C.N 11
 Joined by the cranial part of accessory
 Superior ganglion 1. Meningeal branch (post cranial fossa)

 Inferior ganglion 2. Auricular branch (root of auricle,
posterior ½ of external meatus &
tympanic memb.)
 Descend within the carotid sheath
Pharyngeal branch (muscles of
 (between & posterior to the internal jugular vein & pharynx & soft palate except
internal/common carotid arteries) tensor veli palatini)
 At the root of the neck Carotid branch (carotid sinus)
 Right cross 1st part of the subclavian left b/w Superior laryngeal nerve
common carotid & subclavian (cricothyroid: ex laryngeal,
mucosa up to vocal folds: int
laryngeal)
Recurrent laryngeal (muscles of
larynx, mucosa up to vocal folds,
inferior constrictor, trachea)
Cardiac branches
Clinical
Nerve damage
Paralysis of palatine muscles (uvula pulled to normal side) Dysphagia
Nasal regurgitation of swallowed fluids Cadaveric
position of vocal cords Hoarseness of voice
Irritation of auricular branch ear cough

Stimulation of auricular branch appetite
Herpes zoster skin of auricle communication with
geniculate ganglion of CN 7

Accessory nerve (CN XI)
Cranial & spinal roots
Cranial root distributed via vagus (vago accessory complex)
Nuclei
1. Nucleus ambiguus
2. Spinal nucleus (lateral part of the anterior grey column-C1-C5)
Cranial root
 B/w olives & inf cerebellar peduncle (posterolateral sulcus)
 Unite with the spinal root
 Middle part of the jugular foramen
 Separate from the spinal root
 Fuse with Vagus below inferior ganglion
 Distributed through its branches to palate, pharynx, larynx
Spinal root
 B/w ventral & dorsal roots of spinal cord up to C5
 Enters the cranium through foramen magnum
 Unite with the cranial root
 Middle part of the jugular foramen
 Separate from the cranial root
 Descend b/w internal jugular vein & internal carotid artery
 Deep to styloid process
 Deep to sternocleidomastoid
 Pierce the posterior border of it near its middle
 Enter the posterior triangle
 Pass deep to ant border of trapezius 5cm above clavicle
 Supply sternocleidomastoid & trapezius
Clinical
Ask the patient to shrug the shoulders against resistance
Ask the patient to turn the chin to opposite side against resistance
Nerve damage torticollis/ wry neck

Hypoglossal nerve (CN XII)
Supplies the muscles of the tongue
Nuclei
Hypoglossal nucleus (floor of the 4th ventricle) – Medulla
Part of the nucleus supplying the genioglossus receives fibres ONLY from the Contralateral cortex.
Course
Intraneural
1. Lateral to medial longitudinal fasciculus & medial lemniscus & pyramids
2. Medial to olives
3. Anterolateral sulcus
4. Leave the skull through hypoglossal canal (anterior condylar canal)
Extracranial
1. Lies deep to internal jugular vein
2. Then b/w internal jugular vein & internal carotid artery
3. Crosses the vagus laterally deep to parotid & styloid process
4. At the lower border of the posterior belly of the digastric hooks around the occipital artery
5. Crosses the external & internal carotid arteries & the loop of the lingual artery
6. Pass deep to the posterior belly of digastric
7. Enter the submandibular region
8. On hyoglossus & genioglossus deep to submandibular gland& mylohyoid
9. Supply the all the tongue muscles except palatoglossus (supplied by the vago accessory
complex)
10. Spinal nerve C1 joins & form the descendens hypoglossi→ supply strap muscles (thyrohyoid
& geniohyoid supplied directly by C1 via CN 12)
Nerve lesion – tongue deviates to the paralyzed side

CEREBELLUM
 Relations of cerebellum
 Situated in posterior cranial fossa

 Anteriorly
o 4th ventricle
o Brain stem (Pons, Medulla oblongata)
o Choroid plexus of 4th ventricle
o Superior & Inferior colliculus
 Superiorly
o Occipital lobe
o Tentorium cerebelli
o Straight sinus
 Consists of two hemispheres and a vermis.
 3 peduncles
 Superior – midbrain with cerebellum
 Middle – pons with cerebellum
 Inferior – medulla oblongata with cerebellum
 3 lobes
 Anterior
 Middle / posterior (largest)
 Flocculonodular
 3 fissures
 Primary - separates anterior and middle lobes
 Uvulonodular - separates middle and flocculonodular
lobes
 Horizontal - no importance
Outer cortex (gray matter)
 Cerebellum consists of Inner white matter
Intracerebellar nuclei
Outer cortex
 Larger sheets with folds → arbor vitae appearance

 Structural layers of cortex: (My Poor Granny from
superficial to deep)
 Molecular cell layer – outer stellate, inner basket cells
 purkinje cell layer – purkinje cells, Golgi type 1
neurons
 granular cell layer – granular cells, Golgi cells

 Functional areas of cortex:
 Flocculonodular node (vestibulo-cerebellum) - axial
movements
 Vermis + intermediate zone (spino-cerebellum) -
distal limb movements
 lateral zone (cortico-cerebellum) - planning
sequential movements
Internal white matter
 Afferent fibres → via inferior and middle cerebellar

peduncles
 Intrinsic fibres
 Efferent fibres → via superior and
inferior cerebellar peduncles
Intracerebellar nuclei:
 Dentate, emboliform, globose, fastigial

(Dental Embolies Grow Fast from
lateral to medial)
 Cerebellar outflows from fastigial
nucleus run through inferior peduncle,
while outflows from other nuclei run
through superior peduncle)
Cerebellar cortical mechanism

 Cortex receives 2 main types of afferent
inputs
1. Climbing fibres (olivocerebellar
tract)
2. Mossy fibres (all other afferents)
 They are excitatory to Purkinje cells
 Inhibitory cells: Stellate, Basket, Golgi
cells

Cerebellar afferent fibres
Brain stem, spinal cord, cerebrum→mossy fibres→granular cells→parallel fibres→purkinje cells
Inferior olivary nucleus→climbing fibres→purkinje cells
 From cerebrum
 Corticopontocerebellar pathway (middle peduncle)
 Cerebroolivocerebellar pathway (inferior peduncle)
 Cerebroreticulocerebellar (middle, inferior peduncles)
 From spinal cord
 Anterior spinocerebellar tract
(superior peduncle)
 Posterior spinocerebellar tract
(inferior peduncle)
 Cuneocerebellar tract (inferior
peduncle)
 Vestibular afferents
Cerebellar efferent fibres
 Entire output via purkinje cells
 Purkinje cells→deep cerebellar nuclei→efferent
fibers from deep nuclei→brain stem→spinal
cord, cerebrum
 Globose-emboliform-rubral pathway
(superior peduncle)
 Dentothalamic pathway (superior
peduncle)
 Fastigial vestibular pathway (inferior
peduncle)
 Fastigial reticular pathway (inferior
peduncle)
Blood supply of cerebellum
 Basilar artery
 Superior cerebellar artery
 Anterior inferior cerebellar artery
 Posterior inferior cerebellar artery

Functions of cerebellum
Cerebellum has no direct neuronal connections with the lower motor neurons, but exerts its influence
indirectly through the cerebral cortex and brainstem.
 Coordination of precise movements (cerebellum survey as a comparator)

How?
1. By continuously comparing the output of the motor area of cerebral cortex with the proprioceptive
information received from the site of muscle action.
2. Bringing about necessary adjustment by influencing the activity of the lower motor neurons.
 Control tone and posture
 Control of equilibrium
 Control of voluntary movements
CLINICALS
Signs & symptoms are limited to the same side of the body.
1. Hypotonia
2. Postural changes & alterations of gait
3. Ataxia- disturbance of voluntary movement.
-Decomposition of movement.
(Muscle groups fail to work harmoniously)
-Past pointing with gross corrections.
4. Dysdiadochokinesia-inability to perform alternating movements regularly and rapidly
5. Disturbance of reflexes
-pendular knee jerk
6. Disturbance of ocular movements
Nystagmus-rhythmical oscillation of eyes
7. Disorder of speech-Dysarthria(slurred speech)
THE CEREBRUM
Diencephalon – central core
 Divided into 2 parts Telencephalon – cerebral hemispheres
 The largest part of the brain, Situated in the anterior and middle cranial fossae
 Developed from the forebrain
 Each hemisphere has a covering of gray matter, the cortex and internal masses of gray matter, the basal nuclei,
and a lateral ventricle
Cerebrum
Diencephalon the third ventricle and the structures that Telencephalon

form its boundaries - Cortex (Gray matter)
- 3rd ventricle - Internal white matter
- the thalamus - Basal ganglia
- subthalamus - Lateral ventricle
- epithalamus
- hypothalamus
Diencephalon
 Extent – from interventricular foramen of Monro to commencement of cerebral aqueduct.
 Inferior surface – anterior to posterior – optic chiasma, infundibulum with tuber cinereum, mammillary
bodies
 Superior wall – roof of 3rd ventricle
 Lateral wall – internal capsule
 Medial wall – thalamus, hypothalamus (lateral wall of 3rd ventricle)

Thalamus
 on either side of 3rd ventricle
 Relays all sensations except olfactory
 Important in crude sensation (for detailed localization & interpretation→cerebral cortex) – pain &
temperature
 Below – hypothalamic sulcus
Relations
● Anterior - Interventricular foramen of Monroe
● Posterior - Forms pulvinar which overhangs superior colliculus
telachoroidea, fornix
choroid plexus of lateral ventricle
● Superior -
body of the caudate nucleus (thalamus forms part of the floor of the body of lateral
ventricle)
Hypothalamus
● Inferior - tegmentum of mid brain
3rd ventricle
● Medial - interthalamic connection (gray matter)
internal capsule
● Lateral - lentiform nucleus
● Poster superiorly - Epithalamus (pineal gland + 2 habenular nuclei)

Important thalamic nuclei
Ventral posterior nucleus
Ventral posterolateral Ventral posteromedial

Relays spinal & medial lemnisci Relays trigeminal & taste
(sensations from the body) (sensations from face)
lateral geniculate body (LGB) -relays vision (optic tract)

medial geniculate body (MGB) - relays hearing (lateral lemniscus → inferior colliculus)
3rd ventricle
 Slit like cleft between 2 thalami
 Anterior wall – lamina terminalis with anterior commissure
 Posterior wall – opening of cerebral aqueduct,
posterior commissure
pineal recess
habenular commissure
 Roof – ependymal + telachoroidea,
Choroid plexus of 3rd ventricle,
More above - fornix & corpus callosum
 Floor – optic chiasma,
Tuber cinereum
infundibulum
mammillary bodies
cerebral peduncles
tegmentum
 Lateral wall – thalamus
hypothalamus
 Communicate,
o Anteriorly – lateral ventricle (via interventricular foramen)
o Posteriorly – 4th ventricle (via cerebral aqueduct)
Regarding the thalamus
a) Has the body of the fornix on its superior aspect.

b) Is separated from the lentiform nucleus by the external capsule.
c) Has bands of gray matter connecting the thalami of both sides.
d) Has the medial lemniscus ending in its VPL.
e) Has the anterior pole forming the posterior boundary of the interventricular foramen.

Hypothalamus
 Controls autonomic nervous system
 Controls endocrine system (via the pituitary gland)
 Maintains body homeostasis, emotion & behavior
 Controls body temperature, hunger, thirst,
fatigue, sleep, and circadian cycles, sexual
behavior
Relations
● Anterior - optic chiasma
lamina terminalis
anterior commissure
● Posterior - tegmentum of the mid brain
● Superior - thalamus
● Inferior - optic chiasma
tuber cinereum & infundibulum
mammillary bodies
● Medial - 3rd ventricle
Hypothalamo - hypophyseal tract
 Supraoptic nucleus - Vasopressin
 Paraventricular nucleus - oxytocin
Clinical syndromes of hypothalamus
 Carried by axons to the pituitary
 Obesity/wasting
Hypophyseal portal system  Sexual disorders
 Carries releasing & release inhibitory hormones to the pituitary  Sleep disorders
(GnRH, GHRH, GHIH)
 Hyperthermia/hypothermia
 Formed by the superior hypophyseal artery of the internal carotid
 Diabetes insipidus
Epithalamus
 consists of the habenular nuclei and the pineal gland
Subthalamus
 Lies inferior to the thalamus
 Superior to the tegmentum of the mid brain

Sulci
Gyri
Telencephalon
Parietal
Cerebral cortex
 thin layer of gray matter Frontal
 The largest part of the brain
Temporal Occipital
 Two hemispheres are
separated by a deep midline
sagittal fissure, the
longitudinal cerebral fissure.
 In the depths of the fissure,
the corpus callosum connects
the hemispheres.
 The surface of each cerebral
hemisphere is thrown into
folds or gyri, which are
separated from each other
by sulci or fissures
 Each hemisphere is divided
into lobes which are named
according to the cranial
bones under which they lie.
o Frontal
o Parietal
o Temporal
o Occipital

Important cortical areas
 Frontal lobe
o Precentral area
 Primary motor area (4) -
carry out the individual
movements of different
parts of the body
 Premotor area, secondary
motor area - store
programs of motor activity
assembled as the result of
past experience
o Frontal eye field - control
voluntary scanning
movements of the eye and
is independent of visual
stimuli
o Motor speech area of Broca
- formation of words by its
connections with the
adjacent primary motor
areas
o Prefrontal cortex - the
makeup of the individual's
personality
 Parietal lobe
o Primary somatic sensory
cortex (SI)
o Secondary somesthetic area
(SII)
o Somesthetic association
area–stereognosis
 Occipital lobe
o Primary visual area (17) -
afferent from LGB
o Secondary visual area (18) -
relate the visual information
received by the primary visual area to past visual experiences, thus enabling the individual to recognize and
appreciate what he or she is seeing
o Occipital eye field - reflex and associated with movements of the eye when it is following an object
 Temporal lobe
o Primary auditory area (41, 42)
o Secondary auditory area (22) – interpretation of sounds and for the association of the auditory input with
other sensory information
o Sensory speech area of Wernicke - permits the understanding of the written and spoken language and
enables a person to read a sentence, understand it, and say it out loud.

Basal Ganglia
 Collection of grey matter in cerebral hemisphere.
 Control voluntary movements by influencing the cortex (no direct control on descending pathways)
 Set posture before a movement
1. Caudate nucleus
Separated almost entirely by the internal capsule
2. Lentiform nucleus
I. Globus pallidus
II. Putamen
3. Amygdaloid nucleus
4. Claustrum
Lentiform nucleus
Corpus Striatum
Caudate nucleus
Caudate nucleus
 C shaped
 Closely related to lateral ventricle
 Lateral to thalamus
 Laterally internal capsule
Lentiform nucleus
 wedge shaped
 Medially – internal capsule –
separates it from caudate nucleus
and thalamus
 Laterally – external capsule –
separates it from claustrum
Diseases of basal ganglia
Huntington’s disease - Chorea

(involuntary jerky movements)
Parkinson’s disease
1. Resting tremor (pill rolling tremor)
2. Lead pipe rigidity (cogwheel, plastic)
3. Bradykinesia (slurred speech,
expressionless face, can’t initiate
movements)
4. Postural instability (Shuffling gait)

Internal white matter
1. Commissural fibers - between 2 hemispheres
 corpus callosum
 anterior & posterior commissures
 fornix
 habenular commissure
2. Association fibers - various cortical regions of the same hemisphere
3. Projection fibers - afferents & efferent from brainstem to cortex
 Internal capsule
 corona radiata
 optic radiation
Commissural fibers
1. Corpus callosum- At the
bottom of the longitudinal
cerebral fissure
2. Anterior commissure-
Rostrum (continuous with
the lamina terminalis)
3. Posterior commissure
4. Hippocampal
commissure - Genu, body,
splenium
5. Fornix – from
hippocampus to
mammillary bodies

Internal capsule
 Compact band of fibers
 Separates the caudate nucleus
and the thalamus from the
putamen and the globus pallidus
 Contains both ascending and
descending fibers
 In a transverse section the
internal capsule is V-shaped
 The bend in the V is the genu
 The anterior limb is between the
head of the caudate nucleus and
the lenticular nucleus
 The posterior limb is between the
thalamus and lenticular nucleus
 The retrolenticular part contains
fibers from the optic system,
coming from the lateral
geniculate nucleus of the
thalamus. More posteriorly, this
becomes the optic radiation
 The sublenticular part contains

fibers connecting with the
temporal lobe. These include the
auditory radiations
 The anterior limb of the internal
capsule contains:
o Frontopontine fibers
project from frontal
cortex to pons
o Thalamocortical fibers
connect the thalamus to
the frontal lobes
 The genu contains corticobulbar
fibers, which run between the
cortex and the brainstem.
 The posterior limb of the internal capsule contains
1) corticospinal fibers
2) sensory fibers (including the medial lemniscus and the anterolateral system) from the body
Blood supply
1. Middle cerebral artery- medial & lateral striate central branches
2. Anterior cerebral artery- central branches
3. anterior choroidal artery
 Anterior limb: middle cerebral artery (superior half) & anterior cerebral artery (inferior half)
 Genu: middle cerebral artery
 Posterior limb: middle cerebral artery (superior half) & anterior choroidal artery of the internal carotid artery
(inferior half)
Lesions
 Cause: high blood pressure
 Even a small lesion causes severe damage
 contralateral hemiparesis or hemiplegia

Blood Supply of the CNS
 Supplied by the
 2 internal carotid arteries
 2 vertebral arteries
 These 4 arteries unite to form the Circle of

Willis.
 Lies in the interpeduncular cistern
 At the base of the brain
 Around the Optic Chiasma and the infundibulum
of Pituitary
 Internal Carotid Artery

 Arises from the common carotid artery
 Common carotid artery bifurcates into the
internal and external carotid arteries
 at level of the Fourth Cervical Vertebra (at the
upper border of the thyroid cartilage)
 Internal carotid artery has 4 main parts
1. Cervical part
2. Petrous part
3. Cavernous part
4. Cerebral part
 The 1st 3 parts give no branches.

Cerebral part of the Internal Carotid Artery
Anterior Cerebral Artery

 Anastomoses with the opposite artery by Anterior Communicating artery
 Supplies;
 Medial surface of the cerebral cortex upto parieto-occipital sulcus
 Strip of cortex on adjoining lateral surface.
 Leg area of pre central gyrus.
 Anterior limb of the internal capsule
 Runs medially superior to the optic nerve

 Enters the longitudinal fissure
 Connects with the opposite artery by the Anterior Communicating Artery
Ophthalmic Artery
Middle Cerebral Artery
 Largest branch
 Supplies;
Internal Carotid  Entire lateral surface of hemisphere
(except the part supplied by anterior
cerebral artery)
 All the parts of the Internal capsule
via lateral & medial striate arteries
 Lentiform and Caudate nuclei
Anterior Choroidal Artery

 Passes posteriorly close to the optic tract
Posterior Communicating Artery
 Enters the inferior horn of the lateral ventricle
 Runs above the
 ends in choroidal plexus
oculomotor nerve
 Supplies;
 the posterior limb of the internal capsule
 Crus cerebri
 Lateral geniculate body
 Optic tract
 Vertebral Artery
 Vertebral arteries are major arteries of the neck
 branch of 1st part of the subclavian artery
 Ascends through foramen transversarium of upper 6 cervical vertebrae (not through C7)
 Grooves the superior surface of posterior arch of atlas
 Enters the skull through Foramen Magnum
 Pierces dura and arachnoid maters to enter the sub arachnoid space (cerebellomedullary cistern)
 2 vertebral arteries join up to form the Basilar Artery at the lower border of Pons.

Posterior Inferior Cerebellar Artery (PICA)
Basilar Artery  Largest branch of the Vertebral artery
 Supplies;
 Upper lateral Medulla
 Cerebellum
 PICA syndrome
Anterior Spinal Artery
 Arises as 2 arteries; then unite and
form one Anterior Spinal Artery
Vertebral Artery  Descends on the anterior aspect of
Medulla Oblongata and Spinal Cord
along the Anterior Median Fissure
embedded in the Pia Mater
 Supplies anterior 2/3 of the Spinal
Cord
2 Posterior Spinal Arteries

 Descend on the posterior surface close
to the posterior roots of the Spinal Cord
 Supplies posterior 1/3 of the Spinal Cord
 Basilar Artery
 Ascend in a groove on the anterior surface of the Pons (pontine cistern)
Posterior Cerebral Artery Communicates with

 Supplies; Posterior Cerebral
 Occipital Lobe artery to form the
 Visual Cortex Circle of Willis
Superior Cerebellar Artery
 Supplies;
 Pons
 cerebellum
Pontine Arteries
 Supplies;
Basilar Artery  Pons
Labyrinthine Artery
 Accompany Facial & Vestibulo-Cochlear
nerves to Internal Acoustic Meatus
 Supplies;
 Inner ear
Anterior Inferior Cerebellar Artery (AICA)

 Supplies;
 Cerebellum
Vertebral  Pons
arteries  Upper medulla

 Circle of Willis
Medulla Pons
 Vertebral artery  Basilar artery
 Ant. and post. spinal arteries  Anterior inferior cerebellar
 Posterior inferior cerebellar artery artery
 Basilar artery  Superior cerebellar artery
Cerebellum
Mid brain  Anterior inferior cerebellar
 Basilar artery Circle of Willis artery
 Superior cerebellar artery (Regions supplied)  Posterior inferior cerebellar
 Posterior cerebral artery artery
 Superior cerebellar artery
Thalamus Corpus Striatum

 Basilar artery  Mainly Middle Cerebral Artery
 Posterior communicating artery  Also by Anterior Cerebral Artery
 posterior cerebral artery
Blood supply of internal capsule

Clinicals
 No anastomoses after circle of Willis.
 More capillaries can be seen in grey matter (metabolic activity of cell bodies are high)
 Anterior cerebral artery occlusion – Contralateral Hemiparesis & hemi-sensory loss involving leg & foot.
 Middle cerebral artery occlusion – Contralateral Hemiparesis & hemi-sensory loss involving face & arm (+
Aphasia if left-sided lesion) (legs are spared)
 Posterior cerebral artery occlusion – Contralateral Homonymous Hemianopia with macula sparing due to
collateral supply from middle cerebral artery.
 Aneurysms in posterior communicating artery can compress oculomotor nerve (surgical oculomotor nerve
palsy)
 Occlusion of the posterior inferior cerebellar artery (PICA) or vertebral artery causes Lateral Medullary
Syndrome (of Wallenberg)
 Occlusion of the medullary branch of vertebral artery (or anterior spinal artery) causes Medial Medullary
Syndrome
 Affect the Hypoglossal nerve, Medullary Pyramids and Medial Lemniscus
 Occlusion of a branch of the posterior cerebral artery that supplies the midbrain causes Weber syndrome
 Ipsilateral occulomotor nerve palsy
 Contralateral hemiparesis

01. In lesions of the right posterior inferior cerebellar artery is
a. Loss of pain and temperature on the same side
b. Paralysis of facial muscles on the opposite side
c. Deviations of the protruding tongue the same side
d. Dysphagia
e. Hypotonia
02. Posterior inferior cerebellar artery thrombosis give rise to

a. Hoarseness of voice
b. Hypotonia
c. Loss of pain and temperature sensation on the opposite half of the face
d. Loss of pain and temperature sensation on the opposite lower limb
e. Loss of cough reflex
03. Left posterior inferior cerebellar artery syndrome causes

a. Left sided incoordination in the upper limbs
b. Paralysis of muscles of the upper right extremity
c. No taste sensation in the anterior 2/3 of the tongue
d. Deafness in the right year
e. Difficulty in swallowing
04. Regarding medial medullary syndrome

a. Condition may be caused by thrombosis of the posterior inferior cerebellar artery
b. Nucleus ambiguus of the same side may be affected
c. There may be analgesia on the same side of the face
d. There may be thermoanesthesia on the same side of the face
e. There may be nausea
05. Features of basilar artery occlusion includes

a. Monoplegia
b. Contralateral cerebellar signs
c. Quadriplegia
d. Hypopyrexia
e. Contralateral cranial nerve palsies
06. Features of posterior inferior cerebellar artery occlusions include

a. Contralateral Horner’s syndrome
b. Ipsilateral analgesia
c. Contralateral ataxia
d. Dissociated analgesia
e. Ipsilateral analgesia in the face

VENTRICULAR SYSTEM
 Four CSF filled cavities located within the brain
 Lined throughout with ependyma
 Derived from the cavity of neural tube
 Consists of 2 lateral ventricles, 3rd ventricle, cerebral aqueduct and 4th ventricle
Lateral ventricle
 Largest of the ventricles

 One is present in each cerebral hemisphere
 C shaped cavity
 Divided into
 Body – extends to parietal lobe
 anterior horn – extends to frontal lobe
 posterior horn – extends to occipital lobe
 inferior horn – extends to temporal lobe

 Two lateral ventricles and third ventricle
communicate with each other through
interventricular foramen
Relations of the body of lateral ventricle
 Roof - corpus callosum

 Floor- caudate nucleus , lateral margin of
the thalamus
 Medial wall- septum pellucidum
3rd ventricle
 Slit like cleft between the 2 thalami
 The interthalamic adhesion runs through the ventricle
 Communicate with the lateral ventricles anteriorly by the interventricular foramen (of Monroe)
 Communicate with the 4th ventricle posteriorly by the cerebral aqueduct of Silvius
Relations of the 3rd ventricle
 Anterior wall – lamina terminalis with anterior commissure

 Posterior wall – opening of cerebral aqueduct,
posterior commissure
pineal recess
habenular commissure
 Roof – ependymal + telachoroidea,
Choroid plexus of 3rd ventricle,
More above - fornix & corpus callosum
 Floor – optic chiasma,
Tuber cinereum
infundibulum
mammillary bodies
cerebral peduncles
tegmentum
 Lateral wall – thalamus
hypothalamus
Cerebral aqueduct
 Narrow channel which connects the 3rd ventricle with the 4th ventricle
 No choroidal plexus

4th ventricle
 Diamond shaped
 Situated anterior to the cerebellum
 Posterior to the pons and the superior half of the medulla oblongata
 Roof/Posterior wall– cerebellum(Superior and inferior medullary velum)
 Floor – medulla oblongata,Pons
 Walls – cerebellar peduncles
 Posterior wall is pierced by a large medial aperture – foramen of Magendie
Laterally – foramen of Luschka
 Communicate with subarachnoid space
CEREBRO-SPINAL FLUID (CSF)
FORMATION
 From choroid plexus of the
ventricles

 Which is a vascular fold composed
of pia mater covered with
ependymal cells lining the
ventricular cavity
 CSF is actively secreted
 Production is not pressure
dependent
 Continuous even if the reabsorption
is obstructed
ABSORPTION
 By arachnoid villi (arachnoid granulations)
 They are projected in to the Dural venous sinuses, especially Superior Sagittal Sinus (SSS)
 Grouped together to form Arachnoid granulations
 Which is diverticulum of the subarachnoid space that pierces the dura mater
 Covered by endothelium of the venous sinuses.
 Absorbed when, CSF fluid pressure in sub-arachnoid space > Venous pressure in sinuses
 Villi act as valves
BLOOD BRAIN BARRIER

 Tight junctions between adjacent endothelial cells in the blood capillaries
 Assisted by a thick basal lamina and enveloping foot processes of surrounding astrocytes
 Blood-CSF barrier – Barrier similar to the BBB exist in choroid plexus.
CLINICAL NOTES
1. Papilledema
 Intracranial subarachnoid spaces extend forward around the optic nerve
 High CSF pressure compress the retinal wall → bulging forward of the op c disk causes edema of
the disk
2. Hydrocephalus - abnormal increase in the volume of CSF within the skull
 Communicating hydrocephalus – due to obstruction of interventricular foramen or cerebral
aqueduct by tumors
 Non-communicating hydrocephalus – due to increased formation or decreased absorption of CSF
The third ventricle

a. communicates with the 4th ventricle through the interventricular foramen
b. is related superiorly to the transverse fissure
c. is bounded anteriorly by the lamina terminalis
d. is recessed in to the mamillary body
e. is related to the posterior perforated substance

The autonomic nervous system controls the internal environment of the body
Controlled by higher centers
Anterior – parasympathetic
1. Hypothalamus Posterior – sympathetic
2. Lower brainstem Vasopressor
Vasodilator
Cardio accelerator
Cardio deaccelerator
Respiratory center
3. Cerebral cortex
Through hypothalamus
Limbic system
Autonomic Ganglia Autonomic Plexuses Enteric Nervous System
Sympathetic Parasympathetic
Autonomic ganglia
Basic structure
Preganglionic neuron Postganglionic neuron

Myelinated Ganglion Non-myelinated
Relatively slow conducting B fibers Relatively slower conducting C fibers
One preganglionic axon→synapse→several post ganglionic neurons

Visceral receptors→chemoreceptors, baroreceptors, osmoreceptors, pain receptors
Sympathetic nervous system

Outflow(preganglionic) → thoracolumbar ou low
Lateral grey column (horns) T1 - L2 (L3)
Preganglionic nerve fiber leave through anterior nerve root
Pass via white ramus communicantes to paravertebral ganglia of sympathetic trunk
Sympathetic ganglion – preganglionic fibers synapse with post ganglionic neuron
Lies lateral to vertebral column as a chain

1. They synapse with a postganglionic neuron in the
ganglion. The postganglionic nonmyelinated axons
leave the ganglion and pass to the spinal nerves as
gray rami communicantes (the gray rami are gray
because the nerve fibers are devoid of myelin).
They are distributed in branches of the spinal nerves
to smooth muscle in the blood vessel walls, sweat
glands, and arrector muscles of the hairs of the skin.
2. They travel superiorly in the sympathetic trunk to
synapse in ganglia in the cervical region. Many of the
preganglionic fibers entering the lower part of the
sympathetic trunk from the lower thoracic and upper
two lumbar segments of the spinal cord travel
inferiorly to synapse in ganglia in the lower lumbar
and sacral regions.
3. They may pass through the ganglia of the sympathetic trunk without synapsing. These myelinated
fibers leave the sympathetic trunk as
I. greater splanchnic (5-9 II. lesser splanchnic (9-11 III. least splanchnic
thoracic ganglions) thoracic ganglions) nerves (12th thoracic
It descends and pierces the crus It descends with the greater ganglion)
of the diaphragm to synapse with splanchnic nerve and pierces the The least splanchnic nerve (when
the ganglia of the diaphragm to join with the ganglia present) pierces the diaphragm,
i. celiac plexus in the lower part of the celiac and synapses with the ganglia of
ii. renal plexus plexus. the renal plexus
iii. suprarenal medulla.

Sympathetic trunk – ● in the Neck - anterior to transverse processes of cervical vertebrae
● Thorax – anterior to the heads of the ribs or on the sides of the vertebral bodies
● Abdomen – anterolateral to the sides of the bodies of the lumbar vertebrae
● Pelvis – anterior to the sacrum
Ganglion impar
Afferent →Without synapsing in ganglion via white rami communicans → Posterior root ganglion
(myelinated)
afferent component of local reflex arc Central axons
Ascend to higher centres
Supra-renal medulla
A few preganglionic fibers, traveling in the greater splanchnic nerve, end directly on the cells of the
suprarenal medulla. These medullary cells, which may be regarded as modified sympathetic excitor
neurons, are responsible for the secretion of epinephrine and norepinephrine.
CERVICAL SYMPATHETIC TRUNK
 The sympathetic chain continues upwards from thorax by crossing the neck of the first rib 
 Then ascends embedded in the posterior wall of the carotid sheath to the base of the skull 
 No white rami communicans from cervical part of sympathetic chain 
 Preganglionic fibres origin from lateral grey horn of T1-T4 & ascend to the cervical ganglia. 
  3 ganglia –Superior, Middle, Inferior 
Superior cervical ganglion (fusion of C1-C4 ganglia)
 Largest
 Lies opposite C2 and C3 vertebrae
 Sends grey rami communicans to C1-4 spinal nerves 

Middle cervical ganglion (fusion of C5-C6 ganglia)
 Lies level with C6 vertebra 
 Sends grey rami to C5 and 6 nerves 

Inferior ganglion (fusion of C7-C8 ganglia)
 Lies level with C7 Tucked behind the vertebral artery 
 Frequently fuses with the first thoracic ganglion to form stellate ganglion at the
neck of the first rib. 
 Grey rami pass from it to C7 and 8 nerves 
Superior Cervical Ganglion
Internal carotid plexus External carotid plexus
Ciliary Ganglion Pterygopalatine Otic Ganglion Submandibular

ganglion Ganglion
Dilator pupillae Lacrimal gland Parotid gland Submandibular &
Sublingual gland
Parasympathetic nervous system

Outflow – brainstem parasympathetic nuclei
Craniosacral outflow
Pelvic splanchnic nerves (S2, S3, S4)
Parasympathetic ganglia – lies close to the viscera

 Cranial outflow
1. Ciliary
2. Pterygopalatine
3. Submandibular
4. Otic
 Sacral outflow
 Pelvic splanchnic nerves synapse in ganglia of hypogastric
plexuses
Afferent – cell bodies sensory ganglia of cranial serves
(myelinated) posterior root ganglia of sacrospinal nerves
SYMPATHETIC PARASYMPATHETIC
Action Prepares body for emergency Conserves & restores energy
Outflow T1 - L2(3) Cranial nerves III, VII, IX, & X;
S2,3 & 4
Preganglionic fibres Myelinated B Myelinated B
Ganglia Paravertebral (sympathetic trunks), Small ganglia close to viscera
prevertebral (ex: celiac, superior (eg: otic, ciliary) or ganglion cells
mesenteric, inferior mesenteric) in plexuses
(eg: cardiac, pulmonary)
Neurotransmitter within ganglia Acetylcholine Acetylcholine
Postganglionic fibres Long non-myelinated C Short non-myelinated C
Characteristic activity Wide spread due to many post-ganglionic Discrete action with few post
fibres & liberation of epinephrine & ganglionic fibres
norepinephrine from supra renal medulla.
Neurotransmitter at postganglionic Norepinephrine at most endings & Acetylcholine at all endings
endings acetylcholine at few endings (sweat glands)
Higher control Hypothalamus Hypothalamus

Autonomic plexuses
Large collections of sympathetic and parasympathetic efferent nerve fibers and their
associated ganglia, together with visceral afferent fibers, form autonomic nerve plexuses.
Thorax
1. Cardiac plexus
Sympathetic – cardiac nerves, fibers from upper thoracic ganglia
2. Pulmonary plexus
Parasympathetic – vagal fibers
3. Esophageal plexus
Abdomen
1. Coeliac plexus Sympathetic – Greater, lesser, least splanchnic nerves, upper two
2. Superior mesenteric plexus lumbar splanchnic nerves
3. Inferior mesenteric plexus Parasympathetic – vagal fibers (coeliac branch of posterior gastric
nerve)
4. Superior hypogastric plexus Sympathetic – lower two lumbar splanchnic

Parasympathetic – pelvic splanchnic nerves
Pelvis
1. Inferior hypogastric plexus
The postganglionic fibers arise from the peripheral plexuses and are distributed to the
smooth muscle and glands of the viscera.

Two parasympathetic plexuses of nerve cells and fibers extend continuously along and
around the length of the gastrointestinal tract from the esophagus to the anal canal.
Submucous/Meissner plexus between mucous membrane and control of the glands of the
circular muscle layer mucous membrane
Myenteric/Auerbach plexus between circular and longitudinal controls muscle and

muscle layers movements of the gut wall

CLINICALS
1. Horner’s syndrome
1. Partial ptosis – slight drooping of the eyelid –partial paralysis of levator palpebrae
2. Miosis – constriction of the pupil –due to unopposed parasympathetic innervation via CNIII
3. Anhydrosis –loss of sweating –sudomotor denervation
4. Enophthalmos – retraction of the eyeball
Due to interruption of the sympathetic nerve supply to the head and neck.
Causes
- Lesion in the brain stem or cervical part of the spinal cord- damage to the descending tracts from
hypothalamus (Reticulospinal tract)
-Lesion of the preganglionic fibre from the T1 spinal segment

Multiple sclerosis, syringomyelia, Compression from a cervical rib, Klumpke’s paralysis
-damage to the postganglionic fibres from the superior cervical ganglion
2. Argyll Robertson pupil

– Does not contract in response to the light
– Contracts in accommodation
– Because lesion of the fibres from the pretectal nucleus to the Edinger Westphal nuclei due to mostly
neurosyphilis
3. Frey’s syndrome
– Nerves will supply the sweat glands instead of the salivary tissue (sweating at the time of salivation)
– Nerves will supply the lacrimal gland instead of submandibular and sublingual (tearing with salivation)
called crocodile tears
4. Hirschsprung’s disease
– Aganglionic segment in the colon
– No peristalsis
– Proximal colon distended
5. Vagotomy
– Delayed gastric emptying
– Diarrhoea
The autonomic nervous system:

a. Supplies the glands, smooth muscles & cardiac muscle.
b. Rises from the special visceral column of the spinal cord.
c. Has peripheral ganglia near the walls of the organ it supplies.
d. Prepares the body for fight & flight.
e. Has no distribution to the lower limbs.
2. The sympathetic nervous system:

a. Has myelinated postganglionic fibers passing from the sympathetic trunk to the spinal nerves.
b. Has trunks extending from the base of the skull to the coccyx.
c. Has usually only 5 ganglia in the sympathetic trunk.
d. Fibers passing to the head & neck leave the spinal cord in the 5th-8th cervical spinal nerves.
e. Sends preganglionic fibers to the cortex of the suprarenal gland.

PERIPHERAL PARASYMPATHETIC GANGLIA
In all the following ganglia only the parasympathetic fibers are relayed.
Others (sympathetic, motor, sensory ) just pass through without relay
1. CILIARY GANGLION
 Location: - Near the apex of the orbit. Between the optic nerve & the tendon of the lateral rectus
 Topographically - related to optic nerve
 Functionally - related to oculomotor nerve
Parasym. root
Sensory root Sympathetic root
Edinger Westphal
nucleus Trigeminal nerve Sup. cervical
ganglion
Oculomotor nerve
Ophthalmic Post ganglionic

div. fibres
Inferior division
Internal carotid plexus

Nasociliary nerve
( Ophthalmic Artery)
Nerve to Inf.
Oblique
Ciliary
Ganglion
Short ciliary
nerves
Dilator pupillae&
Sphincter blood vessels
pupillae & eyeball (vasomotor)
Ciliaris

2. OTIC GANGLION
∗ Topographically related to mandibular nerve * only ganglia with four roots

∗ Functional component of glossopharyngeal nerve
∗Location:-Infratemporal fossa, just below the foramen ovale, medial to the mandibular nerve, lateral to
the Tensor veli palatini.
Parasympathetic root
Inferior Salivatory
nucleus
Sensory root & Motor root Sympathetic root

Glossopharyngeal
nerve Trigeminal nerve Superior cervical ganglion
Tympanic Branch Trigeminal Postganglionic fibres

ganglion
Tympanic plexus
Mandibular nerve External carotid plexus (middle meningeal artery)
Lesser petrosal
nerve
Auriculotemporal
nerve Nerve to Medial
Pterygoid
(Middle Cranial
cavity) Tensor veli
palatini &
Tensor tympani
Auriculotemporal
Parotid gland

3. PTERYGOPALATINE GANGLION
● Largest peripheral parasympathetic ganglia
● Topographically related to maxillary nerve
● Functional component of Facial nerve (Greater petrosal nerve)
● Location :- Pterygopalatine fossa,
Just below the maxillary nerve,
In front of pterygoid canal,
Lateral to the sphenopalatine foramen.
Lacrimatory nucleus Parasympathetic root
Nervus Intermedius
Maxillary nerve Nasal branches
{ Medial posterior superior
Facial nerve nasal nerves ( largest one
Sensory roots called nasopalatine nerve ) and
Lateral posterior superior
nasal nerves }
Geniculate ganglion
Greater petrosal nerve PTERYGOPALATINE

GANGLION Orbital branches
Nerve of
pterygoid canal Pharyngeal branches
Deep petrosal nerve Maxillary nerve

Greater & Lesser
Zygomatic nerve palatine nerves
Internal carotid plexus
Zygomaticotemporal
Postganglionic fibres
nerve
Superior cervical
ganglion Lacrimal nerve Lacrimal gland
Sympathetic root
5
4. SUBMANDIBULAR GANGLION
● Topographically related to Lingual nerve
● Functional component of Facial nerve (Chorda tympani branch)
● Location :- Lies on the Hyoglossus muscle,
Just above the deep part of the submandibular
gland, suspended from the lingual nerve.
Parasym. root Sensory root Sublingual gland
Superior salivatory Trigeminal nerve

nucleus
Sym root
Sup. Cervical ganglion
Trigeminal ganglion
Nervus intermedius
Mandibular nerve Post ganglionic fibers
Chorda tympani
Lingual nerve External carotid plexus
(facial artery)
Lingual nerve
Submandibular gland

MCQ
The Pterygopalatine ganglion;
a) Supplies the sphincter pupillae muscle through its zygomatico temporal fibres
b) Supplies secretomotorfibres for the lacrimal gland
c) Gives passage to sympathetic fibres
d) Distributes secretomotorfibres to the glands of the nose, palate and nasopharynx
e) Receive fibres from the maxillary nerve
The submandibular ganglion
a) Distributes secretomotorfibres to the sublingual gland

b) Distributes fibres from the lesser petrosal nerve to the submandibular ganaglion
c) Gives passage to the taste fibres from the circumvallate papillae
d) Is situated medial to the hyoglossus muscle
e) Is closely related to the mandibular nerve

Hormones & Receptors
 Chemical transmitters
 Shows ductless secretion into blood/interstitial fluid
 Act on target organs distant or nearby
 Has specific receptors
 Regulate cellular activities in multiple places simultaneously
 Maintains homeostasis
Types of hormone activity

 Endocrine – Thyroid hormone, Growth hormone -> messenger secreted by a gland, transport via
blood
 Paracrine – Estrogen, Testosterone, All GIT hormones -> messenger secreted by a cell, acts on
nearby cells
 Neuroendocrine – Oxytocin, Vasopressin -> Messenger secreted by a neuron, transport via blood
 Autocrine – Interleukins, Lymphokines -> Acts on the secreting cell itself
Hormones
Polypeptide Steroid Amines-Derivatives of tyrosine
Most hormones in the body Gonadal hormones Thyroid, adrenal medullary hormones
Anterior & Posterior pituitary Adrenocortical hormones Epinephrine, NE
Hormones, Insulin, Glucagon
PTH
Synthesis
RER Golgi Packed to from cholesterol Derivatives of tyrosine
vesicles Exocytosis By SER
Storage
As prohormone in the Are not stored Thyroid-Bound to thyroglobulin in
secretory granules follicles
Catecholamine-in the secretory
granules
Secretion
Exocytosis diffuse through the Thyroid- first pinocytosis then
(Ca2+/cAMP dependent) membrane diffuse through membrane
Catecholamine-Exocytosis
Transport
Dissolved in plasma Bound to plasma protein Thyroid - Bound to plasma
(Biologically active) (Biologically inactive, TBG (biologically inactive)
Only free form is active) Catecholamine - Dissolved in
plasma (Biologically active)
Receptors & Activation Systems
Ion-channel
linked
G-protein
Cell membrane receptors
linked
Enzyme
Receptors linked
Within
cytoplasm
Intracellular receptors
Within
nucleus
Ion-Channel Linked Receptors
Messenger binds to receptor
Conformational change in receptor
Ion channel opens (Na+)
Influx of ions
G Protein Linked Receptors

Hormone binds to the extracellular domain of the
receptor
Conformational change in the receptor
G protein coupled to intracellular domain becomes

active
GDP exchange for GTP
α subunit dissociates
Alters the activity of ion channels / intracellular enzymes
Change the physiological activity of the cell

1.Leptin binds
to EC part of
3. receptor
Enzyme Linked Receptors
Phosphorylation
(Eg: - Leptin receptor)
of STAT
Receptor exists as a homodimer

2.
Phosphorylation
Leptin binds to the extracellular domain of the receptor & activates JAK2
Causes phosphorylation and activation of intracellular JAK2
Causes phosphorylation of STAT proteins

4. Activates
target gene.
STAT activates the transcription of target genes and protein synthesis
JAK2 phosphorylation also activates several other enzyme systems leading to more rapid effects of leptin
Most hormones belongs to HPT pathway act this way.

Intracellular Receptors – Activates or inhibits transcription of specific genes and transcription of
mRNA
Second Messenger Systems
1. Adenylyl Cyclase – cAMP Second Messenger System
Hormone receptor activation
G protein coupling to Adenylyl Cyclase DAG – Diacylglycerol
Stimulation of adenylyl cyclase IP3 – Inositol Triphosphate

Conversion of ATP to cAMP PIP2 – Phosphatidyl Inositol
Biphosphate
Activation of cAMP dependent protein kinase
Phosphorylation of specific proteins in the cell
Bio-chemical reactions leading to cell’s response to hormones
2. Cell Membrane Phospholipid Second Messenger System
Hormone receptor activation
Activated G protein activates Phospholipase C
Phospholipase C stimulation conversion of PIP2 into DAG and IP3
Response of the cell via DAG and IP3

3. Calcium Associated Calmodulin Second Messenger System
Hormone binds with the receptor
Intracellular Ca2+ concentration increases
Ca2+ binds with calmodulin
Ca2+-Calmodulin complex activates calmodulin dependent protein kinases
Cellular response
Regulation of Hormone Receptors
Receptor molecules
inactivated
Down Regulation Intracellular protein

signaling molecules
inactivated
Regulation of
Receptors
Internalization of
receptors
Up Regulation
Reduced receptor
production
Regulation of hormone activity

 By feedback control (positive & negative)
 By regulation of the receptors
 By substrate

Hormone receptor regulation
 Down regulation - when hormone level increases, number of receptors on the cell surface decreases.
Reasons
1. Receptor molecules are inactivated/destroyed
2. Intracellular protein signaling molecules are inactivated
3. Internalization of the receptors
4. Reduced production of the receptors
 Up regulation - when hormone level decreases number of active receptors increases.
Other factors that affect hormone secretion

 Higher centers of brain (e.g. – Stress hormones)
 Time of day (Cortisol)
 Sleep
 Starved or fed status (Insulin, Glucagon)
Hormones bound to plasma proteins are –

1. Not diffused easily
2. Biologically inactive
3. Don’t engage in feedback controls
4. Serve as stores
5. Slow to clear from plasma. Why??
Inactivation / Clearance
1. Metabolic destruction by the tissues
2. Binding with the tissues
3. Excretion by liver (Bile) or kidney (urine)
Metabolic clearance rate =
Rhythms of Hormone Secretion
Ultradian rhythm –
Episodic/ pulsatile secretion in repeated cycles within 24 hrs. e.g. – Growth hormone
Circadian rhythm –
Secretion following day & night cycles (responding primarily to light & darkness) e.g. – Cortisol, melatonin
Infradian rhythm –
Periods longer than 24 hr cycles. E.g. – FSH, LH, Estrogen

Measurement of Hormones
1. Radioimmunoassay (RIA)
A synthesized antigen is made radioactive, usually by iodine
A known quantity of radiolabeled antigen is added to the assay
A known quantity of antibody specific to the above antigen is added to the assay
The radiolabeled antigens bind reversibly with the antibody
The sample which should be measured is added to the assay
Antigens present in the sample is bound with the antibodies in the assay
It displaces radiolabeled antigens from the antibodies, making them 'free' antigens
The 'free' antigens are separated from the assay and measured

2. Enzyme-linked Immunosorbent Assay (ELISA)
A surface is prepared to which a known quantity of capture antibody is bound.
The antigen-containing sample is applied to the plate and captured by antibody.
The plate is washed to remove unbound antigen.
A specific antibody is added and binds to antigen.
The plate is washed to remove the unbound antibody.
A specific enzyme is added which binds to antibody.
The plate is washed to remove the ‘free’ enzymes.
A substrate is added to be converted by the enzyme into a color or fluorescent or electrochemical

signal.
The absorbance or fluorescence or electrochemical signal (e.g., current) of the plate wells is measured
to determine the presence and quantity of antigen.
Capture Antibody Enzyme Antigen
Specific Antibody

Central Nervous System
Ascending Tracts
Sensory Afferent Pathways
To sensory cortex and other cortical areas

Cranial nerves→ Ascending pathways→ Sensory cortex
Dorsal rots of spinal nerves→ Ascending tracts in spinal cord→ Thalamus→ Sensory cortex
Results in organized higher order responses/memory
Primary afferents/ first order neurons (receptor to the second order neuron)
- Sensory fibers from head area (trigeminal) join the anterolateral and lemniscal systems
in the brain stem
- Rest of the body – along spinal nerves
Secondary afferents/ second order neurons (along ascending tracts of the spinal cord t o
Tertiary afferents/ third order neurons (thalamus to sensory cortex)
Physiological classification of nerve fibers that transmit different types of sensation
Number Origin Fiber Type

Ia Muscle spindle, Annulo-spiral ending, Mechanical Aα
Ib Golgi tendon organ, Muscle spindle, Flower-spray Aα
II ending, Mechanical Aβ
III Pain and cold receptors, some touch receptors Aδ
IV Pain, Temperature and other receptors Dorsal root C
Carry information to the central integrating areas
Dorsal horn of spinal cord
Dorsal horn acts as a ‘gate` - Action potentials in sensory nerve fibers translated into
Action potentials in ascending tracts; passage dependent on the nature and pattern
of impulses – modified by the inputs from the descending tracts

7
Fine touch – Dorsal column/Lemniscal system
- First order neurons ascend in dorsal columns (collaterals to SG)

- Synapse with second order neurons in the medulla (gracile and cuneate nuclei)
- Cross the midline – ascend in the medial lemniscus
- Synapse in the thalamus – third order neurons to sensory cortex
- Lesions in the dorsal column won’t cause total loss of ‘touch’ – Crude touch preserved
Dorsal columns – detailed localization, spatial and temporal pattern of touch
Other forms of touch – Anterolateral system
- First order neurons synapse with second order neurons in the dorsal horn
- Second order neurons cross the midline and ascend in the ventral spinothalamic tract
Ventral spinothalamic – poorly localized gross tactile sensation
Pain and temperature – Anterolateral system
- First order neurons synapse with second order neurons in the dorsal horn
- Second order neurons cross the midline and ascend in the lateral spinothalamic tract
Lateral spinothalamic tract – Pain and temperature – discrete pathways in the tract
Proprioception/ Vibration – Dorsal Columns

- First order neurons ascend in dorsal columns
- Synapse with second order neurons in the medulla (gracile and cuneate nuclei)
- Cross the midline – ascend in the medial lemniscus
- Some fibers end in cerebellum
Dorsal Columns – Joint position sense/ Vibration/ stereognosis
What happen when the dorsal columns are destroyed??

