St

udentNot
es

PHYSI
OLOGY
1stEdi
t
ion

Uni
t10
RenalSys
tem
 CONTENTS
ESSAY:
1. Define GFR and describe about the factors that regulate Pg No: 3
GFR. Add a note on measurement of GFR

2. Explain about the counter current mechanism in Pg No: 7

concentration of urine

3. Renal circulation, measurement of RBF, regulation of Pg No: 10

RBF

4. Mechanism of acidification of urine, explain about the Pg No: 13

factors that influence acidification of urine

SHORT NOTES:
1. Juxtaglomerular apparatus Pg No: 19

2. Renin angiotensin system Pg No: 21

3. Tubulo glomerular feedback Pg No: 23

4. Water reabsorption Pg No: 24

5. Diuresis with examples of diuretics Pg No: 27

6. Difference between osmotic and water diuresis Pg No: 28

7. Micturition reflex Pg No: 29

8. Renal clearance Pg No: 30

9. Response of kidney to acid-base disorders Pg No: 31

1
 GLOMERULAR FILTRATION RATE
Glomerular filtration rate (GFR) is defined as the amount of filtrate formed by the glomerular
filtering membrane of both kidneys in a unit time. Normally, it is 125 mL/min (7.5 L/h or 180
L/day).

Factors affecting glomerular filtration rate: factors affecting renal blood flow,
pressure gradients, glomerular capillary permeability, and surface area of filtration influence
GFR.
1. Renal blood flow: this is the most important determinant of GFR. RBF is directly
proportional to GFR. Renal vasodilation maintains GFR.
2. Capillary permeability: integrity of the glomerular capillary is an important determinant of
GFR. Kf is the product of capillary wall permeability and size of the capillary bed.
● Permeability of the glomerular capillaries is increased in abnormal conditions like
glomerulonephritis and presence of toxic agents. In such conditions GFR is increased,
because plasma proteins are also filtered to a variable degree.
● Decreased capillary permeability occurs due to thickening of capillary membrane in some
diseases leading to decreased GFR.
● Alteration in GFR filtration area of glomerular capillaries can alter the Kf. Mesangial
cells contraction or relaxation is associated with alteration in coefficient of filtration.
● Contraction of mesangial cells leading to decreased Kf is also caused by vasoconstrictors
like angiotensin II, endothelin, norepinephrine, thromboxane A2, leukotrienes C4 and D4
and histamine.
● Relaxation of mesangial cells leading to increased Kf is caused by vasodilators like
dopamine, cAMP, ANP, nitric oxide (NO) and prostaglandins (PGE).

3. Hydrostatic pressure in bowman’s space fluid: opposes filtration, and therefore GFR is
inversely related to it. It is increased in acute obstruction of urinary tract (e.g., a ureteric
obstruction by stone).
4. Glomerular capillary hydrostatic pressure: GFR is directly related to PGC. Changes in
PGC serve as a primary means for physiological regulation of GFR. PGC is mainly dependent on
arterial pressure, renal blood flow, afferent arteriolar resistance and efferent arteriolar resistance.
● Arterial pressure. GFR is auto regulated between arterial pressure of 80 to 200 mmHg.
Increased arterial pressure above 200 mmHg may raise GFR and decreased arterial
pressure below 70 mmHg may lower GFR.
● Renal blood flow: GFR is directly proportional to the renal blood flow. However, renal
blood flow is controlled by auto regulatory mechanisms.
● Afferent and efferent arteriolar resistance: Decreased renal vascular resistance increases
the Renal blood flow in turn increases the GFR and vice versa.
● In acute renal failure, GFR declines because of fall in PGC.

3
5. Glomerular capillary oncotic pressure (πGC). GFR is inversely proportional to πGC. In
hyperproteinaemia and in Hemoconcentration ratio, the πGC is raised leading to decrease in
GFR. Conversely, in hypoproteinaemia and haemodilution the πGC is reduced leading to
increased GFR.
6. Sympathetic stimulation: GFR decreases in exercise due to sympathetic stimulation that
causes more afferent arteriolar constriction than constriction of efferent arteriole. Also,
maintaining body in standing position for a longer duration decreases GFR due to sympathetic
stimulation.
7. Size, shape and electrical charge of the macromolecule:
● Any substance having molecular weight of <10,000 daltons can be freely filtered by the
glomerular filtration barrier
● Slender and supple molecules can pass easily through the membrane
● Due to the presence of negative charge on the basement membrane, substances with a
negative charge cannot pass through the membrane and get filtered.

MEASUREMENT OF GFR:
Renal Clearance
● Measurement of GFR and RBF is based on the principle of renal clearance. Renal
clearance of a substance is defined as the volume of plasma from which that substance is
completely cleared (removed) per unit time.
● When a substance is removed in urine, a certain volume of plasma is cleared (freed) of
that substance.
● The clearance of a substance can easily be assessed by determining the concentrations of
the substance in plasma and urine, and by estimating the urine flow rate. The formula is
as follows:

Where,
● CX is the clearance of the substance
● UX is the concentration of substance in urine
● V is the urine flow in unit time
● PX is the concentration of substance in the arterial plasma.

Inulin Clearance Test

# Inulin clearance test is commonly used for the assessment of glomerular filtration.

4
# It can be measured by measuring the concentration of the substance in urine and the plasma
concentration of the substance.
# The substance should be freely filtered through the glomeruli and should neither be secreted
nor be reabsorbed by the tubules.

Where,
● UX is the concentration of substance in urine
● V is the urine flow in unit time
● PX is the concentration of substance in the arterial plasma.
As the substance is not metabolized in the body the concentration in the venous plasma can be
taken for the concentration in arterial plasma. This value of GFR is called the clearance of the
substance (CX).

Criteria of the substance used:

1. It should be freely filtered by the glomeruli.
2. It should be neither reabsorbed from nor secreted in the renal tubules.
3. It should not be synthesized or stored or altered in the kidney.
4. It should not be metabolized in the body.
5. It should be non-toxic to the body.
6. Its concentration in plasma and urine should be easily measured.
The substance usually used is inulin, a polymer of fructose, as it meets all the criteria of an
ideal substance for measuring GFR.
It is injected intravenously initially as a bolus dose and then through continuous infusion to
maintain a constant concentration in the arterial plasma. Once, inulin equilibrates with body

fluids, the urine and plasma sample are collected for its estimation.
For example, if the urine concentration is 40 mg/mL, the plasma concentration is 0.25 mg/mL,
and rate of urine flow is 0.8 mL/min. Then:

As inulin is neither reabsorbed nor formed, altered, and stored in the kidney, the filtered load of
inulin equals the rate of inulin excretion. Therefore, inulin clearance equals the GFR.

5
Creatinine Clearance Test
#Endogenous creatinine clearance is used clinically to estimate GFR.
#Creatinine is the end product of creatinine phosphate, a skeletal muscle derivative.
#It is produced continuously in the body and excreted continuously in urine.
#Therefore, the concentration of creatinine in plasma and urine are normally stable.
#Its concentrations are measured in plasma and urine and the urine flow rate is (volume of urine
formed per unit time) determined.
#Then, creatinine clearance is calculated as

#The advantages are that no infusion of creatinine is required

6
 COUNTER CURRENT MECHANISM IN FORMATION OF
URINE
● The mechanism by which urine is concentrated is known as counter-current mechanism
● In medulla, there is an increasing gradient of osmolality from outer region to inner
region, highest osmolality is at the tip of the renal papillae
● The osmolality is maintained by the counter current mechanism which is an essential part
of urine formation
● Countercurrent means flow of fluid in opposite directions

Requirements:
● 2 tubes that lie parallel
● The fluid flow should be opposite
● Tubes should be in close proximity
● Should be selectively permeable

In the kidney, there are 3 countercurrent processes that take place:

● Countercurrent multiplier: done by the loop of Henle, this establishes an osmotic gradient
in the medulla
● Countercurrent exchanger: done by the vasa recta, this maintains the osmotic gradient in
the medulla by passive exchange of solutes
● Equilibrating device: done by the collecting duct that is near the vasa recta and LOH

7
Countercurrent multiplication system:
This is the process by which a small osmotic gradient established at any level of LOH is
multiplied into a larger gradient.
The osmotic gradient at any level is called single effect, which is caused by the movement of
solutes out of the ascending LOH that is impermeable to water
Axial gradient: along the axis of the loop, as the loop enters the deeper layers, there is an
increase in osmolality. This is influenced by 3 main factors
🡺 Rate of fluid flow
🡺 Strength of single effect
🡺 The length of LOH
Steps:
1) Flow of fluid to the medulla until it reaches the tip of LOH
2) Fluid moves to the ascending limb
3) Solutes in this region move out and accumulate in interstitium as ascending LOH is
impermeable to water
4) If water is present in the interstitium, it is removed by the vasa recta
5) Additionally, urea in the collecting duct also diffuses out to reach the interstitium to
increase the osmolality

8
Counter current exchange:
● It is maintained by the vasa recta
● The exchange of solutes and water takes place passively and this process decreases the
dissipation of gradient from the medulla
● Water is removed by the descending limb of vasa recta which is taken up by the
ascending limb of vasa recta
● There is a constant exchange of water and solutes between both the limbs of vasa recta
that maintain the medullary osmolality
● The movement of water is opposite to the movement of solutes
● In the descending limb, solutes diffuse into the vessel, in the ascending limb solutes
diffuse out of the vessel

Role of collecting duct:

Collecting duct contributes to urine formation in 2 ways
🡺 Collecting duct is permeable to water so water mooves out of the tubular fluid in the
interstitium and is taken up by the collecting duct
🡺 Some part of the urea transported into the collecting duct is secreted into the tubular fluid
in the descending limb of LOH as the medullary part of collecting duct is somewhat
permeable to urea. Urea passively moves along with water from the interstitium that
helps to maintain osmotic balance

Applied aspect:
The amount of protein controls the urine concentration. Urea amount depends on the amount of
protein consumed.

9
 RENAL BLOOD FLOW, REGULATION, MEASUREMENT
🡺 Kidneys receive about 2.35% of the cardiac output
🡺 The blood flow rate in cortex is 5ml/min/g and 0.5ml/min/g in the medulla
🡺 The low blood flow in medulla is important to maintain the hyperosmolality in the
interstitium

Blood supply of kidney:

🡺 Arterial: renal artery 🡪 anterior and posterior division 🡪 5 segmental arteries🡪 interlobar
artery🡪 arcuate artery 🡪 interlobular artery 🡪 afferent arteriole 🡪 glomerular capillary
network
🡺 Venous drainage: efferent arteriole 🡪 peritubular capillaries 🡪 arcuate veins 🡪 interlobar
veins 🡪 segmental veins 🡪 renal vein

10
Importance of renal blood flow:
🡺 Supplies oxygen, nutrients and hormones that control kidney functions
🡺 Delivers metabolites and waste products for excretion
🡺 Controls concentration and dilution of urine
🡺 Influences solute and water reabsorption from kidney
🡺 Determines GFR and is the main determinant

Principle of measurement of RBF:

Fick’s principle is the major governing principle: the amount of a given substance taken up by
the organ per unit time is proportional to the arteriovenous difference of the substance across the
kidney
Criteria of substance:
🡺 Should be measurable in arterial and venous blood
🡺 Should not be metabolized
🡺 Should not be stored
🡺 Should not be produced by the kidney
🡺 Should not affect the blood flow by itself
The most ideal substance for measuring RBF is para-amino hippuric acid (PAH)

First, RPF should be measured. It can be measured by injecting PAH and determine the
concentration of PAH in urine and plasma.
The extraction ratio for PAH is high
RPF is calculated by dividing the amount of PAH in urine by the plasma levels of PAH. This
value is called the effective renal plasma flow.

11
Regulation of RBF:
Neural factors:
🡺 Sympathetic control: vasoconstriction that decreases RBF
🡺 Conditions that activate sympathetic response like hemorrhage, cold, pain, exercise,
anesthesia decrease blood flow to the kidney
🡺 Angiotensin 2 formation and sympathetic stimulation to kidneys stimulate the production
of local hormones like PGE2 and PGI2 that produce vasodilation and oppose
vasoconstriction effects.

Hormonal factors:
🡺 Dopamine in high dose can cause renal vasodilation
🡺 It is the preferred treatment for cardiogenic shock

Local factors:
🡺 CO2 and PGs produce vasodilation
🡺 Adenosine causes vasoconstriction in renal vascular bed

Autoregulation:
Myogenic mechanism:
🡺 Renal autoregulation of blood flow is an intrinsic phenomenon
🡺 The autoregulation is mainly due to the direct contractile response of the renal smooth
muscle of afferent arteriole to stretch.
🡺 Increased pressure causes opening of cation channels that result in depolarization,
🡺 This leads to voltage dependent influx of Ca that causes vasoconstriction

Metabolic mechanism:
🡺 Local secretion of PGs, adenosine, NO influence the blood flow

Glomerulo tubular feedback:

🡺 The composition and flow of tubular fluid determine the RBF and glomerular filtration.

12
 MECHANISM OF ACIDIFICATION OF URINE
The kidney is an important organ in maintaining the acid base balance of the body.
It excretes the excess acid from the body, thereby preventing acidosis in the body

ACIDIFICATION IN PROXIMAL TUBULE

● CO2 combines with H2O to form carbonic acid

● This carbonic acid dissociates to form HCO3- and H+ ions, that dissociates with the help
of carbonic anhydrase
● The H+ ions enter the tubular lumen with the help of a Na-H antiport and the HCO3
diffuses into the interstitium.
● The acidification of urine in PCT is dependent on the Na concentration in the tubular
fluid.

Effects of parathormone and carbonic anhydrase:

● Parathormone inhibits Na+-H+ exchanger in apical cell membrane of PCT and therefore
affect pH
● As carbonic anhydrase plays a vital role in PCT, drugs that inhibit its action decrease the
acidification of urine

13
ACIDIFICATION IN DISTAL TUBULE AND COLLECTING DUCT

● Aldosterone increases distal tubular acid secretion by acting on these pumps directly.
● I cells of DCT are equivalent to the parietal cells of stomach as they actively secrete acid.
These cells are rich in carbonic anhydrase
● Band 3 protein, an anion exchanger protein located at the basolateral membrane acts as
chloride-bicarbonate exchanger
● H+-K+ ATPase to some extent secretes H+ and absorbs K+ in the collecting tubule

FURTHER MODIFICATIONS IN ACIDIFICATION

● IN PCT

● The bicarbonate ion

after it diffuses into the

14
 interstitium reaches a concentration of 24 mmols.
● This is an effective buffer that forms CO2 and breaks down to form acid again that
diffuses into the tubular lumen for excretion.

IN DCT AND COLLECTING DUCT

● In the DCT, the phosphate buffer is more effective.

● The secreted acid reacts with dibasic phosphate buffer to form monobasic phosphate.
● The monobasic phosphate is excreted and Na is reabsorbed
● In DCT and collecting tubules, the phosphate gets concentrated due to the absorption of
water, hence this is an even effective buffer.

IN PCT AND DCT:

● The ammonia buffer plays an important role.
● The ammonia through a transporter diffuses into the tubular fluid where it reacts with the
acid to form ammonium ion, that is subsequently excreted.
● This serves as an important route to create a constant gradient for further ammonia
diffusion. This is also called as nonionic diffusion
● This is an important pathway used in metabolic acidosis

15
FACTORS AFFECTING ACIDIFICATION OF URINE
Four important factors contribute to acidification of urine:
1. Renal acid excretion
2. Renal bicarbonate reabsorption
3. Acid-base status of the body
4. Other factors (mainly hormonal)

RENAL ACID EXCRETION:

● Kidney contributes to acid-base balance by excreting acid, which is proportionate to the
production of non-volatile acids in the body. Kidney also prevents bicarbonate loss
● Most of the H+ secreted into the tubular fluid, which is about 4400 meq/day, serves to
reabsorb the filtered HCO3–, and only about 100 meq/day is excreted in urine. Therefore,
normally urine is mildly acidic.

RENAL BICARBONATE REABSORPTION

● Amount of bicarbonate reabsorbed from tubular fluid equals the amount filtered.
Therefore, under normal conditions, HCO3– is not excreted in urine.
● About 80% of the total filtered bicarbonate is reabsorbed in PCT and 15% in thick
ascending limb of LOH and 5% in the collecting duct
● The mechanism of bicarbonate reabsorption in PCT involves Na+-H+ antiporter in the
apical surface of the epithelial cells
● In the thick part of ascending limb of LOH, mechanism is similar to that in the PCT.
● In DCT and collecting duct, reabsorption does not require Na+-H+ antiporter.

ACID BASE STATUS OF THE BODY

● In metabolic acidosis, acidification of intracellular fluid increases H+ gradient between
tubular cell and lumen. This results in increased H+ secretion.
● In metabolic alkalosis, HCO3 − reabsorption as well as acid secretion from kidney is
decreased thereby causing a decrease in urine acidification rate. In metabolic alkalosis,
when plasma bicarbonate level goes beyond 28 mmol/L, renal threshold for bicarbonate
reabsorption crosses its limits and the bicarbonate ions start appearing in the urine.
Hence, urine acidification drops down.
● In respiratory acidosis, when pCO2 increases, the H+ formation increases by the action
of carbonic anhydrase. This causes increased reabsorption of bicarbonate and
acidification of urine.
● The reverse happens in case of respiratory alkalosis.

16
OTHER FACTORS
● Aldosterone, parathormone, angiotensin II and plasma K+ contribute to acidification of
urine.
● Aldosterone increases H+ secretion from the tubular cells into the tubular fluid.
Therefore, it contributes to urine acidification and alkali reabsorption in the kidney.
● Angiotensin II secondarily affects Na+ concentration and Na+-H+ exchange, hence
affects urine acidification

17
SHORT NOTES

18
 JUXTAGLOMERULAR APPARATUS
The juxtaglomerular apparatus is formed when the loop of Henle comes in contact with the
glomerulus of the same renal corpuscle.
The entire modified structure is called the juxtaglomerular apparatus (JGA) that includes:
● the extraglomerular mesangial cells.
● the macula densa.
● the granular cells.
The JGA is part of a complex feedback mechanism that regulates renal blood flow and filtration
rate and it also indirectly modulates Na+ balance.

Mesangial cells:
● They are also called as Lacis cells.
● They are found in a triangular space formed by the efferent and afferent arterioles and the
macula densa.
● Help in the regulation of glomerular filtration. They also secrete extracellular matrix
● Mesangial cells are especially common between two neighbouring capillaries.
● They are agranular cells that secrete some quantities of renin and erythropoietin.

The macula densa:

● Region of specialized modified epithelial cells of the thick ascending limb, where it
contacts its glomerulus between afferent and efferent arterioles.
● The terminal portion of the thick ascending limb of LOH that passes through the angle
formed by the afferent and efferent arterioles of the same nephron posses this tubular
epithelial modification that appears as a dense area, hence called macula densa as the
epithelial cells are closely packed in this region.
● They act as the sensor that monitor the change in ionic composition and rate of flow of
the tubular fluid in the lumen of the tubule.
● It provides feedback signal to the renal corpuscle to change the rate of filtration to meet
the need of kidney functions.
● It is an important component of the tubuloglomerular feedback.

The juxtaglomerular cells:

● Also called as epithelioid cells or Polkissen cells.
● They are present in the tunica media of the afferent arteriole that come in contact with the
terminal part of the thick ascending limb of LOH.

19
 ● They are modified vascular smooth muscle cells with an epithelioid appearance.
● They contain many secretory granules and are responsible for secreting and storing renin
that activate the renin angiotensin system.

Functions of JG apparatus:
● Activate the renin-angiotensin system that is involved in the regulation of blood volume
and pressure
● Macula densa acts as a sensor that detects the change in the rate of flow and volume of
flow in the tubule, which provides a feedback signal to the glomerulus is the
physiological basis of tubuloglomerular feedback
● Lacis cells secrete renin and erythropoietin.

20
 RENIN-ANGIOTENSIN SYSTEM
● The renin-angiotensin system is a mechanism by which blood volume and pressure are
regulated.
● The main trigger is the release of renin from the JG apparatus that takes part in further
actions.

Renin:
● It is an acid protease that is secreted from the JG cells of the kidney.
● It is responsible for the conversion of angiotensinogen to angiotensin 1 which is further
activated.
● Conditions like hypovolemia, hemorrhage, hypotension, and hyponatremia act as
triggers for the release of renin
● Sodium is an important electrolyte that controls renin secretion.

Angiotensin-2:
● This is the most important of all angiotensins that acts via angiotensin receptors AT1 and
AT2
● It is a potent vasoconstrictor, but the action decreases in conditions like liver cirrhosis and
hyponatremia
● It increases the synthesis and secretion of aldosterone from the adrenal cortex that aids in
sodium and water reabsorption.
● It directly stimulates the release of norepinephrine from the post ganglionic sympathetic
neurones and causes contraction of mesangial cells

Clinical importance of RAAS:

● RAS is implicated in the genesis of hypertension that forms the most important
physiological basis of renal hypertension
● Goldblatt hypertension: renal hypertension produced by constriction of renal artery
● Hypertension can be classified as normo renin, hyper renin and hypo renin hypertension
● ACE inhibitors and ARBs (angiotensin receptor blockers) are the first line treatment for
hypertension

21
22
 TUBULOGLOMERULAR FEEDBACK:
Signals originating from the renal tubule provide feedback for the control of glomerular filtration
The rate and flow of concentration of NaCl in the distal part of thick ascending loop of Henle is
an important feedback mechanism
The change in glomerular filtration maintains a constancy of tubular load
The most important sensor is the macula densa that is an important part of juxta glomerular
apparatus

Steps:
Macula densa acts as a sensor

Senses the rate of flow of tubular fluid and the NaCl content

If there is more NaCl, they will enter through the Na-K-2Cl transporter in the macula densa cells

Increase Na-K ATPase activity

Formation of adenosine

Release of Ca from macula densa

Constriction of afferent arteriole

Decreased glomerular filtration

Feedback regulation of GFR

Applied aspect:
Tubulo glomerular feedback of renal blood flow plays a very important role in autoregulation of
renal blood flow to maintain the pressure between 80-180 mmHg

23
 WATER REABSORPTION
The volume of urine excreted is determined by the quantity of water reabsorbed from renal
tubule.
Kidneys reabsorb more than 99% of the filtered water, which is a major mechanism of volume
homeostasis of the body.

TYPES OF WATER REABSORPTION

Water reabsorption in renal tubules is of 2 types
Obligatory Reabsorption Facultative reabsorption

Water reabsorption that occurs secondary to Water absorption that occurs secondary to the
reabsorption of solutes. effects of hormones (ADH, aldosterone).

This accounts for about 85%of total water This accounts for about 15% of total water
reabsorption reabsorption from the kidneys.

MECHANISM OF WATER REABSORPTION

● In Proximal Convoluted Tubule

About 65 % of filtered water is reabsorbed here.
1. The driving force is transcellular osmotic gradient, established by absorption of sodium ions
and accompanying solutes.
2. Due to presence of aquaporins 1, the permeability of PCT is extremely high
3. Small amount of water also passes through water channels present in paracellular route,
through tight junctions between epithelial cells

● In Loop of Henle
Nearly 15% of filtered water is reabsorbed here.
1. Ascending limb of LOH is impermeable to water and water reabsorption occurs mainly in
descending limb
2. It is a passive process that occurs secondary to higher osmolarity of medullary interstitium.

● In Distal Convoluted Tubule

It is relatively impermeable to water. Only 5% of water reabsorption takes place in DCT, which
is influenced by ADH and aldosterone

24
 ● In Collecting Duct
1.Reabsorption of both solute and water depends on concentration of ADH acting on collecting
duct.
2.About 12 to 25% of water is reabsorbed in CD.
Collecting duct has 2 parts
● Cortical CD
In the presence of ADH there is substantial reabsorption of water.

ADH binds to V2 receptors of tubular cells

Activation of adenylate Cyclades

Increase production of cAMP

Activation of protein kinase A

Increased water permeability

● Medullary CD
In this part water is reabsorbed along the osmotic gradient that accounts for 5 – 10% of water
reabsorption. This plays an important role in countercurrent mechanism and makes the urine
concentrated.

Applied aspects
Nephrogenic diabetes insipidus is characterized by decreased expression of aquaporin 2 in
collecting duct and distal convoluted tubule.

25
26
 DIURESIS
Diuresis is a condition where urine output is increased. It occurs due to failure of mechanisms
that concentrates urine.
Diuresis is categorised into 2 types : Water diuresis and Osmotic diuresis.

DIURETICS
Diuretics are substances which enhance the output of urine. These substances increase the
excertion of water, sodium, chloride through urine.
Diuretics are usually used to decrease the ECF volume and blood pressure.

Class of diuretics Mechanism of action Site of action

Osmotic diuretics (mannitol, Inhibit water and solute proximal tubules

glucose, sucrose) reabsorption by increasing
osmolarity of tubular fluid

Loop diuretics (furosemide, Inhibit Na-K-Cl cotransporter Thick ascending loop of

bumetanide) Henle

Thiazide diuretics Inhibition of Na-Cl cotransporter early part of distal

(chlorothiazide, (hence increased NaCl secretion) tubules
hydrochlorothiazide)

Carbonic anhydrase inhibitors Inhibit H+ secretion and HCO3 Proximal tubules

(acetazolamide) reabsorption. Hence reduced Na
reabsorption

Aldosterone antagonist K+ sparing diuretics. Inhibits Collecting Duct

(spironolactone, eplerenone) action of aldosterone on tubular
receptors and decreases Na
reabsorption

Sodium channel blockers Blocks Na channels and decrease Collecting ducts

(triamterene, amiloride) its reabsorption. Decrease
secretion of K ions

27
Site of action of various diuretics 1. Loop diuretics 2.Thiazides 3.Aldosterone antagonist
4.Antagonist to V2 vasopressin receptors

WATER DIURESIS AND OSMOTIC DIURESIS

Diuresis is the excess excretion of water in urine.
Diuresis is classified into 2 broad categories - water diuresis and osmotic diuresis

WATER DIURESIS OSMOTIC DIURESIS

It is the excretion of large volume of water Increase in excretion of water due to

without loss of excess of solutes. increased concentration of osmotically active
particles in tubular fluid.

This occurs when the capacity of tubules to This occurs when osmolality of tubular fluid
reabsorb water is impaired. is more

Seen in ADH Deficiency like in diabetes Typically seen in diabetes mellitus. Due to
insipidus, where urine is dilute and more in increased glucose load on tubules, solute
volume. holds water and prevents its reabsorption from
the tubules.

It can be physiologically demonstrated by This can be produced by administration of

drinking a large amount of hypotonic fluid mannitol, and also by infusion of large
like water (polyuria occurs in 15-40 minutes amounts of NaCl or urea.
of ingestion)

28
 MICTURITION REFLEX:
● It is the process of passing urine.
● This is a reflex phenomenon that is integrated in the spinal cord.
● This is influenced by the activity of the higher centres.
● Unless the bladder is filled, urine accumulates in urinary bladder without much increase
in the intravesical pressure, this property is called plasticity
● Due to plasticity, tension produced by the stretching is not maintained. This relationship
between the bladder volume and the pressure is best studies by cystometry.

MECHANISM:

⬇️
Bladder volume (450ml)

⬇️
Bladder stretches

⬇️
Stretch receptors activates

⬇️
Impulse sent to sacral centres (S2, S3,S4) via parasympathetic centres

⬇️
Impulse relayed to detrusor

⬇️
Internal sphincter relaxes

⬇️
Stretch receptors activated further

⬇️
Increases impulse traffic to and from spinal centre

⬇️
Stronger contraction of the bladder muscle making the reflex process stronger

⬇️
Urine pushed into urethra

⬇️
Afferent through pudendal nerve to sacral centre

⬇️
Inhibition of pudendal nerve to the external urethral sphincter

⬇️
Relaxation of external urethral sphincter

Passage of urine

29
Applied aspect:
Abnormalities of micturition:
The lesions at different segments of the neuraxis result in bladder dysfunctions.
There are 3 major neural defects that produce bladder dysfunctions
● De-afferentation: results in hypotonic and thin bladder, seen in tabes dorsalis
● Denervation: leads to flaccid and distended bladder, seen in denervation hypersensitivity
of the bladder
● Spinal cord transection: phase of shock, recovery and failure; micturition reflex is the 1st
to return in the phase of recovery,

RENAL CLEARANCE

Definition:
Renal clearance of a substance is defined as the volume of plasma from which that substance is
completely removed from plasma per unit time

Cx =Ux *V /Px

● Cx: clearance of the substance

● Ux: concentration of substance in urine
● V: urine flow in unit time
● Px: concentration of substance in the arterial plasma

Criteria of the substance used:

● It should be freely filtered by the glomerulus

● It should be neither reabsorbed from nor secreted in the renal tubules
● It should not be synthesized or stored or altered in the kidney
● It should not be metabolized in the body
● It should not be toxic to the body
● Its concentration in the plasma and urine should be easily measured

Inulin clearance test:

Inulin meets all the above criteria and hence used as an ideal substance for measuring GFR

GFR =Ux *V /Px , this value of GFR is called the Clearance of the substance(Cx)

30
Here inulin given as bolus dose and the plasma concentration maintained by continuous
infusion….

For ex, if Ux =40 mg/ml

Px =0.25 mg/ml
V =0.8ml/min…. then by applying formula,

Cx =128ml/min….as seen above the filtered inulin equals rate of inulin excretion.
Inulin clearance equals GFR

Creatinine clearance test:

Creatinine is an endogenous skeletal muscle derivative. Its concentration in plasma and urine
used to measure creatinine clearance.

RESPONSE OF KIDNEY TO ACID BASE DISORDERS

Respiratory Acidosis:

⬇️Ventilation
⬇️
⬆️ Arterial PCO2 and CO2
⬇️
⬆️H+ ions formed.
In this case the kidney facilitates:
1. H+ secretion
2. HCO3- and Na+ reabsorption
3. Excretion of Cl-
4. Ammonia secretion, which can tie up more H'ions in the lumen.

31
Respiratory Alkalosis:
There is a fall in the arterial PCO2 and CO2 level as CO2 is washed out due to hyperventilation
either voluntarily or in
respose to hypoxia. Now CO2 is formed from HCO3-.
In this case,H+ ion formation is less. Therefore,
1. H+ secretion is less.
2. Filtered HCO3- is excreted
3. Na+ absorption is accompanied by Cl-
4. K+ excretion increases.

Renal Compensation in Metabolic Acidosis and Alkalosis

When acids stronger than Hb and other buffer acids are added to blood, metabolic acidosis is
produced.
When the free H+ level falls as a result of addition of alkali or removal of acid, metabolic
alkalosis results.

Metabolic Acidosis :
Seen in
-diabetic ketosis
- lactic acidosis
- uraemic acidosis
- diarrhoea.
The rise in plasma H+ stimulates respiration, so that CO2 is eliminated and H2CO3 level falls.
Plasma HCO3- is also reduced. The kidneys filter the acid anions that replace HCO3- in plasma
each with a cation, mainly Na+.
H+ ions are secreted into the luminal fluid. For each H+ ion secreted, one Na and HCO3- are
reabsorbed so that more HCO3- is added to blood.
1. Na and HCO3- are reabsorbed.
2. Acid causing anions like CI-, SO4-, and PO4-, are excreted.
3. NH3 is secreted.
4. H+ ions are secreted.

32
Metabolic Alkalosis:
Seen in
-prolonged vomiting
-treatment with diuretics.
As the acids are lost, H+ concentration decreases. This inhibits respiration, so PCO2 gradually
rises and pH is brought down to the normal level. In metabolic alkalosis as in vomiting:

⬇️
1. HCO3- is excreted into urine.
2. H+ secretion
3. Increase in Cl- HCO3, exchange, i.e., Cl- is absorbed and HCO3-, excreted.
4. K+ is secreted.

33
St
udentNot
es

PHYSI
OLOGY
1stEdi
t
ion

Uni
t6
Res
pirat
orySys
tem
 CONTENTS
ESSAY

1. Neural control of respiration, add a note on periodic Pg:4

breathing

2. Chemical control of respiration, add a note on Cheyne Pg:11

stokes breathing

3. Hypoxia: types, causes, features Pg:17

4. Oxygen dissociation curve with diagram, add a note on Bohr Pg:22

effect

5. Mechanics of breathing with muscles involved and Pg:27

significance. Add a note on pressure changes during
breathing and its significance

SHORT NOTES

1. Non respiratory functions of lung Pg:33

2. Pulmonary circulation and its special features Pg:35

3. Lung volumes and capacities Pg:37

4. Ventilation perfusion ratio Pg:41

5. Pulmonary surfactant Pg:42

6. Alveolar capillary membrane Pg:45

7. Transport of O2 and CO2, add a note on Hamburger Pg:47

phenomenon and Haldane phenomenon

1
8. Lung compliance with measurement, diagram, stages and Pg:49
clinical significance

9. Timed vital capacity and its significance Pg: 51

10. Dead space, measurement, types and significance Pg:53

11. Hering Breuer reflex and its significance Pg:56

12. Stages of compensation in hypoxia Pg:58

13. Caisson’s disease Pg:59

14. CPR Pg:60

15. Obstructive and restrictive lung diseases Pg:62

2
 NEURAL REGULATION OF RESPIRATION
RESPIRATION
1. Exchange of gases between the organism and environment.
2. The normal respiratory rate in adult is 12 to 16 per min.
3. Respiration is regulated by two mechanisms. They are
a. Neural respiration
b. Chemical respiration

RESPIRATION CENTRES:

VOLUNTARY SYSTEM

4
FUNCTIONS

1.PONTINE CENTRE
PNEUMOTAXIC CENTRE

● Located in nucleus parabrachialis in upper pons.

● Primary function is to limit the inspiration.
● This is done by inhibiting apneustic centre.
● It increases the respiratory rate.

APNEUSTIC CENTRE
● It prolongs the inspiration. Which means increase in the depth of inspiration.

MEDULLA

PREBOTZINGER COMPLEX: pacemaker [involuntary]

DORSAL RESPIRATORY GROUP [DRG]

● Generates ramp signal leads to smooth rise in tidal volume

VENTRAL RESPIRATORY GROUP [VRG]

● Expiration is a passive process at rest.
● This is needed during forceful expiration. [active process mainly during exercise ]
● This is so called over dive phenomenon

5
INTEGRATION OF NEURAL AREAS

● Prebotzinger complex →signal from medulla to → spinal cord →activated phrenic

nerve →diaphragmatic contraction →initiation of inspiration.
● Death is inevitable if this circuit is disrupted.

MAINTAINANCE OF INSPIRATION

● Apneustic centre →activates DRG →generates ramp signal

TERMINATION OF INSPIRATION

● Pneumotaxic centre →inhibits apneustic centre→-termination of inspiration

● Tidal volume reaches 5oo ml → stretched lung →activates vagal afferents →
inhibits apneustic centre
● Complete inhibition of apneustic centre occur if both the sources are present
● Partial inhibition occurs if only one source is present
● If apneustic centre is inhibited DRG is automatically inhibited

EXPIRATION
● Passive process at rest
● For forceful expiration needs VRG.
● MEDULLA: initiates the respiration
● PONS: regularizes respiration

LESIONS
1.Lesion below medulla

● Death is inevitable
● Circuit between prebotzinger complex and phrenic nerve is cut.
● Involuntary respiration is very essential during sleep. Absence of prebotzinger complex

→ respiration becomes voluntary →if they sleep, they die

● This is called as Ondine curse
● Treatment: mechanical ventilation during sleep.

2. Lesion at pontomedullary junction

6
 ● Initiation is normal
● Regulation of respiration does not that leads to irregular respiration.

3.Lesion at mid pons with cut vagus nerve

● Both cause constant stimulation to apneustic centre leads to prolongation of respiration

● This is called apneustic spasm.

PULMONARY REFLEXES:
HERING BRUER REFLEX [PROTECTIVE REFLEX]

This reflex stops

inspiration and
decreases the duration of inspiration and increases expiratory duration.

7
HERING BRUER DEFLAATION REFLEX
● Prolonged expiration stops that leads to continued inspiration.
● Prolonged expiration can cause lung collapse
● Prevent lung collapse

HEADS PARADOXICAL REFLEX

● Prolonged inspiration → overstretch → increase further inspiration

● Opposite to Hering Bruer reflex

NEW BORN FIRST BREATH

J REFLEX:
● It is seen in juxta pulmonary capillary receptors
● It is activated by inflammation and oedema
● It contributes to rapid shallow breathing
● It causes weakness of skeletal muscles.

8
PERIODIC BREATHING

9
CHEYNE STOKES RESPIRATION

● Gradual hyperpnea→mode of hyperventilation→-absence of respiratory centre

stimulus → gradual hypopnea →apnoea →stimulation of respiratory centre →
next cycle of respiration
● Seen in normal, congestive heart failure, uraemia.

BIOTS /ATAXIA BREATHING

● Hyperpnea → leads to apnoea

● Seen in: damage to medulla and meningitis

ACIDOTIC BREATHING /KUSSMAUL BREATHING

● Respiration is fast and deep
● Stimulated by acid
● Seen in diabetes

LESION AT MID PONS WITH CUT VAGUS NERVE

● Prolonged inspiration spasm

10
 CHECMIAL CONTROL OF RESPIRATION
Overview:
● The hydrogen ion concentration and the respiratory gas composition of the arterial blood
influence respiration.
● There are 2 sets of receptors that detect the chemical changes in the blood

Peripheral receptors:
● They are mainly located in the carotid and aortic bodies
● They response to changes in the PO2, PCO2 and Ph in arterial blood
● They are more sensitive to hypoxia
● They send signals to the dorsal respiratory group in the medulla to increase ventilation.

1)Carotid bodies:
🡺 They are very small chemo sensitive receptors that are located at the bifurcation of the
common carotid arteries
🡺 There are 2 special features of carotid bodies
o Blood flow is 2L per 100g of tissue
o Higher metabolic rate
🡺 They detect very minor changes in the blood PO2, PCO2 and pH due to the high blood
flow
🡺 They consist of type 1 and type 2 cells
🡺 Type 1 cells are the chemo sensitive cells called the glomus cells. They release
catecholamines, mainly dopamine that is released in hypoxia
🡺 Type 2 cells are called sustentacular cells that act as glial cells for support

2)Aortic bodies:
🡺 They are located along the ascending aorta and arch of aorta
🡺 They are innervated by vagal efferent and contain glomus cells
🡺 They are relatively less sensitive when compared to carotid bodies.

Sensitivity of chemoreceptors:
● Chemoreceptors respond more to hypoxia, hypercapnia and acidosis
● The sensor is the glomus cell, which responds to all 3 chemical changes.
● They final pathway is the inhibition of K+ channels that results in depolarisation induced
opening of voltage gated Ca2+ channels

11
1) Mechanism of stimulation by hypoxia:
Hypoxia

In cAMP
levels

Inhibition of Kchannels

Decreased K efflux

Depolarisation of glomus cells

Opening of voltage gated Ca channels

Influx of Ca

Release of neurotransmitters

Increased discharge from 9th cranial nerve

Stimulation of respiratory centre

Increased ventilation

12
● Hypoxia is the major stimulus for activation of peripheral chemoreceptors
● The response is most effective at PO2 <60mm Hg
● Unless hypoxia is strong enough to overcome the inhibitory effect of decreased H+ and
PCO2 in arterial blood, there is no prominent effect.
● The response of peripheral chemoreceptors depends on the PaO2 of the blood and not on
the O2 content.

1) Mechanism of stimulation of hypercapnia:

Increase in PaCo2

Entry of more CO2 into glomus cell

More CO2 forms more H+ in the cell

Increased H+ inhibits K+ channel

K+ efflux causes depolarisation

Opening of voltage gated Ca channels

Ca++ influx increases cytosolic Ca++

Ca++ mediated neurotransmitter release

9th cranial nerve discharge

Stimulation of ventilation

13
 ● The actual stimulus is the formation of H2CO3 in the glomus cells that causes closure of
K+ channels
● Hypercapnia affects ventilation mainly by central chemoreceptors
● Hyperventilation removes CO2 from the blood and decreases alveolar PCO2
● High hypercapnia can lead to CO2 narcosis that leads to coma

2) Mechanism of stimulation by acidosis:

Acidosis stimulates the peripheral chemoreceptors and increases the sensitivity of the receptors
to PaCO2.

Central chemoreceptors:

● Central chemoreceptors are bilaterally located as cell groups just below the surface of the
venterolateral medulla caudal to the pontomedullary junction
● On each side, the receptors are divided into rostral, caudal and intermediate group
● They respond to the change in H+ of the surrounding interstitial fluid

14
Mechanism of stimulation:
● Bicarbonate ions are the main buffer in CSF
● Molecular CO2 diffuses readily into the CSF, therefore blood PCO2 influences the pH of
CSF.
● The ventilatory response to hypercapnia is more in the presence of hypoxia
● Increase in pH (respiratory alkalosis) allows hypoxic stimulation to be less effective
● The interaction of hypercapnia, hypoxia and acidosis is best studied in metabolic and
respiratory acidosis.

Response in metabolic acidosis:

● Metabolic acidosis is due to the accumulation of non-volatile acids like lactic acid, ketone
bodies etc.
● In the initial phase, hyperventilation is produced by the increase in H+, so there is
excessive wash off CO2 from the bloodstream leading to compensatory respiratory
alkalosis
● Profound hyperventilation occurs in metabolic acidosis, eg: Kussumaul breathing

Response in respiratory acidosis:

● Respiratory acidosis occurs due to accumulation of carbon dioxide
● It mainly occurs in COPD like emphysema, asthma or due to failure of respiratory
apparatus or failure of respiratory centres
● In the acute phase, there is an acute increase in minute ventilation proportional to the rise
of PaCO2
● If hypercapnia continues for a few days, acute severe hyperventilation subsides due to
compensatory increase in bicarbonate that shifts the response curve to the right (central
adaptation).
● Therefore, in chronic lung diseases, inspite of persistent hypercapnia, the central
chemoreceptor drive for ventilation is less. In such patients, the hypoxic stimulus for
ventilation will be lost which will result in severe hypercapnia and acidosis. The mainstay
of management in such patients is adequate support for ventilation.

15
16
 HYPOXIA
The term hypoxia is used to denote deficiency of oxygen supply at the tissue level.

Causes
Hypoxia can occur because of any one or more of the following defects:

● Decreased oxygen tension (pO2) of the arterial blood,

● Decreased oxygen carrying capacity of the blood,
● Decreased rate of blood flow to the tissue or
● Decreased utilization of oxygen by the tissue cells.

Types
Depending upon the mechanism of occurrence, there are four types of hypoxia:

● Hypoxic hypoxia,
● Anaemic hypoxia,
● Stagnant hypoxia and
● Histotoxic hypoxia

HYPOXIC HYPOXIA
It occurs due to decrease in O2 tension (decreased arterial pO2). In this type of hypoxia, PO2
decreases in the blood. O2 saturation of Hb is reduced. However, the Hb content and O2-carrying
capacity of blood is normal.

Causes:
● Low PO2 in inspired air: It occurs at high altitude and in ill-ventilated rooms.
● Hypoventilation: It occurs in obstructive diseases such as asthma, respiratory muscle
paralysis, damage to respiratory centers, and pneumothorax.
● Decreased diffusion: It occurs in conditions such as pulmonary edema, emphysema, and
fibrosis of lungs.
ANEMIC HYPOXIA:
It occurs when there is a decrease in the O2-carrying capacity of blood.
Causes:
● Severe anemia as seen in bone marrow depression
● Formation of carboxy hemoglobin due to carbon monoxide poisoning
● Altered hemoglobin like methemoglobin in which iron is present in ferric form

17
 STAGNANT HYPOXIA:
It occurs due to sluggish low of blood through the tissues. The oxygen content of the blood is
normal and hemoglobin is present in adequate amounts.
Causes:
● Circulatory shock due to haemorrhage causing decrease in tissue blood low
● Cardiac failure causing decreased venous return and decreased cardiac output
● Localized vascular obstruction caused due to atherosclerosis and thrombosis
HISTOTOXIC HYPOXIA:
The tissues are unable to use oxygen in spite of normal PO2 in the blood. It occurs due to
destruction of cellular enzymes by poisonous substances causing damage of the cytochrome-
oxidase enzyme system.
Causes:
● Cyanide poisoning
● Sulphide poisoning
Symptoms of Hypoxia:
i. Impaired judgment,
ii. Drowsiness and excitement,
iii. Disorientation,
iv. Loss of time sense, headache.
Other symptoms include anorexia, nausea, vomiting, and tachycardia

Hypoxia affects the brain. A sudden drop in PO2 to 20 mm Hg causes unconsciousness in 10–15
seconds and death in about 4–5 minutes.
Types of hypoxia and their characteristic features:
Hypoxic Anemic Stagnant Histotoxic hypoxia
hypoxia hypoxia hypoxia
Po2 in blood Decreases Normal Normal Normal
O2 carrying capacity Normal Decreases Normal Normal
O2 content of blood Decreases Decreases Normal Normal
Blood flow rate Normal Normal Decrease Normal
Tissue utilization of Normal Normal Normal Decreases
O2
O2 therapy Very Moderate Less useful Not useful
useful
Av difference of O2 Normal Normal Increased Decreases
Cyanosis Present No Present No

18
Effects of hypoxia on body systems:
Normally, the effects are not severe when the ascent is slow with camping at different heights.

However, the effects of hypoxia on a subject vary depending on the severity of hypoxia. Sudden
exposure to a low pressure occurs when an aircraft loses cabin pressure. Slow and prolonged
exposure as is seen in mountaineers taking several days to climb a mountain, and life-long
exposure is seen in permanent residents at high altitudes.

1. Severe hypoxia (altitude more than 20,000 feet)

When a subject is suddenly exposed to severe hypoxia, the effects are mainly on the CNS,
cerebral ischaemia and cerebral oedema develops. The subject becomes unconscious and feels as
if he is knocked down within 10-15 sec. This is equivalent to sudden arrest of circulation, e.g.: -

● Sudden entry into the mines where there is methane. CO2 and other gases in excess.
● Sudden cutting of O2 supply to a pilot flying at a high altitude.
● Severe hypoxia may cause instant death due to cerebral ischaemia and cerebral oedema
within 4-5 min.

2. Moderate hypoxia (gradual onset of hypoxia < 15,000 feet)

When the mountaineers ascending a high altitude are exposed slowly to a moderate hypoxia. The
effects are seen on several systems.

a) Nervous system: Brain is highly susceptible to hypoxia. All types of hypoxia affect the brain
function. The symptoms resemble alcoholic intoxication.

● The subject may be depressed and at times elated with a sense of well-being.
● There is a general loss of self-control and the subject becomes talkative.
● The subject may become quarrelsome, ill-tempered, and rude.
● Loss of co-ordination and easy fatiguability present.
● Power of judgement is impaired. Loss of memory and euphoria are seen.

b) Respiratory system: All types of hypoxia stimulate respiratory centres through peripheral
chemoreceptors. As a result, the rate and depth of respiration increases. This may cause
alkalaemia due to loss of CO2 Some people develop pulmonary oedema and dyspnoea due to
pulmonary vasoconstriction. Periodic breathing may develop in some people.

c) CVS: Initially the subject develops tachycardia and an increase in the myocardial contractility.
Cardiac out- put and BP increase. There will be an increase in the cerebral and coronary blood
flow and a decrease in cutaneous and splanchnic blood flow. After some time, there is reduction
in cardiac output and BP, but tachycardia persists.

19
d) Digestive system: The subject develops loss of appetite (anorexia), nausea, vomiting and
diarrhoea.

e) Kidney: Erythropoietin production increases due to hypoxia. It starts producing alkaline urine.

f) Blood: RBC, WBC and platelet count increases. This is due to: (i) Shift of storage pool to
circulating pool, (ii) Slight increase in the production. O2 saturation of blood declines
proportional to the hypoxia.

TREATMENT OF HYPOXIA:

In mild hypoxia, O2 therapy is not indicated. Only in severe hypoxia with dyspnoea, 100% O,
therapy is indicated. This increases O2 in dissolved state from 0.3 mL to 2.0 mL per 100 mL of
blood.

Pure oxygen can be administered by using: -

1. An oxygen tent 2. A mask 3. An intranasal tube.

Oxygen therapy is highly useful in only some types of hypoxia and not all hypoxia

O2 Therapy in Hypoxic Hypoxia: -

Oxygen therapy is highly beneficial in hypoxic hypoxia caused by low Po2 in the atmosphere,
hypoventilation, and impaired diffusion in the lung. It increases alveolar Po2 by several times
and increases arterial O2 content both in dissolved and combined states. However, it is harmful
to subjects with depressed respiratory centres due to a rise in Pco2 to higher levels. Pure O2 is
not beneficial due to A-V shunts.

O2 Therapy in Anaemic Hypoxia: -

Oxygen therapy in this case is moderately beneficial 100% O2 therapy increases O2 content in a
dissolved form from 0.3 mL to 2.0 mL per 100 mL of blood and thus helps in providing extra
supply of O2 to tissue. Although this is small, yet this small amount of extra O2 may be the
difference between life and death. In CO poisoning when 100% or hyperbaric O2 is given, it
facilitates not only dissociation of CO2 from Hb but also increases the transport of O2 in
dissolved state. blood transfusion will be more beneficial to these patients.

O2 Therapy in Stagnant Hypoxia: -

O2 therapy is less useful in this hypoxia. When the therapy is given, it increases the transport of
O2 in a dissolved state. This little extra O2 in the dissolved state sometimes is useful.

O2 Therapy in Histotoxic Hypoxia: -

20
Tissues are unable to utilize O2 Hence O2 therapy may not be beneficial. However, if the
metabolic poisoning is not severe, hyperbaric O2 therapy may benefit the individual

Hyperbaric O2 Therapy in Clinical Practice: -

At one atmosphere of PO2 about 2.0 mL of O2 is present in 100 mL of blood in dissolved state.
This is proportional to the increase in O2 pressure. At two atmospheres, dissolved O2 in blood
doubles (4 mL/100 mL).

Hyperbaric O2 therapy is useful in the following clinical conditions:

1. CO poisoning

2. Dysbarism

3. Gas gangrene

4. Anaemic crisis

5. Air embolism

6. Leprosy.

Gas gangrene is caused by Clostridium, an anaerobic organism which stops multiplying in the
presence of O2 and the same is the case in leprosy. However, the toxic effects of hyperbaric O2
therapy are proportionate to the pressure at which it is administered

21
 OXYGEN-HEMOGLOBIN DISSOCIATION CURVE

● It is the curve that demonstrate the relationship between partial pressure of oxygen and
the percentage saturation of the haemoglobin with oxygen
● The sigmoid shape of the curve results from haemoglobin affinity for oxygen at various
PO2 levels
● Saturation of hemoglobin with oxygen depends upon the partial pressure of oxygen.
● When the partial pressure of oxygen is more, hemoglobin accepts oxygen and when the
partial pressure of oxygen is less, hemoglobin releases oxygen.
● The curve is divided into two major phases: - steep phase and plateau phase
STEEP PHASE

● It is in between po2 of 10mmHg and 60mmHg.

● Oxygen saturation of Hb is about 90% at PO2 60 mm Hg.

Significance of steep phase

⮚ oxygen saturation of Hb is very high
⮚ facilitates oxygen loading.
⮚ causes unloading of oxygen in the tissues
⮚ Large quantities of hemoglobin is released by shifting the curve to right by increased H+
or increased CO2

PLATEAU PHASE
● It is in between PO2 around 60mmHg and flattens at PO2 of 70mmHg
● Above 60mmHg only small amount of increase in oxygen binding and then it remains
apparently constant

22
Significance of plateau phase
There are two significances
1. Plateau in the curve provides a safety factor through which even a significant
decrease in lung function can allow normal saturation of Hb.
2. Oxygen saturation and content remain constant in spite of wide fluctuations in
alveolar PO2
This is the reason why oxygen content cannot be raised to 100% by hyperventilation
because Hb is already been saturated with oxygen atPO2 of 100mmHg. This only true
for normal people at sea level.

P50
P50 is the partial pressure of oxygen at which hemoglobin saturation with oxygen is 50%.
● It occurs at a PO2 of 27mmHg.
● It has great impact on steep phase
● If P50 is high, decrease in affinity of Hb for oxygen and right shift of curve
occurs
● If the P50 is low, increase in affinity of Hb for oxygen and left shift of curve
occurs.

Factors Affecting Hb-binding Affinity with Oxygen

1. The important factors are temperature, PCO2, PH and 2,3-Diphosphoglycerate.
2. Rise in PCO2, fall in PH and rise in temperature all shifts the curve to the right. And
vice versa.
3. Shift to right is physiologically advantageous at tissue level. As it facilitates unloading
of oxygen

Temperature
● High temperature decreases the affinity of Hb for oxygen.
● This helps in release of oxygen in metabolically active tissue in which temperature is
high.

23
pH:

● Decrease in PH shifts the curve to right and vice versa

● When blood passes through capillaries, CO2 enters red cell that decreases intracellular
pH and shifts the Oxy-Hb dissociation curve to right.
● when blood passes through tissue capillaries, the acidic environment facilitates release of
oxygen from Hb into the tissues

24
Carbon Dioxide
● During cellular metabolism, CO2 is released into circulation that increases generation of
H+ and decreases pH.
● This shifts the curve to the right.
● This helps in release of oxygen from Hb.

2,3-diphosphoglycerate [2,3-DPG]
o It is a byproduct formed as a result of anaerobic respiration (glycolysis) in the red blood
cells.
o Thus, binding of 2,3 DPG with Hb shifts the Oxy-Hb dissociation curve to right and
facilitates release of oxygen.
o At tissue level, it helps on the unloading of oxygen from red blood cell.
o 2,3-DPG increases in anemia, exercise, and hypoxic condition.

Factors that shift Oxy-Hb Dissociation Curve

Factors that shift the curve to right
1. Increased temperature
2. Increased PCO2
3. Increased 2,3-DPG
4. Decreased PH
5. Hypoxia
Shift of curve to right increase P50 which facilitates oxygen release.

25
Factors that shift the curve to the left:
1. Decrease temperature
2. Decrease PCO2
3. Decreased 2,3-DPG
4. Increase PH
5. Fetal Hb
6. Carbon monoxide.
Shift of curve to left decrease P50 which facilitates oxygen uptake.

