Physiology Notes (Gold - Only What Has Come Up) PDF

PHYSIOLOGY NOTES
CELL PHYSIOLOGY
Total body water 7

Cell membrane 7
Gibbs Donnan Effect 8
Ions inside & outside of cells 8
Junctions between cells 9
Intercellular communications 9
Na-K ATPase 10
Intracellular Calcium 10
Others 11
NERVES & SYNAPTIC TRANSMISSION
Action potential 12
Presynaptic vesicles 12
Acetylcholine 12
Nerve growth factors 13
Cholinergic neurons 13
Noradrenergic neurons 14
Glycine 14
Pain 14
Others 15
MUSCLES
Skeletal muscle 16
Ionic membrane potential 16
Smooth muscle 17
Cardiac muscle 17
METABOLISM
Metabolism & respiratory quotient 19

Oxidative phosphorylation 19
Carbohydrate metabolism 19
Fat metabolism 20
Uric acid 20
Response to starvation 21
Metabolism in injury & trauma 22
Heat 22
CVS REGULATORY MECHANISMS
Key principles 24
Autoregulation 24
Prostacyclin & thromboxane A2 25
Nitric oxide 25
BSE Notes 2006 L.Lai PHYSIOLOGY 1
Endothelins 25
Kinins 26
Atrial natriuretic peptide 26
Serotonin 26
Histamine 27
Carcinoid syndrome 27
Neurocontrol of blood vessels 27
Baroreceptors 28
CIRCULATION THROUGH SPECIAL REGION
Coronary artery disease 29

Neurocontrol of coronary blood flow 29
Cerebral blood flow 29
Fetal circulation 30
Blood flow to muscles 30
CONDUCTION SYSTEM OF THE HEART
Cardiac electrical activity 31

Control of cardiac electrical activity 31
Synchronization of heart beat 31
Time sequence of cardiac cycle 32
Atrial flutter 32
Wolff-Parkinson-White syndrome 32
QT interval 32
THE HEART AS A PUMP
Basic principles 33
Ionotropes 33
Cardiac output 33
End diastolic volume 34
Valvular disease 34
Isovolumetric contraction 35
DYNAMICS OF BLOOD & LYMPH FLOW
Bernoulli’s principles 36
Variations in venous pressure 36
Oedema 36
Gravity & blood flow 37
Brodie-Trendelenburg test 37
CVS CONDITIONS
Shock 38
Effects of bleeding 38
Heart failure 38

THE ADRENAL GLAND
Adrenal cortex 40
Glucocorticoids 40
Aldosterone 41
Adrenal Medulla 42
THE THYROID GLAND
TSH 44
Iodine metabolism 44
Transport & metabolism of thyroid hormones 45
Effects of thyroid hormones 45
Hypo & hyperthyroidism 46
CALCIUM METABOLISM
Calcium 47
Phospherous 47
Bone physiology 48
Vit D metabolism 48
Parathyroid hormones 49
Calcitonin 50
PANCREAS & CARBOHYDRATE METABOLISM
Islets of Langherhans 51
Insulin 51
Diabetes mellitus 52
Glucagon 53
THE ANTERIOR PITUITARY GLAND
Key principles 54
Growth hormone 54
Prolactin 55
THE POSTERIOR PITUITARY GLAND
Vasopressin 57
Thirst 58
Water intoxication 58
Oxytocin 59
The pineal gland 59
THE GONADS
Pituitary regulation of sex hormones 60

Testosterone 60
Estrogen 61
Progesterone 61
Menstrual cycle 62
Pregnancy 62
Placental function 63
Lactation 63
THE LIVER & BILIARY SYSTEM
Liver functions 64
Ammonia 64
Bile 64
Bile salts 65
Bilirubin 65
Gallbladder 66
Control of biliary secretion 66
Pancreatic juice 67
THE GASTROINTESTINAL FUNCTIONS
Salivary glands & saliva 69

Lower oesophageal sphincter 69
Stomach properties 70
Gastric secretions 70
Pyloric stenosis 71
Small intestine 72
Malabsorption syndrome 72
Colon 72
GASTROINTESTINAL HORMONES
Key principles 74
Gastrin 74
CCK 74
Secretin 75
Somatostatin 75
GIP 75
VIP 75
Enteroglucagon 76
ABSORPTION & DIGESTION
Key principles 77
Carbohydrate absorption 77
Protein absorption 77
Fat absorption 78
Na absorption 79
Iron absorption 78
Vitamin B12 absorption 80
Fibres 81
Glutamine 81
Arginine 81
Others 81
RENAL FUNCTIONS
Key principles 83
Renin 83
Angiotensin II 83
Aldosterone 84
Diuretics 84
Renal blood flow 85
GFR 86
Diuresis 87
Urea 87
Effects of renal nerve stimulation 88
Creatinuria 88
PARTS OF A NEPHRON
Proximal convoluted tubule 90

Loop of Henle 91
Distal tubule 91
Collecting duct 92
Na & K HOMEOSTASIS
Sodium homeostasis 93
Potassium homeostasis 94
ACID BASE BALANCE
Key principles 96
Hydrogen ions 96
Buffer systems 97
LUNG STRUCTURE AND FUNCTIONS
Lung structure 99
Pulmonary blood flow 99
Pulmonary functions 100
VENTILATION
Volumes 101
Alveolar ventilation 102
Dead space 102

DIFFUSION
Fick’s law 103

Diffusion Vs perfusion limitation 103
Oxygen uptake 103
Diffusion capacity 103
Diffusion limitation 104
RESPIRATORY BLOOD FLOW & METABOLISM
Pulmonary blood flow 105

Pulmonary vascular resistance 105
Hypoxic pulmonary vasoconstriction 105
VENTILATION-PERFUSION RELATIONSHIP
Oxygen 107
Hypoventilation 107
Shunt 107
Ventilation-perfusion mismatch 108
GAS TRANSPORT BY BLOOD
Oxygen transport 109

Carbon monoxide 109
Carbon dioxide 110
Acid base disturbances 111
MECHANICS OF BREATHING
Muscles of respiration 114

Compliance 114
Regional differences in ventilation 115
Expiratory flow volume 115
Control of ventilation 116
Miscellaneous 118

CELL PHYSIOLOGY
TOTAL BODY WATER

Consider a 70kg man
1. 60% of him is water ! i.e. his total body water (TBW) is ~60% of his body weight
2. of this,
• 40% is ICF ! which CANNOT be measured, but can be calculated ! using TBW – ECF ! measure TBW with D2O
• 20% is ECF ! so a 70kg man would have 14L of fluid in ECF
3. of the 14L ECF,
• 25% is vascular (i.e. 5% of body weight)
• 75% is interstitial (i.e. 15% of body weight)
4. Some important notes regarding ECF
• Think of it like an ‘internal sea’ ! a medium for exchange O2 & waste ! crucial for cell function & survival
• ECF is iso-osmotic with ICF at osmotic equilibrium
• ECF is best measured using inulin, a polysaccharide, MW5200
• transcellular water = that component of ECF that has been processed through cells into special compartments ! e.g.
aqueous humour, CSF, synovial fluid
Total body water is

1. ~60% of body weight
2. higher in men than women
3. reduced with age
4. used to measure ICF
5. inversely proportional to fat ! so it is decreased by obesity ! thus also reduced in Cushing’s disease
CELL MEMBRANE
Fundamental properties of plasma membrane include
1. semipermeable membrane ! permeable to water, Na, K, Ca, etc…
2. preferential permeability to lipid-soluble substances
3. low surface tension
4. high electrical resistance ! practically impermeable to organic anions
There are 4 ways a substance can cross a membrane

1. diffuse through it freely ! if small, and uncharged, e.g. O2, N2, CO2
2. by endocytosis ! a/w clathrin ! the ‘clathrin mediated endocytosis complex’
3. by exocytosis
4. via transport proteins ! e.g. glucose, urea, amino acids, aquaporins for water
So it makes sense that ! how well a substance crosses the membrane depends on
1. how small it is ! smaller is better
2. electrical charge on the surface of the substance ! positive is preferred, negative is repelled
3. lipid solubility ! fat soluble is good
Transport protein is like a gate ! that opens or close depending on

1. charge of the particle ! voltage gated ! Na channel
2. an activating substance ! ligand gated, e.g. hormone, neurotransmitter or internal Ca, cAMP " Ach receptor
3. Carriers ! carry things across the channels
• things normally move by electrical or chemical gradient
• if moving from high to low ! no energy required ! thus facilitated diffusion, e.g. glucose transporter
• if moving from low to high ! energy is required ! active transport (# this energy comes from ATP), e.g. Na-K ATPase,
H-K ATPase
Note that
1. understand the concept of uniport (!), symports (!!) and antiports (!")
2. the equilibrium potential across a membrane for any particular ion exists when there is no net passive movement of the ion
across the membrane
3. equilibrium has nothing to do with ! concentration being the same on both sides or potential difference across the membrane
being zero
In the cell membrane

1. of nerve & muscle, the resting membrane potential is -70 to -90mV
2. potassium permeability is greater than Na permeability
3. insulin causes an increase in resting membrane potential (hyperpolarization)
With regards to capillary membrane

1. different tissues may have greatly differing permeability
2. liver capillaries are readily permeable to plasma proteins
3. glucose transfer across the capillary wall occurs mainly by passive diffusion
Scurvy is associated with blood vessel fragility

BECAUSE
Ascorbic acid is an essential cofactor for the synthesis of collagen
GIBBS DONNAN EFFECT

(understand this concept ! almost always examined in one form or another!)
when an ion on one side of a membrane cannot diffuse across, the distribution of other ions will move appropriately to balance the
charge
Thus Cl- levels in the interstitial fluid are higher than in the blood plasma
BECAUSE
Capillary membranes are not freely permeable to protein anions
IONS INSIDE & OUTSIDE OF CELLS

Consider this
1. we have more total Na than K
2. total amount of the exchangeable Na in the body is ~3000mmol, this being 70% of the total body sodium
3. total body potassium is ~3000mmol and of this, 90% is exchangeable
4. serum osmolality is ~300mmosmoles/kg
5. the pH of the ECF is ~ 7.36 to 7.44
Cell Interstitial Plasma
Cations
1. Na = 15 Na = 150 Na>150
2. K = 150 K = 5.5 K>5.5
3. Mg+ Mg+ Mg+
H+ H+ H+
Anions
1. Phosphates
2. Cl = 9 Cl = 125 Cl<125
In intracellular fluid
1. K concentration is ~ 150 - 160
2. K, Mg, Na are the main cations present
3. organic phosphates are present in high concentration ! the main anion inside the cell, not Cl-
4. the H ion concentration exceeds that in extracellular fluid
Concerning plasma, it has

1. a higher sodium concentration than interstitial fluid
2. higher magnesium concentration than interstitial fluid
3. higher protein concentration than interstitial fluid
But the chloride content ! is not higher than interstitial fluid ! due to Donnan’s effect
When extracellular K concentration is reduced to 3.0

1. K will diffuse out of the cell
2. H+ will diffuse into the cell
3. the intracellular net charge will remain unchanged ! again Donnan’s effect
JUNCTIONS BETWEEN CELLS

2 types of junctions to know for exam ! tight junction & gap junction
Concerning tight junction ! Zona occludens

1. characteristically surround the apical margins of cells in epithelia, e.g. intestinal mucosa, walls of renal tubules
2. restrict molecular movement across the epithelium
3. facilitate cell-to-cell adhesion ! but NOT communication, that’s not it’s job
4. are found just below the luminal surface
Concerning Gap junction

1. are spanned by corresponding connexons
2. connexons lined up with one another ! the only way things can pass between cells, without entering ECF
3. allows ions, sugars, amino acids, and anything <MW 1000 ! denies access to larger or negatively charged molecules
4. thus facilitate cell-to-cell communication
5. thus allow cardiac or smooth muscle to contract simultaneously
6. Charcot-Marie-Tooth disease ! X-linked, peripheral neuropathy ! a/w defective connexin gene
INTERCELLULAR COMMUNICATION
How do cells communicate?
1. among themselves by messengers ! via gap junctions
2. or others, via ECF in 4 way ! autocrine, paracrine, endocrine, or neural communication
3. these messengers are ! amines, amino acids, steroids, polypeptides, lipids ! in various parts of the body, the same chemical
messenger can be a neurotransmitter, a paracrine mediator, or a hormone
4. communication involves ! (1) a receptor, (2) intracellular messengers
Thus, Intercellular communication via chemical messengers that bind to receptors are typical of
1. neural communication
2. endocrine communication
3. paracrine communication
Receptors
1. these are proteins
2. numbers are not static ! increase or decrease depending on stimulus
3. when too much hormone ! number of active receptors are decreased ! i.e. ‘down regulated’ ! how?
• Ligand binds to receptor ! ligand-receptor complex gets ‘internalised’ or endocytosed ! decreased number of available
receptor
• Or chemically desensitized ! so they are less responsive

4. when too little hormone ! they are up-regulated ! ANGII on adrenal cortex is an exception ! it upregulates rather than
downregulates its receptors
Intracellular messengers
1. different mechanisms, depending on cell type, and stimuli
2. ligand/stimulus is called first messenger; and these intracellular mediators are called ‘second messenger’
Stimuli Mechanism
Ach on nicotinic receptor Open or close ion channels in cell membrane
NA on K+ channel in the heart
Thyroid hormones Act via cytoplasmic or nuclear receptors

Retinoic acid Increase transcription of selected mRNAs
Steroid hormones
ANG II (+) phospholipase C

NA via A-adrenergic receptor increased intracellular production of DAG, IP3 and other inositol phosphates
ADH via V1 receptor
NA via B1-receptor ! increase cAMP (+) or (-) adenylyl cyclase ! increased or decreased intracellular cAMP
Glucagon
Vasopressin
NA v A2-receptor ! decrease cAMP
ANP Increase cGMP in cell

NO
Insulin, EGF, PDGF, M-CSF Increase tyrosine kinase activity
3. second messengers can do a couple of things

• changing enzyme function
• trigger exocytosis
• alter transcription of various genes
Na-K ATPase
1. use energy from ATP ! get rid of 3Na out of cell, in exchange for 2K into cell ! ratio 3:2
2. structure is made up of single alpha and single beta subunits
3. use a lot of energy ! account for 24% of energy usage in cells; 70% in neurons
4. (+) by
• high level of intracellular Na concentration
• 3 hormones ! thyroid, insulin, aldosterone
5. (-) by
• decreased ATP production
• 3 things ! dopamine, ouabain, digoxin
6. Intracellular oedema may occur in areas where local blood flow is depressed BECAUSE inadequate oxygenation depresses
cell membrane ionic pumps and allows Na to leak into cells
INTRACELLULAR CALCIUM
1. Ca does everything ! proliferation, neural signaling, learning, contraction, secretion, fertilisaiton, etc…
2. inside the cell, [Ca] = 100nmol/L ! most bound to ER + other organelles ! these provide storage, and release when
appropriate
3. outside cell ! [Ca] 12000x higher ! thus Ca always wants to get into the cell.
• It may do this via 3 Ca channels ! voltage gated, ligand gated, stress activated
• Voltage gated divided into T (transient) or L (long standing) types
4. But cell always wants to get rid of Ca ! pumps it out in exchange for
• 2H+ ! via Ca-H+ ATPase
• 3Na ! via Ca-Na ATPase
5. so when a cell is activated, and the intracellular [Ca] needs to increase, this is achieved by
• more Ca moving into cell
• Ca released from storage, mainly ER
6. increase intracellular Ca ! further (+) SOCC (store-operated Ca channels) ! which opens for more Ca to enter, so storage
can be replenished
7. Ca released inside cell needs to bind to a protein ! troponin, calmodulin, and calbindin
• Troponin ! involves in contraction of skeletal muscle
• Calmodulin ! when (+) by binding to Ca ! can (+) 5 different calmodulin-dependent kinases
a. Myosin light-chain kinase ! phosphorylates myosin ! contraction of smooth muscle
b. Phophorylase kinase ! (+) phosphorylase
c. Ca/calmodulin kinase I, II ! concerned with synaptic junction
d. Ca/calmodulin kinase III ! concerned with protein synthesis
OTHERS
Microtubules
1. are composed of tubulin and make up part of the cytoskeleton
2. make up the filaments of the spindle at mitosis
3. fix the shape of platelets
4. assist the transport of materials within the cell
5. are NOT part of the Golgi complex
Lysosomes
1. are found in granulocytic WBCs
2. may be involved in gouty arthritis
3. merge with intracellular membrane lined vacuoles containing exogenous substances forming a phaocytic vacuole
4. are released intracellularly ! NOT extracellulary, in normal host response to infection to cause bacteriolysis

NERVE & SYNAPTIC TRANSMISSION
ACTION POTENTIAL
Action potential of neuron
1. resting membrane potential = -70mV
2. stimulus comes along ! raise it by 15mV ! -55mV ! this is the threshold, or firing level
3. this overshoots to +35mV and drops back down ! sharp rise and fall is known as spike potential
4. after depolarization = slower fall
5. after hyperpolarisation ! heading back towards resting membrane potential
6. all or none theory ! if threshold not reached, nothing happens. If threshold ‘over reached’, no extra increment
7. the refractory period is divided into
• absolute ! from time of firing to repolarisation
• relative ! from this point to start of after-depolarisation
8. During the absolute refractory period ! no stimulus, no matter how strong, will excite the nerve
9. but during relative refractory period ! stronger than normal stimuli can cause excitation
10. the Na-K ATPase in nerves ! use ~70% of energy
11. during maximal activity, metabolic rate of nerve doubles
12. by comparison, metabolic of skeletal muscle increases as much as 100 folds
13. inhibition of lactic acid production does not influence nerve function
during the relatively refractory period following an action spike in a single squid axon, the intensity of stimulus required to elicit
another spike is " increased
PRESYNAPTIC VESICLES
1. 3 types
• small & clear ! contain Ach, glycine, GABA or glutamate
• small, with dense core ! cateholamines
• large with dense core ! neuropeptides
2. made in axonal body, transported along axoplasmic transport to nerve endings
3. released by exocytosis into synaptic cleft
4. Ca channels (voltage gated) hangs around the active zone ! control release of these vesicles
5. things that block this normal process
• zinc endopeptidases ! (-) proteins in the fusion-exocytosis complex
• tetanus toxin ! blocks presynaptic transmitter release in CNS ! cause spastic paralysis
• botox ! (-) release of Ach at NMJ ! flaccid paralysis
ACETYLCHOLINE
1. Acetyl CoA + choline ! Acetylcholine (catalysed by acetylcholinesterase)
2. Ach released from nerve endings into synaptic cleft
3. Ach acts on 2 types of receptors
• Muscarinic # block by atropine selectively
• Nicotinic ! 2 type ! those found at NMJ and those at autonomic ganglia & CNS
This is why atropine does not cause problems at NMJ when administered
The firing of motorneurons

1. can be inhibited by nerve terminals which release glycine
2. can be inhibited by nerve terminals which release GABA
3. is subject to supraspinal control
4. is subject to negative feed-back control by means of Renshaw cells

NERVE GROWTH FACTORS
1. proteins, necessary for survival & growth of nerve ! also called neurotrophins
2. produced by muscles they innervate or come from astrocytes
3. these bind to receptors at nerve ending ! internalized & then transported retrograde to neuronal cell body ! (+) production of
proteins a/w neuronal development, growth & survival
4. does not (+) the growth of myelinated motor neurons
5. 4 types of neurotrophins we know of
• nerve growth factor (NGF) ! acts on receptor trk A
• brain-derived neurotrophic factor (BDNF) ! trk B
• neurotrophin 3 (NT-3) ! trkC, less on trk A, and B
• neurotrophin 4/5 ! trk B
6. Nerve growth factor ! Protein, 2alpha, 2 beta, 2 gamma subunits,
• Beta subunits ! MW13,200 ! have all the nerve growth-promoting activity; structure similar to insulin
• Alpha ! has trypsin-like activity
• Gamma ! serine proteases
In the skin where complete nerve degeneration has occurred the triple response to stroking is absent
BECAUSE
The flare of the triple response is mediated by an axon reflex
CHOLINERGIC NEURONS
ANS can be cholinergic or noradrenergic
Cholinergic neurons are
1. all preganglionic neurons
2. parasympathetic postganglionic neurons
3. sympathetic post-ganglionic neurons that innervate sweat glands
4. sympathetic neurons that end on blood vessels in skeletal muscles and produce vasodilation when stimulated
the remaining postganglionic sympathetic neurons are noradrenergic
the adrenal medulla is really a sympathetic ganglion ! their postganglionic cells secrete NA, adrenaline, some dopamine
General principles
1. any hollow viscera ! their smooth muscle must have dual supply
• Ach from parasympathetics
• NA from sympathetics
2. not hard/fast rule about which (+) or which (-) ! they do different things at different times
3. Ach doesn’t go into the blood ! most are concentrated at nerve endings ! hence fast release, fast action
4. NA spread further and has more prolonged action
5. NA, adrenaline and DA are all found in blood ! adrenaline and DA from adrenal medulla, most NA are from nerve endings
6. the axons of postganglionic parasympathetic neurons are typically short
Concerning ANS
1. the axons of postganglionic parasympathetic neurons are typically short
2. the adrenal medulla is functionally a sympathetic ganglion
3. transmission at parasympathetic ganglia and sympathetic ganglia are pharmacologically the same
4. salivary glands receive both sympathetic & parasympathetic supply
5. most blood vessels have a sympathetic nerve supply
Micturition is a function of
1. a nervous reflex triggered by intravesical pressure
2. postganglionic parasympathetic nerve fibre stimulation

NOR-ADRENERGIC NEURONS
NA discharge ! generally got to do with preparing for action, coping with emergency
1. relaxes accommodation and dilates pupils ! letting light in
2. accelerates HR and raises BP ! better perfusion to vital organs to run and concentrate
3. dilate blood vessels in muscles
4. constricts blood vessels of skin ! limit bleeding from wounds
5. stimulate sweatglands ! cooling while we’re running
6. lower thresholds in retibular formation ! so we’re more alert
7. elevate plasma glucose and mobilize FFA ! provide energy
Cholinergic discharge ! anabolic nervous system

1. helps digestion and absorption of food
2. by increasing activity of intestinal musculature, increasing gastric secretion, and relaxing pyloric sphincter
Atropine abolishes normal reflex salivary secretion

BECAUSE
Parasympathetic innervation is probably most important for salivary secretion
Destruction of the conus medullaris may almost completely paralyse defecation

BECAUSE
Spinal cord mediated defecation reflex is integrated in the conus medullaris
The vagus nerve supplies

1. sensation to skin of part of the external auditory canal
2. preganglionic cholinergic axons to the cardiac ganglia
sympathetic vasodilator fibers are characterized by the fact that they

1. liberate Ach at preganglionic endings
2. cannot sustain vasodilatation for more than 30 seconds
Alpha-adrenergic receptors at sympathetic postganglionic nerve endings

1. are blocked by phenoxybenzamine (dibenzyline)
2. are present in the presynaptic location on the nerve endings
3. are blocked by phentolamine (regitine)
GLYCINE
the amino acid glycine
1. is probably the mediator responsible for direct inhibition in the spinal cord
2. when directly applied to the membranes of neurons causes hyperpolarisation
3. with arginine and methionine ! is responsible for the synthesis of creatine in muscle
4. has an inhibitory function in the spinal cord ! but is NOT antagonized by atropine
PAIN
Sensation of painful stimuli
1. is transmitted by 2 different nerve fibres systems ! one nociception system, the other unmyelinated C fibres
2. is a/w significant levels of substance P in the substantia gelatinosa
3. travel via ascending pathways in the dorsal column of spinal cord ! lateral spinothalamic tract
if conscious, pain would be experienced in response to which of the following stimuli applied to bowel?
1. visceral distention
2. visceral ischaemia
3. NOT surgical diathermy
4. not cutting with a sharp instrument
OTHERS
In the brain
1. representation of lower limb sensation is expected in the midline
2. projections of afferents on the post-central gyrus are not innate and immutable but may be changed by experience
3. postcentral gyrus ! motor, NOT sensory
4. little glycogen is stored in neurons
5. the main energy supply is glucose
6. metabolic rate is much higher than the body average
7. neuronal uptake of glucose is insulin-independent
Differences b/n tremors seen in cerebellar lesions and basal ganglia disease (Parkinsonism) include
1. at rest ! cerebellar is hypotonia whereas Parkinsonian is hypertonia
2. during movement ! tremor worsen with cerebellar disease; whereas tremor improve with Parkinsonian
3. Parkinsonian tremor is present during sleep
Disorder of cerebellum are a/w

1. dysmetria
2. dysdiadochokinesia
3. intention tremor
4. hypotonia
Below a hemisection of the spinal cord, there is

1. ipsilateral paralysis
2. contralateral pain and temperature loss ! cos these fibres decussate immediately
3. ipsilateral loss of vibrational sense ! these fibres decussate late
Anterolateral cordotomy
1. produces contralateral analgesia
2. leaves discriminative touch sensation intact
3. produces contralateral thermal anaesthesia
4. leaves proprioceptive sensation intact
likely sequelae within the first week of complete transection of the lower cervical spinal cord include
1. bradycardia
2. a negative nitrogen balance
3. hypothermia
Spinal shock following transection of cord in man

1. profoundly depresses spinal tendon reflexes ! because immediately after transection, the resting membrane potential of distal
nerves rises up 6mV > than normal
2. renders the patient poikilothermic
3. usually lasts longer than 1-2 weeks
4. is a/w the disappearance of vasomotor responses
Denervation hypersensitivity
1. is seen with both skeletal & smooth muscle
2. the iris will become hypersensitive to circulating adrenaline
3. smooth muscle does not atrophy whereas skeletal muscle does atrophy after denervation
4. skeletal muscle also shows sporadic contraction of individual fibres termed fibrillation
5. exocrine glands, with exception of sweat glands, also show denervation hypersensivity

MUSCLES
SKELETAL MUSCLE
1. a bunch of fibers, arranged in parallel, so that contraction is additive
2. each fiber is a single cell, multinucleated, long, cylindric, surrounded by plasma membrane (the sarcolemma)
3. the basic contractile unit of striated muscle is the SARCOMERE
4. Intracellular calcium is thus VERY NECESSARY for muscle contraction
5. Know these structures
• Thin filament
a. made up of actin, tropomyosin and troponin (I,T,C)
b. form I bands ! shrink with contraction
• Thick filament
a. 2x as thick ! made from myosin
b. form A bands ! DOES NOT shrink with contraction
• H-band ! just pure thick filaments
• M line ! in middle of H band
• Z line ! where thin filaments are attached
Steps in contraction of skeletal muscle

1. discharge of motor neuron
2. release of transmitter (Ach) at motor end plate
3. binding of Ach to nicotinic Ach receptors
4. increased Na & K conductance in end-plate membrane
5. Generation of end plate potential ! initiating AP along muscle fibers
6. inward spread of depolarization along T tubules
7. release of Ca from terminal cisterns of sarcoplasmic reticulum & diffusion to thick & thin filaments
8. lateral movement of tropomyosin
9. binding of Ca to troponin C, uncovering myosin binding sites on actin
10. formation of cross-linkages between actin & myosin and sliding of thin on thick filaments ! producing movement
Steps in relaxation
1. Ca is actively pumped back into sarcoplasmic reticulum
2. release of Ca from troponin
3. cessation of interaction between actin & myosin
During vigorous exercise

1. the efficiency of conversion of nutrient energy into muscle work is of the order of 20-25%
2. oxygen consumption may increase 20 fold in the trained athlete
3. heatstroke is likely to develop when the body temperature passes 41’C
Striated muscle fibre

1. contains numerous nuclei which are usually peripherally located
2. has only one motor end plate
IONIC MEMBRANE POTENTIALS

1. resting membrane potential ! -90mV
2. AP last 2-4ms, conducted along muscle fiber at ~5m/s
3. absolute refractory period is 1-3ms, and after polarizations are prolonged
4. like nerve cells ! depolarization needs Na influx, and repolarisation needs K efflux
5. signals always start from motor end plate ! a single AP causes a brief contraction followed by relaxation ! muscle twitch
• fast fibres ! twitch duration ~7.5ms
• slow fibres ! twitch duration ~100ms
6. So when a muscle contraction ! thin & thick filament overlap each other
• Width of A band ! constant
• Z lines move closer together
• Contraction occurs when myosin heads bind firmly to actin ! then sliding along ! needing ATP as energy of course
All the energy of an isometric muscle contraction is dissipated as heat

BECAUSE
No external work is done in an isometric contraction
SMOOTH MUSCLE
1. different to skeletal & cardiac muscles in that
• there are no striations
• no Z lines, just dense bodies
• contain few mitochondria ! and so depend to a lot on glycolysis for their metabolic needs
2. calmodulin is the regulatory Ca binding protein
3. the Ca pump is slow acting in comparison with the Ca pump in skeletal muscle
Different to skeletal muscle in ‘contraction/relaxation’ process by

1. binding of Ach to muscarinic receptors
2. increased influx of Ca into the cell
3. (+) of calmodulin-dependent myosin light chain kinase
4. phosphorylation of myosin
5. increased myosin ATPase activity & binding of myosin to actin
6. contraction
7. dephosphorylation of myosin by myosin light chain phosphotase
8. relaxation, or sustained contraction due to the latch bridge and other mechanisms
Muscular arteries adapt to changing requirements for blood flow in the distal tissues
BECAUSE
Muscular arteries sense & adapt to the flow & pressure in their lumen
CARDIAC MUSCLE
1. similar to skeletal in terms of striations, contractions
2. contains more mitochondria
3. a couple of things that are different
• intercalated disks ! occur at Z line ! provide a strong union between fibers, maintaining cell-to-cell cohesion ! so that
one pull is transmitted along to the next
• gap junctions ! allow easy spread of excitation
• T system is located at the Z lines rather than at the A-I junction
• Contraction is due to influx of Ca rather than release of stored Ca from sarcoplasmic reticulum
4. resting membrane potential = -90mV (inside negative compared to outside)
5. this resting potential is affected by K+ on the outside
6. note the 4 phases of cardiac AP
• phase 0 ! initial rapid depolarization & overshoot ! due to opening of voltage gated Na channels, similar to skeletal
• phase 1 ! initial rapid repolarization ! due to closure of Na channels
• phase 2 ! prolonged plateau ! due to slower but prolonged opening of voltage gated Ca channels
• phase 3 ! final repolarisation to resting membrane potential ! due to closure of Ca channels and efflux of K
How digoxin works

1. comes along ! (-)Na-K ATPase in the cardiac muscle
2. so Na can’t get out of cell and remain inside
3. this decreases Na influx ! thus affects Na-Ca exchange ! i.e. no Na can come in, Ca can’t get out
4. so there is an increase in intracellular [Ca] ! increases strength of contraction of cardiac muscle
How does catecholamines work?