1
Descending Tracts
Motor Unit
− Functional unit of motor control system which is responsible in carrying

out a movement
− Components - each single motor neuron and all the muscle fibers innervated by it
− The number of muscle fibers in a motor unit varies (muscles concerned with
fine movements - lesser number of fibers for each motor neuron and vice
versa
− Each motor neuron innervates only one kind of muscle
Voluntary motor activity
Idea and complex plan (memory, emotions, motivation etc…. Areas - supplementary
and association cortex……)
Transfer of the complex plan to programs (sensorimotor cortex, basal ganglia,

lateral cerebellum)
Brain stem thalamus
Spinal cord spinal cord
Actions (skeletal muscles) receptors
Descending motor pathways
Pyramidal tracts

Pyramidal tracts
 All pyramidal fibers converge from the surface of the brain like a fan - corona radiata
 These come down and join together to form the internal capsule at the level
of the thalamus
 Some fibers are densely packed in the internal capsule, lesions in this region
produce dense weakness (paresis) of the contralateral side
 Pyramidal tracts start crossing to the opposite side at the level of medulla
 80% cross to the opposite side - lateral corticospinal tracts

 20% remain uncrossed - anterior corticospinal
 Distal muscles are supplied by lateral corticospinal tract and responsible
for fine, skilled movements
 Axial muscles supplied by anterior corticospinal tract – Gross,
posture maintaining movements
Extra pyramidal system

• Descending motor pathways other than the corticospinal tracts
• Components - red nucleus, substantia nigra, reticular formation,

vestibular nuclei (outputs from basal ganglia and cerebellum)
• Extra pyramidal projections to lower motor neurons
Rubrospinal tract – lateral Excites the flexors and inhibit the extensors
Reticulospinal tract
Tectospinal tract medial
Vestibulospinal tract Excites proximal limb extensors/ anti-gravity muscles
Involved in - autonomic motor movements (facial expressions)
- control of proximal muscles (so gross rather than fine movements)

- control of posture

SENSORY DIVISION OF THE NERVOUS SYSTEM.
Conscious - external
Unconscious – internal
Sensory modality / Stimulus

 Changes in the external and internal environment.
Sensory Receptor
 Specialized dendritic endings of afferent nerve fibers which convert various forms of energy into
action potentials in sensory neurons.
Sensory Organ
 Sensory receptors and associated non-neural cells that surround them
Adequate stimulus
 The particular form of energy to which a receptor is most sensitive
 Almost not sensitive to the normal intensities of other forms of energy.
Different types of sensations

Sensory Modality Receptors Afferents
(modality)
Touch – Pressure Meissner’s corpuscles (Texture and Aα
 Thermal slow vibration)
Aβ
Mechanical Merkel cells (sustained pressure and touch)
 Chemical Ruffini endings (motion)
 electromagnetic Pacinian corpuscles (deep pressure
and fast vibration)
Different types of receptors according Warmth Free nerve endings C

to their function Cold Free nerve endings Aδ, C
Pain or nociception Free nerve endings Aδ, C
• Teleceptors :- for vision, smell (stimulus- at a distance)
• Exteroceptors (Cutaneous) :- free nerve endings are more in dermis than epidermis, Pacinian
corpuscles are more in superficial fascia (stimulus- in the external environment
near at hand)
• Interoceptors:- visceral (stimulus- in the internal environment)
• Proprioceptors:-muscle tendon, inner ear (monitor body position)
Different types of receptors according to the sensory modality
• Touch and pressure :-

Fast adapting Meisner’s Texture and slow vibration
(Phasic) Pacinian corpuscle Deep pressure and fast vibration
Cutaneous Slow adapting Ruffini’s Sustained pressure

(Tonic) Merkel cells Sustained pressure and touch
Hair end organ Motion
• Pain and temperature:- free nerve endings
• Hearing and acceleration :- hair cells

Receptors according to the stimulus
 Electromagnetic receptors  Thermoreceptors

 Chemoreceptors  Nociceptors
 Mechanoreceptors
Chemo R
Nociceptors
Thermal R
(Pain-Temp)
Mechano R
Polymodal R
Generation of an Action potential in a sensory receptor
• Stimulus acts on the unmyelinated nerve end / Pacinian corpuscle

• Changes in the receptor membrane occur (eg: mechanical-deformation; Thermal-temperature; EM-
EM energy; chemical-chemical composition)
• Receptors transduce various types of energies into action potentials.
• Opening of Na+/ Ca2+ channels or,
• Inhibition of K+ channels or,
• Inhibition of Na+/K+ ATPase pump, may lead to produce non propagated receptor potential
• Magnitude of the receptor potential α log [intensity of the stimulus ]
• Receptor potentials are graded potentials
• Receptor potential reaches the threshold (about 10 mV)
• Propagating action potentials are produced in the first node of Ranvier
• Action potentials are produced as long as the receptor potential is above threshold
• Frequency of the propagating AP α magnitude of the receptor potential α Intensity of
stimulus
 Intensity of the stimulus α generator

potential amplitude
 Intensity of the stimulus α Action potential

frequency
 But at very high magnitudes of stimulus

strength, the increase of amplitude is less
than expected according to the graph

Sensory coding
Sensory unit: - single sensory axon with
 Converting a receptor stimulus to a recognizable
all its peripheral branches which is
sensation
sensitive to one type of sensation
 Brain identifies four aspects of the stimulus
(modality)
 Type of stimulus (modality)
Receptive field:-the area of the sensory unit
 Intensity of stimulus
that produces a response
 Location of stimulus
 Duration of stimulus
 Cortical plasticity and Adaptation of sensory receptors affect these
Functions of sensory coding
1. Identifying the type of a stimulus
a) Doctrine/law of specific nerve energies
• says that, Specific receptors for one type of sensory modality
• Their associated fibers carry the nerve impulse to the spinal cord
• The impulse is transmitted to a specific sensory pathway
• Ends in a specific area of the brain
• Type of the stimulus is identified
• Stimulation of this pathway anywhere from the receptor to the area of the brain makes
the person to feel the particular type of sensation that it normally transmits.
b) Adequate stimulus
 Is the type of energy that a receptor is most sensitive?
 Receptors has a very high threshold for other modalities while lowest threshold is
for the adequate stimulus
2. Identifying the location of a stimulus

o Law of projection
o Lateral inhibition
o Sensory unit & receptive field
a) Law of projection
• The sensory pathway extends from the receptor to the cortex
• If we stimulate anywhere along this pathway
• The conscious sensation produced is always referred to the location of the receptor
Phantom limb phenomenon

• Amputation of a limb/part of a limb
• neuromas are formed on the cut end of nerve fibers
• They spontaneously discharge or discharge when pressure is applied
• Earlier these fibers transmitted impulses coming from the amputated limb
• Pain and proprioception sensations felt
• As if coming from the absent limb
• Cortical plasticity is also involved here. How??

b) Lateral inhibition
• Information from sensory neurons whose receptors are at the peripheral

edge of the stimulus is inhibited compared to information from the
sensory neurons at the center of the stimulus.
• Improves discrimination and sharpens the edges of a stimulus
• Collateral nerves at different levels inhibit adjacent neurons
• Can occur at any level from the receptor to the cortex
3. Identifying the intensity of a stimulus

• Number of activated receptors/sensory units.
• Variations in the frequency of action potentials.
a) Number of activated receptors
• Receptors for one modality can have very high threshold for another modality
• Weak stimulus activates low threshold receptors
• Moderate stimulus activates low and high threshold receptors of same modality
• Strong stimulus activates receptors of same and different sensory modalities
• When the number of activated receptors increases, more afferent pathways are activated
• Spatial summation can occur
• Sensory units of same as well adjacent overlapping receptive fields get stimulated.
• This is known as recruitment of sensory units
• Due to these reasons, intensity of the sensation felt increases
b) Variation in the frequency of Action Potential
• Increase in the frequency of the AP - brain interprets as increase in intensity [Law of Weber-
Fechner]
• When magnitude of the stimulus raises rate of discharge by same pathway increases.
• Temporal summation can occur
• Log [intensity of stimulus] α magnitude of receptor potential

(Above threshold level) α frequency of AP
4. Identifying Duration
 As long as the AP come to the brain
 Adaptation represses AP & decreases duration
Cortical plasticity
• Neurons in the cortex have high degree of convergence and divergence

• Which can become strong with use and weak with disuse
E.g.:-
1. Increased afferent information in a sensory pathway - expansion of the cortical area receiving
that input
2. Amputation of a limb-Cortical area receiving inputs from that limb becomes silent, adjacent
cortical areas spread into it, makes use of that area
• Stroke
Damaged area spreads into adjacent cortical areas. Loss of function is partially regained

Adaptation (Desensitization)
• When a stimulus of constant strength is applied to a receptor, the frequency of action potential
generation decreases over time
• Receptor sensitivity decreases
Degree of adaptation
Slowly adapting (tonic receptors) rapidly adapting (phasic receptors)

: - baroreceptors, proprioceptors, : - Pacinian corpuscles, olfactory receptors,
nociceptors, Meissner’s, some Taste receptor endings
mechanoreceptors (Merkel cells,
Ruffini endings)
 Adaptation occurs due to,

- Accommodation
Progressive inactivation of Na+ channels in the receptor membrane
-Change in the structure of the receptor
Stimulus intensity on the receptor reduces with this morphological change (e.g. - Pacinian
corpuscles)
PAIN PERCEPTION AND MODULATION
Pain: Unpleasant
Emotional
Withdrawal
Treatable
Pain Afferents:
 Aδ & C
 Lateral spinothalamic tract S1
S11
Cingulated gyrus, Cerebellum, Insular cortex, Amygdala, PAG,
Reticular formation
Pain types
Fast pain Slow pain

Sharp, pricking pain Aching, burning pain
Well localized Diffuse
Aδ fibers C fibers
Glutamate at dorsal horn Substance P at dorsal horn
Site of pain Cause of pain
Somatic pain Ischemic pain
Deep pain inflammatory pain Bad Pain (Chronic)
Muscle pain Neuropathic pain
visceral pain Psychogenic pain
Physiological pain – Good pain (acute)
Ischemic pain/muscle pain

• Decreased blood supply results muscle ischemia
• Causes accumulation of P factor (K+?) → RMP more posi ve → Excitability ↑
• Stimulates pain fibers
• No pain when the blood supply is restored.
Ex: Angina pectoris,
intermittent claudication
Inflammatory pain
• Due to tissue damage
• Chemical mediators like bradykinin, cytokines, and prostaglandins are released
• They act on pain receptors and dorsal horn, producing
Hyperalgesia – Exaggerated response to minor painful stimuli due to chemical mediators

like bradykinin, cytokines, prostaglandins, substance P, CGRP
Allodynia – Pain to innocuous stimuli (touch)

Due to sprouting and formation of new synapses by touch fibers (Aα and Aβ)
and autonomic fibers onto pain conducting fibers.
Neuropathic pain (Resistant Pain)

• Due to damage or inflammation of nerves (Toxins, diabetes, DDHF, CGRP, Glutamate, Sub P)
• Hyperalgesia and allodynia - abnormal connections by sprouting Aα and Aβ in dorsal horn
• Occurs in various forms
 Hard to treat
E.g.:
• Pain in the phantom limb
• Causalgia – burning pain long after a trivial injury
• Reflex Sympathetic Dystrophy – after damage to a peripheral nerve trunk, noradrenergic
sympathetic fiber may over grow to the dorsal root ganglia. Sympathetic discharge gives
pain.
Deep somatic pain

• Pain from injured bones, tendons, joints, and periosteum
• Poorly localized & slow pain (lack of Aδ)
• Accompanied by autonomic symptoms: - sweating, nausea, vomiting, pallor, and change in BP
• Pain from deep structures results in painful skeletal muscle spasms (setting up a vicious cycle)

Visceral pain
• Due to distension, spasms, ischemia, inflammation in visceral organs
• Relative deficiency of Aδ nerve fibers in deep structures
• Afferents come via sympathetic and parasympathetic fibers
• Pain is poorly localized (carried out by C fibers)
• Associate with autonomic symptoms
• Causes reflex spasms in nearby skeletal muscles - guarding
• Radiates or referred to other area
• Radiation of pain – pain felt in the viscus spreads to another somatic area
• No proprioceptors in viscera, Temperature and touch receptors are less in number
REFERRED PAIN
• Irritation of a viscus or a deep somatic structure produces pain perception in another distant
somatic area
E.g.: -
O Myocardial pain is referred to the arm and neck (T1-T4)
O Pain in the knee joint is referred to the hip joint
O Subdiaphragmatic → p of shoulder (C3-C5)
O Ureter → tes s
O Appendix/ SI → Paraumbilical (T10)
1. Dermatomal Rule of referred pain

The structure where the pain originates and the dermatomal segment where the pain is
referred have the same embryonic origin
2. Convergence of peripheral and visceral pain fibers on the same second order neuron. (In the
dorsal horn)
• Somatic pain is more common than visceral pain
• Brain has learnt that impulses coming in this pathway as produced by the somatic structure
• When the visceral pain fibers discharge, the brain cannot differentiate
• And identifies as coming from the somatic structure
• And also, pain can be referred to scars in that dermatome
(sites where there was previous pain)

• This is due to plasticity of the brain
3. Also, visceral pain may facilitate the firing of the somatic nerve ending
which in turn stimulate the 2nd order neurons.
Thus, brain identifies it as coming from the somatic fibers .

Pain modulation
• Physical (Dorsal horn gate) 2. Release of opioids 3. Psychological methods 4.other
Gate control theory of pain
• Rubbing the site of pain temporally relieves the pain.

• Small diameter pain fibers (Aδ and C) transmit impulses to the second order neuron at the
dorsal horn
• This transmission can be inhibited by the activity of large diameter sensory fibers (Aα and Aβ
Carrying touch, pressure)
• These fibers conduct impulses faster than Aδ fibers.
• When Aα and Aβ are stimulated they inhibit pain transmission presynaptically and postsynaptically via an
inhibitory interneuron.

• Activity of the descending serotonergic pathways may also be involved in this (Descending analgesic system)
 Stimulation of periaqueductal grey matter (PAG) (by higher centers and by pain conducting C fibers via
Hypothalamus) in mid brain activates Enkephalin releasing neurons that project to,
Nucleus of raphe Magnus & Rostral ventro medial medulla (RVMM)
Serotonin Catecholaminergic/noradrenergic
Inhibitory inter neurons that release

endogenous opioids, enkephalin or dynorphin.
E.g.:-
O Rubbing on the site of pain
O Acupuncture
O Psychological factors
Release of opioids
• Opioids are peptides
• Endogenous opioids are
enkephalin and endorphin
• Exogenous opioids are morphine,
pethidine… etc.
• They bind to opioid receptors
• Opioid receptors are produced in
dorsal root ganglia cells
• And transported centrally and
peripherally along their nerve
fibers
 Morphine→ Descending tr.→ IN
→ Opioids

Mainly are 3 sites where opioids act,
• At the site of injury,
• Inflammation causes production of opioid peptides by immune cells
• They act on the opioid receptors in the afferent nerve fiber
• Open K+ channels/ Close Ca2+ channels
• Decreases the transmission of impulses in that nerve
• At the dorsal horn
• Act presynaptically. close Ca2+ channels
• Reduce release of substance P & glutamate
• Act postsynaptically. open K+ channels
• Thereby reduce the transmission of pain impulse
Placebos and acupuncture results in release of endogenous opioids
Psychological methods
• Distraction
• Stress analgesia
Other
• Aspirin (NSAIDs) and paracetamol
• Cannabinoids
• NMDA antagonists
• TRPV1 receptor antagonists
• TENS
SPECIAL SENSATIONS
Itch (Pruritus)
• Due to repeated local mechanical stimulation
• Chemicals involved are kinins, histamines (antihistamines reduce pruritus)
• Specific receptors are present
• Pathway – spinothalamic tract, thalamus and cortex
• has an emotional component
• Itching ↑ - CKD, Atopic dermis HIV, Hepatic diseases.
Tickle
• Due to repeated light touch
Synthetic Sensations
Vibration
• Stimuli – A pattern of rhythmic pressure stimuli
• Pacinian corpuscles – fast vibration Meissner’s corpuscles – slow vibration
• Pathway – dorsal column, thalamus, cortex
• Tested by using 128 Hz tuning fork to the skin of fingertip, tip of toe or a bony prominence
• Loss of vibration (associated with proprioception) is an early sign of degeneration of dorsal
columns. (Buzzing sensation)
• Ability to feel vibration; Pallesthesia
• E.g.:- DM, Pernicious anemia (vit B12)

Two-point discrimination
• Ability to distinguish simultaneous two touch stimuli as coming from two different areas
• Has both cortical and receptor component
• Depend on the size of the receptive fields of sensory units & receptor density
• 2-point threshold – minimum distance by which 2 touch stimuli must be separated, to be
perceived as separate
Stereognosis
• Ability to identify objects by handling without looking at them
• Touch, pressure and large cortical component
• Affected when dorsal column or parietal cortex is damaged
Sensory cortex
Primary sensory Cortex (SI) – Post central gyrus
Secondary sensory cortex (SII) – Walls of sylvian
fissure SI projects to SII
Sensory homunculus
 Thalamic projections are arranged representing body parts
 Legs on the top and head at the foot of the gyrus
 Size of the cortical area proportional to the number of receptors in the part (large area for
hand)
 Face bilaterally represented
 Cells are arranged in vertical columns responding to specific sensory modality from a
particular region
 Information mainly from opposite side of the body
Projections of sensory cortex

• To association areas - meaningful identification
• motor areas - control motor function
• feedback to thalamus
Lesions in the sensory cortex

Sl: - deficits in proprioception, stereognosis, fine touch
Pain and temperature, crude touch slightly affected
Affects Sll functions
Sll: - deficits in learning based tactile discrimination
No effects on Sl
Association area: - deficits in spatial orientation of the other side

ORGANIZATION OF MOTOR CORTEX
Supplementary motor area

- Involved in planning learned sequences of movements
- Projects to motor cortex
- Somatotopically organized
- Both sides of body are represented
- Reciprocal connections with basal ganglia
Premotor cortex
- Sets posture at the start of a movement (mainly proximal muscles)
- Organized somatotopically
- Projects into brain stem, motor cortex, descending motor pathways
Primary motor cortex

- Located in precentral gyrus
- Somatotopically organized
- Representation is contralateral & inverted. Face bilateral representation
Anterior edge -axial & proximal limb muscles Nice to know

Posterior edge -distal limb muscles
- Both muscles & movements are represented – size & skill

- Cortical area representing the body part is proportionate in size to the skills done by that part
- Cells arranged in columns

Plasticity
Ability of an area of motor cortex to expand as a skill is learnt & mastered. (detectable at 1 week
maximal at 4 weeks)
Damage to small area of the motor cortex results in taking over the function of that area by the
adjacent undamaged cortex with return of function
Posterior parietal cortex

 Aids in executing learned sequences of movements (Like eating with knife & fork)
 Somatic sensory area
 Project to pre-motor cortex
Reflex motor activity
Reflex: an automatic response to a stimulus occurring by a relatively simple neuronal network. (Reflex arc)
Stimulus Receptor Afferent pathway Integrating station
Effect Effector Efferent pathway
Reflexes
A) Monosynaptic reflexes B) Polysynaptic reflexes
Stretch reflex Withdrawal reflex
 Reaction time – time between the application of the stimulus and response. (20-24ms)
 Central delay – Time taken for the reflex activity to transverse the spinal cord. (0.6-0.9ms)
Ways of contracting a muscle

1. Alpha stimulation
2. Stretching a muscle
3. Gamma loop
1. Stretch Reflex – Maintain the muscle length

a. Stimulus – Stretch
b. Sensor – Muscle spindle
c. Afferents – Ia, II
d. Neurotransmitter – Glutamate
e. Efferents – γ motor
f. Response – muscle contraction

Muscles have 2 types of fibers.
1. Extrafusal fibers 2.Intrafusal fibers
 Major component of contraction  Functions in muscle spindle
 Supplied by α and β (efferents).  Ends are contractile
 Center is non-contractile
 Supplied by Ia, II (afferents)
γ (efferent)
β (efferent
Muscle Spindle
 Pure sensory organ
 3 components
o Intrafusal fibers
o Afferents (large diameter, myelinated)
o Efferents (small diameter, myelinated)
Intrafusal
fibers
nuclear chain
Nuclear bag
(static)
Dynamic Static
Afferents Efferents (γ)

(Central)
(peripheral)
II (many)
Ia (single)
Static
Dynamic Static
Dynamic Static
 Dynamic response: very sensitive for velocity, speed information, quick connective movements.
 Static response: steady, state length information.

Stretch of tendon (up to a limit)
Stretching of extrafusal fibers
Stretch of muscle spindle
Distortion of sensory endings

Reciprocal innervation
Action potentials in sensory fibers (Ia)
collateral
Synaptic transmission(glutamate) Inhibitory interneuron

(glycine)
Stimulation of α efferents to protagonist
Inhibition of α efferents to
Protagonist contracts antagonist
Antagonist relaxes
When cut- hypotonia
Contraction of contractile ends
Increase in sensitivity of
Collaterals of α-γ linkage
muscle spindle
Spontaneous γ discharge
discharge keeps
the muscle tone
2. Inverse stretch reflex

 Not monosynaptic
 Sensory organ
o Golgi tendon organ
o In series with extrafusal fibers
 Maintain muscle tension.
 Supplied by Ib afferent fibers.

Stretch of tendon (up to a limit) Passive stretch
Cleft-Knife effect
(lengthening effect)
Tension increased up to a certain level Active stretch
 Initially resistant to flex
(antagonist stretch reflex)
Golgi tendon organ is stretched  Then flex easily (inverse
stretch reflex of
Ib fibers Interneuron α motor neurons antagonists)
e to antagonists
Inhibitory inter neuron
Inhibits alpha motor neuron

Antagonist contracts
Muscle relaxes
 Low threshold but compensated by muscle fibers.
Control of γ motor neuron discharge
 Increased by
o Anxiety
o Stimulation of skin by noxious agents
o Jendrassik’s maneuver
o Descending fibers from
 Reticular facilitatory area (Pons)
 Vestibular nuclei
 Decreased by
o Descending fibers from
 Motor cortex
 Basal ganglia
 Cerebellum
 Reticular inhibitory area (medulla)
- co-activation
Descending tracts from higher centers will stimulate both α and ϒ motor neurons
simultaneously.
 To keep the muscle spindle sensitive throughout the contraction. (to transmit
sensory information)
α-γ linkage/servo-assisstance
Stimulated alpha fibers send colaterals to gamma fibres and activate them to maintain the
sensitivity of the muscle spindle.

Stimulation of γ efferents
Shortening of contractile ends of intrafusal fibers
Stretching nuclear bag portion of the spindle
Distortion of nerve endings
Afferent impulses via Ia fibers
Contraction of extrafusal fibers
Net effects
1. contraction of muscle (Poor)

2. Increase sensitivity of the muscle spindle to stretch
Muscle tone
Resistance of a muscle to stretch is referred as its tone.
Due to spontaneous discharge of the γ efferents.
Hypotonia Normal tone Hypertonia
 Flaccid  Spastic
 Occurs when the motor nerve to muscle is cut  Occurs when the γ efferent
discharge is high
Polysynaptic reflexes
- Withdrawal reflex
- Shorter pathways initiate the reflex.
Longer pathways maintain the reflex.
Can be inhibited by brain
 Stimulus - noxious (painful)
higher centers.
 Receptors - nociceptors (free nerve endings)
 Afferents - A, C fibers
 Effect - flexor contracts
Extensor relaxes
Cortical pathway for awareness, memory.

a) If the stimulus is not very strong
 Local sign
o Ability to confine withdrawal (flexion) to portion of the body affected →
Protection
o
b) If stimulus is strong,
 Moderately high stimulus → crossed extensor response → support to body
 Very high stimulus → can involve all 4 extremities →Escaping
 This happens due to irradiation.

Irradiation is the spread of excitatory impulses up and down the spinal cord to
recruit more neurons (recruitment of motor units)
A pre-potent reflex
Ant other reflex activity taking place at that spinal level at that moment is suppressed.
After discharge
Continuation of reflex withdrawal even after cessation of sensory receptor firing.
This is due to
1. Presence of short and long pathways
2. Presence of reverberating pathways
 Many Pathways → Prolonged response
Posture
 Way of stand/walk/sit
 Postural reflexes; produced, maintained, restored by a series of coordinated reflexes.
 Cortex, brain stem, basal ganglia, cerebellum
 Stimulus → gravity, visual, stretch, pressure on the body
 Sense organs → muscle spindle, proprioceptors, eyes, ears
Stance reflex
Postural reflexes Static
(Spinal cord Righting reflex
Brain stem)
Stretch Other
(Most important postural reflex) Placing reaction
Phasic
(cortex)
Hopping reaction

Basal Ganglia
Basal ganglia consist of
1.Caudate nucleus
2.Putamen
3.Globus pallidus - Internal and external segments
4.Subthalamic nucleus
5.Substantia nigra – Pars compacta  Dopamine
Pars reticulata  GABA
Lenticular nucleus = Globus pallidus + putamen

Striatum = Caudate nucleus +putamen
Corpus striatum = Caudate nucleus + Lentiform nucleus
 Parts of the thalamus are intimately related to the basal ganglia
Basal ganglia Connections

 These nuclei have complex interconnections
 No direct connection with the spinal cord
Afferents
1. Corticostriate projections - from cortex
2. Thalamostriate projecti0ns – from intralaminar nucleus of thalamus
Both end in striatum and are excitatory
Interconnections between basal ganglia

1. Nigrostriatal dopaminergic system - from substantia nigra to striatum
2. GABA-ergic system
3. Intrastriatal cholinergic system
2 Main circuits
1. Putamen circuit – executing patterns of motor activity
2. The caudate circuit – Cognitive control of sequences of motor patterns

Neural connections between different parts of basal ganglia

Basal ganglia connections with brain stem nuclei
1. Reticular Formation
2. Red Nucleus
3. Vestibular Nucleus
4. Inferior Olive Nucleus
Efferents
 Thalamus receives inhibitory impulses from Globus pallidus and substantia nigra, which
in turn project to the cerebral cortex completing the feedback loop.
 Excitatory projection to the prefrontal & premotor cortex.
Functions of basal ganglia

1. Planning and programming of the movements
2. Postural adjustments
3. Monitoring the progress of a movement
4. Involved in cognition (Caudate nucleus)
Movements influenced by the basal ganglia

a. Postural Movements
b. Automatic movements (swinging arms
while walking)
c. Skilled, volitional movements of
trunk and limbs
d. Eye movements
Diseases of Basal Ganglia
 Produce marked and characteristic abnormalities of the motor functions

 Generally, two types of motor disorders
 Hyperkinetic
 Hypokinetic
Hyperkinetic disorders
Huntington’s chorea
There are excessive abnormal movements include
 Chorea – rapid involuntary dancing movements Sydenham chorea - Due to Rheumatic
 Athetosis – continuous, slow writhing movements fever
 Ballism – sudden, intense, violent jerky movements of the body
 Dystonia – especially axial muscles are contracted for longer periods
Hypokinetic disorders
Poverty of movement
 Akinesia - difficulty in initiating movements

 Bradykinesia - slowness of movements

Parkinson disease
 -common neurodegenerative disorder
 -Degeneration of nigrostriatal dopaminergic system TRAP
1. Imbalance between excitatory discharge of cholinergic T- Tremor at rest
interneurons & the inhibitory dopaminergic input to the R- Rigidity
striatum. A- Akinesia
2. Overall increase in inhibitory output to the thalamus & P- Postural instability
brainstem disorganizes movements.
 -Has both hypo and hyperkinetic features
 -Hyperkinetic features are
 Tremor at rest (Disappears with activity) – regular alternating contraction of
antagonist
 Muscle Rigidity (Lead pipe /cogwheel)-increased motor neuron discharge to
both extensors and flexors
 -Hypokinetic features are
 Akinesia
 bradykinesia
 -Postural instability(gait)
 -Decreased associated movements (Swinging arms during walking)
 -Lack of facial expressions and gestures
Treatment
Dopamine does not cross blood brain
barrier
Therefore, L-dopa is used as it crosses
the blood brain barrier
Huntington disease
-Autosomal dominant disorder

-Loss of intra-striatal cholinergic and GABAergic neurons.
-Releasing of inhibition
-Hyperkinetic features- chorea
Wilson disease (Hepatolenticular Disease)
 Wilson's disease is a genetic disorder in which copper builds up in the body.

 Copper accumulates in the liver tissue;
 When the amount of copper in the liver increases it causes oxidative damage
 This damage eventually leads to chronic active hepatitis
 This free copper precipitates throughout the body but particularly in the kidneys,
eyes, and basal ganglia, particularly in the putamen and globus pallidus
 This causes basal ganglia disorders.

Cerebellum
Has two lateral cerebellar hemispheres joined by a medial vermis. Anatomically divided in to
 anterior lobe
 posterior lobe
 flocculonodular lobe
Organization of the cerebellum

Cerebellum has,
-an external cortex-gray matter
-four deep cerebellar nuclei in the internal white matter
Deep cerebellar nuclei

1. Dentate
2. Globose
3. Emboliform Interpositus nucleus
4. Fastigial
Functional Divisions
Vestibulocerebellum
 Includes nodulus in vermis and flocculus in hemispheres
 Has vestibular connections
 concerned with equilibrium and eye movements
Spinocerebellum
 Formed by rest of the vermis and adjacent medial portions of the hemispheres
 Receives proprioceptive inputs from the body and copy of motor plan from
motor cortex
 Compares the plan with performance and smooths and coordinates the
movements
 Vermis is concerned with the control axial and proximal limb muscles
 Hemispheres are concerned with the control of distal limb muscles
Neocerebellum
 Formed by the rest of the lateral portions of the hemispheres
 Concern with the planning and the programming of the movements
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Afferents to the cerebellum
 from brain stem and cerebral cortex
 from Periphery-Tracts are
1. Anterior and posterior spinocerebellar tracts
2. Cuneocerebellar tract
3. Vestibulocerebellar tract
4. Pontocerebellar tract
5. Tectocerebellar tract
6. Olivocerebellar tract
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Efferents from cerebellum
 Leave from deep nuclei
 Spinocerebellum via
-fastigial
-emboliform
-globose nuclei
 Neocerebellum via
-dentate nucleus
 Vestibulocerebellum outputs directly to the brain stem
Functions of the cerebellum

 Plans and programs the movements
 Compares the intended movement with the actual movement
 By comparing plan with performance, smooths and coordinates the ongoing
movements
 Coordinates sequential motor activities
 Maintains the posture and equilibrium
 Maintains the muscle tone via stretch reflexes
 Therefore, it plays a role in maintaining the muscle tone
 Planning and execution of motor movements
 Also involved in learning motor activities
Control of tone & posture (Spinocerebellum) Control of equilibrium (Vestibulocerebellum)
Wrong posture, proprioceptive from body Change in head position / acceleration
Via Spinocerebellar Labyrinthine afferents from ear

Cuneocerebellar tracts via vestibular cerebellar tracts
Tectocerebellar
Reflex correction of muscle tone
Reflex correction of muscle tone
Via cerebro-vestibular, vestibular spinal tracts
Via fastigial vestibular, vestibulospinal tracts
fastigial reticular, reticulospinal tracts Anterior horn cell
Maintenance of body equilibrium
Anterior horn cell
Easy maintenance of new posture
Control of voluntary movements Learning new skilled voluntary movements
 Compare motor plan with  From inferior olivary nucleus

proprioceptives  Climbing fibres into cerebellum
 Error calculated  Complex spike – cause burst of spikes in
 Correct errors via output signals by purkinje cells
 Motor cortex via thalamus  Long term modification of mossy fibres
 Corticospinal tracts   Climbing fibre input with learning
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Features of cerebellar disease (occurs in same side of the body, No paralysis, No sensory loss)
1. Ataxia
Incoordination of the movements
Lateral lobe lesions produce - ataxia of the limbs
Midline lesions in vermis produce - truncal ataxia\ Not made worse by
closing the eyes
2. Disturbances of posture and gait
 head tilted to the side of the lesion; patient tends to fall to
the side of the lesion- ‘drunken gait’
3. Dysathria / scanning speech (slurred speech) - defects of skilled movements
4. Dysmetria
 inability to predict the extent of a movement
 also called past pointing
 when attempting to touch an object with the finger overshooting to
one side
5. Intention tremor
6. Rebound phenomenon
 inability to stop the movements suddenly
7. Dysdiadochokinesia
 inability to perform rapid alternating opposite movements
8. Nystagmus
 involuntary movements of the eyeballs
9. Muscle hypotonia
10. Pendular knee jerk
 loss on influence on stretch reflexes movement continuous as a series
of flexion & extension movements at the knee joint.
11. Decomposition of the movements
 inability to perform movements involving more than one joint
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Lesions in the motor system
UMN Vs LMN
FEATURE LMN UMN
Muscle Mass Decreased(due to loss of MEPPs) Less decreased
Muscle Power Decreased Decreased
Muscle Tone Decreased-flaccidity Increased(Due to increased γ
discharge)-spasticity
Tendon Reflexes Absent Exaggerated
Ankle Clonus Absent Present
Babinski sign Absent Present
Fasciculation Present Absent
Fibrillation Present Absent
Upper motor neuron lesion - A lesion above anterior horn cell

 Corona radiata - mild contralateral hemiparesis
 Internal capsule - dense contralateral hemiparesis
 Brain stem - above pyramidal decussation- contralateral hemiparesis
 Spinal cord above AHC - ipsilateral spastic hemiparesis
Clonus
Occurrence of regular, repetitive, rhythmic contractions of a muscle subjected to sudden, maintained

stretch.
 Only sustained clonus with 5 more beats is considered abnormal.
 Ankle clonus is a typical example.
It may occur due to
1. The stretch reflex and inverse stretch reflex of the same muscle (alternates).
 Initially due to stretch (along with increased γ efferent discharge), the muscle strongly
contracts.
 The ankle will plantar flex.
 But this contraction will increase the tension in the tendon of the same muscle.
 Impulses from the Golgi tendon organ will cause relaxation of the muscle.
 Since the force on the ankle is maintained, the ankle will return to its dorsiflexed state.
 This cycle repeats.
2. It can occur even without the inverse stretch reflex. (without Golgi tendon discharge)
 Stretch causes muscle contraction-plantar flexion.
 But as the muscle contracts, the spindle is unloaded and ankle is pushed back into the
dorsiflexed state.
 This cycle repeats.
3. It can also occur as a result of repetitive sequential contraction of flexors and extensors.
 Due to damage to the descending cortical tracts that activate the Renshaw cells
(which inhibits the extensor)
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Complete transection of spinal cord
02 phases
1. Spinal shock
2. Appearance of the signs of an UMN lesion
Spinal shock
 Paralysis of skeletal/ smooth muscles below the level of lesion
 Loss of tone in skeletal muscles
 Loss of bladder, bowel function – due to interruption of descending autonomic pathways
 Loss of sensation below the level of lesion
 Loss of tendon reflexes
Reason;
 Cessation of excitatory inputs on stretch reflex by descending pathways Duration of
spinal shock depends on the degree of encephalization of motor functions (human
normally 2 weeks)
Reasons for 2nd phase;

 Removal of inhibitory influences
Denervation hypersensitivity
Sprouting of excitatory collaterals
 Bladder, bowel function become automatic
 No return of sensory deficits
Mass reflex
 Stroking any part of the limb or perineum cause evacuation of bladder and bowel.
 Due to afferent stimuli irradiating to the autonomic centers of bladder and bowel function
 Intentional mass reflex
 Could be lethal
 Can even cause retinal detachment due to excess autonomic activation and increased pressure

Decerebrate rigidity
Separation of brainstem between the levels of superior and inferior colliculi
Inhibition of cerebral cortex/ corticospinal tract, basal ganglia, rubrospinal tract on  discharge
 motor discharge due to the hyperactivity of the medial tracts (vestibular nuclei and
reticular facilitatory area)
extensor muscle hyperactivity is exaggerated
Extension of all 4 limbs (mostly the proximal muscles)
Destruction of dorsal horns – theses hyperactivity of the extensors is gone. Also there is a direct
activation of α motor neurons independent of γ loop
Decerebrate rigidity seen in uncal herniation (uncus of the temporal lobe herniates into subtentorial
region of midbrain and compresses midbrain)
Uncal Herniation
Before;
− Decreased consciousness
− Lethargy
− Poor pupil reactivity
− Hyperactive reflex
− Bilateral Babinski
After;
− Pupil fixation
− Waxing & Waning respiration with apnoea
− Medullary function loss and breathing ceases
Decorticate rigidity
Separation of brainstem above the level of midbrain, removal of cerebral cortex.

E.g. – At the internal capsule cause hemi decorticate rigidity
- Flexion of the upper extremities, extensor hyperactivity of the lower extremities
Flexion of the upper extremities – Facilitation of flexors in upper limb by rubrospinal pathway Extension
of the lower limb – Facilitation of extensors in lower limb by reticulospinal and vestibulospinal pathway
Reticulospinal facilitatory and inhibitory tracts are intact ascending sensory fibers activate the
reticulospinal facilitatory tract.
Autonomic Dysreflexia
Sensory input carried Massive sympathetic

to Spinal cord via surge from
Bladder/bowel intact Peripheral Thoracolumbar
nerves outflow
Widespread vasoconstriction
Relayed via IX & X to Detected by baroreceptors (mostly in Splanchnic
brain vasculature)
damage at the T6 level prevent inhibitory signals

from reaching the Greater Splanchnic Nerve (T5 - T9)
Bradycardia via which carries sympathetic innervation to constrict
Vagus (insufficient) the vascular bed
Taste and Smell
Smell
- Receptor – Receptor cells in olfactory mucosa
- No relay in thalamus
- Centre – Olfactory cortex
Taste Adaptation to the taste occurs very rapidly
-Receptor – taste bud
Supertasters – Particular to bitter taste
- Relay in thalamus
- Centre – Post central gyrus
Smell & Taste both show early adaptation. Threshold increases with age.
Taste Bud
 Sense organ for taste.
 Adults - 3000-10,000 taste buds (child >>elderly)
Tongue – vallate, circumvallate and fungiform papilla
Pharynx, Palate, epiglottis, proximal esophagus
 Von Ebner’s glands secrete saliva into the cleft around papillae
 Composed of gustatory receptors and sustentacular cells.
Mechanism of taste perception
Gustatory Receptor
Binding of the taste

chemical
Receptor potential
initiated
Post-Receptor
actions
Stimulation of taste afferent

fibres
Taste chemicalgrdually washed away from the taste

villus by saliva (stimulus removed)
VIIth Cranial Taste Pathway

nerve - Ant 2/3
tongue Posteriomedial
IXth- Post 1/3 NTS ventral nucleus of Postcentral gyrus
tongue thalamus
Xth - larynx,
Pharunx

Basic taste modalities
 Sweet – sugar, Alcohol, glycols etc. – Act via G protein gustducin
 Sour – acids (H+)
 Bitter – quinine, caffeine, nicotine – some act via G protein gustducin
 Salt – NaCl (Na+)
 Umami – Monosodium glutamate
 All modalities sensed from all parts of the tongue.
 Afferent nerves contain fibers from all types of taste buds – No clear localization.
Taste threshold
 Different substances have different thresholds.
 Crude intensity discrimination – needs 30% change
Flavor - Mainly synthesized from basic 5 tastes, Smell, Pain, Consistency, Temperature

Smell
 Humans recognize > 10,000 odors. (High discrimination of type. But poor intensity
discrimination)
 Strong odor – more lipid/ water soluble.
 Odorant Binding Protein
o Dissolving odorant (by removing hydrophobic parts )
o Concentrate
o Transfer to receptor
o Control toxic odorants
Olfactory mucous membrane

 Contains olfactory receptor cell, Supportive cells & Progenitor cells.
 Olfactory receptor cells – Bipolar neurons
 Small in humans – Micro-osmic
 Pseudostratified columnar epithelium
 Covered by mucus produced by bowmen’s gland
 Poorly ventilated
Olfactory pathway
Olfactory receptor cells Mitral & tufted cells
Olfactory Cortex
(Bipolar cells) (Olfactory bulb)
Inhibition
Periglomerular cells
& Granular cells

Olfactory cortex
 Piriform cortex – Primary olfactory cortex
 Lateral & anterior orbitofrontal gyri – Olfactory discrimination
 Amygdala – emotional responses to smell
 Entorhinal cortex – olfactory memories
Olfactory thresholds
 Increase with age.
 Methyl mercaptan can be smelled when concentration reaches 1/25 trillion gram per ml.
All odorant receptors

coupled to G proteins
cAMP
Phospholipase C
Smell also has a products of phosphatidyl inositol hydrolysis
rapid adaptation
Most open cation channels
Depolarization of membrane
Generates action potential in olfactory

neuron

Vomeronasal organ –
Signal transduction
Perception of odors that act as
Complex odor discrimination pheromones.
 About 10-20 million odorant receptors
 One type of olfactory receptors project into one Closely related with sexual
olfactory glomerulus function
 Each olfactory neuron carries only one odor.
 Lateral inhibition by periglomerular & granule cells. Poorly developed in human
Smell more in women

Abnormalities
Taste
 Ageusia – absence of taste sensation
 Hypogeusia – diminished taste sensation
 Dysgeusia – unpleasant perception of taste
Smell
 Anosmia – inability to smell
 Hyposmia / Hyper-osmia –diminished / enhanced olfactory
sensation
 Dysosmia –distorted sensation of smell
T/F
a) Monosodium glutamate is used as an artificial sweetener
b) Receptors for bitter taste are localized to the posterior aspect of the tongue
c) Taste fibers relay in the nucleus of tractus solitarius
d) Taste perception has a high intensity of discrimination
e) Vagus carries afferent from taste receptors

Vision
From outer to inner,
 Sclera- anteriorly replaced by cornea

 Choroid- anteriorly forms ciliary body
 Retina- posterior 2/3 containing
photo receptors
3 chambers
– Anterior
– Posterior
– Vitreous
 Separated by 2 groups
– Iris
– Zonule and lens
Functional anatomy
2 types of fluids
 Aqueous humour
 Vitreous humour
Aqueous humour
 Produced by ciliary body

continuously
 Flows through pupil from
posterior to anterior
chamber
 Reabsorbed through
network of trabeculae to
canal of Schlemm
 Supply nutrition for lens &
cornea
 Intraocular pressure – 10-
20mmHg

Treated with-
 Carbonic anhydrase inhibitors - reduce rate of aqueous production and improves
glaucoma.
 β adrenergic blockers
 Cholinergic against, prostaglandin, corticosteroids
Retina
• Extends anteriorly almost to the ciliary
body
• Organized in layers with different types
of cells
• Contain photoreceptors (rods and
cones)
• Has retinal blood vessels and optic
nerve fibers.
Nourishments-
Bipolar & ganglion cells –retinal vessels
Receptors -capillary plexus of choroid.
(This is why retinal detachment is cause so
much damage to the receptors)
• Blind spot/optic disc:
o Site where optic nerve leaves the eye
o No photoreceptors, do not response to
light
• Macula:
Yellowish pigmented spot near the posterior
pole of eye
• Fovea:
o Centre of macula
o No rods, cones only (tightly packed)
o Has the highest visual acuity
o No blood vessels overlying receptors
• Extrafoveal portion of retina: Mostly rods
*Ganglion cells are the only output of retina, and their axons form the optic
nerve

In the fovea each cone synapses on a single bipolar cell,
which in turn synapses on a single ganglion cell, providing
direct pathway to the brain.
This arrangement increases visual acuity of cones but
decreases its sensitivity.
Macular sparing in lesions of visual cortex

Macular sparing is the loss of peripheral vision with intact
macular vision.
Is common with occipital lesions, because
 the macular representation is separate from that of
the peripheral fields and
 Very large relative to that of the peripheral vision.
 Visual cortex had dual blood supply from MCA and
PCA. Therefore, occlusion of one artery might result in macular sparing, if another
artery still provides blood supply to the macular region.
Photoreceptors: Contains photosensitive pigments (conjugated proteins)
1. Rods
2. Cones
11- cis retinal in rhodopsin
All trans retinal • Na+ channels of outer segment open at dark.

• So,light
When a current flow
falls on thefrom
outerinner to outer
segment segment
of photo &
receptor
to synaptic terminal.
Conformational Changes in opsin
• Release of synaptic transmitter (glutamate) is
constant in the dark.
Activation of transducin
o Dark current.
Bind GTP to the G protein (transducin) Retinal separates from opsin (bleaching)
Activate phosphodiesterase
Cyclic GMP regeneration
Decreased intracellular cGMP
Light reduces concentration of
Na+ and Ca2+ in photo receptors
cGMP dependent Na+ channel of outer segment blocked
Activates guanylyl cyclase
Hyperpolarization Inhibits phosphodiesterase
Generates cGMP
Decreased release of glutamate
Neural response
Photo pigment
Rods & Cones Opsin is a G protein coupled receptor. The
Rhodopsin G protein is called Transducin
Opsin Retinal
Protein aldehyde of vit A Red goggles – Allow cones to work

Dark adaptation well but don’t stimulate rods
significantly
Moving from brightly lit area to a dimly lit area
Thus, time for dark adaptation is
 Retina slowly becomes more sensitive to light. reduced.
 This decline in visual threshold is called Dark Night blindness
adaptation.
 Max 20 min  Decreased vit. A level
 Inadequate reforming of
Light adaptation rhodopsin from retinal
 Difficult to see at night
 Due to disappearance of dark adaptation.
 Visual threshold rises. Occurs over 5 mins.
RODS CONES
Extremely sensitive to light (detect a single Higher threshold for stimulation (up to 100-
photon of light) fold less sensitive than rods)
Scotopic vision Photopic vision
vision in dark bright light
Can’t determine Can
Details
Boundaries
Colours (black & white vision)
Less visual acuity Greater visual acuity
Saturate in even moderately bright light and Remain photosensitive even in the
remain nonfunctional most of the day extremely bright light.
Image formation
R C
Photoreceptors and horizontal
cells-
H
 Hyperpolarising
Bipolar cells
B B  Hyperpolarising or
Depolarising
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Amacrine cells and ganglion cells
G
G  Depolarising
1st image Light on photoreceptors
Horizontal cells –lateral inhibition &
enhance visual contrast
2nd image Bipolar cells
Amacrine cells - produce spikes, act as

generator potential for bipolar cells
3rd image Ganglion cells
Axons from ganglion cells form the optic nerve

(only ganglion cells produce action potentials)
Optic chiasma
Optic tract
Lateral geniculate body
Optic radiation
Visual cortex

Refraction in the eyes
 Allow focusing of image on retina

 Occur at two structures
o Cornea (3/4 of the refraction)
o Lens (1/4 of the refraction)
Refractive power measured in diopters – Increases when the curvature increases
Refractive power in diopters α 1/Principal focal length
 When the ciliary muscles contract near objects focus on the retina, distant objects focus in
front of the retina.
 When the ciliary muscles relax distant objects focus on the retina, near objects focus behind
the retina.
However, human can see the both objects due to the accommodation.
Accommodation
Process by which the curvature of the lens is increased (up to 12 in youth)
Done by the ciliary muscles.
• When the ciliary muscles contract lens relaxes and curvature increased.
• When the ciliary muscles relax lens tenses and curvature decreased.
Near point of vision
• is the nearest point to the eye at which an object can be brought in to clear focus by
accommodation
• Reduces throughout the life – Cause presbyopia
• Headache occurs with aging

• Astigmatism – Curvature of the lens is not uniform Hyperopia/ Far Myopia/
• Amblyopia – Refractive error in one eye sightedness Near
• Strabismus (Squint) – Misalignment of eye sightedness
Short eyeball Long eyeball
Partially corrected Associated
by sustained with sleeping
accommodation in lighted
May lead to rooms <2
strabismus years
Too much
studying in
childhood
Strabismus (squint)
Visual images do not fall on corresponding retinal points. (Misalignment of eyes)
Chronic – one visual image permanent loss of vision in one

If not corrected before age 6
eye is suppressed (In children)
(Cortical effect)
Amblyopia
Refractive error in image is blurred Decreased vision in affected eye
one eye & distorted (permanent)
Binocular vision
Defect cause diplopia
Direct and consensual light reflex

Mapping the visual field
Peripheral - perimeter, this process is called perimetry
Nasal fields
Temporal fields
Central - tangent screen
Lesions in the optic signaling pathway
B
A
 A-Total blindness of right eye – damage to right optic nerve

 B-Bitemporal hemianopia – damage to optic chiasma
 C-Left Homonymous hemianopia – damage to right optic tract
8  D- Left upper quadrant hemianopia © 2017 A/L Repeat Campaign
 E- Left homonymous hemianopia with macular sparing
Damage to Result
Left optic nerve total blindness of left eye
Optic chiasma Bitemporal heteronymous hemianopia
Left optic tract right homonymous hemianopia
Left geniculo-calcarine tract right homonymous hemianopia
Left Visual cortex right homonymous hemianopia with macular
sparing
Near response
3-part response occurring when an individual looks at a near object
 Accommodation
 Convergence of axes
 Pupillary constriction

Colour vision
Colours have 3 attributes
- Hue
- Intensity
- Saturation
* Complimentary colour when properly mixed with the counterpart, forms white
Red
Primary colours Green
Blue
Young-Helmholtz theory
 3 kinds of cones
 Each have a different photo pigment maximally sensitive to one of the primary colours.
 Colour perception determined by relative frequency of impulses from different cones.
 colour vision depend on colour of other objects in visual field
Colour blindness
• Red-Green colour blindness shows X linked recessive transmission

• 8% of males
• 0.4% females
• Colour weakness - anomaly
• Colour blindness - anopia
• Trichromats - has all 3 cone systems.

o May have an anomaly
Protanomaly ,deuteranomaly ,tritanomaly
• Dichromats - only 2 cone systems.

o Can match their colour spectrum by mixing only2 primary colour systems.
o Can have protanopia -red
Deuteranopia -green
tritanopia – blue(rare)
• Monochromats - only 1 cone system.

o Match their colour spectrum by varying intensity of only 1.
• Ishihara chart is used to test for colour blindness
Blind site –residual response to visual stimuli after bilateral destruction of occipital cotex

Visual acuity
1. Visual acuity – Snellen chart
Shortest distance by which two lines can be separate & still be perceived as two lines.
distance at which the subject reads the chart

𝑉𝑖𝑠𝑢𝑎𝑙 𝑎𝑐𝑢𝑖𝑡𝑦 = greatest distance from the chart at which a normal person can read the smallest line
Normal visual acuity = 6/6 m 20/20 ft

Subnormal = 6/9 or 6/60
Better than normal = 6/5
Tested by using Snellen letter charts
Factors affecting visual acuity

1) Optical factors - State of image forming mechanism
2) Retinal factors – State of cones
3) Stimulus factors – illumination
- Brightness of the stimulus
- Contrast between the stimulus & the background
- Length of time the subject is exposed to the stimulus
If the patient can’t recognize any of the letters, numbers or shapes at 6m, 3m, 1m distances due
to poor vision,
1. Finger counting
2. Perception of light sources
3. Detecting hand movements
are done

HYPOTHALAMUS
 Part of the limbic system.
 Neural pathways are mostly unmyelinated.
 Hypothalamus connects with –ant. pituitary via portal vascular connections
-post. pituitary via neural connection
Functions of Hypothalamus
1) Controls ant. pituitary secretions
 CRH, TRH, GHRH, GnRH, GHIH-somatostatin, PIH-dopamine
2) Controls post. pituitary secretions.
 Vasopressin (ADH)
 Oxytocin
*synthesized in supraoptic (ADH) & paraventricular nuclei (Oxytocin)
3) Control of autonomic nervous system
 Post. & lateral nuclei during stress conditions
Produces sympathetic discharge
 Adrenal medullary catecholamine secretion.
 Ant. Group of nuclei (supra optic & paraventricular nuclei)
Produce parasympathetic discharge
4) Cardiovascular regulation
 Post. & lateral nuclei- HR & BP
 Pre-optic area- HR & BP
5) Regulation of body temp
 Heat activates- ant. Hypothalamus heat loss
 Cold activates- post. Hypothalamusheat gain
6) Regulation of sleep & wakefulness
 Sleep ant. Hypothalamus
 Wakefulness mamillary body
7) Regulation of sexual behavior
 Ant. Ventral hypothalamus
 Piriform cortex- in male
8) Role of defensive reactions
 Two centers (diffuse in the limbic system & hypothalamus)
 Reward center- satisfaction / punishment center- displeasure
9) Role of circadian rhythm / rhythmic fluctuations
 Occurs in response to light dark cycle in the environment
 Circadian rhythm is synchronized by the pair of Suprachiasmatic nuclei (SCN) in
hypothalamus
 It receives afferent info. from retina via retino-hypothalamic fibers
 Efferents from SCN Neural and hormonal signals Synchronize many
circadian rhythms
 Rhythms-
1. Secretion of ACTH & other pituitary hormones
2. Sleep- wake cycle
3. Secretion of pineal hormones- melatonin (nocturnal peaks)
4. Activity patterns
Cyclical phenomenon
 Circadian rhythm – 24 hour length cycles

– Entrained by SCN (suprachiasmatic nucleus)

Secretion of ACTH and other pituitary hormones
+
Photosensitive Sleep-wake cycle
retinal Afferents SCN
Activity patterns
ganglion cells Retino-hypothalamic
-
fibers Secretion of ‘Melatonin’ from pineal gland
10) Regulation of water balance

 In lateral superior hypothalamus
 2 mechanisms - thirst mechanism, ADH mechanism
Thirst mechanism
 Center- anterolateral areas of hypothalamus
 Stimuli
a) Plasma osmolality (Hypertonicity)- via osmo-receptors in ant.
hypothalamus
b) ECF volume(hypovolemia)- via baroreceptors in heart & blood vessels
-via angiotensin II (acting on subfornical organ & OVLT)
c) Dryness of pharyngeal mucosa/ mouth
d) Psychological factors
e) Social factors
f) Prandial drinking-intake of water is increased during eating
This increases due to
 Learned or habit response
 plasma osmolality when food is absorbed. When protein
uptake, products of protein metabolism causes an osmotic
dieresis. So, the amount of water needed is large.
 Due to action of one or more GIT hormones on the hypothalamus
Summary
Osmolality, hyper tonicity ex: -vomiting hypovolemia ex: -blood loss

High pressure
Osmo-receptors baro-receptors, angiotensin II
ADH hypothalamus Low pressure
Thirst
11) Regulation of food intake – to maintain the body weight in a given set point
 Orexigenic stimuli stimulate food intake, circulating levels during fasting
 NPY- neuropeptide Y
 MCH- melanin concentrating hormone
 AGRP
 Orexin A & B
 Ghrelin (release from stomach when it is empty)
 Anorexigenic stimuli inhibit food intake
 α- MSH- melanin stimulating hormone
 CART- cocaine & amphetamine regulating transcript
 CRH- corticotrophin releasing hormone
 PYY- peptide YY
 CCK
 GLP-Glucagon like peptide
 Leptin
 Insulin

Inputs to regulate food intake
Neural signals
-GIT (via vagus) regarding stomach filling
-cerebral cortex (smell, sight, taste)
Chemical signals Thermal signals

-nutrients in blood HYPOTHALAMUS
-exposure to heat or cold
Hormonal signals
GIT – CCK, PYY, Insulin
Adipose tissue - Leptin
 Regulation is mainly by 2 centers & facilitated by others

1) Feeding center
- Always active, temporally inhibited by satiety center after food intake.
- In lateral nuclei
- Stimuli- desire to eat
- Destruction- anorexia
2) Satiety center
- Ventromedial nuclei
- Stimuli sense of satisfaction
- Destruction- Hyperphagia - hypothalamic obesity
Afferent mechanisms which regulate food intake- 4 hypothesis
2) Lipostatic hypothesis
1) Glucostatic hypothesis Hypothalamus

Food intake
Food intake (-)
Blood glucose levels
Fat deposition
Stimulate glucostats in satiety
center Leptin synthesis
Inhibiting feeding center

Activation of hypothalamic Leptin receptors
Stop food intake
3) Gut peptide hypothesis
Food in gut
4) Thermostatic hypothesis
↑Secretion of polypeptides
↓Body tempstimulate appetite
Inhibit feeding center
↑Body tempinhibit appetite
Inhibit food intake

Hormones of hypothalamus
1. TRH – Stimulates TSH release from anterior pituitary.

2. GnRH – Secretion starts at onset of puberty.
Primary effect is on FSH, LH.
Secondary effects on oestrogen, progesterone in females and testosterone in males.
3. GHRH – GH stimulation by anterior pituitary.
4. CRH – ACTH stimulation by anterior pituitary.
5. Somatostatin(GHIH) – Inhibits release of GH & TSH
6. Dopamine – Derivative of Tyrosine.
Inhibits PRL release from anterior pituitary.
7. Oxytocin – Ejection of milk (secretion is NOT stimulated).
Contraction of myometrium of uterus.
8. Vasopressin – Peripheral vasoconstriction.
Stimulates water re-absorption in the kidney.
 Both Oxytocin and Vasopressin are secreted from the posterior pituitary (neurohypophysis).

Hearing and Equilibrium
Receptors of the ear: The Hair Cell
Structure of Hair Cells
 Hair cells are mechanoreceptors

 There are 6 patches of hair cells in the inner ear: Organ of Corti (1),
Utricle (1), Saccule (1), and Semicircular canals (3)
 Base lies in perilymph whereas apex lies in endolymph.
 In hair cells, there is a single kinocilium which is stationary.
 In cochlear however Kinocilium is ABSENT
 There are several rows of Stereocilia, which are movable.
 Stereocilia are arranged in increasing order of their heights, along
an axis towards the kinocilium.
 Small processes called Tip Links connect tip of shorter stereocilia
with the sides of taller ones
 The taller stereocilia have mechanically sensitive cation channels
that are activated by tension in the tip links
Adaptation and Repolarization

Mechanism of Depolarization
 Myosin motor protein moves the ion channel
Shorter stereocilia are pushed towards taller stereocilia towards the base of taller cell.
 Tension in the tip links released.
Tension of the Tip Links rises  Cation influx reduces.
 Hair cells get repolarized.
 K+ is recycled back into endolymph
Ion channels mechanically opened
K+ and Ca2+ enters cells via these channels Mechanism of Hyperpolarization

 Stereocilia are pushed in the opposite
Cells get depolarized direction
 Tension of tip links reduce
 Cation influx reduces
Depolarizes afferent neurons  Cells get hyperpolarized
(Glutamate maybe the neurotransmitter released by hair
 Glutamate discharge is reduced
cells)

Hearing
Humans are sensitive to sounds waves of 20Hz – 20 000 Hz.
Highest sensitivity is in the range of 1000 to 4000 Hz
Sound conduction
1. Ossicular conduction – transmission of sound via tympanic membrane, ossicles to cochlea via oval
window (most efficient)
2. Bone conduction – transmission of sound via bone to inner ear
3. Air conduction – by vibrating secondary tympanic membrane of round window
Middle ear
● Pressure of Sound is multiplied by 22 times.
1. Lever action of ossicles (by 1.3 times)
2. Surface area difference of tympanic membrane and oval window (by 17 times)
● Middle ear muscles
1. Tensor tympani – Attached to handle of malleus
Pulls malleus medially
2. Stapedius – Attached to stapes
Pulls stapes laterally out of oval window
 Both are skeletal muscles
Tympanic reflex
Contraction of the tensor tympani

Very loud sounds and stapedius causes ossicular
rigidity.
Reflex contraction of both
This reduces the transmission of low
tensor tympani and stapedius
frequency sounds (i.e. Background
noise)
Makes ossicles relatively rigid
Decrease sensitivity to person’s own
Protects from excessive stimulation voice.
by very loud sounds Lesions to the Vth and VIIth cranial
nerve will cause paralysis of the
above muscles and cause
The Reaction time of this reflex is long. hyperacusis.
(40 – 160 ms). So this reflex does not
protect the ear from abrupt loud noises.
(Eg. Gunshots)

Inner ear
Bony labyrinth Perilymph
Membranous labyrinth Endolymph
Cochlea
Perilymph Endolymph
↑[Na+] ↓[K+] ↓[Na+] ↑[K+]
Composition similar Composition similar
to CSF, serum & ECF to ICF
(maintained by Stria
Vascularis)
Within scala Within membranous
vestibule and scala labyrinth
tympani
 Basilar membrane has a Tonotopic arrangement

Organ of Corti
Inner hair cells –
● Primary receptor cells
● Majority of afferents of the VIIIth Nerve
● Tips are not embedded in the
tectorial membrane.
Outer hair cells –

● Majority of efferents from the VIIIth Cranial Nerve
(From Olivocochlear bundle)
● Efferent impulses modulate sensitivity of the hair cells.
● Help in increasing amplitude
● Increases clarity of sound
● Tips are embedded in the Tectorial membrane
Auditory cortex of Temporal lobe

● Hearing- B41 (localization and sensitivity of sound)
● Discrimination of sound- area 41,42,22, planum temporale
● Complex sounds/languages - Iry(B41,42) and IIry(B22) auditory cortices
● Bilaterally represented
● Tonotopic organization (similar to the basilar membrane)

Detection of qualities of sound
1. Frequency
● Point of maximum vibration of the
basilar membrane varies with the
frequency
Cochlear base: high frequencies
Cochlear apex: low frequencies
● Loudness also influences perception of frequency.
o When <500Hz – When loudness is increased the pitch of sound seems to decrease than
actual value.
o When >4500Hz – When loudness is increased the pitch of sound seems to increase than
actual value.
2. Loudness
● As sounds become louder amplitude of vibration of basilar membrane and hair cells increases.
● More hair cells are stimulated. Causes spatial summation
● Outer hair cells are also stimulated. Increases clarity of sound
Sound Localization
1. Lower frequencies: Time difference between two ears

2. Higher frequencies: Loudness difference between two ears
3. Sounds from front and behind: Change in sound quality due to shape of pinna
4. Movement of sound in the vertical plane: Reflection from pinnal surface
● Auditory cortex is needed for localization of sounds.
● Markedly disrupted by lesions in auditory cortex.
Pitch Discrimination
● Average person distinguishes about 2000 pitches
● Trained musicians can distinguish even more.
● Pitch discrimination most sensitive in 1000Hz – 3000Hz range.
● Planum Temporale is the cortical area responsible for pitch discrimination.
Masking
● Presence of one sound decreases the ability to hear other sounds.
● Due to the relative or absolute refractoriness of previously stimulated receptors and nerve fibers to
the new stimuli.
● The degree to given tone masks others are related to its pitch.

