Untitled

AfraTafreeh.
com
Concept Based Learning
Video Companion on Each Chapter
Next Generation
AfraTafreeh.com
Comprehensive Review Series
“PHYSIOLOGY”
Active Recall Based
Integrated Edition
Published by Delhi Academy of Medical Sciences (P) Ltd.
HEAD OFFICE
Delhi Academy of Medical Sciences (P.) Ltd.
4-B, Grovers Chamber, Pusa Road,
Near Karol Bagh Metro Station,
New Delhi-110 005
Phone : 011-4009 4009
http://www.damsdelhi.com
Email: info@damsdelhi.com
ISBN : 978-93-89309-31-7
First Published 1999, Delhi Academy of Medical Sciences
© 2021 DAMS Publication AfraTafreeh.com

All rights reserved. No part of this book may be reproduced or transmitted in any form or by any
means, electronic, mechanical, including photocopying, recording, or any information storage and
retrieval system without permission, in writing, from the author and the publishers.
This book contains information obtained from authentic and highly regarded sources. Reprinted
material is quoted with permission. Reasonable efforts have been made to publish reliable data and
information, but the authors and the publishers cannot assume responsibility for the validity of all
materials. Neither the authors nor the publishers, nor anyone else associated with this publication,
shall be liable for any loss, damage or liability directly or indirectly caused or alleged to be caused
by this book.
Neither this book nor any part may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, microfilming and recording, or by any
information storage or retrieval system, without permission in writing from Delhi Academy of
Medical Sciences. The consent of Delhi Academy of Medical Sciences does not extend to copying
for general distribution, for promotion, for creating new works, or for resale. Specific permission
must be obtained in writing from Delhi Academy of Medical Sciences for such copying.
Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are
used only for identification and explanation, without intent to infringe.
Typeset by Delhi Academy of Medical Sciences Pvt. Ltd., New Delhi (India).
Contents
Chapter-1 Basic Concepts 1 – 28
Chapter-2 Nerve and Muscle 29 – 72
Chapter-3 Kidney 73 – 100
Chapter-4 Cardiovascular System 101 – 156
Chapter-5 Respiratory Physiology 157 – 200
Chapter-6 Central Nervous System 201 – 252
Chapter-7 Endocrinology 253 – 298
Chapter-8 Gastrointestinal Tract 299 – 333
AfraTafreeh.com
AfraTafreeh.com
1 Basic Concepts
CONCEPTS
Â Concept 1.1 Total body water

Â Concept 1.2 Measurement of solute concentration

Â Concept 1.3
Cell membrane and intercellular

junctions
Â Concept 1.4 AfraTafreeh.com

Transport across cell membrane

Â Concept 1.5 Starling’s forces in a tissue capillary

Â Concept 1.6 Donnan effect & Gibbs- Donnan

equlibrium
Â Concept 1.7 Nernst equation

Â Concept 1.8 Goldmann- Hodgkin Katz equation

and genesis of resting membrane
potential
Â Concept 1.9 Composition of ECF and ICF

2 | Physiology
Concept 1.1 : Total Body Water
Learning Objectives: To understand
• Body composition as percentage of body weight
• Distribution of total body water
• Measurement of different body fluid compartments
• Indicators used for the measurement of different body fluid compartments
• Factors affecting total body water
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Body composition: values and measurement Value

a) Body Composition (as % of Body weight)
Water 60%* Minerals 7%
Proteins 18% Fats 15%
Distribution of Total Body Water

Total Body Water
AfraTafreeh.com
(60% of Body Weight)
2/3 or 66% 1/3 or 33%
Intra Cellular Fluid Extra Cellular Fluid

(40% of Body Weight) (20% of Body Weight)
Plasma
(5% of Body Weight)
Interstitial Fluid
(15% of Body Weight)
• A third component of ECF is Transcellular fluids- it is the fluid contained in the

secretions and cavities of the body e.g., CSF, intraocular fluids, joint fluid, pleural
fluid, pericardial fluid, bile, saliva, sweat, lacrimal fluid, luminal fluids of the gut,
thyroid, cochlea. Transcellular fluid volume is relatively small, about 1.5% of the body
weight, i.e., 15 ml/kg body weight (about 1 liter in a person of 70 kgs).
• Total blood volume = 8% of body weight; since plasma volume is 5% of body weight,
blood cell volume = 3% of body weight.
• If the plasma volume and the hematocrit are known, the total blood volume can be
calculated by
Blood volume = (100/100- Hct) X plasma volume

Basic Concepts | 3
Measurement of the various body fluid compartments
This is done by the dye dilution technique or the principle of volume of distribution. A known
quantity of a suitable dye/ indicator is added to an unknown volume. After equilibration a sample
is withdrawn and the concentration of the indicator/ dye is measured in the sample. The volume of
the fluid compartment is measured by using the following:-
Q-e
V = where
C
V = volume
Q = quantity of indicator given
C = concentration of the indicator
e = the amount of indicator which has either been lost or metabolized
Indicators used for measurement of different body fluid compartments

Compartment Indicator used
Total body water D2O is most frequently used ; also, tritium oxide, antipyrine
Q
ECF volume Nonmetabolizable saccharides- Inulin, sucrose, mannitol, raffinose; Radioisotopes of

selected ions- Na+, Cl-, Br-, SO42-, S2O32-(thiosulfate) (most accurate measurement of
ECF volume is by Inulin)Q
Plasma volume Evans’ blue (T1824), Albumin tagged with RAI (131I- albumin) or RISA- Radio iodinated
serum albumin)
Interstitial fluid AfraTafreeh.com
It is an indirect measurement; can be calculated from: ECF volume – Plasma volume
ICF It is also an indirect measurement; can be calculated from: Total body water – ECF
volume
RBC volume Can be determined by Total blood volume - Plasma volume; or measured independently
by tagging RBC with Cr51, Fe59, P32; also by antigenic tagging
Note: Non invasive and more convenient method like bio impedance spectroscopy (BIS) is gradually replacing the dilution
method to measure various body fluids including TBW. BIS is based on the principle of measurement of electrical resistance/
impedance. Our body contains ionic fluid that acts as a conductor and offers resistance proportionally to the fluid volume.
Factors affecting total body water:

1. Fat
Total body water as a percentage of body weight varies inversely with the body’s fat
content.
Water content of lean body mass = 71-72 mL/ 100 gm of tissue.
(Lean body mass = body mass devoid of fat; Note that fat does not hold water)
Total body water is less in
Obese personsQ

Women (total body water in women is 50% of body weight)

2. Age
In both sexes, the values tend to decrease with age.
Total body water is highest in newborns and adult males. During the first year of life
there is a marked decrease in the total body water as a percentage of body weight.
This is because the cell mass which contains at least 20% solids grows at a faster rate
than the ECF volume, in which the percentage of solids is much less.
4 | Physiology
Concept 1.2 : Measurement of Solute Concentrations
• Concepts of mole, equivalent, osmole
• Difference between osmolality and osmolarity
• Normal plasma osmolality and contribution of different substances to plasma
osmolality
• Concept of tonicity
• Formula for calculation of plasma osmolality
• Osmole gap
• Osmotic Pressure
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Mole (or mol)

Definition: It is molecular weight of a substance in grams i.e. it is gram molecular
weight.
Example:
a) Calcium → Molecular weight = 40; therefore, 40 gm = 1 mol of calcium
AfraTafreeh.com
b) NaCl → Atomic weight of Na = 23 and that of Cl = 35.5
Therefore, 23+35.5 = 58.5 gm of NaCl = 1 mol of NaCl
Note: In S.I. system, mole is the standard used to express amount of any substance
Millimole is 1/1000 of a mole. 58.5 mg of NaCl = 1 mmol
Dalton: It is a unit of mass; 1 Dalton = 1/12th of the mass of carbon–12; 1000Da = 1
kilodalton
Equivalent (Eq.)
Definition: One mole of a solute with valence ‘v’ is equal to ‘v’ equivalents of solute
1 Mol of
an ionized substance
1 Equivalent =
valency
(in case of an element)
Example: 1 mol of Na+ (valence 1) is equal to 1 Eq of Na+
Osmole
1 osmole of a substance = 1 mole of that substance/ no. of freely moving particles
liberated in solution
It expresses concentration of osmotically active particles
1 milliosmole = 1/1000 of osmole
Examples:
1 mole of NaCl = 2 osmoles of NaCl, because each NaCl molecule splits into one Na+ and
one Cl- particle is solution.
1 mole of CaCl2 = 3 osmoles, because each molecule of CaCl2 splits into 3 particles (1
calcium and 2 Cl-) in solution
Basic Concepts | 5
1 mole of Glucose = 1 osmole of glucose, because glucose being an organic compound
remains undissociated in solution
1 mole of albumin = 1 osmole of albumin, because albumin being an organic compound
is undissociated in solution
Note :
One osmole (or one can say 1 mol of an undissociated substance in an ideal solution) of
any substance has the following properties:
a) It depresses freezing point by 1.860C (freezing point of an aequous solution is lower
than pure water). This fact can be used to measure the osmolal concentration of a
substance (the number of millimoles per liter in a solution equals the freezing point
depression divided by 0.00186)
b) It exerts an osmotic pressure of 22.4 atmospheres or 19300 mm Hg (or 1 milliosmole
of a substance exerts an osmotic pressure of 19.3 mm Hg)
c) It has 6.023 × 1023 molecules (Avogadro’s number)
Osmolarity and osmolality:

Osmolarity is the number of osmoles per litre of solution.
osmolality is the number of osmoles per kg of solvent. Osmolality is not affected by
presence of other solutes in solution or by temperature.
Plasma osmolality
Normal plasma osmolality is 290 milliosmoles/L (280-290 milliosmoles/L).
Out of the 290 mosm, AfraTafreeh.com
1) Na and its associated ions (Cl / HCO3-)
+ -
= 270 mosmQ
2) Urea = 5 mosm
3) Glucose = 5 mosm
4) Plasma proteins = less than 2 mosm
5) Remaining ions = 8 mosm
N.B. Although the concentration of plasma proteins is large when expressed in grams per liter, it becomes very small when
expressed in moles per liter, because of very high molecular weights of proteins. Since the molar concentration of proteins is
very small (because of their very high molecular weight), they contribute less than 2 mosm/LQ to plasma osmolality. (Osmole
= mole/ number of freely moving particles liberated in solution; proteins liberate 1 freely moving particle in solution,
therefore for proteins, no. of osmoles = no. of moles).
Approximate formula for finding the plasma osmolality:

Plasma osmolality (in mOsm/L)
= [Na++ K+concentration (in mEq/l)] × 2 + glucose(mg/dL)/18 + BUN (mg/
dL)/2.8
OR
= 2 [Na+ + K+] + 0.055 X glucose (mg/dL) + 0.36 X BUN (mg/dL)
Tonicity
Definition: This is the osmolality of a solution with respect to plasma osmolality.
Example: 0.9% NaCl is isotonic; 5% glucose is isotonic initially, but since there is a
peripheral uptake of glucose and glucose gets metabolized, the same solution after
some time becomes hyptonicQ
6 | Physiology
Osmolal Gap:
The most accurate way of finding out the osmolality is by freezing point depression (see
above)
The approximate formula is also given above. If the difference between the two
calculations is more than 10 mOsm, it is called osmolal gap. Osmolol gap indicates the
presence of a foreign substance, such as ethanol, mannitol or poisons such as ethylene
glycol or methanol (components of anti freeze).
Osmotic pressure
• Osmosis of water molecules across a selectively permeable membrane can be opposed
by applying a pressure in the direction opposite that of the osmosis.
• The precise amount of pressure required to prevent the osmosis or solvent migration
is called osmotic pressure.
• Expressed mathematically, according to the van’t Hoff’s law, osmotic pressure (π)
can be calculated as
π = nCRT,
where n is the number of dissociable particles per molecule, C is the concentration of
solutes in osmoles per litre, R is the ideal gas constant, and T is the absolute temperature
in degrees Kelvin (2730 + centigrade0)
• Osmotic pressure for an ideal solution is
P= nRT
ν
where
AfraTafreeh.com
P = osmotic pressure
n = number of particles
R = Gas constant
ν = volume
T = Absolute temperature
• For a solution with a concentration of 1osm/L,osmotic pressure or π is equal to 19300
mm Hg or for a solution with a concentration of 1 mosm/L,osmotic pressure or π is
equal to 19.3 mm Hg
• Osmotic pressure of a solution = osmotic coefficient X No. of milliosmoles/L X 19.3
mms of Hg
• Osmotic pressure of a solution = osmotic coefficient X No. of osmoles/L X 22.4 atm
• Osmotic coefficient varies with the specific solute and its concentration. It has values
between 0 and 1. For example, the osmotic coefficient of NaCl is 1.00 in an infinitely
dilute solution but decreases to 0.93 at the physiological concentration of 0.15 mol/L.
• Osmotic pressure depends on the number rather than the type of particles in solution.
Such properties which depend on the number (or the concentration of solutes
present) rather than the type of particles (or their chemical properties) are called
fundamental colligative properties.
• Other examples of fundamental colligative properties are:
Vapour pressure lowering

Freezing point depression

Boiling point elevation

Basic Concepts | 7
Concept 1.3 : Cell membrane and intercellular junctions
• Thickness and composition of cell membrane
• Types of intercellular junctions and their identifying features
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Cell Membrane
AfraTafreeh.com
• Thickness- 7.5 nm (or 75 Å).

• Cell membrane is a lipid bilayer.
• Major lipids are- phospholipids (phosphatidylcholine, phosphatidylserine,
phosphatidyethanolamine)
• Phospholipids are ‘amphipathic’, that is, they have a ‘hydrophobic’ tail (nonpolar),
which is insoluble and towards the inside of the plasma membrane and a ‘hydrophillic’
head (polar), which is soluble and towards the outside.
• Many different types of proteins are embedded in the plasma membrane- these can
be integral proteins or peripheral proteins.
• Proteins form slightly more than 50% of the mass or the dry weight of the plasma
membrane.
• The proteins can be integral (or intrinsic) or peripheral (extrinsic)
• Proteins can have any of the following functions
Receptors

Carriers or transport proteins

Pumps

Ion channels

Enzymes

Structural proteins

8 | Physiology
Intercellular connections
These are of two types
1. Junctions that fasten the cells to one another

Tight junctions

Desmosomes

Hemisdesmosomes

Focal adhesions
2. Junctions that permit transfer of ions and molecules from one cell to the other

Gap junctions
Junctions that fasten the cells to one another

These include
(i) Tight junctions

Tight junctions hold the cells together and give tissues strength and stability.

They form the zonula occludens.

They allow the movement of some ions and solutes in between adjacent cells
(“paracellular pathway”), but the degree of this ‘leakiness’ varies from tissue to
tissue.

Tight junctions surround the luminal margins of epithelial cells, such as the
intestinal mucosa, walls of renal tubules, choroid plexus.

AfraTafreeh.com
They are also found between endothelial cells of cerebral capillaries and contribute
towards formation of the blood brain barrierQ.

Three main families of transmembrane proteins contribute to tight junctions:
occludins, junctional adhesion molecules (JAMs), claudins.
(ii) Desmosomes

Desmosomes hold the cells together.

They form the zonula adherens.

Zonula adherens is a continuous structure on the basal side of the zonula occludens.

It is the major site of attachment of intracellular microfilaments.

Contain cadherins, Ca++ dependent molecules that mediate cell-to-cell adhesion
by hemophilic reactions.
(iii) Hemidesmosomes

They attach cells to the basal laminas.

They are connected intracellularly to intermediate filaments.

The cell adhesion molecules (CAMs) present here are integrins rather than
cadherins.
(iv) Focal adhesions

They also attach cells to their basal laminas.

These are labile structures associated with actin filaments inside the cell.

They play an important role in cell movement.
Basic Concepts | 9
Junctions that permit transfer of ions and molecules from one cell to
the other
These are
(i) Gap junctions
Gap junctions are made of units called connexons.

AfraTafreeh.com
Each connexon is made of six protein subunits called connexins.
The connexins surround a central pore.
The diameter of each channel is about 2 nm and the pore diameter in the channel
is estimated to be 0.8 to 1.4nm.
Connexon of one cell is aligned with the connexon of a neighboring cell- this
permits an easy passage of ions, sugars, amino acids and other solutes with
molecular weights up to 1000, from one cell to the other without entering the ECF.
Gap junctions form electrical synapsesQ.
They reduce the intercellular distanceQ from a normal of 20 nm to 2-4 nm.
10 | Physiology
Concept 1.4 : Transport across cell membranes
Learning objectives: To enumerate and understand
• Differences between passive and active transport across the cell membrane
• Different types of passive transport- simple diffusion, facilitated diffusion, non-ionic
diffusion and osmosis with examples of each
• Different types of active transport across the cell membrane- primary and secondary
active with examples of each
• Exocytosis, endocytosis, transcytosis
Time Needed
1 reading
st
20 mins
2 look
nd
15 mins
Passive transport Active transport

“Downhill” transport “Uphill” transport
Along an electrochemical gradient Against an electrochemical gradient
Does not require energy Requires energy
Types of passive transport: - Types of active transport: -
Simple diffusion Primary
Facilitated diffusion Secondary, can be
Non-ionic diffusion
AfraTafreeh.com
Co-transport or symport
osmosis Counter- transport or antiport
Passive transport
a. Simple diffusion
All gases and lipid soluble substances move across the cell membrane by simple

diffusion.
No carrier molecule involved.

No Tm (No transport maximum i.e., not saturable).

Examples: O2/CO2 exchange in alveoli; alcohols, steroids and other lipid soluble

substances, weak organic acids and bases being lipid soluble move by simple
diffusion, (movement of water through aquaporins or water channels, movement
of ions through ion channels is also by the process of diffusion i.e., from an area
of high concentration to an area of low concentration).
Follows Fick’s law of diffusion. The Fick’s Law of diffusion states that

J = - DA ΔC / Δx
Where
J = Net rate of diffusion
D = Diffusion coefficient
A = Cross sectional area
∆ C = Concentration difference on the two sides of the membrane
∆ x = thickness of the membrane
Basic Concepts | 11
The negative sign indicates the
direction of diffusion. (For diffusion
from higher to lower concentration,
∆ C/ x is negative, so multiplying by–
∆
DA gives appositive value.)
In simple diffusion, more the concentration gradient,

more the rate of transport.
Factors affecting diffusion are:

1. Diffusion coefficient of the substance.
AfraTafreeh.com
Lipid Solubility
Diffusion coefficient ×
(Molecular Diameter) √(Molecular weight)
Diffusion coefficient in turn depends on

Lipid solubility of the substance- this is the most important characteristic which
determines the movement of a substance across the cell membrane.

Molecular size or diameter.

Valency or charge and sphere of hydration (polar versus nonpolar)- any substance
which is charged (eg. any ion) will attract water molecules. Water molecules
carry no charge but act as if they do. The H+ containing end of H2O acts as if it
is positively charged and the O2-containing end acts as if it is negatively charged.
Thus, the H+ bearing end of H2O is attracted to anions and the O2-bearing end is
attracted to cations. Molecules of H2O will literally form a “ball of water” or “sphere
of hydration” that will diffuse along with the ion they surround. This ball of water
makes the ion physically bigger and, therefore, less lipid soluble. Typically, the
greater the valency, the greater the size of the sphere of hydration.

Molecular weight.
Temperature

2. Surface area- net diffusion of the substance is directly proportional to the total area
of the membrane. In emphysema there is breakdown of alveolar walls producing a
decrease in the alveolar surface area available for diffusion. Emphysematous patients
have a decreased diffusing capacity of the lungs.
3. Concentration gradient- more the gradient, more is the rate of transport.
12 | Physiology
4. Thickness of membrane- the net transport of a substance is inversely proportional to
the thickness of membrane. In lung fibrosis, there is an increase in the thickness of
the respiratory membrane producing a decrease in diffusing capacity.
ION Channels
Movement of ions through ion channels is passive and by diffusion, that is, from higher to lower
concentration without requiring energy or a carrier protein.
Types of ion channels are:
• Voltage-gated, where changes in membrane potential alter channel openings
• Ligand-gated, which open in response to ligand binding. Ligand can be external (eg., a
neurotransmitter or a hormone), or internal (intracellular Ca2+, cAMP, lipids or one of the
G proteins produced in cells can bind directly to channels and activate them)
• Phosphorylation-gated, where protein phosphorylation or dephosphorylation regulate
opening or closing
• Stretch or pressure-gated or mechano-sensitive, where mechanical stretch of the membrane
results in channel opening
Ion channels can be
• Specific, for Na+, K+, Cl-, Ca2+
• Non specific –these permit the movement of cations and ions
• Each channel exists in multiple forms with diverse properties.
• Cl- channels from the CIC family (in plants, bacteria and animals)- dimers
• Na+ channels, including the epithelial sodium channels (ENaCs) are trimers (3 subunits- α,
β, γ)
• K+ channels- tetramers, the four subunits forming a central pore
AfraTafreeh.com
• Acquaporins- tetramers, having a pore in each subunit; additionally these four subunits
form acentral pore
• Ligand gated, such as the acetylcholine receptor, GABAA receptor, Gycine receptor-
pentamers
• Cl- channels in humans- pentamers
The patch clamp technique
• It is a laboratory technique in electrophysiology that allows the study of single or multiple
ion channels in cells.
• The ion current through a simple voltage gated channel can be studied by the patch clamp
technique.
• The patch clamp technique is a refinement of the voltage clamp. In the the voltage clamp
method ion currents through the membranes of excitable cells, such as neurons, are
measured while holding the membrane voltage at a set level.
• Erwin Neher and Bert Sakmann developed the patch clamp in the late 1970s and early
1980s. They received the Nobel Prize in Physiology or Medicine in 1991 for this work.
• A micropipette of tip diameter 1-2 micrometers is abutted on the outer surface of the
membrane and suction is applied to form a tight seal to the membrane. The patch of
membrane under the pipette usually contains only a few transport proteins, allowing for
their detailed biophysical study.
• Different types of patches can be made:
Cell-attached or on-cell patch clamp

Inside-out patch clamp

Whole cell recording or whole-cell patch

Outside-out patch

Perforated patch

Automatic patch clamping method

Basic Concepts | 13
b. Facilitated diffusion:
Characteristics:
No energy is required and is therefore passiveQ.

Occurs along an electrochemical gradient similar to simple diffusion.

A carrier molecule is involved to which the substance binds, therefore, it is also

called passive carrier – mediated transport.

Exhibits stereospecificity.

Has a Tm (it is saturable)Q.

It can be competitively and noncompetitively inhibited.

It follows the enzyme – substrate kinetics of Michaelis – Menten.

Examples of facilitated diffusion- transport of glucose by glucose transporters (GLUT),

transport of urea by urea transporters, transport of amino acids by amino-acid
transporters.
Comparison between simple diffusion and
Comparisonfacilitated
between diffusion
simple diffusion and facilitated diffusion
Facilitated diffusion
AfraTafreeh.com
Simple diffusion
c. Non – ionic diffusion

Non-ionic diffusion is seen in case of weak acids or bases, where the acid / base

can cross the membrane in the non – ionized (undissociated) form but cannot
cross the membrane in the ionized form.
The molecules of the undissociated substance diffuse from one side of the

membrane to the other and then dissociate- this causes further movement of the
undissociated substance from one side to the other.
Ammonia transport in kidney- in the inner medullary collecting duct, is an

example of non-ionic diffusion. Ammonia is secreted into the urine of the cells
in an undissociated form but acquires the H+ in the lumen to become NH4+.
This decreases the concentration of NH3 in the lumen, thereby maintaining the
concentration gradient for diffusion of ammonia.
14 | Physiology
Another example of non-ionic diffusion is the absorption of salicylates in the

stomach. In the acidic pH of the stomach aspirin is in an undissociated form (pK of

aspirin is 3.0, which is close to the ph in the stomach). Aspirin moves across the
gastric mucosa by non- ionic diffusion.
Salicylates and other weak acids are secreted in the kidney by non-ionic diffusion,

though the rate of diffusion depends on the pH of the urine.

Absorption of bile acids in the distal ileum is another example of non- ionic diffusion.

d. Osmosis
Diffusion of a solvent (water) from a dilute to a concentrated solution through a

semi permeable membrane is known as osmosis.
Active Transport
Transport is ‘uphill’, that is against an electrochemical gradient.
Energy is used.
Types:
• Primary active transport:
Energy is derived directly by hydrolysis of ATP by the transporter itself.

Note: All transporters ending with “ATPase” are primary active).

Examples of primary active transport - Na+- K+ ATPase pump, H+- K+ ATPase

in the parietal cells of stomach and in the collecting duct of the kidney, SERCA
(sarcoplasmic endoplasmic reticulum calcium pump) in sarcoplasmic reticulum of
skeletal and cardiac muscles.AfraTafreeh.com
Na K ATPase
+ +
• The sodium potassium pump is found in all cells.

• It has ATPase activity- hydrolyzes ATP to form ADP, inorganic phosphorus and energy.
• It utilizes the energy generated to move 3 Na+ ions from inside to outside the cell (Na+ is in a lower
concentration inside the cell and higher concentration outside), and 2 K+ ions from the ECF to ICF (again
from lower to higher concentration). Therefore, It has a coupling ratio of 3:2Q.
• Activity of the sodium potassium pump causes the net loss of one positive charge- therefore, is an
electrogenic pump, causing the inside of the cell to become negative with respect to the outside.
• It is a heterodimer- has an α (molecular weight 100,000) and a β subunit (molecular weight 55,000).
• α subunit has three intracellular binding sites- (i) Na+ binding site (ii) ATP binding site, and (iii)
phosphorylation site (Asp 376 is the phosphorylation siteQ); it also has two extracellular binding sites for
(i) K+ and (ii) OuabainQ
• β subunit is a glycoprotein and has three extracelluar glycosylation sitesQ.
• α and β subunits are heterogeneous, with α1, α2, α3 isoforms and β1, β2, β3 subunits described so far.
The different α and β subunits in various tissues represents specialization for specific tissue functions.
▫ α1 isoform is found in membranes of most cells

▫ α2- in muscle, heart, adipose tissue and brain

▫ α3- in heart and brain

▫ β1 subunit is widely distributed but is absent in certain astrocytes, vestibular cells of inner ear, and

glycolytic fast-twitch muscles

▫ β2 is present in fast twitch muscles

Basic Concepts | 15
• It is inactive at 40 degrees Celsius.

• Main function is regulation of cell volumeQ.
• It is not needed for the generation of a single action potential but it helps in restoring ionic balance after
a few thousand action potentials.
• Even though it is electrogenic it has a small contribution to RMP, about –4mV.
• Accounts for about 24% of the energy utilized by cells and in neurons it accounts for 70%.
Regulation of Na– K ATPase activity
• Thyroid hormones increase the number of Na– K ATPase molecules by a genomic action.
• Aldosterone increases the number of pumps (genomic action) as well as the activity of pre existing pumps
(non- genomic action).
• Thyroid hormones act by increasing the number of pumps, thereby increasing overall activity.
• Insulin increases pump activity.
• ANP and Dopamine decrease pump activity
• Dopamine inhibits pump activityQ by phosphorylating it, thereby producing natriuresis.
• Secondary active transport-

Does not use ATP directly.

Activity of the sodium potassium pump establishes an electrochemical gradient

for sodium- sodium moves along its electrochemical gradient established by the
sodium potassium pump and this movement of sodium provides the energy for
AfraTafreeh.com
active transport of some other substance- if this sodium coupled transport is in
the same direction as sodium, it is k/a co-transport or symport and if it is in the
opposite direction as sodium, it is k/a counter transport or antiport.
Eg. Sodium – linked glucose transport (i.e. SGLT) in kidney & GIT.

(Note: All transport mechanisms which are linked to Na+ entry or K+ exit are

secondary active).
Examples of secondary active transport co-transport are:
16 | Physiology
• Kidney
PCT- SGLT, Na+- aminoacid co-transport,Na+- Pi co-transport in the PCT

TAL- Na+- K+- Cl- co-transport

DCT- Na+- Cl- co-transport

• Intestinal epithelial cells- SGLT, Na+- aminoacid co-transport

• Distal ileum- Na+- Bile salt co-transport,
• Thyroid cells- NIS (sodium iodide symport)
Examples of counter-transport are:
• Myocardial cells- Sodium- calcium counter transport
• PCT cells- Na+- H+ exchange
AfraTafreeh.com
Exocytosis, Endocytosis, Transcytosis

Exocytosis
• Requires Ca2+, energy and docking proteins.
• Docking proteins are-
syntaxin (also known as t-snare protein)

synaptobrevin (v-snare protein)

SNAP-25

• Botulinum toxin interferes with these

docking proteins, thereby prevents the
release of Ach at the neuro muscular
junctions resulting in a flaccid paralysis).
There are two pathways by which exocy
tosis or secretion from the cell occurs:
(a) Non-constitutive or regulated
pathway, involves synthesis, processing
of the prohormones to mature hormones
and storage before exocytosis. Examples:
secretion of insulin by beta cells of
pancreas, glucagon by the alpha cells of
Basic Concepts | 17
pancreas, pancreatic enzymes by the acinar cells of pancreas, serotonin by the raphe
magnus nucleus.
(b) Constitutive pathway which involves the prompt transport of proteins with little or
no processing and storage. Examples: secretion of immunoglobulins by plasma cells,
collagen by fibroblasts.
In exocytosis, cytoplasmic sides of the two membranes fuse.

Exocytosis increases the total area of cell membrane.

Endocytosis
• Consists of
Phagocytosis (“cell eating”)

Pinocytosis (“ cell drinking”)

Clathrin- mediated endocytosis (receptor mediated

endocytosis)
Caveolae- dependent uptake (caveolae are prominent

in endothelial cells, where they help in the uptake of

nutrients from the blood)
Nonclathrin/ noncaveolae endocytosis

• Clathrin mediated endocytosisQ is responsible for the

internalization of many receptors and the ligands bound
to them, e.g., NGF, LDL, etc. It also plays a major role
AfraTafreeh.com
in synaptic function. Once a complete vesicle is formed,
clathrin falls off and is recycled to form another vesicle.
• Dynamin or “pinchase” is involved in pinching off the
vesicle from the cell membrane.
• Also requires energy, calcium and contractile element in
the cell.
• In endocytosis the two non- cytoplasmic side of
membranes fuse.
• Endocytosis results in removal of cell membrane,
decreasing the total area of cell membrane.
• Exocytosis- endocytosis coupling maintains the surface
area of the cell at its normal size.
Transcytosis
Absorption by endocytosis and exocytosis occurring on two opposite sides of the cell;
e.g.,IgA in the maternal colostrum is absorbed in the intestinal epithelium of the infant
by the process of transcytosis.
18 | Physiology
Concept 1.5 : Starling’s Forces in a Tissue Capillary
• Concepts of hydrostatic and colloid osmotic pressures
• Forces responsible for filtration
• Formulae for the net filtration pressure and rate of tissue fluid formation
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Hydrostatic and colloid osmotic pressures

Filtration is the movement of fluid across capillaries; this is governed by Starling’s forces.
The starling’s forces are:
(a) Hydrostatic pressure (a ‘push’ force) and
(b) Colloid oncotic pressure (a ‘pull’ force)
Hydrostatic pressure
• Hydrostatic pressure difference across a membrane is a push force which forces fluid
out of the capillary into the interstitium.
• It results in bulk flow of fluid (not diffusional flow of fluid, which depends on
concentration gradients). AfraTafreeh.com
• Bulk fluid movements occur across the endothelium and into the interstitium.
Colloid osmotic pressure or Oncotic pressure
• The colloid osmotic pressure due to the plasma colloids is called oncotic pressure.
• The capillary wall behaves like a membrane impermeable to colloids, and these exert
an osmotic pressure of 25 mms of Hg.
• Colloid osmotic pressure or the oncotic pressure acts like a “pull” force pulling the
fluid in to the capillaries.
Basic Concepts | 19
• Forces which favor movement of fluid out of the capillaries into the interstitium are
Capillary hydrostatic pressure (Pc)
Interstitial fluid colloid osmotic pressure (πi)
• Forces which oppose the movement of fluid out of the capillaries are
Capillary colloid osmotic pressure (πc)
Interstitial fluid hydrostatic pressure (Pi)
• Net filtration pressure = (Forces which favor filtration) - (Forces which oppose
filtration)
• Net filtration pressure = (Pc + πi) – (πc + Pi)
= Pc – πc - Pi+ πi
• Rate of tissue fluid formation α (Net pressure)
• Rate of tissue fluid formation = Kf X (Net pressure)
= Kf X (Pc – πc - Pi+ πi)
• Kf is ultrafiltration constant
• Kf = Capillary permeability X surface area
• Factors affecting rate of tissue fluid formation are
Capillary permeability
Surface area

AfraTafreeh.com
Capillary hydrostatic pressure (Pc)
Capillary colloid osmotic pressure (πc)
Interstitial fluid hydrostatic pressure (Pi)
Interstitial fluid colloid osmotic pressure (πi)
Clinical application
• Right heart failure causes a decrease in venous return which, because of back
pressure, increases the hydrostatic pressure especially in the lower limb capillaries-
this increases the capillary hydrostatic pressure (“push force”) resulting in increased
tissue fluid formation and edema.
• Hypoalbuminemia seen in patients of liver disease and nephrotic syndrome results
in a reduction in colloid osmotic pressure (“pull force”) which in turn increases tissue
fluid formation and edema.
Solvent drag: As water moves across the tight junctions by osmosis, it can also carry
with it some of the solutes, a process referred to as solvent drag
Important: Rate of transport in different types of membrane proteins: Pores
(aquaporins) > channels, when open (voltage gated channels, mechanosensitive
channels) > transporters (carriers)Q
20 | Physiology
Concept 1.6 : Donnan effect and Gibbs- Donnan equilibrium
Learning Objectives:
• To understand the concept of Donnan effect and Gibbs- Donnan equilibrium and
derivation of the Gibbs- Donnan equation.
Time Needed
1st reading 10 mins
2 look
nd
5 mins
Donnan effect
• For Donnan effect to occur, two compartments must be separated by a semi permeable
membrane and on one side of this semi permeable membrane is the presence of
proteins which are impermeant and negatively charged.
• Presence of an impermeant ion (e.g A– in side 1) on one side of the membrane repels
similarly charged permeant ions to the other
side and holds oppositely charged permeant Side 1 Side 2
ions to the same side, i.e., negative charge of
a non-diffusible anion (eg., proteins) hinders Eg. A–
diffusion of diffusible cations and favors diffusion
of diffusible anions
Gibbs – Donnan Equilibrium
AfraTafreeh.com
This can be considered as the ‘mathematics’ of the Donnan effect.
The effects of the presence of the impermeant ion on the distribution of permeant ions
at equilibrium are:
a) It causes an asymmetric distribution of the permeant ions.
b) More osmotically active particle on the side containing the impermeant ion.
c) The product of the concentration of the permeant ions on one side equals the product
of the concentration of the permeant ions on the other side. This is the Gibbs Donnan
equation. It holds good for any pair of cations and anions of the same valency.
d) However, the total number of positive charges on one side equals the total number
of negative charges,i.e., electroneutrality is maintained on the same side of the
membrane.
Side X Side Y
Example to illustrate the above
Donnan and Gibbs showed that in the presence of an
K+ 9 K+ 6
impermeant or non diffusible ion, at equilibrium Cl- 4 Cl- 6
[K x]
+
=
[K ]+
y
Protein 5
[K+y] [Cl ]-
x
Therefore, at equilibrium: [K+x][Cl-x] = [K+y][Cl-y]. This is the Gibbs- Donnan equation.

It holds for any pair of cations and anions of the same valency.
Basic Concepts | 21
Concept 1.7 : Nernst equation
• Movement of ions across a freely permeable membrane
• Concept of equilibrium potential
• Mathematical calculation of magnitude of the equilibrium potential by the Nernst equation
• Normal values of equilibrium potential of different ions
Time Needed
1 reading
st
10 mins
2 look
nd
5 mins
Nernst Equation
• If the cell membrane if freely permeable, ions will move across the cell membrane
along their concentration gradients.
• If the cell membrane becomes freely permeable to chloride, chloride will move from
outside to inside the cell along its concentration gradient but the presence of proteins
on the inside opposes this move.
• At equilibrium there is no net flux (that is chloride influx equals efflux) and at this point
there is an unequal distribution of chloride across the cell membrane- the potential
difference at equilibrium is known as the equilibrium potential of chloride and the
magnitude of this equilibrium potential can be calculated by the Nernst equation.
AfraTafreeh.com
• Nernst equation gives the value of equilibrium potential or isoelectric potential.
(E) Equilibrium potential is the membrane potential at which equilibrium is reached
(equilibrium is reached when the influx equals the efflux i.e. there is no net flux of
that ion)
• Its magnitude can be calculated from the Nernst equation, as follows
2.3 RT log[C1]
E(mV) =
FZCl [C2]

Where ECl = equilibrium potential in mV
R = gas constant
T = absolute temperature
F = faraday (number of coulombs per mole of charge)
Z
= valency of the ion
[C1] = concentration of the ion on one side of the cell membrane
[C2] = concentration of the ion on the other side of the cell membrane
Replacing some of the constants with numerical values, the equation for Cl- (negatively
charged ion) and K+ (positive charged ion) becomes
[Cli] [Ko]
ECl = 61.5 log (at 37° C); EK+ = 61.5 log (at 37° C)
[Clo] [Ki]

The equilibrium potential for the different ions, calculated from the standard values in
most mammalian spinal neurons, is as given below
E Na+ = +60mV E K+ = –90mV
E CL = –70mV
–
E Mg++ = 0mV
E Ca = +125mV
++
22 | Physiology
Concept 1.8: Goldman – Hodgkin – Katz (G-H-K) equation or, Goldman
constant field equation or chord conductance equation
and genesis of RMP (resting Membrane Potential)
• To understand the concept of G-H-K equation and its application in calculation of the
resting membrane potential.
• To enumerate the factors responsible for genesis of RMP and the contribution of each
• To know the normal values of RMP of different cells of the body
• To understand the effect of changes in ECF sodium, potassium and calcium on RMP
and therefore, excitability of cells and their clinical implications.
Time Needed
1 reading
st
10 mins
2 look
nd
5 mins
Goldmann Hodgkin Katz Equation

• This equation gives the magnitude of the resting membrane potential.
• It depends on

The distribution of Na+, Cl-, K+

AfraTafreeh.com
Permeability of the membrane to each of these ions
CK+Inside × PK+ + CNa inside × PNa + CCl–outside × PCl–
RMP (mV) = –61.5 log
CK+outside × PK+ + CNa outside × PNa + CCl–inside × PCl–
• The cell membrane is semi permeable- at rest, it is maximally permeable to potassium

and almost impermeable to sodium.
• Sodium, therefore, makes no contribution to the resting membrane potential. An
increase or decrease in extracellular sodium will not affect the RMP.
• Since the membrane is maximally permeable to potassium at rest, the RMP is due to
potassium.
• In motor neurons and skeletal muscles, the RMP is -90mV. In these cells RMP is ‘due
to’ K+, ‘close to’ equilibrium potential of K+ and ‘equal to or identical to’ equilibrium
potential of K+.
• In most neurons where the RMP is -70mV, RMP is ‘due to’ K+, ‘close to’ equilibrium
potential of K+ but numerically ‘equal to or identical to’ equilibrium potential of Cl-.
Genesis of R.M.P.
The factors which contribute towards genesis of RMP are:
• Diffusion of K+ : This is the most important causeQ
• Na+–K+ ATPase
By itself, it contributes a small percentage.

In cells with RMP of –90mV, contribution of Na+–K+ ATPase is only –4mV (its

contribution towards RMP is more in those cells with low RMP)

Basic Concepts | 23
More importantly, it maintains the diffusion gradient for K+
▫ Donnan effect: This also maintains the diffusion gradient for K+

Normal Value (mV) of RMP in Different Cells :

Cell RMP
Most neurons -70mV
Large motor neurons -90mV
Skeletal muscle fibres -90mV
SA Node -50 to -60mV
Ventricular muscle -90mV
Smooth muscle -45 to -65mV

(-20 to -65mV)
Thyroid cells -50mV
Epithelial cells -52mV
RBCs -10mV
Inner hair cells of cochlea AfraTafreeh.com

-65mV
Effect of change in extracellular Na+ and K+ on RMP

(1) Changes in extracellular Na+ produces no change in RMPQ
Reason: Low permeability of cell membrane to sodium at rest
(Note: However, a decrease in external Na+ concentration decreases the height of the
action potential whereas an increase in external Na+ concentration increases the height
of the action potential.)
(2) Change in extracellular K+
• Increase in K+ concentration in ECF decreases the concentration gradient for K+and
therefore, the diffusion potential of potassium
• Hyperkalemia decreases RMPQ resulting in depolarization and increased excitability of
cells. Eg. In hyperkalemia, RMP from a normal value of – 70 mV may become – 65
mV or -60mV.
• One of the common features of mild-to-moderate hyperkalemia is arrythmias.
[Note: While commenting on the change in the membrane potential (eq. From – 70 mV
to – 65 mV) the sign (positive or negative) has to be ignored. Thus, -70mV to – 65mV
should be considered as a decrease in potential or depolarization. -70mV to – 90mV is
an increase in potential or hyperpolarisation.]
Decrease in extracellular K+ increases the concentration gradient for potassium
and therefore, increases the diffusion potential for potassium.
Increase in potential causes the cells to hyperpolarize, that is, the RMP becomes
24 | Physiology
more negative.

Hyperpolarization causes a decrease in excitability of the cells.

Muscle weakness is a common symptom of hypokalemia.

On ECG, decreased excitability causes a widened QRS.
(3) Changes in ECF calcium
• ECF calcium regulates the entry of sodium ions in to the cells through voltage gated
sodium channels and is therefore, called “membrane stabilizing factor”.
• Decrease in extracellular calcium increases the permeability of the cell membrane to
sodium, which in turn increases excitability.
• Increased neuronal and muscle excitability in hypocalcemia causes carpopedal spasm.
Effect of local anesthetics on membrane potential

Local anesthetics, such as procaine, tetracaine act directly on the activation gates of sodium channelsQ
on the outside of the cell membrane, making it more difficult for these gates to open, thereby reducing
membrane excitability. When excitability has been reduced so low that the ratio of the action potential
strength to excitability threshold (called the ‘safety factor’) is reduced below 1.0, nerve impulses fail to pass
along the anesthetized nerves.
AfraTafreeh.com
Basic Concepts | 25
Concept 1.9 : Composition of ECF and ICF
• To enumerate the differences in composition of ECF and ICF with attention to the
differences in distribution of ions
Time Needed
1st reading 10 mins
2 look
nd
5 mins
• Electrolytes constitute about 7% of the total body weight
• The following table shows the distribution of the electrolytes in the ECF and the ICF
ECF ( in mEq/litre)
Cations Anions
Na 145 Cl 100
K 5 HCO3 27
Ca 2 PO4--- 2
Mg 2 SO4-- 1
Organic acids 5
AfraTafreeh.com
Proteins 19
Total 154 Total 154
ICF ( in mEq/litre)
Cations Anions
Na 10 Cl 10
K 150 HCO3 10
Ca 3 PO4--- 90
Mg 15 SO4-- 15
Organic acids -
Proteins 52
Total 177 Total 177
Important points to remeber:

• In ECF, major cation is sodium; major anions are chloride and bicarbonate.
• In ICF, major cations are potassium and magnesium; major anions are organic
phosphates (ATP, ADP, AMP) and proteins.
26 | Physiology
• There is a high sodium: potassium ratio in ECF & ICF.
• Intracellular protein concentration >> plasma protein concentration.
• Most osmotically active particle in ECF- sodium.
• Most osmotically active particle in ICF- potassium.
• Most abundant and most effective buffer in ECF is bicarbonate.
• Most abundant buffer in ICF- miscellaneous phosphates.
• Most effective buffer in ICF- proteins (pK of proteins is close to the intracellular pH,
making proteins very effective buffers).
• There is a higher protein content in the plasma than in the ISF which plays an
important role in maintaining fluid balance.
Total Exchangeable
Na 3900 mEq (90 gm) in 70 kg man or 56 meq/Kg 60-70%
K 3400 mEq (90 gm) in 70 kg man or 50 meq/Kg 95%
Important:
• Essentially all of the body potassium is in the exchangeable pool
• Only 65-70% (two-third) of the body sodium is exchangeable
• Almost all of the body Ca and Mg are non-exchangeable
• Only the exchangeable solutes are metabolically active
ELECTROLYTES
AfraTafreeh.com
Losses
(in mEq/day in a 70 kg man in temperature climate)
Na K Cl
Urine 40-90 20-60 40-120
Sweat 50-100 5 50-100
Feces 1.5 4 0.5
Total 140 (3.2 gm) 60 (2.4 gm) 200 (7 gm)

Basic Concepts | 27
Worksheet
• MCQ OF “BASIC CONCEPT” FROM DQB
• EXTRA POINTS FROM DQB

AfraTafreeh.com


28 | Physiology
Important Tables (Active recall)
Ion Equilibrium Potential
AfraTafreeh.com
Cell RMP
2 Nerve & Muscle
CONCEPTS
Â Concept 2.1 Functional anatomy

Â Concept 2.2 Axoplasmic transport

Â Concept 2.3 Nerve degeneration and regeneration

Â Concept 2.4 Recording potential changes in cells

Â Concept 2.5 Electrotonic potentials, local potential and

action potential
Â Concept 2.6 Phases of an action potential

Â Concept 2.7 Strength-duration curve

Â Concept 2.8 Conduction of an action potential
AfraTafreeh.com

Â Concept 2.9 Nerve fibre classification

Â Concept 2.10 Properties of nerve fibres

Â Concept 2.11 Functional anatomy of skeletal muscles

Â Concept 2.12
Transmission across the neuromuscular

junction
Â Concept 2.13 Excitation- contraction coupling

Â Concept 2.14 Actin-myosin cross bridge formation and

cross bridge cycling
Â Concept 2.15 Muscle fibres and motor units

Â Concept 2.16 Isotonic and isometric muscle contractions

Â Concept 2.17 Length- tension relationship

Â Concept 2.18 Force (or load)- velocity relationship

Â Concept 2.19 Sources of energy for muscle contraction

30 | Physiology
• The human central nervous system contains 100 billion neurons.
• There are 2-10 times as many glial cells as neurons
• 40% of the human genes participate in the formation of the central nervous system.
Concept 1.1 : Functional Anatomy

• To enumerate the types of glial cells in the central nervous system
• To classify different types of neurons
• To identify different parts of a neuron and their importance
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Glial cells
• 10-50 times as many glial cells as neurons.
• Do not conduct impulses.
• Retain ability to divide throughout life.
• Glial cells have an important role to play in communication along with neurons and
unlike neurons, continue to undergo cell division in adulthood.
• Types of glial cells- AfraTafreeh.com
Microglia- these are the scavenger cells.

Macroglia include Schwann cells (form myelin in peripheral nervous system)

oligodendrocytes (form myelin in CNS), astrocytes- fibrous astrocytes in white

matter and protoplasmic astrocytes in gray matter.
Functions of astrocytes:

▫ Both fibrous and protoplasmic astrocytes send processes to blood vessels, where

they induce formation of tight junctions between endothelial cells of cerebral

capillaries which in turn form blood brain barrier
▫ produce neurotropic substances

▫ help maintain the appropriate concentration of ions and neurotransmitters by

taking up K+ and the neurotransmitters glutamate and GABA.

Types of neurons
1. Depending upon the number of poles
Unipolar- have a single pole from which both the processes- axon and dendrite

arise. True unipolar cells are present only in the embryonic stage in human beings.
The primary sensory neuron is psuedounipolar.
Bipolar- have two poles, one for axon and other for dendrite. E.g., found in

vestibular and cochlear ganglia, in the nasal olfactory epithelium, and as bipolar
cells in the retina.
Multipolar have many poles. Most vertebrate neurons are multipolar.

2. Depending upon the function

Motor neurons

Sensory neurons

Nerve & Muscle | 31
3. Dending upon the length of axon
Golgi type I/ projection neurons- have long axons, includes neurons forming

peripheral nerves and long tracts of brain and spinal cord.

Golgi type II/ short circuit neurons- usually small with short axons; they are

especially numerous in cerebral cortex, cerebellar cortex and retina.

Functional Anatomy of Neuron:
• Axon hillock- thickened area of cell body from which the axon arises.
• Initial segment- the first unmyelinated portion of the axon; has a high concentration
of sodium channels per square micrometer (but the highest concentration of sodium
channels per square micrometer is at the nodes of ranvierQ).
• In myelinated nerve fibers:-
Area No. of Na+ channels per sq micrometer of membrane
Nodes of Ranvier 2000- 12000
Initial segment 350- 500
Cell body 50-75
Axon terminals 20-75
Surface of myelin Less than 25
In unmyelinated nerve fibers, the number of Na+ channels per sq micrometer of
membrane is 110.
AfraTafreeh.com
• Axon telodendria- also called synaptic knobs or terminal buttons.
Myelin formation
• In peripheral nerves: By schwann cells; Schwann cell forms myelin on one axon.
• In CNS: By oligodendrogliocytes; Oligodendrocyte forms myelin on many axons.
Myelin is absent at
Nodes of Ranvier
Axonal endings
Soma
Initial segment
Position of cell body
It is often at the dendritic zone end of axon.
Sometimes, it is within the axon e.g. auditory nerve.
Sometimes, it is attached to the side of the axon e.g. cutaneous nerve.
Functional areas of neuron
Receptor zone Dendrites
Generation of action potentials The initial segment in spinal motor neuronQ
The initial node of Ranvier in cutaneous sensory neuronsQ
Transmission of action potential Axonal process
Release of synaptic transmitter Nerve endings
32 | Physiology
Concept 2.2 : Axoplasmic Transport
Learning Objectives: T
o understand the significance of axoplasmic transport and to
enumerate the differences between the two types
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
• Axoplasmic transport is the physical transport of substances in the axoplasm.