1. comes along ! (+) B1 receptors ! (+) cAMP production ! (+) protein kinase A ! (+) phosphorylation of voltage dependent
Ca channels, making them open ! leading to influx of Ca into cardiac cells ! hence increase contraction
2. cAMP also increases active transport of Ca to sarcoplasmic reticulum ! accelerating relaxation, thus shortening systole !
this is important when there’s tachycardia ! because it allows adequate diastolic filling
Metabolism of cardiac muscle

1. heart has lots of blood supply, plenty of mitochondria, lots of myoglobin
2. myoglobin is a muscle pigment that stores O2
3. normally <1% of total energy liberated is provided by anaerobic metabolism
4. during hypoxia, this may increase to 10% ! but under totally anaerobic condition, the energy liberated is not enough to
sustain ventricular contraction
5. normally, heart takes energy from the following sources
• 35% from CHO
• 5% from ketones and amino acids
• 60% from fat ! ½ of which comes from circulating FFA
6. these figures vary according to nutrition status
• when there’s plenty of glucose, more lactate and pyruvate are used
• during prolonged starvation ! more fat is used
• in poorly controlled DM ! less CHO, so more fat is used.
Spontaneous electrical activity is seen in

1. cardiac muscle
2. visceral type smooth muscle

METABOLISM
METABOLISM & RESPIRATORY QUOTIENT

Metabolic rate & respiratory quotient
1. RQ ! indicates how much CO2 is produced ‘by a cell’ compared to how much O2 it has consumed this
2. this is different from respiratory exchange ratio (R) ! which measures that ratio of CO2/O2 at any given time
3. RQ for CHO = 1.0, RQ for fat = 0.7, RQ for protein = 0.82
4. actual amount at any time ! depends on proportions of these fuels being catabolised
5. how much fat, protein & CHO are oxidized in the body at any given time can be calculated from the RQ & urinary nitrogen
excretion
6. Specific dynamic action (SDA) ! is the % of energy of a food use to burn itself ! CHO6%, fat4%, and protein30%
7. the whole point of burning these fuel is to generate ATP ! the currency of the cells
The measured RQ may rise during severe exercise ! because more CO2 is produced
BECAUSE
Hyperventilation will result from lactic acidosis
Fick’s principles
1. the amount of a substance taken up by an organ (or by the whole body) per unit time
2. is equal to the arterial level of substance minus the venous level (A-V difference) x blood flow
OXIDATIVE PHOSPHORYLATION
With regard to energy metabolism
1. ATP is the most important source of energy for cellular metabolism
2. more ATP is formed when glycogen is metabolized to pyruvate than when glucose is metabolized to pyruvate
3. phosphocreatine is used to resynthesize ATP during exercise
4. phosphocreatine is the most abundant source of high energy phosphate bands
Energy transfer
1. energy is stored in bonds when phosphoric acid bind to something
2. when this bond breaks ! energy is released
3. so anything that contains these bonds are called ! high energy phosphate compounds, and these include
• ATP
• Phosphocreatine
• Co-enzyme A ! a high energy Thioesters
Concerning biological oxidation

1. oxidation = adding O2 to something or taking hydrogen away, or losing electrons
2. reduction is the reverse
3. oxidative phosphorylation ! is an oxidation reaction that generates ATP
4. therefore the conversion of NADH2 to NAD, which is an oxidative reaction, if coupled with the conversion of ADP to ATP !
is an oxidative phosphorylation
5. the energy content of acetyl CoA is greater than that of acetic acid
6. one end product of the flavoprotein cytochrome system is water
7. oxidative deamination takes place in the liver
8. the liver is the major site of urea formation
9. FFAs are oxidized in muscle & heart
CARBOHYDRATE METABOLISM
Memorise fig 17.8, 17.9 ! page 286
1. glucose enter cell via facilitated diffusion ! converted to G6P
2. from here, it can be stored as glycogen (glycogenesis) or broken down to give energy
3. 2 ways that G6P can be broken down ! Embden-Meyerhof pathway or hexose monophosphate shunt
4. eventually pyruvate ! which enters mitochondria and become acetyl CoA ! enter the Kreb cycle ! energy is generated
5. Under anaerobic conditions " Glucose ! 2 lactate ! 2ATP
6. Under aerobic conditions " Glucose ! 38ATPs
Glycogenolysis
1. glycogen ! G6P ! glucose (liver ! by glycogen phosphorylase, and glucose 6 phosphatase)
2. glycogen ! G6P ! lactate (muscle ! by phosphorylase)
Gluconeogenesis (occurs only in liver and kidney)

1. lactate ! glucose (liver ! by PEPCK, FBPtase)
2. glycerol ! glucose
3. alanine ! glucose
Proteolysis
• protein ! amino acids (alanin glutamine) ! in muscle
Lipolysis
• TAG ! FA + glycerol (in adipose tissue ! by hormone sensitive lipase)
Ketogenesis (liver only)

• FA ! acetyl CoA ! KB
During glucose metabolism

1. the steps from G6P to pyruvate by the Embden-Meyerhof pathway occur in the cytoplasm
2. conversion of glucose to G6P is irreversible in non-gluconeogenic tissue, e.g. muscle
3. pyruvate is oxidized in mitochondria
4. a high intake of glucose is NOT dealt with in the body by its storage predominantly as glycogen ! it is stored as fat
5. With a high intake of glucose, insulin is secreted & glycogen formation is increased
A high intake of glucose is dealt with in the body by its storage predominantly as ! fat 30-40%, glycogen 5%
BECAUSE
With a high intake of glucose, insulin is secreted and glycogen formation is increased
FAT METABOLISM
Endogenously derived triglyceride circulating in plasma is
1. transported primarily as VLDL
2. increased by CHO excess in the diet
3. removed from the circulation by both muscle & adipose tissue
4. NOT increased when plasma cholesterol level rises
Intracellular lipase
1. is hormone sensitive lipase, only found in adipose tissue ! catalyses breakdown of stored TAG ! FA + glycerol
2. FA then gets released into circulation for energy
3. hormone sensitive lipase ! does not enter the circulation
4. it gets (+) by ! starvation, stress, cortisol, thyrotoxicosis, GH, catecholamines released from sympathetic nerves, etc…
5. it is (-) by insulin and fed state
6. is different from lipoprotein lipase, which is located in the endothelium of the capillaries ! catalyses the breakdown of
circulating TAG ! is not hormone sensitive and requires heparin as a co-factor
Thus, in adipose tissue intracellular lipase

1. activity is increased during starvation
2. is activated by sympathetic nervous system
3. activity is REDUCED following insulin administration
energy derived from fat supplies most of the needs for the peripheral tissues
but fat is not readily converted to CHO in periphery ! in fact this doesn’t happen at all ! FA becomes Acetyl CoA ! ketones
Of the cellular lipid,

1. the chief one that produces heat and aids in thermoregulation is ! brown fat
2. the one that gets burned first during starvation is ! neutral fat
URIC ACID
1. formed by breakdown of purines and by direct synthesis from 5-PRPP and glutamine ! powered by xanthine oxidase
2. excreted in the urine, normal plasma level ~0.2 – 0.4mmol/L
3. in the kidney, it is filtered, 98% reabsorbed and 2% secreted
4. reabsorption in renal tubules can be inhibited by probenecid (Benemid)
5. when too much uric acid in the blood ! deposit in joint ! gout
6. Gout can be primary or secondary
• 2 types of primary gout
a. one ! uric acid production is increased because of various enzyme abnormalities
b. the other ! selective deficit in renal tubular transport of uric acid
• secondary gout ! elevated because of decreased excretion or increased production from some other disease
a. excretion is reduced when there’s renal disease or thiazide diuretics
b. production is increased ! leukemia, pneumonia (due to break down or WBC into uric acid)
7. Treatment ! in acute ! colchicines or NSAIDS, and decreasing uric acid level in the blood
8. colchicines does not affect uric acid metabolism ! all it does is that it relieves gouty attacks by inhibiting the phagocytosis of
uric acid crystals by leukocytes
9. allopurinol basically inhibits xanthine oxidase ! decrease uric acid production ! so reduced urinary uric acid excretion
RESPONSE TO STARVATION
During starvation ! here’s what happens
1. energy is initially derived from stored glycogen ! but this soon depletes ! ~24hrs
2. in seven days ! fat is the major energy source ! resulting in an increase in production of plasma ketones
3. thus a decrease in respiratory quotient
4. the brain has no choice but to adapt to ketone as an energy source
5. the metabolic sequelae are
• increased hepatic gluconeogenesis
• increased hepatic and muscle glycogenolysis
• muscle protein catabolism ! most from liver, spleen & muscles; very little from heart or brain
• increased activity of hormone sensitive lipase
• increase ketones synthesis from FAs
6. despite protein catabolism ! there is REDUCED urea production and renal excretion
7. metabolic acidosis will result from excessive keto-acid production, leading to
• increased renal excretion of titratable acid ! an increase in acidity of urine
• thus increased rate of bicarbonate production
• increased urinary NH4 excretion
• there is decreased pCO2 of the arterial blood
8. Interesting points
• the metabolic response in the post-op period ! FA provide the main metabolic fuel
• if a fatty is starved in hospital, and given only water and vitamin ! she would lose
a. 1kg/day for next few days
b. then 0.3kg/day there after
Ketosis not uncommonly occurs in starvation

BECAUSE
CHO is anti-ketogenic

METABOLISM IN INJURY & TRAUMA
Key changes
1. increased in resting metabolic rate
2. protein catabolism and muscle wasting
3. elevated excretion of urinary nitrogen
4. loss of weight
5. increase gluconeogenesis
6. increase lipolysis
7. resistance of peripheral tissues to insulin ! ability to deal with exogenous glucose (i.e. tolerance) impaired
8. increase circulating concentration of glucagons, adrenaline, cortisol and GH
The usual urinary nitrogen loss following trauma is further increased when
1. parenteral sources of nitrogen are provided
2. the patient has fever
3. BUT NOT when
• Patient has adrenal insufficiency
• Patient is chronically ill & debilitated before trauma
HEAT
1. heat is produced by 3 things ! basic metabolic processes, food intake (SDA) & muscular activity
2. heat is lost via
• radiation and conduction ! 70%
• vaporization of sweat ! 27%
• respiration ! 2%
• urination and defecation 1%
3. understand the concept of conduction, convection and radiation in terms of heat transfer
4. when you’re out in the cold
• heat is lost by conduction to the surrounding air
• by radiation to cool objects nearby
• by convection if you’re swimming in water
5. the reverse is true when the environment is hotter
When we’re out in the cold, out body respond by

1. reducing heat loss by radiation
2. mobilizing FFA
3. increasing metabolic activity in muscles
4. increasing catcholamine secretion
by keeping a patient with a severe burn in a room temperature in the range of 27-30, the excessive MR is reduced
BECAUSE
Heat losses are minimized by raising the room temperature
A man will get colder in water at 25’C than in air at the same temperature
BECAUSE
The thermal conductivity of water is greater than that of air
Regarding sweating
1. when sweating is minimally stimulated, sweat urea is usually very concentrated
2. maximal sweat production in a heat-acclimatised person is ~2L/hr
3. heat-acclimatised persons secrete less Na in their sweat by an aldosterone-dependent mechanism
4. K+ concentration in sweat is greater than in plasma
Concerning fever

1. when fever occurs ! the thermostat is set higher
2. thus, our temperature receptors thinks that the environment is a lot colder
3. therefore, we feel coldest when the central body temperature is rising ! our MR is raised significantly to keep us warm
4. because core temperature is set at a higher level, marked swings do not occur with changes in environment temperature
5. sweating will occur whenever the temperature is elevated, not only when it is rising
Dilatation of skin vessels allows skin temperature to approach core temperature

Temperature regulation in a dry environment temp of 38” IS NOT obtained primaril by skin vasodilation ! why??

CVS REGULATORY MECHANISMS
KEY PRINCIPLES
1. regulation exists to control & direct blood flow to vital organs when appropriate ! brain, heart
2. Linear relationship b/n metabolic rate & blood flow, e.g. 8x increase MR in skeletal muscle is a/w 4x increase in BF
3. BF can be achieved locally by
• Autoregulation ! via myogenic responses, or
• Locally produced vasodilator metabolites, from endothelium, platelets, etc…
4. BF can be controlled systemically via ! nerves to control arteriole, or circulating vasoactive substances (e.g. endothelin 1,
ANGII)
5. in the short term, the above occurs
6. in the long term ! change in size & number of blood vessels in a tissue
AUTOREGULATION
1. tissues always aim for constant blood flow
• if increase flow, they’ll find ways to reduce it, e.g. vasoconstriction
• if reduce flow, they’ll find ways to maximize it, e.g. vasodilatation
• examples are kidneys, mesentery, skeletal muscle, brain, liver and myocardium
2. this ability is called autoregulation ! and there are 2 ways this can happen
• myogenic response ! i.e. the stretch response
• vasodilator response ! increase flow causes more ‘washout’ ! therefore vasoconstriction
Constriction Dilation
Local Factors Think of a lazy muscle Think of a working muscle
1. cold ! drop in temp • hot (increase temp)
2. injured vessels ! constrict strongly • hypoxic
! ?from local release of serotonin from • increase pCO2
platelets that sticks to vessels • lactate ! decrease pH
3. autoregulation • cells leaking K+ & osmolarity
• cells burning energy ! breakdown products of
ATP, e.g. ADP, AMP, adenosine, phosphate
• histamine " release from damaged tissues
note that adenosine ! vasodilator in cardiac muscle,

but not skeletal
Endothelial products 1. endothelin-1 1. NO

2. locally released platelet serotonin 2. kinins
3. thromboxane A2 3. prostacylin
Circulating 1. adrenaline (except in skeletal muscle & 1. adrenaline in skeletal muscle & liver
hormones liver) 2. CGRP-alpha
2. NA 3. substance P
3. Ang II 4. histamine
4. circulating Na/K ATPase inhibitor 5. ANP
5. AVP 6. VIP
6. Neuropeptide
Neural factors 1. increased discharge of noradrenergic 1. decreased discharge of noradrenergic vasomotor

vasomotor nerves nerves
2. activation of cholinergic dilator fibres to
skeletal muscle

Long term autoregulation of local blood flow
1. the body respond by increasing the size and number of blood vessels (via angiogenic factors)
2. an important stimulus for increasing vascularity of a tissues is chronic rise in demand for O2
3. angiogenic factors
• endothelial cell growth factors
• fibroblast growth factor
• angiogenin
4. these are small peptides, cause new capillary loops to sprout from venules
PROSTACYCLIN & THROMBOXANE A2

Prostacylin (PGI2)
1. produced by endothelial & smooth muscle cells in blood vessels
2. inhibits platelet aggregation & promote vasodilation ! thus increasing blood flow
3. (+) renin secretion by a direct action on the juxtaglomerula cells or indirectly by reducing BP
Thromboxane A2 (from platelets)

1. derived from common precursor arachnidonic acid via COX pathway
2. promotes platelet aggregation & vasoconstriction ! thus promoting ‘plug’ formation
Balance between the 2 ! localized clot formation, while maintaining distal blood flow
1. give someone aspirin ! you shift the balance towards prostacyclin ! easy bleeding
2. aspirin produces irreversible inhibition of cyclooxygenase
NITRIC OXIDE
1. also called endothelium derived relaxing factor (EDRF)
2. made from arginine, crosses cell membrane readily, catalysed by NO synthase (NOS)
3. (+) by ! products of platelet aggregation
4. (-) by Hb
5. Action
• vasodilation ! causes ‘flow-induced’ dilation of the large arteries
• tonic release of NO is necessary to maintain BP
• good in penile erection
• vascular remodeling and angiogenesis
• present in brain ! acting via cGMP ! important for brain function
• important for cytotoxic activity of macrophages, including their ability to kill cancer cells
ENDOTHELINS
1. 3 types ! endothelin-1, 2, & 3
2. Endothelin-1
• produced by endothelial cells, made fresh every time via transcription ! ½ life <1 min
• release is (+) by ! stretched wall, hypoxia, AngII, catecholamies, GFs, insulin, oxidized LDL, HDL, thrombin
• release is (-) by ! NO, ANP, PGE2, prostacyclin
3. Actions of endothelin-1
• potent vasoconstrictor, veins>arterioles, particular effect on coronary artery vasoconstriction
• ?renovasoconstriction ! decrease RBF ! decrease GFR ! (+) renin & aldosterone
• Positive chronotropic & inotropic
• (+) ANP
• (+) gluconeogenesis
• Causes bronchoconstriction
• iv injection of ET1 causes transient hypotension, followed by sustained rise in BP (due to vasoconstriction) ! may last for
an hour
KININS
1. vasodilators, increase permeability, chemotaxis
2. 2 types ! bradykinin & lysylbradykinin (kallidin)
3. both formed by HMW and LMW kininogen, after being chopped by proteases called kallikreins
4. formed in sweat glands, salivary glands, exocrine pancreas
5. tissue kallikrein acts on both HMWK and LMWK to form lysylbradykinin
6. plasma kallikrein splits off bradykinin
7. both bradykinin & lysylbradykinin at inactivated either by kininase I or II ! same as ACE
8. the kinins cause the following effects
• increase permeability of capillaries
• chemotactic for leukocytes
• relaxation of vascular smooth muscle ! through action of NO
• contraction of visceral smooth muscle
ATRIAL NATRIURETIC PEPTIDE

1. protein, in atrial muscles that naturally wants to get rid of water ! short ½ life
2. 3 receptors ! A, B & C ! act mainly via Guanylate Cyclase and increasing cGMP
3. (+) by anything that’s ‘overload’
• rise in CVP ! hypervolemia, over infusion of N/saline
• increase HR ! increase venous return
• immersion of body in water
4. note that generally ANP will rise when aldosterone will fall
5. (-) by anything that reduce CVP, e.g. standing form supine, dehydration, blood loss etc…
6. it wants to get rid of water. So it does 5 things
• Inhibits release of ADH (vasopressin) ! water diuresis
• Increases GFR ! increase Na loss
• Inhibit release of renin ! reduce Na retention
• Lowers BP by inhibiting actions of several vasoactive substances
• May have a role in the brain in the central control of BP (ANP & CNP)
SEROTONIN
1. derived from tryptophan
2. found in platelets, chromaffin tissue in gut, tissues in brain, in the retina
3. does the following
• constriction of some vessels
• contraction of the ileum
• potentiates the effect of NA
• may be involved in vasospasm a/w migraine
• also a central neurotransmitter
4. it has NO effect on stimulation of cardiac muscle or secretion of saliva
5. in intestinal tract ! may take part in local regulation of blood flow there
6. in brain ! ? control cerebral circulation
7. after release from serotonergic neurons, much of the released is returned by an active re-uptake mechanism and is inactivated
by monamine oxidase ! forming 5-hydroxyindoleacetic acid
8. 5-hydoxyindoleacetic acid is excreted in the urine

HISTAMINE
1. derived from histidine, found in granules of basophils & mast cells
2. released in response to trauma & allergic reactions
3. does 2 things
• dilate arterioles (powerfully)
• increases capillary permeability
4. thus leading to local swelling in allergic & traumatic reactions
CARCINOID SYNDROME
1. occurs in 1% of all patients with carcinoids & 20% of those with widespread metastasis
2. clinical features include
• flushing
• diarrhea, cramps, N+V
• cough, wheezing, dyspnoea
• nodular liver owing to hepatic metastases
3. carcinoid tumors = tumours arising from endocrine cells, mainly in GIT & lungs
In the carcinoid syndrome, vasoactive substances which may be released include

1. serotonin
2. bradykinin & kallikreins
3. prostaglandin
4. histamine
NEUROCONTROL OF BLOOD VESSELS

Neurocontrol of blood vessels
1. sympathetic fibres (fight or flight response) ! release NA
• increase HR & SV (get ready) ! thus both inotropic & chronotropic
• constrict arterioles & veins ! to appropriate organs
• inhibit effect of parasympathetics (from vagus) ! probably by release of neuropeptide Y
2. these effects are tonical !BP is adjusted by variations in the rate of this tonic discharge
3. when sympathetic nerves are cut (sympathectomy), the blood vessels dilate
4. Parasympathetics, on the other hand ! release ach ! decrease HR
5. the heart receives constant discharges from sympathetics & parasympathetics
6. atropine = parasympatholytic drugs, i.e. blocks effects of parasympathetics
Factors affecting the activity of the vasomotor area in medulla ! central control of BP
1. direct stimulation ! CO2, hypoxia
2. excitatory input
• from cortex via hypothalamus
• from pain pathways & muscles
• from carotid & aortic chemoreceptors
3. inhibitory inputs
• from cortex via hypothalamus
• from lungs
• from carotid, aortic, and cardiopulmonary receptors

BARORECEPTORS
Baroreceptors
1. these are stretch receptors in walls of heart & blood vessels
2. there are 4 of them
• carotid sinus & aortic arch receptors ! monitor the arterial circulation
• receptors in the wall of R) atrium ! monitor venous return
• receptors in wall of L) atrium ! monitor pulmonary circulation
3. if too much volume ! increased wall stretch ! (+) afferent fibres pass via glossopharyngeal & vagus nerves to medulla !
end in nucleus tractus solitarius (NTS) ! causes an efferent response, essentially
• inhibits the tonic discharge of vasoconstrictor nerves
• excites the vagal innervation of the heart, producing vasodilation, a drop in BP, bradycardia & decrease CO
4. in chronic hypertension, the baroreceptor reflex mechanism is ‘reset’ to maintain an elevated rather than a normal BP
Factors affecting heart rate

1. things that increase HR
• reduced CO " decreased activity of baroreceptors in arteries, LV, & pulmonary circulation
• reduced venous return " increased activity of atrial stretch receptors
• hypoxia, exercise, fever, inspiration
• emotions, e.g. excitement, anger, painful stimuli
• hormones, e.g. adrenaline, thyroid hormones
• Bainbridge reflex
2. things that decrease HR
• Increased CO " Increased activity of baroreceptors in arteries, LV & pulmonary circulation
• Increased venous return
• Emotion, e.g. fear, grief, expiration
• NA
• Stimulation of pain fibers in trigeminal nerve
• Raised ICP
Law of circulation
1. In general, HR & BP go hand in hand
• Things that increase HR also increases BP
• Things that reduce HR also reduces BP
2. if they can in opposite direction ! then something is seriously wrong
• increase HR, reduce BP ! shock
• reduce HR, increased BP ! raised ICP

CIRCULATION THROUGH SPECIAL REGIONS
CORONARY ARTERY DISEASE

Characteristic of coronary artery disease
1. coronary flow at rest is about 250ml/min (5% of CO)
2. high oxygen extraction fraction of about 70% at rest
3. flow through coronary arteries occur mainly during diastole ! when the myometrium is relaxed, and pressure is low
4. thus, flow is reduced during tachycardia because diastole is shorter when HR is high
5. no flow occurs during systole in the subendocardial portion of LV ! thus is prone to ischemic damage ! most common site
for MI
6. rise in venous pressure in CCF reduces coronary flow because it decreases effective coronary perfusion pressure
7. So during exercise, a couple of key changes
• Oxygen extraction is almost 100%
• Flow is increased to 5 or 6 times
• This increase is limited however, if there’s proximal stenoses
NEUROCONTROL OF CORONARY BLOOD FLOW

1. 2 receptors on coronary arterioles
• alpha adrenergic ! vasoconstriction
• beta adrenergic ! dilatation
2. when giving a patient iv NA ! it goes to the coronary vessels ! (+) both A & B adrenergic receptors
3. naturally, NA wants to constrict coronary flow
4. But why does it dilate the coronary arteries instead?
• Because at the same time ! it also increases HR, CO, & SBP initially ! causing an accumulation of vasodilator
metabolites in the coronary vessels
• This causes dilation of coronary arteries
5. if we take away the chonotropic & inotropic effects of NA by B-blockers ! then give some iv NA ! this would cause
vasoconstriction ! a good way to kill ICU patients
6. thus the direct effect of NA on the heart is vasoconstriction ! but clinically, it indirectly causes vasodilatation
7. stimulation of vagal fibres to the heart dilates the coronaries
Injections of NA cause coronary vasodilation

BECAUSE
Injections of NA produce vasodilator metabolites as a result of increased myocardial activity
So what happens when slow infusion of adrenaline or NA?

1. in slow iv adrenaline infusion
• HR &CO increases
• SBP increases,
• but 2 things decreases !DBP &TPR
2. in slow iv NA infusion
• SBP & DBP increases
• TPR increases ++
• But 2 things decrease ! HR & CO
3. thus, adrenaline causes widening of pulse pressure
4. that’s why in ICU ! we use NA & not adrenaline, because of all of the above effects
CEREBRAL BLOOD FLOW

5 Factors influence cerebral blood flow (figure 32-8, page 617)
1. intracranial pressure
2. mean arterial pressure at brain level
3. mean venous pressure at brain level
4. local constriction & dilation of cerebral arterioles
5. viscosity of blood
In the brain
1. autoregulation maintains a normal cerebral blood flow at arterial pressures of 65-140mmHg
2. cerebral metabolism always remains constant
Increased ICP causes hypertension & bradycardia

BECAUSE
With increased ICP, there is stimulation of the vasomotor centre due to local accumulation of CO2
FETAL CIRCULATION
Fetal circulation (figure 32.21, page 628)
1. blood from mother goes into baby via umbilical vein ! 80% oxygenated
2. enter the liver, gets diverted into IVC via ductus venosus ! 67%
3. enters the heart through IVC, diverted directly through to LA via patent foramen ovale
• gets pumped into LV and then aorta ! to head ! 65%
4. blood coming SVC preferentially enters the RV and is expelled into pulmonary circulation
• blood in the pulmonary artery get shunted into aorta via ductus arteriosus
• this way, unsaturated blood form RV go to the trunk & lower body ! 60%
5. while better oxygenated blood go to the brain ! 65%
6. from the aorta, some of the blood is pumped into the umbilical arteries and back to the plancenta
7. 55% of fetal CO goes through the placenta
8. the portal & systemic venous blood of the fetus is only 26% saturated
At birth, 3 things are closed

1. umbilical vein is cut off ! ductus venosus shuts off
2. fetal lung expands ! generating intrathoracic negative pressure; blood start to flow into the lungs and returning into LA;
therefore pressure in LA rises ! closure of foramen ovale
3. aortic pressure increased ! closure of ductus arteriosus
Features of congenital ventricular septal defect include

1. a pansystolic murmur
2. increased pulmonary blood flow
3. possible late RVF
4. possible late pulmonary hypertension
BLOOD FLOW TO MUSCLES

1. the most important factors maintaining the high BF in skeletal muscle during exercise are the local mechanisms
• a fall in pO2
• accumulation of vasodilator metabolites
2. some decrease in tonic vasoconstrictor discharge (reduced constrictor tone in the arterioles) may be involved
3. the ‘muscle pump’ in exercising muscle, improves venous return, lowers venous pressure, & helps increase blood flow but is
NOT the primary factor in the initiation & maintenance of high muscular blood flow
4. blood flow in the resting muscle doubles after sympathectomy but once exercise has commenced, there is no difference in flow
in normal & sympathectomised muscles
Thus the most important factor increasing blood flow through an active muscle is local action of metabolites on vessels of the
muscle

CONDUCTING SYSTEM OF THE HEART
CARDIAC ELECTRICAL ACTIVITY

1. SA node ! transmission via atrial myocardium, 3 atrial internodal pathways (anterior, middle & posterior) ! AV node !
bundle of HIS ! R) & L) bundle branches ! Purkinje fibres
• bundle of his ! the only fibres to traverse fibrous cardiac skeleton
• purkinje fibres ! convey electrical excitation to ventricular muscle
2. normal myocardial cells cannot themselves spontaneously generate an action potential
3. SA node located in wall of RA, below SVC
• Depolarization within node moves at 0.05m/s
• Then spreads to atrial muscle at 0.3m/s
• Through the internodal pathway at 1m/s
4. AV node located in posterior interatrial septum, behind tricuspid valve
• Conduction through it is slow ! 0.05m/s
• Delay of 0.1 to 0.13s
• This delay allows completion of atrial systole before ventricles begin to contract
• Slow because small size of fibres, low resting membrane potential & paucity of gap junction
5. the interventricular septum is activated from L) to R)
6. depolarization spreads from apex to base of heart to reach the end of the Purkinje system, then from endocardium !
epicardium
7. the last parts of the heart to depolarized are
• pulmonary conus
• top part of interventricular septum
• basal, posterior parts of LV
CONTROL OF CARDIAC ELECTRICAL ACTIVITY

1. constant balance b/n sympathetic & parasympathetic activities
2. parasympathetic ! vagus nerve ! release Ach at SA node and AV node ! here’s what happens
• in SA node ! Ach binds to M2 muscarinic receptors ! (+) G protein ! opens up special K+ channels !
hyperpolarisation of membrane ! so that it takes longer for cell to reach threshold ! therefore reduce HR
• similar effects delay transmission through AV node as well
• so net effect of vagal parasympathetic on SA & AV node ! reduce HR & delay AV nodal conduction
3. Sympathetic (NA) ! has opposite effects
• acting on SA node & AV node ! increase HR and increase transmission
• NA binds to B1 receptors, which causes an increase in cellular cAMP ! increased permeability of sarcolemma to Na & Ca
ions ! in addition to a more steeply sloping prepotential ! cells reach threshold more quickly
In summary
1. stimulation of cholinergic vagal fibres to nodal tissue increases K+ ion conductance, leading to hyperpolarisation
2. depolarization of the ventricular muscles starts on the L) side of the interventricular system
3. the last of the heart depolarized is the epicardial surface of the posterior parts of LV, pulmonary conus & top part of
interventricular septum
4. stimulation of sympathetic cardiac nerves results in increased cAMP
SYNCHRONIZATION OF HEART BEAT

With regards to synchronization of the heart beat
1. RA systole precedes LA systole
2. LV contracts before RV
3. RV ejection begins before LV ejection (!since pulmonary arterial pressure is lower than aortic pressure)

4. during inspiration, the aortic valve closes slight before pulmonic valve
5. during expiration, the pulmonary & aortic valves close at the same time
TIME SEQUENCE OF CARDIAC CYCLE

1. diastolic filling (with atrial systole in late diastole increasing filling)
2. QRS complex
3. ventricular contraction commencing at the peak of the R wave
4. A-V valve closure
5. isometric ventricular contraction with rapid rise in ventricular pressure (isometric means equal size; the volume does not
change)
6. rapid ejection in the first third of systole, slow ejection
7. the T wave ! ventricular relaxation with falling ventricular pressure
8. aortic & pulmonary valve closure ! dicrotic notch in arterial pressure waveform
9. isomeric relaxation ! opening of A-V valves
10. rapid phase of diastolic filling
11. isometric contraction occurs at the commencement of systole ! does not involve any ejection of blood, and is the steepest part
of the pressure-time graph
ATRIAL FLUTTER
1. sawtooth pattern, 200-350/min
2. in the most common form of this arrhythmia, there is a large counterclockwise circus movement in RA
3. almost always a/w 2:1 or greater AV block ! because in adults, AV node cannot conduct > 230/min
4. ventricular rate can be slowed by carotid sinus pressure
WOLFF-PARKINSON WHITE SYNDROME

1. a/w an additional aberrant muscular or nodal tissue connection (bundle of Kent) b/n atria & ventricles
2. this conducts more rapidly than the slowly conducting AV node ! one ventricle is therefore excited early
3. ECG manifestations
• Short PR interval
• Wide, slurred QRS complex
• Normal PJ interval
• Paroxysmal atrial tachycardia
4. circus movement tachycardia is usually initiated by an atrial premature beat
5. AF is a life threatening arrhythmias
QT INTERVAL
1. from start of QRS complex to end of T wave ! about 0.35-0.42sec
2. indicates period of ventricular depolarization & repolarization
3. varies inversely with HR
4. corresponds to electrical systole
5. is NOT prolonged in hypokalemia