Hearing deficits
Hearing deficits
Conductive deafness Sensorineural deafness

● Impaired conduction of sound 1. Damage to sensory components of ear or neural
from exterior to cochlea pathway
● All frequencies are affected. ● Higher frequencies more affected.
● Eg: wax in ear, otitis externa, ● Eg: Tumors of VIII nerve or cerebellopontine
otitis media angle
o Presbycusis: A progressive sensorineural type hearing loss associated with aging

o Noise induced hearing loss: Hearing loss upon exposure to sounds of loudness ≥ 85dB. Hair cells
are damaged
o Tinnitus: Ringing sound in the ears. Major cause is NIHL.
Hearing tests
TEST Weber Rinne

Tuning fork on mastoid then in air
Method Tuning fork on vertex
near the ear
Vibration in air heard after bone
If normal Both ears heard normally
conduction is over
Vibration of air not heard after bone
Conduction deafness Louder in that side
conduction is over
Sensorineural deafness Louder in contralateral side Not heard anything
Partial sensorineural Vibration in air heard after bone
Louder in contralateral side
deafness conduction is over
Pure tone audiometry

● To detect a hearing loss
● Sound proof room
● Pure tones tested
● Measures Auditory Acuity

Equilibrium
Inputs from,
1. Vestibular system
2. Proprioception
3. Vision
4. Cutaneous exteroceptors
5. Cerebellum
Vestibular system
● Maintains position of head in static and dynamic states.
● 5 groups of hair cells,
1. Utricle
Maculae (hair cells & otolithic membrane)
2. Saccule
3. 3 semicircular canals – Crista ampullaris
● Utricle – Macula lies horizontally

Helps detect - Orientation when upright
and horizontal acceleration.
● Saccule – Macula lies vertically

Helps detect - Orientation when supine
and vertical acceleration.
● Semicircular canals –
Lie in 3 perpendicular planes
Detect rotational acceleration
Cannot sense the effect of gravity
Static Equilibrium Mechanism of action

Sensed by Utricle and Saccule  Macula contains hair cells and Otoliths (CaCO3 crystals)
 The specific gravity of Otoliths are 2-3 times higher than
the surrounding fluid, so the otoliths slightly bend the
stereocilia of hair cells.
 So even when head is upright there is a tonic firing rate.
 When the head is tilted, weight of the otoliths pulls the
processes of the hair cells towards the direction of
gravity.
 The hair cell processes are oriented to different
directions. (With Kinocilia and Stereocilia in different
positions in each cells)
 For each head position, a specific pattern of hair cells
stimulation occurs. The brain recognizes this pattern and
determines the position of head.

Dynamic Equilibrium Vertical Saccule
Linear
Horizontal Utricle
Dynamic Equilibrium
Rotational Semicircular canals
Linear Acceleration
 Otoliths are denser than endolymph

 When linear acceleration occurs in one
direction, the otolith displaces to the
opposite direction of acceleration due to
greater inertia.
 This bends the processes of the hair cells
and generates action potentials.
 These are recognized by brain.
Rotational Acceleration
 Detected by semicircular canals.

 The 3 semicircular canals lie in three plains perpendicular to each other, so they can detect rotatory
movements in any direction.
 The sensory organ in the Crista Ampullaris is the Cupula.
 Cupula lies in endolymph and has the same density of endolymph.
 The processes of hair cells extend into the gelatinous matter of cupula, so when the cupula moves
the processes of hair cells are pulled.
Mechanism of Action
When rotation commences in one direction
Inertia of endolymph resists movement
Relative movement of endolymph in opposite direction
Pushes Cupula to opposite direction of rotation
Hair cells depolarize
When rotation stops the endolymph continues to move due to inertia.
Cupula pushed towards the opposite direction than what it used to before.
Hair cells hyperpolarize.

 When head rotates, semicircular canals of
both ears are stimulated,
 One side is depolarized (nerve excited) and
the other side is Hyperpolarized (nerve
inhibited).
 The brain recognizes the plane from
excitation-inhibition pattern of vestibular
nerves, and recognizes the direction of
rotational acceleration.
Central connections
● Vestibulocerebellar –Balance
● Vestibulospinal – Send impulses to motor neurons & facilitates tone of extensors
● Vestibulothalamocortical –Conscious awareness of position & movement of head
● Vestibulo-ocular pathway – medial longitudinal fasciculus
Vestibulo-ocular reflex
● Stimulation of vestibular receptors evokes eye

movements of equal magnitude in the direction opposite
to movement of head to maintain the visual field.
● Mediated by the coordination of VIIIth , VIth and IIIrd

Cranial nerves through the medial longitudinal fasciculus

Nystagmus
● Repetitive jerky movements of the eye (horizontal/ vertical/ rotatory)

● fast and slow components
Physiological Nystagmus
Nystagmus is a reflex that maintains visual fixation on a stationary point

It can be divided into a slow and fast component
SLOW COMPONENT
When head rotation starts the eyes move together slowly in a direction opposite to that of head rotation maintaining
a visual fixation. (Vestibulo-Ocular reflex)
FAST COMPONENT
When the limit of this movement is reached, the eyes quickly snap back to a new fixation point and the repeats the
slow component.
By convention, the direction of Nystagmus is considered to be the direction of the fast component.
Pathological Nystagmus
Pathological nystagmus is when nystagmus occurs when the head is not rotating.
Occurs due to abnormalities in the vestibular system.
Caloric Test
A test used to assess the function and integrity of Vestibular system.

Cold or Warm water is instilled into ear.
The temperature difference induces convention current in endolymph and stimulates
the semicircular canals, causing nystagmus.
“COWS”
C O – Cold water induces nystagmus to the opposite direction than the ear to
which water was instilled.
W S - Warm water induces nystagmus to the same direction
Vertigo
● Sensation of rotation in the absence of rotation due excessive stimulation of the vestibular system.
Motion sickness
● Due to prolonged and excessive stimulation of the system

TEMPERATURE REGULATION
Poikilothermic (cold blooded) – mechanism rudimentary
Vertebrates – can adjust their
Body temperature Homeothermic (warm blooded) – mechanism well developed
Invertebrates – cannot adjust their body temperature
 Core temperature (36.3 – 37.1 0c) is closely represented by rectal temperature – varies least with
environmental changes
Oral temperature (36.3 – 37.1 Axillary

Temperature
Surface (skin)
Temperature
(29.5 – 33.9
Rectal temperature
°C)
Scrotal Temperature
32 °C
Core Temperature (36.3 -37.1°C)
Factor Temperature change

variation in body /core physiological Age ↑
temperature
Gender Males > females
Exercise ↑
Emotional excitement ↑
Diurnal Variation 6PM-highest
6AM-lowest
Sleep ↓ (lowest)
After Meals ↑
Female after ovulation ↑
Pathological Hyperthyroidism ↑
Lesion to brain (Ant ↑
Hypothalamus)
Infection ↑
Hypothyroidism ↓
Lesion to hypothalamus ↓
(Post)

Core temperature > rectal temperature > oral temperature > surface temperature
 The normal human core temperature undergoes a regular circadian fluctuation of 0.5 – 0.7 0C
Balance between heat production and heat loss determines Body temperature
Heat production (gain)

 muscular activity (mainly) 
 basic metabolic process Brown adipose tissue is important in
 food intake /assimilation
generation of heat in new born infants
 hormones
 radiation from environment
Heat loss
 Loss of heat by evaporation of sweat can be controlled 𝐸𝑣𝑎𝑝𝑜𝑟𝑎𝑡𝑖𝑜𝑛

∝ 𝐸𝑛𝑣 𝑇𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒
 Insensible water loss can’t be controlled 𝑅𝑎𝑑𝑖𝑎𝑡𝑖𝑜𝑛
Regulation of body temperature
Thermo regulatory Responses

 Autonomic eg: Shivering
 Somatic eg: stamping, dancing
 Endocrine eg:
Catecholamines – produce a rapid short-lived increase in heat
TSH – produce a slowly developing prolonged increase in heat
 Behavioral eg: Wearing suitable clothes when expose to cold weather

Hypothalamic Regulation of Body Temperature
Cold Cold Cold
Hot
Hot Hot Posterior
Cold hypothalamus
hot Anterior
hot (Heat gain center) Cold
hypothalamus
(Heat loss center) Cold
Cold Cold
hot hot
 Integration is done by hypothalamus in response (reflex) to information from sensory

receptors in the skin, brain, deep tissues & etc., spinal cord, hypothalamus
 In these places there are more cold receptors than hot receptors.
 There are threshold temperatures for each of the main
temperature regulating responses and when threshold is Response set points are changed
reached, the response begins. with skin temperature
Shivering (35.5 0C)

Hunger
Increase Heat Voluntary activity ↑
Production Sympathetic activity ↑
(Secretion of catecholamine) ↑
Rate of cellular metabolism ↑
Stimulation of Heat Gain center

Exposure to “Cold”
(Posterior hypothalamus)
Cutaneous vasoconstriction – Threshold at 36.8 0C

Decrease Heat Curling up
loss Horripilation
Order of response to cold

1. Vasoconstriction – 36.8 0C
2. Non shivering thermogenesis – 36 0C (Catecholamines uncouple oxidative phosphorylation)
3. Shivering – 35.5 0C
Decrease Heat Anorexia (lack of appetite)

Production Apathy & Inertia (Lethargy)
Stimulation of Heat Loss center

Exposure to “HEAT”
(Anterior hypothalamus)
Cutaneous vasodilation37 0C
Increase Heat
Sweating 370C
loss
Increased respiration
Fever/Pyrexia
“As if thermostat is reset” - to a new point above normal body temperature
Protective response which inhibits pathogen growth and increase antibody production
Inflammation
Endotoxins from bacteria (exogenous pyrogens)
Pyrogens released from degenerative tissues
Acts on monocytes, Kupffer cells, macrophages
Cytokines (act as endogenous pyrogens) Cytokines

Act on OVLT IL-1, IL-1β, TNF-α,
IFN-γ
Activate pre-optic area of hypothalamus
Prostaglandins released and act on hypothalamus
Raise temperature set point
Heat conservation & increase in heat production
Fever

Hyperthermia
 It occurs as a response to infection

 Beneficial effects of hyperthermia;
 Rise in temperature inhibits the growth of microorganisms
 Antibody production is increased
 Slows growth of some tumors
 Temperature more than 410c is harmful – permanent brain damage

 More than 43 0C – heat stroke and death
Constitutional hyperthermia – Chronically elevated body temperature above normal range
Hypothermia
 Metabolic & physiologic processes will slow down

 Respiration and heart rate are slow
 Blood pressure is low
 Consciousness is lost
 Useful to do open heart surgeries & to perform brain operations
Hypothalamus loses its ability to regulate body temperature below 28 0C
Thermogenic function of Brown Fat / Thermogenin (UCP1)

Brown fat,
 More abundant in infants
 Located - between the scapula, at the nape of the neck & along the great vessels in the thorax &
abdomen
Brown Fat White Fat
 Fat cells contain several small droplets of fat  Fat cells contain only a single large droplet of
fat
 Fat cells as well as blood vessels have an
extensive sympathetic innervation  Principal sympathetic innervation is solely on
blood vessels
 Fat cells contain many mitochondria
 1 method of oxidation which generates ATP
 2 methods of oxidation
 Oxidative phosphorylation which generates
ATP
 Uncoupled oxidative phosphorylation
which doesn’t generate ATP, but produce
HEAT
 Heat stroke – Body temperature higher than 41.10c. Neurological dysfunction occur.
 Complete spinal cord transection at neck above sympathetic outflow impairs internal body
temperature regulation

Micturition
Is the process by which the urinary bladder empties when it becomes filled.
 Step1: progressively fill till threshold is reached.
 Step 2: Initiation of micturition reflex, conscious desire to urinate.
Micturition reflex: an autonomic spinal cord reflex, facilitated and inhibited by higher brain centers in the
cerebral cortex or brain stem.
 Self – regenerative reflex – initial contraction of bladder activates stretch receptors in the bladder and
posterior urethra which causes a further increase in reflex contraction of the bladder.
Then the reflex fatigue and regenerative reflex cycle ceases & bladder relaxes
 Cycle
1. progressive & rapid↑ of pressure
2. sustained pressure
3. return to basal tone
Urine is made in the kidneys and comes down to the bladder for storage.
Oblique passage through the bladder wall keeps the ureters closed except during peristaltic waves which bring in
urine.
 During contraction of detrusor muscle, reflux of urine from the bladder to the ureter is prevented.
Abnormally short oblique passage, valve malfunctions results in Vesicoureteral reflux (back flow of urine from
bladder to ureter)
Once micturition reflex has occurred but not emptied, nervous elements of the reflex usually remain inhibited for a
few minutes to 1 hour till the next reflex
As the bladder progressively fills, reflexes occur more frequently and powerfully
Innervations
- Pelvic nerves (S2, S3, S4) - Sensory → detect degree of stretch of bladder wall
Preganglionic parasympathetic Motor → (parasympathe c) postganglionic fibres to
detrusor muscle
- Pudendal nerve (S2, S3, S4) – skeletal motor fibers to external sphincter
- Hypogastric nerves - sympathetic innervations (No part in micturition)
Sphincters – Internal muscle bundles on either side of urethra prevent reflux of semen in to the
bladder during ejaculation (sympathetic innervations, no parasympathetic innervation)
External ring of skeletal muscles, voluntary control of micturition
Pressure of the bladder is investigated using cystometrogram.

Micturition reflex
Stimulus - stretch in the posterior urethra at the back of the bladder

Afferent - pelvic nerves (sensory – parasympathetic)
Coordinating center - sacral portion of the spinal cord
Higher center inputs - facilitatory center in the pons (PMC), posterior hypothalamus, inhibitory area in midbrain,
cortex
Efferents - pelvic nerve (motor – parasympathetic)
Effector – Detrusor
Effect – micturition
Voluntary micturition – voluntary contraction of abdominal muscles

Initiate micturition before reflex is naturally initiated
↑ Pressure in bladder → stretch receptors s mulated →Micturi on reflex excited → ext. sphincter inhibited →
voiding of urine
During micturition – Perineal muscles are relaxed

Lowering of pelvic floor
External urethral sphincter relaxed
Detrusor muscles contract
After urination - Female - urethra empties by gravity

Male- expelled by several contractions of bulbocavernosus muscle
Voiding can be initiated without straining even when the bladder is nearly empty by the effect of higher centres
Ureterorenal reflex - when a ureter becomes blocked (eg-: urethral stone)

Intense reflex contraction + pain
Causes sympathetic reflex
Constricts renal arterioles of kidney of same side - GFR
Prevents excessive flow of fluid into the pelvis of the kidney with a blocked ureter.
Cystometrogram
 By cystometry
 Plot of intravesicular pressure vs. volume

of urine in bladder as it fills.
Cystometrogram has 3 phases

Ia. Initial slight rise – Due to increase in
urine volume (till 50mL)
Ib. Long flat segment – Law of Laplace
(Till 400mL)
II. Sharp rapid rise (over 400ml)

Flat segment is a manifestation of the law of Laplace
P=2T\R
As T rises so does R
P remains constant
 When the bladder is filled, volume increases. So, the R of viscus increases. This causes a decrease in
intramural pressure (P). P is maintained by increasing muscular tension (T) of the bladder wall. So, P returns
to basal level.
Abnormalities in micturition
1. Deafferentiation
 Sacral dorsal roots are damaged or tabes dorsalis (Tabetic bladder)
 All reflex contractions of the bladder are abolished. But intrinsic myogenic contractions to stretch
can happen,
 Results in atonic neurogenic bladder– distended, thin walled and hypotonic & Overflow
incontinence (non-periodically emptying- dribbles a bit when filled to capacity)
2. Denervation
 Both afferent and efferent nerves are destroyed. By damage to cauda equina.
 Results in autonomous bladder. Bladder becomes shrunken and hypertrophic, dribbling urine
present under denervation hypersensitivity
3. Spinal cord transection
 During spinal shock, bladder is flaccid and unresponsive
 Results in overflow incontinence
After spinal shock, voiding reflex returns gradually with denervation hypersensitivity resulting in spastic
neurogenic automatic bladder. no voluntary control and no inhibition or facilitation from higher centers
 Voiding can be initiated in such patients by mild mass reflex
4. Nocturnal micturition (enuresis) – normal until 3 to 7 years

Cerebrospinal Fluid
 Fluid present around the brain and spinal cord
Formation: -
 Choroid plexus of lateral ventricles / other ventricles (60% - 70% CSF)
 Ependymal surfaces of ventricles
 Perivascular spaces
 Formed by passive filtration of plasma and

 Transfer of ions and water into the filtrate. (Mainly active)
 Rate of CSF formation is constant. It is independent of intra ventricular pressure
 CSF volume 150ml in circulation / daily production is 550ml / daily turnover 3.7 times per day
What is choroid plexus?
 Plexus of cells that produces the cerebrospinal fluid in the ventricles of the brain.
 The choroid plexus consists of modified ependymal cells.
 Ependymal tissue surrounds the capillaries of the choroid plexus separating them from the
cerebral ventricles.
 Ependymal cells filter water and other substances from capillary blood and transport them
across the ependymal layer into the brain ventricles.
 This clear fluid is the cerebrospinal fluid (CSF) that fills the cavities of the cerebral
ventricles, the central canal of the spinal cord, and the subarachnoid space of the
meninges.
Circulation: - Lateral ventricle 3rd ventricle 4th ventricle

interventricular foramen cerebral aqueduct
foramen of Magendie & Luschka
cerebral venous sinuses arachnoid villus Subarachnoid space
Composition
 CSF is almost identical with perilymph & with brain ECF
 Color of CSF – “clear”, Plasma – “yellow”
 protein in CSF [20 mg/dL] <<<< blood [ 6000 mg/dL]
 K+, Glucose in CSF < blood
 osmolality in blood = CSF
 pH CSF < blood (due to CO2 in CSF)

Composition of
Features of CSF in Meningitis

Features Normal Pyogenic Tuberculosis Viral Meningitis
Meningitis Meningitis
Colour Clear Yellow turbid Turbid + fibrin web Clear
Cells No neutrophils High (as acute) Very low Very low
Lymphocyte Less High High
<5/mm3
Glucose 66% of plasma Low (consumed by Low
glucose bacteria)
Plasma proteins 0.4g/L High High Not very high
(virus disrupts
permeability microcirculation)
Absorption: -
 Through arachnoid villi  into cerebral venous sinuses
 Smaller villi  into spinal veins
 Through the cribriform plate  into cervical lymphatics
 Rate of absorption depends on intraventricular pressure
 Absorption is unidirectional (bulk flow)
 When CSF pressure is elevated
o Possibly increased expression of aquaporin channels in choroid plexus and cerebral micro
vessels.
o More and more arachnoid villi open up
 Below 68 mmH2O absorption stops
Absorption  intra - ventricular pressure

112 mmH2O
Function of the CSF

 Protection of brain
o Cushioning effect
o Brain floats in CSF suspended by arachnoid trabeculae, blood vessels & nerve fibres
o Any movement of the brain within the cranial cavity is gently slowed
CSF pressure
 Lumbar CSF pressure 70 – 180 mmH2O (Average normal – 112 mmH2O)
 CSF pressure can go up by laughing, sneezing, coughing & straining
Head injuries
Cerebral damage results with blows to the skull
Mild/ moderate moderate/severe
CSF protects brain by cushioning effect

coup injury contrecoup injury
damage to the damage to the opposite

same side of the brain side of the brain
 CSF protects brain in mild to moderate head injuries

Raised Intracranial Pressure
Cerebral perfusion pressure = Mean arterial Pressure – Intracranial Pressure
Raised intracranial pressure leads to,
 Decreased cerebral perfusion & cerebral ischemia  shift of cerebral contents within the skull
hypoxia mid line shift
hypercarbia herniation
hypoglycemia cranial nerve palsies
cerebral vasodilation pressure on vital centers
cerebral oedema irregular HR, RR
convulsion loss of consciousness
loss of consciousness death
death
Lumbar puncture
 Safest level to enter the needle to withdraw CSF is between L3 – L4
 5 ml is maximum volume
 In increased ICP lumbar puncture should not be preformed
 Headache after lumbar puncture due to traction of vessels & nerve roots from which the brain
hangs stimulate pain fibres
 Pain relieved by sterile isotonic saline into subarachnoid space
How do you differentiate traumatic tap from sub-arachnoid hemorrhage?
 A "traumatic tap" occurs if the needle inadvertently has entered an epidural vein during
insertion.
 Xanthochromia is the yellow discoloration indicating the presence of bilirubin in the
cerebrospinal fluid.
 Xanthochromia is usually caused by red blood cell degeneration in the CSF as would be
seen in subarachnoid hemorrhage (SAH).
Traumatic Tap Subarachnoid hemorrhage

Decreasing amount of blood with each tube Blood evenly distributed throughout the
drawn collection tubes
May contain clots No clots

No Xanthochromia Xanthochromia

Clinical Relevance
Hydrocephalus - accumulation of large amount of CSF
 external hydrocephalus  internal hydrocephalus

communicating hydrocephalus non communicating hydrocephalus
re-absorptive capacity of arachnoid villi ↓ CSF can’t exit ventricular system

- Intraventricular haemorrhage blockage of the foramen Magendie & Luschka
- Meningitis Aqueduct stenosis
- Tumors
- Traumatic head injuries
- Subarachnoid haemorrhage
- Choroid plexus papilloma
 Infection/inflammation of the meninges – meningitis (eg: bacterial meningitis-turbid appearance)

 Bleeding into CSF (immediately red, later yellow)
BLOOD BRAIN BARRIER

 Cerebral capillaries do not allow certain substance to pass through them into CSF & brain ECF
 Due to presence of tight junctions between,
o Capillary endothelial cells
o Epithelial cells in the choroid plexus
 Passive diffusion is restricted, specific transport systems present
 Active transport systems
 Carrier mediated transport systems
 Uniquely limited exchange of substances into the brain is referred to as BBB
BBB is not seen in,

 Posterior pituitary & median eminence
 Area postrema Circumventricular organs
 SFO, OVLT
 Allow hormones to enter general circulation - Posterior pituitary

 Contains chemical receptors = chemoreceptor trigger zone
o Initiation of vomiting/CVS regulation – area postrema
o Water intake – SFO, OVLT
o Osmoreceptor controlling vasopressin secretion
o Circulating IL – 1 produce fever OVLT
Penetration of substances through the BBB
 Easily penetrated – water, lipid soluble free hormones, L – Dopa, 5 – hydroxytryptophan, CO2, O2,
Alcohol, Anesthetics, NH3
 Slow penetration – Urea, Dopamine, Serotonin
 Specific transport systems – Na+, K+, Cl-
 Impermeable – plasma proteins, water, non-lipid soluble large organic molecules
 Water soluble compounds do not cross BBB effectively

 Drugs that intend to act on the brain should be lipid soluble
Development of BBB
 Continuous non-fenestrated vessels

 With complete basement membrane
 Support of different cell types
Neurons
Pericytes
Astrocytes  Known as neurovascular unit
Microglia
Epithelial cell
 Development of fight junction at about 12 weeks of gestation
 Immature at birth
 CNS epithelial cells undergo transcytosis (restricts the vesicle mediated transcellular movement of
solutes)
 Transporters
o Facilitate passive penetration into the brain tissue
Eg: glucose – GLUT1
 Reverse Transporters
o Transports drugs and peptides back into the cerebral vessels
Eg: P – glycoprotein (multi drug nonspecific transporter)
Effects of inhibition of this transporter??
Functions of BBB
 Maintains homeostasis of brain ECF
 Prevent entry of toxic substances to brain
 Prevent escape of neurotransmitters
Clinical Relevance
 Immature BBB
 Neonatal jaundice – kernicterus
 Occurs due to elevation of unconjugated bilirubin
 Bilirubin conjugation is impaired due to the immaturity of the liver.
 Neonatal hyperbilirubinaemia will cause lipid soluble unconjugated bilirubin to cross the BBB
which is not matured fully.
 Deposition of bilirubin in basal ganglia causes kernicterus/bilirubin encephalopathy.
 Disruption of the BBB
 Head injuries
 Cerebral Infections
 Tumors
 Selectivity of the BBB
 Pharmacological agents – degree of penetration
o Antibiotics for cerebral infections
o Anesthetics
o L-Dopa
o CNS side effects of drugs – eg: antihistamine
o Drugs that act outside BBB

SLEEP & EEG
 Consciousness
- being awake & responding to one’s surroundings Sensory stimulation
 Coma ↓
- Complete loss of consciousness Ascending activity
↓
 Pathway activated in arousal Specific pathways
↓
Collaterals to RAS
Reticular activating system (In reticular formation)
↓
 RAS situated in midventral brainstem Intra laminar nuclei of thalamus
 Activated by nonspecific stimuli ↓
 State of thalamocortical neurons determines the sleep-awake status. Project to cortex
Hyperpolarize - sleep
Depolarize (partially) - awake
EEG / Electro encephalogram
 Electrical events of the brain are recorded as patterns by placing electrodes on pial surface of cortex.
 Measured in microvolts (Doesn't record the action potentials but summation of dendritic postsynaptic
potentials)
 Frequency increases with high degree of activity but becomes asynchronous and voltage drops
50-100 microvolts
RAS is located in the reticular

formation.
Reticular formation also contains

areas concerned with regulation
of HR, BP and RR.
δ θ α β Υ
<4 4-7 8-13 13-30 30-80
Alpha (α) Beta (β) Gamma (γ) Theta (ϑ) Delta (δ)
Awake but rest with Mentally alert Focused attention Large amplitude Large slow waves
mind wandering Marked in frontal aroused slow waves Deep sleep in adults
Eyes closed region Involved in high Early
marked in parieto- mental activity Seen in children childhood(infancy)
occipital area Seen in infants  Perception Abnormal if in adults
 Problem in awareness (raised
Gradually appears solving ICP)/Brain disease -
during adolescence  Fear & tumor, haematoma,
consciousness encephalopathy
 Block /
desynchronization -
by opening eyes.
(Replace α waves
with fast irregular
waves of low
voltage- β waves)

Flat tracing- seen during death
Waves seen in childhood (without sleeping)

 β Rhythm Waves during
 θ Rhythm Sleep – Low frequency, high amplitude
 δ Rhythm Awake – high frequency, low amplitude
factors affecting waveform
1. age
2. sleep/awake status
3. level of consciousness –
metabolic abnormalities, head
trauma, sleep onset latency
4. Epilepsy
α frequency
Low blood glucose
Low body temperature opposite
↑ PaCO2
↓cortisol
Alcohol, barbiturates and antipsychotics
- Hyperventilation brings out hidden EEG abnormalities
Arousal Sleep
 Sensory system stimulation * stimulation of sleep zones
- Up to midbrain level - slow wave sleep
 Activation of MB reticular area * pontine reticular area
 Mid-thalamic neurons are partially depolarized * Mid-thalamic neurons are hyperpolarized.
(Electrical state of the thalamo-cortical neurons influences the sleep-wake cycle)

Sleep
REM NREM
 4 stages
 Rapid eye movement (irregular muscle
1 - drowsy, α waves start to disappear, low
movements)
voltage fluctuations, theta waves, δ waves
 Occurs after 90m of onset of sleep
intermittent
 Voluntary activity of muscle Inhibited -motor 2 - light sleep, sleep spindles-sinusoidal waves
paralysis (12-14 Hz), short bursts of waves-k
 Tone of neck muscles reduced complexes
 Snoring 3 - δ waves appear, dreams, deep sleep
4 - very deep sleep δ waves prominent. No
 Tooth grinding
dreams
 Bizarre imagery, illogical thoughts, not stored in
memory  Vital signs decline (BP, HR, RR) more regular –
 Digestive system activity decreased. stage 3 & 4 has skeletal muscle activities,
 Body temperature, BMR, HR, RR, BP & irregular reflexes intact
 O2 consumption in brain  BMR, sympathetic activity
 EEG pattern is very irregular (Rapid low voltage)  increased release of GH
Sleep is not interrupted & threshold for Arousal
increased. (Paradoxical sleep)
Penile erection/nocturnal emission
 Core body temperature is low, but skin/hand Temperature high

 ADH secretion increased, urine formation decreased
Sleep cycle
 Sleep starts off with NREM
NREM REM NREM……….
- 4-6REM periods per night.
- Cycle repeated-90min intervals
- More REM & less Stage 3,4 towards morning
 % of REM ↓ with age
- Premature infants 80%
- Full term neonates 50%
- Adults 25%
- Elderly 20%
Factors influencing sleep wake cycles –
 circadian rhythm – Regulated by suprachiasmatic nucleus (SCN) of hypothalamus according to the impulses
coming from retino-hypothalamic tract.
 Neurochemical mechanisms
 Melatonin – Secretion regulated by efferents from SCN

Circadian rhythm & sleep
- Sleep become synchronized to day night light cycle.

- Rhythm operated by suprachiasmatic nuclei of hypothalamus
- SCN receive level of illumination information via retinohypothalamic fibers
Origin of REM sleep

 Pontine reticular formation
 Spike discharge in cholinergic neurons
 Noradrenergic neurons in locus ceruleus and
serotonergic neurons in mid brain raphe
become silent
 Shifting of balance of neurotransmitters
Agonist & Antagonists of sleep
PGD2 Serotonin
PGE2
Caffeine
Children need more sleep than adults

 Newborn 16-18 hrs.
 Teenagers 8-10 hrs.
 Old adults 6 hrs.
Why do we sleep??
 Poorly understood.
o Replenishment of brain glycogen stores
o Memory is consolidated
o Facilitation of learning and memory, cognition
o Maintain metabolic-caloric balance
o Immune competence
What happen after sleep deprivation??

 Degradation of cognitive and physical performance
 Decrease overall productivity and health
 Impaired judgment and irritability
 Impaired concentration
 Slowing of reaction time
Disorders of sleep
- Insomnia-insufficient or nonresponsive sleep in spite of adequate opportunities
- Narcolepsy - sudden onset of REM sleep
- Sleep walking/somnambulism - during NREM
- Sleep apnoea - Day time sleepiness due to fragmented sleep at night, caused by upper airway obstruction.
- Parasomnias- disorders associated with arousal from REM or NREM sleep – Somnambulism, Nocturnal enuresis,
Night terrors

Memory and Learning
 Procedural (skills and habits) –Once acquired become unconscious &automatic

 Priming- recognition of words, objects by prior exposure
 Associative learning –learn relationship between one stimulus & another
 Non-associative learning (habituation & sensitization)
 Explicit memory initially required for a task can become implicit when a task is
learnt.
Eg: riding a bicycle
Explicit memory & many forms of implicit memory involve,

A. Short term memory - Process in hippocampus & change the synaptic strength
(memory traces disrupted by trauma)
B. Long term memory - (memory traces resist to disruption)
 Hippocampus convert short term memory to long term memory
 Working memory-form of short-term memory. Keep information available for a very
short time while action is planned. – prefrontal cortex & connections with
hippocampus
Eg: remembering a phone number before texting

Neural basis of learning (converting short term to long term memory)
 Strengthening the existing synapses
 activation of genes
 protein synthesis
 Increase in neurotransmitters & post synaptic receptors
Short term Synaptic plasticity -

Post-tetanic potentiation- enhanced postsynaptic potential after a tetanizing train of
stimulus
Due to accumulation of Ca2+ in presynaptic neuron
Habituation- less & less postsynaptic response to a repeated stimulus

Decrease of neurotransmitter due to decrease Ca2+ by gradual inactivation of Ca2+ channels
Sensitization –opposite of habituation

Prolong occurrence of postsynaptic response for noxious stimulus
Due to discharge of serotonin
LTP (long term potentiation) –

 Persistent enhancement of the postsynaptic potential response to presynaptic
stimulation after a brief period of rapidly repeated stimulation of the presynaptic neuron.
 Some depend on NMDA receptor
 LTD (long term depression)- opposite of LTP
Decrease in synaptic strength by slower stimulation of presynaptic neuron
Memory disorders
 Amnesia (Retrograde & anterograde)
 Dementia - Alzheimer’s
- Senile dementia
Anterograde amnesia - Due to damage to the hippocampus or medial temporal lobe.

Can't covert the short term memory to long term memory.
Stored long term memory is not affected.
Retrograde amnesia - After a sudden shock, trauma to head or after being anesthetized
people forget what happened just before the incident
.
Neurogenesis occurs in brain mainly in hippocampus & olfactory bulb throughout the life.

Language and speech
1. Sensory association areas

2. Wernicke’s area-posterior end of superior temporal gyrus
Sensory area of speech -comprehension of auditory and visual information
3. Broca’s area- in frontal lobe, immediate in front of inferior end of motor cortex.
Motor area of speech -convert received information to a pattern of vocalization.
( An individual who learns a new language in adulthood has two Broca's areas
adjacent to each other. But in contrast a child who speaks two languages has only
one Broca's area)
4. Angular gyrus- visual cortex to Wernicke’s area :
process information from words and convert them into auditory form of the words
in Wernicke’s area
The Wernicke’s area and the Broca's area are connected together by arcuate fasciculus
Disorders of speech
1. Non fluent aphasia - lesion in Broca’s area: slow speech words hard to come
Limit to 2, 3 words
2. Fluent aphasia - lesion in Wernicke’s area: Speech excessive & full of

jargon
3. Anomic aphasia - lesion in angular gyrus :trouble in understanding written

languages & pictures

Cerebral dominance
 Neocortical function
 Categorical/dominant hemisphere-categorization and symbolization
(language function, mathematical problem solving)
 Representational hemisphere- spatiotemporal relations (recognizing objects,
places, faces, music etc.)
 Hemispheric specialization is related to the handedness
Cerebral dominance of Left handed people,
70% -left, 15% -right, 15% -no clear lateralization
Right handed people,
96% -left, 4% -right
Features of lesions
Categorical hemisphere Representational hemisphere
 Language disorders  Astereognosis – Inability to identify
 Fluent, non fluent and anomic aphasia objects by feeling
 Acalcuia  Agnosia - Inability to identify objects by
 difficulty in mathematics particular sensory modelity
Patients are disturbed and often depressed  Unilateral inattention and neglect
about their disability  prosopagnosia
Patient are unconcerned and euphoric about their
disability
Limbic system –cognitive & emotional functions

Includes,
1. Hippocampus -formation of memory
2. Hypothalamus -Temperature, appetite, autonomic responses ,sexual behavior
3. Amygdala -Processing emotions ( rage and fear)
4. Cingulate gyrus -Autonomic functions (regulation of HR & BP)
5. Entorhinal cortex
6. Olfactory bulb
7. VTA (ventral tegmental area)
Functions
1. Involved in emotions 2. Autonomic responses
 Cognition (higher functions) – 3. Sexual behavior
as an awareness of sensation 4. Rage and fear
and cause 5. Motivation and addiction
 Affect-the feeling itself 6. Connections-learning and memory
 Conation-the urge to take
action
 Physical changes-BP, PR,
sweating

HORMONES
 What is a hormone?
Chemical messenger produced in the body that interact with receptors of the target
tissue to cause a change in function of that tissue.
Characteristics of hormones
1. Secreted in very small amounts.
2. Transport – blood / other body fluids
3. Have a relatively long-lasting effect on distant target cells.
4. Target cells have specific receptors.
5. Regulating cell reactions by affecting gene expression.
6. Have no effects on the cells that produce them.
Endocrine system
 A system of ductless glands that secrete hormones.
Endocrine system
Purely endocrine organs Endocrine cells in other organs

Pituitary gland , Thyroid, Pineal, PT Pancreas, Thymus, Hypothalamus, Heart
 Acts along with the nervous system to coordinate body functions.
Endocrine system Nervous system

Hormones Electrical signals+chemical
Slower High-speed
Longer acting Short lasting
Via blood/other body fluids Along neurons
Hormone signaling pathways
 Types of chemical signals

1. Autocrine signals - act on the cell that synthesized them
2. Paracrine signals - acts on nearby cells
3. Neural signals - released by one neuron & acts on the adjacent neurons
(Neurotransmitters)
4. Endocrine signals - travel via blood stream
5. Neuroendocrine signals - secreted from a neuron
Travel via blood stream
6. Pheromone signals - released to the environment
Acts on another individual
 Hormones act via 3 pathways

1. Endocrine pathway – through the blood stream
2. Neuroendocrine pathway – ex: hypothalamus control over the adrenal medullae to
produce epinephrine/norepinephrine

3. Paracrine pathway – insulin secretion by beta cells affect secretion of glucagon secretion
by alpha cells
 Normally these are regulated by negative feedback mechanism.
Hypothalamus and pituitary

Hypothalamus – boss
Pituitary – manager
 Most dominant portion of the entire endocrine system.
Other endocrine organs - workers
 Hypothalamus regulates hormone secretion via
1. Endocrine pathway
2. Neuroendocrine pathway
 Hypothalamus controls hormone release of the anterior pituitary
 There are two types of hormones.
1. Releasing hormones (6)-

 TRH (Thyroid releasing hormones)
 CRH (Corticotrophin releasing hormone)
 GnRH (Gonadotrophin releasing hormone)
 PRF (Prolactin releasing factor)
 GHRH (Growth hormone releasing hormone)
 MSH-RH (Melanocyte stimulating hormone – releasing hormone)
2. Inhibiting hormones (2)-
 PIF (Prolactin Inhibiting Factor)
 GHIH (Growth hormone inhibiting hormone)
Anterior pituitary control

T3
Skin Thyroid
MSH TSH* T4
Mammary PRL Anterior pituitary ACTH* Adrenal

Gland cortex
GH FSH*/LH* corticosteroids
Bones aldosterone
Muscles cortisol
Adipose tissue Ovary Testis
Estrogen androgen
Mechanisms of hormone release
1. Hormonal - stimulation received from other hormones

2. Neural - stimulation by nerves
3. Humoral - in response to changing levels of ions or nutrients in blood
Functions of hormones
Primary sex determination is NOT
 Growth & development Promote cell division
determined by hormones.
Increase whole body mass
Limit cell division
 Energy production Catabolic

Storage
Anabolic
 Reproduction
 Environmental challenges Short term: Noradrenaline, Adrenaline
Long term: Cortisol, Aldosterone
 Homeostasis – maintaining constant internal environment
Eg: BP, HR, AB balance, Body temperature
How hormones coordinate the activities of the cells
 Hormonal effects on the body are complex.

One hormone → multiple actions
Multiple hormones → one function
 Example for a multi hormonal process – maintenance of blood glucose
Insulin Glucagon Epinephrine

Structure of hormones
Catecholamine
Tyrosine
Derivatives Thyroid
hormones
Amino acid
Derivatives
Tryptophan Melatonin
Derivatives
Short polypeptides
Peptide Small proteins TSH

Hormones Hormones FSH
LH
Glycoproteins EPO
Inhibin
PG
Prostacyclin
Eicosanoids TH
LT
Lipid
Derivatives Steroid Cortisol
hormones Aldosterone
Estrogen
Progesterone
Androgen
Calcitriol
Synthesis of amine hormones

Tyrosine
(Rate limiting step)
Tyrosine hydroxylase*
DOPA - Dihydroxyphenylalanine
DOPA
Dopamine feedback inhibition
Noradrenaline Catecolamines
Adrenaline

a) Catecholamines in the adrenal medulla
 Dopamine is a very important neurotransmitter in the brain.
 It controls release of other hormones.
 But Dopamine cannot cross the Blood/Brain Barrier.
 So the brain has to make its own catecholamine.
Parkinson’s disease (local deficiency of dopamine synthesis)

 Due to lack of tyrosine hydroxylase
 Treatment – DOPA (readily cross the BBB)
b) Biosynthesis of thyroid hormones

 Two types – T3 & T4
 Precursor (of both T3 and T4) – thyroglobulin
 Thyroglobulin has tyrosine residues
 Thyroglobulin is a glycosylated protein
Step 1: - Oxidation of iodine in plasma

Peroxidase
2I- + H2O2 I2
Step 2: - Iodination of tyrosine (of thyroglobulin)

I2 + Tyrosine portion of thyroglobulin
(Monoiodotyrosine) MIT DIT (Diiodotyrosine)
Step 3: - Coupling of MIT and DIT

MIT + DIT
T3* T3 (inactive)
OR
Step 3: - coupling of DIT and DIT
DIT + DIT T4

 When the thyroid gland is stimulated Hypothalamus
via TSH, T3 and T4 are secreted to the ↓TRH
blood stream. Anterior pituitary
 They bind to plasma carrier proteins. ↓TSH
Thyroid
Negative feedback
Inadequate Iodine adequate Iodine

↓(Iodine deficiency) ↓
Low T3 and T4 T3 and T4
↓
Low negative feedback
↓
Excess TSH
↓
Thyroid
↓
Abnormal growth
(Goiter)
Biosynthesis of steroid hormones
Mitochondrial side chain

cleavage enzyme
Main precursor – cholesterol Pregnenolone (21C)
(Desmolase)
+
Isocaproic
Aldehyde (6C)
Adrenal cortex hormones
 Mediated by the increase of Adrenal cortex

 cAMP
 Ca+2
 Inositol-triphosphate, in response Adrenocorticosteroid/ Androgens
Sexual
to hormonal stimulus. Corticosteroid development
& function
Mineralcorticoid glucocorticoid
•Aldosteron •cortisol
(Regulate salt & water excretion (Affect CHO/Protein/Lipid metabolism
by kidney) in a manner opposite
to insulin)
•corticosteron
e

Sex hormones in gonads
Pregnenolone Progesterone Testosterone Estradiol
DHT
Calcitriol
Actions of Calcitriol
Calcitriol
Intestine KIDNEY Bone
Increased absorption of Ca+2 and phosphate Increased release of Ca+2 and phosphate to the ECF
What happens to hormones after secretion;

 Freely circulate
 Circulation with carrier proteins
 Degraded in blood stream
 May be excreted/removed by kidneys/liver
 May be activated
 May reach a target cell and cause responses by binding to receptors

Receptors
 Protein
 There are 3 types of receptors.
1. Membrane bound
2. Cytoplasmic
3. Nuclear
 Fits / tightly binds with the active site of the hormone
 Convert the signal to a response.
 Highly specific for a particular hormone.
 Tissues have their own pattern of distribution of receptors.
Ex: Liver has glucagon receptors but skeletal muscles doesn’t have
 The number of receptors in a cell is not constant.
1. Up regulation-
 Increased gene expression
2. Down regulation
 Inactivation
 Separation of the receptor from the surface
 Destruction within lysosomes
 Decreased production/repair
 Hormones are categorized by their solubility.
Hydrophilic Ex: - catecholamine, peptide, eicosanoids
 Membrane bound receptors
Hydrophobic (Lipophilic) Ex: - thyroid and steroid hormones

 Cytoplasmic receptor
 Nuclear receptors
Hormone signal transduction

 The series of events and components that takes part in transmitting hormonal signal to the
interior of cells
Hormone (first messenger)
↓
Membrane / cytosolic receptor
↓
Signal initiator → initiation
↓
Signal mediator – second messenger → amplification
↓
Target molecule
↓
Action
 Each of the above steps are more powerfully activated.

 So a very low concentration of hormones brings out a huge effect.

Classification of receptors according to their mechanism of hormone signal
transduction
 Ion channel linked receptors – open / close Ca+2 channels

 G protein linked receptors – regulate cellular actions via G proteins
 Adenyl cyclase receptor
 Phospholipase
 Enzyme linked receptors
 Outside – hormone binding site
 Inside – catalytic domain site (Inbuilt enzyme)
 Intracellular receptors
 Cytoplasmic receptors
 Nuclear receptors
1. Ca+2 channel linked receptors

Hormone binds to the receptor
↓
Opening of Ca+2 channels
↓
Ca+2 influx
↓
Increased cytoplasmic Ca+2 levels
↓
Biochemical effect
2. G protein linked receptors
 Exist in two states

 Active state bound to GTP
 Inactive state bound to GDP
 Work with many receptors
 Can both
 Stimulate
 Inhibit hormone signals
 When GTP is hydrolyzed to GDP, stimulation is stopped
G protein mediated transduction activating adenylate cyclase (second messenger – cAMP).

Ex: - Epinephrine binding to its β adrenergic receptor.
↓
Conformational change transferred to the cytoplasmic domain
↓
Interaction of the receptor with G protein in the cytoplasmic surface of the membrane
G protein has 3 domains; α, β and γ. α subunit has GDP bound to it.
(Heteromeric GTP Binding Protein)
↓
The binding of the G protein to the receptor causes the replacement of GDP by GTP

↓
α subunit dissociate from the others.
↓
α subunit bind to adenylate cyclase
↓
Activation of adenylate cyclase
↓
ATP is converted to cAMP→ cAMP activates protein kinases (phosphorylation)
↓
Inherent GTPase activity in the α subunit
↓
GTP hydrolyzes to GDP
↓
α subunit re-associate with the other two subunits
Ex:
 β adrenergic receptors Epinephrine

Norepinephrine
 Glucagon
 TSH, FSH, LH, ACTH
 PTH
 ADH
 Calcitonin
Transduction via G protein activating phospholipase C (Second messengers – IP3 and DAG)
Ex: - Epinephrine binds its α adrenergic receptor

↓
Conformational change transferred to the cytoplasmic domain
↓
Interaction of the receptor with G protein in the cytoplasmic surface of the membrane
G protein has 3 domains; α, β and γ. α subunit has GTP bound to it.
↓
GTP hydrolyzes to GDP
↓
α subunit dissociate from the others.
↓
α subunit bind to phospholipase C
↓
Activation of phospholipase C
↓
Phosphatidylinositol bisphosphate hydrolyze into Diacylglycerol (DAG) and inositol triphosphate (IP3)
↓
IP3 release stored Ca+2 from ER
DAG opens Ca+2 ion channels and increase Ca+2 influx (via PKC)
↓
Increased Ca+2 levels inside the cell
↓
Calmodulin binds with Ca+2
↓
Activate PKs
↓
Activation of enzymes

 Therefore, epinephrine can act through two second messenger systems.
1. α adrenergic receptor system
2. β adrenergic receptor system
Eg: α1 adrenergic receptors Epinephrine
Norepinephrine
Hypothalamic hormones
Eicosanoids
Oxytocin
Transduction via phosphodiesterase (inhibition)
Hormones bind to receptor

↓
G protein activation
↓
↓
Activation of phosphodiesterase
↓
cAMP is hydrolyzed to AMP
↓
Inhibition of enzymes
Eg: - α2 receptors Epinephrine

Norepinephrine
Clinically important G protein linked receptors
Α → α1 and α2
Adrenergic receptors
Β → β1 and β2
Adrenaline – excite both α and β receptors

Noradrenaline – excite mainly α (β to a lesser extent)
 Many antihypertensive drugs are β blockers. They block the binding site of catecholamine to
β receptors. Eg: Propranolol (Blocks β1 and β2)
3. Enzyme linked receptor action
 The binding of a hormone to the receptor directly activate its inherent enzyme activity.
Ex: - insulin receptor is a kinase by itself
 The insulin receptor has 2 α chains on the outside of the membrane and 2 β transmembrane
chains.
 The transmembrane β chains have tyrosine residues on the cytosolic surface.

 When insulin binds the tyrosine, residues get phosphorylated. This is called
autophosphorylation.
 Autophosphorylation activate the kinase activity of the receptor.
 Then the cytosolic target proteins are activated to bring about the effect of insulin.
Intracellular receptors – steroid hormones
 Steroid receptors are of two types

o Type 1 – cytosolic
o Type 2 – nuclear
 Cytosolic receptors have heat shock protein (hsp) associated with the inactive receptor.
 Nuclear receptors don’t have hsp.
 Steroid hormone crosses the cell membrane

↓
Interaction with the cytoplasmic receptor
↓ Or directly bind
Dissociation of the hsp with nuclear
↓ receptors
The complex is transported into the nucleus
↓
Formation of dimers
↓
The complexes bind to HRE (hormone response element) of the enhancer region
↓
Activation of gene transcription
↓
Protein synthesis
↓
Cellular response
 Thyroid hormone diffuses across the cell membrane
Hormone binds to mitochondrial receptors Hormone binds to nuclear receptor

↓ ↓
Increased ATP production Complex bind to DNA
↓ ↓
Cellular response Gene activation
↓
Cellular response

Actions of TH
 Stimulates protein synthesis

 Promotes maturation of nervous system
 Stimulates rate of cellular respiration by;
 Production of uncoupling proteins
 Increase active transport by Na+/K+ pumps
 Lower cellular [ATP]
 Increases basal metabolic rate (BMI)
 Stimulates increased consumption of glucose, fatty acids and other molecules
 Promotes growth and brain development in the fetus and young children

GLYCOLYSIS
Importance
 Provides energy and metabolic intermediates.
 Provides ATP directly by substrate level phosphorylation
 Emergency energy supply in hypoxia - does not need O2
 Myocardial infarction.
 Strenuous exercise in skeletal muscle
 Tumor cells
 Major energy supply of RBC (lack of mitochondria)
 Provides NADH which provides ATP by ETC – oxidative phosphorylation
 Provides intermediates for other metabolic pathways
 Maintain blood glucose level in the body.
 Aerobic – glucose to pyruvate
Anaerobic – glucose to lactate
Transporters of glucose
Occurs in cytosol - Glucose is polar – can’t cross membranes – need transporters (tissue specific)
Passive transporters (Na+ independent unipolar - Facilitated diffusion) - along conc. Gradient
GLUT transporters – exist in 2 conformation states
Transporter Km value Affinity Special features

GLUT 1 RBC, Endothelial (BBB), Low High take up even when
Fetal tissues, choroid blood levels are low
plexus
GLUT 2 Renal medulla, Liver, High low glucose sensing for insulin
Pancreatic β cells secretion
High capacity
DUAL ROLE: transport glucose in
both directions
GLUT 3 Neurons, Placenta, testis Low High High capacity
GLUT 4 Adipose tissue, striated Insulin dependent (DM)
muscles ( skeletal, cardiac) Stored in intracellular vesicles
GLUT 5 Small intestine, testis Fructose transport
Active transporters (Na+ Dependent) – against conc, gradient

Na+-Glucose cotransporter (luminal side)
Eg: SGLT 1 – Duodenum
SGLT 2 - Kidney tubules

SGLT 1 & 2 - choroid plexus (BBB)
Na-K-ATPase pump (basal side) – establishes electrochemical gradient

Regulation of Glycolysis (Irreversible reactions)
1. Hexokinase or Glucokinase (HK/ GK)

2. Phosphofructokinase 1 (PFK 1) RATE LIMITING / COMMITTED STEP
3. Pyruvate kinase(PK)
1. Phosphorylation of glucose (commits glucose for further metabolism in the cell, by trapping
glucose)
Hexokinase/glucokinase
Glucose Glucose - 6-P
Glucokinase –liver and pancreatic beta cells

Hexokinase – all tissues (Inc. liver)
 Hexokinase - Low Km [high affinity] low Vmax

 efficient phosphorylation of glucose at low concentration
 broad substrate specificity(catalyzes phosphorylation of other monosaccharides as well)
 inhibited by high G6P
 Glucokinase - high Km (low affinity) High Vmax

 high Vmax
 NOT inhibited by G6P
 Indirectly regulated by GKRP (Glucokinase regulation
protein in nucleus)
 Efficient phosphorylation in the liver while glucose
concentration is high in the portal vein
 prevents excess glucose entering the systemic circulation
 In the pancreas determines the glucose threshold for
insulin secretion (glucose sensing)
 Mutations in GK- Maturity onset diabetes of the young
people type 2 (MODY 2)

2.Phosphorylation of Fructose-6-P by Phosphofructokinase 1 (rate limiting and committed
step in glycolysis)
AMP
F-2,6-BP – most potent activator
PFK 2 +
PFK 1
F-6-P F-1,6- BP
-
ATP
Citrate
PFK 2 – Phosphofructokinase 2 / FBP 2 – fructose- 2,6-bis phosphatase
(PFK 2 / FBP 2) is a bifunctional enzyme – covalently modified

When phosphorylated – PFK 2 inactive / FBP 2 active
When dephosphorylated – PFK 2 active / FBP 2 inactive
PFK 2
F-6-P F-2,6- BP
FBP 2
Adenylate
cyclase
Glucagon cAMP Active protein kinase A phosphorylates the bifunctional enzyme
In Fed state high insulin/glucagon ratio low cAMP dephosphorylaton
Activates PFK 1 Formation of F-2,6- BP
Fructose-2,6-bisphosphate is an inhibitor of gluconeogenesis enzyme fructose-1,6-bisphosphatase.

Therefore, reciprocal regulation of glycolysis and gluconeogenesis.

3. Formation of pyruvate by pyruvate kinase
Pyruvate kinase
PEP Pyruvate
+ Feed forward regulation
F-1,6-BP
When blood glucose level is low, HEPATIC pyruvate kinase is phosphorylated (via cAMP) and thereby
inactivated inhibiting glycolysis and driving gluconeogenesis.
Energy Production in Glycolysis (Aerobic)
 For 1 glucose molecule

2 ATP –consumed
4 ATP –produced by substrate level phosphorylation
Net production – 2 ATP and 2 NADH (directed to ETC)
Fate of pyruvate
Pyruvate
Aerobic Anaerobic
Acetyl CoA Lactate / NAD+

(cytosol)
TCA
Cycle (mitochondria)
CO2 /H2O/ATP/
NADH/FADH

Effect of insulin and glucagon
Regular consumption of carbohydrates and administration of insulin  increase synthesis of regulatory

enzymes
In DM, due to reduced insulin levels  decrease synthesis of regulatory enzymes
Clinically important facts
Lactic Acidosis
 In glycolysis 2 NADH are formed using NAD+

 There is only a limited amount of NAD+ in a cell. So NADH should be re oxidized and NAD+ should
be regenerated.
 This is normally achieved by transporting NADH in to the mitochondria and oxidizing into NAD +
via electron transport chain.
 When this process is impaired, NAD+ is regenerated by converting pyruvate into lactate.
 Accumulation of lactate (lactic acidosis) will lead to;
1.Reduction of pH→ Accumulation of water →Loss of membrane integrity →Leakage of
cellular proteins →Death of cell (MI)
2.Neurological disturbances
3. Low pH - cramps
4. Low pH within liver - increase glucose production in the liver
Causes:
1. Low O2 concentration as a result of collapse of circulatory system due to
 MI
 Pulmonary embolism
 Severe haemorrhage
 Shock
2. Inhibition of ETC - reduce oxidation of NADH
 Hypoxia
 Inherited diseases of mitochondria
 Absence of ATP/ADP translocase

 Inhibitors and uncouplers of ETC
 CN- poisoning (inhibition of complex IV of ETC) inhibitors- oligomycin,
Uncouplers - thermogenin, 2,4 DNP
Pyruvate kinase Deficiency (autosomal dominant)
RBCs entirely depend on glycolysis for ATP production as they lack mitochondria. In the deficiency of
the enzyme ATP production by glycolysis is reduced. Premature lysis of RBCs occurs due to inability of
maintaining ion pumps in the cell membrane. Hemolytic anemia results. (prickle cells, jaundice and
splenomegaly)
Impaired activity of PDH
Accumulation of pyruvate → Excessive lactate production → lactic acidosis

Eg:
 Mercuric and Arsenic poisoning (Heavy Metals) - binds to SH (thiol) groups of lipoic acid which
is a coenzyme of PDH
 Alcoholism – poor nutrition & impaired absorption of thiamin
→thiamin deficiency (TPP is a coenzyme for PDH)
 Inherited PDH deficiency
Treatment- give a ketogenic diet (rich in lipids and low in carbohydrates)
Alcoholism (refer gluconeogenesis)
Haemolytic anaemia -Deficiency of aldolase and pyruvate kinase

Conversion of Glyceraldehyde-3-P to 1,3-BPG catalyzed by glyceraldehyde-3-P dehydrogenase is the first
oxidation reduction reaction in glycolysis. It produces 2 NADH per glucose molecule. Arsenate (a
structural analog of phosphate) does not inhibit the pathway but can prevent the net ATP and NADH
production by competing with phosphate for Glyceraldehyde-3-P dehydrogenase forming a complex that
spontaneously hydrolyzes to 3PG without forming NADH.

Fluoride ions in the presence of phosphite ions inhibit the glycolysis enzyme Enolase by forming a
fluorophosphate complex with Mg which is the co-factor of the enzyme. Blood collection tubes for
glucose estimation contain NaF to inhibit glycolysis and prevent further utilization of glucose. Water
containing fluoride reduces lactate production by mouth bacteria, decreasing dental caries.
Role of 2,3-BPG in RBCs made from 1,3-bisphosphoglycerate in response to chronic hypoxia. (high
altitudes, etc.) Binds with beta chain of hemoglobin and reduces its affinity for oxygen. More oxygen is
released in the tissues.