• Axoplasmic transport requires the following:
Ca2+

ATP

Microtubules- serve as ‘tracks’ or ‘guidewires’ for the movement of molecular

motors
Molecular motors- kinesin, dyenin, myosin V: these carry their ‘cargo’ from one

end of the neuron to the other
Types of axoplasmic transport

I. Fast (20-400mm/day) II. Slow
1. Anterograde AfraTafreeh.com
• Occurs at a rate of 0.5-10mm/day
• Occurs at the rate of 400mm/day • This is always anterograde
• Movement is towards the “+” or “assembly” end • Transport of soluble enzymes, tubulins of
of the microtubules microtubules, protein subunits of neurofilaments,
• By kinesin etc
• Transport of mitochondria, short tubules of
reticulum, small vesicles, lysosomes, actin,
myosin and the clathrin used in recycling of
synaptic vesicle membrane etc.
2. Retrograde
• Occurs at a rate of 200mm/day
• Movement is towards the “-“ or “disassembly”
end of the microtubules
• By Dyenin
• Transport of proteins, small molecules, also
tetanus toxin, neurotropic viruses (e.g., polio,
herpes simplex and rabies), nerve growth factor
Nerve & Muscle | 33
Concept 2.3 : Nerve degeneration and regeneration
• To enumerate the Seddon’s classification of nerve injuries
• To differentiate between the different types of nerve injuries
• To learn the sequence of events in Wallerian degeneration and regeneration
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Nerve injury can occur due to injury, disease (diabetic neuropathy, leprosy)
Seddon’s classification of nerve injuries
Features Neuropraxia Axontemesis Neurontemesis
Pathology No anatomical disruption Axon disrupted but Complete

Both sheath and axon intact endoneural sheath division of nerve
Physiological disruption of is intact Axon and endoneural
conduction only sheath both are divided
Degeneration No degeneration Degeneration present Degeneration present

AfraTafreeh.com
proximal and distal proximal and distal
(Wallerian) (Wallerian)
Prognosis Excellent; recovery is Good/ fair/ poor Poor

complete Occurs as regenerating
axons grow into intact
sheath
Tinel’s sign* Absent Advancing Static
Tinel’s sign is a way to detect irritated nerves. It is performed by lightly tapping

(percussing) over the nerve to elicit a sensation of tingling or “pins and needles” in the
distribution of the nerve. It takes its name from French neurologist Jules Tinel (1879-
1952).
For example, in carpal tunnel syndrome where the median nerve is compressed at
the wrist, Tinel’s sign is often “positive” causing tingling in the thumb, index, middle
finger and the radial half of the fourth digit. Tinel’s sign is sometimes referred to as
“distal tingling on percussion” or DTP. This distal sign of regeneration can be expected
during different stage of somatosensory recovery.
Nerve degeneration Nerve regeneration
Anterograde (Wallerian) Anterograde

• Axoplasm breaks down • Macrophage eat away the debris, leaving an
• Myelin breaks down empty endoneural tube (‘ghost tube’)
• Schwann cell regeneration
• Axonal sprouting
34 | Physiology
Retrograde Retrograde
• Same changes as above but only upto the nearest • Same as above
node of Ranvier
Cell Body Cell Body

• Chromotolysis (Nissl bodies break down) • Nissl bodies and Golgi apparatus gradually
• Cell swelling reappear
• Nucleus move to periphery • Cell regains its normal size
• Golgi bodies disappear • Nucleus returns to central position
• Neurofibrils disappear
Degeneration- sequence of events

• Cell body- chromatolysis, within 24-48 hrsQ
• Axonal degeneration – starts within a few hours of injury, complete by 3 to 5 days
(within 1 week)
• Myelin degeneration- starts on the 8th day (after 1 week), complete by 32nd day (after
1 month)
Regeneration
• Regeneration will occur if
AfraTafreeh.com
The distance between the two cut ends is less than 3mms

The neurilemma is intact

• Regeneration complete by 1 year

• Regeneration occurs at the rate of 1mm/day (1-4 mms) or 2.5 cm/month
Nerve & Muscle | 35
Concept 2.4 : Recording potential changes in cells
• To enumerate the different methods of recording potential changes in excitable cells
• To understand the concepts of depolarization and hyperpolarization
• To understand the mechanism of recording potential changes by the use of stimulating
and recording electrodes and the differences between monophasic and biphasic action
potentials
Time Needed
1 reading
st
05 mins
2nd look 03 mins
1. CRO (Cathode ray oscilloscope)

This is used to measure electrical events in living tissue.

The advantage of CRO is that it is inertia less, instantaneously responding lever

2. Concept of polarity
All cells have a resting membrane potential.

If a cell with a R.M.P. of say, -70mv changes to say –60mv, the cell is said to

be depolarized and the potential of the cell decreases (note that it is a potential
difference and therefore, one has to ignore the negative sign while commenting
AfraTafreeh.com
on the change of polarity).
If the membrane potential changes from the resting potential of -70mV to a more

negative value, of say -80mV, the cell is said to be hyperpolarized and there is an
increase in potential.
Other illustrative examples:

From To State
-70mv -90mv Hyperpolarized
-70mv +40mv Depolarized
-70 -40mv Depolarized
Electrodes used in recording changes seen during stimulation of a nerve

One would require a set of stimulating electrodes (S) and a set of recording electrodes
(R)
(S) (R)
• The recording electrodes can be such that one electrode is on the surface and the
other, inside the cell; or else, both recording electrodes can be on the surface.
36 | Physiology
• When both the electrodes are on the surface, a biphasic action potentialQ is
recorded but when one electrode is on the surface and the other inside the cell a
monophasic action potentialQ is recorded.
Note:
• Nerve is a poor conductor of electricity.
• Nerve can conduct impulses in both directions (bi-directional conduction).
• However, once it starts going in one direction, it cannot come back because it finds
the previous part of the nerve refractory.
• Stimulation almost always occurs at cathode.
AfraTafreeh.com
Nerve & Muscle | 37
Concept 2.5 : Electrotonic potential, local potentials and action
potential
• To understand the concepts of electrotonic potentials, local and action potential
• To enumerate the differences between local and action potentials
• To understand the mechanism of depolarization in different cells
• To enumerate the differences between voltage gated sodium and voltage gated
potassium channels
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Electrotonic potentials, local potentials and action potential

While stimulating the nerve, the following changes/ events occur
1. Electrotonic potentials
These are potential changes that occur in the nerve due to passive addition of charge;
for example, at the cathodal end of the stimulating electrode, negative charge are added
on the surface and at the anodal end of the stimulating electrode, positive charges are
added
AfraTafreeh.com
Illustrative Examples
RMP -70mv
Addition of ‘1’ negative -69mv (Depolarized)

charge at cathodal surface [-70 –(-1) = -69]
Addition of ‘1’ positive charge -71mv (Hyperpolarized)

At anodal end [-70 -1 = -71]
Therefore, electrotonic potential, can be either cat-electrotonic or an-electro tonic.

Cat-electrotonic potentials (at the cathodal end) are depolarizing.
An-electrotonic potentials (at the anodal end) are hyperpolarizing.
2. Local potential
Upto say –70mv to –63mv, electrotonic potentials can be seen i.e., the addition of ‘7’
negative charge at the cathode causes exactly 7mv change. However, beyond this, a
further addition of ‘1’ negative charge may cause the potential to change by more than 1
eg. from –63mv, it may become –61mv. This is called the local response i.e. the change
in the potential is more than what you would expect on the basis of passive addition
of charge. This shows that the membrane is now participating is the process. The local
response in due to opening up to some of the voltage gated sodium channels.
38 | Physiology
3. Action potential
When the local response brings out a change of say 15mv (i.e. from –70mv to –55mv),
the firing level is reached wherein a large number of voltage – gated sodium channels
open up by a positive feedback mechanism and cause the action potential.
To Summarise,
Electrotonic potential (is due to) Passive addition of charge
Local response (is due to) Opening of some of the Na+ channels
Action potential (is due to) Opening of many Na+ channels by positive feedback mechanism
Differences between Local potentials and Action potential

(Example of Local potential: EPSP/IPSP, dendritic potentials, Motor End-plate potential,
receptor potential, synaptic potential, generator potential)
Local Potential Action potential
Graded responses All-or-none response
Produced by a sub threshold stimulus Produced by a threshold or supra threshold stimulus
Amplitude is proportional to the intensity of stimulus Amplitude of action potential remains constant with
AfraTafreeh.com increasing strength of stimulus
Can be generated either spontaneously or in response Action potential is generated only in response to
to either physical or chemical stimuli membrane depolarization
Not self – propagating Self – propagating
Travels with decrement (magnitude of the response Travels without decrement

drops off rapidly as the distance between the
stimulating and recording electrodes is increased)
Can be depolarizing/hyperpolarizing Always depolarizing
May or may not be followed by action Always followed by action
• Can be summated Cannot be summated

• There are two types of summation- spatial and
temporal
• When a number of subthreshold stimuli are given
simultaneously an action potential is produced
and this is k/a spatial summation
• When an increased frequency of subthreshold
stimuli produce an action potential this is k/a
temporal summation.
Nerve & Muscle | 39
Mechanism of depolarization in different cells
Tissue Depolarization due to
Nerve Na influx through voltage gated sodium channels
+
Skeletal muscle Na+ influx through voltage gated sodium channels

Smooth muscle Ca2+ influx
SA Node Ca2+ influx
Ventricular muscle Na+ influx
Inner hair cell of the cochleaQ K+ influx
Voltage gated sodium and voltage gated potassium channels

Voltage gated sodium channel Voltage gated potassium channel
Fast to open Slow to open
Open in voltage range of -70 to +30mV Open in voltage range of -70 to +30mV
Two gates- activation gate (m gate) towards the One gate (n gate) towards the outside
outside and inactivation gate (h gate) towards the
inside
Channel Gating duringAfraTafreeh.com

an action potential
40 | Physiology
Concept 2.6 : Phases of an action potential
• To enumerate different phases of the action potential and understand ionic fluxes
during these phases
• To understand the feedback control in voltage-gated sodium and potassium channels
in the cell membrane
• To understand the membrane conductance for sodium and potassium during different
phases of the action potential
• Absolute and relative refractory periods and their significance
Time Needed
1st reading 15 mins
2nd look 10 mins
Phases of action potential
AfraTafreeh.com
1. Stimulus artefact This is due to the leakage of current from stimulating to recording electrodes
(Advantage: it marks the point of stimulus).
2 Latent period Time taken for the impulse to travel from stimulating to recording electrodes
If the distance between the two is known, the speed of the conduction can
be calculated.
3 Change from RMP of This is due to opening of voltage gated sodium channels, causing a sodium
–70mv to –55 mv influx and decrease in membrane potential.
4 Firing level Once firing level is reached a large number of sodium channels open up (by
a positive feedback loop) and an action potential results.
5 OvershootQ This is the potential change from 0 to +35mv.
6 Repolarization This is due to closure of inactivation gates of sodium channels which
decreases the sodium influx AND opening of voltage gated K+ channels
producing an efflux of potassium.
7 After depolarization During this phase, the excitability of nerve is increased when compared with
resting phase.
8 After- hyperpolarisation During this phase, the excitability of nerve is decreased when compared with
resting phase. This phase is due to a slow closure of the potassium channels.
Nerve & Muscle | 41
Feedback control in voltage gated sodium and potassium channels during
an action potential
Sodium channels exert a positive feedback during the depolarization phase of an action
potential. This positive feedback spiral is also k/a Hodgkin Cycle.
Potassium channels bring the action potential to an end and cause closure of their gates
AfraTafreeh.com
through a negative feedback process
Membrane conductance for sodium and potassium during the different

phases of the action potential
• Changes in membrane conductance of Na+ and K+ that occur during the action
potentials are shown above.
• Conductance of an ion is the reciprocal of its electrical resistance in the membrane and
is a measure of the membrane permeability to that ion. In response to a depolarizing
stimulus, some of the voltage-gated Na+ channels open and Na+ enters the cell and
the membrane is brought to its threshold potential.
42 | Physiology
• Entry of Na+ causes the opening of more voltage-gated Na+ channels and further
depolarization, setting up a positive feedback loop– the rapid upstroke in the
membrane potential ensues.
• The membrane potential moves toward the equilibrium potential for Na+ (+60 mV)
but does not reach it during the action potential, primarily because the increase in
Na+ conductance is short-lived.
• Na+ channels rapidly enter a closed state called the inactivated state and remain
in this state for a few milliseconds before returning to the resting state, when they
AfraTafreeh.com
again can be activated. In addition, the direction of the electrical gradient for Na+ is
reversed during the overshoot because the membrane potential is reversed, and this
limits Na+ influx; also the voltage-gated K+ channels open. These factors contribute
to repolarization.
• Opening of voltage-gated K+ channels is slower and more prolonged than the opening
of the Na+ channels, and consequently, much of the increase in K+ conductance comes
after the increase in Na+ conductance.
• Net movement of positive charge out of the cell due to K+ efflux at this time helps
complete the process of repolarization.
• The slow return of the K+ channels to the closed state also explains the after-
hyperpolarization, followed by a return to the resting membrane potential. Thus,
voltage-gated K+ channels bring the action potential to an end and cause closure of
their gates through a negative feedback process.
Refractory period
• Refractory period is the period during which a neuron is refractory to stimulation.
• It is divided into an absolute refractory period and a relative refractory period.
• Absolute refractory period is the period from the time the firing level is reached until
repolarization is about one- third complete.
• During this period, no stimulus, no matter how strong, will be able to excite the nerve.
• Relative refractory period lasts from the point where repolarization is one- third
complete till the end of hyperpolarization.
• During this period, stronger than normal stimuli can cause excitation.
Nerve & Muscle | 43
Concept 2.7 : Strength- duration curve
• To understand the concept of strength-duration curve
• To define rheobase, utilization time and chronaxie
• To understand the significance of chronaxie
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Strength- duration curve

• The relation between the strength and the duration of a threshold stimulus is called
the strength-duration curve.
• The relationship between strength and duration of stimulus has been studied by
varying the duration of stimulus and finding out the threshold strength for each
duration.
• The record of results plotted on a semilog- graph paper gives the strength-duration
curve.
AfraTafreeh.com
(i) Rheobase The minimum strength of stimulus (electric current) which if applied for
adequate time produces a response.
(ii) Utilization time Time taken for the rheobase current to stimulate a nerve
(iii) Chronaxie Time taken for twice the rheobase current to stimulate a nerve.
• Within limits, chronaxie of a given excitable tissue is constant. In other words,

chronaxie is an index of excitability of a tissue and can be used to compare the
excitability of various tissues.
• Chronaxie of nerve is shorter than that of skeletal muscle fiberQ, indicating greater
excitability of the nerve as compared to muscle.
• Normal value of chronaxie in human skeletal muscle varies from 0.08 milliseconds to
0.32 milliseconds. Chronaxie is 10 times more in skeletal muscle of infants than in
adults.
44 | Physiology
• When stimulus of weaker intensity than rheobase is applied, it will not produce a
response, no matter how long the stimulus is applied.
• Stimulus of extremely short duration will not produce any response, no matter how
intense that may be.
Other Terms
(i) Biphasic action potential This type of record is obtained when both the recording electrodes
are on the surface of the nerve.
(ii) Monophasic action potential This type of a record is obtained when one electrode is on the
surface and the second electrode is inserted into the nerve.
(iii) Compound action potential Seen in a mixed nerve, wherein there may be several fibre types.
(multi peaked action potential)
(iv) Adaptation Slowly rising currents fail to fire (stimulate) the nerve because
the nerve adapts to the applied stimulus
Cause: The opening of slow K+ channels balances the gradual
opening of Na+ channels.
AfraTafreeh.com
Nerve & Muscle | 45
Concept 2.8 : Conduction of an Action Potential
• To understand the mechanism of conduction of action potential and concept of
“current sink”
• To enumerate and understand the factors affecting velocity of conduction of nerve
impulse
• To understand the concepts of axoplasmic resistance, membrane resistance and
membrane capacitance and their effect on velocity of conduction of nerve impulse
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Mechanism of conduction of action potential

Action potential
Causes
Local currents (“current sink”)

AfraTafreeh.com
Which in turn causes
Action potential, and so on
• Due to successive depolarization of the neighbouring area, the action potential is

propagated along the entire length of the axon- this type of conduction is known as
electrotonic conduction
46 | Physiology
• The nerve fiber is polarized at rest with positive charges lined up outside the cell
membrane and negative charges lined up on the inside of the cell membrane.
• During the action potential this polarity is reversed- the inside now becomes positive
and the outside is negative.
• Current flows from a positive to negative area.
• Positive charges from the membrane ahead of and behind the action potential flow
into the area of negativity represented by the action potential (“current sink”).
• Movement of positive charges decreases the polarity of the membrane ahead of and
behind the action potential.
• Such electrotonic depolarization initiates a local response, and when the firing level
is reached, a propagated response occurs that in turn electrotonically depolarizes the
membrane in front of it (conduction of a nerve impulse occurs electrotonically).
AfraTafreeh.com
• In a myelinated nerve the local circuit of current flow occurs only from one node of
Ranvier to the adjacent node. That is, the impulse or the action potential jumps from
one node of Ranvier to the next- this is saltatory conduction.
Factors affecting conduction velocity

Axon diameter
• More the diameter, more the speed of conduction.
• Axon diameter affects the conduction velocity through the resistance offered by the
axoplasm (Ri) to the flow of axoplasmic current- greater this resistance, weaker is
the electrotonic conduction.
• Larger the diameter of the axon, leser is the axoplasmic resistance (Ri) and hence,
faster the velocity of conduction.
• (Several properties of nerve are correlated with the diameter of fibers: the larger
the diameter, the greater the conduction velocity, the greater the magnitude of
electrical response, the lower the threshold of excitation and the shorter the duration
of response and the refractory period).
Nerve & Muscle | 47
• In an unmyelinated nerve fiber the conduction velocity is directly proportional to the
square root of the fiber diameter.
• In a myelinated nerve fiber the conduction velocity is directly proportional to 6 X
axonal diameter (in µ).
Myelination
• Increases conduction velocity by saltatory conduction
• Resistance offered by the membrane (Rm) is high in thick myelinated nerve fibers.
• Nodes of Ranvier are areas with no myelin, therefore, these are areas of low membrane
resistance.
• Action potential jumps from one area of low resistance to another area of low
resistance resulting in a faster velocity of conduction which is k/a saltatory conduction
• Electrical capacitance is low in thick myelinated nerve fibers. The lesser the membrane
capacitance the stronger the electrotonic conduction, and faster the velocity of
conduction.
A large diameter, myelinated nerve fibre has low axoplasmic resistance (Ra), high membrane resistance
(Rm) and low membrane capacitance, all of which contribute to a faster velocity of conduction.
(A nerve has the properties of an electrical cable, namely electrical resistance and
capacitance (the ability to store charge)
Capacitance, C, is defined as the charge, Q, which must be placed on two surfaces in
order to set up a unit potential difference, V, between them
AfraTafreeh.com
C = Q/V
The units of C are farads when Q is expressed in Coulombs and V in Volts.

Pure lipid bilayers show capacitances of around 0.8 microFarads per square cm (µF/
cm2), whereas cell membrane capacitances are around 1.0 µF/cm2. These values are
large as capacitors go, i.e., cell membranes can generate a large membrane voltage with
the movement of relatively few ions/ charges across the membrane. In fact, movement
of 6000 ions over a membrane area of 1 µm2 will generate a potential difference across
the membrane of 100mV. Presence of myelin decreases the membrane capacitance]
Other factors affecting velocity of conduction (factors attributable to action
potential generation):-
1. Temperature: affects the conduction velocity by its affect on duration of action
potential. A decrease in temperature causes a marked increase in the duration of
action potential (specially the spike) and thus delays the conduction, i.e., slows the
conduction velocity
2. Level of RMP: affects the conduction velocity variably. When the RMP is less negative,
it slows down the generation of both the action potential and electrotonic conduction.
While, when RMP is more negative, it slows the generation of action potential but
speeds up the electrotonic conduction. The resultant effect on conduction velocity is
variable but usually a decrease.
3. Level of threshold potential: if it is low the conduction velocity is increased. A
decrease in the firing level occurs when the concentration of divalent ion in the ECF
is decreased.
48 | Physiology
Concept 2.9 : Nerve fiber Classification
• To understand and learn Erlanger & Gasser classification for all types of nerve fibers-
sensory, motor, autonomic and Lloyd & Hunt’s numerical classification for sensory
nerve fibers
• To study the susceptibility of nerve fibers to pressure, hypoxia and local anesthetics
Time Needed
1st reading 10 mins
2 look
nd
05 mins
Erlanger and Gasser Classification

Fibre types Functions Fibre diameter Conduction
(µm) velocity (m/s)
A Alpha Proprioception; somatic motor 12-20 70-120
Beta High discrimination touch (fine touch), 5-12 30-70

vibration, deep pressure
Gamma Motor to muscle spindles 3-6 15-30
Delta AfraTafreeh.com
Fast pain, temperature (cold), touch
2-5 12-30
B Preganglionic autonomic <3 3-15
C Dorsal root Slow pain, temperature (cold & warmth), 0.4-1.2 0.5-2
crude touch, pressure, itch, tickle, some
reflex responses
Sympathetic Postganglionic sympathetic 0.3-1.3 0.7-2.3
A and B are myelinated; C are unmyelinated

Lloyd and Hunt’s Numerical classification (for sensory neurons only)
Number Origin Fibre type
Ia Muscle spindle, annulo spiral ending Aα

Ib Golgitendon organ Aα
II Muscle spindle, flower-spray ending; high discrimination touch (fine touch), Aβ

deep pressure
III Fast pain, temperature (cold), crude touch Aδ
IV Slow pain, temperature (cold and warmth), crude touch, pressure, itch, Dorsal root C
tickle
Nerve & Muscle | 49
Relative susceptibility of mammalian A, B and C nerve fibers to conduction
block produced by various agents.
Susceptibility to Most susceptible Intermediate Least susceptible
Pressure A B C
Hypoxia B A C
Local anesthetics A B C
• A alpha nerve fibres are the most susceptible to pressure.

• Pressure causes loss of conduction in the large diameter, myelinated group A motor,
touch and pressure nerve fibers while pain sensation remains relatively intact.
• ‘Saturday night paralysis’ or ‘Sunday morning paralysis’ is a common example of the
effect of pressure on nerve conduction. After a night of partying and alcohol intake
on Saturday evening, the individual reaches home in an intoxicated state and goes
to sleep with his arm under his head for long periods of time causing compression of
the nerves. The next morning (‘Sunday’), he gets up with palsy of the affected arm!
• Local or regional anesthesia is used to block conduction in sensory and motor nerve
fibers. This occurs as result of blockade of voltage- gated Na+ channels on the nerves
of the cell membrane. This causes a gradual increase in the threshold for electrical
excitability of the nerve, a decrease in the rate of rise of the action potential and
slowing of axonal conduction velocity.
AfraTafreeh.com
• A-gamma nerve fibers have been found to be most susceptible to local anesthetics.
• Susceptibility to local anesthetics: Aγ > Aδ = Aα > Aβ > B > C.
• Researchers have concluded that susceptibility to lidocaine does not always follow the
generally acceptable size principle, i.e., that susceptibility to local anesthesia depends
inversely on fiber diameter.
50 | Physiology
Concept 2.10 : Physiological properties of nerve fibers
• To enumerate the properties of nerve fibers
Time Needed
1 reading
st
05 mins
2nd look 02 mins
1. Excitability
2. Conductivity- conduction is an active, self-propagating process, and the impulse
moves along the nerve at a constant amplitude and velocity (the nerve is in fact a
poor passive conductor of electricity).
3. All or none response- A single nerve fiber always obeys the ‘all or none law’.
4. Refractory period-
Absolute refractory period corresponds to the period of action potential from

firing level until repolarization is almost one third complete. During the absolute
refractory period there is no response irrespective of strength of stimulus.
Relative refractory period extends from the end of absolute refractory period to

the start of after depolarization of the action potential. During this period response
may occur if stimulus strength is increased.
AfraTafreeh.com
5. Summation- can be temporal or spatial summation.
6. Accommodation- a slowly rising current fails to stimulate a nerve. If the rate of
rise of the current is too slow, the nerve accommodates to the passage of current.
To minimize accommodations, stimulus currents which rise extremely rapidly are
employed.
7. Indefatiguability.
Nerve & Muscle | 51
Concept 2.11 : Functional anatomy of skeletal muscle
Learning Objectives
• To understand and enumerate the hierarchy of skeletal muscles
• To enumerate the sarcolemmal proteins (dystroglycan-sarcoglycan complex),
understand their functions and discuss the clinical conditions which arise because of
mutation of these proteins
• To enumerate the different types of proteins in skeletal muscles and their functions
• To clearly differentiate the bands and lines in skeletal muscle
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Hierarchy of muscle structure

Muscle
Made up of
Muscle fiber (or muscle cell)
Made up of

AfraTafreeh.com
Muscle fibril
Made up of
Muscle filaments
( Made up of contractile proteins)

• The structural and functional unit of skeletal muscle is a sarcomere. It extends
between two adjacent Z-lines.
Sarcolemmal proteins (Dystroglycan- sarcoglycan) complex

• Dystrophin connects F-actin to a member of the dystroglycan complex, β-dystroglycan,
which in turn is linked to the α-dystroglycan, which in turn connect to the merosin
subunit of laminin 211 in the extracellular matrix.
• Dystrophin is associated with syntropins, and sarcospans are associated with the
dystroglycan complex.
• Dystroglycans are associated with the sarcoglycans.
• The sarcoglycan complex consists of four glycoproteins- α-, β-, γ- and δ-sarcoglycan.
• Function: They add strength to the muscle by providing a scaffolding for the fibrils,
connecting them to the extracellular environment.
52 | Physiology
• In Duchenne muscular dystrophy- dystrophin is absent from muscle.

• In Becker muscular dystrophy- dystrophin is present but altered or reduced in amount.
• In limb-girdle dystrophy- associated with mutations of the genes coding for sarcoglycans.
AfraTafreeh.com
Proteins in skeletal muscle

Nerve & Muscle | 53
1. Contractile proteins
Myosin (The type of myosin present in skeletal muscle is myosin II)
▫ Each myosin molecule has a tail, arm, neck and two heads.

▫ Myosin contains heavy chains and light chains.

▫ Heads are made up of the light chains and the amino terminal portions of the

heavy chains
▫ Heads contain an actin-binding site and a catalytic site that hydrolyzes ATP and

has ATPase activity

Actin
▫ Each thin filament consists of two strands of actin in a double helix

2. Regulatory (‘relaxing’)
Tropomyosin
▫ Tropomyosin are long filaments located in the groove between the two chains

of actin.
▫ Each molecule of tropomyosin covers seven active sites on actin.

Troponin
▫ Troponin are small globular proteins located at intervals along the tropomyosin

molecules.
▫ Each troponin has three subunits- Troponin T binds troponin to tropomyosin;

AfraTafreeh.com
troponin I inhibits the interaction of myosin and actin; troponin C contains the
binding sites for calcium that initiates contraction.
3. Anchoring/ structural
α-actinin- binds actin to Z lines
Titin- connects Z lines to M lines; provides a scaffolding to the sarcomere, provides
muscle with its elasticityQ; titin is the largest known protein with a molecular
weight of 3000000.
Desmin- binds Z lines to plasma membrane
Bands / Lines
Bands – A, I, H ; Lines – Z, M
• A band – Dark, ‘anisotropic to light’, made up of myosin and overlapped actin.
• I band – Light, ‘isotropic’ to light, made up of mainly actin; half of I-band lies in one
sarcomere and half lies in the neighboring sarcomere.
• H band – The lighter portion in the middle of A band, where there is no overlap of
actin and myosin (that is, it is made of only myosin).
• Z line – The actin filaments get anchored here; the area between 2 adjacent Z-lines
is called a sarcomere.
• M line is a transverse line seen in the middle of the H band- this is the site of reversal
of polarity of the myosin molecules in each of the thick filaments.
• Pseudo-H zone - M line plus the narrow light areas on either side of it are called the
pseudo-H zone.
54 | Physiology
• When a muscle contracts, the two Z- lines come closer; the length of the A band
remains constant whereas the length of I and H band decreasesQ and M – line becomes
more prominent.
AfraTafreeh.com
Nerve & Muscle | 55
Sarcotubular System
Made up of
1. L-tubule (Longitudinal tubule)
This is the sarcoplasmic reticulum.

2. T – tubule (Transverse tubule)

This is formed by the invagination of the sarcolemma into the muscle cell. In the

skeletal muscle
T-tubule is located at the A-I junction.

In cardiac muscle, the T- tubule is located at the Z- line.

The L-tubule (Sarcoplasmic reticulum) has got ‘distended ends’ called cistern.

AfraTafreeh.com
The 2 cisterns associated on either side of the T-tubule – is called a triad.
Cistern is a storehouse of calcium.
Receptors
1. T-tubule has dihydrophyridine receptor- this is a voltage-gated Ca++ channel.
2. The L tubule cistern has ryanodine receptors- ryanodine receptor is a ligand gated
calcium channel.
• Mutation of Ryanodine receptors gives rise to malignant hyperthermia.

• Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications
used during general anesthesia, such as halothane, ether, etc., among those who are susceptible. Symptoms
include muscle rigidity, high fever, and a fast heart rate. Complications can include muscle breakdown
and high blood potassium.
Functions of the T – tubule

• The transverse tubule is continuous with the membrane of muscle fiber. It forms a
grid perforating the individual muscle fibrils. The space between the 2 layers of the
T- system is an extension of the extra cellular space
• The T system allows rapid transmission of action potential from cell membrane to all
fibers in muscle
Functions of L-tubule
• The L-tubule (sacroplasmic reticulum) is concerned with Ca++ movement and muscle
metabolism.
56 | Physiology
Concept 2.12 : Transmission across neuro-muscular junction and
excitation-contraction coupling
Learning Objectives
• To understand transmission across neuro-muscular junction and generation of motor
end plate potential
• To understand the spread of action potential over the muscle fiber membrane and
excitation- contraction coupling triggering muscle contraction
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
AfraTafreeh.com
Nerve & Muscle | 57
Sequence
Action potential reaches the nerve terminal
Opening of voltage-gated calcium channel
Influx of calcium
Release of Acetylcholine
Ach diffuses across the synaptic cleft
Ach binds with Ach receptors

AfraTafreeh.com
(ligand gated sodium and potassium channels) at the motor end plate
Influx of sodium
(predominates over efflux of potassium)
Muscle fiber membrane depolarizes

58 | Physiology
Concept 2.13 : Excitation – contraction coupling
Learning Objectives: The process by which depolarization of the muscle fiber initiates
contraction is called excitation – contraction coupling
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
Events
• The depolarization at the motor-end plate is called end plate potential (EPP)
• The depolarization at motor-end plate, if large enough, causes action potential in the
adjacent parts of the muscle cell membrane
• The action potential thus generated spreads over the muscle fiber membrane and
reaches the muscle cell interior via the T-tubules
• The DHPR (dihydropyriidne) receptor on the T-tubule membrane acts as a voltage
sensor and triggers release of Ca++ from the terminal cisterns of the L-tubule via a
physical interaction with the ryanodine receptor (RyR) on the sarcoplasmic reticulum
• The released calcium is amplified through ‘calcium induced calcium release’
• The released, Ca++ binds to troponin – C. This allows the troponin to get ‘lifted off’
the tropomyosin
AfraTafreeh.com
• The tropomyosin ‘moves away’, uncovering the active sites where myosin heads bind
to actin
• This triggers the cross-bridge cycling, including the power-stroke
• Relaxation is brought about by the active pumping of Ca++ back into the sarcoplasmic
reticulum (by the sarcoplasmic or endoplasmic reticulum Ca++ATPase or SERCA pump)
Note:- (i) the troponin – tropomyosin complex is the relaxing protein that inhibits the
actin myosin interaction, (ii) ATP provides energy for both contraction (at the myosin
head) and relaxation (via SERCA)Q
ContractureQ- if transport of Ca++ into the SR is inhibited due to any cause, relaxation
does not occur; the resulting sustained contraction is known as contracture. This is a
reversible condition.
Rigor- when muscle fibers are completed depleted of ATP and phosphorylcreatine, they
develop a state of rigidity called rigor. When this occurs after death, the condition is k/a
rigor mortis.
Nerve & Muscle | 59
Concept 2.14 : Actin-myosin cross bridge formation and cross bridge
cycling
Learning Objectives: To understand the sequence of events in actin- myosin cross
bridge formation and cross bridge cycling
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
AfraTafreeh.com
At rest, myosin head is in a high energy, high affinity state (“Cocked” state)
Inorganic phosphorus is released
Release of calcium from SR uncovers active sites on actin triggering muscle contraction
Myosin head binds with active site on actin (cross bridge formation)
ADP is released
Power stroke
Attachment of new ATP causes detachment of head
Hydrolysis of ATP causes “recocking” of myosin head

60 | Physiology
Concept 2.15 : Muscle fibers & motor unit
• To differentiate between the two major types of muscle fibers
• To define motor unit and its different types
• To understand the size principle
• To understand summation of muscle contractions, including multiple fiber summation
and frequency summation
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Types of muscle fibers

Charactestics Type I muscle fibre Type II muscle fibre
Slow, small, red, involved in tonic Fast, large, white involved in phasic
activity activity
Further fiber types – Type II fibres are further sub-divided
into IIA, IIB, IIC and IIM
Diameter Small Large
Myosin ATPase activity AfraTafreeh.com
Slow Fast
Twitch duration Longer Shorter
Metabolism Aerobic, low glycolytic, high Anaerobic, high glycolytic, low
oxidative capacity oxidative capacity
(Type IIA- oxidative glycolytic;
Type IIB- glycolytic)
Synonym based on twitch and SO (slow oxidative) Type IIA- FOG (fast oxidative
metabolic properies glycolytic)
Type IIB- FG (fast glycolytic)
Mitochondria number High Low
Glycogen content Capillary density Low High
Blood supply High Low
Myoglobin content High Low
Enzymes:- High Low
NADH dehydrogenase High Low
Phosphorylase activity Low High
Myosin ATPase activity Low High
Fatiguability Delayed Early
Note: Type I fibers are also known as slow, oxidative (SO).
IIA are fast, oxidative, glycolytic (FOG) and fatigue resistant.
IIB are fast, glycolytic (FG) and fatiguable.
IIC: muscle fibers found in fetal life.
IIM are superfast, having a unique myosin structure and present mainly in jaw muscles.
Nerve & Muscle | 61
Motor unit- definition:
• Each single motor neuron and all the muscle fibers it innervates constitute a motor
unit.
• In general, small muscle that react rapidly and whose control must be exact have
fewer muscle fibers in a motor unit (e.g., 3-6 muscle fibers in one motor unit of ocular
musclesQ). Conversely, large muscles that do not require fine control, such as the
soleus muscle, may have up to 600 muscle fibers in each motor unit.
• Each spinal motor neuron innervates only one kind of muscle fiber, so that all the
muscle fibers in a motor unit are of the same type.
Types of motor units

• On the basis of the type of muscle fiber they innervate, and thus on the basis of their
twitch duration, motor units are divided into S (slow), FR (fast fatigue resistant), and
FF (fast fatiguable) units.
Size principleQ:
• Small motor units are driven by small motor nerve fibers and larger motor units by
larger nerve fibers.
• In large muscles, the small, slow units are recruited first; then if required, the large
units are recruited (small motor neurons in the spinal cord are more excitable than
the larger ones, so these are excited first).
• In other words, a specific muscle action is developed by the recruitment of S muscle
AfraTafreeh.com
units that contract relatively slowly to produce controlled contraction.
• Next, FR muscle units are recruited, resulting in a more powerful response over a
shorter period of time.
• Lastly, FF muscle units are recruited for the most demanding tasks.
For example, in muscles of the leg, the small, slow SR motor units are first recruited
during standing. As one starts walking, the FR motor units are recruitedQ. As this motion
turns to running or jumping the FF motor units are recruited.
Summation of contraction: This means the adding together of individual twitch
contractions to increase the intensity of overall muscle contraction. Summation occurs
in 2 ways:
1. By increasing the number of motor units contacting simultaneously- multiple fiber
summation
2. By increasing the frequency of contraction- frequency summation- this can lead
to tetanization (In complete tetanus no relaxation occurs between stimuli and in
incomplete tetanus relaxation takes place between the summated stimuli)
62 | Physiology
Concept 2.16 : Isotonic and isometric muscle contractions
• To differentiate between the two types of muscle contraction
• To differentiate between contractile and elastic components in muscle
• To understand mechanism of isometric muscle contractions
• To understand efficiency of muscle contraction
• To enumerate the types of heat produced during muscle contraction
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Isometric and Isotonic contraction

Isometric Isotonic
Constant length Constant load
Length remains same Length decreases
No external work is done External work is done
Heat released is less Heat released is more
AfraTafreeh.com
Contractile and elastic components of a muscle
According to the three component model, the skeletal muscle consists of;
• Contractile component
Represents the thick and thin filaments present in myofibrils

Offers no resistance to stretch

Comprises 60% of the total muscle proteins

• Series elastic component

Refers to the elastic tissue present in series with the contractile component

Consists of Titin and the elastic fibres in the tendon of the muscle

In resting conditions, the SEC offers resistance to passive stretch and also explains

how a muscle contracts isometrically

• Parallel elastic component
Refers to the elastic tissue attached in parallel to the CC

It is represented by the structural elastic tissue of the muscle such as connective

tissue sheaths of the muscle, sarcolemma and gap filaments

It also offers some resistance to passive stretch. Presence of this component

explains why the muscle regains its original length after it is passively stretched.
In isotonic contraction this component gets folded up.
Mechanism of isometric muscle contractions

In isometric muscle contractions there is
• Contraction of contractile component
• Stretch of series elastic component
• Total length of muscle remains unchanged but there is increase in muscle tension
Nerve & Muscle | 63
Efficiency of muscle contraction
• Mechanical efficiency = work done/ total energy expenditure
• Efficiency under the best of conditions is less than 25% with the remainder becoming
heat (Guyton 11th edition)
• (Ganong 26thedi: overall mechanical efficiency of skeletal muscle ranges upto 50%
while lifting a weight during isotonic contraction and is essentially 0% in isometric
contraction); consequently, heat production is considerable
• Maximum efficiency is seen when the muscle contracts at moderate velocity which is
about 30% of maximum - if the muscle contracts slowly or without any movement,
small amounts of maintenance heat are released during contraction, even though
little or no work is performed, thereby decreasing the conversion efficiency to as little
as zero.
• If contraction is too rapid, large proportions of energy is used to overcome viscous
friction within the muscle itself, and this, too, reduces the efficiency of contraction
Heat production during muscle contraction

Heat produced in muscles can be accurately measured by using suitable
thermocouples.
Isotonic Isometric
Resting heat + +
Initial heat
Activation heat
AfraTafreeh.com
+ +
Shortening heat + +
Recovery heat + +
Relaxation heat + -
Total heat ↓
Different phases of heat production during muscle contraction are:

1. Resting heat is the heat given off at rest and is the external manifestation of the basal
metabolic processes.
2. Initial heat is the heat produced in excess of the resting heat during contraction. This
is made of
Activation heat, the heat a muscle produces whenever it is contracting.

Shortening heat, which is proportionate in amount to the distance the muscle

shortens.
3. Recovery heat is the heat produced in excess of resting heat, following a contraction-
it is the heat liberated by the metabolic processes that restore the muscle to its
precontraction state. Recovery heat of muscle is approximately equal to the initial
heat; that is, the heat produced during recovery is equal to the heat produced during
contraction.
4. Relaxation heat- in an isotonically contracting muscle extra heat, in addition to
recovery heat, is produced to restore the muscle to its original length- this is k/a
relaxation heat. External work must be done on the muscle to return it to its previous
length, and relaxation heat is mainly a manifestation of this work.
Relaxation heat is produced only in a muscle contracting isotonically.
64 | Physiology
Concept 2.17 : Length – tension relationship (Frank- Starling’s Law)
• To define the length- tension relationship
• To apply the length- tension relationship to the heart
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
1. There is definite length – tension relationship in skeletal muscle contracting

isometrically.
2. More the initial length of muscle fiber more is the tension generated, but within
physiological limits- this is the Frank- Starling’s Law.
3. The initial length at which the active tension developed is maximum is called the
resting length (also called optimum length).
4. Optimum length corresponds to a sarcomere length of 2.2μ.
5. The tension developed depends upon the number of cross-bridges that can be formed
between actin and myosin.
6. At the optimum length, there is optimum overlapping between actin and myosin
filaments, so maximum cross bridges are formed between them.
AfraTafreeh.com
7. At initial lengths less than or more than the optimum length, the overlap between
actin and myosin and the number of actin- myosin cross bridges decreases.
Nerve & Muscle | 65
Length- tension relationship applied to the heart
• The relationship between initial fibre length and tension generated in cardiac muscle is similar to skeletal
muscle.
• The initial length of the ventricular muscle fibre is determined by the end diastolic volume (EDV), which
in turn depends on venous return.
• More the venous return, more is the EDV, more is the tension generated which increases stroke volume
and therefore, the cardiac output BUT up to a physiological limit.
• In patients of dilated cardiomyopathy the initial length of ventricular muscle fibres is beyond optimum
length which decreases the tension generated- therefore, failure is common in patients of dilated
cardiomyopathy.
AfraTafreeh.com
66 | Physiology
Concept 2.18 : Force- velocity relationship
• To determine the relationship between afterload/ force and velocity of contraction and
to study the force- velocity curve
• To appreciate the facts that the maximum velocity of contraction (Vmax) is when
afterload is zero and when velocity is zero (work done = zero) the contraction is
isometric
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Force- velocity relationship

• Velocity of contraction (shortening) of a muscle fiber decreases with progressively
increasing load.
• More the afterload (load opposing the muscle contraction), less is the velocity of
contraction.
• Velocity of contraction or shortening is maximum (Vmax) when the afterload is zero.
Force- velocity Curve

AfraTafreeh.com
Phases of muscle contraction with afterload

In an after loaded preparation, when a muscle contracts against a load, it shows the
following three phases
1. Initial isometric contraction phase- in this phase there is no shortening; contraction of
contractile components (CC) stretches the series elastic component (SEC) and there
occurs a rise in tension till the tension equals the load- this is the end point of the
isometric phase
Nerve & Muscle | 67
2. Intermediate isotonic contraction phase- starts when the muscle tension exceeds the
load and load starts moving; there occurs shortening of the muscle without further
stretching of SEC
3. Terminal isometric phase- after the muscle becomes shorter than the resting length;
any further shortening is associated with a decrease in the tension. And, when
the tension generated equals the load, the muscle once again starts contracting
isometrically- this is the terminal isometric phase.
AfraTafreeh.com
68 | Physiology
Concept 2.19 : Sources of energy for muscle contraction during
exercise
Learning Objectives: To enumerate the sources of energy for muscle contraction
during exercise and understand the significance of each.
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Sources of energy during exercise

1. ATP stores (about 4 millimolar in the muscle fiber)- sufficient for 1 to 2 seconds only.
2. Combined energy of stored ATP and ATP from creatine phosphate or phosphorylcreatine
- can sustain muscle contraction for 5 to 8 seconds.
3. ATP from anerobic glycolysis - can sustain muscle contraction for 1 minute. Use of the
anerobic pathway is self- limiting because of the accumulation of lactate.
4. ATP from aerobic metabolism- major source of the energy for muscle contraction is
aerobic/ oxidative metabolism.
For example, in a 100m dash that takes less than 10 seconds, 85% of the energy is
derived anerobically. In a 2- mile race that takes 10 mins, 20% of the energy is derived
anerobically but in a long distance race that takes 60 mins only 5% of the energy comes
from anerobic metabolism. AfraTafreeh.com
Muscle Hypertrophy
• Increase in total muscle mass is known as muscle hypertrophy.
• This increase is due to an increase in the number of actin and myosin filaments and an increase in
glycolytic enzymes in each muscle fiber.
• Hypertrophy occurs to much greater extent when the muscle is in the afterloaded stateQ.
Muscle Hyperplasia
• Increase in number of muscle fibers is muscle hyperplasia.
• This occurs only under rare conditions of extreme muscle force generation and is usually due to linear
splitting of previously enlarged fibers.
Fibrillation / Fasciculation
Fibrillation:
• Potentials arising spontaneously in single denervated muscle fibres.
• Due to denervation hypersensitivity.
• Disruption of nerve supply causes muscle atrophy but also leads to abnormal excitability of the muscle
due to increased sensitivity to circulating acetylcholine.
• This increased sensitivity is due to up-regulation of acetylicholine receptors on the muscle fibre membrane.
• Fibrillation occurs for several weeks and then ceases as the muscle cell atrophies.
• Not visible by the naked eye.
• Potentials are recorded from single muscle cells with the help of bipolar needle electrodes inserted into
the muscle.
Nerve & Muscle | 69
Fasciculation:
• Involuntary, jerky, visible contractions of one or more motor units.
• Occur due to abnormal and spontaneous discharge of spinal motor neurons.
• Common in lower motor neuron diseases.
• Spontaneous impulses arise as the distal axon atrophies. Until atrophy is complete, the muscle cells
composing the motor unit will contract in response to these spontaneous impulses.
• Visible grossly.
• These contractions are strong enough to allow measurement of potentials with skin electrodes.
Strength of Skeletal Muscles

Human skeletal muscle can exert 3 to 4 kg of tension per square centimeter of cross-
sectional area.
Training Induced Changes in Muscle Fiber Types
Endurance and resistance training cannot change fast fiber to slow type but does result
in shift from type IIB to type IIA i.e., towards more oxidative properties
AfraTafreeh.com
70 | Physiology
Worksheet
• MCQ OF “NERVE & MUSCLE” FROM DQB

AfraTafreeh.com


Nerve & Muscle | 71
Type I muscle fibre Type II muscle fibre
AfraTafreeh.com
72 | Physiology
Isotonic muscle contraction Isometric muscle contraction
AfraTafreeh.com
3 Kidney
CONCEPTS

Â Concept 3.2 Glomerular filtration

Â Concept 3.3 Renal handling of sodium

Â Concept 3.4 Renal handling of potassium

Â Concept 3.5
AfraTafreeh.com
Renal handling of glucose

Â Concept 3.6 Renal handling of water

Â Concept 3.7 Renal handling of H+

Â Concept 3.8 Renal handling of urea

Â Concept 3.9 Renal handling of phosphate

Â Concept 3.10 Renal handling of calcium

74 | Physiology
Concept 3.1: Functional Anatomy
Learning objectives:
At the end of this segment the student will be able to
• Enumerate functions of kidney
• Define nephron
• Enumerate differences between the cortical and juxtamedullary nephrons
• Parts of nephron
• Enumerate important histological features cells of different segments of tubule
• Enumerate layers of glomerular filtration membrane
• Understand why the basement membrane is the limiting factor for filtration
• Understand the importance of mesangial cells in regulating GFR
• Identify the factors which cause mesangial cell contraction and relaxation
• Identify the components of Juxtaglomerular apparatus
• Enumerate the agents causing constriction and dilatation of renal blood vessels
• Enumerate the effect of sympathetic stimulation on kidneys
• Differentiate between renal blood flow and renal plasma flow
Time Needed
1st reading 20 mins
2 look
nd
15 mins
AfraTafreeh.com
Functions of kidney
• Excretion of metabolic waste products (eg., urea, ammonia) and foreign chemicals
(such as drug metabolites)
• Regulation of water and electrolyte homeostasis
• Regulation of ECF volume (and therefore, blood pressure)
• Acid- base homeostasis
• Gluconeogenesis during fasting
• Endocrine functions- kidneys can secrete kinins, 1,25-dihydroxycholecalciferol,
erythropoeitin
Excretion = Filtration – Reabsorption + Secretion

Kidney | 75
Definition of nephron:
• Nephron is the structural and functional unit of the kidney.
• Nephron = Renal tubule + glomerulus.
• Each kidney has approximately 1 million nephrons.
• There are two types of nephrons- cortical and juxtamedullary.
Differences between cortical and juxtamedullary nephron:

Cortical nephron Juxtamedullary nephron
Form 85% of the nephrons Form 15% of the nephrons
Short loop of Henle Long loop of Henle
Peritubular capillary network is short Loops of henle associated with vasa recta
Blood flow is large Blood flow is less
O2 extraction is very less O2 extraction is large
PO2 is 50mmHg PO2 is 15mmHg
Major function- excretion of waste products in urine Concentration of urine by the counter current system
Parts of nephron:
AfraTafreeh.com
76 | Physiology
Differences between cells of PCT and CD
PCT CD
Brush border present Reduced or no brush border
Carbonic anhydrase present in luminal membrane No carbonic anhydrase in luminal membrane
Has ‘leaky’ tight junctions Has ‘tight’ tight junction
More mitochondria Fewer mitochondria
AfraTafreeh.com
Brush border “Leaky” tight junctions
PCT CD
Note: There are “tight junction” between the tubular epithelial cells towards the luminal side- the tight junctions are “leaky”
in the PT and “tight tight junctions” in the CD.
Cells in collecting tubule

(i) P (Principal) cell: Relatively tall with few organelles; For Na+ reabsorption and ADH
stimulated water reabsorption.
(ii) I (Intercalated) cell: Lesser in number, have more microvilli, cytoplasmic vesicles
and mitochondria; Concerned with acid secretion and HCO3- transport.
Kidney | 77
Glomerular filtration membrane
The total area of the glomerular membrane across which filtration takes place is about
0.8m2.
The barriers through which filtration has to take place
a. Glomerular endothelial cell layer- it is fenestrated (i.e., it contains pores with diameter
of 70-90nm) and is freely permeable to water, small solutes and even small proteins.
b. Basement membrane- consists of a matrix of glycoproteins and mucopolysaccharides;
composed of three layers: lamina rara externa or the outer cement layer, lamina
densa and lamina rara interna. It has no pores but its permeability corresponds to
pore size of 8nm.
c. Visceral epithelial layer of Bowman’s capsule. The visceral epithelial cell is called
a podocyte; each podocyte has many foot processes which inter digitate to form
filtration slits- of approximately 25nm in diameter.
Glomerular membrane permeability
Depends on
a. Size of particle
Substances which are < 8 nm are freely filtered and those > 8nm are not filtered at
all.
b. Charge of the particle
Since the sialoproteins in the glomerular capillary wall are negatively charged, filtration
of positively charged particles is facilitated whereas negatively charged particles are
AfraTafreeh.com
repelled. Neutral substances <4 nm in size are freely filtered but neutral substances
8 nms cannot be filtered at all. Albumin is 7 nm in diameter but since it carries a
negative charge it is not filtered at all.
Mesangial cells
Mesangial cells are present at 2 sites:
(i) Glomerular mesangial cells-
These cells lie in glomerular capillary loops between the basal lamina and
endothelium. They are contractile cells, receive sympathetic fibers and play a role
in regulation of glomerular filtration.
(Note: On sympathetic stimulation the mesangial cells contract, causing ‘kinking’
of glomerular capillaries and a decrease in GFR because the effective area of
filtration is reduced).
Other functions: mesangial cells secrete extracellular matrix, take up immune
complexes, and are involved in the progression of glomerular disease.
Agents causing mesangial cell contraction and relaxation

Agents causing mesangial cell contraction Agents causing mesangial cell relaxation
(and hence a reduction in GFR)
Endothelins ANP
Angiotensin II Dopamine
Vasopressin PGE2
Norepinephrine cAMP
78 | Physiology
Platelet activating factor

Platelet derived growth factor
Thrombaxane A2
PGF2
Leukotrienes C4 and D4
Histamine
(ii) Extra glomerular mesangial cells (Lacis cells)- these form part of the juxta –
glomerular apparatus
Renal medullary interstitial cells (RMICs)
• These are specialized fibroblast-like cells.
• They contain lipid droplets and are a major site of cycloxyegenase (COX-2) and
prostaglandin synthase (PGES) expression.
• They secrete PGE2 (also secreted by the macula densa and by cells of the collecting
ducts), which is a major regulator of salt and water homeostasis. PGE2 causes a
mesangial cell relaxation, increasing the GFR and sodium excretion.
Juxtaglomerular apparatus
Components are
(i) Juxtaglomerular cells
AfraTafreeh.com
These are modified smooth muscle cells in the tunica media of the afferent arteriole.
The cells have renin – containing granules. These cells secrete ReninQ.
(ii) Macula densa
This is the modified region of the tubular epithelium; it marks the beginning of DCT
(Macula Densa cells are derived from DCTQ)
(iii) Lacis cells or extra glomerular mesangial cells
Renal vessels / Renal nerves
Renal vasodilation is produced by- Dopamine, prostaglandins, acetyl choline, high
protein diet
Renal vasoconstriction is produced by-
(i) Angiotensin II
In low concentration, angiotensin II constricts efferent arteriole more than afferent
arteriole
In high concentration, angiotensin II constricts both afferent and efferent arteriole
(ii) Norepinephrine
Constricts afferent arteriole more than efferent arteriole
Effect of stimulation of sympathetic nerves to kidney
(i) Increases sensitivity of JG cells
(ii) Increases renin output
(iii) Increases Na+ reabsorption
(iv) Vasoconstriction- afferent arteriole > efferent arteriole (Which decreases renal
blood flow and GFR)
Kidney | 79
Pressure in the renal vessels
When the mean systemic arterial pressure is 100 mms Hg, glomerular capillary pressure
is 45 mms Hg (40% of arterial pressure- this is because the afferent arterioles are short,
straight branches of the interlobular arteries); pressure in efferent arteriole- 42-44 mms
Hg (drop of 1-3 mms of Hg); pressure in peritubular capillaries – 8 mms Hg; pressure
in renal vein- 4mms Hg
Capillary bed with the maximum hydrostatic pressure is the glomerular
capillary bed.
Kidney blood flow and O2 consumption