THE HEART AS A PUMP
BASIC PRINCIPLES
1. systolic pressure = peak pressure in ventricles during contraction
2. diastole pressure = lowest pressure in ventricles during relaxation
3. pulse pressure = systolic – diastolic
4. MAP = diastolic + 1/3 pulse pressure
5. isovolumetric (isovolumic, isometric) ventricular contraction lasts 0.05s ! during which pressure in ventricles exceed above
! blood squirt out
6. isometric contraction of the L) ventricle involves the most rapid change in pressure per unit time in the cardiac cycle
7. pressure in LV during systole/diastole = 120/80
8. pressure in RV during systole/diastole = 25/12
9. when aortic valve closes ! the pressure in RV is 15mmHg
10. Know this shit
• EDV = 130ml
• SV = 70-90ml
• ESV = EDV – SV = 130-80 = 50mls remain in each ventricle at end of systole
• EF = SV/EDV ~65% ! very important in evaluating index of ventricular function
11. Starling’s law of the heart ! if there’s increase venous return, there is increase CO ! i.e. all that the heart wants to do is to
pump blood out ! give it more, and it will pump out
12. Frank-starling curve !looks at the relationship b/n EDV & SV (fig. 29.8, pg 574)
• Curve shift UP & to the LEFT ! with increased contractility, e.g. inotropes
• Shifts down & to right ! with decreased contractility
IONOTROPES
1. Inotropes increases cardiac contractility ! leading to increased SBP
2. they ideally should reduce afterload & preload as well as increasing CO & ejection fraction
3. their safe use requires a full range of monitoring being available
4. they include
• catecholamines ! adrenaline and NA
• dopamine
• digoxin
• glucagons (in high dose)
5. Essentially the final common pathways are
• Increased intracellular cAMP ! influx of Ca ! stronger contraction
1. adrenaline & NA ! act on B1 receptors ! (+) adenylyl cyclase ! increased cAMP
2. Dopamine, when injected, stimulates heart via B1 receptors ! as above
3. glucagons ! increases formation of cAMP in cardiac muscles
4. xanthines (caffeine, theophylline) ! these inhibit the breakdown of cAMP
• digoxin ! due to their inhibitory effect on Na-K ATPase in myocardium ! influx of Ca
Negative inotropes
1. hypercapnia, hypoxia and acidosis
2. heart failure
3. drugs, e.g. beta-blockers, Ca channel blockers, barbiturates, and many anaesthetics
CARDIAC OUTPUT
1. CO = SV x HR = 70 x 72 beats/min = 5L/min
2. CO is the amount of blood pumped by each ventricle per minute
3. resting CO is directly related to surface area
4. CI = CO/SA (square meter) ! varies between 2 to 5
Effects of various conditions on CO
No change 1. sleep
2. moderate changes in environmental temp
Increase 1. anxiety & excitement (50-100%)

2. eating (30%)
3. exercise (up to 700%)
4. high environmental temp
5. pregnancy
6. adrenaline
Decrease 1. Sitting or standing form lying position (20-30%)

2. Rapid arrhythmias
3. Heart disease
Factors controlling CO
1. cardiac rate is controlled by cardiac innervation, sympathetic & parasympathetic stimulations
2. SV increases when the strength of contraction increases without an increase in fibre length
3. force of contraction of cardiac muscle depends on its preload and afterload
• preload = the degree to which myocardium is stretched before it contracts
• afterload = the resistance against which it has to pump against
4. preload is therefore proportionate to the EDV
END DIASTOLIC VOLUME

decrease in
1. reduced ventricular compliance (e.g. MI, infiltrative disease)
2. pericardial effusion
3. reduced venous return to heart, e.g. standing
increase in
1. stronger atrial contraction
2. negative intrathoracic pressure during inspiration
3. increased venous return to heart, e.g. muscle pumps during exercise, increase in blood volume, venous tone, negative thoracic
pressure
in a failing LV, all the following parameters are reduced

1. ejection fraction
2. rate of rise of pressure (dP/dt) at the commencement of systole
3. stroke-volume at a given filling pressure
4. systolic shortening of myocardial fibres
VALVULAR DISEASE
Regarding aortic stenosis
1. someone with aortic stenosis is likely to have features of pressure overload ! hypertrophy, fibrosis, vascular insufficiency &
changes in myosin isoform expression
2. their cardiac status is likely to be stuffed as well
3. when this aortic stenosis is fixed surgically
• their cardiac status is improved, often dramatically
• but the pressures changes, i.e. hypertrophy, fibrosis, etc.. may persist postoperatively
In someone with mixed aortic stenosis & insufficiency, cardiac function is made worse by
1. increased pressure gradient across the aortic valve
2. increased reflux through the aortic valve
3. increased aortic systolic pressure
4. rapid HR
ISOVOLUMETRIC CONTRACTION
1. back flow in the proximal aorta occurs only transiently during the initial phase of diastole, before the aortic valve closes
2. during systole, blood in the coronary artery
• still flow to the RA & RV
• but flow to LV is diminished,
• and flow to the subendocardial portion of the LV stops
3. the aortic valve shuts before the period of isovolumetric phase starts
4. its opening signals the end of the period of isometric contraction
5. following closure of aortic valve, the pressure in the aorta falls until the valves reopen again at the end of period of isometric
contraction
6. thus during the isometric contract phase of the ventricles, the aortic pressure is falling

DYNAMICS OF BLOOD & LYMPH FLOW
BERNOULLI’S PRINCIPLES
1. the sum of the kinetic energy of flow & the pressure energy is constant
2. the energy lost in overcoming resistance is irreversible
3. the pressure drop due to conversion of potential to kinetic energy is reversible
4. the greater the velocity of flow in a vessel, the lower the lateral pressure distending its walls
5. when a vessel is narrowed, the velocity of flow in the narrowed portion increases and in the distending pressure decreases
VARIATIONS IN VENOUS PRESSURE

Head
1. when standing, anything above the heart is negative ! veins tends to collapse
2. superior sagittal sinus may be as much as -10mmHg ! negative is only relative ! i.e. the pressure is 10mmHg less than that
of heart
3. magnitude of negative pressure is proportionate to the vertical distance
4. dural sinuses have rigid walls and cannot collapse ! the pressure in them during standing or sitting is therefore
subatmospheric
5. Dural sinus pressure, however, is NOT constantly negative ! positional
Thorax
1. CVP at RA ~4.6mmHg, but fluctuates with respiration & heart action
2. a high CVP reading may be caused by ! anything that puts strain on the R) heart
• a rapid fluid bolus
• pulmonary embolism
• tension penumothorax
• cor pulmonale
3. inspiration generate negative thoracic pressure ! helps venous return
4. pressure in the subclavian vein, as it crosses the first rib, is positive above atmostpheric pressure, when lying down
Venous pressure in the leg

1. during standing, with full effect of gravity, venous pressure in ankle is 85-90mmHg
2. MVP in the foot is higher when standing still than when walking ! because in walking, muscle pumps venous blood back to
heart
Venous pressure in the veins of the foot exhibits the following features
1. in all subjects, increases on standing
2. in normal subjects, diminished on exercise
3. in subjects with incompetence of the perforators & valves of the deep veins, remains elevated during exercise
4. in all subjects, diminishes on elevation of the legs
OEDEMA
Oedema ! is when fluid hangs around ECF and wouldn’t go away
A couple reasons for this
1. increased filtration pressure (pushing force) ! arterial dilation, venular constriction, increased venous pressure
2. decreased osmotic pressure (pulling force) !low proteins, proteins leak into interstitial space
3. increased capillary permeability ! histamine, bradykinin, substance P, etc…
4. inadequate lymph flow, e.g. lymph obstruction
interstitial fluid production is increased in patients who have

1. extensive thermal burns
2. irreversible shock
3. major deep vein thrombosis
4. acute hypoalbuminaemia
GRAVITY & BLOOD FLOW

1. when standing, gravity pulls, therefore (fig 33.1, page 631)
• arterial pressure in the leg =180-200mmHg; and in the head = 60-70mmHg
• venous pressure in the leg = 85-90mmHg; and in the head = 0
2. so prolonged standing, venous pulling in leg ++ ! increased hydrostatic pressure ! fluid in interstitial space ! reduced
venous return ! reduced SV & CO ! fainting
3. a couple of things happen when you stand up from lying
• slight drop in arterial BP initially, then increase
• SV decrease by 40% ! CO decrease by 25%
• CVP drop by 3mmHg
• blood flow to abdomen & limb ! drop by 25% " increase abdominal & limb resistance
• central blood pool ! 400ml in leg
4. the body quickly respond by
• increasing HR (drop in BP sensed by carotid sinus & aortic arch)
• prompt increase in circulating levels of renin & aldosterone (juxtaglomerular apparatus)
• arterioles constrict to maintain BP ! TPR increase by 25%
5. In the head, a couple of interesting things happen
• arterial pressure drops by 20-40mmHg
• but JVP falls by only 5-8mmHg
• cerebral vascular resistance is reduced (because ICP falls ! a fall in pressure on cerebral vessels)
• reduced cerebral blood flow 20% ! reduced pO2 and increased pCO2 ! reduced pH ! dilate cerebral vessels
• increase O2 extraction from each unit of blood
• Net effect ! cerebral O2 consumption is about the same in supine and upright position
Negative gravitation forces acting on the body (i.e. when you’re upside down)
1. increased CO
2. increase cerebral arterial pressure
3. ecchymoses around the eyes
4. mental confusion
BRODIE-TRENDELENBURG TEST
The procedure & interpretation of the Brodie-Trendelenburg test include all the following
1. the patient reclines with the leg elevated to empty the veins
2. the superficial veins are compressed in the thigh
3. the patient then stands while the veins are observed
4. rapid filling on standing of the superficial veins below the knee during the phase of compression indicates incompetent leg &
ankle perforators
5. Brodie-Trendelenburg test can sometimes be additionally useful in detecting incompetent lower leg & ankle perforators, which
indicate severe dysfunction of the venomuscular pump

CVS CONDITIONS
SHOCK
Types of shock & their causes
1. hypovolemic shock (decreased blood volume)
• bleeding, trauma, surgery
• burns
• fluid loss due to vomiting & diarrhoea
2. distributive shock (marked vasodilation, vasogenic or low resistance shock)
• fainting (neurogenic shock)
• anaphylaxis
• sepsis ! also cause hypovolemic shock due to increased capillary permeability with loss of fluid into tissue
3. cardiogenic shock (inadequate CO by the diseased heart)
• MI, arrhythmias
• CCF
4. obstructive shock (obstruction to flow)
• tension pneumothorax
• pulmonary embolism
• cardiac tamponade, cardiac tumours
hypovolemic shock is characterized by ! low CVP, low CO, and high peripheral resistance
EFFECTS OF BLEEDING
Compensatory reactions activated by bleeding
1. vasoconstriction, venoconstriction
2. tachycardia, tachypnea (thoracic pumping)
3. restlessness ! increased skeletal muscle pumping (in some cases)
4. increased movement of interstitial fluid into capillaries
5. increased secretion of
• NA and Adrenaline
• Vasopressins
• Glucocorticoids
• Renin & aldosterone
• EPO
6. increased plasma protein synthesis
HEART FAILURE
1. CCF ! heart inadequate during exercise, but adequate at rest
2. as the disease progress, output is inadequate even at rest
3. 2 types ! systolic & diastolic failure
4. Systolic failure
• more common ! caused by IHD, myopathy, severe volume or pressure overload from valve pathology
• results in a dilated ventricle (increased EDV)
• SV is reduced because ventricular contraction is weak ! ejection fraction reduced from 65% (normal) to 20%
• increased in ESV.
• The heart responds by
• Hypertrophy
• Increased sympathetic discharge
• increased secretion of rnnin & aldosterone ! Na & water retention
5. Diastolic failure
• ventricular compliance is reduced ! from extreme myocardial hypertrophy, e.g. hypertrophic subaortic stenosis,
longstanding severe hypertension
• the stiff ventricle requires increased diastolic filling pressure
• EF initially maintained, but elasticity of myocardium is reduced ! decreased filling ! inadequate SV ! hypertrophy, Na
& water retention (as above)
The essential difference b/n cardiac failure with diastolic dysfunction & failure with systolic dysfunction include
1. ejection fraction ! reduced in systolic failure; initially maintained in diastolic failure
2. myocardial wall thickness ! loose and dilated in systolic; bulky in diastolic
3. EDV ! increased in SHF, reduced in DHF
4. ESV ! increased in SHF, reduced in DHF
The only mechanism that is similar b/n the 2 are ! diastolic filling pressure " bo

THE ADRENAL GLAND
ADRENAL CORTEX
3 layers ! from outer in
1. zona glomerulosa ! secrete aldosterone (mineralocorticoid)
2. zona fasciculata ! secrete cortisol (glucocorticoids)
3. zona reticularis ! secrete cortisol
When this cortex doesn’t work ! we call it Primary adrenal insufficiency ! Addison’s disease
1. used to be a common complication of TB; but now usually due to autoimmune inflammation destroying the adrenal cortex
2. no aldosterone and cortisol so
• circulating ACTH level are high
• patients lose weight, are tired and become chronically hypotensive
• chronically hypotensive ! small heart (due to atrophy)
• eventually hypotension can be so severe they develop shock ! we call this addisonian crisis
3. fasting causes fatal hypoglycemia; any stress causes collapse
4. water is retained and there is always danger of water intoxication
5. diffuse tanning of skin and spotty pigmentation ! is sometimes a/w melanin
GLUCOCORTICOIDS
Here’s how it works
1. Trauma, emotion, stress, hypoglycemia ! (+) hypothalamus to release CRH
2. CRH acts on anterior pituitary ! release ACTH
3. ACTH goes to adrenal cortex & does 2 things
• It is essential for the trophic effect on adrenal cortex
• It acts on cells in zona fasciculata & reticularis ! (+) G protein ! increase intracellular cAMP ! convert cholesterol to
cortisol
4. Cortisol then released into blood (1/2 life 60-90mins)
• 75% bind to CBP ! aka transcortin ! increased in pregnancy; and decrease in cirrhosis, nephrotic syndrome & MM
• 15% bind to albumin
• 10% free cortisol ! this is the part that acts on effector cells
• the above is always in ‘equilibrium’ ! if low free cortisol, (+) ACTH to increase cortisol production ! normal free cortisol,
but elevated total plasma cortisol ! just like the thyroid
5. cortisol enter cell cytoplasm ! nucleus ! (+) mRNA ! produce multiple effects via transcription of DNA
6. metabolized in liver via glucuronyl transferase ! same system as bilirubin ! therefore competition
7. there is an enterohepatic circulation of glucocorticoids, and ~15% of the secreted cortisol is excreted in stool
Effects of glucocorticoids (cortisol)

On metabolism • increase protein breakdown in peripheral tissues ! i.e. mobilization of extrahepatic amino acids
• (+) liver to make glucose and glycogen
• decrease glucose utilization by cells ! thus opposes effect of insulin ! making diabetes worse
• increases utilization of FFA by adipocytes
• decrease ACTH secretion via a feedback control mechanism
Helping others small amounts of glucocorticoids must be present for the following to work
• helps adrenaline to (+) lipolysis
• helps catecholamines to exert their pressor responses & bronchodilation ! thus essential for
vascular smooth muscle responses to catecholamines
• helps glucagons to (+) glycogen breakdown
Effects on blood • Immunosuppression ! decreases eosinophils & lymphocytes, decreases antibody production,
shrinks LNs, thymus, spleen

• Paradoxically increases platelets, neutrophils & erythrocytes
Resistance to stress • increases HCL & pepsin secretion

• increases resistance to stress
Others • modulate sensitivity to oldfactory stimuli

• allows excretion of water load
• inhibits growth, decrease GH secretion
• induce PNMT
• decrease TSH
• during fetal life ! important for maturation of surfactant in the lungs
Excess glucocorticoids ! Cushing’s syndrome

1. this is prolonged increases in plasma glucocorticoids
2. can be ACTH-independent or ACTH dependent
3. Causes of ACTH independent are
• Glucocorticoid secreting adrenal tumours
• Adrenal hyperplasia
• Prolonged administration of exogenous glucocorticoids
4. Causes of ACTH dependent are
• ACTH secreting tumours of the anterior pituitary gland
• Tumours of other organs, e.g. usually lungs, that secrete ACTH (ectopic ACTH syndrome) or CRH
5. Features of Cushing’s syndrome ! too much glucocorticoids will lead to
• Protein depleted ! from excessive protein breakdown therefore
a. muscles small, thin skin, thin hair
b. wounds heal poorly, and bruises easily
• abnormal fat deposition ! central obesity, abdominal purple striae, buffalo hump
• abnormal glucose metabolism ! many aa from protein breakdown are converted to glucose in liver ! leading to
a. hyperglycemia
b. decreased peripheral utilization of glucose ! DM ! hyperlipidemia & ketosis
• salt and water retention ! moon facies
• hypertension 85% cases " due to increased deoxycorticosterone secretion, increased ANG secretion or direct effect of
glucocorticoids on blood vessels
• Osteoporosis & aseptic necrosis of bone
• Peptic ulceration
• significant K depletion and weakness
• Mental aberration ! ranging from increased appetite, insomnia, and euphoria to frank toxic psychosis
ALDOSTERONE
Concerning aldosterone
1. ANGII (+) cells in zona glomerulosa ! (+) phospholipase C ! secretion of aldosterone
2. ½ life ~20minutes, amount secreted small
3. factors that increase aldosterone secretion
• alone ! high K+ intake, low Na intake, constriction of IVC in the thorax, standing, secondary hyperaldosteronism
• also stimulate glucocorticoids release ! surgery, anxiety, physical trauma, bleeding
4. Released aldosterone has the following effect in the blood
• Increase Na reabsoprtion in exchange for K & H ! in the kidney and large bowel
Excess mineralocorticoid secretion leads to

1. K depletion & Na retention ! usually without edema but with weakness
2. Hypertension
3. Tetany
4. Polyuria
5. Hypokalemic alkalosis (hyperaldosteronism)
Causes of excess mineralocorticoid
1. primary adrenal disease ! primary hyperaldosteronism, Conn’s syndrome ! here renin secretion is depressed; think of
• an adenoma of the zona glomerulosa,
• unilateral or bilateral adrenal hyperplasia,
• adrenal carcinoma, or
• GRA
2. Secondary with high plasma renin acitivty ! caused by cirrhosis, heart failure, and nephrosis
3. increased renin secretion is also found in individuals with the salt-losing form of the adrenogenital syndrome
ADRENAL MEDULLA
1. a modified sympathetic ganglion ! 2 reasons
• receives preganglionic input
• embryologically arise from same neural crest as sympathetic nerve
2. chromaffin cells in medulla secrete 3 things ! adrenaline, NA & dopamine
• adrenaline acts on all receptors ! A1,2 and B1,2 ! 85% secreted here
• NA acts on all, except a little weaker effect on B2 ! 15% secreted here
• dopamine acts on all A1,2, B1,2 + specific dopaminergic receptor ! very little secreted here
3. Note that ! isopreterenol acts mainly on B1 & B2 (selective)
4. NA comes from tyrosine ! after it’s been hydrolysed and decarboxylated
5. adrenaline comes from NA ! by a converting enzyme PNMT ! phenyethanolamine-N-methyltransferase
• PNMT is found only in brain and adrenal medulla
• Medullary PNMT is induced by glucocorticoids (cortisol from cortex) ! so after hypophysectomy, plasma
[glucocorticoids] decreases ! decrease adrenaline synthesis
What regulates adrenal medullary secretion?

1. secretion is stimulated by
• stress, i.e. physical, trauma, emotional (fright, fear)
• exercise
• hypoglycemia
2. Secretion is inhibited by sleep
Effects of Adrenaline
A1 Vasoconstriction & venoconstriction
(increase intracellular Ca) Contraction of smooth muscle sphincters
Increase sweating
Dilation of pupil
Increased glyconeolysis
A2 Vasoconstriction ! no effect on cerebral & coronary arterioles

Decrease insulin secretion
B1 Increase HR, contractile force, SBP, but unchanged or decrease DBP

(increase cAMP ! activates Increase conduction velocity & excitability ! causing extrasysole and arrhythmias
phophorylase) Increase O2 consumption
Increase lipolysis
B2 Vasodilatation in muscle & liver

Relaxation in gut, bladder, bronchioles
Increased glycogenolysis
Thus adrenaline
1. (+) glycogenolysis in liver & muscle
2. mobilizes FFA from adipocytes
3. increase BMR
4. increases pulse pressure
5. BUT has NO effect on protein synthesis
Activation of adrenergic nervous system may lead to the following physiological response
1. increase in circulating renin levels
2. arteriolar coronary dilatation
3. hepatic glycogenolysis
Alpha-adrenergic receptors are found in

1. intestinal smooth muscle
2. cutaneous vascular smooth muscle
3. pupils
4. sweat glands
Effects of B2 antagonist
1. bronchoconstriction
2. coronary constriction
3. peripheral vasoconstriction
4. bradycardia
Effects of Noradrenaline
1. effect on the heart, via B1, is similar to adrenaline as above ! causing both increased cardiac contractility & excitability
2. but a couple of differences
• while adrenaline (+) vasodilation in skeletal tissue & liver via B2, NA causes vasoconstriction in most tissues via A1
• causes a reflex bradycardia and hence reflex decreased CO
• thus maintain a normal pulse pressure
So what happens when slow infusion of adrenaline or NA?

5. in slow iv adrenaline infusion
• HR &CO increases
• SBP increases,
• but 2 things decreases !DBP &TPR
6. in slow iv NA infusion
• SBP & DBP increases
• TPR increases ++
• But 2 things decrease ! HR & CO
7. thus, adrenaline causes widening of pulse pressure
8. that’s why in ICU ! we use NA & not adrenaline, because of all of the above effects
Alpha adrenergic blocking agents can be used in refractory shock to

1. increase renal blood flow
2. prevent the imbalance between precapillary & venular tone
Effects of Dopamine
1. physiological effect unknown
2. but when injected
• renal vasodilatation via specific dopaminergic receptors
• (+) vasodilatation in the mesentery
• (+) heart via B1 receptors ! therefore inotropic effect
• (+) general vasoconstriction ! therefore increasing SBP ! a net increase in peripheral vascular resistance
• decrease appetite via specific dopaminergic receptors
3. thus the net effect of injecting DA
• increase SBP
• no changes in DBP
• preserving RBF & GFR
• but NO effect on prolactin
4. thus it’s a useful treatment in traumatic and cardiogenic shock

THE THYROID GLAND
TSH
1. glycoprotein hormone, A & B subunits, ½ life 60minutes, degraded in mainly in kidneys, and a little bit in the liver
2. requires glycosylation for full biological activity
3. secretion pulsatile, start to rise ~9pm, peak at midnight, declines during day
4. A-unit of hCG is similar to that of TSH ! thus large amount of hCG (pregnancy) ! can activate the thyroid receptors
5. go to thyroid gland ! (+) G protein ! (+) adenylate cyclase ! increase cAMP ! has the following actions
• stimulates production of T4,3 and binding to iodide ! increase trapping of iodide
• secretion of thyroglobulin into the colloid and endocytosis of colloid ! the word is ENDOCYTOSIS not exocytosis
• increase blood flow to gland
• with chronic TSH stimulation ! gland hypertrophies ! goitre
6. TSH release is stimulated by
• TRH ! a hypothalamic releasing factor
• Reduced blood level of T4
• Cold, e.g. in infants
7. TSH release is inhibited by
• Negative feedback by T4
• Somatostatin
• Stress, glucocorticoids, dopamine
In general
1. hypothalamus secrete TRH ! (+) thyrotrophs of anterior pituitary ! (+) increase phospholipase C ! (+) increase
intracellular Ca ! release of TSH
2. TSH go to thyroid gland ! (+) G protein ! (+) adenylate cyclase ! increase cAMP ! release T4,T3, and rT3
IODINE METABOLISM
1. raw material, essential for making thyroid hormone
2. we eat iodine ! this gets converted to Iodide (I-) ! then absorbed ! ~500ug/L I- in diet, of these
• 380 go into ECF
• only 120 go into thyroid, of which
a. 40 remain in thyroid ECF and then return to circulation
b. only 80 actually enter thyroid cell ! via active transport
i. this step is (+) by TSH,
ii. but (-) ouabain, CLO4, and other anions
• this 80ug/l then exist in T3,T4 ! go to liver & other cells
a. here 20 enter bile ! excreted in stool
b. 60 then release into ECF post metabolism
• the I in ECF ! 380+40+60 = 480 are excreted in urine
Thus in the thyroid

1. iodide enters cells against a concentration gradient
2. thiocyanate (or perchlorate) competitively inhibits iodide uptake
3. LATS (long acting thyroid stimulator) resembles TSH in its actions
4. thyroid stimulating immunoglobulin (TSI) resembles TSH in its actions
5. daily synthesis of T4 (thyroxine) is MORE than that of T3 ! but T3 is the potent one

TRANSPORT & METABOLISM OF THYROID HORMONES
1. thyroid release T3, T4, rT3
2. T4 ! 80ug released, ½ life 7days ! 70% TBG, 20%TBPA, 10% to albumin ! 0.02% free
3. T3 ! 4ug released, ½ life 1-2 days ! 50% TBG, 50% albumin ! 0.2% free
4. thus more T4 is produced and released than T3 ! but concentration of free T3 in plasma is higher than T4
5. most circulate in plasma predominantly bound to proteins
6. TBPA = thyroxin binding prealbumin ! now called transthyretin
7. ½ life
• of TBPA = 2 days
• TBG = 5 days
• Albumin = 13 days
8. TBG are elevated in eostrogen treated patients and during pregnancy
9. TBG are depressed by glucocorticoids, androgens, severe liver disease, nephrotic syndrome, and drugs which compete for the
binding sites, e.g. aspirin, phenytoin, clofibrate
10. Note the principles of euthyroid ! estrogen present ! (+) TBG level increases ! therefore less free T4,3 ! (+) TSH release,
so more thyroid hormone is made ! a new equilibrium is reached ! same amount of free T4,3, but increased total TBG
EFFECTS OF THYROID HORMONES

1. T3 & 4 cross cell membrane ! bind to thyroid hormone receptors in nucleus (Zinc finger protein)
2. T4 has much lower affinity than T3, but there are more T4 than T3
3. in the cell, T4 gets converted to T3 ! then binds to receptor (Zinc finger protein) ! modulate production of specific mRNA
Calorigenic effect 1. increase O2 consumption of almost all metabolically active tissues

• ?via increased activity of Na-K ATPase
• exceptions are brain, testes, uterus, LNs, spleen, anterior pituitary
2. increase BMR
Metabolic effect Fat

1. mobilise FFAs & thus (+) lipolysis
2. stimulate formation of LDL receptors ! lower plasma cholesterol
Protein
3. increase protein breakdown in muscles ! increase nitrogen excretion
CHO
4. increase absorption of CHO from the gut ! increase glucose absorption from small intestine
5. increase gluconeogensis in liver
6. decrease glycogen content in muscle
Effects on the heart 1. Increase number & affinity of B-receptors

2. Enhances level of A-myosin heavy chain & decreases the level of B-myosin heavy chain
3. Increase its sensitivity to catecholamines
• CO is increased
• Tremor, increased sweating, hyperdynamic circulation ! due to increased effects of
catecholamines
Essential for 1. brain development ! note O2 consumption is not increased in the brain
2. normal growth of muscle & bones
3. conversion of B-carotene to Vit-A
4. regulation of mucopolysaccharide in subcutaneous tissue
5. decrease duration of tendon reflexes
6. Has an effect on erythropoeisis

Thus, thyroid hormone excess causes
1. creatinuria and increased uric acid excretion in urine ! from protein breakdown
2. increased glucose absorption from small intestine
3. increased pulse pressure ! from sensitivity to plasma catecholamines
HYPO & HYPERTHYROIDISM

Hypothyroidism
1. primary due to failure of thyroid gland ! TSH is high; T4,3 low
2. secondary due to pituitary or hypothalamic disease ! TSH low; thus T4,3 low
3. features
• slow mentation, poor memory
• myxodema ! from increased mucopolysaccharides a/w water ! puffy thickening
• husky voice ! myxodema in larynx
• slow pulse
• low BMR, cold intolerance
• carotenaemia
• increased plasma cholesterol
• sparse dry hair
• slow tendon reflex
Cretinism
1. hypothyroidism from birth with impaired skeletal growth & mental development
2. thyroid agenesis or dysgenesis
3. familial (goitrous) due to inherited dyshormonogenesis
4. iodine deficiency or dietary goiterogen
Hyperthyroidism
1. causes
• graves’s disease
• toxic nodules ! single, or multiple toxic nodular goiter
• secondary to pituitary or hypothalamic disease (TSH increased very rare)
• thryoiditis
• ectopic thyroid tissue
• exogenous thyroid hormone administration
2. Features
• Nervousness, tremor
• Increased BMR
• Warm skin (vasodilation) increased sweating
• Fast pulse
• Increased pulse pressure
• Atrial fibrillation

CALCIUM METABOLISM
CALCIUM
Key notes (see fig 21.1, page 383)
1. 1100g in body, 99% in bone, 1% intracellular, 0.1% in ECF
2. exists in blood in 2 forms ! free, or bound to albumin ! again, like all hormones, it’s the free Ca that’s active
3. What’s Ca2+ used for? ! 2nd messengers, blood coagulation, muscle contraction, nerve function
4. Ca in intestine ! absorption
• Active transport via Ca-dependent ATPase " control by 1,25 dihydroxychole-calciferol
• the absorption of Ca from the upper intestine is facilitated by
a. 1,25 dihydroxycholecalciferol
b. a Ca binding protein in small intestinal epithelium ! i.e. a high protein diet
c. a low ionized Ca in plasma
• Absorption is decreased by
a. phosphates and oxalates, fatty acids, phytates ! favours formation of insoluble Ca soaps
b. high plasma calcium
5. Ca in bones ! 99% in storage ! 2 types
• readily exchangeable system ! 500mmol of Ca moves in and out of bone daily ! this regulate plasma Ca
• a larger, slowly exchangeable system ! bone resorption and deposition ! 7.5mmol/day
6. Ca in kidneys
• 99% of filtered Ca is reabsorbed ! 60% from proximal tubules, the remainder in ascending limb + distal tubule
• PTH acts at the distal tubule to increase Ca reabsorption
7. hypercalcemia can be rescued by giving iv bisphosphonate
Factors that affects Ca level in plasma

1. 3 key hormones
• 1,25 Dihydroxychole-calciferol ! vit D by liver and kidney ! (+) increase Ca absorption from intestine
• PTH ! from parathyroid gland
a. (+) osteoclast ! Release Ca from bone
b. Increase urinary phosphate excretion
• Calcitonin ! from thyroid gland ! (-) osteoclast ! reduce Ca level in blood
2. a 4th hormone ! PTHrP (parathyroid hormone related protein) ! acts on PTH receptor ! important in skeletal development
in utero
3. Other factors affecting Ca ! glucocorticoids, GH, estrogens, various GFs
4. plasma protein levels ! inverse relationship ! i.e. if increase, more Ca binds, therefore hypocalcemia
5. pH ! higher pH ! plasma proteins more ionized ! easier for Ca to bind ! worsening hypocalcemia
• so if a patient has tetany, and hyperventilates ! pCO2 reduces ! pH increases ! worsening tetany
PHOSPHORUS
1. 500-800g in body, 85-90% in bone, 1.2mg/L in plasma, 1/3 being organic compounds, 2/3 in PO3, HPO4, H2PO4
2. phosphate is found in ! ATP, cAMP, 2,3DPG, many proteins ! thus it’s important
3. adding or taking phosphates away are important in regulating cell function
4. so it makes sense that phosphate metabolism needs to be closely controlled
5. ~3mg/kg/day enter bone ! some amount leave
6. absorbed in duodenum and small intestine ! by active transport and passive diffusion ! things that increase Ca absorption
also increase Pi absorption
7. Pi (inorganic phosphorus) in plasma is filtered daily ! 85-90% is reabsorbed via active transport in proximal tubule " PTH
acts here