TCA CYCLE
Intermediate reaction,
PDH
Pyruvate +CoA + NAD + Acetyl CoA + NADH + H+ + CO2
 Irreversible reaction, which occurs in mitochondrial matrix. (but not a part of TCA cycle)
 Pyruvate needs to enter the mitochondrial matrix, so a specific transporter helps
to cross the inner mitochondrial membrane -H+ symport by pyruvate translocase
 Needs aerobic conditions (O2) - (to regenerate NAD+ and FAD+ via ETC)
 Catalyzes by Pyruvate Dehydrogenase enzyme (PDH), which is a multi-enzyme complex
(multiple copies of three enzymes) in the mitochondrial matrix
Decarboxylation
cAMP insensitive.
Dehydrogenation
 PDH requires 5 co-enzymes Trans acetylation
 CoA (vitamin B5) PHD kinase and
 NAD (vitamin B3) PDH phosphatase
 Lipoic acid
 FAD (vitamin B2)
 TPP (vitamin B1)
(mnemonic – CFL Nethi Torch)
Regulation of PDH complex

PDH P
(inactive)
Acetyl CoA/CoA ADP
ATP/ADP + Insulin(adipose)
NADH/NAD+ + Ca2+/ Ma2+
PDH kinase PDH Phosphatase
-
Pyruvate
ATP
Ca2+
PDH
(active)
NAD+ NADH + H+
Pyruvate Acetyl CoA
CoA CO2

PDH kinase Phosphorylates the PDH enzyme (Inactivation)
 Activators - NADH/NAD+, ATP/ADP, Acetyl CoA/CoA
 Inhibitors - Pyruvate, Ca²⁺ (skeletal muscles)
PDH phosphates Dephosphorylates the PDH enzyme (Activation)
 Activators - Ca²⁺, Mg²⁺, Insulin (only in adipose tissue), Ca²⁺, Mg²⁺
High energy signals PDH turned off
PDH kinase and PDH phosphatase  cAMP insensitive
End product inhibition of PDH

 Acetyl CoA
 NADH
PDH activity affected in
 Dietary deficiency of Thiamine,

 Inadequate ingestion of Thiamine
 Alcoholism- poor nutrition & impaired absorption of Thiamine → Thiamine
deficiency (TPP is the active form of Thiamine -Vit B1)
 Inherited PDH deficiency.
 The presence of agents that oxidize or complex with the enzyme - inhibit PDH.
 Mercuric and Arsenic poisoning (Heavy Metals) - binds to SH (thiol) groups of Lipoic acid
which is a coenzyme of PDH (also affects α KGDH)
Impaired activity of PDH Accumulation of Pyruvate Excessive lactate production Lactic Acidosis
Treatment - give a Ketogenic diet (rich in lipids and low in carbohydrates)
Citric acid cycle

Final catabolism / oxidation of
acetyl CoA

Regulation of TCA cycle
 If O2 is adequate, rate of respiration & TCA cycle depends on energy status, which is
reflected by utilization of ATP.
 Continuity of TCA cycle depends also on regeneration of electron acceptors.
 Also, enzymes are responsive to energy status:
 ATP/ADP
 NADH/NAD+
Control step - Product inhibition

Citrate synthase
OAA+ Acetyl CoA Citrate
-
ATP
LCFACoA
One of the rate limiting step
Isocitrate DH
Isocitrate α ketoglutarate +NADH +CO2
- +
ATP ADP
NADH
PDH and αKGDH

 Structurally similar
 3 distinct enzymes are identical (αKGDH, Transsucinylase, dihydrolipoyl dehydrogenase)
 Coenzymes are similar
 αKGDH is not subjected to regulation by phosphorylation & dephosphorylation.
 αKGDH is inhibited by
a) Succynyl CoA
b) NADH
c) ATP, GTP (high energy)
d) Arsenite
 Activated by
a) Ca2+
Succinate dehydrogenase
 Embedded in inner Mitochondrial membrane (complex II in ETC)

 Inhibited by OAA, Malonate
Aconitase
 Inhibited by Fluoro-acetate (use as pesticide)
 Citrate Isocitrate
Steps which are important
 NADH formation
Isocitrate DH
Isocitrate αKG
NAD+ NADH + H+
α KGDH
αKG Succinyl CoA
NAD + NADH + H+
Malate DH
Malate OAA
NAD+ NADH + H+
 Substrate level phosphorylation
succinate thiokinase
Succinyl CoA succinate
GDP GTP
 FADH2 formation
Succinate DH
Succinate Fumarate
FAD+ FADH2

Summary of production,
At the end of the TCA Cycle, For one glucose molecule,

 6 CO2
 2 from PDH
 4 from TCA cycle
 10 NADH
 2 from glycolysis
 2 from PDH
 6 from TCA cycle
 2 FADH2 (from TCA cycle)
 4 ATP (from glycolysis)
 2 GTP (from TCA cycle)
Energy Production
By intermediate reaction (PDH),
 For one molecule of Glucose,
2x NADH 2 x 3 = 6 ATP
By TCA cycle,
 For one molecule of Acetyl CoA,
1 x FADH2 1 x 2 = 2 ATP
3 x NADH 3 x 3 = 9 ATP
Substrate level phosphorylation 1 GTP
12 ATP
For one glucose molecule (for 2 acetyl CoA molecules) 24 ATP
Biosynthetic precursors from TCA
TCA is a central pathway in metabolism

of Carbohydrates, Proteins (Amino
Acids) & Lipids…

HEXOSE MONOPHOSPHATE PATHWAY(HMP)/PPP
 Important source of
1) NADPH (other source is via mallic enzyme reaction.) Malate Pyruvate
 For reductive biosynthesis
 Counter free radical damage NADP+ NADPH
2) Ribulose-5-phosphate
 Rapidly dividing cells to make DNA & RNA
 Occurs in cytosol.
 No ATP is directly consumed or produced in the cycle.
 2 parts- 1. Irreversible oxidative reactions 2. Reversible non-oxidative reactions.
Irreversible Oxidative Reaction
active in liver, adipose tissue, adrenal cortex, RBC, lens, corneal cells
6 phosphoglucono lactone
Glu -6- P -DH
hydrolase
Glucose-6-P 6-phosphogluconolactone 6-phosphogluconate
NADP+ NADPH NADP+
NADPH (-) competitive CO2

6-phosphogluconate
inhibitor dehydrogenase
 Important in cells with high demand of NADPH.

NADPH
Eg: - RBC - to keep glutathione reduced NADPH
- Mammary gland - for fatty acid bio synthesis.
Ribulose-5-P
- Liver- adipose tissue
Ribulose-5-
- Testis, ovaries, placenta, adrenal cortex - steroid hormone synthesis
phosphate
 Glucose-6-Phosphate dehydrogenase is the regulatory enzyme. (G6PD)
 High NADPH/NADP+ ratio inhibits the enzyme.
 Insulin enhances gene expression of the enzyme.
 HMP glucose oxidation = 1/6 of Aerobic respiration
Reversible non-oxidative reaction….

The reversible non-oxidative steps will
Catalyzes inter conversion of 3,4,5,6, &7 carbon sugars. supplement the requirements when the
demand for nucleotide synthesis exceeds the
Ribulose-5-phosphate demand for NADPH
Transaldolase
(3C units) &
Transketolase
Ribose-5-P (2C units) Glyceraldehyde-3-P + Fructose-6-P
Nucleotide synthesis Glycolysis

 In the cell, phases of HMP taking place is altered according to demand.
1) Cells, needed only NADPH (Eg: RBC)
Glucose Glucose-6-P Ribose-5-P glyceraldehyde-3-P + fructose-6-P
NADPH Glycolysis for energy
2) Cells that only need Ribose-5-P

When NADPH is abundant in a cell, high [NADPH] completely inhibits Glucose-6-P dehydrogenase.
Raw materials for reversible phase taken from glycolysis produce ribose-5-P.
Glyceraldehyde-3-P
Ribulose-5-P Ribose - 5- P
Fructose-6-P
NADPH
Ratios of reduced/oxidized forms in cytosol of hepatocytes favor:
 Reductive biosynthesis for NADPH NADPH: NADP+ = 10:1

 Oxidative role for NAD+ NADH: NAD+ = 1: 1000
Functions of NADPH
1) Detoxification
A. Maintains the stability of the cell membrane. (esp.in RBCs)
 Metabolic reactions formation of free radicals. Eg: peroxides, superoxides
 Attack lipid bilayer and cause lipid peroxidation Cell membrane breakdown (hemolysis)
 H2O2 is reduced by glutathione. NADPH reduces Oxidized glutathione into its reduced form.
G-Glutamate
C-Cysteine
G-Glycine

 Sulfohydryl groups of proteins/ Hb undergo auto oxidation and undergo denaturation to form
insoluble 'Heinz' bodies. NADPH thus prevents formation of Heinz bodies.
G6PD deficiency – hemolytic anemia
 X linked
 G6PD → main regulatory enzyme in HMP
 Production of NADPH in RBC is entirely dependent on HMP. (occurs in all cells, but most
severe at RBCs)
 In G6PD deficiency, lack of NADPH → Can’t reduce oxidized glutathione → Can’t maintain
stability of RBC membrane → Hemolysis.
 Commonly manifests when exposed to oxidative stress
 Oxidant drugs Eg: antimalarial (primaquine), herbicides
 Favism (fava beans)
 Infection (from oxidants produced during inflammation)
 Ionizing radiation
B. Cytochrome P450 mono oxygenase pathway
 involved in biosynthesis of steroid hormones, bile acids.

 detoxify foreign compounds
 vitamin D synthesis

C. Destruction of bacteria by WBC
Phagocytosis by WBC O2 independent mechanism
O2 dependent mechanism
.
 Respiratory burst
 Reactive Oxygen species
O2- , H2O2 , OCl-, OH-
2) Reductive biosynthesis
 Fatty acid biosynthesis

 Fatty acid chain elongation
 Cholesterol biosynthesis
 Neurotransmitter synthesis
 Nucleotide synthesis
NO synthesis
NADPH NADP+
NO synthase
Arginine Citrulline
O2 NO
Functions of NO
 Relax smooth muscle
 Prevent platelet aggregation
 Act as a neurotransmitter in brain
 Mediate tumoricidal & Bactericidal action in macrophages

Importance of pentose phosphate pathway in testis.
 Cholesterol is a precursor for testosterone synthesis.

 NADPH is the co-enzyme used here for reduction.
 Ribose-5-P for nucleotide synthesis.
 NADPH is used to synthesis fructose (the main energy source of spermatozoa) via sorbitol
pathway.
 NADPH has an antioxidant defence.
Sorbitol Pathway
Reduction of monosaccharides to polyol by Aldolase reductase –an alternative mechanism for
metabolizing sugars in tissues. (Ex- lens, retina, liver, kidney, ovaries, seminal vesicles, Schwann
cells)
glucose Elevated Sorbitol

Glucose
Aldose reductase NADPH
 Sorbitol can’t pass efficiently through
Sorbitol NADP+ membranes.
 Due to osmotic effect water comes in & cells
Sorbitol dehydrogenase NAD+ swell Causing cataracts etc.
NADH
fructose
Fructose & Galactose entry to cells is not insulin dependent
Fructose Metabolism
Hereditary fructose intolerance

Essential Fructosuria
(HFI)
Fructokinase Aldolase B
Fructose Fructose-1-P Glyceraldehyde
DHAP

Lactose synthesis
Lactose synthase – (UDP: galactose: glucose galactosyl transferase)
Normal tissues Lactating mammary gland

UDP galactose + N acetyl -D-glucosamine In the presence of lactalbumin,
β-D-galactosyltransferase UDP galactose + glucose
N-acetyllactosamine + UDP Lactose + UDP

(lactalbumin synthesis is stimulated by
Prolactin – a peptide hormone)

GLYCOGEN METABOLISM
Glycogen
 Major carbohydrate storage in animals.
 Highly branched, homo-polysaccharide. (one reducing end-more non reducing ends)
 Stored in liver (10% /100g) and muscle (1-2% /400g) as large particles
containing enzymes. (Total amount of glycogen is higher in skeletal muscles
because more mass)
 Also in brain – single most conc. carbohydrate stores in brain.
 Main storage site is liver.
Why more branches?

1. For efficient glycogen synthesis. (More free non-reducing endings-glycogen synthase)
2. To maximize the rate at which glucose can be released to meet high energy demand-
(glycogen phosphorylase-attack non-reducing ends)
3. To store the most amount of glucose in the least amount of space.
Advantages
 Than glucose,
 Insoluble
 low osmotic activity
 no influx of water into cell
 Than Fats,
 Can provide energy under anaerobic conditions by glycolysis
(FAs can’t net produce glucose)
 Formation of glu-1-PO43- no ATP is needed to channel glucose into glycolysis
Importance
Liver glycogen : - Maintain blood glucose level between meals- lasts 24h in fasting
Muscle glycogen: - Provide energy for muscle to perform strenuous exercise (aerobic & anaerobic)

Muscle glycogen is not affected by short period of fasting
Glycogen synthesis
 Glycogen synthase is the key regulatory enzyme

 Occurs in cytosol
Glucose activation
Glucose Glucose-1-P
UDP-Glucose pyrophosphorylase
Glucose-1-P + UTP UDP-Glucose + PPi (Pyrophosphate)
(Activated form)
PPi + H2O 2Pi
 Therefore, all reactions producing PPi are shifted to right & almost irreversible
Initiation of glycogen synthesis
 Glycogen synthase needs a primer to initiate synthesis.

 Homodimeric protein called glycogenin (Autocatalytic activity- glucose transferase)-has
Tyrosine
 Glycogen fragment
Chain elongation
Glycogen synthase
(Glycogen)n + UDP-Glucose (Glycogen)n+1 +UDP
 Glucose is added to non-reducing ends. → α-1-4-glycosidic bonds
Nucleotide diphosphate kinase

ATP + UDP UTP + ADP
 So, for each α added 1 ATP is consumed
Branching (4:6 Transferase)
 Branching enzyme cuts a string of glycogen (8-10 glycosyl units) from the growing end and
grafts onto the 6th C atom of a glucose residue in the chain. →α-1-6-glycosidic bonds
 Further elongation by glycogen synthase.

GLYCOGEN BREAKDOWN
 Best pathway for glucose regeneration.

 Not the reversal of synthesis. Has separate set of enzymes
 Occurs in cytosol.
Glycogen phosphorylase is the key regulatory enzyme
Glycogen(n) + Pi Glucose-1-P + Glycogen(n-1)
 Breaking of α-1-4 bonds at non reducing ends to release Glucose-1-P,

 By glycogen phosphorylase – needs vit B6 (pyridoxal phosphate) as coenzyme
 Vit B6 is required to mobilize glucose from glycogen

Phosphoglucomutase Brain
Glucose-1-P Glucose-6-P Glycolysis directly
Liver
Muscle Use to HMP pathway
Glucose 6-phosphatase s
Glucose Used for muscle contraction via

Glycolysis as phosphorylated
Glucose cannot leave
Blood the cell
Lysosomal degradation of Glycogen. Pyruvate Lactate

 Glycogen granules are engulfed by e
lysosomes and degraded. Using enzyme
acid maltase (α-1-4 glucosidase)
 Important in neonates
 Function unknown in adults but defects cause
diseases
Eg: Type II – Pompei disease
REGULATION OF GLYCOGEN METABOLISM
Glycogen metabolism is regulated by regulating

glycogen phosphorylase and glycogen synthase.
Allosteric
Two types
Covalent Hormonal
Hormonal regulation
Synthesis increases in:
Well-fed state (liver) By insulin

Resting state after a meal(muscle)

Breakdown increases in;
Fasting state (Liver) Glucagon, Epinephrine

Exercise state (muscle) Epinephrine (NOT glucagon)
 Muscle is not responsive to glucagon

 Both hormones use G protein dependent
signal transduction pathway
 Both affect the first reaction (glycogen phosphorylase)
Actions of insulin (after a meal)

 Stimulates glucose uptake via
GLUT 4
 Promotes glucose use by
activating glycogen synthase – by
dephosphorylation
 Decreases glycogenolysis
by inhibiting glycogen
phosphorylase – by
dephosphorylation

Allosteric Regulation
Synthetic Pathway
Glycogen Synthase a Glycogen Synthase b

(Active) (Inactive)
+
Glucose – 6- P
Degradative Pathway
Ca2+- Calmodulin
Complex
+
Glycogen phosphorylase Glycogen phosphorylase
Kinase b Kinase a
(Inactive) (Active)
Glycogen Phosphorylase
Muscles a
ATP (Active)
Muscles
G–6-P
AMP
Liver
ATP
G–6–P Glycogen phosphorylase
Glucose b
(Inactive)
LIVER MUSCLE
Glycogen acts as a glucose reserve. Glycogen acts as an energy reserve.
Maintains blood glucose level – buffers glucose Provide ATP for muscle action.
End product is glucose. End product is Glucose-6-phosphate.
Glucose-6-phosphatase enzyme is present. Glucose-6-phosphatase enzyme is absent.
Hormonally regulated by glucagon, insulin, Insulin, epinephrine. (no glucagon influences.)
epinephrine.
Receptors: insulin, glucagon, adrenergic (α,β) Insulin, β adrenergic.
2nd messengers: 2nd messengers:
cAMP, Ca2+, IP3, DAG cAMP, Ca2+
Ca2+ released from SER due to epinephrine via α1 Ca2+ released from SER during muscle
receptors activates phosphorylase kinase contraction activates phosphorylase kinase
without phosphorylation (partially without phosphorylation (partially
active)→activates glycogen phosphorylase active)→activates glycogen phosphorylase
AMP has no role in regulating glycogen AMP directly activates glycogen phosphorylase
phosphorylase without phosphorylation.
Glucose allosterically inhibits glycogen Glucose has no action in regulation of glycogen
phosphorylase. phosphorylase.
Glycogen stores: Glycogen stores:
Increased- during well-fed state. Increased- during resting state
Depleted- during fasting. Depleted-during muscle contraction.
Glycogen storage diseases.
VON GIERKE DISEASE POMPE DISEASE McARDLE DISEASE CORI DISEASE

(type 1 glycogen storage
disease)
Due to inborn lack of Due to lack of - Loss of 4:4
Glucose-6-phosphatase 1,4- glucosidase glycogen transferase
enzyme or Glucose 6-P phosphoryl deficiency
CAUSE
transporter deficiency ase in

muscles
Glucose-6-P can’t be converted Accumulation of Occasional Debranching is
into glucose, leads to glycogen in vacuoles are filed interrupted
hypoglycemia. lysosomes. with glycogen.
RESULT
Hepatomegaly, fasting Massive Temporary Fasting

hypoglycemia, fatty liver, cardiomegaly, weakness, hypoglycemia
renomegaly, hyper lactic excessive glycogen cramping after
SYMPTOMS
academia, hyperlipidemia, concentration. exercise.

hyperuricemia Abnormal vacuoles
in lysosomes.

PROTEIN METABOLISM
 Amino acids that undergo modifications in proteins
Proline 3, 4 hydroxyl proline
Glutamic acid y carboxy glutamic acid
Cysteine Cystine
 Some amino acids are not found in proteins
 Ornithine, Citrulline, Epinephrine, Homocysteine.
Protein turnover
 Constant degradation and synthesis of body proteins

 No AAs are stored.
 Daily protein turnover 500g -- 1-2% of body weight
 In healthy adults
 Total amount of protein is constant.
 Rate of synthesis equals the rate of catabolism.
 400g broken down daily & 400g synthesized daily.
 100g of amino acids catabolized & 100g of dietary amino acids maintain amino acid pool.
 Total amino acid pool 500g per day.
Body Proteins
(400g)
Synthesis of
Dietary Proteins
non-essential
A.A (Varies) (100g)
AA
Pool
(100g)
Catabolism Synthesis of other
of A.A N containing
(Varies 14%) compounds (30g)
Body proteins
(400g)
 Proteins are subjected to environmental influences and are damaged.

Eg: - Reactive Oxygen species
 The capacity to repair this damage is limited, therefore all proteins are degraded and re-
synthesized as a form of quality control.
 Functions of protein turn over,

 Synthesis or degradation of proteins depending on demand.
 Degradation of unnecessary and defective proteins.
Amino acid pool
 50% of total amino acid pool in skeletal muscle.

 Only a small percentage is in plasma.
 All amino acids are found but glu, ala predominate.
 Rate of turnover is expressed as half-life (t 1/2)

 Half-life → time required to reduce concentration of a given protein by 50% of initial value.
 Functional proteins - short half-life (E.g. - enzymes, plasma proteins)
 Structural proteins - long half-life (E.g. - muscle proteins, collagen)
 Key regulatory proteins are rapidly degraded.
Eg: -HMG CoA Reductase, Tyrosine transaminase, Tryptophan oxygenase
 Some regulatory enzymes have long half-lives.
Eg: - LDH, Aldolase
Clinical
Redistribution HB level
Dietary AA pool Degradation
to meet Reduce
Protein of HB
reduce essential resulting
Reduce
needs anaemia
 Anaemia is more tolerant than other protein deficiency.
Degradation of Proteins
Protein Degradation
ATP Dependent ATP independent

Ubiquitin Proteasome system Degradative enzyme system
Cytosol Lysosome
 Selectively degrade  Non selectively degrade
 Proteins tagged with ubiquitin  Using acid hydrolases
 Recognized by proteasome  Extracellular, membrane associated,
 It unfolds, deubiquinate and cut the glycoproteins and long lived
protein into AA by proteases intracellular proteins are degraded.
 Degradation of regulatory proteins with
short half-life or misfolded proteins.
 Target intracellular proteins

Chemical signals for degradation
1) Ubiquitination
2) Oxidation of amino acid residues
3) PEST sequence
4) N terminal amino acid residues
1) Ubiquitination
 Ubiquitin is a small heat stable highly conserved protein (76 AAs)

 Present in all eukaryotes in cytosol.
 Binding with ubiquitin targets an intracellular protein for
degradation via the proteasomes.
 Degradation depend on N terminal AA.
 Asp, Arg - accelerate ubiquitination
 Met, Ser - retard ubiquitination
 Ubiquitin is recycled.
2) Oxidation of amino acid residues
 Lys and Arg in proteins can be oxidized

 Cellular ageing
3) PEST sequence
 Repeated sequence of P E S T
 Pro, Glu, Ser, Thr, are known as pest sequences
 Usually half-life less than 2 hours
 Target proteins for rapid degradation.
 Hydrolyze by ubiquitin-proteasome system
4) N terminal amino acid
 Proteins with and amino terminal of Phe, Leu, Tyr, Trp, Lys, Arg
 Have short metabolic half life
Nitrogen balance
 The amount of nitrogen retained in the body. (Balance = Intake - Output)
States of balance
1. Zero N balance (equilibrium)/Healthy

 In a healthy adult intake and output of N are equal.

2. Positive N balance (Increased Synthesis)
 Intake > output (loss)
 Pregnancy
 Growth - Adolescents, children
 Convalescent / recovering from trauma
3. Negative N Balance
 Intake < output (loss)
 Starvation / Fasting
 Trauma (protein malnutrition, diet low in essential amino acids)
 Wasting
 Poorly controlled diabetes - because amino acids degraded to gluconeogenesis.
AMINO ACID METABOLISM
Transamination
 Primary and 1st step of catabolism of L-amino acids.
α keto acid 1 glutamate

aminotransferase/transaminases
α amino acid α ketoglutarate
 Freely reversible reactions

 Glutamate / αKG obligate pair
 Occur in mitochondria and cytosol
 Vitamin B6 – Pyridoxal Phosphate required for transamination – covalently attach to enzyme
 Thr & Lys do NOT take part in transamination reactions. They lose their alpha amino group by
deamination.
 Proline and hydroxyl proline also doesn’t take part
 Vit. B6 requirements increase with protein intake
Eg: - Alanine transaminase (ALT) / Glu- Pyr Amino Transferase. (GPT)
Pyruvate glutamate
ALT
Alanine α KG

Aspartate transaminase (AST) / Glu – OAA aminotransferase (GOT)
OAA glutamate
AST
Asp α KG
 ALT & AST Important in diagnosis of liver and heart damage, because they are normally
intracellular enzymes.
Oxidative Deamination
 Catalyzed by Glutamate Dehydrogenase enzyme – main pathway for deamination.
NAD(P)+ NAD(P)H + H+
Glu α KG
GDH NH4 +
 Mitochondrial enzyme (matrix)

 Found in high amounts in liver and kidney
 Reversible reaction (but strongly favors glutamate formation)
 Both NAD+ /NADP+/NADH +H+ can be used
 Allosteric enzyme
 α-amino groups can be removed at a high rate.
NAD(P)+ NAD(P)H + H+
Glu α KG
(+) Glutamate Dehydrogenase
Some AAs (-) NH4+
(+) (-) (-)
LOW
Energy GTP High ATP NADH
High Energy

Combined action of transamination and deamination. (Trans-deamination)
Urea cycle
Urea
(Transamination) (Oxidative
deamination)
TCA cycle & amino acid metabolism
 α Keto acids are metabolized and can be used to replenish the TCA cycle.
 Ketogenic amino acids

 Amino acids that only yield acetyl CoA can’t be used for gluconeogenesis, but used for
ketogenesis
 Lys, Leu

 Ketogenic and Gluconeogenic amino acids
 Amino acids that yield both Acetyl CoA and TCA cycle intermediates
 Trp, Tyr, Phe, Ile, Thr
 Gluconeogenic/Glucogenic amino acids

 Yields TCA cycle intermediates, so can be used for gluconeogenesis
 Ala, Asp, Asn, Cys, Glu, Gln, Gly, Pro, Ser, Arg, His, Met, Thr, Val
Degradation of Branched chain amino acids (BCAA)
 Leucine, Valine, Isoleucine
1) Transamination
2) Oxidative decarboxylation (branched chain keto acid dehydrogenase - TPP, NAD, FAD, lipoic
acid, CoA)
3) Dehydrogenation.
Amino Acid Oxidation
 Alternative pathway for AA catabolism other than the Transamination.

Transamination
Trans Deamination
Bacterial urease in GIT
AMP deamination
Adenosine is a coronary
vasodilator.
Production of Ammonia
 At physiological pH it mostly exists as NH4+
Toxicity of NH3
 Symptoms of NH3 toxicity

 Tumors
 Slurring of speech
 Vomiting
 Cerebral oedema
 Particularly toxic to CNS – cross blood brain barrier
1) Depletion of α KG
GDH Glutamine Synthase.

NH4++ α KG Glutamate + NH4+ Glutamine
NADH NAD+ ATP ADP

 High NH4+ levels convert α KG to glutamate and glutamate to glutamine.
 Therefore [α KG] is reduced
 TCA cycle activity reduced
 ATP production impaired
2) Inhibition of Glutaminase
Glutaminase Glutamate
Glutamine isozyme
Glutamate
NH3
GABA
 +
NH4 inhibits Glutaminase
 Therefore [glutamate]↓ [Glutamine]↑
 Glutamate is an excitatory neurotransmitter
 Low neurotransmitter levels synaptic transmission impaired
 Glutamate is required for GABA synthesis
 Gln is osmotically active
 Accumulation leads to brain oedema. (brain swelling and cell death)
3) Neuronal membrane dysfunction
 NH4+ increase permeability of K+ and Cl-

 NH4+ increase 6 Phosphofructokinase activity ↑glycolysis ↑H+
4) High [NH4+] increase transport of Trp Astroglial
high Trp increase [serotonin] and

[quinolinic acid]
Hepatic Encephalopathy
Anorexia, pain insensitivity, insomnia
NH4+ NH3 + H+
 When NH4+ concentration increases equilibrium shifts producing more NH3.

 NH4+ can’t cross the BBB. But NH3 can.
 Therefore, NH3 enters totally to brain.

Alters Mitochondrial
Increased
permeability and Loss of H+ function
Glutamine
transition pores(MPT)
Low ATP and high oxygen Loss of ETC and oxidative

CELL DEATH
reactive agents phosphorylation
Transport of NH3
Glutamine
ATP ADP
Glutamate Glutamine
Glutamine Synthatase
NH3
 Involved in transport of amino acid in AA in blood.

 Needs ATP
 Excessive glutamine transported in to the liver and converted to ammonia and glutamate
 Produced ammonia in liver used to urea synthesis

Glutaminase
Glutamine Glutamate + NH3
H 2O
 2 Isoforms of mitochondrial Glutaminase,

 Liver type - rises in response to high protein intake.
 Renal type - increase in metabolic acidosis where the ammonium is excreted directly
into urine (remove H+ as NH4+ Using NH3)
 Glutamine serves as a fuel for gut, kidney and cells of immune system.
 It removes ammonia in brain by producing glutamine.
Glucose Alanine Cycle
Formation of Alanine by the transmission of pyruvate produced from aerobic glycolysis etc. (in
skeletal muscles)

UREA CYCLE & NITROGENOUS PRODUCTS
Urea cycle
 Intermediates are
 O - Ornithine
 C - Citrulline
 A - Arginosuccinate
 A – Arginine
 Irreversible.
 1st two reactions occur in mitochondria and others in cytosol.
 Occurs in liver and transported to the kidney.
 3 ATP used (needs energy)
 1st N from ammonia and 2nd N from Asp. (Asp is an immediate precursor of Glutamate)
 C from CO2 / HCO3-
 Arginase is present only in liver.
 Dietary ornithine is requiring for continued activity of urea cycle but not dietary aspartate
 Act as both ammonium and bicarbonate disposal.
 From all the excretion products 80% is disposed as urea.
 Urea diffuses from liver transport to kidney and excreted in urine.
 Portion of urea diffuse from blood to intestine.

Bacteria Urase
Urea CO2 + NH3
Bridge between
gluconeogenesis
TCA cycle
Malate
OAA
Glucose
Regulation of Urea cycle.

Rate limiting step
1) Short term regulation.  NH3 provided by Glutamate
by GDH reaction.
 Allosteric enzymes - CPS-1 (Present in mitochondria)

 Carbomyl phosphate is a structural analog of N acetyl glutamate
 In the well-fed state:

 ↑ Glycolysis ↑ Acetyl Co A
 ↑ A.A. uptake ↑ Arginine & ↑ Glutamate
 ↑ Arginase activity & ↑ [ornithine] by dietary arginine
 Therefore ↑ activity of Urea Cycle
 In the fasting state:

 ↑ β oxidation of fatty acids ↑ Acetyl Co A
 ↑ Degradation of proteins ↑ Arginine, ↑ Glutamate & Acetyl CoA
 Again ↑ activity of urea cycle
 Long term regulation - Gene expression.

 The levels of all the enzymes of the urea cycle are influenced by,
 Long term very high protein diet.
 Prolonged starvation (Protein degradation)
Defects in Urea Cycle
 In each enzyme of urea cycle.

 CPS 1 deficiency treated with Arg
 OTC deficiency
 ↑ Carbomyl phosphate & NH3
 ↑ CPS II activity
 ↑ [Orotic acid] - Orotic aciduria
 In the cytosol,
Carbomyl Phosphate + Asp Orotate Uridine
 Often mental retardation and death.
 X linked
 Membrane associated ornithine permease.
 Ornithine permease / translocase / ORNT deficiency.
 N-Acetyl glutamate (NAG) synthase deficiency

 Treated with Carbomyl glutamate – An analogue of NAG
Metabolism in different tissues

Liver.
 Metabolism of amino acids except branched chain amino acids (Val, Leu, Ile) Because liver
has low levels of BCFA.
 Production of non-essential amino acids. (heme, purines)
 Urea synthesis - presence of arginase.
 Plasma protein synthesis. (Albumin etc.)

 Liver amino acid catabolizing enzymes with high Km.
 Only excess amino acids are metabolized.
Skeletal muscle
 Uptake of amino acids for protein synthesis
 Major site for amino acid pool
 Release of amino acids during starvation mainly alanine
and glutamine (During starvation,
 Acetyl Co A↑ from FA oxidation → Inhibit PDH → ↑ Pyruvate → Alanine (from
Transamination)
Small intestine mucosa

 Use Glu and Asp as fuels.
 Metabolize dietary - Glu, Gln, Asp, Asn
 Nucleotide synthesis - rapid cell division
 Use some BCAAs
 Contains urea cycle enzymes including CPS 1 except Arginase because it’s primary role is to
produce Citrulline for use by the liver.
 In the gut Glutamine is mainly used for
 TCA cycle.
 Production of C skeletons of Citrulline, Ornithine, Lactate.
Kidney
 Major site of production of Ser
 Uptake of Gln NH4+ production for acid base regulation
 Also produce the Ala.
Brain
 Uptake of Branched Chain Amino Acids (Val, Leu, Ile)
 Val as an energy source
Degradation of Branched chain amino acids (BCAA)
 Leucine, valine, isoleucine
 Transamination
 Oxidative decarboxylation (branched chain keto acid dehydrogenase – TPP, NAD, FAD, lipoic
acid, CoA)
 Dehydrogenation
Leucine Acetoacetyl CoA
Valine
Propionyl CoA Succinyl CoA
Isoleucine

Metabolism of Cysteine and Methionine
 Methionine is an essential amino acid
 Cysteine is a non-essential amino acid and that can be synthesized from methionine.
 Homocysteine is a toxic intermediate
 Produce free radicals O°, O°°
 Homocysteine is removed via 2 pathways
 Conversion to Methionine by methionine synthase
 Conversion to Cysteine by condensing with Ser
Methionine Cobalamin N5 methyl THF
MS MTHFR
Methyl THF (DNA and

Homocysteine
Cobalamin (B12) RNA synthesis)
Vitamin B6
CBS Serine
(-) Cystathionine
Vitamin B6
CGL
Cysteine
 Deficiency of enzymes that convert Homocysteine to Cysteine

Eg: - Cystathione β synthase, Cystathione γ lyase (CBS and CGL)
 Hypermethionemia
 hyperhomocystenemia CVS and neurological diseases
 homocysteinurea
 Skeletal abnormalities, Mental retardation
 Deficiency of vitamins required for the conversion to methionine (Vit. B12, Folate)
 hyperhomocystenemia (increased level of total HC in urine and plasma.)
 homocystenemia
 Metabolism of Homocysteine involve Folate, Vit B12, Vit B6 and Riboflavin

Glutathione (Y glutamyl cysteinyl glycine)
 Tripeptide
 Widely distributed cytosolic antioxidant
 Protect cells from oxidative damage
 Takes part in amino acid transport across membranes, in kidney tubules
 Reductant (maintain stability of RBC membrane)
 Conjugate with drugs to make them water soluble
 Synthesis of leukotrienes
 Cofactor for enzyme reactions
 Rearrangement of disulfide bonds
γ-Glutamyl cycle in AA transport
 Glutathione is a tripeptide, γ-Glutamyl cysteinyl glycine Transport is catalysed by γ-glutamyl

transpeptidase
 AA reacts with glutathione in the cell membrane forming γ-glutamylamino acid and
cysteinylglycine
 cysteine and glycine residues are
released
 γ-glutamyl amino acid is cleaved
forming free AA and 5-oxoproline,
which is recycled into glutathione.
Insulin
 Contains 2 polypeptide chains with disulphide bonds. (A and B chain)

 1 inter chain s-s bridge (in A chain)
 2 intra chain s-s bridges
Creatine phosphate
 Energy is obtained by hydrolysis of ATP

 But ATP/ADP affect activity of many enzymes
 So ATP cannot be stored in high concentration
 So energy is stored as phosphocreatine for rapid muscle activity
 Creatine phosphate is broken down to creatinine & excreted in urine
 Creatinine production depends on muscle mass

 Declines during first minute of high power output muscle contraction.
 In resting state when ATP production increased than the ATP utilization CP reservoirs refilled.
Creatinine
 Creatinine is usually released from the muscles at a constant rate

 Proportional to muscle mass Can be used to estimate muscle mass
 Muscle mass decreases Creatinine levels falls in urine
 Is removed from the circulation by the kidneys
 Elevates creatinine in the blood and urine in kidney dysfunction
 Relates to impaired renal function
 Creatinine is filtered by the glomerulus, but not secreted or re-absorbed by the renal tubules
Creatinine clearance
Clearance (mL/min) = creatinine excreted per unit time

= (U x V)/P
 U - concentration of the measured analyte in a timed sample of urine (usually 24 hours)

 P - plasma concentration of the analyte
 V - volume of urine produced per minute
Serotonin
 A neurotransmitter in brain
 involved in mood, sleep, appetite, temperature regulation
 Serotonin is produced from tryptophan
 When a protein meal is taken, all amino acids are available in blood; traffic jam occurs in
amino acid transport system so tryptophan the bulkiest amino acid is taken up very
slowly, serotonin production is low, so protein meals cause alertness
 When a carbohydrate rich meal is taken, insulin secretion is increased, will lower the
amino acid concentration in blood, so tryptophan easily enters brain cells, so
carbohydrates will induce sleep.
NO production
 NO, a simple gas

 Soluble in water
 Small and able to diffuse across the membrane,
 Alters the activity of intracellular target enzymes.
 Highly reactive molecule
 Potent vasodilator formed by vascular endothelial Cells
 Short half-life.

NADPH NADP+
Arginine + O2 Citrulline + NO
NOS
 Produced by the NO synthase enzyme, by utilizing Arginine.
Physiological functions
 relaxation of smooth muscle
 inhibition of platelet aggregation
 neurotransmission
 cytotoxicity
 Reduced NO production
 hypertension
 impotence
 susceptibility to infection
 artherogenesis
 Increased NO production
 septic shock
 inflammatory diseases
 neurotransmission
 cytotoxicity
Types of NO Synthase
1) neuronal nitric oxide synthase (nNOS, isoform I) (Ca2+ and Calmoduin dependent)
2) inducible nitric oxide synthase (iNOS, isoform II)
3) endothelial nitric oxide synthase (eNOS, isoform III) (Ca2+ and Calmoduin dependent)
1) Neuronal nitric oxide synthase (nNOS, isoform I)
 Ca2+ dependent, used for neuronal communication
2) Inducible nitric oxide synthase (iNOS, isoform II)

 Involved in regulation of the immune response
 Independent of intracellular Ca2+
 Found in vascular smooth muscle cells and in macrophages and neutrophils.
 Stimulates free radical formation & cell death
3) Endothelial nitric oxide synthase (eNOS, isoform III).

 Vascular endothelial cells
 eNOS is constitutively (constantly) expressed in the endothelium
 Ca2+ dependent
 Vascular regulation
 Inhibition of platelet aggregation

NO in Muscular system
NO signals inhibition of smooth muscle contraction

↓
NO is synthesized from NOS III in vascular endothelial cells
↓
Diffuses to vascular smooth muscle
↓
This causes Guanylyl cyclase to produce cGMP (not membrane bound)
↓
Activation of protein kinase G
↓
Phosphorylation of Ca2+ channels, decreases entry of Ca2+ in the cell
↓
Decreases smooth muscle contraction
↓
This causes muscle relaxation
NO in the heart
 NO-induced relaxation of cardiac muscle

 Unstable and its action is brief within seconds it undergoes oxidation to nitrite or nitrate.
 Nitroglycerin is used as a treatment for angina
 Releases NO in a steady state Glyceryl Trinitrate, commonly used to relieve chest pain caused
by angina
 Dilates coronary arteries by stimulating NO release
 A decrease in NO production contributes to arterial Hypertension
Clinical conditions related to Amino acid metabolism
Alkaptonuria
Homogentisic oxidase
Homogentisic acid Maleyactoacetic acid
 Deficiency of Homogentisate oxidase (enzyme of degradation pathway of tyrosine & phenyl

alanine)
 Excretion of Homogentisic acid
 Autosomal recessive
 Blackening of urine on standing (Homogentisic acid is oxidized to benzoquinone acetate, it is

then polymerized to black colored alkaptone bodies)
 Chronosis → deposition of alkaptone bodies in intervertebral discs, cartilages…
 Ferric chloride test positive.
 Benedict’s test strongly positive.

Phenylketonuria
Phenyl acetate
Phenyl pyruvate
Phenyl lactate
Phenylalanine
Phenylalanine hydroxylase
Tissue proteins
Tyrosine Melanin
Catecholamine
Fumarate
Acetoacetate
 Autosomal recessive
 Deficiency of phenylalanine hydroxylase.
 Accumulation of phenylalanine
 Deficiency of tyrosine
 ↑[Phe] ssues, plasma, urine
 ↑Phenyl lactate, Phenyl acetate, Phenyl pyruvate
 Cause;
 mental retardation
 Failure to talk and walk
 Seizers hyperactivity tremor
 Microcephaly
 Hypopigmentation because high [Phe] competitively inhibit hydroxylation of Tryosine by
tryosinase.
 Treatment- low [Phe] diet. Supply Tyr in diet.
Maple syrup urine disease
 The disorder of the oxidative decarboxylation of alpha keto acids derived from
Branched chain AAs which are Valine, Isoleucine, and Leucine caused by the missing or
defect of branched-chain dehydrogenase.
 The levels of branched-chain amino acids and corresponding alpha keto acids are
markedly elevated in both blood and urine.
 The urine has the odor of maple syrup.

Hartnup disease (was first observed in the Hartnup family)
 Defect intestinal and renal transport of neutral amino acids.

 Tryptophan are precursors of NAD+ and NADP+
 Reduced tryptophan intake
 Results in reduced nicotinamide production
 Dietary deficiency of tryptophan may develop pellagra- like manifestations (photosensitivity
rash), ataxia, and neuropsychiatric symptoms.
 Treatment is to administer niacin (nicotinic acid) and also a high-protein diet
Treatment of Leukemia with Asparaginase enzyme
Asparaginase
Asparagine Aspartate
 This reduce Asparagine available for Leukemic cells since they cannot synthesize it by their
own.
 Cause death of leukemic cells. (Refer Enzymes note)

GLUCONEOGENESIS
 All pathways responsible for converting non carbohydrate precursors to glucose or
glycogen
 During prolonged fasting,
a. No glucose from diet → hepatic glycogen stores are depleted
b. But glucose is essential for RBC(sole), nervous tissue, brain (main), testes, kidney medulla,
embryonic tissue
c. Gluconeogenesis is the only source of blood glucose
d. During an overnight fast → 90% in liver & 10% in kidney
e. During prolonged fasting → 40% in kidney (substrate- Gln)
Importance of gluconeogenesis
1) Maintains glucose levels within a narrow range in blood

2) Maintains level of intermediates of TCA cycle (in skeletal muscles) even when fatty acids are
the main source of acetyl CoA in tissues
3) Clears lactate produced by muscle and erythrocytes
Lactate Pyruvate OAA PEP Glucose (Cori cycle)
4) Clears glycerol produced by adipose tissue

Glycerol Glycerol phosphate DHAP
Glucogenic substrates
 Lactate: The Cori cycle- from exercising skeletal muscle, mitochondria less cells (RBC)
 Amino acids: Except leucine & lysine (which are ketogenic) all other A.A are glucogenic.
Eg: glucose- alanine cycle
 Alanine, Glutamine are the major sources of Glucose during fasting
 Amino Acid α KG OAA
 Glycerol: glucagon activates HS lipase→hydrolyses TAG in Adipocytes→ glycerol & Fatty acids
 Glycerol → transports to liver → forms DHAP (glycerol Kinase is not present in
adipocytes)
 Fatty Acid → Acetyl Co A → no net production of glucose (not glucogenic)
 Odd chain F.A → propionyl Co A → glucogenic
 occurs in cytosol and mitochondria

 Highly energy consuming process (4 ATP, 2GTP, 2NADH required)
 ATP → FA oxidation (mostly)
 NADH → FA oxidation, lactate → pyruvate, malate → OAA
 Not Merely the reverse of glycolysis. Common Intermediates are there
 Bypass the irreversible glycolytic steps

Special enzymes in both pathways in the irreversible steps
Glycolysis Gluconeogenesis
Hexokinase Glucose 6 Phosphatase
PFK1 FBP 1
Pyruvate Kinase Pyruvate Carboxylase and PEP Carboxykinase
 Locations of Enzymes: All cytosolic except,

 Glucose 6 Phosphatase (Endoplasmic Reticulum)
 Pyruvate Carboxylase (Mitochondria)
 PEP Carboxykinase (Cytosol and/or Mitochondria)
Key Regulatory Step

Sources of pyruvate
 From lactate (transported into MT)

 Transamination of alanine (within MT)
Regulation of gluconeogenesis
1) Pyruvate OAA Step
 Pyruvate Carboxylase(PC) (found in mitochondria)

 Use ATP
 Biotin- prosthetic group
 Activated by acetyl Co A
 Inhibited by ADP
 Importance- gluconeogenesis, replenish OAA for TCA cycle in muscle
 OAA cannot cross the mitochondrial membrane. It’s done via following shuttles.
OAA- malate shuttle or OAA- Asp shuttle

2) OAA PEP Step
 PEP Carboxykinase
 In both Cytosol and Mitochondria
 If Substrate Alanine, Cytosolic PEP CK (not subject to allosteric regulation)
 If substrate Lactate, Mitochondrial PEP CK (NADH already produced, no need of
malate/aspartate shuttle)
 Use GTP
OAA PEP
GTP GDP
3) Conversion of fructose 1,6 BP to F6P – KEY REGULATORY STEP
F6P
+F26BP -F26BP
+AMP -AMP
PFK1 F1,6BPase
-ATP +ATP
-Citrate +Citrate
-H+
F1,6BP
 Dephosphorylation of G6P
G6P Glucose
G6Pase
 Liberate free glucose
 Primarily a function of liver to buffer blood glucose level (liver, kidney)
 G6Pase is absent in brain and muscle
 G6Pase is present in ER lumen of hepatocytes and renal cells
 Genetic defects in either G6Pase or T1 (G6P transporter) lead to;
↓
increase in glycogen synthesis
↓
glycogen storage disease (Von Gierke’s disease)
↓
Severe fasting Hypoglycemia

Reciprocal Regulation of Gluconeogenesis & Glycolysis
 Glycolysis and Gluconeogenesis – Reciprocally Regulated to prevent a futile cycle
1) Substrate availability (Ala, glycerol, lactate)
2) Energy state
↑ATP / AMP
 PK inhibited. PEP guided to form glucose
 PFK 1 is inhibited
 F 1,6 Bisphosphatase activated
↓ATP/AMP
 PK activated
 PFK 1 activated Gluconeogenesis Inhibited
 F-1,6- bisphosphatase inhibited
↑ADP
 Pyruvate Carboxylase and PEP Carboxykinase inhibited
3) Allosteric regulation
 Acetyl CoA activates PC
 AMP & F-2,6 BP inhibit fructose-1,6-bisphosphatase
 Citrate & ATP activates Fructose 1,6 Bisphosphatase
4) Covalent Modification
 Glucagon - Phosphorylate Pyruvate Kinase and inactivates it
 Phosphorylate PFK 2 and inactivate it.
 So F 2,6 Bisphosphate level is reduced.

5) Induction & repression
 Glucagon induces glucogenic enzymes
1. F 1,6 BPase
2. PEPCK
3. G6phosphatase
 Glucagon represses glycolytic enzymes
1. GK
2. PFK 1
3. PK
Glucagon stimulates gluconeogenesis in following 3 mechanisms
1) Short term regulation
 Allosteric regulation
 Lowers F2,6BP level so activates F1,6BP and inhibits PFK
 Covalent modification
 Elevation of Cyclic AMP increase cyclic AMP dependent PK activity PK
phosphorylated PK is inactivated
2) Long term regulation
 Induction of enzyme synthesis

 Increase transcription of PEP Carboxykinase gene ↑ availability of this enzyme’s
activity.

Alcohol intoxication
Alcohol DH AldehydeDH
CH3CH2OH CH3CHO CH3COONAD+
NAD+ NADH NAD+ NADH
 Due to ↑NADH/NAD+ ratio; rate of following reactions increases

Pyruvate+ NADH + H+ NAD+ +Lactate
OAA +NADH + H + NAD+ + Malate
DHAP + NADH Glycerol -3-Phosphate + NAD+
 Pyruvate & OAA and DHAP for gluconeogenesis decrease & hence the rate of GNG decreases
 which leads to (Fasting) Hypoglycemia & (Hyperuricemia)
 NADH accumulates. Prevents Lactate Pyruvate. (Lactic acidosis.) Uric acid excretion ↓
 when NADH↑ Fatty acid bio synthesis increases Fatty Liver
 Cytosolic NADH is transported to mitochondria via Malate-Asp shuttle
 It is necessary for OAA transportation from mitochondria to cytosol
 Limits availability of malate & OAA for gluconeogenesis
Because lactate and Urate
compete for the same
*Ethanol Metabolism – 2nd pathway: transporter for secretion
MEOS from renal tubules
Oxidize NADPH to NADP+.
Oxygen free radicles.
Glutathione regeneration reduced.
Alcohol DH
CH3CH2OH CH3CHO
MEOS
NADPH NADP+ + O Radicals

PURINE & PYRIMIDINE METABOLISM
N - Glycosidic bond Ester bond
N base C1 pentose sugar C5 P --- P --- P
Purine - N9 High energy bonds

Pyrimidine - N1
 Purines
1) De Novo Synthesis - base can`t synthesize separately always built upon a PRPP
2) Salvage Pathway
3) Catabolism - no breakage in purine ring just a conversion
 Pyrimidine
1) De Novo Synthesis - primary base orotate is synthesized separately & attach to a PRPP
2) Salvage pathway (few pyrimidines - bases in treating Orotic aciduria)
3) Catabolism - ring is broken
PURINE METABOLISM
 Adenine, Guanine
 Double ringed structures
 Cannot be opened in human cell
 Purine ring primarily constructed in liver
1) De Novo Synthesis
 Energy consuming process

 Which requires;
 Aspartate
 Glycine (only for the purine
synthesis)
 Glutamine
 N5N10 Methenyl - THF
 N10 Formyl - THF
 CO2

 4 major steps,
a) PRPP synthesis
b) Amido - transferase reaction
c) IMP synthesis
d) Conversion to AMP, GMP
 Normal [PRPP] is much less than km value of Amido-transferase reaction.

 So reaction rate is proportional to [PRPP]
 Amidotransferase is subjected to end product inhibition by AMP, GMP, and IMP by converting
active dimer to inactive monomer.
AMP, GMP, IMP
Dimer (active) monomer (inactive)

 IMP is a precursor of adenine and guanine containing nucleotides & it contains “Hypoxanthine”
as the nitrogen (purine) base.
 Both AMP and GMP inhibit de-novo synthesis of purine (inhibit amidotransferase step)
 Reactions above the level of IMP production,

 independent control
 synergistic control
 feed forward activation by PRPP
 Reactions below the level of IMP production,

 Reciprocal control - because the, ATP is needed for conversion IMP to GMP, GTP is needed
for convert IMP to AMP.
 So that total amounts of purine nucleotides & relative amounts of ATP & GTP controlled.
Ribonucleotide Reductase (RNR)
 It converts, Ribonucleoside Diphosphate to Deoxyribonucleoside Diphosphate via a free

radical mechanism.
 It’s a hetero-tetramer which consists with 2 different subunits (R1 & R2)
 This enzyme is,
 inhibited by dATP (important in Adenosine Deaminase deficiency)
 activated by ATP
 RNR is oxidized in the process, so that it should be reduce to regenerate the original
functioning enzyme, which is done by ‘Thioredoxin’ by using NADPH.
Regulation
 Active sites
 Substrate specific
sites
2) Salvage pathway of purine synthesis
 Uses catabolic products of nucleic acids (purine bases) to resynthesize nucleotide

monophosphate.
 Requires less energy than de-novo pathway.

APRT
Adenine + PRPP AMP + PPi
HGPRT
Guanine + PRPP GMP + PPi
HGPRT
Hypoxanthine + PRPP IMP + PPi
[APRT = Adenine phosphoribosyl transferase]

[HGPRT= Hypoxanthine - guanine phosphoribosyl transferase]
Clinical
Lesch-Nyhan syndrome (Juvenile Gout)
 X-linked recessive disease

 Occurs due to HGPRT deficiency
 Symptoms,
 Neurological features (self-mutilations, involuntary movements)
 Hyperuricemia - urate crystals in joints, urate crystals in kidney
HGPRT Deficiency
 HGPRT is an enzyme in the salvage pathway of purine metabolism, which catalyzes the
following reactions,
Guanine + PRPP GMP + PPi
Hypoxanthine + PRPP IMP + PPi
 HGPRT deficiency can lead to hyperuricemia due to,

a) Over production of uric acid due to decreased reutilization
 Because Guanine & Hypoxanthine are not reutilized & they are directed to catabolize into
uric acid, so the uric acid levels increased in the blood (Hyperuricemia).
b) Over production of uric acid due to increased De-novo synthesis

 Because excess PRPP is directed to De-novo synthesis pathway
 Decreased levels of inhibitors - IMP & GMP, leads to stimulation of De-novo synthesis
pathway.
Purine autism
 25% of autistic patients may overproduce purines
 To diagnose, must test urine over 24 hours
 Pink urine due to uric acid crystals may be seen in diapers

3) Purine Catabolism
 Excess nucleotides should be degraded, but most of the ingested (dietary) nucleic acids are
degraded & excreted, because the enzymes which need for purine catabolism are present in
the mucosa of the gut.
 Major sites of purine catabolism,
 Dietary nucleic acids → intes ne mucosal cells
 De-novo synthesized nucleic acids → primarily degraded in liver
 Salvaged by peripheral tissues
Pathway of Purine Catabolism
 Xanthine is the point of convergence for the catabolism of purine bases, & it’s converted to Uric
acid by Xanthine Oxidase.
Nucleotide → Nucleoside → Base → Xanthene → Uric acid
AMP Deaminase
AMP IMP XMP GMP
5’nucleotidase NH3
Adenosine Inosine Xanthosine Guanosine

Adenosine Deaminase
Hypoxanthine Guanine
Xanthine oxidase
Xanthine
Xanthine oxidase
[-]
[-]
Allopurinol further modification

[Purine analog] Uric acid urine
Alantoine Alantoic acid urea

Clinical
Adenosine Deaminase (ADA) deficiency /SCID (severe combined immune deficiency syndrome)
 ADA catalyzes the following reaction,

Adenosine Inosine
 All known ADA mutants structurally perturb active site. (ADA contains a “TIM Barrel” structure)
 ADA enzyme is present in all the cells, but it’s highly active in lymphocytes.
 So,
 ↑ Adenosine, AMP and dATP level
 dATP inhibit Ribonucleotide Reductase (RNR)
 ↓ deoxyribonucleo de levels
 DNA synthesis interrupted
 ↓ T cell B cell growth
 Treatments,
 Bone marrow replacement, enzyme replacement done (Gene therapy)
 Without treatments - die at age 2
Gout (Hyperuricemia)
 Hyperuricemia is increased levels of uric acid in blood, which leads to accumulation of urate
crystals in synovial fluid lead to gouty arthritis, especially in cooler areas like distal limb joints.
a) Primary hyperuricemia
 Mainly due to enzyme dysfunctions (congenital),
 5-PRPP Amido-transferase not sensitive to feedback inhibition

o by nucleotides
 Abnormal PRPP synthetase → no allosteric inhibition → ↑ Purine produc on

↑PRPP produc on ↓
↑ Purine breakdown
 Deficiency of salvage enzymes → ↑PRPP produc on & ↓ purines → ↓
Inhibit feedback inhibition → ↑PRPP ↑ Produc on of uric acid
E.g.: Lesch-Nyhan syndrome
 Glucose 6 phosphatase deficiency → ↑Glucose 6 phosphate →

↑ HMP pathway → ↑Ribose 5 phosphate → ↑PRPP
(Von-Gierke disease)
 Lactic acidosis can be occurred

b) Secondary hyperuricemia
1. Increased turnover of nucleic acids

 Rapidly growing malignant tissue
 Increased tissue breakdown
2. Reduced excretion of urate
 Thiazide diuretics, renal glomerular dysfunction, chronic lead intoxication
 Lactic acidosis - lactic acid and uric acid both compete for the same transporter to secrete
3. Combined
 High alcohol intake
 Von Gierkes disease (overproduction, reduce renal excretion)
 Treatments for gout:

 Allopurinol - suicide inhibitor of xanthine oxidase
 Uricosuric drugs
Eg: - Probenecid, Sulfinpyrazone - ↓ reabsorp on of uric acid (under excretors)
 Reduce alcohols & dietary purine intake (meat, sea food)
 Colchicine - anti-inflammatory agent
Drugs related to Purine metabolism
Dihydrofolate synthase Dihydrofolate reductase

PABA folic acid Tetrahydrofolate
Sulphonamide[Antibiotic] DHF Methotrexate[ Anticancer] THF
Trimethoprim[Antibacterial]
Sulphonamide → Is a structural analogue of PABA [para amino benzoic acid]

 So, it binds with and competitively inhibits dihydrofolate synthase & inhibits folic acid
synthesis in microorganism.
 Folic Acid is required to from THF which is in from need in purine synthesis
 Humans do not synthesize folic acid, but obtain it from diet.
 Sulphonamides can be used as an antibiotic without affecting Humans.
Methotrexate → Is a structural analogue for folic acid

 Methotrexate competitively inhibits Dihydrofolate reductase.
 Dihyrofolate reductase is needed for synthesis of THF which is needed in purine
synthesis.
 Leukemia consists of rapidly dividing white blood cells. Any drug that
 Rapidly dividing cells have high demand of purines for DNA replication blocks nucleotide
 Decreases in purines have more effect on cells with high demand synthesis will
 Methotrexate is used as a drug for leukemia regulate
neoplastic cells

IMP dehydrogenases
IMP Xanthosine monophosphate GMP
Mycophenolic acid - reversible uncompetitive inhibitor of IMP dehydrogenase.