BOHR EFFECT
Bohr effect is the effect by which presence of carbon dioxide decreases the affinity of
hemoglobin for oxygen.
● In the tissues, due to continuous metabolic activities, the partial pressure of carbon
dioxide is very high and the partial pressure of oxygen is low
● Due to this pressure gradient, carbon dioxide enters the blood and oxygen is released
from the blood to the tissues.
● Presence of carbon dioxide decreases the affinity of hemoglobin for oxygen.
● It enhances further release of oxygen to the tissues and oxygen dissociation curve is
shifted to right
Factors influencing Bohr effect
● All the factors, which shift the oxygen-dissociation curve to right (mentioned above)
enhance the Bohr effect.

26
 MECHANISM OF BREATHING
Breathing: -
The process of respiration, during which air is inhaled into the lungs through the mouth or nose
due to muscle contraction and then exhaled due to muscle relaxation. It compromises of both
inspiration and expiration with pressure changes during it.

Inspiration: -
Drawing in of oxygen rich air inside the lung by contraction of diaphragm &EICM to make
intrapleural pressure more negative

Muscles of inspiration =>

Primarily diaphragm & External intercostal muscles are involved in the process of inspiration.
Other than the above-mentioned muscles scalenes, sternocleidomastoid and muscles of upper
respiratory tract facilitate the inspiration.
1) Diaphragm:
This is the main muscle of inspiration. Contraction of the diaphragm expands the thoracic cavity
in 2 ways
⮚ Because of the contraction of diaphragm, the dome shape is flattened and the thoracic
cavity expands in a rostro-caudal direction
⮚ Contraction of the diaphragm also pushes the rib cage outwards that enlarges the thoracic
cavity in the antero-posterior plane.
Clinical significance
⮚ In cases of severe obesity, tight clothing around the thoracic and abdominal walls, there is
decreased expansion of the thoracic cage
⮚ Diaphragm is innervated by the phrenic nerve, so lesions can cause diaphragm palsy
2) External intercostals:
⮚ Contraction of external intercostals increases the transverse and antero-posterior
diameter.
⮚ The 2nd to 10th ribs rotates upwards and outwards by a bucket handle movement
⮚ The upper 4 ribs rotate the sternum in upward and outward direction by a pump handle
effect.
3) Accessory muscles of inspiration:
⮚ Scalenes: elevate the upper part of the rib cage
⮚ Sternocleidomastoid: lift the sternum outwards and elevate the rib cage by pump handle
effect.

27
 ⮚ Neck and back muscles: they elevate the pectoral girdle and extend the back that
increases the transverse and vertical area of the thorax

Mechanism of inspiration: -

● From the above flowchart we can see that inspiration is an involuntary process.
● As the volume of lungs is increased it creates a negative intrapulmonary pressure due to
which the air from external atmosphere into the lungs.
● The accessory muscles will assist in forced inspiration.

Expiration: - It is a simpler process when compared to inspiration as it is a passive process in

which CO2 rich air is released from the lungs

Muscles of expiration: -

28
 ⮚ There is no primary muscle of expiration. It mainly involves the elastic recoil of the
lungs. But in case of forced expiration, accessory muscles like abdominal muscle,
intercostal muscles, neck and back muscles are involved.
⮚ Abdominal muscles increase the intra- abdominal pressure and pushes the diaphragm
upwards into the chest cavity. This decreases the rostro-caudal diameter of thorax.
⮚ Internal intercostals pull the rib cage downwards and decrease thoracic volume both in
anteroposterior and transverse diameter. These muscles are helpful in conditions that
involve forced expiration like coughing, vomiting and strenuous defecation.

Mechanism of expiration: -

● From the above flowchart we can see that in normal expiration that no muscles are
involved.
● But in forced expiration the accessory muscles will help to overcome the resistance to
airflow unlike in forced inspiration where increase in lung volume is done by accessory
muscles of inspiration
● Quiet expiration is purely passive but in case of patients suffering from lung disease
airway resistance is high. Here they require participation of accessory expiratory muscles

Pressure changes during breathing :-

Alveolar pressure:

29
 ● The pressure within the pulmonary parenchyma is known as intrapulmonary pressure
which mainly focuses on facilitating respiration
● Normal intrapulmonary pressure: - 0 mmHg
● During inspiration intrapulmonary Pressure decreases to -1 mmHg again during breathing
expiration it increases to +1 mmHg
● Significance of intrapulmonary pressure: - During inspiration it decreases which Helps
air to suck into the lungs and during expiration it increases which removes air from the
lungs

Intrapleural pressure:
● Intrapleural pressure refers to the pressure within the pleural cavity. Normally, the
pressure within the pleural cavity is slightly less than the atmospheric pressure, which is
known as negative pressure
● Normal intrapleural pressure: -2.5 mmHg
● During inspiration it decreases to -6 mmHg and while expiration it increases to -4 mmHg
● The intrapleural pressure is negative because of the opposite direction of recoil in lungs
and chest wall
● The chest wall recoils outwards and lungs recoil inward that causes this pressure to be
negative.
● Pleural pressure is negative during quiet breathing and more negative during deep
inspiration.
● The measurement of intrapleural pressure is by recording the intra-esophageal pressure as
intrapleural pressure reflects the intra-esophageal pressure.
● In upright posture, intrapleural pressure is about -2.5 cm H2O at the base of lung and -10
cm H2O at the apex of the lung. This is because of the effect of gravity
● In supine posture, when the person lies straight, there is no gravitational force so there is
no gradient generated.
● Significance of intrapleural pressure: -
⮚ It helps in preventing the collapse of lung
⮚ It helps to increase the venous return
⮚ Loss of normal intrapleural pressure results in lung collapse and barrel shaped
chest.

Transpulmonary pressure:
● It is the pressure difference across the lung wall.
● This is measured by subtracting the pleural pressure from alveolar pressure
● This is the pressure that keeps the lungs inflated and prevents the lungs from collapsing.

Trans-airway pressure:
● This is the pressure difference across the airway which is the difference between the
pressure inside and outside the airway.
● This pressure is important in keeping the airways open during forced expiration.

30
Graph representing the pressure changes during respiration

31
 NON-RESPIRATORY FUNCTIONS OF LUNGS
1) FILTRATION
a) Particles > 6 μm
b) Particles 1- 5 μm
c) Particles < 1 μm

Particles >6 μm: These particles are filtered by

1) Hair in nostrils

2) turbulent precipitation

TURBULENT PRECIPITATION:

● Air passing through nasal passage hits many surfaces such as conchae, septum,
pharyngeal wall
● Now air can change the direction but particles in air can't.
● So they entrapped in the mucosa, then gets expelled or transported to the pharynx by
ciliary movement.

Particle size 1-5 μm: These settle in the terminal bronchiole as a result of Gravitational
precipitation.

⮚ Clinical aspect: Coal particles are of the size 1 to 5 microns, that's why coal workers
disease affects the Terminal bronchioles

Particle size <1 μm: These particles can enter the alveoli, consequently they can diffuse into
alveolar fluid or get expired

⮚ Clinical aspect: Cigarette smoke contains particles of size 0.3 microns. Mostly these
particles can enter alveolar fluid or get expired and don't get precipitated.

33
2) IMMUNE FUNCTION
Alveoli are lined by PAM (Pulmonary Alveolar Macrophages). These can phagocytose particles
entrapped in alveoli

A) if the particle is digestible, then its digested and taken into lung lymphatics

B) if a particle is Not digestible then, a giant cell capsule is formed, slowly digested

Clinical aspect: TB bacillus, silica particles are non-digestible, thus granuloma are formed by
PAM

3) METABOLIC FUNCTIONS OF PULMONARY ENDOTHELIUM

A) ACE (Angiotensin Converting Enzyme): Present in pulmonary endothelium. Converts
Angiotensin 1 to Angiotensin 2

B) Metabolize serotonin inside pulmonary endothelium

34
C) Pulmonary endothelium secretes prostaglandins, NO, clotting factors, cytokines

4) PHONATION AND ARTICULATION

● Phonation is by Larynx (Vocal cords/ folds, muscles)
● Articulation is by structures of mouth, nose, PNS, Pharynx, chest

5) ACID BASE BALANCE: By eliminating CO2 from the body

PULMONARY CIRCULATION AND ITS SPECIAL FEATURES

Pulmonary circulation consists of

A) Pulmonary arteries

B) Pulmonary arterioles

C) Pulmonary capillaries

D) Pulmonary veins

PULMONARY CIRCULATION SYSTEMIC CIRCULATION

1) less extensive so low peripheral resistance More extensive, high peripheral resistance

2) RV can pump at low Pressure of 25 mm LV (Left Ventricle) pumps at high pressure of

Hg owing to low resistance 120 mm Hg

3) Pulmonary arteries Aorta

Thin walled Thick walled
Highly distensible Elastic
Large lumen comparatively narrow lumen

4) Pulmonary arteries have Rich sympathetic Aorta has Rich sympathetic innervation with
innervation but lack resting vasomotor tone high resting vasomotor tone

35
5) Pulmonary arterioles Systemic arterioles are the main reason for high
Responds to Hypoxia by Vasoconstriction peripheral resistance

They respond to hypoxia by Vasodilation

6) Pulmonary capillaries Systemic capillaries

Blood flow is pulsatile Blood flow is continuous

7) In pulmonary capillaries, gas exchange In systemic capillaries, exchange of O2,

takes place across alveocapillary membrane, nutrients takes place across the capillary
no interstitial fluid is present endothelium between blood and interstitial fluid

8) Pulmonary veins Systemic veins

Has a pressure of about 8 mm Hg Pressure of 5mm Hg
Carry Oxygenated blood Carry deoxygenated blood

9) Lymphatics Relatively fewer lymphatics in systemic

Abundant circulation

36
 LUNG VOLUMES AND CAPACITIES
Pulmonary ventilation is studied by recording volume of movement of air in and out of lungs by
spirometry

● To easily describe the events of pulmonary ventilation

● Air in the lungs is divided into

4 VOLUMES
A) Tidal volume (TV)

B) Inspiratory Reserve Volume (IRV)

C) Expiratory Reserve Volume (ERV)

D) Residual volume (RV)

5 CAPACITIES
A) Inspiratory Capacity (IC)

B) Expiratory Capacity (EC)

C) Functional Residual Capacity (FRC)

D) Vital Capacity (VC)

E) Total Lung Capacity

1) Tidal volume (TV)

Volume of air moving in and out of lungs with each breath, normal value: 500ml

37
2) IRV (inspiratory reserve volume)

● Extra volume of air inspired in excess of inspiratory TV, normal value: 3000 ml
● For example, swimmer about to swim will inspires IRV

3) IC (inspiratory capacity):
● IC = TV + IRV
● Maximum volume of air that can be inspired from the resting expiratory level.

4) ERV (expiratory reserve volume): Extra volume of air expired forcefully in excess of
Expiratory TV, normal value: 1100 ml.

38
5)RV (residual volume): Volume of air remaining in lungs sheet most forceful expiration,
normal value: 1100-1200 ml

6)FRC (functional residual capacity):

● It is the volume of air that remains in the lung at the end of tidal expiration, normal
value: 2200-2500 ml
● FRC = ERV + RV

39
7) VC (vital capacity):
● VC = IRV + TV + ERV = IC + ERV

● Volume of air that can be forcefully expired after maximum inspiration, normal value:
3000-4000 ml.

8) TLC (total lung capacity):

● Maximum volume of air present in lungs after maximal inspiration
● Normal value: 4200-6000 ml

Values to be memorized

Volumes and Capacities Normal Values mL

Tidal volume 500

IRV 3000

ERV 1100

Residual Volume 1200

IC 3500

FRC 2300

Vital Capacity 4600

TLC 5800

40
 VENTILATION-PERFUSION RATIO

DEFINITION: Ratio of Alveolar ventilation to blood flow in the lung

= Alveolar Ventilation (Va)

Blood flow in the lung (Q)

Normal value = 0.8

Regional difference:
- APEX- increased ventilation
Decreased perfusion (blood flow)
Ratio is increased – 3.6
- BASE- increased perfusion
Decreased ventilation
Ratio is decreased- 0.6

There is twofold difference of ventilation and 5 fold difference in blood flow

PHYSIOLOGICAL IMPORTANCE – regional difference of the ratio

CLINICAL IMPORTANCE-
Altered ventilation perfusion ratio causes specific disease to specific part of the lung (eg.
tuberculosis)

Wasted perfusion: shunt

Shunt is the admixture of oxygenated and unoxygenated blood
Shunt can be anatomical or physiological
ANATOMICAL SHUNT- atrial septal defect, ventricular septal defect
PHYSIOLOGICAL SHUNT- in bronchial circulation

41
 PULMONARY SURFACTANT

● Pulmonary surfactant is a mixture of lipoprotein rich in phospholipid.

● Chief component- DIPALMITOYLPHOSPHATIDYLCHOLINE (DPPC)

COMPOSITION:
- LIPIDS- 90%
Dipalmitoyl phosphatidylcholine 62%
Phosphatidylglycerol 5%
Other phospholipids 10%
Neutral lipids 13%
- PROTEINS- 8%
Albumin
Immunoglobulin A
Apoproteins (SP- A, B, C, D)

SOURCE:
● Type 2 pneumocytes
● Contain more mitochondria, lamellar inclusion bodies

SYNTHESIS AND SECRETION:

Palmitate, choline, glucose are substrates

42
SYNTHESIS IN FETAL LIFE
Starts about 34 weeks and 90% at term
Premature newborn has low surfactant and it causes lung collapse

REGULATION OF SURFACTANT SYNTHESIS

- Hormonal: Glucocorticoids, thyroxine, insulin ( all promote synthesis)
- Quantity and quality of proteins: surfactant proteins A, B, C, D
SP A controls reuptake of surfactant by type 2 cells
- Stretching of lungs: yawning and sighing, slow pranayama
- Pharmacological agents: beta agonists, calcium
- Exercise

FUNCTIONS:
- Prevent lung collapse by decreasing the surface tension
- Promotes alveolar stability
- Prevent edema in the lung
- Decreases the work of breathing
- Immunoglobulin A and apoproteins provide innate immunity by acting as opsonin.

CLINICAL IMPORTANCE:
- Infant respiratory distress syndrome
- Atelectasis following surgery

43
44
 ALVEOLAR CAPILLARY MEMBRANE

● Also called respiratory membrane

● Form Blood gas interface
COMPOSITION:
Alveolar epithelium, interstitial fluid layer, capillary endothelium

LAYERS: 10
- Surfactant
- Alveolar epithelial cell
- Basement membrane of alveolar epithelium
- Interstitium
- Basement membrane of capillary endothelium
- Capillary endothelial cells
- Plasma
- RBC membrane
- Intraerythrocyte fluid
- Hemoglobin
Thickness: – 0.2 to 0.5 µ

FACTORS:
- Difference in partial pressure of gases on both sides
- Diffusing capacity of membrane for the gases
- Surface area of membrane
- Solubility of gas
- Thickness of membrane
- Molecular weight of the gas
CLINICAL SIGNIFICANCE:
ALVEOLAR CAPILLARY OBSTRUCTION SYNDROME
- Due to increased thickness of membrane
- Increased distance between alveolar and capillary membrane (edema due to heart
failure)

45
In hypoxemia only oxygen diffusion is affected (pO2 decreased) and no changes in pCO2
because CO2 solubility is 20 times more than O2

46
 Transport of O2 & CO2 & add a note on Hamburger phenomenon
and Haldane phenomenon
Transport of O2:
⮚ Transport in 2 forms: dissolved form & combined form as HbO2
⮚ Each gram (Hb) can carry 1.34 ml of O2
⮚ 100 ml blood delivers about 5ml of O2 to tissue
⮚ 5 litres of blood flows to organ & tissue in one minute, so total O2 delivered to tissue in
1min is 250 ml

Dissolved Combined form Total

form
Arterial 0.30ml/100 18.7ml/100 ml 19ml
ml
Venous 0.12 13.88 14.0ml
Difference (A-V) 0.18 4.82 5.0ml

Delivery of O2 to tissue:
⮚ Arterial blood ---🡪 interstitial tissue ---🡪 Intracellular

⬇️ ⬆️ ⬆️
⮚ Due to pressure gradient, O2 diffuse from arterial blood to tissue
⮚ In tissue, delivery of O2 affected by: PO2, PCO2, Temperature,
2,3 -DPG
⬆️ H+ ions ⬆️

Transport of CO2:
⮚ Each 100 ml of blood picks up of 4ml of CO2
⮚ CO2 is transported in arterial & venous blood in various form:
A) dissolved form – 10%
B) Carbamino compounds – 20%
C) Bicarbonate – 70%
⮚ The total CO2 content of either arterial or venous blood gives an idea about HCO3-
content
⮚ HCO3- Content is referred to alkali reserve

47
 ⮚ 100 ml of blood transports 4ml of CO2 from tissue to lung
⮚ 5 litres carry 200ml/min to lungs
Arterial Venous blood Difference
blood
Dissolved 2.6ml 3.0ml 0.4ml
form
Carbamino 2.6ml 3.4ml 0.8ml
compounds

HCO3 42.8ml 45.6ml 2.8ml

Total 48.0ml 52.0ml 4.0ml

Delivery of CO2 to lung:

⮚ Venous blood delivers CO2 to lung --🡪 expired air
⮚ Two influence factors: (Dissociation of CO2)
o Pressure gradient (PCO2)
o PO2 (Haldane effect)
o Temperature

Hamburger effect / chloride shift:

⮚ H2CO3 ready diffuse into H+ & HCO3-
⮚ At that time, HCO3- Increase in RBC
⮚ HCO3- diffuse out of the cell & simultaneously Cl- goes into the cell from
plasma (Neutrality maintain)
⮚ Also known as: chloride shift, anion exchanged 1, chloride – bicarbonate
exchanger

Haldane effect:
⮚ Blood passes through pulmonary capillary, O2 diffuse into blood to form HbO2
⮚ Oxygenation of Hb leads to dissociation of CO2 curve to right
⮚ Loading of O2 leads to unloading of CO2
⮚ Deoxygenated Hb binds to H+ Vigorously than that of oxygenated Hb, binding
of O2 with Hb, decrease CO2 affinity

48
 LUNG COMPLIANCE
⮚ Compliance – ability to recoil or ability to stretch
⮚ Assessed by pressure / volume relationship
⮚ Compliance is measure of its distensibility
⮚ Volume change per unit pressure change
⮚ Compliance = ∆V/∆P
Measurement:
⮚ Static compliance
⮚ Dynamic compliance

49
Static compliance :

Stages of compliance:
⮚ Stage 1: stage of stable lung volume
⮚ Stage 2: stage of opening of airways
⮚ Stage 3: stage of linear increase in lung volume
⮚ Stage 4: stage of cessation of inflation

50
Dynamic compliance:

Clinical significance:
⮚ Low compliance – less distensibility: more work required for lung to inflate to
achieve TV
~ Occurs in restrictive lung disorders & lung fibrosis
⮚ High compliance – more distensibility: occurs in obstructive lung disease &
emphysema

TIMED VITAL CAPACITY

TVC or FVC

⮚ If VC is recorded on a spirograph at known speed, volume of air expelled can be

timed
⮚ Thus, FVC – maximum volume of air which can be breathed out as forcefully &
rapidly followed by maximum inspiration
⮚ TVC – special stress on rapid, forcible & complete exhalation

Components of TVC:
⮚ Forced exploratory volume in 1 sec (FEV1) – Volume of FVC expired in 1st sec
of exhalation, Normal: 80% of FVC

51
 ⮚ Forced expiratory volume in 2 sec (FEV2) – Volume of FVC expired in first 2
sets of exhalation, Normal: 95% of FVC
⮚ Forced expiratory volume in 3 sec (FEV3) – Volume of FVC expired in first 3
sec of exhalation, Normal 98 to 100% of FVC

Clinical significance:
⮚ To distinguish between restrictive & obstructive lung disorders
⮚ In restrictive Disorder (emphysema, kyphoscoliosis) – arthritis of vertebral
column leads to chest expansion is restricted
⮚ Therefore, VC decrease while FEV normal

52
 DEAD SPACE
DEFINITION :
> It
is the amount of air in the respiratory passage which does not take part in
exchange of gases

Types:
1. Anatomical dead space
2. Physiological dead space or total dead space

1.Anatomical dead space:

⮚ It is the volume of air present in the 'conducting zone' of the respiratory passage i.e., from
nose and mouth up to terminal bronchioles.
⮚ Dead space is due to the structural arrangement (anatomy) of the airways
⮚ Often it is referred to as anatomical dead space where exchange of gases does not take
place.
⮚ Normal value: 150 mL (approx. equal to the body weight pounds).

⮚ The volume of wasted air is known as dead space volume

2.Physiological dead space or total dead space:

⮚ The volume of air in these alveoli is referred to as alveolar dead space
⮚ Physiological dead space = anatomical dead space + alveolar dead space
⮚ Normal healthy individuals: anatomical dead space is almost equal with the physiological
dead space
⮚ Various lung disease: alveolar dead space is high in which the physiological dead space is
more than anatomical dead space

Measurement of dead space

Dead space is estimated by three methods:
1.Radford formula
2.Single-breath co2 technique
3.Single-breath n2 technique

53
1.Radford formula:
⮚ Radford formula predicts the anatomical dead space of the individual
⮚ >The anatomical dead space of an individual in milliliters is equal to his weight in
pounds
⮚ E.g : person with body weight of 150 lbs (70kg) , the dead space is 150ml

⮚ This prediction is fairly reliable for healthy individuals, but not in patients with
respiratory problems

2.Single-breath co2 technique:

⮚ The volume of dead space (VD) is usually measured by the single-breath uses Bohr’s
equation in the form of a gas such as CO2.
⮚ CO2 used because it is almost absent in the inspired air, and its alveolar concentration is
same as in systemic arterial blood
⮚ Equation:

▪ VD is the volume of dead space,

▪ VE is the volume of expired air,
▪ FAX and FEX represent the concentration of gas in the
▪ expired air respectively. As alveolar concentration of gas is
▪ same as arterial blood
▪ Fax (concentration of substance in arterial blood) replaces
▪ FAX.

By using CO2 as the gas for this estimation,

PaCO2 and PECO2 represent the PCO2 in the arterial blood and mixed expired air respectively.

3.Single Breath Nitrogen Technique

⮚ The subject sitting comfortably breathes room air calmly for few breaths.
⮚ Then, he is instructed to take a deep breath from a normal mid-inspiration during which
he is switched over to a pure oxygen source (takes deep breath with pure oxygen).

54
⮚ The subject is then asked to expire slowly and steadily to the maximum, so that the
volume expired is his vital capacity.

⮚ As he expires, a simultaneous record is made of the volume flow rate and the percentage
concentration of N2 in the expired air is obtained from the single-breath N2 test in two
ways:
i. By constructing the equivalent dead space-alveolar air boundary
ii. By planimetry measurement

1.The initial gas exhaled is the phase I, which fills the dead space and therefore does not
contain N2.
2.The phase II is the mixture of dead space and alveolar gas, and
3.phase III is the alveolar gas
4.In phase IV, content of expired air increases, which ends at residual volume.

55
Clinical importance:
⮚ Alveolar ventilation represents the amount of air reaching the alveoli. This is the air that
takes part in gas exchange.
⮚ Even in the absence of lung diseases, if anatomic dead space volume is increased due
to any cause, alveolar ventilation decreases.
⮚ For example, a patient on mechanical ventilator, alveolar ventilation decreases due to
increased dead space volume (by tubing etc.). In such patients, if minute ventilation
remains constant, alveolar gas exchange suffers.

Physiological Significance
⮚ In rapid and shallow breathing, though minute ventilation does not change much,
alveolar ventilation is grossly impaired because most of the air inhaled is utilized to
occupy the anatomic dead space (the air available to enter into alveoli is less).
⮚ Therefore, patients with rapid and shallow breathing develop hypoxia and hypercapnia.
⮚ In contrast, a subject with deep and slow breathing will have adequate alveolar
ventilation though the minute ventilation does not change much. Such subjects have
alveolar ventilation even greater than subjects with normal breathing.
⮚ Thus, to improve alveolar ventilation, it is important to increase the depth of breathing
than to increase the frequency.
⮚ In fact, during moderate to severe exercise, a trained athlete achieves the target alveolar

ventilation by mainly increasing the depth rather than the frequency of breathing

56
 HERING-BREUER REFLEX
Lung inflation decreases tidal volume and increases respiratory frequency. There are two Hering
Breuer reflexes:
⮚ Hering-Breuer inflation reflex and
⮚ Hering Breuer deflation reflex.

1. In Hering-Breuer inflation reflex:

⮚ Steady increase in lung volume (lung inflation) results in increase in duration of
expiration.
⮚ Marked inflation of lungs with sustained pressure may even abruptly terminate
inspiration in progress in addition to the prolongation of expiration.

2. In Hering-Breuer deflation reflex:

⮚ Marked deflation of lung results in decrease in duration of expiration.
⮚ As described above, the receptors are slowly adapting stretch receptors in lung
parenchyma and airways and afferent and efferent pathways are vagus nerve

Significance of Hering-Breuer Reflex

⮚ This is a protective reflex that protects lung from over inflation

⮚ It is more useful in infants than in adults.
⮚ It controls tidal volume during eupnea (normal breathing) in infants.
⮚ In adults, this reflex does not operate unless tidal volume is much greater than the normal
inspiration.

Slowly adapting receptors:

⮚ The slowly adapting receptors are located within the smooth muscle of the conducting
airways.
⮚ They are sensory terminals of myelinated afferent nerve fibers.
⮚ As they respond to airway stretch, they are also known as pulmonary stretch receptors

Rapidly adapting receptors:

⮚ The rapidly adapting receptors are sensory terminals of myelinated afferent fibers that are
found in the larger conducting airways
⮚ They respond to a sudden maintained inflation with rapid increase in firing rate.
⮚ They are very sensitive to various chemokines like bradykinin, histamine, serotonin and
prostaglandins
⮚ They are also called as irritant receptors as they respond to irritation of the airways by
various noxious substances like smoke, dust, ammonia. They are also stimulated by acute
congestion and inflammation.

57
 STAGES OF COMPENSATION IN HYPOXIA
⮚ At a high altitude, there is decrease in PO2 that decreases O2 supply to the tissues.
⮚ To deliver the normal amount of O2, there are certain compensatory mechanisms
⮚ The most immediate mechanism is hyperventilation that is not prominent until the PO2
decreases to 60 mmHg
⮚ Normally, the drop of PO2 occurs in an altitude of approximately 4500m.
⮚ The hyperventilation induced by hypoxia at high altitude appears in two stages.

In First Stage
⮚ In the first stage that appears immediately on exposure to hypoxia ventilation increases
instantly though the increase in ventilation is small compared to the increase in
ventilation in the second stage.
⮚ The hyperventilation in first stage is mainly due to hypoxic stimulation of the carotid
bodies.
⮚ The magnitude of increase in ventilation is less because the hypoxic stimulation of
peripheral chemoreceptor is opposed by the decrease in arterial PCO2 that occurs due to
excess removal of carbon dioxide induced by hyperventilation.
⮚ This also increases arterial pH.
⮚ Decreased arterial PCO2 and alkalosis together blunt the hypoxic response.
In Second Stage
⮚ In second stage, ventilation increases slowly in 8 to 10 hours and then remains sustained.
⮚ The sustained increase in ventilation is due to the ventilatory acclimatization at high
altitude.
⮚ Ventilatory acclimatization is a physiological response that occurs during prolonged
exposure to hypoxia. After about 2 weeks, hyperventilation induced by hypoxia reaches a
stable plateau.
⮚ There are two mechanisms for ventilatory acclimatization
1. Chemoreceptor mechanism:
⮚ The pH of CSF is alkaline in the acute phase
⮚ Ventilation stimulated by hypoxia brings pH close to normal by the movement of
HCO3 outside the CSF
⮚ In prolonged exposure to hypoxia, sensitivity of carotid bodies to arterial PO2 alters.
2. Renal mechanism
⮚ The alkaline blood pH that occurs due to hypoxia induced hyperventilation opposes
the hypoxic response that decreases ventilation.
⮚ Kidney compensates pH by excreting more bicarbonates
⮚ This decreases the blood pH towards normal in about 3 days
⮚ This allows hypoxic drive to further increase minute ventilation and then attain a
steady state.

58
 CAISSON’S DISEASE
Definition: A chronic form of decompression sickness in which recurrent or persistent gas
emboli in the bones lead to multifocal ischemic necrosis is called caisson disease.

• It commonly occurs in deep sea divers or people working in watertight chambers

underwater (caisson) who return/ascend to surface rapidly. It also occurs when
ascending up in sky.
• At sea level, press is 1atm, and increases by 1atm for 10 meters increase in depth of water.

• Prevention is usually by gradual ascent to sea level and reduction should not be less than
50% and use saturation diving technique by mixing helium oxygen mixtures while deep
diving.
• Treatment is by recompressing immediately in a pressurised cabin. slow decompression
after this should be done. Hyperbaric oxygen can also be used.

Note: Important factor that severity of sickness depends on is percentage decrease in pressure.
Nitrogen narcosis

59
 CPR
Definition: The supportive and specific treatment given immediately to patients, in whom for some
reasons the cardiac and ventilatory activities have stopped, is called cardiopulmonary resuscitation.

Indications:
1. Acute and healed MI
2. Arrhythmias
3. Accidents
4. Cardiomyopathy
5. Drowning
6. Electric shock
7. Embolism

Objectives: A) To initiate and maintain circulation

B) To provide adequate pulmonary ventilation

Steps: 3 stages
1. Initial evaluation and basic life support

Mouth to mouth respiration: clear airway and extend the airway, close patient’s nostrils and take a deep
breath, exhale forcefully into his mouth and Look for chest expansion and abdominal distension,
maintain the rate at 10-15 per minute.
60
2. Advanced life support
A) primary therapy
*Defibrillation- It is control fibrillations and converts it into flutter or normal rhythm so
effective ventricular pumping occurs
*Airway management and O2 therapy- 100% O2 administration and endotracheal tube
intubation should be done

B) Adjunctive therapy includes self-induced cough, atropine sulphates, pacemakers, sodium

bicarbonate.

3. Post Resuscitation care

- Treatment of underlying cause for cardio respiratory arrest
- Managing the effects of arrest like hypoxia encephalopathy, cerebral edema.

61
 OBSTRUCTIVE AND RESTRICTIVE LUNG DISEASE

Restrictive lung disease Obstructive lung disease

Reduction in lung volumes, so volume of Reduction in airflow into lung
inhaled air decreases
Decrease in FEV1 and FEV1/FVC ratio Normal FEV1/FVC ratio
Work of breathing is increased due to work of breathing is increased due to more
increased effort exerted by patient to energy usage to overcome increased
inhale as lung compliance is reduced airway resistance
Patients take rapid and shallow breaths Patients take slow deep breaths
Increased respiratory rate Decreased respiratory rate
Eg: COPD, Asthma, Bronchiectasis Eg: Marked obesity, Scoliosis

62
St
udentNot
es

PHYSI
OLOGY
1s
tEdi
ti
on

Uni
t5
Cent
ralNervousSys
tem
 CONTENTS
ESSAY:

1. Enumerate the descending tracts of the spinal cord and Pg: 5

describe in detail the pyramidal tract. Mention its functions
and effect of lesions in different levels

2. Enumerate the nuclei of the hypothalamus and mention its Pg: 9

connections and functions

3. Classify pain pathways and explain the receptors of pain. Add Pg: 13
a note on the analgesic pathway and describe the dual
pathway for pain in detail.

4. List the ascending tracts of the spinal cord in detail about the Pg: 16
dorsal column pathway.

5. explain in detail about the basal ganglia and its internal and Pg: 19
external connections. Explain the clinical disorders and it’s
management.

6. Name the functional and anatomical lobes of the cerebellum Pg: 23

and enumerate on the structure, connection and functions.
Mention about the clinical features of a cerebellar disease
and lesion.

7. Explain in detail about the muscle spindle with it’s role in Pg: 26
control of tone in muscle. Add a note on Golgi tendon and it’s
regulation of muscle tone.

8. Explain the organs forming the vestibular apparatus and their Pg: 31
functions during angular and linear motion.

1
9. Explain about the otolith organs and their role in Pg: 39
acceleration. Add a note on Meniere’s disease

10. Explain about the synapse and explain about the properties Pg: 41
of synapse

SHORT NOTES

1. Role of the hypothalamus in satiety and hunger. Pg: 48

2. Thermostat mechanism of the hypothalamus. Pg: 48

3. Blood-brain barrier. Pg: 49

4. Parkinson’s disease. Pg: 51

5. Stretch reflex, inverse stretch reflex. Pg: 52

6. EEG waves and their clinical significance Pg: 55

7. Brown Sequard Syndrome, Pg: 57

8. Describe the formation, circulation and functions of CSF, Pg: 58

9. Decerebrate rigidity. Pg: 60

10. Differences between UMN and LMN lesion Pg: 61

11. REM and NREM sleep, Pg: 63

12. Properties of receptors. Pg: 65

2
13. Wallerian degeneration and regeneration Pg: 66

14. Types of memory, Pg: 69

15. Aphasia. Pg: 71

16. Kluver Bucy syndrome Pg: 72

17. Functions of frontal lobe Pg: 73

18. Functions of parietal lobe Pg: 74

19. Papez circuit. Pg: 75

3
 DESCENDING TRACTS OF SPINAL CORD

PYRAMIDAL TRACTS:
1. Anterior corticospinal tract
2. Lateral corticospinal tract

EXTRAPYRAMIDAL TRACT:
1. medial longitudinal fasciculus
2. anterior vestibulospinal tract
3. lateral vestibulospinal tract
4. reticulospinal tract
5. tectospinal tract
6. rubrospinal tract
7. olivospinal tract

PYRAMIDAL TRACT
● Pyramidal tracts are the descending tracts concerned with voluntary motor activities of
the body
● Also known as corticospinal tract.
● There are two corticospinal tracts- the anterior and lateral corticospinal tracts.
● While running from cortex to spinal cord, the fibers give the appearance of pyramid.

5
ORIGIN:
Fibers of pyramidal tract arise from:
1. Primary motor area (area 4)
2. Premotor area (area 6)
3. Supplementary motor area
4. Somatosensory area
All these fibers form the upper motor neurons of motor pathway.

COURSE:
Corona radiata:
● After origin, the nerve fibers run downwards through the white matter of cerebrum and
converge in the form of fan like structure.
● This fan like structure is called corona radiata.
● Corona radiata contains both ascending and descending fibers.
Internal capsule:
● Corona radiata converge in the form of internal capsule while passing through the brain
stem.
● It is situated between thalamus and caudate nucleus on medial side and thalamus and
lenticular nucleus on lateral side.
Pons:
● The fibers are divided into different bundles at the upper part of pons which are then
grouped into a compact bundle at the lower border.
Medulla:
● The fibers give the appearance of pyramid in the medulla region.
● At the lower border of medulla, the fibers are divided into bundles of unequal sizes.
● 80% of fibers cross the opposite site. While crossing, they form pyramidal decussation.
Spinal cord:
● The fibers which crossed the midline are called crossed pyramidal tract or lateral
corticospinal tract or indirect corticospinal tract.
● The uncrossed fibers are called uncrossed pyramidal tract or anterior corticospinal tract or
direct corticospinal tract.

6
TERMINATION:
● The fibers terminate both on the alpha and gamma motor neurons.
● Neurons giving origin to the pyramidal tract are called upper motor neurons.
● Alpha and gamma motor neurons are the lower motor neurons.

FUNCTIONS:
● Pyramidal tracts are concerned with voluntary movements of the body.
● Responsible for fine skilled movements.

EFFECTS OF LESION:
● Lesion in the neurons of the motor cortex and pyramidal tract is called upper motor
neuron lesion.
● Loss of voluntary movements in the extremities initially, later it involves other parts of
the body like hip and shoulder.
● Muscle tone is increased due to spasticity.
● Groups of muscles are affected
● Spastic paralysis of muscles.
● Hypotonia occurs in pure pyramidal tract lesions which is rare because extrapyramidal
tracts are also damaged during lesions.
● Superficial reflexes are lost.
● Deep reflexes are exaggerated.
● Abnormal plantar reflex called Babinski sign is present.

EFFECTS OF LESION AT DIFFERENT LEVELS:

Cerebral cortex:
● Hypertonia
● Spasticity
● Contralateral monoplegia (paralysis of one limb) or contralateral hemiplegia.
Internal capsule:
● Contralateral hemiplegia.
Brainstem:
● Contralateral hemiparesis (weakness of muscles in one side of the body)
● Sixth and seventh cranial nerve palsies.

7
Spinal cord:
● Unilateral lesion of lateral corticospinal fibers at upper cervical segment causes
ipsilateral hemiplegia.
● Bilateral lesion of lateral corticospinal fibers at upper cervical segment causes
quadriplegia (paralysis of all four limbs) and paralysis of respiratory muscles.
● Bilateral lesion in thoracic and lumbar segment results in paraplegia (paralysis of both
lower limbs)

8
 HYPOTHALAMUS

NUCLEI OF HYPOTHALAMUS:
Hypothalamus consists of large number of nuclei and nuclear groups
4 Main Nuclear Groups are
● Anterior group: includes supraoptic, preoptic, paraventricular nuclei (spp)
● Middle group: Tuberal, ventromedial, arcuate, dorsomedial nuclei (TV ad)
● Posterior group: Supramammilary, mammilary, posterior hypothalamic nuclei (psm)
● Lateral group: lateral preoptic area, lateral hypothalamic nuclei

Connections of hypothalamus:
● Through fornix it is connected to the limbic system
● Through the median forebrain bundle it is connected to the brainstem
● Through periventricular system it is connected to the sensory pathways and midbrain
● Through the mamillothalamic tract it is connected to the anterior nucleus of thalamus
● Retinohypothalamic fibers connect the retina to the suprachiasmatic nucleus
● Connected to the tegmental nucleus through the mamillotegmental tract
● The hypothalamohypophyseal tract connects the supraoptic and paraventricular nuclei to
the posterior pituitary
● Arcuate and venteromedian nuclei are connected to the infundibulum via the
tuberoinfundibular tract
● Locus ceruleus and dorsal hypothalamus are connected by the dorsal noradrenergic
pathway
● Serotonergic pathway connects raphe nucleus to hypothalamus
● Mesolimbic dopaminergic system connects the hypothalamus to the third ventricle
● Corticohypothalamic fibers connect the cerebral cortex to the hypothalamus

9
FUNCTIONS OF HYPOTHALAMUS:
1. Endocrine Functions
2. Autonomic Functions
3. Temperature Regulation
4. Circadian rhythm
5. Regulation of food
6. Regulation of water intake
7. Reproductive Functions
8. Immunological Functions
9. Influence on emotions
10. Role in sleep

Endocrine Functions
● Controls anterior and posterior pituitary functions.
● Connected with anterior pituitary via portal hypophyseal vessels and posterior pituitary
through hypothalamohypophyseal tract.
● Control of anterior pituitary function
By secreting various releasing and inhibiting hormones
The main releasing and inhibiting hormones are
● Growth hormone releasing hormones (GRH) - controls GH secretion
● Somatostatin- inhibits GH, TSH, prolactin secretion
● TRH - stimulate TSH secretion
● Corticotropin releasing hormones (CRH)- regulate ACTH secretion

Control of posterior pituitary functions

Neurons of supraoptic and paraventricular nuclei of Hypothalamus secretes 2 hormones:
● Antidiuretic hormone
● oxytocin
They are stored and released from posterior pituitary.

Autonomic functions
● Sympathetic control
Hypothalamus has profound influence on sympathetic functions
Stimulation of lateral area results in rise in BP, heart rate, sweating, pupillary dilation
Stimulation of posterior hypothalamus results in activation of emotional behavior pattern
● Parasympathetic control:
Stimulation of anterior hypothalamus results in parasympathetic response

10
Temperature regulation
● Depends on balance between mechanism that controls heat loss and heat gain
● Anterior hypothalamus- activates mechanism that promotes heat loss
● Posterior hypothalamus- activates the mechanism that increases heat production and
causes heat gain

Circadian rhythm
● Means 24hrs fluctuations in body function i;e. day- night variation
● Most of these circadian fans are regulated by hypothalamus
● Suprachiasmatic nucleus (SCN)- regulate and maintain circadian rhythm
● SCN aka biological clock - its accuracy of execution is achieved through
retinohypothalamic fibres that convey the retinal information of light and darkness via
optic chiasma to SCN
● Nocturnal secretion of melatonin
● Provide important hormonal signal for other functions

Regulation of food intake

By maintaining balance between intake and energy expenditure hence body weight is maintained
in normal range
Neural factors
● Feeding center - lateral hypothalamus
Satiety center- ventromedial hypothalamus
Hormonal factors
● Hormones that increase food intake- Neuropeptide Y, orexins, gherkin, MCH, GHRH
● Hormones that decrease food intake- estrogen, dopamine, peptide YY, leptin, CRH, gut
hormones, CCK
Metabolic factors
● Plasma glucose
● Malonyl CoA
● Amino acid and fatty acids
● Body temperature

Regulation of water intake

● Change in osmolality
● Change in fluid volume

Reproductive functions
Hypothalamus secretes Gonadotropin releasing hormone-crucial role

11
Immunological functions
Influence immunity by controlling the secretion of ACTH, cortisol via hypothalamo pituitary
adrenal axis

Influence on emotions
Hypothalamus forms one of the output pathways of limbic system (principal seat of emotions)

Role in sleep
● Diencephalic sleep zone (major part of posterior hypothalamus) induces slow wave sleep
● Preoptic area also induces sleep.

12
 PAIN
DEFINITION:
Pain is defined as an unpleasant sensory and emotional experience associated with actual or
potential tissue damage or described in terms of such damage

PAIN PATHWAYS
Pain is transmitted to the higher centers in the brain in the lateral spinothalamic tract of the
anterolateral system. The pain pathways are divided into two types:

1. Paleospinothalamic pathway
2. Neospinothalamic pathway

Paleospinothalamic Pathway
This pathway mainly carries the sensation of slow pain. The fibers are mostly C fibers.

First Order Neurons: enter the spinal cord and terminate mainly in the laminae II of the
dorsal horn.
Second Order Neurons: decussate and ascend up in the contralateral spinothalamic pathway.
In the brain-stem on their way to thalamus, fibers project to three major nuclear groups
forming three subsystems:
1. At the level of medulla: spinoreticulothalamic pathway.

2. Fibers also project heavily to the midbrain nuclei: (spino-mesencephalic fibers)

3.Fibers also project to hypothalamus forming spino-hypothalamic fiber system.

Third Order Neurons

In the thalamus, the fibers terminate mainly in the medial nuclear group (the midline and
intralaminar nuclei; also called as non-specific nuclei) from where the third order of neurons
arise and project to different areas of the cortex including limbic cortical areas.

Neospinothalamic Pathway:
This pathway carries mainly the fast pain. The fibers are mostly Aδ fibers.

First Order Neurons: terminate mainly in the lamina I and V in the dorsal horn of the spinal
cord. The neurotransmitters released at the terminals of primary nociceptive afferents (1st
order of neurons) are glutamate and neuropeptides (substance P).

Second Order Neurons: cross over to the opposite side in the same segment of the spinal cord
and ascend in the lateral spinothalamic tract. In the spinal cord - topographic organization of

13
 fibers: The fibers from lower body parts are placed laterally and fibers from upper body parts
are located more medially in the lateral fasciculus.

Third Order neurons: originate from specific thalamic nuclei and project to the postcentral
gyrus. The topographic organization of these fibers in the thalamus and cortex is very
concrete, and in the sensory cortex, the neurons are organized in modality specific columns.
Therefore, the fast pain is better localized.

Types of Nociceptors
Receptors for pain are called nociceptors. Nociceptors are the free nerve endings. They are
distributed widely throughout most parts of the body. However, there are few tissues like brain
(only the neural tissue of the brain) that are devoid of nociceptors.

The nociceptors are broadly divided into three categories:

1. Aδ mechanical nociceptors
2. Multimodal C fiber nociceptors
3. Other nociceptors.

Aδ Mechanical Nociceptors:

These are the terminals of Aδ fibers. The Aδ fibers are small myelinated axons that discharge
only in response to intense mechanical stimuli (but, not to thermal or chemical stimuli).
Aδ fibers conduct the fast pain.

Polymodal C Fiber Nociceptors:

Activated by high-intensity mechanical, chemical and thermal (both hot and cold) stimuli.
These are terminals of C fibers. The C fibers carry the slow pain.

Other Nociceptors: These include thermal nociceptors (Aδ and C fiber terminals that respond
to very low and high temperature, i. e. < 5°C and > 45°C respectively), Aδ fibers responding
to heat and non-multimodal C fibers responding to strong mechanical stimuli:

Vanilloid Receptors: Vanilloid receptor–1 (VR–1) at C fiber terminals - they respond to

vanillin, a group of pain producing compounds that include capsaicin and also responds to
increase in temperature > 43°C, and change in pH.

Local anesthetics and many centrally acting analgesics act by raising the pain threshold.

14
15
 ASCENDING TRACTS OF SPINAL CORD
Tracts which carry sensory information from external and internal environment to higher center

Various ascending tracts

1.Dorsal columns or posterior column
A.Tract of gracilis
B.Tract of cuneatus
2.Spinothalamic tracts
A.Lateral spinothalamic tract
B.Anterior or ventral spinothalamic tract
3.Spinocerebellar tract
A.Dorsal spinocerebellar tract
B.Ventral spinocerebellar tract
4.Spinotectal tract
5.Spino-olivary tract
6.Spinovestibular tract
7.Spinopontine tract
8.Spinoreticular tract
9.Comma tract

Dorsal column pathway

Other names
● Medial leminiscal pathway
● Tract of Goll and Burdach
● Posterior column
● Fasciculus of gracilis and cuneatus
Sensations carried
● Fine touch
● Pressure
● Vibration
● Proprioception

16
 ● Tactile localization
● Tactile discrimination
● Graphesthesia
● Stereognosis

First order Neuron

Peripheral nerves carrying sensations from various mechanoreceptors and proprioceptors
⬇️
Enter the spinal cord through dorsal root (Bell Magendie law)
⬇️
Cell bodies in the DRG; Axons after entering the spinal cord immediately ascends up in the
posterior white column of same side
⬇️
Ascend up and end in the Nucleus gracilis and Nucleus cuneatus in the medulla
● Fibres carrying sensation from the lower limb and trunk occupy the medial side
(Fasciculus gracilis or Tract of Goll);
● Fibres carrying sensation from the upper limb occupy the lateral side (Fasciculus
cuneatus or Tract of Burdach)

Second order Neuron

Second order neurons arise from nucleus gracilis and nucleus cuneatus
⬇️
Most of the fibres arising from the second order neuron crosses to the opposite side and form the
internal arcuate fibres
⬇️
Internal arcuate fibres decussate with opposite side internal arcuate fibre and form the Great
sensory decussation at the lower level of medulla
⬇️
After the decussation it is also called as medial lemniscal pathway
⬇️
It ascends up and synapse in thalamus (VPL Nucleus)
*Few external arcuate fibres which take origin from accessory cuneatus and ascend up in the
same side carrying unconscious tactile and proprioceptive sensations to cerebellum

17
Third order Neuron
Third order neurons are present in the VPL nucleus of thalamus
⬇️
Axons ascend through the internal capsule and reach the somatosensory area I (3,1,2) and
somatosensory area II

Some fibres also reach hypothalamus, limbic system and reticular formation

Diseases of posterior column:

● Subacute combined degeneration of spinal cord (B12 def)
● NeuroSyphilis –Tabes dorsalis
● Multiple sclerosis
● Gullian –barre syndrome
● Brown –Sequard syndrome

Sensory cortex

thalamus

medulla

Anterior STT
Lateral STT

Spinal cord
Crude
Pain, touch
temperature and
pressure

18
 BASAL GANGLIA

They are a group of deep subcortical nuclei located at the base of the forebrain that are primarily
involved in the control of posture and movement.
Anatomical organization:
● Caudate nucleus
● Putamen
● Globus pallidus: divided into internus and externus
● Subthalamic nucleus
● Substantia nigra

Inputs to the basal ganglia:

Contralateral
Ipsilateral cortex
cortex

thalamus

Dorsal raphe Pedunculopontine

nucleus nucleus

Globus striatum
pallidus
● The main inputs come from the cerebral cortex
● Most afferent information enter the basal ganglia through the striatum
● The afferent fibers are corticostriate projection, thalamostriate projection, raphestriate
projection and pedunculostriate projection.

19
Outputs of the basal ganglia:
Thalamus

CM
VPL

Superior
colliculus

GP
GP internus
externus PP
N

Subthalami
c nucleus
Substantia
nigra

● The principal outputs of the basal ganglia is from the GP internus

● The fibers mainly project into the ventral and centeromedian nuclei of the thalamus that
further projects into the cortices
● The output from the GP to thalamus is inhibitory, the output from thalamus to cortex is
excitatory.
● The main feature of input and output of basal ganglia is that the cerebral cortex projects
to the striatum, striatum projects to the GP, GP projects to the thalamus and the thalamus
projects back to the cortex that completes the motor loop.

Connections within the basal ganglia:

● Nigrostriatal projection: dopaminergic in nature, projects from the substantia nigra to
the striatum
● Striatonigral pathway: GABA-ergic in nature, projects from the striatum to the
substantia nigra.

20
Neural pathways through basal ganglia:
Direct pathways:
Cortex

Striatum

GP internus

Thalamus

Motor cortex
● The projection from cortex to striatum is excitatory, the further projections are inhibitory
● Stimulation of the striatum results in stimulation of thalamus by disinhibition

Indirect pathway:
Cortex

Striatum

GP externus

Subthalamic nucleus

GP internus

Thalamus

Motor cortex

● Striatum inhibits globus pallidus externus that further inhibits subthalamic nucleus
● Subthalamic nucleus activates globus pallidus internus
● Stimulation of striatum activates the GP internus and the final pathway is inhibitory.

21
Functions of basal ganglia:
● Involved in planning and programming of movements
● Controls posture
● Inhibits stretch reflex by stimulation of caudate nucleus
● Regulation of subconscious gross movements
● Role in cognitive functions
● Skilled movement regulation

Applied aspect:
Parkinson’s disease:
A disease of the old age
Characterized by the degeneration of the nigrostriatal pathway that leads to excessive loss of
dopamine and dopamine receptors
Features:
● Akinesia
● Bradykinesia
● Mask face
● Rigidity (cogwheel and lead pipe rigidity)
● Resting tremors
● Festinant gait

Treatment: anticholinergics, dopamine agonists, dopamine precursors

Huntington’s chorea:
Autosomal dominant type that occurs due to a defective gene on chromosome 4
Caused by the degeneration of the striatonigral pathway
Features:
● Chorea: rapid and involuntary movements
● Dementia

Treatment: no definitive treatment.

CEREBELLUM
● It is also called as little brain
● It is responsible for the integration and regulation of motor function

22
 ● It determines the rate, range, force and direction to the termination of movement

Cerebellar organisation:
Located in the posterior cranial fossa behind the brainstem
Connected to midbrain through superior cerebellar peduncle
Connected to the pons through middle cerebellar peduncle
Connected to the medulla through inferior cerebellar peduncle

Functional divisions of cerebellum:

Vestibulocerebellum:
● It is the oldest part, also called as archicerebellum
● Consists of flocculonodular lobe
● Involved in equilibrium and learning induced changes in the vestibulo-ocular reflex
Spinocerebellum:
● Also called as palaeocerebellum
● Consists of the vermis and the paravermal regions
● Also called as spinocerebellum as it receives inputs from the spinal cord
● It is involved in smooth and coordinated voluntary movements.
● Vermal portion projects into the brainstem area that control posture
● Paravermal region controls skilled voluntary movements
Cerebrocerebellum:
● Also called as neocerebellum, newest phylogenetically
● Projects into the cortex
● Involved in planning and programming of movements.

Cerebellar connections:
● Vestibulocerebellar tract: receives inputs from the vestibular apparatus and from
vestibular nuclei
● Dorsal spinocerebellar tract: receives inputs from spinal cord
● Cuneocerebellar tract: originates from lateral cuneate nucleus, provides inputs from head
and neck
● Tectocerebellar tract: conveys visual and auditory input to the cerebellum
● Pontocerebellar tract: motor cortex inputs
● Olivocerebellar tract: proprioceptive inputs that reach from the whole body through the
inferior olive.

Mode of inputs:
● Mossy fibers: proprioceptive inputs
● Climbing fibers: project to purkinje cells

23
Mode of output:
● Vestibulospinal tract
● Reticulospinal tract
● Rubrospinal tract
● Corticospinal tract

Internal connections of the cerebellum:

● There are 2 sources of input: mossy fibers and climbing fibers
● Purkinje cells are directly stimulated directly by the climbing fiber input
● Purkinje cells are indirectly stimulated by the mossy fibers via granule cell parallel fiber
pathways
● Basket and stellate cells are activated by mossy fibers and finally inhibit purkinje cells.
This is an example of feed forward inhibition.
● Granule cells also stimulate golgi cells which in turn inhibit the activity of granule cells,
this is an example of feedback inhibition.

Functions of cerebellum:
● Control of posture and equilibrium
● Vestibulo-ocular reflex
● Smoothening and coordination of movement
● Control of skilled voluntary movements
● Planning and programming of movements
● Control of muscle tone and stretch reflex
● Control of movement of one side of the body
● Learning and improvement of motor skills
● Eyeball movement
● Vestibular functions.

Cerebellar disorders:
No paralysis, normal reflexes
● Pendular knee jerk
● No sensory deficit
● Hypotonia is present
● Ataxia: defect in coordination due to errors in rate, range, force and direction of
movement
● Drunken gait, scanning speech, intention tremor, dysmetria, rebound phenomenon,
adiadochokinesia, decomposition of movement.
● Pathological nystagmus

24
 ● Charcot’s triad: nystagmus, intention tremor, scanning of speech
● Friedrich’s ataxia: hereditary ataxia because of the degeneration of spinocerebellar
tract.

cortex Hemispheric Paravermal Vermis

zone zone

Purkinje
cells

Intermediate
nucleus Deep
cerebell
ar nuclei
Dentate N
thalamu
s

Red Ves, N Reticular

Pyrimida nucleus nuclei
Reticulospinal tract
l tract Vestibulospinal tract Rubrospinal tract

MUSCLE SPINDLE AND GOLGI TENDON ORGAN

Definition -

25
● Muscle spindles are the receptors that respond to change in muscle length and the velocity
of lengthening.
● Present in all skeletal muscles.
● Fibers of the muscle spindle are known as intrafusal fibers as they are present inside the
fusiform capsules.
● They lie parallel to the extrafusal fibres (extrafusal fibres are the fibres involved in muscle
contraction)

Structure -
1. Intrafusal fibers are of two types: the nuclear bag fibers, and the nuclear chain fibers.
2. Named so because of their spindle/fusiform shape.