BONE PHYSIOLOGY
1. 2 types
• compact ! 80% of bone ! low surface to volume ratio ! nutrients via haversian canals and systems
• trabecular/spongy bones ! 20% ! nutrients via diffusion from ECF to trabeculae
2. bones form in 2 ways
• chondral ossification ! cartilage first, then bone takes over
• membranous ossification ! tissues first, then bone ! e.g. clavicles, mandibles, skull bones
3. key features of bone growth
• shaft ! diaphysis
• ends ! epiphysis
• growth plate in b/n ! epiphysial plate ! this is the shit that makes bone grow longer by laying down new bone cells
a. width of this plate is proportional to rate of growth
b. GH, IGFI affects the width of this plate
4. bone still grows as long as the plate does not fuse with shaft ! cartilage cells stop proliferating, become hypertrophic, and
secrete VEGF ! leading to vascularization & ossification
5. Bone remodelling
• osteoblast (from fibroblast) ! laying down bones ! bone formation
• osteoclast (from monocyte) ! bone resorption
• osteoclast eat away first, then osteoblast follow behind and lay down bone
• in infants ! 100% bone remodeling every year
• in adults ! 18% each year
Bone disease
1. really a balance between osteoblast and osteoclast
2. too much blast activity and not enough clast ! osteopetrosis (rare) ! steady increase in bone density ! compression of
nerves and haematological consequences
3. too much clast and not enough blast ! osteoporosis ! easy fractures, commonly Colles, vertebral body and hip ! because of
high content of trabeculae bones
4. How does menopause affect osteoporosis?
• Estrogen normally (-) IL-1, 6 and TNF-a ! these help osteoclast to break down down
• Estrogen also (+) production of TGF-B ! this (+) apoptosis of osteoclast
• In menopause, low estrogen level ! these cytokines act unopposed ! increased osteoclast activity ! osteoporosis
• Estrogen therapy reverses this
VITAMIN D METABOLISM
1. important for Ca and Pi absorption in the intestine
2. activated vit D ! we call it ‘calcitriol’
3. here’s how vit D is formed
• sun shines on skin ! (+) cholesterol to cholecalciferol (vit D3)
• vit D3 goes into blood ! reach the liver, gets converted to 25-hydroxycholecalciferol (calcidiol) by cytocrome p450
• 25-hydroxycholecalciferol reaches the proximal tubules of kidneys ! converted to 1,25-dihydroxycholecalciferol
(calcitriol)
• calcitriol is also made in ! placenta, keratinocytes in skin, and macrophages
4. it is degraded in liver by microsomal enzymes ! so any drugs that induce these enzymes (e.g. phenytoin) ! cause a lower
calcitriol level ! osteomalacia
It’s key actions are

1. intestinal cell ! (+) nucleus to produce mRNA ! net effect ! increase Ca-H ATPase transport ! (+) Ca and phosphate
absorption
2. kidney ! again (+) increase Ca-H ATPase expression ! increase Ca reabsorption
3. osteoblast ! (+) it to make more bone cells
4. (+) differentiation in keratinocytes and immune system cells

5. (-) PTH secretion and 1-hydroxylation
receptors for calcitriol are also found in ! skin, lymphocytes, monocytes, skeletal, cardiac muscle, breast, and anterior pituitary !
exact role is unclear
Factors that (+) 1 hydroxylation ! i.e. the final 1,25 dihydroxycholecalciferol

1. PTH
2. low Ca (via increased PTH levels)
3. prolactin
4. growth hormone
5. calcitonin
Factors that (-) it are

1. high phosphate
2. calcitriol
3. acidosis
4. insulin deficiency
PARATHYROID HORMONE
1. made from chief cells of parathyroid glands, release into blood, ½ life 10mins, cleaved by kupffer cells
2. secretion (+) by
• low levels Ca2+
• low Mg (but low Mg also blunts the response to hypocalcemia)
• B-adrenergic discharge
• cAMP
• high phosphate (indirectly by lowering Ca)
• chronic renal disease
3. secretion (-) by
• high Ca
• high Mg
• severe Mg deficiency
• calcitriol
4. Actions of PTH ! (+) Gs protein and adenylate cyclase
• Go to osteoclast ! (+) bone resorption ! therefore mobilize Ca2+
• (+) 1 hydroxylation of 25 hydroxy vit D ! indirectly (+) Ca absorption from intestine
• (+) distal tubular reabsorption of Ca
• decrease plasma phosphate by (-) proximal tubular resorption of phosphate & HCO3 ! thus in excess causes
hypophosphatemia
5. there’s usually a net urinary loss of Ca ! here’s why
• increase renal tubular Ca resorption
• but more Ca is filtered due to increase plasma Ca
Parathyroidectomy
1. PTH is essential to life ! after total parathyroidectomy ! plasma Ca drops steadily ! signs of neuromuscular
hyperexcitability ! followed by full blown hypocalcemic tetany
2. plasma phosphate levels usually rise as Ca level drops
3. signs of tetany
• Chvostek’s sign ! quick contraction of ipsilateral facial muscles, elicited by tapping over facial nerve at angle of jaw
• Trousseau’s sign ! spasm of muscles of upper limb that causes flexion of wrist and thumb with extension of fingers
What’s happens when there’s too much PTH?

1. In PTH excess ! raise plasma Ca, lower phosphate (hypophophatemia), and mild acidosis
2. in chronic renal disease and rickets ! vit D can’t be activated ! reduced Ca absorption from intestine ! plasma Ca
chronically low ! chronic (+) parathyroid hormone ! hypertrophy ! secondary hyperparathyroidism
Hypercalcemia of malignancy
1. common metabolic complication of Ca
2. ~20% of hypercalcemic patients have bone metastasis
3. this erosion is produced by prostaglandins, e.g. PGE from tumour
4. the hypercalcemia in remaining 80% is due to elevated circulating levels of PTHrP ! common among cancer of breast,
kidney, ovary and skin
PTHrP
1. a protein with PTH activity, produced by many tissues in body ! like a pirated version of PTH
2. both PTHrP and PTH bind to same receptors ! but physiological effects are very different
3. PTHrP does the following
• (+) growth and development cartilage in utero
CALCITONIN
1. made from C cells (parafollicular or clear cells of thyroid), ½ life 10mins
2. physiologically, it’s not much use. But in paget’s disease and hypercalcemia ! it’s useful
3. Actions ! it wants low calcium
• Goes to osteoclasts in bones ! stops resorption ! thus leading to ! lowered Ca & phosphate levels (mechanisms unclear)
• Goes to kidney ! Increases Ca excretion in urine
4. secretion is (+) by
• high Ca2+ ! is only secreted when Ca levels in blood exceed 2.4mmol/L (9.5mg/dl)
• Gastrin, CCK, secretin
• B-adrenergic agonists
• Dopamine
• estrogen

PANCREAS & CARBOHYDRATE METABOLISM
ISLETS OF LANGERHANS
1. a group of cells, ovoid, scattered throughout pancreas ! more in the tail
2. 1-2 millions islets, make up 2% of volume of pancreas ! lots of blood supply; blood drain to portal vein
3. 4 types of cells
• A ! glucagons, 20% of islets, around the periphery ! catabolic, moving glucose, aa and FFA into blood stream
• B ! insulin, most common, 60-75% of islets, usually in center ! anabolic, moving glucose, aa and FFA into storage
• D ! somatostatins ! just wants to shut off everything ! (-) glucagons, insulin, GH, etc…
• F ! pancreatic polypeptides
4. A cell rich islets arise embryologically from dorsal pancreatic bud, whereas F cell rich from ventral bud
INSULIN
1. made in rER in B cells, preproinsulin ! transported to golgi apparatus, packed into granules as proinsulin
2. once stimulated ! cleaved by C-peptide to insulin ! release by ‘exocytosis’
3. release into portal vein, ~50% destroyed by a single pass through the liver, ½ life 5minutes
4. destroyed by receptor mediated endocytosis and proteolytic cleavage ! liver and kidney are the major site of destruction
Things that (+) insulin secretion

1. glucose ! threshold 5mmol/L, anything above this, insulin is released
• glucose enter B cells via GLUT 2 ! (+) glucokinase ! increases ATP ! closes K channel
• increase intracellular K ! (+) depolarization of cell ! open voltage sensitive Ca channel
• (+) intracellular [Ca] ! (+) insulin release by exocytosis
2. arginine, leucine & other amino acids ! via ATP (as above)
3. anything that increase cAMP ! e.g. Glucagon & theophyllin, B-agonists
4. Vagal stimulation
• R) vagus ! Ach ! M4 receptor ! (+) insulin release
• Atropine blocks this effect
5. GIT hormones ! GIP, enteroglucagon, secretin, CCK
6. Oral hypoglycemic drugs, e.g. sulphonylureas ! close ATP sensitive K channels
Things that (-) insulin secretion

1. Somatostatin
2. B-blockers
3. Sympathetics
• (+) of sympathetic nerves ! NA ! (+) A2 receptor ! (-) insulin release
• but paradoxically if we block A-receptor ! NA will (+) B-receptor and (+) insulin release
4. K depletion ! e.g. thiazide diuretics; primary hyperaldosteronism ! develop diabetes
5. Galanin
6. Insulin (via negative feedback)
Insulin has the following effects on the following tissues

Fat cells • Brings glucose & K into cell
• (+) lipoprotein lipase to store fat ! making more FA, glycerol, & triglyceride deposition
• (-) hormone sensitive lipase which normally breaks down fat
Muscle • brings glucose, K, amino acid, ketones, into cell

• makes glycogen for storage
• makes more proteins, and (-) protein catabolism
• decrease release of gluconeogenic aa ! e.g.arginine, leucine
Liver • increased protein synthesis and fat deposit

• decreased ketogenesis
• decreased glucose output due to increased glycogen synthesis, and increased glycolysis
General • increase cell growth
Substances with insulin like activity are

1. prosulin and insulin
2. IGF1 and 2
Insulin differs from GH in that it

1. (-) hormone sensitive lipase in fat cells
2. (+) lipoprotein lipase in vicinity of fat cells
Changes resulting from insulin deficiency include

1. diminished growth
2. reduced lipogenesis
3. decreased glucose transport into muscle
DIABETES MELLITUS
1. not producing enough insulin or at all
2. due to destruction of B cells ! can be caused by giving alloxan, streptozocin or other toxins
3. characterized by ! polyuria, polydipsia, weight loss in spite of polyphagia, hyperglycemia, glycosuria, ketosis, acidosis, and
coma
4. fundamental problems
• reduced entry of glucose into various ‘peripheral’ tissues
• liver thinks we’re starving ! so increased release of glucose into circulation
• too much glucose outside cell, but not enough inside cells ! so cells burn fat for energy ! hence increased lipolysis
5. 4 places where glucose uptake is not affected
• intestinal absorption of glucose ! via SGLT 1 and 2
• reabsorption of glucose in proximal tubule is also normal ! also via SGLT 1 and 2
• brain
• RBC
6. normally
• 50% of ingested glucose is burned to CO2 and H2O
• 5% converted to glycogen
• 30-40% converted to fat to be deposited
7. Thus increasing glucose in your diet ! the major of them will be stored as fat, very little to glycogen
8. In diabetes
• <5% is converted to fat
• <50% of ingested glucose is burned
• ~5% still converted to glycogen
• so where do they all go? ! hanging out in the blood and causing problems
Effects of decrease glucose into tissues

1. hyperglycemia
• hyperosmolality of blood
• glycosuria ! polyuria (due to osmotic diuresis) ! increase Na and K loss in urine with glucose
• dehydration ! polydipsia
• increased deposition of glucose on RBC ! increase HbA1C
2. cells deprived of glucose ! body thinks we’re starving
• hyperphagia
• liver releases glucose from storage and so does skeletal muscles ! further contribute to hyperglycemia
• increased protein breakdown to convert to glucose ! diminished protein synthesis, protein depletion and wasting
3. cells start making their own glucose ! gluconeogenesis ! happens from several reasons
• glucagons

• adrenal glucocorticoids
• more amino acids in blood available to make glucose
4. Fat catabolism increased ! system is flooded with triglycerides and FFA; fat synthesis is inhibited ! the overloaded
catabolic pathways cannot handle excess acetyl CoA formed
5. in the liver ! acetyl CoA is converted to Ketone bodies ! metabolic acidosis develops as ketones accumulate
6. Na & K depletion is added to the acidosis because these plasma cations are excreted with the organic anions not covered by
the H+ and NH4+
7. Coma due to ! acidosis, dehydration, hyperosmolarity on CNS
GLUCAGON
1. 29aa peptide, secreted from A cells
2. glucagons + Glicentin (a larger molecule with some glucagons activity)
• both are secreted from mucosa of gut
• both derived from preproglucagon
3. secreted into portal circulation, most removed by single pass through liver
Things that (+) glucagon release

1. hypoglycemia ! exercise, stress, infection
2. amino acids, esp ! alaine, serine, glycine
3. CCK & gastrin
4. cortisol
5. ANS
• vagus nerve (+)
• Alpha (-); Beta (+) ! the balance is stimulation
Things that (-) glucagons release

1. glucose & insulin ! need insulin to bring glucose into A cell, so that glucagons is inhibited
2. GABA ! released along with insulin, next door ! paracrine (-) glucagon release
3. somatosatin
4. secretin
5. FFA and ketones
6. alpha adrenergic agents
Actions of glucagons
1. main site of action is the liver ! glucagons (+) glucagon receptor ! (+) G proteins and adenylate cyclase ! increase cAMP
2. In the liver ! it wants to make glucose
• Glycogen breakdown
• Gluconeogenesis
• Ketogenesis in the liver ! thus increases ketone body formation
3. In other tissues
• (+) lipolysis in adipose tissue (& liver)
• in large doses, it is a positive inotropes
• (+) secretion of insulin & GH
• it is calorigenic via increased hepatic clearance of amino acids
4. GLUCAGON HAS NO EFFECTS ON MUSCLE

THE ANTERIOR PITUITARY GLAND
KEY PRINCIPLES
1. the anterior pituitary secretes 6 hormones
• ACTH ! CRH from hypothalamus
• TSH ! TRH
• FSH & LH ! GnRH
• PRL ! PRH
• GH ! GRH, GIH (somatostatin)
2. secretion of above is controlled by portal hypophysial vessels from hypothalamus
3. so NO nerves are involved " that’s posterior pituitary
Concerning the effect of anterior pituitary

1. FSH maintains spermatogenesis
2. LH is responsible for progesterone secretion from the corpus luteum
3. LH acts via receptors on theca interna cells
4. FSH & LH are secreted in both male and female
5. pulsatile release of GnRH from the hypothalamus is vital
6. prolactin causes milk secretion from the estrogen and progesterone primed breast
7. GH produces a fall in blood urea nitrogen
GROWTH HORMONE
1. protein, anabolic, secretion is pulsatile, ½ life 20mins, bound to carrier protein in circulation
2. increased secretion is by increased frequency and increased amplitude of pulses
3. control is by GHrH (+), while somatostatin (-)
4. acts on the following receptors " these have tyrosine kinase activities
• Type I receptor " bind IGF-I > IGF-II > insulin
• Type II receptor " bind IGF-II > IGF-I
• Insulin receptor " bind insulin > IGFI
5. IGF-II is not greatly affected by GH, but is important in fetal growth " formed in fetal liver and other tissue ! stimulated by
hCS and progesterone
6. in adult, IGF-II s only found in significant amounts in parts of brain and meninges
7. IGF-I and II are somatomedins
8. many of the growth promoting effects of GH are thought to be due to synergistic actions of GH & IGF-I
Release is (+) by
1. reduced metabolic fuels, e.g. hypoglycemia, exercise, fasting, deep sleep, stress
2. certain amino acid, e.g. arginine
3. sex steroids (E>A)
4. glucagons
5. L-dopa
Release is (-) by
1. cortisol
2. FFA
3. glucose
4. light or REM sleep
5. GH
There are direct effect and indirect effect of GH on the body

Direct Effect Indirect Effect
1. (+) lipolysis in adipose tissue " release FFA In direct effect is when GH acts on the liver cells to produce
2. (+) hepatic glucose output IGF-I.
3. (+) protein synthesis IGF1 has the following insulin like effect
4. (+) growth ! therefore increase mitosis 1. increase glucose uptake into cells
5. (+) erythropoiesis 2. anti-lipolysis (probably via insulin receptors)
6. (-) glucose uptake & utilization ! thus reducing insulin 3. increase protein synthesis (and increase urinary
sensitivity ! diabetogenic effect hydroxyproline excretion)
7. also increase Na retention, phosphate retention in kidney, 4. (+) epiphyseal growth
and Ca absorption by gut
Release of IGF-I from liver is (+) by
1. T4
2. sex steroids
3. increase CHO utilization
Release of IGF-I is (-) by

1. high cortisol
2. starvation
3. insulin deficiency
4. high estrogen level
Growth hormone
1. in excessive amounts produces ketosis
2. DOES NOT stimulate pancreatic B cells directly to secrete insulin ! but instead, it increases the ability of the pancreas to
respond to insulinogenic stimuli
3. DOES NOT affect carbohydrate utilization
4. acts INDIRECTLY on bone and cartilage to promote growth
PROLACTIN
1. secreted from lactotrophs in anterior pituitary, similar structure to GH
2. dopamine = prolactin release inhibiting hormone
3. lactotrophs is chronically stimulated to release prolactin
4. cutting the stalk ! no dopamine inhibition ! all anterior pituitary hormone reduce, but prolactin level increase
5. so what is the role of PRH
6. prolactin goes into system, ½ ~20mins, prolactin receptors similar to GH receptors in structure and MOA
Actions of prolactin
1. promotes milk secretion by the breast (in conjunction with estrogen and progesterone) ! NOT milk ejection (that’s oxytocin)
2. anti-gonadotrophin effect
• high [prolactin] ! (-) actions of LH and FSH on gonads
• can cause infertility in both male and female (i.e. prolactinoma)
3. Role in male unknown
Things that (+) release

1. nipple stimulation in non-lactating women (via T5 reflex)
2. stress ! surgery, psychological, hypoglycemia, exercise
3. pregnancy, esp. 3rd trimester
4. phenothiazines (blocks dopamine receptors)
5. TRH (in high concentration)
6. vasopressin, thirst
7. estrogen ! slow (+) on lactotrophs
Things that (-) release

1. L-dopa (increase dopamine synthesis)
2. bromocriptine (dopamine agonist)
3. apomorphine
Features of hyperprolactinemia
1. galactorrhea
2. secondary amenorrhea
3. hypogonadism ! can lead to osteoporosis in women; impotence in men

THE POSTERIOR PITUITARY GLAND
VASOPRESSIN
1. nonapeptide, just like oxytocin, made in posterior pituitary in paraventricular and supraoptic nuclei
2. different from oxytocin in that
• 2 of their amino acids in the 9 are different
• is synthesized in neurone different form those which synthesise oxytocin
a. oxytocin ! from neurophysin I; vasopressin ! from neurophysin II
3. both are NOT bound in the plasma ! they are small in size, therefore penetrate capillary wall easily and distribute ECF
4. ½ life ~20mins, degraded by receptor mediated proteolysis
Actions
1. antidiuretic ! (+) P cells in collecting duct via V2 receptor ! inserts aquaporin
• increases permeability to water of the collecting duct of the kidney
• facilitates urine concentration in the collecting ducts ! NO effect on the distal tubule ! water reabsorption is passive
• increases permeability of the collecting ducts of the inner medulla of the kidney to urea
2. vasoconstriction ! constrict the vasa recta vessels in the renal medulla ! therefore decreases blood flow in the renal medulla
3. (+) ACTH release by corticotrophs of anterior pituitary
4. (+) glycogen breakdown in the liver via V1a receptor
Things that (+) release

1. anything that says we’re underfilled
• mild hyperosmolality of the ECF
• severe hypovolemia
• mild hypovolemia + mild hyperosmolality of the ECF
• severe hypovolemia + severe hypo-osmolality of the ECF
2. drugs, e.g. morphine, nicotine, chlorpropamide, chlofibrate
3. Physiological ! Stress & pain, exercise, sleep
4. Others, e.g. ANGII, standing, N+V
Things that (-) release

1. alcohol ! e.g. beer in moderate amount causes diuresis because
• water in beer inhibits ADH release
• alcohol in beer inhibits ADH release
• Note that alcohol in beer does not have any effect on tubular Na reabsorption
2. overfilled
• increase plasma volume
• decreased plasma osmotic pressure
Thus secretion is affected by

1. osmoreceptor in the hypothalamus
2. low pressure receptor in the great veins and atria
The increase in ADH secretion which follow operation is due to

1. pain
2. administration of morphine
3. loss of ECF
In the syndrome of inappropriate ADH secretion (SIADH), the urine volume/day may be normal
BECAUSE
With SIADH secretion, the GFR may be increased
Diabetes insipidus
1. 2 types ! central DI or nephrogenic DI
2. In central DI ! no or not enough ADH is released ! ?from e.g. from tumour in hypothalamus, surgery, trauma
• No ADH therefore can’t concentrate urine ! polyuria and thirst
3. In nephrogenic DI ! kidney doesn’t respond to ADH ! x-linked recessive disorder, involving the V2 receptor
THIRST
1. thirst is (+) by 2 things ! low volume or high osmolality
• increased plasma osmolality ! (+) osmoreceptors in hypothalamus
• low ECF volume ! detected by 2 key systems
a. renin-ang system ! ANGII release ! ANGII (+) subfornical organ ! (+) thirst center in brain
b. baroreceptors of heart and blood vessels
2. So, that’s why haemorrhage can cause increased drinking even if there is no change in osmolality of the plasma
3. other factors that increase water intake
• psychological and social
• dryness of the pharyngeal mucous membrane causes a sensation of thirst
To recap, thirst is
1. controlled by a hypothalamic mechanism
2. caused by intracellular dehydration
3. caused by extracellular dehydration
4. (+) by haemorrhage or low CO
5. (+) by ANGII (levels after haermorrhage)
6. (+) by increased osmolality of plasma due to increased Na concentration ! extracellular hypertonicity
7. (+) decrease ECF
Thirst can occur without a change in plasma osmolality

BECAUSE
Haemorrhage (+)s thirst by a different mechanism to that evoked by osmoreceptors
With haemorrhage, thirst can occur without any change in plasma osmolality
BECAUSE
With haemorrhage, increased amounts of angiotensin are liberated which stimulate the hypothalamic thirst area
WATER INTOXICATION
Let’s say we drink 10L of water in 5 mins ! here’s what happen
1. rapid volume expansion in intravascular space ! rapid reduction in plasma osmolality
2. water leak into ECF ! interstitial oedema
3. To maintain osmotic equilibrium, water will pass into the cells
4. out cerebral neurons are most sensitive ! when this happens, they swell ! altered consciousness
5. our plasma osmolality will reduce ! normally 300, but if below 200mmOsm/kg ! spontaneous haemolysis will occur ! as
water leaks into RBC and blow it up
6. Urea is a freely diffusible compound and rapidly obtains equilibrium with ECF ! so it’s concentration will not be affected
A plasma osmolality of 230mOsm/kg inducd by rapid water infusion would be associated with
1. an immediate expansion of ECF
2. an increase in interstitial fluid volume
3. altered consciousness
4. know that
• spontaneous haemolysis will only occur when the osmolarity is < 20mOsm/kg
• urea is freely diffusible compound and rapidly obtains equilibrium with ECF without any significant changes in its
concentration in plasma

OXYTOCIN
What it does
1. (+) contraction of myoepithelial cells in breast ! resulting in milk discharge
2. contraction of smooth muscle of uterus ! potentiated by estrogen, and inhibited by progesterone
3. possible effect on decay of corpus luteum
4. possible role in male ejaculation
5. antidiuretic effect in high concentration
Things that (+) secretion ! all the fun things we do at night

1. mechanical distention of vagina
2. stimulation of the nipples
Things that (-) release ! alcohol
THE PINEAL GLAND

1. is outside of the blood brain barrier
2. secrete melatonin ! made from tryptophan via serotonin ! thus it contains both serotonin and melatonin
3. periodic pattern secretion ! higher during night and low during day
4. postganglionic fibers which release NA mediate this cylic behaviour
5. synchrony is ultimately controlled by suprachiasmatic nuclei in hypothalamus
6. NA from postganglionic fibers (+) cAMPsynthesis and hence melatonin synthesis and secretion
7. has no influence over K+ metabolism

THE GONADS
PITUITARY REGULATION OF SEX HORMONES

1. GnRH, 10aa peptide, (+) gonadotrophs in anterior pituitary to secrete LH & FSH
2. constant high level of GnRH are ineffective ! due to receptor down regulation ! an hourly pulse, on the other hand, will (+)
LH secretion
3. FSH & LH are glycoprotein hormones, A & B subunits, both function via G-protein & stimulation of adenylate cyclase
4. Both FSH & LH are secreted in the male and female
In male
1. FSH does the following
• (+) seminiferous tubules to make sperm
• (+) sertoli cells to control maturation of spermatids to spermatozoa
• (+) production of inhibin ! a protein, no known hormonal function, acts as a negative feedback on pituitary to (-) FSH
release
2. LH
• Is trophic on the interstitial Leydig cells ! stimulating androgen production
In Female
1. FSH
• (+) accelerated growth of 6-12 primary follicles with rapid proliferation of granulose cells + theca interna and externa !
i.e. it stimulates follicles maturation
• in the hours before ovulation ! there is a rapid rise in both LH & FSH
2. LH
• Acts via receptors on theca interna cells ! stimulate ovulation and luteinisation of the ovarian follicle
• For final development of the follicle and ovulation
• LH convert the granulose and theca interna cells into a more progesterone secreting type of cell
TESTOSTERONE
Where it’s made
1. main hormone from the testes, 19 carbon steroid, made from cholesterol in Leydig cells
2. also formed from androstenedione, secreted by adrenal cortex
Travels in the blood

3. 90% bound to protein in plasma
• 60% to sex steroid binding globulin (GBG)
• 30% to albumin
• plasma testosterone = free + bound ! 10.4-34.4nmol/L in men, and a lot less in women ! both declines with age
4. secretion is under the control of LH ! so LH released, go to Leydig cell ! acts on LH receptor ! (+) G protein ! increase
cAMP ! (+) protein kinase A ! (+) converts cholesterol to pregnenolone
Effects of Testosterone
1. anabolic ! (+) growth, increase protein synthesis, but eventually cause epiphyseal closure and so stops growth
2. retention of Na, K, phosphate, Ca and water
3. increase libido
4. maturation of Wolffian structures and male internal genitalia
How it’s metabolized

5. T is metabolized in liver and excreted in urine
6. small amount of T can be converted to oestradiol in peripheral tissue (adipose tissue)
7. but most is converted to 17-ketosteroidsainly androsterone and its isomer etiocholanolone ! excreted in urine
8. about 2/3 of urinary 17-ketosteroids are of adrenal origin, 1/3 of testicular origin
9. in some tissues, T can be converted to dihydrotestosterone (DHT) by 5a-reductase
10. DHT binds to ABP and has a higher affinity for the T receptor
11. 5a-reductase thus amplifies the effect of T in those tissues where it is found
12. T is secreted at 4-9mg/d ! small amount secreted in females, probably from ovary but possibly from adrenal as well
Dihydrotestosterone
1. development of male external genitalia
2. male pubic hair pattern (triangle with apex up)
3. pubertal development
In summary, testosterone is
1. mainly bound to protein while circulates in the plasma
2. synthesized from cholesterol in Leydig cells
3. elaborated in the male embryo esp. during the 7th to 12th weeks
4. almost absent in the male up to the age of about 10 years
5. an inhibitor of LH production working through the hypothalamus
6. necessary for normal spermatogenesis
ESTROGEN
1. increases the amount of uterine muscle and content of contractile proteins ! 2x increase in size of uterus
2. changing vaginal epithelium from cuboidal to more infection-resistant squamous
3. makes cervical mucus thinner and more alkaline
4. are the growth hormone of the breast during puberty ! (+) proliferation of mammary ducts, stroma tissue and fat deposit
5. increase osteoblastic activity, and at puberty, uniting the epiphyses to shafts of long bones
6. increased secretion of thyroid binding globulin ! euthyroid
7. slight increase in total body protein
8. increase secretion of angiotensinogen
9. sensitise the myometrium to oxytocin
10. increase deposition of subcutaneous fat
11. causes skin to become softer, smoother and more vascular ! androgens are primarily responsible for pubic and axillary hair at
puberty
12. decrease FSH, and depending on circumstances, may increase/decrease LH
PROGESTERONE
secreted by both placenta and corpus luteum
Effects of progesterone
1. Uterus
• Promotes secretory epithelium in endometrium
• Decreases excitability of myometrial cells
2. Uterine cervix ! thickens mucus and makes it more tenacious and cellular
3. fallopian tube ! promotes secretory changes of mucosa
4. breasts ! stimulate development of breast lobules and alveoli
5. vagina ! epithelial proliferation and thick viscous mucus production
6. endocrine organs ! (-) LH secretin; potentiates inhibitory effect of estrogens
7. others ! thermogenic, probable cause of BMR rise at time of ovulation
Production of progesterone by corpus luteum is not necessary during the last ½ of pregnancy
BECAUSE
During the last ½ the placenta secretes sufficient amounts of progesterone to maintain pregnancy

MENSTRUAL CYCLE
Concerning the menstrual cycle
1. hypothalamus secrete GnRH ! (+) anterior pituitary ! release both FSH & LH ! these go to ovaries and control their
function
2. FSH (+) the accelerated growth of 6-12 primary follicles
3. one is chosen and becomes ‘mature’
4. 3 layers of cells are formed in this follicle ! granulose, theca interna and externa
• granulosa & theca interna cells secrete ! oestrogens
• granulose cells initially have FSH receptors, but later develop LH receptors
• theca interna cells have LH receptors, not FSH ! and also secrete oestrogen under the stimulus of LH
5. LH is needed for the final development of the follicle, as well as ovulation
6. there is a rapid rise of both LH & FSH in the hours before ovulation
7. LH then seems to convert the granulose and theca interna cells into a more progesterone-secreting type of cell
8. plasma oestrogen levels peak near ovulation in midcycle
9. the progesterone secreted by ovarian corpus luteum in the second half of the menstrual cycle prepares a receptive endometrium
for the fertilized ovum
10. after implantation, ongoing nutrition of this conceptus is dependent on corpus luteum secretion of progesterone, oestrogen and
relaxin
11. after about 6 weeks, the placenta is able to produce enough oestrogen and progesterone to maintain pregnancy
12. Oophorectomy before the 6th week will thus lead to abortion
During the follicular phase of the menstrual cycle