 T, B cell division is impaired
 Used to prevent graft rejections
PRPP amidotransferase
PRPP Phosphoribosyl amine
Glutamine Glutamate
 These two are glutamine antagonists
Mercaptopurine  The reaction cannot go ahead without glutamine
Azaserine (diazo acetyl – L – serine)  So purine synthesis is blocked at PRPP.
 PRPP accumulates
PYRIMIDINE METABOLISM
 Thymine, Cytosine
 Uracil (only in RNA)
 Single ringed structures
 Can be opened in human cell
 Easily opened and degraded to soluble β-alanine and β-amino isobutyrate
1) De Novo Synthesis
2 ATP + Glutamine + HCO3 -

↙ + PRPP, ATP
Key regulatory & 2 ATP + Glutamate Carbamoyl P synthetase ΙΙ (in cytosol)
committed step in + Pi ↖ - UTP, UDP CAD
mammals
Carbamoyl Phosphate (multi-
functional
↙ + ATP
Aspartate Aspartate Transcarbomoylase Polypeptide)
↖ - CTP
Carbamoyl aspartate
Prokaryotic cells
Mitochondrial enzymes
Orotate

 Mammalian CPS-2 is inhibited by UTP & activated by PRPP.
 Prokaryotic aspartate transcarbomoylase is inhibited by CTP and activated by ATP
Orotate
PRPP
Orotate phosphoribosyl transferase
irreversible
2Pi PPi OMP
H2O
OMP decarboxylase ← - UMP, CMP
CO2
UMP
Two domains of one enzyme - UMP synthase
Deficiency;
 Anaemia
 Increased excretion of orotate in urine
OMP decarboxylase: The most catalytically proficient enzyme
 Another mechanism for decarboxylation

 A high energy carbanion intermediate not needed
 No cofactors needed
 Some of the binding energy between OMP and the active site is used to stabilize the transition
state (“Preferential transition state binding”)

NADPH +H+ NADP+
Thioredoxin reductase
UMP Reductive Oxidized

Thioredoxin Thioredoxin
UDP dUDP
Ribonucleotide reductase
UTP
dUMP
CTP Synthase
(add amino group from glutamine)
CTP
Methylene H4 folate
[Permanently
bind to enzyme]
[-] 5-FdUMP
Thymidylate
Tetrahydrofolate
synthase
[-] Methotrexate
Dihydrofolate
NADPH + H+ reductase
Dihydrofolate
dTMP
NADP+
5 florouracil
[Thymine analogue
- suicide inhibitor]
Orotic aciduria
 Absence of orotate phosphoribosyl transferase or OMP decarboxylase or both

 Retarded growth, anemia
 Can also occur due to Ornithine transcarbomylase deficiency, allopurinol-compete with OPT
 give uridine, cystidine as treatment
 then they Converted to UTP, CTP by salvage pathway & inhibit pyrimidine synthesis process
OTC
Ornithine Citrulline
Carbamoyl phosphate

OTC deficiency
↑ Carbamoyl phosphate in Mitochondria & cytosol

↓
↑ Convert to carbamoyl aspartate
↓
↑ Pyrimidine synthesis
↓
↑ Production of orotic acid
↓
Orotic aciduria
↓
Hyperammoneamia NH3 ↑
↓
Mental retardation & death
Association of HMP pathway in nucleotide synthesis
HMP pathway
NADPH Ribose -5- P

↓ ↓
Pyrimidine synthesis purine synthesis
2) Salvage of pyrimidines
 Few are salvaged in humans

 Pyrimidine nucleosides nucleoside kinases (uses ATP)
 Basis for using uridine/cytidine for treatment of orotic aciduria
3) Pyrimidine Catabolism
 Easily opened and degraded to soluble liver -alanine and -amino isobutyrate
Cytosine Thymine
NADPH
Uracil Dihydro thymine

NADP+
Dihydro Uracil -amino isobutyrate
-Alanine

METABOLIC INTEGRATION & FEED FAST CYCLE
Metabolic Integration
 In living systems numerous metabolic pathways are operating simultaneously, and also they are
connected with each other.
 So, each pathway needs to be able to “sense” the status of the other pathways.
 Metabolism attempts to fulfill 3 needs of the organism,
 ATP
 Reducing power (NADPH, NADH)
 Building blocks for biosynthesis
 Metabolic integration can be discussed according to 5 major guidelines. (W4H1)

 When - Fed/Fasting state
 Where – Contributing organs
 Who – Controlling Hormones
 What – Metabolic pathways & their intermediates
 How – Regulatory mechanism
 Fed/Fasting State (Refer feed fast cycle)

 Contributing organs
 Four major organs,
 Liver
 Skeletal muscle
 Adipose tissue
 Brain
 Partially,
 Intestine (in fed state)
 Kidney (in fasting state)
 Controlling Hormones
 Primarily
 Insulin
 Glucagon
 Secondarily (supporting role)
 Catecholamines (Epinephrine & Norepinephrine)
 Counter regulatory hormones (opponents of Insulin)
 Glucagon
 Catecholamines
 Cortisol
 Growth Hormone
Actions of Insulin (Actions related to catabolism)
 Recruitment of GLUT4 transporters

 Inhibit HSL by Dephosphorylation
 Expression of LPL gene

 Stimulates protein synthesis by activating translation initiating factors
 Inhibition of enzymes required for Glycolysis & Gluconeogenesis
 Activation of AC Carboxylase enzyme.
Actions of Glucagon (Actions related to Catabolism)
 Activation of enzymes required for Glycogenolysis & Gluconeogenesis

 Inhibition of AC Carboxylase enzyme
 Increase uptake of Amino Acids by liver.
 Glucagon plays a role in lipolysis in adipose tissue but the major activators of HSL, are the
Catecholamines.
 Both Insulin & Glucagon affects the gene transcription of related enzymes.
Major metabolic pathways & their intermediates
 Metabolic Pathways
 Glycolysis  Gluconeogenesis
 Glycogen Synthesis  Glycogen Breakdown
 FA & Cholesterol synthesis  FA β oxidation
 TCA Cycle  HM Pathway
 Urea Cycle  AA metabolism
 Major Intermediates
1) Pyruvate
Alanine
Lactate
(LDH)
OAA (PC)
Glycolysis Pyruvate Acetyl CoA

(PDH)
Glucose
AA (Gluconeo
Degradation genesis)
Lactate
(LDH)

2) Acetyl CoA
NAG
synthesis
(Urea cycle)
AA
(degradat TCA Cycle
ion)
KB FA
(ketolysis) synthesis
Acetyl
CoA
FA (beta KB
oxidatio) synthesis
Pyruvate Cholesterol
(PDH) synthesis
Aerobic
Glycolysis
Ethanol
Oxidation
ETC
NADH
Beta
Oxidation
Pyruvate
to lactate
PDH
Reaction TCA Cycle

Regulation Of Metabolic Pathways
Short term regulation

Long term regulation
a) Substrate availability (min)
a) Induction and synthesis of enzyme
b) Allosteric regulation (min) synthesis (days)
c) Covalent modification (min-hours)
Compartmentalization
 Metabolic fate of certain molecules depends on their location, which is regulated by location of
their relevant transporters & enzymes.
Feed Fast Cycle
1) Fed/absorptive state (Just after meal)
 High plasma levels of glucose, amino acids, TAG(chylomicrons)

 Stimulation of pancreatic islet cells → secrete insulin
 ↑ Insulin/glucagon = 10:1
 ↑ Synthesis of glycogen, TAG& protein to replenish fuel stores-anabolic period
 All tissues - use glucose

Liver (nutrient distributing center)
 Portal blood is rich in absorbed nutrients and insulin secreted from pancreas.
Carbohydrate
 ↑ Supply of glucose to liver via portal vein.

 ↑ Glucose uptake by hepatocytes via GLUT-2
 insulin independent
 Km high
 uptakes only when blood glucose level is high
 ↑ Glucose 6 Phosphate (Glucokinase activity)
Activation of glycogen synthase

↑ Glycogenesis 1) Allosteric activation by G6P
2) Dephosphorylation by insulin
G6P ↑
G6PD Activated
↑ HMP Pathway
NADP/NADPH ↓
LCFA ↑
Glucose 6
phosphate ↑
↑ Glycolysis FA Synthesis
(Insulin/glucagon Acetyl CoA

high, hepatic PK
activated) TCA Cycle
Inactivation of PC,
↓ Gluconeogenesis PEPCK, FBP 1,
G6Pase
Fat
 Liver is the primary tissue for de novo synthesis of fatty acids.

 Fat is not stored in liver.
a) Increased FA synthesis
↑ Metabolism of ↑ Acetyl CoA

dietary glucose and AA
↑ FA synthesis
↑ HMP ↑ NADPH

b) Increased TAG synthesis
Hydrolysis of TAG component

of chylomicron remnant
FA
De novo synthesis Utilized by

TAG VLDL muscle and
adipose tissue
Glycerol 3
Glycolysis
Phosphate
Proteins
 Metabolism of all amino acids except Branched Chain Amino Acids (Val, Leu, Ile)
 Liver AA catabolizing enzymes with high Km
 Therefore, only excess AA are catabolized
 Liver t-RNA charging enzymes low Km
 Ensures metabolism of AA for hepatic protein synthesis
a) ↑ Protein synthesis
 Only a transient increase in synthesis of hepatic proteins resulting in replacement of any
proteins that may have been degraded during fasting period.
b) ↑ AA degradation(excess)
 More AAs are present than the amount that the liver can use in the synthesis of proteins
 Excess is not stored but either released to blood or deaminated.
 Resulting C skeletons
NH3 Group - ↑Urea synthesis

AA deamination
C Skeleton - Degraded to Pyruvate, Acetyl CoA &
TCA cycle intermediates → used for FA synthesis
Adipose tissue (energy storage depot)
Carbohydrate
 ↑glucose uptake - Insulin dependent GLUT-4

 ↑ glycolysis → ↑ glycerol 3 phosphate (utilized for TAG synthesis)
 ↑HMP → ↑ NADPH

Fat
 ↑ Synthesis of FA (not a major source of FA Synthesis)

Chylomicron Lipoprotein lipase
VLDL FA
↑ TAG synthesis
 ↑ Glycolysis ↑ Glycerol 3 phosphate
 ↓ degradation of TAG,
 ↑ Insulin/Glucagon → inactivation of HSL
Resting skeletal muscle
Carbohydrate
 Skeletal muscle is unique in being able to respond to substantial changes in the demand for
ATP that accompanies muscle contraction.
 ↑ glucose uptake by GLUT 4
 ↑ Glycolysis - to provide energy needs.
 ↑ Glycogen synthesis (Particularly if glycogen stores have been depleted as a result of
exercise.)
Lipids
 FAs are released from VLDL & Chylomicrons – lipoprotein lipase

 However fatty acids are of IIry importance as a fuel for muscle during well fed state in
which glucose is Iry energy source.
Amino acids
 ↑ Protein synthesis
 ↑ uptake of branched chain AAs (principle site for degradation of the BCAA)
Brain
Carbohydrate
 Brain uses glucose exclusively as a fuel (GLUT 1)

 No significant stores of glycogen.
 Therefore, completely dependent on the availability of blood glucose.
Lipids
 No significant stores of TAG.

 Oxidation of FAs provides little contribution to energy production (protein bound FA cannot
cross BBB)

Intestines
 Assembly of dietary TAG to Chylomicrons lymphatic blood

 Metabolize amino acids (Aspartate, Asparagine, Glutamate, Glutamine)
2) Fasting state
 ↓ Glucose, AAs & TAG plasma levels.

 ↓ insulin/glucagon
 Degradation of TAG, glycogen & proteins.
 Two priorities: -
1. Need to maintain adequate plasma levels of glucose to sustain energy by metabolism of
brain, RBC & other glucose requiring tissues.
2. Need to mobilize FAs from adipose tissue & the synthesis & releasing of ketone bodies from
the liver to supply energy to all other tissues.
Liver
Carbohydrate
 Primary role - maintenance of blood glucose level by

 Glycogen degradation
 Gluconeogenesis
 ↑ glycogen degradation
 Glycogen phosphorylase - activated
(↑ Glucagon and epinephrine levels→ phosphorylates glycogen phosphorylase)
 Glycogen is nearly exhausted after 10-18 hours of fasting
 Hepatic glycogenolysis is a transient response to early fasting
 ↑ gluconeogenesis
 Substrate
 Proteins → Gluconeogenic AA
 TAG → Glycerol
 Muscle → Lactate

↑ Glucagon
Induction of PEPCK Phosphorylate hepatic

synthesis ↑ Phosphorylate pyruvate kinase (inactive)
PFK2 (inactive)
F-2, 6-BP
FBP-1 inhibition ↓ PFK 1 actively inhibited
Gluconeogenesis ↑ Glycolysis ↓
Pyruvate carboxylase PDH
In adipose tissue, FA oxidation → Acetyl CoA
Lipids
 ↑ glucagon/insulin ratio - Phosphorylates Hormone sensitive lipase (active form)
a) ↑ FA oxidation
↓ Malonyl CoA (inactivation of ACC by phosphorylation)
CAT-1 activated (carnitine shuttle)
NADH FADH2 Acetyl co A (facilitate PC)
Energy via ETC Gluconeogenesis
b) ↑ ketone body production

 ↑ FA oxidation → ↑ acetyl CoA (exceeds liver’s oxidative capacity of the TCA cycle)
 What is the importance of making ketone bodies?
 Small water soluble molecules
 Energy source for most tissues including brain during high plasma concentration
 Reduce gluconeogenesis from AA carbon skeleton preserving essential proteins
 Liver cannot utilize ketone bodies - liver lacks thiophorase, an enzyme needed for its
degradation.

Adipose tissue
Carbohydrate
 ↓ glucose uptake & metabolism

 ↓ glycerol-3-phosphate
 ↓ acetyl CoA
Lipids
 ↑ Degradation of TAG - Activation of HSL

 ↑ Release of FA - Transported to various tissues
↑Glycerol → glycerol phosphate → gluconeogenesis (liver)
 ↓ Uptake of FA - Inhibition of LPL
Resting skeletal muscle
Carbohydrate
 ↓ Uptake
Lipids
 During first two weeks’ muscles use FAs

 FAs ← adipose
 Ketone bodies ← liver
 After about 3 weeks
 ↓ use of ketone bodies
 & oxidizes FAs almost exclusively
 So ↑ ketone body concentration in plasma
Proteins
 During the first few days, there is some breakdown of protein → AAs → gluconeogenesis
 Mostly Alanine & Glutamine
 Catabolism of branched chain AAs
 By several weeks’ rate of proteolysis decreases
 After several weeks of starvation, when ketone bodies also reduce, proteolysis begins
Brain
Carbohydrate
 Exclusively uses glucose

 After 2 or 3 weeks → Ketone bodies becomes the Iry fuel

Kidney
Carbohydrate
 Late fasting 50% of gluconeogenesis occurs in kidney
Glutaminase
& GDH
BCAA breakdown (Muscle) → Glutamine α-KG + NH3
Substrate for Compensates the

gluconeogenesis acidosis accompanied
by ketogenesis.

Feed fast cycle - Summery

DIABETES MELLITUS
Diabetes
Diabetes Mellitus Diabetes Insipidus
Diabetes Mellitus
 Metabolic disorder of multiple aetiology.

 Characterized by chronic hyperglycaemia due to relative or absolute deficiency of
insulin.
 “Starvation among plenty”
 Due to defects in insulin release, action or both.
Functions of insulin in cells.
 Effects of carbohydrate metabolism
 Acts on liver, muscles and adipose

 Muscle
 Increase glycogen synthesis
 Increase GLUT 4 transporters thereby increase glucose uptake
 Liver
 Increase glycogen synthesis
 Inhibit gluconeogenesis and glycogenolysis
 Adipose
 Increase GLUT 4 transporters thereby increase glucose uptake
 Effects on lipid metabolism
 Decrease TAG degradation

 By inactivating hormone sensitive lipase by dephosphorylation
 Increase uptake of FAs from VLDLs and chylomicrons
 By increasing the activity of lipoprotein lipase
 Increase TAG synthesis from the FAs taken in
 2 types: -
1) Type 1 diabetes
2) Type 2 diabetes

1) Type 1 Diabetes Mellitus (IDDM)
 Complete absence of insulin production.

 Due to destruction of β cells in Islets of Langerhans resulting from autoimmune
reactions within the body.
 Leads to deficiency of insulin.
 Blood insulin levels do not increase in response to glucose.
Metabolic changes in uncontrolled type 1 DM
1. Hyperglycaemia
Deficiency of Insulin Decreased activity of GLUT 4 Reduced uptake of

transporters in adipose tissue glucose in the peripheries
and skeletal muscles
Hyperglycaemia
Accelerated hepatic
gluconeogenesis using amino acids
obtained from peripheral tissues
2. Hypertriacylglycerolemia
Starved state within cells Increased lipolysis in Increased transport of

adipocytes and Fatty Acids to liver
mobilization of Fatty Acids
Excess Fatty Acids converted

to TAG and transported in
blood as VLDL
Decreased synthesis and Reduced degradation of

Hypertriacylglycerolemia
activity of lipoprotein lipase VLDL and chylomicrons

3. Ketoacidosis
Increased mobilization β oxidation of Fatty acids and Ketoacidosis

of fatty acids to the liver production of ketone bodies
(acetoacetate and 3-hydroxybutyrate)
2) Type 2 Diabetes Mellitus
 Result of insulin resistance in peripheral tissue coupled with insufficient production of

insulin by dysfunctional β cells. (Partial insulin deficiency with insulin resistance.)
Insulin resistance
 Decreased ability of the target tissues (liver, adipose and muscles) to respond to
normal circulating concentrations of insulin.
 Caused by weight gain and obesity.
 Insulin resistance itself does not cause type 2 DM. Initially with insulin resistance,
insulin secretion by β cells increase causing hyperinsulinemia.
 However, with time β cells dysfunction and insulin secretion decreases leading to type
2 DM.
Metabolic changes in type 2 Diabetes Mellitus
1. Hyperglycaemia
Deficiency of Insulin Decreased activity of GLUT 4 Reduced uptake of

& insulin resistance transporters in adipose tissue glucose in the peripheries
and skeletal muscles
Hyperglycaemia
Accelerated hepatic
gluconeogenesis using amino acids
obtained from peripheral tissues

2. Hypertriacylglycerolemia
Starved state within cells Increased lipolysis in Increased transport of

adipocytes and Fatty Acids to liver
production of Fatty Acids
Excess Fatty Acids converted

to TAG and transported in
blood as VLDL
Decreased synthesis and Reduced degradation of

Hypertriacylglycerolemia
activity of lipoprotein lipase lipoproteins
 Ketosis is usually minimal/absent because of presence of insulin even with insulin

resistance restrains hepatic ketogenesis.
Glucose homeostasis
 The body naturally tightly regulates blood glucose levels as a part of metabolic
homeostasis.
Phases of glucose homeostasis
Phase Duration Origin of glucose Tissues using glucose Major fuels

of brain
1 Well-fed state Exogenous All Glucose
Glycogenolysis, All except liver, muscle
2 After 6-12 hrs of fasting Hepatic and adipose tissue at Glucose
Gluconeogenesis diminished rates
All except liver, muscle
Hepatic
and adipose tissue at
3 After 20 hrs of fasting Gluconeogenesis, Glucose
rates intermediate
Glycogen
between phase 2 and 4
Brain, RBC, renal Glucose,
After several days of Gluconeogenesis
4 medulla, small amount Ketone
fasting (Hepatic ,Renal)
by muscles bodies
Ketone
Brain at a diminished
After prolong starvation Gluconeogenesis bodies,
5 rates, RBC, renal
(after 2-3 weeks) (Hepatic ,Renal) Glucose
medulla

Enzymes active in phosphorylated form
 Glycogen phosphorylase
 Fructose 2,6 BP
 HSL
 In the Glucogenic state of the liver, when glucagon/insulin is high, action of glucagon
converts them to the phosphorylated form and activates them.
 In lipogenic state, glucagon/insulin is low and these enzymes are inactivated.
 Other enzymes are activated in lipogenic state
(Eg: - PFK2, glycogen synthase, ACC)
 These enzymes are activated by dephosphorylation.
Metabolic profiles of various tissues
 Liver as fuel provider for other tissues

 Glucose provider - Glycogenolysis < gluconeogenesis
 Fatty acid provider - Excess fuel converted to triacylglycerol then to VLDLs
Provide fatty acids to other tissues or for storage in adipose tissue
 Ketone body provider - Soluble form of fatty acid fuel
 Produced when blood glucose level is low
Metabolic Profiles
Liver
 Fuel(s) - Major fuel fatty acids

 Fuel use(s) - Biosynthesis of glucose, fatty acids, glycogen, triacylglycerol, cholesterol,
bile salts, proteins, urea
 Main metabolic pathways - Metabolic hub
 Carbohydrate
 Incoming - glycolysis, glycogenesis, Lipogenesis, ETC, Citric acid cycle
 Low blood glucose - glycogenolysis, gluconeogenesis
 Lipid
 Incoming - fatty acid oxidation, citric acid cycle, ETC, Cholesterol synthesis,
Ketone body synthesis
Skeletal muscle
 Fuel(s)
 Resting muscle - fatty acids
 Highly active muscle
 Initially - glycogen
 During intense exercise - G-6-P, lactate

 When glycogen stores are depleted - free FAs provided from increased
mobilization of TAGs from adipose tissue
 Fuel use(s) - contraction, active transport (Ca2+)
 Main metabolic pathways
 Resting muscle(aerobic) - fatty acid oxidation, Citric acid cycle, ETC
 Highly active muscle (anaerobic) - glycogenolysis, glycolysis.
Adipose tissue
 Fuel(s) - major fuels glucose, fatty acids

 Fuel use(s) - biosynthesis of triacylglycerol, fatty acids synthesis (high blood glucose)
 Main metabolic pathways - glycolysis, fatty acid oxidation, citric acid cycle, ETC,
triacylglycerol synthesis, lipolysis.
Brain
 Fuel(s) - glucose is prime fuel. Uses 120g per day

 Fuel use(s) - active transport, (Na+, K+), biosynthesis
 Glucose uptake - transporter of half-saturated at 1.6 mM
Normal blood glucose level ~ 5 mM (90% mg)
Hexokinase saturated at 0.5 mM
Hypoglycaemic danger level 2.2 mM (40% mg)
 Main metabolic pathways - totally aerobic metabolism; glycolysis, citric acid cycle,
electron transport chain
Heart Muscle
 Fuel(s) - main fuel fatty acids

 Fuel use(s) - contraction, active transport (Ca2+)
 Main metabolic pathways - totally aerobic metabolism, fatty acid oxidation, citric acid
cycle, ETC
Kidney
 Fuel(s) - major fuels glucose, fatty acids

 Fuel use(s) - active transport, biosynthesis(glucose)
 Main metabolic pathways
 Normal conditions - glycolysis, fatty acid oxidation, citric acid cycle, ETC
 During starvation - gluconeogenesis

Embryology
Embryology
Oogenesis
Oogenesis begins in fetal life.

Spermatogenesis
Spermatogenesis – All the events by which spermatogonia are transformed into spermatozoa
begins at puberty.

First week of development
Fertilization
  Male (sperm) and female (ovum) gametes fuse. 

 Occurs at the ampullary region of the uterine tube. 
1. Deposition of sperms in the female genital tract.

2. Movement of sperms to the isthmus of uterine tubes. (self-propulsion by flagellum/tail,
muscular contraction of uterus)
3. Capacitation
o A modification of sperms increasing its motility and the capability to fertilize. (Only
capacitated sperms can pass through corona radiata and undergo acrosome reaction)
o Epithelial interaction between sperm and mucosal surface of uterine tube – removal of
glycoprotein coat and seminal plasma proteins from the plasma membrane that overlies the
acrosome region of the sperm
o In uterine tube – lasts for 7 hours
4. Movement towards the ampulla – meet the ovum
5. Penetrate the corona radiata (Only the capacitated sperms)
6. Penetration of zona pellucida
a. Acrosome reaction
i. Induced by zona proteins (After binding to zona pellucida)
ii. Acrosin / Trypsin-like-enzymes (proteases) released – digestion of zona pellucida
b. Cortical reaction
i. Release of lysosomal enzymes from cortical granules lining the plasma
membrane of the oocyte.
ii. Induced by contact of head of sperm with oocyte surface.
iii. Enzymes prevent further penetration of sperms and inactivate receptors on zona
surface by altering the composition of the zona pellucida. [the changes of the zona
pellucida is called the – zona reaction]
iv. Prevents polyspermy.
v. Oocyte membrane becomes impenetrable to other spermatozoa.
vi. DID YOU KNOW – that there are receptor sites for sperms on the zona which are
species specific.

i Fusion of oocyte and sperm cell membrane.
a. Oocyte membrane and membrane that covers the posterior region the sperm head.
b. Why?????
c. Both the contents of the head and tail of the sperm enter the oocyte leaving behind the plasma
membrane of the sperm.
ii Resumption of second meiotic division. (which is arrested in meiosis II of metaphase)
a. Immediately after the entry of spermatozoon.
b. Oocyte completes meiosis II.
c. Divides into a definitive oocyte and a second polar body.
i. Definitive oocyte
1. Contains the majority (almost all) of the cytoplasm of the ovum.
2. 22+X chromosome in a vesicular nucleus – female pronucleus
ii. Second polar body
1. Hardly any cytoplasm.
2. 22+X chromosomes.
3. Functions in removing the sister chromatids of the secondary oocyte – halving the
amount of DNA.
iii Metabolic Activation of oocyte
iv Fusion of male and female pronuclei.
a. Paternal
i. The male pronucleus moves toward the female pronucleus ;)
ii. The nucleus of the sperm (now inside the ovum) swells – called the male pronucleus
iii. The tail and mitochondria of the sperm degenerates
iv. DID YOU KNOW – that you cannot distinguish male and female pronuclei by external
appearance
b. Replication of DNA in each pronucleus
c. Chromosomes arrange in a spindle
d. Longitudinal splitting of DNA – sister chromatids move to opposite poles
e. Plasma cleavage resulting in two diploid daughter cells
10. Initiation of cleavage

RESULTS OF FERTILIZATION
 Restoration of the diploid number of chromosomes. (zygote contains a new combination

of chromosomes different from both parents)
 Determination of chromosomal sex.
 Initiation of cleavage. (without fertilization oocyte degenerates 24 hrs after ovulation)
CLEAVAGE
  The two celled zygotes undergo a series of mitotic divisions. 

  BUT – Not as other cells- these cells do not GROW IN SIZE during their cell cycle. 
  Therefore, the total plasma content remains the same. 
  But the number of cells increase. 
  Therefore, the size of each cell reduces after each cleavage. 
  BUT – DNA replication occurs – Therefore amount of DNA increases – All cells are diploid 
 These cells are called – BLASTOMERES 
 Cell stage  Zygote

Loosely arranged clumps
 4 cell stage
 8 cell stage  - Cells maximize contact with each
other.
- Cells hold together by tight
junctions. (compactation)
- Segregate into inner and
outer cells (communicate with gap
junctions)
 16 cell stage  morula  Inner cell mass

(By 3rd day) Outer cell mass

Eventually
 The Inner cell mass
become the – Embryo Proper –
Baby 
 Outer cell mass –
Trophoblast – Placenta 
WHAT IS THE STAGE OF THE

EMBRYO WHEN IT ENTERS THE
UTERINE CAVITY? – ‘Morula’
(Morula enter uterine cavity
in 4th day)
BLASTOCYST FORMATION
 Fluid in the uterine
cavity penetrates the zona
pellucida into the intercellular
spaces of the inner cell mass. 
 Intercellular spaces
become confluent and forms a single cavity – blastocoel 
 At this time, the embryo is called the –
BLASTOCYST 
BLASTOCYST
 Outer cell mass (trophoblast) flattens to form the epithelial wall of the blastocyst. 
 Inner cell mass (embryoblast) is concentrated to a pole of the blastocyst. 
 The fluid filled cavity between the abembryonic pole and the embryoblast is the blastocoel.

HATCHING
 The embryo getting out of the zona pellucida on the 5th day.
IMPLANTATION
 On the sixth day. 
 Trophoblastic cells over the embryoblast pole penetrate into the uterine endometrium. (mucosa)
 The endometrium is in the – SECRETORY PHASE 
 SECRETORY PHASE 
o Coiled uterine glands
o Coiled uterine arteries
o Glycogen granules found in cells
 Implantation occurs usually in the posterior (or anterior) wall of the uterus.
(Where it becomes embedded between the openings of the glands)

SECOND WEEK OF DEVELOPMENT – The week of twos
At the beginning – Blastocyst is partially embedded in the endometrial stroma. The embryonic pole of
the blastocyst is facing the endometrium.
TWO number ONE

The trophoblast over the embryoblast differentiates into the following by day 8.
1. Cytotrophoblast
a. The inner layer of trophoblast
b. Made out of cells
c. Cells divide (mitotic figures found)
2. Syncytiotrophoblast
a. Outer layer of the trophoblast
b. Multinucleated zone without distinct cell
boundaries, therefore called syncytium
c. Cells from cytotrophoblast migrate into
syncytiotrophoblast, fuse and lose their cell
membranes
TWO number TWO

The embryoblast differentiates into two layers
1. Hypoblast layer
a. Adjacent the blastocyst cavity
b. Cuboidal cells - these form the exocoelomic cavity/primitive yolk sac/Heuser’s membrane
by migrating to the abembryonic pole
2. Epiblast layer
a. Amniotic cavity – between epiblast and amnioblasts
b. High columnar cells

TWO number THREE
Two cavities appear
1. Amniotic Cavity
a. A cavity named ‘AMNIOTIC CAVITY’ develops in the epiblast.
1. Cells towards the cytotrophoblast are called the – amnioblasts
2. Cells towards the hypoblast - Epiblast
Therefore, the amniotic cavity is surrounded by amnioblasts in one pole and epiblast layer in the
opposite pole
2. Primitive Yolk Sac/ Exocoelomic cavity

a. Cells from the hypoblast migrate and line the inner surface of the cytotrophoblast of the
abembryonic pole.
b. Thin/flattened cells
c. The lining is called the ‘exocoelomic membrane’ / Heuser’s membrane
The blastocyst is more deeply embedded in the endometrium and the penetration defect is closed by
a fibrin coagulum by day 9. Later the coagulum is replaced by endometrial surface epithelium.
Also, on day 9 syncytial vacuoles appear at embryonic pole, thus called lacunar stage of trophoblast .
Days 11 & 12
Uteroplacental circulation is established.
STATE OF THE ENDOMETRUIM [Decidua reaction]

  Odematous 
  Highly vascular – spiral arteries – later the capillaries become congested and dilated - sinusoids 
  Large tortuous glands which secrete glycogen and mucus 
 Cells become polyhedral and loaded with glycogen & lipids 
DEVELOPMENT OF THE TROPHOBLAST

Development in the embryonic pole is faster than that of the abembryonic pole.
Syncytiotrophoblast
1. Vacuoles develop -> vacuoles fuse -> form lacunae [lacunar stage of the trophoblast] - day 9
2. Penetrates deeper and erode endothelial lining of maternal sinusoids / capillaries
3. Maternal blood enters the lacunar system – [Uteroplacental circulation] - days 11 & 12

By the 13th day of development the uteroplacental circulation extends to the abembryonic pole as well. If
the implantation site of the endometrium is not healed properly, bleeding occurs and can be confused as
normal menstrual bleeding. – Leads to inaccuracy of the expected delivery date
Cytotrophoblast
1. Columns of cells develop into the syncytium. - day 13
2. Known as ‘Primary Villi’ (outer layer of syncytiotrophoblast surrounding core of cytotrophoblast)
DEVELOPMENT OF THE EXTRAEMBRYONIC MESODERM (days 11 & 12)

 Cells derived from the yolk sac occupy the space between the cytotrophoblast externally and the
 amnion and the exoceolomic membrane/primitive yolk sac internally. 
  Fine, loose connective tissue 
 Called the ‘Extraembryonic mesoderm’ 
DEVELOPMENT OF THE EXTRAEMBRYONIC COELOM

  Cavities develop in the extraembryonic mesoderm 
  The cavities coalesce 
  Form a single cavity 
 Called the ‘Extraembryonic coelom’/ chorionic cavity 
Therefore, the extraembryonic coelom separates the cytotrophoblast (lined internally by the
extraembryonic somatopleuric mesoderm) from the primitive yolk sac and amniotic cavity. (lined
externally by the extraembryonic splanchnopleuric and somatopleuric mesoderms respectively)
BUT the germ disc is connected to the trophoblast by a ‘connecting stalk’ made of extraembryonic
mesoderm.
Therefore, the only place where the extraembryonic mesoderm traverses the chorionic
cavity/extraembryonic coelom is the ‘connecting stalk’ - later becomes the umbilical cord
Extraembryonic mesoderm lining the inside of the cytotrophoblast is called the – chorionic plate

EXTRAEMBRYONIC MESODERM
Lining;
  Cytotrophoblast + Amnion = Extraembryonic somatopleuric mesoderm 
 Yolk sac = Extraembryonic splanchnopleuric mesoderm 
DEVLOPMENT OF THE SECONDARY / DEFINITIVE YOLK SAC

 Cells produced from the hypoblast migrate along the inside of the exocoelomic membrane and
form a new cavity within the primitive yolk sac by pinching off its portions. 
 These portions are called - exocoelomic cysts 
Therefore the exocoelomic cysts are found in the chorionic cavity / extraembryonic coelom
Secondary yolk sac is smaller than the primitive yolk sac.
Normal site of pregnancy: Posterior or anterior wall of the uterus
Sites of ectopic pregnancies: abdominal cavity, ovary, uterine tubes

THIRD WEEK OF DEVELOPMENT
Day 15: primitive streak appears. This establishes laterality (all 3 axes of embryo)
GASTRULATION
Process that establishes the three germ layers (ectoderm, mesoderm, and endoderm) of the embryo
Where are we? – Embryoblast – Two layered – Epiblast & Hypoblast

All three germ layers are derived from the cells of the epiblast
How?
 The ‘primitive streak’ appears on the surface of the epiblast 
o A narrow groove with slightly bulging regions on either side
  The cephalic end of the streak is ‘primitive node’
o Slightly elevated area surrounding the ‘primitive pit’
Cells of the epiblast migrate toward the primitive streak
Invaginate (become flask shaped, detach and slip)
Invagination occurs from the primitive node and then proceeds

along the primitive streak.
The invaginated cells that
 Displaced the hypoblast become the endoderm (therefore
hypoblast cells do not contribute to the body of the fetus except
 the part of the definitive yolk sac incorporated to the gut)
 Lie between epiblast and endoderm become the mesoderm
The remaining cells of the epiblast become the ectoderm
The mesoderm spreads laterally and fuses with the extraembryonic mesoderm
Therefore now,
 The ectoderm is in continuation with the amnioblasts 
 The mesoderm is in continuation with the extraembryonic mesoderm (both splanchnopleuric and
 somatopleuric) 
 The endoderm is in continuation with the cells of the secondary yolk sac 

MIDLINE STRUCTURES OF THE TRILAMINAR GERM DISC
Cranial to caudal in order
1. Oropharyngeal/ buccopharyngeal membrane
(ectodermal + endodermal)
2. Prechordal plate – (mesodermal)
3. Notochord- (mesodermal)
4. Primitive node – (ectodermal)
5. Primitive streak – (ectodermal)
6. Cloacal membrane (ectodermal + endodermal)
OROPHARYNGEAL MEMBRANE
 Tightly adherent ectoderm and endoderm 
 Gives rise to the opening of the oral cavity in the
future 
PRECHORDAL PLATE
 Derived from some of the cells that
migrate through the primitive node in
the midline 
 Induction of the forebrain
development 
 located between notochord and
oropharyngeal membrane
NOTOCHORD
 Represents the primitive skeletal
structure characteristic to the
chordates 
 Development of the Notochord 
The caudal end of the primitive streak continually supplies

new cells until the end of the fourth week. By this time the
germ layers are established and differentiation initiated in
cephalic regions. Therefore, the caudal regions of the
embryo are developmentally lagging in comparison to
cephalic regions
Therefore, most of the structures develop cephalocaudally
1. Prenotochordal cells invaginate through the primitive
node, move cranially in the midline towards the prechordal
plate.
2. Become intercalated in the hypoblast
Therefore, at this moment the midline between the primitive
node and the prechordal plate is composed of two layers
 only – called the notochordal plate
3. Cells of the notochordal plate proliferate and detach from
the endoderm
4. Form a solid cord of cells – definitive notochord
5. The formation of the notochord is cranial to caudal
The notochord then signals/induces formation of the neural tube and axial skeleton. The nucleus
pulposus of IV discs is a remnant of it.
PRIMITIVE PIT
 At this stage of the embryo the primitive pit connects the amniotic cavity and the yolk sac through
the neurenteric canal. 
 This canal is closed in eventual development 
 Migratory gateway of epiblastic cells which form midline mesoderm and endoderm (and paraxial
mesoderm) 
PRIMITIVE CHORD
 A shallow groove in the ectoderm. 
 The migratory gateway of epiblast cells which form mesoderm and endoderm 
CLOACAL MEMBRANE
 Tightly adherent ectodermal and endodermal cells that later form the anal membrane and the
urogenital membrane (separated by the urorectal septum).
 After the appearance of the cloacal membrane the posterior wall of the yolk sac forms a small
diverticulum which extends into the connecting stalk called – allantoenteric diverticulum /
allantois
GROWTH OF THE EMBRYONIC DISC

 The initial embryonic disc is round and flat 
 Because the cells migrate through the streak forwards and laterally
o Expansion of the disc occurs mainly in the cephalic region
 o Primitive streak remains more or less the same size
 Therefore the embryonic disc is elongated with a broad cephalic and a narrow caudal end 
 By the fourth week the primitive streak disappears.
 Starts to disappear by day 21, finished by day 28
By day 20:
o neurulation begins
o primary villi become secondary villi
o allantois diverticulum forms
o mesoderm differentiates into paraxial, intermediate and lateral plate
o somites appear

DEVELOPMENT OF THE TROPHOBLAST
Primary villus –
Cytotrophoblastic core
covered by syncytium
Then Primary villus core

penetrated by mesodermal
cells to form, Secondary villus
Secondary villus –
Mesodermal core, covered by
cytotrophoblast and
syncytium
Then differentiation of
mesodermal cells into blood
vessels, to form Tertiary villi
Tertiary villus/definitive placental villi–blood vessels covered by mesoderm, cytotrophoblast and

syncytiotrophoblast, connect the intraembryonic and uteroplacental circulations with the villi as a
barrier.
EXTRAEMBRYONIC CIRCULATION
o Blood and blood vessels are derived from the mesoderm 
o Mesoderm in the core of secondary villi, chorionic plate, connecting stalk and intraembryonic
mesoderm are in continuity 
o Therefore when blood vessels develop in each of the above structures, a connected
extraembryonic, and intraembryonic circulation is established 
o I.e.; capillaries in tertiary villi  capillaries in the chorionic plate capillaries in the connecting
stalk intraembryonic capillaries 
o The connecting stalk will develop into the umbilical cord eventually

In the 4th week
o Cytotrophoblastic cells penetrate the syncytium until it meets the decidua basalis of the
 endometrium. 
o Neighboring
 villi are connected forming a thin outer cytotrophoblast shell. 
 o These villi + cytotrophoblast shell firmly attaches the chorionic sac to the endometrium. 
 o Villi that extend from the chorionic plate to decidua basalis – anchoring/stem villi
o Villi branching from the sides of stem villi – free villi

3rd to 8th weeks of development
THE EMBRYONIC PERIOD (Organogenesis)

The germ layers give rise to specific tissues and organs which leads to establishment of main organ systems.
Major features of the external body form can be recognized by the end of this period.
ECTODERM
Neurulation
Formation of the ‘neural tube’

Notochord and prechordal plate induces the overlying
ectoderm to thicken and form the – neural plate,
neuroectoderm
1. Lateral edges of the neural plate become elevated –
neural fold
2. Depressed mid region – neural groove
3. Neural folds approach each other in the midline and fuse – neural tube formed
 Fusion begins at the cervical region and proceed cranially and caudally 

4. Cephalic and caudal ends communicate with the amniotic cavity by way of anterior (cranial), posterior
(caudal) neuropores respectively.
Neural tube begins to close on day 22. Starts from 5th somite and proceeds cranially and caudally.
  Closure of cranial/anterior neuropore – 25th day 
  Closure of caudal /posterior neuropore – 28th day 
5. Closed tubular structure – represents the central nervous system
6. Cephalic portion widens and dilate – brain vesicles
7. Narrow caudal portion – spinal cord
Neural Crest Cells

Cells at the crest of the neural folds detach and leave the neuroectoderm and enter the underlying
mesoderm.
These cells become mesenchymal cells.
Therefore neural crest cells must undergo epithelial to mesenchymal
transition as it leaves the neural folds.
Mesenchyme refers to loosely organized embryonic connective
tissue regardless of origin

Neural crest cells from the trunk region
o Dorsal pathway
 Skin – melanocytes, hair follicles
 
o Ventral pathway

Sensory ganglia 

Sympathetic neurons 

Enteric nervous system

Schwann cells 
 Cells of adrenal medulla

Neural crest cells from the cranial neural folds 
o Craniofacial skeleton and connective tissue & meninges
o Endocardial cushions forming cornutruncal septum, etc. 

Therefore it is common to find facial and cardiac abnormalities together
 
o Neurons of cranial ganglia
Glial cells 
o
o Melanocytes
o c-cells of the thyroid gland
o Odontoblasts
 Following are derivatives of

the ectoderm.
o CNS
o PNS
o Sensory epithelia
o Epidermis, hairs, nails
o Subcutaneous glands
o Mammary glands
o Pituitary gland
o Enamel of teeth
MESODERM
1. Paraxial mesoderm
2. Intermediate mesoderm
3. Lateral plate mesoderm
The mesoderm beside the midline thickens and forms the paraxial mesoderm.
Lateral plate mesoderm splits into two, giving rise to a cavity the intraembryonic cavity which becomes
continuous with the extraembryonic cavity.
The mesodermal layer continuous with the extraembryonic somatopleuric mesoderm (covering the amniotic cavity)
becomes the parietal/somatic mesoderm.
The mesodermal layer continuous with the extraembryonic splanchnopleuric mesoderm (covering the yolk sac)
becomes the splanchnic/visceral mesoderm.
The unsplit mesoderm connecting the lateral plate and paraxial mesoderm is called the intermediate mesoderm.
Paraxial mesoderm
Become organized into segments – somitomeres- mesodermal cells organized in concentric whorls. (In the 3rd
week)

Formation
 of somitomeres is cephalocaudal 
From
 occipital region caudally somitomeres further organize into - somites at around 3 per day for 15 days

At the end of 5th week 42-44 somites are present 
o 4 occipital (1st occipital disappear later) o 8 cervical
o 12 thoracic
o 5 lumbar
o 5 sacral
o 8 – 10 coccygeal (last 5 -7 disappear later)
The age of an embryo is determined by counting somites.
SOMITE DIFFERENTIATION
1. Presomite mesoderm – ball of mesoderm
2. Arrange into a donut shape by epithelization
3. Differentiation
a. Sclerotome – form the vertebrae and ribs
b. Dermatome – form the dermis of the back
c. Myotome – form segmental muscular component

Each somite and subsequently its derivatives, retain their segmental innervation, giving rise to specific dermatomes
and myotomes which are exclusively supplied by a specific spinal segment.
Each dermatome and myotome has its own segmental nerve component, and retains it no matter where the cells
ultimately migrate.
In addition to axial structures, the paraxial mesoderm gives rise to the muscles of the limbs .
INTERMEDIATE MESODERM
Differentiate into urogenital structures (i.e.

Gonads, internal genitalia, kidneys and
ureters) Cervical and upper thoracic – form
segments – nephrotomes
More caudally – unsegmented –nephrogenic
cord
LATERAL PLATE MESODERM

1. Parietal (somatic) mesoderm
 o Parietal mesoderm together with overlying ectoderm forms lateral body wall folds
 o Dermis of the skin of body wall and limbs 
 o Bones and connective tissue from the limbs 
 o Sternum 
o Parietal layer of serous membranes lining body cavities (pleural, pericardial, peritoneal) 
Sclerotome and myotome cells that migrate into this layer form costal cartilages and limb and body wall
muscles respectively
2. Visceral (splanchnic) mesoderm

 o Wall of the gut tube (with the endoderm) 
o Visceral layer of serous membranes lining body cavities (pleural, pericardial, peritoneal) 


BLOOD AND BLOOD VESSELS

Of mesodermal origin (mesodermal cells  hemangioblasts
blood cells/vessels)
2 ways
1. Vasculogenesis – vessels arise from blood islands
2. Angiogenesis – sprouting from existing vessels
Vessel development start from the mesoderm surrounding

the yolk sac and spread into lateral plate mesoderm and
other regions
Hematopoietic Tissue Development (Blood cell forming
tissue)
First blood cells appear in the mesoderm surrounding wall
of yolk sac but lose its function eventually
The mesoderm surrounding the aorta colonize the liver and
form the definitive hematopoietic stem cells
After seven months of gestation these stem cells colonize
the bone marrow and form definitive blood forming tissue
(later the liver loses its hematopoietic function)
ENDODERM
Endoderm forms the ventral surface of the trilaminar germ disc, which is the roof of the yolk sac

Body Folding
Formation of a tubular body from a trilaminar germ disc
1. Cephalic folding
 Cephalic part of the germ disc (head fold) folding towards the middle of the disc 
  The endodermal germ layer is incorporated into the body to form the foregut 
2. Caudal folding
  Caudal part of the disc (tail fold) including the connecting stalk fold towards the middle 
 Endodermal germ layer is incorporated into the body to form the hind gut 
 The allantois initially incorporated to the connecting stalk develops a connection with the hind gut forming
the cloaca – (discussed later in system based embryology) 



3. Lateral folding
 Lateral parts of the germ disc fold toward the anteroposterior midline(axis) 
After folding the yolk sac is connected to the midgut by the vitelline duct
As a result of cephalocaudal and lateral body folding ventral

body wall of the embryo is closed except for the umbilical
region where,
1. Connecting stalk
2. Vitelline duct
3. Umbilical vessels are attached.
The vitelline duct is wide initially. But with further growth of the embryo it
becomes narrower and longer.
1. The cephalic end of the foregut is closed by the oropharyngeal

membrane
 Primitive oral cavity is derived from the ectoderm and is called the
 stomodeum 
 Pharynx is a part of the foregut (endodermal origin) 
 The oropharyngeal membrane separate the stomodeum from
pharynx 
 In the fourth week oropharyngeal membrane ruptures
establishing open connection between oral cavity and primitive
gut 
2. Caudal end of the hindgut is closed by the cloacal membrane
  Lower part of the anal canal is developed from the ectoderm and is called the proctoderm 
  The upper part of the anal canal is derived from the endoderm 
  These two parts are separated by the cloacal membrane 
 Cloacal membrane ruptures in the seventh week 

In humans the yolk sac is vestigial (suspected to have a nutritive role in early development).
Therefore the endoderm basically forms the epithelial lining of the primitive gut tube, intraembryonic portion
of allantois, and vitelline duct.
All gut tube derivatives too are of endodermal origin.

1. Epithelial lining of the respiratory tract
2. Epithelial lining of urinary bladder and urethra

PLACENTA
Placenta – is the organ that facilitates material exchange between maternal and fetal compartments
So far learnt -
• Tertiary (& some secondary) anchoring villi are extending from the chorionic plate to the
cytotrophoblastic shell
• Uteroplacental circulation established
o Cytological process of erosion of maternal blood vessels – endovascular invasion
▪
Cytotrophoblast cells undergo – epithelial to endothelial transition
▪
Invade terminal ends of maternal spiral arteries
▪
Create hybrid vessels (of maternal and fetal origin)
▪
Connect the vessels to ‘lacunae’ / intervillous spaces
▪ The hybrid vessels are large – sinusoids – low resistance
• Extraembryonic vascular system established
• Free villi extend from stem villi to intervillous spaces
o Develop as buds from stem villi
o Initial structure
▪ Vascular mesoderm covered by
▪ Cytotrophoblast which in turn is covered by

▪ Syncytiotrophoblast
o To reduce the resistance some (occur mainly in smaller villi)

▪
Cytotrophoblastic cells disappear
▪
Connective tissue disappears
▪
Syncytium becomes thin – by shedding parts of syncytium as syncytial knots –
degenerate after entering maternal circulation
PLACENTA
• Disc shaped
1. Fetal Portion – Chorion frondosum
2. Maternal portion – Decidua basalis [ mostly the decidual plate]
Embryonic pole Abembryonic pole
Chorion Chorion frondosum Chorionic leave (villi degenerate)
(Fetal part of placenta – expanded villi)
Decidua Decidua Basalis (Maternal part of placenta Decidua capsularis (degenerate later,
– endometrium) fuse with decidua parietalis)
Decidua parietalis ➔ Chorionic covering the uterine wall
Fuses with Decidua capsularis

EXTENT OF THE PLACENTA
• Fetal side – chorionic plate
• Maternal side – decidua basalis
• The placenta grows throughout the
pregnancy along with the uterus
• The increase in thickness of the placenta is
due to arborization of existing villi, not by
further penetration into maternal tissue
Junctional zone of the placenta – The

intermingling zone of decidual and trophoblast
cells
Decidual septa project into intervillous spaces but do not reach the chorionic plate. Therefore, the
placenta is divided into number of compartments called – cotyledons
BUT – connection is maintained between adjacent intervillous spaces. Why? – The decidual septa don’t reach
the chorionic plate
EXTERNAL APPEARANCE OF THE FULL-TERM PLACENTA

Maternal side
• Outermost thin layer of decidua basalis
• 15–20 cotyledons separated by grooves demarcating the decidual septa on fetal side
• Innermost chorionic plate – smooth – no cotyledons
• Chorionic vessels converge towards the umbilical cord (the attachment of the umbilical cord is
usually eccentric)
CIRCULATION OF THE PLACENTA

• Maternal and fetal blood do not mix (occasionally few blood cells escape)
• Hemochorial placenta –(maternal blood in the intervillous spaces is separated from the fetal blood by a chorionic derivative)
• Materials can be exchanged with least resistance
• Placental exchange does not occur in large anchoring villi
• Why?
o Placental Membrane
1. The layers that separate the maternal and fetal blood
1. The endothelial lining of the fetal vessels
2. Connective tissue of the villus core
3. Cytotrophoblastic layer
4. Syncitium
• But exchange occurs in free villi and small anchoring villi
• Why?
o Placental Membrane
1. Endothelial lining of fetal vessels
2. Syncytium
• Microvilli are found in the maternal surface of the syncytium of free villi, increasing the surface
area and therefore the exchange rate
• Many substances pass through the placental membrane/ placental barrier freely.
TWINS
1. Dizygotic twins
2. Monozygotic twins
Dizygotic Twins
Fertilization of two ova by two different spermatozoa
• Genetically different zygotes
• Can be of same or different sex
• No more than the resemblance of brothers and sisters – fraternal
• Implant separately in the uterus
• Has separate placenta and all other fetal membranes for each embryo
• BUT if implanted close together, placentae, chorionic sacs can fuse
o Erythrocyte mosaicism?
Monozygotic twins
Develops from a single fertilized ovum
• Identical (morphologically, genetically, of the same sex)
Depending on the stage of separation monozygotic twin placentae and fetal membranes differ
Separation at
• Two cell stage (Zygote divides to form two zygotes)
• Earliest separation
• Two zygotes
• Separate implantation
• Separate placentae
• Separate chorionic sacs
▪
As in dizygotic twins the placentae and chorionic sacs can fuse if implanted close
by
• Early blastocyst stage (separation occurs in the inner cell mass only)
• Common chorion
• Common placenta
• Separate amnions

• Bilaminar germ disc (before the appearance of the primitive streak)
• Common chorion
• Common placenta
• Common amniotic cavity
• After the appearance of primitive streak, node (partial splitting of primitive node, streak)
• Conjoined twins (craniopagus, pygopagus, thoracopagus)
• Common chorion
• Common placenta
• Common amniotic cavity

Embryology
Development of body cavities
Lateral plate mesoderm is involved in forming body cavity.

Parietal
(Somatic) (Parietal)
clefts coalesce &
clefts appear in
Solid the lateral plate
split the solid Somatic
mesoderm layer
mesoderm
into 2
Visceral
 space created between the two layers of lateral plate mesoderm constitutes the primitive body
cavity
Cephalocaudal & lateral folding
In cooperation of yolk sac cavity into the

intraembryonic cavity
Endoderm layer folds ventrally and closes
Forms the GUT tube
Lateral body wall folds meet in the

midline and fuse to close the ventral
1 body wall © 2017 A/L Repeat Campaign
Serous membranes
 Parietal layer of lateral plate mesoderm Parietal layer of peritoneal pleural

pericardial cavities secrete serous
fluid (mesothelial cells)
 Visceral (splanchnic) layer of lateral plate mesoderm Visceral layer of pleural pericardial
and peritoneal cavity
 Space between parietal and somatic layers Intra embryonic cavity
 Dorsal mesentery Connects the parietal and visceral

layers.
Extends from caudal part of the foregut
 Ventral mesentery Extends from caudal part of foregut to

upper portion of duodenum
Results from septum transversum
Closure of the ventral body wall is complete except in the region of connecting stalk
Closure of the gut tube is complete except in midgut region (forms vitelline duct)
Clinicals
Ventral body wall defects
1) Cleft sternum – thoracic region 3) Gastroschisis – abdominal region
2) Omphalocoele 4) Bladder or cloacal exstrophy – pelvic region

Cleft sternum
Ventral body wall defect.
Two lateral mesodermal bars fuse to form the sternum If failed Cleft sternum
In some ectopia cordis (heart protrudes through sternal cleft)
Sometimes defect involves both the thorax and abdomen
Cantrell pentalogy
1- Cleft sternum
2- Ectopia cordis
3- Omphalocele
4- Diaphragmatic hernia
5- Congenital heart defects (VSD, TOF) & pericardial defects
Development of diaphragm
Diaphragm is derived from 4 components.
1- Septum transversum
 Is a thick plate of mesoderm occupying the space between the thoracic cavity and the
stalk of the yolk sac.
 It is developed at cervical segments.
 And during cephalocaudal folding it descends to thoracic level.
 By dragging its nerve supply from C3, C4, C5, spinal segments (phrenic nerve).
 And forms the central tendon of the diaphragm.
2- Pleuroperitoneal membranes
• Closes the foetal communication between pleural and peritoneal cavities. Form a part of
the diaphragm
3- Dorsal mesentery of the esophagus forms the crura of the diaphragm.
4- Fetal body wall forms the peripheral muscular rim.