Weight = 300 GM
Renal Blood Flow
• Renal blood flow in mL/min- 1200-1300mL/min or slightly less than 25% of cardiac
output (24-25% of cardiac output)
• Renal blood flow per 100g per min- 420mL/100g/min
• Cortical blood flow- 500mL/100g/min (5mL/g/min)
• Blood flow in outer medulla- 250mL/100g/min (2.5mL/g/min)
• Blood flow in inner medulla- 60mL/100g/min (0.6ml/g/min)
• Of the total RBF, 90% perfuses the cortex, 10% perfuses the medulla (9% to outer
medulla and 1% to inner medulla)
Total 1200 mL/min or 420mL/100g/min
AfraTafreeh.com
Cortical 500 mL/100g/min or 5 mL/g/min (compared with 0.5mL/g/min in the brain)
Outer Med. 250 mL/100g/min or 2.5 mL/g/min
Inner Med. 60mL/100g/min or 0.6 mL/g/min
Effective Renal Plasma Flow (ERPF) = 625 mL/min (ERPF is determined by measuring
clearance of PAH)
Actual Renal Plasma Flow (RPF) = ERPF/ Extraction ratio of PAH = ERPF/ 0.9= 700 mL/
min
Renal Blood Flow = RPF × 1/1-Hct
O2 Consumption
Oxygen consumption by the kidneys per min- 18mL/min
• Oxygen consumption per 100g per minute- 6mL/100g/min
• Renal O2 consumption is very high (approximately 6mL/100g/min), being only second
to the heart (8mL/100g/min)
• Arterio venous oxygen difference in the kidney is 1.5mL/100g/min- this is the smallest
of the major organ systems in the body
• Oxygen consumption by cortex- 5.4mL/100g/min
• Oxygen consumption by medulla- 0.6mL/100g/min
• O2 consumption in the kidneys is directly proportional to the renal blood flow and
the renal arteriovenous O2 difference does not change with change in renal blood
flow. This is a unique feature of the kidneys, because in most other organs the A-V
O2 difference is inversely proportional to their blood flow. If the blood flow increases,
80 | Physiology
the arteriovenous O2 difference decreases and vice versa. Thus, unlike other organs,
where the blood flow is related to O2 requirements of the organ, in the kidneys, the
O2 consumption is a function of RBF.
Total 18 mL/min or 6mL/100g/min
Cortex 5.4 mL/100 gm/min
Inner Med. 0.6 mL/100 gm/min
(A-V) O2 Diff. = 1.5 ml/100g/min
Arterio venous oxygen difference for the whole kidney is 14mL/L of blood (compared
with 62mL/L for brain and 114mL/L for heart)
IMPORTANT POINTS
1. Total Blood Flow Liver > Kidney > Sk Muscle > Brain
mL/min (1500) (1200) (840) (750)
mL/100g/min Kidney > Heart > Liver > Brain
(420) (84) (58) (54)

2. A-V O2 Diff Heart > Brain > Sk muscle > Liver > Kidney
(mL/L of blood) (114) (62) (60) (34) (14)

3. O2 Consumption Liver > Sk muscle > Brain > Heart > Kidney
AfraTafreeh.com
(mL/min) (51) (50) (46) (29) (18)

4. O2 Consumption Heart > Kidney > Brain > Liver

(mL/100g/min) (9.7) (6) (3.3) (2.0)

Important questions from the above table:-

• Organ with maximum blood flow in ml/min- Liver
• Organ which receives the maximum blood flow per 100g of tissue- Kidney
• Organ with maximum arteriovenous difference at rest- Heart
• Organ with minimum arteriovenous oxygen difference- Kidney
• Organ with maximum oxygen consumption in ml/min- Liver
• Organ with maximum oxygen consumption in ml/min per 100gms of tissue- Heart
• PO2 of the cortex is about 50 mm of Hg whereas PO2 of the medulla is 15 mm of Hg.
• This is because relatively large amounts of O2 are extracted from the blood vessels in the medulla as there
is considerable metabolic work being done to reabsorb Na+ in the thick ascending limb of loop of henle.
This makes the medulla vulnerable to hypoxia.
Kidney | 81
Concept 3.2: Glomerular filtration
Learning objectives
• Enumerate the Starling’ forces responsible for filtration and understand the importance
of each
• Define filtered load and excretion rate
• Define clearance
• Understand that clearance is a mathematical concept used in assessment of renal
functions
• Understand free water clearance and its importance
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Glomerular Filtration
This is governed by the same forces (Starling’s forces) as that across capillary.
GFR = Kf [(PGC-PBC) + (pBC - pGC)]
Where Kf = filtration coefficient
PGC
AfraTafreeh.com
= Glomerular capillary hydrostatic pressure
PBC = Bowman’s capsule hydrostatic pressure
ΠBC = Bowman’s capsule colloid osmotic pressure
πGC = Glomerular capillary colloid osmotic pressure
(Hydrostatic pressure is a ‘push’ force and Oncotic pressure is a ‘retaining’ or ‘pull’ force)
Organ with the maximum Kf is the kidney.
Organ with maximum Pc is also the kidney.
The net filtration pressure is 15 mms of Hg at the afferent end of the glomerular
capillaries but it falls to zero, i.e., filtration equilibrium is reached- proximal to
the efferent end of the glomerular capillaries. This is because fluid leaves the
plasma and the plasma oncotic pressure rises as blood passes through the
glomerular capillaries.
Filtered load and excretion rate
Filtered load = GFR X Px; where Px is the plasma concentration of substance x
Amount excreted = Ux X V; where Ux is the urinary concentration of x and V is the rate of urine flow
Filtration fraction is the ratio of the GFR to the RPF. Normally, the filtration fraction is 0.16 to 0.20
or 16-20%.
82 | Physiology
Clearance
Definition: Clearance for a substance ‘A’ is defined as that volume of plasma that
is required to contain that much amount of the substance A which is present in one
minute’s urine or the volume of plasma from which a substance is removed by the
kidney in unit time. Its unit is mL/min
Formula
It is given by the formula:
U V
C = P×
×
Where
C = clearance
Ux = concentration of the substance in the urine
V = urine flow
Px = concentration of the substance in the plasma
Uses
• Clearance of Inulin gives GFR (125ml/min)
• Clearance of paramino hippuric acid (PAH) gives renal plasma flow (625 ml/min)
Since the extraction ratio (arterial concentration minus renal venous concentration
AfraTafreeh.com
divided by arterial concentration) of PAH is 0.9 (90%), the value obtained is effective
renal plasma flow (ERPF)
ERPF
The actual RPF =
0.9
Other Points
Clearance is just a mathematical (theoretical) concept e.g. Clearance of glucose is
normally zero because there is no glucose in the urine. It does not mean that no glucose
is filtered!
For any Substance X that is freely filtered at the glomerulus:
How can you say whether a substance has been reabsorbed / secreted?
If: Then:
Filtration is greater than excretion There is net reabsorption of X
Excretion is greater than filtration There is net secretion of X
Filtration and excretion rate are the same X passes through the nephron without reabsorption
or secretion
Significance of clearance
For example, the clearance of urea is 75mL/min, what is the actual meaning of this
number? What significance does this number have for you?
Kidney | 83
A urea clearance of 75mL/min means that 75mL of plasma is completely cleared of urea
in 1 minute by excreting urea in urine.
The following table can be used to determine whether a substance has been
reabsorbed or secreted from its clearance
Clearance of X is less than inulin clearance There is net reabsorption of X
Clearance of X is greater than inulin clearance There is net secretion of X
Clearance of X is equal to inulin clearance X is not reabsorbed or secreted
Free Water clearance (CH2O)

This is the difference between actual urine output and the urine output calculated based
on clearance of osmoles
That is,
Uosm × V
CH20 = V – where V = actual urine output/ rate of urine flow
Posm
(If the value of free water clearance is positive, the urine is hypotonic; if the
value is negative, the urine is hypertonic)
Important point:
Free water clearance equal to zero when the urine is isotonic with plasma.
AfraTafreeh.com
84 | Physiology
Concept 3.3: Renal handling of sodium
Learning objectives
• Calculate the filtered load of sodium
• Enumerate the mechanisms of sedum reabsorption in the luminal membrane of cells
in different segments of the nephron
• Understand tubuloglomerular feedback and glomerulotubular balance and their
importance in regulating GFR and sodium excretion
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Renal handling of sodium

• Sodium is freely filtered.
• Filtered load of sodium = GFR × plasma concentration of sodium
• = 180L/day × 140mMol/ L = 25,200 mMol/ day
• Since there is filtration of very large quantities of sodium, it needs to reabsorbed.
• Tubular reabsorption of sodium occurs in all parts of the tubule except the thin
descending part.
AfraTafreeh.com
• Transport of sodium on the basal side of cells to the plasma is by the sodium-
potassium ATPase pump.
Mechanisms of sodium transport across luminal membrane in different

segments of nephron are
PCT (67%) SGLT (Sodium glucose linked transport)
Na – Amino acid co transport
Na – Citrate / PO4 / SO4 / Lactate co transport
PST Cl– driven Na+ transport
DTS No reabsorption of Na+
ATS Passive
TAL (20%) Na+–K+–2Cl– co transport; Na–H exchange
DCT (7%) Na+–Cl– co transport
CD (5%) P cell (ENaC)
*P cell = principal cell; ENaC = Epithelial sodium channel
• Aldosterone acts on collecting duct to increase Na+ reabsorption.

• Aldosterone increases the number of open ENaCs in the luminal membrane and also
increases the number of Na+ – K+ ATPase pumps on the basolateral membrane
Kidney | 85
• Out of the total filtered load of Na+, 99.4% is reabsorbed → 65% in PCT; 25% in
Henle; 10% in DCT/CT.
• Na+ reabsorption is increased by aldosterone (which acts on collecting duct) and by
angiotensin II (which acts on PCT).
• PGE2, IL-1, ANP, ouabain, Endothelin cause natriuresis.
Tubuloglomerular feedback and Glomerulotubular balance

Tubuloglomerular feedback
• In TGF, feedback signals from the renal tubules in each nephron affect filtration in its
glomerulus.
• TGF helps maintain the constancy of the load delivered to the distal tubule.
• Sensor for TGF is the macula densa.
• ↑ in GFR→ ↑ in Na+ and Cl– in the thick ascending limb of loop of henle→ ↑ in entry
of Na+ and Cl– in the macula densa cells (via the Na-K-Cl co-transporter in the
apical membranes)→ ↑ in Na-K ATPase activity→ ↑ ATP hydrolysis→ ↑ in adenosine
formation→ adenosine acts on A1 receptors on the macula densa→ ↑ release of Ca++
which affects vascular smooth muscle in the afferent arteriole→ causes afferent
vasoconstriction→ ↓ in GFR.
Glomerulotubular balance
Known as the “third factor”- comes into play when autoregulation and TGF fail.
In GTB, increase in GFR results in an increase in reabsorption of solutes (mainly Na+),
AfraTafreeh.com
and consequently of water, primarily in the proximal tubule, so that in general the
percentage of the solute reabsorbed remains constant.
86 | Physiology
Concept 3.4: Renal handling of potassium
• Calculate the filtered load of potassium
• Understand the mechanisms of potassium reabsorption in PCT, TAL and its secretion
in late DCT and CD
• Understand the role of aldosterone in potassium secretion
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
Renal handling of Potassium

• K+ is the only electrolyte that is reabsorbed as well as secreted.
• Filtered load of potassium is very less in comparison to the filtered load of sodium.
• Filtered load of potassium = GFR X Plasma potassium = 180L/day X 4mMol/L =
720mMol/day.
• Reabsorption of potassium in PCT is both passive (by “solvent drag”) and active
(?pump).
• Reabsorption of potassium in TAL is by secondary active co-transport (Na+-K+-2Cl-
co=transport). AfraTafreeh.com
• Passively secreted in late DCT and CD, under the influence of aldosterone.
• More the secretion of aldosterone, more will be the secretion of potassium in CD.
• K+ secretion is decreased when the amount of Na+ reaching the DCT is small.
• K+ secretion is also decreased when the H+ secretion is increased
• (In DCT, Na+ is reabsorbed and K+ and H+ compete for their secretion for the amount
of Na+ reabsorbed).
• 65% of the K+ is reabsorbed in PCT, 25% in loop and < 10% reaches the distal
rephron.
• For K+ and H+, remember ‘hypokalemia causes alkalosis and hyperkalemia causes
acidosis’.
Kidney | 87
Concept 3.5: Renal handling of glucose
• Identify the mechanisms of glucose reabsorption in the PCT
• Understand the concept of TmG
• Understand the concept of splay
Time Needed
1st reading 05 mins
2 look
nd
03 mins
Glucose
• Glucose is freely filtered and completely reabsorbed in the PCT.
• Glucose is reabsorbed by secondary active transport on the luminal side and by
facilitated diffusion on the basal membrane.
• In early PCT, reabsorption is by SGLT-2 (sodium- glucose linked transport) on the
luminal membrane and Glut-2 on the basal membrane.
• In late PCT, reabsorption is by SGLT-1 (sodium- glucose linked transport) on the
luminal membrane and Glut-1 on the basal membrane.
• Most of the glucose reabsorption occurs in early PCT itself.
AfraTafreeh.com
• The TmG (tubular maximum for glucose i.e. the maximum rate of absorption of
glucose by the tubule) is 375 mg/min in males and 300mg/min in females.
• Given that the TmG is 375mg/min in males, by calculation, the renal threshold for
glucose in blood would be 300mg/dL.
• However, the actual value of renal Threshold is much less than this; it is 200mg/dL in
arterial and 180mg/dL in venous blood.
• This deviation in the renal threshold (from the calculated predicted value) in called
splay.
• The reason for splay is heterogeneity of nephrons (i.e. not all nephrons have TmG of
375 mg/min); further, not all nephrons are maximally active simultaneously.
88 | Physiology
Concept 3.6: Renal handling of water
• Enumerate the acquaporins indifferent segments of the nephron
• Enumerate the percentage of water reabsorption in different segments of the nephron
• Understand the change in tonicity along the nephron
• Understand the difference in permeability of the tubular segments to water and NaCl
• Understand the counter- current mechanism and its importance in concentration of
urine
• Enumerate the differences between water and osmotic diuresis
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Renal handling of water

• Water reabsorption is passive, following the osmotic gradient.
• The total glomerular filtered load is approximately 180L/day.
• Normal daily urine output is 1 – 1.5L/day.
AfraTafreeh.com
• The amount of urine output can vary from a minimum of 500mL per day (with
maximum possible urinary osmolality of 1200 mosm/L) when ADH secretion is
maximum to 23.3 Litres (osmolality of 50 mosm/L) when ADH is completely absent.
• Water reabsorption is facilitated by water channels (aquaporins).
• There are various types of aquaporins (till date 13 aquaporins have been cloned).
Only 4 aquaporins (aquaporin-1, aquaporin-2, aquaporin-3, aquaporin-4) play a key
role in kidney.
Acquaporins in different segments of the nephron

Type Site
Aquaporin 1 Both basolateral and apical membranes of PCT
Aquaporin 2 Luminal membrane of CD
Aquaporin 3 Basolateral membrane of CD
Aquaporin 4 Basolateral membrane of CD; brain
Aquaporin 5 Salivary, lacrimal, respiratory system
Aquaporin 9 WBCs, liver, lung and spleen
Percentage of water reabsorption in different segments of the nephron

a) PCT 66% (60-70%) – water reabsorption in PCT is k/a obligatory
reabsorption.
b) Loop of Henle 15%
Kidney | 89
c) Distal Tubule 20% (facultative reabsorption- under the influence of ADH)
(i) late DCT 5%
(ii) CD 13 – 15%
Cortical CD 10%
Medullary CD 5%
Changes in tonicity of tubular fluid in different segments of the nephron
(a) At the end of PCT : Isotonic
(b) As it goes down the descending limb : Hypertonic
(c) As it goes up the ascending limb : At first, isotonic, then hypotonic. At the
top of ascending limb, it is hypotonic
(The ascending limb is called the diluting
segment).
Permeability of the tubular segments to water and NaCl is as follows:

Water NaCL
a) Thin Descending Limb Highly permeable ±
b) Thin ascending limb Not permeable Highly permeable
c) Thick ascending limb (TAL) Not permeable ±
[However, TAL has Na+ - K+ - Cl– cotransporter]
AfraTafreeh.com
(d) The DCT is relatively impermeable to water (Therefore, there is continued dilution of
the tubular fluid as it goes along the DCT).
(e) Collecting Duct
It becomes permeable to water in the presence of ADH; ADH inserts aquaporin 2
channels in the luminal at membrane of collecting duct cells.
Counter current mechanism

There are 2 counter current mechanisms in kidney
(i) Counter current multiplier, in loop of Henle
(ii) Counter current exchanger, in vasa recta
The counter current mechanism depends on the gradient of osmolality in the
medullary interstitium. The medullary interstitial gradient depends on
(i) Active transport of Na+ at thick ascending limb (by Na+ - K+ - 2Cl- Co- transporter)
(ii) Passive movement of Na+/Cl- out of thin ascending limb without water
(Refer to the permeability characteristics of the tubule)
(iii) Permeability of thin descending limb to water
(iv) Urea, also contributes
The inner medullary collect duct is significantly permeable to urea; ADH
increase this permeability.
• The longer the loop of Henle, the greater can be the medullary interstitial osmotic
gradient created; thus, the concentration ability is determined by the length of the
loop of Henle.
90 | Physiology
• Once the interstitial osmotic gradient is established by the counter current multiplier,
it is maintained by the counter current exchange mechanism of the vasa recta;
without the counter current exchange mechanism, all the good work of the counter
current multiplier will soon be lost.
• The counter current multiplier mechanism is active whereas the counter current
exchange mechanism is passive.
• Once the medullary interstitial osmotic gradient is established, water can move from
the collecting duct in the presence of ADH
• Note that in the cortical collecting duct segment, the urine can at best be concentrated
up to isotonicity only; as it moves down the medullary collecting duct, the urine can
be concentrated up to the maximum limit determine a by the maximum gradient
existing in the medullary interstitium.
• Polyuria is urine output of >3L/day.
• Polyuria results from two potential mechanisms:
excretion of non- absorbable solutes (such as glucose)

excretion of water (neurogenic or nephrogenic diabetes insipidus).

• To distinguish a solute diuresis from a water diuresis, a urine osmolality is measured.
Difference between Water and Osmotic diuresis

Water diuresis Osmotic diuresis
i) Due to inadequate secretion of ADH (central D.I.) This is by osmosis
AfraTafreeh.com
or failure of kidneys to respond to ADH (nephrogenic
D.I.)
ii) Urine osmolality is < 300 mOsmol/L urine osmolality is > 300 mOsmol/L
ii) Absorption in PCT is normal Absorption in PCT is decreased
iii) Maximum limit of diuresis is 16ml/min No such limit
iv) Specific gravity of urine < 1.010 Specific gravity > 1.010
Kidney | 91
Concept 3.7: Renal handling of H+
• Enumerate the mechanisms of H+ secretion in different segments of the nephron
• Enumerate the urinary buffers
• Enumerate factors affecting H+ secretion
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Renal handling of Hydrogen ions

Occurs in PCT, late DCT and CD
Mechanisms
a) In PCT
Na+ - H+ exchanger

For each H+ that is secreted, effectively 1 Na+ and 1 HCO3- are reabsorbed.

(In PCT, H+ is generated by the reaction between H2O and CO2 in the presence of

carbonic anhydrase)
The secreted H+ in PCT does not acidify the urine; it only helps in the reabsorption

of Na+ and HCO3-. AfraTafreeh.com

Since the secretion H+ in the PCT is quickly handled, it is called a high-capacity,

low-gradient system in the PCT. i.e. the capacity of H+ secretion is high but
acidification of urine does not take place.
Reabsorption of HCO3–
At proximal tubule = net reabsorption of Na+ and HCO3–

The H+ is recycled across the luminal membrane on the Na+ – H+ exchanger
b) In late DCT and CD
(i) ATP – driven proton (H+) pump
92 | Physiology
(ii) H+ - K+ ATPase
▫ The secreted H+ here helps to acidify the urine.
▫ Since the secreted H+ is not as quickly handled (recall that there is no carbonic
anhydrase in the luminal membrane of DCT), the limit of H+ secretion is reached
quickly.
▫ Therefore, the H+ secretion here can be called a low-capacity, high-gradient
system, i.e., the capacity is low but the acidification is significant.
▫ Aldosterone increases H+ secretion in late DCT and CD.
Urinary buffers
Type of buffer PK Sites
Bicarbonate 6.1 In PCT, it is mostly bicarbonate buffer
Phosphate 6.8 In DCT/CD
Ammonia 9.0 Both PCT & DCT
Phosphate buffer
AfraTafreeh.com
Ammonia buffer
Kidney | 93
Limiting pH of urine = 4.5
Factors affecting acid secretion
• Intracellular PCO2- when PCO2 in high, acid secretion is increased.
• K+ depletion- this increases acid secretion.
Note: Hypokalemia tends to cause alkalosis and vice versa.

Hyperkalemia tends to cause acidosis and vice versa (not always)

• Carbonic anhydrase inhibitors inhibit the action of carbonic anhydrase and acid
secretion is decreased.
• Aldosterone- this increases Na+ reabsorption and increases K+ and H+ secretion.
AfraTafreeh.com
94 | Physiology
Concept 3.8: Renal handling of urea
Learning objectives
• Understand urea handling in different segments of the nephron
• Understand the concept of urea cycling and its role in increasing osmolality of the
medullary interstitium
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Renal handling of urea

• In the PCT, 52% (40 to 50%) of the filtered urea is reabsorbed.
• TAL, DT and cortical CD are impermeable to urea.
• Water is reabsorbed in these areas leading to an increase in concentration of urea in
the tubular fluid.
• Urea passively reabsorbed from the inner medullary collecting ducts into the
interstitium.
• High concentration of urea in the inner medullary collecting duct causes urea to
diffuse out of the tubule into the renal interstitium with the help of specific urea
transporters (urea transporter UT-AI is activated by ADH- ADH increases reabsorption
of both water and urea). AfraTafreeh.com
• In ATS- urea re-enters the tubule from the medullary interstitium.
• The process of urea entering into the medullary interstitium from the medullary CD,
increasing the medullary interstitial osmolality and then re-entering the nephron via
the ATS is k/a urea cycling.
Final excretion of urea- 20 to 50% of the filtered load.
Kidney | 95
• Recirculation of urea absorbed from the medullary collecting duct into the interstitial fluid- urea diffuses
into the thin loop of Henle, and then passes through the distal tubules, and finally passes back into the
collecting duct.
• The recirculation of urea helps to trap urea in the renal medulla and contributes to the hyperosmolarity
of the renal medulla.
• The heavy dark lines, from the thick ascending loop of Henle to the medullary collecting ducts, indicate
that these segments are not very permeable to urea. (Numerical values are in milliosmoles per liter of urea
during antidiuresis, when large amounts of antidiuretic hormone are present. Percentages of the filtered
load of urea that remain in the tubules are indicated in the boxes.)
AfraTafreeh.com
96 | Physiology
Concept 3.9: Renal handling of phosphate
Learning objectives: To appreciate the effect of PTH on phosphate reabsorption
Time Needed
1st reading 01 mins
2 look
nd
05 seconds
• 85% of the filtered load is reabsorbed in the proximal tubule

• Rest 15% is excreted
• Regulation: Parathyroid hormone inhibits the Na+ phosphate cotransporter and stops phosphate
reabsorption and causes phosphaturia
AfraTafreeh.com
Kidney | 97
Concept 3.10: Renal handling of calcium
Learning objectives: to recognize the sites and mechanisms of calcium reabsorption
Time Needed
1st reading 03 mins
2 look
nd
01 minute
• Parallels Na+ reabsorption

• Regulation : Parathyroid hormone and thiazide diuretics increase Ca2+ reabsorption (given for idiopathic
hypercalciuria)
• Furosemide inhibits Ca2+ reabsorption
AfraTafreeh.com
Renal handling of magnesium

• Reabsorbed in the PCT (30%), Thick ascending limb (maximum - 60%) and Distal tubule (5%)
• Amount excreted - 5%
• Furosemide inhibits Mg2+ reabsorption at thick ascending limb
98 | Physiology
Worksheet
• MCQ OF “KIDNEY” FROM DQB

AfraTafreeh.com


Kidney | 99
Cortical nephron Juxtamedullary nephron
Agents causing mesangial cell contraction

Agents causing mesangial cell relaxation
AfraTafreeh.com
100 | Physiology
Nephron segment Mechanism of sodium reabsorption
AfraTafreeh.com
4 Cardiovascular System
CONCEPTS
Â Concept 4.1 Cardiac muscle

Â Concept 4.2 Origin and conduction of the cardiac

impulse
Â Concept 4.3 ECG

Â Concept 4.4 Cardiac cycle

Â Concept 4.5 Cardiac output

Â Concept 4.6 Myocardial oxygen demand
AfraTafreeh.com

Â Concept 4.7 Blood vessels

Â Concept 4.8 Hemodynamics

Â Concept 4.9 Cardiovascular regulation

Â Concept 4.10 Vasomotor centre

Â Concept 4.11 Regulation of blood pressure

Â Concept 4.12 Cardiovascular reflexes

Â Concept 4.13 Sinus arrhythmia

Â Concept 4.14 Blood pressure waves

Â Concept 4.15 Effect of Valsalva on blood pressure and

heart rate
Â Concept 4.16 Cardiovascular response to exercise

102 | Physiology
Concept 4.1 : Cardiac muscle
Learning Objectives: - To understand
• Functional histology of cardiac muscle
• Electric activity in cardiac muscle, including the plateau potential and pacemaker
potential
• Effect of vagal stimulation on pacemaker potential
• Effect of sympathetic stimulation on pacemaker potential
• Concepts of after depolarization or after potentials
• Mechanism of contraction and relaxation of cardiac muscle
• Relationship between electrical and mechanical events in cardiac muscle
• Significance of the length- tension relationship in the heart
Time Needed
1 reading
st
20 mins
2 look
nd
15 mins
Functional histology
• Cardiac muscle fibers branch and interdigitate.
• Intercalated discs are present at Z-lines; Intercalated discs provide a strong union
between fibers, maintaining cell-to-cell cohesion, so that the pull of one contractile
AfraTafreeh.com
cell can be transmitted along its axis to the next.
• Gap junctions are present at Z-line. Gap junctions are made of proteins k/a connexons.
Gap junction of one cell is in alignment with the gap junction of the neighboring cell,
so that ions, molecules can be easily transferred from one cell to the next. Electrical
coupling between cells is by means of these gap junctions.
• The T-tubule system is at Z lines (In skeletal muscle it is at A-I band function).
Cardiovascular System | 103
Conducting system of the heart:-

1. SA Node (which is the normal
pacemaker of the heart)
2.
Anterior internodal tract of
Bachmann, middle internodal
tract of Wenckebach and
posterior internodal tract of
Thorel
3. AV Node
4. Bundle of His
5. Right and left bundle branches
6. Purkinje fibers
**Conducting cells are nothing but modified contractile cells.
Electrical activity in cardiac muscle

This is different in the pacemaker and contractile cells
AfraTafreeh.com
Plateau potential in ventricular muscle (also known as the fast response)
RMP of myocardial cell is -90mV
The cardiac action potential has five phases:-

a. Rapid depolarization phase or phase 0- this is due to Na+ influx through rapidly
opening Na+ channels or fast sodium channels
b. An initial rapid repolarization phase or phase 1- this is due to inactivation of Na+
channels and opening of K+ channels
104 | Physiology
c. Plateau phase or phase 2- this is due to Ca++ influx through more slowly opening Ca++
channels (called slow calcium channels or slow calcium-sodium channels, since a large
quantity of both calcium and sodium ions flow through these channels to the interior
of the cardiac muscle fiber maintaining a prolonged period of depolarization causing
the plateau). During this phase there is a fivefold decrease in the permeability of the
cardiac muscle membrane for potassium ions, probably due to entry of calcium ions,
resulting in a decreased efflux of potassium. The slow calcium channels close at the
end of 0.2 to 0.3 seconds- the influx of calcium and sodium stops and the membrane
permeability for potassium increases rapidly
d. Slow repolarization phase or phase 3- this is due to net K+ efflux through multiple
types of K+ channels
e. In phase 4 the potential returns to the resting membrane potential
Pacemaker potential (also known as the slow response)
Action Potential of SA node (slow response):
AfraTafreeh.com
The pacemaker potential has three phases:-

Phase 0 or the depolarization phase is produced by the influx of Ca++ due to opening of
Ca-L channels (L for long lasting)
Phase 1 and 2 are absent
Phase 3- at the peak of phase 0, K+ efflux begins through slow potassium channels
Phase 4- due to
1. decline in efflux of K+
2. opening of the “h” (“h” for hyperpolarization) or the “f” (“f” for funny because of its
unusual activation) channel- a channel that can pass both Na+ and K+, and
3. Ca++ influx through Ca++- T channels (T for transient). There is local Ca++ release from
the sarcoplasmic reticulum (Ca++ sparks) that occurs during the pre-potential phase.
Effect of vagal stimulation on the pacemaker potential (SAN)
a. Stimulation of M2 muscarinic receptors, which, via the βγ subunit of the G protein,
causes the opening of a special set of K+ channels→ this results in a slowing of the
depolarizing effect of opening of Ih→ Membrane becomes hyperpolarized and slope of
pre-potential phase is decreased, decreasing the rate of discharge of SA node.
b. Activation of M2 receptors decreases cAMP in the cells and this slows the opening of
the Ca++ channels- this results in a decrease in firing rate
Normal heart rate
AfraTafreeh.com Heart rate after

parasympathetic
stimulation
Effect of sympathetic stimulation on pacemaker potential (SAN)

a. Stimulation of sympathetic cardiac nerves speeds the depolarizing effect of Ih→ rate
of spontaneous discharge increases
b. Norepinephrine binds to β1 receptors results in an increase in intracellular cAMP-
this facilitates the opening of the L channels→ increases ICa→ increases rapidity of
depolarization in phase 0→ increases heart rate
Normal heart rate

106 | Physiology
Heart rate after

sympathetic
stimulation
After depolarization or After potentials

Introduction: It’s occurrence is abnormal. As the name suggests, these are basically
potentials or depolarisations that develop after a conducted action potential.
Classification: Depending on which phase of the ventricular action potential the after
depolarisations occur, it can be classified as
1. Early after depolarisations (EAD)
2. Late after depolarisations (DAD)
Significance: Both EAD and DAD can set up tachycardia. They can do this either on
their own or because they can trigger an activity in an already formed automatic tissue
(secondary to ischaemia is an infarcted tissue etc.)
EAD: Appears at the end of phase 2 or in phase 3 of the ventricular action potential.
AfraTafreeh.com
They are associated with prolonged Q-T interval i.e. it tends to occur at slower heart
rates. Thus, quinidine, which decreases the heart rate, can actually set up tachycardia
(by causing EADs); this is called torsades de pointes. The exact cause of EAD is not
known.
DAD: Appears near the very end of phase 3 or beginning of phase 4 of ventricular
action potential. They are exaggerated by tachycardia. The cause is due to increased
intracellular calcium; this induces a transient diastolic inward current, possibly by
promoting Na-Ca exchanger. The current causing the repetitive after depolarization is
switched on by an increased intracellular calcium level. Therefore, the Ca++ antagonist
verapamil and a low external Ca++ level both inhibit DAD. DADs are thought to be
underlying the development of ventricular automaticity during digitalis poisoning.
Mechanism of contraction and relaxation of cardiac muscle

• This is similar to skeletal muscle, with some important differences. The dihydropyridine
receptor on the t-tubule membrane is a voltage gated Ca channel and the source of
calcium in cardiac muscle is ECF (mainly) and sarcoplasmic reticulum.
• The T tubules are wide and filled with mucopolysaccharides that are negatively
charged and bind an abundant store of calcium ions, keeping these always available
for diffusion to the interior of the cardiac muscle fiber when a T-tubule action potential
appears.
• There is also the phenomenon of calcium triggered calcium release (or calcium-induced
calcium release). This means that Ca++ entry from ECF into the cardiac muscle cell
through the DHPR on the t-tubule membrane activates the calcium release channels
(also k/a as ryanodine receptor channels), triggering the release of more Ca++from
the sarcoplasmic reticulum.
• Calcium ions in the sarcoplasm then interact with troponin to initiate cross bridge
formation and contraction (similar to that described in skeletal muscle).
Relaxation
Na+- Ca++ antiport/ exchange

in cardiac muscle cell
Relaxation is by decreasing the cytosolic Ca++ level by

AfraTafreeh.com
1. Ca++ ATPase pump in sarcoplasmic reticulum(known as SERCA pump- sarcoplasmic
or endoplasmic reticulum Ca++ ATPase pump; SERCA is a Ca++ stimulated Mg-ATPase
which spans the membrane of the sarcoplasmic reticulum and is responsible for the
rapid reuptake of Ca++ from the cytoplasm into the sarcoplasmic reticulum), which
pumps Ca++ back into the sarcoplasmic reticulum.
2. Ca++ Na+ antiport/ exchange which results in movement of Ca++ into the ECF.
Phospholamban is a protein associated with SERCA. Phospholamban typically

inhibits SERCA activity. This activity of phospholamban is inhibited by its

phosphorylation.
Increased level of adrenal medullary Epinephrine or increased NE from sympathetic

nerve endings activates β- adrenergic receptors on cardiac muscle cells. This in

turn activates adenylcyclase enzyme resulting in an increase in cAMP. This causes
phosphorylation of phospholamban. Phosphorylation of phospholamban by a
cAMP- dependent protein kinase inhibits the activity of phospholamban. Inhibition
of phospholamban causes increased activity of SERCA.
Increased activity of SERCA facilitates (i) Relaxation of heart because of rapid

calcium uptake by SERCA (ii) Increased force of contraction because more calcium
is available for release during the next contraction, and (iii) Decreased duration of
contraction because of rapid reaccumulation of calcium by sarcoplasmic reticulum.
Relationship between electrical and mechanical events
The action potential in ventricular muscle fibers is prolonged one and therefore the
refractory period is also relatively prolonged- it remains relatively refractory until phase
4. This is the reason as to why cardiac muscle cannot be tetanised.
108 | Physiology
Length – tension relationship

Within physiologic limits, force of contraction (as reflected by stroke volume) is directly
proportional to the initial length of the muscle fiber (as determined by the end-diastolic
AfraTafreeh.com
volume). This is known as the Frank-starling’s law.
Frank-Starling’s curve or Cardiac function curve
•There is a curvilinear
relationship between
CO and EDV
Cardiac output
Stroke volume
•Curve informs about the

or
ventricular pumping capacity

at different ventricular filling
End diastolic volume (EDV)

or
Right atrial pressure (RAP)
Concept 4.2 : Origin and conduction of the cardiac impulse
Learning Objectives: - To understand
• SA node is the normal pacemaker of the heart
• Innervation of SAN and AVN
• Effect of vagal and sympathetic stimulation
• Conduction speeds in different parts of the heart
• Ventricular depolarization and repolarization
Time Needed
1 reading
st
20 mins
2nd look 15 mins
SA Node is the normal pacemaker of the heart

• Heart has the property of automaticity. That is, any part of the heart can become the
pacemaker.
• Though there are ‘latent pacemakers’ in other portions of the conducting system, the
SA node is the normal pacemaker of the heart as the SA node has the maximum rate
of discharge.
• SA node is situated at the junction of superior vena cava and right atrium.
• AV node is situated in the right posterior portion of the inter atrial septum.
AfraTafreeh.com
Innervation of SA node & AV node
SA node AV node
Parasympathetic Right vagus Left vagus
Sympathetic Right stellate ganglion Left stellate ganglion
Effect of vagal and sympathetic stimulation

Right vagus Inhibits SA node ↓es heart rate (can even stop the firing)
Left vagus Inhibits AV node Inhibits A-V conduction to produce varying degrees
of heart block
Right stellate ganglion Stimulates SA node ↑es heart rate
Left stellate ganglion Stimulate AV node Shortens AV conduction time and refractoriness
• Parasympathetic tone usually predominates in healthy, resting individuals (called
“resting vagal tone”.
• When a resting individual is given atropine (muscarinic receptor antagonist) there is
a substantial increase in heart rate but if a resting individual is given propranolol the
heart rate decreases only slightly.
• When both divisions of the autonomic nervous system are blocked, the heart rate is
about 100 beats per minute.
• The rate that prevails after complete autonomic blockade is called the intrinsic heart
rate. (A transplanted heart, therefore, beats at a rate of 100 per minuteQ).
110 | Physiology
Conductions Speeds
Tissue Conduction rate (m/s)
SA node 0.05
Atrial pathways 1
AV node 0.05 (SLOWEST)
Bundle of His 1
Purkinje system 4 (FASTEST)
Venticular muscle 1
Ventricular depolarization and repolarization

Spread of cardiac excitation – (Depolarization begins in SA node)
a) Ventricular depolarization-
First part of the ventricle to get depolarized is the left endocardial surface of the
interventricular system; then the right endocardial surface of the interventricular
septum (spread of depolarization in the inter ventricular septum is from left
to right) across the mid portion of the septum. It then passes down the septum
to the apex of the heart and then through the rapidly conducting Purkinje system
depolarizing all parts of the ventricles. Spread of depolarization is from the
endocardium to epicardium. Last parts of the heart to be depolarized are the
AfraTafreeh.com
posterobasal portion of the left ventricle (base of heart), the pulmonary conus, and
the uppermost portion of the interventricular septum.
Transmission of cardiac impulse through
the heart, showing the time of appearance
(in fractions of a second after the initial
appearance at the SA Node) in different
parts of the heart. AV nodal delay is 0.09
to 0.1s. Note the total delay at the AV node
and bundle of His is 0.13s, so that the im-
pulse reaches the two bundle branches at
0.16s from start. Cause of nodal delay: AV
nodal fibers are smaller and sparsely stri-
ated with diminished number of gap junc-
tions between successive cells. They are less
conductive due to high internal resistance.
b) Ventricular repolarisation- The apical epicardial surface is the first to repolarise;

the base endocardial surface is the last to repolarise (repolarization is from epi
to endocardium in an intact heart)
Concept 4.3 : ECG
Learning objectives: To understand
• Difference between bipolar and unipolar limb and chest leads
• Einthoven’s law
• Hexaxial system
• Calculation of mean electrical axis of heart
• Definition and duration of various intervals on ECG
• ECG in abnormal conditions
• His bundle electrogram
Time Needed
1 reading
st
20 mins
2 look
nd
15 mins
ECG (Standard 12 lead ECG)

• The body is a volume conductor and therefore, potential fluctuations during the
cardiac cycle can be recorded on the surface as an electrocardiogram.
• ECG is recorded by using an active or exploring electrode connected to an indifferent
electrode at zero potential (unipolar recording) or by using two active electrodes
(bipolar recording).
AfraTafreeh.com
The bipolar leads measure the potential difference between two points whereas
the unipolar leads measure the actual potential at that point.
In a standard 12- lead ECG, there are
• 3 bipolar limb leads viz lead I, II, III (also called standard limb leads).
• 3 unipolar (augmented) limb leads viz., aVR, aVL, aVF.
• 6 unipolar chest leads viz., V1 to V6.
Bipolar limb leads – the connections of the bipolar limb leads are as follows :
RA – I + LA +
– – RA- Right arm
LA- Left arm
LL- Left leg
II III The three electrode locations form
the points of an equilateral triangle
(Einthoven’s triangle) and the heart
lies in the center of the triangle
+ +
LL
For example, lead I is between LA and RA, with the LA ‘positive’ and RA ‘negative’. The
direction of the lead axis is taken from negative to positive (the arrow indicates the
direction of lead II).
Einthoven’s law: Mean deflection is lead II = Mean deflection in lead I + Mean
deflection in lead III i.e., II = I + III
112 | Physiology
The basic electrical recording principles are:-
1. If the direction of the cardiac impulse is towards the recording electrode, a positive
(upward) deflection is recorded; if it is moving away from the recording electrode, a
negative (downward) deflection is recorded.
2. The height of deflection depends on
a. The strength of the cardiac impulse vector.
b. Orientation of the vector to the lead axis. If it is parallel, it records maximum
deflection; if it is perpendicular, it records minimum deflection.
In the unipolar leads, one electrode that is kept at the point where the potential is to
be measured is called the exploring electrode. The other electrode (called indifferent
electrode) is kept at near zero potential.
• In Augmented unipolar limb leads- two limbs are connected through a very high
electrical resistance (5000 ohm) to the negative terminal –this is the indifferent
electrode, third limb is connected to the positive terminal- this is the exploring
electrode. The augmented leads do not use the “V” electrode as the zero, rather they
are recordings between the one, augmented limb and the other two limbs.
• In unipolar chest leads (V1- V6) - one electrode on anterior surface of heart is
connected to positive terminal of the ECG (exploring/ reference/ positive electrode),
second/ indifferent/ reference electrode to negative terminal. Reference electrode
is connected to RA, LA, LL through high resistance; also called central terminal of
Wilson and is considered to be at zero potential
AfraTafreeh.com
Hexaxial system- Axes of the bipolar and unipolar limb leads

The axes of the limb leads helps to explain why there
is maximum deflection in lead II- the mean electrical
axis is almost parallel to axis of lead II- (height of
deflection depends on the orientation of the vector to
the lead axis- if it is parallel it records the maximum
deflection, if it is perpendicular, it records the
minimum deflection)
From this one can also understand why all the
deflections in lead aVR are negative.
Mean electrical axis of heart
The bipolar limb leads are used to calculate the mean electrical axis of the heart- Average
direction of flow of current is called the electrical axis of heart.
To calculate the electrical axis of the heart:-
• ECG records from leads I and III are taken
• Net QRS deflection is measured in the two leads
• Net deflection is plotted on the axes of the two
leads
• Perpendiculars are dropped from the apices of the
projected vectors on the two lead axes
• Point of intersection of the two perpendiculars
represents the apex of the actual QRS vector
• Apex of the actual QRS vector is joined to the
point of intersection of the two lead axes- this is
the electrical axis of the heart
The normal direction of the mean QRS vector is generally between- 300 to +1100.
Normally, the maximum deflection is recorded in lead II because the direction of the
mean QRS vector is most parallel to lead II.
AfraTafreeh.com
I
II
III
If there is a left ventricular hypertrophy, the vector will ‘shift’ in the direction shown
by dotted arrow; in which case, the vector would become most parallel to lead I. So, if
one wants to know the value of vector, the vector can be ‘superimposed’ on the triaxial
system.
I I
III II III II
Value of V = +150 0
Value of V = -30 or +3300
0
114 | Physiology
Causes of Right Axis deviation (Big S in Lead I and a big R in Lead III)
RVH (Mitral Stenosis, Emphysema)
Left posterior fascicular block
Causes of Left Axis deviation (Tall R in Lead I and a big S in Lead III)
LVH (Chronic hypertension, Aortic Incompetence)
Some generalizations in normal ECG

Lead Feature(s)
aVR All the deflections are negative
aVL / aVF Predominantly positive or biphasic
V1 , V 2 No Q wave; deep S wave
V3 , V 4 Biphasic
V5 , V 6 Small Q wave, Tall R wave
Lead I, II, III All positive deflection; largest in lead II
Definition and duration of different interval on ECG

AfraTafreeh.com
Normal duration (s)
Intervals Average Range Events in the heart during
interval
PR interval (from the 0.18 0.12- 0.20 Atrial depolarization and
beginning of P wave conduction through AV Node
to the beginning of the (PR interval shortens as heart rate
QRS complex) increases from average of 0.18s at a
rate of 70 beats per minute to 0.14s
at a rate of 130 beats per minute)
QRS duration 0.08 to 0.10 Ventricular depolarization and
atrial repolarization
QT interval 0.40 To 0.43 Ventricular depolarization plus
ventricular repolarization
ST interval (QT minus 0.32 Ventricular repolarization
QRS)
• PR interval is measured from the beginning of the P wave to the beginning of the QRS
complex.
• PR interval shortens as heart rate increases from average of 0.18s at the rate of 70
beats/ min to 0.14s at a rate of 130 beats/min.
• J point is at the end of S wave (Zero potential).
ECG in some abnormal conditions:
i) Accelerated A-V conduction:
Wolff- Parkinson White Syndrome

▫ Short P- R interval

▫ Prolonged QRS deflection, which is slurred on the upstroke

▫ P- J interval is normal

Lown- Ganong- Levine syndrome

▫ Short P - R interval

▫ Normal QRS

▫ P – J interval is decreases

ii) Myocardial infarction
AfraTafreeh.com
A. Normal ECG prior to MI

B. Hyperacute T wave changes - increased T wave amplitude and width; also mild ST
elevation
C. Marked ST elevation with hyperacute T wave changes
D. Pathologic Q waves, less ST elevation
E. Pathologic Q waves, T wave inversion
F. Pathologic Q waves, upright T waves (fibrosis, old infarct)
a) Changes due to current of injury – ST segment elevation. This is most noticeable
in chest leads just over the infarcted area (current of injury: the infarcted area is
negative (extra cellularly) relative to the surrounding area; this results in flow of
current into the infarcted area from the surrounding areas).
The ST segment elevation is because of 3 basic abnormalities of cardiac
muscle in M.I
Rapid repolarization (seconds after the infarct).
↓in RMP (minutes after the infarct)
Delayed depolarization (half an hour after infarct).
116 | Physiology
b) Changes due to electrical silence –(after days/ weeks, the infarct becomes
electrically silent):
▫ Q wave changes.
▫ R wave changes (failure of progression).
c) Changes due to conduction abnormalities
▫ Heart block.
▫ Arrhythmias (due to reentry and increased automaticity).
iii) Effect of dyselectrolytemia on ECG:
Effect of hyponatremia: Causes low voltage ECG
Effect of hyperkalemia:
• Abnormal repolarization of myocardium.
• At extremely higher level, myocardium is unexcitable.
• Since the RMP ↓es as ECF K+ ↑es, heart stops in diastole.
• ECG changes: Tall peaked T waves (defective repolarization).
• At higher levels: Paralysis of atria, prolonged QRS, ventricular arrhythmias.
AfraTafreeh.com
Effect of hypokalemia:
• Produces hyperpolarization of resting membrane potential in myocardial cells of the
whole heart
• Decreased excitability of the myocardial cells
• ECG changes: Prolongation of PR interval; prolonged QRS
Prominent U waves
Flat T wave or inversion of T wave
Effect of hypercalcemia: increases myocardial contractility; if large amount of calcium

is infused in experimental animals, and the heart stops in systole (calcium rigor).
Effect of hypocalcemia
• ST segment prolongation
• QT interval prolongation
AfraTafreeh.com
His Bundle Electrogram (HBE)
This is used to study events in the:
• AV node
• Bundle of His
• Purkinje system
The HBE is recorded with the help of a catheter containing an electrode at its tip

that is passed through a vein to the right side of the heart and manipulated into
position close to the tricuspid valve.
Three or more standard electrographic leads are recorded simultaneously- the

record of the electrical activity obtained with the catheter is known as the His
bundle electrogram (HBE)
There are 3 waves in HBE: A deflection, H spike, V deflection

118 | Physiology
Wave Denotes
A deflection AV nodal activation
H spike Transmission through bundle of His
V deflection Ventricular depolarization
There are 3 intervals described (marked with the help of HBE and standard
(ECG) :
Interval From – to Represents
PA (27 ms or 0.023s) First appearance of atrial Conduction time from SA node to AV node
depolarization to ‘A’ wave in HBE
AH (92 ms or 0.092s) ‘A’ wave to start of ‘H’ AV node conduction time
HV (43 ms or 0.043s) Start of ‘H’ to start of QRS Conduction in bundle of His and branches
[Note that PA + AH + HV internal = PR interval]

From the HBE, a distinction can be made between supra ventricular tachycardia
(H spike present) and ventricular tachycardia (No H spike)
AfraTafreeh.com
Concept 4.4 : Cardiac cycle
• To enumerate and understand
The mechanical events in the cardiac cycle

Phases in the cardiac cycle

• To understand the LV pressure, aortic pressure, atrial pressure and LV volume changes
in different phases of the cardiac cycle as seen in the Wigger’s diagram
• To correlate ECG and heart sounds in the cardiac cycle on the Wigger’s diagram
• To define and illustrate QS2, LVET and PEP on the Wigger’s diagram
• To understand the LV pressure and LV volume changes in the LV pressure- volume
loop
• To understand the arterial pulse and its significance
Time Needed
1 reading
st
20 mins
2 look
nd
15 mins
Mechanical events in the cardiac cycle

Note that mechanical events follow electrical events;
Atrial systole starts after ‘P’ wave and ventricular systole starts near the end of ‘R’ wave
and ends just after ‘T’ wave. AfraTafreeh.com
Duration of 1 cardiac cycle = 0.8 second
Ventricular systole = 0.3 second
Ventricular diastole = 0.5 second
Atrial systole = 0.1 second
Atrial diastole = 0.7 second
Phases in the cardiac cycle:
Ventricular systole

▫ Isovolumetric contraction

▫ Phase of rapid ejection

▫ Slow ejection phase

Ventricular diastole

▫ Isovolumetric relaxation

▫ Rapid filling phase

▫ Slow filling phase(diastasis)

(70% of the ventricular filling is passive; 30% is because of atrial contraction)

Note that during isovolumetric phase, all the 4 valves are closed.
Protodiastole- seen in early diastole; once the ventricular muscle is fully contracted
the already falling ventricular pressures drop more rapidly; lasts 0.4 seconds; ends
when the momentum of the blood is overcome and aortic and pulmonary valves close.
Closure of these valves marks the onset of iso volumetric relaxation.
120 | Physiology
Wigger’s diagram showing changes in LV pressure, aortic pressure, atrial
pressure, LV volume, ECG and heart sounds in the cardiac cycle
AfraTafreeh.com
Aortic pressure changes in the cardiac cycle