1. progresterone levels are depressed ! only rises after ovulation in the luteal phase
2. oestradiol secretion is steady, NOT inhibited,
3. vaginal mucus is thin & alkaline
4. basal body temperature is not elevated
Thus concerning the menstrual cycle

1. new ova are formed during the proliferative phase
2. FSH is essential to allow the follicle to progress to ovulation
with respect to the ovarian hormones

1. during the luteal phase of the menstrual cycle urinary pregnanediol excretion normally exceeds 2mg/24hrs
2. plasma oestrogen level peaks about 24-48hrs preceding ovulation
3. progesterone decreases the response of the uterus to oxytocin
4. progesterone induces secretion of thick, tenacious and cellular cervical mucus
PREGNANCY
Changes during pregnancy
1. anterior pituitary ! 50% increase in size, with increased secretion of corticotrophin, thyrotropin and prolactin
2. adrenal ! increase glucocorticoid secretion; 2x aldosterone secretion
3. Thyroid ! 50% increase in size and production thyroxine ! from (+) by human chorionic gonadotropin and placental human
chorionic thyrotropin
4. Parathyroid hormone ! gland enlargement and increased parathyroid hormone, more marked increased during lactation
5. ovaries and placenta
• produces estrogens, progesterone and relaxin
6. mother’s body ! uterus increases 22x; breasts double in size, vagina and introitus enlarge, general weight gain
7. metabolism ! 15% increase BMR in latter half pregnancy; increased absorption & storage of protein, Ca, phosphates and iron
through pregnancy
8. circulation
• CO increase by 30-40% by 27th week, but near normal in final 8 weeks
• Blood volume increases during second half pregnancy by about 30% (1-2L)
9. Respiration
• minute ventilation increases 50% and a fall in arterial pCO2
• RR increases as diaphragm less effective with enlarged uterus
10. urinary
• slight increase in urine production
• near balance of increased GFR and increased reabsorption of Na, Cl, and water
11. Immune system ! decrease in maternal antibody production
During pregnancy
1. oestiol is synthesized by the combined effect of fetal and placental tissue (i.e. by fetal placental unit)
2. human horionic somatomammotropin (HCS) has some of the actions of GH
3. plasma level of oestriol is higher at the 36th week than at the 20th week
4. increased aldosterone production, combined with marked estrogen secretion is the cause of fluid retention
5. maternal thyroxine production increases by some 50%, but they are euthyroid
6. the position of the mother’s appendix can be pushed into the RUQ
PLACENTAL FUNCTION
The placenta secrete a number of hormones
1. human chorionic gonadotropin (hCG)
• hCG can be detected in blood as early as 6 days after conception, and possibly in urine at 14 days
• prevents normal involution of corpus luteum ! promoting increased ovarian secretion of estrogen and progesterone !
which prevent shedding of endometrium
2. human chorionic somatomammotropin (hCS) ! lactogenic, growth stimulating and causes reduced insulin sensitivity and
decreased glucose utilization in mother
3. estrogen
4. progesterone
Concerning placental function

1. the placental trophoblast prevents rejection of ‘foreign tissue fetus’ by the mother
2. secretion of human chorionic gonadotropin is vital to prevent expulsion of an implanted ovum
3. secretes human chorionic somatomammotropin
LACTATION
Concerning the breast
1. estrogen is primarily responsible for proliferation of mammary ducts
2. progesterone responsible for development of lobules
3. prolactin promotes milk secretion (in conjunction with estrogen and progesterone primed breast)
4. oxytocin causes contraction of the myoepithelial cells lining the duct walls, with consequent ejection of the milk through the
nipple
During pregnancy
1. breast enlarges in response to ! high circulating levels of estrogens, progesterone, prolactin +/- hCG
2. some milk secreted into ducts at ~5months
3. After expulsion of placenta at delivery, levels of circulating estrogen and progesterone abruptly decline ! this drop initiates
lactation
4. Note that prolactin and estrogen synergize in producing breast growth, but estrogen antagonizes milk producing effect of
prolactin
5. thus only until after delivery of placenta, where estrogen level drops ! prolactin effect unopposed ! lactation starts
Regarding breast development & lactation

1. prolactin initiates milk secretion
2. oxytocin induces milk ejection (‘let down’)
3. oestrogen stimulate duct growth
4. GH alone does not stimulate lobule-alveolar growth
THE LIVER & BILIARY SYSTEM
LIVER FUNCTIONS
1. maintains BSL ! gluconeogenesis, glyconeogenesis
2. Protein metabolism
• Breaks down protein ! converts ammonia to urea ! 50% excreted by kidney
3. Fat metabolism
• converts free fatty acids to ketones
• synthesis of VLDL
• processes chylomicron remnants from the blood
• formation & secretion of bile
• processes fat soluble vitamins
4. others
• synthesis of somatomedin C (IGF-1)
• plasma proteins ! acute phase proteins, albumin, clotting factors, steroid binding & other hormone-binding proteins
5. inactivate stuff
• toxins
• steroids ! chemical modification & excretion of thyroxine
• other hormones
6. Immunity ! kupffer cells
AMMONIA
1. formed in cells by converting glutamine to glutamate, catalysed by glutaminase
2. glutaminase is abundant in renal tubular cells ! hence ammonia may be formed from glutamine in the kidney
3. glutamic dehydrogenase catalyses the conversion of glutamate to A-ketodehydrogenase
4. it is taken up by glutamic acid in brain
5. it is converted to urea in the liver ! 50% gets excreted in the kidney
6. It is NOT a substrate for urea production in the kidney ! the kidney DOES NOT produce urea, it just excretes it
7. in the kidney, it is secreted in the proximal & distal tubule to buffer acids
The abnormally high blood ammonia levels commonly found in hepatic coma are due to
1. porto-systemic shunting of blood
2. reduced capacity for urea synthesis in the liver ! i.e. ammonia can’t be converted to urea
3. bacterial production of ammonia in the gut
4. decreased hydrogen ion excretion by the kidney
BILE
1. bile is 97% water, 0.7% bile salt, 0.2% bile pigments & other substances
• bile salts ! Na, K of bile acids
• bile pigments ! responsible for yellow color ! from glucuronides, bilirubin & biliverdin ! by breakdown of RBCs
• others substances ! cholesterol, inorganic salts, fatty acids, lecithin, fat, alkaline phosphatase
2. thus, if bile is analyzed chemically ! bile salts are the most abundant of all ! the main ingredient of bile
3. cholesterol solubility in bile depends on 2 factors ! presence bile salts and lecithin
4. liver secretes 500ml of bile daily ! some excreted in faeces & urine, some gets reabsorbed & resecreted (enterohepatic
circulation)
5. Note that ! reabsorption of bile salts from the intestine leads to further secretion of bile

BILE SALTS
1. liver makes ~ 0.2-0.4g/d, total pool ~3.5g ! recycles repeatedly via enterohepatic circulation
2. amphipathic, form micelles, therefore they do 2 things
• reduce surface tension
• assist fat emulsification, digestion & absorption in small intestine (in conjunction with phospholipids & monoglycerides)
3. a certain concentration of bile salts is required for the formation of micelles
4. bile salts contain bile acids, which are made from cholesterol.
5. there are 4 types of bile acids
• primary (i.e. formed in liver)
a. cholic acid 50%
b. chenodeoxycholic acid 30%
• Secondary (made elsewhere) ! in the colon, bacteria convert
c. cholic acid ! deoxycholic acid (15%)
d. chenodeoxycholic acid ! lithocholic acid (5%)
6. bile acids are then conjugated with taurine & glycine to form bile salts
7. regarding bile salts absorption
• 95% absorbed from small intestine (mainly terminal ileum) ! by Na-bile salt co-transport, powered by basolateral Na-K
ATPase
• some are absorbed by non-ionic diffusion along the way
• remaining 5-10% enter the colon ! converted to salts of deoxycholic acid & lithocholic acid
a. lithocholate is relatively insoluble, mostly excreted in stools; only 1% is absorbed.
b. deoxycholate is absorbed
8. the absorbed bile salts are transported back to liver in portal vein ! re-excreted in bile (enterohepatic circulation)
9. those lost in stool are replaced by synthesis in liver
What happens when enterohepatic circulation is interrupted? e.g. terminal ileum resection, Crohn’s
1. 50% of ingested fat will appear in the feces ! because liver cannot increase rate of bile salt production fast enough
2. severe malabsorption of fat-soluble vitamins
In summary, with respect to bile salts

1. they are absorbed largely from the ileum ! ~ 95% of cholate & chenodeoxycholate are reabsorbed and recirculate to the liver
2. the primary bile salts are cholate & chenodeoxycholate & are conjugated with glycine or taurine in the liver
3. they are synthesized from cholesterol & are concentrated in the GB
4. it is bile salts, when in excess, that makes the jaundice skin itchy
Steatorrhoea may follow resection of the terminal ileum

BECAUSE
95% of the bile salts are absorbed in the terminal ileum & recycled by the enterhepatic circulation
BILIRUBIN
1. formed in the reticuloendothelial system & BM; when some old & scraggy RBCs breakdown (life span ~120days)
2. it then has to travel in the blood to get to the liver. It does this 2 ways
• free bilirubin ! floats freely in blood, less water soluble, enters liver cells directly, attaches to cytoplasmic proteins
• bound to albumin ! some tightly, others not so
3. thus unconjugated bilirubin rises in the plasma when there is excessive destruction of RBCs
4. it gets to the liver cell ! enters it
• goes to sER, where glucuronyl transferase is located
• gets conjugated to glucuronic acid (making it more water soluble)
a. note that glucuronyl transferase also catalyses other things as well, e.g. steroids, drugs, etc… so presence of these
substances can interfere with conjugation ! causing jaundice
5. of the conjugated glucoronide formed
• most gets transported against a concentration gradient via active process into the bile canaliculi
• a small amount escapes into blood, where it binds less tightly to albumin than free bilirubin, and is excreted in the urine
so when we measure plasma bilirubin clinically ! it’s really the free bilirubin + some conjugated bilirubin that we are looking at
6. The bilirubin that gets ‘pumped’ into the small intestine with bile ! here’s what happens
• Enters at D2 ! some meet the bacteria there ! gets converted to urobilinogens " these are colorless
• the intestinal mucosa now has some rules
a. only urobilinogens and unconjugated bilirubin are allowed back in ! 10-20% of urobilinogens are reabsorbed here
b. conjugated bilirubin can’t be reabsorbed ! so we loose this in stool
• small amounts of urobilinogens enter the general circulation & are excreted in the urine
To recap, bilirubin is
1. formed in the reiculoendothelial system & bone marrow
2. normally transported in the blood bound to albumin
3. conjugated in the liver with glucuronic acid
4. normally converted to urobilinogen in the small intestine
Jaundice
1. happens when plasma bilirubin (i.e. free bilirubin + some conjugated bilirubin) ! >34umol/l or 2mg/dL
2. these excess bilirubin accumulate in the blood, skin, scleras & mucus membranes
3. hyperbilirubinemia may be due to
• too much production (haemolytic anaemia)
• not enough uptake into liver cells
• not conjugated properly
• conjugated bilirubin can’t be released into bile canaliculi
• obstruction of bile flow ! inside & outside of liver
4. obstructive jaundice a/w complete obstruction of bile duct can cause intense skin itching mainly contributed to by bile salt
retention
5. note that cholesterol & alk phos are excreted in the bile as well
• so someone with obstructive jaundice intra or extrahepatically, plasma level of cholesterol & alk phos are raised
• but if jaundice is due to non-obstructive causes (e.g. haemolytic anemia) ! their plasma level is normal
Patient who has obstructive jaundice due to gallstone may have an increased tendency to bleed
BECAUSE
In obstructive jaundice, decreased absorption of vitamin K occurs in the gut
GALLBLADDER
1. when the sphincter of oddi is closed, bile flows into the GB
2. here the GB ‘mutilates’ the bile in several ways
• actively reabsorbs Na+ ! Cl- & HCO3 follow passively ! water is thus follow ! liver bile 97% water; GB 89%
• bile salts contents become more concentrated ! liver bile 10-20mmol/L; GB50-200mmol/L
• adds acid to it ! liver bile pH 7.8-8.6; GB pH 7.0-7.4
3. active transport of NaCl out of the GB is the mechanism by which bile is concentrated
CONTROL OF BILIARY SECRETION

1. when food enters mouth, the resistance of sphincter of oddi decreases
2. FAs & aa in duodenum release CCK ! (+) GB contraction ! squeezing bile into CBD ! D2
3. that’s why patient’s with gallstone gets pain after a fatty meal
a. cholagogues are things that cause contraction of GB, e.g. CCK
b. choleretics are things that increase secretion of bile, e.g. bile salts
4. the most potent stimulators of bile salts secretion are the bile salts themselves
5. production of bile is increased by
• stimulation of vagus nerve
• hormone secretin ! which increases water & HCO3 content of bile
PANCREATIC JUICE
1. ~1500ml secreted daily, alkaline, high HCO3 content (~4-5x compared to plasma HCO3)
2. together with bile & intestinal juices ! these neutralize the gastric acid, raising the pH in duodenum to 6.0 – 7.0
3. pancreatic juice contains
• Cation ! NA, K, Ca, Mg ! pH ~8.0
• Anions ! HCO3, CL, SO4, HPO4
• Digestive enzymes ! amylase, lipase, trypsin, chymotrypsin, elastase, ribonuclease & deoxyribonuclease, peptidase, etc…
4. most enzymes are protein splitting, and inactive when secreted
5. trypsinogen ! trypsin, by brush border enzyme enteropeptidase (enterokinase) ! thus enterokinase is not a GIT hormone
6. what does trypsin do?
• Converts more trypsinogen to trypsin ! (+) feedback
• Converts chymotrypsinogens to chymotrypsins ! and hence start a cascade of chain reaction
• Converts prolastase to elastase
• (+) phospholipase A2 ! splits a FA off lecithin ! lysolecithin ! damages cell membrane ! acute pancreatitis if
inappropriately activated
7. to handle this, pancreas has trypsin inhibitor
Regulating pancreatic juice secretion

1. nerve & hormonal control ! but mainly under hormonal control
2. the pancreas exocrine glands have 2 options
• secrete lots of juice, but high in pH ! (+) secretin
• secrete ‘concentrated’ juice, low volume, but high in acid content, so low pH ! (+) by CCK and vagal stimulation
3. secretin ! via increasing intracellular cAMP
• (+) pancreatic ducts to make lots of very alkaline pancreatic juice, rich in HCO3 and poor in enzymes
• (+) bile secretion
4. when injecting someone with iv secretin, here’s what happens
• volume of pancreatic juice increases
• amount of HCO3 in the juice increases significantly
• [Cl] in the juice decreases
• level of amylase is reduced
5. Note that HCO3 rich pancreatic juice is secreted ONLY in response to secretin, & nothing else
6. CCK ! via phospholipase C ! (+) acinar cells to release zymogen granules & producing pancreatic juice rich in enzymes,
but low in volume
7. like CCK, Ach from vagus nerve ! also (+) acinar cells ! secrete juice rich in enzymes, but low in volume
8. a vagally mediated conditioned reflex secretion of pancreatic juice occurs in response to the sight or smell of food
9. this effect is blocked by atropine and by denervation of the pancreas
10. the sympathetic nerve supply of the pancreas is vasocontrictive, and has minimal effect on exocrine secretion
In summary, the pancreas secretes

1. proelastase
2. prolipase from nucleic acids
3. phospholipase A
4. ribonuclease & deoxynuclease which split nucleotides from nucleic acids
5. inactive precursors of trypsin and lipase
6. a bile salt activated lipase capable of hydrolyzing cholesterol esters
7. the main anions being HCO3 & Cl-
• [HCO3] being 80mmol/l normally, rising to 150 on stimulation by secretin
• [Cl-] being 55mmol/l normally, decreases with stimulation by secretin
8. glucagons, in decreased quantity following administration of somatostatin
9. insulin in increased quantity following cholinergic stimulation
In the absence of pancreatic enzymes, the faeces contain more fat MAINLY because there is little enteric lipase in the epithelial
cells of the small intestine
Serum amylase may be elevated during

1. acute renal insufficiency
2. administration of morphine
3. acute perforation of a duodenal ulcer
4. mumps

THE GASTROINTESTINAL FUNCTIONS
SALIVARY GLANDS & SALIVA

1. 1500ml secreted daily, pH normally 7.0, but during active secretion, can go up to 8.0
2. Saliva contains
• Lingual lipase
• Salivary A-amylase
• Mucins ! glycoprotein that lubricate food, bind to bacteria & protect oral mucosa
• IgA
• Lysozyme ! attack bacteria walls
• Lactoferrin ! binds iron & is bacteriostatic
• Proline-rich proteins ! protect tooth enamel & bind toxic tannins
3. Saliva has a number of important functions
• Helps swallowing
• Keeps mouth moist
• Serves as a solvent for molecules that stimulate taste buds
• Helps speech by lubricating tongue
• Keeps mouth & teeth clean
• Antibacterial action
4. patient with deficient salivation ! xerostomia ! higher dental caries
5. 3 types of salivary glands ! parotid, submandibular & sublingual
• parotid ! serous cells ! secrete ptyalin ! watery secretions ! 20% contribution to daily saliva
• sublingual ! mucous cells ! secrete mucin ! viscous ! 5% contribution
• submandibular ! mixed serous & mucous cells ! moderately viscous secretions ! 70% contribution
• remaining 5% is contributed by lingual & other minor glands in the oral cavity
Control of salivary secretions

1. under neural control
2. (+) parasympathetic ! profuse secretion of watery saliva, little organic material
3. atropine & other cholinergic blocking agents reduce salivary secretion
4. (+) sympathetics ! vasoconstriction + small amounts of saliva rich in organic constituents from submandibular glands
5. what produce secretion of saliva?
• Food in the mouth ! reflex secretion
• Parasympathetics ! vagal stimulation
• Vagal afferent stimulation at the gastric end of eosophagus
LOWER OESOPHAGEAL SPHINCTER

1. LES is tonically active, but relaxes on swallowing ! this prevents reflux ! under neural control
2. made up of 3 components
• the smooth muscle of LES ! intrinsic sphincter ! (+) by Ach from vagus
• crural parts of the diaphragm ! extrinsic sphincter ! controlled by phrenic nerve of diaphragm, hence respiration
• oblique or sling fibres of the stomach wall
3. the oesophagus is normally closed at both ends
4. the LES exhibits tonic muscular activity unlike the body of the esophagus ! but not 5mmHg above gastric pressure in resting
state
In Achalasia
1. due to increased resting LES tone & incomplete relaxation on swallowing ! thus food accumulates in esophagus ! therefore
esophagus dilates
2. myenteric plexus of esophagus is deficient at the LES ! release of NO & VIP is defective
3. treated y pneumatic dilation of sphincter or incision of esophageal muscle (myotomy)
4. (-) of Ach by injecting botox into LES is also effective ! relief last several months

STOMACH PROPERTIES
Physiological properties of the stomach include
1. receptive relaxation ! when bolus is coming from oesophagus, myenteric inhibitory nerve (+) ! stomach relaxes
2. control of the rate of access of food to the small intestine
3. secretion of a lipase, amylase, gelatinase
4. secrete intrinsic factor which are essential for VitB12 absorption and thus erythrocyte formation
The body of stomach contain several cell types

1. parietal (oxyntic) cells ! secrete HCL & intrinsic factor ! lie closer to gland opening
2. chief (zymogen, peptic) cells ! secrete pepsinogens ! lie deep within gland
3. ECL cells (enterochromaffin-like cells) ! secrete histamine
4. Goblet cells ! secrete mucus
5. surface epithelial cells ! produce HCO3 rich secretions
Key notes
1. removal of the part of the stomach nearest the pylorus (i.e. antrum) would be expected to reduce gastric acid secretion
2. the antrum, however, does not secrete most of the HCL. The body & fundus do this
3. vagal stimulation increases the secretion of acid & pepsin
4. resection of large segments of small intestine is a/w hypersecretion of acid
5. vagotomy only affect the cephalic phase of secretion
• it diminishes (but does not abolish) acid secretion
• it diminishes (but does not abolish) gastric motiliy
6. gastric drainage procedures are required if total truncal vagotomy is performed ! but not with high selective vagotomy
7. acid in the antrum inhibits gastric secretion by a feedback mechanism involving somatostatin
8. after the operation of high gastro-jejunostomy (gastric bypass) for obesity, the level of plasma gastrin may rise following a
meal
9. respiratory quotient of the stomach during secretion of gastric juice is <1 BECAUSE the stomach takes up more CO2 from
arterial blood than it puts into the venous blood
GASTRIC SECRETIONS
1. cells of gastric glands secrete ~2500ml of gastric juice daily
2. this juice contains
• cations ! Na, K, Mg, H+ (pH ~1.0)
• anions ! Cl-, HPO4, SO4
• pepsins, lipases, mucus, intrinsic factor
3. HCL secreted does several things
• Kills many ingested bacteria
• Provide necessary pH for pepsin to start protein digestion
• Stimulates flow of bile
4. secreted mucus forms a viscid layer ! traps HCO3 ions, and protect underlying epithelial cells from lysing " mucus
secretion is stimulated by prostaglandins
5. Pepsin ! works best at pH2-3, formed from pepsinogens ! they initiate breakdown of proteins to aa
6. gastric lipase ! fat digestion
7. intrinsic factor ! essential for VitB12 absorption in terminal ileum
• normal daily secretion can bind 10-50times the amount of B12 needed for the day
• secretion is depressed in gastric atrophy ! if untreated ! can lead to pernicious anaemia
8. the secretion of acid from the stomach is reduced when chyme enters the duodenum
Concerning HCL secretion

1. via H-K exchange
2. when parietal cells is stimulated ! inserts H-K exchange into luminal surface ! detects K in lumen, start exchanging
3. HCL secretion is stimulated by
• Histamine, acting on H2 receptors ! (+) adenylyl cyclase ! increase intracellular cAMP ! (+) protein kinase
• Ach, acting via M3 muscarinic receptors ! increase intracellular Ca ! (+) protein kinase ! insertion of H-K to luminal
surface
• Gastrin ! directly on cell surface or via ECL cells to secrete histamine
Regulation of gastric secretion

1. hormone & nerves control gastric secretion
• nerves control are via ! local autonomic reflexes & vagus nerve
• hormonal control via ! histamine, gastrin, prostaglandin
2. vagal stimulation ! release 2 things ! GRP and Ach
• GRP (gastrin releasing peptide) ! increases gastrin secretion
• Ach ! increase acid & pepsin secretion
3. note that vagotomy does not abolish the secretory response to local stimuli
4. resection of large segments of small intestine is a/w hypersecretion of acid
5. stimulation of gastric secretion is divided into 3 phases
• cephalic influences ! vagally mediated
• gastric influences ! local reflex response and responds to gastrin
• intestinal influences ! reflex & hormonal feedback effects on gastric secretion, initiated from mucosa of small intestine
Thus vagotomy DOES NOT

1. abolish acid production
2. abolish gastric motility
Regarding the anatomy of the vagus nerve

1. the main terminal branch of the anterior vagus nerve crosses the stomach distal to the incisura angularis ~5-6 cm from the
pylorus
2. some vagal fibres traveling to the parietal cell mass may sink into the muscular wall at the oesophagus some distance above
the cardia
A decrease in gastric antral pH to 2.0

1. inhibits the release gastrin release
2. occurs due to the synergistric action of histamine, gastrin & Ach
3. reflexly inhibits gastric secretion
PYLORIC STENOSIS
1. this occurs when gastric outlet is ‘obstructed’ ! by a benign duodenal or prepyloric ulcer or by a stomach cancer
2. loss of gastric acid from prolonged vomiting can cause extracellular metabolic alkalosis ! esp when there’s hypersecretion of
acid
3. serum bicarbonate rises & serum chloride falls, with a rise in blood pH
4. renal response or urinary bicarbonate excretion is initially a/w an alkaline urine containing Na, K, & HCO3
5. subsequently the urine can become acid (‘paradoxical aciduria’) after prolonged vomiting & continuing combined GIT &
urinary losses of water & electrolytes ! a/w gross deficiencies in water, Na, Cl, & K with low serum K
6. correction requires iv isotonic saline with added K
In summary, prolonged vomiting from severe pyloric stenosis may be a/w

1. Hypokalemia from loss of K into the gastric juice
2. hypokalemia from increased renal loss of K
3. low serum K
4. metabolic alkalosis ! from a rise in plasma HCO3 concentration
5. low pH of the urine

SMALL INTESTINE
1. 9L a day, 2L from dietary sources, 7L from GIT secretions, only 1-2 L go to the colon, 100-200ml in stools
• K is absorbed by small intestine & secreted by large intestine
• active absorption of Na from the colon is accompanied by water absorption
• the absorptive surface of the small intestine is increased 600 fold by the valvulae conniventes, villi & microvilli
2. mucosal cells are formed from undifferentiated cells in the crypts of Lieberkuhn
3. the frequency of slow waves decreases from the jejunum to the ileum
4. the most significant single factor that increases the luminal surface area is the presence of the MICROVILLI
5. peristalsis is NOT the only type of movement demonstrated
6. diarrhea can cause significant loss of electrolyte, including K ! hypokalemia
7. the intestinal mucosa below the duodenum produces
• mucus
• secretin
• CCK
• Isotonic intestinal secretion
8. substances maximally absorbed in the upper part of small intestine include
• iron
• calcium
• NOT bile salts and NOT vit B12 ! these are at the terminal ileum ! maximally absorbed
MALABSOPRTION SYNDROME
1. normally small intestine resection is ok ! intestinal adaptation
2. when resection >50% of small intestine ! malabsorption syndrome
3. small intestine resection ! (+) increased gastric acid secretion
4. resection of ileum prevents absorption of bile acids
• leading to deficient of fat absorption ! malabsorption of fat soluble vitamins ADEK
• malabsorption of vit B12
• steatorrhea follows resection of terminal ileum BECAUSE 95% of the bile salts are absorbed there and recycled via the
enterohepatic circulation
5. distal small bowel resection (e.g. ileum) causes greater degree of malabsorption
6. Common complications of resecting small bowel
• Lowered serum calcium
• Hyperuricemia ! increased likelihood of renal stone
• Hypergastinaemia
• Lowered serum protein
• Intractable diarrhoea
• Arthritis
• Fatty infiltration of the liver, followed by cirrhosis
Patients who undergo massive resection of the proximal small bowel are likely to develop peptic ulcer disease
BECAUSE in such patients
1. there is hypersecretion of gastric acid
2. there is decreased secretion of secretin & GIP
COLON
Features of colonic function include
1. constancy of faecal content despite variation in diet
2. active transport of Na out of the colonic mucosa ! water follows
3. sterile contents at birth
4. secretion of K & HCO3 into lumen
5. absorption is so good that rectal drug administration is ideal
Blind loop syndrome

1. surgeon’s fault; creating a loop of small bowel that end blindly, like a diverticula
2. hence stasis of contents
3. hence bacterial overgrowth ! malabsorption, thus leading to
• macrocytic anaemia ! malabsorption of vit B12
• stearrhoea ! from excessive hydrolysis of conjugated bile salts by bacteria ! the word is HYDROLYSIS not oxidation
• metabolic derangements
A narrowed segment of the distal third of colon is more likely to produce symptoms than a narrow in proximal third
BECAUSE
Faecaes are more fluid in the proximal third of the colon than they are in the distal third
Key notes
1. ~1-2L of isotonic chyme enter the colon each day from the ileum
2. as it passes through the colon, 90% of water is absorbed by the colon until 200-250ml of semi-solid feces are found at the
distal colon
3. semi solid feces pass more easily through a constriction than solid faeces
4. thus a proximal tumour will not stop fluid & semi-solid colonic contents and will be quiescent

GASTROINTESTINAL HORMONES
KEY PRINCIPLES
Regarding GIT hormones
1. the intestinal mucosa below the duodenum produces the following ! secretin, mucus, CCK, isotonic intestinal secretion
2. common features of the GIT hormone VIP, GIP, secretin & glucagon are ! portions of similar amino acid sequence
3. enteroglucagon or glucagon is part of GIT hormones ! whereas enterokinase is not
GASTRIN
1. produced by G cells in the gastric antrum & first part of duodenum
2. also found in foetal pancreatic Islets, pituitary, hypothalamus, medulla, vagus and sciatic nerve
3. Actions
• (+) both oxyntic & peptic cells to secrete ! gastric acid & pepsin
• Trophic effect on stomach & small & large intestinal mucosa ! gastrin stimulates gastric mucosal growth
• (+) gastric motility
• (+) insulin secretion, however, only after a protein meal and not after a CHO meal
4. things that stimulate/increase gastrin secretion
• distension of the antrum
• peptides & amino acids presenting to the antrum ! esp. tryptophan, phenylalamine
• increased vagal discharge via GRP
• hypercalcemia or adrenaline in the blood
• after a massive small bowel resection
5. things that inhibit gastrin secretin
• acid at the antrum
• somatostatin
• presence of secretin, GIP, VIP, glucagons, or calcitonin
6. important to note that
• gastrin is functionally and structurally related to CCK
• both gastrin & CCK are stimulated by protein meal, and both stimulate glucagons secretion
• circulating gastrin levels are high in ! Zollinger-Ellison syndrome, pernicious anaemia
CCK
1. secreted by I cells in the upper intestine ! duodenum, jejunum and ileum ! mainly small bowel
2. Also found in nerves of distal ileum & colon exerts a trophic effect on the pancreas
3. functionally and structurally related to gastrin
4. CCK secretion by cells of upper small intestine is enhanced by aa & F.A
5. Actions
• It wants to secrete bile ! thus it (+) hepatic flow of bile, relaxes sphincter of oddi, and (+) GB contraction
• (+) pancreas to secrete enzyme rich juice
• Augments secretin in producing alkaline pancreatic secretion
• Stimulates glucagon secretion
• Inhibits gastric emptying and enhances intestinal motility
• Trophic effect on the pancreas
• Increase secretion of enterokinase

SECRETIN
1. secreted by S cells deep in glands of upper small intestine, in the mucosa of the duodenum
2. is structurally similar to glucagons, GLI, VIP & GIP
3. Action
• ↑ secretion of HCO3- by pancreas & biliary tract duct cells producing alkaline watery secretion
• Augments CCK in producing enzyme rich secretion
• ↓ gastric acid secretion
• may cause contraction of the pyloric sphincter
• inhibits gastric motility
• is a powerful stimulant of pancreatic enzyme
4. released by
• acid in the duodenum
• aa in upper small intestine
SOMATOSTATIN
1. is secreted from D cells of pancreas
2. somatostatin 14 & 28 ! found in various parts of brain as neurotransmitter
3. release is stimulated by
• glucose
• amino acids, esp. arginine & leucine
• CCK
4. Actions
• inhibits gastrin release into blood stream
• inhibits parietal cell function
• inhibits release of insulin, glucagons, CCK & pancreatic polypeptide
5. Somatostatinomas develop ! hyperglycemia, gastroparesis & gallstones
6. in the control of gastric acid secretion, the main action of somatostatin is to stimulate the secretion of bicarbonate
GIP
1. produced by K cells of duodenum & jejunum
2. release is stimulated by glucose & fat in duodenum
3. actions
• inhibits gastric secretion & motility ! in large doses
• gastric inhibitory peptide (GIP) increases the sensitivity of insulin response to raised blood glucose
Patients who undergo massive resection of the proximal small bowel are likely to develop peptic ulcer
BECAUSE
In such patients, there is decreased secretion of secretin and gastric inhibitory polypeptide (GIP)
VIP
1. found in nerves of GIT, also found in brain & many autonomic nerves
2. release is stimulated by fat
3. Action
• Markedly (+) intestinal secretion of electrolytes & hence of water
• Relaxation of intestinal smooth muscle, including sphincters
• Dilation of peripheral blood vessels
• Inhibition of gastric acid secretion
• Potentiates action of Ach in salivary glands
4. VIPomas cause severe diarrhoea
ENTEROGLUCAGON
1. produced by L cells in distal ileum & colon
2. similar structure to glucagons, but quite different effect
3. release is stimulated by presence of glucose & fat in ileum
4. actions
• inhibits gastric & intestinal motility
• has trophic effect on intestinal crypt cells