● Innervation of Muscle Spindle The muscle spindles have both afferent (sensory) and
efferent (motor) innervations.

✔ Afferent Innervation Sensory Fibers are Ia and II fibers.

There are two types of sensory endings in each muscle spindle: the primary endings, and
the secondary endings.
Primary Endings Secondary Endings

terminals of type Ia afferent fiber terminals of type II afferent fiber

also called annulospiral endings as they are also called flower-spray endings, as they appear
coiled spirally around the center of the intrafusal like flowers.
fibers

✔ Efferent Innervation (Motor Fibers)

✔ The spindles are innervated by the γ motor neurons. They are also called fusimotor fibers,
constituting 30% (70% of fibers are α motor neurons).

26
✔ The γ motor neurons are of two types: the dynamic γ motor neurons and the static γ motor
neurons.

Dynamic γ motor neurons Static γ motor neurons

Terminate on the nuclear bag fiber 1 Terminate on the nuclear bag fiber 2 and
nuclear chain fiber
Stimulation of dynamic γ motor neurons Stimulation of static γ motor neurons
increases response in type Ia afferent fibers increases response in type II afferent fibers
(only during the dynamic phase of muscle (only during the static
stretch; i.e. during change in muscle length) phase of muscle stretch; i.e. the maintained
stretch

Functions of Muscle Spindle

● Muscle spindles are receptors that are sensitive to stretch.

● Spindle is stretched by the stretch of the muscle, as the spindle is present in
parallel with the extrafusal fibers (actual contractile fibres).
● Thus, stretch of the muscle causes muscle contraction by stretching the
muscle spindle whereas contraction of the muscle causes muscle relaxation
by inhibiting the spindle.

MECHANISM OF ACTION IN RESPONSE TO MUSCLE SPINDLE

Stretch of muscle

Stretch of muscle spindle (as

intrafusal fibres are present in
parallel with muscle fiber)

Distortion of primary sensory

endings located at the centre of
nuclear bag fiber

Generation of action
potential in Ia afferent fibres

27
 Stimulation of α motor neurons in the
spinal cord (as Ia fiber directly
terminates on α motor neurons in spinal
cord)
0

Muscle contraction

● MECHANISM OF MUSCLE CONTRACTION IN RESPONSE TO γ MOTOR

NEURON STIMULATION

Activation of γ motor neurons

Contraction of peripheral parts of muscle

spindle (as peripheral part contain contractile
proteins and innervated by γ motor neurons)

Stretching of central part of spindle

Distortion of primary sensory

endings located at the centre of
nuclear bag fiber

Generation of action
potential in Ia afferent fibres

28
 Stimulation of α motor neurons in the
spinal cord (as Ia fiber directly
terminates on α motor neurons in spinal
cord)
0

Muscle contraction

● STATIC AND DYNAMIC RESPONSES

Static response Dynamic response
Stimulus - Muscle stretch (change in muscle Stimulus - Rate at which muscle is stretched
length at maintained stretch) (velocity of muscle lengthening)

Nuclear chain fiber involved Nuclear bag fiber involved

Impulse rate is the same throughout stretch Impulse rate is increased i.e., dynamic

● α–γ coactivation - The descending pathways that stimulate the γ motor neurons also
stimulate the α motor neurons.
1. Therefore, γ efferent discharge increases along with the increased discharge of α motor
neurons. This is called a-γ colinkage.
2. Thus, spindle adjusts motor neurons discharge throughout the period of muscle
contraction.

29
● GOLGI TENDON ORGAN

1. Location - Golgi tendon organs (GTO) are found in the tendon of the muscles.
2. Structure The GTOs are formed by the terminals of the group Ib afferent fibers. The Ib fibers
from GTO terminate indirectly on a motor neurons via interneurons.
As the interneurons are inhibitory, stimulation of Ib fibers inhibit the motor neuron
activity.
3. Function - Because of their arrangement (in series) with the muscle, GTO can be activated
either by muscle stretch or by contraction of the muscle.
4. Passive stretch does not effectively stimulate GTO. But, the afferents from GTO discharge
actively in response to muscle contraction as muscle contraction stretches the tendon to a
greater extent.

5.. The actual stimulus for activation of GTO is the

force that develops in the tendon by muscle
contraction or muscle stretch.
Therefore, GTO provides the force feedback
whereas muscle spindle provides the length
feedback

VESTIBULAR
APPARATUS
Ear is popularly known for its sensory function of audition, but equally important for its
non -auditory function like maintenance of equilibrium at rest and balance during
movement.

FUNCTIONAL ANATOMY:

30
 ● Vestibular apparatus also known as membranous labyrinth is enclosed in bony labyrinth

● Membranous labyrinth-contains endolymph rich in potassium similar to intracellular

fluid.
● Space between membranous labyrinth and bony labyrinth-resembles ECF.
Vestibular apparatus consists of:

● Otolith organ-Saccule and Utricle

● 3 semicircular canals
● Hair cells are the receptors in the vestibular apparatus

HAIR CELLS:

31
 ● Large number of cilia arranged according to length
● Kinocilium-longest cilium.
● Stereocilium-other cilia arranged in graded length.

Hair cells have directional sensitivity

Hair cell activity conveyed through eighth cranial nerve.

Bending of cilia towards kinocilium

Opens potassium channels

Ca enters hair cell through these channel

Depolarization

Bending of cilia away from kinocilium

Closes potassium channels

Prevent entry of Ca

Hyperpolarization

32
OTOLITH ORGANS:

● Receptors-Hair cells located in macula.

● Macular hair cells are covered with otolith membrane containing CaCO3
crystal.

● Macula of saccule-oriented vertically-detects linear acceleration in vertical

direction
● Macula of the utricle-oriented horizontally-detects linear acceleration in horizontal
direction.
● Also detect change in head position.

MECHANISM OF ACTION:
Otolith organs are heavier than endolymph, thus specific gravity is more than endolymph.

CHANGE IN HEAD POSITION:

Tilting of head

Change in the direction of gravitational pull in otolith membrane

As cilia are entrenched in otolith membrane

Bends cilia of some of the hair cells towards kinocilium.

33
Action potential generated.

34
 Linear acceleration of head

Due to higher specific gravity of otolith membrane

Membrane lags behind because of inertia

This causes bending of cilia

Action potential generated.

SEMICIRCULAR CANALS:
● Hair cells located in ampulla
● Cilia of ampullary hair cell located in cupula.
● Specific gravity of cupular fluid is same as endolymph.

35
MECHANISM OF ACTION
When head rotates to one side

Semicircular canals rotate to that side

For 20 sec due to natural inertia endolymph does not move

Initially endolymph lags behind

As if endolymph moves in opp direction to canal

For example, if head rotates to right

Initially endolymph practically rotates to left

Cupular fluid having same specific gravity moves with endolymph

Cupular deflection bends cilia of hair cell

In ampulla kinocilium located towards utricle

Hence displacement of cupula towards utricle

Stimulates hair cell.

36
 Head rotation is detected in the first 20 secs

After initial lag movement of endolymph equalizes the canal

Rotation not detected after initial movement

When head rotation stops

Endolymph continues to move in the same direction for about 20 sec

Causes deflection of cupula away from utricle

Hair cells are inhibited.

Arrangement of hair cells in the canals of both the ear is such that the beginning of rotation is
detected by hair cells in the ear toward which rotation takes place and termination of rotation is
detected by hair cells in the opposite ear.

APPLIED PHYSIOLOGY:
● VERTIGO-illusion of motion
● Physiological vertigo-MOTION SICKNESS due to overstimulation of vestibular
apparatus.
● Central positional vertigo-lesion of the 8th cranial nerve

37
● Peripheral or labyrinthine vertigo

● Benign positional vertigo.

38
 OTOLITH ORGANS AND THEIR ROLE IN ACCELERATION
There are 2 otolith organs:
o Utricle
o Saccule
● Utricle lies in posterior part of bony vestibule.
● Saccule lies anterior to the utricle opposite the footplate of stapes
● It receives the 5 openings of 3 semicircular canals
● It is also connected to the saccule through utriculosaccular duct.
● Sensory epithelium of utricle and saccule is macula.
● Macula is made of hair cells similar to hair cells of crista amupllaris
● A gelatinous membrane lies over the hair into which the hair gets embedded.
● Crystals of calcium carbonate called otoliths or otoconia are present in the membrane
● The gelatinous membrane with otoliths is called otolith membrane
● The otoliths increase the specific gravity of otolith membrane to about twice that of the
endolymph, hence it tends to respond to gravity changes.
● In utricle, macula is situated in horizontal plane so that hair cells are in vertical position
● In saccule, macula is in vertical position so that hair cells are in horizontal position
● They respond to linear acceleration (utricle to horizontal; saccule to vertical)
o Movement of head in horizontal/vertical axis
o Otoconia moves in opposite direction
o Stimulation of hair cells
● Utricle also detects dorsiflexion and ventrifelxion
● Saccule also detects side to side movement of neck.
● A tilt of 2.5 degree is enough to stimulate appropriate maculae.

INNERVATIONS AND CONNECTIONS OF VESTIBULAR APPARATUS

● Vestibular or scarpa’s ganglion is situated in lateral part of internal acoustic meatus
● It contains bipolar cells
● The distal part of bipolar cells innervates sensory epithelium while the central processes
aggregate to form vestibular nerve.
● The fibers of vestibular nerve end in vestibular nuclei and some goes to cerebellum
directly
● Vestibular nuclei are 4 in number (superior, medial, lateral, descending)
● Afferents to these nuclei comes from:
o Peripheral vestibular receptors
o Cerebellum
o Reticular formation
o Spinal cord
o Contralateral vestibular nuclei
● Efferent from vestibular nuclei goes to

39
 o Nuclei of CN 3, 4, 6 via medial longitudinal bundle. It is the pathway for vestibulo-
occular reflexes and the reason for nystagmus
o Motor part of spinal cord. This coordinates the movements of head, neck and body
in maintenance of balance
o Cerebellum. It helps to coordinate input information to maintain the body balance
o Automatic nervous system. Reason for nausea, vomiting, palpitation, sweating and
pallor seen in vestibular disorders.
o Vestibular nuclei of opposite side
o Cerebral cortex. Responsible for subjective awareness of motion

APPLIED ASPECT:
MENIERE’S DISEASE
● Also called endolymphatic hydrops
● It is a disorder of inner ear where endolymphatic system is distended with endolymph.
● It is characterized by vertigo, sensorineural hearing loss, tinnitus and aural fullness.

40
 SYNAPSE AND ITS PROPERTIES
Definition: Physiological junction without anatomical union two neuron or between a neuron
and an effector such as muscle or a gland.
Usually a neuron may receive 10,000 synaptic inputs.

Classification
Anatomical classification
1. Axodendritic: most common, formed between axon of presynaptic neuron and
dendrite of postsynaptic neuron, often excitatory
2. Axosomatic: synapses between axon and the cell body, mostly inhibitory
3. Axoaxonic: synapses between two axon, rare, often modulatory in nature
4. Dendro-dendritic: between dendrite of one neuron and dendrites of other
neuron, seen in olfactory bulb

Based on type of transmission

1.Chemical:
Transmission of impulse takes place by release of chemicals, unidirectional, present in
vertebrates including humans

2.Electrical:
Transmission of impulse by transfer of ions directly in both directions, seen in invertebrates.
In mammals,
a. Lateral vestibular nucleus, hippocampus and cerebral cortex
b. Cardiac and smooth muscle
c. Respiratory neuron in mammals

3.Conjoint:
Transmission is both chemical and electrical

Based on response
1.Excitatory synapse
2.Inhibitory synapse
3.Modulatory synapse

Structure of synapse(Axodendritic)
Junction between two neuron

41
 ● 1st neuron presynaptic neuron(axon)
● 2nd neuron postsynaptic neuron(dendrite)

1.Presynaptic nerve terminal

This is dilated terminal nerve endings. This contains
a. Vesicles that store the neurotransmitters
b. Mitochondria
c. Microtubules
Membrane present called presynaptic membrane, contains dense bar or active zone at which
vesicles fuse, rupture and release of neurotransmitters into the synaptic cleft

2.Post synaptic nerve terminal

● Membrane present called the postsynaptic membrane
● Part of postsynaptic membrane that is in opposition with presynaptic membrane called
subsynaptic membrane, contains a number of protein receptor

3.Synaptic cleft
● Space between presynaptic and postsynaptic terminal
● Measures about 200-400 deg A
● Filled with amorphous tissue, containing enzymes that destroys the released
neurotransmitters after its action is over

Mechanism of transmission of impulse(excitatory) :

Impulse (AP) is conducted along the nerve fibre to the presynaptic nerve terminal causing its
depolarization.

⬇
Voltage-gated Ca++ channels open and Ca++ enters the presynaptic nerve terminal.

⬇
Vesicles fuse (docking) with the presynaptic mem brane and rupture, releasing the
neurotransmitter into the synaptic cleft.
⬇
Neurotransmitter combines with the receptor sites present on the subsynaptic membrane.

42
This leads to the opening of ligand-gated Na+ channels & Na moves into postsynaptic nerve
terminal.
⬇
A local potential called Excitatory Post Synaptic Potential develops (amplitude 15 mV).
⬇
This triggers an action potential at the initial segment of postsynaptic neuron, which is more
sensitive due to the presence of more number of voltage-gated ionic channels.
⬇
This is conducted in both directions, i.e., towards somato dendritic tree and along the axon of the
postsynaptic neuron.

43
INHIBITION OF THE TRANSMISSION AT SYNAPSE
Conduction of nerve impulse along the nerve fibre to the presynaptic nerve terminal causing its
depolarization.
⬇
Voltage-gated Ca++ channels open and calcium enters the presynaptic nerve terminal.
⬇
Vesicles fuse with presynaptic membrane and rupture releasing the neurotransmitter into the
synaptic cleft.
⬇
Neurotransmitter combines with the receptors present on the subsynaptic membrane.
⬇
This leads to opening of ligand-gated Cl channels and Cl enters the postsynaptic nerve terminal.
⬇
Inhibitory Post Synaptic Potential develops due to hyperpolarization (IPSP).
⬇

44
 Impulse conduction is blocked.

Properties of synapse
1.One-way conduction:
● Conducts impulse in one direction only
● Reason: presence of receptor only on the postsynaptic membrane to the
neurotransmitter released from the presynaptic nerve terminal
● Useful for orderly function of neural function

2.Synaptic delay:
● Due to various mechanism involved in the synaptic transmission, some time is lapsed at
the synapse
● For one synapse the delay is 0.5msec
● Synaptic delay depends on the number of synapse present in the pathway

3.Summation:
A facilitated response to repeated stimuli applied simultaneously or one after the other is
called summation. It is of two types,

● Spatial summation: When one subthreshold stimulus is applied to one afferent

nerve fibre no response is obtained but it produces a local EPSP on the post

45
 synaptic new When subthreshold stimuli are applied to two or afferents, which
make synaptic connections with the motor neuron, simultaneously, then a response
is obtained due to summation of EPSPs on the postsynaptic ne This is referred to
as spatial summation.
● Temporal summation: When a single subthreshold stimulus is applied to an
afferent nerve fibre synapsing with a motor neuron, only an EPSP is produced.
When afferent fibre is stimulated with same subthreshold repeatedly at a rapid
rate, a propagating spike potential develops on the motor neuron due to summation
of the previous stimuli. This is called temporal summation.
4.Fatigue:
On repeated stimulation, the synapse goes into easy fatigue due to exhaustion of
neurotransmitters

5.Occlusion:
● Decline in response than normally expected
● Reflex response that is obtained by stimulating two afferent neuron is less than the
response obtained when they are stimulated separately
● This is due to presence of common neuron in both groups.

6.Subliminal fringe:
● Partial state of excitation
● Reflex response that is obtained by stimulating two afferent neurons together is more
than the response when they are stimulated separately

7.Facilitation:
● When a stimulus is applied to an afferent nerve, some response is obtained.
● When a second and third stimuli are applied immediately the response obtained are better
than first one
● Due to beneficial effects, increased Ca++ influx into the presynaptic neuron

8.Divergence:
● One neuron connecting to several neuron
Present in
a. Reticular activating system which is required for wide spread activation of brain
b. SNS for wide spread activation of body
c. Focal epileptic seizures

9.Convergence:

46
 Several neuron connecting to single neuron
a. Anterior horn cell receiving impulse from several sources
b. Several sensory neuron converging on a single relay neuron in the sensory tracts
c. Retinal to visual cortex

10.Reverbertory circuit:
Activity in the neuronal circuit continues for longer period even after cessation of stimulus.
This is basis for after discharge
a. Short term memory
b. Smooth decline and termination of a movement.

SHORT NOTES
47
 ROLE OF HYPOTHALAMUS IN SATIETY AND HUNGER
Role of hypothalamus in satiety
● Satiety center: ventromedial hypothalamus, its stimulation causes cessation of eating
● Decreases food intake by inhibiting feeding center

Role of hypothalamus in feeding

● Feeding center: lateral hypothalamus, its stimulation greatly increases food intake
● Remains chronically active and gets inhibited by satiety center once satiety is achieved

THERMOSTAT MECHANISM OF HYPOTHALAMUS

● Thermosensor cells in the hypothalamus detect changes in the temperature of blood and
receive inputs from thermo sensitive receptors in the skin which is matched with set point
of body temperature and initiate temperature regulating mechanisms
● Done depending on balance between mechanism that controls heat loss and heat gain
Anterior hypothalamus- activates mechanism that promotes heat loss by causing cutaneous
vasodilation & sweating
Posterior hypothalamus- activates the mechanism that increases heat production and promotes
heat gain by vasoconstriction and piloerection

48
Applied aspect:

Global hypothalamic syndrome:

● The disease involves either all parts or a large part of hypothalamus
● Primary tumors or metastatic carcinomas, lymphoma or granulomatous diseases like
sarcoidosis results in such syndromes
● Patient dies due to visceral homeostatic mechanism failure
Partial hypothalamic syndrome:
Occur due to specific lesions of a specific part of hypothalamus resulting in deficiency or
overproduction of a single hormone. Some of the important syndromes are
● Diabetes insipidus
● Neurogenic salt wasting
● Precocious puberty
● Body weight alteration
● Anorexia nervosa and bulimia
● Disturbance in temperature regulation
● Hypothalamic cardiovascular disorder
● Neurogenic pulmonary edema
BLOOD BRAIN BARRIER
A special barrier that exists between the blood and the brain tissue is the blood-brain barrier
(BBB). This was first demonstrated by Paul Ehrlich.

Anatomical basis
BBB is formed by two special structures

1. In the endothelium of capillaries of the brain, cells are joined by tight junctions. This
significantly decreases the permeability of the capillaries.
2. The capillaries are surrounded by the foot processes of astroglia. These glial processes form
a complete sheath around the capillaries.

49
CIRCUMVENTRICULAR ORGANS

Normally, BBB is deficient in some regions of the brain that are collectively called as
circumventricular organs

The important circumventricular organs are:

1. Organum vasculosum of lamina terminalis (OVLT)

2. Subfornical organ (SFO)

3. Area postrema in medulla oblongata

4. Posterior pituitary and median eminence (ventral part) of hypothalamus

5. The pineal gland

50
51
 Functions of BBB:
1. Neurons depend on a normal concentration of various ions in the fluid bathing them,
especially Na+, K+, Ca++, H+ and Mg++. Alteration in these ion concentrations in ECF of
brain tissue results in severe consequences. BBB maintains constancy of these ions in brain
fluids.

2. Many toxins either produced endogenously or admini-stered exogenously circulate in blood.

These toxins are harmful to the neurons that are highly sensitive. BBB protects neurons from
these harmful substances.
3. BBB prevents escape of neurotransmitters from brain into circulation.
4. Disruption of BBB helps in identifying the location and extent of lesions in the brain.

5. BBB influences drug permeability into the brain.

Clinical Importance
● Kernicterus
● Brain Tumor
● Infection and Injury

PARKINSON’S DISEASE
A disease of the old age
Characterized by the degeneration of the nigrostriatal pathway that leads to excessive loss of
dopamine and dopamine receptors
Features:
● Akinesia
● Bradykinesia
● Mask face
● Rigidity (cogwheel and lead pipe rigidity)
● Resting tremors
● Festinant gait

Treatment: anticholinergics, dopamine agonists, dopamine precursors

52
 STRETCH REFLEX
● DEFINITION - The reflex contraction of the muscle to stretch when a skeletal muscle
with its intact nerve supply is stretched is called the stretch reflex.
● STIMULUS - stretch of the muscle
● RESPONSE- contraction of the stretched muscle.
● There are two types of stretch reflexes: the phasic stretch reflex and the tonic stretch reflex.

■ Phasic Stretch Reflex

1. Stimulus - sudden stretch of the muscle.
2. Receptor - muscle spindle
3. Afferent group - Ia afferent fiber (2 branches)

4. Function -

One branch terminates Other branch terminates

monosynaptically on the disynaptically on motor neuron
motor neuron (heteronymous) supplying
(homonymous) supplying antagonist muscle via inhibitory
protagonist muscle interneuron

✔ Thus, activity in the Ia afferent fiber stimulates the homonymous motor neuron
that causes contraction of the protagonist muscle, and inhibits the heteronymous
motor neuron that causes relaxation of the antagonist muscle.
✔ Such an innervation that causes activation of a set of motor neuron and inhibition of
another set of motor neuron is called reciprocal innervation.
Therefore, when the agonist muscle contracts, simultaneously the antagonist
muscle relaxes.

■ Tonic Stretch Reflex

53
1. Stimulus - sustained stretch of the muscle.
2. Receptor - Muscle spindle
3. Afferents - both Ia and II afferent fibers.
4. Function -
✔ Tonic stretch reflex contributes to the muscle tone.
✔ Tonic stretch reflex is also important for regulation of posture.
✔ To maintain standing position, the extensors of knees should contract so that knees
remain extended and legs do not bend. This is achieved by the action of gravity on
medial extensors of the thigh.
✔ The sustained stretch of extensors results in sustained contraction of these
antigravity muscles that maintains extension at knee joint. Thus, the standing
position is maintained.
✔ After assuming standing posture for a longer duration, due to fatigue, gradually
the knees bend
that further stretches the quadriceps muscles. The flexion at knee joints elicits additional
tonic stretch reflex that, causes added sustained contraction of quadriceps. This
maintains further extension of knees and prevents the person from falling.
Thus, stretch reflex helps to restore and maintain the posture for a very long period.

INVERSE STRETCH REFLEXETCH REFLEX

(INVERSE MYOTATIC REFLEX)
● DEFINITION -Relaxation of the muscle in response to a strong stretch is called inverse
stretch reflex.

● REFLEX ARC
1. Receptors - Golgi tendon organs
2. Stimulus - stronger stretch or An active muscle contraction .
3. Afferent fibers Ib fibers that terminate on the inhibitory interneurons that, in turn, project
to the homonymous α motor neurons.
4. This results in inhibition of the agonist muscle.

54
● FUNCTIONS - Golgi tendon organ monitors force developed in the muscle.
1. The force is detected either by strong stretch or by an active contraction. Stimulation of
the GTO inhibits the agonist muscle through its reflex connections.
2. The agonist muscle relaxes in response to activation of GTO.
3. Thus, a stronger stretch imparted on the muscle automatically inhibits the muscle.
Therefore, the reflex is also called autogenic inhibition.

● PHYSIOLOGICAL SIGNIFICANCE -
Muscle spindle (stretch reflex) monitors muscle length and GTO (inverse stretch reflex)
monitors muscle tension, i.e. the force of contraction.
Inverse stretch reflex, by allowing the muscle to relax, prevents rupture of muscle when
the muscle is stretched to greater extents.

● EFFECT OF γ MOTOR NEURON ON STRETCH

1. Descending fibers from supraspinal segments increase the discharge of γ motor
neurons, which, in turn, increases the sensitivity of the spindle to stretch.
2. In upper motor neurons paralysis, the increased γ motor neuron discharge (due
to loss of inhibitory suprasegmental inputs on the γ motor neurons) increases the reflex
activity.
3. The muscle becomes hyper-reactive due to increased phasic stretch reflex
activity and becomes hypertonic due to increased tonic stretch reflex activity.

● MUSCLE TONE - Resistance of the muscle to stretch is called tone.

1. Muscle becomes hypertonic or spastic due to hyperactive stretch reflexes (increased γ
motor neuron discharge).
2. Muscle becomes hypotonic or flaccid when the motor neurons supplying the muscle
are damaged or when the discharge of γ motor neurons is decreased.

● CLASP KNIFE PHENOMENON

✔ When a hypertonic muscle as seen in upper motor neuron paralysis is stretched, muscle
contracts, but if the stretch is continued then muscle relaxes.
✔ This type of high resistance followed by sudden collapse is known as clasp-knife
phenomenon as it resembles the closing a clasp-knife.

55
 EEG
(electroencephalogram)
● Record of spontaneous electrical activities generated in cerebral cortex
● Electroencephalography- procedure
● Electroencephalograph- instrument
● Unipolar and bipolar leads are used for recording
● Unipolar lead consists of one exploring electrode and one indifferent, which is kept at
zero potential
● Bipolar lead consists of two exploring electrodes and potential difference between the
two electrodes is recorded

EEG PATTERN
● Alpha rhythm:
o Frequency:8-13Hz
o Amplitude: 50-100µV
o Most prominent wave
o Can be recorded with closed eyes from parieto-occipital area in resting man
o When eyes are opened alpha is replaced by beta. This is referred to as alpha block
● Beta rhythm:
o Frequency:12-32Hz
o Amplitude: 5-10µV
o Faster rhythm with lowest voltage
o Indicates alert stage
o Recorded from parietal and frontal region
● Theta rhythm:
o Frequency:4-7Hz
o Amplitude: 10µV
o Seen normally in children and during moderate sleep in adults
o Recorded from parietal and temporal region
● Delta wave
o Frequency:0.5-4Hz
o Amplitude: 20-200µV
o Seen during deep sleep in adults
o Recorded from occipital area
o Appearance in alert state indicates serious organ damage.

56
Clinical use of EEG:
o Diagnose epilepsy
o Confirm type of epilepsy
o Identify cortical site of abnormal discharge
o Intracranial space occupying lesion
o Sleep analysis
o Diagnose sleep disorders

Applied physiology:
o Epilepsy: Intermittent disorder characterized by sudden uncontrolled discharge of
cerebral neurons with or without loss of consciousness
o Types:
▪ Generalized:
● Grand mal epilepsy (generalized tonic clonic seizure)- discharge
from both hemispheres
● Petit mal epilepsy (absence seizures)
▪ Focal (temporal lobe and jacksonian epilepsy)

57
 BROWN SEQUARD SYNDROME
● Brown Séquard Syndrome is a functional hemisection of the spinal cord.
● It is usually seen in injury to the spinal cord or in tumors of the spinal cord that affects
only half of the cord.
● Damage occurs to ipsilateral dorsal-column pathway, contralateral spinothalamic tract
and ipsilateral descending motor (corticospinal tract) pathways.

Sensory deficit:
● On the side of lesion, the fine touch sensation, proprioceptive sensations (sensations from
tendons, muscles, joints and vibration sense) and tactile discrimination are lost.
● On the opposite side, pain and thermal sensations are lost.
● This occurs because sensation for fine touch, proprioception, and two point
discrimination ascend up in the dorsal column of the same side, whereas the sensation for
pain and temperature ascend up in the anterolateral system in the opposite side of the
spinal cord.

58
Motor deficit:
There is also damage to corticospinal tract on the side of hemisection of spinal cord. This causes
paresis (muscle weakness) and spasticity of muscles of the same side of the body.

CEREBROSPINAL FLUID
Formation of CSF:
⮚ Choroid plexuses, located in the floor of lateral, third and fourth ventricles, are the major
source of CSF. The other sources of CSF are the blood vessels of subependymal regions
and pia mater.
⮚ CSF accounts for about 70–160 ml. CSF occupies less than 10% of the volume of total
intracranial space.
⮚ The rate of formation of CSF is about 0.35 mL/min or, 20 mL/hour or, 500 mL/day. As a
whole, CSF is totally replaced four to five times daily

Mechanism of CSF formation:

CSF is formed by a combination of passive diffusion, active transport and facilitated diffusion.

59
 ● Formation occurs in two steps namely ultrafiltration and active secretion.
● Ultrafiltration of plasma occurs across the fenestrated capillary wall into the ECF that
baths the basal surface of epithelial cells of choroid plexus.
● Choroidal epithelial cells transport ions and solutes into CSF, mainly by active secretion.

Circulation and Absorption of CSF:

Circulation of CSF was described by Harvey Cushing as the third circulation in the body.

❖ The CSF is mainly formed in the lateral ventricle, from where it flows downward
into the third ventricle through foramen of Monro, and from the third ventricle
into the fourth ventricle though aqueduct of Sylvius.
❖ Finally, CSF comes out of fourth ventricle through the foramen of Magendie and
Luschka to enter the subarachnoid space.
❖ In the subarachnoid space, CSF moves upward toward the cerebral hemispheres
and downward toward the spinal cord (Fig. 141.3).
❖ Thus, obstruction of foramen of Monro results in distension of lateral ventricles,
occlusion of aqueduct of Sylvius causes distension of third ventricle, and
blockage of foramina of Magendie and Luschka initially distends fourth ventricle
and later the entire ventricular system is distended.
❖ Absorption of CSF occurs through the arachnoid villi.The main factor that
facilitates the movement of the fluid is the oncotic pressure .Other factor
promoting this mechanism is the hydrostatic pressures of CSF.

Functions of CSF:
✔ Protection from mechanical injury: A major function of CSF is to protect brain from
mechanical injury. Due to higher specific gravity, brain floats freely in CSF rather than
resting heavily on the skull box. Thus, the risk of routine acceleration-deceleration
injuries is eliminated and also the impact of major injuries is greatly diminished.
✔ Provides microenvironment for brain cells: Brain is metabolically fragile. Neurons in the
brain are highly sensitive to changes in oxygen, glucose, pH, temperature, etc. in their
external environment. However, the CSF ensures constancy in the external environment
of neurons. CSF accomplishes this by buffering the changes in blood on one side and
with the brain interstitial fluid on the other.
✔ Role in homeostasis: CSF is indirectly involved in regulation of respiration, blood
pressure, water intake and visceral function by bringing about the chemical changes like
hydrogen ion concentration (pH), osmolality, etc. in cerebral interstitial fluid. The
changes in blood PO2, PCO2 and pH are transmitted to chemosensitive respiratory
neurons and central chemoreceptors via CSF for appropriate homeostatic responses.
✔ Removal of proteins and waste products: There are no lymphatic channels in brain and
spinal cord. CSF removes proteins and waste products of metabolism, especially H+,

60
 lactate and CO2 through its sink action. In the brain, small amount of protein that leaks
into the interstitial fluid is drained by the CSF and returned to the blood stream. Thus, the
CSF serves the function of lymphatics in brain.

DECEREBRATE RIGIDITY
After a mid-collicular section (section between superior and inferior colliculi in an experimental
animal), severe spasticity is immediately observed in the extensor group of muscles of the body.
This is called decerebrate rigidity. Rigidity is so prominent that the limbs are fully extended and
the spine is hyperextended.

Mechanism of Decerebrate Rigidity:

● In midcollicular lesion, the influence of cortex and basal ganglia on inhibitory reticular
area is abolished (only cerebellar drive remains).
● Therefore, inhibitory output of the medullary reticulospinal tract becomes less inhibitory,
whereas facilitatory area continues to discharge spontaneously.
● Consequently, the net output of reticulospinal tract becomes more facilitatory. As motor
neurons are primarily driven by reticulospinal tract influence, decerebration causes severe
rigidity.

Importance of Decerebrate Rigidity:

61
Rigidity observed in decerebrate animal is more marked in the extensor muscles.
⮚ Extensor muscles are the most important components of posture regulating system as
they maintain erect posture of the body by keeping the limbs extended.
⮚ The tone of these muscles, which is a static postural reflex, is highly essential to support
the animal against gravity. Therefore, these muscles are called antigravity muscles.
⮚ In humans, the major antigravity muscles are the extensors of the lower limbs.
⮚ The increased extensor rigidity in decerebrate preparation indicates that medulla controls
the tone of the antigravity muscles that are involved in maintaining posture.

UMN AND LMN PARALYSIS

UMN paralysis:
It is the paralysis that results from the lesion of descending fibres between their origin from
cortical motor areas and their termination on the anterior horn cells of the spinal cord .

Features:
● Increased muscle tone (spasticity).
● No muscle atrophy, over prolonged time disuse atrophy can occur.
● Muscles affected in groups.
● Exaggerated tendon reflexes.
Physiological basis:
● Spasticity occurs due to increased motor neuron discharge and increased excitability
of the motor neurons
● There is a normal physiological inhibition that is exerted on the reticulospinal pathway by
the corticoreticular fibres which is interrupted in UMN paralysis, Thereby, there is
facilitatory action o the reticulospinal fibres causing hypertonia and spasticity
● Because of the loss of inhibition of the reticulospinal pathway, there is an increased
gamma motor neuron discharge that increases the sensitivity of the muscle spindle to
stretch 🡪 exaggerated deep tendon reflex.
● Superficial reflexes are abolished in UMN paralysis as the efferent pathway is
abolished.

LMN paralysis:
● This type of paralysis occurs in diseases that cause destruction of anterior horn cells or
their axons in dorsal root.
● Examples are poliomyelitis, motor neuron disease and lesion of nerve roots.

62
Features:
● Hypotonic muscles (flaccidity)
● Pronounced muscle atrophy
● Individual muscles affected
● Tendon reflexes are absent
● Babinski sign is negative
● Fibrillation, fasciculation and sharp waves (defibrillation potentials) seen
● Nerve conduction either decreased or absent

Physiological basis:
● Individual innervation to the muscle is lost, thereby muscles are affected individually.
Pronounced muscle atrophy is seen
● Loss of reflex arc is seen so superficial and deep reflexes are lost
● Decreased gamma motor neuron discharge causes the hypotonia of muscles
● Babinski sign is not elicited due to loss of motor neuron activity.

UMN paralysis LMN paralysis

Muscles affected In groups Individual
Size of muscles No atrophy Atrophy is pronounced
Type of paralysis Spastic paralysis Flaccid paralysis
Tendon reflexes Exaggerated Diminished/absent
Superficial reflexes Absent Absent
Babinski sign Extensor plantar response Flexor plantar response
(sign positive) (sign negative)

Involuntary movements Absent Present (in form of

defibrillator potentials)

EMG changes No denervation potential Denervation potential seen

Nerve conduction study No abnormalities Decreased nerve conduction

63
 REM AND NREM SLEEP
🡺 In the normal sleep cycle, the sleep begins with a phase of NREM sleep, also called as
the slow wave sleep.
🡺 There are 4 stages in slow wave sleep after which the person progresses to REM sleep
🡺 With the completion of REM phase, sleep cycle completes.

NREM sleep:
● There are 4 stages of progressive deepening of sleep.
● It is difficult to wake the subject in this phase and the EEG pattern progresses to slower
frequency waves.
● Stage 1: the subject becomes drowsy, there is a change from beta to alpha rhythm, light
sleep begins
● Stage 2: the amplitude of EEG waves slightly increases, sleep spindles and k complexes
are the characteristic features
● Stage 3: stage of moderate sleep, low frequency and high amplitude
● Stage 4: stage of deep sleep, delta rhythm is prominent, maximum slowing, very difficult
to wake the subject up, decrease in all the autonomic functions

REM sleep:
● Also called paradoxical sleep.
● Rapid low voltage EEG activity is seen, the activity resembles the beta rhythm as seen in
awakened state

64
Features:
● Rapid eyeball movements visible under the closed eyelids
● EEG pattern shown desynchronised rapid beta rhythm, subject likely to wake up
spontaneously from REM sleep
● PGO spikes: phasic potentials that originate from pons and through LGB travel to
occipital cortex (ponto geniculo occipital spikes)
● Dream seen in this stage is easily remembered
● Stimulation of sympathetic system is seen, increase in the autonomic functions
● In males, penile erection occurs – important to diagnose erectile dysfunction
● Profoundly depressed muscle tone, widespread hypotonia except extraocular and
middle ear muscles

NREM sleep REM sleep

Timing in sleep cycle Occurs first Occurs after NREM

Duration 75% of total sleep 25% of sleep

Autonomic functions Sympathetic inhibition Sympathetic excitation

Eyeball movement No eye movement Rapid eye movement

Dreams Not memorised Memorized

Muscle tone Inhibited Depressed

Type of sleep Enters into deep sleep Sleep lightens

EEG waves Slow wave amplitude High frequency low voltage

Mechanism Inhibition of RAS Activation of PGO axis

65
 PROPERTIES OF RECEPTORS
Definition:
● Receptors are transducers that convert various forms of energy in the environment to
action potentials in sensory neurons
● They are the ending of afferent nerve fibres
● The receptor is usually associated with non-neural cells that surround it, together they are
known as a sense organ
● They are specific for a particular stimulus, the form of energy that the receptor is most
sensitive to is called adequate stimulus

Properties of receptors:
Specificity: they are specific to a particular type of stimulus
Adequate stimulus: the form of energy to which the receptor is most sensitive to is called
adequate stimulus
Adaptation: when a stimulus of constant strength is applied continuously, frequency of
action potential in the sensory nerve decreases, also called as desensitisation, forms the basis
of classification of receptors as phasic and tonic receptors.
🡺 Phasic receptors: adapt rapidly, eg., touch and pressure receptors
🡺 Tonic receptors: adapt slowly, eg., baroreceptors in carotid sinus
Acuity: the precision of stimulus localisation, depends on the number of receptors present
in the area of application of stimulus
Intensity: receptors discharge based on the strength of stimulus.
🡺 If low strength stimulus is applied, receptors with less threshold are activated

66
 🡺 If more strength is applied, neurons are activated quickly and receptors present further are
also activated- receptor recruitment
Weber Fechner law: the magnitude of sensation is directly proportional to the log of
intensity of stimulus
Law of projection: no matter where a specific sensory pathway is stimulated along the
course, the sensation formed is referred to the location of the receptors. Forms the basis of
phantom limb
Muller’s Doctrine of specific nerve energy: the sensation evoked by a stimulus that
generates impulse in the pathway depends on the precise area of the brain that is activated by
the stimulus.
Sensory unit and receptive field:
🡺 Sensory unit is defined as every single sensory axon and all of its peripheral branches
🡺 Receptive field of a sensory unit is the area from which a stimulus produces a response in
that unit.

WALLERIAN DEGENERATION
Degenerative changes take place at three levels:

1. Changes in the distal-stump

2. Changes in the proximal stump (at the site of injury)
3. Changes in the cell body

CHANGES IN DISTAL STUMP

● When a peripheral nerve is cut, the part of the nerve separated from the cell body shows a
series of chemical and physical degenerative changes. These constitute Wallerian
degeneration.
● They appear within few hours and continue for several days.
● Degenerative changes also appear in the proximal part and in the cell body.
● These changes are called retrograde degeneration. Regeneration starts from the proximal
stump and proceeds distally at a slower rate.
The degenerative period may be divided into:

A. Early phase
B. Late phase

A. Early phase (1-7th day):

67
 ● During an early phase, only functional changes appear without physical changes.
● This phase lasts for about a week.

The following changes appear during an early phase in a sequential order:

1. Changes in the enzymatic activity of choline acetylase and ACh esterase.
2. Changes in the activity of ionic channels (decrease).
3. Change in amplitude and conduction velocity of nerve impulse appears within 2-3
days.
4. Ultrastructural changes in the organelles appear.
5. Failure of conduction of nerve impulse by 5th day. "B" fibres are the first to fail to
conduct impulses followed by "A" and finally "C" type fibres.

6. No gross structural changes take place until 7 days.

B. Late phase (8-32 days):
During this phase, histochemical and physical changes appear.
The changes are:

1. Neurofibrils swell and then disappear.

2. Axis cylinder breaks up into short lengths.
3. Myelin sheath disintegrates into droplets of fat.
4. Axon debris and disintegrated myelin are removed by macrophages
5 Neurilemmal sheath with its nucleus and endoneural tubes are tent intact at the end of
32 day
The entire degenerative process is completed by 4 weeks.

CHANGES IN PROXIMAL STUMP

In the central stump (proximal stump), where the nerve fibres are still attached to their cell
bodies, degeneration is usually confined to a centimeter or so next to the point of section. These
changes are very similar to the changes that take place in the distal stump.

CHANGES IN CELL BODY

Degenerative changes also appear in the cell body.
changes depend on:
1. Severity of injury
2. Proximity of lesion to the cell body

68
The changes are:
1. Chromatolysis: Nissl granules which represent endoplasmic reticulum and ribosomes break up
in to fine dust and lose their staining reaction. Hence the name chromatolysis. This process is a
reaction to injury and is necessary for synthesis of proteins required for neuronal survival.

2. Golgi apparatus, mitochondria and neurofibrils disappear.

3. The cell draws in more fluid and swells up.
4. The nucleus is pushed to one side. In severe cases, it may be totally extruded leading to the
death of the neuron.

These changes, which are associated with an alteration in the excitability of the cells begin on the
first day and reach the maximum in the third week, after which the cell regains its normal
appearance.

WALLERIAN REGENERATION
Regeneration begins at the central end while the degeneration of peripheral stump is proceeding.
Regeneration is seen in peripheral nerves due to the following factors.
1. Neurilemma along with its nucleus is present in peripheral nerves. This is essential for
regeneration of axon.
2. Schwann cells, fibroblasts, macrophages and injured peripheral neurons release growth
promoting factors (neurotrophins), which stimulate regeneration.
3. Schwann cells multiply and form continuous cords. This bridges the gap between the
cut ends and guides the growing filaments from the proximal stumps.
CHANGES IN CELL BODY DURING REGENRATION
The regenerative changes start within 3 weeks and will be completed in 80 days.
1. Nissl granules reappear.
2. Golgi apparatus, neurofibrillae and other organelles reappear.
3. The nucleus occupies central position again.
Regeneration in the cell body may occur even when the axon does not regenerate.
MECHANISM OF REGENERATION OF AXON
1. A large number of thin filaments called fibrils (upto hundred) sprout from the cut fibres
in all directions.
2. One of these fibrils enters the peripheral stump successfully, while the other branches
disappear.

69
 3. Schwann cells proliferate and form continuous cords of cells within the endoneurial
tubes. This bridges the gap between the proximal and distal stumps, and also guides the
growing filaments from the central end towards periphery.
4. The fibres grow at a rate of 1-4 mm/24 hrs towards the denervated muscle fibres due to
some chemical attraction called "neurotrophism." The chemical may be released by the
denervated muscle fibres and macrophages.
5. The growing filament reaches the muscle fibre and establishes contact with it and forms a
functional neuromuscular junction. The formation of a junction (synapse) between axonal
ending and the muscle membrane is guided by several chemicals released from both the
structures.
6. Myelin sheath begins to appear in about 15 days and proceeds peripherally at a slower
rate, and takes a long time (1) year) for a complete functional recovery. Final diameter
attained is 80-85% of the normal.
7. Occasionally, when the regeneration fails the fibres from the central end intertwine and
form an expanded mass called "neuroma." If neuroma contains sensory fibres, it is highly
painful.

TYPES OF MEMORY
● Memory is defined as the retention of learned information and experiences.
● Physiologically, according to the type of information that is stored, the memory can be
classified as:

1. EXPLICIT OR DECLARATIVE MEMORY: the memory of facts (sematic)

and memory of events (episodic)

● Short term memory

● Long term memory
2. IMPLICIT OR NONDECLARATIVE MEMORY
▪ Procedural memory: skills and habits
▪ Priming
▪ Non associative learning: habituation and sensitisation
▪ Associative learning: classical and operant conditioning

EXPLICIT OR DECLARATIVE MEMORY

● Explicit Memory, (Declarative or Recognition Memory) refers to the factual knowledge
of people, places or things.

70
 ● Associated with consciousness or at least awareness.
● The hippocampus and parts of medial temporal lobes – for its retention.

Episodic memory: for events

● Examples: recollection of a birthday party celebrated three days ago; events taken place
while taking breakfast etc

Semantic (factual) memory:

● Knowledge of objects, facts and concepts, words and their meaning

● Form of long-term explicit memory

For example, If you think about the word alarm clock,
🡪VISUAL MEMORY reminds us about its shape etc.
🡪AUDITORY MEMORY reminds us about its sound.
🡪SOMATOSENSORY MEMORY reminds us about that it is made of a plastic, glass etc.

Short term memory:

● It is the memory that lasts for seconds to hours, processing in the hippocampus and other
circuit changes take place.
● Working memory is a type of short- term memory. Repeated training can lead to short
term memory getting converted to long- term memory which is called consolidation

Long term memory:

There is storage of information for years together in long term memory. They are resistant to
disruption and is broadly divided into explicit and implicit memory.

IMPLICIT OR NONDECLARATIVE MEMORY

● Does not involve awareness, also called as reflexive or nondeclarative memory

● For its retention there is no processing in the hippocampus

● Procedural memory includes skills and habits. refers to the information about how to
perform a task. Eg. motor skills, habits, behavioural reflexes and the learning of certain
types of procedures and rules which, once acquired, become unconscious and automatic
● Priming is facilitation of recognition of words or objects by prior exposure to them
● Non-associative learning - the organism learns about a single stimulus. It
includes: Habituation and Sensitization.

On repeated stimulation, habituation produces less and less response, but sensitisation
produces a greater response.

71
 ● Associative learning -organism learns about the relation of one stimulus to another. It
includes: Classical conditioning and Operant conditioning.

APHASIA
It is defined as the loss or impairment of production and comprehension of spoken or written
language due to an acquired lesion of the brain

Causes
1. Cerebral thrombosis
2. Cerebral infarction
3. Injury to the brain during accidents
4. Inadequate blood flow to the parts of the brain due to vascular changes

5. Tumors of the brain.

6. Congenital

The following faculties of the speech are affected:

1. Speech production
2. Speech comprehension

3. Writing
4. Reading

TYPES OF APHASIA:

72
1) Pure word blindness
2) Pure word deafness

3) Wernicke's aphasia (sensory aphasia)

4) Broca's aphasia (motor aphasia)
5) Global aphasia
1. Pure word blindness: The person is unable to read printed matter or comprehend visual
signs. He cannot name the colors or objects. He is able to understand spoken words and can write
and repeat on dictation. The lesion is in the visuo-psychic area or angular gyrus in the dominant
hemi-sphere.

2. Pure word deafness: The person is unable to comprehend spoken word. He is unable to
repeat or write on dictation. Comprehension of visual signs and written matter is normal. The
lesion is present in the audito-psychic areas in the dominant cerebral hemisphere. Pure word
blindness and pure word deafness is called conduction aphasia.

3. Wernicke's aphasia:
● It is also called sensory/fluent/receptive aphasia.
● Speech is fluent but totally incomprehensible due to errors in word usage, structure and
tense. There is impairment of comprehension of speech and usage of paraphasic speech
(malformed words used)
● The lesion is in Wernicke's area of dominant hemisphere.
● There is no lesion in the motor apparatus of speech, but written letters are often combined
into meaningless words

4.Broca's aphasia (non-fluent motor aphasia):

● The lesion is in Broca's areas (45,44) of dominant hemisphere.
● Speech output is sparse, slow, poorly articulated and telegraphic.
● There is a severe writing impairment.
● Comprehension of written and spoken language is intact.

5.Global aphasia:
● The lesion around Wernicke's area involving the frontal (Broca's area), parietal, occipital
and temporal lobes is responsible for this type of severe form of aphasia.
● All aspects of speech and language are impaired.
● The patient cannot read, write, repeat and has poor auditory comprehension.
● Speech output is non-fluent and is minimal

KLUVER BUCY SYNDROME

73
Klüver Bucy syndrome (was first described by H Klüver and PC Bucy) is experimentally
induced in rhesus monkey by bilateral temporal lobectomy, particularly involving the amygdala.
⮚ Animal exhibits placidity and inability to recognize object visually in spite of good vision
(visual agnosia), but will pick up almost all objects and explore them orally.
⮚ They also show hypersexuality and hyperphagia (omniphagic).
⮚ The striking abnormality is to examine everything orally.
⮚ Animal fails to ignore peripheral stimuli (hypermetamorphosis), and therefore, respond
to every stimulus and explore everything.
⮚ Similar picture is observed in human beings following bilateral surgical removal of
temporal lobes, cerebral atrophies and meningoencephalitis following toxo plasmosis,
herpes simplex or AIDS.

FUNCTIONS OF FRONTAL LOBE

● The part of the cortex rostral to central sulcus (precentral sulcus) and medial to sylvian
fissure is the frontal lobe.
● It is divided into three parts: precentral region, transitional region and prefrontal
association cortex.

✔ Precentral region: contains primary motor cortex (area 4) and premotor cortex (area 6).
These areas control movements, both skilled and postural.
✔ Transitional region: it is the area between precentral gyrus and prefrontal cortex. This
includes area 44 and area 8. Area 44 is the motor speech area that controls motor
activities of speech apparatus, and area 8 is the frontal eye field that controls eye
movement.
✔ Prefrontal Association Cortex: (Prefrontal Lobe) includes area 9–14. This is subdivided
into orbital region (area 11–14 and 47), and dorsolateral region (area 9, 10, 45, and 46).
Area 24 of prefrontal lobe (in cingulated gyrus) is a part of Papez circuit. Orbital region

74
 is connected with temporal lobe, olfactory cortex and limbic structures. The dorsolateral
region receives inputs from various sensory modalities that include visual inputs and
auditory inputs. The prefrontal cortex provides powerful neocortical connections to basal
forebrain structures including hypothalamus that are involved in control of visceral
functions and emotional behaviours. Prefrontal cortex is the seat of human personality.

FUNCTIONS OF PARIETAL LOBE

✔ Parietal lobe lies posterior to the central sulcus and rostro dorsal to lateral sulcus (sylvian
fissure). It is divided into two regions:
✔ The anterior region that mainly contains primary somatosensory cortex (SI), i.e. the
Brodmann’s area 3, 1, and 2.
✔ The posterior region that contains other sensory areas, which is considered to be the
association sensory cortex. This includes the area 5 and 7 in the upper part, and area 39
and 40 in the lower part.

75
Functions
⮚ Area 3, 1 and 2 are meant for perception of sensations, especially the cortical sensations
(stereognosis, tactile localization and two-point discrimination), fine touch,
proprioception and vibration
⮚ Area 5 is more involved in processing of somatosensory information to produce
movement.
⮚ Area 7 primarily processes visual information in order to produce not only movement,
but also arousal, attention and emotion.

PAPEZ CIRCUIT
Papez circuit is a fundamental component of the limbic system. It is a closed neural circuitry that
starts and ends in the hippocampus. It plays an important role in genesis and control of emotion.

76
 ● The major circuit connects hippocampus to the mamillary body of the hypothalamus, the
hypothalamus to the anterior thalamic nuclei via the mammillothalamic tract and the
anterior thalamus to the cingulate gyrus by thalamic projections.
● The circuit is complete by the cingulate gyrus projecting to the hippocampus

Functions: information about learning and memory from cortex, especially from the prefrontal
cortex is referred to the limbic system through the cortical hippocampal connections

77
St
udentNot
es

PHYSI
OLOGY
1stEdi
t
ion

Uni
t7
Endocri
nol
ogy
 CONTENTS
ESSAY
1. Growth hormone: secretion, effects, regulation, Pg No: 4
disorders related to GH secretion

2. Thyroid hormone: secretion, steps, effects, regulation, Pg No: 13

thyroid disorders

3. Glucose homeostasis: hormones involved and their Pg No: 20

effects, add a note on diabetes mellitus

4. Adrenocortical hormones: hormone synthesis, Pg No: 25

functional anatomy of adrenal cortex, functions of
cortisol and aldosterone, applied aspect.

5. Calcium homeostasis, role of various hormones, add a Pg No: 35

note on osteoporosis

SHORT NOTES:
1. Functions of insulin, mechanism of action, note on Pg No: 41
somatomedin C

2. Adrenal medulla Pg No: 43

3. Milk ejection reflex Pg No: 47

4. Gigantism Pg No: 48

5. Acromegaly Pg No: 49

6. Dwarfism Pg No: 50

1
7. Diabetes insipidus and its types Pg No: 52

8. SIADH Pg No: 54

9. Secondary messenger mechanisms Pg No: 55

10. Cushing’s syndrome Pg No: 59

11. Pheochromocytoma Pg No: 61

12. Addison’s disease with a brief note on Addisonian Pg No: 62

crisis

13. Myxedema Pg No: 63

14. Cretinism Pg No: 64

15. Hashimoto’s thyroiditis Pg No: 65

16. Grave’s disease Pg No: 66

17. Hypothalomo-puititary axis Pg No: 67

18. G Protein coupled receptor Pg No: 68

19. Prolactin Pg No: 70

20. Insulin like growth factor Pg No: 72

2
 GROWTH HORMONE: SYNTHESIS, STORAGE, FUNCTIONS,
DISORDERS RELATED TO GH
Synopsis:
1. Introduction
2. SSS -structure, synthesis, secretion
3. Plasma level of growth hormone
4. Metabolism of growth hormone
5. Growth hormone receptor
6. Mechanism of action of growth hormone
7. Regulation of growth hormone secretion
8. Abnormalities of growth hormone secretion

INTRODUCTION:

❖ Growth hormone/somatotropin: most important hormone for post-natal growth and

development to adult size.
❖ Helps to maintain lean body mass and bone mass in adults

STRUCTURE:
❖ Single unbranched chain
❖ 191 amino acids
❖ Molecular weight;2000
❖ GH exhibit species specificity.

SYNTHESIS:
❖ GH is synthesized by acidophilic cells called somatotrophs of anterior pituitary.

SECRETION:
● GH is released in pulsatile fashion.
● Increased by sleep, stress and starvation.
● Decreased by obesity, hyperglycemia, pregnancy.
● Somatomedins decrease secretion of GH.