• Aortic pressure changes closely follow the LV pressure changes but the aortic presure
will vary from a mximum of 120mm Hg during systole and a minimum of 80mm Hg
during diastole.
• The incisura on the aortic pressure cuve (also k/a as dicrotic notch on the carotid
pressure curve) coincides with the closure of the aortic valve.
• A small oscillation on the falling phase of the pulse wave caused by vibrations set up
when the aortic valve snaps shut is visible as the incisura on the aortic pressure curve
or dicrotic notch on the carotid pressure curve (but is not palable at the wrist).
• The incisura is caused by a short period of backward flow of blood immediately before
the closure of the valve, followed by a sudden cessation of the backflow.
Heart Sounds with the cardiac cycle
• S1 Due to closure of A-V valves, marks the onset of systole
• S2 Due to closure of semilunar valves, marks the end of systole
• S3 Heard in first rapid ventricular filling
• S4 Heard in second rapid filling phase; usually pathological- heard when
the atrial pressure is high or the ventricle is stiff as in ventricular
hypertrophy
• S3 is heard in overloaded hearts, as in CCF, when the ventricular volume is very large
and the ventricular walls are stretched maximally. When S3 and S4 (due to atrial
contraction) are accentuated as in heart failure, triplets of sounds resembling the
sound of a galloping horse (called gallop rhythm) may occur.
JVP changes in the cardiac cycle
• The right atrial pressure changes during the cardiac cycle can be seen in the right
internal jugular vein (k/a JVP).
• JVP is better seen than felt.
• JVP has multiple positive and multiple negative waves.
• It has a definite upper level.
• The upper level rises if one presses on the liver (hepatojugular reflux).
Waves Due to
a Atrial systole
c Bulging of the closed tricuspid valve into right atrium during isovolumetric ventricular
contraction produces a positive wave in the JVP seen as the c wave
x descent: AfraTafreeh.com
Downward pull of the closed tricuspid valve during rapid ejection phase of ventricular
systole
v Filing of right atrium just before the tricuspid valve opens in diastole
y descent Due to rapid flow of blood from the RA into the RV during the first rapid ventricular filling
phase
Some abnormalities in JVP:-

• Giant ‘c’ wave: Seen in tricuspid regurgitation
• Giant ‘a’ wave: Seen in complete heart block
QS2, LVET and PEP
The following can be obtained by recording the ECG, phonocardiogram, and the
carotid pulse simultaneously:-
• Total electromechanical systole (QS2)- this is the period from the onset of the QRS
complex to the closure of the aortic valve, as determined by the onset of second heart
sound
• Left ventricular ejection time (LVET)- this is the period from the beginning of carotid
pressure rise to the dicrotic notch
• Pre ejection period (PEP)- this is the difference between QS2 and LVET and represents
the time for the electrical as well the mechanicAL events that precede systolic ejection.
• PEP/ LVET is normally 0.35. it increases without a change in QS2 when left entricular
perforance is comprised in a variety of cardc diseases.
122 | Physiology
PEP
PEP LVET
LVET
QS22
AfraTafreeh.com
!
LV Pressure volume loop
Left ventricular pressure-volume loop

1 to 2 : Isovolumetric ventricular contraction
2 to 3 : Left ventricular ejection
3 to 4 : Isovolumetric ventricular relaxation
4 to 1 : Left ventricular filling
Aortic valve
closes(S2)
3 Aortic valve
opens
ESV 2
SV
Mitral valve Mitral valve
opens closes(S1)
4 1
EDV
Changes in left ventricular P-V loop by:

Increase in preload
Examples: Infusion of fluid, excess water retention
Loop A: Normal
SV Loop B: Increased
preload
A B
EDV increases
AfraTafreeh.com
Increase in afterload
Example: Patient with systemic hypertension
Loop A: Normal
Left ventricular pressure
Loop B: Increased
afterload
•Increase in ventricular
pressure during systole
•Decrease in SV
A
•Increase in ESV
B
Left ventricular volume

124 | Physiology

Increase in myocardial contractility
Example: Digitalis, catecholamines
Loop A: Normal
Loop B: Increased
contractility
Left ventricular pressure
•Increase in ventricular
A pressure during systole
•Increase in SV
B •Decrease in ESV
Left ventricular volume
Arterial pulse
Arterial pulse is felt because of the pressure wave set up in the walls of the vessels. The
rate of the pressure wave is
AfraTafreeh.com
i) Aorta 4 m/s
ii) Large arteries 8 m/s
iii) Small arteries 16 m/s
(Note that the rate of blood flow at the root of the aorta is 40cm/s)
• The pulse is felt in the radial artery at the wrist about 0.1 second after the peak of
systolic ejection into the aorta. With age, the arteries get thickened and the pressure
wave moves faster.
• The strength of the pulse is determined by the pulse pressure (the difference between
systolic and diastolic pressure); it bears no relation to the mean arterial pressure.
• The dicrotic notch corresponds with the closure of aortic valve. It can be seen when
the pressure wave is recorded but is not palpable at the wrist.
Postextrasystolic potentiation-
• After a ventricular extrasystole, the succeeding contraction is stronger than the preceding normal
contraction- this is due to increased availability of intracellular calcium- this is k/a postextrasystolic
potentiation.
• It is independent of ventricular filling.
• It can occur in an isolated cardiac muscle.
• This is sometimes used therapeutically- a paired electrical stimuli is given to the heart in such a way that
the second stimulus is delivered shortly after the refractory period of the first- the strength of the second
contraction will be higher because of increased availability of intracellular calcium.
Concept 4.5 : Cardiac output
• To define cardiac output and cardiac index
• To enumerate and understand the principles behind different methods of measurement
of cardiac output, including
Measurement of cardiac output on Fick’s principle
Indicator or dye-dilution technique and thermodilution technique
• To understand heterometric and homometric regulation of cardiac output and the
effects of various conditions on cardiac output
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Cardiac output:
• Definition: Amount of blood ejected by each ventricle per minute
• Value = 5L/ min
• Cardiac output = S.V X H.R
• Cardiac output = MAP/TPR
AfraTafreeh.com
• Cardiac index is cardiac output per m2 body surface area. Normal value = 3 L/m2
Measurement of cardiac output:
(i) Methods based on the Fick’s Principle
The Fick’s principle states that the amount of substance taken up by an organ (or
by the whole body) per unit time is equal to the arterial level of the substance
minus the venous level (A-V difference) times the blood flow.
Amount of substance taken up by organ in unit time
Blood flow =
Arteriole-venous concentration diff of sub

This principle can be used to determine cardiac output by measuring the amount
of O2 consumed in a given period and dividing this value by the A-V difference
across the lungs.
Arterial O2 content is measured in a sample obtained from any convenient artery.
Venous O2 content is measured in a sample obtained from the pulmonary artery
by means of a cardiac catheter.
▫ Pulmonary blood flow/min = right ventricular output, and

▫ right ventricular output = left ventricular output = CO

126 | Physiology
Fick Principle:
Output of Left Ventricle
Oxygen Uptake by Lungs ml/min
=
Ao2-Vo2
200 ml/min
=
200 ml/L – 160 ml/L
Art blood – Venous blood
(Pul artery)
200 ml/min
= = 5 L/min
40 ml/Liter
(ii) Indicator/ Dye dilution / thermo dilution technique (in which the indicator
used is warm or cold saline)
Known quantity of dye (cardiogreen) or a radioactive isotope “Q” is injected into

a large vein or into the RA

Mean concentration of dye “C” during the first passage through an artery is

determined from successive samples of blood taken from the artery

Blood flow in L/min (F) is given by the following formula:

F = Q/ Ct, where AfraTafreeh.com

F = blood flow in L/min
Q = quantity of dye injected
C = average concentration of dye in arterial blood after a single circulation through
the heart (obtained from area under the curve)
t = time duration in seconds of the first passage of dye through the artery
(In practice, the log of the indicator concentration in the serial arterial samples is plotted
against time- the initial decline in concentration, linear on a semilog plot, is extrapolated
to the abscissa, giving the time for the first passage of the indicator through the
circulation; the cardiac output for that period is calculated and then converted to output
per minute)
Cardiac output measurement by Dye dilution technique:
In the thermodilution technique, the indicator which is used is cold saline.
Cold saline is injected into the right atrium through one channel of the Swan- Ganz
catheter and the temperature change in the blood is recorded in the pulmonary
artery using a thermistor in the other, longer side of the catheter.
The temperature change is inversely proportional to the amount of blood flowing

through the pulmonary artery; that is, to the extent that the cold saline is diluted
by blood.
This technique has two advantages, (i) saline is harmless, and (ii) cold is dissipated

in the tissues so recirculation is not a problem, and it is easy to make repeated

determinations.
iii) Echocardiography and Doppler studies- these are non- invasive and most
commonly used in clinical practice.
Regulation of cardiac out put

Since C-O = HR X SV, it can be regulated by HR and SV
(i) HR: This is influenced by sympathetic and parasympathetic innervation
(ii) S.V: This can be changed by
Heterometric regulation:- This is based on Frank Starling Law; more the initial length
of the cardiac muscle (or the preload, as indicated by EDV), more will be the SV (BUT
with in physiologic limits).
Factors affecting EDV
a) Increase in blood volume increases venous return and EDV
b) Sympathetic stimulation causes venoconstriction, decreases venous complianceQ
AfraTafreeh.com
and increases venous return
c) Increase in the negativity of the intrathoracic pressure increases venous return
d) Posture- standing causes peripheral pooling of blood, thereby decreasing venous
return
e) Muscular activity increases the pumping action of skeletal muscles thereby increasing
venous return
Frank-Starling’s curve or Cardiac function curve
•There is a curvilinear
relationship between
CO and EDV
Cardiac output
Stroke volume
•Curve informs about the

or
ventricular pumping capacity

at different ventricular filling
End diastolic volume (EDV)

or
Right atrial pressure (RAP)
128 | Physiology
f) Increase in pericardial pressure (due to an infection or pressure from a tumor)
decreases the filling of the ventricle causing a decrease in EDV and SV
g) Decrease in ventricular compliance or increased ventricular stiffness produced by
myocardial infarction, infiltrative disease, etc. decreases diastolic filling
Homometric regulation:- Regulation of cardiac output due to changes in contractility
independent of length is called homometric regulation. This includes the following:
(i) Factors which increase or decrease the heart rate- e.g., sympathetic stimulation
increases the heart rate and therefore the cardiac output. Increase in heart rate >
180- 200/ min in fact decreases the cardiac output- this is because the ventricular
filling time is drastically reduced- further increase in heart rate therefore causes a
decrease in cardiac output. Parasympathetic stimulation decreases the heart rate
and the cardiac output.
(ii) Factors which increase or decrease myocardial contractility
For example, sympathetic stimulation, positive inotropic agents like catecholamines
(action via β1 adrenergic receptors and increase in cAMP), xanthenes (inhibit
breakdown of cAMP), glucagon and digitalis - increase the myocardial contractility
and therefore, the stroke volume;
Negative inotropic states like hypercapnia, hypoxia, acidosis, certain drugs (e.g.
barbiturates, procainamide, quinidine), heart failure (intrinsic depression), M.I
(loss of myocardium)- decrease the myocardial contractility and therefore, the
stroke volume.
(iii) Factors which affect the afterload- increase in afterload decreases the cardiac
AfraTafreeh.com
output, whereas a decrease in afterload increases cardiac output e.g., anemia
causes a generalized vasodilatation and a decrease in peripheral resistance- this
decreases the afterload and increases cardiac output (hyper dynamic circulation is
commonly seen in anemia)
To summarise, C.O can be either regulated by heterometric regulation (Frank
starling law) with regulation based on a change in initial length or EDV) or by
homometric regulation (changes in contractility independent of length).
Effect of various conditions on the cardiac output
Increases in
Anxiety and excitement (50-100%)
Eating (30%)
Exercise (upto 700%)
High or low environmental temperature
Pregnancy
Epinephrine
Decreases in
Sitting or standing from lying position (20-30%)
Rapid arrhythmias
Heart disease
No change
SleepQ
Moderate changes in environmental temperature
Concept 4.6 : Myocardial oxygen demand
Learning objectives: To understand and enumerate
• Coronary blood flow as a percentage of cardiac output, basal oxygen consumption by
the heart and high oxygen extraction by the heart
• Factors which increases myocardial oxygen demand
• Factors which increase coronary blood flow
• Effect of sympathetic stimulation on coronary blood flow
• Type of metabolism in the heart
Time Needed
1st reading 10 mins
2 look
nd
05 mins
Important points on coronary blood flow and oxygen consumption by the heart:
• Heart receives <5% (4.7%) of cardiac output at rest
• Coronary blood flow is 250mL/min at rest- this can increase by 200-300% (500-
750mL/min)
• In terms of per 100g/ min, coronary blood flow- 84mL/100g/min (blood flow in
resting skeletal muscle is 3- 4mL/100g/min; increases to 50 to 80mL/100g/min
during exercise)
AfraTafreeh.com
• Basal oxygen consumption (ref Ganong pg 550 24th edi)- 2mL/100g/min (much
more than the oxygen consumption by resting skeletal muscle, which is 0.2mL/100g/
min)
• Oxygen consumption by a beating heart at rest- 9mL/100g/min
• At rest heart extracts 70-80% of the oxygen from each unit of blood delivered to it
(“heart is the organ with maximum oxygen extraction at rest”). So whenever
there is an increase in oxygen demand coronary blood flow will also show an increase.
Factors which increase myocardial oxygen demand

• Heart is a hard working organ and therefore needs a lot of oxygen!
• The O2 consumption is determined by:-
(a) Heart rate
(b) Duration of systole
(c) Intramyocardial tension
(d) Contractile state of myocardium
(e) Work done by the heart;
Work done = stroke volume X MAP
Work done is the product of stroke volume and mean arterial pressure in the pulmonary
artery or the aorta (for the right and left ventricle respectively). Ventricular work per
beat correlates well with O2 consumption.
Left ventricular work/ beat = S.V. X M.A.P in aorta
Right ventricular work/ beat = S.V. X M.A.P in pulmonary artery
(MAP= Means Arterial pressure)
130 | Physiology
• Since aortic pressure is nearly 7 times pulmonary arterial pressure, the left ventricular
stroke work is 7 times right ventricular stroke work.
• Out of pressure work and volume work (since work= volume X pressure), pressure
work produces a greater increase in O2 consumption than volume work. In other
words, an increase in afterload causes a greater increase in O2 consumption than
does an increase in preload (this explains why angina is a common symptom in
aortic stenosis but not in aortic regurgitation- AS causes an increase in pressure work
whereas AR causes an increase in volume work).
Note
• Higher the heart rate greater is the myocardial O2 usage, for any given cardiac output.
• Myocardial O2 usage is most closely related to the tension time index (TTI).
• The tension time index is a product of the mean left ventricular systolic pressure and
the duration of systole.
Factors which can increase coronary blood flow

• Hypoxia of the myocardium
• Local increase in CO2, H+, K+, lactate, prostaglandins, adenine nucleotides, adenosine
Effect of sympathetic stimulation on coronary blood flow

Sympathetic stimulation causes CORONARY VASOCONSTRICTION, BUT, sympathetic
stimulation also increases heart rate and the force of contraction- increase in cardiac
activity increases the release of vasodilator metabolites (especially adenosine), resulting
in a vasodilation. AfraTafreeh.com
• Effect of vagal stimulation- coronary vasodilation
Type of metabolism in the heart

• 99% of the energy requirement of the heart is obtained from aerobic (oxidative)
metabolism.
• Preferred fuel for the heart- fats (60%) > carbohydrates (35%) > ketones and amino
acids (5%)
• The heart does not fatigue because of the following:-
Heart has a prolonged absolute refractory period

Heart muscle cannot be tetanised

Heart has a very good blood supply

Heart has a high content of myoglobin

Heat has aerobic metabolism

Heart has a large concentration of mitochondria

Concept 4.7 : Blood vessels
• To understand the different types of blood vessels in the cardiovascular system and
unique features of each.
• To understand the role of capillaries and pericytes
• To understand the concepts of critical closing pressure, vascular distensibility and
vascular compliance
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Vessels
Type of vessel Features
Wind Kessel vessels E.g. aorta, major arteries; have a lot of elastic tissue; show elastic
recoil (wind kessel effect), when stretched
Resistance vessels E.g. arterioles; have some elastic tissue. Have a lot of smooth muscle (
have the maximum wall thickness-to-lumen ratio)
Precapillary sphincters No innervation , respond to local metabolitesQ
Exchange vessels
AfraTafreeh.com
Capillaries; No innervation; Controlled by precapillary sphincters
Capacitance vessels (Veins) Have some innervation (Vena cava have minimum thickness-to-
lumen ratio)
Shunt vessels Form arteriovenous anastomoses. They have thick muscular wall;
very richly innervated. E.g. fingertips, earlobes etc.
• Total cross-sectional area is minimum in aorta and maximum in capillaries.

• Since velocity of blood flow is inverse to the total cross sectional area, it is maximum in the aorta and
least in the capillaries.
• Percentage of blood volume is maximum in capacitance vessels (64%) and minimum in arterioles.
• The greatest resistance to blood flow and hence the greatest pressure drop in the systemic circulation
occurs at the level of the small arteries and arterioles.
Capillaries:-
There are 3 types
(a) Continuous e.g. brain, skin
(b) Fenestrated e.g. GITQ, glomeruli of kidney, endocrine glands, circum ventricular
organs,
(c) Discontinuous (Sinusoids) e.g. liver, bone marrow
The least permeable capillaries are those of the brain while the most permeable

capillary is that of the liver.

132 | Physiology
Pulsatile pressure is progressively damped by the elasticity in the arterial walls
and the frictional resistance of the small arteries and arterioles- therefore, the
capillary blood flow is essentially nonpulsatile.
In a patient with hyperthyroidism (Grave’s disease) basal metabolism is elevated
and is associated with arteriolar dilatation. This reduction in arteriolar resistance
diminishes the damping effect on pulsatile arterial pressure and is manifested as
pulsatile flow in the capillaries, as observed in the fingernail bed of patients with
this disease.
Capillaries do not have sympathetic innervation but respond to local metabolites.
Local decrease in PO2 causes a dilatation in all capillary beds except in the
pulmonary circulation.
Pericytes:
• These are associated with capillaries and post capillary venules.
• They are similar to the mesangial cells in the renal glomeruli.
• They are contractile.
• They release vasoactive agents.
• They synthesize and release constituents of basement membrane and extra cellular
matrix.
• Regulate the flow through the junction between the endothelial cells, especially during
inflammation.
AfraTafreeh.com
Critical closing pressureQ
• It is the pressure below which flow completely stops in thin walled vessels; the value
of this pressure is not zero but above zero (about 20 mms of Hg- this is because
vessels are surrounded by tissues that exert a small but definite pressure on them,
and when the intraluminal pressure falls below the tissue pressure, they collapse).
• The critical closing pressure has different origins:
Collateral inflow to the arteriolar meshwork.

In certain situations due to Rouleaux formation by red blood cells in the blood

vessels.
External tissue pressure compressing the blood vessels.
High vascular smooth muscle tone with closure of small arteries (as sen in terminal
arterioles).
• Sympathetic stimulation produces an increase in vasomotor tone and a vasoconstriction-
this increases the critical closing pressure to 60 mms of Hg, shifts the curve to the
right and decreases the slope.
• Inhibition of the sympathetic system decreases the critical closing pressure to less
than 20 mms of Hg, shifts the curve to the left and increases the slope.
Vascular distensibility
• This is the fractional increase in volume for each mm of Hg rise in pressure.
Increase in volume
• Vascular distensibility =
Increase in pressure × original volume
• Veins on an average are 8 times more distensible than arteries.
Vascular compliance/ capacitance
Increase in volume
• Vascular compliance =
Increase in pressure
• Compliance is distensibility × volume
• Compliance of a vein is 24 times that of a corresponding artery because it is 8 times
AfraTafreeh.com
as distensible and it has a volume about 3 times as great (8 × 3 = 24)
• Sympathetic stimulation decreases vascular complianceQ.
• Control of vascular compliance by sympathetics is especially valuable in hemorrhage
when an increase in vascular tone cause shift of blood from the veins to the heart,
resulting in increased heart pumping.
• Compliance is lower in veins of the lower limbs as compared those at or above the
level of the heart. Veins in the lower limbs are also thicker than those in the brain or
the upper limbs. The compliance of the veins, like that of arteries decreases with age,
and the vascular thickening that occurs is accompanied by a reduction in elastin and
an increase in collagen content.
134 | Physiology
Concept 4.8 : Hemodynamics
Learning Objectives: T o understand the different principles of biophysics for flow of
blood, such as
• Relationship between flow, pressure and resistance (based on Ohm’s law)
• Relationship of velocity of flow and total cross sectional area
• Hagen- Poiseuille’s law
• Laminar and turbulent flow (use of Reynold’s number to determine tendency for
turbulence)
• Shear stress
• La place’s law
• Vascular resistance in series and in parallel
• Distribution of blood in different parts of the circulation
• Blood viscosity and the factors determining it
• Newtonian and non- Newtonian fluids
While applying the biophysical principles, one must bear in mind that vessels are not
rigid tubes and that blood is not a perfect fluid. Thus there can be differences between
in vivo and in vitro conditions.
Time Needed
1 reading
st
20 mins
2 look
nd AfraTafreeh.com
15 mins
Relationship between flow, pressure and resistance (based on Ohm’s law)

F = ∆P/R (Where F= flow, ∆P = pressure gradient, R= resistance)
or
Resistance = ∆P/F
*If P is expressed in mm Hg and flow is expressed in ml/second, then resistance will be expressed in ‘R’ units or PRU
(peripheral resistance units).
** If P is expressed in mm Hg and flow is expressed in L/minute, then resistance will be expressed in ‘Wood’ units.
Blood Flow Measurement:

Direct method Indirect method
a) Electro magnetic flow meters a) Fick’s method
b) Doppler flow meter b) Indicator method e.g. Kety method for cerebral
blood flow using N2O; determination of renal
plasma flow by measuring the clearance of
paraamino hippuric acid
c) Plethysmography
Relationship between velocity of flow and total cross- sectional area

V= Q/A (Where V= velocity, Q= Quantity / amount of fluid and A= Area)
So, if area is more, velocity is less, therefore, the flow is least in the capillaries
(maximum cross-sectional area) and maximum in the aorta (least cross-
sectional area).
Hagen-Poiseuille law:
R= 8ηL/π r4 (Where R= resistance, η= viscosity, L= length of the vessel and r= radius)
Since Flow = Pressure/Resistance,
(P1-P2) × πr4
Flow =
8ηL
The above formula is called the Poisuille – Hagen formula
N.B. Flow is directly proportional to the fourth power of radius.
• Units of resistance- if the pressure difference between two points is 1 mm Hg and
the flow is I ml/sec, the resistance is said to be 1 peripheral resistance unit, usually
abbreviated PRU. Resistance in CGS (centimeters, grams, seconds) is expressed in
dyne seconds/ centimeters5.
• The rate of blood flow through the entire circulatory system is equal to the rate of
blood pumping by the heart- that is, it is equal to the cardiac output. In the adult
human being, this is approximately 100 ml/sec. the pressure difference between
the systemic arteries and the systemic veins is about 100 mm Hg. Therefore, the
resistance of the entire systemic circulation, called the total peripheral resistance, is
100/100 or 1 PRU.
• Conductance = 1/ resistance
Laminar (streamline)and turbulent flow:

AfraTafreeh.com
Laminar Turbulent
Silent Noisy
Parabolic velocity profile – flow is maximum in the center of the flow No such gradient in flow rate from
and goes on decreasing towards the wall center of the flow towards the vessel
wall exists
More efficient (less energy consumption) less efficient
The probability of turbulence in a given flow can be determined by Reynold’s number:

Re = PDV/ η
(Where Re = Reynold‘s number, P = Density of the fluid, D= Diameter of the vessel, V=
Velocity of flow and η = Viscosity)
• More the Reynold’s number, more the chances of turbulence.
• If D is measured in cms, V in cm/s, η in poises, then if Re is < 2000 there is usually
no turbulence; if Re is > 3000, turbulence is almost always present.
• Laminar flow can be disturbed at the branching points of arteries, and the resulting
turbulence may increase the likelihood that atherosclerotic plaques will be deposited.
• Turbulence is considerable in proximal aorta and pulmonary artery because of (1) high
velocity of blood flow especially during the phase of rapid ejection by the ventricles,
(2) pulsatile nature of blood flow, (3) sudden change in vessel diameter, (4) large
vessel diameter
136 | Physiology
Shear Stress:
• Flowing blood creates a force on the endothelium that is parallel to the long axis of
the vessel. This shear stress (γ) is proportionate to the viscosity (η) times the shear
rate (dy/dr), which is the rate at which the axial velocity increases from the vessel
wall towards the lumen
Γ = η (dy/dr)
• Changes in shear stress produce marked changes in the expression of genes by
endothelial cells
La Place’s law
This gives the relationship between the transmural pressure or distending pressure (P),
the wall tension (T), the wall thickness (w) and the radius (r) in a hollow viscous organ
Pr
T=
w
(Transmural pressure is the pressure inside the cylinder minus the pressure outside the
cylinder, but because tissue pressure in the body is low, it can generally be ignored and
P is equal to the pressure inside the viscus)
Law of Laplace helps to explain as to why
1) Capillaries do not rupture in spite of being thin walled.
2) Dilated hearts have to work more.
3) Alveoli do not collapse during expiration
AfraTafreeh.com
In thin walled structure, ‘w’ can be ignored (but it becomes significant factor in

vessels such as arteries)

In a spherical structure, P= 2T/r

In a cylindrical structure, P= T/r

Consequently smaller the radius of a blood vessel, the lower the tension in the wall

necessary to balance the distending pressure

Vascular resistance in series and in parallel
Amputation of a limb or surgical removal of a kidney removes a parallel circuit and reduces the total vascular
AfraTafreeh.com
resistance and total blood flow (i.e., cardiac output) while increasing the total peripheral vascular resistance.Q
Distribution of blood in different

parts of the circulation
• Least volume of blood (<1%) is in
the arterioles.
• Maximum volume of blood is in the
venules, veins and vena cava
138 | Physiology
Viscosity
• As seen in the calculation of resistance, one of the factors on which resistance depends
is the viscosity of the blood.
• Viscosity in turn depends mostly on haematocrit.
• In large vessels, increases in hematocrit cause appreciable increases in viscosity.
However the change in viscosity with change in haematocrit is much less in smaller
vessels, such as arterioles, capillaries and venules. This is due to the difference in the
nature of flow through the small vessels. Therefore, the net change in viscosity per
unit change in hematocrit is much less in the body than in vitro.
Viscosity also depends on :-
• Composition of plasma (viscosity is high when immunoglobulins are markedly
elevated)
• Resistance of the cells to deformation (viscosity is high in hereditary spherocytosis)
Newtonian and Non- Newtonian fluid: -
• A Newtonian fluid is a fluid whose viscosity is independent of the rate of shear e.g.
plasma, saline.
• A non-Newtonian fluid is a fluid in which the viscosity changes with the changes in
the shear rate.
• At very low shear rates, the viscosity is greatly increased; at high rates of flow the
fluid behaves almost as a newtonian fluid. Blood is a non-Newtonian fluid.
AfraTafreeh.com
Concept 4.9 : Cardiovascular regulation
o understand the different regulatory mechanisms in the
cardiovascular system, such as
• Myogenic and metabolic mechanisms of autoregulation
• Effect of circulating hormones on cardiovascular system
• Sympathetic cholinergic vasodilator system
• Axon reflex
• Neural control
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Autoregulation:
• Autoregulation is the ability of an organ to regulate its blood flow (on its own,
independent of nervous/ systemic influences) with changes in perfusion pressure
(within a range).
• Many organs show auto regulation e.g. brain, kidney, skeletal muscle, liver, heart,
etc.
AfraTafreeh.com
• Skin does not show autoregulation.
• Theories of auto regulation
(i) Myogenic: This depends upon the inherent property of the smooth muscle to
contract, when stretched. More the perfusion pressure, the more it contracts to
decrease the caliber of the vessel and hence to decrease the blood flow
(ii) Metabolic: - Less the perfusion pressure, more is the accumulation of local
metabolites which can dilate the vessel and thus increase blood flow. Some of
the vasodilator metabolites are ↓O2, ↑CO2, ↓pH, ↑ Osmolality, ↑temperature, K+,
Adenosine (plays a vasodilator role in cardiac muscle but not in skeletal muscle),
Lactate etc.
(iii) Tissue pressure theory – This is applicable in encapsulated organs e.g. kidney
(Note: T
he local effect of hypoxia is vasodilatation in all the blood vessels
except pulmonary vessels where they cause vasoconstriction).
Effect of circulating hormones:

These can be vasoconstrictors / vasodilators.
Examples of vasoconstrictors:
(i) Epinephrine / Norepinephrine
Norepinephrine causes generalized vasoconstriction whereas epinephrine dilates
the vessels in skeletal muscle and liver.
140 | Physiology
Parameter Norepinephrine Epinephrine
Systolic B.P ↑ ↑
Diastolic B.P. ↑ ↓
Mean arterial Pressure ↑ Only slight ↑
Pulse pressure only slight ↑ ↑↑
Heart rate Reflex bradycardia ↑
(ii) Dopamine: Causes vasoconstriction everywhere except in renal vessels where it

causes renal vasodilatation
(iii) Angiotensin II: It causes generalized vasoconstriction, increases water intake
and stimulates aldosterone secretion.
Sympathetic cholinergic vasodilator system

Site: Vessels of skeletal muscles
Pathway: Originates in the cortex, relays in the hypothalamus and mesencephalon
and passes through to the medulla to the IML horn of the spinal cord. The preganglionic
neurons activate the post ganglionic neurons to the blood vessels. It does not influence
AfraTafreeh.com
the vasomotor center in the medulla.
Neurotransmitter: The neuro transmitter at their postganglionic neurons is
acetylcholine.
Functional role: It plays no role in the vasodilation in skeletal muscles during exercise.
It may play a role in the vasodilation by the thought of exercise; may be responsible for
fainting in emotional situations.
N.B. There is no tonic activity in the vasodilator fibers, but vasoconstrictor fibers to most
vascular beds have some tonic activity. In skeletal muscle, vasodilation is produced
by decreasing the rate of tonic discharge in the vasoconstrictor nerves AND also by
activating the sympathetic cholinergic vasodilator system.
Axon reflex:
(i) It is a local neural reflex; the impulse does not reach the spinal cord: present after
total sympathectomy, absent in locally anesthetized skin, also absent in denervated
skin.
(ii) It is responsible for local vasodilatation and does not contribute in systemic control
of blood pressure.
(iii) Antidromic conduction (conduction of normal sensory and afferent impulse from
the skin to spinal cord is orthodromic conduction)
(iv) It is responsible for the ‘flare’ of triple reaction (Flare is because of arteriolar
dilatation).
Triple response is a three- part response, consisting of red reaction, wheal and flare, which occur when the
skin is stroked firmly with a pointed instrument.
• Red reaction
▫ Refers to the reddening which appears at the site of injury in about 10 seconds.

▫ Occurs due to capillary dilatation, a direct response of the capillaries to pressure.

▫ Since it is not neurally mediated, local anesthetics do not prevent the red reaction.

• Flare
▫ It is a diffusely spreading and irregularly outlined redness of the skin surrounding the red line

▫ Occurs within a few minutes of the appearance of the red reaction

▫ It is due to arteriolar dilatation.

▫ Flare is mediated by the axon reflex in the cutaneous fibers.

▫ It occurs due to antidromic conduction of impulses in cutaneous nerves to the blood vessels supplying

the area.
▫ Neurotransmitters responsible for flare are substance P and CGRP.

▫ Flare is absent in locally anesthetized skin and in denervated skin, but it is present immedilately after

nerve block or section ABOVE the site of injury, indicating it is a local neural response.
• Wheal
▫ Refers to the swelling or localized edema that develops within the area of flare.

▫ It occurs due to increased capillary permeability with consequent extravasation of fluid produced by

substance P.
AfraTafreeh.com
Neural regulation: T
he main cardiovascular ‘center’- the vasomotor center is in the
medulla.
142 | Physiology
Concept 4.10 : Vasomotor center
Learning Objectives: To understand and enumerate
• Components of the vasomotor center and their location
• Factors affecting the activity of the VMC
• Excitatory inputs into the VMC
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Components of the vasomotor center

• Sensory area
located in the tractus solitarius in the posterolateral portion of the medulla and

lower pons
• Vasoconstrictor area or “pressor area”
In anterolateral portion of upper medulla (neurons in the RVLM project directly to

sympathetic preganglionic neurons in the IML of spinal cord)

Excite the preganglionic neurons of the sympathetic nervous system- causes

vasoconstriction and increases heart rate and contractility

• Vasodilator area or “depressor area”
In anterolateral portion of lower medulla (CVLM, IVLM)

Inhibits the vasoconstrictor area causing vasodilatation

AfraTafreeh.com
• Cardioinhibitory area
Medial portion of the vasomotor center→ dorsal motor nucleus of vagus→ sends

parasympathetic impulses to the heart→ decreases heart rate
Factors affecting the activity of VMC:

Direct stimulation-
• CO2
• Hypoxia
Excitatory Inputs
• Cortex (particularly the limbic cortex) via hypothalamus- responsible for the increase
in b.p. and heart rate produced by emotions such as sexual excitement, anger
• Periacqueductal gray
• Reticular formation
• Pain pathways- pain usually causes a rise in blood pressure via afferent impulses in
the reticular formation converging in the RVLM. (however, prolonged severe pain can
cause vasodilation and fainting)
• Somatic afferents
• Carotid and aortic chemoreceptors
Inhibitory inputs
• Cortex via hypothalamus
• CVLM
• Lung inflation afferents inhibit vasomotor damage cause vasodilation abd decrease
in b.p.
• Carotid, aortic and cardiopulmonary baroreceptors
Concept 4.11 : Blood pressure and its regulation
Learning Objectives: To define
• Systolic blood pressure
• Diastolic pressure
• Pulse pressure and its determinants
• Mean arterial pressure
To understand the physiological significance of the following reflexes in
maintaining blood pressure:-
• Baroreceptor reflex
• Chemoreceptor reflex
• Atrial stretch receptor response
• Renin- angiotensin- aldosterone system
Time Needed
1st reading 20 mins
2 look
nd
15 mins
Systolic blood pressure:

It is the maximum pressure recorded during systole.
AfraTafreeh.com
Diastolic blood pressure
It is the minimum pressure recorded during diastole.
The two determinants of DBP are
• Elastic recoil of aorta and large arteries during diastole
• Total peripheral resistance
Pulse pressure
• Arterial pulse pressure is systolic pressure minus diastolic pressure. It is principally a
function of stroke volume, which determines a change in arterial blood volume during
ventricular systole, and arterial compliance.
• The two determinants of pulse pressure are: (i) Stroke volume, and (ii) Arterial
compliance.
• Arterial pulse pressure gives valuable clues about a person’s stroke volume, provided
the arterial compliance is essentially normal. Patients with severe CCF or who have
suffered a severe hemorrhage are likely to have a very small arterial pulse pressure
because their stroke volumes are abnormally small. Conversely, individuals with large
stroke volumes as in aortic regurgitation, are likely to have increased arterial pulse
pressure. Similarly, well- trained atheletes at rest have large stroke volumes because
their resting heart rates are usually low→ a prolonged ventricular filling time→ large
stroke volume→ large pulse pressure
• Arterial compliance also affects pulse pressure. When cardiac output and TPR are
constant, a decrease in arterial compliance results in an increase in pulse
pressure (seen in the elderly where atherosclerosis causes stiffening of blood vessels,
decreases arterial compliance and causes an increase in pulse pressure). Diminished
arterial compliance imposes a greater workload on the left ventricle (i.e., increased
afterload), even if stroke volume, TPR and MAP are equal in two individuals.
144 | Physiology
• If the heart rate and stroke volume are constant, an increase in TPR will increase
MAP. When arterial compliance is constant, an increase in TPR leads to a proportional
increase in systolic and diastolic pressure such that pulse pressure is unchanged.
However, arterial compliance is not linear. As MAP increases and the artery is stressed,
compliance decreases. Because of the decrease in arterial compliance with increased
arterial pressure, pulse pressure will increase when arterial pressure is elevated.
Mean arterial pressure

**Effect of gravity on B.P.: Above the level of the heart, the B.P. falls and below the level of the heart, the B.P
increases. The value of blood pressure changes by 0.77 mm Hg per cm. This is true for arterial as well as for
venous pressure.
Mean Pressure = Diastolic B.P. + 1/3 pulse pressure
*The maximum pressure drop in the vascular circuit is at the level of the arterioles (as the maximum
resistance is at the arterioles).
Baroreceptors reflex:
• One of the important inputs to the VMC is the input from the baroreceptors.
• Baroreceptors are stretch (mechano) receptors.
• The high pressure baroreceptors are present in the carotid sinus and aortic arch (in
the adventitia of the vessels).
• The threshold for activation of baroreceptors is a MAP of 50 mm Hg.
AfraTafreeh.com
• Maximum activation is at a MAP of 200 mm Hg.
• At a normal MAP of 100 mm Hg, baroreceptor activation occurs during both systole
and diastoleQ (burst of action potentials during systole and few during diastole).
• At lower mean pressure, activity occurs only during systole whereas at MAP of 200
mm Hg activity occurs throughout the cardiac cycle.
Schematic depiction of baroreceptor (negative) feedback regulation of BP
Nucleus Ambiguus
(parasymapthe c)
!
• Bilateral section of the nerves from the carotid sinus (carotid sinus nerve or Hering’s
nerve) and aortic arch receptors (and also bilateral lesions of the NTS) produces
neurogenic hypertension.
Note: Increase in BP→ Stimulates baroreceptors→ increase firing rate→ inhibits tonic
discharge of sympathetic nerves and excites vagal innervations of the heart→ produce
vasodilation, venodilation, decrease in BP, bradycardia, decrease in cardiac output
• Therefore,
Stimulation of baroreceptors→ decreases BP
Chemoreceptor reflex:
Hypoxia
Stimulation of peripheral chemoreceptors
Stimulate VMC in Medulla
Vasoconstriction, Increases bp, Increases heart rate
• Therefore, AfraTafreeh.com
Stimulation of chemoreceptors→ increases BP
N.B. Increase in blood pressure can cause a reflex decrease in heart rate through the
baroreceptor mechanism
Effect of hyperpnoea
Causes increase in catecholamine secretion from adrenal medulla
[Note that the effect of hypoxia on heart rate is an increase (because of hyperpnoea)
and a reflex decrease because of stimulation of VMC. Therefore, its effect on heart rate
is variable]
Atrial Stretch receptor response

• Atrial stretch receptors are volume receptors.
• They are present in low pressure zones, such as, in the walls of the right and left
atrium and in the pulmonary circulation (atrial stretch receptors are also k/a cardio
pulmonary receptors.
• There are two types of atrial stretch receptors:-
Type A: Discharge primarily in atrial systole

Type B: Discharge primarily (late in) atrial diastole.

• The atrial stretch receptors respond to changes in blood volume.

• Response is increased secretion of ANP, decreased secretion of ADH, vasodilatation
and ↓ BP but an increase in heart rate (decrease in heart rate is because of atrial
stretch receptors inhibit vagal action on SAN)
146 | Physiology
Decrease in ECF volume
Increase in sympathetic discharge Decreased central venous pressure
Increase in Renin Decreased fir ng of atrial

stretch receptors
Increase in Aldosterone ↓ ANP ↑ ADH
Renin- angiotensin- aldosterone system
AfraTafreeh.com
Stimuli which increase Renin secretion

• Hemorrhage • Decrease in renal afferent arteriolar
• Hypovolumia pressure
• Trauma • Prolonged standing
• Surgery • Renal artery stenosis
• Hyponatremia • Constriction of thoracic inferior vena cava
• Dehydration • Heart failure, cirrhosis, nephrosis (Causes
• Increased sympathetic discharge of secondary hyperaldosteronism)
Concept 4.12 : Cardiovascular reflexes
Learning Objectives: To understand and enumerate features and causes of different
cardiovascular reflexes, such as
• Mary’s law
• Bainbridge reflex
• Bezold – Jarisch reflex
• Cushing’s reflex and Cushing’s triad
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
Mary’s law
• Mary’s law states that the heart rate is inverse to the blood pressure.
• Physiological basis of the Mary’s law is the baroreceptor response.
• The first change which occurs in response to increase or decrease in bp in the
baroreceptor reflex is a decrease or increase in heart rate respectively, which is called
the Mary’s law.
Bainbridge reflex:
• Sudden increase in blood volume by infusion of blood or saline causes increase in
AfraTafreeh.com
heart rate (if the initial heart rate is low).
• Receptors involved: Atrial stretch receptors
Bezold – Jarisch reflex: - (Coronary chemoreflex)

• Injections of veratridine, serotonin, capsaicin, phenyguanides, etc into the coronary
arteries supplying the left ventricle causes apnea followed by rapid, shallow breathing,
↓ in BP (hypotension) and ↓ in heart rate (bradycardia).
• Receptors involved: Left ventricular C fibre nerve endings
Cushing’s reflex: (C.N.S. Ischemic response)

• Increase in intracranial pressure causes decreased cerebral blood flow, hypoxia and
hypercapnia, which in turn directly stimulates the V.M.C. This results in an increase
in B.P.
• The ↑ in B.P., through the baroreceptor mechanism, causes reflex Bradycardia
(bradycardia is an important sign of raised intracranial tension)
• Cushing’s triad consists of hypertension with wide pulse pressure, bradycardia and
irregular respirations.
148 | Physiology
Concept 4.13 : Respiratory sinus arrhythmia
o understand and enumerate features and causes of respiratory
sinus arrhythmia
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Respiratory sinus arrhythmia

Heart rate increases during inspiration and decreases during expiration- this is
known as respiratory sinus arrhythmia. This arrhythmia is detectable in most individuals
and is more pronounced in children.
Respiratory sinus arrhythmia may be due to:
• Neural activity increases in sympathetic fibres during inspiration and in vagal fibres
during expiration.
• Stretch receptors in the lungs are stimulated during inspiration and this action leads
to a reflex increase in heart rate. The afferent and efferent limbs of this reflex are
located in the vagus nerves.
• Intrathoracic pressure also decreases during inspiration and thereby increases venous
return to the right side of the heart. The consequent stretch of the right atrium elicits
the Bainbridge reflex.
AfraTafreeh.com
• During inspiration, decrease in intrapleural pressure causes dilatation of the pulmonary
veins, which decreases flow to the left side of heart, decreasing output of the LV and
systemic arterial pressure. Fall in bp increases heart rate by the baroreceptor reflex.
• After the time delay required for the increased venous return to reach the left side of
the heart, left ventricular output increases during expiration and raises the arterial
blood pressure. This rise in blood pressure reduces the heart rate through the
baroreceptor reflex.
• Central factors are also responsible for respiratory sinus arrhythmia. The respiratory
centre in the medulla directly influences the cardiac autonomic centers.
Concept 4.14 : Blood Pressure Waves
Learning Objectives: To understand and enumerate
• Different types of blood pressure waves recorded during intra arterial recording of
blood pressure
• Features of Traube-Hering waves
• Features of Mayer’s waves
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Blood Pressure Waves:

In direct record (intra arterial) of B.P., many types of waves can be seen;
(i) Cardiac waves - These are the waves because of the systolic rise and diastolic fall
in blood pressure.
(ii) Traube – Hering (T-H) or the respiratory waves –
▫ These are the fluctuation in the B.P., synchronous with respiration.

▫ Usual rise and fall is between 4 and 6 mms of Hg.

▫ The waves result from several different effects, such as spillover of impulses

AfraTafreeh.com
from respiratory center to the vasomotor center with each respiratory cycle.
▫ With inspiration, the pressure in the thoracic cavity becomes more negative

than usual causing the blood vessels to expand- this reduces the quantity of
blood returning to the left side of heart and thereby momentarily decreases
cardiac output and arterial pressure.
▫ The pressure changes in the thoracic vessels during respiration can excite

vascular and atrial stretch receptors.

▫ During deep inspiration, the blood pressure can rise and fall as much as 20 mms

of Hg with each respiratory cycle.

(iii) Mayer or vasomotor waves –
▫ These are seen in conditions like hypotension.

▫ The Mayer waves are slow, regular oscillations in arterial pressure that occur at

the rate of about one per 20- 40 seconds during hypotension.

▫ These are larger waves, as great as 10 to 40 mms of Hg at times.

▫ These rise and fall more slowly than respiratory waves.

▫ Cause of vasomotor waves is “reflex oscillation” of one or more nervous pressure

control mechanisms, such as oscillation of the baroreceptor and chemoreceptor

reflexes or oscillation of the CNS ischemic response.
▫ In conditions such as hypotension, hypoxia stimulates the chemoreceptors,

which raises the B.P. and improves the blood flow to the receptor organs- this
eliminates the stimulus to the chemoreceptors, so that the pressure falls and a
new cycle is initiated
150 | Physiology
AfraTafreeh.com
Concept 4.15 : Effect of Valsalva on blood pressure and heart rate
• Pleural pressure changes during a Valsalva
• Changes in blood pressure and heart rate during and after a valsalva
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Pleural pressure changes during a valsalva maneuver:-

• Valsalva is forced expiration against a closed glottis.
• Valsalva maneuvers occur during coughing, defecation, heavy lifting, etc.
• During a Valsalva, the pleural pressure becomes positive.
• Heart rate changes during and after a Valsalva is one of the tests used for assessing
the autonomic nervous system responses.
Changes in blood pressure and heart rate during and after a valslava
1. At the beginning of the maneuver: ↑ in BP
(because ↑ in intrathoracic pressure is added
to pressure in the aorta)
2. During the maneuver: ↓ in B.P (high
AfraTafreeh.com intrathoracic pressure compresses the veins,
decreasing venous return and cardiac output);
↑ in H.R. (due to the baroreceptor mechanism)
3. Transient ↓ in B.P. 1 to 2 seconds after release
of strain (due to release of pressure; events in
this phase are opposite to that in phase 1)
4. Within 10 seconds after the end of the
maneuver: ↑ in B.P.(though the intrathoracic
pressure returns to normal and cardiac
output is restored peripheral vasoconstriction
persists for some time causing an ↑ in B.P.);
↓ in H.R. (B.P. returns to normal 1.5 minutes
of strain release)
152 | Physiology
AfraTafreeh.com
Concept 4.16 : Cardiovascular response to exercise
o understand and enumerate cardiovascular responses to
isotonic and isometric exercise
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
Isotonic exercise Isometric exercise
Heart rate ↑ ↑
Systolic BP ↑ ↑
Diastolic BP ↓ or remains the same ↑
Pulse Pressure ↑ Unchanged
Peripheral vascular resistance ↓ ↑
Mean arterial pressure Remains unchanged or may show ↑

a slight decrease
Venous return AfraTafreeh.com

↑ ↓
Cardiac output ↑ ↓Q
*In isotonic exercise, release of local metabolites will cause a vasodilation in the exercising muscles which in turn decreases
vascular resistance, increases blood flow and therefore, venous return and cardiac output.
**In isometric exercise increase in tension in the muscles compresses the blood vessels in the exercising muscles. This in
turn increases the vascular resistance, decreases flow of blood, and therefore, supply of oxygen and nutrients to the muscles.
Decrease in blood flow to the muscles will, therefore, also cause a decrease in venous return.
154 | Physiology
Worksheet
• MCQ OF “CARDIOVASCULAR SYSTEM” FROM DQB

AfraTafreeh.com


Definition and duration of different interval on ECG
Normal duration (s)
Intervals Average Range Events in the heart during
interval
AfraTafreeh.com
Waves Due to
156 | Physiology
Type of vessel Features
Wind Kessel vessels
Resistance vessels
Precapillary sphincters
Exchange vessels
Capacitance vessels (Veins)
Shunt vessels
AfraTafreeh.com
Isotonic exercise Isometric exercise
Heart rate
Systolic BP
Diastolic BP
Pulse Pressure
Peripheral vascular resistance
Mean arterial pressure
Venous return
Cardiac output
5 Respiratory Physiology
CONCEPTS

Â Concept 5.2 Gas laws

Â Concept 5.3 Mechanics of ventilation

Â Concept 5.4 Compliance

Â Concept 5.5 Surface tension and surfactant

Â Concept 5.6 Work of breathing

Â Concept 5.7 Hysteresis loop

Â Concept 5.8 Ventilation-perfusion gradient in the erect

posture
Â Concept 5.9
AfraTafreeh.com
Dead space and its measurement

Â Concept 5.10 Diffusing capacity of lungs

Â Concept 5.11 Spirometery

Â Concept 5.12 Flow-volume loops

Â Concept 5.13 Gas transport

Â Concept 5.14 Oxygen- hemoglobin dissociation curve

Â Concept 5.15 Carbon dioxide transport

Â Concept 5.16 Regulation of respiration

Â Concept 5.17 CO2 response curves

Â Concept 5.18 Respiratory reflexes

Â Concept 5.19 Types of hypoxia

Â Concept 5.20 Acclimatization to high altitude

Â Concept 5.21 Important formulae and calculations in

Respiratory system
158 | Physiology
Concept 5.1: Functional anatomy
Learning Objectives: To enunciate
• Weibel’s classification of airways
• Different types of cells in the lungs
• Agents causing bronchoconstriction and bronchodilatation
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Weibel’s classification of airways

From trachea to alveolar sacs, the airways divide 23 times.
• Trachea is generation ‘0’
• The first 16 generations form the conducting zone (consisting of bronchi, bronchioles
and terminal bronchioles)
• 17th to 18th generations are the respiratory bronchioles
• 19th to 22nd generations are the alveolar ducts
• 23rd generation is the alveoli
• Volume of the alveolar region is about 2.5 to 3.0 liters
• Gas movement in the alveolar region is chiefly by diffusion
AfraTafreeh.com
Presence of cilia, smooth muscle, glands, cartilage in the airways
• Cilia : Present in the generations 0- 11; absent in bronchioles
• Cartilage : Only in trachea and bronchi; absent in bronchioles; present upto the 11th
generation, absent thereafter
• Glands : Only in trachea & bronchi
• Smooth muscle : Maximum in terminal bronchiole
Types of cells in the lungs

Alveolar epithelial cells
These are of 2 types
• Type I (primary lining cells)
Type I cells form 40% of the total number of cells but they constitute 95% of the

surface area.
Cells are joined by tight junctions.

These tight junctions prevent the escape of large molecules, such as albumin,

into the alveoli (although they permit the free passage of macrophages and
polymorphs).
• Type II (also called granular pneumocytes):
They secrete surfactant.

These are stem cells from which type I cells arise.

They form 60% of the total number of cells but only 5% of the alveolar surface

area; they do not function in gas exchange.