Clinicals
1- Congenital diaphragmatic hernia-Pleuroperitoneal membranes fail to close the space completely
2- Parasternal hernia-A small part of the muscular fibers fails to develop. Small peritoneal
sac containing intestinal loops enter to the chest through the anterior
portion of the diaphragm.
3- Esophageal hernia-Due to congenital shortness of esophagus. Upper portion of
stomach is retained in the thorax
• Pleuropericardial folds appear as small ridges of mesoderm of the body wall

• Project into primitive undivided thoracic cavity
• Contain phrenic nerve and common cardinal veins
• Finally fuses with opposite pleuropericardial fold and with the lung root
• Forms the fibrous pericardium
Respiratory system
4th week of gestation
Outgrowth from the ventral wall of the foregut
Lung bud (respiratory diverticulum)

At first the lung bud communicates with the foregut
2 longitudinal ridges appear
Fuse
Tracheoesophageal septum formed

The esophagus is separated posteriorly & trachea anteriorly

 Epithelium of internal lining of larynx, trachea & lungs - Endoderm
 Cartilaginous, muscular and connective tissue of trachea and lungs – Splanchnic
mesoderm
 Cartilages and muscles of larynx – 4 th and 6th pharyngeal arches
Clinicals
Oesophageal atresia with or without tracheoesophageal fistula
 upper portion of the esophagus ending in a blind pouch and the lower segment forming a
fistula with the trachea
 Isolated esophageal atresia and H-type TEF without esophageal atresia
TEF associated other defects
1. Vertebral abnormalities
2. Anal atresia
3. Cardiac defects
4. Tracheo-esophageal fistula
5. Esophageal atresia
6. Renal abnormalities
7. Limb defects
Tracheo-esophageal fistula
• Respiratory diverticulum formed by ventral wall of the foregut.
• 2 longitudinal ridges appear

• They fused in the midline
• And forms trachea anteriorly and oesophagus posteriorly.
• Posterior deviation of this septum or
• Mechanical pulling of foregut anteriorly
• Resulting in tracheo-oesophageal fistula and
• Oesophageal atresia.
• Upper oesophagus ends in a blind pouch
• Lower oesophagus connects to trachea above bifurcation.
• Prevent normal passage of amniotic fluid.
• Causes accumulation of amniotic fluid.
• Resulting in polyhydramnion.
Trachea, bronchi and lungs
Lung bud gives 2 lateral out pouches [bronchial buds]
Bronchial buds enlarge
Form right and left main bronchi
3 2
Secondary bronchi
Divides in a dichotomous fashion
Tertiary bronchi forming bronchopulmonary segments
 Mesoderm, which covers the outside of the lung - visceral pleura

 Somatic mesoderm layer, covering the body wall from the inside – parietal pleura
 Space between the parietal and visceral pleura - pleural cavity

Maturation of lungs
By the end of 6th month

• 17 subdivisions are formed (additional 6 divisions formed during postnatal life)
• Type 2 epithelial cells appear – produce surfactant
By the end of 7th month
• Cuboidal cells become flat in respiratory bronchioles
• Sufficient number of capillaries present
• Primitive alveoli (terminal sacs) appear
• Respiration becomes possible
Last 2 months
• Number of alveoli increases steadily
• Amount of surfactant increases in last 2 weeks
By the time of birth

• Mature alveoli are absent
• Breathing movements begins before birth (aspiration of amniotic fluid)
• Only 1/6 of the adult number of alveoli are present
• Bifurcation of trachea is opposite the T4 vertebra
• At birth – In the 1st aspiration, most of the lung fluid is absorbed into blood and
lymph
After birth
• Growth of lung is due to an increase in number of respiratory bronchioles and alveoli
(due to increase in size)
• New alveoli are formed (5/6 of adult alveoli) during 1 st 10 years of postnatal life)
Clinicals
Respiratory distress syndrome
 Insufficient surfactant in premature babies
 Alveoli coalesce during expiration
 Treatment – Artificial surfactant (glucocorticoids to stimulate surfactant production)

Development of the CVS
Vascular system develops in the middle of the 3rd week before the folding of the embryo
as it is no longer able to satisfy its nutritional requirement by diffusion.
Development of heart involves,

 Cardiac Tube formation
 Cardiac looping
 Septum formation
 Positioning of heart tube
Development of vessels
 Arterial Aortic arch, Umbilical vessels, vitelline
 Venous  Cardinal system, umbilical, vitelline
1) Cardiac Tube formation
 Heart, all blood vessels and all blood cells originate from mesoderm.
 Cardiac progenitor cells which are in the splanchnic layer of the lateral plate
mesoderm forms cardiac myoblasts.
 Also, blood islands (blood islands - The innermost cells of these blood islands
are hematopoietic cells that give
rise to the blood cell lines. The
outermost cells give rise to the
endothelial cell layer of blood
vessels) which appear in the
mesoderm
 A horse-shoe shaped cluster of cells called the primary heart field is formed.
 These cells form the atria, left ventricle & part of the right ventricle.
 The secondary heart field which is present in the splanchnic mesoderm gives
rise to the rest of the ventricle & the outflow tract.
 Blood islands unite and forms a horseshoe shaped endothelial lined tube
(Endocardial Tube) that is surrounded by cardiac
myoblasts.
 Endocardial tube- Primary heart tube
Heart initially formed as two parallel tubes on
either side of embryo, anterior to the
Oropharyngeal membrane
 As a result of growth of the brain and
cephalic folding of the embryo the cardiogenic
field is brought ventrally thoracic region
 As a result of the lateral folding of the
embryo the two parallel tubes merge and forms
the Heart tube

 Primary heart tube has a dorsal mesentery but not ventral.
 Disappearance of the middle section of the dorsal mesentery forms the
transverse pericardial sinus.
Expansions appear in
the cardiac loop
throughout its
length.
Dorsal mesocardium
↓
Epicardium
↓
Coronary arteries
From venous end they are:

1. Sinus venosus 2. Primitive atrium 3. Primitive ventricle
4. Bulbus Cordis Proximal ⅓ - (Trabeculated part of right ventricle)
Middle ⅓ - [Conus cordis] (Outflow tract of both ventricles)

Distal ⅓ - [Truncus Arteriosus] (Roots of ascending aorta and
pulmonary trunk)
2) Cardiac looping
Day 23-28
 Cephalic portion bends ventrally, caudally & to the right
 Caudal portion shifts dorsally, cranially & to the left
This bending due to cell shape change in Cardiac loop

Externally, junction between the Bulbus cordis & Primitive ventricle →
Bulboventricular junction→Primitive interventricular foramen
Primitive ventricle and the primitive atrium → Atrioventricular canal

3) Septal formation
Two methods.
1. By 2 actively growing tissue mass that approach each other or single mass
approaching the other end until they fuse. These tissue masses are called
Endocardial cushions.
2. By merging of 2 expanding portions of the wall of the heart (never completely

separates 2 cavities)
Does not involve endocardial cushions.

Atrial Septal formation (End of 4th week)
Septum primum Appears as a sickle shaped fold on the roof of common
atrium towards the endocardial cushions
↓
Ostium Primum Opening between the free margin of Septum primum &
Endocardial cushions
↓
Closes Ostium primum by fusion of septum primum with Inferior and Superior
Endocardial cushions
↓
At the same time cell death occurs in the upper part of the Septum Primum
↓
Forms the Ostium Secondum
↓
Septum Secondum appears from the common atrium, right to the Septum primum
↓
The septum secondum overlaps the ostium secondum
↓
The opening left by septum secondum -Foramen Ovale
↓
The upper part of septum primum disappears
The rest of septum primum act as the valve of foramen ovale
↓
At birth Left atrial pressure increases as the lung circulation begins  foramen ovale
closes  becomes Fossa ovale

Septum formation in the atrioventricular canal
Primitive atrium and primitive ventricle are separated by the formation of endocardial
cushions that form AV septum.
Endocardial cushions appear in the atrioventricular canal as superior, inferior and two
lateral.
They approach each other and fuse forming the left and the right atrioventricular
orifices.
AV Valves
Each AV orifice Is surrounded by local proliferations of mesenchymal tissue and flow of
blood hollows them out and the AV valves are formed
Septum formation in the ventricles

Ventricular septum
1. Muscular portion
2. Membranous portion
Muscular portion
The ventricles expand Medial walls merge 
Forms the muscular Interventricular septum
Membranous portion
 The two ventricles are connected by
interventricular foramen which is above
muscular portion of the ventricular septum
 The interventricular foramen is closed by
fusion of inferior endocardial cushion with
muscular part of interventricular septum
 Conus septum also helps

Septum formation of Truncus arteriosus
2 Swellings/truncus cushions appear in the Truncus arteriosus (Supported by the
Neural crest cells)
 Right superior truncal swelling grows towards left.
 Left inferior truncal swelling grows towards right.
 They twist around each other and then fuse to form aorticopulmonary septum.
 It separates truncus arteriosus into aortic channel and pulmonary channel.
2 swellings appear in the Conus cordis (Supported by the Neural crest cells)
1. R: dorsal
Unite each other → Unite with the Truncus septum →
Conotruncal septum → 2 Outflow tracts for two ventricles and
roots of aortic and pulmonary arteries
2. L: ventral
Neural crest cells migrate through the 3, 4, 6 Pharyngeal arches. They are important in
craniofacial development.
Therefore, heart defects and craniofacial abnormalities are associated.
Semilunar valves
Appear on truncus swelling when the partition is completed

↓
Swellings hollow out and produce semilunar valves
↓
Neural crest cells have a contribution
Conducting System
SA node – Initial pacemaker lies in the caudal part of the left cardiac tube.
Then in the sinus venosus and finally in the right atrium as the sinus venosus
is incorporated into the R atrium.
AV node and bundle of His – derived from 1. Cells in the left wall of the sinus venosus.
2. Cells from the atrioventricular canal.
4) Vascular development
1.Vasculogenesis – coalescence of angioblasts. (dorsal aorta and cardinal veins)

2.Angiogenesis – Vessels develop from existing vessels.

Arterial System
Aortic arches:
 Supply the pharyngeal arches.
 Arise from the aortic sac (distal part of the truncus arteriosus.
 6 pairs appear.
 5th arch either never forms or forms incompletely.
 Terminates in the Right and Left dorsal Aortae.
 R and L dorsal aortae are fused caudally to form a single vessel.
1starch – Maxillary artery

2nd arch – Hyoid & Stapedial arteries
3rd arch – Common carotid & 1st part of Internal Carotid. (The rest of the internal carotid is formed by the
c cranial part of the dorsal aorta)
th
4 arch – Right – R: subclavian artery, Proximal part (Distal part →R: Dorsal aorta)
Left - Part of the Aortic arch between L: Common carotid & L: Subclavian
th
6 arch – Right- R: Pulmonary artery (Distal part regresses & Looses connection with the Dorsal aorta) **
- Left - L: Pulmonary artery & Ductus Arteriosus
 The external carotid arteries sprout from the 3rd arch.
 The aortic sac forms the proximal part of the brachiocephalic trunk the proximal
part of the dorsal aorta.
 Both Recurrent Laryngeal nerves hook around the 6th Aortic arch.
 With further development, 5tharch and distal part of right 6th arch disappear.
 So;
 R: side →**Hooks around the 4th arch
 L: side → Due to the Persistence of the Ductus arteriosus as Ligamentum
arteriosum, it has to remain winding round the 6th arch
Vitelline arteries -Forms 2 arteries of the GUT (Coeliac & Superior mesenteric arteries)
Inferior mesenteric artery is derived from the umbilical arteries.
Umbilical arteries – Earlier arises from the dorsal aorta
Later from the common iliac arteries
Distal part →(obliterated)Medial umbilical ligament

Proximal part →Internal iliac artery & Superior vesical artery

Development of Venous System
Sinus Venosus
 It receives venous blood from R & L sinus horns.
Vitelline Vein = Omphalomesenteric vein

Sup: Mesenteric Vein
 After left to right shunting most of left sinus horn disappears and the right horn
enlarges greatly. All that is left of this sinus horn is
Oblique vein of the L: atrium
Coronary sinus
 At the sinoatrial orifice (Opening of the sinus venosus to right atrium, R: & L:
venous valves are present.
 The only remaining part, Inferior part of the R: venous valve →→ Valve of IVC,
Valve of Coronary sinus
 The right sinus horn expands and is absorbed into right atrium →→Sinus venarum
 Crista terminalis divides the trabeculated part& Sinus venarum of the right atrium
 In the left atrium Initially → 1 Pulmonary vein → The pulmonary vein and its
branches are incorporated to the L: atrium → 4 Pulmonary veins
So smooth walled part of the L: atrium → from Pulmonary veins
Vitelline veins→ Plexus around the Duodenum→ Portal vein and the liver sinusoids
Proximal part of the R vitelline vein forms the hepatic part of the Inferior vena cava
Umbilical veins –Right completely regresses

Proximal part of the L umbilical vein regresses
Distal part of the left vein connects the placenta to the liver
Before birth it bypasses the live sinusoids through the ductus venosus

Cardinal Veins
Both posterior cardinal veins

disappear entirely
The formation of the vena cava
system is characterized by the
appearance of anastomoses
between left and right in such a
manner that the blood from the
left is channeled to the right.
As the cardinal system develops

additional to the anterior and
posterior cardinal veins –
subcardinal, supracardinal,
sacrocardinal etc. appear.
Inferior vena cava

Has, Hepatic - Formed by the R vitelline vein
Renal - Formed by the R subcardinal vein
Sacrocardinal - Formed by the R sacrocardinal vein
Circulation before and after birth

Before Birth:
Blood from placenta- 80% saturated with O2
Returns to the fetus via the umbilical vein
Short circuit the Liver by the Ductus Venosus (But a small amount enters
the liver and Mixes with blood of Portal vein)
And enters the IVC (Here it Mixes with deoxygenated blood from LLs)
RA (Mixes with SVC)
Foramen ovale (@ the Opposite side of the Opening, by the Valve of IVC)
LA (Mixing with Pulmonary veins)
LV
Ascending aorta (Coronary & Common carotid arteries receive well
oxygenated blood)
Receives blood from Ductus arteriosus (Mixes with blood from the RV –
As lungs are collapsed, Blood flow in lungs are negligible)

Descending aorta
2 Umbilical arteries
Placenta
Changes at Birth
1. Closure of umbilical arteries  medial umbilical ligament
2. Closure of umbilical vein ligamentum teres hepatis
3. Closure of ductus venosus  ligamentum venosum
4. Closure of ductus arteriosus  ligamentum arteriosum
 Functionally closed  just after birth (Muscular contraction)
 Anatomical closure  1-3 months
5. Closure of foramen ovale
 Up to 1-year closure is reversible
 Lungs are functioning → Pulmonary venous return ↑ →LA
Pressure ↑
Clinicals
Atrial septal defects (ASD)
Females: Males= 1:2
Can be due to
1-Ostium secondum defect –
Excessive cell death (Enlarged ostium secondum). Too short septum secondum
2-Complete absence of atrial septum
3-Ostium primum defects
VSD – Ventricular Septal Defects
 Most common cardiac congenital defect  Usually involves the membranous portion
 Often associated with abnormalities in partitioning of the conotruncal septum.
Dextrocardia
 Cardiac looping to left instead of right.  Related to the laterality establishment.
 Associated with - situs inversus (complete reversal of all organs)
- reversal of some organs.
Tetralogy of Fallot
Due to an unequal division of the conus
1. Pulmonary infundibular stenosis 3. VSD
2. Hypertrophy of the right ventricle 4. Overriding Aorta
Persistent truncus arteriosus
 The conotruncal ridges fail to fuse.  VSD is always present.
Transposition of great vessels

 Conotruncal septum follows is normal spiral course.
 Aorta from the  right ventricle
 Pulmonary artery from the  left ventricle
 Sometimes VSD is present
 Usually there is opened ductus arteriosus
 Neural crest cells contribute to the formation of conotruncal septum. Conotruncal
septal defects are accompanied by craniofacial defects.

Valvular defects
 valvular stenosis  valvular atresia
Coarctation of aorta
 Defect in tunica media.

 Leads to proliferation of tunica intima.
Constriction of aorta beyond the origin of left subclavian artery.
Preductal Postductal
Constriction above the Constriction below the entrance of
entrance of ductus ductus arteriosus
arteriosus ↓
↓ Ligamentum arteriosum
Patent ductus arteriosus more common
Collateral circulation between
proximal and distal parts of the aorta
(intercostal and internal thoracic
arteries)
Collateral circulations
1. Subclavian artery  internal thoracic artery  anterior intercostal artery 
posterior intercostal artery  descending thoracic aorta.
2. Subclavian artery  axillary artery  scapular anastomosisposterior intercostal
artery  descending thoracic aorta
3. Subclavian artery  internal thoracic artery  superior epigastric artery  inferior
epigastric artery  external iliac artery
Intercostal arteries get dilated and torturous  erode lower surface of the ribs
(notching of ribs)
Right arm pressure increases & lower limb pressure decreases radio-femoral delay

1
Embryology – Digestive System
endoderm
Portion of endoderm lined yolk sac cavity => Primitive gut

 Pharyngeal gut – From Buccopharyngeal membrane to tracheo-bronchial diverticulum
Important for the development of head and neck
Forms pharynx and related glands
 Foregut – Up to liver bud
 Midgut – Up to junction between right 2/3rd& left 1/3rd of the transverse colon
 Hindgut – Up to cloacal membrane
MESENTERY
1. Ventral Mesogastrium – Derived from the Septum Transversum
Foregut (only) => divided by the liver
Ventral part – Falciform, Coronary, Triangular lig.
Dorsal part – Lesser omentum
2. Dorsal Mesogastrium – Divided by the spleen
Ventral part – Gastrosplenic lig.
Dorsal part – Lienorenal lig.
Duodenum => Dorsal mesoduodenum
Midgut => Mesentery proper
Hindgut => Dorsal mesocolon
FOREGUT
 Derivatives – Lung, Liver, Gall bladder & Pancreas
 Supplied by – Celiac artery
1. Oesophagus
Tracheo-oesophageal septum separates – Dorsal oesophagus from the ventral trachea
At first it is short. It elongates with the descent of heart and lungs.
Surrounding splanchnic mesoderm forms the muscular coating Lamina Propria, Mucosa, Submucosa and
Adventitia
Abnormalities
I. Oesophageal atresia and/or Tracheo-oesophageal fistula
Due to - Posterior deviation of tracheo-oesophageal septum
Dorsal wall of foregut pushed anteriorly
II. Oesophageal stenosis (usually in lower 1/3rd) – Failure to Recanalize
1 © 2017 A/L Repeat campaign

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2. Stomach
At fourth week begins as a fusiform dilation in foregut.
Rotations
I. 900 Clockwise in longitudinal axis
- Left side become anterior =>
Left vagal fibers – Anterior vagal trunk
- Right side become posterior =>
Right vagal fibers – Posterior vagal trunk
II. In anteroposterior axis
- Pylorus => to right & upwards
- Cardia => to left & downwards
Rotation of stomach causes changes in mesogastrium.

1.Around Longitudinal axis
Pulls dorsal mesogastrium to the left.
Formation of vacuoles and fusion of them Lesser Sac
2.Around Antero –Posterior axis

Bulging down of dorsal mesogastrium as Greater Omentum
Growth Difference
Posterior wall > Anterior wall
- Greater curvature => to the left
- Lesser curvature => to the right
 Spleen (mesodermal origin), in the 5th week grows in the left leaf of dorsal mesogastrium with the
rotation of stomach around longitudinal axis, dorsal mesogastrium rotates to the left. Mesogastrium
between spleen and dorsal midline of the body fuses with the peritoneum over the posterior abdominal
wall and disappears and connect to the body wall in left kidney.
3. Duodenum
Formed by – both foregut &midgut (Therefore blood supply by both coeliac and superior mesenteric
arteries)
- Due to rotation of the stomach, it becomes ‘C’ shaped & rotates to the right.
- Right surface of the dorsal mesoduodenum presses against the posterior abdominal wall and disappears.
- Become retroperitoneal [secondarily]
- Duodenal cap – intraperitoneal
- Solidification => recanalization

3
4. Liver & Gall bladder
- Liver bud appears as an outgrowth of endodermal epithelium, at the distal end of foregut (3 rd to 4th week)
- Hepatic cells of the liver bud proliferate & penetrate septum transversum
- Mesoderm of septum transversum forms hematopoeitic cells, kupffer cells, connective tissue
- Invasion by liver cells into the septum transversum forms
Lesser omentum – between liver & foregut
Falciform, coronary, triangular lig. – between liver & body wall
- Cranial surface of the liver remains in contact with the original septum transversum & forms the bare area
of the liver
- Connection between the liver bud & the foregut form the bile duct
-Bile duct moves dorsally due to rotation of duodenum
- Ventral out growth from the bile duct gives rise to the gall bladder & cystic duct
Hepatic sinusoids  by vitelline & umbilical veins + intermingled liver cords
Functions of liver in fetal life

1.Haematopoiesis- not after birth-last 2 months
2.Production of bile – from 12th week
5. Pancreas
- 2 buds originate from the endodermal lining of the duodenum

I. Dorsal pancreatic bud – in the dorsal mesentery
II. Ventral pancreatic bud – close to the bile duct
- Ventral pancreatic bud moves dorsally, in a manner similar to shifting of entrance of bile duct
- Finally comes to lie immediately below & behind the dorsal bud

4
- Parenchyma of the buds fuse

I. Ventral bud => Uncinate process & inferior part of head
II. Dorsal bud => remaining part
- Duct systems fuse
I. Main pancreatic duct =>(wirsung)
- Distal part of the dorsal pancreatic duct + entire ventral pancreatic duct
- Opens into the major duodenal papilla
II. Accessory pancreatic duct =>(santorini)
- Proximal part of the dorsal pancreatic duct
- Opens into the minor duodenal papilla
Exocrine pancreas – Dorsal and ventral pancreatic buds

Islets of Langerhans - Migrating neural crest cells
Abnormalities
I. Annular pancreas
- Ventral pancreatic bud usually consists of right & left parts which fuse & rotates around the
duodenum
- If they fail to fuse, left part migrates in the opposite direction
- But the right part goes in the normal direction
- Duodenum surrounded by the pancreatic tissue =>
Obstruction
II. Accessory pancreatic tissue
-It may show all characteristics of pancreas
Frequently found in => Mucosa of the stomach
Meckel’s diverticulum
-Can be found anywhere from distal end of oesophagus to
tip of primary intestinal loop
MIDGUT
 Supplied by – superior mesenteric artery
 Elongation of the gut & mesentery proper => Primary intestinal loop
 At the apex, communicates with the yolk sac via the vitelline duct
Cephalic limb – Distal part of duodenum, jejunum, part of ileum

Caudal Limb – Lower part of ileum, caecum, appendix, ascending colon, proximal 2/3rd of transverse colon
Elongation of Loop

5
Jejunum and Ileum – coil formation

Large Intestine –Does not coil
Physiological herniation – 6th week  rapid elongation of cephalic limb

- Intestinal loops bulge out through the umbilicus => Physiological umbilical herniation
-with developing liver, abdominal cavity become too small
Rotation
When viewed from the front -
Counterclockwise around an axis formed by the superior mesenteric artery
I. While herniating - 900 [6th week]
II. While retracting - 1800 [10th week]
Retraction
-During 10th week due to decreased growth of liver and adequate expansion of abdominal cavity and
regression of mesonephric kidney
- Herniated intestinal loops return to the abdominal cavity
- Cecal bud => Conical dilation of the primary intestinal loop
Last part of the gut to reenter the abdominal cavity
Then lies below the right lobe of the liver, which descends into the right iliac fossa
Distal end of the cecal bud => Appendix
-first to reenter abdominal cavity  proximal part of jejunum

6
 Mesentery of ascending & descending colon press against posterior abdominal wall =>
to become retroperitoneal
Abnormalities
Mesentery defects
I. Mobile caecum – Persistence of mesentery of ascending colon, without fusing
Body wall defects

II. Omphalocele – Herniation of abdominal viscera, through an enlarged umbilical ring [eg- liver]
Due to failure of retraction from physiological herniation
Associated with cardiac anomalies, neural tube defects and chromosomal abnormalities
III. Gastroschisis – Protrusion of abdominal contents through body wall directly in to amniotic cavity
Lateral to umbilicus, viscera are not covered by peritoneum or amnion.
Due to abnormal closure of body wall around connecting stalk
Not associated with chromosomal abnormalities.
Vitelline duct defects
IV. Meckel’s diverticulum - Normally disappears in 6th week of intrauterine life,
2 inches long
Persistence of a small part of vitelline duct
Found in antimesenteric border of ileum, 2ft proximal to ileocecal valve
May cause ulcerations, bleeding, perforations
V. Vitelline cyst – Both ends of duct become fibrous, middle portion become a cyst
VI. Vitelline fistula – Duct remains patent over entire length
Gut Rotation abnormalities

VII. Incomplete Rotationtwisting of intestinevolvuluscompromise blood flow
VIII. Reverse rotation
HINDGUT
Derivatives – Distal 1/3rd of transverse colon, descending colon, sigmoid colon, rectum, anal
canal(upper part)
(Endoderm of Hindgut also forms internal lining of bladder and urethra)
 Supplied by – Inferior mesenteric artery
 Terminal part of hindgut enters the posterior part of cloaca.
 Allantois enters the anterior part of cloaca.
 Urorectal septum (a layer of mesoderm) separates anterior Allantois & posterior hindgut. Those which enter
the cloaca, grows caudally with the caudal folding of embryo. Tip of urorectal septum comes close to cloacal
membrane.
 Cloacal membrane ruptures
o Anterior opening – for the urogenital sinus
o Posterior anal opening – for the hindgut
In between urorectal septum forms perineal body.

7
 Anal canal
-Upper 2/3rd – From endoderm of hindgut. Supplied by Superior rectal artery (branch of inferior mesenteric)
- Lower 1/3rd – From ectoderm around proctodeum. Supplied by inferior rectal artery (branch of internal
pudendal)
Junction is delineated by pectinate line just below anal columns (Epithelium => Columnar to Stratified Squamous)
Abnormalities
I. Imperforated anus – Failure to breakdown the anal membrane
II. Congenital megacolon (Hirschsprung Disease)–Dilation of colon due to absence of parasympathetic
ganglia in the bowel wall. Defect in neural crest cell migration.
III. Rectourethral/Rectovaginal fistula
- When the urorectal septum does not extend far enough caudally
- When the cloaca is too small, causing the opening of the hindgut to shift anteriorly
IV. Rectoanal atresia

8
Organization of the Abdominal GI Tract
Foregut Midgut Hindgut

Oragans Stomach 2nd half of duodenum Left 1/3 of transverse
Liver Jejunum and ileum colon
Gallbladder Cecum Descending colon
Pancreas Ascending colon Sigmoid colon
Spleen 2/3 of transverse colon Rectum
1st half of duodenum
Arteries Celiac trunk; Superior mesenteric; Inferior mesenteric;
Splenic artery ileocolic Left colic
Left gastric Right colic Sigmoid branches
Common hepatic Middle colic Superior rectal
Ventral mesentery Lesser omentum
Falciform ligament None None
Coronary/triangular
ligaments
Dorsal mesentery Gastrosplenic ligament Mesointestine Sigmoid mesocolon
Splenorenal ligament Mesoappendix
Gastrocolic ligament Transverse mesocolon
Greater omentum
Motor nerve supply Vagus Vagus Pelvic splanchnic nerves
Reffered pain T8 dermatome T10 T12

Development of Urogenital System
Urogenital system
Develops from the
 Upper parts - …………………………………………………………………………….
 Lower parts - …………………………………………………………………………….
Intermediate mesoderm  urogenital ridges

Medial → gonadal/genital ridge
Urogenital ridge
Lateral→ nephrogenic ridge
Urinary system
Kidney system
 Three slightly overlapping kidney systems formed In cranial to caudal sequence (in nephrogenic ridge)
 Pronephros
 Mesonephros
 Metanephros
1. Pronephros 2. Mesonephros
Appear at the beginning of the 4th week and completely
Appear during the regression of the pronephros (4th week)
regress at the end of the 4th week
In cervical region In thoracic & upper lumbar
Non functional Functional in intrauterine life
No duct system Duct system – mesonephric duct
Completely disappears – Not associated to form any Important to produce genital organs. Not associated to form the
urogenital structure definitive kidney

Mesonephros and the mesonephric duct
3. Metanephros (In 5th week)

 Form the definitive kidney.
Duct System
 Collecting system - formed by ureteric bud

o Ureteric bud – an outgrowth of mesonephric duct close to the entrance of cloaca
o It forms;
 Collecting tubules
 Major and minor calices
 Renal pelvis
 ureter
 Excretory system - formed by metanephric mesoderm

o Newly formed collecting tubule is covered at its distal end by a Metanephric tissue cap
o Cells of the tissue cap form Renal vesicles; which in turn give rise to “S” shaped tubules
o Capillaries grow into the pocket at one end of the “S” and differentiate into glomeruli.
o glomeruli + renal tubules = Nephron (excretory units)
o Renal tubules give rise to;
 PCT
 Loop of Henle
 DCT
o Nephrons are formed until birth (after birth nephrons grow without increasing in number). And the
urine production takes place in early gestation

Position of the Kidney
 Initially lie in the pelvic region; later ascend to the abdomen
 In pelvis, receive arterial supply from pelvic branch of the aorta
 In the ascent, receive arterial supply from the corresponding higher levels of aorta.
 Lower vessels usually degenerate but, some may remain. (seq – accessory renal arteries)
Clinicals
 Congenital polycystic kidney disease –(Autosomal recessive) – cysts form from collecting ducts
o Kidney- very large. Renal failure occurs in childhood
 Adult polycystic kidney disease- (Autosomal dominant) – Cysts form from all segments of the nephron
o Usually renal failure occurs in adulthood
 Duplication of ureter – early splitting of ureteric bud (partial or complete)
 One ureter may be ectopic. In such cases it may open into,
o Vagina
o Urethra
o Vestibule
 Abnormal locations of kidneys
o Pelvic kidney - Remain in the pelvis close to the common iliac artery.
o Horseshoe kidney - Lower poles fuse due to fusion of two metanephric masses in the midline. So
ascent is blocked by inferior mesenteric artery. Ureters pass anterior to the isthmus.

Development of Bladder and Urethra
 Cloaca is divided into Urogenital sinus (anteriorly) and anal canal (posteriorly) by the Urorectal septum
 Tip of the urorectal septum forms the perineal body
 Urogenital sinus
o Upper part - Urinary bladder
Allantois (continuous with the upper part of the urogenital sinus) Urachus
median Umbilical ligament
o Pelvic part prostatic urethra & membranous urethra
o Definitive urogenital sinus ( phallic part) associate to form external genitalia/penile urethra
Trigone of bladder
 Mesonephric ducts move close together to enter the prostatic urethra and become ejaculatory ducts
 Mesonephric ducts and ureter originates from mesoderm. Mucosa of the bladder formed by incorporation of
the mesonephric duct (so trigone is also mesodermal)
 With the time, mesodermal lining of the trigone is replaced by endodermal epithelium
(Finally, inside the bladder is completely endodermal)
 Urethra
o Epithelium is formed by the endoderm
o Smooth muscles – by the splanchnic mesoderm
o In males; epithelium of the prostatic urethra proliferate to form the Prostatic gland
o In females; cranial part of Urethra give rise to urethral and para-urethral glands

Clinical
 Urachal fistula-persistence of the lumen of the intraembryonic portion of the allantois
 Urachal cyst –cystic dilation in a local area of the persistent part of allantois
 Urachal Sinus-lumen in the upper part persist
 Exstrophy of bladder – ventral body wall defect.
o Epispadias is a constant feature
o Opening extends along the dorsal aspect of the penis through the bladder to the umbilicus
 Exstrophy of cloaca – more severe ventral body wall defect
o Exstropy of the bladder, spinal defects, imperforate anus, omphalocoele may associate.
 Nephrons are formed until birth

 At the time of birth each kidney contains 1 million of nephrons (become functional near 12 th week)
 Urine production starts by the 10th week of gestation ( soon after differentiation of glomerular capillaries)
 At the birth kidneys have lobulated appearance (lobulation disappears during infancy)

Genital system

Development of testis
Development of Ovary
Genital ducts
1. Mesonephric duct (Wolffian duct) - Duct system of Mesonephros
2. Paramesonephric duct (Mullerian duct)
o Connects the peritoneal cavity with cloaca
o Crosses the mesonephric duct (lateral to medial)
 Genital ducts in males (mainly - mesonephric duct)
o Efferent ductules – remaining parts of the excretory tubules of mesonephric mesoderm
o Vas difference
Ejaculatory duct mesonephric/wolfian duct
Epididymis

o Appendix epididymis – vestigial cranial position of mesonephric duct
o Seminal vesicle – out budding of mesonephric duct
o Appendix testis – vestigial small cranial portion of the paramesonephric duct in males
o Utriculus prostaticus – homologous to female vagina in males
 Genital ducts in Females (mainly - paramesonephric duct)

o Paramesonephric duct
 Cranial, vertical part + Horizontal part = Uterine tubes
 Caudal vertical part - uterine canal
o Mesonephric duct - epoophoron , paroophoron , (Gartner’s cyst)
Vagina
 Fornix + upper part –uterine canal (paramesonephric duct)
 Lower part –urogenital sinus (sinovaginal bulb vaginal plate)
Clinicals – Defects of vagina and uterus
External genitalia
 Indifferent stage
o Cloacal folds – Slightly elevated
folds around the cloacal
membrane
o Genital tubercle – Fused cranial
part of cloacal folds
 th
In 6 week – Urogenital membrane
Cloacal membrane
Anal membrane
Urethral folds
Cloacal folds
Anal folds
 Genital swellings- Pair of elevations on each side of urethral folds
External genitalia in the Male

 Genital tubercle  Rapidly elongate  forms phallus  Glans penis
 Urethral folds fuse  penile urethra
 Tip of the glans penis penetrates inwards  External urethral meatus
 Genital swellings  scrotal swellings  Scrotum
Clinicals
Hypospadias – Fusion of the urethral folds is incomplete
o Abnormal openings of the urethra occur along the inferior (ventral) aspect of the penis
(Near the glans, shaft or base of penis)
Epispadias – (rare) A ventral body wall defect
o Urethral meatus is found on the dorsum of the penis
o Associated with exstrophy of bladder

External genitalia in the Female
 Genital tubercle  Clitoris
 Urethral swellings  Labia minora
 Genital swellings  Labia majora
 Urethral groove  Vestibule
Decent of the testis

 Testis develops inside the abdominal cavity; later it descents into
scrotum
 Urogenital mesentery attached to posterior abdominal wall
degenerates
 Caudal end of the testis is attached to the gubernaculum, which
terminates in the inguinal region
 Later testis begins to develop towards the inguinal region, while
gubernaculum grows towards the scrotal floor
 Therefore the extra abdominal course of the gubernaculum produces
the intra-abdominal migration
 regression of the gubernaculum completes the descent
 Processes vaginalis follows the course of the gubernaculum;
remaining part forms the parietal & visceral layers of tunica vaginalis
 3th month - reach the iliac fossa

 4th – 8th months - rest at deep ring
 7th month - traverses the inguinal canal
 8th month - superficial inguinal ring
 9th month - reach scrotum

Embryology – Head and Neck
Mesenchyme Structure
Paraxial mesoderm  Membranous & cartilaginous components of skull

 All voluntary muscles of craniofacial region
 Dermis & connective tissue in dorsal region
 Meninges caudal to the prosencephalon
Lateral plate mesoderm  Laryngeal cartilages (arytenoid, crinoids)

Neural crest cells  Hyoids
 Skeletal structures in face
 Temporal bone
 V, VII, XI, X nerves
Ectodermal placodes  Sensory ganglions of V, VII, IX, X
Pharyngeal Arches
 Core – mesoderm and neural crest cells

 Internal lining – endoderm
 External lining – ectoderm
 Artery – aortic arch
 Nerve – cranial nerve
 Internal depressions –pouches
 External depressions –clefts
 Appear in the 4th- 5th weeks
 All the muscular components of each pharyngeal arch has its own nerve and arterial
supply

Derivatives of the pharyngeal arches and their innervations
Pharyngeal Nerve Muscles Skeleton

arch
1-Mandibular V (Trigeminal) Muscles of mastication Premaxilla, maxilla, zygomatic
Mandibular & (temporal, masseter, medial bone, part of the temporal
Maxillary divisions & lateral pterygoids) bone, Meckel’s cartilage,
Mylohyoid, anterior belly of mandible, malleus, incus,
digastric, tensor palatines, anterior ligament of malleus,
tensor tympani sphenomandibular ligament
2-Hyoid Muscles of Facial Expressions Stapes, styloid process,

VII - facial (Buccinator, auricularis, stylohyoid ligament, lesser
frontalis, platysma, horn and upper portion of body
orbicularis oculi) of hyoid bone
Posterior belly of digastric,
stylohyoid, stapedius
3 IX - Stylopharyngeus Greater horn and lower portion
glossopharyngeal of body of hyoid bone
4-6 X - vagus Cricothyroid, levator palatine, Laryngeal cartilages (thyroid,

 Superior constrictors of pharynx, cricoids, arytenoids,
laryngeal branch Intrinsic muscles of larynx corniculate, cuneiform)
(4th arch)
 Recurrent
laryngeal nerve
(6th arch)

Pharyngeal pouches
 4 pairs
 5th is rudimentary
 Epithelial endodermal lining give rise to several structures
Pharyngeal pouch Derivative

Tympanic (middle ear) cavity
1
Auditory(Eustachian) tube
Palatine tonsil
2
Tonsillar fossa
Inferior parathyroid gland
3
Thymus
Superior parathyroid gland
4 Ultimo bronchial body
(Parafollicular[c] cells of the thyroid gland)
 Thymus migrates in caudal and medial direction pulling inferior parathyroid with it &
then fuses with the counterpart from opposite side. (Final position – Anterior part of
thorax)
Pharyngeal clefts
1st External auditory meatus

2nd, 3rd, 4th Cervical sinus (normally obliterated)
 Proliferation of 2nd arch overlaps 3rd and 4th clefts

 2, 3, 4 clefts lose their contact with outside
Clinical
Birth defects
1) Ectopic thymic and parathyroid tissue
 Accessory glands remain in the migration pathway
 May found in the neck
 Inferior parathyroids may found at the bifurcation of the common carotid
artery

2) Branchial fistula
External
 2nd arch fails to fuse with epicardial ridge
 2,3,4th clefts open to the surface
 Anterior to the sternocleidomastoid
 Provides drainage for lateral cervical cyst
Internal
 Cervical sinus connected to the pharynx via a canal
 Due to rupture between the 2nd pharyngeal pouch & cleft
3) Cervical cysts
 Remnants of cervical sinus
 Found anywhere along ant. border of SCM, frequently just below the angle of
jaw
 Become evident in child head
Tongue
Structure in embryo Arch Nerve Structure in adult

Lateral lingual Sensory – cranial V3 Body of the tongue anterior 2/3
swellings 1 Taste – cranial VII
Tuberculum impar 1 Overgrown by lateral lingual swellings
Copula 2 Overgrown by 3rd arch
(Hypobranchial 3 Cranial IX Posterior 1/3 of tongue
eminence) Posterior most part of the tongue
4 Cranial X
root
Occipital myoblasts Tongue musculature
- Cranial XII
(Except palatoglossus)
Epiglottal swelling Cranial X (Superior
4 Epiglottis
laryngeal)

Clinical
Ankyloglossia (tongue tie)
 Normal –tongue become free from floor by cell degeneration except frenulum.
 Abnormal – cell degeneration doesn’t occur.
Thyroid Gland
 Epithelial outgrowth from floor of the tongue - Foreman cecum (between tuberculum
impar and copula)
 Connected to the tongue by thyroglossal duct
 Descends in front of pharyngeal gut in midline
 Descend in front of hyoid bone, thyroid & cricoid cartilages
 Positioned in front of trachea in 7th week - with an isthmus & two lobes
 Ultimobranchial body (4th pouch) – incorporated into the gland – give rise to C cells
 Starts function at the end of 3rd month
o Follicular cells  thyroxine & triiodothyronine
o Parafollicular cells( C cells)  Calcitonin
Clinical
 Thyroglossal Cyst
o Always in the midline
o Cystic remnant of thyroglossal duct
o 50% under hyoid bone
 Thyroglossal fistula
o Thyroglossal cyst connected to the outside by canal
o May be present at birth
 Aberrant thyroid tissue
o Remnants of tissue along the migratory pathway
Development of face
Facial prominences formed by

 Neural crest cells
 1st pair of pharyngeal arches
At the end of the 4th week
 Lateral to stomodeum – Maxillary prominence
 Superiorly – Frontonasal prominence
 Inferiorly – Mandibular prominence – appear and grow
th
5 week
 Nasal placodes appear on both sides of frontonasal prominence
 Medial nasal and lateral nasal prominences are formed in each side

6th-7th weeks
 Maxillary prominence grow & push medial nasal prominences toward midline
 Medial nasal prominences fuse
Structures contributing to formation of the face
Prominence Structure formed

Frontonasal Forehead, bridge of nose and medial and
lateral nasal prominences
Maxillary Cheeks, lateral portion of upper lip
Medial nasal Philtrum of upper lip, crest and tip of nose
Lateral nasal Alae of nose
Mandibular Lower lip
Nasolacrimal groove
 Between maxillary & lateral nasal prominence
 Floor forms a solid epithelial cord
 By canalization forms nasolacrimal duct with lacrimal sac
Development of palate
Primary palate
o Formed by intermaxillary segment
Secondary palate
o Formed by palatine shelves of maxillary bones

Intermaxillary segment
Formed by two merged medial nasal prominences
3 parts
o Labial – philtrum of upper lip
o Upper jaw – Upper 4 incisor
o Palatal – triangular primary palate
Palatine shelves
 Two shelf like outgrowths
 Forms main part of palate
 At 6th week directed obliquely by sides of the tongue
 Later ascends and fuse with each other and nasal septum
 Anteriorly fuse with primary palate
 Incisive foramen is the landmark between primary and secondary palates
Clinical
1.Facial clefts
 Two types- anterior and posterior cleft deformities
 Incisive foramen is the landmark
Anterior Posterior
Lateral cleft lip Secondary cleft lip
Cleft uvula
Cleft upper jaw
Primary cleft palate

Intermaxillary segment fail to fuse with Palatine shelves fail to fuse with each other
maxillary processes or palatine shelves
2.Oblique facial clefts

 Nasolacrimal ducts exposed to surface
 Maxillary prominences fail to fuse with lateral nasal prominences

3.Median cleft lip
 Incomplete merging of two medial nasal prominences in midline
Nasal cavities
 6th week – nasal pits deepen
 Oronasal membrane which separates it from nasal cavity disappears
 Primitive choanae formed
 Secondary palate develops
 Definitive choanae formed
MCQ
1. In the development of the face
A. Mandibular process is derived from the second pharyngeal arch
B. Maxillary process is developed from the first pharyngeal arch
C. Nasolacrimal canal develops along the line of fusion of the frontonasal and
maxillary processes
D. Part of the upper jaw bearing the incisor teeth develops from the frontonasal
process
E. Forehead is formed from the maxillary processes
2. Regarding the pharyngeal and branchial arches
A. Cartilage of the first arch is called Reichet’s cartilage
B. Mesoderm of the 2nd arch gives rise to muscle supplied by the maxillary
division of the third cranial nerve
C. Palatine tonsils are derived from the endoderm of the second pharyngeal
pouch
D. Branchial cyst form the persistence of the epicardial ridge
E. Only blood vessels remaining from the 5th aortic arch on the right side is the
proximal part of the subclavian artery
3. In the development of the pharyngeal arches
A. Nerve of the 4th arch is the superior laryngeal
B. External acoustic meatus is derived from the 2nd pharyngeal cleft
C. Sphenomandibular ligament is a remnant of the 2nd pharyngeal arch cartilage
D. Greater and lesser horns of the hyoid bone have the same origin
E. Larynx is derived from cartilage of the 4th and 6th arches
4. First pharyngeal arch
A. Gives rise to the malleus and the incus
B. Is innervated by the trigeminal nerve
C. Gives rise to the palatine tonsil
D. Gives rise to the muscles of facial expressions
E. Gives rise to the external auditory meatus

5. Following structures are derived from the 2nd pharyngeal arch
A. Posterior third of the tongue
B. Incus and stapes
C. Maxillary artery
D. Stylohyoid ligament
E. Stylohyoid muscle
Answers
1-FTFTF
2-FFTFF
3-TFFFT
4-TTFFT
5-FFFTT
Development of central nervous system
Central nervous system appears at the beginning of the 3rd week as neural placodes.
Lateral edges elevate and form neural folds
Neural folds fuse forming neural tube
Closure of cranial neuropore 25th day
Closure of caudal neuropore 28th day
 Cephalic end of neural tube forms 3 dilations (Primary brain vesicles)

1. Prosencephalon – Forebrain
2. Mesencephalon – Midbrain
3. Rhombencephalon – Hindbrain
 Primary vesicles form 5 secondary vesicles.

1. Prosencephalon – Telencephalon, Diencephalon
2. Mesencephalon
3. Rhombencephalon – Metencephalon, Myelencephalon
Development of pituitary gland
 Develops from 2 different parts.

1. Ectodermal out pocketing of stomodeum (Primitive oral cavity – Rathke’s
pouch)
2. Downward extension of the diencephalon – infundibulum

 In 3rd week of gestation Rathke’s pouch appears and grows towards the
infundibulum.
 At the end of 2nd month Rathke’s pouch loses the connection with oral cavity & come
into contact with infundibulum.
 Anterior wall of Rathke’s pouch - Forms the anterior lobe of the pituitary gland
 Extension of the anterior lobe grows along the stalk of the infundibulum – Forms
pars tuberaslis
 Posterior wall of Rathke’s pouch – Forms pars intermedius
 Infundibulum gives rise to – Pituitary stalk, Posterior lobe (Pars nervosa– Contains
nerves & neuroglial cells)
Clinicals
Ossification defects in bones of skull
Squamous part of occipital bone is mostly common.

 Meningocele – meninges bulge through the opening
 Meningoencephalocele – neural tissue protrudes with meninges
 Meningohydroencephalocele – part of ventricle protrudes with neural tissue &
meninges
 Can be prevented by maternal use of folic acid

Neural tube defects(NTDs)
 Exencephaly – Failure of cephalic part of neural tube to close (Vault of the skull
doesn’t form, Brain locates outside the skull)
 Anencephaly – As an exencephalic pregnancy progresses neural tissue gradually
degenerates
 Spina bifida – Neural tube fail to fuse anywhere from cervical region caudally.
(Common in lumbosacral region)
Exencephaly Spina bifida

Genetics
Genetics
Human DNA
Nuclear DNA Mitochondrial DNA
3% Coding 97% Non-coding 37 Genes
Microsatellite DNA Minisatellite DNA

• scattered throughout the genome • concentrated near telomeres &
centromeres
• Used to track inheritance of disease • used for DNA fingerprinting due to
alleles high variability
Mitochondrial genes
• The only organelles outside the nucleus that have their own DNA (extranuclear DNA)
• Circular rather than linear
• Double helix arranged as rings (2-10 rings)
• Unique sequences rather than repetitive
• Slightly different genetic code
• Exclusively transmitted to next generation by mothers through oocytes.
Chromosomal structure & function
Somatic chromosome complements consist of 46 chromosomes (23 pairs).
22 pairs are Autosomes.
23rd pair is a pair of sex chromosomes.
Male-46, XY Female-46, XX
Nucleosome: fundamental packaging unit made up of 8 histone proteins & DNA – In

metaphase chromatin is more condensed than in interphase
Chromatosome: the nucleosome plus the H1 histone occupying the linker region

Euchromatin: forms the main body active, high proportion of coding genes Lightly stains
Heterochromatin: genes are absent or inactive
Depending on the position of the centromere, chromosomes have short arms(p) / long arms(q)
 Metacentric –Centromere is in the middle (p=q), ex: - 1, 3, 16, 19 and 20
 Submetacentric - Centromere is displaced from the center (p< q), ex: - 6-12, X
 Acrocentric- centromere is at one end (p<< q), ex: - 13-15,21,22 & Y
Telomeres
• Are ends of chromatids
• Specific telomeric proteins binds to this site forming a cap
Functions;
• prevent abnormal end to end fusion of chromosomes ensure complete replication of ends
• assist chromosome pairing in meiosis
• maintain stability/link chromosomes to the nuclear membrane during interphase and help
establish internal structure
• may be involved in aging process
Cytogenetics / chromosome cultures

• performed on rapidly dividing somatic cells from metaphase stage of mitosis
• prenatal / postnatal cells can be used
• to detect birth defects, cancer etc.
Chromosome analysis & classification (at metaphase of division)

Commonly used cells: peripheral lymphocytes, fibroblasts, bone marrow cells, fetal cells
(amniocentesis, chorionic villi extraction), cordocentesis, fetoscopy
(Liver cells, Skin cells and Blood cells)

Karyotype: photographic representation of the entire chromosome complements
• G banding: Uses the Trypsin and Giemsa • High resolution banding to detect
stain to detect numerical defects. micro deletions.
• Light band: Active-lightly stained bands, • Detect structural defects.
G-C rich.
Other staining methods- fluorescent dyes and examination under UV light

Mitosis (25 marks)
• Process by which parent cell divides giving rise to two daughter cells
• Which are genetically identical to the parent cell
• Each daughter cell receives the complete complement of 46 chromosomes
• Is an intermediate stage in cell cycle
• Has 4 phases
o Prophase
o Metaphase
o Anaphase
o Telophase
• Before cell entering the mitosis, each chromosome will replicate its DNA
• During this replication process chromosomes are extremely long & diffusely spread through
the nucleus
• With the onset of mitosis chromosomes begin to coil, contract & condense
• Marks beginning of prophase
• Each chromosome consists two parallel subunits, chromatids
• Joined to each other by centromere
• Throughout the phase chromosomes continue to condense, shorten & thicken Metaphase
• Line up in the equatorial plane
• Each attached by microtubules
• Extending from centromere to centriole
• Form mitotic spindle Anaphase
• Division of centromere followed by migration of chromatids to opposite poles of the spindle
telophase
• Chromosomes uncoil & lengthen
• Nuclear envelope reforms
• Cytoplasm divides giving rise to two genetically equal daughter cells
• Each daughter cell receives half of doubled chromosome material
• Maintains equal number of chromosomes as that of mother cell
MEIOSIS
• Before cell entering the meiosis, each chromosome will replicate its DNA
• Each chromosome resulting two sister chromatids
• In prophase l
• Chromosomes become visible as threads
• Homologous chromosomes pair
• Formation of synapsis
• Cross over of chromosomal material
• Further condensation of chromosomes
• Homologous pair begin to separate but held together at the point of cross over -
chiasmata

• Metaphase l
• Homologous pair position on either side of equatorial plane
• Spindle formation
• Independent assortment
• Anaphase l
• Homologous chromosomes separate from each other & move to the opposite poles of the cell
• Telophase l
• Two haploid sets of chromosomes reach each pole & cytoplasm divide forming two new daughter
cells secondary oocyte & 1st polar body
• Enters meiosis ll following a brief interphase
• Arrest in metaphase ll
• Chromosomes attached to spindle at kinetochores
• Anaphase ll
• Centromeres separates allowing the chromatids to pull to opposite poles
• Telophase ll
• Chromosome begins to uncoil assuming the extended state characteristic of interphase
Additionally,
Meiosis Prophase 1:
 Leptotene -Chromosome visible as threads, chromatids unable to be distinguished

 Zygotene -homologues chromosomes pair along their lengths side by side. Synaptonemal complexes
appear which assist in synapsis and crossing over.
 Pachytene -Chromosomes condense further. Visible in fours(tetrads). Recombination through crossing
over.
 Diplotene -Homologous chromosomes begin to separate but held together at chiasmata
 Diakinesis -Chromosome pairs attempt to separate & reach maximal condensation
The process of meiosis differs in males and females. In males this is a continuous process which begins in the
mature seminiferous tubules of adolescents. In females by birth the process is arrested in prophase 1 in a stage
called Dictyotene. After menarche with each ovulation meiosis 1 is completed and meiosis 2 begins. Meiosis 2
completes only following the entry of the spermatozoon into the egg.
 Meiosis differs from Mitosis for the following reasons:

1.It occurs only in germ cells, whereas mitosis occurs in somatic cells.
2.It consists of two sequential cell divisions, whereas mitosis has only one.
3.Pairing of homologous chromosomes occurs, which is not seen in mitosis.
4.Recombination of homologous chromosomes takes place, which is not seen in mitosis.
5.There is a reduction in the number of chromosomes from 46 to 23, unlike in mitosis.
 The genetic consequences of meiosis are:

1.It helps in the reduction of the number of chromosomes, and thereby assists gamete formation.
2.It helps in the segregation of alleles, thereby allowing only one of an original gene pair to be included
in each gamete.
3.It assists in the independent assortment of homologous chromosomes, so that each gamete contains a
mixture of paternal and maternal chromosomes.
4.By the process of crossing over, it ensures that each gamete carries genes inherited from both the
father and the mother.

Meiosis
PROPHASE I
1st meiotic division2nd meiotic

Leptotene Zygotene Pachytene Oeplotene Oiakinesis
METAPHASE I
ANAPHASE I
TELOPHASE I
METAPHASE II
division
ANAPHASE II
Mutation
• A heritable change in genetic material in less than
1% of the population
[More than 1% polymorphism]
• Occur in a coding or non-coding sequence

• In somatic cell cannot be transmitted
• Gonadal tissue / gametes transmitted to future generations
Mutations
Structural mutations Numerical mutations
Chromosomal Disorders
I. Polyploidy
Presence of more than 2 sets of chromosomes Ex: - triploids - 69, XXX
69, XXY
69, XYY
tetraploids
Imprinting is shown in triploidy [phenotypic expression varies depending on whether the extra set of
chromosomes are paternal or maternal in origin]
maternal: - small fetus, placenta is not cystic
paternal: - large head, cardiac anomalies, cystic placenta
Triploidy (69 chromosomes) may result from a failure of meiosis in a germ cell or dispermy. Tetraploidy
(92 chromosomes) results from a failure of the first cleavage division after fertilization.
II. Trisomy
• Presence of 3 copies of a single chromosome
• commonest cause is nondisjunction in meiosis I (80%)
• secondly in meiosis II (20%)
• in either sex (oogenesis 80%, spermatogenesis 20%)
• in early mitotic division of the zygote, anaphase lag.
• Most triosomic embryos are lost in early pregnancy. Usually only
trisomies 13,18 and 21 survive

Autosomal:
Down Syndrome (trisomy 21)
• Karyotype: - [47, XY, +21 or 47, XX, +21]
96% - trisomy 21
4% - translocation to 13,14,15,21 or 22 – very small percentage are mosaics
Can be diagnosed prenatally by ultrasound scan
My CHILD HAS a PROBLEM

C - congenital heart diseases
H– hypotonia, hypothyroidism
I- increased sandal gap
L - low set ears
D - duodenal atresia
H - hypertelorism, Hirschsprung disease
A - aplasia of middle phalanx of 5th digit, Alzheimer’s disease
S - simian crease, stubby hands
P - protruding tongue
R - respiratory infections
O - occiput flat
B - behavioral problems
L - low flat nasal bridge
E - epicanthic folds
M – mental retardation
Trisomy 13-Patau Syndrome

• Growth retardation
• Microcephaly with severe mental retardation
• Midline abnormalities (Scalp defects, Holoprosencephaly)
• Facial defects (Micrognathia, central/unilateral clefts)
• Eye defects (Hypotelorism, Micropthalmia, Anopthalmia or Cyclopia)

Trisomy 18-Edward Syndrome
• Growth deficiency
• Small faces
• Prominent occiput
• Sloping forehead
• Small malformed and low set ears
• Micrognathia
• Overlapping fingers
• Prominent heels
• Cardiac and renal malformations common
Sex chromosomes:
Klinefelter syndrome: - 47 XXY or 48XXXY or 49XXXXY
• Adult phenotype is basically male though
• Gynecomastia
• poor musculature, eunuchoid habitus
• Feminine body hair distribution small genitalia
• Tall stature
• Long lower legs / forearm scoliosis/osteoporosis varicose veins and ulcers
• Infertility due to azoospermia or subfertility due to oligospermia are evident.
• Only 47XXY is accompanied with advanced maternal age [ intracytoplasmic sperm injection
ICSI is done]
XYY syndrome
• Karyotype-[47, XYY]
• Affected males have a normal physical appearance
• Problems in motor coordination
• Above average stature
• Mildly impaired intelligence
• Aggressive behavior
Triple X Syndrome
• Karyotype-[47, XXX]
• Affected girls are physically normal
• Taller than average
• Arises form an error in meiosis 1
III. Monosomy- autosomal monosomies are lethal but monosomy for X is compatible with life.
Turners syndrome: - 45X
• Phenotype basically female but streaky ovaries can be diagnosed prenatally
• Neck webbing, cutis laxa, shield shaped chest, coarctation of aorta, lymphoedema of hands
and feet,
• Short stature and cardiac murmur in childhood.
• Iry or IIry amenorrhea, lack of IIry sexual characteristics
• Estrogen replacement therapy should be initiated at adolescence
• Normal mentality.

• Adults may present with infertility
• Thyroiditis and kidney abnormalities may be present.
Random X inactivation/ Dosage compensation / lyanisation

• During late blastocyst stage
• In females either maternal / paternal X is permanently inactivated randomly in each cell
• Forms a Barr body ---- seen in interphase
• Areas crucial for development remain active
• In the extra-embryonic trophoblastic cells, the paternal X is preferentially inactivated.
• Hence every woman is a mosaic in expressing her X chromosomes.
4. Mosaicism
• Presence of two or more cell lines with different karyotypes in a person
• caused by chromosomal nondisjunction during mitosis
• Clinical feature depends on proportion of abnormality to normal cells
• The abnormal cell line may be confined to a particular tissue if the aberration took place in
the late embryonic or fetal development
• To multiple tissues if the changes took place in very early development. Ex: 46, XX/47, XX,
+21
Structural anomalies
1. Deletion
leads to a loss of chromatin
 terminal deletions
• Ex: - cri du chat syndrome: - deletion of tip of the short arm
of the chromosome [ 5p] malformed larynx [cat like cry].
• low birth weights and have failure to thrive.
• round faces, low set ears, profound learning disability, Hypotelorism, epicanthic folds
 micro deletions
• syndromes-Very small deletions often detected by high resolution banding.
Imprinting is seen chromosomal 15q
paternal: Prader -Willi syndrome
maternal: Angelman syndrome
detected only by special high-resolution banding.
 Interstitial deletions
2. Isochromosomes
Formed when a chromosome with two chromatids splits at right angles to the normal
length wise separation seen in normal division. Chromosomes will have both short arms or
both long arms. Ex: - 20% of Turner Syndrome individuals
Down syndrome (long arm trisomy and short arm monosomy)

3. Inversion
Chromosomes break at two points & the intervening broken segment turns 180 degrees to
reverse the order of chromatin.
If the break points are on the same arm - paracentric inversion
If it’s on either side of the centromere including it in the broken segment – pericentric
inversion. This leads to chromosomally unbalanced gametes.
4. Translocation
Exchange of chromosomal material between chromosomes 3 types:
I. centric fusion or Robertsonian translocation
• Fusion of whole arms of acrocentric chromosomes. Breakpoints are at or near the
centromere.
• Fused long arm chromosome survives while the fused short arm chromosome is lost.
• No effect is produced as short arm of acrocentric contain genetically inert material or RNA
genes.
(4% downs are of this type. commonest involving - long arms of chromosome 14 &
21t(14q21q))
II. Reciprocal
• Breakage and then exchange of segments of chromosomes. Point of exchange may be
anywhere along the chromosome.
• No loss of chromosomal material.
Ex: Philadelphia chromosome – deleted chromosome 22 in which long arm has been
translocated to the long arm of chromosome 9. Used to indicate prognosis of chronic
myeloid leukemia (CML) & acute lymphocytic leukemia.
The absence of the Ph chromosome in CML indicates bad prognosis.
III. Insertional
• Insertion of a deleted segment of a chromosome interstitially or inside another
chromosome following a break at that point
• Insertion of a deleted segment of a chromosome interstitially or inside another
chromosome following a break at that point
Other anomalies
Fragile X syndrome:
• More frequent in males
• Tip of the long arm of X is fragile.
• Speech delay, mental retardation with moderate educational sub normality. triangular
• Face, prominent mandibles, macrochidism, closely set eyes, large ears.
• Females with fragile x are mentally normal.
Chromosome breakage syndrome

Due to errors in DNA repair & synthesis
Ex: Fanconi Anaemia, Ataxia Telangiectasia show multiple fragility .