PLASMA LEVELS OF GH:

⮚ Basal plasma GH level;2-4 ng/ml
⮚ Its concentration graph shows fluctuation. after every 1-2 hr interval there is rise in plasma
GH level.
⮚ Diurnal variation in plasma levels of GH is seen.
⮚ Levels of GH increase from birth to early childhood.
⮚ Puberty is associated with peak period plasma GH levels.

4
CIRCULATION: GH bound to plasma protein. (GH binding protein)

HALF-LIFE: 0-20 min

DAILY GH OUTPUT: 0.2-1.0 mg/day

METABOLISM;
● GH is metabolized rapidly in the liver.
● Metabolic clearance rate: 350 L/day

GH RECEPTORS;
⮚ Present in liver and adipose tissue
⮚ Vary in size
⮚ Belongs to cytokine family of receptors.
⮚ Large extracellular portion- a transmembrane domain
⮚ Large intracellular portion -cytoplasmic portion

5
Mechanism of action:
On cartilage directly or indirectly

IGF-1 main component in post-natal life

IGF-2 responsible for intrauterine development

GH + receptor = GH secretagogue receptor (GHS - R)

Transmembrane receptor

Present in liver cells mainly

Induce JAK - STAT pathway and transcription of genes responsible for production of proteins
required for growth.

REGULATION:

◆ Hypothalamic control by growth hormone releasing hormone and growth hormone

inhibiting hormone from ant pituitary.

6
Stimulant for GHRH secretion:
✔ Hypoglycemia
✔ Physical stress
✔ Emotion
✔ Ghrelin
✔ Slow wave phase of sleep

Stimulant for GHIH secretion:

✔ Hyperglycemia
✔ Increase free fatty acids in plasma
✔ IGF - inhibit GHRH from hypothalamus
- inhibit GH from pituitary
✔ GH (autoregulation)
GHRH- inhibition on hypothalamus

Negative feedback control mechanism for GH involves he role of

⮚ Somatomedins
⮚ GH
⮚ GHRH
OHER FACTORS;
■ THYROXINE, CORTISOL: +ve production of GH
■ INSULIN: -ve GH gene expression
■ OBESITY: -ve GH response
■ ESROGEN: -ve GH secretion

7
ACTIONS OF GH;
◆ Growth promoting actions
◆ Metabolic actions

HYPOTHALAMUS GHRH ANTERIOR PITUITARY GH

Chondrogenesis

Tissue growth and

Skeletal Differentiation
growth

8
Physiological function:

◆ Growth and development:

❖ Increase in protein synthesis skeletal development tissue differentiation.

❖ Development of neurons and dendritic development.

◆ Effect on metabolic rate:

⮚ BMR and O2 consumption except retina, brain, gonads, spleen, lungs.

Effect on metabolic rate:

Lipolysis protein synthesis results in

Blood glucose
+ve N balance
relative vit deficiency
Effect on respiration;
Resting respiratory rate, minute ventilation, O2 carrying capacity

Effect on CVS;
Contractility by action of adrenaline- HR

CO🡪 systolic BP

Peripheral vasodilatation 🡪 diastolic BP

Effect on CNS;
Critical for development of CNS
wakefulness, responsiveness, speed of reflexes
Potentiates catecholamine associated effects.

9
Effect on GIT;
Appetite and food intake
Secretion of juices
Motility of gut

Effect on reproductive system;

● Responsible for proper functioning of reproductive system
● In males in aids in libido
● In females it regulates menstrual cycle.

Effect on kidney;
GFR and T max

ABNORMALITIES OF GH SECRETION;

HYPERSECRETION HYPOSECRETION

GIGANTISM DWARFISM[CHILDREN]
ACROMEGALY MILD ANEMIA [IN ADULT]

1. Gigantism:

Introduction:
Clinical condition characterized by increased secretion of GH prior
to the epiphyseal closure .

Etiology:
It is usually due to a pituitary tumor secreting excess GH.

Clinical features:
● Abnormal height: Affected individual is very tall around 7-8 feet with long bones.
● Large hand and feet.
● Gynecomastia due to prolactin like effect.
● Coarse facial features - thick lips, broad nose, macroglossia.
● Hyperglycemia due increased GH secretion.
● Headache, vomiting, diplopia, visual field defect.

10
Diagnosis:
Tumor by CT scan / MRI high GH level in plasma.

Treatment:
Surgical removal of tumor.

2. Acromegaly:

Introduction:
Clinical condition that occurs due to increase in GH in adults after epiphyseal closure of long
bones causing excessive growth in those areas where cartilage persists.

Clinical features :
● Acromegalic face: thick lips, macroglossia, broad and thick nose , prominent eye
browse.
● Prognathism ----- protrusion of lower jaw.
● Acral par abnormalities.
● Kyphosis.
● Increased sympathetic activity.
● Excessive growth of internal organs, cardiomegaly, splenomegaly, hepatomegaly.

3)Hyposecretion:
Mild anemia in adults

Features:
✧ Reduction in muscle mass
✧ Hypoglycemia

Treatment : Hematinic like iron

11
4. Dwarfism:
Introduction: Short stature due to deficiency of GH.

Etiology:

Endocrinal causes Non-Endocrinal causes

Growth hormone- related dwarfism;

● PITUITARY DWARFISM – GH deficiency in childhood
● retarded growth in all parts of the body
● 20yrs looks like 7-10 years of age

FEATURES
● Shortness of stature
● normal mental activity
● Plumpness-fatness
● Immature face
● Delicate exremities
● No sexual maturity due to gonadotrophin deficiency
DIAGNOSIS: low level of GH/ IGF1 in plasma
TREATMENT: administration of GH preparation using recombinant human GH

❖ IGF synthesis in liver AFRICAN PYGMIES

❖ or unresponsive GH receptors LARON DWARFISM/

GH INSENSITIVITY
SYNDROME

12
 THYROID GLAND
CHEMISTRY
Primary hormone secreted is thyroxine T4 along with lesser amounts of T3. T3 has much greater
biological activity than T4.
Both hormones are iodine containing amino acids.

SYNTHESIS
1. Iodine homeostasis: - Iodine is an essential raw material for thyroid hormone synthesis.
Dietary iodide is absorbed by intestine and enters the circulation.
2. Iodine pump/ tapping: - Transport of iodide from blood into thyroid cells and follicles.
This pump is achieved by sodium - iodide sympathetic which cotransports one iodide ion
with two sodium ions across basolateral membrane. The energy for this IODINE
transport comes from ATPase pump. This process of concentrating the iodide in the cells
is called iodide trapping. A protein called PENDRIN helps transport iodide out of thyroid
cells into colloid.
3. Formation and secretion of thyroglobulin: - A large glycoprotein is synthesised by
endoplasmic reticulum and Golgi apparatus and secreted into follicles. For one molecule
of thyroglobulins is equal to 70 tyrosine amino acid. They are the major substrates that
combine with iodine to form thyroid hormones.
4. Oxidation of iodide ion: - This oxidation of iodide is promoted by enzyme
PEROXIDASE and its accompanying hydrogen peroxidase in membrane of cells.
5. Organification of thyroglobulin: - The binding of iodine with thyroglobulin molecule is
called oganification of thyroglobulin. The first product formed is monoiodothyronine.
6. Coupling of iodotyrosine residues: -
MIT + DIT ——> T3
DIT + DIT ——> T4
Small amount of reverse T3 is also formed.

13
STORAGE
Thyroid gland has ability to store large amount of hormone. In normal human thyroid the
average distribution of iodinated compounds is
3% of MIT
33% of Di iodide thyroxine
35% of T4
7% of T3

14
RELEASE
a. MIT and DIT are rapidly deiodinated by deiodinase with follicular cells
b. Iodine and tyrosine are recycled for resynthesis of thyroid hormone.
c. Thyroid cells at the apical surface extended around small portion of colloid to form
pinocytic vesicles.
d. Pinocytic vesicles enters thyroid cells.
e. Lysosome fused and digest thyroglobulin in pinocytic vesicles.
f. T3 and T4 are in free form are released into cells, into surroundings capillaries and thus
enters into circulation.

MECHANISM OF ACTION
1. At cellular level: -
● T3 and T4 diffuse into cell and combine with nuclear receptor. This acts as DNA and
increase the mRNA. rRNA increases and increases, functional and structural proteins
synthesis.
● Increase in number and activity of mitochondria, which in turn increases the rate of ATP
to energise cellular functions.
● Increase in activity of sodium potassium ATPase. This leads to hydrolysis of ATP,
releasing energy and heat.
2. Effect on growth: -
● Promote growth and development
● Growth and development of brain during foetal life and for first few years of postnatal
life
● In adult, brain, T3 and T4, stimulate synapse formation, branching myelination of nerve
fibres, neurotransmitter, synthesis and vascularity
3. Effect on metabolism: -
A. Carbohydrates metabolism: -
● Increase glucose absorption
● Increase gluconeogenesis
● Increase glycogenolysis
● Accelerates insulin breakdown
● Increasing blood glucose level
● Hyperthyroidism- increase in blood glucose
● Hypothyroidism- decrease in blood glucose
B. Fat metabolism: -
● Thyroid hormone promotes cholesterol synthesis. At same time promote a hepatic break
down and military excretion of cholesterol.
● Hyperthyroidism- decrease in blood cholesterol
● Hypothyroidism- increase in blood cholesterol

15
C. Protein metabolism: -
● Hyperthyroidism causes breakdown of protein
● Potassium excretion- breakdown of tissues
D. BMR: -
● Stimulate metabolism of tissues
● Hyperthyroidism- BMR is high (intolerance to heat)
● Hypothyroidism- BMR is low (intolerance to cold)
E. Thermogenesis: -
● T3 and T4 increases heat production in body.
● T3 and T4 increases, futile cycles, in which oxidative phosphorylation dissociated from
ATP generation. This happens in brown fat and caused by a protein called thermogenin.
4. Effect on systems: -
A. CNS: -
● Essential for growth and activity of CNS
● Adult brain, hormone stimulates branching of dendrites and increases number of synapses
● Thyroid hormone deficiency during development causes mental retardation, motor
rigidity and deaf mutism.
● Hypothyroidism- low memory, slowness of thought and speech, low IQ
● Hyperthyroidism- irritable, emotional, restless, anxious and paranoia
B. CVS: -
● Increase in blood flow meets the need for heat elimination from the body. As a
consequence of the increase in blood flow., cardiac output also increases
● Increase in heart rate
● Increase in heart strength
● Mean arterial pressure is normal. Increase blood flow through tissues between heart beats
the pulse pressure is often increases with the systolic pressure elevated in
hyperthyroidism and diastolic pressure reduced.
C. Blood: -
● Stimulates erythropoiesis and necessary for maturation of RBC.
● Hyperthyroidism- polycythaemia
● Hypothyroidism- Anaemia
D. GIT: -
● Stimulates appetite and food intake, motility and secretion of digestive juice
● Hyperthyroidism- diarrhoea
● Hypothyroidism- constipation
E. RS: -
● Increase in carbon dioxide formation, increase in oxygen utilisation, increases rate and
depth of respiration

16
 F. GONADS: -
● In males hyperthyroidism- impotence, hypothyroidism- loss of libido
● In females hyperthyroidism- oligomenorrhoea, hypothyroidism- menorrhagia and
amenorrhea
G. Effect on function of muscles.
● Both in hyper and hypo - present of muscle weakness
● In hypothyroidism weakness is due to general depression of metabolism.
● In hyperthyroidism weakness is due to thyrotoxic myopathy. And also increase in
irritability of CNS.
H. Skin: -
● In hypothyroidism- accumulates, promoting water retention. Puffiness of skin.
● In hyperthyroidism- excess, heat is produced so it dissipates, with increase in sweat
production
I. Effect on kidney: -
● Maintain renal plasma flow, GFR, reabsorption of secretory activities.

REGULATION
1. Effects of TSH on thyroid secretion: -
● Present in anterior pituitary
● Increases secretion of T3 and T4
2. TSH is regulated by TRH from hypothalamus: -
● TSH is controlled by TRH which is synthesised by neurons in the PVN of hypothalamus
and secreted from their nerve endings in median eminence of hypothalamus.
3. Feedback effect: -
● Thyroid hormone has a negative feedback effect to prevent over secretion of hormone or
overactivity of target tissues.

17
APPLIED/ CLINICAL ASPECTS
HYPERTHYROIDISM
● Primary hyperthyroidism- hyperactivity of gland, follicular carcinoma, LATS
● SECONDARY HYPERTHYROIDISM- Due to increase secretion of TSH and TRH
● Graves diseases- autoimmune disease in which antibody called TS immunoglobulin form
against the TSH receptor in thyroid gland. High level of TH secretion caused by TSIs in
turn suppress anterior pituitary.
● Thyroid Adenoma: - as long as adenoma, continues to secrete, large quantities of thyroid
hormone, secretory function in the remainder of thyroid gland is almost totally inhibited
because thyroid hormone from the adenoma depress production of TSH.
SYMPTOMS: -
● Exophthalmos: - protrusion of eyeball, epithelial surface of eyes becomes dry and
irritated and often infected, resulting in ulceration of cornea. Oedematous swelling of
retro orbital tissues and degenerative changes in extraocular muscles.
● Decrease body weight
● Insomnia
● Restless, emotional, anxious, highly irritable.
● Hand tremor - increase secretion of catecholamines
● Polycythaemia
● Intolerance to heat- increase sweating
● Hypertension
● Varying degree of diarrhoea
● Muscle weakness
● Hyperglycaemia

HYPOTHYROIDISM
● Primary hypothyroidism: - defect in gland itself
● Secondary hypothyroidism- either due to decrease in TSH or TRH
● Hashimoto disease: - the autoimmunity destroys the gland rather than stimulates it.
● Thyroiditis: - causes progressive deterioration and finally fibrosis of gland, with resultant
diminished or absent of thyroid hormone.
● Hypothyroidism in infants: -
a. Persistence of physiological jaundice
b. Difficulty in feeding
c. Delay in eruption of teeth
● Persistent untreated hypothyroidism in infants leads to CRETINISM
● CRETINISM: - characterised by failure of body growth and by mental retardation.
Features: -
● Infantile features are seen- nose broad, flattened widely placed eyes, large protruding
tongue

18
 ● Non pitting oedema
● Dwarf stature
● Mentally retarded, low IQ, myelination and synapse formation affected.
● Dry, rough and scaly skin
● Hypogonadism - impotence and sterility are common.
● Sluggish slow and lethargic movement.
● Low BMR
SYMPTOMS: -
● Myxoedema feature of hypothyroidism
● Swelling of thyroid gland- goitre
● Puffy face
● Hoarseness of voice
● Dry, rough and scaly skin
● Anaemia
● Atherosclerosis- decrease in thyroid hormone and increase in quantity of blood
cholesterol.
● Intolerance to cold.
● Constipation
● Low sperm count in male
● Abnormal menstrual cycle in females
Myxoedema Madness - untreated cases- severe mental deficiency
Myxoedema Coma- medical emergency in which there is depressed level of consciousness with
body temperature going down to 25 degree C

19
 GLUCOSE HOMEOSTASIS; HORMONES INVOLVED AND
THEIR EFFECTS; ADD A NOTE ON DIABETES MELLITUS

NORMAL PLASMA GLUCOSE LEVEL

● Normal fasting plasma glucose level is 70-99mg/dl.
● After food intake, this value increases, but remains within 200mg/dl. Therefore, random
blood glucose when <200mg/dl is considered clinically normal.
● The normal postprandial 2 hours blood glucose level is <140mg/dl

FACTORS REGULATING BLOOD GLUCOSE LEVEL

LIVER
● Liver is the main organ in regulation of blood glucose level.
● It serves as a receiving (glycogen synthesis), manufacturing (gluconeogenesis and
glycogenolysis), storing (glycogen storage) and distributing centre for glucose
● Glycogen is the storage form of glucose

● The secretion of glucose by the liver raises the blood glucose

● Removal of glucose by actively metabolizing tissues by the liver lower blood glucose
level
GLYCOGENESIS - When the blood glucose level is high, liver takes up the glucose and
stores it as “Glycogen” under the influence of Insulin
GLYCOGENOLYSIS - When the blood glucose level is low, glycogen breakdown happens
and the glucose output to the blood stream increases under the influence of glucagon and
epinephrine
● The liver thus functions as a GLUCOSTAT maintaining a constant circulating level of
glucose

20
HORMONES:
▪ Insulin and glucagon are the main hormones that regulates blood glucose level in the
body
Insulin
● It is a peptide hormone secreted by β cells of pancreas
● Elevation of glucose level in plasma is an important stimulator of insulin secretion
● It facilitates glucose entry into the hepatic cells
● It stimulates glycolysis, lipogenesis, and glycogen synthesis
● It inhibits glycogenolysis and gluconeogenesis
● Therefore, the primary function of the insulin is to lower the plasma glucose
concentration
● It is the only hormone that decreases the plasma glucose level (only effective
anti-diabetogenic hormone)
Glucagon
● It is a peptide hormone secreted by α cells of pancreas
● Physiological action of glucagon is almost opposite to that of insulin
● It stimulates glycogenolysis and gluconeogenesis
● It inhibits glycogen synthesis by inhibiting glycogen synthase
● It facilitates lipolysis and thus increases free fatty acids in the blood
● It especially facilitates hepatic glucose output and thus increases blood glucose level

INSULIN-GLUCAGON RATIO:
● Ratio of Insulin to the Glucagon is the I/G ratio
● Because of their opposing effects, a balance should be maintained between the secretion
of insulin and glucagon for maintaining normal metabolic functions
● Therefore, insulin-glucagon molar ratio (I/G ratio) in plasma is more important than their
individual concentration.
● Normally, the I/G ratio following a balance diet is approximately 3
● Following overnight fasting, it decreases to 1, and after prolonged fasting the ratio may
be as low as 0.4
● Following glucose infusion, the ratio may rise to 30.

PHYSIOLOGICAL SIGNIFICANCE:
a) During starvation: -
Low I/G ratio 🡪 glycogen break down and gluconeogenesis 🡪 increases glucose level
b) During high-fed state: -
High I/G ratio 🡪 favouring deposition of nutrients in the form glycogen, protein and fat 🡪
decreases glucose level
c) In diabetes: -Inappropriate I/G ratio influences metabolic status
● Secretion of glucagon is inappropriately elevated in insulin deficiency

21
 ● The metabolic derangements are affected by this abnormal ratio.

DIABETES MELLITUS
● It is a group of metabolic diseases due to destruction of β cells of pancreas or decreased
sensitivity of insulin receptors (insulin resistance) characterized by hyperglycaemia.
● Diabetes is called “a disease of starvation in the midst of plenty”

TYPE 1 TYPE 2
Develops in childhood before the age of Develops after the age of 40 (Maturity onset
40 (Juvenile diabetes mellitus) diabetes mellitus)

Plasma insulin level - low Plasma insulin level – Normal or high

Cause: Insulin resistance, β cell morphology is
Cause: Autoimmune Destruction of β cells normal
Not obese Obese
Hyperglycaemia with high incidence of Hyperglycaemia with low incidence of
ketoacidosis ketoacidosis
Genetic susceptibility is less than 50 % Genetic susceptibility is more than 50 %
Treatment: sulphonyl urea, biguanides, exercise,
Treatment: Insulin replacement diet control, yoga

22
FEATURES OF DIABETES MELLITUS:
POLYPHAGIA:

POLYURIA: When plasma glucose level exceeds renal threshold (180 mg/dl),glucose appears in
urine
POLYDIPSIA: Osmotic diuresis(dehydration) & hyperglycaemia 🡪 increased osmolality of
blood which acts on thirst centre (pre-optic area) 🡪 polydipsia
HYPERGLYCEMIA: Glucose cannot enter the cells in the absence of insulin 🡪 High plasma
glucose
GLYCOSURIA: Occurs when plasma glucose level exceeds renal threshold (180 mg /dl)
WEIGHT LOSS: Glucose is not utilized by the cells

23
COMPLICATIONS:-

INVESTIGATIONS: -

Fasting Blood Glucose Tolerance Test HbA1c

Glucose
NORMAL < 99 mg/dl < 140 mg/dl < 5.7%
PREDIABETES 100- 125 mg/dl 140- 199 mg/dl 5.7 -6.4%
DIABETES > 126 mg/dl > 200 mg/dl > 6.5%

24
 ADRENOCORTICAL HORMONES
INTRODUCTION
Outer adrenal cortex:
● 80% - 90% of adrenal gland
● MESODERM origin
● Secretes steroid hormones
Inner adrenal medulla:
● 10% - 20% of adrenal gland
● NEUROECTODERM origin (related to sympathetic ganglia)
● Secretes catecholamines
GLUCOCORTICOID MINERALOCORTICOID SEX STEROIDS
S S
HORMONES Cortisol Aldosterone Dehydroepiandrosterone
Corticosterone Deoxycorticosterone Androstenedione

SECRETED FROM Only Zona fasciculata Mainly Zona glomerulosa Mainly Zona reticularis
(Long columnar cells) (Small clumps of cells) (Network of intercalated
cells)
FUNCTIONS Metabolic Maintenance of Maintenance of secondary
Anti inflammatory extracellular fluid volume sexual characteristics
Immunosuppressant and electrolyte balance

FUNCTIONAL ANATOMY
SYNTHESIS:

25
ENZYME DEFICIENCIES
● 21 β hydroxylase deficiency
o Causes congenital adrenal hyperplasia
o Decreased glucocorticoid, mineralocorticoid
o Increased pregnenolone due to feedback increase in ACTH levels
o Excess production of androgen – virilization
o It is known as ADRENOGENITAL SYNDROME characterised by hirsutism,
small breast, heavy arms and legs, clitoromegaly, receding hairline, male
distribution of suprapubic hair, androgenic flush. In severe forms it may cause
female pseudo hermaphroditism
o Also causes hyponatremia
o (SALT LOSING FORM OF CONGENITAL VIRILIZING ADRENAL
HYPERPLASIA)

● 11 β hydroxylase deficiency
o Increased 11 β deoxy cortisol / 11 β deoxy corticosterone levels
o Excess mineralocorticoid leads to hypertension
o (HYPERTENSIVE FORM OF CONGENITAL VIRILIZING ADRENAL
HYPERPLASIA)

● 17 α hydroxylase deficiency: Causes hypertension and hyperkalaemia

● 3 β hydroxysteroid dehydrogenase deficiency: Masculinization of females and

hypospadias in males

● Cholesterol desmolase deficiency: Fatal; causes termination of pregnancy

METABOLISM:
● Average plasma concentration
Aldosterone – 0.0006 µg/dl
Cortisol – 14 µg/dl
● Binds to TRANCORTIN (80%)
ALBUMIN (10% - 15%)
Remaining 5% - 10% free form
● Cortisol is metabolised in liver and excreted in kidneys
● 17 keto steroids (etiocholanolone) is metabolite of adrenal androgen; its accumulation in
blood causes ETIOCHOLANOLONE FEVER

26
PHYSIOLOGICAL IMPORTANCE (of metabolism): -
● Normal transcortin level is 3mg/dl
It is elevated in pregnancy
Hence in pregnancy, the symptoms of cortisol excess does not appear even when cortisol
is synthesised excess (more cortisol will be bound to more transcortin)
● Half life of cortisol is 60-90 mins whereas of aldosterone is 20 mins as aldosterone is less
protein bound

GLUCOCORTICOIDS
Follows the pattern of ACTH secretion (diurnal variation)
ACTH and cortisol levels peaks at early morning 4am to 10am

PHYSIOLOGICAL IMPORTANCE: -
● Steroids should not be stopped abruptly
● It causes suppression of HPA axis
● If stopped patient may not tolerate stress and may collapse
● It takes about 10 months for pituitary to function normally after a prolonged steroid
therapy
● Hence steroid dose should be tapered and gradually reduced over weeks

FUNCTIONS OF GLUCOCORTICOIDS: -
1)EFFECT ON CARBOHYDRATE METABOLISM:
o Increases blood glucose levels
o Stimulates gluconeogenesis
o Increases secretion of glycogenolytic hormones
o Anti insulin effect
o Physiologic importance – Complicates diabetes, defensive role in fasting
2)EFFECT ON PROTEIN METABOLISM:
o Facilitates proteolysis
o Inhibits protein synthesis
3) EFFECT ON FAT METABOLISM:
o Promotes lipolysis
o Promotes ketogenesis

27
4) EFFECT ON FOOD INTAKE:
o Increases appetite by increasing neuropeptide Y
o Increases leptin levels
o Causes redistribution of fat

5)PERMISSIVE ACTIONS: Glucocorticoid is essential for some physiological actions of other

hormones to take place

6)EFFECTS ON CARDIOVASCULAR SYSTEM

o Increases myocardial performance
o Maintains vascular reactivity and increases responsiveness of arterioles to catecholamines
and angiotensin II

7)EFFECT ON CENTRAL NERVOUS SYSTEM

o Influences mood and behaviour
o Decreases REM sleep, excessive levels cause insomnia
o Impairs memory
o Decreases responsiveness to stimuli

8)EFFECT ON MUSCULOSKELETAL SYSTEM

o Increases performance of cardiac and skeletal muscles by increasing acetyl choline synthesis
o In excess causes proteolysis, decreases muscle mass and strength
o Inhibits bone formation
o Decreased bone mass and mineralisation – in excess cause osteoporosis

9)EFFECT ON CONNECTIVE TISSUE

o Inhibits collagen synthesis
o Decreases thickness of skin and capillary walls
o Excess causes intracutaneous rupture (increased capillary fragility)
10)EFFECT ON KIDNEY AND WATER METABOLISM
o Increases GFR
o Inhibits ADH secretion
o Infusing iv solution in cortisol deficit patients – water intoxication

28
11)EFFECT ON FETUS
o Causes maturation of CNS in intrauterine life
o Essential for lung development – pulmonary surfactant synthesis
12)EFFECT ON BLOOD CELLS: Causes mild leucocytosis, erythrocytosis and
thrombocytosis
13)EFFECT ON ALLERGY: Anti allergic, prevents release of histamine and growth of mast
cells

14)EFFECT ON GIT:
o Stimulates HCl secretion, causes gastritis
o Decreases Calcium absorption

15)EFFECT ON OTHER ENDOCRINE HORMONES: Inhibits secretion of GH, TSH,

ACTH
16)ROLE IN STRESS
o Stress is defined as condition in which plasma ACTH is high
o Things that increase plasma ACTH – Stressors
o In cortisol deficiency ACTH levels will high so the patient will succumb
o Glucocorticoids are essential for FFA mobilisation and for maintenance of vascular reactivity
hence to withstand stress
17)EFFECT ON INFLAMMATION

29
18) EFFECT ON IMMUNITY

HYPERSECRETION OF GLUCOCORTICOIDS (CUSHING SYNDROME):

ETIOLOGY
o Excess cortisol
o ACTH independent : Tumor of adrenal cortex
o Exogenously administered excess steroids
o ACTH dependant : Tumors of pituitary (CUSHING DISEASE)
o The common causes include
o Adrenal hyperplasia
o Adrenal tumors
o Adrenal macronodular hyperplasia
o Familial adrenal dysplasia (CARNEY SYNDROME)
o Iatrogenic (prolonged use of steroids or ACTH)
FEATURES OF CUSHING SYNDROME
● Centripetal obesity and weight
● Buffalo hump
● Moon face: Due to fat deposition, salt and water retention

30
 ● Fatigability and weakness
● Hypertension: Glucocorticoid excess has significant mineralocorticoid activity
● Hirsutism and amenorrhoea: Due to increased adrenal androgens
● Reddish purple striae: Excess fat deposition in abdomen causes rapid stretching of skin
that results in striae
● Ecchymoses: Capillaries become thin and fragile – subcutaneous and intracutaneous
haemorrhages
● Proximal myopathy: Legs – thin proteolysis of muscles and reduced bone mass
● Poor wound healing: Due to hyperglycemia
● Hyperglycemia: 20% develop insulin resistant diabetes mellitus
● Osteoporosis: May cause pathological fractures
● Emotional changes
● Hyperacidity and peptic ulcer
● Hairs – thin and scraggly
DIAGNOSIS
● Increased plasma cortisol
● Failure to suppress cortisol levels by dexamethasone
(DEXAMETHASONE SUPPRESSION TEST)
● Plasma ACTH levels
(High – ACTH dependant, Low – ACTH independent)
TREATMENT
● Surgical resection
● Inhibiting steroidogenesis by ketoconazole

ADRENOCORTICAL INSUFFICIENCY:
PRIMARY ADRENAL INSUFFICIENCY: - (ADDISON’S DISEASE)
● Atrophy
● Surgical removal
● Infection
● Bilateral hemorrhage into gland
● Metastatic invasion
● Drugs like ketoconazole
SECONDARY ADRENAL INSUFFICIENCY
● Pituitary disease (Decreased ACTH)
● Hypothalamus disease (Decreased CRH)

31
ADDISON’S DISEASE – ETIOLOGY
● Atrophy – idiopathic (Mostly autoimmune)
● Tubercular infection of adrenal gland
● Secondary metastasis to gland
● Amyloidosis
● Cytomegalovirus infection
CLINICAL FEATURES: -
● Loss of weight and easy fatigability
● Pigmentation of skin: Hyperpigmentation of skin over pressure points, sun exposed areas,
scar marks due to increased levels of ACTH (As ACTH has MSH activity –
pigmentation)
● Hypotension: Due to decreased mineralocorticoid activity
● Hypotensive shock – in severe cases
● Anorexia, nausea, abdominal pain
● Hyponatremia
● Eosinophilia: As cortisol causes eosinopenia, deficiency causes eosinophilia
● Rapid hypoglycaemia on fasting
● Collapse during stressful conditions
DIAGNOSIS: Decreased cortisol + Increased ACTH
TREATMENT: Hormone replacement therapy

MINERALOCORTICOID
REGULATION OF ALDOSTERONE SECRETION

32
HYPERKALEMIA
o Aldosterone synthesis stimulated by increased K+ levels in ECF
o Rise in ECF K+ activates voltage gated calcium channels that increases intracellular
calcium
o Increased cytosolic calcium increases aldosterone secretion
o Acute decrease in Na+ levels also stimulate its secretion
o K+ levels – natural regulator of K+ in ECF

ANGIOTENSIN RECEPTORS
o AT I – Present on Zona glomerulosa of adrenal cortex
o AT II – Binds to AT I receptor increases intracellular calcium that facilitates aldosterone
secretion

MECHANISM OF ACTION
o Binds with glucocorticoid receptor in cytoplasm
o Displaces inhibitory heat shock protein from receptor
o Causes hyperpolarisation of receptor
o Binds with specific glucocorticoid regulatory elements on target DNA molecule
o Translation of mRNA’s that regulate various genes

ACTIONS
● Increase Na+ and water reabsorption
● Promote K+ and H+ excretion
MECHANISMS
o Increases number of Na+ channels in tubular epithelium
o Stimulates Na+ - K+ activity
o As Na+ is reabsorbed Cl- is transported same direction to maintain electrical neutrality
o Reabsorption of Nacl – osmotic reabsorption of water
o Reabsorption of salt and water – ECF expansion

ALDOSTERONE ESCAPE PHENOMENON

● Increased reabsorption of salt and water – ECF expansion
● Increased ECF volume – increases venous return to heart
● Causes distension of atria during filling
● Atrial stretching increases secretion of ANP (Atrial natriuretic peptide)
● ANP causes profound natriuresis and diuresis
● Thus, ECF volume return back to normal – kidney escapes from the effect of aldosterone

33
HYPERSECRETION OF ALDOSTERONE
PRIMARY HYPERALDOSTERONISM
o Due to adrenal adenoma, adrenal hyperplasia, adrenal carcinoma
o Renin secretion – decreased (feedback)
CONN’S SYNDROME
● Due to adenoma of zona glomerulosa of adrenal gland
● Hypertension (sodium retention, ECF expansion)
● Muscle weakness (potassium depletion)
● Polyuria (impairment of urine concentrating ability)
● Edema – usually not a feature
● Hypokalemia, hypernatremia, low renin, metabolic alkalosis – lab findings
SECONDARY HYPERALDOSTERONISM
● Activation of RAAS due to increased renin
● Occurs in congestive heart failure, cirrhosis of liver, nephritic syndrome, renin secreting
tumors
● Edema – usually present
BATTER SYNDROME
● Due to hyperplasia of JG cells
● Mutation in Na+K+2Cl- co transporter gene
● High renin and increased aldosterone synthesis
● Hyperaldosteronism – K+ depletion
● Hypokalemic alkalosis and hypercalciuria – common features
● BP remains normal and no edema

HYPOSECRETION OF ALDOSTERONE
CAUSES
● Adrenal insufficiency
● Inherited defects in aldosterone synthesis
● Decreased renin production (Hyporeninic hypoaldosteronism)
● Surgical removal of gland
● Protracted heparin administration
● Pretectal disease of nervous system
● Severe postural hypotension
● Unresponsiveness to Ang II (Hyperrenimic hypoaldosteronism)

34
 CALCIUM HOMEOSTASIS
PLASMA LEVEL OF CALCIUM:

Normal plasma Ca2+ concentration – 9-11 mg/dl (avg: 10 mg/dl)

PHYSIOLOGICAL FUNCTIONS OF CALCIUM

● Activation of enzymes
● Blood coagulation
● Contraction of muscles via calmodulin
● Development of bone and teeth
● Exocytosis (for secretion of various exocrine and endocrine glands)
● Genesis of pacemaker potential and maintenance of action potential
● Hormonal actions [ Ca2+ acts as 2nd messenger]
● Integrity of cell membrane
● Junction – for neurotransmitter release in neuromuscular junction & impulse transmission

MNEMONIC: “ABCDE GHIJ”

DISTRIBUTION IN BODY
Total body content 1200g average
In bones and teeth 99% of total
In ICF 0.9%
In ECF 0.1%

VARIOUS FORMS OF CALCIUM

1. Ionized form = 50% (biologically active form)
2. Protein bound = 40%
3. Non ionized form= 10%

35
METABOLISM OF CALCIUM INSIDE BODY:

ROLE OF VARIOUS HORMONES:

1)PTH: increases plasma calcium

Plasma calcium

PTH secretion

Kidney bone

Ca reabsorption 1,25-OH cholecalciferol formation resorption

Ca retention Ca absorption Ca release into plasma

36
 2. VITAMIN D :
1,25 -OH cholecalciferol

Kidney intestine bone

Ca reabsorption Ca absorption osteoblastic activity &bone resorption

Plasma calcium levels increased

3.CALCITONIN:
Calcium in plasma

Calcitonin secretion

Kidney Bone

Calcium reabsorption Resorption

Plasma calcium levels decreased

37
SUMMARY OF CALCIUM HOMEOSTASIS:

38
APPLIED ASPECT:

OSTEOPOROSIS:

● decrease in bone mass and density

● types: involutional and post-menopausal
● as age progresses, osteoclastic activity increases and osteoblastic activity decreases 🡪
reduction in bone mass

CAUSES:

❖ hyperparathyroidism
❖ hyperthyroidism
❖ alcoholism
❖ vitamin c deficiency
❖ Smoking
❖ Ovarian diseases
❖ Cushing’s syndrome
❖ Inadequate dietary Ca

CLINICAL FEATURES:

✔ Increased susceptibility of bone fracture common in elderly

✔ Trabecular bones are lost more rapidly
✔ Commonly affected: vertebra, hip bone, bones in distal forearm

TREATMENT:

▪ Administration of calcium tablets

▪ Vitamin d tablets
▪ Estrogen therapy (rarely)

39
 FUNCTIONS OF INSULIN, MECHANISM OF ACTION, NOTE
ON SOMATOMEDIN C
INSULIN:
o Insulin is a peptide hormone (51 amino acids) consisting of A and B chain connected by
Disulphide bond
o Insulin was discovered by Banting and best in 1921
o It is secreted by the β cells of pancreas
o Insulin secretion is regulated by plasma glucose concentration
o Normal basal rate of insulin release is 1- 2Units/hour

FUNCTIONS OF INSULIN:
ON CARBOHYDRATE METABOLISM
● The primary function of insulin is to lower the plasma glucose concentration
(Insulin is secreted at the fed state)
In skeletal muscle and adipose tissues,
● Insulin facilitates glucose entry by activating hexokinase and GLUT-4 activity
In liver,
● Insulin promotes glycogen synthesis by activating glycogen synthetase
● It inhibits hepatic glycogenolysis by inhibiting glycogen phosphorylase and
glucose-6-phosphatase
● It inhibits gluconeogenesis by inhibiting enzymes participating in gluconeogenesis
● It stimulates glycolysis by activating the enzymes phospho-fructo kinase and pyruvate
kinase
● It facilitates glucose entry into hepatocytes by stimulating glucokinase

ON FAT METABOLISM:

● Insulin is the only anti-ketogenic hormone in the body

● It promotes lipogenesis and increases the entry of free fatty acids, glucose into the
adipose tissue
● It stimulates lipoprotein lipase and inhibits hormone sensitive lipase

41
ON PROTEIN METABOLISM:
● Insulin promotes protein synthesis in ribosomes and increases uptake of amino acid into
liver and skeletal muscle cells

ON MINERALS:
● Insulin causes rapid entry of K+ into the cell, thus causing hypokalaemia
● It stimulates renal reabsorption of K+ , Na+ and phosphates

GROWTH PROMOTING ACTION

● Insulin stimulates transcription of genes for growth factors such as IGF-I and II

MECHANISM OF ACTION:

42
SOMATOMEDIN- C:

● Insulin like growth factor- I (IGF- I) is also called as “Somatomedin- C”

● IGFs are polypeptide(70 amino acids) growth factors synthesized mainly in liver and it
mediates the effect of growth hormone
● IGF- I is secreted independent of GH before birth. After its secretion and actions are
dependent on GH
● It peaks at puberty and declines in old age
● Plasma concentration – 10 -700ng/ml
● ACTIONS:
🡺 Growth stimulating activity
🡺 Control of skeletal and cartilage growth

ADRENAL MEDULLA
CHROMAFFIN CELLS
● Gland has clumps of chromaffin cells
● Store catecholamines
● Epinephrine secreting type (90%) - Larger and less dense granules

HORMONES
● Epinephrine
● Norepinephrine
● Dopamine
● Adrenomedullin
● Enkephalin
● Endorphins
● Neuropeptide Y
● Chromogranin

43
CATECHOLAMINES
SYNTHESIS

REGULATION
● Glucocorticoid – increases synthesis of epinephrine
● 21β hydroxylase – necessary for development of adrenal medulla
● Exercise, hypoglycaemia, trauma, anger, anxiety, pain, cold – increases synthesis
METABOLISM
● Under the influence of COMT and MAO epinephrine and norepinephrine are converted
to Vanillylmandelic acid (VMA)
● Urinary excretion of VMA is 400 – 600 µg , its urinary excretion is the index of
sympathetic activity

ACTIONS
Acts through α and β receptors

44
METABOLISM
● CARBOHYDRATE: Increase plasma glucose levels
● FAT: Promote lipolysis and stimulates FFA and ketone body formation
● THERMOGENESIS: Increases BMR
● FIGHT OR FREIGHT RESPONSE
o Increases cardiac output
o Promote blood flow to organs
o Increase ventilation
o Stimulate energy supply
o Relax smooth muscles of GIT and urinary system
o Causes piloerection
● EFFECT ON CVS
o Increases heart rate, force of contraction and hence increases cardiac output
o Cause selective arteriolar constriction in renal, splanchnic, cutaneous vascular bed
o Pulse pressure widens
o Diverts blood and maintains cerebral and coronary blood flow
● EFFECT ON GIT: Inhibit gastrin secretion and motility
● EFFECT ON RS: Cause bronchial dilatation and stimulate respiration
● EFFECT ON EYE: Pupillary dilation
● EFFECT ON ENDOCRINE GLANDS
o Stimulate ADH release
o Increase renin secretion
o Increase thyroid hormone secretion and promotes peripheral conversion of T4 to T3
● EFFECT ON KIDNEY
o Increases Na+ reabsorption
o Increases renin formation and increases Na+ and water retention
● EFFECT ON ELECTROLYE BALANCE
o Stimulate entry of K+ into muscle cells
o Decrease plasma K+

ACTIONS OF DOPAMINE
● Renal and mesenteric vasodilation
● Vasoconstriction in other parts
● Positive inotropic effect and increases cardiac output
● Increases systolic pressure
● Natriuresis
USES OF CATECHOLAMINES
● AGONISTS – nasal decongestant, appetite inhibitor, stimulation of general body
functions
● ANTAGONISTS – Hypertension, Hyperthyroidism, treatment of shock

45
PHEOCHROMOCYTOMA
● Tumor of adrenal medulla
● Hyperplasia of chromaffin cells
● Proliferation of chromaffin cells of paraganglia
● Concentration of epinephrine and norepinephrine is very high
FEATURES
● Sustained hypertension
● Increased metabolic rate
● Tachycardia
● Hyperglycaemia
● Loss of body weight and appetite
● Burst of catecholamine release during change in posture or sympathetic stimulation –
severe headache, tachycardia, palpitation, extreme anxiety, perspiration, pallor/ flushing,
severe rise in BP, feeling of impeding death
DIAGNOSIS
● Increased catecholamines in blood
● Urinary excretion of metanephrine and VMA (Vanillylmandelic acid) also increased
TREATMENT
● Surgical removal of tumor
● α blocker

ROLE OF CATECHOLAMINES IN STRESS

● Stress activates CRH and ADH which in turn increases catecholamine levels
● They together increase glucose concentration in plasma
● They also shift glucose utilization from peripheral tissues to neural tissues
● Increases supply of FFA to heart
● Increase cardiac output and BP
● In chronic stress, reproductive functions, sexual activity, feeding – suppressed

46
 MILK EJECTION REFLEX
DEFINITION:
Discharge or expulsion of milk from the breast of the mother into mouth of the baby when baby
suckles during breastfeeding is called milk ejection reflex

SIGNIFICANCE:

● It is an example of neurohumoral reflex ~ hormones form efferent limb in reflex

pathway
● Involves both neurons and hormones in the reflex pathway

RECEPTORS:

● TACTILE [ touch] receptors in and around the nipple

REFLEX ARC:

● STIMULUS: Nipple stimulated by suckling of baby

● AFFERENT: Neural impulses from nipple spinal cord spinothalamic
tract to brain stem
● CENTRE: HYPOTHALAMUS (para ventricular nucleus)
● EFFERENT: Via hypothalamo-pituitary axis, oxytocin is released from posterior
pituitary
● EFFECTS: Oxytocin causes contraction of myoepithelial cells of alveoli
Due to initiation of this reflex, milk from mother’s breast is forcefully discharged into baby’s
mouth. So, it is called milk ejection reflex

47
 GIGANTISM
● Also called as pediatric Gigantism / Giantism
● It is due to the overproduction of GH during adolescence (before epiphyseal closure)
and is characterized by excessive growth of long bones.
Causes:
🡺 Adenoma: tumor of the pituitary gland
Adenoma of pituitary gland

Excessive production of GH

Gigantism
● A hypothalamic tumor causing excess GHRH can also cause gigantism.

48
Features
1. Tall Stature (excessive) tallness as much as 2.5metre or 8 feet
2. Bilateral gynecomastia (enlargement of breast)
3. Large hands and feet
4. Associated Features
i. Coarse facial features
ii. loss of libido
5. The patient will have all features of acromegaly except the acromegalic facies.

Treatment
● Surgery - to remove the pituitary tumor
● Radiotherapy – to slow me growth of the tumor
● Growth hormone antagonists

ACROMEGALY
● It is due to the excessive secretion of GH during adulthood (after epiphyseal closure)
● In 20-40% it is associated with hyper secretion of prolactin
● It causes excessive growth in those area where cartilage persist

Causes:
❖ Occurs due to tumor of the somatotroph of anterior pituitary
❖ Or also occurs due to the excess secretion of hypothalamic GRH (extra pituitary causes)
❖ In most of these patients, there is also consequent prolactin increase that is associated
with proliferation of lactotrophs.

Features
🡺 Enlargement of acral parts of the body, especially hands and feet.
🡺 prognathism: enlargement of mandible and protrusion of lower jaw.
🡺 Cardiomegaly

49
 🡺 Hepatomegaly
🡺 Thickening of skin
🡺 Splenomegaly
🡺 Hypertrophy of tongue and muscles
🡺 Acromegalic facies: overgrowth of malar, frontal and facial bones
🡺 Increased amount of body hair
🡺 Osteoarthritis due to skeletal changes
🡺 Glucose intolerance
🡺 Hirsutism
🡺 Bitemporal hemianopia: due to the compression of the tumor on the optic chiasm.

Treatment
🡺 Growth hormone antagonists
🡺 Surgery or radiation to remove for reduce the size of tumor

DIFFERENCE BETWEEN GIGANTISM & ACROMEGALY

Gigantism Acromegaly

Hyper secretion of GH before the closure of Hyper secretion of GH after the closure of
epiphyseal center epiphyseal center

50
 DWARFISM
🡺 It is due to the deficiency of GH secretion in immature individual
🡺 It results in stunted growth
Causes
Endocrinal causes
● Growth hormone deficiency (Pituitary Dwarf)
● Panhypopituitarism
● Hypothyroid dwarfism
● Cushing’s syndrome
Non- Endocrinal Causes
● Familial dwarfism
● Achondroplasia
● Nutritional defects
● Chromosomal abnormalities
Features
● Retardation of growth in all parts of body
● Normal mental activity (except in cretinism where the baby will have mental retardation)
● Plumpness (Fatness)
● Immature faces
● Delicate extremities
● Low levels of IGF-1 in plasma

Laron Dwarfism
🡺 It is due to be abnormality of GH receptors
🡺 It is a congenital defect and is otherwise called growth hormone insensitivity syndrome
Treatment
🡺 Surgical treatment correcting the direction which bones are growing
🡺 Placing a short to remove excess fluid around the brain (If hydrocephalus has occurred)
🡺 Recombinant human growth hormone

51
 DIABETES INSIPIDUS & ITS TYPES

● Definition: Deficiency of ADH in which an abnormally large volume of dilute

urine is produced.
● Clinical Features

○ Polyuria (3 to 20 L/day)
○ Polydipsia (Secondary to dehydration caused by Polyuria)
○ Dehydration

*Polyuria and Polydipsia are also featuring of Diabetes Mellitus

52
 There are two types of Diabetes Insipidus

Nephrogenic Neurogenic/ Central

1. Kidney not responsive to ADH 1. Deficiency of ADH secretion
2. ADH secretion is normal, but there is 2. Causes are
receptor deficiency or abnormality a. CNS Diseases
3. The causes are genetic or acquired i. Hypothalamus
4. The genetic causes are (Central Diabetes
a. Autosomal Defect: Aquaporin 2 Insipidus)
deficiency ii. Hypothalamo-
b. X-linked recessive disease: V2 hypophyseal tract
receptor gene deficiency (Neurohypophyseal
5. Acquired causes are Diabetes Insipidus)
a. Metabolic Disorder iii. Post pituitary
i. Hypercalcemia (Pituitary diabetes
ii. Hypokalemia Insipidus)
b. Ischemia b. Head Injury, tumors
i. Acute tubular necrosis i. Craniopharyngioma
c. Infiltrative diseases ii. Suprasellar
i. Neuro Sarcoidosis Pituitary tumors
ii. Amyloidosis iii. Infections
d. Drugs 1. Meningitis
i. Demeclocycline 2. Encephalitis
ii. Rifampicin iv. Vascular lesions
iii. Aminoglycoside 1. Sheehan’s
iv. Lithium syndrome
v. Cisplatin 2. Aneurysm
vi. Amphotericin B of ICA
v. Congenital/genetic defects

Treatment
○ Vasopressin Injection
○ Clofibrate therap

53
 SYNDROME OF INAPPROPRIATE ADH SECRETION
● Excessive secretion of ADH occurs in clinical syndrome.
● ADH secretion is inappropriately high relative to serum osmolality.
● Syndrome of Inappropriate ADH is seen in:
➔ Head injury
○ Ectopic produces of ADH
■ Some malignant tumors
■ CA lungs, pancreas, ovary, bladder
➔ Neurologic diseases like
● Multiple sclerosis
● Guillain Barre syndrome
● Brain abscess
● Meningitis
● Encepliatis
➔ Drug
● Desmopressin
● Chlorpropamide
● High dose of oxytocin
● Phenothiazine
● Carbamazepine

● In SIADH, there is dilutional hyponatremia caused by increased absorption of large quantity of water
and natriuresis secondary to decreased aldosterone secretion
● If the SIADH is due to brain disease, the condition is called cerebral salt wasting.
● If the SIADH is due to lung diseases, then the condition is called pulmonary salt wasting.

Vasopressin escape:

● In lung cancers and other malignant tumors, ADH secretion is very high.
● In such conditions, the water retaining action of ADH is countered by a process called vasopressin
escape that limits the degree of hyponatremia
● This escape phenomenon occurs due to the down regulation of aquaporins in the collecting duct.
● Thus, the urine output increases despite high levels of ADH in plasma, which indicates that the kidney
has escaped from the effects of vasopressin.

54
 SECONDARY MESSENGER MECHANISM
● Secondary messengers: The intracellular signal molecules that are formed by a series of
enzymatic reactions subsequent to the formation of HR complex are designated as second
messengers.
○ Second messengers are formed depending on the hormone signaling of the effector cells.
○ The signal transduction pathways are activated depending on G protein activation of
membrane enzymes.
○ E.g.: cyclic AMP, diacylglycerol (DAG), inositol triphosphate (IP3), cyclic GMP,
phosphoproteins, transcript new mRNAs, and intra-cellular calcium.
Second messengers are formed by activation of four main transduction systems:
○ Adenylyl cyclase–cyclic AMP system
○ Membrane phospholipase–phospholipid system
○ Guanylyl cyclase cyclic GMP system
○ Transcription of mRNAs.

Mechanism of hormone action through adenylyl cyclase-cyclic AMP system

55
● Termination of cAMP Actions: cAMP is degraded to 5’-AMP in the cell by the cytoplasmic enzyme
phosphodiesterase (PDE)
Clinical importance:
○ Not only many hormones act through cAMP, but also, toxins released by various pathogens
produce toxic features by altering cAMP concentration in the cell
○ Cholera and pertussis toxins are examples of stimulation and inhibition of cAMP respectively

Membrane phospholipid-Phospholipase System (via IP3 and DAG)

56
Guanylyl Cyclase-Cyclic GMP System

57
 Intracellular Receptor (Transcription of mRNA) System:
○ The receptors for thyroid and steroid hormones, 1,25-dihydroxycholecalciferol and retinoids
are located inside the cell.

Intracellular receptor system

58
 CUSHING’S SYNDROME

DEFINITION: It is a pathological condition with cortisol excess (Hypersecretion of glucocorticoids)

CAUSE:
ACTH DEPENDENT
• Pituitary tumors (Cushing disease)
ACTH INDEPENDENT
• Adrenal hyperplasia
• Adrenal macro nodular hyperplasia
• Adrenal tumors
• Familial adrenal hyperplasia (Carney syndrome)
• Prolonged use of cortisol

CLINICAL FEATURES:

59
Mnemonic:
C: centripetal obesity and comedones (acne)
U: urinary free cortisol excess
S: suppressed immunity
H: hyperglycemia, hypertension, hypercortisolism, hypercholesterolemia, healing of wound is poor
I: iatrogenic (increased administration of corticosteroid)
N: Neoplasms
G: growth impairment
M: moon faces, myopathy of the proximal muscles
O: obesity
O: osteoporosis
N: neurological problems (Frank psychosis)
S: striae and ecchymosis

DIAGNOSIS:
1.Increased plasma cortisol levels
2.Dexamethasone suppression test

TREATMENT:
1.Surgical resection of tumor
2.Medical adrenalectomy
3.High dose of ketoconazole: inhibit cortisol synthesis

60
 PHEOCHROMOCYTOMA

DEFINITION:
• Tumor of adrenal medulla
• Occurs due to hyperplasia of chromaffin cells
• Causing the increase in concentration of both epinephrine and norepinephrine.

FEATURES:
• Most common feature -SUSTAINED HYPERTENSION
• Cardiovascular feature
o Tachycardia
o Palpitations
o Perspiration
o Flushing
o Rise in bp

• Metabolic features
● Hyperglycemia
● increased metabolism
● Weight loss
● Loss of appetite
• Gastrointestinal features

● Nausea
● Vomiting
● Constipation

DIAGNOSIS:
● BLOOD-Increased concentration of catecholamine
● URINE-excretion of metanephrine and VMA increases

TREATMENT: Surgical removal of tumors

61
 ADDISON’S DISEASE

DEFINITION:
1. Hyposecretion of glucocorticoids
2. CAUSE: progressive destruction of adrenals
o Idiopathic
● Autoimmune destruction (hypothesis)
● TB infection of adrenals
● Secondary metastasis of tumor
● CMV infection
● Amyloidosis

CLINICAL FEATURES:
A -anorexia, abdominal pain (nausea, vomiting)
D-Dark skin (hyperpigmentation -less cortisol will increase ACTH by feedback mechanism and ACTH has
intrinsic MSH activity)
D-decreased vascular reactivity
I-irritability
S-salt craving, stress, shock (hypotensive)
O-orthostatic hypotension
N-Na low (hyponatremia), hyperkalemia

ADDISONIAN CRISIS:
Addisonian crisis is a serious medical condition caused by the body’s inability to produce a sufficient
amount of cortisol in response to a sudden stress event, such as an illness or infection.

● Hyponatremia
● Hyperkalemia
● Hypoglycemia
● Hypotension
● Dehydration

DIAGNOSIS: decreased plasma cortisol level

TREATMENT: hormone replacement therapy

62
 MYXEDEMA

Hypothyroidism in adult is known as myxedema. Characterised by generalised oedematous appearance.