Respiratory Physiology | 159
They are also involved in pulmonary defence mechanisms; secrete cytokines
and contribute to pulmonary inflammation; they are resistant to oxygen toxicity,
tending to replace type I cells after prolonged exposure to high concentrations of
oxygen
Other cells in lungs:-
Capillary endothelial cells, alveolar macrophages (very effective bactericidal agents;
dead macrophages release the enzyme trypsin which causes tissue damage in patients
deficient in α1 antitrypsin), lymphocytes, plasma cells, APUD cells, mast cells (contain
heparin, histamine, proteases which participate in allergic reactions)
Agents causing bronchoconstriction and bronchodilation
Bronchoconstriction : Reflexly (by irritants, chemicals; this is cholinergically
mediated), cool air, exercise, expiration, coughing, leukotrienes, substance P, cholinergic
stimulation, early morning (around 6 A.M.)
Bronchodilation : Adrenergic stimulation, VIP by non adrenergic – non cholinergic
nerve stimulation (NANC), inspiration, in the evening (around 6 P.M.)
AfraTafreeh.com
160 | Physiology
Concept 5.2: Gas Laws
Learning Objectives: To understand and define the different gas laws and their
application in respiratory physiology, such as
• Dalton’s law of partial pressures
• Boyle’s law
• Charles’ law
• Henry’s law
• Graham’s law
• Fick’s law of diffusion
Time Needed
1 reading
st
05 mins
2nd look 02 mins
PO2 = partial pressure of O2; this refers to the dissolved oxygen

PaO2 = partial pressure of O2 in arterial blood
SO2 = O2 saturation or the saturation of Hb with O2
Gas Laws
Dalton’s law of partial pressure:
AfraTafreeh.com
• The partial pressure of a gas in a mixture of gases is equal to the total pressure times
its percentage. Partial pressure = Total pressure X fractional gas concentration.
• For example, dry air has 20.93% of O2. Its partial pressure (PO2) at sea level (where
the atmospheric pressure or the total pressure of gases in the atmosphere is 101 kPa
or 760 mms of Hg), is 20.93/100 X 760 = 159 mm Hg or 21 kPa.
• When air is inhaled into the upper airways, it is warmed and moistened, and the water
vapor pressure is then 47 mm Hg, so that the total dry gas pressure is only 760 – 47
= 713 mm Hg. The PO2 of inspired air is therefore 20.93/100 X 713 = 149 mm Hg.
• A liquid exposed to a gas until equilibration takes place has the same partial pressure
as the gas.
Boyle’s Law:
• Pressure (P) of a given mass of gas is inversely proportional to its volume (V) (i.e., P
α 1/ V), if T is constant.
Charles’ lawQ:
• Volume of a gas is directly proportional to its absolute temperature i.e., V α T (if P is
constant).
• From the above, it can be derived that P α T
Henry’s law:
• The partial pressure of a dissolved gas is equal to its partial pressure above the
solution.
Graham’s law:
• The rate of diffusion or effusion (i.e., diffusion that takes place through an orifice and
from high to low pressure) is inversely proportional to the square root of density (or
mass) when temperature and pressure are constant.
Fick’s law of diffusionQ

• The rate of diffusion of a gas through a tissue slice is proportional to the area but
inversely proportional to the thickness.
• Diffusion rate is proportional to the difference in partial pressure.
• Diffusion rate is proportional to the solubility of the gas in the tissue but inversely
proportional to the molecular size and inversely proportional to the square root of its
molecular weight.
AfraTafreeh.com
162 | Physiology
Concept 5.3: Mechanics of ventilation
• To understand the different pressure responsible for ventilation, such as
Intrapleural

Intrapulmonary

Transpulmonary or distending pressure

• To understand the changes in these pressures during the respiratory cycle

• To enunciate the formulae for total ventilation and alveolar ventilation
• To enumerate the muscles involved in quiet and forceful respiration
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Intrapleural (also k/a pleural or intrathoracic or oesophageal pressure :

• This is pressure within the pleural space. Intrapleural pressure is always negative with
respect to atmosphere.
Intrapulmonary (also k/a alveolar or airway pressure)
• This is the pressure in the airways/ alveoli.
AfraTafreeh.com
Pressure changes during respiration
(i) Intrapleural pressure : At the beginning of quiet inspiration, it is – 2.5 mm of Hg
with respect to atmosphere i.e. 2.5 mmHg less than atmospheric pressure of 760
mmHg; at the end of inspiration, it becomes – 6.0 mmHg w.r.t. atmosphere.
(ii) Intra alveolar pressure: At the peak of inspiration, it is – 1 mmHg; at the peak of
expiration, it is +1 mmHg.
At the beginning and at the end of both inspiration and expiration (when there is
no airflow), the intralveolar pressure is zero i.e. same as atmosphere pressure.
(iii) Transpulmonary or the transmural pressure or the distending pressure is the
difference between intrapulmonary and intrapleural pressure.
Total Ventilation
• Total ventilation = tidal volume × respiratory rate
Alveolar ventilation
• Alveolar ventilation is the amount of fresh (non-dead space) gas entering the alveoli
per minute i.e., (tidal volume- dead space volume) × respiratory rate. It can be
determined from the alveolar ventilation equation, that is, the CO2 output divided by
the fractional concentration of CO2 in the expired gas.
• The concentration of CO2 (and therefore its partial pressure) in alveolar gas
and arterial blood is inversely related to the alveolar ventilation.
Muscles involved in quiet respiration
• Inspiration : Diaphragm is the main muscle; also external intercostal muscle
AfraTafreeh.com
• Expiration : No expiratory muscle (passive)
Muscles involved in forceful respiration
• Inspiration : Scalene, sternocleidomastoid
• Expiration : Internal intercostal muscles, Anterior abdominal muscle
164 | Physiology
Concept 5.4: Compliance
• To define compliance
• To understand the relaxation- pressure curve and to understand the
significance of relaxation volume, minimum lung volume and residual volume
from the relaxation- pressure curve
• To enunciate the types of compliance measurements- static and dynamic
compliance
• To define specific compliance
• To enumerate the factors affecting compliance and the conditions causing
decrease or increase in lung compliance
Time Needed
1st reading 10 mins
2 look
nd
05 mins
Compliance
This is defined as the change in volume for a unit change in pressure
∆V
Compliance =
∆P
AfraTafreeh.com
• Lung compliance is greater than that of lungs plus chest wall, being 0.2 liters
per cm of H2OQ. compliance of lungs and chest wall is 0.1L/cm H2O.
Lung- thorax relaxation pressure curve
• A plot of the change in volume with a change in pressure is the volume-pressure
curve or the relaxation-pressure curve.
• When the relaxation – pressure curve is plotted for the total respiratory system (i.e.
taking into account the interaction between the recoil of the lungs and recoil of the
chest) the volume of the gas in lungs when the pressure is zero is called the relaxation
volume.
• The relaxation volume equals the functional residual capacity.
Types of compliance measurements
(i) Static compliance: This is the measurement made without taking into account the
effect of the different phases of respiration.
(ii) Dynamic compliance: Compliance measurement during the difference phases of
respiration.
Specific compliance
• Specific compliance = Compliance / FRC
• In emphysema there is an increase in lung compliance but decrease in specific
compliance.
Factors affecting compliance
(i) Lung volume: Smaller the lungs, smaller is the compliance. Specific compliance
measurement removes the effect the effect of lung size on compliance.
(ii) For a given lung size, the compliance becomes less at extremes of lung volume.
AfraTafreeh.com
(iii) Compliance is more during deflation than during inflation
(iv) If surface tension is more, compliance is less
Conditions in which compliance is affected
• Compliance decreased : Pulmonary congestion, pulmonary fibrosis etc.
• Compliance increased : Emphysema, old age
Elastance is the reciprocal of compliance or 1/compliance or ∆ P/∆ V
166 | Physiology
Concept 5.5: Surface tension and surfactant
• To understand the concept of surface tension and its significance in the lungs
• To understand the role of surfactant in lowering surface tension
• To enumerate functions of surfactant
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Alveolar surface tension

• In an air-liquid interface, the molecules on the top most layer are attracted towards
each other and this creates the surface tension.
• Surface tension is less at lower lung volumes (this is due to the effect of surfactant)
Surfactant
• The alveolar fluid also has a surface-tension lowering agent called surfactant.
• This is secreted by type II (granular pneumocytes) alveolar epithelial cells.
• It is a mixture of dipalmitoyl phosphatidylcholine (phosphatidyl choline is also called
lecithin) other lipids, protein and carbohydrates.
AfraTafreeh.com
• The maximum percentage in the surfactant is that of dipalmitoyl phosphatidyl choline.
Functions of surfactant
(i) Prevents alveolar collapse; maintains alveolar stability
(ii) Prevents pulmonary edema
The surface – tension lowering ability of surfactant depends upon its concentration
per unit area. When the lung volume is less, the alveoli are smaller and therefore the
concentration E.g. surfactant per unit area is more. Consequently, the surface tension is
less at lower lung volumes.
Concept 5.6: Work of breathing
• To enumerate the types of work done in quiet breathing
• To understand and enumerate the conditions which increase work of breathing
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Work of breathing
This is required to do
(i) Elastic work (66% or 2/3rds)
a. Tissue elasticity (1/3rd or 22% of the total work done)
b. Surface tension elasticity (2/3rd or 44% of the total work done)
(ii) Non-elastic work (35%)
c. Viscous resistance (7%)
d. Airway resistance (28%)
f The work of breathing can be calculated from the relaxation – pressure curve.
f Work done in quiet breathing is 0.3 to 0.8kgm/min.

respiratory system.
AfraTafreeh.com
f The work of breathing for the lung alone is more than that for the total
f Since the airway resistance becomes more during turbulent flow, the work of
breathing is more during turbulent flow than during laminar flow.
f The work of breathing is increased in conditions such as emphysema, asthma,
congestive heart failure
168 | Physiology
Concept 5.7: Hysteresis loop
• To understand the reason behind hysteresis
• To understand the differences in
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Hysteresis Loop
• An important factor affecting the compliance of the lungs is the surface tension of the
thin film of fluid lining the alveoli.
• More the surfactant, less is the surface tension, more will be the compliance.
• During expiration, as the alveolar size reduces, concentration of surfactant molecules
per unit area increases- this decreases surface tension and increases compliance;
compliance is, therefore, more in expiration than inspiration.
• For a saline-filled lung, the distending pressure is the same during inspiration and
expiration.
• The difference between saline and air curves is much smaller when lung volumes are
small.
AfraTafreeh.com
• Differences become obvious in the curves generated during inspiration and expiration-
this difference is called hysteresis and is notably not present in a saline- filled lung.
• The alveolar environment, and specifically the surfactant that helps reduce surface
tension and keep the alveoli from collapsing, contribute to hysteresis.
The figure shows the static

pressure- volume curves of
saline-filled and air-filled excised
lungs. In the saline-filled
lung, the distending pressure
is the same during inflation
and deflation. The air-filled
lung shows hysteresis (that is,
higher pressures on inflation
and decreased pressures on
deflation). The hysteresis results
from the effects of surface
tension forces caused by the air-
liquid interface in the alveoli.
Concept 5.8: Ventilation- perfusion gradients from base to apex in
the erect posture
• To understand the differences in ventilation, perfusion and V/Q ratio from base to
apex in the upright position
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Ventilation – perfusion gradients from base to apex of the lung (in the
upright position)
(i) The intrapleural pressure decreases from base to the apex; intrapleural pressure is
higher at base and less at apex.
(ii) Ventilation per unit lung volume decreases from base to the apex; ventilation is
higher at base and less at apex.
(iii) Perfusion decreases from base to the apex; perfusion or blood flow is higher at
base and less at apex.
(iv) The ventilation – perfusion ratio increases from base to apex; V/Q ratio is less at
base (0.63) and higher at apex (3.3).
AfraTafreeh.com
170 | Physiology
Concept 5.9: Dead space
• To understand the two types of dead space- anatomic and physiologic, and their
measurement
Time Needed
1st reading 10 mins
2 look
nd
05 mins
Dead space
(i) Anatomical dead space is the volume of the conducting airways, which is = the
respiratory system volume up to alveoli.
Normal value is about 150mL.
It can be measured from the nitrogen concentration in the expired air following a
single inspiration of 100% oxygen.
It increases with large inspirations because of traction or pull exerted on the
bronchi by the surrounding lung parenchyma.
The anatomic dead space also depends on the size and posture of the subject.
(ii) Physiologic dead space (or total dead space) is the volume of gas that does not
eliminate CO2.
Physiologic dead space = Anatomic dead space + wasted ventilation (due to over
AfraTafreeh.com
ventilated or under-perfused alveoli).
In other words, physiologic dead space is the volume of gas not equilibrating with
blood.
It is measured by the Bohr’s method using arterial and expired CO2.
Normally, physiologic dead space = anatomic dead space = 150 mL, but the
physiologic dead space is increased in many lung diseases.
Measurement of anatomic dead space by the single breath nitrogen technique
• Also k/a Fowler’s technique.
• It can also measure
Closing volume (the lung volume above the residual volume of which the airways

in the lower, dependent parts of the lung begin to close off because of lesser
transpulmonary pressure in these areas).
Physiologic dead space by Bohr’s equation

VD PACO2 – PECO2
=
VT PACO2
Where VD is the dead space volume and VT is the tidal volume; A and E refer to alveolar
and mixed expired air respectively
The normal ratio of dead space to tidal volume is in the range of 0.2 to 0.35 during
resting breathing. In normal subjects, the PCO2 in the alveolar gas and that in the arterial
blood are virtually identical so that the equation is therefore often written
VD PaCO2 – PECO2
=
VT PaCO2
Diffusion of oxygen across the blood brain barrier

At rest the PO2 of the blood reaches an equilibrium with that of the alveolar gas after
about one third of its time in the capillary. Blood spends only about 0.75 second in the
pulmonary capillary at rest (pulmonary capillary transit time).On exercise this time is
reduced to 0.25 second AfraTafreeh.com
172 | Physiology
Concept 5.10 : Diffusing capacity of lungs
• To define diffusing capacity of lungs
• To enumerate the factors affecting diffusing capacity
• To understand measurement of diffusing capacity of the lungs using CO
• To enumerate the conditions affecting diffusing capacity of the lungs
Time Needed
1st reading 05 mins
2 look
nd
02 mins
Diffusion capacity of lung

Definition: The diffusion capacity of the lung (DL)is defined as the volume of gas
diffusing across the respiratory membrane in 1 minute when the pressure gradient is 1
mmHg.
Factors affecting diffusion capacity
K× A×S
DL =
d×w
Where k is proportionality constant

AfraTafreeh.com
A = Area of the membrane
S = Solubility of the gas
W = molecular weight of the gas
D = thickness of the membrane
s is called the diffusion coefficient; the diffusion coefficient is entirely based on the
√w characteristic of the gas.
Measurement of diffusion capacity
Diffusion capacity of carbon monoxide (DLCO) is taken as an index of diffusion capacity.
DLO2 is never measured directly; it is expressed with DLCO as the index.
(Carbon monoxide is used to measure diffusing capacity because the uptake of the gas
is diffusion limited).
Value
DLO2 = 25 mL/ min / mm Hg
DLCO2 is 20 times DLO2
Conditions in which DL is affected
(i) DLO2 increases in exercise
(ii) DLO2 decreases in sarcoidosis, beryllium poisoning, pulmonary fibrosis etc.
Concept 5.11: Spirometery
• To define various lung volumes and capacities and their normal values
• To enumerate and understand the different methods for measuring FRC
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Methods for measuring lung volumes, capacities and dead space

Spirometry: Measures all volumes and capacities except those involving measurement
of residual volume; therefore, it cannot measure residual volume, functional residual
capacity and total lung capacity
AfraTafreeh.com
Volume (L)
Men Women
{ }Inspiratory capacity
IRV 3.3 1.9
Vital capacity TV 0.5 0.5

ERV
RV
1.0
1.2
0.7
1.1
}Functional residual capacity
Total lung capacity 6.0 4.2
Respiratory minute volume (rest): 6L/min Timed vital capacity: 83% of total in 1s; 97%
Alveolar veritilation (rest): 4.2 L/min in 3 s works of quite vreathing: 0.5 kg-m/min
Maximum voluntary ventilation (BTPS): Maximal work of vreathing: 10kg-m/breath
125-170 L/min
174 | Physiology
Techniques for measurement of FRC
• Helium dilution method
AfraTafreeh.com
• Nitrogen washout method
AfraTafreeh.com
• Whole body plethysmography
176 | Physiology
• The plethysmograph is a large airtight box, like a telephone booth, in which the
subject sits.
• At the end of a normal expiration, a shutter closes the mouth piece and the subject is
asked to make respiratory efforts.
• As the subject tries to inhale, he expands his lungs, lung volume increases and airway
pressure decreases whereas the volume of the air in the room/ box decreases and
the pressure increases.
• Boyle’s law states that pressure X volume is constant (at constant temperature).
• Therefore, if the pressure in the box before and after the inspiratory effort are P1
and P2, respectively and V1 is the preinspiratory box volume, and ∆V is the change in
volume of the box (or lung), it can be written
P1V1 = P2 (V1 - ∆V)
• Thus ∆V or change in the volume of lung can be obtained.
• Next, Boyle’s law is applied to the gas in the lung.
P3V2 = P4 (V2 + ∆V)
• Where, P3 and P4 are the mouth pressures before and after the inspiratory effort, and
V2 is the FRC. Thus, FRC can be obtained.
Advantage of whole body plethysmography:
• The whole body plethysmography measures the total volume of gas in the lung,
including any that is trapped behind closed airways and that does not communicate
with the mouth. On the other hand, helium dilution technique cannot measure the
AfraTafreeh.com
trapped air and can only measure the communicating gas or ventilated lung volume.
• In young normal subjects, these volumes are almost the same, but in patients with
lung disease, the ventilated volume may be considerably less than the total volume
because of air trapped behind obstructed airways.
Concept 5.12: Flow-volume loops
• To study the flow volume loops in different conditions
Time Needed
1 reading
st
15 mins
2nd look 10 mins
AfraTafreeh.com
Features of the flow- volume loop in obstructive lung disease are:-

• Total lung capacity- increased
• Residual volume- increased
• Vital capacity- normal to decreased
• FEV1/ FVC- decreased
• PEFR- decreased
• MEFR- markedly decreased
• Most characteristic feature is the “scooped out or coved” (upward concavity) shape
of the descending limb of the expiratory curve-It is due to non uniform and abrupt
emptying of large central airways associated with vigorous exhalation that causes
these airways to collapse. This loss of linearity is related to the severity of the
obstruction as well as the type of disease.
• Diffusing capacity- normal except in Emphysema
• LOOP SHIFTS TO THE LEFT
178 | Physiology
Features of flow- volume loops in restrictive lung disease due to parenchymal
causes:
• Total lung capacity- decreased
• Residual volume- decreased
• Vital capacity- decreased
• FEV1/ FVC- normal to increased
• Flow rates (PEFR, MEFR) are more or less preserved
• The expiratory curve is typically described as a “tall and narrow curve”- tall, because
the flow rates are preserved, and narrow, because the volumes are decreased
• LOOP SHIFTS TO THE RIGHT
AfraTafreeh.com
Features of flow- volume loops in restrictive lung disease due to chest wall
deformities (kyphosis, scoliosis):
• FEV1/ FVC- normal to increased
• Flow rates (PEFR, MEFR) are more or less preserved
• CURVE LIES WITHIN NORMAL CURVE
Features of flow- volume loop in fixed, large, central airway obstruction:
• Both the inspiratory and expiratory limbs are truncated- the shape is quite characteristic
with more or less equal restriction of both inspiratory and expiratory flow rates
Features of flow- volume loop in variable, intrathoracic, large, central airway

obstruction:
• In this type of large airway obstruction, expiration is affected more than inspiration.
• Inspiratory curve is almost normal.
• Expiratory curve is flattened or truncated.
Features of flow- volume loop in variable, extrathoracic, large, central airway
obstruction:
• In this type of large airway obstruction, inspiration is affected more than expiration.
AfraTafreeh.com
• Expiratory curve is almost normal.
• Inspiratory curve is flattened or truncated.
180 | Physiology
Concept 5.13: Gas transport
• To enumerate the normal values of partial pressure of O2 and CO2 in the atmosphere,
inspired air, alveolar air, arterial blood, venous blood and expired air
• To understand O2 transport and calculation of O2 content of the blood
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Symbols P = partial pressure

I = Inspired air
E = Expired air
A = Alveolar
a = arterial
v = venous
v = mixed venous
B = Barometric
F = Fractional percentage
Partial pressuresAfraTafreeh.com
PIO2 means partial pressure of O2 in inspired air
of O & CO in inspired air,
2
Partial pressure of O2 / CO2 at different sites2(in mmHg)
alveolar
Partial pressure of O / CO inair
2
& blood
inspired
2
air, alveolar air & blood:
PO2 =160 Dry inspired air

PCO2=0
PO2=150 Humidified tracheal air

PCO2=0
PO2=100 Alveolar air

PCO2=40
PO2=40 PO2=100 PO2 is

PCO2=46 actually less
PCO2=40
than
Mixed venous Systemic arterial 100mmHg
blood blood (95mmHg)
Pβ Insp Alveolus Arterial Capillaries Veins Exp

O2 160 150 100 95* 40 40 116
CO2 0.3 0.3 40 40 46 46 32
• The partial pressure of blood leaving the pulmonary capillaries is 97 mmHg but it
falls to 95 mmHg in the systemic arterial blood because of physiologic shunt. The
physiologic shunt is due to a part of the bronchial blood flow and a part of the
coronary blood flow which bypasses the pulmonary capillaries
O2 transport
• Most of the O2 in the blood is carried along with Hb (99%).
• Each Hb carries 4 molecules of O2.
• Hb exhibits the ‘relaxed’ and the ‘tense’ state.
• When Hb takes up O2 the beta chains move closer and the heme enters the relaxed
state.
• The relaxed state favors binding of O2 while the tense state decreases binding.
Calculation of O2 carried by the blood (O2 content)
(i) 1 gm of Hb, when fully saturated, contains 1.34 ml of O2. At a pO2 of 40 mmHg (as
exists in Venous blood), Hb is only 75% saturated. Therefore, 1 gm of Hb would
carry 1.34 X 75 / 100 mL of O2 at pO2 of 40 mmHg
(ii) The amount of dissolved O2 in plasma is 0.003/ dL / mmHg of pO2. At a pO2 of
AfraTafreeh.com
40mmHg, the amount of dissolved O2 is 0.003 X 40 = 0.12 mL of O2 / dL.
Therefore,
O2 content = (O2 in combination with Hb) + (Dissolved O2)
= [Hb (gm/dL) X 1.34 X percentage saturation] + [Po2 (mm Hg)
× 0.003mL/dL/mm Hg]
182 | Physiology
Concept 5.14: Oxygen-hemoglobin dissociation curve
• To understand the basics of the Oxygen-hemoglobin dissociation curve
• To enumerate the conditions causing shift of OHDC
• To understand the Bohr’s effect and its significance
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Oxygen – Hb dissociation curve (O-HDC)

This is a plot of the partial pressure of O2 and the % saturation of Hb with O2 It is
normally sigmoid-shaped.
If the OHDC is shifted to the right, it means that the affinity of Hb for O2 has become
less (which favors O2 delivery).
Shift of OHDC to the right is caused by
• Increase in PCO2 • Increase in H+
• ↓ pH
• ↑ in temperature • ↑ in 2,3 – DPG • HbS
Factors affecting 2,3 DPG

AfraTafreeh.com
(i) ↓ in pH inhibits red cell glycolysis, 2,3 – DPG
(ii) Banked blood → Glycolysis is inhibited, therefore 2,3 – DPG is decreased (this
decrease in 2,3-DG is less if the blood is stored in citrate-phosphate-dextrose
solution rather than the usual acid-citrate-dextrose solution)
(iii) Thyroid hormones, Growth hormone, androgens, high attitude, exercise, anemia,
disease causing hypoxia → all increase 2,3 – DPG
(iv) 2,3-DPG binds poorly with the γ chain of HbF, therefore, HbF has a greater affinity
for O2
Shift of OHDC to the left is

caused by
• Decrease in PCO2
• Decrease in H+
• ↑ pH
• ↓ in temperature
• ↓ in 2,3 – DPG
• HbF
• Myoglobin
• Banked blood
Myoglobin
This is present in skeletal muscles. 1 molecule of myoglobin binds 1 molecule of O2. The
shape of O2 myoglobin dissociation curve (OMDC) is a rectangular hyperbola. It lies to
the left of the O2 – Hb dissociation curve.
AfraTafreeh.com
Bohr effect
• Decrease in O2 affinity of Hb (and a shift of the OHDC to the right) with a decrease in
pH is called the Bohr’s effect.
• It is closely related to the fact that deoxyhemoglobin bunds H+ more actively than
does oxyhemoglobin.
• pH of the blood falls as its CO2 content increases, so that when the Pco2 rises, the
curve shifts to the right and P50 rises.
• Most of the unsaturation of Hb that occurs in the tissues is secondary to the decline
in Po2, but an extra 1-2% unsaturation is due to the rise in Pco2 and consequent shift
of the dissociation curve to the right.
184 | Physiology
Concept 5.15: CO2 transport
• To understand the different mechanisms of CO2 transport
• To understand the concept of Haldane effect
• To understand chloride shift (also k/a hamburger effect) in venous RBC
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Mechanisms of CO2 transport

Out of the 49ml of CO2 / dL in arterial blood, 2.6 mL is dissolved 2.6 mL of CO2 exists as
carbamino compound and 43.8 mL is transported as bicarbonates.
Mechanisms of CO2 is transport in :
(a) Plasma
In dissolved form; solubility of CO2 is 0.067mL/dL/mm Hg
As carbamino compound with plasma proteins
As bicarbonates:- CO2 + H2O H2 CO3 H+ + HCO3- . The H+ gets buffered
with plasma proteins. Since there is no carbonic anhydrase in plasma, the process
of hydration is slow. AfraTafreeh.com
(b) RBC
In dissolved form
As carbamino compound with Hb
As bicarbonates
CO2 + H2O H2 CO3 H+ + HCO3-. H+ gets buffered by Hb; 70% the HCO3-
enters plasma and Cl- enters RBC (chloride shift)
(Since carbonic anhydrase is present in RBCs, the process of hydration is rapid.)
Haldane effect
• Reduced hemoglobin is less acid (that is, a better proton acceptor) than oxyhemoglobin.
• Deoxyhemoglobin in the peripheral tissues binds more H+ than oxyhemoglobin and
forms carbamino compounds more readily whereas binding of O2 to hemoglobin in the
pulmonary capillaries reduces its affinity for CO2.
• The Haldane effect refers to the increased capacity of deoxygenated hemoglobin to
bind and carry CO2.
• Consequently, venous blood carries more CO2 than arterial blood.
• Unloading of O2 in the peripheral tissues facilitates uptake of CO2, whereas oxygenation
in the lungs facilitates CO2 release.
Chloride shift or Hamburger effect
• It is clear from the above that for each CO2 molecule that goes into RBC, there is
either one HCO3- or one Cl- inside the RBC; the chloride content of the venous blood
RBC is more than that of arterial blood RBC.
• To maintain electrical neutrality, Cl- ions move from the plasma into the RBCs- this is
k/a chloride shift.
• The venous RBC has a higher osmolal content, and consequently, water enters the
cell, thus increasing its volume.
• For this reason, plus the fact that a small amount of fluid from the capillaries enters
into the interstitial spaces and returns to the circulation via the lymphatics, the
hematocrit of venous blood is higher 3% greater than arterial blood.
• Chloride shift occurs rapidly and is complete within 1 second.
AfraTafreeh.com
186 | Physiology
Concept 5.16: Regulation of respiration
• To understand the neural control of respiration and the role of medulla, pons and
higher centers in regulating respiration
• To understand the role of vagus in controlling the depth of inspiration
• To understand the chemical control of respiration and the role of peripheral and
central chemoreceptors in regulating respiration
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Neural Control of respiration

Role of medulla
• The automatic pattern generator or the pacemaker of ventilation lies in the medulla
(Pre-Bottzinger nucleus).
• In addition, dorsal and ventral group (DRG & VRG) of neurons are present in the
medulla.
• DRG is responsible for normal, tidal respiration.
• DRG has “I” neurons which send inspiratory signals to neurons in cervical spinal cord
AfraTafreeh.com
that activate the diaphragm.
• VRG has both “I” and “E” neurons that can send signals for both inspiration and
expiration to neurons in cervical and thoracic spinal cord.
• VRG takes over whenever the requirement increases (for example, during exercise).
Role of pontine centers
• Although the rhythmic discharge of medullary neurons concerned with respiration is
spontaneous, it is modified by neurons in the pons and afferents in the vagus from
receptors in the airways and lungs.
• Besides regulating the depth of inspiration, pontine centers are responsible for a
smooth transition between inspiration and expiration.
• The pneumotaxic center lies in upper pons and the apneustic center lies in the lower
pons.
• The pneumotaxic center and the vagi put the brakes on depth inspiration.
• When pneumotaxic center is damaged, depth of inspiration increases.
• When pneumotaxic center is damaged and the vagi are also cut, there are prolonged
inspiratory spasms that resemble breath holding (k/a apneuses or apneustic
breathing).
• One could say that automatic respiration originates in the medulla and the pons does
the fine tuning.
Role of vagus
• Stretching of the lungs during inspiration initiates impulses in afferent vagal fibers.
• These impulses inhibit inspiratory discharge (decrease the depth of inspiration).
• Depth of inspiration is increased after vagotomy.
• Apneustic breathing develops if the vagi are cut after damage to the pneumotaxic
center.
• Vagal feedback does not alter the rate of rise of the neural activity in respiratory
motor neurons.
Chemical control of respiration

The chemoreceptors for chemical control are the
1. Peripheral chemoreceptors viz., the carotid and the aortic bodies
2. Central chemoreceptors situated in the ventral surface of the medulla
Peripheral chemoreceptors
• Carotid and aortic bodies are located at the bifurcation of the carotid and along the
arch of aorta respectively.
• Stimuli for peripheral chemoreceptors include
Decrease in PO2

Increase in PCO2

Increase in H+

Increase in lactic acid

Increase in K+

Cyanide

• Each carotid and aortic body contains 2 types of cells, type I and type II cells.
• The type I (glomus cells) responds to hypoxia; they have O2 – sensitive K+ channels.
AfraTafreeh.com
• The carotid body has a very high blood flow (2000mL/100g/min compared with brain
which has a blood flow of 54mL/100g/min). Because of this, if does not respond to
anemic hypoxia (since the dissolved oxygen meets the needs).
Central chemoreceptors
• Central chemoreceptors are present on the surface of medulla.
• Most potent stimulus for the central chemoreceptors is H+.
• They are sensitive to the H+ in the CSF and the brain interstitial fluid.
• Since H+ cannot cross the blood brain barrier, the most potent stimulus for central
chemoreceptors in the blood is CO2.
• CO2 can influence these central chemoreceptors only indirectly by crossing the blood
brain barrier and getting converted into H+.
• CO2 is able to act on both central (60-70% of the effect of CO2) as well as on peripheral
(30-40% of the effect of CO2) chemoreceptors.
Ventilatory response to CO2

• The link between metabolism and ventilation is CO2 and not O2
• There is a linear relationship between respiratory minute volume and alveolar pCO2
Ventilatory response to O2 lack
There is no increase in ventilation till the PAO2 (alveolar PO2) becomes less than 60
mmHg. The reasons for this lack of response are:
(i) Hb is a weaker acid than HbO2; therefore with less O2, there is more Hb which by
being weaker acid tends to inhibit the ventilation
(ii) Also, as ventilation increases, the CO2 that is washed out counters the increase in
ventilation
188 | Physiology
Concept 5.17: CO2 response curves
• To understand CO2 response curves
• To understand the effect of hypoxia on CO2 response curves
• To understand the Effect of H+ on CO2 response curves
Time Needed
1 reading
st
10 mins
2nd look 05 mins
CO2 response curves and the effect of hypoxia on CO2 response curves
• Increase in PCO2 stimulates the peripheral and central chemoreceptors increasing the
rate and depth of ventilation, resulting in increase in total and alveolar ventilation.
• The relationship of PCO2 and ventilation is linear.
• Effect of hypoxia on CO2 response curves exhibits a complex relationship, the effect
of CO2 excess and O2 lack is more than additive.
• If one were to plot a curve between CO2 and ventilation at different fixed O2 levels,
one would get a fan of curves.
• The slope of the curves (between CO2 and ventilation) increases significantly with
AfraTafreeh.com
decreased O2 levels (however, the alveolar PCO2 level at which the curves intersect is
unaffected).
pO2 = 80
pO2 = 90
pO2 = 100
Ventilation
(L/min)
0 40 80
PAco2 (mmHg)
• This increase in slope at lower PO2 levels indicates at an increase in sensitivity of the
chemoreceptors to PCO2 in the presence of hypoxia. In other words, hypoxia makes an
individual more sensitive to an increase in arterial PCO2.
• Since this point of intersection is below the normal value of PACO2 of 40 mmHg, it
shows that there is normally a slight but definite CO2 drive of the respiratory center.
Effect of H+ on CO2 response curves
The stimulatory effects of H+ and CO2 on ventilation is additive.
In metabolic acidosis, the CO2 response curves are similar to those in the above figure
except that they are shifted to the left.
In other words, the same amount of respiratory stimulation is produced by lower arterial
PCO2 levels.
CO2 response curve shift 0.8 mm Hg to the left for each nanomole increase in arterial H+.
AfraTafreeh.com
190 | Physiology
Concept 5.18: Respiratory reflexes
• To understand the important respiratory reflexes and their significance- Hering- Breur
inflation and deflation reflexes, J-receptor reflex, Head’s paradoxical reflex
Time Needed
1st reading 05 mins
2 look
nd
02 mins
Hering Breur Inflation reflex

• Stimulus: Lung inflation > 1-1.5L (2-3 times tidal volume).
• Receptors: Slowly adapting pulmonary stretch receptors in tracheobronchial tree
(airway smooth muscle).
• Afferents: Vagus.
• Response: decrease in depth of inspiration and increase in expiration time.
Hering- Breur deflation reflex
• Stimulus: Marked deflation of lungs
• Response: increase in depth of inspiration and decrease in expiration time.
• Significance: prevents atelectasis of lung.
J- receptor reflex
AfraTafreeh.com
• J- receptors or juxtacapillary receptors are unmyelinated C fibers close to pulmonary
capillaries in the lung interstitium.
• Stimuli: hyperinflation of lungs, intravenous of intracardiac administration of chemicals
such as capsaicin, pulmonary congestion, pulmonary edema, pulmonary embolism.
• Responses: apnea (transient) followed by rapid, shallow breathing, hypotension,
bradycardia.
Head’s paradoxical reflex
• This reflex is provoked when lung inflation increases the afferent output from the
rapidly adapting irritant receptors into the respiratory center, stimulating inspiration
(inflation causes further inflation of lungs).
• The inflation inhibition by Hering-Breur inflation reflex is annulled and a deep breath
occurs.
• Importance: Head’s paradoxical reflex is responsible for the first breath in newborns
and also in augmented breath of adults.
Breath Holding
Breaking point is the point at which breathing can no longer be voluntarily inhibited
(because of increase in CO2 and decrease in O2).
Breath holding can be prolonged by:-
1) Removal of carotid bodies
2) Breathing 100% O2 before breath holding
3) Hyperventilating room air (because of the initial ↓ in CO2 of arterial blood)
4) By breathing gas mixture low in O2 and high in CO2, breath holding can be prolonged
for an additional 20 seconds
5) Encouragement
Concept 5.19: Hypoxia
• To enumerate the different types of hypoxia and understand their causes and features
• To understand CO poisoning
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Types of Hypoxia
Hypoxic Anemic Stagnant Histotoxic
Underlying cause PaO2 is ↓ed Amount of O2 carrying No utilization of O2
available Hb capacity is normal at tissue level
decreases but O2 delivery is
decreased
Examples High altitude, Anemia, CO Heart failure Cyanide poisoning
h y p o v e n t i l a t i o n poisoning
due to any cause
PaO2(dissolved O2) ↓ed Normal Normal Normal
O2 combined with ↓ed
Hb (SO2)
AfraTafreeh.com
↓ed Normal Normal
Arterio-venous O2 Normal Normal ↑ed ↓ed

difference
Peripheral Stimulated Not stimulated Stimulated Stimulated
chemoreceptors (cyanide directly
stimulation stimulates
peripheral
chemoreceptors)
Amount of reduced ↑ed Total Hb ↓ed, HHb ↑↑↑ed ↓ed
Hb ↑ed
Cyanosis Can be present Unlikely Can be present -
C.O. Poisoning
• Affinity of Hb for CO is 210 times that for O2.
• Binding of CO with Hb reduces SO2 and therefore, the O2 carrying capacity of the
blood.
• CO poisoning produces anemic hypoxia.
• C.O. poisoning is especially dangerous because
1) Less Hb is available for carrying O2, resulting in a decrease in SO2.
2) Since the dissolved O2 is normal there is no peripheral chemoreceptor stimulation.
3) There is a shift of the O2 – Hb dissociation curve to the left which increases the
affinity of Hb and O2.
192 | Physiology
Concept 5.20: Acclimatization to high altitude
• To understand the changes in high altitude
• To understand the processes involved in acclimatization to high altitude
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
On ascent to high altitude the following are seen

1) PB (the atmospheric pressure) decreases.
2) Composition of the air remains the same.
3) Partial pressure of O2 in the atmosphere decreases.
4) Alveolar partial pressure of O2 (PAO2) decreases
5) Arterial partial pressure of O2 (PaO2) and therefore, saturation of Hb (SO2) decrease
resulting in hypoxic hypoxia.
Acclimatization to High Altitude
Acclimatization to high altitude is due to operation of a variety of compensatory
mechanisms.
AfraTafreeh.com
Minimum time for acclimatization is 2-3 days (48-72 hrs).
The following occur in acclimatization:-
(i) Increase in ventilatory response-
▫ Hypoxia stimulates the peripheral chemoreceptors which in turn increase the

rate and depth of ventilation.

▫ The initial increase in ventilatory response causes a CO2 washout and respiratory

alkalosis, which suppresses the ventilatory drive produced by hypoxia.

▫ However, ventilation steadily increases due to

f Increased renal excretion of bicarbonates, which increases urinary output

f Active transport of H+ into the CSF, or a possibly developing lactic acidosis in

the brain causes a fall in CSF pH that increases the response to hypoxia.
(ii) Hypoxia causes ↑ in erythropoietin, which in turn increases the red cell mass and
therefore, the oxygen carrying capacity.
(iii) At tissue level, there is increase in mitochondria, cytochrome oxidase myoglobin.
(iv) O-HDC (Oxygen – Hb dissociation curve)
▫ Alkalosis tends to shift the O-HDC to the left, but a concomitant increase in red

cell 2, 3 – DPG tends to shift the O-HDC to the right.

▫ Net effect is a slight shift of the O-HDC to the right (i.e. the P50 increases slightly).

▫ However, the value of the increase in P50is limited because when the arterial

PO2is markedly reduced, the decreased O2 affinity interferes with O2 uptake in

the lungs.
Acute mountain sickness

• Develops 8-24 hours after arrival at high altitude and lasts 4-8 days.
• It is characterized by headache, irritability, insomnia, breathlessness, nausea, vomiting.
• Hypoxia causes vasodilation of the cerebral vessels, which in turn increases the capillary pressure that
favours transudation of fluid into brain tissue.
High-altitude cerebral oedema
• This is a more serious syndrome associated with high altitude.
• Capillary leakage in mountain sickness progresses to frank brain swelling, with ataxia, disorientation,
and in some cases coma and death due to herniation of the brain through the tentorium.
High- altitude pulmonary oedema
• Hypoxia causes ‘patchy vasoconstriction’ in the lungs.
• Increased flow to those areas where there is little or no vasoconstriction causes the capillary pressure to
increase which increases transudation of fluid and disrupts their walls (stress failure).
Treatment of high-altitude cerebral oedema and high-altitude pulmonary oedema
• O2 and if available, use of hyperbaric chamber
• Descent to a lower altitude
• When cerebral oedema is marked, large doses of glucocorticoids have been found to be helpful.
• Nifedepine, a calcium channel blocker, lowers pulmonary artery pressure and has been found to be useful.
The diuretic acetazolamide has been found to be useful in preventing acute mountain sickness. It is a
AfraTafreeh.com
carbonic anhydrase inhibitor. It causes acidosis which results in stimulated ventilation.
194 | Physiology
Concept 5.21: Important formulae in respiratory system
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
In conclusion, important formulae/calculations from Respiratory system

1. Dalton’s Law of Partial Pressures states that: the total pressure exerted by a
mixture of gases is equal to the sum of the partial pressures exerted by each gas.
Mathematically, Pressure Total = Pressure1+Pressure2+…….
Pressuren
2. Total or Pulmonary ventilation (L/min) = respiratory rate per minute X tidal volume
(L)
3. Alveolar ventilation (L/min) = respiratory rate per minute X (tidal volume – dead
space volume)
4. PCO2 α 1/ VA. PCO2 is inverse to the alveolar ventilation. If alveolar ventilation is
doubled, PCO2 level will be halved.
▫ Sample question- If alveolar ventilation is doubled, how much is the PaCO2

▫ Remember PACO2 = PaCO2

AfraTafreeh.com
5. Physiological or total dead space = Anatomic dead space + wasted ventilation
6. Normally, wasted ventilation = zero, so physiologic dead space = anatomic dead
space
7. When V/Q ratio >1, it is wasted ventilation
8. When V/Q ratio <1, it is wasted perfusion (or shunting), which causes incomplete
oxygenation of the blood
9. Anatomic dead space is calculated by Fowler’s technique (or Nitrogen analysis in
expired air after a single deep breath of 100% oxygen. Also k/a single breath N2
analysis.
10. Physiologic dead space can be calculated by Bohr’s equation.
11. Bohr’s equation can also be used to calculate dead space/tidal volume ratioQ
PECO2 X tidal volume = PACO2 X (tidal volume – dead space volume)
PECO2/ PACO2 = (VT - VD)/ VT
PECO2/ PACO2 = (1- VD/ VT)
PECO2/ (PACO2 = 1- VD/ VT
VD/ VT = 1 – PECO2/PACO2
12. Spirometery
▫ Tidal volume is volume of air inspired or expired during a normal, tidal respiration

▫ Inspiratory reserve volume is the volume of air inspired forcefully over and

above a normal tidal inspiration with maximum effort

▫ Expiratory reserve volume is the volume of air expired forcefully over and above

a normal tidal expiration with maximum effort

▫ Residual volume is the volume of air which remains in the lungs at the end of a

maximum expiration
▫ Inspiratory capacity = IRV + TV

▫ Expiratory capacity = ERV + TV

▫ Functional residual capacity is the volume of air which remains in the lungs at

the end of a normal expiration

▫ FRC= ERV + RV

▫ Vital capacity is the volume of air expired forcefully after a forceful inspiration

▫ VC= IRV + TV + ERV

▫ Total lung capacity = IRV + TV + ERV + RV

▫ FEV1 is the volume of air expired forcefully at the end of one second after a

forceful inspiration. Normal FEV1/ FVC = 0.7 to 0.8 or 70 – 80%

13. Ventilation at base = 0.82 L/min
Perfusion at base = 1.29 L/min
V/Q ratio at base = 0.63
14. Ventilation at apex = 0.24L/min
Perfusion at apex = 0.07L/min
V/Q ratio at apex = 3.3 AfraTafreeh.com
15. Ventilation and perfusion decrease from base to apex BUT V/Q ratio increases from
base to apex
16. Average V/Q ratio for the whole lung = 0.8
17. Intrapleural pressure is also k/a pleural or intrathoracic or esophageal pressure
18. Intrapulmonary pressure is also k/a airway or alveolar pressure
19. Transpulmonary or transmural or distending pressure = Intrapulmonary –
intrapleural
20. Compliance is defined as change in volume per unit change in transpulmonary
pressure.
▫ Sample question- If change in lung volume is 500mL and the esophageal pressure

changes from -4cm H2O to -8cm H2O, how much is the lung compliance?
21. Specific compliance = compliance/ FRC
22. Elastance is inverse to compliance. Elastance is defined as change in pressure per
unit change in lung volume.
23. La place’s Law states that tension (T) in the wall of an organ is equal to the product
of the pressure surrounding it and its radius ( r)
T= Pr
P=T/r
In case of an alveolus, which is a spherical viscus
P = T(1/r1+ 1/r2)
196 | Physiology
But since r1 = r2
P = T (2/r)
P = 2T/r
24. Compliance is inverse to the surface tension
25. Compliance during inspiration and expiration- graph obtained is called as Hysteresis
loop.
AfraTafreeh.com
▫ Inspiration (Inflation of the lungs) & expiration (deflation) of lungs follow

different curves, because of changes in radius of alveoli and surface tension.

This is in accordance to Laplace Law.
▫ During inspiration, radius of alveoli increases and tension also increases.

Therefore, compliance decreases.

▫ During expiration, radius of alveoli decreases and tension also decreases.

Therefore, compliance increases.

26. Surface tension is inverse to the amount of surfactant
27. Compliance is directly proportional to the amount of surfactant. More the surfactant,
more is the lung compliance
28. To calculate partial pressure of a gas in the atmosphere
Partial pressure = Fractional concentration X atmospheric pressure
29. To calculate partial pressure of O2 in inspired air (PIO2)
PIO2 = (PB – PH2O) X Fractional concentration of O2
▫ Sample question – If a patient is given 100% oxygen, how much is the PIO2 at

sea level?
30. Alveolar gas equation is used to calculate partial pressure of O2 in the alveolus
PAO2 = PIO2 - (PACO2/ R)
▫ Sample question- If a patient is given 80% O2, how much is the alveolar O2 at

sea level?
▫ Another one- if an individual is given 100% O2 at 4 times atmospheric pressure,

how much is the alveolar partial pressure of oxygen?

31. R is respiratory quotient (RQ). Also k/a respiratory exchange ratio (RER)
RQ = volume of CO2 produced in unit time/ volume of O2 consumed in unit time =
200mL per minute/ 250mL per minute = 0.8 (on a mixed diet)
RQ on a pure carbohydrate diet = 1.0
▫ Sample question- If an individual on a mixed diet utilizes 500mL of O2 per
minute, how much is the CO2 production in unit time?
32. To calculate O2 content of the blood
▫ O2 content (mL/dL) = (O2 in combination with Hb) + (Dissolved O2)
▫ O2 in combination with Hb = Hb in gm/dL X 1.34 X percentage saturation of Hb
▫ To calculate the dissolved Oxygen, remember the solubility of O2
▫ Solubility of O2 is 0.003mL/dL/mm Hg
▫ Sample question – If the dissolved O2 is 0.0024mL/mL of blood, how much is
the PO2
33. Solubility of CO2 is 20 times the solubility of O2
34. Solubility of CO2 is 0.067mL/dL/mm Hg
AfraTafreeh.com
198 | Physiology
Worksheet
• MCQ OF “RESPIRATORY PHYSIOLOGY” FROM DQB

AfraTafreeh.com


Lung volumes and capacities
Differences between obstructive and restrictive lung diseases

AfraTafreeh.com
OLD RLD
Total lung capacity
Residual volume
FRC
Vital capacity
FEV1/FVC
PEFR
MEFR
Diffusing capacity
200 | Physiology
Shift of oxygen hemoglobin dissociation curve
Factors causing shift of OHDC to left Factors causing shift of OHDC to right
AfraTafreeh.com
Types of hypoxia
Type of hypoxia Causes Diagnosis Peripheral
chemoreceptor
stimulation present/
absent
Hypoxic hypoxia
Anemic hypoxia
Stagnant hypoxia
Histotoxic hypoxia
6 Central Nervous System
CONCEPTS
Â Concept 6.1 Synapses

Â Concept 6.2 Types of inhibition

Â Concept 6.3 Neurotransmitters and neuromodulators

Â Concept 6.4 Receptors

Â Concept 6.5 Laws of sensory physiology

Â Concept 6.6 Ascending tracts

Â Concept 6.7 Reflexes

Â Concept 6.8 AfraTafreeh.com
Reticular formation

Â Concept 6.9 Thalamus

Â Concept 6.10 EEG

Â Concept 6.11 Evoked cortical potentials

Â Concept 6.12 Sleep

Â Concept 6.13 Effect of transection at different levels

Â Concept 6.14 Motor system- control of movement

Â Concept 6.15 Basal ganglia

Â Concept 6.16 Cerebellum

Â Concept 6.17 Brodmann’s areas

Â Concept 6.18 Hypothalamus

Â Concept 6.19 Taste

202 | Physiology
Concept 6.1 : Synapse
Learning Objectives :
• To define synapse
• To enumerate the characteristics of synapses
Time Needed
1 reading
st
05 mins
2 look
nd
02 mins
Synapse (also k/a neuronal junction)

• It is the site of transmission of electric impulses between two neurons or between a
neuron and a gland or muscle cell.
• Synapses can be chemical (most commonly) or electrical.
• Synapses can be axo-dendritic, axo-somatic or axo-axonal.
Characteristics of synapses
• Summation (a) The effect of summing post synaptic potentials by activating multiple
terminals on widely spaced areas of the neuronal membrane is spatial summation and
(b) Successive discharges from a single pre synaptic terminal, if they occur rapidly
enough, can add to one another- this is temporal summation.
• Facilitation- often the summated post synaptic potential is excitatory but has not
AfraTafreeh.com
decreased enough to reach the threshold for firing by the post synaptic neuron. When
this happens, the neuron is said to be facilitated.
• Fatigue may occur due to exhaustion/ partial exhaustion of stores of transmitter
substance in pre synaptic terminal.
• Alkalosis- increases synaptic transmission.
• Acidosis- decreases synaptic transmission (diabetic ketoacidosis/ uremic acidosis→
coma).
• Hypoxia- decreases excitability.
• Effect of drugs- caffeine, theophylline→↑ excitability by ↓ing the threshold;
strychnine→ ↑ excitability by inhibiting the action of some inhibitory transmitters
especially Glycine; most anesthetics increase the threshold for excitation, thereby
decreasing excitability.
• Synaptic delay across a single synapse is 0.5 millisec.
Central Nervous System | 203
Concept 6.2 : Types of inhibition
• To classify and distinguish between the different types of inhibition
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Types of inhibtion
1. Post- synaptic 2. Pre-synaptic
3. Feedback 4. Feedforward
5. Lateral
Inhibitory A A
Neuro-
Trans
Mitter AfraTafreeh.com Inhibitory
– + Neuro-
Trans
Mitter
B B
Direct or post-synaptic Inhibition Pre- synaptic inhibition
This is because of the release of an inhibitory ‘A’ releases an excitatory NT, to excite B. But ‘C’
neurotrasmitter (NT), e.g., Glycine from neuron A; ends presynaptically on ‘A’, releases an inhibitory
this produces an IPSP in neuron B. neurotransmitter, which hyperpolarizes ‘A’
decreasing the release of the excitatory NT. Salient
Features of Presynaptic Inhibition:
• It is example of axo-axonic synapse.
• It is stimulated by general anaesthetics.
• It is inhibited by picrotoxin.
• It is mostly due to GABA.
204 | Physiology
A
A
+
B
B +
–
-
C
C
Eg. Basket / Stellate cell

Renshaw Cell Inhibition
inhibiting the purkinje cell in
the cerebellum
Feed-forward inhibition Feedback or Renshaw cell inhibition

‘A’ stimulates ‘B’; but ‘B’ inhibits ‘C’. ‘A’ stimulates the muscle. However, collateral from
Feedforward inhibition is seen in the cerebellum. A (‘B’) ends on an inhibitory interneuron (C) in the
Granule cell stimulates the Basket cell which in turn anterior horn of the spinal cord.
inhibits the Purkinje cell. This inhibitory interneuron is called a Renshaw
AfraTafreeh.com
Granule cell stimulates the Stellate cell which in turn cell. Renshaw cell secretes an inhibitory
inhibits the Purkinje cell. neurotransmitter→ slows/ stops the discharge of
motor neurons.
Importance- for fine, precise movement
Lateral or afferent or surround inhibition

• This is one of the cornerstones of sensory physiology.
• Stimulation of a particular neuron is associated with inhibition of the activity of a
nearby neuron (by a collateral).
• This is seen in the retina- enhances contrast and sharpens the image, improves
discrimination.
• Lateral inhibition is also the physiological basis of two-point discrimination.
Concept 6.3 : Neurotransmitters and neuromodulators
• To classify the different neurotransmitters and neuromodulators into two major
groups- small molecule, rapidly acting and large molecule, slowly acting
• To further classify small molecule, rapidly acting neurotransmitters into four classes
and to enumerate the neurotransmitters in each class.
Time Needed
1st reading 05 mins
2 look
nd
02 mins
Small molecule, rapidly acting transmitters:

Class I
• Acetylcholine- released at neuro muscular junctions, autonomic ganglia, post ganglionic
parasympathetic, post ganglionic sympathetic to sweat glands and muscle vasodilator
endings, many parts of the brain (basal forebrain complex, pontomesencephalic
cholinergic complex- these systems are involved in sleep- wake states, learning,
memery), endings of some amacrine cells in the retina
Class II- amines
• Nor- epinephrine- post ganglionic sympathetic, adrenal medulla, locus ceruleus, other
medullary and pontine nuclei (from the locus ceruleus the axons of the nor adrenergic
AfraTafreeh.com
neurons descend into the spinal cord, enter the cerebellum, ascend to innervate the
paraventricular, supraoptic, periventricular nuclei of the hypothalamus, the thalamus,
the basal telencephalon, the entire neo cortex- this forms the locus ceruleus system)
• Epinephrine- adrenal medulla
• Dopamine- dopaminergic neurons are found in the nigro striatal system, which
projects from the substantia nigra to the striatum, and in the mesocortical system
which arises from the ventral tegmental area and projects to the nucleus accumbensQ
and limbic subcortical areas and is involved in reward behavior and addiction
• Serotonin- raphe nucleus, etc
• Histamine
Class III- amino acids
• GABA • Glycine • Glutamate • Aspartate
Class IV
• Nitric oxide
Large molecule, slowly acting neurotransmitters and neuropeptides
Includes
• Hypothalamic releasing hormones- TRH, LH-RH, GH-IH.
• Pituitary peptides- ACTH, β- endorphin, α- MSH, PRL, LH, TSH, GH, vasopressin,
oxytocin.
• Peptides that act on gut and brain- leu- enkephalin, met- enkephalin, substance
P, gastrin, CCK, VIP, NGF (nerve growth factor), BDNF (brain derived neurotropic
factor), neurotensin, insulin, glucagon.
• Peptides from other tissues- angiotensin II, carnosine, calcitonin, bradykinin, sleep
peptide.
206 | Physiology
Concept 6.4 : Receptors
• To define receptors
• To understand sensory coding
• To define and understand adequate stimulus
• To classify tactile receptors and study examples of each
• To understand the mechanism of adaptation
• To understand TRP channels- their types, location and role
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Receptors
Sensory receptors are transducers that convert various forms of energy in the
environment into action potentials in the neurons.
Sensory coding
Converting a stimulus into a recognizable sensation is termed as sensory coding.
AfraTafreeh.com
Receptors “code” for four elementary attributes of a stimulus, which are:-
(i) Location or site on the body where the stimulus originated.
(ii) Modality is the type of energy transmitted by the receptor.
(iii) Intensity- with increase in strength of stimulus, (a) number of receptors activated
increase, and (b) the frequency of action potential generation increasesQ
(iv) Duration refers to the time between start and end of a response in the receptor
Adequate stimulus
The form of energy to which a receptor is most sensitive or to which a receptor responds
at low energy levels is called its adequate stimulus.
Sensory receptors can respond to forms of energy other than their adequate stimuli, but
the threshold for these non-specific responses is much higher.
Rods and cones can respond to light and pressure but the adequate stimulus for rods
and cones is light. Pressure on the eyeballs can stimulate rods and cones, but the
threshold of these receptors to pressure is much higher than for light.
Tactile receptors
These can be classified as
A. Rapidly Adapting
B. Slowly Adapting
A. Rapidly Adapting
• Also called phasic receptors, rate receptors, movement detectors.
• Activated only when stimulus strength changes (rate of change of stimulus strength
is detected by a rapidly adapting receptor).
• These are encapsulated nerve endings.
• Examples
Pacinian corpuscles- for light touch, vibration (30-800 cps), deep pressure (such

as poking).
Meissner’s corpuscles in glabrous skin- for light touch, vibrations up to 80 cps,
textureQ, topognosis, Braille.
Hair end organs- detect light movement of objects over the skin surface that
displace hair.
B. Slowly Adapting
• Also called tonic receptors.
• Activated by a steady stimulus (signal stimulus strength over extended periods of
time)- they transmit a continuous signal.
• These are expanded nerve endings or free nerve endings.
• Examples
Merkel’s disc- signal continuous touch in glabrous and hairy areas, also sustained
pressure.
Ruffini endings- for touch and sustained pressureQ on skin.
C- mechanoreceptors- for crude touch and pressure.
Receptors for position sense- muscle spindles, receptors in joint capsules.
Receptors in the macula of the vestibular apparatus.