Early development:
At the beginning of week 5 primordial germ cells migrate from endoderm cells of the yolk sac and infiltrate
primitive sex cords within mesodermal genital ridges which are products of coelomic epithelium.
Paired indifferent gonad is identical in males and females.
Bipotential external genitalia Male external genitalia

{After 8th week
Androgen receptors are coded by a gene on the X chromosome

1. Which of these are autosomal dominant disorders.
a) Huntington’s disease
b) Marfan syndrome
c) Oculocutaneous albinism
d) Achondroplasia
e) Duchenne muscular dystrophy
2. Regarding autosomal dominant inheritance
a) Every affected person has an affected parent.
b) Variable expressivity can be seen in Marfan syndrome.
c) The heterogenous carriers may show clinical features.
d) Achondroplasias are usually caused by new mutations.
e) More males are affected than females.
f) Is transmitted through both males and females.
g) Reduced penetrance is seen.
h) There are more affected females than males.
i) Achondroplasia belongs to this category.
3. Regarding Down syndrome
a) Short stature is a common feature.
b) The disorder can be diagnosed prenatally.
c) Trisomy 21 is the commonest variety.
d) Carrier states can be detected in the translocation types.
e) AV canal defects are the commonest cardiac complication.
f) Karyotype may be 47, XX, +21.
g) Hypertonia is seen at birth.
h) Mental retardation is a common feature.
i) Complete atrioventricular canal defect is the
commonest cardiac lesion in these patients.
J) The commonest cause is non-disjunction in meiosis II in oogenesis.

Genetics –II Patterns of Inheritance.
Definitions (pg33 Basic Medical Genetics)
 Gene
 Locus
 Alleles
 Genotype
 Phenotype
 Homozygous
 Heterozygous
 Dominant
 Recessive
 Autosomal
 X or Y linked
Pedigree: - graphical representation of a family tree which shows the biological

relationship of the index case.
Birth defects
Genetic Non-genetic
Single gene defects Chromosomal Mitochondrial Multifactorial (Gene +

anomalies environment
Single gene defects
(Mendelian inheritance)
Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked
Autosomal dominant

Vertical inheritance –Transmission of the trait
continues from generation without skipping.

Both sexes are affected equally.

Every affected child has an affected parent except for a
new mutation.

Affected heterozygous + normal homozygous = risk 50%

1. New mutation
e.g.:- achondroplasia osteogenesis imperfecta
 Isolated case
 Increased paternal age
2. Reduced penetrance
e.g.:-multiple neurofibromatosis, marfan syndrome, BRCA, retinoblastoma
 Expression of number of individuals who have the gene & show the trait.
 If the frequency is less than 100%, reduced penetrance exists.
3. Variable expressivity
e.g.:-marfan syndrome, multiple neurofibromatosis
 Degree of expression of a trait.
 The individuals of a family may show mild to moderate to severe forms of the disease.
4. Variation in age onset
e.g.:-adult polycystic kidney disease
Huntington’s disease - clinical features manifest in the 3rd or 4th decades of life
5. Variation in severity dependent on sex. ‘Anticipation’
Eg:- Huntington’s disease-manifest earlier if the affected parent is the father
myotonic dystrophy- manifest earlier if the affected parent is the mother
6. Genetic heterogeneity
e.g.:-Retinitis pigmentosa – caused by both autosomal dominant and recessive inheritance
 similar clinical picture
 different mutations at same locus or different loci
7. Influence of non-genetic factors
diet→expression of familial hypercholesterolemia
barbiturates→precipitate porphyria
8. Variable severity
 All offspring will not have the entire severity of the
disease e.g.:-tuberous sclerosis
9. Phenocopy
It is an environmentally caused phenotype which resembles one produced by a mutant gene.
e.g: Warfarin induced embryonic defects resembling Conradi’s syndrome.
Clinical examples for autosomal dominant

1) Huntington’s disease- Adult onset disease. Associated with choreiform movements and progressive loss
of mental activity, mood disturbances.
o Gene-short arm of chromosome 4 (4p)
o Anticipation
o Triplet repeat expansion (CAG)
2) Marfan syndrome
 Long arm of chromosome 15 (15q)
 Shows variable expression
 Connective tissue disorder
 Abnormal body proportions, Kyphosis, Scoliosis, Arachnodactyly, Mitral and Aortic valve
defects, dissecting aneurisms, Lens dislocations.
3) Familial hypercholesterolemia
 Deletion of a gene producing LDL receptors
 Increased cholesterol levels
 Premature coronary artery disease
In autosomal dominance heterozygous normally survives. Homozygous does not survive.
But in hypercholesterolemia, homozygous also survives.
Autosomal Recessive
 Only manifest in homozygous genes.
 Horizontal inheritance.
 Both sexes affected.
 Normal parents, some normal offspring with affected
siblings among them.
 Parental consanguinity increases the incidence.
 Heterozygote male + heterozygote female. →25% risk
 Carriers –usually normal, exception-sickle cell anemia
 Certain racial groups →recessive genes at higher
frequency
 If the recessive genes are alleles, all the children of two
affected parents are affected.

Clinical example
1) Homocystinuria –Deficiency of cystathione beta synthase.

2) Cystic fibrosis- short arm of chromosome 7 (7p). Chronic respiratory i nfections and
malabsorption. Secretions of the gut and lungs are thick and sweat is thick with high NaCl.
3) Phenylketonuria –Severe mental retardation due to accumulation of phenylalanine in blood, tissues and
urine. Mutation in long arm of chromosome 12.
4) Sickle cell anemia
- Mutant β-globin polypeptide chains on chromosome 11
- Glutamate is replaced with valine at position 6 from the amino end
- Normal HbA/HbA
- Trait HbA/HbS
- Disease state HbS/HbS
5) Thalassemia
- Imbalance of synthesis of globin chains
- The excess accumulates in RBC, insoluble precipitates are formed causing hemolysis
- Causes anaemia leading to hyperplasia of bone marrow.
- 2 types (α & β)

X- linked dominant
 Mutant gene is dominant and on the X chromosome.

 Males may be normal or affected and female
heterozygotes are more variably affected due to random
inactivation of X chromosomes.
 Affected males never transmit it directly to sons. But do
transmit to all the daughters.
 Heterozygous females transmit it to half their sons & their
daughters.
 More females than males; lethal in male.
 All daughters of an affected father are affected.
 E.g.: Vit.D resistant rickets.
Incontinentia Pigmenti
Rett syndrome
X- linked recessive
 Hemizygous affected males→ heterozygous carrier daughters

 More males than females
 Affected male-heterozygous mother except for a new mutation.
 Female heterozygote-random inactivation of X - wide spectrum of
clinical features.
 If the gene on the X is normal then the male is normal. There are no
carrier states in the male.
 Heterogeneity may be seen where the clinical features are
similar but inherited through different mechanisms
 X linked lethal conditions are those where affected males die before
birth.
 ZIg-zag inheritance
e.g.:- Classical hemophilia A
red-green colour blindness Ocular albinism *unaffected parents (3&4) have affected
G6PD deficiency children
Becker muscular dystrophy *skipping -> recessive
Duchene muscular dystrophy *males get it from mother, thus x-linked
 Short arm of X (Xp21)
 Absence of dystrophin protein
(maintain muscle Ca permeability)
 Progressive wasting and weakness of proximal
muscles of all limbs accompanied with hypertrophy of calf muscles
 Death in teens due to cardiac or respiratory failure
Fragile X syndrome-
 a chromosome aberration.
 fragile sites are at tips of long arms of the X chromosome.
 Commonest inherited mental retardation (more common in males)
 Megalotestis (macrochidism)
Y-linked
-Directly from father to son.
-No father to daughter transmission
-Hairy ears, webbed toes.
-Only males are affected.
Multifactorial Inheritance
Genes + environment → final outcome – occurrence of the disease depends on the environmental
conditions at which both the parents and offspring live.
Accounts for the majority of congenital malformations and responsible for many normal variations in
humans.

 Non-syndromal malformations
- ASD, tetralogy of Fallot, VSD, PDA.
- Anencephaly, meningocephalocele, spina bifida.
- Cleft lip with or without a cleft palate.
- Congenital hip dislocation.
- Diabetes mellitus
- Hypertension
- Pyloric stenosis which is more common in males
- Systemic lupus erythematosus which is more common in females
 The diseases tend to be familial
 Occurs more in one sex than the other
 The recurrence risk is the same for all the relatives who share the same proportion of genes.
 The recurrence risk reduces as the relationship becomes distant
 It’s more common among children of consanguineous parents
Mitochondrial Inheritance
Inheritance is matrilineal
- Only mothers transmit the condition to both sexes
Tissue rich in mitochondria are mostly affected
- Heart
- Striated muscle
- Kidney
- CNS
e.g.:- Leber’s hereditary optic neuropathy

Diabetes mellitus with sensorineural deafness
1. Following conditions are autosomal dominant

a) Familial hypercholesterolemia
b) Huntington’s disease
c) Phenylketonuria
d) Congenital polycystic kidney
e) Sickle cell anaemia
2. Which of the following conditions are caused by mutations in mitochondrial DNA?
a) Leber’s hereditary neuropathy

b) Diabetes mellitus with sensorineural deafness
c) Marfan syndrome
d) Fragile X syndrome
e) Duchenne muscular dystrophy

 Guide to solve pedigree charts
*There are unique features for all 4 types.
Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive
*Don’t skip *Skip generations *never transfers from *males are more
generations *unaffected parents father to son affected
*affected parents can can have affected *all daughters of an *tend to transmit from
have unaffected children affected father will be mother to son & father
children affected to daughter
*no father to son
transmission
Dark-affected
Both 1 & 2 parents are affected but they
have an unaffected child
This is possible in Autosomal dominant
disorders & that is enough to identify.
Although 8 & 9 parents are unaffected,

they have an affected child which means
this is an Autosomal recessive disorder.
Skipping generations
Both genders are affected
All affected fathers have affected

daughters and there’s no father to son
transmission. But there’s mother to son
transmission, which are the key features
of X-linked dominant disorders

Histology
LYMPHOID TISSUE
Lymphocytes
 20-50% of WBC in circulation.

 Most of them are small lymphocytes & 3% large lymphocytes.
 Two types: T cells & B cells
T cells
1. T helper cells 2. Cytotoxic T cells 3. Suppressor T cells

[TH cells] [TC cells] [TS cells]
‘Help’ B cells, TC Kill virus infected Suppress immune

cells & cells & cancer responsiveness to
macrophages to cells self antigens.
perform their
function. Switch off immune
response.
4. Memory T cells
B cells
 Formation & maturation in bone marrow.

 Synthesize immunoglobulins IgG, IgA, IgM, IgE & IgD. [GAMED]
 Once activated:
a) Undergo mitosis.
b) Cells mature into plasma cells.
Few cells become memory B cells – [Respond quickly to subsequent encounter of
the antigen.]

THYMUS
 Location: - Upper anterior mediastinum and lower part of the neck.

Origin: - From epithelial outgrowths of the ventral wings of the 3rd pharyngeal
pouch.
 Most active during childhood, undergoes slow involution with age.
 But secret hormones continuously
 Involution due to
a) Fatty infiltration
b) Lymphocyte depletion
Structure:-
 Lobulated.
 Invested by loose collagenous capsule.
 Interlobular septae arise from the capsule.
 No afferent lymphatics.
 Outer cortex – deeply basophilic
 Inner medulla – eosinophilic
 Immature T lymphocytes enter thymus through Post capillary venules
 Thymic epithelium forms blood thymic barrier.
 Cortex
- Highly cellular. T cells present.(maturing thymocytes)
- Mitotic figures present.
- Undergo further maturation as they move deeper.
(Cortex to medulla)
 Medulla
- Dominant feature – Epithelial component
- Hassall’s corpuscles present
- contain dendritic cells
maturing thymocytes migrates from cortex to medulla

 Hassall’s corpuscles
- Lamellated.
- 1st appear in fetal life.
- Increase in number and size with age.
- Formed from degenerating keratinized epithelial cells.
 At the end of their journey through thymus mature T cells enter blood vessels and
lymphatics.
 Thymus secretes hormones throughout life.(Thymosine)
LYMPH NODE
 Location:- Along course of lymphatic vessels.

Occur in groups where lymphatics converge to form larger trunks.
e.g.: neck, axillae, groins
Structure:-
 Bean shaped.
 Surrounded by collagenous capsule.
 Trabeculae extend from the capsule
 Afferent lymphatics pierce the capsule.
 Afferents drain in to subcapsular sinuses.
 Then through cortical and medullary sinuses.
 Lymph drains in to efferents at the hilum. One efferent usually
 Blood vessels also enter and leave at the hilum.
 Two zones : Outer cortex and central medulla

 Cortex
- Highly cellular/densely staining
- Densely packed with lymphocytes
- Lymphoid follicles are present in the superficial part
- Deep cortex / Paracortex is devoid of lymphoid follicles
- Cortical sinuses are found in the cortical cell mass
 Medulla
- Less cellular.
- Pale staining.
- Medullary cords are extensions of cortical cell mass.
- Medullary sinuses converge upon hilum.
 All the sinuses kept patent by a skeleton of reticulin fibers
 Blood supply
- High endothelial venules are the site of entry of
most circulating lymphocytes in to the node
- HEV lined by tall cuboidal cells
 3 functional compartments are found within a node
a) Lymphatic sinuses
b) Blood vessels
c) Interstitial compartment
 Zones of immunological activity Main cell type

Sup. Cortex B lymphcytes
Para cortex T lymphocytes
Medulla Plasma cells
Sinuses Macrophages
 Final stages of maturation to form plasma cells occur in the medulla.
Lymphoid follicles
Primary follicles Secondary follicles
- unstimulated - has two zones: germinal center and

- consists entirely of the mantle zone
same cell type: - Pale stained Germinal center: Actively
resting B cells dividing B cells
- Mantle zone: Resting B cells
- (Other cells in the germinal center:
- Follicular dendritic cells
- Tingible body macrophages)

MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT)
Total mass of lymphoid tissue in GI, respiratory & genitourinary

tracts is collectively known as MALT.
Large non-encapsulated aggregations.

No afferent lymphatics but efferents.
Consist of both T & B lymphocytes, antigen presenting cells,
M cells (specialized epithelial cells with invaginations, involved in antigen uptake
via transcytosis)
PALATINE TONSIL
Palatine+ lingual+pharyngeal+tubal tonsils  Waldeyer’s ring
 The luminal surface is covered by stratified squamous epithelium,( except tubal

tonsils which is covered in respiratory epithelium.)
 It invaginates the tonsil forming tonsillar crypts.
 The base is separated from the underlying muscle by collagenous hemicapsule.
 Parenchyma contains lymphoid follicles.
 Efferent lymphatics pass to deep cervical chain.
 Mainly T lymphocytes. Small number of B lymphocytes.
GUT ASSOCIATED LYMPHOID TISSUE
 Organized lymphoid tissue is found in all parts of GI tract except in the stomach.
 Largest aggregates are Peyer’s patches of SI. (non encapsulated)

 Peyer’s patches are least numerous in duodenum & most prominent in terminal
ileum.
 Epithelium overlying is specialized for antigen uptake. E.g.: M cells (contain
microfolds, not microvilli)
 HEV (High endothelial Venules) present.
SPLEEN
Structure:-
 Surrounded by a thin fibroelastic outer capsule.
 Trabeculae extend into parenchyma.
 Macroscopically-white nodules in a red matrix
 White nodules represent white pulp.
 Red matrix represent red pulp.
 White pulp
- contains lymphoid aggregations.
- is of two types T cells & B cells.
- small fraction (5-20%) of total mass.
- T cell areas surround central arteries forming
periarteriolar lymphoid sheath (mainly TH cells).
- B cells form follicles.
 Red pulp
- is vascular tissue.
- consists of parenchyma with an interconnected
network of venous sinuses.

- parenchyma is composed of macrophages of sheathed
capillaries, other macrophages & blood cells.
- vascular sinuses are lined by stave cells.
- sinuses drain ultimately into portal vein.
 Splenic vasculature
- Splenic artery branches repeatedly.
- Central arteries are surrounded by a cuff of lymphoid
tissue.(PALS) – Periarteriolar lymphatic sheath (contain
TH cells)
- Central arteries give off penicilliary arteries at right
angles.
- Penicilliary arteries terminate in 2-3 sheathed
capillaries.
- Sheathed capillaries are blind ending capillaries
surrounded by macrophages instead of endothelial
cells.
Thymus Lymphoid tissue Spleen MALT

Afferent lymphatics χ   
Efferent lymphatics    
Post capillary High endothelial Central
venules venules arteries and -
branches
Hassall’s B follicles White pulp- Mainly T cells
corpuscles T & B cells
Primary Secondary
Red pulp- Small number of T
Germinal Mantle PALS cells
center zone
Encapsulated Non encapsulated
1. Regarding lymphoid tissue

a) T lymphocytes are found mainly in the paracortex of the lymph node.
b) Thymic epithelium forms the blood thymic barrier.
c) Post capillary venules are characteristics in all lymphoid tissue.
d) Hassel’s corpuscles are formed by degenerated lymphocytes.
e) Sub capsular sinus is found in the tonsil
f) In lymph nodes trabeculae are lined by sinuses.
g) Hassal’s corpuscles are first seen at birth.
h) Peyer’s patches in small intestine are encapsulated.

Epithelia
Epithelial type Adaptation Function Site where found
1.Simple squamous Flattened Passive transport Lung(alveolar wall)

pavemented Irregular shaped (diffusion) Blood capillaries
epithelium Buldged nuclei to Cavities- pleural
surface Pericardial
Peritoneal
Excretory PCT of kidney

2.Simple cuboidal Polygonal in shape Secretory Excretory ducts of
Rounded nucleus Absorptive function salivary gland,
pancreas and
thyroid
3.Simple columnar Taller cells Absorption Small intestine

Polarity of the Secretory function Stomach
nucleus abs.
Sometimes may be Secretory function Gall bladder
ciliated
microvilli/stereocillia Female
may present reproductive
goblet cells may also system + cilia
present (fallopian tube)
*simple columnar 1.predominant

cilliated cilliated(nuclei
within mid zone)
2.non cilliated
secretary(basal
nuclei)
4.Pseudostratified Nuclei may be Mucociliary

columnar ciliated disposed at different escalator
(Respiratory epi: ) levels Respiratory tract
Ciliated
Found goblet cells
Nuclei confined to
the basal 2/3 of
epithelia

5.Stratified Basal layer cuboidal,
squamous surface layer Withstand abrasion
flattened Protection of Oral cavity
Dividing stem cells in drying Pharynx
basal layer Esophagus
May have keratin Anal canal
layer Vagina
tight junctions Skin (keratinized)
6.Stratified cuboidal Thin cell layer

(2 or 3) Robust lining
large excretory
ducts
7.Transitional Surface cells are e.g.:- Salivary
epithelium large & rounded Great degree of glands
(urothelium) Basal cells roughly stretch
cuboidal, Withstand the
intermediate cells toxicity of urine only in urinary tract
are polygonal of mammals
transit between
stratified cuboidal
&stratified
squamous
Cilia are never present in true stratified epithelium.

Stem cells do not contain cilia and do not extend up to the luminal surface.
Epithelia - glands
Exocrine glands
They maintain continuity with the epithelial surface (duct system)

goblet cells are simplest exocrine glands
Structure
Contains secretary component and duct system

Duct system – Unbranched (simple) Branched (compound)
Secretary component may be tubular or acinar
Both types of secretory component may also be coiled or branched
Any combination of duct system and secretory component can occur
Secretory portion of some glands contain myoepithelial cells

Simple
 Tubular cells secrete mucus and are pale staining.
 Acinar cells are serous secreting cells and are darkly staining
1.Tubular 2. Coiled 3. Branched 4. Acinar 5. Branched acinar

- colon , tubular tubular -mucus secreting - sebaceous glands
large intestine - sweat glands - GIT , stomach glands of
The penile urethra
Compound
1.Tubular 2. Acinar 3. Tubulo – acinar
- Brunner’s glands of - Pancreas - Submandibular salivary glands
duodenum 3 types of secretory units
I. branched tubular
II. branched acinar
III. branched tubular with
acinar ends(demilunes)
 3 types of glands according to their glandular secretion
1. Merocrine / eccrine – exocytosis (protein secreting glands)

2. Apocrine – release granules/vesicles (mammary glands, sweat glands)
3. Holocrine – secretory cells disintegrate (sebaceous glands)
2. Regarding epithelial and glandular tissue

a) Metaplasia is the regeneration of the epithelial tissue.
b) Serous demilunes are characteristics of the purely serous secreting glands.
c) In endocrine glands secretory cells are usually arranged as acini.
d) Secretory granules are characteristics of merocrine secretions.
e) Most cytoskeletal proteins are coded by multi gene families.
3. Epithelia
a) At region of adherent junctions the cytoskeleton is attached to the BM.
b) Gap junctions play an important role in cell recognition in embryonic development.
c) BM is a thickened area of connective tissue which has no fibers.
d) In apocrine secretion the entire cell disintegrates during secretion.
e) At region of adherent junctions the cytoskeleton is attached to the BM.
f) Gap junctions play an important role in cell recognition in embryonic development.
g) BM is a thickened area of connective tissue which has no fibers.
h) In apocrine secretion the entire cell disintegrates during secretion.
4. T/F about epithelium & glands

a) Nucleoli of cell represent the active site of synthesis of RNA.
b) Cilia can never be found in stratified epithelium.
c) Exocrine glands are compound glands with branched excretory ducts.
d) Sweat glands are compound tubular glands.
e) Numerous functional complexes are found between epithelial cells & their basement
membranes.

Connective tissue
Origin: - Mesoderm
Types: - Loose connective tissue
Dense connective tissue
Adipose tissue
Bone & cartilage
Cells of immune system
Composition: - 1. Cells
2. Extracellular matrix
3. Blood vessels & lymphatics
1. Cell types: - Synthesize & maintain the ECM

I. Fibroblasts
- Commonest
-Produce precursors of ECM (GAG, collagen, elastin)
-Active cells- large cell with cytoplasmic processes
-Inactive cells- small, spindle shaped
II. Myofibroblasts
- Contractile function, tissue repair after damage
III. Adipocytes
Lipoblasts ==> Adipocytes
- Store energy
-Regulate fat uptake & release
White adipose tissue

- Adults 20-25% of TBW
- In the deep layer of the skin
- Energy store, thermal insulator, shock absorber
- Single large droplets
Brown adipose tissue

- Newborns
- Thermoregulation , unique uncoupling proteins
- Rich vascular network
- Several droplets
IV. Defense cells

Macrophages – derived from monocytes, scavenger in tissue, 1 st cell to
make contact with antigen
Mast cells –derived from basophils, important in allergic reactions, secret
histamine
V. Chondrocytes & Osteocytes
2. Extracellular matrix (ground substance + fibers)

Secreted by,
I. Fibroblast- most of CT
II. Chondrocytes- cartilage
III. Osteocytes- bone
Ground substance
- Transparent molecules
- Semi fluid gel
- Fibers are embedded
- Formed by GAGs
Fibers
- Collagen (secreted as tropocollagen)& elastin
Collagen – Type 1 fibrous supporting tissue
Type 2 hyaline cartilage
Type 3 (reticulin) supporting framework (Of lymphoid tissue, bone marrow)
Type 4 Basement membrane
Type 7-anchoring fibrills(link ECM to BM)
- Elastin – stretching & elastic recoil
Short, branching, secreted as tropoelastin
Deposition requires fibrillin
Basement membrane
Constituents- GAGs- heparin sulphate
Fibers- collagen type 4
Glycoproteins- fibronectin, laminin, entactin (Nidogen1)
Reticuloendothelial system/Macrophage phagocytic system
Function; - 1. Phagocytose particular matters, microorganism, affected cells
2. Store iron & certain metabolic products
Structure; - Diverse group of cells

E.g.; in bone marrow, liver, spleen, lymph nodes, thymus
Supporting frame work of reticulin fibers
Reticular cells- similar to primitive mesenchymal cells
Long cytoplasmic processers
Phagocytic cells – similar to endothelial cells

Cell junctions
Tight junctions Adhering junctions Communication junctions
-Intestinal epithelium -In most tissues -Cardiac muscles
5. T/F regarding connective tissue

a) Primitive mesenchyme is the embryological tissue from which all types of connective
tissues are derived.
b) Type I collagen is the main type.
c) Type III collagen is an important constituent of the basement membrane.
d) Fibroblasts synthesize reticulin tissue in connective tissue.
e) Macrophages are derived from blood monocytes.
6. T/F
a) Type I collagen is found in bone.
b) Reticulin fibers are formed from type II collagen.
c) Type III collagen is found in hyaline cartilage.
d) The arrangement of the tropocollagen is responsible for the branching pattern.
Excitable Tissue
Muscles (Contractile Tissue)
Single cell contractile units
 Myoepithelial cells - Secretory glands (salivary)

 Pericytes -Around blood vessels
 Myofibroblasts - Scar tissue
contractile/secretory
Skeletal muscles–“Voluntary” “striated”

Sites: - 1. Limbs
2. Tongue
3. Globe of the eye
Development Proliferation &

Differentiate Fusion
Mesenchymal cells Myoblasts Myotube
(Mesoderm) (Long, mono Nucleus, (long, multi n.)
Precursors of mitochondria)
Histology
1. Extremely elongated
2. Unbranched
3. Cylindrical cells

4. Flatte , Peripheral nuc.
5. Cross striations
Functioning
Large motor nerves “motor unit”
(Fasciculation)
Contractile proteins *Ca2+ is most necessary ion of muscle contraction

-Cross striations
-Arranged in highly ordered Thin Filaments
1. Actin
2. Tropomyosin
3. Troponin complex

Conducting system
 T system – Extension of sarcolemma in to the muscle to around muscle fibers
 Sarcoplasmic reticulum (SER) – Contains Ca2+
 T tubule + terminal cisternae – Triad (at the junction of the I & A bands)
Cardiac muscles
Histology Sarcomere
- Long cylindrical - mitochondria with closely packed cristae
- Branching fibers - glycogen granules
- Some striations - well developed sarcoplasmic reticulum
- 1 -2 central nuc. - T tubule system in Z line
- Intercalated discs
Junction between 2 cells
Conduction – spreads from cell to cell as a syncytium (mass of cell)
*Cardiac muscle tissue contains lot of spaces with capillaries
Smooth muscles
- Continuous contractions
- Contraction of whole muscle
- Spindle shaped cell
- Independence of neurological innervation
- Elongated spindle shape with tapered ends
- Central single nuc.
- No striations
- Invaginations of plasma membrane “calveolae”(not unique)
Contractile proteins
Actin (tropomyosin) & Myosin (only bind to actin) in Criss-cross
Sites: - Walls of hollow viscera

Iris of the eye (rapid contractions)

Nerve Tissue
1. CNS 2. PNS
Nerve system
1. Somatic 2. Autonomic
Neurons
Structure
Cell body Processes Nucleus – large,
Nucleus Axons Prominent
Perikaryon Dendrites
(Cytoplasm) Nissl bodies - RER
(Darkly stained)
*Lack in axons
Types
Multipolar neuron Bipolar neuron Pseudo unipolar neuron
e.g.:- Motor e.g.:- Receptoneurons e.g.:- primary sensory

smell, sight, balance nerve
Axons
Myelin sheath - formed by Oligodendrocytes in the CNS

- Supporting cells of PNS
- Bright pink cytoplasm in stains
Myelinated N. fibers Non myelinated N. Fibers
Myelination – protection
Increase axon conduction velocity (saltatory conduction)
All axons in PNS enveloped by schwann cells
Synapses
Between 2 neurons -Axodendritic

-Axosomatic
-Axoaxonic
Between neuron & muscle – neuromuscular junction / Motor end plate

1. Peripheral nervous system
Contain afferent & efferent fibers of somatic or autonomic system
Structure
- Nerve fibers form fascicles
- Surrounding layers of supporting tissue
- Rich blood supply
- Fibers follows a zig zag, longitudinal course (for stretching of the nerve)
- Supporting cells – schwann cells
Ganglia
- Aggregations of neuronal cell bodies located outside the CNS
- Cell bodies – surrounding satellite cells ( structural & metabolic support )
- Capsulated by supporting tissue
1. Spinal ganglia – Cell bodies of primary sensory nerves (pseudo unipolar)

(Somatic sensory ganglia)
2. Sympathetic ganglia –Multipolar cells – eccentrically located

-Widely spaced
3. Parasympathetic ganglia – Cell bodies of terminal efferent cells
-Cells – large N / dispersed chromatin
-Basophilic cytoplasm
2. Central nervous system

Brain & spinal cord
Gray matter- Cell bodies White matter- Tracts of axons
Neuroglia (Non neural cells) – mechanical & metabolic support
1. Astrocytes- most numerous

- Star shaped, long branched processors
Function: - Mechanical support

Mediate exchange of materials between neurons &vascular system
Form part of blood-brain barrier
Repair of CNS tissue after damage
2. Oligodendrocytes – Responsible for myelination of axon

- Absent in Gray matter/organized in tracts
3. Microglia – Small cells

- Nucleus—small, elongated / Cytoplasm- Scanty
Branched processes
Function: - Represent the monocyte- macrophage system

4. Ependyma- Make the specialized epithelium of ventricle & spinal cord
- Cuboidal cells
Choroid plexus – produce CSF

-Consist of mass of capillaries projecting into ventricles
Meninges
1. Dura mater – Dense fibroelastic layer, lined by flat cells
-Strongest layer
-Skull: - merges with the periosteum
Subdural space
2. Arachnoid mater – Cobweb like
- Pia + Arachnoid = Leptomeninges leptomeninges
(Both found together)
Subarachnoid space
3. Pia mater – Delicate, glia limitants
- formed of collagen, elastin, fibroblasts
7. Regarding muscle tissue

a) Skeletal muscle fibers are multinucleated.
b) Intercostal muscles are smooth muscles.
c) Smooth muscle fibers have no myofilaments.
d) The interval between two z lines is a sarcomere.
e) Cardiac muscle fibers communicate through gap junctions.
8. Regarding nerves
a) In unmyelinated nerves conduction is salutatory.
b) Action potential is generated in the cell body.
c) Myelin sheath of an axon is formed by several Schwann cells.
d) Myelin is absent in Ranvier nodes.
e) In the CNS the myelin sheath is formed by oligodendrocytes.
9. T/F
a) Has mesaxons wrapping spirally around the?
b) Have the axons in the extracellular compartment within the Schwann cell.
c) Ranvier nodes conduct impulses in a continuous manner.
d) Most of the nuclei which are seen in the fascicle belong to the neuron.
e) Wavy bands of nuclei are a characteristic feature.

10. T/F regarding excitable tissue
a) Sarcomere extends from z-line to z-line.
b) In myelinated nerves a single Schwann cell can form myelin sheaths in more than one
fiber.
c) Gap junctions of the intercalated discs of cardiac muscles provide ionic continuity
between adjacent cells.
d) Smooth muscles have cross striations in their cytoplasm.
e) Neuroglia show highly phagocytic activity.
Bone & Cartilage
Cartilage
Cells
1. Chondroblasts (in outer) 2.Chondrocytes

-Synthesize the matrix - former chondroblasts
-Immature cells, very active - mature cartilage cells
Function- Secrets ground substance & - initially located as clusters (2-4)
Fibrous materials - strapped in cartilaginous matrix
Function- maintain the integrity of
matrix
Secrets ground substance &
matrix
ECM
-Ground substance – Proteoglycans
-Fibers – Collagen & elastin
Perichondrium
- At the periphery of mature cartilage tissue
-Zone of condense tissue
-Collagen fibers & spindle shaped fibroblasts
Types
1. Hyaline Cartilage
2. Fibro Cartilage
3. Elastic Cartilage
1. Hyaline Cartilage
- Translucent, homogenous appearance
- Small aggregations of chondrocytes

- Ground substance—collagen fibers (type 2)
Sites: - fetal skeleton

Nose, larynx, trachea
Articular surfaces
Costal cartilage
*In articular surfaces of joints -> no perichondrium
2. Fibro Cartilage
-resistance to stretching
-collagen fibers in dense bundles
Sites: - Intervertebral discs

Pubic symphysis
Joint capsule
Ligaments
3. Elastic Cartilage
- Equal to hyaline cartilage
- Many branching elastin fibers
- gives flexibility
Sites: - External ear

External auditory canal
Epiglottis
Formation
- Mesenchymal cell
- Differentiate into chondroblasts
- They divide & secrets ground substance & fibers
- Clusters of mature cells—chondrocytes
Nutrition
Most of cartilage devoid of blood vessels
Substance diffuse through ECM
In thick cartilage-- “cartilage canals” convey small vessels into cartilage mass
Bone
Cells
1. Osteoblasts 2.Osteocytes
-Synthesize osteoid - assist in nutrition of bone
-Mediate the mineralization - large, inactive osteoblasts
- Inside the large lacunae

3. Osteoclasts
- Important in constant turnover & refreshing of bone
- Phagocytic cells formed by fusion of monocytes
- Large, multinucleated, eosinophilic cytoplasm
- present within Howship lacunae
Periosteum
- Condensed fibrous tissue
- Inner layer – contain osteoprogenitor cells & osteoblasts
Sites: - outer shed of the bone
*Diaphysis
Types
1. Woven bone
-immature bone—fetal skeleton
-- fracture sites
-randomly arranged collagen fibers
2. Lamellar bone
Regular parallel bands of collagen sheets
I. Compact bone/Cortical bone

 Osteon (Haversian system)
 Contain neurovascular bundles
 Connect each other by Volkmann’s canals
 Lacunae contain osteoclasts
 Between adjacent lacunae & central canal  canaliculi
 In canaliculi, cytoplasmic/filopodial processes of osteocytes communicate via gap
junctions
 Between Haversian systems  interstitial system
II. Trabecular bone (medullary / spongy/cancellous bone)

 Network of inter connecting structures
 Scanty lacunae containing osteocytes
Sites: - medullary cavity
Formation
1. Intra membranous ossification  membrane bone
Sites: - clavicle
Vault of skull
Mandible (most part)

Mesenchymal cells
Sheets of cells with good blood supply

Differentiation in to osteoblasts
Synthesize & secret osteoid matrix
Multiple ossification centers (osteoprogenitor cells osteoblasts)

Mineralization of osteoid
Oss: centers fuse
Bone is formed (spongy like)
Woven bone lamellar bone
2. Enchondral ossification  cartilage bone

Sites: - long bones
vertebrae
pelvis
Mesenchymal cells
Sheets of cells with good blood supply

Cell differentiation – form a cartilage model (solid hyaline cartilage)
Chondrocytes reabsorb the cartilage matrix and die
Cartilage matrix becomes calcified
Only a thin layer of matrix left
Empty spaces – infiltrated by B. vessels & mesenchymal cells
Periosteum lays down
Mesenchymal cells become the osteoblasts
Osteoblasts synthesize & secret the osteoid
Formation of the 1ry ossification site (woven bone)
Growth of long bone

Epiphysis – areas of cartilage remains at the ends
Metaphysis – bone is laid down
Growth plate – between epiphyseal cartilage & diaphysis
 Growth in length of the bone
 Epiphyseal end- proliferation of cartilage
 Diaphyseal end – bone formation
 Less stratified cell columns
Bone growth
Shaft woven bone
-Cartilage layer of non-lamellar bone formed – primary osteons

-Erosion & deposition of concentric lamellae of bone – secondary osteons (Haversian
system)
Remolding of bone
Osteoclastic & osteoblastic activity
Old osteons remove deposition of new, shaft diameter increase
-occurs throughout life

-due to mechanical stress
Repair of bone
Blood clot highly vascular collagenous tissue hyaline cartilage

Newly formed primary bone secondary bone
11. Regarding bone & cartilage

a) Cartilaginous tissue gets its blood supply from a vascular perichondral network.
b) Chondroitin sulfate is a major component in a calcified cartilage.
c) Osteoclasts are multinucleate.
d) Resting zone is found adjacent to the epiphysis in the epiphyseal plate.
e) In endochondral ossification chondroblasts are transformed into osteoblasts.
12. T/F regarding bone & cartilage

a) All hyaline cartilages are covered by perichondrium.
b) Mature chondrocytes synthesize type II collagen.
c) Osteoblasts have a high alkaline phosphate level when they are actively synthesizing bone
matrix.
d) The filopodial processes of the adjacent osteocytes make contact via gap junctions.
e) Osteoclasts are formed by fusion of monocytes.
f) Type I collagen is found in bone.
g) Reticulin fibers are formed from type II collagen.
h) Type III collagen is found in hyaline cartilage.
i) The arrangement of the tropocollagen is responsible for the branching pattern.
13. Osteoclasts
b) Has mesenchymal origin.
c) Are within the howship’s lacunae.
d) Cytoplasm is basophilic.
e) Are multinuclear cells.

Histology – RS
Layers of the respiratory tract

− Respiratory epithelium-pseudostratified columnar ciliated epithelium
− Lamina propria-underlying connective tissue
− Smooth muscle layer
− Submucosa
− Cartilage
− Adventitia
 Smooth muscles are more prominent in lower airways –
Regulate airway diameter
 Cartilage amount decreases from trachea downwards
Regional differences
Epithelium Lamina propria Smooth submucosa cartilage adventitia

muscles
1. Nasal Pseudostratified − Serous,
cavity columnar mucous glands
ciliated − Thin walled
blood vessels
− MALT
− Venous plexuses  
(for
humidification
and temperature
regulation)
** Olfactory mucosa
Nasopharynx Pseudostratified -Serous and mucous
columnar glands
 
ciliated - MALT
(nasopharyngeal tonsil)
2. Larynx
− False vocal Pseudostratified Serous and
cords columnar mucous
ciliated

− True vocal Non-Keratinized glands
cords stratified squamous present
3. Trachea -Tall pseudostratified -Blood Mixed C shaped Fibro-
columnar ciliated vessels seromucous hyaline elastic
-Neuroendocrine present gland (decline cartilage tissue
cells (reg. smooth in no. moving (patency elastin↑
muscle tone) downward) without
-upper – rich in collapsing)
goblet cells Posteriorly
connected
by
Trachealis
muscle
4. Main (Iry Progressive ↓ in More elastin Discontinuous Fewer glands Flat, few
layer
bronchus goblet cells & intercalate
tallness of epithelial d plates
cells
5. IIIry Few goblet cells Thin elastic layer Prominent MALT present Irregular
bronchus Arranged Fused with few
spirally cartila
adventitia
ge
plates
6. − Ciliated columnar Elastin Thick layer No Merge
Bronchioles epithelium submucous with lung
D<1mm − No goblet cells glands  parenchy
− Clara cells present ma
(secrete surfactant)
7. Terminal Simple columnar Less thick Submucous
bronchioles − Goblet cells folded glands
absent than 
− Clara cells present bronchioles
8. −cuboidal
Respiratory epithelium
  
bronchioles − Clara cells
− Goblet cells

Alveoli
1)Alveolar lining cells
 Type I pneumocytes – large squamous cells, form gas diffusion border
 Type II pneumocytes (60%) – small, secrete surfactant
Differentiate into type I pneumocytes
 Alveolar macrophages – phagocytic action
2)Supporting tissue
3)Capillaries
 Lymph capillaries are not found in alveolar wall. But present in walls of respiratory
bronchioles and above
Alveolar capillary membrane (Air blood barrier)
• -alveolar epithelium composed of type 1 pneumocytes

• -fused basement membrane
• -capillary endothelium
Surface epithelium
Alveolar septum Supporting tissue
Central area of alveolar

capillaries
Pleura
 Lined by mesothelium – flattened cuboidal cells with surface microvilli
 Outer parietal pleura
 Inner visceral pleura – contains fibrous septa, lymph vessels, blood vessels and capillaries

Histology - CVS
 Consists of heart and circulatory system
Heart
 3 layers
− Pericardium
− Myocardium
− Endocardium
 Heart valves
Conducting System
 Modified cardiac muscle fibres, subendocardial purkinje fibres (larger than normal
muscle fibres)
 Has no T tubule system
 Connect with each other by desmosomes, gap junctions rather than intercalated discs
Pericardium
 Consists of outer fibrous pericardium and
inner serous pericardium
 Fibrous pericardium is made of fibrous tissue
 Serous pericardium is a thin double layered membrane lined by mesothelium
 Outer layer of serous pericardium – parietal pericardium is fused with
the fibrous pericardium
 Inner layer of serous pericardium – visceral pericardium (epicardium) is
fused to the heart
 Mesothelial cells are flattened epithelial cells that secrete a fluid for
lubrication
Myocardium – Cardiac muscle
Endocardium
 Line the cavities of the heart and
continuous with blood vessels
 Consists of simple squamous epithelium
 Sub epithelial layer (beneath the epithelium) consists of fibrous tissue and
elastic fibres to prevent endocardial damage during contraction
Heart valves
 Lined by thin endothelium layer with a fibro-elastic tissue core (collagen and
elastin)
 Avascular
 A sinus is present around the valve to facilitate opening and closing of the valve
 Central fibroelastic core – lamina fibrosa

Circulatory system
 Formed by blood vessels

(arteries, veins and capillaries)
 Blood vessels consists of 3
layers − Inner layer – tunica intima
− Middle layer – tunica media
− Outer layer – tunica adventitia
Tunica intima
− Consists of endothelium and subendothelium
− Endothelium is a single layer of simple squamous epithelial cells lying on a
basement membrane
− Intercellular junctions connect the cells together
− Cytoplasm contains membrane bound organelles that store and secrete
substances important in blood clotting
− Sub endothelium consists of fibroblasts and myointimal cells
− Fibroblasts secrete collagen fibres
− Myointimal cells have a contractile function and responsible for lipid
accumulation with age
Tunica media
− Consists of smooth muscle, collagen and elastin
− Smooth muscles contain receptors for adrenal medullary hormones to
control the diameter of the vessels
− Elastic arteries have a high content of elastin fibres and low content of
smooth muscles. Elastin fibres are arranged as sheets with collagen in
between
− Muscular arteries have a high content of smooth muscles and elastin
fibres are arranged in two well defined sheets
1.Internal elastic lamina – between tunica intima and media
2.External elastic lamina – between tunica media and tunica adventitia
Tunica adventitia
− A fibrous connective tissue, consists of collagen and elastin
− Vasa vasorum are small arteries in the adventitia of large arteries (eg:-
aorta) that supply the thick wall. They penetrate outer half of tunica
media

Arterial system
Arteries (muscular, elastic)
Arterioles
Micro-circulation
Sinusoids
Elastic artery Muscular artery

Site Aorta and its major branches Main distributing branches
Eg:-femoral, brachial
Function Maintain a pulsatile blood flow Controlling peripheral
resistance
Tunica media High elastin High smooth muscle content
Less smooth muscles Elastin arranged as 2 layers
 Arterioles
− Smooth muscles > elastin
− Major site of controlling peripheral resistance
 Micro-circulation
− Composed of smallest blood vessels (small arterioles,
metarterioles, capillaries, venules, AV shunts)
− Capillaries contain only a tunica intima with a single layer of
flattened endothelial cells resting on a basement membrane
and pericytes
− Nuclei bulge in to the lumen
− Pericytes are flattened cells with a contractile function. They surround
the endothelial cells
− At origin of each capillary, Pre-capillary sphincter found
Capillaries
Continuous (endothelium) Fenestrated(endothelium)

− In most of the tissue *small intestine
*kidney
*Endocrine gland
With a diaphragm Without a diaphragm Discontinuous basement membrane

Eg. Glomerulus Eg. sinusoids
 Metarterioles
− Larger diameter capillaries
− Discontinuous outer layer of smooth muscles
− Make direct communication on between arterioles & venules

 Sinusoids
− Diameter is larger than capillaries
− Irregularly shaped
− Discontinuous endothelial cell layer
− Sites – liver, spleen(red pulp), lymph node, bone marrow
 AV shunt (Arteriolar-venular shunt)

− A direct communication between an arteriole and a venule
Venous system
Venules
Post capillary venules size increases
Collecting venules tunica media acquire more smooth muscles
Muscular venules Usually thickest layer is adventitia
Veins
Lymphatic system
 Wall structure is similar to veins
 Contain valves
 Endothelium – extremely thin cell cytoplasm
− Basement membrane is rudimentary or absent
− No pericytes

GIT - Histology
Layers of GI tract
1.Mucosa epithelium
Lamina propria
Muscularis mucosa
2.Submucosa  supportive tissue collagenous fibres
Blood vessels, lymphatics
3.Muscularis propria  smooth muscle (Inner circular and outer longitudinal)
(oblique layer present innermost in stomach)
4.Serosa  loose supportive tissue, lined by mesothelium
 Meissner’s plexus- in submucosa
 Myenteric plexus/ Auerbach’s plexus – between 2 muscle layers of muscularis propria
Parts of GIT Type of Cell types in epithelium Distinctive features

tract epithelium
Lips Outer zone- stratified squamous -
keratinized(hairy)
Transitional zone- lightly keratinized (thin, Richly vascular dermis(prominent reddish
hairless) colour)
Vermillion border
1). Devoid of sweat and sebaceous
glands
2). Has rich innervations
3). Prominent place for oral cancers
Inner zone stratified squamous non- Continuous with oral mucosa
keratinized Submucosa-Accessory salivary gland
Oral cavity Stratified squamous Submucosa- loose connective tissue (soft
squamous non- palate, floor of mouth)
keratinized -dense connective tissue (hard palate,
epithelium tooth bearing ridges)
Palate – str.sq.
keratinized epi.
Tongue Stratified Anterior 2/3 – mucosa form papillae
squamous non- Taste buds containing pale columnar
keratinized cells with microvilli are found within
epithelium with papillae
taste receptors Posterior 1/3 – lamina propria contain
lymphoid follicles (lingual tonsils)

Oesophagus Stratified squamous -Mucosa contain folds
squamous -Lamina propria contain scattered
epithelium lymphoid aggregates
-Submucosa –seromucous glands
-Muscularis propria-
Upper1/3- skeletal muscle
Middle1/3- both
Lower 1/3- smooth muscle
Stomach Simple columnar Mucous cells No lymphoid aggregates (due to acidity

epithelium with Parietal cell / oxyntic cells of stomach)
mucous secreting Fried egg appearance Mitotic figures can see after
cells Chief/peptic cells damage to mucosa -gastritis
Endocrine cells Lamina propria contain gastric glands
Stem cells Stomach body contains an additional
Pylorus – G cells (secrete inner layer of oblique muscle in
gastrin) muscularis propria
Fundus/body pylorus
Glands- straight tubular Glands- Branched coiled tubular
Occupies ¼ of thickness of gastric mucosa Occupies half the thickness of the mucosa
Small Simple columnar  Lining cells of villi – Mucosa – contain folds called villi
intestine epithelium with 1.Enterocytes (simple Lamina propria forms the core of each
villi and crypts of columnar with microvilli) villus containing loose connective tissue,
Lieberkühn 2.Goblet cells lymphoid cells, lymphatics and capillaries
Crypts contain  Paneth cells -
simple tubular Defensive function
glands Base of crypts
 Neuroendocrine
cells
 Stem cells – at the
crypt bases
 Lymphocytes
 Plasma cells –
secrete IgA
Duodenum Villi are shorter

Submucosa -

(Compound tubular)
Plicae circularis -
Submucosa and mucosal folds
Jejunum Glandular with Enterocytes with microvilli Plicae circularis

and villi
ileum and crypts of Goblet cells Ileum – submucosa contains payer’s
Lieberkühn Paneth cells patches
Colon and Simple columnar Goblet cells No villi but crypts present
rectum epithelium Straight tubular glands in mucosa(main
feature)
Crypts – goblet Absorptive Smaller aggregates of lymphocytes in
cells cells submucosa
Taeniae coli formed by longitudinal
muscle layer in muscularis propria
appendix Simple columnar Goblet cells Prominent lymphoid tissue in submucosa
with goblet cells Tall columnar cells No villi
Crypts present
Anal canal Simple columnar Above the pectinate line mucosa forms
above the longitudinal folds called anal columns
pectinate line Upper ¾ - circular muscle layer forms the
Stratified internal anal sphincter
squamous below Outer longitudinal muscle layer is thin
the pectinate Outer to this is the external anal
line sphincter made of skeletal muscles
Lower 8mm
resembles true
skin with sweat
and sebaceous
glands

Villi longest in duodenum, Shortest in ileum

Lymphoid – most important in the ileum (payer’s patches)

Goblet cells – number high distally

Plicae circularis – absent in proximal duodenum & distal ileum. More prominent in
jejunum & proximal ileum

Junctions of GI tract
1. Gastro-oesophageal junction –
Contains a physiological sphincter
Transition from stratified squamous to simple columnar epithelium
Abrupt change
Clinicals-Barrett’s oesophagus
2. Gastroduodenal junction –
No change in the type of epithelium
Pyloric sphincter – thickening of circular layer
3. Ileocecal junction -
Contains a valve formed by thickening of muscularis propria
4. Anorectal junction –

Liver
 Structural unit of liver- Hepatic lobule
-Hexagonal boundary
-Hepatic lobule contains
 Sinusoids intervening between
cords
 Cords of hepatocytes
 Central vein
 Portal triad- Arteriole of hepatic artery
-Terminal branch of portal vein
-Bile ductulus
-(lymphatics)
 Sinusoids are lined by discontinuous
fenestrated endothelium
 Sinusoidal lining cell types-
 Endothelium cells
 Kupffer cells
 Stellate cells- storage vitamin A
 Space of Disse -space between

hepatocytes and sinusoids
 Bile canaliculi- fine channels formed
by plasma membrane of adjacent
hepatocytes
 Hepatic acinus
 Functional unit of liver
 Ellipsoid mass of hepatocytes
 Lies between 2 or more terminal
hepatic venules
 Centered on a portal tract
 Divided into 3 zones
Zone 1 – closer to portal tract, receive
more oxygenated blood
Zone 2 – intermediate in oxygen
supply
Zone 3 – receive less oxygen, more prone to ischaemic injury

Gall bladder
• Small amount of smooth muscles in the wall
• Mucosa –
o epithelium - simple columnar (absorptive function) with microvilli
o Folds-honeycomb appearance in the body
o Spiral valve of Heister in the neck
o No goblet cells
• Muscle layer – longitudinal, transverse, oblique
• Submucosa contains mucous glands (specially in neck and extrahepatic biliary tree)
Pancreas
• Exocrine component- secretory acini and duct system
• Endocrine component –islets of Langerhans
β-cells-insulin α-cells-glucagon δ-cells-somatostatin
• Acinar cells –> intercalated ducts –> intralobar ducts –> interlobular duct (small ducts- cuboidal, large
ducts - stratified cuboidal) pancreatic duct

Male Reproductive System
Testis-Male Gonad
• Tunica vaginalis
- Double layer of mesothelium (parietal and visceral)
- Mesothelial cells secrete serous fluid
- Covers the testis except posteriorly
- Collection of fluid within tunica vaginalis is called Hydrocele
• Tunica albuginea(capsule)
- Dense fibrous tissue with fibroblast and myofibroblast
- Thickened posteriorly to form the mediastinum testis
- Incomplete fibrous septa arise from the mediastinum testis and
divide the testis into lobules
• Deepest layer (Tunica vasculosa)
- Lines the inner surface of lobules
- Loose connective tissue
- Blood vessels
- Lymphatics
Seminiferous tubules
• Tubules within testicular lobules
• Tightly packed, highly convoluted
• Each lobule has 1-4 seminiferous tubules
• Production of spermatozoa
• Tubules lining cells(stratified)
-germ cells
-non germ cells: Sertoli cells (support and nourish
spermatozoa)
• Between tubules (interstitial space)
-Leydig cells
-Very vascular
• Seminiferous tubules converge upon the mediastinum testis which consist of plexus of channels
known as Rete testis
Rete Testis
• Surrounded by highly vascular collagenous supporting tissue containing myoid cells.
• The rete testis is lined by a single layer of cuboidal epithelial cells with surface microvilli and a single
cilium.
• Myoid cell contraction helps to mix the spermatozoa and move them towards the epididymis.
• The lining epithelium reabsorbs protein and potassium from the seminal fluid.

Ductuli efferentes
• The rete testis drains into the head of the epididymis via some 15-20 convoluted ducts, the ductuli
efferentes.
• The ductuli are lined by a single layer of epithelial cells,
-tall columnar and ciliated
- short and non-ciliated
• Ciliary action in the ductuli propels the still non-motile spermatozoa towards the epididymis.
• A thin band of circularly arranged smooth muscle surrounds each ductulus and aids propulsion of the
spermatozoa towards the epididymis
Epididymis
• The epididymis is a long extremely convoluted duct extending down the posterior aspect of the testis
to the lower pole where it becomes the ductus deferens.
• The epididymis consists of a head at the upper pole of the testis, a body lying along the posterior
margin and a tail at the lower pole of the testis.
• The major function of the epididymis is the accumulation, storage and maturation of spermatozoa in
the epididymis, the spermatozoa develop motility.
• The epididymis is a tube of smooth muscle lined by a pseudostratified epithelium with stereocilia.
• Smooth muscle wall changes from single to 3 layers distally
• Proximally, the smooth muscle exhibits slow rhythmic contractility which gently moves spermatozoa
towards the ductus deferens.
• Distally, the smooth muscle is richly innervated by the sympathetic nervous system which produces
intense contractions of the lower part of the epididymis during ejaculation.
• The epithelial lining of the epididymis exhibits a gradual transition from a tall pseudostratified
columnar form in the head, to a shorter pseudostratified form at the tail.
Ductus deferens
• The ductus (or vas) deferens, conducts spermatozoa from the epididymis to the ejaculatory ducts.
• It is a thick-walled muscular tube consisting of inner and outer longitudinal layers and a thick
intermediate circular layer.
• Like the distal part of the epididymis, the ductus deferens is innervated by the sympathetic nervous
system, producing strong peristaltic contractions to expel its contents into the urethra during
ejaculation.
• The ductus deferens is lined by a pseudostratified columnar epithelium.
• Epithelium and lamina propria are highly folded
• The dilated distal portion of each ductus deferens, known as the ampulla, receives a short duct
draining the seminal vesicle, thus forming the short ejaculatory duct; the ejaculatory ducts from each
side converge to join the urethra as it passes through the prostate gland

Exocrine glands in the male reproductive system
Seminal vesicle
• Each seminal vesicle is a complex glandular diverticulum of the associated ductus deferens.
• Between them the seminal vesicles secrete up to 85% of the total volume of seminal fluid,
most of the rest being secreted by the prostate gland.
• The epithelial lining is usually of a pseudostratified tall columnar type.
• The prominent muscular wall is arranged into inner circular and outer longitudinal layers
and is supplied by the sympathetic nervous system; during ejaculation, muscle contraction
forces secretions from the seminal vesicles into the urethra via the ampullae
• Irregular, honeycomb shaped lumen

Prostate gland
• prostate consists of branched tubulo acinar
The
glands embedded in a fibromuscular stroma.
• There is a partial capsule enclosing the
posterior and lateral aspects of the prostate
but the anterior and apical surfaces are
bounded by the anterior fibromuscular stroma,
a part of the gland consisting, as the name
implies, only of collagenous stroma and
fibres.
• The transition zone surrounds the proximal prostatic

urethra and comprises about 5% of the glandular
tissue.
• The central zone (20%) surrounds the ejaculatory
ducts.
• The peripheral zone makes up the bulk of the gland
(approximately 70% ).
• The anterior fibromuscular stroma contains no
glandular tissue and lies anteriorly.