Hypothyroidism

Primary hypothyroidism Secondary hypothyroidism

Due to defect in thyroid gland. Due to defect outside thyroid gland.
1.Autoimmune: Hashimoto’s thyroiditis 1. Pituitary resection, pituitary tumour
2.Thyroidectomy 2. Injury involving hypothalamus, tumour
3.Iodine deficiency 3. Thyroid hormone resistance
4.Excess of iodine, excess use of
Antithyroid drugs.
5.Congenital hypothyroidism

Signs and symptoms:

Typical feature is oedematous swelling, associated symptoms-
1. Swelling of face
2. Bagginess under eyes
3. Non pitting oedema-accumulation of hyaluronic acid and chondroitin sulphate
4. Fatigue and muscular sluggishness
5. Increase in body weight, BMR decreases
6. Decrease in cardiovascular functions(bradycardia)
7. Depressed hair growth
8. Cold intolerance
9. Thick and husky voice
10. Menorrhagia

Diagnosis: -
T3 and T4 levels are decreased but TSH is increased

Treatment: -
Thyroid hormone replacement. T4 is instituted at a dose to maintain normal level in plasma.

63
 CRETINISM

● Hypothyroidism in children is known as cretinism.

● Hypothyroidism develops from or before birth.
● Patient is called as cretins

Causes:
1. Maternal iodine deficiency during pregnancy
2. Maldevelopment of thyroid gland during foetal life
3. Inborn errors of thyroid hormone synthesis
4. Hypopituitarism in foetal life
5. Use of antithyroid drugs during pregnancy

Features:
1. Dwarf
2. Bloated body (pot belly)
3. Protrusion of tongue
4. Mentally retarded
5. Reproductive system affected
6. Other features of hypothyroidism also present

Treatment:
● Mental retardation can be prevented if the disease is diagnosed and treated
immediately after birth.
● Thyroid hormone replacement early in infancy can totally cure the disease.
● Prompt replacement of thyroxine.

64
 HASHIMOTO’S THYROIDITIS
● It is an auto-immune disease.
● Common in late middle-aged women.
● In most patients start with glandular inflammation called thyroiditis caused by autoimmune
antibodies.
● Antibodies act against thyroglobulin and thyroid peroxidase.
● Therefore, thyroid cells are damaged.

65
Clinical features:
● Cold intolerance
● Weakness, easy tiredness
● Dry, thick skin
● Loss of hair
● Poor memory
● Inability to concentrate
● Constipation
● Weight gain despite poor appetite
● Thick and husky voice
● Yellow skin due to carotenemia
● Psychosis
● Menorrhagia, galactorrhoea, infertility
● BMR decreases to about -40, elevated plasma cholesterol levels
● Diastolic hypertension, decreased reaction time of tendon reflexes
● Carpal tunnel syndrome, periorbital oedema

Treatment:
● Thyroid hormone supplements
● T4 at a daily dose of 25mcg then increased/decreased based on the patient response.
● Serial T3 and T4 level monitoring required.

GRAVE’S DISEASE
Autoimmune disease and most common cause of hypothyroidism.
There is diffuse enlargement of thyroid gland usually associated with exophthalmos.
1. Due to autoantibodies against TSH receptors. Antibodies activate receptors.
2. Thyroid gland becomes hypertrophied and hyperactive.
3. Plasma level of T3 and T4 is very high.
4. TSH concentration is less as excess thyroid hormones inhibit TSH secretion.

Signs and symptoms: -

1. Intolerance to heat
2. Increased sweating due to vasodilatation
3. Decreased body weight
4. Increase in BMR
5. Diarrhoea due to increased GI motility
6. Nervousness, extreme fatigue, tremors
7. Tachycardia
8. Toxic goitre

66
 9. Exophthalmos occurs due to swelling of extraocular muscles and oedematous swelling of
retro-orbital tissues.
10. Oligomenorrhea or amenorrhea.

Treatment: -
The Disease is treated by using antithyroid drugs, by decreasing thyroid hormone synthesis, or by reducing
the amount of thyroid tissue.
- Treatment of radioactive iodine I131
- Subtotal thyroidectomy

HYPOTHALAMO PITUITARY AXIS

1)Tubero-infundibular tract and hypothalamo–hypophyseal portal system
Fibres arising from the arcuate nuclei of the tuberal region of the hypothalamus and extends to the median
eminence

Cell bodies of these hypothalamic neurons synthesize hypothalamic hormones (Releasing and inhibiting
hormone) to the median eminence region Where they are stored in the nerve terminals

From where enter the capillary plexus of the Superior hypophyseal artery are transported down the portal
vessels (long portal veins) and then exit from the secondary capillary plexus to reach the endocrine target
cells in the adenohypophysis where they regulate the secretion of it

67
 ● The releasing hormones secreted from the hypothalamus reach the anterior pituitary via the
hypophyseal tract. These hormones are also called as hypophysiotropic hormones
● Hypophysiotropic hormones are synthesised in the hypothalamic neurones (parvocellular
neurones), the axon terminals contact the capillary network in the medial eminence and
infundibulum that give rise to long portal vessels
● Short hypophyseal vessels communicate with the capillaries of anterior pituitary with the capillaries
of the posterior pituitary which derives blood from the inferior hypophyseal artery.

2)Hypothalamo–hypophyseal tract:
It arises from the posterior pituitary and the hypothalamus. It is a completely neural connection.
The neurones for this tract are larger than the other neurones and are called as magnocellular neurons.

Axons of the large neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus
(secrete peptide hormones i.e vasopressin and oxytocin)

These Fibres pass to neurohypophysis through the infundibular Stem and form a series of dilated terminals
known as Herring bodies.

Upon stimulation of the cell bodies, the granules are released from the Axonal terminals by exocytosis.

Hormones then enter the peripheral circulation via the capillary plexuses of Inferior hypophyseal artery

68
 G PROTEIN COUPLED RECEPTORS
● Transmembrane receptors winds around cell membrane 7 times (serpentine receptor)
● G protein coupled receptors belong to several families of intrinsic membrane proteins that link
receptors to the nearby effector molecules.
● G protein coupled receptors convert the signals to biological activities

Mechanism:
Hormone binds to receptor ---🡪 confirmational change ----🡪 Receptor binds to G protein intracellularly
---🡪 protein gets activated and bound to GTP ----🡪 alpha subunit dissociates from beta and gamma ----🡪
alpha subunit activates effector (Gs ,Gi,Gq)

Types of GPCR:
the classification is based on the alpha subunit of the GPCR
Gs:
● It uses the enzyme adenylyl cyclase
● The second messenger used is cAMP
● Effects: increase cell functions and increase protein synthesis
Gi:
● It inhibits the adenylyl cyclase enzyme
● As a result, it decreases the functions of cAMP that causes a decrease in cell protein synthesis
Gq:
● It uses the second messenger IP3-DAG
69
● It uses the enzyme phospholipase C that increases the activity of protein kinase C that cauzes the
activation of many intracellular enzymes and proteins.

70
 PROLACTIN
(Hormone for milk synthesis)

STRUCTURE
o Polypeptide hormone
o 198 AA
o Similar structure with human GH

SOURCE & SYNTHESIS

o Secreted from acidophilic cells of anterior pituitary
Preproprolactin proprolactin prolactin stored in lactotrophs

REGULATION OF SECRETION
Factors that increase secretion Factors that decrease secretion

⮚ Prolactin releasing factor, ⮚ Dopamine

⮚ TRH ⮚ Somatostatin
⮚ Pregnancy ⮚ Feedback inhibition
⮚ Estrogen therapy
⮚ Breastfeeding
⮚ Sleep
⮚ Oxytocin

Feedback inhibition
Hypothalamus

Dopamine, somatostatin PRF, TRH

Anterior pituitary (lactotrophs)

Prolactin

Lactogenesis (mammary gland secretion)

71
FUNCTIONS
o Stimulate the milk synthesis
o Hyperplasia of breast tissue, increase the lobules of alveoli of mammary gland
o In females: inhibits hypothalamic GnRH in high prolactin concentration, prevent ovulation,
inhibit libido &stimulate maternal behavior
o In males: decreased spermatogenesis,
o Immunogenic balance of maternal tissue to fetal tissue
o Increased synthesis of synlactin in liver (intermediary GF from liver)
CLINICAL ASPECT
Lactational Amenorrhea
o Prevents ovulation
o Also called physiological contraception
Amenorrhea galactorrhea syndrome
o Excess production from tumor lactotrophs (hyperprolactinemia) causes amenorrhea &
infertility
o Treatment: Dopaminergic drugs

INSULIN LIKE GROWTH FACTORS

(SOMATOMEDINS)
● The indirect effect of GH on cartilage and protein depends on the production of IGFs
● Growth hormone stimulate IGFs production by gene expression by tyrosine phosphorylation of
signal transduction & activation of transcription (STAT)

TYPES
IGF- 1 IGF- 2

Also called somatomedin Multiplication stimulating activity (MSA)

Receptor: similar to insulin receptor Receptor: mannose 6 phosphate
Secretion: before birth independent of GH Secretion: independent of GH its level
After birth its secretion remains constant
stimulated by GH
Effects: skeletal and cartilage growth Effects: major role in fetal growth

72
St
udentNot
es

PHYSI
OLOGY
1s
tEdi
ti
on

Uni
t3
Bl
oodI
mmuni
ty
 CONTENTS

ESSAY:

1. Describe in detail the steps involved in erythropoiesis and Pg.4

the factors affecting it.

2. Explain in detail about the clotting process and the intrinsic Pg.9
and extrinsic pathways with the steps involved.

3. Define and classify immunity, describe in detail about cell Pg.13

mediated immunity

4. Describe in detail about anemia, write about the important Pg.17

investigations and explain them.

5. Describe in detail about humoral immunity with the steps Pg.23

involved

SHORT NOTES:

1. Functions of plasma proteins Pg.27

2. Functions of platelets Pg.29

3. Primary hemostasis Pg.30

4. Mononuclear phagocyte system Pg.32

5. Erythroblastosis fetalis Pg.33

6. Fibrinolysis, clot retraction and dissolution Pg.34

1
7. Autoimmune disorders Pg.36

8. Transfusion reactions Pg.37

9. Hemophilia Pg.39

10. Thalassemia Pg.41

11. Blood indices Pg.42

12. Starling forces and pathophysiology of edema Pg.44

13. Phases of hemopoiesis and regulation Pg.45

14. Composition of blood Pg.47

15. Steps in phagocytosis Pg.48

16. Types of hemoglobin and synthesis of hemoglobin Pg.49

17. Polycythemia and its causes Pg.52

18. ABO and Rh blood grouping Pg.53

2
 ERYTHROPOIESIS
Definition:
● The process of production of red cells is called erythropoiesis.
● RBCs has a life span of 120 days

Sites:
Mesoblastic stage:
● This occurs during intrauterine life in the mesoderm of the yolk sac.
● Erythropoiesis is intravascular

Hepatic stage:
● Happens from the 5th week of gestation
● Erythropoiesis takes place in the liver and spleen

Medullary stage:
● From the 5th month the bone marrow starts forming red cells
● Medullary erythropoiesis takes place more effectively towards the end of 3 rd trimester.
● Extramedullary erythropoiesis in postnatal life is always pathological
● At adolescence, all the marrow cavities synthesise RBCs
● After 20-30 years of age, erythropoiesis is limited to sternum, ribs, vertebrae, skull,
pelvic and pectoral girdles.

Stages of erythropoiesis:
There are 3 major cellular events that occur in erythropoiesis
● Progressive reduction in cell size
● Size of nucleus and number of nucleoli decrease, chromatin condensation and
disappearance of nucleus
● Staining reaction changes from deep basophilic to polychromatophilic to acidophilic
type.

1.Stem cells:
Pluripotent stem cells:
They have the property of self-renewal and differentiation

Committed stem cells:

● They develop from pluripotent stem cells
● There are 2 categories: myeloid and lymphoid series
● Myeloid: erythroid, megakaryoid, monocytic and granulocytic series

4
2.Progenitor cells:
There are 2 types of progenitor cells:
🡺 BFU-Es: burst forming units, they give rise to large number of CFU
🡺 CFU-Es: colony forming units, they give rise to the blast cells of erythrocytic series.

3.Precursor cells:
● Blast cells are the 1st morphologically identifiable cells in the bone marrow
● Erythroblasts are the precursors for RBCs. They are also called as normoblasts.
● There are 3 successive forms of normoblasts: early, intermediate and late.

Type of Characteristic features Image

normoblast

Pronormoblast ● Large cell, diameter of 15-20 um

● Irregular or slightly oval
● Presence of high concentration of
polyribosomes makes the
cytoplasm intensely basophilic
● Large nucleus, occupies about
80% of cell space
● Nucleoli present
● Mitosis present
● Hb is not yet formed
Early ● First erythroblast to appear in the
normoblast bone marrow
● Diameter: 12-18 um
● Active mitosis
● Cytoplasm is scanty, basophilic
● Also called basophilic
erythroblast
● Dark violet heterochromatin
clumps present in the nucleus
● Connection of clumps by linear
strands gives the appearance of
wheel spokes
● Hb appears for the 1st time in
these cells.

5
 Intermediate ● Also called polychromatophilic
normoblast erythroblast
● Diameter of 10-15 um
● Change of cytoplasm colour from
blue to pink
● Checkerboard pattern of
heterochromatin clumps.
● No nucleoli
● Hb synthesis increases, makes the
cell appear acidophilic
● Sluggish mitosis
Late ● Also called orthochromatic
normoblast erythroblast
● Smallest of the series, diameter:
7-12 um
● Deeply eosinophilic cytoplasm
● Pyknotic and small nucleus,
cartwheel appearance
● Hb synthesis almost complete in
this stage.

4.Mature cells:
Reticulocytes:
● They are the immediate precursors of juvenile red cells
● They are mature cells with full complement of Hb
● Slightly larger than red cells
● Have a network of reticular material, hence called reticulocytes
● Stained by supravital stain
● Hb synthesis continues to some extent in these cells.

Erythrocytes:
● Final cells in erythropoiesis
● Have a biconcave disc
● Diameter of 7.5 um.

6
Regulation of erythropoiesis:
Feedback control:
1) Functional feedback:
● This is the feedback that originates from the tissues signalling the rate of requirement
which is normally served by red cells
● O2 requirement of the tissue is the main functional feedback of RBC production
● Erythropoietin is the chief mediator of functional feedback
2) End product feedback:
● End product feedback is due to the end products of red cell destruction
● Products of haemolysis influence red cell production
● Haemolytic anaemia is associated with more erythroid hyperplasia and reticulocytosis.

Factors controlling erythropoiesis:

1)Hormonal factors:
Erythropoietin:
● Erythropoietin is produced by the interstitial cells in the peritubular capillary bed of
kidney
● Kidney secretes about 85% of erythropoietin, the rest is secreted by liver
● Erythropoietin acts on the cytokine receptor superfamily and causes the initiation of serine
and threonine kinases that lead to the activation of JAK 2 protein
● Functions:
⮚ Acts on the progenitor cells and early precursor cells
⮚ Decreases cell cycle length and enhances mitosis
⮚ Facilitates the maturation of normoblasts
⮚ Increases Hb synthesis
⮚ Stimulates early release of reticulocytes into the circulation
● Factors that increase Ep production: hypoxia, low blood volume, anaemia, lung disease,
hormones like adrenaline, nor adrenaline, androgen, thyroxine, prolactin, ACTH.
● Factors that decrease Ep production: oestrogen, adenosine antagonist like theophylline

Interleukins:
● Interleukin 1, 3 and 5 that are produced from T cells act on the stem cells to convert them
to the progenitor cells.
● GM- CSF facilitates the production of committed stem cells.

Androgens:
● Androgens stimulate erythropoiesis
● This is the major reason for higher blood count in men than women

7
Oestrogen:
● Oestrogen inhibits erythropoiesis by inhibiting erythropoietin production
● Oestrogen also decreases the hepatic synthesis of globulin.

Thyroxine, cortisol and growth hormone:

● Thyroxine stimulates erythropoiesis
● Growth hormone increases mitosis and maturation of erythroid precursors
● Cortisol produces mild erythrocytosis

2)Dietary factors:
Iron:
● Iron is the raw material for haem synthesis.
● Iron deficiency results in microcytic hypochromic anaemia

Vit B12 and folic acid:

● They are necessary for red cell maturation and promote DNA synthesis
● Thymine is obtained from tetrahydrofolate, that is obtained from folic acid
● The regeneration of tetrahydrofolate is dependent on vit B12.
● Deficiencies of these cause megaloblastic anaemia.

Protein:
● Protein is essential for globin component of haemoglobin

Other nutritional factors:

● Vit C helps in absorption of iron
● Minerals like copper and cobalt influence haemoglobin synthesis.

Intrinsic factor of Castle:

● It is secreted from the oxyntic cells of stomach
● It helps in the absorption of vit B12
● Deficiency of this leads to pernicious anaemia

Environmental factors:
● Hypoxia is the major stimulant for erythropoiesis
● It mainly occurs in high altitude, cardiac and respiratory diseases.

8
 BLOOD COAGULATION/ CLOTTING

Introduction:
When blood comes out of the blood vessel, it loses its fluidity & becomes a semisolid jelly. This
process is called clotting.
Definition: Defined as the sequence of events leading to the formation of fibrin from fibrinogen

Coagulation factors:
- these are substances required for coagulation
- all these substances are present in plasma in an inactive form
- these are activated and take part in coagulation when the blood vessel wall is injured
I - Fibrinogen
ii - Prothrombin
iii - Tissue thromboplastin
iv - Calcium
v - Proaccelerin, labile factor
vi - Accelerin
vii - Proconvertin, stable factor
viii - Anti hemophilic factor A
ix - Plasma Thromboplastic Component (PTC), Christmas factor, antihemophilic
factor b
x - Stuart-Prower factor
xi - Plasma Thromboplastin antecedent (PTA),Anti Hemophilic factor C
xii - Hageman factor,
xiii - Fibrin stabilizing factor
HMW- K - High Molecular Weight Kininogen,
pre-k - Prekallikrein
ka - kallikrein
PL - Platelet Phospholipid

Mechanism of coagulation:
3 main steps are involved
1. Damage to the blood vessel wall/ blood - Formation of Prothrombin Activator
Complex
2. Prothrombin Activator Complex activates prothrombin to thrombin
3. Thrombin converts fibrinogen to fibrin

9
Pathways of coagulation:
1. Extrinsic pathway
2. Intrinsic pathway

10
Clot: A meshwork of fibrin threads entrapping the blood cells and a fluid called serum

Functions of thrombin in blood coagulation:

● It converts fibrinogen to fibrin monomers by removing fibrinopeptides A and B from
fibrinogen
● It activates formation of prothrombin activator by stimulating the activation of VIII, V
and XIII and creates a positive feedback mechanism
● It is a potent activator of platelets
● It activates pro-carboxypeptidase B that inhibits plasmin mediates fibrinolysis
● It also has an anticlotting activity. It binds to cofactor thrombomodulin on endothelial
cells that allows protein C to be activated.
● It helps in repair of vessel wall. It has growth factor and cytokine like activities that play
a role in inflammation, wound healing and atherosclerosis
Polymerization of fibrin monomers:
● About 15 to 20 protofibrils aggregate to form thick fibers of fibrin.
● Protofibrils also branch out to form into a meshwork of interconnected thick fibers. This
is called polymerization of fibrin monomers.
● Factor XIIIa completes the process of polymerization that is activated by thrombin.
● The fibrin polymer is stabilized by cross linkage. Calcium acts as a cofactor for this
process. This stabilized meshwork forms the blood clot.

11
Applied aspect:
Anticoagulants:
● These are substances that inhibit the process of clotting by inhibiting the various factors.
● They are classified as oral and parenteral anticoagulants.
● This is important to prevent excessive clot formation and to clear the pathway of blood
vessels that is blocked by a clot, as seen in stroke or any thromboembolism.
● Heparin is a natural anticoagulant that facilitates the action of antithrombin III. It
prevents the formation of fibrin from fibrinogen.
● Oral anticoagulants are mainly vitamin K antagonists like warfarin, dicoumarol.
● Factor Xa can also be inhibited by oral anticoagulants.
● Hirudin is obtained from Hirudo medicinalis. It is a more naturally occurring specific
inhibitor of thrombin.

Clotting disorders:
Hemophilia:
● It is a disorder of the clotting factors that results in prolonged bleeding from a small cut.
● There are 3 types of hemophilia.
● Hemophilia A, also called classical hemophilia is the most common. It is caused by a
defect or deficiency in factor VIII.
● Hemophilia B, also called Christmas disease is caused by a deficiency of factor IX.

Tests for clotting:

● Partial thromboplastin time
● Activated partial thromboplastin time
● Thrombin time
● prothrombin time
● clotting time.

IMMUNITY

12
Definition:
the ability of the body to defend against invading agents is called immunity. The invader can be a
living or a non-living substance.

Types:
Types of immunity

Innate immunity Acquired immunity

Non-specific defence Natural active: CMI, humoral

immunity
Relatively specific defence by
NK cells Natural passive: IgG via placenta
Artificial active: vaccination
Artificial passive: IV antibodies

Cell mediated immunity or cellular immunity:

Definition:
● Cell mediated immunity is mediated by T cells.
● Cellular immunity is particularly effective against intra-cellular organisms like viruses,
parasites and fungi, cancer cells, tumor cells, and transplanted tissues.
● This immunity is induced following entry of an antigen into the body.

Steps of Cellular Immunity:

13
1. Antigen recognition, processing and presentation
2. Activation and proliferation of T cells
3. Elimination of the invader

1. Antigen recognition, processing and presentation

1: Phagocytosis of antigen (Ag);

2a: Partial digestion of Ag into its peptide fragments in the vesicle;
2b: Synthesis of MHC-II molecule;
3: Fusion of vesicles containing Ag fragments and MHC molecules;
4: Single vesicle containing antigen fragments attached to MHC molecules;
5: Incorporation of MHC-Ag complex on the membrane of APC during exocytosis)

Immunological synapse: for antigen recognition, there are 2 signals transmitted that is
necessary to produce activation. If any 1 signal is not present, then T cell activation will not
occur.

2. Activation and proliferation of T cells

● An activated T cell undergoes differentiation into effector T cells, that eliminates the
antigen
● Activation of cellular immunity occurs in 2 steps: proliferation and differentiation of T
cells

14
 Antigen presenting cell with MHC-II Virus infected cell or APC containing
Ag on surface MHC-I Ag

Contacts inactive T4 cells TCR identifies MHC-Ag complex

Activation of T4 cells and

differentiation and proliferation Activation of T8 cells

Memory T4 cells Effector T4 cells

costimulation
IL-2 Proliferation and differentiation
of T8 cells

Effector T8 cells Memory T8 cells

Killing of invader by cytolysis

3. Elimination of the Invader

1. Cytolysis: Killer cells synthesize and secrete perforins, and incorporate them into the
membranes of the invading organisms. The invading cell swells and finally undergoes osmotic
lysis.
2. Lymphotoxin: Activated T cells secrete lymphotoxins that kill the microbes. Tumor necrosis
factor (TNF)-β is an important known lymphotoxin
3. Interferons: Cytotoxic T cells secrete gamma-interferons that are mainly antiviral increase
the phagocytic activity of neutrophils and macrophages by promoting opsonization.

15
Cellular immunity is activated mainly against intracellular pathogens and tumor cells, as in:
1. Viral infections
2. Fungal infections
3. Tumor cells, especially cancer cells
4. Transplanted cells
5. Chronic bacterial infections like tuberculosis, brucellosis, etc.
6. Parasitic infections

ANAEMIA

16
Definition: -
Anaemia is defined as a quantitive or qualitative reduction of rbc counts, leading to decreased
oxygen carrying capacity, usually anaemia is present when the blood count is less than 4 million
/mm3 or hb levels less than 12g%.

General features: -
Anaemic patients have low blood oxygen reserve as a result the remain normal under resting
state, but devolop breathlessness on exertion, the features follow: -
⮚ Tiredness, fatigue, muscular weakness
⮚ Pallor on general examination
⮚ Dyspnoea
⮚ Angina on elderly people.etc.

Grading of anaemia (W.H.O grades): -

● This classification is based on the hb levels of the blood, and it is classified as mild,
moderate, severe.
● Mild has hb level of 8-12g, moderate has level of 5-8g, severe has hb less than 5g,
difficult to live if hb is less than 2g.

Classification of anaemia:
(A) Based on causative factors
(B) Morphological basis

A. Aetiological Classification
Based on causative factors (aetiological), anaemia is classified into three types:
I. Anaemia due to decreased production of erythrocytes
II. Anaemia due to excess loss of blood.
III. Anaemia due to increased destruction of RBC

1. Anaemia due to Decreased Production of Erythrocytes: -

1. Nutritional Deficiency Anaemia
a) Megaloblastic anaemia - Due to B, or folic acid deficiency or both.
b) Iron deficiency anaemia - Due to iron deficiency.

Megaloblastic Anaemia: -
● It is due to deficiency of maturation factors B₁, and folic acid.
● Both these vitamins are required for synthesis of DNA.
● Vitamin B, acts as a co-enzyme and is absorbed from the ileum.

17
 ● Intrinsic factor produced by the gastric parietal cell is necessary for the absorption of
B12.
● Megaloblastic anaemia due to specific deficiency of the B₁₂ is called pernicious anaemia
as it is associated with severe neurological disorder.

B12 Deficiency: -
Causes: -
1. Inadequate intake
2. Intrinsic factor deficiency
3. Defective absorption.

B12, deficiency affects both the haemopoietic system and the nervous system and is mainly due
to defective absorption.

Features: -

1.Type of anaemia: Macrocytic normochromic anaemia

2. Blood changes
a) RBC are larger and normochromic.
b) RBC, WBC and platelet counts decrease.
c) Hb content per 100 mL is reduced.
d) Shortened lifespan: The large RBC (8.2 µ) as they pass through the capillary are prone
to get damaged, there by the shortened life span.
e) MCV and MCH increase while MCHC remains normal.
3. Bone marrow changes
a) Bone marrow shows hyperactivity due to anaemic hypoxia.
b) Megaloblasts, large proerythroblasts accumulate in large numbers.

4. GIT changes
a) Achlorhydria with intrinsic factor deficiency may be present
b) Glossitis (inflammation of tongue).
c) Anorexia is present.

5. Changes in nervous system

a) Subacute combined degeneration of spinal cord in which both sensory and motor tracts
are affected.
b) Peripheral neuropathy is present.
c) Loss of memory, depression and ataxia are present
d) Hyper reflexia and paralysis.

18
Folic Acid Deficiency: -

Causes: -
1. Inadequate intake
2. Increased demand
3. Poor absorption as in sprue
4. Persons on anti-metabolite treatment

In folic acid deficiency the same features are seen except neurological symptoms

Management:
● Vitamin B, therapy restores both haematological and neurological function.
● In pernicious anaemia, B should be given parenterally along with large oral dose
● Administration of folic acid restores the haematological function but not neurological
function.
● Neurological com- plications may worsen with folic acid treatment alone although its
deficiency does not itself cause neurological disturbances.
● Hence both B, and folic acid are given together.

Iron Deficiency Anaemia

This is the most frequently seen anaemia and is due to iron deficiency. The erythrocytes are
smaller and pale, hence the name microcytic and hypochromic anaemia. Iron is required for
haem synthesis. It is mainly absorbed from the duodenum.

Causes:
(i) Inadequate intake
(ii) Increased loss

i. Acute haemorrhage as in accidents

ii. Chronic haemorrhage as in:
a) Excess menstruation
b) Bleeding ulcers
c) Piles, etc
iii. Increased demand as in:
a) Pregnancy
b) Lactating mother c
c) Growing children
iv. Poor absorption due to disease of stomach and duodenum

v. Copper deficiency also causes as it is required for iron absorption.

19
Features: -
1. Type of anaemia: Microcytic hypochromic anaemia
2. Blood changes
a) RBC are smaller (<6.2 µ) and pale
b) RBC count is less
c) Hb content /100 mL is less
d) MCV, MCH and MCHC are less than normal
e) Platelet count is increased
f) Low serum and urine iron levels.

3. Bone marrow: Bone marrow is normoblastic and hyperplastic

4. Cardiorespiratory changes
a) Breathlessness and palpitation on exertion
b) Repeated lung infections due to decreased immunity

5.Nails: nails become dry and soft and spoon shaped

6. tongue: - glossitis, red in colour and atrophy of tongue.

Hypoplastic anaemia: -
This kind of anaemia caused by hypoactivity of bone marrow due to some drug effect or
irradiation or due to unknow cause, all cell counts exe agranulocytes are reduced normochromic
normocytic anaemia develops.

Renal disease: -
Even in renal disease the erythropoietin production is getting low so decrees in rbc production
causes anaemia.

Thyroid deficiency:
In hypothyroid condition the metabolic rate reduced so the rbc production is also reduced this
also causes anaemia.

2.Anaemia due to excess loss of blood:-

In acute injuries sever loss of blood results in anaemia e.g., some trauma or accidents in some
cases like menorrhagia, pilis and hookworm infection leads to blood loss this causes
normochromic normocytic anaemia develops.

3.Anaemia due to increased destruction of rbc: -

The breakdown of rbc resulting the release of hb into cytoplasm is called haemolysis and the
anaemia that develops due to excess destruction of rbc is called haemolytic anaemia.

20
 corpuscular defect

Haemolysis

extracorpuscular defect

Corpuscular defect:
E.g., Spherocytosis, sickle cell anaemia, thalassaemia, in all these cases, anaemia develops due
to a shortened life span of erythrocytes.

a) Spherocytosis: The shape of RBC is spherical, and fragility is increased. Deficiency of a

protein called sceptrin leads to spherocytosis.

b) Sickle cell anaemia: This is due to abnormal haemoglobin called HbS. ẞ(BETA) chains are
abnormal. Due to this, RBC get destroyed.

c) Thalassaemia (Cooley's anaemia): This is also due to abnormal haemoglobin and is

genetically determined RBC get destroyed due to abnormal Hb and cause anaemia. Thalassaemia
is of two types-a and B.

Extra corpuscular defect: -

a) Certain antibodies against RBC (erythroblastosis fetalis).

b) Drugs, snake venom. when present in the plasma cause haemolysis.
c) Transfusion reaction causes haemolysis.
d) In hypersplenism due to overactivity of RES, haemolysis takes place leading to anaemia.

21
(B) Morphological classification of anaemia:
Microcytic hypochromic anaemia:
MCV, MCH and MCHC are below normal
Micro-normoblasts are seen in bone marrow examination
This occurs due to the result of a defect in red cell production
Common examples are
o Iron deficiency anaemia
o Thalassemia

Normochromic normocytic anaemia:

● MCH, MCV, MCHC are within normal limits, but there is a decrease in the number of
RBCs.
● This can be seen in conditions where the bone marrow is suppressed, like malignancies or
anticancer drugs or in conditions with haemolysis.

Macrocytic anaemia:
● MCV is more than the normal limit that corresponds to macrocytosis
● Megaloblasts are seen in bone marrow examination
● The typical example is seen in B12 and folic acid deficiency anaemia.

22
 HUMORAL IMMUNITY

Definition:
The process by which the body defends itself against harmful substances is called immunity.
Humoral immunity is the immunity that is mediated by antibodies that are produced by plasma
cells.
B cell activation does not depend on the antigen presenting cells and antigens can directly
stimulate B cells

Steps in humoral immunity

1)Presentation of antigen:
● Antigen presenting cells in humoral immunity are the B cells themselves.
● APCs present the antigen combined with MHC-II molecules to activate the B cells.

2) Activation of B cells:
● When an antigen directly binds on to the receptors present on surface of B cells, the B
cells are activated.
● This process of activation is accentuated by the co-stimulation from type 2 helper cells.
● TH2 cells stimulate B cells by secretion of IL-2, IL-4 and IL-5.

3)Differentiation of B cells to plasma cells:

● The activated B cells enlarge in size that undergo complete transformation to form a
plasma cell.
● The cell is transformed completely in structure and function.
● Plasma cell has larger cytoplasm content that has many RERs.
● The enlarged B cell almost appears like a lymphoblast called B immunoblasts.
● This differentiation is also called as blast transformation.

4)Proliferation of plasma cells and production of antibody:

● Activated B cells undergo differentiation into plasma cells that secrete a large quantity of
antibodies.
● A specific antigen stimulates activation of specific B cells that undergo proliferation of a
selective clone of plasma cells.
● This is called clonal selection of plasma cells that produces specific antibodies.

5)Killing of the invaders:

● Neutralizing antigen by detoxifying the bacterial toxins
● Immobilization of the microbes
● Activation of complement system
● Precipitation of antigens that cause agglutination and precipitation reactions
● Facilitation of phagocytosis
● Providing immunity to new-borns by crossing of IgG through placenta

6) Formation of memory B cells:

23
 ● A small subset of activated B cells differentiates into memory B cells.
● Memory B cells usually remain inactive unless they are stimulated by the same antigen
● The subsequent immunological response to the antigen is more intense and of shorter
duration than the 1st response.

Types of humoral response:

Primary response:
● When antigen enters into the body for the 1st time, the immune response mounted is slot
and has a latent period of about 4 weeks
● The concentration of antibodies gradually rises and attain a small peak
● This is mainly mediated by IgM.
Secondary response:
● This occurs when the same antigen enters the body for the second time
● This time, there is stimulation of the memory B cells that secrete antibodies under a much
faster rate
● The response mounted is more intense and of shorter duration than the primary response.
● IgG is the main mediator of this phase.

IMMUNOLOGICAL RESPONSES
Secondary response
Antibody concentration

Primary response

duration

Applied aspect:
Monoclonal antibodies: These are synthesised from a single clone of plasma cells that are
useful for targeted therapy of certain diseases like cancers.
Severe combined immunodeficiency: This is caused by a deficiency of the enzyme
adenosine deaminase that causes a defect in humoral immunity.

24
 antigen

Directly contacts
inactive B cell

Formation of memory
Activation of B cells cells

Transformation into
plasma cells

Differentiation and
proliferation

Synthesis and secretion

of antibodies

Killing of invaders

25
 PLASMA PROTEINS
TYPES
● Pre -albumin
● Albumin(3-5gm/dl)
● Globulin(alpha, beta, gamma) – 2-3gm/dl
● Fibrinogen- 200-450 mg/dl
● Prothrombin

ORIGIN
● In embryo- messenchyme cells
● Adults-liver

Albumin:
● It is the major component of plasma proteins
● It is formed in the liver
● Being smallest in diameter, it appears early in the urine in case of kidney diseases
● Decrease of albumin decreases the oncotic pressure which is the major cause of edema
formation.

Globulin:
● It is formed in the reticuloendothelial cells and plasma cells
● They are divided as alpha, beta and gamma globulins
● The molecular weight is 90000-150000
● The normal albumin globulin ratio is 1.5:1 and is altered in many inflammatory conditions.

Fibrinogen:
● The molecular weight is 340000
● It is produced in the liver
● It plays an important role in coagulation of blood
● It also plays a role in erythrocyte sedimentation rate.

FUNCTIONS OF PLASMA PROTEINS:

● Helps in coagulation of blood
● Helps to maintain colloidal osmotic pressure
● Maintains systemic arterial blood pressure constant
● Provides stability to blood
● Maintains acid base balance in body
● Immune function
● Transport function

27
 ● Reservoir function
● Buffer function
● Protein reserve
● Determination of ESR (erythrocyte sedimentation rate)

APPLIED:
● Hypoproteinaemia- decrease in plasma protein level leading to edema.
● In liver diseases, there can be alteration of the AG ratio and can cause clotting disorders
due to deficiency of fibrinogen
● Albumin is an important protein for drug binding, therefore in decreased albumin levels,
there can be defective binding of drugs leading to decreased efficacy of the drug. It can
also cause decrease in transport of various metals and hormones.

FUNCTIONS OF PLATELETS

28
STRUCTURE
● Smallest blood vessels, colourless, oval granulated bodies.
● Count – 1.5-4lacs/microlitre
● The cell membrane is covered by an outer glycocalyx coat that consists of glycoproteins
that facilitates the aggregation of platelets.
● Spectrin molecule is present in the cell membrane that provides stability
● Microtubules help in maintaining the discoid shape of platelets
● Microfilaments aid in changing the shape of platelets during activation and helps in
release reaction.
● The canalicular and tubular system in the platelets aid in release reaction.
● Platelet granules are of 2 types: alpha and dense granules
● Alpha granules contain vWf, PDGF, fibronectin, plasminogen, proaccelerin,
coagulation factors V and XI, tPA.
● Dense granules contain serotonin, ADP, calcium, ATP and pyrophosphate.

Properties of platelets:
● Adhesion: platelets easily adhere to the damaged vascular endothelium, this is facilitated
by von Willebrand factor. In von Willebrand disease, there will be defective adhesion of
platelets leading to excessive blood loss
● Aggregation: platelets can also stick to each other. This is mediated by Gp IIb-IIIa and
thrombin
● Release reaction: activation of the platelets is facilitated by thrombin. They undergo
change in shape and discharge their granular contents.

FUNCTIONS
● Haemostasis- platelet adhesion, platelet activation, platelet aggregation
● Blood coagulation
● Clot retraction
● Phagocytic function
● Storage and transport function
● Thrombolysis
● Vascular growth by secretion of PDGF (platelet derived growth factor)

Applied aspect:
Bleeding disorders:
● These are caused by a defect in the steps of primary haemostasis.
● Defects in adhesion, aggregation or release reaction can cause bleeding disorders
● There will be an increase in bleeding time

29
 ● Thrombocytopenia can also cause bleeding disorders.

PRIMARY HEMOSTASIS
Haemostasis is the arrest of blood, two steps temporary and definitive haemostasis
● platelet adhesion
● platelet aggregation
● platelet activation and release

PLATELET ADHESION
● platelets have high affinity to adhere to the exposed wall
● exposed collagen and von Willebrand factor

PLATELET AGGREGATION
● fibrinogen, glycoprotein, thrombin promotes platelet aggregation
● ADP, platelet activating factor facilitate platelet aggregation

RELEASE REACTION:
Platelets are activated by tissue factors and chemicals released from granules of the platelets,
especially PAF.
There are various mechanisms by which the release reaction takes place.
● PAF: causes activation of IP3-DAG pathway🡪 influx of Ca🡪 contraction of
microfilaments🡪 release reaction
● Thrombospondin: facilitate the contractile system
● Thromboxane: DAG pathway activation🡪 activates phospholipase A2🡪 synthesis of
thromboxane A2🡪 vasoconstriction

30
31
 MONONUCLEAR PHAGOCYTE SYSTEM
DEFINITION:
1.The fixed macrophages are present in specific tissue sites in the body.
2.These macrophages are mononuclear cells, and therefore this system of phagocytes is called as
mononuclear phagocyte system (MPS).
3. Previously, this system of cells was known as reticuloendothelial system,

Cells of MPS:

● Kupffer cells of the liver

● Alveolar macrophages in the lungs
● Microglia of the brain
● Tissue macrophages in the spleen and lymph nodes
● Osteoclasts in bone
● Mesangial cells in the kidney
● Histiocytes in connective tissues
● Langerhans cells seen in the skin

Functions of MPS:
● These provide defense at a tissue level and prevent the infection of the organ.
● They kill the pathogen by phagocytosis

32
 ERYTHROBLASTOSIS FETALIS
Etiopathogenesis:
This is a hemolytic disease of the newborn which occurs due to Rh incompatibility when an
Rh-negative mother carries Rh positive fetus during pregnancy

🡺 No reaction occurs in the first pregnancy

🡺 At the time of delivery during placental separation, a small amount of fetal blood leaks
into the maternal circulation
🡺 This induces formation of anti-Rh agglutinins in the mother.
🡺 In subsequent pregnancies, the anti-Rh agglutinin from mother, which is predominantly
IgG type crosses placenta to enter into fetal circulation and causes hemolysis. In
third and subsequent pregnancies, the degree of hemolysis becomes severe

Clinical Features:
1. Anemia: it is proportionate to the degree of hemolysis
2. Hemolytic jaundice: serum bilirubin levels can be >25mg/dl
3. Generalized edema: Edema occurs in the whole body due to anemia and hypoproteinemia.
This is called hydrops fetalis.
4. Kernicterus: due to the deposition of bilirubin in the basal ganglia. The blood brain barrier
is not well developed in the fetus. Hyperbilirubinemia occurs due to hemolysis. Hemolysis in
adults does not produce kernicterus as the BBB is well developed.

5. Extramedullary hemopoiesis: due to severe anemia, extramedullary hemopoiesis occurs.

Nucleated red cells are released into the blood stream and plenty are seen.

Treatment:
1. Intrauterine fetal transfusion
2. Exchange transfusion: exchange transfusion removes the sensitized red cells, bilirubin
and maternal antibodies from the plasma. A double volume exchange transfusion
replaces 90% of the infant’s blood volume with antigen negative red cells.
3. Phototherapy: on exposure to light, bilirubin becomes non- toxic. It undergoes structural
configuration and photo oxidation. Neonatal jaundice is mainly hemolytic and
unconjugated.

Prevention:
1. Prevented by administering a single dose of anti-Rh antibodies in the form of Rh
immunoglobulin during the postpartum period following the first delivery
2. The disease can also be prevented by passive immunization of the mother with a small
dose of Rh immunoglobulins during pregnancy.

33
 FIBRINOLYSIS, CLOT LYSIS, DISSOLUTION
Fibrinolysis
Plasmin acts as an enzyme to cause fibrinolysis (lysis of clot).
1. This process is facilitated by cofactors thrombin, tissue-type plasminogen activator and
urokinase-type plasminogen activator.
2. Fibrin is degraded by plasmin to fibrin degradation products (FDP)

Vascular endothelium

Release of thrombomodulin

Thrombin from
clotting process

Inactivates Va and VIIIa

Protein C Activated protein C

Protein S

Inhibition of intrinsic mechanism

Activation of plasminogen activator

plasminogen plasmin fibrinolysis FDP formation

Inhibitors of Fibrinolysis:
1. Plasmin Inhibitors (alpha 2 antiplasmin and alpha 2 macroglobulin)
2. Plasminogen-Activator Inhibitors (PAI) (PAI-1 and PAI-2.)

34
Clot retraction:
1.The clotted blood consists of fibrin meshwork containing red cells and platelets trapped within
the clot. Fibrin threads spread in all directions and adhere to the endothelial wall.

2. When blood is allowed to clot in a test tube, the fibrin mesh spreads all around trapping all the
serum within it. However, within minutes to hours, clot shrinks expressing serum out of it.
3. This phenomenon is called clot retraction.
4.The process of clot retraction is believed to occur in vivo that causes consolidation of
thrombus (intravascular clot).

5.Clot retraction is the function of platelets.

6.For effective clot retraction to occur, normally functioning platelets must be present in
adequate number.

7. Retracted clot decreases the efficiency of thrombolysis (fibrinolysis). Therefore, a thrombus

rich in platelets is resistant to fibrinolytic agents.

Mechanism of Clot Retraction

● The platelets form spicules (filopodia) that extend along the fibrin threads.
● Also, protofibrils of thick fibrin strand get embedded within the filopodia by the action of
membrane cytoskeleton.
● Later, platelets shrink with contraction of their filopodia. This causes internalization of
fibrin within the contracted platelets. Thus, retraction of clot occurs.
● Thrombin and calcium accelerate clot retraction.
● Glycoprotein IIb/IIIa receptors on platelets facilitate clot retraction.

Functions of Clot Retraction

1. A retracted clot is a consolidated and stable thrombus,

2. Retracted clot (thrombus) strongly seals injured vessel.
3. It facilitates wound healing
4. It prevents thrombolysis

Prolongation of Clot Retraction Time

● Normally, clot retraction begins within thirty seconds after clot formation
● The process of retraction is very slow.
● About 50% retraction occurs at the end of one hour and completes in 18 to 24 hours.

35
Dissolution of blood clots:
It can become invaded by fibroblasts, subsequently form connective tissue all through the clot or
it can dissolve. The usual course for a clot that forms in a small hole of a vessel wall is invasion
by fibroblasts, beginning within a few hours after the clot is formed, which is promoted at least
partially by growth factor secreted by platelets. This process continues to complete organization
of the clot into fibrous tissue within about 1 to 2 weeks.

AUTOIMMUNE DISORDER
● Autoimmune disease is defined as a condition in which the immune system mistakenly
attacks body’s own cells and tissues
● Normally, the immune system does not react against self-proteins
● The condition in which the immune system fails to give response to an antigen is called
tolerance
● This is true with respect to body’s own antigens that are called self-antigens or
autoantigens
● Normally, body has the tolerance against self-antigen
● However, in some occasions, the tolerance fails or becomes incomplete against self-
antigen. This state is called autoimmunity
● It leads to the activation of T lymphocytes or production of autoantibodies from B
lymphocytes.
● The autoimmune disease is produced when body’s normal tolerance decreases and the
immune system fails to recognize the body’s own tissues as ‘SELF’
● Autoimmune diseases are of two types:
1. Organ specific diseases which affect only one organ
2. Organ nonspecific or multisystemic diseases, which affect many organs or systems.
● The common examples are SLE, rheumatoid arthritis, insulin-dependent diabetes
mellitus, myasthenia gravis, Grave’s disease, etc

36
 TRANSFUSION REACTIONS
o Transfusion reaction can be due to ABO incompatibility or Rh incompatibility.

TRANSFUSION REACTION DUE TO ABO INCOMPATILIBITY

o Transfusion reactions are the adverse reactions in the body, which occur due to
transfusion error that involves transfusion of incompatible (mismatched) blood
o In mismatched transfusion, the transfusion reactions occur between donor’s RBC and
recipient’s plasma.
o So, if the donor’s plasma contains agglutinins against recipient’s RBC, agglutination does
not occur because these antibodies are diluted in the recipient’s blood.
o But, if recipient’s plasma contains agglutinins against donor’s RBCs, the immune system
launches a response against the new blood cells. Donor RBCs is agglutinated resulting in
transfusion reaction.

Severity of Transfusion Reactions

Severity of transfusion reactions varies from mild (fever and chills) to severe (acute kidney
failure, shock and death). Severity depends upon the amount of blood transfused, type of reaction
and general health of the patient.

Cause for Transfusion Reactions

o Transfusion of incompatible blood produces haemolytic reactions.
o The recipient’s antibodies (IgG or IgM) adhere to the donor RBCs, which are
agglutinated and destroyed.
o Large amount of free haemoglobin is liberated into plasma. This leads to transfusion
reactions.

Signs and Symptoms of Transfusion Reactions

Non-haemolytic transfusion reaction
● Non-haemolytic transfusion reaction develops within a few minutes to hours after
the commencement of blood transfusion.
● Common symptoms are fever, difficulty in breathing and itching.

Haemolytic transfusion reaction

● Haemolytic transfusion reaction may be acute or delayed.
● The acute haemolytic reaction occurs within few minutes of transfusion.
● It develops because of rapid haemolysis of donor’s RBCs.
● Symptoms include fever, chills, increased heart rate, low blood pressure, shortness
of breath, bronchospasm, nausea, vomiting, red urine, chest pain, back pain and
rigor.
● Some patients may develop pulmonary oedema and congestive cardiac failure.
● Delayed haemolytic reaction occurs from 1 to 5 days after transfusion.

37
 ● The haemolysis of RBCs results in release of large amount of haemoglobin into the
plasma.
● This leads to the complications like jaundice, cardiac shock, renal shut down etc

TRANSFUSION REACTIONS DUE TO Rh INCOMPATIBILITY

● When a Rh-negative person receives Rh positive blood for the first time, he is not
affected much, since the reactions do not occur immediately.
● But the Rh antibodies develop within one month. The transfused RBCs, which are still
present in the recipient’s blood, are agglutinated.
● These agglutinated cells are lysed by macrophages.
● So, a delayed transfusion reaction occurs. But it is usually mild and does not affect the
recipient.
● However, antibodies developed in the recipient remain in the body forever.
● So, when this person receives Rh positive blood for the second time, the donor RBCs are
agglutinated and severe transfusion reactions occur immediately.
● These reactions are similar to the reactions of ABO incompatibility.

38
 HEMOPHILIA

HEMOPHILIA A
ETIOLOGY:
⮚ Haemophilia A, also known as classic haemophilia, is a bleeding disorder that occurs due
to deficiency of factor VIII.
⮚ It is an X-linked recessive hereditary disease. Though it is less common than von
Willebrand disease, it is more common than other inherited defects of coagulation.
⮚ Women are carriers and generally do not suffer from the disease as they are protected by
the second X-chromosome which is usually normal.

CLINICAL FEATURES
1. Soft tissue hematomas and hemarthroses (bleeding into joints) leading to severe crippling
hem arthropathy are highly characteristic of the disease.
2. In severe cases, spontaneous hem arthropathy from infancy is the common feature.
3. In mild to moderate cases, continuation of haemorrhage secondary to trauma or surgery is the
feature.
4. Bleeding usually persists from days to weeks in spite of formation of clots.
5. Bleeding may also occur spontaneously into tissues, and cavities of the body

DIAGNOSIS
⮚ Patients have prolonged activated partial thromboplastin time (APTT).
⮚ Prothrombin time and bleeding time are normal. Assay of factor VIII in plasma is
diagnostic.
⮚ Functional factor VIII coagulant activity can also be measured.

TREATMENT
⮚ The treatment consists of transfusion of fresh blood (as on storage factor VIII is rapidly
lost), or transfusion of factor VIII-concentrate.
⮚ Many plasma products are available for raising factor VIII to haemostatic level.
⮚ Fresh-frozen plasma and cryoprecipitate both contain factor VIII.
⮚ Attempt should be made to avoid aspirin, nonsteroidal anti-inflammatory drugs and other
drugs that interfere with platelet aggregation.

HEMOPHILIA B
ETIOLOGY

39
 ⮚ Christmas disease or haemophilia-B occurs due to deficiency of factor-IX
(antihemophilic factor-B or Christmas factor).
⮚ This is a sex-linked recessive haemorrhagic disease.

FEATURES
⮚ The disease is clinically indistinguishable from haemophilia A.
⮚ Bleeding episodes are clinically identical to those in haemophilia A.
⮚ Therefore, this is also called haemophilia-B. Hematoma, hemarthroses and crippling hem
arthropathy occur.

DIAGNOSIS
⮚ In most cases, PT is normal and partial thromboplastin time (PTT) is prolonged.
⮚ Specific assay of factor IX coagulant activity confirms diagnosis.

TREATMENT
⮚ The specific treatment of haemophilia B is the replacement of factor IX

40
 THALASSEMIA
1. The rate of synthesis of one or more types of hemoglobin polypeptide chain is
decreased
2. There are two major classes of thalassemia: α thalassemia and β thalassemia, in
which α and β globin genes are involved respectively

β thalassemia
1. In β thalassemia (failure to synthesize β chain), which is more common, there
is excess α chain production that damages red cell precursor and red cells.
2. β thalassemia major, anemia develops in first few months of life and becomes
progressively severe
3. Splenomegaly, hepatomegaly and skeletal deformities are common.
4. Though anemia is usually microcytic and hypochromic, all forms and
combinations are not uncommon

α-thalassemia
Anemia of α-thalassemia (failure to synthesize α chain) is more hemolytic than
dyserythropoietic.

The thalassemias are diagnosed by:

1.Hemoglobin electrophoresis

41
2. Demonstration of Hb-H inclusions (in the absence of sufficient alpha chains, excess of beta or
gamma
chains aggregate to form Hb-H)

3. Study of rate of globin chain synthesis

4. Alkali denaturation test
5. Acid elution test

BLOOD INDICES
The values of hemoglobin, PCV and total RBC count are used to calculate red cell volume and
red cell hemoglobin content and concentration. These are called red blood cell indices.
The commonly estimated blood indices are:
1. Mean cell volume (MCV)
2. Mean cell hemoglobin (MCH)
3. Mean cell hemoglobin concentration (MCHC)

MCV defines the volume or size of the average RBC,

MCH defines the weight of hemoglobin in the average RBC,
MCHC defines the hemoglobin concentration or color of the average RBC

1. Mean Corpuscular Volume:

Mean corpuscular volume (MCV) is the average volume of an RBC expressed in femtoliters

Normal value: The MCV in normal adults is between 78 and 96 fL.

Applied aspect: The MCV is the index of the size of red cells. It depicts whether the red cells
are microcytic,
normocytic or macrocytic.
If the MCV is less than 78 fL, the red cells are considered microcytic
if greater than 96 fL, they are considered macrocytic.

42
2. Mean Corpuscular Hemoglobin: expressed in picograms

Normal value: The normal range for MCH is 27 to 33 pg.

It may be as high as 50 pg in macrocytic anemia, or
as low as 20 pg or less in hypochromic microcytic anemia.

3. Mean Corpuscular Hemoglobin Concentration (MCHC)

It is expressed as g/dL, or percent.

Normal value: The normal range of MCHC is between 33 and 37 g/dL (or %).

Applied aspect: MCHC above 40% indicates malfunctioning of the instrument or error in the
calculation of the manual measurements used, as an MCHC of 37% is near the upper limits for
hemoglobin solubility, thus limiting the physiologic upper limit of the MCHC.

In hypochromic anemias, the hemoglobin concentration is reduced and values as low as 20% to
25% are not uncommon.

4. Color Index (CI)

This is the ratio of hemoglobin percent and RBC percent.

Normal value: The normal range of CI is between 0.85 and 1.10.

CI less than 0.85 indicates hypochromic anemia

STARLING FORCES

43
 ● Starling forces regulate NaCl and water reabsorption across the proximal tubule.
● The peritubular capillary oncotic pressure and the hydrostatic pressure in the interstitial
space favor this process.
● The interstitial space oncotic pressure and peritubular capillary hydrostatic pressure
oppose this process.
● When solutes are reabsorbed from the tubular cells into the interstitial space,
● osmolality of the interstitium increases, this favors movement of water from tubular
fluid into the interstitium via transcellular and paracellular pathways.

PATHOPHYSIOLOGY OF EDEMA

Increased Filtration of Fluid into the Interstitial Tissues Space

This can occur by three mechanisms:
● increased hydrostatic pressure of capillary blood,
● decreased oncotic pressure
● increased capillary permeability

Increased hydrostatic pressure of capillary blood

Causes:

● Increased venous pressure that increases capillary pressure, e.g., congestive cardiac
failure.
● Venular constriction, e.g., a tumor pressing on a vein causes edema in its territory of
drainage.

● Increased extracellular fluid volume, e.g., fluid retention.

● Arteriolar dilation, e.g., local inflammation.

Decreased oncotic pressure

Causes:
The oncotic pressure decreases due to hypoproteinemia that occurs in
● liver diseases (decreased production of plasma proteins)
● kidney diseases (increased excretion of plasma proteins)
● malnutrition (decreased intake of proteins)
● burns (exudation of protein rich fluid from the burn surface).