AfraTafreeh.com
Carotid and aortic baroreceptors (adaptation time is two days).
Chemoreceptors (do not adapt).
Pain receptors (pain receptors are free nerve endings, they do not adapt or adapt
very slowly).
Itch is detected by slowly adapting chemical nociceptorceptors.
Mechanism of adaptation:
Adaptation results from (i) readjustments in the structure of the receptor itself, and
from (ii) an electrical type of accommodation in the terminal nerve fibril.
TRP channels
These are a family of non selective cation channels on sensory nerve endings. They
respond to a variety of noxious thermal, mechanical or chemical stimuli. Examples:-
• TRPV1 (V stands for vanilloid)- activated by intense heat, acids, chemicals such as
capsaicin
• TRPV3- activated by intense heat; TRPV3 can activate TRPV1
• TRPA1 (A stands for ankyrin)- activated by noxious mechanical, cold and chemical
stimuli
• ASIC (acid sensing ion channel)- activated by pH changes within physiological limits;
dominant receptor for acid-induced pain
• P2X, P2Y (purinergic receptors)- nociceptive (painful) mechanical stimuli cause the
release of ATP that acts on P2X and P2Y
208 | Physiology
• TrkA (tyrosine receptor kinase A)- tissue damage releases nerve growth factor which
acts on TrkA, producing pain
• B1 and B2 receptors are activated by bradykinin, prostanoid receptors by
prostaglandins, cytokine receptors by interleukins and are therefore, responsible for
inflammatory pain
Nociceptive Receptors on unmyelinated nerve terminals

(pain producing) stimulus
Mechanical Directly on TRPA1

Indirectly, by release of ATP acting on P2X, P2Y; by release of NGF
acting on TrkA
H+ TRPV1, ASIC
Heat TRPV1, indirectly by activation of TRPV3
Cold TRPA1
Capsaicin TRPV1
AfraTafreeh.com
Concept 6.5 : Laws of sensory physiology
• To enumerate the different laws related to sensory physiology and to understand their
significance
Time Needed
1st reading 05 mins
2 look
nd
02 mins
1. Bell-Megendie Law
This law states that the dorsal root is sensory and ventral root is motor
2. Muller’s Doctrine of specific nerve energies:
No matter where along the nerve pathway one stimulates, the type of sensation
will depend on which part of the brain is finally going to be stimulated. The specific
sensory pathways are discrete from sense organ to cortex. Therefore, when the nerve
pathways from a particular sense organ are stimulated, the sensation evoked is that
for which the receptor is specialized no matter how or where along the pathway the
activity is initiated.
3. Law of Projection:
No matter where along the nerve pathway one stimulates, the sensation will be felt
AfraTafreeh.com
at the location of the receptor.
4. Weber Fechner Law
This law relates the sensation felt (S) to the intensity of the stimulus (I).
S = K log I, where K is a constant
5. Stevens’ Power law
Sensation felt (S) = K × Ia, where K and a are constants
210 | Physiology
Concept 6.6 : Ascending tracts
• To understand differences between the two major ascending pathways, anterolateral
system and posterior columns
• To understand course of ascending tracts
• To understand the divisions of spinocerebellar tracts and their role in proprioception
• To enumerate the features of Brown Sequard syndrome
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
Anterolateral system:
This includes
1. Anterior (or ventral) spinothalamic tract: This carries crude touch, detection of
pressure (barognosis), itch, tickle, sexual sensations
2. Lateral Spinothalamic tract: This carries pain and temperature
Anterolateral system is more primitive in terms of evolution whereas DCML system

appeared later.
Anterolateral system conveys rather crude senses, whereas the leminiscal system
AfraTafreeh.com

conveys rather fine senses.

Velocities of transmission less in the anterolateral system than those in the dorsal

columns.
In the anterolateral system, fibers from the sacral and lumbar regions are situated

most laterally.
Anterolateral system gives collateral to periacqueductal gray and reticular

activating system.
Localization much better in lemniscal system.

Gradations of intensities far less accurate in the anterolateral system.

Ability to transmit rapidly changing or repetitive signals is poor in anterolateral

system.
Dorsal column medial lemniscal system (DCML system)
This carries the rest of the sensations e.g. proprioception, vibration, fine touch, tactile
localization, two- point discrimination, stereognosis, ability to judge different degrees
of pressure.
Lesions of the dorsal column medial lemniscal system
• Only very extensive lesions completely interrupt touch sensation.
• Vibration and proprioception reduced.
• Touch threshold is elevated; touch localization impaired.
• Sensory ataxia (because of interruption of proprioceptive input into the cerebellum)-
Romberg’s sign with eyes closed is positive.
Lesions of the anterolateral tracts
• Loss of pain and temperature sense.
• Slight touch deficit- increase in touch threshold and decrease in the number of touch-
sensitive spots on the skin surface.
• Touch localization is normal.
Diagram showing the sensory pathways
AfraTafreeh.com
Dorsal Column Pathway
Receptors for touch, vibration, proprioception

↓
Fibers enter the dorsal horn
↓
Dorsal columns (tractus gracilis and tractus cuneatus)
↓
Synapse in the gracilis and cuneate nuclei in the medulla
↓
Second-order neurons cross the midline and ascend in the medial lemniscus
↓
End in the contralateral ventral posterior lateral (VPL) nucleus
↓
Somatic sensory area I and area II
Note: Touch and proprioception from the face are relayed via the main sensory and mesencephalic nuclei of the trigeminal
nerve
212 | Physiology
Lateral Spinothalamic Tract
Fibers from nociceptors and thermoreceptors

↓
Enter dorsal horn- Aδ fibers synapse in laminae I and V, C fibers synapse in lamina II
(Substantia Gelatinosa of Rolando)
↓
Axons of the second-order neurons cross the midline
↓
Form the lateral division of the ventrolateral spinothlamic tract
↓
Fibers terminate in the VPL of thalamus
↓
Third-order sensory neurons project to SI and SII
Ventral Spinothalamic Tract

AfraTafreeh.com
Fibers from touch receptors (crude touch)
↓
Enter dorsal horn and synapse
↓
Axons of the second-order neurons cross the midline
(the second- order neurons constitute the STT)
↓
Form the anterior division of ventrolateral spinothlamic tract
↓
Fibers terminate in the VPL of thalamus
↓
Third-order sensory neurons project to SI and SII
Note: Visceral sensations travel along the same pathways as somatic sensations in the spinothalamic tracts and thalamic
radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas.
AfraTafreeh.com
Spinocerebellar tracts
Division Receptors Region of innervation
Dorsal spinocerebellar tract Muscle spindles (mainly) and Ipsilateral lower limbs
Golgi tendon organs
Ventral spinocerebellar tract GTO Ipsilateral lower limb
Cuneocerebellar tract Muscle spindles (mainly) and Ipsilateral upper limb
GTO
Rostral spinocerebellar tract GTO Ipsilateral upper limb
Dorsal spinocerebellar tract/ posterior spinocerebellar tract/ Flechsig’s

fasciculus/ Flechsig’s tract (named after German neuroanatomist, psychiatrist and
neuropathologist Paul Flechsig)
• Convey unconscious proprioception.
• Carries proprioceptive information from muscle spindles and GTO of ipsilateral lower
limb
• Location-lateral funiculus of the spinal cord along the posterolateral periphery of the
spinal cord
• Course-
First order sensory neurons are the DRG cells.

214 | Physiology
Central processes travel through the dorsal horn where they synapse with second
order neurons of Clarke’s nucleus.
Fibres travel upwards through the medulla, pass through the inferior cerebellar

peduncle and into the cerebellum, where unconscious proprioception is processed.

• Collateral branches of some of the axons of the dorsal spinocerebellar tract are
given off in the lower medulla, where they terminate in the 2-nucleus of Brodal and
Aonpeine (this nucleus lies rostral to nucleus gracilis and forms part of the pathway
for conscious proprioception for the lower limbs)
Ventral spinocerebellar tract/ anterior spinocerebellar tract/ Gower’s column
• Conveys unconscious proprioceptive information from GTO of lower limbs.
• First order sensory neurons: DRG
• Course: after origin majority of fibers cross over to the opposite side in the spinal
cord as a part of the anterior white commissure and then cross again to end in the
cerebellum (referred to as a “double cross”).
• Fibers of the ventral spinocerebellar tract enter the cerebellum via the superior
cerebellar peduncle.
• Termination: in the lower limb area of cerebellum.
Brown Sequard Syndrome

This is hemi-section of the spinal cord.
Features:
AfraTafreeh.com
• Loss of pain and temperature of opposite side below level of lesion (due to spinothalamic
tract damage).
• Touch is least affected (because of dual transmission in same side posterior column
and opposite side anterior spinothalamic tract).
• All other sensations lost on same side (due to posterior column damage).
• Ipsilateral motor paralysis below level of lesion (due to corticospinal tract damage).
• Paralysis is UMN type below level of lesion and LMN type at level of lesion.
Concept 6.7 : Reflexes
• To classify reflexes on the basis of number of synapses
• To understand the pathway of the axon reflex asynaptic)
• To understand the stretch reflex (monosynaptic) and inverse stretch reflex (bisynaptic)
• To understand pathways of flexor withdrawal and crossed extensor reflexes
(polysynaptic)
Time Needed
1st reading 15 mins
2 look
nd
10 mins
Classification of reflexes based on number of synapses

1. Asynaptic reflex e.g. Axon reflex
2. Monosynaptic reflex e.g. Stretch reflexes (deep tendon reflexes)
3. Di or Bi-synaptic reflex
Examples
Inverse stretch reflex.

Reciprocal innervation.

4. Polysynaptic reflex
Examples AfraTafreeh.com
Superficial reflexes

Flexor withdrawal response

Crossed extensor response

Axon reflex (asynaptic)

216 | Physiology
Axon reflex
• It is an example of asynaptic reflex.
• It is responsible for the spreading redness k/a ‘flare’ in triple response and is a part of the normal reaction
to injury.
• Antidromic conduction of impulses in branches of sensory nerve fibres to the blood vessels supplying
the area, causes release of substance P and CGRP, both of which cause arteriolar dilatation and ‘flare’
response.
• This is a neural response and an asynaptic reflex.
• It is absent in locally anesthetized skin and in denervated skin, but is present immediately after nerve
block or section above the site of injury.
Stretch reflex (monosynaptic) and inverse stretch reflex (bisynaptic)

Stretch reflex Inverse stretch reflex
Stimulus Increase in muscle length (Stretch) Increase in muscle tension
Receptor Muscle spindle Golgi tendon organ
Afferent fibers Ia, II Ib
Center Spinal cordAfraTafreeh.com

Spinal cord
Efferent A alpha A alpha
Response Muscle contraction Muscle relaxation
No. of synapses 01 02
Stretch reflex
Inverse stretch reflex
The Golgi tendon reflex (inverse stretch reflex)
Flexor withdrawal and crossed extensor reflexes (polysynaptic)
AfraTafreeh.com
218 | Physiology
Concept 6.8 : Reticular formation
• To define the reticular formation
• To enumerate its connections, both afferent and efferent
• To enumerate the functions of reticular formation
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
It is a loose network of nerve cells and fibers in the central core of the brainstem
(It is present in the mid ventral portion of the medulla, pons and midbrain).
It is a complex poly-synaptic pathway and has many of the important centers in
the medulla viz deglutition center, vomiting center, respiratory center, center for
cardiovascular regulation
Connections of reticular formation

Afferents
• Collaterals from the specific sensory pathways (ascending sensory tracts)
• Cerebral cortex (corticofugal fibres)
• Cerebellum
• Basal ganglia
AfraTafreeh.com
Efferents from reticular formation
• Ascending pathway – the ascending reticular activating system (ARAS) to the cerebral
cortex (via the thalamus – cf thalamus)
• Descending pathway- the reticulo spinal tract
Functions of the reticular system
• Maintenance of sleep / wakefulness cycle: stimulation of ARAS causes arousal,
awakefulness and alertness
• Modulation of muscle tone: reticular formation and the tracts which arise from it-
pontine or facilitatory reticulospinal tract and medullary or inhibitory reticulospinal
tract, is one of the supraspinal influences for the stretch reflex (regulation of tone
and posture)
• All vital centers are located in the medulla as mentioned above
• EEG
• Stimulation of reticular formation : resynchronizations of EEG
• Inhibition of reticular formation : synchronization of EEG
• Sensation
It modulates / controls sensory input to CNS e.g. supraspinal control of pain

It modulates sensory impulses of muscle spindle

It has role in focusing of attention (selective attention) probably by cutting off all

other signals
It is necessary for learning and conditioned reflex

Concept 6.9 : Thalamus
Learning Objectives
• To understand the functional classification of thalamus and classification of dorsal
thalamic nuclei
• To enumerate functions of thalamus
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Functional classification of thalamus

Thalamus consists of
1. Epithalamus- has connections to the olfactory system
2. Ventral thalamus- has connections and projections which are undetermined
3. Dorsal thalamus (thalamus proper)
Classification of dorsal thalamic nuclei
A. Non-specific sensory relay nuclei
These include midline and intralaminar nuclei.

They project diffusely and non-specifically to the whole of the neocortex.

AfraTafreeh.com
These nuclei receive input from the reticular formation (the ARAS).

Impulses from the nuclei are responsible for the diffuse secondary response in

cortical evoked potential.

The alerting effects of reticular activation, are relayed through them.

B. Specific nuclei :-
1. Sensory relay nuclei
(i) Medial geniculate body (concerned with hearing – relay auditory impulses to
auditory cortex)
(ii) Lateral geniculate body (concerned with vision – relay visual impulses to visual
cortex)
(iii) Ventro posterior lateral- These nuclei are the sites of termination of the ascending
somatic afferent tracts; the medial lemniscus (carrying sensation from all parts
except the face) ends in the ventroposterior lateral ; the trigeminal lemniscus
(carrying sensations from face and taste sensation ) ends in the ventroposterior
medial nucleus.
(iv) Ventro-postero medial- relays taste.
(v) Medio-dorsal thalamic- relays olfaction.
2. Nuclei concerned with control of posture and movement (motor control
nuclei)
(i) Ventrolateral nucleus -This is the chief motor nucleus of the thalamus. It receives
fibres from the cerebellum (the dentato – thalamic fibers of cerebellum). Fibers
from the ventrolateral nucleus project to the primary motor cortex (area 4) and
premotor cortex (area 6)
(ii) Ventro anterior nucleus -It receives fibers from the cerebellum and basal ganglia.
It projects to the premotor cortex.
220 | Physiology
3. Thalamic nuclei concerned with Papez circuit
(i) Anterior thalamic nuclei, which receive afferents from the mamillary bodies and
project to the cingulate gyrus, which is a part of the limbic system.
The above circuit is known as the Papez circuit.

Almost any type of sensory experience causes activation of at least some part of
the hippocampus, and the hippocampus in turn sends signals to mamillary bodies
of hypothalamus and then via the mammillothalamic tract to anterior thalamic
nuclei, cingulate gyrus and other parts of limbic system.

AfraTafreeh.com
It is concerned with recent memory and emotions and aspects of behavior that are
related to survival and preservation of the individual and species.
(Note: Most thalamic nuclei described are excitatory neurons that release GLUTAMATE. The thalamic reticular nucleus
contains inhibitory neurons which release GABA- these neurons do not project to the cortex, instead they are thalamic
interneurons and modulate the responses of other thalamic neurons to input from the cortex)
Functions of thalamus
These can be predicted from the connections mentioned above
1. It is a sensory relay station- it is an important relay station for all sensations
except smell
2. Center for integration and modification of peripheral sensory impulses
3. Also a crude center for perception of sensations
4. Motor function- it is also a relay station for the motor fibers from the basal ganglia
and cerebellum on their way to the cerebral cortex
5. It also relays a part of the ARAS – has a role in arousal and alertness reaction
6. Involved in subjective feeling of various emotions
7. Role in language- integration between different cortical parts by subcortical
connections in the thalamus helps to achieve speech
8. Role in synchronization of EEG
9. Thalamus receives somatic as well as autonomic sensations, and is also connected
with hypothalamus. Because of this it also acts as a center for integration of visceral
and somatic function
10. Center of sexual sensations
11. Center of reflex activity- since all sensory fibers relay in the thalamus, it forms the
center for many reflex activities.
Concept 6.10 : EEG
Learning Objectives :
• To enumerate the different waves of EEG and discuss salient features of each
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Hans Berger made the first systematic analysis of EEG
Waves in the EEG
Delta, theta, alpha, beta (from delta to beta, the frequency increases and the
amplitude decreases)
Salient features of the different waves

1. Delta rhythm
Frequency is < 4/second.

Occur in deep sleep (slow wave sleep/ stages III and IV of NREM sleep), infancy,

serious organic brain disease, animals with subcortical transection (i.e., delta
waves can occur in cortex independent of activities in lower areas).
2. Theta rhythm
Frequency is 4-7/second.
AfraTafreeh.com

It has large amplitude, regular, 4-7 Hz.

It occurs in children and in degenerative brain states.

Generated in the hippocampus, especially during disappointment and frustration.

3. Alpha rhythm –
Seen at rest, with the eyes closed and the mind wandering.

Frequency is 8-13 /second.

Amplitude is 50-100 mv.

Intralaminar nuclei of the thalamus give rise to the α waves.

Most marked in the parietal and occipital lobes.

It is associated with decreased level of attention.

The frequency of the alpha rhythm is decreased by

▫ low blood glucose

▫ low body temperature

▫ low level of adrenal glucocorticoid hormones

▫ high Paco2

▫ alcohol, phenytoin, phenobarbiturates

Alpha block (also called arousal response / alerting response /

desynchronisation)
The alpha rhythm can be made to disappear by focusing attention on something, by
mental concentration (such as solving arithmetic problems), sensory stimulation and
on opening eyes- the alpha rhythm is replaced by an irregular 13- 30 Hz low voltage
activity, the beta rhythm.
222 | Physiology
(the ascending reticular formation activity is responsible for the EEG alerting response;
stimulation of ARAS causes the EEG rhythm to change from slow to high frequency small
waves).
4. Beta rhythm
Has a frequency of 18-30 / second; lower amplitude.

Seen over the frontal and parietal regions.

Seen when the eyes are opened.

It is the wave seen in the alerting response (stimulation of ARAS→ β).

Gamma oscillations at 30-80 Hz are seen when the individual is aroused and focuses
attention on something. This is replaced by irregular fast activity as the individual
initiates motor activity in response to the stimulus.
Sources of EEG
It is due to the constantly shifting / fluctuating dipole between the dendrites of the
cortical cells and the cell bodies.
AfraTafreeh.com
Concept 6.11 : Evoked cortical potentials
• To understand primary and secondary evoked cortical potentials
Time Needed
1 reading
st
03 mins
2nd look 01 mins
Electrical events that occur in the cortex after stimulation of a sensory receptor can be
monitored with a recording electrode.
The EEG changes produced by stimulation of a sense organ are k/a evoked cortical
potentials.
Evoked cortical potential consist of
1. Primary evoked potential
This consists of positive and a small negative wave. It has a latency of 5-12 ms. It
is highly specific in its location (over the primary receiving area of the cortex for
the particular sensory pathway that has been stimulated to evoke). It is produced by
conduction of sensory signal through a specific sensory pathway.
2. Diffuse secondary response
This consists of a larger, more prolonged positive deflection. It has a latency of 20-80
AfraTafreeh.com
ms and may last 30 seconds. Its activity can be recorded at the same time over most
of the cerebral cortex. It is produced due to activity in projections from midline and
related thalamic nuclei
224 | Physiology
Concept 6.12 : Sleep
• To enumerate the differences between REM and NREM sleep
• To enumerate EEG waves recorded in different stages of sleep
• To enumerate different mechanisms involved in genesis of REM and NREM sleep
• To understand the role of neurotransmitters in sleep
Time Needed
1st reading 05 mins
2 look
nd
02 mins
REM sleep
(i) Also called paradoxical sleep.
▫ During this phase, beta waves of EEG are recorded which are normally seen in

alert awake states.

▫ In REM sleep, threshold for awakening is elevated.

▫ Spontaneous awakening occurs usually in REM sleep.

(ii) It is a period of autonomic instability- heart rate & respiratory rate become
irregular; partial or full penile erections occur.
(iii) Rapid eye movement – present.
AfraTafreeh.com
(iv) Dreaming (with vivid dream recall).
(v) Tone of neck muscles is markedly decreased, other muscles keep their tone; but
there is locus ceruleus dependent relative paralysis of voluntary activity.
(vi) P-G-O (ponto-geniculo-occipital) spikes – present (not detectable in humans by
scalp EEG but are recordable by depth EEG recordings).
NREM sleep (slow – wave sleep)
(i) It is generally a restful state.
(ii) BP, heart rate and respiratory rate decrease during NREM sleep.
(iii) Body metabolism is decreased.
(iv) Somnabulism, somniloquy, nocturnal enuresis, bruxism are associated with slow –
wave sleep, especially NREM stage 2
(v) Dreaming occurs in NREM but no recall (night terrors)
EEG in different stages of sleep

Stage 1 of NREM Low amplitude, high frequency EEG activity (theta)
Stage 2 of NREM Sleep spindles (alpha – like sinusoidal waves 12-14 Hz , 50 mv amplitude), K
complexes (high voltage biphasic waves)
Stage 3 of NREM Low frequency, increased amplitude delta rhythm
Stage 4 of NREM Maximum slowing - least frequency, large waves (rhythmic slow waves
indicating marked synchronization) (delta)
REM Rapid, low voltage EEG (therefore k/a paradoxical sleep)
Duration of REM, as percentage of total sleep time, in different age groups
• Premature infants - 80%
• Full term neonates - 50%
• 20-65 years - 25%
• After 65 years, it decreases- in elderly - 15%
Genesis of sleep
1. REM
The mechanism that triggers REM sleep is located in the pontine reticular formation.
PGO spikes originate in the lateral pontine tegmentum. The spikes are due to discharge
of cholinergic neurons
2. NREM
Stimulation of certain sleep zones can produce sleep
Diencephalic sleep zone (In the posterior hypothalamus and the near by

intralaminar and anterior thalamic nuclei); for producing sleep it requires low
frequency stimulation
Medullary synchronizing zone (In the reticular formation of the medulla oblongata

at the level of the nucleus of the tractus solitarius); this also requires low frequency
stimulation for producing sleep
Basal forebrain sleep zone (includes preoptic area and the diagonal band of Broca);

this can produce sleep by both low as well as high frequency stimulation
AfraTafreeh.com
Neurotransmitters in sleep
226 | Physiology
Concept 6.13 : Effect of transection at different levels
• To understand the effect of transection above the spinal cord the to enumerate the
spinal reflexes that can be seen
• To understand the effect of transection at upper border of pons and enumerate
features of decerebration
• To understand the effect of transection at superior border of midbrain leaving the
midbrain intact
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Transection above the spinal cord (spinal cord is intact)

There is initially a period of spinal shock during which all spinal reflexes are profoundly
depressed.
Features after the spinal shock is over:
• Hyperactive stretch reflexes.
• Presence of positive supporting reaction (magnet reaction)and negative supporting
reaction.
AfraTafreeh.com
• When suitably stimulated, spinal animals can even produce walking movements
indicating the presence of locomotor pattern generators. However, the spinal loco-
motor pattern generator needs to be turned on by the mesencephalic locomotor
region.
• Automatic reflexes
Reflex contraction of the urinary bladder and rectum can occur
BP is generally normal at rest but there are wide swings
Bouts of sweating and blanching of the skin occur
• Sexual responses -Erection and ejaculation is possible by local stimulation.
• Mass reflex-Irradiation from one reflex center to another can occur. Minor stimulation
of skin of inner thigh or perineum can cause evacuation of the urinary bladder rectum,
sweating, pallor, BP swings, in addition to withdrawal response
Transection at superior border of pons

Transection at the superior border of the pons causes decerebration.
It leaves the following components intact: the spinal cord, medulla, pons and cerebellum.
Features
• No stage of spinal shock- decerebrate rigidity occurs immediately. The reason for this
is
Increased general excitability of the motor neuron pool

Increased discharge of gamma motor neurons (because the inhibitory influence of

the cerebral cortex and basal ganglia on the gamma motor neuron is removed).
(Although the cerebellum also has an inhibitory influence on gamma motor neuron,
removal of the cerebellum in humans causes hypotonia)
• The decerebrate rigidity in animals is most marked in the antigravity muscle. However,
in humans the pattern of decerebrate rigidity is extensor in all the 4 limbs.
(note that in decorticate rigidity, there is extensor rigidity in the legs and moderate
flexion in arms)
• Tonic labyrinthine and tonic neck reflexes (center- medulla) are present: these
reflexes are responsible for the change in the pattern of rigidity with change in the
position. They are not righting reflexes.
• Righting reflexes (center- midbrain) are absent.
Transection at superior border of midbrain

Features
• Transection at upper border of midbrain causes decortication.
• In decorticate rigidity in humans, there is extensor rigidity in the legs and moderate
flexion in arms.
• In decorticate animals, extensor rigidity is seen only when the animal lies quietly on
its back.
• The animal can rise to standing position, walk, and right itself
• Righting reflexes are present. All the righting reflexes (except the optical righting
reflex, which is cortical) are integrated at the mid brain (the rightly reflexes operate
AfraTafreeh.com
to maintain the normal standing position and keep an animal’s head upright)
• Grasp reflex present
• Pupillary light reflex present (if the optic nerves or intact)
• Nystagmus present
• Vestibular placing reaction present
228 | Physiology
Concept 6.14 : Motor system- control of movement
• To elaborate the roles of cortical association areas, motor cortex, cerebellum, basal
ganglia in planning, execution and control of motor movement
• To classify the descending tracts into medial and lateral descending tracts
• To understand origin and course of corticospinal and corticobulbar tracts
• To enumerate differences between UMN and LMN paralysis
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
General principle of central organization of motor pathways

• Commands for voluntary movement originates in the cortical association areas (this
is any area in the brain that is lies between and connects a sensory projection area
with another).
• Cortex, basal ganglia and neocerebellum work cooperatively to plan the movement.
• Movement executed by the cortex is relayed by the corticospinal tracts and
corticobulbar tracts to motor neurons.
• Cerebellum provides the feedback to adjust and smoothen the movement.
AfraTafreeh.com
Descending tracts
• Medial desceding tracts are mainly for control of axial and proximal muscles. They are
meant for tone and posture.
• Anterior corticospinal, vestibulospinal, tectospinal tracts innervate the A alpha motor
neurns to the extensors (especially those of lower limb or the anti-gravity muscles-
extensors of hip and knee).
• Reticulospinat tracts supply the A-gamma motor neurons to extensors (especially
lower limb extensors); pontine reticulospinal tract increases A-gamma activity;
medullary reticulospinal tract decreases A-gamma activity.
• Lateral descending tracts are meant for control of distal muscles and for fine, skilled
movements.
• Lateral descending tracts innervate the A-alpha motor neurons to the flexors
(especially upper limb flexors).
• The major tract for fine, skilled movement is lateral corticospinal tract; rubrospinal
tract is k/a alternate pathway.
Descending Tracts (motor pathways)

Medial Descending tracts Lateral Descending tracts
• Anterior conrticospinal tract • Lateral corticospinal tract (Pyramidal tract)
• Vestibulospinal tract • Rubrospinal tract
• Tectospinal tract
• Retibulospinal tract
• Pontine / Excitatory
• Medullary / Inhibitory
Origin of corticospinal tracts

1. Motor cortex (the primary motor cortex)- this is in the precentral gyrus (area 4)
Contributes 31% of the fibers of the fibers of corticospinal and corticobulbar tracts.

Fibers of corticospinal and corticobulbar tracts originate in the large pyramidal

cells in layer V of the cortex.

AfraTafreeh.com
There is a point for point representation of the whole body in the precentral gyrus

k/a motor homunculus.

The arrangement is such that the feet is represented at the top and the face at

the bottom.
Except the face area (which has bilateral representation), the rest of the

representation is unilateral to the opposite side musculature.

More complicated the movement, larger is the cortical representation e.g. muscles

involved in vocalization and muscles of hand have large areas of representation.

230 | Physiology
2. Premotor cortex (area 6) and Supplementary motor area (in the medial side of the
hemisphere on and above the superior bank of the cingulated sulcus)
These contribute another 29% of the fibres.

Premotor cortex is concerned with setting posture at the start of planned

movement.
Supplementary motor area is involved primarily in programming motor sequences

3. Somatic sensory area and related portions of the posterior parietal lobe
Contribute 40% of the fibers.

Project to premotor area.

Lesions of somatic sensory area results in inability to execute learned sequence of

movements, such as eating with knife and fork.

Course of corticospinal and corticobulbar tracts
AfraTafreeh.com
• Axons of neurons that form the corticospinal tract pass through the anterior two-
thirds of the posterior limb of the internal capsule, descend downwards crossing at
the level of the medulla and project to spinal motor neurons in the anterior horn of
spinal cord.
• 80% of the fibers cross the midline in the medulla forming the lateral pyramidal tract.
• The motor decussation forms the pyramids in the medulla.
• Remaining 20% make the ventral corticospinal tract, which does not cross the midline.
• The corticobulbar tract is made of fibers that pass from the motor cortex to motor
neurons in the trigeminal, facial and hypoglossal nuclei.
• Fibers of the corticobulbar tract pass through the genu of the internal capsule to
descend with corticospinal tract fibers in the pons and medulla.
LMN and UMN:
The motor system can be divided into lower and upper motor neurons.
• Lower motor neurons refer to the spinal and cranial motor neurons that directly
innervate skeletal muscles.
• Upper motor neurons are those in the cortex and brain stem that activate lower motor
neurons.
Features of UMN and LMN paralysis

Upper Motor Neuron (UMN) vs. Lower Motor Neuron (LMN Syndrome)
UMN Syndrome
AfraTafreeh.com LMN Syndrome
Type of Paralysis Spastic Paresis Flaccid Paralysis
Atrophy No (Disuse) Atrophy Severe Atrophy
Deep Tendon Reflex Increase Absent DTR
Pathological Reflex Positive Babinski Sign Absent
Superficial Reflex Absent Present
Fasciculation and Fibrillation Absent Could be present
232 | Physiology
Concept 6.15 : Basal ganglia
• To enumerate parts of the basal ganglia and the neurotransmitters secreted by them
• To enumerate major connections between the different parts of the basal ganglia
• To understand (by line diagrams) circuitry of the basal ganglia
• To enumerate and understand functions of the basal ganglia
Time Needed
1st reading 20 mins
2 look
nd
10 mins
Parts of the basal ganglia

(There is one on each side)
Basal ganglia consist of
• caudate nucleus
• putamen
• globus pallidus
• subthalamic nucleus (body of Luys)
• substantia nigra
AfraTafreeh.com
The caudate nucleus and putamen together are referred to as the striatum; caudate
nucleus, putamen and globus pallidus are called corpus striatum; putamen and globus
pallidus together are k/a the lenticular nucleus
Connections of the basal ganglia
1. Afferents
The afferents to the basal ganglia end in the striatum.
Afferents are from a wide region of cerebral cortex to striatum (corticostriate pathway)
and from the intralaminar nuclei of thalamus to striatum (thalamostriatal pathway).
The two inputs into the basal ganglia are excitatory (glutamate).
2. Efferents
Efferent output of basal ganglia is mainly from the globus pallidus internal segment
to thalamus and from substantia nigra pars reticularis to the thalamus. Both are
inhibitory (GABAergic).
3. Inside connections
Intrastriatal cholinergic pathway

Striatopallidal GABAergic pathway

Striatonigral GABAergic pathway

Nigrostriatal Dopaminergic pathway

Subthalamic nucleus (Glutamate) → Globus Pallidus (IS & ES)

Overall circuitry
Main features :
(i) Cerebral cortex projects to striatum; the striatum to internal segment of globus
AfraTafreeh.com
pallidus, internal segment of globus pallidus to thalamus & from thalamus back to
cerebral cortex, completing a loop, k/a thalamo-cortico-striatal loop.
(ii) Output from internal segment of globus pallidus to thalamus and pedunculo-
pontine nuclei (PPN) is INHIBITORY, whereas output from thalamus to cerebral
cortex is EXCITATORY.
(iii) Output from substantia nigra pars reticularis to thalamus is INHIBITORY.
234 | Physiology
Activation of direct pathway results in facilitation of movement.
Activation of the indirect pathway results in inhibition of movement

AfraTafreeh.com
• Dopaminergic receptors are present on the striatum.

• There are two types of Dopaminergic receptors- D1 and D2.
• D1 receptors activate the direct pathway causing facilitation of movement.
• D2 receptors activate the indirect pathway causing inhibition of movement.
• Dopamine acts on D1 recptors activating the direct pathway resulting in facilitation
of movement.
• Dopamine inhibits the D2 receptors- inhibition of inhibitory pathway also results in
facilitaion of movement.
Functions of basal ganglia

AfraTafreeh.com
1. Planning and programming of movements. Basal ganglia in the process by which an
abstract thought is converted into voluntary action.
Via thalamus
basal ganglia motor cortex
cortico – spinal tract
motor neurons
2. Basal ganglia have some role in cognitive processes (especially that of the caudate
nucleus).
3. Control and co-ordinate complex patterns of movement, automatic, skilled movements
(eg., using scissors to cut paper) and associated movements (eg., swinging of the
arms while walking, facial expressions while talking).
4. In close association with the cerebral cortex, timing (how rapidly a movement has to
be performed) and scaling (how large a movement will be) of movements.
236 | Physiology
PARKINSON’S DISEASE
• Described by James Parkinson in 1817.
• Also k/a paralysis agitans. AfraTafreeh.com
• It results form degeneration of the dopaminergic neurons in the substantia nigra pars compacta.
• It has both hypokinetic and hyperkinetic features.
• Hypokinetic features- bradykinesia (difficulty in initiating movement) and akinesia (absence of motor
activity).
• Hyperkinetic features- tremor at rest (disappears with activity), pill rolling movements, cogwheel rigidity,
lead pipe rigidity (rigidity is different from spasticity because motor neuron discharge increases to both
agonist and antagonist muscles).
• In Parkinson’s disease, the dopaminergic input to the putamen is lost- this results in decreased inhibition
and increased excitation from the subthalamic nucleus to the GPi.
• The overall increase in inhibitory output to the thalamus and brainstem disorganizes movement.
• An important consideration in Parkinson’s is the balance between the excitatory discharge of cholinergic
interneurons and the inhibitory dopaminergic input into the striatum.
• Some improvement is produced by decreasing the cholinergic influence with anticholinergic drugs.
• More dramatic improvement is produced by administration of L-DOPA. Unlike dopamine, this dopamine
precursor crosses the blood-brain barrier and helps repair the dopamine deficiency.
• However, the degeneration of these neurons continues and in 5-7 years the beneficial effects of L-dopa
disappear.
Concept 6.16 : Cerebellum
• To understand functional divisions of the cerebellum, their functions and connections
• To understand organization of the cerebellum- outer cerebellar cortex and deep nuclei
• To enumerate afferent connections of the cerebellum the tracts forming climbing and
mossy fibers
• To understand inside connections (circuitry) of cerebellum
• To understand functions of cerebellum
• To enumerate features of cerebellar disease
Time Needed
1 reading
st
25 mins
2nd look 15 mins
Functional divisions of cerebellum

(i) Vestibulocerebellum- involved in balance and eye movements
(ii) Spinocerebellum- involved in co-ordination of voluntary movements
(iii) Cerebrocerebellum (or neocerebellum)- for motor planning
AfraTafreeh.com
238 | Physiology
Part Constituents Connections Functions
Vestibulo cerebellum Nodulus and flocculus Vestibular *Equilibrium (balance)

(or the floculo- nodular *Eye movements
lobe) *Learning induced change
in vestibulo ocular reflex.
Spinocerebellum Vermis (except the Afferent By comparing plan with

nodulus) and the Proprioceptive input performance, it smoothens
adjacent medial portions from body and coordinates
of the hemispheres Copy of the motor plan Movements, medial part
Efferent of spinocerebellum is
involved in co-ordination
From vermis of axial and proximal
↓ to muscles; lateral part
Brains stem area (for of spinocerebellum is
axial and proximal limb involved in control and
muscles) co-ordination of distal
From the hemispheres muscles.
↓ to
brain stem area (For
distal muscles)
AfraTafreeh.com
Cerebro cerebellum (or The lateral portions of Interact with motor Planning and programming
neocerebellum) hemispheres cortex movements
Organization of cerebellum
The cerebellum is organized as
(i) Outer cerebellar cortex
(ii) Deep cerebellar nuclear
Outer Cerebellar cortex has 3 layers and 5 types of cells:
The 3 layers are
• The outer molecular
• Middle purkinje
• Inner granular
The 5 cells are:
• Purkinje
• Granular
• Golgi
• Stellate
AfraTafreeh.com
Deep nuclei (4 on each side)

(i) Fastigeal- it is associated with the medial part of spinocerebellum, and is therefore,
concerned with control and co-ordination of axial and proximal muscles.
(ii) Globose
(iii) Emboliformis- globose and emboliformis are together k/a nucleus interpositus and
is associated with the lateral parts of spinocerebellum and therefore, concerned
with control and co-ordination of distal muscles.
(iv) Dentate- it is associated with cerebrocerebellum and is therefore, involved in motor
planning.
Afferent connections
240 | Physiology
There are 2 main primary afferent inputs
a. Mossy fibers
b. Climbing fibers
Both of these are excitatory; they send collateral to the deep nuclei & pass to the

cerebellar cortex.
The climbing fibers ends on the Purkinje cell; the mossy fibers innervate the

granule cell, which in turn give rise to parallel fibers that in turn form excitatory
synapses with the multiple Purkinje cells.
The input to the Purkinje cell from the climbing fibre is 1:1; it is a stong excitatory

input and produces a complex spike whereas the input to the Purkinje cell from
the mossy fibre is 1 million : 1; it is a weak input and produces a simple spike.
Climbing fibers
• Climbing Fibers come from one single source viz., the inferior olivary nuclei.
• Climbing fibers convey proprioceptive inputs from all over the body.
• Proprioceptive input from all over the body → Inferior olivary nuclei → Climbing fibers
→ Purkinje cell
Mossy fibers:
• They come from many sources.
• The fibers first end on the dendrites of the granule cells in “glomeruli”.
• The mossy fibers convey proprioceptive input from all parts of the body and also input
AfraTafreeh.com
from the cerebral cortex via pontine nuclei to the cerebellar cortex.
The various tracts forming the mossy fibers are:

1. Vestibulo- cerebellar Vestibular impulses from labyrinth.
Direct and via vestibular nuclei (Ipsilateral)
2. Dorsal spinocerebellar Proprioceptive and exteroceptive impulses from body (trunk/ leg)
(Ipsilateral)
3. Ventral spinocerebellar Proprioceptive and exteroceptive impulses from body (trunk/ leg)
(Contralateral)
4. Cuneo cerebellar Proprioceptive impulses from head and neck (Ipsilateral)
5. Tecto – Cerebellar Auditory and visual impulses via inferior and superior colliculi
6. Ponto- cerebellar Impulses from motor and other parts of cerebral cortex via pontine nuclei
(From Opposite cerebral cortex)
7. Rubro- cerebellar Impulses from opposite red nucleus
8. Reticulo- cerebellar Impulses from brain stem reticular formation
N.B : The sensory input to the cerebellum is mostly ipsilateral.
Efferent (output) connections of cerebellum

• From vestibulo cerebellum – directly to the brain stem (not via the deep nuclei)
• From spinocerebellum
• From the medial portions of the spinocerebellum → Fastigial nuclei → brainstem.
• From adjacent lateral parts of the spinocerebellum → Emboliform and globose nuclei
→ brainstem.
• From neocerebellum to the dentate nucleus → Ventrolateral nucleus of Thalamus →
Cortex dentato thalamocortical pathway).
N.B : Output from the vestibulo cerebellum does not go via the deep nuclei.
Inside connections of cerebellum

• Climbing fibers end directly on the Purkinje cells
• Mossy fibers end on the Purkinje cell through the granular cell.
• Purkinje cell projects to the deep nuclei; input from the Purkinje cell to the deep
nuclei is inhibitory.
• Deep nuclei then give their output out of the cerebellum; deep nuclei output is always
excitatory.
• Even at rest deep nuclei continuously discharge excitatory inputs.
• When movement occurs, the deep nuclei discharge increase at first; within a few
milliseconds, inhibition of this discharge occurs by the Purkinje cell- this allows
damping.
• Output from the granule cell- axons of the granule cells bifurcate into “T” and give
rise to parallel fibers.
• Granule cell stimulates the Purkinje cell; however, the granule cell also ends on
AfraTafreeh.com
basket/ stellate cells and stimulates them.
• Basket and stellate cells, being inhibitory cells, in turn inhibit the Purkinje cell (this
inhibition by the basket/ stellate cell is an example of feed forward inhibition).
• Granule cell itself is inhibited by the Golgi cell in a feedback inhibition.
242 | Physiology
Neural Connection of the cerebellum
Functions of cerebellum
(i) Maintenance of equilibrium – this is the function of the vestibulo cerebellum (i.e. the
flocculonodular lobe). There is inter connection between the vestibular apparatus and
the flocculonodular lobe.
(ii) Role in regulation of tone/ posture – the effects of the cerebellum on the stretch
reflex are complex. With cerebellar disease one would expect an increased in tone. But
in humans, hypotonia occurs in cerebellar disease. The spinocerebellum projects on
AfraTafreeh.com
The alpha motor neurons (through efferent output to vestibular nuclei)

The gamma motor neurons (through efferent output to reticular formation)

There is a perfect co ordination between the alpha and gamma motor neuron
discharge (the alpha- gamma linkage). The linkage exists at the level of the spinal
cord; the ‘switch’ for the linkage is in the cerebellum.
(iii) Error control function / effects on movement- By comparing plan with
performance, (the cerebellum gets input from the cortex as well as various sensory
inputs) the cerebellum makes anticipatory corrections.
(iv) Planning functions – This is the function of the neocerebellum
(v) Role in learning: The cerebellum is concerned with learned adjustments to
repetitive tasks.
Features of Cerebellar lesions/ disease
No paralysis
No sensory deficit
No abnormalities at rest (except the changes in stretch reflexes)
Ataxia (drunken gait)
Slurred/ scanning speech
Dysmetria (past- pointing)
Intention tremor
Rebound phenomenon
Adiadochokinesia
Decomposition of movement
Concept 6.17 : Brodmann’s areas
• To enumerate Brodmann’s areas and their functions
Time Needed
1 reading
st
05 mins
2nd look 03 mins
S. No. Area Number
1. Primary sensory area = 3, 1, 2

(Post central gyrus)
2. Primary Motor area = 4

(Pre – central gyrus)
3. Premotor area = 6
4. Frontal eye field = 8
5. Sensory association area = 5, 7
6. Primary visual area AfraTafreeh.com= 17

(Visual association area) = 18,19
7. Primary auditory area = 41

Auditory association area = 41, 42
8. Broca’s area = 44
Wernicke’s area = 22
9. Cingulete gyrus = 24
Angular gyrus = 39
244 | Physiology
Concept 6.18 : Hypothalamus
• To enumerate nuclei of hypothalamus and their functions
Time Needed
1 reading
st
05 mins
2nd look 03 mins
Hypothalamic nuclei
Function Nucleus
Temperature regulation Posterior hypothalamus; respond to cold (heat gain
center)
Anterior hypothalamus including the preoptic
nucleus; responds to warmth (heat loss center)
Endocrine control of
↑TSH via TRH Paraventricular
↑ACTH via CRH Paraventricular
↑FSH, LH via GnRH Arcuate
AfraTafreeh.com
↑GH via GHRH Arcuate
↓GH via Somatostatin Arcuate
↓Prolactin via PIF Arcuate
Neuroendocrine
Vasopressin Supraoptic (mainly) and paraventricular
Oxytocin Supraoptic and paraventricular(mainly)
Hunger Lateral hypothalamus
Satiety Ventromedial hypothalamus
Thirst Lateral hypothalamus
Rage Lateral hypothalamus
Reward (pleasure) Ventromedial hypothalamus
Circadian rhythm Suprachiasmatic nucleus
Sexual behavior Anterior most hypothalamus (anterior ventral
hypothalamus) and posterior most parts of
hypothalamus and in males, piriform cortex
Concept 6.19 : Taste pathway
• To enumerate location of taste buds and different cells in taste buds
• To enunciate the taste pathway
• To enumerate different taste modalities, their receptors and transduction
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Taste buds
• Specialized sense organ for taste (gestation) consists of approximately 10,000 taste
buds.
• Each taste bud is an ovoid body measuring 50- 70 µm.
• Taste buds are located in the mucosa of epiglottis, palate, pharynx and in the walls of
the papillae of the tongue. The papillae of the tongue are
Fungiform- rounded, most numerous near the tip of the tongue; each papilla has

up to five taste buds, mostly located on the tip of the tongue

Circumvallate- arranged in a V on the back of the tongue; each has up to 100 taste

buds located along the sides of the papillae

AfraTafreeh.com
Foliate- on the posterior edge of the tongue; each has up to 100 taste buds

located along the sides of the papillae

• There are four types of cells in each taste bud:-
Basal cells- these arise from the epithelial cells surrounding the taste bud- they

differentiate into new taste cells; old cells are continuously replaced with a half
time of about 10 days
Taste cells- three types, representing various stages of maturity (light cells being

the most mature)

▫ Dark cells or type I taste cells

▫ Light cells or type II taste cells

▫ Intermediate cells or type III taste cells

• Taste buds are located in the mucosa of epiglottis, palate, pharynx and in the walls of
the papillae of the tongue. The papillae of the tongue are
Fungiform- rounded, most numerous near the tip of the tongue; each papilla has

up to five taste buds, mostly located on the tip of the tongue

Circumvallate- arranged in a V on the back of the tongue; each has up to 100 taste

buds located along the sides of the papillae

Foliate- on the posterior edge of the tongue; each has up to 100 taste buds

located along the sides of the papillae
Taste pathway
• Taste buds on the anterior two- thirds of the tongue are innervated by the chorda
tympani branch of the facial nerve.
246 | Physiology
• Taste buds on the posterior one- third of the tongue are innervated by the lingual
branch of the glosso pharyngeal nerve
• Fibers from other areas, such as the pharynx reach the brain stem via the vagus.
Nucleus of tractus solitaries in the medulla
Second order neurons ascend in the ipsilateral median lemniscus
Second order neurons synapse in the ventral posteromedial nucleus of thalamus
Anterior insula and frontal operculum in the ipsilateral cerebral cortex
Taste modalities
Humans have five basic taste modalities:
• Salty AfraTafreeh.com
• Sour
• Umami
• Bitter
• Sweet
All tastants (taste stimuli) are sensed from all parts of the tongue and the adjacent
structures.
Taste receptors and transduction