ABSORPTION & DIGESTION
KEY PRINCIPLES
1. absorption depends on S.A and time ! that’s why motility is important for normal absorption
2. things are easily absorbed (permeable) if they are
• more lipid soluble
• smaller
• have their own ‘protein-carrier’ channels ! facilitated diffusion, active transport, etc…
3. little absorption is happening in the mouth
4. little absorption in stomach, except for alcohol, aspirin
5. most of absorption occur in the small intestine ! Na, K, CL, HCO3, water, etc…
CARBOHYDRATE ABSORPTION
1. digested & then absorbed almost entirely as monosaccharides (i.e. glucose, galactose & fructose)
2. disaccharides are broken down into mono by disaccharidases in brush border of epithelial cells
3. monosacs are largely absorbed in the duodenum & upper jejunum
4. Rate of glucose absorption is largely dependent on luminal [Na] ! via SLGT
• Na then go to lateral intercellular space ! interstitial fluid
• Glucose transported out of cell into blood via GLUT2
5. fructose absorption is not dependent on Na ! occurs by facilitated diffusion via GLUT5, and out of cell into interstitium by
GLUT2
6. Insulin has little effect on intestinal transport of sugars
7. maximal rate of glucose absorption form intestine is about 120g/h
8. absorption of glucose in gut and kidney is similar
• neither require phosphorylation
• both are essentially normal in diabetes
• both are depressed by drug phlorhizin
PROTEIN ABSORPTION
Protein absorption
1. protein gets broken down into peptides or amino acids
• ~50% from ingested food
• 25% from gut secretions
• 25% from desquamated epithelial cells
2. digestion
• gastric & pancreatic enzymes cut these down to short-chain peptides
• at brush border ! they are further broken down into free amino acids
• so the final digestion to amino acids occur in 3 places
• intestinal lumen,
• brush border
• cytoplasma of the mucosal cells
3. absorption
• absorption normally occurs in the duodenum & jejunum
• 7 transport systems ! 5 require Na co-transport, 2 with Cl transport
• amino acid absorption is enhanced by luminal Na ! due to co-transport
4. once absorbed ! they leave enterocytes along basolateral borders ! enter hepatic portal blood
Ingestion of protein foods such as eggs can sometimes provoke antibody formation in infants
BECAUSE
In infants, there is absorption of whole protein from the alimentary canal
although protein has a theoretically higher caloric content than carbohydrate, in the body similar values are obtained from protein
and carb
BECAUSE
The oxidation of protein is incomplete
Regarding digestion and absorption of amino acids from the intestine ! less than 5% of protein in the small intestine escapes
digestion and absorption
with regard to the parenteral administration of protein ! the protein requirement is about 1.2 to 1.5g/kg/day
1. consider reducing this dose when there is a rise in blood urea level that exceeds 100mg/dL or a rising blood ammonia level
that is a/w with clinical encephalopathy
2. a nutritional requirement for nucleic acids has not been established, but they are being investigated as beneficial nutrients for
proliferation of intestinal crypts cells, lymphocyte proliferation, and cellular DNA and RNA synthesis
3. glycine is the simplest of the amino acid, i.e. a convenient source of nitrogen
4. incidentally, as opposed to chronic renal failure, there is no need to alter the amount of protein administered to patients with
acute renal insufficiency
5. there is also no demonstrable advantage to be gained by administering just essential amino acids
6. haemodialysis and haemofiltration remove amino acids in the range of 3 to 5g/hr
7. these losses need consideration when adjusting the amount of protein to be administered
Albumin ! serum concentration <30g/l strongly correlate with a poor clinical outcome
Half life 28 days
FAT ABSORPTION
Fat absorption
1. we eat ~150g of fat a day, 5g go into feces, the rest we absorb ! thus we absorb >95% of the fat we eat
2. dietary fat comes in many forms ! triglycerides, phospholipids, cholesterol & plant sterols
3. infants may not have a well developed system to absorb fat, so they may only absorb < 90% of what they eat
4. we need fat because? ! cell membrane, hormone production, energy storage, etc…
In the digestion phase ! when we eat

1. 2 preliminary lipases act first ! ‘foreplay’ of fat digestion
• lingual lipase (from Ebner’s glands on dorsal surface of tongue) ! digest ~ 30% of dietary triglyceride in the stomach
• gastric lipase ! of little significance, unless in cases of pancreatic insufficiency
• these 2 liberate mainly medium & short chains FAs, i.e. they can only cut small pieces out, not large chunks
• these liberated medium & short chains FAs become emulsified in the stomach
2. In the duodenum,
• More fat are broken down ! by the real shit ! pancreatic lipase, with the help of colipase and bile acids
• Pancreatic lipase produces fatty acids & monoglycerides from dietary triglycerides
• emulsification is refined by bile salts and lecithin ! making even smaller droplets for easy absorption ! micelles
• bile salts combine with fatty acids & monoglycerides to form micelles
• a certain amount of bile salts needs to be present to form micelles
In the absorption phase,

1. fat absorption is the greatest in the upper intestine
2. micelles get close to luminal membrane ! then FFAs & monoglycerides leave the micelles and diffuse across
3. micelles DOES NOT get actively absorbed across the lumen
4. in the mucosal cell
• short & medium chain FA (i.e. <10-12 carbons) ! gets packaged into chylomicron ! send directly into portal blood
• large chain FA (>12carbons) ! get further broken down inside ! then repackaged and sent
• absorption of most long chain FA is mainly in upper small intestine, but some do get absorbed in ileum
• the larger FA chain are NOT absorbed directly into the portal blood
5. inside the cell ! Chylomicrons are formed (in Golgi apparatus), each containing
• 87% triglycerides, 9% phospholipids, 3% cholesterol esters, 1% apoproteins
• fat soluble vitamins & free cholesterol
6. chylomicrons then enter lymphatic channels ! thoracic duct ! systemic circulation, thus bypassing the liver
7. between 80-90% of all fat absorbed from gut is transported to the blood via the thoracic duct as chylomicrons
8. in the blood, it visits places that has binding sites for it, mainly ! adipose tissue & muscle
9. once it get near these places, the Apoprotein CII within it activates the enzyme lipoprotein lipase ! FFAs & monoglycerides
are released ! and so enter the adipose & muscle cells
10. the remaining chylomicron return to liver cells ! thus dietary triglycerides are delivered to peripheral tissues, whereas
cholesterol is delivered to the liver
A few examinable points

1. pancreatic lipases are important for fat breakdown and hence absorption ! without pancreatic lipase ! we get steatorrhoea
2. Bile is also important for fat absorption ! without bile, 50% of ingested fat will NOT be absorbed
3. chylomicrons are droplets of fat combined with apoproteins ! BUT are formed inside mucosal cells ! and aid transport in
lymph
4. Fat in duodenum delays stomach emptying BECAUSE Fat in duodenum releases CCK, secretin & gastric inhibitory peptide
(GIP)
5. Plasma cholesterol levels are decreased by ! thyroxine & oestrogens
6. Endogenously derived triglyceride circulating the plasma is
• transported primarily as very low density lipoprotein (VLDL)
• increased by carbohydrate excess in the diet
• removed from the circulation by both muscle & adipose tissue
Na ABSORPTION
Concerning Na absorption
1. 60mmol/l in duodenum, 140 jejunum, 140 ileum, 40 colon ! 90% absorbed in small intestine, 10% in colon
2. absorption is via secondary active transport ! Na/glucose, Na/amino acid cotransport and via Na/H exchange
3. thus Na absorption here is enhanced by glucose & amino acids ! that’s why in severe diarrhea & vomiting ! drink sugar
water to help Na absorption
4. primary transport from cell to interstitial fluid
IRON ABSORPTION
Concerning Iron absorption
1. we have a large storage, and we can’t control how much iron we lose
• men lose about 0.6mg/d of iron, mostly in stools
• women lose twice as much 1.2mg/d ! due to menstruation
2. the only thing we can control is how much iron we absorb
3. average daily intake ~20mg ! the amount absorbed depends on how much is loss ! so any where from 3 – 6% of iron
ingested
4. factors that increase iron absorption
• low iron stores in the body
• increased erythropoiesis in BM
• ascorbic acid ! chelates the iron
• low pH of stomach ! changes FE3+ to FE2+
5. things that inhibit iron absorption include
• phytic acid in cereals
• high pH ! i.e. pH of pancreatic juice
• phosphates
• oxalates
6. most iron in diet is Fe3+ (ferric form), whereas it is the ferrous FE2+ form that is absorbed
In the stomach
1. very little iron is absorbed here, but the gastric secretions help dissolve the iron ! low pH facilitates iron absorption
2. this allows ascorbic acid to chelate to iron, thus helping absorption
3. so it’s not surprising, that patients with partial gastrectomy are often iron deficiency anaemic
4. but acid is NOT a requirement for iron absorption within the stomach
5. anaemia may be a consequence of peptic ulcer surgery BECAUSE there are less gastric secretions to convert dietary FE3+ to
its more easily absorbable form FE2+ after peptic ulcer surgery
In the duodenum
1. almost all iron are absorbed here
2. FE2+ are absorbed into enterocytes via DMT1
• Some is stored in ferritin ! FE3+-ferritin in the cells here
• Some get transported out of enterocytes by basolateral transporter ! ferroportin 1
In the blood
1. here FE2+ ! FE3+ and bound to iron transport protein transferrin ! FE3+-transferrin
2. Thus transferrin is essential for iron absorption to happen properly
3. transferrin has 2 iron-binding sites ! normally it is ~35% saturated with iron
• in men, plasma iron ~130ug/dL (23umol/L)
• in women, plasma iron ~110ug/dL (19umol/L) in women
In the body
1. 70% of iron is in Hb
2. 3% in myoglobin
3. the rest as ferritin ! in enterocytes, and many other cells
To recap
1. large iron storage, no control over how much iron we lose, but main control is degree absorption ! ~3-6% of 20mg average
intake
2. very little is absorbed in stomach, almost ALL are absorbed in duodenum
3. 4 factors facilitate absorptions; 4 factors inhibit it
4. IDA is a complication of gastrectomy
5. iron absorption requires the presence of transferrin
6. iron found in body ! 70% in Hb, 3% Mb, the rest ! ferritin in enterocytes and many other cells
7. too much iron ! haemochromatosis; too little ! IDA
VITAMIN B12 ABSORPTION

absorption of vitB12 requires
1. intrinsic factor binding with vitB12 in the small intestine
2. trypsin which facilitates efficient absorption
3. NOT high oral intake of vit B12, not pepsin
Pernicious anaemia is typically a/w

1. a reduced packed cell volume
2. megaloblastic marrow
3. gastric atrophy
4. thrombocytopenia
Resection of the last meter of small bowel leaving the ileo caecal valve intact DOES NOT result in macrocytic anaemia developing
within 3 months ! why?
The last meter of ileum is the major site of vit B12 absorption
Scurvy is a/w blood vessel fragility

BECAUSE
Ascorbic acid is an essential co-factor for the synthesis of collagen

FIBRES
With regard to the inclusion of fibre in solutions of enteral nutrients ! Butyrate, an endogenous product of fibre fermentation, is
an important fuel for colonocytes
Endogenous products of fibre fermentation are important for colonocyte integrity and function
However the provision of fibre has not been clearly demonstrated t be of any clinical advantage
GLUTAMINE
Glutamine
1. it is the main fuel consumed by rapidly dividing cells, e.g. gut mucosa, immunocytes, and some tumours
2. is not included in standard solutions of parenteral nutrients because it is unstable in solution and breaks down to form toxic
amounts of pyroglutamate and ammonia
3. remains to be determined whether administereing glutamine to catabolic patients results in improved outcome
4. the kidney consumes glutamine during periods of metabolic acidosis
ARGININE
With regard to arginine
1. it is a unique substrate for the production of nitric oxide
2. synthesized endogenously in the kidney from gut derived citrulline ! small intestine converts dietary amino acids, including
glutamine, to citruline
3. arginine participlates in a variety of metabolic function ! urea synthesis, lymphocytes proliferation, and wound healing
4. in addition, it is a unique substrates for production of nitric oxide ! this is present in many tissues and cells including
endothelium and inflammatory cells
5. role of arginine in critically ill patients remain to be defined but doses of up to 30g/day have been used in evaluate studies
6. combinations of nutrients with immune function activity ! arginine, fish oil, and nucleic acids ! are being evaluated as
enteral nutrients in crticially ill patients
7. although sometimes they are referred to as ‘immunonutrients’ ! their clinical efficacy has yet to be confirmed
OTHERS
with regard to trace elements
1. iron deficiency may cause anaemia
2. cobalt deficiency may cause megaloblastic anaemia
3. iodine deficiency may cause goiter formation
4. chromium deficieny may cause insulin resistance
artic explorers developed headache, diarrhea and dizziness eating polar bear liver
BECAUSE
Liver is a rich source of vitamen A
diarrhea during enteral tube feeding may be due to

1. excess volume of feed
2. hyperosmolarity of feed
3. malabsorption
4. short bowel syndrome
with regard to the parenteral administration of CHO ! patients require 25kcal/kg/day

1. giving 25kcal/kg usual body weight/day appears to be adequate for most patients
2. from 30-70% of the total calories administered per day, can be given as glucose
3. the dose should be adjusted to maintain a blood glucose level <225mg/dL
4. it may be desirable to administer insulin in patients with higher levels of glucose in the blood
5. the calorie to nitrogen ratio should be 150kcal per gram of nitrogen (about 6.25gm of protein contains 1gm of nitrogen)
sources of CHO which may be used in parenteral nutrition solutions include

1. glycerol
2. sorbitol
not maltodextrins, not starch

RENAL FUNCTIONS
KEY PRINCIPLES
With respect to the kidney in general
1. K+ is largely reabsorbed in the proximal tubules ! 65%
2. K+ is secreted by the distal tubules & collecting ducts ! in response to negative charge resulting from Na resorption in these
places
3. Urea is passively reabsorbed from the tubules
4. glucose is removed from the glomerular filtrate by active transport in the proximal tubule ! 100%
5. protein concentration of blood in efferent arterioles is higher than afferent arteriole ! due to loss of fluid to tubule in between
6. mean hydrostatic pressure in the peritubular capillaries is lower than that in glomerular capillaries
7. in the proximal tubule, water moves passively out of the tubule along an osmotic gradient
8. in the presence of hypokalemia & metabolic alkalosis the renal response is to retain K+ in preference to H+
9. in presence of hyponatremia, aldosterone is released ! kidney retains Na in exchange for K+ secretion in collecting duct !
hypokalemia
Renal changes a/w severe haemorrhage include

1. afferent & efferent arteriole constriction
2. increased filtration fraction
3. enhanced Na retention by the renal tubules
RENIN
1. an enzyme, ½ life 80 minutes
2. the only known function is to convert ANG ! ANG1; it doesn’t do anything else
3. produced in 2 places in the nephron
• JG cells in the media of afferent arterioles
• Lacis cells (located b/n afferent & efferent)
4. Renin secretion is controlled by
• Intrarenal baroreceptors ! macula densa ! sensitive to Na & Cl-
• Prostaglandins
• Na content of the proximal & distal tubular fluid
5. Note that GFR has NO effect on renin secretion
6. Renin secretion is (+) by ! anything that
• Decrease ECF ! dehydration, haemorrhage, diuretics, Na+ depletion
• Decrease BP ! hypotension, upright posture, cardiac failure, constriction of renal artery or aorta, cirrhosis
• Increase sympathetic output (via renal nerves) ! catecholamines
• prostaglandins
7. Factors that (-) renin secretion
• Increased Na & Cl reabsorption across macula densa
• Increased afferent arteriolar pressure
• Angiotensin II (via feedback)
• vasopressin
ANGIOTENSIN II
1. derived from ANGI, by ACE, located in endothelial cells in lungs & circulation
2. it has renal & extra renal effects (see diagram)
Extra renal effect Renal effect
1. potent vasoconstrictor, 4 to 8x more potent than NA ! 1. (+) renal tubules directly ! increase Na reabsorption
increases both DBP & DBP 2. (+) arteriolar constriction in both afferent & efferent

2. (+) adrenal cortex ! increase aldosterone secretion ! decrease GFR that filtered & more time for Na
3. (+) brain to decrease sensitivity of baroreflex ! reabsorption
potentiates pressor effects of Ang II 3. (+) constriction mesangial cells ! decrease GFR
4. (+) circumventricular organ outside BBB
• area postrema ! potentiate pressor ! (+) ADH release
• subfornical organ (SFO) & organum vasculosum ! (+)
thirst ! increase water intake
5. facilitates release of NA from sympathetic neurons
3. In summary, regarding effects of Ang II

• It facilitates release of NA from sympathetic neurons
• Has the same aldosterone stimulating activity as Ang III (although AngIII has about 40% pressor activity)
• Acts in the CNS to stimulate release of vasopressin
• DOES NOT cross the blood brain barrier
• Produces arteriolar constriction (potent vasoconstrictor) ! causing both rise in DBP & SBP
• Increases water intake by acting on the subfornical organ
• Increases both ADH & ACTH
ALDOSTERONE
Aldosterone
1. produced in Zona glomerulosa of adrenal cortex; inactivated in the liver
2. it acts on
• P cells in distal tubule & collecting duct to increase Na reabsorption, in exchange for K+ & H+
• epithelium of salivary duct, sweat glands, small intestine, large intestine, rectum ! to reabsorb Na
3. its main role is to retain Na ! takes ~1hr to work, & 24hrs to have full effect ! therefore more of a long term control than
acute
4. it promotes Na retention by
• increasing luminal Na channels ! allow Na to enter cell from lumen
• increasing synthesis & insertion of Na-K ATPase in basolateral membrane ! again, Na into cell in exchange for K
• making more energy available to cells
5. its release is stimulated by
• ANG II mainly
• ACTH has a small effect on its release
• K+ also has a small effect ! plasma K+ need only increase 1mmol/l or less to stimulate aldosterone
6. factors that increase aldosterone secretion
• alone ! high K+ intake, low Na intake, constriction of IVC in the thorax, standing, secondary hyperaldosteronism
• also stimulate glucocorticoids release ! surgery, anxiety, physical trauma, bleeding
DIURETICS
Duretics
agent MOA
Water Inhibits vasopressin secretion
ethanol Inhibits vasopressin secretion
Mannitol/glucose Produce osmotic diuresis
Xanthines, e.g. caffeine & Decrease tubular reabsorption of Na & increase GFR
theophylline
Loop diuretics Inhibit Na-K-2CL cotransporter in thick ascending loop of Henle
• Frusemide
• Ethacrynic acid (Edecrin)
• Bumetanide
Thiazides Inhibit Na-Cl co-transporter in distal tubule
Diuresis is less marked
K sparing diuretics, e.g. Inhibit Na-K exchange in the collecting duct

spironolactone (aldactone) By inhibiting the action of aldosterone or blocking ENaCs (amiloride)
Carbonic anhydrase inhibitors, e.g. Decrease H+ secretion with resultant increase in Na & K excretion
acetazolamide (Diamox) Inhibit HCO3 reabsorption in the tubules
Note that both loop diuretics & Thiazides cause increased delivery of Na to the Na-K exchange area in the collecting duct !
increase K+ excretion ! thus overtime, leading to K+ depletion and hypokalemia
In summary, diuretics
1. inhibit water & solute reabsorption of tubular fluid
2. inhibit Na-K-CL co-transport in the luminal membrane of the loop of Henle
3. inhibit H+ secretion & HCO3 reabsorption in the tubules
Beer in moderate quantity causes diuretics because the

1. alcohol in beer inhibits ADH release
2. water in beer inhibits ADH release
RENAL BLOOD FLOW

1. note that both ends of a glomerular capillaries ! are arterioles
2. so both afferent & efferent can be controlled very precisely ! therefore we can control the driving force for GFR very
accurately
3. some important distinction
• RBF is how much blood goes into the renal arteries from the aorta ! affected of course by BP
• GFR refers to how much is filtered into the tubules ! this depends on several factors other than BP
4. arterial pressure b/n 80-180 have little effect on RBF ! due to autoregulation
5. control of blood flow is independent of extrinsic nerve supply or hormones
6. control of blood flow is largely a result of afferent arteriolar resistance increasing as BP increases ! myogenic response
7. RBF is 92.5% in cortex, 6.5% in outer medulla & 1% in inner medulla
A rise in the rate of RBF results in increased GFR of fluid from plasma
BECAUSE
The rise in colloid osmotic pressure within the plasma of the more distal glomerular capillaries becomes less with increased plasma
flow
Note that
1. glomerular filtration causes a rise in protein concentration and hence colloid osmotic pressure, in the distal glomerular
capillaries
2. this increased colloid osmotic pressure opposes filtration
3. renal blood flow increases glomerular filtration because of the increase in glomerular pressure
4. because a small percentage of plasma is filtered, the rise in distal capillary osmotic pressure is lessened and glomerular
filtration increases overall
An increase in RBF causes an increase in oxygen consumption per gram of renal tissue
BECAUSE
An increase in RBF increases the volume of filtrate to be reabsorbed
Sympathetic nerves to renal vessels causes

1. arteriolar vasoconstriction
2. (+) renin release ! increase circulating ANGII ! further intensifies vasoconstriction
Renal blood flow (RBF) falls in

1. hypovolemia, erect posture, pain, cold or emotion
2. exercise ! via sympathetic (+)
3. stimulation of A1 adrenergic receptors
4. stimulation of the vasomotor area in the medulla oblongata
severe decrease in RBF from shock may precipitate ARF
chronic pathological processes that destroy nephrons decrease RBF
GFR
GFR varies
1. with efferent arteriolar constriction ! more will be filtered due to back log
2. agents affecting the mesangial cells ! more will be allowed through
3. with the permeability of the glomerular capillaries
4. with changes in extracellular volume
5. with erect posture, emotion, pain, cold, exercise and loss of blood ! cos all affect RBF
Factors that affect GFR

1. changes in renal blood flow
2. changes in glomerular capillary hydrostatic pressure ! changes in SBP, afferent or efferent arteriolar constriction
3. changes in hydrostatic pressure in Bowman’s capsule ! ureteric obstruction, edema of kidney inside tight renal capsule
4. changes in concentration of plasma protein ! dehydration, hypoproteinemia
5. changes in glomerular ultrafiltration coefficient ! glomerular capillary permeability, effective filtration S.A
Note that the basement membrane has 2 important properties

1. pores of 8nm
2. negatively charged proteins lining the membrane
Thus ! anything that is larger than 8nm or is negatively charged ! is not permitted to be filtered.
changes after 4hrs of complete ureteric obstruction include

1. a fall in GFR
2. a fall in glomerular blood flow
this is because the ureters have a rich innervation by autonomic nerves
when ureters becomes obstructed ! a ureterorenal reflex produces constriction of renal arterioles, with a resultant fall in RBF,
glomerular blood flow and GFR.
There is no change in renal tissue fluid volume.
An ideal substance that can be used to measure GFR must be

1. freely filtered at the glomerulus
2. not reabsorbed or secreted
3. not metabolized by the kidney
4. not toxic to kidney
5. easily measured in blood & urine
classically ! inulin is used to measure GFR

clinically ! creatinine is used to measure GFR ! best with 24hr excretion
When GFR is reduced, there is decrease in volume of fluid resented to the countercurrent mechanism ! rate of flow in the loops
declines ! urine become more concentrated
the protein concentration in the glomerular capillaries

1. is 20% higher at the efferent end of the glomerular capillary
2. will alter the filtration fraction
3. results in an average colloid osmotic pressure over 30mmHg in the glomerular capillary
Even though the diameter of albumin is 7nm, minimal amounts are found in the urine
BCAUSE
Albumin is a plasma protein that is negatively charge

DIURESIS
2 types of diuresis (increased rate of urine production)
1. Water diuresis
• Results when too much water is ingested or administered
• ADH secretion is suppressed ! collecting duct become relatively impermeable to water ! excess water lost without
solute
• Begins ~15minutes after ingestion of water load, reaches maximum in ~40minutes
• 2 factors depress ADH secretion
a. main factor ! decrease in plasma osmolality
b. some effect ! act of drinking produces a small decrease in ADH secretion
• Inverse relationship b/n urine osmolarity & urine flow rate
• Maximal urine flow during water diuresis is ~16ml/min ! if water is ingested higher than this ! water intoxication !
cells swell in the brain ! convulses & coma ! death
2. Osmotic diuresis
• Results when more solute is presented to the tubules than they can reabsorbed
• E.g. mannitol and glucose (in uncontrolled DM), or when tubular function is inhibited (e.g. by drugs that block
reabsorption of NaCl in one or more nephron segments)
• Here, urinary flow rate depends on urinary solute content
Important to recognize difference b/n osmotic & water diuresis

1. in water diuresis ! amount of water reabsorbed in proximal tubule is normal, & maximal urine flow that can be produced is
16ml/min
2. in osmotic diuresis, increased urine flow is due to decreased water reabsorption in proximal tubules & loops ! thus very large
urine flows can be produced
Thus, in osmotic diuresis

1. the increased UO is caused by substances which are not reabsorbed in renal tubule system
• mainly mannitol
• glucose or urea in amounts exceeding tubular reabsorptive capacity
2. decrease water reabsorption in proximal tubules is the main cause of diuresis
3. as very large amounts of urine can be produced, significant losses of electrolytes, e.g. Na, carried in the urine can occur
4. urinary pH is not affected by this process
The production of urine with a high osmolarity is a/w

1. an increase in membrane permeability of the distal tubule & collecting duct to water
2. a decrease in medullary blood flow
3. an increase in secretion of aldosterone
4. a decrease in secretion of ADH
factors concerned with the onset of a diuresis in a healthy young man who drinks a litre of water in 5 minutes include
1. rise in circulating blood volume
2. rise in glomerular filtration rate
3. suppression of ADH secretion
UREA
1. good for 2 reasons
• as a waste product, eliminated to maintain nitrogen balance
• as a useful, necessary agent used to concentrate urine, in the medulla
2. synthesized in liver from ammonia ! urea production rate
• is constant, never stops
• slows down in liver disease ! level will be low in liver disease
• depends on diet &liver function (protein catabolism)
• decreases with starvation
• DOES NOT depend on the hydration state
3. normal plasma level 3 to 9mmol/l ! not a good indication of renal function because it varies with
• the rate of production of urea (reflecting protein intake & catabolism)
• renal excretion
4. urea is freely filtered ! it leaves the tubules by SIMPLE DIFFUSION
5. 50% is reabsorbed in PCT, but then 50% secreted back to loop of Henle ! 50% again is reabsorbed back in medullary
collecting duct ! net result is that 50% of filtered load is excreted
6. thus at high GFR, less time is in loop ! not enough time to diffuse back ! more is lost in urine
7. ADH increases the permeability of the medullary collecting ducts to urea, so at low urine flow rates (high levels of circulating
ADH) ! net effect is that only 30% of the filtered load is excreted
Blood urea may rise with

1. hypovolemic shock
2. severe infection
3. steroid therapy
4. not liver failure ! because there will be decreased production otherwise
Blood urea concentration may be influenced by

1. GFR
2. dietary protein intake
3. hepatic function
4. body hydration state (but the production is not)
5. Catabolism (e.g. infection, steroid therapy)
Urea clearance is increased at high rates of urine flow

BECAUSE
Reabsorption of urea across the tubular system of the nephron is largely a passive phenomenon
Rise in blood urea in a previously normal man deprived of water is the consequence of
1. increased diffusion of filtered urea from tubular lumen to medullary interstitium
2. reduced tubular flow rate of urine
EFFECTS OF RENAL NERVE STIMULATION

Effects of renal nerve stimulation
1. (+) renin secretion via a direct action on B1-receptor of granular cells
2. (+) Na reabsorption via a direct action on tubular cells (multiple receptors) ! one side affected is the proximal tubules
3. (+) afferent & efferent arteriolar constriction via A-adrenergic receptors ! as a result
• GFR & RBF both decrease, RBF>GFR
• Decreased GFR & increased proximal Na reabsorption ! decreased delivery of fluid to macula densa, which causes
increased renin secretion in addition of effect 1
CREATINURIA
Creatine & Creatinine
1. Creatine is made in the liver from methionine, glycine, & arginine
2. it then gets phosphorylated (in skeletal muscles) and does 2 things
• forming an important energy store for ATP
• converts into creatinine to be excreted in the urine
1. the rate of creatinine excretion is relatively constant from day to day
2. in fact, creatinine output is sometimes measured as a check on the accuracy of the urine collections in metabolic
studies
3. ATP that are made from oxidative phosphorylation react with creatine ! ADP + large amounts of phosphorylcreatine
4. when we exercise, this reaction is reversed, maintaining the supply of ATP ! which is an immediate source of energy for
muscle contraction ! athletes take creatine supplements because it stores ATP
Creatinuria occurs in
1. normal children
2. women during & after pregnancy
3. condition that are a/w extensive muscle breakdown
• starvation
• thyrotoxicosis
• poorly controlled DM
• various primary & secondary diseases of muscle (myopathies)

PARTS OF A NEPHRON
PROXIMAL CONVOLUTED TUBULE

Things that are reabsorbed here
1. Na
• 60% reabsorbed here via Na/H exchange ! thus most H+ are secreted into lumen here
• also via other co-transporters ! Na/glucose, Na/amino acid, Na/lactate co-transporter
2. K
• 65% of K+ is reabsorbed ! mostly by active reabsorption, some passive
3. Glucose
• most are removed from lumen here by secondary active transport
• via Na/glucose cotransporter ! SGLUT ! glucose then exit cell into plasma via GLUT uniporter
• amount reabsorb is proportionate to amount filtered
• renal threshold ! 300mg/dL ! 10-12mmol/L
4. Chloride ! Cl/base exchange
5. Amino acid
• ~98% of filtered load of aa is reabsorbed here ! by cotransport with Na
• normally ~0.5-2% of filtered load is lost in urine
6. Urea
• 50% is reabsorbed here via simple diffusion
• this is possible because most of the water is reabsorbed by the end of the PCT
• this leaves Urea concentration higher in the lumen ! and so passively diffuse back to plasma
7. Water ! 2/3 of filtered water is reabsorbed via aquaporin 1
8. HCO3 ! ~70-85% is reabsorbed
9. Phosphorus
• 85-90% reabsorbed via active transport
• inhibited by presence of PTH here
The PCT secretes the following