Increased Capillary Permeability

44
The capillary permeability increases by the action of chemical substances like histamine,
bradykinin, substance P and bacterial toxins. Edema that occurs in inflammation is due to
increased capillary permeability.

Decreased Removal of Fluid into the Interstitial Tissues Space

● From interstitial space water is removed by lymphatics.
● Thus, decreased lymphatic drainage causes edema formation. This can occur either due
to diseases of the lymphatics (lymphangitis), surgery (radical mastectomy that removes
lymphatic ducts), or by infection (filariasis).
● The decreased lymph flow decreases the removal of excess fluid from the interstitial
tissues space that results in edema formation.
● Edema due to lymphatic obstruction is usually non-pitting type.

HEMATOPOIESIS
It is the process of synthesis of blood cells.
It is also called as hematopoiesis
It is a continuous process as blood cells are constantly destroyed in the body.

Sites and stages of hemopoiesis:

Mesoblastic stage:
● It is the stage of development of blood cells in the yolk sac and non yolk sac regions
during the embryonic phase.
● Yolk sac cells contain cells with multilineage capacities that participate in hematopoiesis.

Hepatic stage:
● During the 2nd trimester of pregnancy, hematopoiesis takes place in the liver and spleen.
● This is called the hepatic stage that starts at 5th week of gestation.
● After birth, hemopoiesis is taken over by the bone marrow, however when there is an
increased demand, there will be pathological hematopoiesis taking place,
Medullary stage:
● This starts in the 5th month of fetal life.
● The bone marrow takes over the process of hematopoiesis
● Initially, granulocytic and megakaryocytic hematopoiesis takes place. Later, the
erythropoiesis starts in bone marrow.
Steps of hematopoiesis
Stem cells

45
 Progenitor cells

Intermediary cells (precursor cells)

Matured cells

Medullary
Mesoblastic hematopoiesis
Hepatic
stage
hematopoiesi
s
% cellularity

splee
n

1 3 7 9
Intrauterine life
(months)
Types of hemopoiesis:
● Erythropoiesis: formation of RBCs
● Leucopoiesis: formation of WBCs
● Thrombopoiesis: formation of platelets.

Regulation of hemopoiesis:
● Erythropoietin: important stimulant for RBC production

46
 ● Interleukins: IL 1, 11 and 5 control eosinophil development; IL 2 and 4 control
lymphocyte development; IL 1 and 2 control monocyte macrophage development.
● Colony stimulating factors; M-CSF stimulates the growth of monocyte precursors; G-
CSF controls granulocyte precursors.

COMPOSITION OF BLOOD
Blood is defined as the liquid connective tissue that fills the heart and blood vessels.
Blood consists of 2 components:
Fluid component: plasma
Formed elements: granulocytes and agranulocytes

When blood is allowed to collect in a tube with anticoagulants and is centrifuged, 3 distinctive
layers are formed
● Red cell layer: this is the bottom most layer and consists mainly of the red cells, this is
important in preparing the packed cell for blood transfusion.
● Buffy coat: it is the layer that lies in between the plasma and red cells. It consists mainly
of WBCs and platelets. This layer is important for analyzing the blood for malignant
conditions like leukemia
● Plasma: it is the fluid component of blood that is 55 %. This can be stored as fresh frozen
plasma that is rich in clotting factors that can be transfused in case of excessive
hemorrhage. Plasma is composed of water and plasma proteins.

Functions of blood:
● Transport of oxygen and carbon dioxide
● Transport of various chemicals like hormones, drugs, metals, nutrients
● Temperature regulation
● Excretory function
● Acid base balance
● Water homeostasis
● Immunity
● Storage
● Body color
● Nutritive functions
● Oncotic pressure

STEPS IN PHAGOCYTOSIS
Phagocytosis is the process of ingestion and killing of microbes or a foreign substance by a
phagocyte.

47
Steps of phagocytosis are
● Chemotaxis
● Adhesion
● Rolling
● Diapedesis
● Ingestion and killing.

Chemotaxis:
● It is the process of migration of neutrophils to the site of infection
● The chemical mediators are released at the site of infection or inflammation that attracts
the neutrophils to the site.
● Such substances are called chemoattractants
● Complement proteins, interleukins, damaged products of microbes act as
chemoattractants.

Adhesion and rolling:

● The activated neutrophils marginate towards the vessel wall and adhere tightly to the
endothelial lining with the help of L selectins

Diapedesis:
● It is the amoeboid movement of the neutrophil through the space between the endothelial
cells.

Opsonization:
● It is the process of making the microbe tasty to the phagocyte
● The chemicals that facilitate this process are called opsonins,
● IgG antibodies and complement proteins like C3b and C5a act as opsonins.
● Adherence helps in the process of ingestion,

Ingestion and killing:

● The adherence of the microbe to the neutrophil wall helps in endocytosis and ingestion of
the microbe.
● This occurs with the help of pseudopodia formation that engulfs the microbe.
● The phagocytic vesicles fuse with the lysosome to form phagolysosomes.
● Killing of the bacteria takes place by oxidative and non oxidative mechanisms
● Oxidative mechanisms include formation of free radicals that cause oxidative damage to
the microbe. There is a respiratory burst that occurs due to the formation of free radicals.
This process is mainly contributed by formation of superoxide anions.

48
 ● Non oxidative mechanism includes secretion of proteolytic and degradative enzymes like
defensins and lysozyme

Applied aspect:
● ALS (amyotrophic lateral sclerosis): it is a progressive degenerative disorder that is
characterized by defective dismutase enzymes.
● Chronic granulomatous disease: it is a genetic disorder in which neutrophils fail to
generate superoxide anion and related metabolites. Neutrophils and monocytes can ingest
a microbe but cannot kill it due to decreased NADPH oxidase activity.

HAEMOGLOBIN TYPES AND SYNTHESIS

Types of hemoglobin:

Hemoglobin can be divided into two classes broadly as normal and abnormal.

Normal hemoglobin:
Adult hemoglobin:
a) Hemoglobin A - Comprising about 97% of total Hb content, it is the major Hb.
-Structural formula α2b2
-detected at 8th week in fetus in small amounts
- HbA replaces HbF in 6months postnatally.
b) Hemoglobin A2- Comprises the minor portion of adult hemoglobin
-Structural formula α2δ2
-Concentration increases in anemia

49
 Fetal hemoglobin
a) Hemoglobin F -major Hb in intrauterine life, comprising a 70 to 90% at birth.
-Structural formula α2γ2
-A rapid fall to 25% is observed in first month and about 1% of
fetal Hb remains in bloodstream through the adult life.
-Increases in Anemia, Haemoglobinopathies and leukemia.

b) Hemoglobin Bart’s (Hb Bart’s) - contains 4 gamma chains and increases in fetal
life in thalassemia.

Embryonic hemoglobin- these are found in early stages of fetal growth and types include
Gower Hb1 (ζ2ε2), Hb Gower2 (α2ε 2), Hb Portland (ζ 2γ2).

50
Abnormal hemoglobin:
Abnormal Hb are present in various inherited hemoglobinopathies.
a) Sickle cell anemia, where valine gets substituted in 6th place of beta chain at the place
glutamic acid. This leads to formation of HbS which sickles on exposure to hypoxia conditions. On
repeated exposure the red cell becomes sticky and forms thrombi blocking blood vessels.
b) Hemoglobin C (HbC), another mutant β-globin, has a lysine residue instead of the
normal glutamic acid residue at position 6. If this occurs along with sickle cell anemia, a
symptomatic sickling disorder called HbSc disease happens.
c) Unstable hemoglobin occurs in conditions like congenital non spherocytic hemolytic
anemia. The Hb gets denatured and precipitates inside red cell as Heinz body, rendering the RBC
useless.

Synthesis of hemoglobin

Site of synthesis- heme in mitochondria and globin in ribosomes

Raw materials- Iron and amino acids like glycine

51
 POLYCYTHEMIA AND CAUSES
Polycythemia generally represents increased number of cells but we use it usually to represent
increase in red cells. Different forms of polycythemia exist.

Primary form: polycythemia vera, a neoplastic condition of hematopoietic stem cells associated
with point mutations. Excessive proliferation of erythroid, granulocytic, and megakaryocytic
elements, but most clinical signs and symptoms are related to an absolute increase in red cell mass.
Therefore, there is a increase in all types of formed elements.
- Signs and symptoms: Headache, plethora (ruddy complexion), pruritus, thrombosis and
Gastrointestinal bleeding.
- Bone marrow: hyper cellular of all cell precursors.
- CBC: Increased RBCs, Leukocytosis (especially neutrophilia), thrombocytosis
- Treatment: Phlebotomy (removing of 500ml of blood in 2 to 4 days), Myelosuppression
drugs.

Secondary form: condition in which red cell production increases due to increased erythropoietin
production either appropriately or inappropriately.
▪ appropriate factors: Tissue hypoxia (high altitude, Right and left shunt, chronic smoking,
red cell enzymes deficiency)
▪ inappropriate factors: tumors of kidneys, liver, brain and endocrine disorders like
pheochromocytoma, ovarian tumors, batter syndrome)

Relative/ apparent polycythemia: Not true increase in cells, but due to dehydration or body fluids
redistribution.

52
 ABO AND RH GROUPING
ABO grouping
ABO grouping is one of the first and most important blood grouping. The ABO blood grouping
system is based on the presence or absence of specific antigens on the surface of red blood cells.

Agglutinogens
▪ Antigens: antigen A (A1 and A) and antigen B. Gene
location: chromosome 9
▪ occurrence: membrane of red cells(mostly), other tissues (lungs, kidneys, pancreas)
▪ Time of appearance: sixth week of intrauterine life and reaches significant levels by 15 to 17
▪ years.
▪ Chemical nature: Oligosaccharides, but terminal sugar varies. For Agglutinogen A- N-acetyl
galactosamine, and for agglutinogen B, terminal sugar is galactose
▪ Therefore, with the presence and absence of A or/ and B antigens on RBC membrane, there are 4
blood groups.

Antigen/
Group A Group B Group AB Group O
blood group

Antigen A Present - Present -

Antigen B - Present Present -

Agglutinins
Agglutinins: anti A (alpha proper and alpha1) and anti B
occurrence: Plasma naturally without requiring previous exposure to antigen Time
of appearance: Second week of neonatal life and peak at 10 years of life. Chemical
nature: globulins of IgM nature. Cold antibodies in nature.

Antibody/
Group A Group B Group AB Group O
blood group

Anti A - Present - Present

Anti B Present - - Present

Landsteiner's law
53
 This law states that if a particular agglutinogen is present on the red cell membrane of an
individual, the correspond ing agglutinin must be absent in his plasma. Conversely, if the
agglutinogen is absent in the red cells, the corresponding agglutinin must be present in the plasma.

Inheritance
There are three genes: O, A, B. O is recessive while the rest 2 are dominant. Therefore, A and B
shows co dominance expressing AB genotype.

Rh grouping
First described in Rhesus monkeys, the second most important blood group system being followed.
Rh antigens: Six (C, D, E, c, d, e), but D antigen is the most immunologically active.
- Therefore, based on presence or absence of D antigen Th grouping is done as
positive and negative respectively.
- Gene location: chromosome 1
- Unlike AB antigens, these are found only on red cell membranes, and
participates in cation transport and membrane integrity.
- Rh antibodies: Anti D antibodies. They don’t exist naturally unlike ABO
antibodies, forms only after exposure to Rh antigens, like in transfusions, child birth.
IgG type of immunoglobulins, so can cross placenta.p and warm antibody.

Inheritance: Dominant gene, therefore Rh positive people can be homozygous(DD) or

heterozygous (Dd).

Rh incompatibility:

54
1. Rh negative people can safely get Rh positive blood for once in their life time.
2. One of the complications include, Erythroblastosis Fetalis.
- hemolytic disease of newborn. Happens when a baby has Rh positive father and Rh-negative
mother. After the delivery of placenta in first pregnancy. The Rh-positive blood of fetus is exposed to
mother.
- the mother produces anti D antibodies against it and during her second pregnancy, the IgG
antibodies cross the placenta and causes hemolysis of Fetal RBCs. This gets severe with subsequent
pregnancies.
-Clinical features:
a) Anemia
b) Hemolytic jaundice
c) Generalized edema (hydrops fetalis)
d) Kernicterus: deposition of bilirubin in basal ganglia
e) Extramedullary hemopoiesis.

55
St
udentNot
es

PHYSI
OLOGY
1s
tEdi
ti
on

Uni
t1
GeneralPhys
iol
ogy
 CONTENTS
SHORT NOTES

1. Functions of mitochondria Pg:2

2. Classify fluid compartments and give their normal values, Pg:2

and give 2 methods to determine ECF volume with
procedure

3. Primary active transport, describe in detail about the Na-K Pg:3

ATPase pump

4. Vesicular transport with types and process Pg:4

5. Secondary active transport Pg:4

6. Feedback mechanism, describe in detail about the negative Pg:6

feedback mechanism and the applied aspects of each

7. Facilitated diffusion Pg:7

8. Ion channels with gating of ion channels Pg:8

9. Cytoskeleton Pg:10

10. Aquaporins Pg:12

11. Phagocytosis and the steps involved Pg:14

12. G protein Pg:15

13. Apoptosis Pg:16

14. Carrier-mediated transport Pg:18

15. Cell junctions Pg:20

1
 FUNCTIONS OF MITOCHONDRIA
Production of energy:
● Energy is produced during the oxidation of digested food particles.
● The released energy is stored in mitochondria and later used for the synthesis of ATP
● Therefore, it is known as the " powerhouse " of the cell

Synthesis of ATP:
● The components of the respiratory chain in mitochondrion are responsible for the
synthesis of ATP by utilizing the energy by oxidative phosphorylation

Apoptosis:
● Cytochrome C and the second mitochondria-derived activator of caspases ( SMAC )
secreted by mitochondria are involved in apoptosis

Storage of calcium:
● Mitochondria also stores calcium in its matrix

Detoxification functions:
● Mitochondria in liver cells are responsible for the detoxification of ammonia

FLUID COMPARTMENT
● The total body fluid is mainly distributed into,
1. Intracellular fluid
2. Extracellular fluid
1. Intracellular fluid compartment:
● It constitutes about 28 of the 42 litres of fluid i.e, about 40 percent of the total
body weight
2. Extracellular fluid compartment:
● It constitutes about 14 of the 42 litres of fluid i.e, about 20 percent of the total
body fluid
● Interstitial fluid and the plasma make up the extracellular fluid compartment

Measurement of Extracellular fluid volume:

● “Indicator-dilution” method is used to measure the volume of a fluid compartment
● This method is based on that the total mass of a substance after dispersion in the fluid
compartment will be the same as the total mass injected into the compartment

2
 ● Indicators used are,
1. Sodium
2. Inulin
3. Iothalamate
4. Thiosulfate

PRIMARY ACTIVE TRANSPORT

● Primary Active Transport:
Primary Active transport is the type of transport mechanism in which the energy is
liberated directly from the breakdown of ATP.
● Sodium-Potassium pump:
The Na+- K+ pump is responsible for the distribution of sodium and potassium ions
across the cell membrane and the development of RMP
● Structure of sodium-potassium pump:
It has one alpha and one beta subunit. Transport of sodium and potassium occurs
only by the alpha subunit.
The alpha subunit of the sodium-potassium pump has got six sites:
1. Three receptor sites for sodium ions on the inner surface
2. Two receptors’ sites for potassium ions on the outer surface
3. One site for enzyme ATPase

Mechanism of action of sodium-potassium pump:

● Sodium ions get attached to the receptor site on the inner surface and potassium ions on
the outer surface of the carrier protein.
● It activates the enzyme ATPase
● It causes the breakdown of ATP into ADP with the release of energy
● The energy liberated causes a conformational change in the molecule of the carrier
protein
● So, sodium ions are released outside and potassium ions are released inside the cell.

3
 VESICULAR TRANSPORT
Some substances are transported through the cell membrane in the form of vesicles. So,
these types of transport mechanisms are called the Vesicular transport
Types:
1. Endocytosis
2. Exocytosis
3. Transcytosis

1. Endocytosis:
● It is the process by which large molecules are transported from the
extracellular space into the cell by invalidating of the cell membrane around
the molecule
● It is of three types
● Pinocytosis
● Phagocytosis
● Receptor-mediated endocytosis

2.Exocytosis:
● It is the process by which large molecules are released to the exterior of the cell
membrane
● Hormones and neurotransmitters are examples

SECONDARY ACTIVE TRANSPORT

ACTIVE TRANSPORT:
Active transport is defined as the transport that occurs against the concentration gradient with the
help of energy.
There are 3 common characteristics of active transport
● Uphill transport
● Utilise metabolic energy
● Exhibit saturation kinetics

SECONDARY ACTIVE TRANSPORT:

● It is defined as the transport that happens with energy that is utilized from the gradient
created by Na ions.
● The Na gradient is maintained by the Na-K pump.

4
 ● Though the transport does not directly depend on the pump, it is dependent on the energy
and the gradient that is generated and maintained by the pump.
● Examples of secondary active transport include the transport of glucose and amino acids
from the kidney tubule and intestine

STEPS INVOLVED:
The primary active transport of Na leads to decreased concentration of Na in cytosol

Causes facilitated diffusion of Na from the lumen into the cells

The carrier protein that transports Na also transports glucose in the same direction

Symport occurs
● The carrier protein needn’t necessarily be a symporter. It can be an antiport also.
● For example, Na-H exchanger in the nephron, Na-Ca exchanger in the heart.

Lumen of gut
interstitium

Na-Glucose co
transporter
Na+

K+
Na+
Na-K
ATPase
pump
Apical
Basolateral membrane
membrane

5
 FEEDBACK MECHANISM
Haemostatic regulation is achieved by feedback mechanisms that operate to safeguard the
physiological variable.
The stimulus for feedback control is detected by a sensor that activates the feedback system
which in turn triggers a response to bring the variable back to the normal range.
There are 2 types of feedback:
● Positive feedback
● Negative feedback

NEGATIVE FEEDBACK:
● The negative feedback mechanism is the most common system that operates in the body
● When the variable is above the set point, the negative feedback is activated that inhibits
the formation of a variable.

Components of negative feedback mechanism:

Disruption of homeostasis

Detection by sensor and generation of input signal

Control center and generation of output signal

Effector that mediates response

Return to homeostasis
● Sensor: the sensor contains receptors that monitor the levels of the variable, eg: control
of blood pressure, hormone levels, reflex regulation.
● Control center: usually, it is the CNS, especially in the brain
● Effector: the effector is the target organ that carries out the command of the control
center to achieve an effective response. For example, blood vessels and the heart are the
effectors of blood pressure regulation. The effect produced depends on the rate of
sympathetic discharge.

6
Examples of negative feedback control:
● Control of pH
● Control of osmolality
● Control of blood sugar, and body weight
● Stretch reflex.
● Control of blood pressure
● Control of body temperature
● Regulation of hormone secretion

FACILITATED DIFFUSION
When diffusion is facilitated by a carrier protein, it is called facilitated diffusion.
It is also called carrier-mediated transport as a carrier protein facilitates it.

CHARACTERISTICS:
1) Faster rate of transport: carrier-mediated transport allows the transport of polar or
hydrophilic molecules at a much faster rate than the rate expected from their partition coefficient.
The partition coefficient is the solubility of a substance in oil compared to its solubility in water.
2) Saturation kinetics: in simple diffusion, the rate of diffusion is proportional to the
concentration of the substance and there is no saturation point. In facilitated diffusion, the
number of carrier proteins determines the rate of diffusion. When all the carriers are occupied,
the system operates at its maximum capacity. This is called the saturation point.
3) Competitive inhibition: many substances share the same carrier protein for their transport.
One substance decreases the transport of the other. This is different from co-transport
mechanisms.
4) Specificity: the carrier proteins are specific for different molecules.

FACTORS AFFECTING FACILITATED TRANSPORT:

● Number of carrier proteins available
● Hormones
● Lipid solubility of the substance
● Electrical gradient
● Pressure gradient
● Molecular size

7
 ION CHANNELS AND THEIR GATING
● Ion channels are integral proteins that span the entire width of the cell membrane
● They are found as several polypeptide units

MECHANISM OF ION CHANNEL WORKING:

● Along the length of the channel, there is an aqueous pore that is present around which the
polypeptide units are arranged
● Ions cross the membrane without entering the lipid bilayer.
● A polypeptide subunit forms the gate of the ion channel that opens to a specific stimulus
● Opening of the gates allows the ions to diffuse at a very rapid rate.
● There is a selectivity filter that permits specific ions to pass through, hence they are
highly specific.
● Examples of ion channels are Na and K channels.

Selectivity filter

Cell
membran
e

Pore of the channel gate

GATING OF ION CHANNEL:

There are 3 mechanisms of gating an ion channel
● Voltage gating
● Ligand gating
● Mechanical gating
1) VOLTAGE GATING:
Change in the membrane potential beyond a certain threshold value opens or closes the gate.
Mechanism of gating:

8
 ● Alteration in membrane potential induces movement of some charged amino acids in a
helical segment that produces a conformational change of the channel protein
● For Na, the gate is located on the outer side of the channel
● For K channel, the gate is located on the inner side of the channel
● Opening of K channel is slower than the opening of Na channel.

2)LIGAND GATING:
Interaction of the channel with a ligand causes opening or closure of the channel
Mechanism of gating:
● The chemical agent binds with the specific receptor protein on the membrane and brings
about a conformational change
● Nicotinic cholinergic receptor in the postsynaptic membrane is an example of ligand-
gated channel
●
3) MECHANICAL GATING:
● Some of the channels are mechanosensitive and they respond to stretch.
● Examples are ion channels in hair cells in the cochlea and vestibular apparatus and
stretch-sensitive channels in the ventricular muscles.

CYTOSKELETON

9
 ● Cytoskeleton is an intracellular system of fibers that not only maintains the structural
integrity of the cell but also allows appropriate change in cell shape for cell mobility and
participation of cell in various physiological activities.
● It consists of
i. Microfilaments
ii. Microtubules
iii. Intermediate filaments

MICROFILAMENTS MICROTUBULES INTERMEDIATE

FILAMENTS
1.Shape Double stranded helical Long, non-branching Tubular hollow
arrangement
2. Diameter 7 nm 25 nm 10 nm
3. Basic Actin Tubulin Various proteins
protein units
4. Location in – Forms a network adjacent – Mitotic spindle – Extend across cytoplasm
cell to cell connecting desmosome and
– Core of cilia hemidesmosome
– Core of microvilli
– The nuclear lamina
– Contractile elements of
muscle – In skin epithelium as keratin

5.Special –Microfilaments are well –Property of –Intermediate filament

characteristics developed in muscle cells disaggregating proteins are cell markers:
and are better organized in (disassembly) and re-
cells that secrete granular aggregating (assembly). For example:
content by exocytosis. –cytokeratin is the marker of
–Interaction with GTP epithelial cells
–Help platelets to change facilitates microtubule –vimentin is the marker of
shape and move granules formation. fibroblast
from interior of cytoplasm to
canaliculi for release of –Microtubule growth is
chemicals temperature sensitive
(release reaction of platelet) with cold conditions
favoring disassembly.
–Cells with microvilli on
their epithelial surface, –Kinesin and dynein are
microfilaments extend into microtubule-based
the microvilli. molecular motors
6. Major –Essential element of –Provides network for –Provide mechanical strength
functions contractile element of movement of organelles and link cells together
muscles
–Movement of cilia –Connect the nuclear
membrane to the cell

10
 –Actin filament interacts –Help in transport of membrane and also
with integrin receptors to vesicles and organelles membranes of cell organelle
form focal adhesion from one part of the cell
complexes (FAC) to another. –form supple skeletal network
for the cell and resist rupture
–Microfilaments in the –Contribute to the of cell from external pressure.
lamellipodia help in cell maintenance of cell used as cell markers
movement on a surface. strength and cell shape
–used as cell markers
–Help in microvilli –They help in the
movement which is present formation of spindles that
on the epithelial surface such move chromosomes
as on the intestinal mucosa, during mitotic cell
and extend up to the tip of division.
microvilli.

AQUAPORINS
● Aquaporins are water channels made up of proteins that help in the transportation of
water across the membrane of epithelial cells.

11
● Thirteen aquaporins have been identified to date.
● In human beings, four types of aquaporins have been characterized so far.
These are aquaporin-1, aquaporin-2, aquaporin-5, and aquaporin-9.
Aquaporins-1 and 2 are mainly involved in water reabsorption from kidney

Types Distribution Functions Expression in

other tissues

A. Renal aquaporins
Aquaporin 1 Apical and 67% of water Multiple organs
basolateral reabsorption in PCT
membrane of PCT is due to AQP-1
and thin descending Imparts free water
limb of LOH permeability in the
thin descending
limb of LOH

Aquaporin 2 Apical membrane of Mediate ADH Testis

late DCT and effects
vesicles of principal
cells of cortical part
of CD

Aquaporin 3 Basolateral Mediate ADH Multiple organs

membrane of late effects
DCT and cortical
CD

Aquaporin 4 Basolateral Mediate ADH Brain, other organs

membrane of late effects
DCT and cortical
CD

Aquaporin 6 Vesicles of Acts as an internal

intercalated cells of ion channel of I
CD cells

Aquaporin 7 Apical membrane of Water absorption in Testis and

PCT PCT adipocytes

12
 Aquaporin 8 Intracellular vesicles Exact function not Testis, epididymis,
in cortex and known pancreas, liver,
medulla; in PCT colon, heart,
placenta

B. Extrarenal aquaporins
Aquaporin 5 Salivary glands,
lungs, eye

Aquaporin 9 Liver, leucocyte,

brain, spleen, lungs,
epididymis, testis

Applied Aspects
● Nephrogenic diabetes insipidus is characterized by decreased expression of aquaporin 2 in
CD and DCT.
● In chronic heart failure, there is increased expression of aquaporin2

PHAGOCYTOSIS AND STEPS INVOLVED

● Phagocytosis is the process of ingestion and killing of microbes or a foreign substance by
a phagocyte.
● Phagocytic cells are neutrophils, monocytes, and macrophages.
● Steps of phagocytosis include

13
 i. Chemotaxis
ii. Diapedesis
iii. Adherence,
iv. Ingestion
v. Killing

CHEMOTAXIS
● Chemotaxis is the process of migration of neutrophils to the site of infection.
● The chemical substances that are released from the site of inflammation or infection by
the infecting organisms or inflammatory cells are called chemotaxins.
● Chemotaxins are usually the microbial products or chemicals secreted from leucocytes or
chemicals released from damaged tissue. C5a and C3 also act as chemotaxins.

DIAPEDESIS
● The process, by which neutrophils pass through the capillary endothelial cells to
reach the invader in the tissue, is called diapedesis.
● The activated neutrophils marginate (margination and paving) adhere tightly to the
endothelial lining (rolling and adhesion) with the help of L-selectins and then by
their ameboid movement they squeeze through the space between endothelial cells
(emigration and diapedesis)

OPSONIZATION
● The process by which the bacteria are made tasty to the phagocyte is called
opsonization.
● In this process, the antigen is coated by opsonins. The chemicals that facilitate the
process of opsonization are called opsonins:
● IgG antibody and complement proteins (C5a, C3b) are known as high-quality
opsonins.

ADHERENCE
● The attachment of the membrane of the phagocyte to the membrane of the microbe is
called adherence.

ENDOCYTOSIS
● The membrane of the phagocyte extends projections from both sides to encroach
onto the microbe. These extensions are called pseudopodia.
● Pseudopodia finally surrounds the microbe and form a phagocytic vesicle.
● The phagocytic vesicle fuses with the lysosome to form phagolysosome

14
KILLING
● The bactericidal (killing of bacteria) mechanisms can broadly be divided into two types:
i. Nonoxidative
ii. oxidative.

i)Nonoxidative Mechanisms:

● Neutrophil granules contain a wide variety of antibacterial chemicals such as degradative

enzymes, proteases, defensins, and cationic proteins:
● Lysozyme hydrolyzes the cell wall of bacteria
● Lactoferrin sequesters iron are nonoxidative components of bacterial killing.
● Defensins released from azurophil granules have unusual cyclic structures and kill
bacteria by disrupting their outer membrane and breaking single-strand DNA structures.

ii)Oxidative Mechanisms

Activated neutrophils produce a number of oxygen metabolites that are antimicrobial.

● The metabolites are superoxide anion (O2 –), H2O2, free hydroxyl radicals (OH·),
hypochlorous acid (HOCl), and singlet oxygen (´O2). These reactive metabolites are
generated by a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent
oxidase that reduces molecular oxygen to O2 –.
● Activation of NADPH oxidase is associated with increased oxygen intake of neutrophils.
This is called a respiratory burst.
● Myeloperoxidase, the enzyme of primary granules facilitates the conversion of Cl– to
HOCl, which is also a potent oxidant

APPLIED ASPECTS
● Neutrophil hypomotility, a primary phagocytic dysfunction of neutrophil, decreases
phagocytic activity.
● Chemotaxis and phagocytosis require active movements of neutrophils. When neutrophil
is activated, its cytosolic calcium concentration increases which promotes contraction of
microfilaments, microtubules, and myosin-1 filaments.
● This increases the ameboid movement and activity of neutrophils.
● Defective adhesion can lead to primary immunodeficiency disorders.

G-PROTEINS
● G-proteins or guanosine ribonucleotide proteins are the membrane proteins situated on
the inner surface of the cell membrane.
● These proteins play an important role in the formation of cAMP.

15
 ● Each G protein molecule is made up of trimeric subunits called alpha, beta and gamma
subunits.
● The alpha subunit is bound with GDP to form alpha-GDP complex.
● The beta and gamma subunits always bind together and form b-g dimer.
● In the inactivated G-protein, both the complex and the dimer are united.

Sequence of events in the formation of cAMP:

● Hormone binds with receptor to form hormone receptor complex.
● Activation of G-protein.
● G protein releases GDP from a-GDP unit.
● Alpha subunit binds with new molecule of GTP to form a-GTP unit.
● Dissociation of a-GTP from b-g dimer.
● Both, the complex and dimer activates second messenger pathways.
● The a-GTP complex activates adenyl cyclase complex which also presents in cell
membrane.
● The adenyl cyclase enzyme converts ATP of cytoplasm to cAMP which activates protein
kinase A.

APOPTOSIS
● Apoptosis is defined as natural or programmed cell death under genetic control.
● It is also called 'cell suicide' since the genes of the cell play a major role in death.

FUNCTIONAL SIGNIFICANCE:
● Plays a vital role in cellular homeostasis.
● Useful for the removal of a cell that is damaged beyond repair by a virus or toxin.
Biological events:
● Physiologically,
❖ Development of embryo
❖ Endometrial shedding
❖ Involution of thymus
● Pathologically,
❖ Graft vs host disease
❖ Decrease in CD4+ T cells -AIDS
❖ Heart diseases

MORPHOLOGICAL FEATURES
● Small, cluster of cells
● Round, oval, shrunken mass
● Eosinophilic cytoplasm

16
 ● Condensation of nuclear chromatin
● Shrinking of organelles
● Formation of apoptotic bodies
● Phagocytosis by macrophages

BIOCHEMICAL CHANGES:
● Proteolysis
● Cross linking in between proteins
● Chromatin breaks into fragments
● Thrombospondin on outer surface of apoptotic bodies.

MECHANISM OF APOPTOSIS:

CARRIER MEDIATED TRANSPORT

● Movement which occurs across membranes such as blood-brain barrier and GIT mucosa.
● The passage of glucose, amino acids, and other polar molecules through the cell
membrane is mediated by carrier proteins in the cell membrane.

17
TYPES:
● Active transport
● Passive transport

ACTIVE TRANSPORT:
● Movement of molecules from a region of lower concentration to higher concentration
against concentration gradient is active transport.
● Active transport is of two types:
-Primary active transport uses ATP
-Secondary active transport that uses an electrochemical gradient.

A) Primary active transport:

B)Secondary active transport:

18
PASSIVE TRANSPORT:
● Passive transport is defined as the movement of substances from higher concentration to
lower concentration without the utilization of energy.

Types of passive transport:

CELL JUNCTIONS

19
 ● Cell junction is the connection between the neighboring cells or the contact between the
cell and extracellular matrix.
● It is also called membrane junction.

Types of cell junctions:

1. Tight junction
2. Adhering junction
3. Gap junction
4. Desmosomes
5. Hemidesmosomes

Junction type Proteins involved Functions Examples

Tight junction Claudin Strength and stability Epithelial lining of

JAMs to tissues intestinal mucosa
Occuldin Selective and renal tubule
Cingulin permeability Endothelium in
Symplekin Fencing function capillary wall and
ZO-1, 2, 3 Maintenance of cell choroid plexus
polarity
Formation of
blood-brain barrier

Adhering junction Connexins Allows passage of Epithelial lining

small molecules, ions Heart
and chemical Intestine
messengers
Propagation of action
potential

Gap junction Cadherins Cell to cell Epithelial lining

attachment Heart
Intestine

Desmosomes Cadherins Cell to cell Epithelial lining

attachment Skin

Hemidesmosomes Integrins Cell attachment to Epithelial lining

Basal lamina
Extracellular matrix

20
St
udentNot
es

PHYSI
OLOGY
1s
tEdi
ti
on

Uni
t9
Gas
troI
ntes
tinalTract
 CONTENTS
ESSAY

1. Describe the mechanism of secretion of HCl in the stomach. Pg: 4

Enlist the factors regulating acid secretion in the stomach.
Describe peptic ulcer

2. Describe the digestion and absorption of proteins in the Pg: 8

GIT. Add a note on malabsorption

3. Composition and regulation of pancreatic secretions Pg: 10

4. Enumerate the types of salivary glands. Describe their Pg: 17

structure, function and regulation of secretion with the
applied aspect

5. Pathophysiology of jaundice with a brief note on liver Pg: 20

function tests

6. Digestion and absorption of carbohydrates Pg: 24

7. Digestion and absorption of fats Pg: 28

SHORT NOTES

1. Phases of GI secretions Pg: 33

2. Exocrine pancreas Pg: 35

4. Composition and functions of saliva Pg: 38

5. Stages of deglutition with applied aspect, gastric emptying Pg: 38,

phases, and applied aspect, gastrin

1
6. Composition and functions of bile, differences between Pg: 44
hepatic and gall bladder bile, secretin

7. Succus entericus, small intestine motility with applied Pg: 47

aspect, functions of the large intestine

8. Peristalsis, migrating motor complex, vomiting Pg: 50

9. Enteric nervous system, dietary fibers, cholecystokinin Pg: 53

10. Enterohepatic circulation Pg: 60

11. Defecation reflex Pg: 61

12. Normal bilirubin metabolism Pg: 62

2
 ● Parietal cells secrete HCL.
● This requires expenditure of energy.
● Energy is supplied by oxidative metabolism of the cells

Secretion of HCI consists of two components

1. Secretion of H' ions into the lumen
2. Secretion of Cl ions into the lumen

1. H+ ions are formed by dissociation of H2O and are actively secreted into the lumen in
exchange for one K+ ion.
● This is coupled by H-K pump.
● H20→OH + H+
2. H2CO3 is formed in the parietal cell by hydration of CO2.
● This is facilitated by carbonic anhydrase (CA).
● CO2+H2O→ H2CO3H→H+ +HCO3
● CO2 is derived either from the plasma or from the metabolism of cells. H2CO3
thus formed splits into H+ and HCO3.
● H+ combines with OH to form H2O.
3.HCO3 thus formed in the cell is transported by antiport into the blood in exchange for Cl-
by an active transport.
4. Cl ions diffuse out passively into the lumen.
5. For each H+ ion secreted one Cl is secreted and one HCO3 ion is absorbed into the blood.
As a result plasma pH increases toward alkalinity.
● The kidney excretes these excess HCO3 ions into the urine.
● This is called postprandial alkaline tide.
6. Water moves into the lumen passively.
7. H+ combines with Cl and forms HCI.
● Acid thus secreted by the parietal cell has a concentration of 0.17 M.
● This acid is neutralised by the other components of gastric juice.

4
 ●

REGULATION OF GASTRIC SECRETION:

4 phases of gastric secretion
● Cephalic phase
● Gastric phase
● Intestinal phase
● Interdigestive phase

Cephalic phase
▪ In this phase there is secretion of gastric juice even before food enters the stomach.
▪ Integrity of vagus nerve is important for cephalic phase of gastric secretion

▪ Rate of production of gastric juice during cephalic phase is high and rich in acid and
pepsin.
▪ conditioned and unconditioned reflexes play an important role in this phase.

Gastric phase
▪ This phase of secretion begins when the food enters the stomach.
▪ 50-60% total gastric acid is secreted and is proportional to the protein content of diet.

5
 ▪ Regulation:
● Neural mechanism: intramural nerve plexus and vagovagal reflex. This causes
release of Ach that acts as a direct stimulant of gastrin secretion
● Hormonal mechanism: gastrin is the major hormone that controls HCl
secretion. Gastrin binds to the gastrin receptor and increases intracellular Ca
that increases gastric acid secretion and enzymes.

Intestinal phase
▪ This phase depends on the type of food entering the intestine.
▪ There may be either secretion or inhibition of secretion and motility of stomach.
▪ Stimulation:
o when there is protein digestion products, it stimulates the G cells of the duodenum
and causes gastrin secretion
o this upregulates the secretion of HCl

▪ Inhibition:
● When acid, fat and hypertonic solutions enter the duodenum and the proximal
part of the jejunum, secretin, Bulbogastrone, CCK-PZ, GIP, VIP and
somatostatin are released.
● These are combinedly referred to as Entero gastrones.
● These inhibit the release of gastrin and also inhibit acid secretions by acting
on the parietal cells.
● Fat appears to have maximum inhibitory effect on gastric acid secretion.
● Enterogastric reflex:
o This is a reflex mechanism mediated through the local nerve plexus.
o When more food enters the duodenum it gets stretched.
o Local plexus is activated due to distension.
o This inhibits through sympathetic nerve fibres both gastric secretion
and motility.
o Afferents are vagal fibres and efferents are sympathetic fibres.

Interdigestive phase
▪ When there is no food in the mouth, stomach or small intestine, there is minimal
secretion of gastric juice.
▪ This is called interdigestive phase and represents basal gastric secretion.
▪ This is due to:
(i) Basal vagal tone and stops after vagotomy and removal of the antrum
(ii) (ii) Basal metabolic rate
(iii) (iii) Basal secretion of histamine and gastrin. This exhibits circadian rhythm
lowest in the morning before awakening and highest in the evening.

6
PEPTIC ULCER
● An ulcer is the erosion of the mucosa of the alimentary tract, which extends through the
muscularis mucosae into the submucosa or deeper.
● Localised erosion and destruction of gastric or duodenal mucosa is called peptic ulcer.
● Usually an imbalance develops between these two factors in the following conditions
facilitating production of peptic ulcers:
a) Disruption of mucosal barrier. This is seen in:
i) Ingestion of steroidal or nonsteroidal anti-inflammatory drugs
ii) Alcohol
iii) Bile salt regurgitation
iv) Ischaemia of gastric mucosa

b) Hypersecretion of acid and pepsin

i) Ingestion of food that stimulates hypersecretion, e.g... spices and condiments.
ii) Increased secretion of gastrin seen in Zollinger-Ellison syndrome.
iii) Chronic stress and anxiety

c) Delayed emptying as in pyloric stenosis

d) Infection by Helicobacter pylori: It causes gastritis followed by peptic ulcer.

Features
1. Severe burning pain in epigastrium immediately after food intake in gastric ulcer patients.
2. In subjects with duodenal ulcer severe pain is felt 1-2 hour after food intake.
3. Nausea and vomiting may be present.
4. Hematemesis in case of bleeding ulcers.
5. Heartburn due to regurgitation of acid into the oesophagus(GERD).
6. Anorexia and loss of weight are present.

Prevention
1. Adequate quantity of water should be taken regularly.
2. Avoiding ingestion of excess amounts of spices.
3. Avoiding ingestion of gastric stimulants like alcohol, smoking, tobacco.
4. Regularity in meals, sleep, etc.

7
 PROTEIN DIGESTION
⮚ Apart from the protein content of food, 10 - 30 gram of protein is added to the intestinal
content from the GI secretions and the ex-foliated intestinal cells.
⮚ Digestion of Proteins Digestion of protein starts in the stomach.
⮚ Pepsinogen (from chief cells) is converted to pepsin by the action of HCl.
⮚ Pepsin hydrolyzes proteins into peptides and amino acids.
⮚ In the duodenum and small intestine, the proteins are digested by proteases (in the
pancreatic secretion).
⮚ Trypsin, chymotrypsin, carboxypeptidases and elastase are Proteases.
⮚ The enterokinase (from mucosal cells of duodenum and jejunum) converts trypsinogen
into Trypsin.
⮚ Trypsin then acts as an enzyme to convert other proteases.
⮚ Peptidases (in the brush border of enterocytes) hydrolyze the peptides into oligopeptides

and amino acids. Amino peptidases, and dipeptidases are among these peptidases.
⮚ Thus, the final products of protein digestion are small peptides and amino acids.

Absorption of Proteins
⮚ Various transport systems are involved.
⮚ Out of seven, five protein transport systems require Na+. (like that of Na+-glucose co-
transporter). The other two transporters use Cl– (independent of Na+).
⮚ Absorption of amino acid is greater in the duodenum and jejunum and slower in ileum.

Applied Aspects
✔ Hartnup Disease - A hereditary disorder - absorption of amino acids in the intestinal and
renal epithelial cells is defective ; Neutral amino acids appear in the stool and urine.
✔ Cystinuria - A congenital disease - amino acid cystine appears in the urine ; defect in the
protein transporter in the mucosal cells of intestine and epithelial cells of PCT of kidney.
✔ Prolinuria - A rare disorder - Proline is not reabsorbed from intestine and kidney ; Leads
to prolinuria and hydroxyprolinuria.

8
MALABSORPTION SYNDROME
❖ Condition in which nutrients are not adequately absorbed from the small intestine even
though the food has been well digested.
❖ Several causes may be present.
❖ May also can occur when large portions of the small intestine have been removed.
❖ Classified together under the general term “sprue.”

Nontropical Sprue
● A type of sprue. Also called by various terms like idiopathic sprue, celiac disease (in
children), or gluten enteropathy.
● Results from the toxic effects of gluten present in certain types of grains (especially
wheat and rye).
● Only some people are susceptible.
● But in such susceptible people, gluten has a direct destructive effect on intestinal
enterocytes.
● Milder forms of the disease - only the microvilli of the absorbing enterocytes on the villi
are destroyed - the absorptive surface area decreases as much as twofold.
● More severe forms - the villi become blunted or disappear altogether - further reduction
of the absorptive area of the gut.
● Management - Removal of wheat and rye flour from the diet - cure within weeks
(especially in children)

Tropical Sprue
● A different type of sprue - occurs in the tropics
● Treatment - antibacterial agents. (But no specific bacterium has been implicated as the
cause).

Malabsorption in Sprue
o Early - intestinal absorption of fat is more impaired than is absorption of other digestive
products.
o Fat that appears in the stools in the form of salts of fatty acids (rather than undigested fat)
- Steatorrhea,
o Severe cases - in addition to malabsorption of fats, impaired absorption of proteins,
carbohydrates, calcium, vitamin K, folic acid, and vitamin B12 also occurs. Thus, the
patient has
o Severe nutritional deficiency leading to wasting of the body
o Osteomalacia (i.e., demineralization of the bones because of lack of calcium); Inadequate
blood coagulation caused by lack of vitamin K
o Macrocytic anemia of the pernicious anemia type, resulting from diminished vitamin B12
and folic acid absorption.

9
 COMPOSITION AND REGULATION OF PANCREATIC
SECRETIONS

⮚ Pancreas is an accessory secretory organ

⮚ Myxocrine gland:
❖ Endocrine part- 2%
❖ Exocrine part- 80%
❖ Ducts and blood vessels- 18%

EXOCRINE PART:

Secretory Apparatus:

⮚ The exocrine tissue of pancreas consists of lobule that contain multiple acini
⮚ Acini are sac-like dilatations composed of single layer of pyramidal acinar cells which
synthesise pancreatic enzymes and store them in zymogen granules as pro- enzymes.
⮚ Also contain few centroacinar cells at the junction of the acinus and the intercalated duct.

Exocrine pancreas- Secretory apparatus

Duct System:
⮚ Pancreas has a main duct called the Duct of Wirsung which combines with common bile
duct to form ampulla of Vater and opens into the second part of duodenum at the major
duodenal papillae as hepatopancreatic duct.
⮚ Sometimes an accessory pancreatic duct called Duct of Santorini and open into second
part of duodenum at the minor duodenal papillae.
↓↓
Intercalated duct

10
Intralobular duct
 ⮚ Ductal epithelial cells secrete the aqueous component of pancreatic juice.

COMPOSITION OF PANCREATIC JUICE:

PANCREATIC JUICE

Water- 98.5 % Solids- 1.5%

Organic Inorganic
Constituents Constituents

INORGANIC CONSTITUENTS

CATIONS: ANIONS:
Sodium Bicarbonate
Potassiu Chloride
m Phosphate
ORGANIC CONSTITUENTS
Calcium Sulphate
Magnesi
um 11
Zinc
AMYLOLYTIC
ENZYMES: LIPOLYTIC ENZYMES:
PROTEOLYTIC ENZYMES:
Pancreat Pancreatic lipase
ic-α- Trypsinogen Pancreatic colipase
amylase Chymotrysinogen Phospholipases
Procarboxypeptidases Cholesterol esterase/
TRYPSIN
A&B hydrolase
INHIBITOR Proelastase
Ribonuclease
Deoxyribonuclease

ACTIVATION OF ENZYMES:
⮚ Brush border cells of intestinal mucosa secrete an enzyme called ENTEROKINASE.
⮚ It activates all the pro-enzymes secreted by the pancreas especially the proteolytic
enzyme trysinogen.

Enterokinase
Trypsinogen Trypsin

Trypsin
Chymotrypsinogen Chymotrysin

Trypsin
Proelastase Elastase

FACTORS INFLUENCING PANCREATIC SECRETION:

12
 ⮚ By neural and hormonal factors

Neural Factors:

❖ Parasympathetic stimulation: Through vagus nerve- innervates acinar cells and Islets of
Langerhans- increases pancreatic secretion
❖ Sympathetic stimulation: Through postganglionic sympathetic fibers from celiac and
superior mesenteric plexuses -innervate pancreatic blood vessel and tissue- inhibits
pancreatic secretion.
Hormonal Factors:
❖ Cholecystokinin-CCK
❖ Secretin
❖ Gastrin
❖ Gastrin Releasing Peptide-GRP
❖ Glucose-dependent Insulinotropic Peptide-GIP
❖ Vasoactive intestinal peptide-VIP

CHOLECYSTOKININ:
⮚ One of the primary regulators of pancreatic secretion along with secretin.
⮚ CCK is a polypeptide hormone.
⮚ It is secreted from I cells located in upper small intestine
⮚ Stimuli: Fatty acids and peptides in duodenum
⮚ Acts on two types of receptors:
● CCK A receptor-peripheral structures like gallbladder, pancreas, GI tract.
● CCK B receptor- brain- anorexigenic neurotransmitter receptor.
⮚ Second messenger system: Phospholipase C- IP3 and DAG.
⮚ CCK increases pancreatic secretion rich in enzymes.

Functions:
⮚ Acts on acinar cells and increase the enzyme content of pancreatic juice.

13
 ⮚ Potentiates secretin.
⮚ Inhibits gastric motility and acid secretion.
⮚ Contraction of gall bladder.
⮚ Relaxation of Spincter of Oddi.
⮚ Increases the secretion of enterokinase
⮚ Trophic effect on pancreas.
⮚ Found in brain and is involved in regulation of food intake as anorexigenic
neurotransmitter.

Negative Feedback Control of Secretion of CCK :

⮚ Pancreatic enzymes digest the fatty acid and peptides in duodenum
⮚ Decrease in fatty acid and peptides gives negative feedback and decrease the secretion of
CCK from I cells.

SECRETIN:
⮚ Secretin is secreted from S cells of upper small intestine.
⮚ Stimuli: Acidic chyme in duodenum.
⮚ Second messenger system: Adenylyl cyclase.
⮚ It increases pancreatic secretion rich in bicarbonate and water.

Functions:
⮚ Acts on ductal cells to release watery juice rich in bicarbonates.
⮚ Potentiates the effect of CCK.
⮚ Stimulates bile secretion.
⮚ Delays gastric emptying.
Feedback Control of Secretion of Secretin:
⮚ The increased amount of bicarbonates neutralise the acidic chime.
⮚ This decreases the secretion of secretin.
REGULATION OF PANCREATIC SECRETION:
⮚ Pancreatic secretion happens in three phases:

14
 ● Cephalic phase
● Gastric phase
● Intestinal phase

PHASES OF PANCREATIC
SECRETION

CEPHALIC PHASE: GASTRIC PHASE: INTESTINAL PHASE:

15-30 % of the total secretion. 40 % of total 40-60 % of the total

Induced by smell, sight, thought secretion. secretion.
and taste of food, and by chewing and Initiated when Initiated when acidic
swallowing of food.
food enters stomach chyme enters duodenum.
Mediated by cholinergic vagal
Secretion rich in Secretion is rich in
fibers.
enzymes. both enzyme and
Gastrin secretion is also
aqueous
stimulated by vagal stimulation.
Secretion is rich in enzymes. ( water and
bicarbonates)
components.

15
(Comprehensive Textbook of Medical Physiology, First edition; Page. No: 385;
Fig:40.7)

SALIVARY SECRETION

16
 ● The salivary secretions arise from the salivary glands
● There are major and minor salivary glands
● Major: submandibular, sublingual, parotid
● There are many minor salivary glands located in the oral cavity, around the buccal
pouches and buccal mucosa
● They are excessively regulated by the neuronal mechanism

Major salivary glands:

1) Parotid gland:
● Largest salivary gland, situated on either side in front of the ears
● Entirely serous secretion
● Pour their secretions out through the duct of Stensen, opens at the level of upper second
molar tooth on either side
2) Sublingual gland:
● Situated beneath the tongue on either side of the opening of the submandibular ducts
● Mucous type of secretion
● Pour their secretions out through the duct of Rivinus
3) Submandibular gland:
● Situated in the mandible bone in the inner ramus on either side
● Mixed type of secretion
● They pour their secretions out through the duct of Wharton
● The gland that is most prone for duct stones due to excessive curvature of the duct of
Wharton

Innervation of salivary glands:

Parasympathetic innervation:
● Parotid gland: Preganglionic fibres arise the inferior salivary nucleus🡪terminate in the
otic ganglion🡪post ganglionic fibres terminate and innervate the gland
● Sublingual and submandibular: preganglionic fibres arise from superior salivary nucleus 🡪
terminate in the submandibular ganglion🡪 post ganglionic fibres innervate both the glands

Sympathetic innervation:
● Upper cervical segments🡪 terminate in the superior cervical ganglion🡪 post ganglionic
fibres arise and innervate the gland
● Always inhibitory

Blood flow:
● Proportionate to the saliva formed

17
 ● 50ml/min/100g is the blood flow
● Parasympathetic stimulation🡪 causes vasodilation🡪 increases the saliva formation
● Sympathetic stimulation🡪causes vasoconstriction🡪 decreases saliva formation

Composition of saliva:
● Organic salts: enzymes such as lysozyme, ptyalin, carbonic anhydrase, DNase, RNase
● Inorganic salts: Na+, K+, Ca2+, Mg2+, Cl-, HCO3-, PO43-, SO42-
● Ph:8
● Tonicity: hypotonic to plasma

Mechanism of secretion:
In the acinus:
● Called as primary secretion
● Almost isotonic to plasma
● Secreted and stored in the zymogen granules, exocytosed on stimulation
● Contains sodium, potassium, chloride and bicarbonate ions
In the ducts:
● Also called as modified secretion
● Hypotonic to plasma
● Na: actively reabsorbed, Cl-: passively reabsorbed
● Modified in the intercalated ducts of the salivary glands

18
Functions of saliva:
● Contains an enzyme called ptyalin (salivary amylase) that splits up starch, action is
maximum in ph of 6.8
● Keeps the mouth clean and prevents oral infection
● Has an enzyme called lysozyme that is antibacterial, also has IgA antibody that
contributes to the local defence
● Facilitates speech by keeping the mouth moist
● Increases the taste of food by dissolving the food particles in a solution
● Helps in mastication and swallowing
● Protects the buccal mucosa
● Protects the enamel of the teeth
● Excretes heavy metals and morphine from the body

Applied aspect:
● Xerostomia: consistent decreased secretion of saliva, causes dryness of mouth,
predisposes to oral cavity infection, most commonly occurs in stress
● Sialorrhea: increased persistent secretion of saliva
● Sialolithiasis: formation of stones in the ducts thereby obstructing the flow of saliva, most
commonly occurs in the submandibular and parotid gland
● Infection of the parotid gland is seen in mumps infection

19
 PATHOPHYSIOLOGY OF JAUNDICE
● Definition- Jaundice is the yellowish discoloration of sclera, skin and mucous membrane
due to the deposition of bilirubin.
● Jaundice clinically presents when concentration of bilirubin exceeds 2 mg/dL in blood.
(Normal Plasma Bilirubin Level: 0.2–0.8 mg/dL)
● Jaundice first appears in sclera, because bilirubin has an extremely high affinity for scleral
protein called elastin.
● Normal bilirubin metabolism-

20
 ● Physiologically, the causes of jaundice are divided broadly into two categories-
1) increased production of bilirubin (that includes hemolytic jaundice)
2) decreased excretion of bilirubin (that includes hepatic and obstructive jaundice)
.
Hemolytic jaundice Hepatocellular jaundice Obstructive jaundice

1. Cause Excessive breakdown Infective or toxic damage to Obstruction of bile ducts

of RBCs that even a liver, hence is not able to like a stone or tumor thus
normal can not
conjugate bilirubin. Also, conjugated bilirubin can not
conjugate all of it conjugated bilirubin can not be excreted into biliary tract
resulting in increase in
be excreted with bile, resulting resulting in increase in
serum unconjugated in increase in both conjugated bilirubin.
bilirubin. unconjugated and
conjugated bilirubin.
2. Blood Anemia and abnormal Normal Normal
examination RBCs in peripheral
smear due to excess
hemolysis.
3. Liver Normal Impaired May be impaired
function

4. Urinary Absent (Bilirubin in Present (conjugated bilirubin Present (the level of

bilirubin plasma forms a is excreted in the urine. This conjugated
complex with albumin, makes urine yellow bilirubin in the blood is high,
which cannot be due to the presence of urinary which is excreted in urine
excreted in the urine. bilirubin) and causes deep yellow
Therefore, urine. )
hemolytic jaundice is
acholuric jaundice)

5. Urinary Increased (more Decreased (Bilirubin excreted Absent (no bilirubin reaches
urobilinogen quantity of bilirubin in bile is reduced. Hence the intestine along with bile)
glucuronide is urinary urobilinogen are
delivered to the reduced)
intestine, inturn the
amount of
stercobilinogen formed
in the intestine is
increased. This leads to
increased excretion of
urinary urobilinogen )

21
6. fecal Increased (same Decreased (same reason as Absent (In obstructive
stercobilinogen reason as urinary urinary urobilinogen.) jaundice, no bile reaches the
urobilinogen.) intestine.
Hence, neither bilirubin nor
bile salts is present in
the intestine. Therefore, no
fecal stercobilinogen is
formed, and stool becomes
clay colored.