Taste Triggered by Receptor
Salty NaCl ENaCs, others
Sour Protons (H )+
ENaCs, K+ channel (H+ bind to and block these channels producing
depolarization), HCN (hyperpolarization- activated cyclic nucleotide-
gated cation channel)
Umami L- glutamate Metabotropic glutamate receptors- mGluR4 in the taste buds
Bitter Many poisons, T2R family of G- protein coupled receptors, (some receptors are coupled
strychnine, quinine to the heterotrimeric G- protein, gustducin)
Sweet T1R3 family of G- protein coupled receptors which couple to the G
protein gustducin
Note : T2R, T1R3 belong to TRP (transient receptor potential) channelsQ, a family of excitatory ion channels
Worksheet
• MCQ OF “CENTRAL NERVOUS SYSTEM” FROM DQB

AfraTafreeh.com


248 | Physiology
Thalamic sensory relay nuclei
Somatic sensations
Visual sensations
Auditory sensations
Taste
Olfaction
Stretch reflex (monosynaptic) and inverse stretch reflex (bisynaptic)

AfraTafreeh.com
Stretch reflex Inverse stretch reflex
Stimulus
Receptor
Afferent fibers
Center
Efferent
Response
No. of synapses
Differences between UMN and LMN paralysis
UMN lesion LMN lesion
Type of paralysis
Atrophy of affected muscles

present or absent
DTJ
Pathological reflex
Superficial reflexes
Fasciculation and fibrillation

AfraTafreeh.com
Parts of cerebellum and their functions

Part Functions
Vestibulo cerebellum
(or the floculo- nodular lobe)
Spinocerebellum
Cerebro cerebellum
(or neocerebellum)
250 | Physiology
Brodmann’s areas
Area Number
Primary sensory area

(Post central gyrus)
Primary Motor area

(Pre – central gyrus)
Premotor area
Frontal eye field
Sensory association area
Primary visual area

(Visual association area)
Primary auditory area

Auditory association area
AfraTafreeh.com
Broca’s area
Wernicke’s area
Cingulete gyrus
Angular gyrus
Hypothalamic nuclei
Function Nucleus
Temperature regulation
Endocrine control of
↑TSH via TRH

↑ACTH via CRH
↑FSH, LH via GnRH
↑GH via GHRH
↓GH via Somatostatin
↓Prolactin via PIF
Neuroendocrine
Vasopressin
Oxytocin
AfraTafreeh.com
Hunger
Satiety
Thirst
Rage
Reward (pleasure)
Circadian rhythm
Sexual behavior
252 | Physiology
Taste receptors and transduction
Taste Triggered by Receptor
Salty
Sour
Umami
Bitter
Sweet
AfraTafreeh.com
7 Endocrinology
CONCEPTS
Â Concept 7.1 Differences between lipid soluble

and water soluble hormones
Â Concept 7.2 Second messengers

Â Concept 7.3 Hypothalamic- pituitary axis

Â Concept 7.4 Anterior pituitary hormones

Â Concept 7.5 Antidiuretic hormone
AfraTafreeh.com

Â Concept 7.6 Thyroid hormones

Â Concept 7.7 Secretions of adrenal glands

Â Concept 7.8 Secretions of pancreas

Â Concept 7.9 Insulin

Â Concept 7.10 Glucagon

Â Concept 7.11 Other hormones secreted by the

pancreas
Â Concept 7.12 Parathormone

Â Concept 7.13 Vitamin D and its role in calcium

metabolism
254 | Physiology
Concept 7.1 : Lipid soluble and water soluble hormones
Learning Objectives
• To enumerate the differences between lipid soluble and water soluble hormones
Time Needed
1 reading
st
05 mins
2nd look 03 mins
Lipid soluble hormones Water soluble hormones

Examples Steroid hormones, Thyroid hormones Peptide hormones (anterior and posterior
pituitary hormones, Insulin, Glucagon,
Parathormone), Biogenic amines (Epinephrine,
Norepinephrine, etc)
Receptors Receptors in cell cytoplasm Membrane receptors- use the G protein and the
(glucocorticoids, progesterone, second messenger system (second messengers
testosterone) or in the nucleus (thyroid, are Ca++, cyclic nucleotides- cAMP and cGMP,
estrogen) IP3, DAG)
*Insulin activates the membrane bound
tyrosine kinase
Mode of action Synthesis of new proteins (enzymes)
By regulation of pre existing enzymes
AfraTafreeh.com
Storage Synthesized as and when needed Stored in vesicles as prohormones
(except thyroid hormones which are
stored in the colloid)
Transport in With the help of transport proteins Transported dissolved in plasma (except IGF-
plasma (except adrenal androgens and DHEA) 1)
Half life Long- Aldosterone- 30 min, Cortisol- Short- Insulin- 7 min, PRL- 12 min, ACTH-
90-120 min, Vitamin D- 15 hours 15-25 min, LH- 15-45 min, FSH- 180 min
Endocrinology | 255
Concept 7.2 : Second messengers
Learning Objectives
• To understand the role of G proteins
• To understand the role of second messengers
• To understand the adenyl cyclase and cAMP second messenger system and enumerate
the hormones which use the adenyl cyclase- cAMP system
• To understand the guanyl cyclase and cGMP second messenger system, enumerate
the hormones using the guanyl cyclase system and to appreciate that ANP, BNP act on
the membrane bound guanyl cyclase whereas nitric oxide acts on the soluble guanyl
cyclase
• To understand the IP3 and DAG and to enumerate the hormones which act by using
IP3 and DAG as second messengers
• To understand the mechanism of action of hormones with enzyme-linked receptors
and to enumerate the hormones which act in this fashion
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
G Proteins
AfraTafreeh.com
• Are GTP- binding proteins that couple hormone receptors to adjacent effector
molecules. For example, in the cAMP second messenger system, G proteins couple
the hormone receptor with adenylate cyclase enzyme.
• Are used in the cAMP and inositol triphosphate second messenger systems.
• Have intrinsic GTPase activity.
• Have three subunits- alpha, beta and gamma.
• Alpha subunit can bind GTP or GDP- when GTP is bound to the alpha subunit, the GTP
is active and when GDP is bound, the G protein is inactive.
• G proteins can be stimulatory (Gs) or inhibitory (Gi). stimulatory or inhibitory activity
resides in the alpha subunits.
Second Messengers
The extracellular ligands are called “first messengers” and the intracellular mediators
are called “second messengers”.
Second messengers bring about many short term changes in cell function by altering enzyme
function, triggering exocytosis, etc, but they also alter transcription of various genes.
• Short lived intracellular signaling molecules
• Elevated concentration of second messenger leads to rapid alteration in the activity
of one or more cellular enzymes.
• Removed or degradation of second messenger terminate the cellular response
• Four classes of second messengers
Cyclic cucleotides

Membrane lipid derivatives

Ca2+

Nitric oxide/carbon monoxide

256 | Physiology
Adenyl cyclase- cAMP second messenger system
AfraTafreeh.com
Hormones that use the adenyl cyclase- cAMP second messenger system
ACTH
Angiotensin II (epithelial cells)
Calcitonin
Catecholamines (β1 & β2 receptors)
CRH
FSH
Glucagon
hCG
LH
PTH
Secretin
Somatostatin
TSH
Vasopressin (V2 receptor, epithelial cells)
MSH
Endocrinology | 257
Guanyl cyclase (cGMP) second messenger system
AfraTafreeh.com
Hormones using guanyl cyclase system

ANP, BNP- act on membrane bound guanyl cyclase
Nitric oxide (NO)- acts on soluble guanyl cyclase
258 | Physiology
Phospholipase- IP3 and DAG second messenger system
AfraTafreeh.com
• Some hormones activate transmembrane receptors that activate Phospholipase C
attached to the inside of the receptors.
• Phospholipase C catalyzes the breakdown of phosphatidylinositol biphosphate into
inositol triphosphate and diacylglycerol.
• IP3 mobilizes Ca++ from mitochondria and endoplasmic reticulum and the calcium
ions have their own second messenger effects such as smooth muscle contraction and
changes in cell secretion.
• DAG activates the enzyme protein kinase C, which then phosphorylates a large
number of proteins, leading to the cell’s response.
Hormones using the phospholipase-IP3 (Ca++) and DAG second
messenger system
GHRH
TRH
GnRH
ADH (V1 and V3 receptors)
Oxytocin
Angiotensin II
Catecholamines (α1 receptors)
Enzyme- linked hormone receptors
• Some receptors, when activated, function directly as enzymes or are closely associated
with enzymes that they activate.
Endocrinology | 259
• These enzyme- linked receptors are proteins that pass through the membrane only
once, in contrast to the seven- transmembrane G-protein coupled receptors.
• Enzyme- linked receptors have their hormone- binding site on the outside of the
cell membrane and their catalytic or enzyme- binding site on the inside. When the
hormone binds to the extracellular part of the receptor, an enzyme immediately inside
the cell membrane is activated (or occasionally inactivated).
• Although many enzyme linked receptors have intrinsic enzyme activity (eg., insulin),
others rely on enzymes that are closely associated with the receptor to produce
changes in cell function (eg., growth hormone, leptin, which utilize the JAK2- STAT
pathway)
Receptors with tyrosine kinase activity
• Hormone binds to extracellular receptors which have tyrosine kinase activity- when
activated, tyrosine kinase phosphorylates tyrosine on proteins, leading to their
physiologic actions.
• Examples-
Nerve growth factor; receptor kinase for NGF is a monomer- binding of the NGF

with its receptor causes dimerization of the receptor, activation of intrinsic tyrosine
kinase activity, and phosphorylation of tyrosine molecules.
Insulin- receptor for insulin and IGF-1 is a dimer. Binding of the hormone with

its receptor causes activation of intrinsic tyrosine kinase activity, leading to

phosphorylation of tyrosine molecules.
AfraTafreeh.com
Tyrosine-kinase associated receptor (JAK2-STAT pathway)

• Mechanism closely resembles that of receptor tyrosine kinases.
• Only difference being that tyrosine kinase activity is not intrinsic to the receptor
molecule.
• Uses JAK- STAT pathway.
260 | Physiology
• It is the mechanism for action of growth hormone, IGF-1, prolactin, cytokines.
Interferons, etc.
• GH receptor has a large extracellular portion, a transmembrane domain, and a large
cytoplasmic portion.
• GH has two domains that can bind to its receptor, and when it binds to one receptor,
the second binding site attracts another, producing a homodimer- dimerization is
essential for receptor activation.
• Intracellular side of the receptor is non- covalently associated with JAK2 (JAK2 is a
member of Janus family of cytoplasmic tyrosine kinases).
• Targets of JAK2 include signal transducers and activators of transcription (STAT),
which upon phosphorylation by KAK kinases, migrate to the nucleus and cause
transcription of new mRNAs and new protein synthesis.
AfraTafreeh.com
Endocrinology | 261
Concept 7.3 : Hypothalamic- pituitary axis
Learning Objectives
• To understand that the secretion of anterior pituitary hormones is under the control
of releasing and inhibiting factors from the hypothalamus
• To understand the concept of neurosecretion by the hypothalmus
Time Needed
1 reading
st
05 mins
2nd look 03 mins
Hypothalamic-anterior pituitary axis

Hypothalamus Anterior Pituitary
TRH ↑TSH, ↑Prolactin
CRH ↑ACTH, ↑β- LPH
GnRH ↑FSH, LH
GHRH ↑GH
Somatostatin ↓GH, ↓TSH
PIF ↓Prolactin
AfraTafreeh.com
All hypothalamic hormones are secreted in a pulsatile fashion except TRH.
Hypothalamus secretes releasing and inhibiting hormones which regulate the secretion
of anterior pituitary hormones.
The two inhibiting hormones are Somatostatin and Prolactin inhibiting factor (PIF).
Growth hormone secretion from the anterior pituitary is mainly under the control of
GHRH from the hypothalamus.
Damage to the pituitary stalk or the ‘stalk effect’Q causes an increase in the level
of Prolactin and galactorrhoeaQ (also a decrease in ADH which causes polyuria and
diabetes insipidus).
Neurosecretion by hypothalamus
• There are neural connections between the hypothalamus and posterior lobe of the
pituitary gland.
• Embryologically, the posterior pituitary arises as an evagination of the floor of the
third ventricle.
• Posterior pituitary is made of the endings of axons that arise from cell bodies in the
supraoptic and paraventricular nuclei and pass to the posterior pituitary.
• The hormones of the posterior pituitary gland (vasopressin and oxytocin) are
synthesized in the cell bodies of the magnocellular neurons in the supraoptic and
paraventricular nuclei and transported down the axons of these neurons to their
endings in the posterior lobe, where they are secreted in response to electrical activity
in the endings.
• Majority of vasopressin is secreted by neurons of the supraoptic nucleus whereas
majority of oxytocin is secreted by the paraventricular nucleus.
262 | Physiology
Concept 7.4 : Anterior pituitary hormones
• To enumerate the different cell types in the anterior pituitary
• To understand actions of growth hormone- direct and indirect (via IGF-1), control of
growth hormone secretion, stimuli that increase and decrease secretion of growth
hormone and disorders of growth hormone secretion
• To understand the actions of prolactin, its control, stimuli which increase prolactin
secretion
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
Cell types in anterior pituitary

• Most numerous are the somatotropes which secrete GHQ.
• Least are thyrotropes.
• Somatotropes and lactotropes are acidophilic; corticotropes, thyrotropes and
gonadotropes are basophilicQ.
• FSH, LH, TSH (and hCG) are made of two subunits- α and β; α subunits are similar in
all; β subunits are different.
Growth Hormone
AfraTafreeh.com
• Anabolic hormone (other anabolic hormones- Insulin, thyroid, androgens).
• Secreted by somatotropes of the anterior pituitary.
• Monkey and human growth hormones are effective in both monkeys and humans;
porcine and bovine growth hormones are ineffective in humans.
• GH acts on the growth hormone receptor on the cell membrane→activation of the
JAK2-STAT pathway. (JAK-STAT pathway mediates the effect of Prolactin and various
other growth factors).
Actions of growth hormone

1. Direct actions
(a) protein synthesis- by increasing uptake of amino acids which in turn increases
protein synthesis; produces a positive nitrogen and phosphorus balance, a fall
in blood urea nitrogen and amino acid levels
(b) Lipolysis (increases circulating free fatty acids and is therefore ketogenic)
(c) Decreases Insulin sensitivity (therefore, it is diabetogenic)
(d) Epiphyseal growth
(e) increases GI absorption of calcium, causes sodium and potassium retention
2. Indirectly via somtomedins or IGF-1:
Somatomedins or polypeptide growth factors are secreted by liver and other

tissues.
Main source of IGF-1 is the liver.

Endocrinology | 263
Secretion of IGF-1 is independent of growth hormone before birth but is stimulated
by growth hormone after birth.
GH acts on cartilage to convert stem cells into cells that respond to IGF-I.
Locally produced as well as circulating IGF-I then acts on these cells producing
growth of cartilage.
Actions of IGF-I (also k/a Somatomedin C):
▫ Insulin- like activity

▫ Anti-lipolytic activity

▫ Protein synthesis

▫ Epiphyseal growth.

*IGF-II (also k/a multiplication stimulating activity or MSA) is secreted in fetal life and its secretion is independent of
growth hormone.
**IGF-I secretion peaks at puberty and is responsible for the growth spurt seen at this stage.
***IGF-I is responsible for growth after birth whereas IGF-II causes growth during fetal life.
Factors controlling growth hormone secretion

• Hypothalamus secretes GHRH and somatostatin which regulate growth hormone
secretion.
• Ghrelin (mainly from the stomach but also from hypothalamus), which has marked
growth hormone- stimulating activity.
• GH secretion is pulsatile- low in the daytime (unless there are specific triggers) but
AfraTafreeh.com
large pulsatile bursts occur at night during sleep.
264 | Physiology
Stimuli that increase secretion:
• Hypoglycemia
• Starvation, fasting
• Exercise
• Protein meal
• Amino acids- arginine, leucine
• Glucagon (response to glucagon has been used to test growth hormone reserve)
• Stressful stimuli- excitement, trauma, fever, psychological stress
• Going to sleep
• Estrogen, androgens (sex hormones induce GH secretion, increase GH responses to
stimuli such as arginine and insulin, increase responsiveness of peripheral tissues to
GH)
• L-DOPA and α adrenergic agonists
AfraTafreeh.com
Stimuli that decrease secretion

• REM sleep
• Glucose (increase in blood sugar level)
• Cortisol
• Free fatty acids
• GH and IGF-I
• Medroxyprogesterone
Disorders of GH secretion
Hypersecretion before fusion of long bones causes gigantism and after puberty causes
acromegaly; hyposecretion causes dwarfism
Endocrinology | 265
Causes of dwarfism:
• GHRH deficiency
• GH deficiency
• Deficient secretion of IGF-1 (African pygmies have a congenital inability to secrete IGF- I)
• Growth hormone insensitivity or Laron dwarf (plasma growth hormone concentration is normal or
elevated but their growth hormone receptors are unresponsive as a result of loss- of- function mutations),
cretinism
• Precocious puberty
• Syndrome of gonadal dysgenesis (XO)
• Constitutional delayed growth
• Chronic abuse and neglect (psychosocial dwarfism or the Kaspar Hauser syndrome)
• Various bone and metabolic disorders
• Achondroplasia
Pituitary dwarf has features consistent with their chronological age until puberty; thereafter because of the
failure to mature sexually they have juvenile features in adulthood
Thyroid dwarf, on the other hand, has infantile features (because thyroid hormones have widespread
effects on the ossification of cartilages, growth of teeth, contours of face, and the proportions of the body),
mental retardation (thyroid hormones are required for the development of CNS), deafness (thyroid hormones
required for development of the internal ear) and mutism.
AfraTafreeh.com
Prolactin
• It is the major hormone responsible for lactogenesis.
• Participates, with estrogen, in breast development.
• Is structurally homologous to growth hormone.
Normal concentration in females-5ng/mL and in males-8ng/mL
Control of prolactin secretion
Secretion of prolactin is tonically inhibited by PIF from the hypothalamus.
266 | Physiology
Factors causing an increase in PRL:
(Mnemonic: Nu PETS SHOP)
• Nursing
• Pregnancy
• Estrogen
• TRH
• Somatostatin
• Stress, strenuous exercise, breast stimulation in a non pregnant female, sleep, sexual
intercourse
• Hypoglycemia
• Hypothyroidism
• Opiates
• Phenothiazines
*L-DOPA and bromocriptine decrease secretion
PRL levels increase during pregnancy, reaching a peak at parturition.

After parturition, PRL levels decrease to normal non pregnant levels in 8 days,

although suckling produces an increase in secretion but the magnitude of this

increase declines in a female who has been nursing for more than 3 months.
With prolonged lactation milk secretion occurs with PRL levels that are in the

normal range.
AfraTafreeh.com
Endocrinology | 267
Concept 7.5 : Antidiuretic hormone
• To understand the mechanism of synthesis and secretion of ADH
• To understand control of ADH secretion, stimuli which increase and decrease secretion
of ADH, ADH receptors- their location and actions.
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Mechanism of synthesis and secretion of ADH

Synthesis is by supraoptic (mainly) and paraventricular nuclei of hypothalamus
ADH is synthesized in the cell bodies and then transported by axoplasmic transport to
the axonal endings.
The secretory granules in the axonal endings are k/a Herring bodies
Supraoptic nucleus
AfraTafreeh.com
Signal peptide + AVP + Neurophysin II + glycopeptide
(precursor molecule K/a prepropressophysin)
Signal peptide is removed in the E.R;

packaged into secretory vesicles in Golgi apparatus
Transported down the axons by axoplasmic flow

to the endings in the posterior pituitary
Free ADH released into the circulation

+
Neurophysin II
+
Glycopeptide
268 | Physiology
Prepropressophysin
Control of ADH secretion

1. Osmotic stimuli- Increase in plasma osmolality stimulates the osmoreceptors (these
osmoreceptors are located outside the blood brain barrier in the circumventricular
organs, primarily the OVLT in anterior hypothalamus) → impulses are sent to the
supraoptic and paraventricular nuclei of the hypothalamus→posterior pituitary → ADH
enters the circulation → ↑ water (& urea) reabsorption in the kidney
AfraTafreeh.com
2. Stimuli from the stretch receptors in the atria and large veins (low pressure areas)
act to chronically inhibit ADH secretion from the posterior pituitary. When there is a
decrease in blood volume → ↓ in signals from the atria and large veins → ↓ in chronic
inhibition → ↑ ADH → ↑ water reabsorption
Endocrinology | 269
Stimuli which increase ADH secretion
• Increased effective osmotic pressure of plasma
• Decreased ECF volume
• Pain, emotions, stress, exercise
• Nausea, vomiting
• Standing
• Clofibrate, carbamazepine
• Angiotensin II
Stimuli which decrease ADH secretion

• Decreased effective osmotic pressure of plasma
• Increased ECF volume
• Alcohol
ADH receptors
There are three kinds of vasopressin receptors- V1A, V1B, V2; all are G- protein
coupled.
Receptor Site Actions Actions
mediated by
V1A • Vascular smooth muscle IP3 & Ca++ • Vasoconstriction
• Heart AfraTafreeh.com
• Myocardial hypertrophy
• Area postrema • Action on area postrema decreases cardiac
• output and Bp; this action is in contrast to the
• Liver direct action of vasopressin on the vascular
smooth muscle- hence a large amount of
• Brain and spinal cord vasopressin is needed to raise the blood
• Platelets pressure in vivo.
• Produces glycogenlysis in liver
• Acts as a neurotransmitter in brain and spinal
cord
• Platelet aggregation
V1B (V3) • Anterior+ pituitary IP3 & Ca++ • Increases secretion of ACTH, PRL,
Endorphins
V2 • Collecting duct cAMP • Causes insertion of acquaporin 2 into the
luminal membrane of P cells of collecting
duct, increasing the water reabsorption
270 | Physiology
Concept 7.6 : Thyroid hormones
Learning Objectives
• To enumerate the steps in synthesis of thyroid hormones
• To understand the mechanism of secretion and transport of thyroid hormones
• To understand the fate of T4, T3
• To enumerate the conditions which cause an increase in RT3
• To tabulate the differences between T4 and T3
• To enumerate the physiological effects and regulation of thyroid hormone secretion
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Thyroid gland
• Thyroid made of multiple acini or follicles.
• Each follicle is surrounded by a single layer of cells and filled with colloid
• Colloid consists mainly of the glycoprotein, thyroglobulin.
Inactive gland Active gland
Colloid Abundant Scalloped/ resorption lacunae are seen
Follicle Large AfraTafreeh.com
Small
Cells Flat Columnar
Steps in synthesis of thyroid hormones

1. Iodide trapping:
By the sodium iodide symporter (NIS) which transports I- from low to high

concentration within the thyroid cells by the process of secondary active transport.
The energy for the secondary active transport is provided by electrochemical

gradient for Na established by the transport of Na out of the cell by the activity of
Na-K ATPase.
Transport of iodide across the apical membrane into the colloid is mediated by

a Cl-/I- exchanger known a pendrin (patients of Pendred syndrome suffer from

thyroid dysfunction and deafness).
2. Synthesis of thyroglobulin and secretion into the colloid by exocytosis.
Thyroglobulin is a glycoprotein, with 10% carbohydrate by weight, contains 123
tyrosine residues but only 4-8 are used to form thyroid hormones
3. Oxidation of I-: reaction catalyzed by thyroid peroxidase. This occurs at the apical
border of the thyroid cell
4. Iodination of tyrosine (or organification of iodine) results in the formation of MIT
and DIT; reaction catalyzed by thyroid peroxidase; occurs within the colloid
5. Coupling reactions: occurs within the thyroglobulin molecule. Thyroid peroxidase is
involved in coupling as well.
Endocrinology | 271
Coupling reactions:
• DIT + DIT → T4 • MIT + DIT → T3
• DIT + MIT → RT3
In the normal human thyroid, the average distribution of iodinated compounds is:
• MIT - 23% • DIT - 33%
• T4 - 25% • T3 - 7%
• RT3 - Traces
Secretion of thyroid hormones:

When stimulated, the thyroid cells ingest colloid by endocytosis- the peptide bonds
between the iodinated residues and the thyroglobulin are broken by the proteases in
the lysosomes, and T3, T4, MIT and DIT are liberated into the cytoplasm. T3 and T4 pass
into the circulation.
T4 : 80mg/day
T3 : 4 mg/day
RT3 : 2mg/day
MIT/DIT : Nil
Microsomal deiodinase removes iodine from MIT, DIT- this iodine is reutilized. This
provides twice as much I- as the iodide pump. Deficiency of microsomal deiodinase
causes symptoms of iodide deficiency and MIT, DIT appear in urine
AfraTafreeh.com
Transport of thyroid hormones
By transport proteins, TBG, TBPA or transthyretin, Albumin
T4 binds maximally to TBG; T3 binds maximally to Albumin
Highest capacity to bind T4: Albumin; Highest affinity to bind T4: TBG
Fate of T4, T3
T4 5’De io dinase T3 (one third of T4 is converted to T3)
T4 5 De io dinase RT3 (45% of T4 is converted to RT3)
T3 13% from secretion

87% from T4
RT3 5% from secretion
95% from T4
• Normally, T3 >>> RT3

• RT3 > T3 in fetal life
• Adult pattern is seen 6 wks after birth
• T4, T3, RT3 are de iodinated in the liver, kidneys, etc., by iodothyronine deiodinase
(different from the microsomal deiodinase which removes iodine from MIT, DIT)
• Selenium is an important part of 5’ DI, which converts T4 → T3; therefore in selenium
deficiency RT3 > T3
272 | Physiology
Conditions which cause RT3 to become more than T3
The graph above shows the sharp fall in T3 and an increase in RT3 during starvation. This
reversal helps to conserve calories. The ratio of T3 and RT3 return to normal by 4 days
of overfeeding.
AfraTafreeh.com
In the following conditions there is ↓T3, ↑RT3 or RT3 > T3 (this helps in energy conservation);
T4 -free & bound, remain almost normal
• Selenium deficiency
• Drugs which inhibit deiodinases
• Burns
• Trauma
• Advanced cancer
• Cirrhosis
• Chronic kidney disease
• Myocardial infarction
• Febrile states
In Over feeding T3↑, RT3↓

Differences between T4 and T3

T4 T3
Plasma
Total 8ng/dl 0.15 ng/dl
Free 2ng/dl 0.3 ng/dl
% Bound 99.98 99.8
% Free 0.02 0.2
Half life Longer Shorter
Binding More Less
Endocrinology | 273
Maximum binding TBG (67%) Albumin (53%)

Action Slower Much more rapid
In colloid More (25%) Less (7%)
Amount secreted More (80 mg/d) Less (4mg/d)
‘Reverse’ No RT4 RT3 is present
Potency Less 3-5 times more potent
Binding to Thyroid Hormone Less More
nuclear receptors
Physiological effects of thyroid hormones

• Heart- positive chronotropic and positive ionotropic effect on the heart (thyroid
hormones ↑ number of β adrenergic receptors and ↑ response to circulating
catecholamines)
• Adipose tissue- stimulate lipolysis
• Muscle- cause increased protein breakdown
• Bone- promote normal growth and skeletal development
• Nervous system- promote normal brain development (thyroid hormones required for
myelination)
• GIT- increase rate of carbohydrate absorption
AfraTafreeh.com
• Lipoprotein- stimulate formation of LDL receptors → hepatic removal of cholesterol →
↓ serum cholesterol
• Others- calorigenic (↑BMR); ↑O2 consumption by metabolically active tissues EXCEPT
in testes, uterus, spleen, lymph nodes, anterior pituitary
Regulation of thyroid secretion

TRH- from hypothalamus; stimulates release of TSH (also PRL, GH) from anterior
pituitary; TRH stimulation testing useful in the diagnosis of
• Hyperthyroidism
• Recurrent acromegaly
• Gonadotropin secreting tumor
• Cases where documentation of PRL deficiency is necessary
TSH- glycoprotein; consists of α and β subunits; α subunit of TSH is similar to the
α subunits of LH, FSH and hCG; β subunit confers functional specificity; secretion-
pulsatile, output increases at 9PM, peaks at midnight and decreases during the day.
T3 is the principal feedback regulator of TSH secretion and NOT T4.
274 | Physiology
Concept 7.7 : Secretions of adrenal glands
• To enumerate the hormones secreted by different zones of adrenal cortex
• To enumerate the hormones secreted by the adrenal medulla and to understand the
difference in their actions
• To understand the chemical structure of the adrenal cortical hormones
• To understand the steps in the synthesis of adrenal hormones
• To understand the role of ACTH in control of cortisol secretion
• To enumerate the actions of glucocorticoids
• To understand the control of Aldosterone secretion
• To enumerate conditions which increase Renin, and therefore, Aldosterone secretion
• To understand the actions of Aldosterone
Time Needed
1st reading 25 mins
2 look
nd
15 mins
Hormones secreted by adrenal cortex and adrenal medulla

Region Percentage of total Hormones Controlled by
mass
Zona Glomerulosa 15%
AfraTafreeh.com
Aldosterone Angiotensin II, K+
Zona Fasciculata 50% Glucocorticoids and androgens ACTH
Zona Reticularis 7% Androgens and glucocorticoids ACTH
Medulla Rest Epinephrine (90%)
NE (10%)
Adrenal. Medulla also secretes
Chromogranin A
Opioid peptides
Adrenomedullin
Hormones secreted by adrenal medulla

Major secretion from the adrenal medulla in humans is Nor epinephrineQ
Differences in the actions of epinephrine and nor epinephrine
• Norepinephrine (NE)
↑ in both SBP, DBP

only slight ↑ in PP

↑ in MAP,

• Epinephrine (E)
↑ SBP, ↓ DBP,

↑↑ PP

Slight ↑ in MAP

Endocrinology | 275
• Heart Rate (HR)
Nor Epinephrine causes a reflex bradycardia
Epinephrine causes a tachycardia
Increase in nor epinephrine and epinephrine in different conditions:
Exercise : NE↑ >> E↑
Asphyxia/Hypoxia : NE↑ > E↑
Pheochromocytoma : NE↑ > E↑
Hypoglycemia, myocardial infarction, ketoacidosis:
E↑ > NE↑
• After hypophysectomy, epinephrine synthesis decreases
Conversion of nor epinephrine to epinephrine is catalyzed by the enzyme
phenylethanolamine-N-methyltransferase (PNMT)
NE E
PNMT
[PNMT is stimulated by glucocorticoids]
• After adrenalectomy,
Free Epinephrine in plasma becomes zero

AfraTafreeh.com
Nor Epinephrine is unchanged

Chemical structure of adrenal cortical hormones

Cholesterol, sex steroids, corticosteroids (and digitalis) have a CPPP nucleus- they differ
in the side chains and the total number of carbon atoms. E.g.,
C27 Cholesterol
C21 17 Hydroxy corticosteroids
Progesterone
Corticosteroids
C19 17- Ketosteroids
Androgens
Source of urinary 17-ketosteroids: In females all the urinary
17- ketosteroids are from the adrenal cortex; in males, the sources are
DHEA from adrenal cortex (two-thirds)
Testosterone derivatives- from testes (one- third)
C18 Estrogens
C17 CPPP ring
Adrenal cortex secretes mainly C21, C19
C19 : Androgenic activity
C21 : Mineralocorticoid & glucocorticoid activity
276 | Physiology
Glucocorticoids
• Cortisol
• Cortico sterone
Mineralocorticoids
• Aldosterone
• Deoxy corticosterone
Androgens
• DHEA
• Androstenedione
(Cortisone: produced from cortisol in liver; does not come into circulation)
(Corticosterone: Has mineralocorticoid activity)
Synthesis of adrenal cortical hormones
AfraTafreeh.com
• 95% of patients of congenital adrenal hyperplasia have deficiency of 21-β hydroxylase,

where there is deficiency of corticosteroids and excess secretion of androgens.
• 5% of patients of congenital adrenal hyperplasia have deficiency of 11-β hydroxylase,
where there is deficiency of corticosteroids and excess secretion of androgens.
The distinguishing feature between 21-β hydroxylase and 11-β hydroxylase is
that blood pressure is elevated in the latter with increased plasma sodium and
decreased potassium. This is because of 11-β hydroxylase have excess of 11-
deoxycorticosterone which has mineralocorticoid activity. Patients of 11-β hydroxylase
have “hypoaldosteronic hypertension”.
• Deficiency of 17, 20-lyase produces deficiency of androgens and excess of
corticosteroids
• Deficiency of 17-α hydroxylase produces deficiency of both cortisteroids and androgens
Deficiency Aldosterone Glucocorticoids Androgens
21-β hydroxylase ↓ ↓ ↑
11-β hydroxylase ↓ ↓ ↑
17, 20-lyase ↑ ↑ ↓
17-α hydroxylase ↑ ↓ ↓
Endocrinology | 277
Role of ACTH and control of cortisol secretion
The following increases the secretion of CRH
• Trauma via the nociceptive pathway
• Emotions via the limbic system
• Stress (physical, emotional, hypoglycemia)
• Time of the day (suprachiasmatic nucleus of hypothalamus- responsible for circadian
rhythm)
CRH
Acts on anterior pituitary

Synthesis and release of POMC (Pro opio melanocortin)
ACTH AfraTafreeh.com
β-Lipotropin (β-LPH) β-endorphin

acts on adrenal cortex to cause
release of glucocorticoids
*Peak CRH and hence cortisol secretion is between 6th and 8th hours of sleep (i.e., early morning); low in late evenings.
**In Addison’s disease there is excessive secretion of ACTH → darkening of skin (because of MSH activity in ACTH).
Cortisol exists in three forms:

• Free cortisol in plasma (< 5%)
• Protein bound cortisol (90-95%)
• Cortisol metabolites
Transport of cortisol
Cortisol is transported in combination with
• CBG (has high affinity low capacity for cortisol)
• Albumin (has low affinity and high capacity)
*Pregnancy, estrogen, OCPs cause an increase in CBG. An increase in CBG causes an increase in total hormone with no
change in free hormone
278 | Physiology
Actions of glucocorticoids
• Cortisol secretion increases in stress (other hormones released in stress are GH,
Glucagon, Epinephrine).
AfraTafreeh.com
• It mobilizes fats (by ↑ lipolysis), proteins and carbohydrates (by ↓ uptake and by
gluconeogenesis).
• Permissive actions- cortisol facilitates the action of Glucagon and catecholamines.
These are: glucagon and catecholamines for glycogenolysis, catecholamines for
lipolysis, vasoconstriction, bronchodilatation.
• Cortisol decreases the number of basophils, eosinophils, lymphocytes (BEL) and
increase the number of neutrophils, platelets, RBCs (mechanism unclear).
• Prevents the release of histamine.
• Inhibits phospholipase A2→ ↓ release of thromboxane acid from tissue phospholipids→
↓ formation of leukotrienes, thromboxane, prostaglandins, IL-1, PGI2.
Aldosterone
Synthesised only in the zona glomerulosa because aldosterone synthase is present only
in the zona glomerulosa.
Secretion controlled by the Renin Angiotensin mechanism and K+ level.
Endocrinology | 279
Conditions which increase Renin (and therefore, aldosterone)

secretion are
AfraTafreeh.com
• Sodium depletion
• Diuretics
• Hypotension
• Hemorrhage
• Upright posture
• Dehydration
• Cardiac failure
• Cirrhosis
• Constriction of renal artery
• Various psychological stimuli (→↑ activity of renal nerves)
• ↑ sympathetic activity (β1 →↑ cAMP) via renal nerves
• ↑ in circulating cortisol
• Prostaglandins
Conditions which decrease Renin (and therefore, aldosterone)

secretion are
• ↑ Na+ and Cl– reabsorption across the macula densa
• ↑ afferent arteriolar pressure
• Angiotensin II
• ADH
280 | Physiology
Actions
• ↑ reabsorption of Na+ from urine (P cells of kidney), sweat, saliva, colon
(mineralocorticoid receptor also present in hippocampus)
• ↑ secretion of K+, H+ (↑ urine acidity)
AfraTafreeh.com
Disorders
Primary and secondary hyperaldosteronism and hypoaldosteronism
(Meq/1)
Na+ K+ CL HCO3–
Normal 142 4.5 105 25
Adr. Insuff. 120 6.7 85 25
Pr. Hyperald,. 145 2.4 96 41
*In primary hyperaldosteronism: Only slight in Na+ plasma, because of there is an associated volume retention. With ed Na+
reabsorption, there is e d H+ excretion resulting in metabolic alkalosis.
**Primary hyperaldsteronism (‘Conn’s syndrome’) causes the following in otherwise ‘normal’ individuals:
• Weakness
• Hypertension
• Tetany
• Polyuria
• Hypokalemia
• Alkalosis
• No edema because of ‘aldosterone escape’ (due to increased secretion of ANP)
Endocrinology | 281
Concept 7.8 : Secretions of pancreas
• To enumerate the cell types in the pancreas and their secretions
• To understand the control of pancreatic islet cell hormones on other islet cell hormones
Time Needed
1 reading
st
05 mins
2 look
nd
03 mins
Cell types and their secretion

β cells
60-75%
Near the center of islets
Contain proinsulin; proinsulin→ insulin + C peptide
Also secrete Amylin
α cells
20%
Located near periphery of the islets
Secrete glucagon AfraTafreeh.com
δ cells
5%
Located between α and β cells
Secrete somatostatin
F cells
Secrete pancreatic polypeptide
e (epsilon) cells
Secrete Ghrelin
Cells in pancreas
α cells – (20% of total cells) – glucagon
β cells – (60-75% of total cells) – insulin, amylin
δ cells – somatostatin
F cells – pancreatic polypeptide
e (epsilon) cells – Ghrelin
Least antigenic insulin
• Human insulin (produced by bacteria by recombinant DNA technology) > porcine
insulin > porcine insulin > bovine insulin
• Porcine insulin differs from human insulin by only one amino acid.
• Bovine insulin differs from human insulin by three amino acids.
282 | Physiology
Pancreatic control in islets
AfraTafreeh.com
Endocrinology | 283
Concept 7.9 : Insulin
• To understand the cellular mechanism of insulin secretion
• To enumerate the unique features of the Insulin receptor
• To enumerate location of different glucose transporters (GluT) and the effect of insulin
on each
• To understand the uptake of glucose by the liver and the role of insulin in facilitating
this uptake
• To enumerate the tissues in which glucose uptake is not affected by insulin
• To enumerate the stimulators and inhibitors of insulin secretion
• To understand the actions of insulin
• To understand features of insulin deficiency
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Cellular mechanism of insulin secretion

• Glucose mediated insulin release in the β cells of pancreas is mediated through ATP
dependent K+ channels.
AfraTafreeh.com
• Metabolism of glucose in the β cells of pancreas → ↓ in K+ efflux → depolarization of
β cell → ↑ Ca++ influx → ↑ release of insulin by exocytosis.
• Insulin secretion starts in the fetus by 12th week.
• (*Glucagon secretion starts in fetus by 8th; thyroxine secretion by 10-12 weeks).
284 | Physiology
Insulin receptor
• Insulin receptor has molecular weight of approximately 340,000.
• It is tetramer made of two α and two β glycoprotein subunits.
• The α subunits bind insulin, whereas the β subunits span the membrane.
• The intracellular portions of the β subunits have tyrosine kinase activity.
• Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing
autophosphorylation of the β subunits on tyrosine residues.
• This autophosphorylation is necessary for insulin to exert its biologic effects.
• It triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of
others.
AfraTafreeh.com
Glucose transporters and peripheral uptake of glucose

SITE TRANSPORT MECHANISM INSULIN
Intestine SGLT & Glut 2 No effect
Kidney SGLT & Glut 2 No effect
β cell of pancreas Glut 2 No effect
Muscle (resting skeletal muscle, cardiac) Glut4 Favours
Adipose Glut4 Favours
Liver Hexokinase Favours
*Placenta has both Glut 1 and Glut 3 but Glut 3 > Glut 1
Endocrinology | 285
Uptake of glucose by the liver and the role of insulin
Insulin (in liver)
↓
Induces Hexokinase
↓
es phosphorylation of glucose
↓
Intracellular free glucose concentration stays low.
↓
Glucose enters into cells
Tissues in which glucose uptake is not affected by Insulin

• Nervous tissue
• Kidney tubules
• Intestinal mucosa
• RBCs
• β cells of pancreas
Control of insulin secretion

Stimulators of insulin secretion Inhibitors of insulin secretion
Glucose, mannose AfraTafreeh.com
Somatostatin
Amino acids- leucine, arginine Sympathetic stimulation (α2 adrenergic receptors)
β keto acids Propranolol
Intestinal hormones- gastrin, CCK, secretin, GIP, K+ depletion
glucagon, GLP-1
cAMP and various cAMP generating substances- β Phenytoin, Alloxan, microtubule inhibitors
adrenergic agonists, glucagon, theophylline
Sympathetic stimulation (β2 adrenergic receptors) Leptin
Ach via M4 receptors
Sulfonylureas
• Net effect of sympathetic stimulation is a decrease in insulin secretion.
• Effect of parasympathetic stimulation is an increase in insulin secretion.
Actions of insulin
• Anabolic action
• Effect on carbohydrate metabolism
• ↑ glucose uptake
• ↑ glucose metabolism
• ↑ synthesis of glycogen
• Promotes glycogenesis
286 | Physiology
• Effect on protein metabolism
• ↑ amino acid uptake
• ↑ protein synthesis
• ↓ protein breakdown
• Effect on fat metabolism
• ↑ glucose uptake
• ↑ activity of lipoprotein lipase → ↑ triglyceride uptake
• ↑ Lipogenesis
• ↓ lipolysis (by ↓ activity of hormone sensitive lipase*)
• Pumps K+ into the cells (by an ↑ in the activity of Na+ – K+ pump)
• (*HSL activated by cortisol, GH, epinephrine, glucagon)
Features of insulin deficiency

• ↑ blood sugar level (due to ↓ peripheral uptake, ↑ glycogenolysis, ↑ gluconeogenesis)
• ↑ protein breakdown, ↓ protein synthesis
• ↑ ureagenesis
• ↑ circulating free fatty acids (↑ breakdown of triglycerides)
• ↑ ketosis (metabolic acidosis)
• ↓ in intracellular K+
• Plasma K+ levels are↑ or normal
• AfraTafreeh.com
Hyperventilation and ↓ in PCO2 (metabolic acidosis → stimulates respiration)
• Glucosuria; urine is acidic because of H+ excretion).
• ↑ Na+ and K+ excretion (Na+ and K+ excreted with organic anions not covered with H+
and NH4+)→ individual is dehydrated and hypovolemic.
• There is loss of urinary Na+ and K+.
• (Ketoacidosis/Ketone Bodies are H+O– where O– = organic acids; Na+ and K+ depletion
occurs because these plasma cations are excreted with the organic anions not covered
by the H+ and NH4+ secreted by the kidneys).
H+
Both
O– (The O– that cannot be covered by H+/NH4+)
are excreted in urine and accompanied by K+/Na+
Endocrinology | 287
Concept 7.10 : Glucagon
• To compare the actions of insulin and glucagon
• To understand the effect of sympathetic and parasympathetic stimulation on insulin
secretion
• To understand the effect of sympathetic and parasympathetic stimulation on glucagon
secretion
• To enumerate factors affecting glucagon secretion
Primary target organ is the LIVER; skeletal muscle is not a target organ for glucagon

Second messenger- cAMP

Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Actions of insulin and glucagon

Insulin Glucagon
Glycogenic Glycogenolytic (but not in skeletal muscle)
Antigluconeogenic Gluconeogenic- glucagon increases gluconeogenesis from
available amino acids in the liver
Anti lipolytic; lipogenic AfraTafreeh.com
Lipolytic (↑ activity of HSL in liver); ↓ lipogenesis
Antiketotic Ketogenic
↑ protein synthesis, ↓ breakdown ↑ ureagenesis
288 | Physiology
Effect of sympathetic and parasympathetic stimulation on the
secretion of Insulin
Sympathetic stimulation: a2 : (–)
b2 : (+)
Net effect : (–)
Vagal stimulation : Insulin (Via M4)
Effect of sympathetic and parasympathetic stimulation on the

secretion of Glucagon
Sympathetic stimulation: a : (–)
b : (+)
Net : (+)
Vagal (+) : ↑Glucagon stimulation
Factors affecting glucagon secretion

Stimulators Inhibitors
Amino acids (especially glucogenic amino acids: Glucose
alanine, serine, glycine, cysteine, and threonine)
CCK, Gastrin Somatostatin
Cortisol AfraTafreeh.com
Secretin
Exercise FFA
Infections Ketones
Other stresses Insulin
β-adrenergic stimulation Phenytoin
Theophylline α-adrenergic stimulators
Acetylcholine GABA
Endocrinology | 289
Concept 7.11 : Other hormones secreted by the pancreas
• To enumerate other hormones secreted by the pancreas and their actions
Time Needed
1 reading
st
10 mins
2nd look 05 mins
Amylin (islet amyloid polypeptide)

• Secreted by beta cells of pancreas.
• It is a 37-residue peptide hormone.
• It is co-secreted with insulin in the ratio of approximately 100:1.
• Actions
Delays gastric emptying

Inhibits secretion of glucagon

Produces satiety, decreasing food intake

Somatostatin
• Secreted by delta cells of pancreas in response to
↑ plasma glucose

↑ plasma amino acids

AfraTafreeh.com
↑ fatty acids

• Somatostatin decreases release of insulin and glucagon.

• It also decreases gastrointestinal motility, secretion and absorption.
Pancreatic polypeptide
• Secreted by F cells of pancreas.
• Pancreatic polypetide contains 36 amino acids.
• Its secretion is stimulated by eating, exercising, and fasting.
• It can inhibit gallbladder contraction and pancreatic exocrine secretion, but its role in
metabolism of nutrients is uncertain.
• Function of PP is probably self regulation of pancreatic secretory activities (exocrine
and endocrine).
290 | Physiology
Concept 7.12 : Parathyroid gland and parathormone
Learning Objectives
To understand the effects of 1,25 dihydroxycholecalciferol, Calcitonin and
Parathormone on Ca++ and PO43– metabolism
• To understand the functional anatomy of parathyroid
• To enumerate the actions of PTH
• To understand the mechanism of action of PTH and the different types of PTH receptors
• To understand the regulation of PTH secretion
Time Needed
1st reading 15 mins
2 look
nd
10 mins
AfraTafreeh.com
Effect of hormones on Ca++ and PO43– metabolism

Ca++ PO43–
1, 25 DHCC ↑ ↑
Calcitonin ↓ ↓
PTH ↑ ↓
Functional anatomy of parathyroid

• There are four parathyroid glands: two embedded in the superior poles of the posterior
thyroid and two in its inferior poles.
• Each parathyroid is a richly vascularized disc, about 3mm × 2mm, containing two
distinct types of cells- chief cells and oxyphil cells.
Endocrinology | 291
• Chief cells are the more abundant parathormone secreting cells.
• Oxyphil cells are less abundant but larger with large numbers of mitochondria; their
function is unknown.
Synthesis of PTH
• PTH is a linear polypeptide with molecular weight of 9500 tat contains 84 amino acids.
• It is synthesized as part of a larger molecule containing 115 amino acid residues
called preproPTH.
• On entry of preproPTH into the endoplasmic reticulum, a leader sequence of 25 amino
acids is removed to form 90 amino acid proPTH.
• Six additional amino acids are removed to from the amino terminal part of proPTH in
the Golgi apparatus to form the 84-amino acid PTH.
• The normal plasma level of PTH is 10-55pg/mL.
Actions of PTH
PTH has the following actions
a. ↑es bone Resorption
b. Phosphaturic action (increases phosphate excretion by decreasing the reabsorption of
phosphate via NaPi-IIa in the PCT)
c. ↑es Ca++ Reabsorption in DCT
d. ↑es formation of 1,25 DHCC, and thus ↑es Ca++/PO43- absorption from intestine

AfraTafreeh.com
*Although PTH increases Ca reabsorption in DCT but in hyperparathyroidism Ca++excretion in the urine is often increased
++
because the increase in the load of filtered calcium overwhelms the effect on reabsorption.
Mechanism of action of PTH

There are at least three different types of PTH receptors.
Receptor Binds Site Second messenger
hPTH/PTHrp PTH, parathyroid hormone Osteoblasts Activates Gs, adenylate
related protein (PTHrP) PCT cyclase & cAMP
DCT Also activates Gq, PLC and
↑intracellular Ca++
PTH2 (hPTH-R) PTH (amino terminal) Brain GPCR (Gs); cAMP
Placenta
Pancreas
CPTH PTH (carboxyl terminal)
*PTHrP
• It is a protein with PTH activity.
• It is produced by many tissues in the body.
• Both bind to hPTh/PTHrP receptor but their physiologic effects are very different.
• PTHrP stimulates growth and development of cartilage in utero.
• PTHrP is also expressed in brain, where it inhibits excitotoxic damage to the developing
neurons.
292 | Physiology
• PTHrP is involved in Ca2+ transport in the placenta.
• PTHrP is also found in keratinocytes in skin, in smooth muscle, and in teeth, where
it is present in the enamel epithelium that caps each tooth. In the absence of PTHrP,
teeth cannot erupt.
PTH homeestasis: Effect of parathyroid hormone (PTH) on calcium and phosphate metabolism.
The net effect is an increase in the plasma calcium concentration with no change or a decrease in the plasma
phosphate concentration.
• PTH receptors are present on osteoblasts and kidney tubules.