1. H+
• most are secreted here in exchange for reabsorption of Na
• every H+ entering lumen will bind to luminal HCO3 ! H2O + CO2
• for every H+ leaving the cell,1 HCO3 is generated & is returned to plasma across the basolateral membrane
• thus the net results is as though HCO3 is reabsorbed
• thus for every H+ secreted, 1 Na and 1HCO3 enter the interstitial fluid
2. Ammonium ions
• NH4+ or NH3+ are secreted here ! important to counter-balance the H+ secreted
• it is generated in PCT cells, largely from glutamine
Examinable section
1. PCT is highly permeable to water which diffuses passively from the tubule
2. solute concentration is nearly the same on both sides of the tubular membrane
3. low plasma Na leads to reduced vascular fluid volume and this (+) aldosterone secretion ! Resulting in Na resorption and K+
secretion in the collecting ducts
4. thus hyponatremia results in a lowering of plasma potassium concentration
5. & in the presence of hyponatremia & hypokalemia ! the renal response is still to lower further plasma K to save Na
6. the peritubular capillaries are more distal in the vascular tree and hence at lower hydrostatic pressure
7. in the presence of hypokalemia and metabolic alkalosis, the renal response is to retain K in preference to H+

LOOP OF HENLE
Things that are reabsorbed

1. Na
• 30% is reabsorbed in the ascending limb
• via Na-K-2Cl co-uptake (! loop diuretics work here) " thus long term frusemide " hypokalemia
• some absorption via Na-H exchange " so some H+ is secreted here
• Na is then transported out of cell into interstium via Na-K ATPase in basolateral membrane
2. K+
• 27% reabsorbed via K+ channels via co-transporter as above
3. Cl-
• via co-transporter Na-K-2Cl
4. Water
• 10% of water is reabsorbed in the descending limb
• None is reabsorbed in the ascending limb " impermeable to water
5. HCO3
• 10-20% reabsorbed " mostly in the thick ascending segment
Things that are secreted

1. H+
• secreted in exchange for the 30% Na reabsorbed here via " Na-H exchange
2. Urea
• 50% is secreted into loop of Henle for osmotic gradient
3. K+
• some K+ leaks back into tubular lumen via ROMK
The operation of the loop of Henle as a counter current multiplier depends

1. on the active transport of Na & Cl out of the thick ascending limb
2. the high water permeability of its thin descending limb
3. the relative water impermeability of the thin ascending limb
4. the concentration of urea in the interstitial spaces
Note that
1. the loop of henle is active in the final event for increasing the osmolar concentration of urine
2. Na and chloride ions are transported into the inner medullary interstitium
3. similarly, only 27% of filtered potassium is actively reabsorbed in the loop of Henle
4. 65% having previously been actively transported in the proximal tubule
Regarding the loop of henle

1. the ascending limb of the loop actively transport chloride ions out of the tubule lumen
2. is active in the final event for increasing the osmolar concentration of urine
3. Na & Cl are actively transported into the inner medullary interstitium
4. only 27% of filtered K+ is actively reabsorbed in the loop of Henle
Osmolarity of the medullary interstitial fluid would become less hypertonic & eventually approach the osmolarity of plasma when
1. the fluid flow through the Loop of Henle increases sufficiently
2. an osmotic diuresis is pronounced
3. the blood flow though the vasa recta increases sufficiently
DISTAL TUBULE
Na 7% via the Na-Cl symporter (! Thiazide acts here)
some Na reabsorption occur via apical Na channels (ENaCs)
Cl- Via Na-Cl symporter with Na
Water 5% reabsorbed here
Ca Reabsorbed here via Ca channel ! PTH acts here " thus major site for Ca homeostasis
COLLECTING DUCT
Na 1. reabsorption of Na & water a/w principal (P) cells " so called because they make up 70% of the cells
there
2. Na reabsorb via ENaC channels (! aldosterone acts here to cause Na retention)
3. P cells also play a major role in maintaining K+ homeostasis
Cl- Reabsorption of Cl by 2 mechanisms

• Via intercalated cells
• Via paracellular pathways
Water water resorption is via aquaporin 2 (! ADH acts here)
Ca Reabsorbed here via Ca channel ! PTH acts here " thus major site for Ca homeostasis
K+ H-K-ATPase containing I cells, cortical collecting duct " 10% reabsorption

H-K-ATPase containing I cells, medullary collecting duct " 5% reabsorption

SODIUM & POTASSIUM HOMEOSTASIS
SODIUM HOMEOSTASIS
1. important cation of ECF ! 15mmol in cells; 135-145 in ECF
2. intake 50-300mmol/day = losses
3. losses may be through
• sweat – variable, maximum 1-2L, up to 15L/day with Na concentration 30-50mmol/L
• faeces 5-10mmol/day
• urinary loss 1-500mmol/day
4. Kidney filters ~26000mmol/day. All Na reabsorption are active
• Proximal tubule ! 60% reabsorbed ! 17000mmol/day ! via Na-H exchange
• Ascending limb of henle ! 30% reabsorbed ! ~7000mmol/day ! Na-2Cl-K cotransporter
• Distal tubule ! 7% reabsorbed ! ~1200mmol/day ! Na-Cl cotransport
• Collecting duct ! 3% reabsorbed ! ~700mmol/day ! via ENaC channels
5. therefore, total Na excreted ! 100mmol/day ! we replace this in diet
6. how does the body monitor Na?
• in the kidney, via the macula densa ! (+) renin ! aldosterone etc…
• elsewhere ! baroreceptors (aortic & carotid) for volume ! brainstem ! appropriate response
Important relationship b/n osmolarity, ECF volume & Na

1. water always follow Na ! for every 150mmol of Na, there is a litre of water
2. Na’s job is therefore to keep the ECF volume constant
3. If ECF volume decreases, we reabsorb more filtered Na. If ECF volume increases, we reabsorb less filtered Na
4. thirst & ADH will keep the EC osmolarity constant
5. since water is free diffusible, the intracellular osmolarity must be the same of EC osmolarity
6. thus we need to
• keep the EC osmolarity constant to ensure cell volume is constant
• keep the EC Na level constant to ensure EC volume is constant
7. Operating on someone’s pituitary is going to fuck all this up!!!
How do we regulate Na?

Na retention is promoted by
1. reduced GFR ! less filtered load ! thus less is lost in urine
2. aldosterone ! (+) P cells in distal tubule & collecting duct to reabsorb Na
3. ADH ! promotes a reabsorption in the thick ascending limb of the loop & collecting duct
4. Renal nerves
• afferent arteriolar constriction ! decrease GFR ! less Na is loss ‘
• increase proximal Na reabsorption
• increased distal Na reabsorption (via ANG II & aldosterone)
Na is excreted by
1. increasing GFR ! increased amount filtered ! increase loss
2. Prostaglandins (e.g PGE2) ! favor renal excretion of Na & water and oppose the effects of renin-angiotensin system
3. ANP increases excretion of Na by
• Increasing the GFR
• Inhibiting Na reabsorption in proximal tubule & collecting duct
• Reduce secretion of renin & aldosterone
4. kallikrein-kinin system, endothelin, adenosine & dopamine ! all affects renal haemodynamics ! hence Na & water excretion
the ability of the kidneys to conserve urinary chloride depends on

1. the efficiency of Na+ reabsorption in the distal tubules
2. active Cl- reabsorption in the ascending limb of the loop of Henle
3. efficiency of Na+ reabsorption in the proximal tubules

POTASSIUM HOMEOSTASIS
1. intake = 50 to 150mmol/day; losses = 10mmol in faeces, 40-140mmol/day in urine
2. an adult contains ! total ~3500mmol
• ~3100mmol in cells (~2700mmol in muscle cells)
• ~80mmol in ECF
• ~300mmol in bone
3. 150mmol in cells; 3.5-5.0mmol in ECF
4. functions
• maintains optimal environment in cells for cellular enzymes ! important for cell growth (DNA, protein synthesis)
• important in cell volume regulation because it is the dominant inorganic cation balancing charge on cell anions
• plays a role in acid-base balance by exchanging for H+ when ECF pH alters
• in acidosis, H+ enter cells in exchange for K+
• in alkalosis, H+ exit cells in exchange for K+
• resting membrane potential
• hypokalemia ! K+ move out of cell ! hyperpolarizes cell ! no transmission or less easily excited
• hyperkalemia ! K+ stays inside cell ! reduce membrane potential ! easily excited first, then paralysis
5. body always try to maintain a constant K+ concentration in ECF
• too little K+ in ECF ! K+ moves out of cell
• following an acute K+ load ! ½ is lost in urine over next 6hrs, the rest go into cells
6. 4 factors that affect K+ distribution
• insulin ! uptake of K+ into cells " via (+) Na-K ATPase
• adrenaline ! (+) cells to uptake K+, reduce K+ loss from muscle cells during exercise " also via Na-K ATPase
• aldosterone ! (+) K+ uptake into skeletal cells ! takes longer to work (hours) than insulin & adrenaline
• acid-base balance ! e.g. acidosis, H+ enter cell in exchange for K; alkalosis, H+ exit cell in exchange for K+ ! more
obvious with metabolic rather than respiratory disturbances
The main excretory route for K+ is through the kidneys ! GFR (120ml/min) x 4.5mmol/l of K+ ! ~800mmol/day filtered ! of
this, ~40-140mmol/day is loss in urine
1. proximal tubule ! 65% of K+ is reabsorbed ! some passive, some active reabsorption
2. proximal straight tubule & thin descending limb ! K secretion
3. Thick ascending limb ! reabsorption of K+
4. Late distal tubule & collecting duct ! K+ both reabsorbed & secreted ! 2 cells here are responsible for this
• Principal cells ! reabsorb Na & secrete K+
• Intercalated cells secrete H+ & reabsorbed K+
Secretion of K+ by the P cells is increased by

1. increased dietary K+ intake ! results in proliferation of basolateral membranes & increased Na-K ATPase activity
2. aldosterone
3. increased rate of luminal Na delivery
4. increased flow rate
5. metabolic alkalosis ! stimulate secretion by increasing the activities of basolateral Na-K ATPase & luminal Na delivery
Secretion of K+ by P cells is decreased by

1. metabolic acidosis ! which inhibits these pathways
2. in contrast respiratory alkalosis & acidosis ! have little effect on distal K secretion
Factors that increase K+ reabsorption by intercalated cells

1. decreased dietary K intake ! a/w changes c/w insertion of additional transporters (presumably H-K ATPase) into luminal
membrane
2. acidosis ! stimulates H+ secretion by these cells, in exchange for K+
If the extracellular K concentration is reduced to 3mmol

1. K will diffuse out of the cell
2. H will diffuse into the cell
3. charges inside the cell will remain unchanged
4. k going out of the cell is not an active process
Extra renal losses of potassium are usually small but may be markedly increase with
1. small bowel fistulae
2. villous tumours of the rectum
3. fulminating ulcerative colitis
Note that NO potassium is loss in profuse sweating
Regarding potassium excretion & the kidney

1. approximately 600mmol of K+ are filtered each day in a normal person
2. secretion of K+ occurs in the distal tubule & the collecting duct
3. approximately 90% of filtered K+ is resorbed in the proximal tubule & loop of Henle
4. the rate of K+ secretion is proportionate to the rate of flow of the tubular fluid
5. urinary excretion of K+ increases in pyloric stenosis ! due to metabolic alkalosis
6. excretion is not influenced by ADH
Concerning hypokalemia
1. clinical manifestations include weakness, fatigue & malaise
2. commonly caused by
• gut ! vomiting, aspiration, fistulas, diarrhea
• renal ! diuretics, steroids (aldosterone increases K+ secretion)
• chronic alkalosis ! decrease plasma H+ concentration ! increase cell K+ concentration ! increase K+ secretion in distal
tubule
3. ECG changes ! Usually none, but if present
• peaking of P wave
• Q-T not prolonged although U waves are often mistaken as a lengthening of the T waves
• Flattening of T waves
Concerning hyperkalemia
1. clinical manifestations ! vague, major risk of cardiac arrhythmias & arrest
2. causes ! loss of K+ from cells in a/w renal failure (anuria)
• shock ! reduced BP ! hypoperfusion of tissues ! anoxia, acidosis, reduced renal function
• crush injury ! K loss from cells to plasma, myoglobinuria ! tubular blockage & anuria
• terminal renal failure ! increase tissue catabolism with decrease GFR ! increase plasma K
3. ECG changes
• Small p wave
• Prolonged PR interval
• Widening of QRS complex
• Peak T wave in precordial leads
• VF
Concerning K and acid-base balance

1. cells exchange K+ & H+ ions with plasma
2. metabolic acidosis ! H+ move into cell, K+ move out of cell ! plasma K+ rises ! increase K+ secretion in distal tubule !
total body K depleted, despite high plasma K+
3. metabolic alkalosis ! H+ move out of cell, K+ move in ! low plasma K+ (initially) ! however, chronic alkalosis may lead
to loss of body K because of increased K secretion by renal P cells
4. respiratory acidosis has little effect on plasma K+ ! maybe because the raised pCO2 generate HCO3-, and K has to stay
inside the cell to balance this
5. Chronic depletion of K can lead to alkalosis ! because when the tubules is depleted of K, it starts to secrete H+ instead !
leading to increase plasma [HCO3], decrease [Cl] ! increased renal secretion of NH4 & H resulting in an increased transfer
of cell HCO3 to plasma ! urine is acid but blood alkaline

ACID BASE BALANCE
KEY PRINCIPLES
1. normal EC pH = 7.35 to 7.45; compatible with life pH = 7.0 to 7.8
2. cells have metabolism ! inevitable production of H+ ! must be buffered before being secreted
3. most important for secreting H+ from tubular cells is by Na-H counter-transport
• where Na is reabsorbed ! for every H+ secreted
4. maximal H+ gradient to pump acid into lumen is at pH of about 4.5, i.e. [H+] 1000x that of plasma ! normally reached in
CDs
5. need buffers in urine cos otherwise, this pH would be reached rapidly ! and so H+ secretion would stop
6. when H+ is secreted into lumen, 3 things can happen
• bind with HCO3 ! H2O + CO2 ! pK is 6.1
• bind with HPO4 ! H2PO4 (monobasic phosphate) ! pK 6.8 ! mainly in distal tubule & CDs, because phosphate is
maximally concentrated here
• bind with NH3 ! NH4+ ! pK 9.0 ! distal tubules
7. the bicarbonate buffer system is the most important in the body
8. the titratable acidity of urine is the amount of alkali that is added to urine to return the pH to 7.4, the pH of the glomerular
filtrate
the phosphate buffer system plays a major role in H+ buffering in the tubules
BECAUSE
The phosphate buffer system has a pK suited to the pH of tubular fluid
Note that
1. phosphate buffers are composed of a mixture of HPO & H2PO and are poorly reabsorbed from the tubules where they become
concentrated in a/w water reabsorption
2. this makes them an important buffer source
3. their pK of 6.8 also makes these active buffers as the urine becomes concentrated through the tubules and the pH falls to about
6
4. that is the phosphate buffers unction in their most effective range near their pK value
HYDROGEN IONS
Hydrogen ions
1. are actively secreted in the proximal, distal tubules & the collecting ducts
• there is no part of a nephron is H+ is wanted back ! most of it are secreted or exchanged
• thus it can be secreted against a concentration gradient until a urine pH of ~4.5 is reached
• So a urine pH of <5 is within normal limits
• thus it can even be secreted against a large concentration gradient in the collecting ducts
• we want to get rid of H+
2. are exchanged for Na, NOT K+ ! has little to do with K+
• note that the body will swap H+ for Na anytime, but it won’t necessarily do the same with K+
• thus in presence of aldosterone ! where Na reabsorption is the aim ! H+ is thus secreted in increased amount in distal
tubule
3. directly stimulate the respiratory centre
4. are excreted in the urine predominately by combining with urinary buffers
• in the PCT! it is buffered by HCO3-
• when there is a large load of H+ to be excreted, most of it appears in the urine in the form of ammonium salts
• Urine pH of <5 contains more H2PO4 than HPO4
5. note that during acidosis ! H2CO3 DOES NOT appear in urine in increased amount because ! most of it would have rapidly
dissociate into H + HCO3
urine pH less than 5

1. is within normal limits
2. contains more H2PO4 than HPO4
3. contains more than normal NH4+
4. does not contain HCO3 in greater than normal concentration
note that ! Hydrogen ion that reacts with bicarbonate DOES NOT contribute to urinary titratable acidity
BECAUSE
The titratable acidity is the amount of alkali that is added to urine to return the pH to 7.4 ! the pH of the glomerular filtrate
Elevated serum bicarbonate is commonly a/w

1. chronic emphysema
2. duodenal ulcer with obstruction
3. milk-alkali syndrome
4. hyperaldosteronism
Total parenteral nutrition DOES NOT lead to elevated serum bicarbonate
A patient suffers from a metabolic acidosis due to excessive production of keto-acids. In this state, all of the following are true
except
1. increased urinary NH excretion
2. decreased pCO2 of the arterial blood
3. increased renal excretion of titratable acid
4. an increased rate of production of bicarbonate
Thus, during acidosis the pH of the glomerular filtrate CANNOT fall below 4.5 in the proximal tubule
BECAUSE
The proximal tubule is the major site for removal of HCO3- from the filtrate
regarding the acidification of urine

1. H+ is secreted into the urine by the cells lining the distal tubules
2. when there is a large load of H+ to be excreted, most of it appears in the urine in the form of ammonium salts
Note that
1. hydrogen ions are secreted by tubular epithelial cells throughout the tubular system
2. CO2 which diffuses into cells with waters is rapidly converted by carbonic anhydrase into carbonic acid which in turn rapidly
dissociates into H+ & HCO3
3. K+ is reabsorbed in the PCT but is predominantly secreted at other sites
4. in the distal tubule, potassium or hydrogen ions are secreted in exchange for Na in an aldosterone dependent process
5. hydrogen ions can only be secreted into urine until urine pH reaches ~4.5
6. to excrete the required acid load, secreted hydrogen ions combine with bufferes, thereby enabling a great increase in capacity
for H+ excretion
7. ammonia produced by the tubular epithelial cells combines readily with H+ to form ammonium
8. ammonium secretion may rise 10 fold to 15 fold in chronic acidosis and under these conditions is the major urinary buffer
9. note that the net flux of K in the distal tubule is secretion rather than absorption
10. most of the secretion is via K channel and is encouraged by the electrical potential difference across the cells, which in turn
results from the aldosterone sensitive utake of Na through amiloride sensitive channels
11. this electrical coupling produces the well known effects of changing the Na load in the distal tubule on K loss and acid base
balance.
BUFFER SYSTEMS
Concerning buffer system
1. buffers = a substance that can take up or release a proton ! keep pH within range
2. buffers work most effectively near their pK
3. 3 important buffer systems in the body ! phosphate, bicarbonate & protein
• phosphate (HPO4) ! pK of 6.8 ! ideal, bcos near plasma pH ! but concentration too low, not enough compared to
HCO3
• proteins (NH4) ! effective buffer, pK close to physiological pH ! one problem, most of them hangs inside the cell
• bicarbonate (HCO3) ! has pK 6.1 ! far from ideal for buffering at pH 7.4 ! but can be easily controlled ! CO2 at
lungs, HCO3 at kidneys ! thus most important buffer system in ECF

So to recap
1. bicarbonate is the most important buffer in the body ! in the ECF ! not because they have ideal pK ! but because they are
most abundant and can be easily controlled by lungs & kidneys
2. bicarbonate is not a good buffer at body fluid pH ! 6.1 vs 7.4
3. phosphate is a good physiological buffer because of its pKa
4. bicarbonate is not the most plentiful buffer in the body fluid
The phosphate buffer system plays a major role in H+ buffering in the tubules
BECAUSE
The phosphate buffer has a pK suited to the pH of the tubular fluid

LUNG STRUCTURE & FUNCTIONS
LUNG STRUCTURE
1. 500ml of air per breath, 12-15 breaths/min ! 6-8L/min = total ventilation
2. 250ml O2 enters body per minute; 200ml CO2 is expired
3. between trachea & alveolar sacs ! airway divide 23 times
• first 16 generations form the conducting zone ! dead space = 150ml/breath
• next 7 form transitional and respiratory zone ! for gas exchange = 350ml/breath = alveolar ventilation
4. note that in a normal person, anatomical dead space = physiological dead space
5. gas movement in the alveolar region is chiefly by diffusion
6. Type I & II cells line the alveoli
• Type I ! flat, large cytoplasmic extensions, primary lining cells
• Type II ! granular pneumocytes, thicker and contain numerous lamellar inclusion bodies ! secrete surfactant
7. other cells also present ! macrophages, lymphocytes, plasma cells, APUD cells, mast cells
Regarding the airway

1. the volume of the conducting zone is about 150ml
2. the volume of the rest of the lung during resting conditions is about 2.5-3L
3. a respiratory bronchiole can be distinguished from a terminal bronchiole because the former has alveoli in its walls
4. in the respiratory bronchioles, the predominant mode of gas flow is diffusion rather than convection
Stability of alveoli
1. the lung is a collection of 300 million bubbles, each 0.3mm diameter
2. such structure is unstable, but presence of surfactants makes it stable
3. surfactants lowers surface tension of the alveolar lining layer
Removal of inhaled particles

1. very large particles are filtered out by the nose
2. particles that deposit on the airways are removed by the mucus escalator
3. the escalator is propelled by millions of tiny cilia
4. the mucus comes from mucous glands and goblet cells in the bronchial walls
5. particles that reach the alveoli are engulfed by macrophages
6. material in the alveoli are then removed from lung via lymphatics
PULMONARY BLOOD FLOW

1. Dual blood supply
• The main supply ! RV output ~5L/min
• Addition supply ! bronchial circulation, from aorta ! supplies conducting airways down to terminal bronchioles
2. the mean pressure in the pulmonary artery is only ~15mmHg at rest
3. the pulmonary arteries branch out just like the airway
4. most of the surface of the alveoli is covered with capillaries
5. the average diameter of the capillaries is about 10um ! just big enough for a RBC
6. thickness of much of the blood-gas barrier is < 0.3um
7. blood spends about ¾ sec in the capillaries
Regarding the blood gas barrier

1. much of the B-G barrier has a thickness of 0.3um
2. the total area of the B-G barrier exceeds 50 square meters
3. most of the area of the alveolar wall is occupied by capillaries
4. if the pressure in the capillaries rises to unphysiologically high levels, the B-G barrier can be damaged
After inspiration commences

1. the intrapleural pressure falls from -2mmHg to -8mmHg

2. the intrapulmonary pressure falls to about -3mmHg ! then air flows into the lung until the intrapulmonary pressure becomes
equal to atmospheric
3. venous return increases

VENTILATION
VOLUMES
Lung Volumes
Insp. reserve volume 3L (1.9-3.3) TLC = IRV + TV + ERV + RV
Tidal volume 0.5L VC = IRV + TV + ERV
Exp. reserve volume 1l (0.7-1.0) FRC = ERV + RV
Residual volume 1l IC = TV + IRV
Anatomic dead space 150ml
Respiratory rate 15/min at rest
Total ventilation 7500ml/min
Alveolar ventilation 5250ml/min
Alveolar capillary blood vol. 70ml
Pulmonary blood flow 5000ml/min
Red cell is exposed to alveolar gas for 750ms at rest (250ms during exercise)
Pressure: 1 atmosphere = 101 kPa = 760 mmHg ≈ 1010 cmH2O = 1.01 bar
Force: 1N = 105dyne
Know that there are 3 volumes we can’t measure with simple spirometer
1. residual volume
2. functional residual capacity ! cos it involves residual volume ! FRC = ERV + RV
3. TLC ! same reason
Thus, the rest of the other parameters can be measured

1. tidal volume
2. vital capacity
3. total ventilation
4. respiratory frequency
The functional residual capacity of the lung cannot be measured by spirometry

BECAUSE
The FRC of the lung includes the RV which cannot be expelled by respiratory effort
The functional residual capacity of the lung is decreased

1. in supine position
2. with term pregnancy
3. post-operative atelectasis
4. chronic bronchitis with sputum retention
an acute fall in lung FRC ! should be treated initially by high flow mask oxygen
a restrictive defect in ventilatory function occurs with

1. fractured ribs
2. upper abdominal surgery
3. lobar pneumonia
4. old T6 spinal cord injury
the closing volume of the lung

1. is the lung volume when small airway closure begins to occur
2. is usually between the residual volume & FRC
3. increases with age
4. is increased by small airway disease

ALVEOLAR VENTILATION
1. is the volume of fresh gas entering alveoli per minute (or volume of gas leaving)
2. = tidal volume – dead space = 500 – 150 = 350ml per breath
3. thus can be increased by increasing tidal volume
4. direct relationship with RR, but when this is increased, TV is compromised
5. inverse relationship with alveolar pCO2 ! i.e. if alveolar ventilation increases (hyperventilation)x3 ! PACO2 decrease x 1/3
Factors determining the alveolar pO2 include

1. inspired oxygen concentration
2. alveolar ventilation
3. oxygen consumption of the body
factors that contribute significantly to the oxygen tension difference b/n alveolar gas & systemic arterial blood (A-a pO2 diff) are
1. anatomical R) to L) shunt
2. low ventilation/perfusion ratio regions of lung
A healthy person hyperventilates leading to doubling of alveolar ventilation. Immediate effects before any renal compensatory
changes would include
1. a PaCO2 of about 20mmHg
2. a decrease in plasma bicarbonate level
3. a decrease in ICP
4. a PaO2 of about 120mmHg
DEAD SPACE
Anatomical dead space
1. volume of conducting airway = 150ml = physiological dead space in normal individual
2. increases with large inspirations because of traction or pull exerted on the bronchi by surrounding lung parenchyma
3. can be measured using Fowler’s method
Physiological dead space

1. is the volume of gas that does not eliminate CO2
2. may be the same as anatomical dead space in normal individual
3. may be significantly increased in patients with lung disease ! due to inequality of blood flow & ventilation within the lung
4. can be measured using Bohr’s equation ! (PACO2 – PECO2)/PACO2
With regard to respiratory dead space

1. physiological dead space is equal to the sum of anatomical & alveolar dead space
2. alveolar dead space is negligible in health
3. physiological dead space may be estimated by use of Bohr’s equation
4. physiological dead space to TV ratio (Vd/Vt) is normally 0.3 ! i.e. 150/500ml
Regarding pulmonary acinus

1. all oxygen uptake occurs in the acini
2. percentage change in volume of the acini during inspiration exceeds that of the whole lung
3. volume of the acini is greater than 90% of the total volume of the lung at FRC
4. each acinus is supplied by a terminal bronchiole

DIFFUSION
FICK’S LAW
Fick’s law of diffusion ! diffusion rate of a gas through a tissue slice is proportional to
1. the surface area
2. the partial pressure difference b/n the 2 sides
3. the solubility of the gas in the tissue
4. but is inversely proportional to the thickness and to the square root of the molecular weight
Note that CO2 diffuses about 20 times more rapidly than does O2
DIFFUSION Vs PERFUSION LIMITATION

Diffusion limited
1. when CO diffuses freely through the B-G barrier,
2. binds intimately with Hb ! exert no effect on pCO in blood
3. more can diffuse through, but only ¾ sec to do so ! therefore is diffusion limited
4. because amount absorbed is entirely dependent on S.A
Perfusion limited
1. when NO diffuses through the B-G barrier
2. it does not bind with Hb ! partial pressure rises rapidly
3. ¾ sec to diffuse, but no NO can be transferred after a while
4. thus the amount of gas taken up by blood depends entirely on amount of available blood flow
OXYGEN UPTAKE
Diffusion of oxygen across the B-G barrier
1. O2 uptake lies between CO & NO
2. at rest the pO2 of blood virtually reaches that of the alveolar gas after 1/3 of its time in the capillary
3. blood spends only ¾ secs in the capillary at rest
4. on exercise, the time is reduced to perhaps 1/4sec
5. the diffusion process is challenged by exercise, alveolar hypoxia, & thickening of the B-G barrier
Oxygen uptake by Hb in lung capillaries

1. varies directly with the blood pH ! i.e. if blood more alkaline ! easier to take O2 onto Hb
2. varies inversely with PaCO2 ! i.e. if too much CO2 in blood, less O2 is taken up by Hb
3. is characterized in the fetus by a shift of the dissociation curve to the left cf that after birth
4. varies inversely with the concentration of 2,3 DPG in the red cell
DIFFUSION CAPACITY
Diffusion capacity
1. CO is used to measure DC because the uptake of this gas is diffusion-limited
2. Normal DC is about 25ml/min/mmHg
3. DC increases 2-3x on exercise
4. DC = V(CO)/PACO
5. in a normal person, doubling the DC of the lung would be expected to increase maximal oxygen uptake at extreme altitude
6. diffusion limitation of oxygen transfer during exercise is more likely to occur at high altitude than sea level
7. breathing oxygen reduces the measured diffusing capacity for CO compared with air breathing
8. DC is decreased by removal of one lung
9. it is decreased in pulmonary fibrosis which thickens the blood gas barrier
10. things that reduce the DC of the lung for CO are
• emphysema which cause loss of pulmonary capillaries
• asbestosis which causes thickening of the B-G barrier
• pulmonary embolism which cuts off the blood supply to part of the lung
• severe anemia
Reaction rates of O2 & CO with Hb

1. reaction rate of O2 is fast but because so little time is available in the capillary, this rate can become a limiting factor
2. the resistance of uptake of O2 attributable to reaction rate is probably about the same as that due to diffusion across the B-G
barrier
3. the reaction rate of CO can be altered by changing the alveolar PO2. This way, the separate contributions of the diffusion
properties of the B-G barrier and the volume of capillary blood can be derived

RESPIRATORY BLOOD FLOW & METABOLISM
PULMONARY BLOOD FLOW

Pressures within the pulmonary blood vessels
1. RA ~ 2mmHg
2. RV ~25/0 mmHg
3. pulmonary artery ! 25/8 ! mean pulmonary pressure = 15mmHg
4. in pulmonary capillary bed ~ 8-12mmHg
5. returning to LA ~ 5mmHg ! LV 120/0mmHg ! systemic
Alveolar & extra-alveolar vessels

1. alveolar vessels are exposed to alveolar pressure & are compressed if this increases
2. extra-alveolar vessels are exposed to a pressure < alveolar, and are pulled opened by the radial traction of the surrounding
parenchyma
3. they tend to be narrowed by smooth muscle & elastic tissue in their wall
4. on the arterial side, they constrict in response to alveolar hypoxia
5. their caliber is increased by lung inflation
PULMONARY VASCULAR RESISTANCE

Pulmonary vascular resistance
1. vascular resistance = (input pressure – output pressure)/blood flow (6L/min)
2. = (15-5)/6 = 1.7mmHg/Lmin
3. is normally very small ! approximately 10% of the systemic vascular resistance
4. locally controlled by the oxygen tension in adjacent alveoli
Increase PVR is a/w

1. high & low lung volumes
2. alveolar hypoxia because of constriction of small pulmonary arteries
3. drugs that cause contraction of muscle, e.g. serotonin, histamine, NA
Decrease PVR is a/w

1. exercise because of recruitment & distension of capillaries
2. (acutely) increasing venous pressure
Causes of a fall in PVR on exercise include

1. increase pulmonary arterial pressure
2. increase in pulmonary venous pressure
3. recruitment of pulmonary capillaries
4. distension of pulmonary capillaries
HYPOXIC PULMONARY VASOCONSTRICTION