7. Van Direct positive (Color Biphasic (Atypical color Direct positive (Color
den bergh test appears late or after develops immediately ) appears immediately)
alcohol addition)
8. Extra Nil Plasma albumin is low as liver As bile salt is reduced in
points synthesis is impaired. Also, intestine, there is an
plasma globulins are high due increased
to gamma golubin increase in fecal excretion of fat
liver disease. Hence, there is (steatorrhea).
reversal of A/G ratio.

Note -
Van den Bergh test:
a) test detects whether bilirubin is conjugated or not.
b) based on the principle that excess of water soluble bilirubin glucuronide gives a reddish-
violet color when brought in contact with diazo reagent.
Neonatal or physiological jaundice-
a) seen in premature babies and neonates having low birth weight.
b) it is due to subnormal activity of glucuronyl transferase that impairs conjugation of
bilirubin in hepatocyte.

Liver function tests-

A. Tests for manufacture and excretion of bile
1. Bilirubin estimation
i. In serum
ii. In faeces
iii. In urine
2. Urobilinogen
3. Bile acids (bile salts)
4. Bromsulphalein excretion
B. Serum enzyme assays
1. Alkaline phosphatase
2. γ-Glutamyl transpeptidase
3. Transaminases (aminotransferases)

22
 i. Aspartate transaminases or AST
ii. Alanine transaminases or ALT
4. Other serum enzymes
i. 5′ Nucleotidase
ii. Lactate dehydrogenase
iii. Choline esterase
C. Tests for metabolic functions
1. Amino acid and plasma protein metabolism
i. Serum proteins
ii. Immunoglobulins
iii. Clotting factors
iv. Serum ammonia
2. Lipid and lipoprotein metabolism
3. Carbohydrate metabolism
D. Immunologic tests
1. Nonspecific immunologic reactions
2. Antibodies to specific etiologic agents
E. Ancillary diagnostic tests
1. Ultrasonography
2. FNAC and/or percutaneous liver biopsy

DIGESTION AND ABSORPTION OF CARBOHYDRATES

23
Carbohydrates constitute
*starch
*Hemicellulose, cellulose
*Lignin
*Pectin
*Gums
*Animal glycogen
*Oligosaccharides like di and trisaccharides
*Monosaccharides

Digestion in mouth
Food is chewed in mouth before it is swallowed, mixes with saliva
Chewed food is subjected to digestive action of alpha amylase(ptyalin) in saliva
Enzyme is active between 4-11 pH and requires cl– ions
This breaks down the1-4 glycosidic linkage and converts them into alpha limit dextrin, maltose,
maltotrioses
Starch ➞➞⍺ -amylase( Cl ions)➞➞Dextrins +Oligosaccharides
(Maltose+Maltotriose)

Digestion in stomach
Action of salivary amylase on starch and glycogen continues till the stomach pH drops below 4
Starch ➞➞⍺ -amylase( Cl ions)➞➞Dextrins +Oligosaccharides
(Maltose+Maltotriose)

Digestion in small intestine

24
All di and trisaccharides are digested into monosaccharides mostly in the brush border of the
epithelial cells.
But to smaller extend they may digested in the lumen also by enzymes the enzymes from the
shed epithelial cells
Dextrins ➞➞⍺ -dextrinase(breaks 1-4 linkages)➞➞Maltose+Maltotriose
Maltose➞➞Maltase(breaks1-4 linkages)➞ ➞Glucose+Glucose
Isomaltose➞ ➞Isomaltose(breaks 1-6 linkages)➞ ➞Glucose+Glucose
Lactose➞➞Lactase➞➞Glucose+Galactose
Sucrose➞➞sucrase➞➞Glucose+Fructose

Absorption of monosaccharides
Glucose
It is absorbed from the upper small intestine(duodenum and upper jejunum)
Absorbed by active transport
There is co transport between the glucose and Na+(Na+ facilities glucose absorption)
Glucose binds with a specific type of transport protein that also requires sodium binding before
transport occurs
Sodium ion then moves down its electrochemical gradient to the inferior of the cell and pulls
glucose or galactose along with it. This is reffered secondary active transport
Along with glucose water is also absorbed due to osmotic influence, it is because of above
features , to facilitate quick absorption of glucose and water solution containing glucose, Nacl
are given for oral hydration for diarrhoea
Glucose first diffuses through the unstirred layer to the brush border. It is transported across the
cell membrane. Then finally it is extruted into the intestial fluid from where it is entered the
bloodstream
Glucose absorption from intestine is not dependent on the insulin
Galactose competes for the same carrier and inhibits the glucose absorption by competitive
inhibition.
Freshly released glucose from disaccharides by brush border enzyme is more rapidly absorbed
than free glucose
Glucose doesn’t exhibit TMG. Absorption is unlimited.

25
Galactose
Mechanism of absorption is similar to that of glucose
Fructose

26
Absorbed by facilitated diffusion(GLUT-5)
Most fructose absorbed is converted into glucose or lactate in the interestial epithelial cells
Small amount of fructose enters the blood
Applied physiology
Lactose intolerance : Due to deficiency of enzyme lactase. Treatment : Elimination of lactose
(milk and milk products) from the diet.

DIGESTION AND ABSORPTION OF FAT

Digestion
✔ Digestion of all Dietary Fats mainly occurs in the small intestine.

27
✔ Oral cavity - lingual lipase - secreted from Ebner’s glands (tongue).
✔ Gastric lipase - Stomach.
✔ However, deficiency of lingual and gastric lipase does not result in malabsorption of fat as
pancreatic lipase is actually important for lipid digestion.
✔ Principal fat digestion Starts in the duodenum
✔ Mechanism of digestion of fats:
1. Emulsification of Fats
2. Hydrolysis of Fats
3. Acceleration of Fat digestion- Micelle formation.
1. Emulsification of Fats
● Emulsification- Breaking of Large fat drops into small droplets
● Pancreatic lipase acts on emulsified lipids
● Emulsification done by bile acids [By lowering surface Tension]
2. Hydrolysis of Fats
● Fat digestion - facilitated by pancreatic co-lipase.
● Duodenum pH 7- Optiomal pH for action of Pancreatic Lipases.
● Pancreatic Lipolytic enzymes:
1. Pancreatic Lipase
2. Cholesterol ester hydrolase
3. Phospholipase A2
● Pancreatic lipase : Hydrolyses 1 and 3 bonds of triglycerides
⮚ Formation of free fatty acid and 2-monoglycerides (2-monoglycerols).
● Another lipase secreted from pancreas called bile salt activated lipase - assists in lipid
digestion.
● The dietary cholesterol - Hydrolyzed by cholesteryl ester hydrolase.
3. Acceleration of Fat digestion- Micelle formation:
● Monoglycerides and Free fatty acids released from digestion gets incorporated
into central fatty portion of Micelles.
● In this way, Bile salts accelerates Fat digestion.

28
Absorption
✔ Most of Fat absorption: Duodenum.
✔ Absorbed by passive diffusion and carrier mediated transport.
✔ STEPS OF FAT ABSORPTION:
1. Transportation Of Micelle to Enterocyte Brush Border
2. Diffusion of Lipids across the enterocyte membrane leaving the bile salt in
lumen.
3. Formation of Chlyomicron in the Endoplasmic reticulum.
4. Diffusion of Lipids from Interstitium into lacteal and through Thoracic duct into
circulation.
✔ As soon as lipids enter the cell they are esterified, therefore a gradient is maintained for
their entry into the cell.
✔ For their absorption, fats are emulsified in the intestine by detergent action of bile salts,
lecithin, and monoglycerides with the help of bile salt, lipids form micelles.
✔ Micelles - cylindrical aggregates of lipids like fatty acids, monoglycerides, and
cholesterol with their hydrophobic ends at the center.
✔ Micelle solubilizes the lipids - provides a medium for their transport to the intestinal
epithelial cells.
✔ Inside the Enterocytes - they disintegrate into the individual lipids and passively diffuse
into the cells.
✔ Short chain fatty acids are produced in the colon by the colonic bacteria and absorbed
there. 60% of short chain fatty acid is acetate, 25% propionate, and 15% butyrate.
✔ Short chain fatty acids
- absorbed in exchange for H+
---> help in acid base balance ; promote the absorption of Na+.
✔ Cholesterol - easily absorbed from the intestine in the presence of bile, fatty acid and
pancreatic juice.
✔ Absorbed cholesterol

29
 - incorporated into the chylomicrons
- enter circulation via lymphatics.
✔ Vitamins A, D, E, and K
- fat soluble. Absorption
- facilitated by presence of bile acids and products of lipid digestion in the intestine
---> Absence of bile acids or malabsorption of fat, deficiency of these vitamins occurs.

30
Clinical Aspects :
Disorders of Fat Digestion
Steatorrhea
⮚ Passage of fatty, bulky, and clay colored stool.
⮚ Due to deficiency of exocrine pancreas (Pancreatic lipase) - impairment of fat digestion.
⮚ Sometimes seen in patients with excess secretion of gastric acid - decreased duodenal pH
inhibits pancreatic lipase ; Acid also precipitates bile salt.
⮚ Another cause - impaired reabsorption of bile salts in the distal ileum.
⮚ Steatorrhea can also occur due to intestinal diseases - Tropical Sprue ---> enterocytes are
distorted and the density of microvilli is decreased - leads to lipid malabsorption -
probably due to decreased surface area for absorption of lipids.

31
 PHASES OF GI SECRETION
● Basal or inter-digestive secretion is that which occurs in the absence of all
gastrointestinal stimulation. Basal secretion is equal to about 10% of the maximal
response to a meal.
● In humans, basal secretion shows a circadian rhythm, with the highest acid output in the
evening and the lowest in the morning.
● Acting at H2 receptors, histamine is the dominant physiological mediator of acid
secretion.
● Secretin, gastric inhibitory peptide, vasoactive intestinal polypeptide also have slight to
moderate effects in inhibiting gastric secretion.
● The stimulation of acid secretion is divided into the cephalic (20-30%), gastric (60-70%),
and intestinal phases (10%). These phases are classified based on stimulus location.

CEPHALIC PHASE
● When stimuli activate the brain mechanisms (cephalic means “head”) to alter GI
secretions, the phase is called cephalic phase.
● Sight, smell, Taste, chewing of food, Various emotional states, and even thought of food
initiates cephalic phase of secretion.
● Physiological Importance of Cephalic Phase : Cephalic phase is important for salivary,
gastric, pancreatic, and bile secretions.It accounts for about 90% of volume of salivary
secretion; 40% of gastric and pancreatic secretions.

33
GASTRIC PHASE
● Gastric phase starts when food enters stomach.
● Stimuli that influence GI secretions when food is present in the stomach are: Distension
of stomach, Chemical composition (especially, amino acids, and peptides) of food in the
stomach, pH of the gastric content, Gastrin secreted from G cells.
● Gastric distension along with acidic chyme in the stomach and gastrin secreted from
stomach, activate short and long GI reflexes to influence gastric, pancreatic, biliary, and
intestinal secretions.

INTESTINAL PHASE
● Intestinal phase is initiated when chyme enters duodenum.
● Products of digestion (fatty acids, peptides, etc.), presence of acidic chyme, intestinal
distension and osmolality of intestinal contents are important stimuli in the intestinal
phase of secretion.
● They activate various intestinal reflexes to alter GI secretions.
● CCK, secretin, GIP, VIP, and many other hormones are secreted during this phase.

34
 EXOCRINE PANCREAS
⮚ Pancreas is an accessory secretory organ
⮚ Myxocrine gland:
❖ Endocrine part- 2%
❖ Exocrine part- 80%
❖ Ducts and blood vessels- 18%

EXOCRINE PART:

Secretory Apparatus:

⮚ The exocrine tissue of pancreas consists of lobule that contain multiple acini
⮚ Acini are sac-like dilatations composed of single layer of pyramidal acinar cells which
synthesise pancreatic enzymes and store them in zymogen granules as pro- enzymes.
⮚ Also contain few centroacinar cells at the junction of the acinus and the intercalated duct.

Exocrine pancreas- Secretory apparatus

Duct System:

⮚ Pancreas has a main duct called the Duct of Wirsung which combines with common bile
duct to form ampulla of Vater and opens into the second part of duodenum at the major
duodenal papillae as hepatopancreatic duct.
⮚ Sometimes an accessory pancreatic duct called Duct of Santorini and open into second
part of duodenum at the minor duodenal papillae.

35
 ↓↓
Intercalated duct

Intralobular duct

Interlobular duct

Main Pancreatic duct or Duct

of Wirsung

⮚ Ductal epithelial cells secrete the aqueous component of pancreatic juice.

COMPOSITION OF PANCREATIC JUICE:

PANCREATIC JUICE

Water- 98.5 % Solids- 1.5%

Organic Inorganic
Constituents Constituents

INORGANIC CONSTITUENTS

CATIONS: ANIONS:
Sodium Bicarbonate
Potassiu Chloride
m Phosphate
Calcium Sulphate 36
Magnesi
um
 ORGANIC CONSTITUENTS

AMYLOLYTIC PROTEOLYTIC ENZYMES: LIPOLYTIC ENZYMES:

ENZYMES:
Trypsinogen Pancreatic lipase
Pancreat Chymotrysinogen Pancreatic colipase
ic-α- Procarboxypeptidases Phospholipases
amylase A&B Cholesterol esterase/
Proelastase hydrolase
Ribonuclease
Deoxyribonuclease
TRYPSIN
INHIBITOR

37
 COMPOSITION AND FUNCTION OF SALIVA
● Organic salts: enzymes such as lysozyme, ptyalin, carbonic anhydrase, DNase, RNase
● Inorganic salts: Na+, K+, Ca2+, Mg2+, Cl-, HCO3-, PO43-, SO42-
● Ph:8
● Tonicity: hypotonic to plasma

Functions of saliva:
● Contains an enzyme called ptyalin (salivary amylase) that splits up starch, action is
maximum in ph of 6.8
● Keeps the mouth clean and prevents oral infection
● Has an enzyme called lysozyme that is antibacterial, also has IgA antibody that
contributes to the local defence
● Facilitates speech by keeping the mouth moist
● Increases the taste of food by dissolving the food particles in a solution
● Helps in mastication and swallowing
● Protects the buccal mucosa
● Protects the enamel of the teeth
● Excretes heavy metals and morphine from the body

38
 STAGES OF DEGLUTITION

Deglutition:
● Process by which food material from oral cavity is transported to oesophagus.
● Also called deglutition reflex as most part of it is involuntary.

STAGES OF DEGLUTITION:

Oral phase:
● Also called buccal phase.
● Initiated when mouth separates a bolus of food from mass of food stuff .
● Once food touches receptors in the pharyngeal opening swallowing reflex is initiated.

Pharyngeal phase:
● Main objective : To push food bolus into esophagus without it's entry into respiratory
passage.
● Reflex pathway:
▪ Receptors:around pharyngeal opening.
▪ Afferent: trigeminal, glossopharyngeal, vagus and hypoglossal nerve
▪ Centre:NTS and nucleus ambiguus.
▪ Efferent:muscles of pharynx and tongue

Oesophageal phase:
● Once food enters into oesophagus facilitated by UES, peristaltic wave is initiated just
below UES.
● Reflexly, UES contracys and prevents regurgitation of food back.
● Peristaltic wave travel about 3-5cm/sec.
● If primary peristaltic wave is not effective secondary wave is initiated

39
DISORDERS OF DEGLUTITION

GASTRIC EMPTYING

40
 The process by which the content of the stomach is emptied into the duodenum

Mechanism of gastric emptying:

Gastric emptying occurs by three mechanisms: peristaltic contraction, antral contraction, and
retropulsion

Peristaltic contraction:
● Usually begin in the middle of the stomach and proceeds in a ring like fashion toward
pylorus.
● These contractions mainly push food into the antral part of the stomach.
● Major amount of mixing takes place in the antrum, as antrum contracts vigorously.
Antral contraction:
● Help thorough mixing of food with the gastric juice.
● Forceful contraction of antrum forces gastric contents toward the pylorus
stomach empties in small squirts with each peristaltic wave
Retropulsion:
● The terminal part of antrum exhibits rapid and forceful contractions that forces the chyme
to be propelled back toward the proximal part of the antrum and body of the stomach .
● This movement is called retropulsion.
● Retropulsion is very effective in mixing and grinding the larger food particles into smaller
ones.

Regulation of gastric emptying:

Regulated by both neural and hormonal mechanisms
Stimuli causing gastric emptying
● Acid in the duodenum
● Products of fat digestion
● Osmolarity of duodenal content
● Products of protein digestion
● Volume of the meal
● Streching of duodenum
● Vagal stimulation
● Cck secretin inhibit gastric emptying

APPLIED ASPECT
Delayed gastric emptying
▪ Occur in autonomic neuropathy as in diabetes mellitus.
▪ Hypertrophic pyloric stenosis can cause gastric stasis

41
Rapid gastric emptying
▪ Vagus stimulation promotes gastric emptying.
▪ Therefore, states of increased vagal activity increase emptying.
▪ Conversely, sympathetic stimulation inhibits emptying

Vomiting
▪ Vomiting is the expulsion of gastroduodenal content from GIT to the external environment
via mouth.

Dumping syndrome
▪ Distressing syndrome consisting mainly of weakness, dizziness and sweating that develop
in about two hours after meal in persons who have undergone gastrectomy or
gastrojejunostomy

GASTRIN

● Produced by G cells in the stomach that are located mainly in the antral region.
● Gastrin producing cells are also present in hypothalamus, anterior pituitary, medulla, and
fetal pancreas
● Gastrin as a neurotransmitter is also secreted from vagus and sciatic nerve.

Structure:
● It is a polypeptide hormone.
● Gastrin exhibits both macroheterogeneity (gastrins having different polypeptide lengths)
and microheterogeneity (gastrins having different molecular structures).
● G 17 is the principal gastrin secreted from the stomach and is the major stimulator of
gastric acid secretion.

Metabolism:
● Gastrin secreted from G cells enters general circulation.
● In blood, half-life of gastrin is less.
● Half-life of G 14 and G 17 is 2–5 min and of G 34 is about 15 min.
● Gastrin is inactivated in the intestine and degraded in the kidney.
Functions:

42
 1. Primary function of gastrin is the stimulation of gastric acid and pepsin secretion. Gastrin is
the most potent natural stimulator of HCl secretion from parietal cells of stomach.
hypergastrinemia causes peptic ulcer.
2. Gastrin stimulates growth of gastric mucosa and mucosa of intestine. This is called trophic
action of gastrin.
3. stimulates gastric motility.
4. causes contraction of muscles at the gastroesophageal junction (lower esophageal sphincter).
Therefore, it prevents reflux esophagitis.
5. stimulates exocrine pancreatic secretion.
6. stimulates insulin secretion.
7. stimulates mass movement of large intestine.
8. causes colonic contraction that initiates gastrocolic reflex after a meal. Therefore, usually
defecation is activated after a meal. 9. It stimulates histamine secretion from ECL
(enterochromaffin like cells) in GI mucosa.
Mechanism of action:
● The primary function of gastrin is to stimulate acid secretion from parietal cells of the
stomach.
● Gastrin acts on gastrin or CCK receptors on parietal cells and increases intracellular
calcium concentration via second messenger, IP3.
● Increased cytosolic calcium activates protein kinase that stimulates H+–K+ ATPase to
promote acid secretion
Control of gastrin secretion:

43
 BILE: COMPOSITION AND FUNCTION

Bile is greenish yellow fluid formed in the liver and stored in gall bladder. About 0.5-1 lit
of bile is secreted daily. The most important substances secreted in the bile are bile salts. Others
like bilirubin, cholesterol, lecithin, electrolytes of plasma are secreted in large concentrations
into the bile.
• Water
• Bile salts
• Cholesterol
• Fatty acids
• Lecithin
• Na+
• K+
• Ca++
• Cl-
• HCO3-

Functions of bile

Cholesterol

Cholic acid, chenodeoxycholic acid

These acids combine with glycine and taurine

Forms glyco and tauro conjugated bile acids

These sodium salts are secreted into the bile.

Functions of bile salts

1. Detergent action on fat particles

2. Absorption of fat
3. Choleretics
4. Absorption of fat-soluble vitamins
5. Activation of pancreatic enzymes
6. Prevention of gallstone formation.

44
 7. Physiological purgatives
8. Stool color
9. Prevention of bacterial growth.

EMULSIFYING FUNCTION

● Helps in absorption of fatty acids, monoglycerides, cholesterol, other lipids.

● They form micelles(bile salts +lipids) and makes it semi soluble in the chyme, helps in
absorption.

HEPATIC BILE VS GALLBLADDER BILE

Hepatic Bile
In liver, bile is secreted by two stages:
i. Initial secretion from hepatocytes
-which contain large amount of bile acids, cholesterol and other organic constituents.
ii. Next, bile flow into canaliculi empty into terminal bile ducts & common bile duct.
iii. In its course through the bile ducts, in response to the hormone secretin. Na+ and
HCO3- are secreted by the epithelial cells that line the ductules and ducts.

Gall bladder bile: Bile is secreted continually by the liver cells and normally stored in the
gallbladder (max vol of 30-60 ml). But 450 ml of bile secretion can be stored in the gall bladder
because water, sodium, chloride and other electrolytes are absorbed through gall bladder mucosa
concentrating bile salts, cholesterol, lecithin, bilirubin.
Most of the gall bladder absorption is caused by the active transport of Na+ followed by
secondary transport of Cl- and other diffusible contents.

SECRETIN

45
Source: from S cells in upper part of small intestine.
Structure: polypeptide hormone.
Function:
• Increases watery and alkaline pancreatic secretion.
• Increases bile secretion
• Decreases gastric acid secretion and motility
• Causes contraction of pylori sphincter.

Regulation-

Contact of intestinal mucosa with acid chyme and peptides

Stimulation of S cells

secretes secretin

Stimulation of pancreatic secretion Rich in water and bicarbonate.

H2O and HCO3-floods duodenum

Neutralization of acid in duodenum (decreases duodenal PH).

SECRETIN IS THE FIRST HORMONE TO BE DISCOVERED.

SUCCUS ENTERICUS
Composition:

46
 ● Intestinal secretion is isotonic and alkaline
● pH is 8, it consists of water (98.5%) and solids (1.5%)
Composition of solids:
● Cations: sodium, potassium, magnesium, calcium,
● Anions: bicarbonate, chloride, phosphate, sulphate
● Enzymes: maltase, lactase, sucrase, enterokinase, dextrinase, peptidase, nucleotidase

Mechanism of secretion:
● The cations are secreted by active transport and the anions move along with the cations to
maintain electrical neturality
● The water moves along with the ions to create an osmotic balance
● The mucous is secreted by the Brunner’s glands, surface epithelial cells and the goblet
cells
● Mucin is the major component that forms a gel to protect the mucosal epithelium from
the chyme that has gastric acid

Regulation of secretion:
● VIP: increases secretion
● Vagal stimulation: increases secretion
● Certain infectious conditions like cholera also increase secretion as they cause increased
cAMP that causes increased secretion of ions in the stool that causes watery diarrhoea

Functions:
● Protects the intestinal epithelium from gastric chyme
● Traps the bacteria and kills them
● Secrete immunoglobulins that play a role in the local defence
● Provides a suitable environment for the enzymes to digest
● Helps in the forward propulsion of the chyme
Applied aspect:
● Malabsorption syndrome: seen in Crohn’s disease, ulcerative colitis
● There is hypoproteinemia, decreased absorption of fat and fat- soluble vitamins.

SMALL INTESTINE MOTILITY

Functions of small intestine motility:

47
 ● Forward propulsion of the chyme
● To bring the chyme in contact with the absorptive surface
● Mix the chyme with secretions

Types of intestinal motility:

1) Segmentation:
● Also called as mixing movements: help to mix the chyme with the digestive
secretions
● This is the most common type of motility
● This is brought about by the rhythmic contraction of the circular smooth muscle
● Rate of contraction: 18/min in duodenum; 15/min in jejunum; 12/min in ileum
2) Peristalsis:
● This is the continuous forward movement of the chyme caused by the circular smooth
muscle
● When chyme enters a segment of the intestine, it stretches the wall
● The part behind the chyme contracts and the part in front of the chyme relaxes
helping in the movement of the chyme forward
● The movement always occurs in an orthograde direction; towards the colon
● When there is increased motility of the intestine, it causes decreased transit time
leading to acute diarrhoea
● When there is decreased motility of the intestine, it causes increased transit time
leading to constipation
● Law of the intestine: the chyme that enters the intestine is always propelled forwards
● Administration of codeine causes decreased intestinal motility
● Administration of laxatives causes increased intestinal motility
● Antiperistalsis results in vomiting
● Peristalsis is only for a short range

3) Migrating motor complex:

● It occurs in the inter-digestive phase

48
 ● There are bursts of electrical and contractile activity once in every 90 minutes
● It occurs throughout the GIT
● There is vigorous and strong contractions that sweep the gut off its contents
● It clears the food off the gut thereby it is called as the “housekeeper of the small
intestine”
● It also inhibits the growth of pathogenic colonic bacteria in the small intestine
4) Villus contraction:
● There are irregular contractions of the villi in the small intestine
● They are more frequent in the upper part of the small intestine
● They are meant to empty the central lacteals of the villi
● They also enhance lymphatic flow to the intestine

Applied aspect:
Adynamic ileus: it most commonly occurs after a surgery the ileum remains paralysed up to
6 hours after surgery

SECRETIONS OF LARGE INTESTINE

Composition:
● Mainly mucous
● Contains HCO3- and K+ in large amounts
● Ph=8

Mechanism of secretion:
● The goblet cells secrete the mucous part and
● HCO3- and water are secreted in significant amounts
● Na is reabsorbed and K is secreted
● The main function of the secretion is to lubricate the stool, protect the intestinal mucosa
and neutralise the acid that was formed by the colonic bacteria
● About 90% of the water is reabsorbed in the large intestine

49
 ● If stool is retained in for a longer time, it causes solid stools that make it difficult to
defecate leading to constipation
● If the contents pass out too quickly as seen in diarrhoea, it causes less reabsorption of
water leading to watery stools

PERISTALSIS
Definition:
● It is defined as the progressive contraction of successive portions of circular smooth
muscles of the small intestine
● The wave always moves in an orthograde direction: the food always moves from the
oral cavity to the anus (aboral spread)
● These involve only a short length of the intestine

Mechanism:

50
 the part the part in ring of
the chyme contraction
behind the front of the
stretches the proceeds in
chyme chyme
intestine wall the forward
contracts relaxes
direction

Short range peristalsis:

● This occurs less frequently
● This along with segmentation decrease the net rate of propulsion of chyme in forward
direction
● This facilitates digestion and absorption in the intestine

Clinical aspect:
● Administration of codeine decreases intestinal motility🡪increases the transit time for the
intestinal contents🡪more nutrients and water are reabsorbed🡪formation of less stool
● Administration of laxative🡪increase intestinal motility🡪decrease transit time🡪more
volume of stool formed🡪causes diarrhoea

MIGRATING MOTOR COMPLEX

Definition:
● It is the burst of intense electrical and contractile activity once in about every 90 minutes
● This usually occurs in the inter-digestive phase
● It starts in the stomach and is propagated throughout the intestine until the terminal part
of the ileum
● It results in vigorous and strong propulsive contraction
● This sweeps the intestine and empties the remaining contents into the lumen
● This is also known as the housekeeper of the small intestine

51
 ● It also inhibits the migration of colonic bacteria into the intestine

VOMITING
Definition:
It is defined as the forceful expulsion of the gastroduodenal contents outside through the mouth

Stimulatory centres:
● The main centre is present in the medulla
● It is present in the form of a reticular formation which consists of scattered group of
neurons that control different aspects of vomiting
● Vestibular nuclei: mediate vomiting in motion sickness
● Pharyngeal stimulation causes vomiting by stimulation of nucleus tractus solitarius
● Area postrema: mediates vomiting activated by drugs such as opiates, chemotherapeutic
agents, and hormones
● Emotion stimulates vomiting influenced by the limbic and diencephalic inputs

Important stimuli:
● Distension of stomach
● Tickling the back of throat
● Painful injury of the genitourinary tract
● Conditions associated with nausea and vomiting
● Drugs

Mechanism of vomiting:

52
 reverse peristalsis sweeps the
relaxation of the
that starts from contents to the
the jejunum stomach pyloric sphincter

forced inspiration vigorous gastric contents

that increases contraction of enter the
intra abdominal abdominal esophagus
pressure muscles (retching)

relaxation of sharp rise in intra cessation of

lower esophageal abdominal inspiration and
sphincter pressure leading vomitus expelled
to opening of through the mouth
upper esophageal
Clinical significance:
Emetics and antiemetics:
● Emetics are drugs that promote vomiting
● These drugs stimulate the chemoreceptor trigger zone that is in the area postrema
● Antiemetics are those substances that prevent the stimulation of the CTZ.
● They act by D2 receptor antagonism, examples are chlorpromazine, haloperidol
● Serotonin stimulates vomiting through 5HT-3 receptor activity: blocked by ondansetron

ENTERIC NERVOUS SYSTEM(ENS)

53
DEFINITION-
The enteric nervous system (ENS) is the local neural network in GI system which has strong
anatomical and physiological link with ANS.

● ENS is considered as the ‘Third division of ANS’.

● This includes myenteric and submucosal nerve plexuses in the GI tract
● The small interneurons of these plexuses connect afferent and efferent neurons to smooth
muscles, secretory cells and epithelial cells which form the anatomical basis of local GI
reflexes.
● Schematic representation of innervation of GI tract

● ENS is capable of coordinating GI activity in the absence of external innervation.

ENS-THE MINIBRAIN OF GUT

● ENS consists of approximately hundred million neurons which are exclusively clustered in
GIT
● They have sensory neuron, interneuron and motor neuron hence called minibrain of gut

54
NEUROTRANSMITTER IN ENS

● Acetylcholine (ACh) is the primary neurotransmitter in preganglionic and postganglionic

neurons that regulate secretory and motor activities of GI tract.
● VIP, serotonin, enkephalins, substance P, norepinephrine, GABA, ATP, NO and CO have
also been described as neurotransmitters in ENS, and these chemicals play important role in
regulation of GI functions.

55
 DIETARY FIBRES

DEFINITION-
● Dietary fibre is the indigestible part of plant derived food that cannot be
completely broken down by human digestive enzymes
● They do not have a calorific value, but they are considered as 6th major nutrient

TYPES OF DIETARY FIBRES

Soluble Fibres Insoluble Fibres
1.It dissolves in water 1.It does not dissolve in water
2.It shows digestion 2.It adds bulk to stool
3.Found in oat,barley,lentils and peas 3.Found in wheat and whole grain
Eg:Pectin,Inulin Eg:Cellulose,Hemicellulose

ADVANTAGES OF DIETARY FIBRES

● It reduces the efficacy of absorption of digested food stuff by forming a barrier

between nutrients and absorptive surface. Thus, it helps in preventing post prandial
hyperglycaemia

● It increases the bulk of undigested residue which helps in preventing constipation

flow chart

● It reduces the blood cholesterol level by binding the bile salts

56
● Dietary fibres decrease the incidence of cancer by diluting the carcinogens, reducing
the duration of contact between carcinogens and mucous membrane and by binding
the carcinogen to dietary fibres.

57
 CHOLECYSTOKININ(CCK)

MISNOMER-
Previously CCK causes contraction of gall bladder to release bile and pancreozymin
stimulate secretion of pancreatic juice but now they have found both are same enzyme,
hence the name CCK-PZ

INTRODUCTION-
It is a polypeptide containing 33 amino acids produced by the upper portion of small
intestine

FUNCTIONS

● It helps in secretion of pancreatic juice by causing discharge of zymogen granules

from the pancreatic acinar cells
● It also contraction of gall bladder to release bile
● It increases the secretion of enterokinase from duodenum
● It may also increase the motility of small and large intestine
● It has a trophic effect on pancreas

FACTORS WHICH INCREASE CCK-PZ RELEASE

● Acid in the duodenum (minor)

● Product of macromolecules in small intestine

INTERACTION OF NERVOUS AND HUMERAL REGULATION

58
59
 ENTEROHEPATIC CIRCULATION

● Bile acids and salts are absorbed from the intestine and re-excreted in the bile, and
this cycle is repeated so many times, which is called enterohepatic circulation.
● Mechanism of circulation-

● The substances that undergo enterohepatic circulation include bile salts, bile acids,
bile pigments, vitamin D, vitamin B12, thyroxine, drugs, etc.

Importance of enterohepatic circulation.

1. The primary function of enterohepatic circulation of bile acids and salts is to
maintain the total bile acid pool of the body.
2. Bile acid is cycled several times a day during meals, so that a small pool of bile
acid can efficiently provide enough bile salts to facilitate adequate lipid
absorption from small intestine.
3., fecal excretion of bile acid accounts for an efficient medium for loss of body
cholesterol.
Determinants of Enterohepatic Circulation
1. Integrity of Intestinal Epithelium
2. Efficiency of Hepatic Uptake

60
 DEFECATION REFLEX
Governing center-sacral spinal segments
Influenced by higher center-Hypothalamus, midbrain, cerebral cortex
Normally rectum is empty.
With the onset of gastrocolic reflux or when the colon is full, faeces enter the rectum.
Pressure in the rectum increases
When the pressure rises to 20-25cm water, a sufficent number of impulse reaches the
spinal center and are relayed backed to rectum causing it to contract and relaxing the
internal sphincter
Both afferent and efferent are present in the pelvic nerve
Mass peristalsis is initiated resulting in evacuation of faeces from the colon into the
rectum.
Myenteric plexus is essential for mass peristalsis.
The desire for defaecation occurs.
Sacral centres are facilitated after attaining a proper posture (squat ting).
The external sphincter is inhibited voluntarily due to inhibition of pudendal nerve by
impulses arising from the cerebral cortex.
The faecal matter is expelled.
During defaecation, abdominal muscles contract and external sphincter and puborectalis
relax.
The anorectal angle becomes straight, thus aiding in smooth expulsion of faeces.

Feacel matter in the rectum

⬇
Stretch of rectum
⬇
Pelvic afferent are stimulated
⬇
Impulse are relayed to rectum, colon and internal sphincter via spinal cord
⬇
Contraction of rectum and colon and relaxation of internal sphincter

61
 ⬇
Faecal matter passes into the anal canal
⬇
Impulse from anal canal reach the sacral centre
⬇
Pudendal nerve inhibited
⬇
External sphincter relaxes
⬇
Expulsion of faecal matter

Applied physiology

1.Appendicitis-Inflammation of the mucous lining of appendix, commonly seen in

adolescents
2.Proctitis-Inflammation of rectal mucosa

NORMAL BILIRUBIN METABOLISM

62
❖ Conjugated bilirubin is excreted into the bile canaliculi and it then enters the bile.
❖ The transport of bilirubin diglucuronide is an active process.
❖ Normally, almost all the bilirubin (> 98%) that enters bile is in the conjugated
form.
❖ Bilirubin glucuronides are hydrolysed in the intestine by specific bacterial
enzymes namely B-glucuronidases to liberate bilirubin.

❖ Bilirubin is then converted to urobilinogen (colourless compound).

❖ A small part of this may be reabsorbed into the circulation.
❖ Urobilinogen can be converted to urobilin (an yellow coloured compound) in the
kidney and excreted.
❖ The characteristic colour of urine is due to urobilin.
❖ A major part of urobilinogen is converted by bacteria to stercobilin which is
excreted along with feces.
❖ The characteristic brown colour of feces is due to stercobilin.

63
St
udentNot
es

PHYSI
OLOGY
1s
tEdi
ti
on

Uni
t2
NeuroMus
cul
arJunct
ion
 CONTENTS
ESSAY

1. Write in detail the electron microscopic structure of the Pg: 4

skeletal muscle and describe the process of skeletal muscle
contraction. Highlight the cross-bridge cycle. Add a note on
rigor mortis

2. Write in detail about the structure of the NMJ and describe Pg: 8
about the mechanism of transmission and the applied aspect.

SHORT NOTES

1. Structure and function of NMJ with the diagram Pg: 16

2. Genesis of resting membrane potential Pg: 18

3. Types of axoplasmic transport Pg: 19

4. Structure of sarcomere Pg: 20

5. Sarcotubular system Pg: 22

6. Strength duration curve Pg: 24

7. Action potential curve Pg: 25

8. Isotonic and isometric muscle contraction Pg: 27

9. Graded potential Pg: 28

10. Classification of nerve fibers Pg: 31

11. Wallerian degeneration and regeneration Pg: 32

1
12. Properties of smooth muscle Pg: 35

13. Properties of skeletal muscle Pg: 36

14. Mechanism of contraction of smooth muscle Pg: 40

15. Latch bridge mechanism Pg: 41

2
 SKELETAL MUSCLE

SARCOMERE - ELECTRON MICROSCOPIC VIEW:

● Z line:
○ perpendicular to the axis of the muscle fiber
○ Thin filament attached to the z-line by alpha-actinin

● Thin filament: 1 micrometre long & 7 nanometres

○ Composed of contractile protein
○ From the z line to the center of the sarcomere (parallel array), where they overlap
with thick filament
○ Each sarcomere contains 2 sets of thin filaments

● Thick filament: parallel array of thick filaments, located middle of the sarcomere
produce A band
○ 1.6 micrometre long & 10-nanometre diameter
○ Formed by myosin (contractile protein)

● I band: between the ends of two adjacent portion of A band where thin filament doesn’t
overlap with thick filament
○ During muscle contraction, the length of sarcomere decreases (distance b/w two
Z line)
○ Results in shortening of I band but not A band length

● H zone: narrow part located at centre of A band

○ This portion doesn’t overlap during relaxation phase of muscle

● M line: transverse line passes mid of the H zone

4
 ○ Titin filament passes from Z line to M line , so it links M line protein, thick
filament & Z line protein
○ Plays a major role in proper organizing & maintaining regular array of thick
filament

SKELETAL MUSCLE CONTRACTION

5
CROSS-BRIDGE CYCLE:
● Interaction between the actin & myosin cross bridge
● During each cycle, the myosin head attached over thin filament
⬇️
Sliding movement proceed
⬇️
Followed by a detachment of myosin head: repetitive fashion
● ATP is required for both cross-bridge as well as for detachment

Events in the resting phase:

● The muscle at rest; cytoplasmic ATP gets attached to a specific binding site in the
myosin head but the head is not attached to actin.
● Even though rotation of the myosin head occurs towards actin but proceeds no
movement due to not being attached to actin.
● This resting conformation is known as the cocked position of the myosin head or
energized state.

6
Events in the stimulated phase :

RIGOR MORTIS:
● During the cross-bridge cycle, the binding of ATP to the myosin head breaks the actin-
myosin interaction & leads to the relaxation of muscle
● If the cellular source of ATP is depleted: cross-bridge detachment doesn’t occur leading
to the contraction of muscle
● Myosin head remains in the attached state
● Elevated calcium concentration in the cytoplasm
● Raised calcium concentration in cytoplasm leads to vigorous contraction further leads
to no cross-bridge detachment – no ATP
● This leads to stiffness of muscle known as rigor mortis
● Disappears 48 to 60 hrs after death, due to disintegration of muscle protein

7
 NEUROMUSCULAR JUNCTION (NMJ)
MYONEURAL JUNCTION
Definition- It’s the junction between motor neurons and skeletal muscle.
NMJ includes:
● Pre-synaptic membrane
● Synaptic cleft
● Postsynaptic membrane

PRESYNAPTIC MEMBRANE - AXON TERMINAL:

● Contains numerous mitochondria and synaptic vesicles

8
 ● These synaptic vesicles contain the neurotransmitter- Ach
● When the axon comes close to the muscle fiber, it loses its myelin sheath. So, the axis
cylinder is exposed. This portion of the axis cylinder is expanded like a bulb & is called
the motor endplate.
● Ach is synthesized by mitochondria present in the axon terminal and stored in the
vesicles.
● Mitochondria contain ATP, which is the source of energy for the synthesis of
acetylcholine.

SYNAPTIC CLEFT:
● The space between the pre and post-synaptic membranes is called synaptic cleft.
● The synaptic cleft contains basal lamina.
● It is a thin layer of spongy reticular matrix through which, the ECF diffuses.
● An enzyme called acetylcholinesterase (AchE) is attached to the matrix of basal
lamina, in large quantities.

POST-SYNAPTIC MEMBRANE:

● It is the membrane of the muscle fiber.

● It is thrown into numerous folds called sub-neural clefts.
● The postsynaptic membrane contains the receptors called nicotinic acetylcholine
receptors.

9
EVENTS OF NEUROMUSCULAR TRANSMISSION:
It includes – pre & postsynaptic events & synaptic cleft events
Major occurrences:
1. release of acetylcholine
2. Action of acetylcholine
3. Development of endplate potential
4. Development of miniature endplate potential
5. Destruction of acetylcholine

10
PRE-SYNAPTIC EVENTS:
Action potential (AP) is initiated in pre-synaptic motor neurons and invades the end plate region

Depolarisation of motor neurons up to terminal buttons results in the opening of voltage-

dependent calcium channels causing, calcium influx down its concentration gradient

The cytoplasmic concentration of calcium increases, enhancing the movement of microfilament

and microtubules which moves the vesicle to the Pre – Synaptic membrane

Vesicles containing Ach fuse to the membrane of the terminal buttons

Exocytosis of Ach

Ach diffuses across the synaptic cleft to the muscle cell

SYNAPTIC CLEFT EVENTS:

Ach degraded by acetylcholinesterase present in the synaptic cleft and some Ach diffuses out of
the cleft

50% Choline returns to the pre-synaptic terminal by sodium choline transport for reuse by Ach
synthesis

11
POST-SYNAPTIC CLEFT EVENTS:
Ach birds to nicotinic Ach-receptors at the end plate

Receptor binding of Ach causes the opening of cation channels causing sodium influx

The resulting depolarization of the muscle cell membrane at the end plate is referred to as
endplate potential

Small quanta of Ach are released randomly from nerve cells at rest

Each produces a small possible change in the membrane potential of the motor endplate-
miniature EPP

Never impulse reaches the ending causing the increase in quanta by several folds resulting in
large EPP

EPP is spread by local current to adjacent muscle fibers which are depolarised to threshold and
fire AP

Local depolarisation causes adjacent regions to get depolarised

Causes an AP in the muscle membrane

AP spreads in all directions from END PLATE & propagates along muscle cells initiating
contraction

12
NEUROMUSCULAR BLOCKADE
Neuromuscular blockade can be achieved by drugs that can act either on the pre-synaptic or the
post-synaptic membrane
Drugs acting on the presynaptic membrane:
● Botulinum toxin: it acts on the presynaptic membrane on a protein called synaptobrevin,
which is responsible for the fusion of Ach-containing vesicles with the plasma membrane
of the axon terminal. It is the most lethal toxin. therapeutically, it is used for achalasia
cardia to relieve the contracted oesophageal sphincter, strabismus, and cervical dystonia.
It is also used for cosmetic purposes.
● Hemicholinium: this drug inhibits choline reuptake by the presynaptic terminal resulting
in the depletion of Ach. Consequently, an action potential cannot be formed.

13
Drugs acting on post-synaptic membrane:
Competitive blockers:
● Curare and gallamine are examples of competitive blockers
● They compete with Ach to bind to the AchR that is on the postsynaptic membrane and
does not open ion channels
● Curare is used as a poison for hunting as it causes paralysis in all skeletal muscles
● Gallamine is given before surgery to relax the skeletal muscles
Depolarising blockers:
● Drugs like succinylcholine and carbamylcholine have the biological activity of Ach, but
there are not hydrolyzed by AchE.
● They have a long-lasting action and they keep the ion channels open that keep the Na
channel in an inactivated state
● Reversible AchE inhibitors: physostigmine, neostigmine
● Irreversible AchE inhibitors: pesticides, nerve gases.

APPLIED ASPECTS:
Myasthenia gravis:
Etiology:
● This results from a decrease in the number of AchR on the motor end plate due to the
presence of circulating antibodies against these receptors.
● The post-synaptic folds are flattened
● Because of these changes, Ach cannot bind to the receptors
● The antibodies compete with Ach to bind to AchR, induce endocytosis of AchR, and
damage the postsynaptic membrane.
Features:
● Fatigue is the most common symptom.
● Women are more affected than men
● The muscle weakness increases during the prolonged use of muscle
● Extraocular muscles and eyelids are involved earlier, causing diplopia and ptosis.
● Proximal muscle weakness
● The symptoms improve with rest.
Treatment:
● Administration of reversible AchE inhibitors like neostigmine

14
 ● Thymectomy
● Immunosuppression
● Plasmapheresis.

Eaton Lambert myasthenic syndrome:

● It is a presynaptic disorder of the NMJ due to autoantibodies against voltage-gated Ca
channels.
● This causes a decreased influx of Ca ions that results in impaired Ach release from the
nerve endings.
● Muscular weakness is particularly seen in the limb muscles.
● Patients show incremental response to repetitive nerve stimulation

15
 STRUCTURE AND FUNCTION OF NMJ WITH DIAGRAM

INTRODUCTION
The junction between a motor neuron and a muscle fiber is known as neuromuscular
junction/motor end plate

STRUCTURE OF NMJ

Broadly divided into three parts-

● Presynaptic
● Synaptic
● Post-synaptic

Presynaptic membrane:
● It is formed by the neuron
● As the axon nears the muscle, it loses its myelin sheath and divides into several branches
called axon terminals.
● The terminals are covered by Schwann cells known as teloglia
● Each terminal forms a junction with the muscle fiber. Thus, each muscle fiber is supplied
by one axon terminal

17
 ● Each terminal is expanded in the end to form a synaptic knob that contains mitochondria
and vesicles containing neurotransmitters.
● The vesicles are clustered around specific active sites called active zones. They are
modified to form a dense bar that contains numerous voltage-gated Ca channels that
mediate Ach release.

Synaptic cleft:
● This is the gap between the terminal button and the muscle fibre
● It is about 40-100 mm wide
● The muscle fibre is covered by a layer of amorphous connective tissue called the
basement membrane or the basal lamina that consists of collagen, glycoproteins, and
other extracellular matrix proteins
● The basement membrane in the cleft contains the enzyme acetylcholinesterase, that is
anchored to the collagen fibrils
● AchE rapidly hydrolyses Ach into acetate and choline

Post-synaptic membrane:
● This is formed by the muscle fibre
● It is also called the motor end plate.
● The area of the end plate membrane is thrown into several folds called junctional folds
● These contain numerous Ach receptors that are concentrated at the crest of the junctional
folds.

APPLIED PHYSIOLOGY
● MYASTHENIA GRAVIS- decrease in the number of ach receptors due to circulating
antibodies
● LAMBERT EATON MYASTHENIC SYNDROME- autoantibodies against voltage-
gated calcium channels

18
 GENESIS OF RESTING MEMBRANE POTENTIAL

DEFINITION
The relatively stable membrane potential (inside cell membrane) of a cell in an unstimulated
state is called the resting membrane potential

THE CONCEPT
● The potassium concentration is great inside a nerve but low outside
● Creating an electro positivity outside the membrane and electronegativity inside
the membrane because of negative ions
● The membrane is highly permeable to sodium ions
● In the human nerve, the RMP is -70mv
● Active transport of sodium and potassium ions through the membrane – (Na-K
PUMP)
● Leakage of potassium through the nerve cell membrane

ORIGIN
● Contribution of potassium diffusion potential
● Contribution of sodium diffusing potential
● Contribution of Na-K pump

19
 TYPES OF AXOPLASMIC TRANSPORT

DEFINITION
Transfer of substances between the cell body and axon terminal is called axoplasmic
transport
1. Proteins, organelles, and cellular substances are transported
2. Transport can be abolished by colchicine, cyanide, dinitrophenol, etc

TYPES
● Anterograde
● Retrograde
● Trans neuronal

Anterograde
● Transport of materials from the cell body towards axon terminals
● E.g.-various neurotransmitters synthesized in cell body are packaged in vesicles and get
secreted at nerve endings
● Fast axoplasmic – the speed at 400mm/day, this is accomplished by a protein called
kinesin
● Slow axoplasmic – speed 0.5-2mm/day, substances like actin, microtubules,
neurofilaments get transported by this method.

Retrograde transport
● Substances from the axon terminals to the cell body
● Speed – 200mm/day, brought by dynein
E.g. –
● transport of virus: varicella-zoster virus gets transported from the skin to the nerve
terminals by retrograde transport.
● transport of toxins: tetanus toxin at motor neuron ending is transported to the cell body by
retrograde process
● transfer of nerve growth factors: nerve growth factor is taken up by presynaptic terminal
and transferred to soma by retrograde transport.

20
 ● Reuptake of synaptic neurotransmitters: NE released at nerve terminals are rapidly
removed from the synaptic cleft by reuptake into the presynaptic neuron, this is an active
retrograde transport process.
Trans-neuronal transport – trophic substance like NGF is transported across the synapse to the
presynaptic membrane of another neuron

SARCOMERE

● Sarco-muscle; mere-part
● Structural and functional unit of myofibril
● Average length:2 micrometer

DEFINITION:
● Portion of muscle fiber between two successive Z lines

21
STRUCTURE:
Z line:
● Aka ‘Z disc’
● Network of interconnecting proteins.
● Oriented perpendicular to the axis of muscle fiber
● Thin filaments are anchored to the two sides of each Z line by alpha actinin
Thin filament:
● Composed of contractile proteins: actin,troponin,tropomyosin-7:1:1
● Each sarcomere contains two sets of thin filaments one at each end
Thick filament:
● The parallel array of thick filaments located in the middle of each sarcomere produces A
band.It contains protein myosin.
I band:
● I band lies between the ends of A band of two adjacent sarcomeres and includes those
portions of thin filaments that do not overlap the thick filaments
● Z line bisects I band.
● Muscle contraction --🡪Sarcomere length decrease--🡪shortening of I band
● A band remains unchanged.
● Thus, sarcomere length is decided by the I band.
H zone:
● Narrow, light band in the center of A band. This is the portion of A band showing no
overlap.
M line:
● A transverse M line runs through the middle of the H band.
● The M line contains proteins that bind the parallel array of thick filaments.
● It helps in organizing and maintaining a regular array of thick filaments.

HEXAGONAL AND TRIANGULAR ARRANGEMENTS:

A cross section through the overlap region of A band shows,
● each thick filament is surrounded by hexagonal array of six thin filaments.

22
 ● each thin filament is surrounded by triangular arrangement of three thick filaments

CROSS-BRIDGES:
● The globular heads of myosin II project from the surface of thick filaments toward the thin
filaments and bridge the gap between them.
● These are called ‘cross bridges’
● During muscle contraction, they attach to thin filaments and push them

SARCOTUBULAR SYSTEM

STRUCTURE:
T-tubules:
● Also called sarcotubules
● Tubular extensions of sarcolemma
● They penetrate to the center of muscle fiber and surround the individual myofibrils at the
junctions of A and I bands
● Lumen contains extracellular fluid
● Once initiated, action potential is rapidly conducted along the sarcolemma by the way of T
tubules, so that deep-lying myofibrils are fast activated.

Sarcoplasmic reticulum:
● Corresponds to ER in other cells
● Forms a membranous network and runs parallel to myofilaments
● Slender tubules have elongated portions in the middle and dilated regions at both ends
known as ‘lateral sacs’ or ‘terminal cisternae’
● Cisternae lying in close contact with the T tubules at the AI junction.
● T tubule+2 neighboring cisternae—triad
● Triad -----links membrane action potentials to muscle contraction
● Cardiac muscle--- diad (one cistern)

RECEPTOR AND CHANNEL PROTEINS:

● T tubules are separated by terminal cisternae by areas of densities called ‘feet’.

23
 ● Junctional feet involve two integral proteins.
● T- tubule is a modified voltage sensitive calcium channel known as ‘dihydropyridine
receptor. DHP receptors are L type calcium channels and they clustered in groups of four
called ‘tetrad’
● Primarily, it acts as ‘voltage sensor'
● Terminal cisternae that face the T tubules contain proteins called ryanodine receptor. They
mainly act as calcium release channels

ROLE OF SARCOPLASMIC RETICULUM IN MUSCLE CONTRACTION:

Ca ATPase pumps Ca into the longitudinal part of SR, Ca is transferred to cisternae and gets
stored

Action potential arrives at the T tubule and gets transmitted deep into the T tubule

Opens voltage-gated Ca channels deep in the T tubules located in dihydropyridine receptor

Confirmational change in ryanodine receptor resulting in calcium release into sarcoplasm

Ca diffuses into sarcoplasm to bind with troponin C and causes muscle contraction

Autoactivation of Ca ATPase pump that pumps Ca from sarcoplasm to the SR

Ca binds with calsequestrin in the fluid of cisternae and remains stored

Decrease in sarcoplasmic Ca concentration causes muscle relaxation.

FUNCTIONS:
● It transfers action potential from the surface of the muscle fiber to the interior, closer to
myofibrils
● It raises cytoplasmic calcium concentration by calcium release from SR

24
● It ensures muscle relaxation by calcium reuptake by SR
● The cisternae of SR act as a storage site for calcium.