Female Reproductive System
Function :- reproduction
endocrine function
Ovaries – female gonads

-flattened
-ovoid structures
-paired
-no anatomical distinct covering
-outer epithelial covering (germinal epithelium),
continuation of peritoneum
- Lined by cuboidal to columnar cells
- Ovarian stroma contains spindle shaped cells,
collagen, bundles of smooth muscles and ground
substance
- Stroma is divided into outer cortex and inner Ovary
medulla
- Outer cortex contains follicles and corpus luteum, superficial cortex contains a fibrous covering (tunica
albuginea)
- Inner medulla is highly vascular and contains hilus cells (=Leydig cells) and helicine /spiral arteries
Follicular Maturation
1. Primordial follicle
 Contains the primary oocyte (large nucleus, small cytoplasm)
 Surrounded by a single layer of flattened follicular cells
2. Primary follicle
 Primary oocyte enlarges
 Follicular cells proliferate to form cuboidal shaped granulosa cells (zona granulosa)
 Zona pellucida – glycoprotein and proteoglycan rich acellular layer between granulosa
cells and primary oocyte
 Surrounding stromal cells (fibroblasts) organize to form a cellular layer around zona
granulosa called theca folliculi

3. Secondary follicle
 Contains the primary oocyte
 Fluid filled spaces develop in the zona granulosa, they coalesce and form the follicular
antrum
 Cumulus oophorus – thickened area in the zona granulosa where the primary follicle lies
 Theca folliculi divide into theca externa (containing spindle cells) and theca interna (round
cells)
4. Graffian follicle
 Initially contains the primary follicle
 Just before ovulation, primary oocyte completes the 1 st meiotic division and forms the
secondary oocyte
 Follicular antrum enlarges
 Zona granulosa forms an even layer around the periphery of the follicle (cumulus
oophorus diminish)
 Corona radiata – a thick cellular layer around zona granulosa, attach to ZG by thin bridges
of cells
 During ovulation, secondary oocyte, zona pellucida, corona radiate are released from the
ovary
5. Corpus luteum
 Contains granulosa and theca lutein cells
 Granulosa cell are large polygonal cells with round nuclei and abundant cytoplasm, SER,
mitochondria, lipid droplets and lipofuscin (yellow colour)
 Theca externa – dark staining
 Theca interna – pale staining due to the presence of lipid droplets
Fallopian tube
 Mucosa contains branched longitudinal folds
 3 types of cells line the mucosa
- Ciliated tall (showing irregular cell margin)
- Non-ciliated secretory cells (prominent in ampulla)
- Intercalated cells
 Non-ciliated cells secrete substances to take ova forward with the aid of cilia
 2 layers of smooth muscles
 Serosa – vascular, covered by mesothelium, cont. with the broad ligament

Uterus
Basic organization - perimetrium, myometrium, endometrium
(1) Endometrium - Epithelium lining tall, columnar cells with microvilli or cilia
Form numerous simple tubular glands supported by endometrial stroma
Histological layers
1. Stratum compactum stratum functionalis – undergo cyclical changes
2. Stratum spongiosum functional layers are shed off during menstrual phase
3. Stratum basalis  No shedding during menstrual cycle
Changes occur in the endometrium during menstrual cycle

Proliferative phase Secretory phase Menstrual phase
-columnar cells (cilia or microvilli) Tall columnar cells Functional layers shed
-glands-initially simples tubular, straight, sparse Coiled tubular glands off due to the absence
But proliferation is started (saw tooth appearance) of implantation
Lined by tall columnar cells Tall columnar cells Stratum functionalis
undergo ischaemia due
to spasm of spiral
arteries
-gradually stroma become thicker, very cellular Stroma reaches to the
maximum thickness, highly
vascular
-Blood vessels less More blood vessels
-Mitotic figures can be seen
-Endometrial surface epithelial cells acquire • Glycogen vacuoles(basal)

microvilli, cilia, cell organelle • Saw tooth appearance
In cross section of glands
When taking endometrial curettings/biopsies the first day of last menstrual cycle is very important

(2) Myometrium – transverse, longitudinal and oblique muscle layers in ill-defined layers
During pregnancy, muscle cells undergo hypertrophy and hyperplasia
Uterine cervix
Endocervix –lined by simple columnar epithelium
Ectocervix – lined stratified squamous epithelium
Cervical canal
Lined by tall columnar mucous secreting cells
Leukocytes are more between junction of endocervix and ectocervix (external os)
Cervical cytology
Cervical smear /pap test
Vagina
(1) Epithelium – stratified squamous, non-keratinized
Superficial cells of epithelium form glycogen
anaerobic
Glycogen respiration lactic acid (inhibit growth of microorganisms)
(2) Lamina propria -no glands, contain elastin fibres

(3) smooth muscle layer – inner circular and outer longitudinal muscle layers
(4) Adventitia – fuse with that of rectum and bladder

Urinary system – histology
Kidney
 Macroscopically, divided into cortex, medulla and pelvis from superficial to deep
 Cortex contains renal corpuscles, PCT and DCT
 Medulla contains collecting ducts
 Structural and functional unit of the kidney – nephron
Nephron
 Structural and functional unit of kidney
 Nephron = renal corpuscle + renal tubule (from Bowman’s capsule to collecting
ducts)
 Renal corpuscle = Bowman’s capsule + glomerulus
 Glomerulus is a capillary network lined by an endothelial cell layer which is

fenestrated and a negatively charged luminal surface

 Glomerular basement membrane is thick. Consists of 3 layers
1. Lamina densa – thick central layer
2. Lamina rata interna – on the endothelial side thin
3. Lamina rata externa – on the Bowman’s capsular side layers
 Bowman’s capsule is cup shaped
 Consists of 2 layers. The space between the 2 layers is called the Bowman’s space
 Lined by flattened squamous epithelial cells
 Visceral layer of the capsule is lined by a special type of squamous epithelium called
podocyte layer
 Podocytes contain primary and secondary processes and filtration slits
 This layer invests the capillary loops exposed to the Bowman’s space
 Glomerular filtration membrane = capillary endothelial layer + basement membrane

+ podocyte layer
 Mesangium is the intervening space between the glomerulus and the Bowman’s
capsule
 Mesangium consists of mesangial cells
 Mesangial cells are modified pericytes. These contractile cells control the diameter
of the glomerular capillaries and thus regulate the glomerular pressure
 Renal tubule consists of,
 Proximal convoluted tubule (PCT) simple cuboidal epithelium +
 Thick descending limb of loop of Henle microvilli (brush border)
 Thin descending limb of LOH simple
 Thin ascending limb of LOH squamous epithelium
 Thick ascending limb of LOH
 Distal convoluted tubule (DCT) simple cuboidal epithelium
 Collecting tubule (connect DCT to collecting duct)

 Features of cells adapted to their function
 PCT – cells contain a large number of mitochondria to provide energy for active
reabsorption and secretion
- Tall microvilli form a brush border to increase the surface area of reabsorption
- Surrounding rich network of capillaries to increase the efficiency of reabsorption
and secretion
 LOH – surrounded by rich network of capillaries and vasa recta that run parallel to
the tubules. This is to produce an increasing osmotic gradient from cortex to the tip
of papilla by counter current mechanism
 DCT – first part forms the macula densa which forms a part of the juxtaglomerular
complex
- Contain a large number of mitochondria (but less than in PCT) for active
reabsorption and secretion
 Collecting ducts – contain 2 types of cells
- Principle cells involved in Na reabsorption
- Intercalated cells involved in acid secretion
 Differences between PCT and DCT
PCT DCT
Lumen smaller Larger
Cell size Larger than DCT cells Smaller than PCT cells
Nuclei Less in cross section More in cross section
Brush border Present due to microvilli Absent
Juxtaglomerular apparatus
 Specialization of glomerular afferent arteriole and DCT of the same nephron
 Situated near the glomerular vascular pole
 Function – regulation of blood pressure

 Consists of 3 components
1. Macula densa of DCT – sensitive to Na ion concentration in the DCT fluid
2. Juxtaglomerular cells of afferent arteriole – modified smooth muscles in the wall
of afferent arteriole that secrete renin
3. Extraglomerular mesangial cells / Lacis cells - flat elongated cells with fine
cytoplasmic processes
4. Important in tubuloglomerular feedback mechanism
Part of tubules Type of Special features

epithelium
PCT Simple cuboidal Microvilli (brush border)
Extensive basolateral interdigitation
Plentiful mitochondria
Pars recta of proximal Simple cuboidal Microvilli (brush border)
tubule (thick No basolateral interdigitation
descending limb)
Thin Simple No basolateral interdigitation or
descending/ascending squamous microvilli
limbs Mitochondria scanty
DCT Simple cuboidal Microvilli absent
Extensive basolateral interdigitation
Thick ascending limb Simple cuboidal Extensive basolateral interdigitation
Mitochondria plentiful
Collecting tubule Simple cuboidal Principal cells
Intercalated cells
Collecting tubule cells
Cortical collecting ducts Simple Principal cells
columnar Intercalated cells
Medullary collecting Simple Mainly principal

ducts columnar

Ureter
 Epithelium – urothelium (transitional epithelium) seen only in the conducting part of
the urinary system
- Stratified epithelium that allows stretching during passage of urine
- Cells of basal layer are compact and cuboidal
- Intermediate cells are columnar
- Surface cell layer contain dome shaped cells
- Tight junctions between the cells prevent leakage of urine
 Lamina propria – contain broad collagen fibres
 Smooth muscle layer
- Upper 2/3 consists of 2 muscle layers
▪ Inner longitudinal
▪ Outer circular
- Lower 1/3 contains an additional outermost longitudinal layer
 Adventitia – contain blood vessels, nerves and lymph vessels
Urinary bladder
• Bladder is histologically similar to the structure of lower 1/3rd of the Ureter
• So, muscle layers are arranged as inner longitudinal, outer circular and outermost
longitudinal. All together these smooth muscle layers are known as Detrusor muscle
• Epithelium is thrown in to folds in relaxed state
Urethra
 Male urethra is lined by stratified or pseudo stratified columnar epithelium (Except
prostatic urethra which is lined by transitional epithelium)
 External urethral meatus is lined by Stratified squamous epithelium (This become
continuous with epithelium of glans) refer

SKIN – HISTOLOGY
 Layers
1. Epidermis
2. Dermis
3. Hypodermis (subcutis)
 Appendages / adnexa
- Downgrowths of the epidermis into the dermis during development
- Hair follicles, nail, sweat gland, sebaceous gland
Epidermis
 Ectodermal origin
 Thickness – variations: eyelid – thin, palms and soles – thick
 Stratified squamous keratinized epithelium
 Avascular, no nerves
Epidermis
Layers cell types
 Stratum basale  Keratinocytes
 Stratum spinosum  Melanocytes
 Stratum granulosum  Langerhan cells
 Stratum corneum  Merkel cells
 Stratum basale – single layer of cells
Cuboidal/low columnar cells
basement membrane- dermal epidermal junction
Epidermal cell renewal – mitotic figures
 Stratum spinosum – prominent epidermal layer
Large cuboidal cells / polyhedral cells
Cells synthesis protein cytokeratin
Desmosomes are seen as spines
Desmosomal bridges used to diagnose epithelial tumours
 Stratum granulosum – cytokeratin aggregate (tonofibrils) + keratohyalin granules
(involucrin) = keratin
 Stratum corneum – by keratin
Dermal epidermal junction

 Epidermal ridges
 Dermal papillae
 Basement membrane – contain 3 layers
1. Lamina lucida
2. Lamina densa
3. Fibroreticular lamina; from superficial to deep
 Damage to the basement membrane causes separation of the epidermis from the
dermis, followed by fluid accumulation in the space resulting in the formation of
blisters.

Dermis
 Mesodermal origin
 Horizontally arranged collagen and elastin fibers
 Blood vessels
 Sensory nerve endings, sensory organs
 2 layers present
1. Papillary dermis – outer, thinner, Meissner corpuscles (encapsulated, sense light,
discriminating touch)
2. Reticular dermis – deeper, loose CT
 Cells – fibroblast, lymphocytes, mast cells, tissue macrophages
 contain 2 arterial plexuses
1. Subpapillary plexus – at the junction between the papillary and reticular dermis
2. Cutaneous plexus- at the junction between subcutis and dermis
 Under the fingertips, dermis contains an arteriovenous shunt called glomus bodies.
Hypodermis
 subcutaneous layer, loose CT, adipose tissue, blood vessels
 contain Pacinian corpuscles – lamellated, sense deep pressure and vibration
Skin appendages
Hair Sebaceous gland Sweat glands
Modified keratinized 1. Branched acinar Simple coiled tubular glands
structure 2. Holocrine secretion Eccrine – present in most part of the body
Hair follicle, hair bulb, hair 3. In relation to hair follicle or
shaft independent of hair follicle Apocrine – present in axillae, genital
Arrector pili muscle – organs, areolar of breasts
smooth muscle attached to Functional after puberty
the follicular sheath below
the sebaceous gland
Breast
 Modified apocrine sweat gland
 Compound tubulo-acinar gland
 Changes during pregnancy
1. Secretory acini – number increased
- Dilated
- Lining cells contain secretory vacuoles that later secrete colostrum
2. Intralobular tissue and intralobular adipose tissue – less
 Breast carcinoma – confined to the breast lobule

Endocrine system - Histology
1. Thyroid gland
 Fibrous capsule
 Fibrous septae, rich supply of blood vessels, nerves, lymphatics
 Fenestrated capillaries
 Septae divide gland into lobules
 Lobules contain thyroid follicles
 Thyroid follicle
 Functional unit, spheroidal structure
 Follicular cells rest on a basement membrane
 Store inactive T3/T4 (colloid)
 Follicular cells
 Secrete T3/T4
 Stored within follicles in inactive form
 Contain
- rER for thyroglobulin synthesis
- golgi apparatus
- mitochondria
- lysosomes
- small microvilli in the free border
 Parafollicular cells
 Secrete calcitonin
 Scattered among follicular cells
 Colloid – fills the interior of thyroid follicle
Active follicle Inactive follicle

 Small  Large
 Cells tall columnar/cuboidal  Cells flattened
 Less colloid  More colloid
 Clinicals
Nodular hyperplasia - increased activity of thyroid tissue nodules
Grave’s disease – all follicles active at the same time
2. Hypothalamus 3. Pituitary gland (hypophysis) 4. Parathyroid gland
Nerve tissue - Anterior pituitary Usually 2 pairs
Neurosecretory cells Fenestrated capillaries – facilitate hormone passage Within thyroid capsule
Glial cells (supporting Cell types identified with immunohistochemical technique – Rich vascular network
cells) – somatotrophs, lactotrophs, thyrotrophs, gonadotrophs, -Principal cells/chief cells-
Blood vessels corticotrophs secrete PTH
Cell types identified with H and E stains -Oxyphil cells-degenerate
-chromophils (basophils, acidophils), chromophobes form of principle cells,
One cell type secretes a single hormone increase in number with age
Different cells are localized in different zones
Posterior pituitary
– Neurosecretory activity
– Dilated end of axons – herring bodies

 Clinicals
1. During pregnancy, in the pituitary gland, the anterior lobe cell size increases to
increase the production of FSH, LH and prolactin.
But the blood supply of the gland does not increase.
If heavy bleeding occurs at the time of birth, cells undergo necrosis – Sheehan
syndrome
2. Pituitary tumors are benign and do not invade surrounding tissues
One cell type can grow uncontrollably – excessive production of the hormone
Acromegaly – excessive growth hormone production
Cushing’s disease – excessive production of ACTH
3. Parathyroid adenoma – increased number of chief cells
Increased levels of PTH – hyperparathyroidism
Bone changes – subperiosteal resorption
Adrenal gland
 Cortex – mesodermal in origin
- Secrete glucocorticoids (ex:-cortisol), mineralocorticoids (ex:-aldosterone),
sex steroids (ex:-testosterone)
 Medulla – neural crest cells
- Secrete epinephrine, norepinephrine
 Vasculature – subcapsular plexus short and long cortical arteries sinusoids
Venules central vein
 Cortex – zona glomerulosa, zona fasciculata, zona reticularis
1. Zona glomerulosa – contain secretory cells in ovoid clusters

- Cells separated by fine collagenous septa containing capillaries
- Secrete aldosterone
2. Zona fasiculata – secretory cells are arranged as narrow cords
- Fine strands between cords contain blood vessels
- Secrete cortisol
3. Zona reticularis – secretory cells are arranged as irregular clusters
- Stain more strongly
- Contain lipofuscin (brown pigment)
- Secretory cells are separated by wide diameter capillaries
- Secrete androgens and glucocorticoids

 Medulla – secretory cells are closely packed
- Contains venous channels and the large central vein
- Cells contain catecholamine granules – oxidized to brown colour with
chromium salts (chromaffin cells)
- No stored lipids
- Contain sympathetic ganglions scattered in the medulla
Pineal gland
 Flattened, cone shaped structure
 Degenerate after childhood
 In adults, seen as a calcified structure in the midline in X-rays
 Cells – pinealocytes, secrete melatonin and serotonin
 Pineal sand – salts of Ca, Mg is a characteristic feature increasing with age
Endocrine pancreas
 Islets of Langerhans – group of secretory cells surrounded by a capsule
- Scattered among exocrine tissue
- Surrounded by a network of fenestrated capillaries
- Largely found in the tail of pancreas

Physiology Practicals
Physiology – Practical
Blood
Identification Increased in
Neutrophil Nucleus with 3-5 lobes, granulated Bacterial infection
(decreased – viral infection, TB)
Eosinophil Nucleus with 2 lobes, reddish orange Chronic hypersensitivity – asthma,
staining with granules parasitic infections
Basophil Highly dense granules, deep blue or purple Immediate hypersensitivity – allergy
granules, small marginal cytoplasm Viral infection
Malignant disease
Monocyte Kidney shaped nucleus, non-granulated Bacterial infection (acute and chronic)
cytoplasm Malignant disease
Lymphocyte Large round nucleus, thin non-granulated Viral infection, chronic lymphocytic
cytoplasm leukaemia
(decreased: AIDS, lymphocytopenia)
Eosinophil
RBC
Platelets Neutrophil
Lymphocyte
Basophil
Monocyte
Packed Cell Volume (PCV)
• PCV ; Percentage of red cells in the blood by volume

• an indicator of diseases that affect
 Red cell number and cell volume
 Plasma volume
• also used to derive MCV, MCHC

• Normal range – Males: 40% - 54% Females: 37% - 47%

 Increased in –
o Physiological – high altitudes (due to acclimatization)
o Pathological – Dengue (due to haemoconcentration), polycythaemia, dehydration
(diarrhoea, vomiting)
 Decreased in –
o Physiological – Pregnancy (due to haemodilution)
o Pathological – anaemia (decrease in red blood cells)
➢ Macrohaematocrit method
• Items needed – Wintrobe tube, Anticoagulant (1.5%
EDTA), Centrifuge
• Blood: EDTA ratio = 10:1
• Reading – Fraction or Percentage of the volume of
the red cell column out of the total blood volume
• Reading is expressed as a percentage. (%- no unit)
• when taking the reading buffy coat should be excluded
• Precautions
✓
Haematocrit should be determined ideally within 6 hours
of collection of blood.
✓
Blood sample should not be haemolysed as it will yield
falsely low results.
✓
Anticoagulant volume should not affect the total blood
volume.
✓
Air bubbles should not be included in the tube
Wintrobe tube
➢ Microhaematocrit method
• Items needed – capillary haematocrit tube (heparinised), micro haematocrit reader, micro
haematocrit centrifuge, anticoagulant Heparin
• Precautions
• When aligning the height of the plasma column, get the lower margin of the meniscus of the
plasma column.
• Exclude the buffy coat when aligning the height of the red blood cell column.
Reading PCV using micro haematocrit reader

➢ Automated methods
• using electronic cell counters
Erythrocyte Sedimentation Rate (ESR)
• Used to detect the presence of inflammation, the extent of

inflammation, response of an inflammation to treatment,
recurrence of inflammatory disease.
• RBC has net negative charge (zeta potential), so they repel
each other.
• changes in concentration of acute phase proteins, such as
fibrinogen, the net negative charge of red blood cells is
reduced. This facilitates rouleaux formation of red blood cells
(arranging red blood cells on top of the other like a stack of
coins).
• When the rate of rouleaux formation is increased the rate of
sedimentation of red blood cells is also increased.
• In inflammations due to accumulation of large molecular weight proteins in plasma (fibrinogen,
immunoglobin) rouleaux formation is facilitated. So, in inflammation ESR increases.
• Items needed – Westergren tube, Anticoagulant (tri sodium citrate dihydrate)

• Reading –Measure the height of clear plasma column after 1 hour (mm/1 st hour) (height of the
buffy coat should not be included in the reading)
1.Newborn : 0 - 2 mm/hour
2. Children : 3 -13 mm/hour
3. Women
range for ages 18 to 50 years : 0 - 20 mm/hour
range for ages > 50 years : 0 - 30 mm/hour
Normal maximum = (Age in years+10)/2 mm/hour
4. Men
range for ages 18 to 50 years : 0 - 15 mm/hour
range for ages > 50 years : 0 - 20 mm/hour
Normal maximum = (Age in years)/2 mm/hour
• ESR increase with age, females > males, pregnancy (due to increase in fibrinogen concentration)
• Increased in – severe anaemia, tuberculosis, rheumatic fever, malignancies, osteomyelitis, Renal
diseases (e.g. end stage renal failure, nephrosis), Gastrointestinal diseases (e.g. Cholecystitis,
peritonitis, acute pancreatitis)
• Decreased in – polycythaemia, red blood cell abnormalities e.g. spherocytosis & sickle cell
anaemia, protein abnormalities, severe leucocytosis
• Heparin should not be used as an anticoagulant as it alters the zeta potential of RBCs.
• The tube should not be kept in direct sunlight or path of draughts, surface on which the stand is
kept should be flat, horizontal and should not vibrate.
• Advantages
✓ Inexpensive and easy to perform
• Disadvantages
✓ Fresh blood samples are required.
✓ Low sensitivity and specificity.

✓ Affected by gender, haemoglobin concentration and temperature
• C-Reactive protein (CRP) is an acute phase protein produced by liver in response to
inflammation. CRP also can be used as a bio marker of inflammation.
• Compared to ESR, CRP
✓ Is more specific and accurate
✓ Has a more rapid rise in levels in response to inflammation.
✓ Quickly returns to normal levels with resolution of inflammation.
Osmotic Fragility Test
• In osmotic fragility test evaluates the ability of red blood cell to increase its volume under an
osmotic load before if bursts.
• Measurement of Surface area (SA)/Volume(V) ratio
✓
SA/V↑ - Fragility↓
✓
SA/V↓ - Fragility↑
• Fragility is increased in – Hereditary Spherocytosis, G6PD Deficiency
Fragility is decreased in – Sickle cell anaemia, thalassaemia
• Items needed – serial dilutions of NaCl (hypotonic)

• Reading –
o Starting point - where haemolysis begins (appearance of reddish colour) o
End point – where haemolysis completes (disappearance of RBC button)
• Normal range – begins at 0.45 – 0.5% completed at 0.3% NaCl solution
• 0.9% NaCl solution is isotonic to plasma
✓
Heparin should be used as an anticoagulant.
✓
Na/ K oxalates, Tri Sodium citrates should not be used as they add salts to the solution
Haemolysis begins Haemolysis completes
Osmotic Fragility Test

Blood Grouping
• ABO system is inherited in mendelian codominant

• Two methods;
1. Slide method
2. Tube Method
• Slide method;
❖ Clumping of RBC observed after adding antisera
❖ Anti A- Blue Anti B- Yellow Anti D – colourless
• Tube Method; Slide method

Forward Grouping Reverse Grouping
4 Tubes with A, B, AB, O antisera 3 Tubes with serum from patient
Drop of red cell suspension from Add commercially prepared

volunteer’s blood sample RBCs of A, B, O blood groups
Centrifuge Centrifuge
Observe Observe
Tube method

Blood cell counting – WBC and RBC
Items needed – Haemocytometer (counting chamber), microscope, cover slip, mouthpiece, lancet,
cotton wool, surgical spirit
• For RBC counting – RBC pipette (red colour ball inside) is filled with blood and RBC counting fluid.
This fluid lyses WBC. (1:200 dilution)
• For WBC counting – WBC pipette is filled with blood and WBC counting fluid. (this fluid lyses RBCs).
(1:20 dilution)
• Haemocytometer is loaded with diluted blood.
RBC pipette
WBC pipette

Hb Concentration – Drabkin’s Test
• Items needed – colorimeter, Drabkin’s solution (CN- present, yellow, with blood turns
orange), Anticoagulant EDTA
Bleeding Time Test (Duke Method)
• Bleeding time is the time taken to stop bleeding from small subcutaneous vessels which have
been severed by a standard lancet.
• Tests vascular response (vasoconstriction) and platelet response (platelet plug formation)
• Items needed – circular filter paper, stopwatch, standard sterile blood lancet
• Reading – I min + (no. of gaps x 30s)
• Normal range – 1 – 5 minutes
• Increased in
✓ Thrombocytopenia - reduction in platelet
count E.g. Dengue fever, bone marrow
malignancies
✓ Thrombasthenia - abnormality of platelet
function.
• Precautions should be taken

✓ Do not rub too much while cleaning the
skin of the ear lobe as rubbing increases
blood flow and alters bleeding time.
✓ The puncture must be superficial (about

4mm).
 Do not squeeze, blood should flow freely. Calculation of bleeding time
✓ Do not allow the blotting paper to press on the bleeding site as it may interfere with
bleeding.
Hess’ Test (Tourniquet test)
• Tests capillary fragility and platelet function (eg. assessment of

collagen matrix, vascular endothelium and platelet adhesion
and aggregation)
• Bedside test
• Items needed- sphygmomanometer, stopwatch, stethoscope,
coin, pen
• Cuff inflated at the mid value between systolic and diastolic
pressure
• Keep cuff for 3-5 minutes.
• Reading – number of haemorrhagic petechiae in 2.5 cm
diameter circle or square of 2.5cm2 where most petechiae are
seen.
• Up to 10 petechiae→ normal → (-) Hess test
• If no. of petechiae > 10 then Hess test is→Abnormal→ (+)
positive Hess test Hess test
• Increased in – dengue haemorrhagic fever (reduced platelet
count), scurvy/vitamin C deficiency (Defective collagen
synthesis), thrombocytopenia

Prothrombin time test –
• Evaluates extrinsic (and common pathway)
• Items needed – anticoagulant (tri sodium citrate), tissue
thromboplastin calcium reagent
• Normal range – 12 – 15 seconds
• International normalized ratio (INR) used as Prothrombin
time can be vary from test to test according to the batch of
tissue factor
• The INR → ra o of pa ent's prothrombin me to a normal
(control) sample, raised to the power of ISI value for the
particular batch of tissue factor.
• Normal INR value is 0.9 - 1.2
• ↑INR -↑Risk of bleeding
• ↓INR -↑Risk of having a clot
• Used for – monitoring of oral anticoagulant therapy (warfarin),

detection of clotting factor deficiencies
Prothrombin time
• Increased in – vit. K deficiency, I, II, V, VII, X deficiency, warfarin
therapy, liver disease, Disseminated Intravascular Coagulation (DIC)
• Decrease in Pregnancy
Activated Partial Thromboplastin Time (APTT)
• intrinsic and common pathway
Whole Blood clotting time test (Lee and white method)
• Bed side test

• Contact of blood with glass activates the intrinsic pathway of clotting
• Evaluate Intrinsic pathway
• Items needed – water bath at 370C, stopwatch, 2 glass test tubes
• Normal range – 6 – 10 min
Commonly used anticoagulants in vitro
Anticoagulant Mechanism of action

Bottle with internal wax coat In vitro exposure to glass surfaces activates intrinsic
clotting pathway. Wax coat prevents exposure of
blood to glass and inhibits intrinsic pathway
Bottle with heparin Activates antithrombin III, activated antithrombin
then inactivates thrombin and factor Xa preventing
clotting
Bottle at 0 0C Clotting factors are proteins. Low temperature

inhibits clotting factors
Bottle with EDTA, Citrate & oxalate Chelating agents. Remove Ca2+as insoluble salts.
(Action of citrate can be reversed by introducing
large amount of Ca2+)

Excitable tissue
Motor nerve conduction of median nerve
 Accessed frequently due to high prevalence of carpal tunnel syndrome

 Materials required
 Stimulating electrode, ground electrode, surface recording electrode, electrode jell, digital
box, computer with a monitor, printer
 Recording electrode place over abductor pollicis brevis
 Reference electrode place over first metacarpophalangeal joint
 Ground electrode Between recording and stimulating electrodes
𝐷𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑝𝑟𝑜𝑥𝑖𝑚𝑎𝑙 𝑎𝑛𝑑 𝑑𝑖𝑠𝑡𝑎𝑙 𝑠𝑡𝑖𝑚𝑢𝑙𝑎𝑡𝑖𝑛𝑔 𝑒𝑙𝑒𝑐𝑡𝑟𝑜𝑑𝑒𝑠

Conduction velocity =
𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑝𝑟𝑜𝑥𝑖𝑚𝑎𝑙 𝑎𝑛𝑑 𝑑𝑖𝑠𝑡𝑎𝑙 𝑙𝑎𝑡𝑒𝑛𝑐𝑖𝑒𝑠
Latency recorded at the proximal electrode 6 ms

(ms)
Latency recorded at the distal electrode 2.8 ms
(ms)
Distance between proximal and distal 200 mm
electrodes (mm)
Calculated conduction velocity 200/ (6 -2.8) = 62.5 mm ms-1

Sensory nerve conduction of median nerve
 Ring electrodes are placed on index finger which receives sensory fibres from median nerve
𝐷𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑝𝑟𝑜𝑥𝑖𝑚𝑎𝑙 𝑎𝑛𝑑 𝑑𝑖𝑠𝑡𝑎𝑙 𝑠𝑡𝑖𝑚𝑢𝑙𝑎𝑡𝑖𝑛𝑔 𝑒𝑙𝑒𝑐𝑡𝑟𝑜𝑑𝑒𝑠
Conduction velocity =
𝐷𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑝𝑟𝑜𝑥𝑖𝑚𝑎𝑙 𝑎𝑛𝑑 𝑑𝑖𝑠𝑡𝑎𝑙 𝑙𝑎𝑡𝑒𝑛𝑐𝑖𝑒𝑠
 The method is same as previous
Electromyography
 Used to accesses muscle function

 Activities observed are insertional activity, resting activity, single motor unit activity, and
recruitment of motor units with increasing voluntary contraction.

Cardiovascular system
1. Electrocardiogram (ECG)
 When reading an electrocardiogram

 10 mm height – 1mv – calibration wave
 Small square – 0.04 s
 Large square 0.2 s
 Heart rate - 1500 300
o No. of small squares in RR interval = no. of large squares in RR interval
HR =1500/No. of small squares in RR interval
HR = 300/ No. of large squares in RR interval
ECG waveforms
ECG lead placement

 Limb leads
 Lead I - Between Left arm and Right arm
 Lead II - Between Left leg and Right arm
 Lead III - Between Left leg and Left arm

 Chest leads
 V1 - 4th intercostal space, just right of sternum
 V2 - 4th intercostal space, just left of sternum
 V3 - Mid way between V2 and V4
 V4 – left 5th intercostal space, midclavicular line
 V5 - Anterior axillary line, same level as V4 (left 5 th ICS)
 V6- Mid axillary line, same level as V4 (left 5th ICS)
2. Pulse and Blood pressure measurement
Pulse
 Rate
 Rhythm
 Volume
 Character
 Radio-femoral delay coarctation of aorta

Items needed: sphygmomanometer, stethoscope
Method – using Korotkoff sounds
Systolic pressure (maximum pressure in systole) – pressure when 1st sound appears
Diastolic pressure (minimum pressure in diastole) – sounds disappear
1. The patient should either be seated or lying comfortably. He should have rested for
at least 3 minutes prior to blood pressure measurement.
2. The sphygmomanometer is placed at the same level of the cuff on the patient’s arm
and the observer’s eye level.
3. The arm should be horizontal and at the heart level.
4. The center of the bladder should be positioned over the line of the artery.
5. Feel the patient’s brachial (or radial) pulse and inflate the cuff to a pressure above
which pulse can no longer be felt.
The point of disappearance of pulse represents the systolic pressure.
6. Place the stethoscope gently over the brachial artery.
7. Inflate the cuff further to raise the pressure to 30 mmHg above the systolic blood
pressure as estimated by palpation.
8. Deflate the cuff at 2-3mmHg per second, listening carefully to the appearance of
Korotkoff sounds.
 Phase 1
Appearance of tapping sound
Indicates systolic pressure
 Phase 2 and 3
Sounds get louder as more blood enters brachial artery
 Phase 4
Sounds become muffled

 Phase 5
Sounds disappear
Indicates diastolic pressure
Pulse pressure = systolic pressure – diastolic pressure
Mean arterial pressure = diastolic pressure + 1/3 of pulse pressure
Jugular venous pressure (JVP)
 JVP is the pressure exerted on internal jugular vein during cardiac cycle.
 Assessed from visible wave form of the internal jugular vein.
 Only seen, not felt.

 JVP is an indirect measure of central venous pressure (CVP) which is the pressure
in the great veins at their entrance to the right atrium.
Important,
 Volunteer lies on a bed with the head end raised to 45 0 angel.
 Measure the vertical height between the highest level of internal jugular vein
pulsations and sternal angel. This value in cm H2O is JVP.
 To obtain CVP, add 5cm to the measurement since right atrium lies 5cm below
the sternal angle.
CVP = (JVP + 5) cmH2o

Respiratory system
1. Counting respiratory rate
 Count the number of respiratory movements per minute by placing hand on
abdomen or observing respiratory movements.
 Normal range- 12 -16 breaths per minute
 If Respiratory rate >25- high respiratory rate (tachypnoea)
 Reasons
 Physiological
 Exercise
 High temperature
 Fear, pain
 Pathological
 Hypoxia
 Hypercapnia
 Obstructive air way diseases
 Metabolic acidosis
 If respiratory rate <10 - low respiratory rate (bradypnoea)
 Reasons
 Physiological
 Sleep
 Pathological
 Hypocapnia
 Metabolic alkalosis
2. Measurement of the peak expiratory flow rate (PEFR)
o Used to monitor the progress of obstructive lung diseases.
 Eg- Asthma
o Unit- liters per minute (L /min)
o Normal rate- 400L/min
o Varies with age, gender, height, ethnicity
o Method
 Should hold the peak flow meter horizontally
 Do not block the indicator with your fingers
 Mouth piece and lips should be sealed
 Inhale deeply then blow as fast as possible
 Do this three times and take the highest reading as the result
o

Advantages of PEFR Disadvantages of PEFR
Portable (can be carried out as a bedside Not much accurate
test)
Direct measurement
Inexpensive
Non-invasive
 Uses of PEFR
o Identifying obstructive airway disease, air way narrowing
o Monitor progression of asthma
o To adjust treatments
Mini peak flow meter Wright peak flow meter
3. Spirometry
o Is a method of studying pulmonary ventilation by recording the movement of air
in and out of the lungs.

 Residual volume, functional residual capacity, total lung capacity
cannot be measured by spirometer
 Measured by body plethysmography, helium dilution method

Difference between VC and FVC
 VC-Begins with full inspiration but the patient is asked to exhale fully but slowly.
 FVC- Same except the patient has to exhale as fast as and hard as he/she can.
 In healthy individuals, there is no/little difference in volume vise.
Advantages of spirometry Disadvantages of spirometry

accurate expensive
Ability to measure several parameters using Takes time to perform
the same apparatus
Non-invasive Cannot measure residual volume,
functional residual capacity and total lung
capacity
Voluntary hyperventilation
 Increased rate and depth of breathing

 Increased PAO2
 Decreased PACO2
 Increased pH
 Cerebral vasoconstriction due to hypocapnia
o Dizziness

o Paresthesia
o Light headedness
 Peripheral vasoconstriction due to hypocapnia

o Cold extremities
 Increased pH→ H+ released from proteins exposing nega ve site→ Ca2+ binds
with those negative sites→ hypocalcaemia
 Hypocalcaemia
o Increased tissue excitability
o Chvostek sign
o Trousseau sign (carpopedal spasm)
Chvostek sign Trousseau sign
 After hyperventilation
Period of apnoea  shallow breathing  Period of apnoea  shallow
breathing
This happens periodically until PACO2 level becomes normal.

Exercise physiology
Assessment of physiological changes occur in isotonic and isometric exercises
 Items required:
1. Bicycle ergometer (To perform the isotonic exercise)
2. Hand dynamometer (To perform the isometric exercise)
3. Stop watch
4. Mercury thermometer
5. Measuring tape
6. Stethoscope
7. Sphygmomanometer
Hand dynamometer
Bicycle ergometer
Steps to use the hand dynamometer

 Physiological parameters checked:
1. Pulse rate  Grip the hand dynamometer with
2. Blood pressure maximum effort using dominant hand
3. Respiratory rate  Repeat the process 3 times
4. Oral temperature  Record the mean value
5. Calf circumference  This value is called maximum
 These parameters will be checked: isometric tension (Tmax)
1. Before the exercise.  Calculate 30% of (Tmax) and ask the
2. Immediately after exercise. volunteer to grip the hand
3. Five minutes after exercise. dynamometer at that value for 4
minutes

 Results in isotonic exercise



 Results in isometric exercise
Before Immediately after 5 min after
Pulse rate 72 115 80

(beats/min)
Blood pressure 110/80 150/100 120/85

(mmHg)
Respiratory 14 20 15
rate(breaths/min)
Oral temperature 36.4 36.8 36.6

(0C)
Calf circumference 40.2 40.4 40.3

(cm)
1. Pulse rate: heart rate increases in both types of exercises from the beginning by decreasing
parasympathetic stimulation on SA node.
2. Blood pressure:
In isotonic exercises- systolic blood pressure increases as CO increases. But vasoactive
metabolites cause vasodilatation resulting decreased diastolic blood pressure.
After exercise BP may fall transiently (persistent vasodilation by metabolites while the CO
has decreased).
In Isometric exercises systolic and diastolic blood pressure sharply increased. Compression
of vessels leads to increased diastolic blood pressure.

3. Respiratory rate:
4. Oral temperature: Total heat production of the body exceeds increased total body heat
dissipation. So, core temperature will increase in both exercises.
5. Calf circumference:
 Fluid transudation to interstitial fluid increases. Despite of increased lymph
flow, calf circumference still increases in both types of exercises
 Dilation of blood vessels.

Measuring the renal concentrating ability
 Renal concentrating ability is measured by urine specific gravity and osmolality.
a. Specific gravity can be measured by
1. Urinometer (when there is an adequate amount of urine)
2. Refractometer (when an adequate amount of urine isn’t available)
3. Dipsticks
b. Urine osmolality can be measured using osmometer.
Urinometer
 Measures specific gravity of

urine
 Reading: 1.0_ _ (normal range:
1.002-1.028)
 Instructions
a. urinometer should not
touch the bottom or
sides of the cylinder.
b. Taking measurements
should be done at eye
level.
 Temperature correction
for every 30C increase,
0.001 has to be added
to the reading.
 If the urine sample is not
enough,
Equal volume of
distilled water could be
added to the sample.
Last 2 digits of the
reading should be
multiplied by 2 in order
to get the correct
reading.

10
20
30
40
50
Refractometer
 The refractive index of urine can be measured by refractometer.

 Urine refractive index is directly proportionate to the number of solutes in the solution
and varies with specific gravity of the solution.

Osmometer
 Digital machine
 Can display the osmolality of an unknown sample when calibrated by a known sample.
 Urine osmolality can be varied from 50 mOsm/kg – 1400 mOsm/kg.
 Measuring the freezing point depression of urine is most

commonly used principle in osmometry.
 Freezing point depends on the number of particles in the
solution.
Urine analysis
 Urine analysis includes

1. Macroscopic examination
2. Chemical analysis (using dipsticks)
3. Microscopic examination (using microscope)
1. Macroscopic examination
This includes assessment of
 Quantity - volume or amount of the urine
 Colour - normal urine ranges from colourless, pale yellow to amber
 Appearance - normal urine is clear or slightly cloudy

A B C D E F
A- Haemoglobinuria
B- Haematuria
C- Bilirubinuria
D- Concentrated urine
E- Diluted urine
F- Pyuria (pus in urine)
2. Microscopic examination
 Take a urine sample a. Types of casts
 Then centrifuge it.  Hyaline, red cell, white cell, epithelial
 Discard the fluid at the top cell casts
 Examine the drops of fluid remaining b. Types of crystals
in the bottom under microscope  Calcium oxalate, triple phosphate urate
 Cells, crystals and casts are observed crystals
and reported as number observed c. Types of cells
per low power field (LPF) or high-  RBCs, WBCs, epithelial cells
power field (HPF).

3. Chemical analysis
 Urine dipstick is used
 It’s a narrow
plastic strip
which has
several
squares of
different
colours.
 Each strip is
dipped in the
urine sample
and colour
changes in
each square
are compared
against a range
of colours
indicated on
brand specific
colour charts.

CNS
Examination of sensory system
Equipment for sensory modality test
1. A key/ a coin – for stereognosis

2. Tuning fork(128Hz) – for vibration
3. Cotton wool – for light touch
4. Toothpick – for pain
5. Divider – for two-point discrimination
6. Hot and cool water - for temperature
7. Joint position sensation –
a. Asking the patient to identify the upward or downward movement of a joint (IP
joint of thumb) with his eyes closed.
Examination of motor system
1. Examination of muscles
• Inspection
Inspect the muscles for
 Wasting
 Fasciculations
 Abnormal movements
 And Skin for scars
• Tone Examination of upper limbs

• Power
 Grade 0 – no muscle movements
 Grade 1 – only a trace or flicker of
movement
 Grade 2 – active movement with
gravity eliminated
 Grade 3 – active movement against
gravity
 Grade 4 – active movement against
gravity and resistance
 Grade 5 – normal power Examination of lower limbs

2. Reflexes
Checking stretch reflex. Equipment needed →Tendon
hammer
• Upper Limb Tendon hammer

 Biceps jerk (C6)
 Triceps jerk (C7)
 Brachioradialis jerk (C5, C6)
Biceps jerk (C6) Triceps jerk (C7)
Brachioradialis jerk (C5, C6)
• Lower limb
 Knee reflex (L3)
 Ankle reflex (S1)
 Plantar response

Ankle reflex
Knee reflex
Planter response
3. Examination of limb coordination • Upper limb

 Finger nose test
 Dysdiadochokinesia
Finger nose test Dysdiadochokinesia

• Lower limb
 Heel knee shin test
4. Examination of gait
Observe for posture, base, length of strides and speed arm swing, symmetry, balance and any
abnormality
Cranial nerve examination

1. Olfactory nerve
• Bottles containing substances of familiar smells
2. Oculomotor, trochlear and Abducens nerves

• By assessing the actions of extra ocular
muscles. Limitation of,
 Abduction – lateral rectus – indicates
Abducens nerve palsy
 Intorsion and depression – superior
oblique – trochlear nerve palsy
 All other movements – oculomotor
nerve palsy
Examination of extraocular muscles

3. Trigeminal nerve
• Motor
 Inspect Temporalis, Masseter, and pterygoid
muscles for any wasting
 Jaw jerk
• Sensory
 Checking sensations over forehead, over cheeks,
and at the chin
4. Facial nerve
• Inspect for facial asymmetry
• Motor examination
• Test for weaknesses in
 Raising eyebrows and observe for loss of
wrinkling
Sensory areas which are checked
 Closing eyes tightly
when examining the divisions of
 Blowing cheeks out trigeminal nerve
 Showing teeth
5. Glossopharyngeal and vagus nerves

• Ask patient to say “aah”.
• Test for any deviation of the palate or lack of movements • Deviation of the uvula away
from the affected side.
6. Accessory nerve
• Ask patient to shrug the shoulders against resistance (Trapezius)
• Ask patient to turn the head to the side against resistance (sternocleidomastoid)
7. Hypoglossal nerve
• Ask the patient to protrude the tongue
• Inspect for tongue atrophy, fasciculations or asymmetry in movement.
o Damage to lower motor neuron
 Atrophy, fasciculations
 Deviation of tongue to affected side o Damage to upper motor
neuron
 Deviation of tongue away from the affected side

Fasciculations and deviation to right Deviation to right side without fasciculations or atrophy
– left side upper motor neuron damage
side – right hypoglossal nerve damage
Vision
1. Visual acuity
a. Visual acuity is the shortest distance by which two lines can be separated
and still perceived as two lines.
𝑇ℎ𝑒 𝑑𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑎𝑡 𝑤ℎ𝑖𝑐ℎ 𝑡ℎ𝑒 𝑐ℎ𝑎𝑟𝑡 𝑖𝑠 𝑟𝑒𝑎𝑑 𝑏𝑦 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 (6𝑚)

𝑉𝑖𝑠𝑢𝑎𝑙 𝑎𝑐𝑢𝑖𝑡𝑦 =
𝑇ℎ𝑒 𝑑𝑖𝑠𝑡𝑎𝑛𝑐𝑒 𝑎𝑡 𝑤ℎ𝑖𝑐ℎ 𝑛𝑜𝑟𝑚𝑎𝑙 𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑐𝑎𝑛 𝑟𝑒𝑎𝑑 𝑡ℎ𝑒
𝑠𝑚𝑎𝑙𝑙𝑒𝑠𝑡 𝑙𝑖𝑛𝑒 𝑡ℎ𝑒 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑐𝑎𝑛 𝑟𝑒𝑎𝑑
𝑁𝑜𝑟𝑚𝑎𝑙 𝑣𝑖𝑠𝑢𝑎𝑙 𝑎𝑐𝑢𝑖𝑡𝑦 =6/6 or 20/20

• Visual acuity is measured using Snellen chart.
• Each eye must be tested separately
• Place the Snellen chart 6m or 20 feet from the patient.
• If patient is using spectacles to read, visual acuity
should be tested with patient wearing spectacles.
• Advice the patient to read from the top large letters to
progressively smaller letters until he cannot go further
• Record the smallest line the patient reads successfully.
• If the patient can’t recognize any of the letters,
numbers or shapes at 6m, 3m, 1m distances due to
poor vision.
 Finger counting
 Perception of light sources
 Detecting hand movements are done.
A Snellen chart is a wall chart that consists of a

series of letters/numbers or shapes arranged in
lines. The size of the letters/numbers gradually
diminishes from above downwards and a
numerical number is written underneath each
line to indicate the distance at which a person
with normal vision can read the specific line.
2. Testing visual field

• 2 methods can be used
1. Confrontation method
2. Perimetry
1. Confrontation method
• Patients visual field is compared with examiners visual field

• Red tipped pin or examiners finger is used.

• Examine one eye at a time (eg- start
with the patients left eye)
• Ask the patient to close his right eye
with his right palm and fix his left eye
on examiners right eye.
• The examiner shuts his left eye and
slowly moves his finger from the outer
towards his field of vision from all 4
quadrants of visual field and asks the
patient to signal when he first sees the
examiners finger.
• The test is then repeated for the right eye of the patient.
• The movement of pin should be in a plane between patient and the examiner.
2. Perimetry
 Perimetry is mapping the peripheral visual fields using a perimeter that flashes lights
randomly at various points in the visual field.
• A computer records the location of each

flash and whether the patient pressed the button
when the light flashed in that location.
• At the end of the test, printout shows any
areas of field of vision where patient did not see the
flashes of light.

Optic tract lesions
3. Testing for pupillary light reflex

When the light is directed into the eye, pupil on the same side (direct light reflex) and opposite
side constrict (consensual light reflex).
Important: During the test, bring the light to the front of patient’s eye from the side to
avoid discomfort.
Left eye Right eye
4. Testing for colour vision

• Ishihara colour plates/charts are used.
• Assess the ability to distinguish colours thereby identifying the prevalence of colour
blindness.

Site of When light shines on right side pupil When light shines on left side pupil
damage
1 Both direct and consensual reflexes Both direct and consensual light reflexes
are lost. are present.
2 Direct reflex is lost. Direct light reflex is present.

Consensual reflex is present. Consensual light reflex is absent.
3 Both direct and consensual reflexes Both direct and consensual light reflexes
are lost. are present.
• Patients are given colour plates and asked to identify the number/trace the line they see
within 3 seconds.
• Colour of the figure and colour of the background will look similar to a patient with a
• particular form of colour blindness, so that the patient cannot distinguish the figure
from the background.
• The type of colour deficiency can be diagnosed according to the chart used.
These charts are made up of dots

of primary colours printed on a
background of similar dots of
confusing colours. The dots are
arranged to form numbers or
certain patterns.

5. Near response
The response which occurs when an individual looks at a near object include.
1. Accommodation
2. Convergence of visual axes
3. Pupillary constriction

Hearing
Types of deafness
1. Conduction deafness
Ex: i. Obstruction of the external auditory canal (ear wax, infections, foreign bodies)
ii. Damage to the tympanic membrane.
iii. Obstruction of the middle ear. (infections, fluid)
iv. Ossicular chain disruptions.
v. Otosclerosis
2. Sensorineural deafness
Ex: i. Damage to hair cells, cochlear nerve or/and organ of Corti.
ii. Acoustic neuroma
iii. Hereditary defects
iv. Infections, Inflammations (mumps, meningitis)
v. Transverse facture of the petrous temporal bone
Hearing tests

Interpretation of Rinne and Weber test
Weber Rinne
Method Tuning fork (512Hz/256Hz) Tuning fork(512Hz/256Hz)
on vertex on mastoid, then in air
Normal Sound is heard in the Vibration in air is heard
midline. after bone conduction is
over. (air conduction is
better than bone
conduction) Rinne
positive
Conduction deafness Sound is louder in the side Vibration in air is not heard
of deafness. in affected side after bone
conduction is over. (Rinne
negative)
Sensorineural deafness Louder on the opposite side Vibration in air is heard
of the deaf ear. after bone conduction is
over. (Rinne positive-partial
sensorineural deafness)
An audiogram obtained using an audiometer.

(1) Fouchet’s Test – Bile Pigments (5) Benedict’s Test – Reducing substances
1. 5ml of urine (a drop of dil. acetic acid) + 1. 5ml of Benedict’s reagent + 8 drops of
3ml of BaCl2 urine
2. Mix and filter using a filter paper 2. Add porcelain pieces
………………………………………………………………… 3. Boil in direct flame for 2 minutes
3. Place filter paper on another filter
paper
4. Add a drop of Fouchet’s Reagent to the (6) Barfoed’s Test – For Monosaccharides
precipitate at the centre 1. 2ml of Barfoed’s reagent + 8 drops of
urine
(2) Test for Haemoglobin (2 tubes) 2. Add porcelain pieces
1. 2ml of urine in tube A 3. Boil in direct flame for 30 seconds
2ml of distilled water in tube B …………………………………………………………………
2. Boil both Cool 4. Observe after few minutes
…………………………………………………………………
3. Add 4 drops of orthotolidine + 4 drops (7) Sulphosalicylic Acid Test – For Proteins
of 1. 3ml of urine + 3ml of sulphosalicylic acid
H 2O2 2. Mix
4. Mix and leave it 3. Turbidity (intensifies when warming)
…………………………………………………………………
5. Observe within 2 minutes (8) Heat Coagulation Test – For Proteins
3
1. Fill 4 of tube with urine
4
2. Do NOT add porcelain
(3) Gerhardt’s Test – For acetoacetic acid and
3. Hold tube at an angle andboil ONLY the
salicylate (2 tubes)
1. 2 tubes – 3ml of urine in each. Label A and upper layer
B. 4. Observe for turbidity against a dark
background
2. Boil tube B for 1 minute (Do not boil tube
A)
3. Cool
4. Add FeCl3 dropwise* Shake and observe
after each drop.
(4) Rothera’s Test – For acetoacetic acid and

acetone
1. 5ml of urine
2. Saturate with ammonium sulphate
(NH4)2SO4
3. Add 6 drops of sodium nitroprusside
4. Mix
5. Carefully place 2ml of conc. ammonia as
a layer over it
6. Observe purple ring (NOT a brown ring)
TEST OBSERVATION INFERENCE PICTURE
A) Proteins
1) 1. Turbidity Protein may be

Sulphosalicylic develops; on present
acid test warming
turbidity
increases
2. No change Proteins are

occurs absent
2) Heat 1. Turbidity Proteins are

coagulation test develops present
Turbidity
2. No change Proteins are

occurs absent

B) Sugar
3) Benedict’s test 1. A brick red Reducing

for reducing colour substances are
substances precipitate present
develops
brick red colour

precipitate
2. Precipitate Reducing
did not appear substances are
absent
4) Barfoed’s test 1. Brick red Monosaccharide

for colour is present
monosaccharides precipitate
develops
brick red colour

precipitate
2. Precipitate Monosaccharide
did not appear is absent

C) Ketone Bodies
5) Rothera’s 1. A purple ring Acetoacetic acid
test for develops and/or acetone is
acetoacetic present
acid and
acetone
2. Purple ring Acetoacetic acid

does not appear and/or acetone is
absent
6) 1. A tube – Purple Salicylate is

Gerhardt’s colour develops present
test for B tube – (Acetocetic acid
acetoacetic Purple colour may also be
acid and develops present)
salicylate (Boiled tube)
2. A tube – Purple Acetoacetic acid

colour develops is present
B tube – No
colour change
(Boiled tube)
3. A tube – No Both salicylate

colour change and acetoacetic
acid are absent
B tube – No
colour change
(Boiled tube)

D) Blood Pigments
7) Test for 1. A tube – Blue Haemoglobin

haemoglobin colour develops present
NO
B tube – No BLUE CHANGE
colour change
(Control tube)
2. A tube – No Haemoglobin
colour change absent
B tube – No
colour change
(Control tube)
E) Bile Pigments
8) Fouchet’s 1. A green or blue Bile pigments

test colour change present in urine
develops at the
centre
2. No colour Bile pigments

change absent in urine

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2017 A/L Repeat Campaign

Flexibility of column 24 movable vertebrae

• 1ry curvatures - concave forward

• 2ry curvature - convex forward

typical vertebra body pedicles

processes transverse processes - 2

1 ©2017 A/L Repeat Campaign

Thoracic vertebra costal facets on body and transverse processes

T11 ●superior costal no facet

T12 ●superior costal ●3 tubercles horizontal

2 ©2017 A/L Repeat Campaign

 Pelvic surface - concave

 Dorsal surface - median sacral crest – spines

T11, T12 – horizontal

Typical Cervical Typical Thoracic Typical Lumbar

3 ©2017 A/L Repeat Campaign

II. Atlanto – occipital joint

• Type : synovial joint of ellipsoid variety

• Articular surfaces : above - occipital condyles

o Nerve supply : first cervical nerve

III. Atlanto – axial joint

 4 Ligaments: Capsular ligament , anterior longitudinal ligament , ligamentum flavum

4 ©2017 A/L Repeat Campaign

Intervertebral foramen – spinal nerve emerges through

Superior & inferior margins – pedicles of vertebra above & below

Posterior margin - articular processes of vertebral arches & zygapophyseal joint

5 ©2017 A/L Repeat Campaign

 Lumbar – articular facets lie in anteroposterior plane, limits rotation greatly

 Thoracic – rotation possible

 Cervical- flexion and extension free

Rupture of annulus fibrosus in its weak posterolateral portion

protrusion of nucleus pulposus mostly posterolateral

pressure on the spinal nerve below

Irritation of the nerve root 01.pain 02 .muscle weakness

02. Spina bifida

6 ©2017 A/L Repeat Campaign

06. Abnormalities of curves

• Normal vertebral column is a straight line in A/P view.

II. Anterior- posterior curvature abnormalities

A. Kyphosis - Increased concavity anteriorly [thoracic]

B. Lordosis - Increased convexity anteriorly [lumbar]

III. Lateral curvature abnormalities

C. Scoliosis - Accompanied by rotation of the vertebrae

07. Lumbar Puncture

• Done to - obtain CSF

7 ©2017 A/L Repeat Campaign

Stability of the spine

Ant. column Middle column post. Column

8 ©2017 A/L Repeat Campaign

 Long bone – shaft, medial & lateral ends

2 © 2017 A/L Repeat Campaign

 Can be from either end

Therefore, the clavicle usually fractures between the two ligaments

3 © 2017 A/L Repeat Campaign

Triangular-shaped, thin bone. from 2nd to 7th rib level

 Glenoid cavity- lies laterally and superiorly

4 © 2017 A/L Repeat Campaign

1. Superior- covered by trapezius

6 © 2017 A/L Repeat Campaign

Upper End Shaft Lower End

1) Head of humerus Rounded in the upper half and triangular Articular

Upper-supraspinatus Nutrient foramen in anteromedial surface