Hypoxic pulmonary vasoconstriction
1. normally, when there’s hypoxia, the body responds by vasodilate
2. the lung is different in the sense that it responds by vasoconstrict
3. therefore shunting blood to better ventilated regions
4. alveolar hypoxia constricts small pulmonary arteries
5. probably a direct effect of the low PO2 on vascular smooth muscle
6. critical at birth in the transition from placental to air breathing
7. directs blood flow away from poorly ventilated areas for the diseased lung in adult
8. its mechanism involves K+ channels in vascular smooth muscle

9. it is reduced by inhaling low concentrations of NO
PULMONARY FUNCTIONS
Vascular function of the lung
1. gas exchange
2. storehouse for blood
3. filter for blood ! clots get trapped in lungs, and not go to brain
The metabolic functions of the lung include

1. converting angiotensin 1 to angiotensin 2 by ACE
2. inactivating bradykinin
3. removing serotonin
4. removing leukotrienes
5. removes 30% of NA
biologically active substances metabolized by the lungs

1. synthesized & used in the lungs ! surfactant
2. synthesized or stored and released into blood ! PGs, histamine, kallikrein
3. partially removed from the blood ! PGs, bradykinin, adenine nucleotides, serotonin, NA, ach
4. activated in the lungs ! AngI to Ang II
Accumulation of water in pulmonary alveoli is chiefly prevented by

1. surfactant, which maintain low surface tension in alveoli
2. a low hydrostatic pressure in alveolar capillaries

VENTILATION-PERFUSION RELATIONSHIP
OXYGEN
Oxygen transport from air to tissues
1. pO2 in air = 150mmHg
2. by the time it reaches the alveoli, pO2 drops to 100mmHg
3. alveolar pO2 is determined by 3 factors
• largely by the alveolar ventilation
• FiO2
• How much O2 is taken up by the Hb
When O2 moves through the B-G barrier from alveolar to RBC, it traverses the following layers
1. surfactant
2. epithelial cell
3. interstitium
4. endothelial cell
5. plasma
6. RBC membrane
arterial hypoxia causes

1. an increased RR
2. dilatation of coronary arterioles
3. respiratory alkalosis
4. constriction of renal arterioles
Four causes of hypoxemia

1. hypoventilation
2. diffusion limitation
3. shunt
4. ventilation-perfusion inequality
HYPOVENTILATION
1. always increases alveolar and arterial PCO2
2. always decreases alveolar and arterial PO2 unless additional O2 is inspire
3. hypoxemia is easy to reverse by adding O2
4. causes of hypoventilation include
• drugs that reduce respiratory drive, e.g. morphine, barbiturates
• damage to chest wall
• paralysis of respiratory muscles
• high resistance to breathing (e.g. diving in deep water)
DIFFUSION LIMITITON
1. in an ideal world, PAO2 = PaO2
2. in normal circumstances PAO2 –PaO2 is small
3. but this difference is increased during exercise or when BGB is thickened in diseased lungs

SHUNT
1. this refers to blood that enters the arterial system without going through ventilated areas of lung
2. hypoxemia responds poorly to added inspired O2
3. when 100% O2 is inspired, the arterial PO2 does not rise to the expected level ! a useful diagnostic test
4. if the shunt is caused by mixed venous blood, its size can be calculated from the shunt equation
VENTILATION-PERFUSION MISMATCH
1. the concentration of O2 (or better PO2) is determined by V/Q, and so is PCO2, NO, etc…
2. regional differences of V/Q in the upright human lung cause a pattern of regional gas exchange
3. ventilation as well as perfusion, in the upright position, declines in a linear fashion from bases to apices
4. however, the V/Q ratios are high in the upper portion ! high PO2 (because perfusion is lower at apices)
5. V/Q inequality impairs the uptake or elimination of all gases by the lung
6. although the elimination of CO2 is impaired by V/Q mismatch, this can be corrected by increasing the ventilation to the
alveoli
7. by contrast, the hypoxemia resulting from V/Q inequality cannot be eliminated by increases in ventilation
8. the different behaviour of the 2 gases results from the different shapes of their dissociation curves

GAS TRANSPORT BY BLOOD
OXYGEN TRANSPORT
1. O2 is carried in the blood in 2 forms
• Combined with Hb ! presence of Hb in blood increases O2 concentration by 70x
• dissolved
2. Dissolved O2 obeys Henry’s law ! amount dissolved is proportional to the partial pressure ! this by itself is not enough to
meet tissue demand
3. O2 + Hb = HbO2 ! O2 dissociation curve is formed
• HbO2 = saturation of O2 on Hb ! directly responsible for how much O2 tissue will get
• pO2 is the drive for HbO2 ! relation via sigmoid curve
4. figures to remember
• at pO2 of 100mmHg (in arterial blood) ! oxygen saturation on Hb 97.5% ! more fresh O2 for peripheral tissues
• at pO2 of 40mmHg (in venous blood) ! O2 sat = 75%
• p50 = the pO2 for 50% of O2 saturation ! normal value 27mmHg
• amount of O2 carried by Hb increases rapidly up to a pO2 of about 50mmHg, above this, curve becomes much flatter
5. flat part of the curve ! even if the pO2 in alveolar gas falls somewhat, loading of O2 will be little affected.
6. steep part of the curve ! means that a small drop in pO2 affects significantly how much O2 will get on the Hb
7. if you want peripheral to get O2 ! pump up the pO2 with high flow O2 ! ensures more O2 get on Hb ! more O2 for tissue
Curve to left (! O2 affiniity) Curve to right (" O2 affinity)

• CO • ! temperature
• HbF • ! pCO2
• " temp • ! H+ ! reduced pH
• "pCO2 • ! 2,3 DPG
• " 2,3 DPG
8. so it can be deduced that

• O2 affinity is INVERSELY related to temperature, pCO2, & 2,3 DPG
• O2 affinity is DIRECTLY related to pH, CO, HbF
9. shifting the curve to the right ! means the O2 affinity of Hb is reduced ! i.e. less come on board, which means more will be
offloaded
10. remember ! exercising muscle is acid, hypercarbic & hot and it benefits from increased unloading of O2 from its capillaries
11. elevated level of 2,3 DPG is a/w chronic hypoxia ! high altitude, chronic lung disease
Thus, it can be deduced that oxygen uptake by Hb in the lung capillaries

1. varies directly with blood pH
2. varies inversely with paCO2
3. is characterized in the fetus by a shift of the dissociation curve to the left compared with that after birth
4. varies inversely with the concentration of 2,3 DPG in the red cell
the delivery of O2 from blood to tissues would be increased by an increase in the tissue capillaries of
1. the 2,3DPG content of the RBCs
2. blood pCO2
3. blood temperature
4. blood H+ content (i.e. reduced pH)
CARBON MONOXIDE
Regarding carbon monoxide (CO)
1. interferes with O2 transport by binding closely with Hb
2. 240 times the affinity of O2 for Hb ! i.e. for the same partial pressure, CO will bind 240x more strongly than O2
3. for this reason, small amount of CO in the blood can tie up a large proportion of Hb in blood, making it unavailable for O2
4. thus Hb concentration in the blood may be normal, but O2 concentration is grossly reduced
5. thus, COHb shift the curve to the left, interfering with unloading of O2
features of CO poisoning include

1. reduced O2 concentration of arterial blood
2. reduced O2 concentration of mixed venous blood
3. O2 dissociation curve is shifted to the left
4. CO is colorless & odorless
5. normal arterial pO2
CARBON DIOXIDE TRANSPORT

1. 3 forms in blood
• dissolved ! obeys Henry’s law, but 20x more soluble than O2
• as bicarbonate ! from CO2 + H2O = H2CO3 = H + HCO3- (all happening on Hb)
• binding with proteins ! carbamino compounds ! Hb.NH2 + CO2 = Hb.NH.COOH (carbamino Hb)
note that cabamino compounds are formed both in the plasma and the RBC
Arterial (%) Venous (%)

Dissolved 5 10
Bicarbonate 90 60
Carbamino 5 30
KNOW THE VALUES IN THIS TABLE

2. so leaving the peripheral tissues, and heading towards the lungs ! i.e. in venous blood
• 60% of CO2 are in bicarbonate form, 10% dissolved, 30% as carbamino form
3. after exchanged in the lungs ! 90% are now carried in bicarb (mostly on RBCs), 5% dissolved and 5% on carbamino
4. as oxygenated blood head out to the peripheral tissue again
• HCO3 ‘leaks’ out of RBCs easily ! leaving H+ behind ! hard to get out because of plasma membrane impermeable to
cations
• to even balance ! CL- comes into cell ! chloride shift ! Gibbs-Donna equilibrium
• Cl- shift into cells ! mosm in cells increases ! cell expand slightly in the peripheral circulation
5. as the Hb unloads the O2 ! Hb becomes ‘reduced’ ! some free space ! CO2 hops on ! we call this bullshit ‘Haldene
effect’
6. so ! reduced Hb in peripheral blood ! helps loading of CO2, while oxygenation that occurs in the pulmonary capillary
assists in unloading
7. Bohr effect ! the uptake of CO2 by blood in the tissue capillaries assists the release of oxygen from Hb
8. as CO2 hops on
• the H+ generated is buffered by the ‘reduced’ or deoxy-Hb
• osmolar content is increased ! therefore water enters cell, increasing its volume
9. when cells pass through the lungs, they shrink a little
10. note that ! in the entire process of CO2 travel ! plasma carbonic anhydrase IS NOT required
In summary,
1. remember CO2 travels to lungs in venous blood as 60,30,10
2. while CO2 comes tissue from lungs as 90,5,5
3. during the carriage of CO2 in the blood,
• there is an increase in the chloride content of the RBCs " chloride shift (from HCO3- leaving & H+ has to stay behind)
• carbamino compounds are formed both in the plasma and the RBC
• in peripheral tissue, CO2 binds to Hb easily because of reduced Hb ! Haldane effect
4. with respect to CO2 uptake by blood in tissue capillaries
• H+ generated is buffered by deoxy-Hb
• There is a chloride & water shift into RBCs
5. The uptake of CO2 by blood in the tissue capillaries assists the release of O2 from Hb
6. Bohr effect = decrease in O2 affinity of Hb when the pH of blood falls ! due to the fact that deoxygenated Hb binds H+ more
actively than does oxy-Hb

Sudden elevation of arterial pCO2 level is a/w
1. raised ICP
2. respiratory acidosis
3. skin vasodilatation
4. increased plasma bicarbonate level
During exercise, there is a decrease in alveolar pCO2 due to hyperventilation

BECAUSE
During exercise venous blood pCO2 increases
ACID BASE DISTURBANCES

Regarding Acid-base status
1. CO2 in the blood makes it acidic ! CO2 + H2O = H2CO3 = H + HCO3
• the kidney takes care of the HCO3
• lung controls pCO2
2. a change in pCO2 and HCO3 (increase or decrease) will affect the body
3. This generates the 4 types of acid base disturbances
Primary Compensation Causes

Respiratory acidosis pCO2 ! HCO3 ! 1. hypoventilation
2. V/Q mismatch
Metabolic acidosis HCO3" pCO2 " 1. accumulation of H+ in blood
2. uncontrolled DM
3. lactic acidosis (from hypoxia)
Respiratory alkalosis pCO2 " HCO3 " 1. hyperventilation, e.g. at high
altitudes
Metabolic alkalosis HCO3 ! Often none 1. excessive ingestion of alkalis
2. loss of acid ! vomiting
Note the relationship of HCO3/pCO2

1. If the pH is reduced ! then the ratio reduced ! which means either HCO3 is reduced or pCO2 is increased
• If pCO2 is increased primarily ! then it’s respiratory acidosis ! we compensate by raising the HCO3 ! to regain
original ratio
• If HCO3 is reduced primarily ! then its metabolic acidosis ! we compensate by reducing pCO2 (so hyperventilating)
2. if the pH is increased ! then the ratio is increased ! which means either HCO3 is increased or pCO2 is reduced
• if pCO2 is reduced primarily ! then it’s respiratory alkalosis ! we compensate by reducing HCO3 (excreting more from
kidney)
• if HCO3 is increased primarily ! then it’s metabolic alkalosis ! often nothing is necessary
Gasses - arterial Hb 150g/l Gasses - venous

PaO2 95mmHg 198ml/l PVO2 40 mmHg 152ml/l
PAO2 100mmHg PVCO2 46 mmHg 527ml/l
PaCO2 40mmHg 490ml/l PaN2 = PVN2 = 573mmHg 9.8ml/l
Respiratory acidosis is a/w

1. elevated arterial pCO2
2. increased plasma HCO3
3. inadequate ventilation
4. ventilation/perfusion inequality
Metabolic acidosis is a/w

1. a reduced plasma HCO3
2. an reduced arterial pCO2
3. lactic acidosis from hypoxia
4. uncontrolled DM

With regard to acid base status, if the arterial blood pH, pCO2 & bicarbonate are all above their respective reference ranges
1. the pattern is primary metabolic alkalosis
2. the pattern is consistent with pyloric obstruction
3. the pattern is consistent with primary hyperaldosteronism
ABGs & acid base status

1. give some assessment of respiratory, renal & cardiovascular function
2. readings consistent with metabolic acidosis could be characterized by ! pH=7.15, HCO3=18, negative base excess of 10
3. an indwelling arterial line causes greater morbidity than a once daily arterial puncture
Following prolonged vomiting a/w complete pyloric obstruction, a patient would be likely to develop
1. a rise in plasma HCO3 concentration
2. a decrease in alveolar ventilation
3. a decrease in CL- concentration
4. a decrease in CSF pressure
Blood-tissue gas exchange

1. rate of transfer of gas through a tissue sheet
• is proportional to the tissue S.A
• the difference in gas partial pressure on the 2 sides
• and inversely proportional to the thickness of the sheet
2. Tissue hypoxia can be due to 4 things
• Low pO2 in arterial blood ! from pulmonary disease ! hypoxic hypoxia
• A reduced ability of blood to carry O2 ! anaemia or CO poisoning ! anaemic hypoxia
• A reduction in tissue blood flow, either generalized, as in shock, or because of local obstruction ! circulatory hypoxia
• Toxic substances, e.g. cyanide, that interferes with the ability of the tissues to utilize available O2 ! histotoxic hypoxia
A patient with severe anaemia and normal lung function will have the following features
1. normal arterial pO2
2. normal arterial O2 saturation
3. low arterial O2 concentration
4. low O2 concentration of mixed venous blood
5. reduced tissue pO2
arterial hypoxia causes

1. an increased in RR (to get more O2 in)
2. dilatation of coronary arterioles (to maximize delivery with what’s available)
3. respiratory alkalosis (hyperventilating)
breathing 60% oxygen by face mask would be expected to correct arterial hypoxemia due to
1. an increase in physiological dead space
2. hypoventilation
3. a small physiological shunt (venous admixture less than 10%)
the pulse oximeter

1. may be inaccurate in hypovolemia
2. may be used to measure pulse rate
3. measures oxygen saturation, which is independent of arterial pH or hypercapnia
4. utilizes both plethysmography & light spectroscopy in producing its output
5. is affected by ambient light
6. is fooled by COHb into giving a normal O2 saturation reading
7. when giving a reading of 97% equates to PaO2 of 50mmHg
patients for whom mask oxygen therapy is inadequate

1. are often tachypnoiec
2. show distress, dyspnoea, exhaustion, sweating & confusion
3. may not show low oxygen saturation or low pulse oximetry until at a late stage
4. include those with vital capacity < 15ml/kg
5. include those with FEV1 < 10ml/kg
the measured respiratory quotient (RQ) may rise during severe exercise
BECAUSE
Hyperventilation will result from lactic acidosis
Note that respiratory quotient = ratio of CO2 production to O2 consumption ! CO2/O2 ! measured for a tissue, organ or body

MECHANICS OF BREATHING
MUSCLES OF RESPIRATION
1. the most important muscle of inspiration is the diaphragm
2. inspiration is active; expiration is passive during rest
3. when diaphragm is paralysed, it moves up rather than down with inspiration because of the negative thoracic pressure !
paradoxical movement
4. other muscles include the intercostals, abdominal muscles & accessory muscles
5. expiration is passive during rest ! lung & chest wall are elastic & tend to return to equilibrium
6. during exercise & voluntary hyperventilation, expiration is active ! via abdominal wall muscles, including rectus abdominis,
IO, EO, & transversus abdominis
7. these muscles are also good for coughing, vomiting & defecation
With normal quiet breathing

1. expiratory work is accomplished by energy stored in stretched elastic structures
2. the work of breathing represents less than 5% of the total resting oxygen consumption
In normal expiration during resting conditions

1. expiration is generated by the elastic forces
2. alveolar pressure is greater than atmospheric pressure
3. flow velocity of the gas in the large airways exceeds that in the terminal bronchioles
4. diaphragm moves headward as expiration proceeds
Forces which are acting on the lung at the end of normal expiration include
1. elastic tendency of the thoracic cage to sustain expansion
2. surface tension effects at the alveolus tending to produce collapse
3. elastic tendency of the lung to collapse
4. a negative intrapleural pressure
COMPLIANCE
Compliance
1. important for how much air gets into the lungs
2. is the slope volume/pressure
3. reduced compliance ! fibrosis, alveolar edema, collapse (atelectasis), increased pulmonary venous pressure
4. increased compliance ! emphysema, normal aging lung
5. depends on the structural proteins (collagen, elastin) & surface tension
Regarding lung compliance

1. compliance increases with age
2. filling an animal lung with saline increases compliance
3. removing a lobe reduce total pulmonary compliance
4. absence of surfactant reduces compliance
Pulmonary surfactants
1. reduces surface tension of the alveolar lining layer
2. produced by type II epithelial (alveolar) cells
3. contains dipalmitoyl phosphatidylcholine
4. helps to prevent transudation of fluid from the capillaries into the alveolar spaces
5. absence results in reduced lung compliance, alveolar atelectasis & tendency to pulmonary edema

REGIONAL DIFFERENCES IN VENTILATION
Causes of regional differences in ventilation
1. lung is vertical ! pulled by gravity on its own weight
2. thus heavier at bottom than top ! therefore pressure near the base is higher (less negative) than at the apex
3. higher pressure means less air inside lung when not inspiring; cf apex where more air is ‘trapped’ when not breathing
4. so during inspiration ! the lower regions of lung ventilate more than the upper zones
5. the paradox ! base of lung is harder to expand but ventilate a lot better than apex
6. we can deduce from the above that, in the upright lung
• intrapleural pressure is more negative at the apex than at the base
• the V/Q ratio is thus greater at the base than at the apex ! because V is greater at the base
• the base regions are better ventilated because it has a small resting volume and a relatively large increase in volume
• alveolar pO2 is higher at the apex than at the base
• the apex is less compliant than at the base
EXPIRATORY FLOW VOLUME

with respect to the forced expiratory flow volume curves
1. expiratory flow declines with decreasing lung volume
2. maximum expiratory flow rate is independent of effort at mid to low lung volumes
3. features of the curve are due to dynamic airway collapse
4. effective driving pressure for expiration is alveolar minus intrapleural pressure
Emphysema would be a/w

1. a reduced FEV/VC ratio
2. an impaired expiratory flow-volume curve
3. a reduced peak expiratory flow rate
4. an increased FRC
A normal subject makes an inspiratory effort against a closed airway

1. tension in the diaphragm increases
2. the external intercostals muscles become active
3. intrapleural pressure falls
4. pressure inside the pulmonary capillaries falls
factors that increase the resistance of the airway include

1. reducing lung volume below FRC
2. diving to a great depth
3. inhaling cigarette smoke
4. breathing a mixture of 21% O2 & 79% sulfur hexafluoride (molecular weight 146)
When a patient develops spontaneous pneumothorax of his right lung,

1. the right lung collapses
2. diaphragm moves down
3. mediastinum may move to the left
4. blood flow to the right lung is reduced
5. chest wall on the right side may expands

CONTROL OF VENTILATION
KEY PRINCIPLES
3 basic elements to control respiration
1. sensors ! gather information & feedback to central control
2. central controller ! in the brain, which coordinates the information & send impulses to effectors
3. effectors ! respiratory muscles, which cause ventilation
Central controllers
1. 3 in the brainstem
• medullary respiratory center ! beneath 4th ventricle, 2 areas ! dorsal group for inspiration, ventral group for expiration
• Apneustic center ! lower pons ! stimulates the inspiratory area
• Pneumotaxic center ! upper pons ! switch off or inhibit inspiration, thus regulating inspiration volume & RR
2. cortex can override all of the above
3. these respiratory centers are responsible for generating the rhythmic pattern of inspiration & expiration
4. receive input from chemoreceptors, lung & other receptors, and the cortext
5. major output is the phrenic nerve
Regarding the respiratory centers

1. the normal rhythmic pattern of breathing originates from neurons in the pons & medulla
2. inspiratory originates in the dorsal respiratory group of cells in the medulla
3. impulses from the pneumotaxic center can switch off inspiratory activity
4. the cortex of the brain can override the function of the respiratory centers
Regarding central chemoreceptors

1. they are located near the ventral surface of the medulla
2. they respond to mainly pCO2
3. they are activated by changes in the pH of the surrounding ECF
4. for a given rise in pCO2, the pH of CSF falls > that of blood
5. if the pCO2 of the blood is increased for a long time, the pH of the CSF is returned to near normal by movement of
bicarbonate into it
6. the most important stimulus controlling the level of resting ventilation is pH of CSF on central chemoreceptors
Regarding peripheral chemoreceptors

1. they respond to changes in arterial blood, mainly !pO2, !pH, & "pCO2
2. under normoxic conditions, the response to changes in pO2 is very small
3. the response to changes in pCO2 is faster than for central chemoreceptors
4. they have a high blood flow per gram of tissue
Concerning ventilatory responses to CO2

1. it depends on both the peripheral & central chemoreceptors
2. it is reduced during sleep
3. it is reduced if the work of breathing is increased
4. it is a major factor controlling the normal level of ventilation
Factors involved in ventilatory control during aerobic exercise include

1. afferent feedback from limb movement
2. an increase in body temperature
an increase in ventilation results from an increase in the rate of firing of arterial chemoreceptors in response to
1. an increase in arterial pCO2
2. a reduction in arterial pH
peripheral chemoreceptors regulating respiration

1. are located in the carotid bodies
2. represent the only chemoreceptors in man able to produce a hypoxic ventilatory response
3. are not stimulated by anaemia
4. do not produce a significant ventilatory response until the PaO2 is reduced to 50-60mmHg
Regarding ventilatory response to hypoxia

1. it is the major stimulus to ventilation at high altitude
2. it increases if the pCO2 is raised
3. it may be a major stimulus to ventilation in patients with severe chronic lung disease
4. it does not play a role in mild carbon monoxide poisoning
Regarding the Hering-Breur inflation reflex

1. the impulses travel to the brain via the vagus nerve
2. it is only seen in adults at high tidal volumes
3. it may help to inflate the newborn lung
4. abolishing the reflex in many animals causes slow deep breathing
Patients can be weaned from the ventilator

1. when an FiO2 of 40% maintains normal PaO2
2. once the original cause of respiratory failure has been treated successfully
3. once sedation is cease, and CO2 elimination is no longer a problem
The stimulatory effect on the respiratory centre that results from acidosis is mediated via the CSF
CO2 is more soluble in CSF than H+ and in the CSF is rapidly converted to H2CO3
Therefore, larger rises in blood pH are required to increase the CSF H+ sufficiently to stimulate the respiroatyr centre
As a consequence of respiroatyr centre stimulation with resultant hyperventilation ! pCO2 levels fall in metabolic acidosis
Increased ICP causes hypertension & bradycardia

BECAUSE
With increased ICP there is stimulation of the vasomotor centre due to local accumulation of CO2
an increase in ventilation results form an increase in the rate of firing of the arterial chemoreceptors in response to
1. an increase in arterial pCO2
2. a reduction in arterial pH
3. not chronic anaemia (less than 9g Hb/dL)
4. not a reduction in arterial pO2 to 70mmHg

MISCELLANEOUS
Erythropoietin
1. is a circulating glycoprotein with a molecular weight of ~23,000
2. level is increased by ! hypoxia, anaemia, haemorrhage, also (+) by cobalt salts & androgens
3. level is decreased by ! increased red cell volume (e.g. post transfusion)
4. 85% of EPO comes from kidney, 15% from liver
5. when kidneys removed or disease ! liver can’t compensate ! anaemia develops
6. main site of inactivation of PEO is liver
7. the EPO system is quite separate from the renin-angiotensin system
8. angiotensin II has no EPO effect and EPO has no effect on BP of aldosterone secretion
Erythropoiesis is
1. subject to feed back control
2. a feature of acclimatization to altitude
3. inhibited by a rise in the circulating red cell level to supernormal values
4. is controlled by EPO produced by kidneys
5000 units of heparin given subcut twice daily perioperatively reduces the incidences of postoperative DVT
BECAUSE
Heparin, in sub-therapeutic dosage, potentiates antithrombin activity
Haemophiliacs usually have a normal ‘bleeding time’ test

BECAUSE
Hahiliacs have a normal platelet aggregatory response to microvascular injury
When freshly taken blood is cooled rapidly to 0’C coagulation will be slowed
BECAUSE
Low temperaturereduces the activity of enzymes necessary for coagulation
Aspirin inhibits platelet aggregation by inhibiting cyclo-oxygenase activity

BECAUSE
Cyclo-oxygenase converts arachidonic acid to endoperoxides PGG2 and PGH2
Patients suffering from von Willebrand’s disease bleed excessively post operatively
BECAUSE
In von Willebrand’s disease there is usually a deficiency of factor VIII and a platelet defect
a child who is group O Rh negative can have a parent who is

1. group B Rh positive
2. group O Rh positive
3. group A Rh positive
4. BUT NOT group AB Rh positive
Concerning Fetal Hb
1. structure similar to HbA, except the B chain are replaced by gamma chains
2. at birth, the circulating HbF is ~40% ! this declines significant and replaced by HbA
3. has more affinity for O2 than adult Hb (HbA) ! because it binds 2-3DPG less effectively than HbA
4. at 4 months, it is ~10% or less of the circulating Hb
5. HbF in fetal blood has a lower P50 than HbA in maternal blood because HbF binds 2,3DPG less effectively than HbA
In the lymphoid and reticuloendothelial systems

1. congenital agammaglobulinaemia is thought to be due to the absence or gross dysfunction of the B series of lymphocytes
2. total thoracic duct lymph flow in a normal adult is about 2 litres in 24hrs
3. the liver and spleen can be shown by gamma scintigraphy after the injection of iv 99mc-Tc sulphur colloid
the reticuloendothelial cells in the liver and spleen take up sulphur colloid
gamma globulin is produced by B lymphocytes
the protein content of lymph from the lower limbs is about 20g/litre
Regarding plasma component

1. the half life of factor VIII infusion is 12-16hrs
2. prothrombin complex concentrates contain factors 2, 9 & 10 and are useful in vitamin K deficiency, warfarin overdose and
patients with haemophilia B
3. FFP plasma contains normal levels of all coagulation factors
4. What does cryoprecipitate contain? ! not facto 8, 9 or vWB & fibrinogen
50 yr man PHx duodenal ulcer and takes aspirin 4hrly for painful rheumatoid arthritis for 2 months. This causes a loss of 30ml of
blood daily in his stools. It’s likely tat
1. his blood will show an IDA
2. his absorption of iron from a full normal diet will be affected by arthritis
3. his plasma iron biding capacity will be increased
4. melaena will not be seen on macroscopic examination until more than 100ml of blood are lost daily into the large intestine
A 65 yr old of 70kg weight is vomiting from a small bowel obstruction. He has lost ~5L of fluid. It is likely that
1. he will pass urine with a high osmolarity
2. his urine output will be decreased
3. his plasma protein concentration will be increased
4. his plasma Na concentration WILL NOT be increased
haemorrhage a/w streptokinase infusion is due to

1. high level of fibrin degradation products and hypofibrinogenemia
under basal conditions, the route of greatest water loss is via the kidney
the vagus nerve supplies

1. sensation to skin of part of the external auditory canal
2. preganglionic cholinergic axons to the cardiac ganglia
3. parasympathetic outflow to the colon up to just before reaching the splenic flexure
serum hyperosmolality is LEAST likely to occur as a possible complication early in the course f ! acute oliguric renal failure
thus serum hyperosmolality occurs as a complication in
1. severe burns
2. hyperpyrexia
3. total enteral nutrition
4. hyperglycemia
Acclimatization to altitude is a/w

1. enhancement of EPO secretion & the circulating red cell mass
2. lactic acidosis in the brain causing a fall in CSF pH to enhance the ventilatory response to hypoxia
3. an increase in tissue content of cytochrome oxidase
4. an increase in red blood cell 2,3 DPG which decreases O\Hb2 affinity of Hb

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PHYSIOLOGY NOTES

Total body water 7

NERVES & SYNAPTIC TRANSMISSION

Metabolism & respiratory quotient 19

CVS REGULATORY MECHANISMS

CIRCULATION THROUGH SPECIAL REGION

Coronary artery disease 29

CONDUCTION SYSTEM OF THE HEART

Cardiac electrical activity 31

THE HEART AS A PUMP

DYNAMICS OF BLOOD & LYMPH FLOW

BSE Notes 2006 L.Lai PHYSIOLOGY 2

THE THYROID GLAND

PANCREAS & CARBOHYDRATE METABOLISM

THE ANTERIOR PITUITARY GLAND

THE POSTERIOR PITUITARY GLAND

Pituitary regulation of sex hormones 60

THE LIVER & BILIARY SYSTEM

THE GASTROINTESTINAL FUNCTIONS

Salivary glands & saliva 69

ABSORPTION & DIGESTION

Proximal convoluted tubule 90

ACID BASE BALANCE

LUNG STRUCTURE AND FUNCTIONS

BSE Notes 2006 L.Lai PHYSIOLOGY 5

Fick’s law 103

RESPIRATORY BLOOD FLOW & METABOLISM

Pulmonary blood flow 105

GAS TRANSPORT BY BLOOD

Oxygen transport 109

Muscles of respiration 114

BSE Notes 2006 L.Lai PHYSIOLOGY 6

TOTAL BODY WATER

Total body water is

There are 4 ways a substance can cross a membrane

Transport protein is like a gate ! that opens or close depending on

In the cell membrane

With regards to capillary membrane

Scurvy is associated with blood vessel fragility

GIBBS DONNAN EFFECT

IONS INSIDE & OUTSIDE OF CELLS

Cell Interstitial Plasma

Concerning plasma, it has

When extracellular K concentration is reduced to 3.0

JUNCTIONS BETWEEN CELLS

Concerning tight junction ! Zona occludens

Concerning Gap junction

BSE Notes 2006 L.Lai PHYSIOLOGY 9

Thyroid hormones Act via cytoplasmic or nuclear receptors

ANG II (+) phospholipase C

ANP Increase cGMP in cell

Insulin, EGF, PDGF, M-CSF Increase tyrosine kinase activity

3. second messengers can do a couple of things

BSE Notes 2006 L.Lai PHYSIOLOGY 11

The firing of motorneurons

BSE Notes 2006 L.Lai PHYSIOLOGY 12

BSE Notes 2006 L.Lai PHYSIOLOGY 13

Cholinergic discharge ! anabolic nervous system

Atropine abolishes normal reflex salivary secretion

Destruction of the conus medullaris may almost completely paralyse defecation

The vagus nerve supplies

sympathetic vasodilator fibers are characterized by the fact that they

Alpha-adrenergic receptors at sympathetic postganglionic nerve endings