AfraTafreeh.com
• PTH binds to its receptors on osteoblasts, increases intracellular cAMP, which in turn
increases production of RANK ligand (receptor activator for nuclear factor kappa beta
ligand) → (1) RANKL binds to RANK, a receptor on osteoclastic precursor cells (2)
increased secretion of monocyte colony stimulating factor (M-CSF) by non-monocytic
cells → M-CSF binds to its receptors on monocytes → stimulates osteoclastic precursor
cells (monocytes) to differentiate into bone resorbing, mature osteoclasts.
• PTH decreases release of OPG (osteoprotegerin), a decoy receptor for RANKL.
Decreased level of OPG allows more interaction between RANKL and its receptor,
increasing osteoclastic activity.
Regulation of PTH secretion

• Circulating calcium acts directly on parathyroid glands in a negative feedback manner
to regulate the secretion of PTH.
• ↑ circulating Ca2+→ activates CaSR (calcium sensing receptor), which is GPCR →
inhibits PTH secretion.
• When Ca2+ level is high, PTH secretion is inhibited and Ca2+ is deposited in the bones.
• When Ca2+ level is low, PTH secretion is stimulated and Ca2+ is mobilized from the
bones.
• 1, 25- dihydroxycholecalciferol acts directly on parathyroid glands to decrease
preproPTH mRNA and therefore, PTH secretion.
• Increased PO43+ levels → direct inhibitory effect on 1α- hydroxylase → inhibits
formation of 1,25-dihydroxycholcalciferol → ↓ plasma Ca2+ → increases PTH secretion
Endocrinology | 293
Concept 7.13 : Vitamin D and its role in calcium metabolism
• To understand the chemistry of vitamin D and the synthesis of 1, 25-
dihydroxycholecalciferol
• To understand the mechanism of action of 1, 25- dihydroxycholecalciferol
• To understand the regulation of 1, 25- dihydroxycholecalciferol
Time Needed
1 reading
st
10 mins
2 look
nd
05 mins
Chemistry of vitamin D
AfraTafreeh.com
Mechanism of action of 1,25- dihydroxycholecalciferol

• 1,25- dihydroxycholecalciferol increases absorption of calcium in intestine.
• It increases synthesis of Calbindin-D proteins in intestine, kidneys and brain.
• It also increases the number of Ca2+-ATPases and TRPV6 molecules in the intestinal
cells and thus, the overall capacity for absorption of dietary calcium.
• 1,25- dihydroxycholecalciferol facilitates Ca2+ reabsorption in the kidneys via increased
TRPV5 expression in the tubules.
• It also increases the synthetic activity of osteoblasts, and is necessary for normal
calcification of matrix.
Regulation of synthesis
• Formation of 1,25 dihydroxycholecalciferol occurs in the kidneys, which is catalyzed
by the renal 1α- hydroxylase, is regulated in a feedback manner by plasma Ca2+ and
PO43+ levels.
• When plasma Ca2+ is high, little 1,25 dihydroxycholecalciferol is produced, and the
kidneys produce the relatively inactive metabolite 24, 25- dihydroxycholecalciferol.
There is, therefore, reduced calcium absorption in the intestines.
• When plasma Ca2+ is low, PTH secretion is increased, and expression of 1α- hydroxylase
is stimulated by PTH.
294 | Physiology
• The production of 1, 25 dihydroxycholecalciferol is also increased by low plasma PO43+
and inhibited by high plasma PO43+ levels, by a direct inhibitory effect of PO43+ on 1α-
hydroxylase.
• 1,25- dihydroxycholecalciferol increases plasma Ca2+ which in turn has a direct
negative feedback effect on 1α- hydroxylase activity, and a positive feedback effect
on the formation of 24, 25-dihydroxycholecalciferol, a less active metabolite.
• Increases plasma Ca2+ levels act on parathyroid gland to inhibit PTH formation.
AfraTafreeh.com
Endocrinology | 295
Worksheet
• MCQ OF “ENDOCRINOLOGY” FROM DQB

AfraTafreeh.com


296 | Physiology
Lipid soluble and water soluble hormones
Lipid soluble hormones Water soluble hormones
Examples
Receptors
Mode of action
AfraTafreeh.com
Storage
Transport in
plasma
Half life
Endocrinology | 297
ADH receptors
Receptor Site Actions Actions
mediated by
V1A
V1B (V3)
V2
AfraTafreeh.com
Differences between T4 and T3

T4 T3
Plasma
Total
Free
% Bound
% Free
Half life
Binding
298 | Physiology
Maximum binding
Action
In colloid
Amount secreted
‘Reverse’
Potency
Binding to Thyroid Hormone

nuclear receptors
AfraTafreeh.com
8 Gastrointestinal Tract
CONCEPTS
Â Concept 8.1 Smooth muscle

Â Concept 8.2 Neural control of the GI tract

Â Concept 8.3 Hormonal control of the GI tract

Â Concept 8.4 Secretions of GI tract

Â Concept 8.5 Digestion and absorption of
AfraTafreeh.com

carbohydrates
Â Concept 8.6 Digestion and absorption of proteins

Â Concept 8.7 Digestion and absorption of fats

Â Concept 8.8 Absorption of water and electrolytes

in different segments of the GI tract
Â Concept 8.9 Movements of GI tract

Â Concept 8.10 Gastrointestinal reflexes

Â Concept 8.11 Metabolic rate

300 | Physiology
Concept 8.1 : Smooth muscle
• To study the anatomy of smooth muscle and its types
• To understand the electrical activity in smooth muscle of GI tract, BER and spike
potentials
• To enumerate the different stimuli for single- unit as well as multi-unit type of smooth
muscle
• To understand the mechanism of contraction in smooth muscle
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
Functional anatomy
AfraTafreeh.com
Gastrointestinal Tract | 301
• Actin, myosin and tropomyosin are present
• No troponin
• Calcium binding protein in smooth muscle is Calmodulin
• No Z – lines (The anchorage for the actin filaments is provided by structures called
dense bodies)
• No T-tubule
• No (or rudimentary) sarcoplasmic reticulum
Types
1. Visceral (single – unit) or unitary
This is the type of smooth muscle present in hollow viscera.

There are gap junctions between muscle fibers; functions in a syncytial fashion.

En passant junctions are fewer and excitation spreads by gap junctions.

2. Multi – unit smooth muscle

It is made of individual units with few or no gap junctions. E.g. Intraocular muscle

of the eye (ciliaris, iris).

It behaves like skeletal muscle in the sense that its response can be graded.

AfraTafreeh.com
Vascular smooth muscle has both single-unit as well as the multi-unit type of smooth muscle
Nerve supply
• The autonomic nerve supplying the smooth muscle shows varicosities along its length.
• The nerve establishes functional contact at several points n the muscle as it courses
alongside the muscle fiber; this is called synapse en passant.
302 | Physiology
• There can be excitatory or inhibitory junctional potentials.
Electrical activity
• The membrane potential has no true “resting” value, being relatively less negative
when the tissue is active and more negative when it is inhibited.
• When the tissue is relatively quiet, the potential varies between -20 and -65mV.
• Smooth muscle of the GI tract shows the presence of slow-waves (pacemaker
potentials) AfraTafreeh.com
• These rhythmic changes in potential are initiated by the interstitial cells of
Cajal, which are also k/a the pacemaker cells of GI tract. - in the stomach
these are located in the outer circular layer near the myenteric plexus; in the colon
they are at the submucosal border of the circular muscle layer.
• These rhythmic changes in potential are believed to be due to oscillation in the activity
of the sodium- potassium ATPase pump.
• The slow waves, also k/a BER or basic electrical rhythm, are not responsible for
contraction.
• The amplitude of the slow waves or BER is 5 to 15 mV and their frequency is variable
in different parts of the GI tract.
• Function of BER is to coordinate peristaltic and other motor activity
• The rate of BER is in
f Stomach
: 4 / minute
f Duodenum
: 12 / minute (maximum)
f Distal ileum
: 8 / minute
f Caecum
: 2 / minute (minimum)
f Sigmoid colon
: 3 / minute (low frequency BER) and 5-6/min
(high frequency BER)
Basic Electrical Activity
AfraTafreeh.com
• Maximum frequency of BER is in duodenum (12/min) and minimum frequency is in
cecum (2/min).
• Action potentials or spike potentials are superimposed on the slow-waves- these are
responsible for contraction.
• Depolarization phase of the spike potential is due to Calcium influx and repolarization
is due to potassium efflux.
• Duration of spike potential in smooth muscle is commonly 50 milliseconds.
Excitation / inhibition in smooth muscle

1. Multi – unit
Excited only by nerves

2. Single unit
The response can be
(i) Spontaneous
(ii) From adjacent cells (through gap junctions)
(iii) Nerves (i.e. by neurotransmitters)
(iv) Hormones
(v) Stretch
(vi) Cold
304 | Physiology
Mechanism of contraction
Sequence of smooth muscle contraction & relaxation:
Binding of acetylcholine to muscarinic receptors
Increased influx of Ca++ into the cell
Ca++ binds to calmodulin
Ca++ calmodulin complex activates calmodulin- dependent myosin light chain kinase (MLCK)
Activation of MLCK causes phosphorylation of myosin
Increased myosin ATPase activity and binding of myosin to actin
This initiates the cross-bridge cycling & contraction

AfraTafreeh.com
Relaxation is by dephosphorylation of myosin by myosin light chain phosphatase
Some unique features of smooth muscle contraction

• Excitation contraction coupling in visceral smooth muscle is a slow process, sometimes
taking up to 500 milliseconds, but usually 150ms.
• It is a low-energy mechanism.
• Sources of calcium for smooth muscle contraction
ECF- calcium influx can occur through voltage- gated or ligand-gated channels.

Intracellular stores- through RyR (ryanoidine receptor) or inositol triphosphate

receptor (IP3R) channels in sarcoplasmic reticulum.

• It shows the presence of latching or latch state. This is the state in smooth muscle
where, even after dephosphorylation of myosin, the cross-bridges continue to ‘cling
on’ for sometime. The advantage is that it allows sustained contraction with minimum
energy expenditure.
• There is a higher percentage of shortening.
• There is no fixed length-tension relationship in smooth muscle. It shows the property
of plasticity.
• Despite approximately 20% of the myosin content and a 100-fold difference in ATP
use when compared with skeletal muscle, Smooth muscle can generate as much or
even more tension than skeletal muscle/cardiac muscle per unit cross sectional area
because of the latch mechanism.
Concept 8.2 : Neural control of GI tract
• To understand the sub-divisions of the Enteric nervous system
• To understand the significance of sympathetic and parasympathetic nervous system
in controlling different functions of GI tract
Time Needed
1 reading
st
05 mins
2nd look 03 mins
Enteric Nervous System

• Enteric nervous system consists of:
Intrinsic nervous system, which in turn consists of two major networks of fibers:

▫ Myenteric or Auerbach’s plexus- lies between the outer longitudinal and middle

circular layers; concerned primarily with motor control.

▫ Submucosal or Meissner’s plexus- lies between the middle circular layer and the

mucosa; controls the intestinal secretory activity and blood supply.

Extrinsic nervous system`

▫ Parasympathetic- increases motor and secretory activity of the GI tract; causes

relaxation of sphincters.
AfraTafreeh.com
▫ Sympathetic- decreases motor and secretory activity of the GI tract; causes

contraction of sphincters.
306 | Physiology
Concept 8.3 : Hormonal control of the GI tract
• To enumerate the two major sub-divisions of GI hormones according to their structural
similarity
• To enumerate the different hormones of the GI tract, their structure, site of secretion,
actions and stimuli increasing their secretion
Time Needed
1 reading
st
20 mins
2 look
nd
12 mins
GI hormones
There are 2 families of gastro intestinal hormones:
(i) Gastrin family → includes gastrin, CCK – PZ
(ii) Secretin family → includes secretin, glucagon, glicentin, VIP, GIP
Gastrin
• It is secreted by ‘G’ cells which are present in the antral mucosa.
• Entero endocrine cells are cells of GIT which secrete hormones (peptides). If these
cells also secrete serotonin, they are called EC (entero chromaffin) cells; if they
secrete amines (in addition to peptide secretion), they are called APUD (amine
precursor uptake and decarboxylate) cells; that is, EC cells – secrete peptides plus
Serotonin; APUD cells – secrete peptides plus amines.
• Gastrin has 3 forms: G14, 17 and 34. AfraTafreeh.com
• The principal form with respect to gastric acid secretion is G17.
• Gastrin (and CCK) shows macroheterogeneity and microheterogeneity
Macroheterogeneity is occurrence of peptide chains of varying lengths.

Microheterogeneity is same length of peptide chain but difference is because of

derivatization of single amino acid residues.

• Vagus stimulates gastrin release; the neurotransmitter is gastrin – releasing peptide
(GRP) and not acetylcholine.
• In pernicious anemia, there is gastric atrophy and a decrease in parietal cell mass;
therefore, there is no acid production. Thus, the negative feedback effect of acid on
gastrin secretion is not there, so, there is more gastrin.
• Gastrin acts on parietal cells via the CCK-B receptor which is related to the primary
receptor CCK-A for cholecystokinin on gall bladder.
• Stimuli that affect gastrin secretion
Stimuli that increase gastrin secretion Stimuli that inhibit gastrin secretion
Luminal Luminal
• Distension • Acid itself (partly by direct action on G cells and
• Peptides and amino acids- phenylalanine and tryptophan partly by release of somatostatin)
• Somatostatin]
Neural
• Increased vagal discharge via GRP
Bloodborne Bloodborne
• Calcium • Secretin
• Epinephrine • GIP
• VIP
• Glycagon
• Calcitonin
Gestro - Intestinal Hormones
Gastrin CCK-PZ Secretin GIP VIP Somatostaun Motilin Neurotensin
Structure Micro and only one form
heterogeneity
Site G - Cells antrum 1- cells - S cells K cells - Nerves D cells of GIT EC cells Nerve in ileum
Upper SI upper SI upper SI dudodenum
Action Stimulates acid Stimulates Stimulates StimulatesStimulates Inhibites Contraction Inhibits
and pepsin; GB; relaxed secretion of insulin; In
intestonal secretion of intestinal gastrointestinal
stimulates gastric sphincter of pancreatic large dosesecretion of of gastric, smooth motility;
motility; Oddi; juice it inhibits
electrolytes VIP, GIP, muscle; increase ilead
Trophic to gastic Stimulates (alkaline); gastric and water; secretion, regulator blood flow
mucosa; pancereatic inhibits motility relaxation motilin; of MMC
stimulates insulin; juice (rich in gastric acid and inhibits
of intestinal inhibits (migrating
enzymes); secretion; gastric smooth pancreatic motor
stimulates may secretion muscle; exocrine
glucagons; inhibits complex)
gastric simulate dilation of secretion;
closure of emtrying; pyloric peripheral inhibites
G-E sphincter may stimulate sphincter; blood vessels; gastric
pyloric stimulates inhibits gastric secretion and
sphincter; insulin; acid secretion motivation;
stimulates augments - stimulated inhibits
insulin and CCk; gastric acid gall bladder
glucagons; action of secretion; contraction;
trophic to secretion is potentiates inhibits
pancreas; to decrease action of Ach absorption of
increase H in SI on salivary aminoacids,
enterokinase; glands; triglycerides,
AfraTafreeh.com
may increase stimulates Increased by
motility of SI pancreatic acid in lumen;
and colon; bicarbonate decresed by
secretion and vagus
augments inhibits H
secretion secretion
Factors Increased Increased Increased Increased by Increased by Increased by
Affecting by: peptides, by peptides, by products fatty acids, fat in jejunum acid in lumen
Secretion distension, vagus, aminoacids, of food amino acids decreased by
cold, epinephrine fatty digestion, glucose vagus
decreased by acids (not acid in
Gastrointestinal Tract |
calcotonin, acid, triglycerides) duodenum

somatostatin,
307
serection, GIP, VIP

308 | Physiology
Concept 8.4 : Secretions of GI tract
• To compare daily secretion, pH, enzymes in various GI secretions- salivary gastric,
intestinal, pancreatic
• To understand the phases and mechanism of salivary secretion, enzymatic action and
control
• To understand the phases and mechanism of gastric secretion, its role in digestion,
enzymatic action and control
• To understand the composition of pancreatic juice and regulation of its secretion
Time Needed
1st reading 20 mins
2nd look 12 mins
Volume (in L/day) Osmolality pH Na+ K+ Cl- HCO3

Plasma 3 300 7.4 150 5 110 24
Saliva 0.8- 1.2 100 Q
7.0- 8.0 40 15 25 30
Gastric Juice 2.5 200 2.0- 3.0 50 10 100 0
Pancreatic Juice 1.5 300 Up to 8.8 140 10 70 80Q
Bile 0.5 300 7.5
AfraTafreeh.com 140 5 80 20
Salivary Secretion
• Total volume of saliva secreted per day- 800- 1200 ml
• pH of saliva- 7.0 (resting gland) to 8.0 (during active secretion).
• Three pairs of salivary glands- parotid, submandibular, sublingual; maximum
contribution by submandibular (70%); parotid- serous, submandibular- mixed,
sublingual- mucus.
• Three phases of salivary secretion- cephalic, oral, gastric; maximum contribution to
saliva is in the cephalic phase.
• Primary secretion from the acini is isotonic; as it flows through the duct sodium
and chloride are absorbed; potassium and bicarbonate are secreted- at low salivary
flow the secretion is hypotonic and at high salivary flow rate there is less time for
ionic composition to change, consequently, although still hypotonic saliva is closer to
isotonic (Final secretion from the salivary glands is always HYPOTONICQ).
• Aldosterone increases sodium reabsorption and potassium secretion in the saliva.
• Enzymes in saliva- salivary amylase and lingual lipase from the Ebner’s glands.
• Also present are mucins, IgA, lactoferrin that binds iron and is bacteriostatic and
proline rich compounds that protect the tooth enamel and bind toxic tannins.
• Control: PS stimulation causes vasodilatation and a profuse, watery secretion;
sympathetic stimulation→ vasoconstriction and secretion of small amounts of saliva
rich in organic constituents.
• Salivary secretion is controlled by parasympathetic reflexes and not by gastrointestinal
hormones.
• Both sympathetic as well as parasympathetic stimulation increase salivary secretion;
parasympathetic stimulation causes watery saliva, relatively less in organic constituent
and causes vasodilatation (VIP mediated). Sympathetic stimulation causes secretion
of small amounts of saliva, rich in organic constituents, from the submaxillary glands.
It also causes vasoconstriction.
• Salivary juice gets modified as it flows through the salivary ducts. NaCl is absorbed
and KHCO3 is secreted into the duct.
• Ducts are impermeable to water, therefore, water does not follow sodium reabsorption.
• With increased flow rate, the ductal modification of the salivary juice decreases. With
decreased flow rate, less NaCl and more KHCO3 appears.
• The salivary juice is always hypotonic, because the duct is more permeable to NaCl
than it is to water
Salivary Secretion
AfraTafreeh.com
Gastric secretion
• Gastric secretion- 2.5L/day.
• 3 phases of gastric juice secretion: cephalic (neural), gastric (neural + hormonal),
intestinal (neural + hormonal), most important being the gastric phase.
• 3 agonists of the parietal cell- gastrin, histamine and acetylcholine.
• Gastrin and acetylcholine act by increasing the cytosolic calcium and histamine acts
by increasing the intracellular cAMPQ (important- these two pathways are synergistic
i.e., they have a more than additive effect on secretion).
310 | Physiology
• Gastric mucosal barrier is formed by mucus, bicarbonate, trefoil peptides (that

stabilize the mucus- bicarbonate layer) and prostaglandins.
• Oxyntic or parietal cells secrete HCl and intrinsic factor.
AfraTafreeh.com
• Chief or peptic cells secrete pepsinogen and gastric lipase.
Cellular mechanism & control of HCI secretion by parietal cells
Pancreatic secretions
• Daily secretion 1500mL/day.
• Highly alkaline (pH- up to 8.8).
• Pancreatic juice is very rich in enzymes.
• Enzymes present in pancreatic juice are:
Pancreatic α-amylase

Trypsin

Chymotrypsin

Elastase

Carboxypeptidase A & B

Colipase

Pancreatic lipase

Cholesteryl ester hydrolase

Nucleotidases- ribonuclease, deoxyribonuclease

Phospholipase A2

• Pancreatic proteolytic enzymes are secreted in an inactive form.

• Conversion of inactive pancreatic enzymes to their active form is by trypsin, which in
turn is secreted in an inactive form- trypsinogen.
• Conversion of trypsinogen to trypsin is by enterokinase.
AfraTafreeh.com
• Trypsin is an activator for chymotrypsin, elastase, carboxypeptidase A and

carboxypeptidase B, colipase (facilitates exposure of active sites of pancreatic lipase),
phospholipase A2 (splits a fatty acid from phosphatidylcholine to form lyso-PC; lyso-
PC can damage cell membranes.
In acute pancreatitis, phospholipase A2 is activated within the pancreatic ducts and this causes the conversion
of PC in the bile to lyso- PC which causes disruption of pancreatic tissue and necrosis of surrounding fat).
• Secretion of pancreatic juice is primarily under hormonal control.

• CCK causes the production of a pancreatic juice rich in enzymes but low in volume.
• Secretin causes the secretion large volumes of alkaline pancreatic juice rich in
bicarbonate but poor in enzymes.
312 | Physiology
Bile
• Daily secretion- 500mL.
• Four major bile acids in bile are primary bile acids- cholic acid (50%), chenodeoxycholic
acid (30%), and secondary bile acids- deoxycholic acid (15%), lithocholic acid (5%)
and small amounts of ursodeoxycholic acid.
• Primary bile acids are converted into secondary bile acids in the colon by the action of
colonic bacteria- cholic acid is converted into deoxycholic acid, and chenodeoxycholic
acid to lithocholic acid and ursodeoxycholic acid.
AfraTafreeh.com
• Bile acids have a number of important actions:-

They reduce surface tension

They help in emulsification of fats

• Critical micelle concentration refers to the critical levels of

A. Cholesterol B. Bile salts
C. Phospholipids D. Free fatty acids
All the following are true of bile secretion except

A. Increased by (+) of vagus
B. Increased by secretin
C. The bile salts reabsorbed from intestine actually inhibit synthesis of new bile acids
D. Bile salts decrease bile flow
Gastrointestinal Secretion
Saliva Gastric secretion Pancreatic Bile
secretion
Main Hypotonic; high HCl; pepsinogen; High bicartonate, Bile, salts,
characteristic bicarbonate; high intrinsic factor isotonic, pancreatic bilirubin,
K+; alpha amylase, lipase, pancreatic phospholipid,
lingual lipase amylase, proteases cholesterol
Factors Stimulated by HCl secretion Bicarbonate: CCK and
stimulating parasympathetic is increased stimulated by parasymp cause
and sympathetic and by histamine, CCK, secretin and contraction of
by food in stomach acetylcholine, parasympathetic; GB
gastrin and by Enzymes: stimulated
parasympathetic by CCK, secretion
stimulation parasympathetic
Factors inhibiting Sleep, dehydration, Inhibited by HCl Inhibited by
atropine ileal resection
Volume (in L/day) Osmolality pH Na+ K+ Cl- HCO3

Plasma 3 300 7.4 150 5 110 24
Saliva 1.5 100 7.5 Q
40 15 25 30
AfraTafreeh.com
Gastric Juice 3 200 1 50 10 100 0
Pancreatic Juice 1.5 300 7.8 140 10 70 80Q
Bile 0.5 300 7.5 140 5 80 20
Ref. A.K. Das (TB physiol.)
At the end of Volume (L/day) Na K+ Cl- HCO3

Duodenum 9.2 55 15 55 12
Jejunum 3.2 145 8 95 35
Ileum 1.2 135 7 55 75
Colon 0.2 35 85 Q
10 25
K+ ions are maximum in colon
Hypotonic secretion- saliva; most alkaline secretion- pancreatic
314 | Physiology
Concept 8.5 : Digestion and Absorption of Carbohydrates
• Different forms of dietary carbohydrates
• Mechanism of digestion of carbohydrates in the mouth and small intestine and the
enzymatic action at these sites
• Cellular mechanism of glucose, galactose and fructose absorption
• Types and location of SGLT and Glucose transporters
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Dietary carbohydrates:
Carbohydrates are in the form of polysaccharides, disaccharides and
monosaccharides
• Dietary polysaccharides/ starches of animal origin:-
Glycogen- glucose molecules in 1:4α linkage with some chain branching produced

by 1:6α linkages
• Dietary starches of plant origin:-
Amylopectin- constitutes 80-90% of dietary starch; similar to glycogen but less
AfraTafreeh.com

branched
Amylose- straight chain with only 1:4α linkages

• Disaccharides in diet:-
Lactose/ milk sugar (glucose + galactose)

Sucrose/ table sugar (glucose + fructose)

• Monosaccharides in diet:-
Fructose

Glucose

Digestion of carbohydrates in the mouth

• By salivary α-amylase.
• Optimum pH for action is 6.7
• Acts on 1:4α linkages; does not act on 1:6α, terminal 1:4α and 1:4α next to branching
points.
• End products of digestion are: maltose (Glucose + Glucose), maltotriose (3 Glucose)
and α-limit dextrins (8 Glucose molecules in 1:6α linkages).
• Note: there are no β linkages splitting enzymes in humans (β linkages are found in
cellulose, etc.).
Digestion in the small intestine

• By pancreatic amylase- similar in action to salivary amylase but more efficient
• By oligo- and di-saccharidases in the brush border
(i) α-dextrinase/ isomaltase- acts on 1:6α; therefore can split maltose, maltotriose
and α-limit dextrins
(ii) trehalase (acts on trehalose which has two glucose molecules in 1:1α linkage)
(iii) sucrase
(iv) lactase
(v) maltase
Absorption of Glucose
• By SGLT-1 on the luminal membrane.
• By GluT 2 on the basolateral membrane.
• Maximum rate of glucose absorption in GI tract is 120g/h.
• From the lumen to the enterocyte, the barrier to diffusion include glycocalyx, brush
border, unstirred layer, mucous coat, villous membrane.
AfraTafreeh.com
Absorption of Galactose
• Competes with Glucose for transport.
• Patients with congenital defect in the sodium/glucose cotransporter, glucose/ galactose
malabsorption causes severe diarrhea that is often fatal if glucose and galactose are
not promptly removed from the diet.
Absorption of fructose
• Absorption is independent of sodium.
• Absorption is by GluT-5 at the luminal membrane and by GluT-2 at basolateral
membrane (facilitated diffusion on both luminal and basolateral membrane).
SGLT (Sodium- glucose linked transporter)

• SGLT is for secondary active transport of glucose.
• These are present in the kidney and in the intestine on the luminal membrane.
316 | Physiology
Features of the SGLT series
(i) Not affected by insulin
(ii) No phosphorylation is required
(iii) Inhibited by phlorhizin
GluT series (Glucose Transporters)

GLUT 1 Blood brain barrier, brain, placenta, kidney etc
GLUT 2 b-cells of islets of pancreas, liver, epithelial cells of small intestinal / renal tubules
GLUT 3 Brain, placenta, kidney etc
GLUT 4 Insulin – stimulated glucose uptake in skeletal muscle / adipose tissue
GLUT 5 Fructose transport in jejunum / sperm
GLUT 6
GLUT 7 Liver, G-6-P in Endoplasmic reticulum
Glucose absorption
Site AfraTafreeh.com
Transport mechanism Insulin
Intestine SGLT-1 No effect
Kidney SGLT-2 No effect
Muscle (SK muscle / cardiac muscle) GLUT 4 Favors
Adipose GLUT 4 Favors
Liver * (Hexokinase) Favors
*Glucose uptake in the liver is also affected by insulin but not via GLUT 4. Instead, insulin stimulates glucokinase in the liver
(glucokinase converts glucose into glucose -6- phosphate) and thus favors the diffusion into the liver cell.
*Insulin does not affect the absorption of glucose in: Kidney, intestine, RBC, brain.
Concept 8.6 : Digestion and absorption of proteins
• Mechanism of digestion of proteins in the stomach and small intestine and the
enzymatic action at these sites
• Cellular mechanism of protein absorption
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Digestion of proteins in stomach

• By the action of pepsins, gelatinase (liquefies gelatin), chymosin (also known as
rennin; found in the stomach of young animals but is probably absent in humans).
• Pepsinogen of gastric mucosa is divided into two immuno histochemically distinct
groups viz
Pepsinogens I - found only in acid – secreting regions

Pepsinogens II - found in pyloric region

• Maximal acid secretion correlates with pepsinogen I levels.

• Pepsins hydrolyze the bonds between aromatic amino acids (such as phenylalanine,
tyrosine) and some other amino acid forming polypeptides of varying length.
AfraTafreeh.com
• Optimum pH for the action of pepsin- 1.6-3.2
Digestion of proteins in small intestine

In the small intestine digestion of proteins is by the following enzymes:-
(i) Pancreatic enzymes, which further digest the polypeptides.
The pancreatic enzymes for protein digestion are:
Endopeptidases (which act on interior peptide bonds), such as
▫ Trypsin
▫ Chymotrypsins
▫ Elastase
Exopeptidases (which act on one end of the peptide chain), such as
▫ Carboxypeptidases
(ii) Intestinal brush border enzymes such as aminopeptidases, carboxypeptidases,
endopeptidases and dipeptidases
(iii) Intracellular di- and tri-peptidases in the intestinal epithelial cells, which hydrolyze
di- and tri- peptides to amino acids
Thus, the final digestion to amino acids occurs in three locations: the intestinal lumen,
the brush border, and the cytoplasm of mucosal cells
Cellular mechanism of protein absorption

There are at least seven different transport systems
• Five transport systems require Na+ (Na+ - amino acid co- transport)- two of these also
require Cl-; in two, transport is independent of Na+.
318 | Physiology
• Di- and tri- peptides are transported by a system known as PepT1 (or peptide
transporter 1) which requires H+ instead of Na+.
• Absorption of undigested protein can occur, especially in infants (e.g., IgAs in the
maternal colostrums are absorbed by the intestinal epithelial cells, by a process of
transcytosis). This decreases with age. (However, adults can still absorb undigested
protein. The M cells (microfold cells) overlying the Payer’s patches absorb antigens
particularly bacterial and viral proteins).
• Absorption of amiono acids is rapid in duodenum and jejunum but slow in ileum.
• Approximately 50% of the digested proteins comes from ingested food, 25% from
proteins in the digestive juices and 25% from desquamated mucosal cells.
AfraTafreeh.com
Concept 8.6 : Digestion and absorption of fats
• Mechanism of digestion of lipids in the mouth and small intestine and the enzymatic
action at these sites
• Importance of pancreatic lipase in fat digestion
• Role of bile acids in fat absorption
• Importance of micelle in fat absorption
• Cellular mechanism of lipid absorption
• SCFAs and their physiological importance
Time Needed
1 reading
st
15 mins
2nd look 10 mins
Digestion of lipids
• Digestion in mouth is by
Lingual lipase, secreted by Ebner’s glands located on the dorsum of the tongue;

not significant in fat digestion

• Digestion in stomach is by
Gastric lipase- it is of little importance except in pancreatic insufficiency

AfraTafreeh.com
• Digestion in duodenum/small intestine
Small intestine is the most important site of triglyceride digestion.

Pancreatic lipase
Pancreatic lipase acts on emulsified fats; it hydrolyzes the 1- and 3- bonds of
triglycerides- the principal products of digestion are 2- monoglyceride and two free fatty
acids; it is activated by colipase also secreted in pancreatic juice
Triglyceride = 3 fatty acids + glycerol
(FA = fatty acid)
i.e.,
CH2 OH - FA Ist bond
|
CHOH - FA 2nd bond
|
CH2 OH - FA 3rd bond
Pancreatic lipase splits 1st and 3rd bond to give a monoglyceride (1 fatty acid + glycerol)
i.e., CH2 OH
|
CHOH - FA
(2 monoglyceride)
|
CH2 OH
320 | Physiology
In Short,
Pancreatic lipase
Triglycerides 2 Monoglyceride + 2 fatty acids
There are 2 types of pancreatic lipase (depending on how they can get activated /
facilitated):
• Colipase – facilitated pancreatic lipase
• Bile – salt activated pancreatic lipase
Colipase in obtained from procolipase by action of trypsin in the intestinal lumen i.e.
Trypsin
Procolipase Colipase
Colipase binds to the –COOH terminal domain of pancreatic lipase,
facilitating the enzyme
Colipase – activated pancreatic lipase Bile – salt activated pancreatic lipase
Secreted in large amounts Represents only 4% of the total protein in the
pancreatic juice
10-60 times more active Less active
Can split only triglycerides Can catalyze the hydrolysis of cholesterol esters,
esters of fat – soluble vitamins, phospholipids and
triglycerides
AfraTafreeh.com
• Fats are emulsified in the small intestine by the detergent action of bile acids,
phosphatidylcholine and monoglycerides
• The ratio of bile acids : phosphatidylcholine : cholesterol is approximately 10:3:1;
deviations from this ratio may cause cholesterol to be precipitate, leading to formation
of gall stones
Micelles:
• These are cylindrical molecular aggregates that solubilize lipids and provide a
mechanism for transport to the enterocytes.
• Micelles have hydrophobic centers which contain fatty acids, monoglycerides and
cholesterol.
• Hydrophilic exterior is formed by phospholipids and bile salts radiating from the center
like the spokes of a wheel.
• Micelles move down their concentration gradient through the unstirred layer to the
brush border of the mucosal cells.
• Lipids diffuse out of the micelles, and a saturated aqueous solution of the lipids is
maintained in contact with the brush border of the mucosal cells.
• Most fat digestion occurs with the help of pancreatic enzymes.
Cellular mechanism of lipid absorption

• Lipids enter the enterocytes by (i) passive diffusion and (ii) with the help of carriers.
• Site of absorption of FAs: upper small intestine.
• Inside the cells the lipids are rapidly esterified- this helps maintain a concentration
gradient from the lumen to inside the cells.
• Bile salts remain in the intestinal lumen, where they are available for the formation
of new micelles.
• Fate of fatty acids in enterocytes depends on their size:
FAs with < 10-12 carbon atoms pass from the mucosal cells directly to the portal
blood and circulate as free unesterified fatty acids.
FAs with >10-12 carbon atoms are re-esterified to triglycerides in the mucosal
cells.
Some of the absorbed cholesterol is also re- esterified.
Triglycerides and cholesteryl esters are coated with a layer of protein, cholesterol,
and phospholipid to form chylomicrons which leave the cell by exocytosis and
enter the lymphatics.
Short chain fatty acids (SCFAs)

• SCFAs are produced by colonic bacteria and absorbed in the colon.
• They are produced by action of colonic bacteria (fermentation) on complex
carbohydrates, resistant starches and dietary fiber (that is, the material which
escapes digestion in the GI tract and enters the colon).
• These are two- to five-carbon weak acids.
AfraTafreeh.com
• Consist of acetate (60%), propionate (25%) and butyrate (15%).
• Average normal concentration is about 80mmol/L in the lumen.
• Absorption in colon is mainly by specific transporters present in colonic epithelial cells.
• Functions: (i) they are metabolized and contribute to total caloric intake (ii) have
a trophic effect on the colonic epithelium (iii) combat inflammation (iv) absorbed
in exchange for H+, helping to maintain acid base equilibrium (v) also promote
absorption of Na+
The Malabsorption Syndrome

• Removal of short segments of jejunum or ileum does not cause does not affect the digestive or absorptive
functions of small intestine significantly and there is compensatory hypertrophy and hyperplasia of the
remaining mucosa.
• When more than 50% of the small intestine is resected or bypassed (short gut syndrome), it results in the
malabsorption syndrome.
• Deficient absorption of amino acids causes wasting and hypoproteinemia with edema.
• Resection of terminal ileum prevents the absorption of bile acids, and this in turn leads to defective
absorption of fats and fat-soluble vitamins A, D, E, K.
• Unabsorbed bile acids on entering the colon activate chloride secretion causing diarrhea.
• Other complications of intestinal resection or bypass include hypocalcemia, arthritis and possible fatty
infiltration of the liver, followed by cirrhosis
322 | Physiology
Steatorrhea
Passage of fatty, bulky, clay coloured stools is k/a steatorrhea.
Causes:-
• Diseases that destroy exocrine pancreas, resulting in lipase deficiency
• Hyper secretion of gastric acid- acidic pH in the small intestine inhibits lipase activity
• Resection of terminal ileum or disease of this portion of the small intestine resulting in decreased or
defective reabsorption of bile acids
Celiac Disease
• This is an auto-immune disorder causing the malabsorption syndrome.
• Occurs in genetically predisposed individuals.
• In these patients gluten and closely related proteins (found in wheat, rye, barley and to a lesser extent
in oats- but not in rice or corn) cause intestinal T cells to mount an inappropriate immune response that
damages the intestinal epithelial cells, resulting in loss of villi and flattening of the mucosa, and causing
the malabsorption syndrome.
• Removal of grains containing gluten from the diet usually restores bowel function.
AfraTafreeh.com
Concept 8.7 : Absorption of water and electrolytes
• Absorption of water in different segments of intestine
• Mechanism of water absorption is along an osmotic gradient
• Absorption of electrolytes
• Absorption of vitamins and minerals
Time Needed
1st reading 15 mins
2 look
nd
10 mins
Absorption of water in different segments of the GI tract

• Maximum water reabsorption takes place in the jejunumQ
• 9000mL of water enters into the small intestine every day, out of which 5500mL is
absorbed in the jejunum, 2000mL in the ileum, 1300mL in the colon and 200mL is
lost in the feces.
• Water absorption is solute (mainly sodium)- driven.
• The osmotically active particles produced by digestion are removed by absorption,
and water moves passively down out of the gut along the osmotic gradient thus
generated.
AfraTafreeh.com
• Except in the duodenum where the contents may be hypo- or hypertonic, in the rest
of the intestine the contents are isotonic.
324 | Physiology
Absorption of water and electrolytes
Na+:
• The luminal membrane of all enterocytes in the small intestine and colon are
permeable to Na+ and their basolateral membranes contain Na+-K+ ATPase, Na+ is
actively absorbed throughout the small and large intestines.
• In the small intestine- secondary active transport of glucose, amino acids and some
other substance occurs along with Na+. (Presence of glucose in the small intestine
facilitates the absorption of Na+- this is the physiological basis for the treatment of
diarrhea by ORS)
Cl :
–
• Cl- enters the cells from the ISF with the help of Na+- 2K+- Cl– cotransporters in their
basolateral membrane, and the Cl- is then secreted into the intestinal lumen via
channels regulated by protein kinases, such as protein kinase A (and hence cAMP).
K :
+
• There is net secretion of K+ in the colon; loss of ileal and colonic fluids in chronic
diarrhea can lead to hypokalemia
Calcium-
• 30-80% of the ingested calcium is absorbed.
• Site of maximum calcium absorption is the jejunum.
• 1,25- dihydroxycholecalciferol increases calcium absorption in the small intestine.
• Calcium absorption increases in Ca deficiency and decreases in Ca excess.
AfraTafreeh.com
• Ca2+ absorption is inhibited by phosphates and oxalates because these anions form
insoluble salts with Ca2+ in the intestine.
Absorption of vitamins and minerals

• Most vitamins are absorbed in the upper small intestine but B12 is absorbed in the
ileum.
• Vit B12 and folate absorption is Na independent; all other water soluble vitamins-
thiamine, riboflavin, niacin, pyrodoxin, pantothenate, biotin, and ascorbic acid are
absorbed by carriers that are Na+ cotransporters
Concept 8.9 : Movements of the GI tract
• To understand and differentiate between peristalsis and segmentation contractions in
the GI tract and their importance
• To understand the features and significance of migrating motor complexes
Time Needed
1 reading
st
10 mins
2nd look 06 mins
Movements in the GIT

Peristalsis
• Reflex response to the presence of food, which produces stretch of the gut wall.
• Ring of contraction behind and relaxation in front of the food- contraction is due to
release of Ach and substance P and relaxation due to release of NO, VIP, ATP.
• Rate varies between 2 to 25 cm/s.
• Can occur independent of the extrinsic nervous system.
• Parasympathetic stimulation increases rate of peristalsis.
Mixing contractions or Segmentation contractions
• These are alternate contractions and relaxations seen in a segment of intestine-
AfraTafreeh.com
promotes progressive mixing of food with the secretions of small intestine.
Migrating motor complex

326 | Physiology
• Seen during fasting; start at least 90-120 minutes after the last meal, and thereafter
occurring at intervals of 90 minutes.
• MMC starts as a ring of contraction from the body of stomach to the distal ileum
• 3 phases: phase I- quiescent phase; phase II- phase of irregular electrical and motor
activity; phase III- phase of regular electrical and motor activity
• Rate of migration 5 cm/minQ
• The GI hormone Motilin is said to be responsible for MMC
• Function: clears the stomach and small intestine of luminal contents in preparation
for the next meal, although gastric secretion, bile flow, and pancreatic secretion
increase during each MMC
• MMCs stop on ingestion of a meal
AfraTafreeh.com
Concept 8.10 : Reflexes of the GI tract
Learning Objectives: T o understand the stimuli, pathways and significance of different
GI reflexes, such as :
• Swallowing reflex
• Receptive relaxation of stomach
• Gastrocolic reflex
• Gastroileal refelx
• Enterogastric reflex
• Defecation reflex
• Mass action contractions
• Vomiting reflex
Time Needed
1 reading
st
15 mins
2 look
nd
10 mins
Swallowing
• Swallowing or deglutition is a reflex response initiated by the collection of oral contents
on the tongue.
• Afferent fibers- trigeminal, glossopharyngeal and vagus nerves.
• Center- medulla AfraTafreeh.com
• Efferent- trigeminal, facial and hypoglossal nerves.
• Stages of the swallowing reflex are:-
Tongue pushes the food bolus to the back of the mouth

Soft palate is elevated to prevent food from entering the nasal passages.

Epiglottis covers the glottis to prevent food from entering the trachea and upper

esophageal sphincter relaxes. Inhibition of respiration at this stage is a part of the

reflex response.
Food descends into the esophagus.

Peristaltic ring of contraction behind the food pushes the food down the esophagus

at a speed of 4cm/s.
Receptive relaxation of stomach

• Relaxation of fundus and upper portion of the body when food enters the stomach is
k/a receptive relaxation of stomach.
• Accommodates food without much increase in pressure.
• Mediated by the vagus during swallowing.
Gastrocolic reflex
• Presence of food in stomach causing defecation.
• Prominent in infants; abolished in adults.
• Vagovagal reflex
• Post prandial increase in tone and motility is maximum in descending colon > sigmoid
colon.
328 | Physiology
Gastroileal reflex
• When food leaves the stomach, the cecum relaxes and passage of chyme through the
ileocecal valve increases.
• Vagovagal reflex.
Enterogastric reflex
• Presence of food in the small intestine inhibits gastric acid and pepsin secretion and
decreases rate of gastric emptying via neural and hormonal mechanisms.
• Stimuli for this reflex:-
Duodenal distension.

Type of food- Food rich in fats cause the greatest prolongation of gastric emptying

as compared to food rich in proteins. Carbohydrate- rich food has the least effect
on gastric emptying time.
Acidity of gastric chyme- acidity of the gastric chyme inhibit gastric motility by

neural and hormonal mechanisms (peptide YY and CCK).

Osmolality of gastric chyme- hyperosmolality of gastric chyme is sensed by

“duodenal osmoreceptors” that initiate a decrease in gastric emptying, which is

probably neural in origin.
Defecation reflex
• First urge to defecate occurs at a rectal pressure of 15 mm Hg.
AfraTafreeh.com
• Expulsion of rectal contents occurs at a rectal pressure of 55 mm Hg.
• Centre for this reflex is the spinal cord.
• External anal sphincter is under voluntary control and is supplied by the external
pudendal nerve- this sphincter is in a state of tonic contraction, and moderate
distension in fact increases the force of its contraction.
• Internal anal sphincter is not under voluntary control but under the control of the
ANS.
• Sympathetic nerve supply to the internal anal sphincter is excitatory, whereas the
parasympathetic supply is inhibitory.
Mass action contractions

• Occur only in the colon.
• Occur about 10 times per day.
• There is simultaneous contraction of the smooth muscle over large confluent areas
of the colon.
• Significance- these contractions move material from one portion of the colon to
another; they also move colonic contents into the rectum triggering the defecation
reflex.
Vomiting
Vomiting center is in the reticular formation in the medulla and controls the different
components of the act of vomiting.
Afferent impulses reach the vomiting center in the medulla from (i) mucosa in the
upper GI tract via visceral afferent pathways in the sympathetic nerves and vagi, (ii)
from the vestibular nuclei (mediating the nausea and vomiting of motion sickness) (iii)
diencephalon and limbic system (responsible for vomiting in response to emotionally
charged stimuli) (iv) chemoreceptor trigger zone, in the medulla can also initiate vomiting.
Drugs, such as, opiods, chemotherapeutic agents can stimulate the chemoreceptors.
Area postrema has 5-HT3 and D2 receptors, therefore, Serotonin, Dopamine and Dopamine agonists can
trigger vomiting.
5-HT3 antagonists, such as, Ondansetron, and D2 antagonists, such as, chlorpromazine and haloperidol are
effective anti-emetic agents.
AfraTafreeh.com
• Vomiting starts with increased salivation.

• Reverse peristalsis empties material from the upper part of the small intestine into
the stomach.
• Glottis closes, preventing aspiration of vomitus into the trachea.
• Breath is held in mid-inspiration.
• Muscle of the abdominal wall contract, and because the chest is held in a fixed
position, the contraction increases the intra-abdominal pressure.
• The LES and the esophagus relax, and the gastric contents are ejected.
330 | Physiology
Concept 8.11 : Metabolic rate
• To define Respiratory quotient and respiratory exchange ratio
• To discuss factors affecting metabolic rate, including specific dynamic action of food
• To understand the concept of basal metabolic rate
• To understand factors affecting food intake and peptides that can influence appetite
Time Needed
1st reading 10 mins
2 look
nd
06 mins
• Energy output = External work + Energy storage + Heat

• The amount of energy liberated per unit time is the metabolic rate
• Efficiency = work done/ total energy expended
• Isotonic muscle contractions perform work at a peak efficiency of approximating 50%
Respiratory quotient (RQ) is the ratio in the steady state of the volume of CO2
produced to the volume of O2 consumed per unit time.
• RQ of carbohydrate is 1.00, and that of fat is 0.70. RQ for protein is 0.82.
Respiratory exchange (RER) ratio is the ratio of CO2 produced to O2 consumed at any
AfraTafreeh.com
given point of time whether or not equilibrium has been reached. RER can be affected
by factors other than metabolism.
Factors affecting metabolic rate:

• Muscular ingestion during or just before measurement
• Recent ingestion of food (increases metabolic rate by specific dynamic action of food-
SDA is the obligatory energy expenditure that occurs during its assimilation into the
body- SDA is maximum for proteins, i.e., it takes 30 kcal to assimilate the amount of
protein sufficient to raise the metabolic rate 100 kcal)
• High or low environmental temperature
• Height, weight and surface area
• Sex
• Age
• Growth
• Reproduction
• Lactation
• Emotional state
• Body temperature
• Circulating levels of thyroid hormones, nor epinephrine and epinephrine levels
Basal metabolic rate
During the measurement of BMR the following have to be observed:-
• The person must not have eaten food for at least 12 hours
• BMR is determined after a night of restful sleep
• No strenuous activity is performed for at least 1 hour before the test
• All psychic and physical factors that cause excitement must be eliminated
• The temperature of the room must be comfortable and between 68 and 80 degrees F.
• No physical activity is permitted during the measurement of BMR
BMR accounts for 50-70% of the daily energy expenditure in most sedentary individuals.
Normal values:- Adult male- 39 cal/m2/hour; adult female- 35 cal/m2/hour
Control of food intake

Modulating factors
Food preferences, wanting (reward, addiction), emotions, cues, hanits, stress,
environment, lifestyle, circadian rhythm
Central stimulators (orexins)
• NPY (neuropeptide Y)
• Orexin-A
• Cannabinoids
AfraTafreeh.com
The following increase appetite by increasing the synthesis and release of centrally
acting orexins:-
• Ghrelin is produced by the stomach (as well as pancreas) and increased preprandially,
• Cortisol
Central inhibitors (anorexins)
• POMC (pro-opiomelanocortin)
• CART (cocaine and amphetamine regulated transcript)
• Neurotensin
• CRH (corticotrophin releasing hormone)
• Norepinephrine
The following decrease appetite by increasing the synthesis and release of centrally
acting anorexins
• Glucose/ AA/ FFA
• CCK
• PYY (peptide YY)
• Insulin
• Leptin
332 | Physiology
Worksheet
• MCQ OF “GASTROINTESTINAL TRACT” FROM DQB

AfraTafreeh.com


GI hormones
Hormone Secreted by (cells) Stimuli increasing Actions
secretion
Gastrin
CCK
Secretin
GIP
AfraTafreeh.com
GLP-1
Somatostatin
Motilin
VIP
AfraTafreeh.com

Untitled

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Untitled

Uploaded by

Copyright:

Available Formats

AfraTafreeh.

First Published 1999, Delhi Academy of Medical Sciences

© 2021 DAMS Publication AfraTafreeh.com

Â Concept 1.4 AfraTafreeh.com

Â Concept 1.7 Nernst equation

Â Concept 1.9 Composition of ECF and ICF

Body composition: values and measurement Value

Distribution of Total Body Water

2/3 or 66% 1/3 or 33%

Intra Cellular Fluid Extra Cellular Fluid

• A third component of ECF is Transcellular fluids- it is the fluid contained in the

Indicators used for measurement of different body fluid compartments

ECF volume Nonmetabolizable saccharides- Inulin, sucrose, mannitol, raffinose; Radioisotopes of

Factors affecting total body water:

 Women (total body water in women is 50% of body weight)

Mole (or mol)

Osmolarity and osmolality:

Approximate formula for finding the plasma osmolality:

 Freezing point depression

 Boiling point elevation

• Thickness- 7.5 nm (or 75 Å).

 Carriers or transport proteins

Junctions that fasten the cells to one another

Passive transport Active transport

 No Tm (No transport maximum i.e., not saturable).

DA gives appositive value.)

In simple diffusion, more the concentration gradient,

Factors affecting diffusion are:

 Inside-out patch clamp

 Whole cell recording or whole-cell patch

 Automatic patch clamping method

 Occurs along an electrochemical gradient similar to simple diffusion.

 A carrier molecule is involved to which the substance binds, therefore, it is also

called passive carrier – mediated transport.

 Has a Tm (it is saturable)Q.

 It can be competitively and noncompetitively inhibited.

 It follows the enzyme – substrate kinetics of Michaelis – Menten.

Examples of facilitated diffusion- transport of glucose by glucose transporters (GLUT),

c. Non – ionic diffusion

stomach. In the acidic pH of the stomach aspirin is in an undissociated form (pK of

though the rate of diffusion depends on the pH of the urine.

semi permeable membrane is known as osmosis.

 Note: All transporters ending with “ATPase” are primary active).

 Examples of primary active transport - Na+- K+ ATPase pump, H+- K+ ATPase

• The sodium potassium pump is found in all cells.

▫ α2- in muscle, heart, adipose tissue and brain

▫ α3- in heart and brain

glycolytic fast-twitch muscles

• It is inactive at 40 degrees Celsius.

• Secondary active transport-

 Activity of the sodium potassium pump establishes an electrochemical gradient

 TAL- Na+- K+- Cl- co-transport

 DCT- Na+- Cl- co-transport

• Intestinal epithelial cells- SGLT, Na+- aminoacid co-transport

Exocytosis, Endocytosis, Transcytosis

 synaptobrevin (v-snare protein)

• Botulinum toxin interferes with these

 Exocytosis increases the total area of cell membrane.

 Pinocytosis (“ cell drinking”)

 Clathrin- mediated endocytosis (receptor mediated

in endothelial cells, where they help in the uptake of

• Clathrin mediated endocytosisQ is responsible for the

Hydrostatic and colloid osmotic pressures

Therefore, at equilibrium: [K+x][Cl-x] = [K+y][Cl-y]. This is the Gibbs- Donnan equation.

Women (total body water in women is 50% of body weight)

Freezing point depression

Boiling point elevation

Carriers or transport proteins

No Tm (No transport maximum i.e., not saturable).

Inside-out patch clamp

Whole cell recording or whole-cell patch

Automatic patch clamping method

Occurs along an electrochemical gradient similar to simple diffusion.

A carrier molecule is involved to which the substance binds, therefore, it is also

Has a Tm (it is saturable)Q.

It can be competitively and noncompetitively inhibited.

It follows the enzyme – substrate kinetics of Michaelis – Menten.

Note: All transporters ending with “ATPase” are primary active).

Examples of primary active transport - Na+- K+ ATPase pump, H+- K+ ATPase

Activity of the sodium potassium pump establishes an electrochemical gradient

TAL- Na+- K+- Cl- co-transport

DCT- Na+- Cl- co-transport

synaptobrevin (v-snare protein)

Exocytosis increases the total area of cell membrane.

Pinocytosis (“ cell drinking”)

Clathrin- mediated endocytosis (receptor mediated

Macroglia include Schwann cells (form myelin in peripheral nervous system)

Microtubules- serve as ‘tracks’ or ‘guidewires’ for the movement of molecular

The neurilemma is intact

The advantage of CRO is that it is inertia less, instantaneously responding lever