STRENGTH DURATION CURVE

● Strength and duration are two important aspects of a stimulus.
● The relationship between the strength and duration of stimuli depicted in graph form is
known as the strength duration curve
● To excite a tissue, the lowest strength of current required is termed as rheobase
● The minimum time for which the rheobase must be applied to elicit an action potential is
known as utilization time. A stimulus weaker than the rheobase does not excite the tissue
and a stimulus stronger then rheobase requires less time to elicit a response
● Chronaxie is the time required for a stimulus of double the rheobase strength to produce
an action potential.
● The lesser the chronaxie, the greater is the excitability.
● Nerves have a shorter chronaxie compared to muscles.

25
 ACTION POTENTIAL
● It is defined as the transient change in the resting membrane potential which is conducted
along the axon in an all or none fashion.
● It is also known as the impulse or spike potential
● Latent period: it is defined as the interval between the application of the stimulus and the
generation of the action potential.
● Duration of the latent period depends on the distance between the stimulating and
recording conducting electrodes and the diameter of the nerve fiber.
● Resting membrane potential (Skeletal muscle) is -90mV
● Site: At end plate region
● Spreads at a speed of 5m/s
● Duration: 2 to 4 ms
● Absolute refractory period: 1 to 3 ms

IONIC BASIS OF ACTION POTENTIAL:

DEPOLARISATION:
● Depolarisation is due to the opening of voltage gated Na channels causing a massive
influx of Na ions
● When a threshold or suprathreshold stimulus is applied, the influx of Na through leaky
channels and voltage gated channels decreases the membrane potential from -70 to -55
mV.
● There is an increase in membrane permeability to Na ions producing a swift, rapid, steep
depolarisation curve.
● There is a positive feedback control that happens with Na channels. (Hodgkin’s cycle)

REPOLARISATION:
● Repolarisation is due to the opening of voltage gated K channels causan ing efflux of K.
● At the peak of an action potential, the voltage gated Na channels enter a closed state
whereas the voltage gated K channels open
● The membrane permeability to K increases by many folds
● Thus, the rapid falling phase in repolarisation is brought by a decline in Na influx with
the increase in K efflux.

26
GENERATION OF ACTION POTENTIAL:
Stimulus is given at the threshold b/w -50 to -55 mV
⬇️
Firing potential developed at the initial point of de polarization
⬇️
Depolarization (rising phase) starts: the influx of Na + occurs
RMP: changes to + 40 to 50 mv
⬇️
Spike potential reaches where the peak attains maximum
⬇️
Repolarization (falling phase) occurs: efflux of K+ occurs
⬇️
Hyperpolarization (refractory period) occurs: further efflux of potassium occurs
⬇️
Then returns into normal Resting membrane potential (-90mV)

27
Action potential doesn’t directly activate contractile proteins but instead by increasing
cytosolic ca2+ concentration, the contractile apparatus gets activated

CLINICAL IMPORTANCE:
● Ion channel blockers block the ion channels and prevent depolarisation of the neuron that
prevents the conduction of nerve impulses
● Na channel blockers: lidocaine, procaine, saxitoxin
● K channel blockers: tetra ethyl ammonium, 4 amino pyridines

ISOMETRIC AND ISOTONIC CONTRACTION

PRINCIPLE:
● Tension - force of contracting muscle acting on object
● Load – force exerted on muscle by an object

● Muscle tension & load act against each other

● Object lift: Tension > opposing load

TYPES:
- Isometric contraction

28
 - Isotonic contraction

ISOMETRIC CONTRACTION:
⮚ No apparent change in length
⮚ Cross bridge: same actin come & bind again & again
⮚ Develop tension but not shorten the length
⮚ During this contraction, muscle tension < load
⮚ No external work is done
Eg. When somebody is trying to lift a heavy object

ISOTONIC CONTRACTION:
⮚ No apparent change in muscle tone
⮚ Sliding thin over thick filament occurs
⮚ Muscle tension > load
⮚ Shortening of fibres occurs
⮚ External Work is done
⮚ Aka: concentric contraction

GRADED POTENTIAL
DEFINITION:
● Local, non-propagated potential of small magnitude
● With response to the stimulus of lesser strength

TYPES:
● Cationic electro tonic potential:
Electrically stimulated
⬇️
Cathodal end of stimulator
⬇️
Leads to depolarizing response

• So, the graph is upward waveform

● Anion electro tonic potential:

Electrically stimulated

29
 ⬇️
Anodal end of stimulator
⬇️
Leads to hyperpolarizing response

• So, the graph is downward waveform

MECHANISM:
● Normal condition:

● Stimulus of smaller strength:

● Stimulus of larger strength:

30
GRADED POTENTIAL: recorded from the membrane of dendrite & cell body

AFTER EFFECT:
⮚ Repolarizing force try to neutralize the effect by Na + entry, Cl – entry, K+ exit.
⮚ All these lead to the gradual return of the membrane potential to resting value.

DECREMENTAL CONDUCTION:
● Recorded near stimulus: larger amplitude
Away from stimulus: smaller amplitude
● Recorded immediately after stimulus: larger amplitude
Delay in recording: smaller amplitude

● Decays occurs progressively with time & distance

SUMMATION:
● If a 2nd stimulus is applied before the potential produced by the 1 st one has disappeared,
both the potential charges add up and produce a larger and prolonged wave.
● This happens due to the increased arrival of Na ions caused by the 1 st stimulus.

PROPERTIES:
● Graded in nature: the magnitude of potential change is proportional to the stimulus
strength
● Decremental conduction
● Depolarising/hyperpolarising in nature
● Summation

31
TYPES: based on the type and location from which they are recorded.
● End plate potential
● Receptor potential
● Synaptic potential
● Pacemaker potential

CLASSIFICATION OF NERVE FIBRES.

● Based on function:
∆Motor
∆Sensory
∆ Secretomotor

● Based on myelination:
∆Myelinated
∆ Unmyelinated

● Based on diameter and conduction velocity:

ERLANGER AND GASSER CLASSIFICATION:
Fibre type Function Fibre Conduction velocity
diameter(micrometer (m/sec)
)
A alpha Somatic motor and 12-20 70-120
proprioception

A beta Touch- pressure 5-12 30-70

A gama Motor to muscle 3-6 15-30
spindle
A delta Pain, cold ,touch 2-5 12-30

32
 B Autonomic 3-15 3-15
preganglionic
fibres
C-dorsal Somatic sensations 0.5-2 0.5-2
root fiber
C- Postganglionic 0.7-2.3 0.7-2.3
sympathetic sympathetic fibres.
fiber

● Numerical classification: Type Ia, Ib, II, IV.

● Classification by susceptibility to various agents (Hypoxia, Pressure, Local anesthetics)

WALLERIAN DEGENERATION AND REGENERATION

The degenerative changes that occur in the distal segment of the axon are called Wallerian
degeneration.

DEGENERATIVE CHANGES:
Transmission of impulse: shortly after the injury, the transmission of impulse at the synaptic
junction stops within hours
Axonal changes:
● The axon swells and the terminals retract from the postsynaptic target.
● Over a period of a few weeks, the axon and all its terminals degenerate.
● If the axon is myelinated, there are fatty enlargements that form all over the myelin
sheath that look like a series of beads.
● They myelin sheath breaks down but the myelinating cells remain viable.
● The debris created is devoured by macrophages
● Phagocytosis is more rapid in PNS than in CNS.
Effect of stimulation:
● on stimulation, the distal axon can conduct an action potential up to 3 days, the ability is
impaired from the 3rd to 5th day.
● An action potential cannot be initiated after the 5th day.

33
Changes in soma and stump:
● There is retrograde degeneration that are seen in the soma and to some extent in the
proximal stump.
● Cell bodies become swollen and round
● Nucleus swells and moves to an eccentric position.
● Endoplasmic reticulum is seen around the periphery of the cell body
● Ribosomes appear disorganized
● Nissl granules gradually disintegrate and stain weakly with basic dyes, this is called
chromatolysis

34
REGENERATIVE CHANGES:
● The soma tries to repair the axon by synthesizing new structural proteins that fill up and
distend the cisterns of the rough endoplasmic reticulum. This is known as axonal
reaction.
● Chromatolysis is reversible if the neuron survives and re-establishes contact with the
appropriate target.

35
Axonal changes:
● Sprouting of the proximal end of axon
● Elongation of sprouts by the formation of growth cone
● The Schwann cells that survived the degeneration multiply and form rows along the
pathway previously taken by the axon
● One of the sprouting branches finds the way through the Schwann cells and finally re-
innervates the original target structure
● The regeneration of axon is about 1-4 mm/day
● The Schwann cells then lay down the bilayer membrane to form the myelin sheath around
the newly formed axon.
Somatic changes:
● The soma regains its size
● The number of Nissl granules slowly starts to reappear and other organelles also
reappear.
● The cell looses excess fluid and regains its normal size.
● The nucleus occupies the central position.

Changes in target structure:

● Decreased neurochemical transmission leads to upregulation of receptors in the target
structure.
● Therefore, when a neurotransmitter is released, the response of the target is increased.
This is called denervation hypersensitivity.

FACTORS INFLUENCING REGENERATION:

● Severity of injury: if the gap between the proximal and distal parts is >3mm, it forms a
tumor-like swelling like neuroma. Once this occurs, regeneration of the nerve can never
occur.
● Condition of soma: if the axonal damage is close to the body, a larger part of the neuronal
membrane and cytoplasm is lost. In such situations, the neuron often dies.
● Location of injury: axons in the PNS regenerate better than those of CNS.
● Neurotrophins: these are given to the site of injury that can enhance neuronal
regeneration.

36
 PROPERTIES OF SMOOTH MUSCLE
Morphological properties:
1. Lack of striations
2. Absence of troponin
3. Absence of T-tubules
4. Absence of well-developed neuromuscular junctions
Electrical properties:
5. Presence of gap junctions
6. Excitability
7. Variable RMP and shifting pacemakers
8. Variable action potential.
Mechanical properties:
9. Tonus: continuous state of spontaneous irregular contraction due to the generation of
basic slow wave rhythm.
10. Plasticity: The adaptability of the muscle to the new length with less increase in tension.
11. Slow and prolonged contractile response
12. Length-tension relationship
13. Force-velocity relationship
14. Muscle hypertrophy.

37
 PROPERTIES OF SKELETAL MUSCLE

Important properties of skeletal muscle-

1) Summation of contraction
2) Staircase phenomenon
3) Tetanisation
4) Post tetanic potentiation
5) Length tension relationship
6) Load velocity relationship

SUMMATION OF CONTRACTION:

● It states that isometric tension developed in a single fibre or a muscle depends on the
frequency of the stimulus applied to it.

1. The action ability of the skeletal muscle is short (1–4 ms) as compared to its contraction
time. the absolute refractory period (which incorporates the depolarization phase and a part
of the repolarization section) of the action ability is over by the point contraction starts.

2. If a 2nd twitch is produced when the contraction segment of the first twitch continues to
be continuing, the phase of contraction of the second twitch is introduced to the section of
contraction of the primary twitch, resulting in a summated contractile response

3. The Ca++ released because of the second one movement potential is introduced to the
Ca++ launched because of the first movement potential, generating a better sarcoplasmic
Ca++ attention that results in a bigger contractile response.

4. Thus, repeated stimulation of the muscle before relaxation has occurred produces a
phenomenon known as summation of contractions.

5. The contractile element have no refractory period; they do not follow all or none law

38
STAIR-CASE PHENOMENON:
1. When a series of stimuli is delivered to skeletal muscle there is an increase in the tension
developed during each twitch until, after several contractions, a uniform tension per
contraction is reached
2. Phenomenon is called trepee phenomenon.
3. Basis of warmup
4. Believed due to increased availability of Ca +2 for binding to troponin C, accumulation
of heat, or effect of ph
5. Also occurs in cardiac muscles a cardiac muscle cannot be tetanised

TETANISATION:
● When the frequency reaches a critical level the successive contractions fuse together, and
the whole muscle contraction appears to be smooth and continuous
● In complete/ fused tetanus, there is no relaxation between the contraction phases
● In clonus/ incomplete tetanus, there are periods of incomplete relaxation between
maintained contractions.
● The tension generated in the muscle gradually rises and summated until a maximal
tetanic tension is reached beyond which tension does not increase further
● The critical frequency at which summation of contractions occur differs from muscle to
muscle
● Post tetanic potentiation: when a single stimulus is applied to a muscle immediately after
the tetanic contraction is over, the amplitude of the contraction is higher than that of a
single twitch.

𝐶𝐹 = 1/𝑡𝑤𝑖𝑡𝑐ℎ 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑖𝑛 𝑠)

39
 Treppe
phenomenon

Length tension relationship

● Isometric tension developed in a muscle depends on the initial length of the muscle.
● For the isometric tension to be recorded in an experimental set-up, the ends of the muscle
are attached to two fixing points so that changing the distance between the fixing points
can alter the length of the muscle
● When the muscle fibre is stretched, the tension registered by it is known as passive
tension.
● If the stretched muscle is stimulated, the tension developed is called total tension
● At any length, the amount of tension actually generated by the cross bridges is called as
active tension that is the total tension minus the passive tension.

40
 Total tension

Active tension
tension

Passive tension

Change in muscle length

Load velocity relationship

● When a muscle contracts against a load (isotonic contraction), the velocity of fibre-
shortening is inversely proportional to the degree of load. When there is no load, the
muscle contracts with maximum velocity and the velocity decreases with increasing load
on the muscle

● When the load becomes equal to the maximum isometric tension, the shortening velocity
is 0. If the load increases further, the muscle lengthens (lengthening contraction)

● The rate of cross bridge cycling in a muscle depends on its ATPase activity, determines
the shortening velocity of the muscle
● The slower the contraction, the more there is time for actomyosin interaction and greater
tension development.

41
 Maximum shortening velocity (zero load)
Shortening velocity

Maximum isometric tension)

zero velocity)

load

42
 MECHANISM OF SMOOTH MUSCLE CONTRACTION
● The strength of the stimulus (the degree of stretch or the amount of
neurotransmitter/hormone reaching the cell membrane) acting on the smooth muscle fibre
can be graded.

● The cytosolic calcium concentration is increased mainly by entry of calcium from the
interstitial fluid or to some extent by its release from cytoplasmic calcium stores.

● However, the concentration of calcium in cytosol decreases due to binding of calcium to

calmodulin, pumping back of calcium to the SR and calcium efflux.

● Calcium-induced calcium release mechanism in which, some amount of calcium influx

stimulates further calcium release from the SR.

● Pumping Back of Calcium to the SR Pumping back of calcium to SR is mediated via a

Ca++ ATPase present on the membrane of SR.

● Calcium Efflux Calcium efflux to the ECF occurs by Na+-Ca++ antiport, a process of
secondary active transport and by Ca++-ATPase, both the mechanisms being present on
the cell membrane.

● In smooth muscles, tension is generated in the same manner as in skeletal muscles, by the
attachment of energized cross-bridges to actin, followed by detachment from and
reattachment to actin.

● Molecular Basis of Contraction As described above, calcium concentration increases in

the cell mainly by influx from ECF, and partly by release from SR.

● The myosin ATPase enzyme is activated in the phosphorylated myosin head causing
hydrolysis of one ATP molecule. Then, the myosin ATPase enzyme hydrolyses ATP
resulting in the attachment of myosin head with actin.

43
 Ca influx from
smooth muscle cell decrease in Ca detatch from
concentration clamodulin
binding of Ca with
calmodulin latch bridge state decrease in
dependent MLCK (sustained MLCK
contraction) activity
phosphorylation
of myosin muscle
dephosphorylation
relaxation
of MLCK
increased myosin
ATPase activity that
results in cross bridge contraction of
formation muscle

44
 LATCH-BRIDGE MECHANISM
Muscle in this state is known as the latch-state, in which dephosphorylation of attached cross-
bridges occurs in an environment of elevated cytosolic calcium level.

● When MLCP-induced dephosphorylation of myosin light-chain takes place, it does not

bring about dissociation of myosin from actin until the cytoplasmic calcium
concentration falls below a critical level.
● The attached cross-bridges following dephosphorylation are known as the latch-bridges.
In this process the rate of cross-bridge cycle is decreased due to slower rate of
detachment of cross-bridges. That means the cross-bridges spend more time in an
attached state.
● Therefore, the ATP utilization is less, which enables the visceral smooth muscles to have
sustained contractions with less expenditure of energy.
● The force of this sustained contraction can be graded over a wide range because the
cytosolic calcium concentration can be finely regulated over a wide range. From the latch
state, the relaxation of the muscle occurs when the cytoplasmic calcium concentration
falls.

45
46
St
udentNot
es

PHYSI
OLOGY
1stEdi
t
ion

Uni
t4
Cardi
oVas
cul
arSys
tem
 CONTENTS

ESSAY:

1. Cardiac cycle, various events, pressure and volume changes Pg.3

in cardiac cycle

2. Define arterial blood pressure and mechanism of regulation of Pg.9

arterial blood pressure

3. Define ECG, normal ECG waves, segments, intervals, note on Pg.14

ECG leads.

4. Define cardiac output, factors regulating cardiac output and Pg.19

methods to measure cardiac output

5. Describe the structure and function of conducting system of Pg.31

heat. List the properties of cardiac muscle

6. Define shock. Enlist the various types of shock. Explain in Pg.43

detail about hypovolemic shock and its treatment modality.

SHORT NOTES:

1. ECG Lead 2 with diagram and changes affecting lead 2, Pg.48

clinical importance

2. Frank starling law of heart, application and clinical Pg.54

significance

3. Heart sounds, cerebral blood flow Pg.57

1
4. Triple response, foetal circulation, Pacemaker potential Pg.60

5. Coronary circulation, Cushing’s reflex, ECG leads. Pg.65

6. Baroreceptor reflex, JVP and its clinical significance Pg.70

2
 CARDIAC CYCLE

DEFINITION:
Cardiac cycle is defined as the sequence of coordinated events taking place in the heart during
each beat. Duration of cardiac cycle is 0.8 seconds.

EVENTS OF CARDIAC CYCLE:

Two events in cardiac cycle
1. Atrial events
2. Ventricular events

ATRIAL EVENTS:
Atrial events are divided into two divisions
1. Atrial systole (0.1s)
2. Atrial diastole (0.7s)
Atrial systole:
● Atria contracts and small amount of blood enters the ventricles.
● This period coincides with last rapid filling phase of ventricular diastole
● Atrial systole causes increase in intra-atrial pressure by 4-6 mmHg in right atrium
& 7-8 mmHg in left atrium. This pressure rise in right atrium is reflected into the
veins and is recorded as a-wave from the jugular vein
● Contraction of atrial musculature causes the production of fourth heart sound.
Atrial diastole:
● After atrial systole, atrial diastole starts.
● This period coincides with ventricular systole and most of the ventricular
diastole
● Atrial filling takes place.

VENTRICULAR EVENTS:
Ventricular events are divided into two divisions
1. Ventricular systole (0.3s)
2. Ventricular diastole (0.5s)
The ventricular systole is divided into two subdivisions:
● isometric contraction period
● ejection period.

3
The ventricular diastole is subdivided into five subdivisions:
● protodiastole
● isometric relaxation
● rapid filling
● slow filling
● last rapid filling (coincides with atrial systole)
Isovolumic (Isometric) contraction period:
● It is characterized by increase in tension without any change in the length of muscle fiber.
● With the beginning of ventricular contraction, the ventricular pressure exceed the atrial
pressure very rapidly causing the closure of AV valves
● Closure of AV valves at the beginning of this phase produces first heart sound.
● Since the AV valves have closed and the semilunar valves have not opened, the ventricles
contract as a closed chamber & pressure inside ventricles rises rapidly to a high level
● Despite the ventricular contraction, the volume of blood in ventricles does not change.
Thus, this called as isovolumic contraction
● Rise in ventricular pressure causes opening of semilunar valves.
Ejection period:
● After the opening of semilunar valves, blood is ejected out of the ventricles.
● Ventricles are not completely emptied at the end of ejection period. The amount of blood
remaining in ventricles at the end of ejection period is called end systolic volume (ESV).
It is 60-80 ml per ventricle.
● Ejection fraction: fraction of end diastolic volume that is ejected out by each ventricle per
beat.
● Ejection period is of two phases:
1. rapid ejection period: during this phase large amount of blood (about 2/3rd of
stroke volume) is rapidly ejected from both ventricles.
2. Slow ejection period: the blood is ejected slowly with much less force.
Protodiastole:
● Interventricular pressure becomes less than the pressure in the aorta and pulmonary
artery.
● Semilunar valves close which produces second heart sound.
Isovolumic (Isometric) relaxation period:
● It is characterized by decrease in tension without any change in the length of muscle
fiber.
● Since semilunar valves have closed & AV valves have not opened yet, the ventricles
continue to relax as closed chambers in this phase. The volume of blood in ventricles
remains constant, hence it is called the isovolumic relaxation phase.
● Ventricles undergo isometric relaxation and pressure in the ventricles falls than the atrial
pressure.

4
 ● Thus, atrioventricular valves open at the end of this phase.
Rapid filling phase:
● As atrioventricular valves are opened there is sudden rush of blood into ventricles.
● 70% ventricular filling takes place during this phase.
● Rushing of blood into ventricles produces third heart sound which is not commonly
audible in adults but may be heard in children.
Slow filling phase:
● Also known as diastasis.
● 20% filling occurs during this period.
Last rapid filling phase:
● This period coincides with atrial systole.
● 10% of ventricular filling takes place.
● End diastolic volume: amount of blood remaining in the ventricles after the end of
diastole. It is 130-150 ml per ventricle.

PRESSURE CHANGES IN CARDIAC CYCLE:

A-B Segment:
● Appears during atrial systole.

5
 ● Pressure increases during this period.
● B denotes closure of atrioventricular valves.
B-C Segment:
● Appears during isometric contraction period.
● Interventricular pressure increases.
● C denotes opening of semilunar valves.
C-D Segment:
● Appears during ejection period.
● Because of the thick wall of left ventricle, the pressure rise in left ventricle is about 4-5
times higher than the pressure rise in right ventricle.
D-E Segment:
● Appears during protodiastole.
● Interventricular pressure decreases.
● E denotes the closure of semilunar valves.
E-F Segment:
● Appears during isometric relaxation period.
● Interventricular pressure decreases.
● F denotes the opening of atrioventricular valves.
F-G Segment:
● Appears during rapid filling phase.
● Pressure decreases.
G-A Segment:
● Appears during slow filling phase.
● Pressure decreases further.

6
VOLUME CHANGES IN CARDIAC CYCLE:

A-B Segment:
● Appears during atrial systole.
● Ventricular volume increases slightly.
● B denotes closure of atrioventricular valves.
B-C Segment:
● Appears during isometric contraction period.
● The ventricular volume is not altered during this period. However, the slight upward
deflection seen is an artifact.
● C denotes the opening of semilunar valves.
C-D Segment:
● Appears during ejection period.
● Ventricular volume decreases.
D-E Segment:
● Appears during protodiastole period.
● There is no change in the ventricular volume.
● E denotes closure of semilunar valves.

7
E-F Segment:
● Appears during isometric relaxation period.
● Volume remains unaltered but the slight upward deflection in the curve is due to artifact.
● F denotes the opening of atrioventricular valves.
F-G Segment:
● Appears during rapid filling phase.
● There is rise in the ventricular volume.
G-A Segment:
● Appears during slow filling phase.
● Ventricular volume increases.

CLINICAL APPLICATIONS:
1.Myocardial infarction:
● Necrosis of myocardium causes by insufficient blood flow due to thrombus,
embolus or vascular spasm.
● Ejection fraction is decreased in myocardial infarction.
2.Left ventricular hypertrophy:
● Enlargement and thickening of left ventricle.

8
 ARTERIAL BLOOD PRESSURE
DEFINITION:
● The lateral pressure exerted by the flowing blood against any unit area of the arterial
vessel wall.
● Measured in mm Hg.
● The maximum arterial pressure during the systole is called Systolic BP.
● The minimum arterial pressure during diastole is called Diastolic BP.

FACTORS AFFECTING BP:

1. Age: Systolic and diastolic BP both increase with age but after 50-60yr due to poor
distensibility of an artery, only systolic BP increases.
2. Gender: Before menopause Males have higher BP after menopause, Systolic BP increases
4-5mmhg higher in Females than in Males.
3. Built of a person: An obese individual has high reading because of increased tissue between
the cuff and artery.
4. Climate: Exposure to cold causes vasoconstriction which increases BP.
5.Diurnal variation: Diurnal variation of 5-10mmhg common in Systolic BP.
6. Exercise: BP comes back to normal after 5min of exercise.
7. Emotions: Excitement, and Fear increase systolic BP.
8. Hereditary
9. Sleep: Systolic BP falls during sleep.
10. Posture: Diastolic BP changes with posture (sudden standing increases Diastolic BP).

FACTORS DETERMINING BP:

1. Cardiac output: CO=HR X stroke volume. Systolic BP depends on stroke volume
2. Peripheral resistance: Diastolic bp depends on this.
It varies according to:-
a)Viscosity of blood: BP is directly proportional to the viscosity of blood.
b)Velocity of blood flow: When a vessel is narrowed. velocity increases and distending
pressure of the blood vessel decreases(according to the Bernoulli principle).

9
 c)Radius of the vessel: Peripheral resistance is inversely proportional to the fourth power of
the radius.
d)Elasticity of vessel: BP is inversely related to the elasticity of the vessel.

REGULATION:
1. SHORT TERM REGULATION(NERVOUS SYSTEM CONTROL):
a) Baroreceptors
b) Chemoreceptors
c)CNS ischemic response (Cushing reflex)

A) BARORECEPTORS (pressure buffer system):

10
 ● Small fluctuations in mean BP activate baroreceptors.
● Important for maintaining postural change in BP.
● Baroreceptors are reset in chronic hypertension(they don't get stimulated even if BP is
high).

B)CHEMORECEPTOR:
Receptor: Carotid and Aortic body.
Stimulus: Oxygen, ph of blood, CO2.
● These are stimulated when mean BP falls below 80 mm Hg.
● Increased accumulation of H+ due to decreased oxygen stimulates the chemoreceptors
and increases BP.

C)CNS ISCHEMIC RESPONSE:

● Activated when mean BP<40 mmHg.
● When intracranial pressure is increased, the blood supply to the vasomotor area is
decreased. This causes local hypoxia and hypercapnia. The vasomotor area is excited to
increase BP which can increase blood supply to the vasomotor area.
● The increased BP decrease the heart rate(the only exception is when BP increases heart
rate increases).

11
2. LONG TERM REGULATION OF BP:
A) RENIN-ANGIOTENSIN SYSTEM:

The function of Angiotensin II:

● Cause sodium and water retention by acting directly on the kidney.
● Release of aldosterone from adrenal glands causes salt and water reabsorption from the
kidney.

B)HORMONAL:
Hormones that help in the long term regulation of BP other than angiotensin are:
● Aldosterone= Causes an increase in BP.
● ADH =Increases BP.
● Catecholamines=epinephrine, norepinephrine.
● Atrial natriuretic peptide =Causes vasodilation and decreases BP

12
3.OTHER MECHANISMS FOR REGULATION OF BP ARE:
A)Capillary fluid shift:
When increase in BP more fluid is filtered through the capillary wall into the interstitial
space. So blood volume decreases, resulting in decreased BP. Reverse changes take place when
BP falls.

B)Stress relaxation of blood vessels:

13
 ELECTROCARDIOGRAM

It is defined as the summated electrical activity of the heart fibres developed during each heart
beat recorded from the surface of the body.

Electrocardiography:
● It is the technique by which an electrocardiogram (ECG) is recorded and analysed .

Electrocardiograph :
● It is the instrument used for recording ECG.

Normal ECG:
● Each beat of the heart will result in a complex of waves called PQRST complex.
● The baseline is called isoelectric or iso potential line.

Positive waves | Negative waves

P,R,T waves Q,S waves

Occasionally
( U wave)

14
1. P-Wave:
● It represents atrial depolarisation.
● Normal duration is 0.08-0.12 sec.
● Normal voltage is 0.1-0.3 mV P.
● Wave represents normalcy of the atrial myocardium.
It under- goes changes with the diseases of the atria.
a)Atrial hypertrophy-‘P’wave becomes larger or bifid.
b) Atrial flutter-Abnormal 'P' waves called 'F' waves.
c) Atrial fibrillation-Abnormal 'P' waves called 'f'waves.
d) Atrial ectopic (or) Atrial tachycardia-Inverted ‘P’ wave.

15
2. QRS complex:
● This represents ventricular depolarisation, i.e, the normalcy and integrity of the
ventricular myocardium.
● Normal duration is 0.05-0.12 sec.
● Normal voltage 1-3 mV.
● ECG from the left ventricle will have more amplitude than that from the right ventricular
ECG
3.Q wave:
● This is a small negative wave.
● Represents the depolarization of the mid portion of the interventricular septum.
● This is absent in right ventricular leads.
● This is present in all the bipolar leads as both electrodes are active.
4. 'R' wave:
● It is a prominent positive wave.
● Amptitude may reach upto 25 mV.
● It is due to the potential travelling to the apex of the ventricle and activating major
portion of both the ventricles.
● Peak of 'R' wave is the safest period as the ventricle is in absolute refractory period at this
time and so does not respond to any external stimulus. Hence cardio version is done by
applying DC shock during this period.
5. S wave:
● It is a negative wave and is due to the potential travelling to the base of the ventricles.
● RS complex is prominent in right ventricular leads.
Abnormalities:
a) Ventricular hypertrophy-QRS amplitude increases.
b) Myocardial infarction
c) Complete AV block.
d) Bundle branch block
e) Ventricular ectopics
f) Constrictive pericarditis

6. T wave:
● It is a rounded positive wave and represents ventricular repolarization.
● Normal duration is 0.27 sec.

16
 ● Volt age varies from 0.2 to 0.5 mV. It is normally a +ve wave except in LIII, a VR and V,
where it is -ve.
● Peak of T wave is the vulnerable period or dangerous period as any stimulus during this
period would cause arrhythmias. During this period ventricular repolarization is in
different stages.
7. U wave: It is a small positive wave caused by delayed repolarization of the papillary muscle,
mostly seen in V2 to V4 leads.

Intervals:
8. PR interval:
● It refers to the time interval between the beginning of 'P' wave to the beginning of Q' or
'R' wave.
● This represents AV conduction time, (time taken by the impulse to travel from SA node
to the ventricle).
● Normal duration is 0.12-0.21 sec.
● It is inversely proportional to the heart rate.
● PR interval is prolonged in:
a) 1°H block, e.g., digitalis toxicity. Simple prolongation of PR interval.
b) 2° H block, e.g., Wenkebach's phenomenon.
In both these conditions, there is a partial AV block.
● In the Wenkebach phenomenon, the PR interval increases with the successive beats and
at one stage only P wave is obtained without QRST. It is followed by an other normal
PQRST complex.
● PR interval is shortened in:
a)Wolf-Parkinson-White syndrome (WPW syndrome)
b) Lown-Ganong-Levine syndrome (LGL syndrome)
9. ST interval:
● Denotes the interval between the end of 'S' to the end of 'T' wave;
● Normal up to 0.32 sec.
● It represents the time taken for ventricular repolarization.
10. QT interval:
● Denotes the interval between the beginning of Q wave to the end of T wave.
● The normal is 0.4 sec.
● It denotes the time taken by ventricular depolarization and repolarization. Normally, the
beginning of ventricular systole coincides with the summit of R wave and ends with the
completion of T wave.

17
 ● QT is shortened in hypercalcaemia and QT prolonged in hypocalcaemia.
● RT interval denotes the duration of ventricular systole.

Segements
11. PR segment:
The region between the end of P wave and the beginning of 'Q' wave. This denotes the time
interval between completion of atrial depolarization and beginning of ventricular
depolarization.
12. J point:
It indicates the end of 'S' wave. It is useful in assessing 'S,T' elevation or depression.

18
 CARDIAC OUTPUT

DEFINITION:

● The amount of blood ejected by each ventricle per min

● CO=Stroke volume×Heart rate

FACTORS AFFECTING CARDIAC OUTPUT:

Factors that affect stroke volume and heart rate affect cardiac output.
Factors affecting Stroke:
1. Preload-end diastolic volume.
2. Myocardial contractility.
3. Afterload-peripheral resistance.
1)PRELOAD:

FRANK -STARLING LAW:

“Within the physiological limit, the force of contraction is directly

proportional to the initial length of muscle Fibre, Increased ventricular
filling Increases the Fibre length Increases the force of contraction.”

19
 Increased ventricular filling

Increases the Fibre length

Increases the force of contraction

Factors affecting preload:

1)Venous return.

2)Atrial pump activity.

3)Ventricular compliance

1)Venous return:

Defined as the amount of blood that returns to the right atrium from systemic venous
circulation
-> Depends on
a)Skeletal muscle pump in lower limbs:
Veins are surrounded by skeletal muscle. Contraction of skeletal muscle during
walking compresses veins and pushes blood towards the heart.
b)Thoracic pump:
Inspiration

Intrathoracic pressure becomes more negative. Negative pressure

Transmitted to the great veins

Central venous pressure falls

Facilitates venous return.

20
c)Abdominal pump:

Inspiration

Descent of diaphragm Increased abdominal pressure

Compresses the intra abdominal blood vessel

Blood is pushed towards the heart Venous return increases

(Blood is not pushed towards leg veins-because of valves)

d)ECF volume:

A- Diarrhea,vomiting

Decreases ecf volume

Decreases cardiac output

B-pregnanacy

Increased ecf volume

Increases cardiac output

21
e)Sympathetic activity:

Veins-sympathetic fibres stimulation in exercise

Vasoconstriction

Increased venous return

f)Right atrial pressure:

Venous return curve

0-6mm hg

Increase in pressure

Decreased venous return

[Above 7 mm Hg venous return =0]

22
● When right atrial pressure falls below -2mmHg

No increase in venous return.

Plateau phase

Bc2 of collapse of veins

negative pressure in right atrium

Sucks the walls of vein chest Vein collapse

No increase in venous return.

g)Degree of filling by systemic circulation:

Effective volume of blood-in the entire circulation determines the venous return.

Temporarily stopping the heart to pump blood

Without blood flow,the pressure everywhere in the circulation becomes equal.

This equilibrated pressure levels that fills the entire circulation called mean circulatory
filling pressure

23
 h)Resistance to venous return:

Venous obstruction

Venous resistance increases

Blood begins to be dammed up

But due to distensible character of the vein ,rise in venous pressure to overcome
resistance occurs little

Hence blood flow into right atrium Decreases. -

Resistances in arterioles and small arteries Blood accumulates in the

arteries

Arteriole -less capacitance

Hence rises the pressure gently It overcomes the increased resistance

MOST OF THE RESISTANCE TO VENOUS RETURN OCCUR IN THE VEINS

2)Atrial pump activity:

● Ventricular filling occurs almost passively.

● Only 15-20 percent of ventricular filling at rest occurs due to the atrial pump.
Hence normally the atrial pump does not contribute significantly to stroke
volume.

24
 3)Ventricular compliance:

● Ventricular muscle is compliant(stretchable).

● In cardiac myopathies, infiltrative disease of the heart

Decreased compliance of Ventricular muscle

Ventricular filling Decreases

CO Decreases.

● Cardiac tamponade: Hemopericardium, Massive pericardial effusion.

EDV decreased ,CO decreases

2)MYOCARDIAL CONTRACTILITY:

Depends on
● Ventricular muscle mass -

Pathology : Muscle atrophy in cardiomyopathy or myocardial infarction.

Decreases muscle mass

Decreases cardiac output.

Normal: Athlete- Physiological hypertrophy

Increases CO mainly by increasing stroke volume, rather than the heart rate.

25
● Autonomic activity:
Ventricles are supplied by sympathetic fibres.

Sympathetic stimulation

Increases contractility

Vagal stimulation

Decreases heart rate Decreases cardiac output.

● Hormonal Factors:

Catecholamines

Increases contractility.

Acetylcholine Decreases the contractility Glucagon and insulin are

inotropic.

Thyroxine causes tachycardia since it Increases the beta1 receptors on nodal tissues.

● Chemical factors:

Digitalis Inhibits Na-K ATPase activity increases intracellular Na Decreases

sodium gradient

Decreases the activity of Na-Ca exchanger Intracellular accumulation of CA

Increased myocardial contractility

26
 3)AFTERLOAD:

● PR is inversely proportional to cardiac output.

● Here CO is altered without a change in Ventricular muscle length-hence
chemometric autoregulation.- The arep effect

Factors affecting afterload:

1. Vessel diameter:
▪ Vasoconstriction
- Increases peripheral resistance
- Decreases stroke volume.
2. Viscosity:
Polycythemia
-Increased viscosity
-Decreases cardiac output
Anemia
-CO Increases.

FACTORS AFFECTING HEART RATE:

● Vagal stimulation: Decreases heart rate

● Sympathetic stimulation: Increases heart rate.

Tachycardia

Diastole duration shortens more than systolic

EDV Decreases

CO does not increase proportionately to that of increase in heart rate.

(Because unless associated with Increased venous return, increased heart rate does not
increase proportionately.)

27
REGULATION OF CARDIAC OUTPUT:

1.Intrinsic or auto regulation

a)Frank starling mechanism
b)Rate induced regulation:Increased frequency force of contraction increases.
2.extrinsic regulation:
a)Afterload
b)Neural influences
c)Hormonal influences.

METHODS FOR MEASURING CARDIAC OUTPUT

1.FICK PRINCIPLE

▪ 200/200-160=5 L
▪ Hence 5 lit of blood must flow through lungs each min-it is the measure of
cardiac output.

CO=O2 absorbed per min(ml/min)÷arteriovenous O2 difference(ml/L).

In humans,
Mixed venous blood obtained through catheter inserted up the brachial vein
Subclavian vein
Pulmonary artery
● systemic arterial blood
● rate of oxygen absorbed by lungs using an oxygen meter.

28
2. INDICATOR DILUTION METHOD:

Indicator-injected into large systemic vein preferably into right atrium

(5 mg of cardiogreen dye at 0 time)

Right side of heart

Blood vessels of lungs

Left side of heart

Systemic arterial system.

-Serial arterial samples were taken.

-None of the dye passed into the atrial tree for about 3 sec.

-In 6-7 sec, the concentration of dye rose rapidly.

-Concentration fell rapidly, but before concentration reached zero, some of the dye already
circulated and returned through the heart for a second time.

29
-To measure CO, the early downslope of the curve is extrapolated to join the x-axis, given the
time taken for a single circulation.

-Calculation of the mean concentration of dye in arterial blood for the duration of the curve was
done by measuring the area under the initial and extrapolated curve and then averaging the
concentration of dye for the duration of the curve.

CO=mg of dye injected ×60÷average concentration of dye in each ml of blood for the
duration of curve × duration of curve in sec

3. OTHER METHODS:

⮚ ECHOCARDIOGRAPHY
⮚ THORACIC ELECTRICAL BIOIMPEDANCE METHOD.

30
 CONDUCTING SYSTEM OF THE HEART

INTRODUCTION:
- The heart is endowed with a special system for
1. Generating rhythmical electrical impulses
2. Conducting these impulses rapidly through the heart
● To cause rhythmical contraction of the heart muscle
● When this system functions normally, the atria contract about one sixth of a
second ahead of ventricular contraction, which allows filling of the
ventricles before they pump the blood

A SECTION THROUGH THE LONG AXIS OF THE HEART

31
CONDUCTING SYTSTEM OF THE HEART:
The conducting system of the heart consists of specialized fibres of the heart muscle
present as the :
● Sinoatrial node.
● Interatrial Tract.
● Internodal Tracts.
● Atrioventricular (AV) node.
● AV bundle of His and its right and left branch.
● Purkinje Fibres (Subdivision of Bundle of His).

SINOATRIAL NODE-THE PRIMARY PACEMAKER:

● Located at the junction of the superior vena cava with the right atrium.
● 15 mm X 2-5 mm X 1 mm.

32
 ● P-CELLS:
▪ Fusiform shape with longitudinal striations.
▪ Highly vascular.
▪ Rich in glycogen and mitochondria
▪ Rate of discharge –more rapid
▪ Determines the rate at which the heart beats: cardiac pacemaker.
● INNERVATION:
▪ -It develops from the structures on the right side of the embryo.
▪ -Innervated by Right Vagus nerve.
▪ -Sympathetic Nerve fibres predominantly of Right side from the cervical ganglia
via Cardiac Nerves.

INTERNODAL PATHWAYS:
● The internodal pathways merge into the AV node.
● Three internodal pathways:
ANTERIOR:Tract of Bachman (Interatrial tract or Bachmann bundle).
MIDDLE:Tract of Wenckebach.
POSTERIOR:Tract of Thorel.

33
AV NODE:
● Located in the right posterior portion of the interatrial septum.
● It is 22 mm in length, 10 mm in width, and 3 mm in thickness.
INNERVATED :
▪ Developed from left side structure of Embryo.
▪ Left Vagus nerve.
▪ Sympathetic from left side.

AV NODAL DELAY:
▪ In AVN, the fibre diameter is small with multiple branches.
▪ The rate of impulse conduction is slow at AVN.
▪ AV Nodal Delay:- A delay of 0.1 second occurs for the impulse to be
transmitted through AVN
▪ Action Potential of AVN: Slow response type.
● SIGNIFICANCE OF AV NODAL DELAY:
-Ensures that appropriate time is provided for the atrial contraction & emptying;
Before ventricular contraction starts
-Low ventricular rate in Atrial Fibrillation
-Drugs like Digitalis and Betablockers: Reduce the HR partially by promoting
the AV Nodal delay.
- Delay is because of:
o Velocity of impulse conduction is less: 0.02 -0.05 m/sec.
o Presence of very few gap junctions.
o Fibre diameter is small

BUNDLE OF HIS:
❖ The atrioventricular bundle (bundle of His) is a continuation of the specialised
tissue of the AV node, and serves to transmit the electrical impulse from the AV
node to the Purkinje fibres of the ventricles.
❖ It descends down the membranous part of the interventricular septum, before
dividing into two main bundles:

34
 ▪ Right bundle branch – conducts the impulse to the Purkinje fibres of the
right ventricle
▪ Left bundle branch – conducts the impulse to the Purkinje fibres of the
left ventricle.

PURKINJE FIBRES:
● Take origin from the terminal divisions of right and left branch of Bundle of His to
penetrate the ventricular wall.
● Larger & thicker than SAN fibers.
● Transmit the impulse at a very FAST velocity of 4 m/sec.
● Because of larger diameter & very high level of permeability of the gap junctions
at intercalated disc.
● Immediate transmission of cardiac impulse throughout the entire ventricles.

BLOOD SUPPLY TO THE CONDUCTING SYSTEM OF HEART:

❖ SAN :
● SA Node artery– usually it’s a branch of the RCA ;or from CIRC.

35
 ● AV Node is supplied by AV Node artery derived from RCA in 90% of human
hearts; & CIRC in 10% .
- The right coronary artery generally supplies the right ventricle and
atrium, and the left coronary artery supplies the left ventricle and atrium
- Left coronary artery divides near its origin into two principal branches:
● The left circumflex artery sends branches to the left atrium and ventricle, and
the left anterior descending artery descends to the apex of the heart and branches to
supply the interventricular septum and a portion of the right as well as the left ventricle.

RESTING MEMBRANE POTENTIAL:

● SA node: -55 to -60 mV
● Atria: -90mV
● Ventricle: -90mV
● Purkinje fibres: -90 to -100mV

PACEMAKER POTENTIAL/PREPOTENTIAL:
1.Unstable resting membrane potential in the SA node
2.The 1st part of the prepotential:
` “h” channel:Open after hyperpolarization
-both Naᶧ and Kᶧ channel – Ih
- “funny current”
-I k
3.The 2nd part of the prepotential:-
-Transient Ca²ᶧ channels open

36
SYMPATHETIC AND PARASYMPATHETIC STIMULATION:

37
RATE OF GENESIS OF ACTION POTENTIAL
● SA node : 60 -100 per minute
● AV node & AV bundle : 40 - 60 per minute
● Atrial muscle: 40–60/min.
● Bundle branches & Purkinje fibers : 20 - 40 per minute
RATE OF DISCHARGE OF SA NODE AND AV NODAL TISSUE:
-Influenced by temperature and by drugs.
-The discharge frequency is increased when the temperature rises- this may contribute to
the tachycardia associated with fever
-Digitalis depresses nodal tissue and exerts an effect like that of vagal stimulation,
particularly on the AV node.

USES OF DIGITALIS DIGITALIS:

● It can strengthen contractions through digitalis inhibitory effects on the Na
, K ATPase, resulting in greater amounts of Ca 2+ release and subsequent
changes in contraction forces.
● Digitalis can also have an electrical effect in decreasing AV nodal
conduction velocity and thus altering AV transmission to the ventricles.
● Digitalis has been used for treatment of systolic heart failure.
● It augments contractility, thereby improving cardiac output, improving left
ventricle emptying, and decreasing ventricular filling pressures.
● Digitalis has also been used to treat atrial fibrillation and atrial flutter. In
this scenario, digitalis reduces the number of impulses transmitted through
the AV node and thus, provides effective rate control.

RATE OF IMPULSE CONDUCTION:

-Both atria get depolarised at 0.1 sec
-SAN to AVN in 0.03 sec
-AVN delay 0.1sec

38
-His bundle of Purkinje in 0.03 sec
-To reach endocardium and epicardium of ventricles:0.03 sec

CONDUCTION SPEEDS IN CARDIAC TISSUE:

● SA node 0.05m/s
● Atrial pathways 1m/s
● AV node 0.05m/s
● Bundle of His 1m/s
● Purkinje system 4m/s
● Ventricular muscle 1m/s

PROPERTIES OF CARDIAC MUSCLE

a. Morphological properties
b. Electrical properties
c. Mechanical properties
d. Metabolic properties

❖ Morphological
1. General features
2. Light microscopic
appearance
3. Electronic microscopic
appearance
4. Sarcotubular system

39
 ❖ Electrical
1. Auto rhythmicity: pacemaker potential produced by conducting system of heart
2. Excitability
● RMP for cardiac muscle is -90mV.
● Ability of cardiac
muscle to respond to different stimuli.
● Process of eliciting an action potential .
3. Conductivity:
● Generated impulse is conducted within the cardiac muscle .
● Specialized conducting pathway

❖ Mechanical
1. Contractility:
Ventricular contraction → pumps blood into the circulation
﹡ Increased contractility increases cardiac output
﹡ Decreased contractility decreases cardiac output.
2. All or none law:
Definition :- Magnitude of response of a tissue to stimuli remains same irrespective of
the strength of stimuli, only when conditions remain the same.
3. Staircase phenomenon:
Gradual increase in height of tracings for first four contractions, remains the same for
subsequent contractions.
4. Summation of subliminal stimuli:
﹡ Series of successive stimuli are applied at a rapid rate→contractile response is elicited
﹡ Series of stimuli local responses add up and propagate an AP→ contractile response

40
5.LengthTensionRelationship:

6. Frequency Force Relationship:

*Bowditch Phenomenon
*Increased heart rate (frequency)➡️Increased FOC➡️Frequency force relationship

7. Load-Velocity Relationship:
﹡ The velocity of muscle contraction varies inversely with the load on the muscle.
﹡ At a given load, the velocity is maximal at the resting length and declines if the
muscle is shorter or longer than this length.

8. Distensibility:
﹡ Ability to stretch
﹡ Helps with adequate filling of all the chambers
﹡ Decrease ventricular distensibility in cardiomyopathy, infiltrative diseases – decreases
end diastolic volume → decreases stroke volume

9. Long refractory Period:

Refractory Period:Period of response to the first stimulus during which second stimulus
will not produce a response
TYPES:
1.Absolute.

41
2.Relative

❖ Metabolic
1. Abundant blood supply:
● Blood flow through the myocardium is high – 80mL/100gm/ min
﹡ Skeletal muscle blood flow is 3mL/100gm/ min
2. Abundant mitochondria:
● Presence of numerous mitochondria in cardiac muscle fibers
3. High myoglobin:
● O2 storing muscle pigment - myoglobin is in high content
4. Aerobic conditions:
● Heart works under complete aerobic condition with essentially no accumulation
of lactic acid

42
 SHOCK
DEFINITION:
Shock is defined as a syndrome where there is inadequate tissue perfusion related to a decrease
in the cardiac output.

TYPES OF SHOCK:
Shock is broadly classified into 4 classes depending on the mechanism that causes a decrease in
cardiac output.

43
HYPOVOLEMIC SHOCK:
It is the most common type of shock
Hemorrhagic shock is the most common type of hypovolemic shock

CAUSES: acute hemorrhage of more than 15 ml/kg body weight results in shock.
FEATURES:

🡺 Hypotension

🡺 Tachycardia

🡺 Rapid and thready pulse

🡺 Cold and pale skin (cold shock)
🡺 Tachypnea

🡺 Intense thirst

🡺 Restlessness

🡺 Patient is conscious

STAGES OF SHOCK:
REVERSIBLE STAGE:
There is activation of compensatory mechanisms. They are further divided into short- term
and long- term mechanisms.
Rapid compensatory mechanisms:
● They are primarily neural and vascular.
● This is mainly due to the sympathetic stimulation
● Tachycardia and vasoconstriction: occur due to stimulation of baroreceptors that
increases the heart rate
🡺 There is redirection of blood from the cutaneous beds to the vital organs like
the brain and the heart, the skin becomes pale: cold shock.
🡺 In kidney, there is renal vasoconstriction🡪 constriction of afferent more than
efferent🡪 decreases GFR🡪 accumulation of waste products (azotemia)
● Increased venous return: occurs due to sympathetic stimulation

44
 ● Increased thoracic pumping: stimulated hyperventilation🡪 contraction of diaphragm🡪
increases venous return.
● Increased skeletal muscle pumping: restless subject🡪increases skeletal muscle
pumping🡪 increases venous return
● Capillary fluid shift: decrease in body blood volume🡪 decrease in capillary hydrostatic
pressure🡪 reversal of pressure gradient🡪 shift of fluids from interstitial tissue to
capillaries🡪 increases venous return
● Activation of chemoreceptor reflex: hypoxia due to decreased perfusion🡪 stimulation
of chemoreceptors🡪 respiratory centre stimulation🡪 hyperventilation
● Activation of Cushing reflex: cerebral hypoxia due to persistent hypotension🡪
stimulation of vasomotor centre🡪 intense vasoconstriction
● Increased secretion of catecholamines: catecholamines cause vasoconstriction and
stimulate the reticular activating system that maintains the wakefulness of the person.
● Increased cortisol secretion: increases responsiveness of blood vessels to adrenaline
● Activation of renin- angiotensin system:

🡺 Angiotensin: potent vasoconstrictor

🡺 Aldosterone: causes sodium and water retention

🡺 ADH: decreases diuresis

🡺 Stimulates dipsogenesis: increases drinking

Long term compensatory mechanisms:

● Increased synthesis of erythropoietin: increases red cell production within 48 hours
● Increased plasma protein synthesis: increases hemoglobin synthesis

45
IRREVERSIBLE STAGE:
Refractory shock:

🡺 There is initial precapillary sphincter constriction that decreases the blood

flow to the viscera
🡺 There is hypoxic tissue damage

🡺 In the long term, there is dilation of precapillary sphincters but there is

venule constriction.
🡺 This causes further decrease in blood flow leading to transudation of fluid.

🡺 Bacteria can also enter the circulation🡪 release endotoxins🡪 bacteremia and
septicemia
🡺 There is medullary depression that causes a decline in the blood pressure that
further decreases myocardial function.
🡺 Disseminated intravascular coagulation (DIC) and pulmonary embolism
are seen🡪 acute respiratory distress syndrome🡪 shock lung

TREATMENT OF SHOCK:
Blood transfusion: required in hemorrhagic shock to increase blood volume
Plasma transfusion: needed in burn shock, high molecular weight dextran can also be used.
Epinephrine: used in anaphylactic shock by causing vasoconstriction
Dopamine: the drug of choice
🡺 Produces renal vasodilation
🡺 Positive inotropic effect on heart
🡺 Causes vasoconstriction in systemic blood vessels
Note: body must not be covered in shock as it causes increase in skin temperature that
causes cutaneous vasodilation and exacerbates shock.

46
 ECG LEADS
A lead is a connection between any two selected points on the surface of the body and the
electrocardiograph. About 12 different leads are used routinely.
● These are divided into twoTypes: 1.Bipolar
2.Unipolar

1. Bipolar leads: There are 3 different leads. These are LI, LIIand LIII. Each lead
consists of two electrodes both are exploring electrodes, one +ve and another -ve.

a) Lead I measures the potential difference (PD) between the right and left arms with the
left arm +ve and right arm-ve.

b) Lead II measures the PD between the left foot and the right arm with left foot +ve and
right arm-ve.

c) Lead III measures the PD between the left foot and the left arm with the left foot +ve
and left arm-ve.
According to the Einthoven's law, LI+LII+LIII=0.

48
 Einthoven's law:
It states that in a volume conductor the sum of the electrical potentials at the three peripheral
points of an equilateral triangle with the current source in the centre is zero. As applicable to
the body, which acts as a 2 volume conductor the heart is the current source and the
equilateral triangle is formed by the junction of right upper extremity with the trunk, left
upper extremity with the trunk and the junction of left lower limb with the trunk. This is
called Einthoven's triangle. But LII is deliberately reversed to get positive waves.
Hence,LI+LIII-LII (or) LI+LIII-LII=0
Lead I mainly records the activities from the superior aspects of the heart, lead II mainly
from the right aspect of the heart, and lead III the left ventricular events mainly.

2. Unipolar leads: There are three types of unipolar leads.

These are:
a) Classical unipolar leads,
b) Augumented limb leads,
c)Unipolar chest leads.
In the above leads there are two electrodes,
one - active electrode - exploring electrode
the other one -indifferent electrode. (The indifferent electrode is formed by joining the three
peripheral points of Einthoven's triangle through 5000 ohms each. This is called Wilson's
terminal (V) or Wilson's common electrode.)
a) Classical unipolar leads:
● There are three leads.
● These are:
(i)VR, (ii) VL and (iii) VF.
● V stands for Wilsons terminal.
● R ,L and F stand for exploring electrodes kept on right arm, left arm and left foot
correspondingly.
● These leads were discarded because of the low voltage ECG complexes.

b) Augmented limb leads:

● These are developed by Goldberger and are not typical unipolar leads.
● These are aVR, aVL, and aVF.
● In each case, the common electrode is obtained by joining the two points
through 5000 ohms each.
● The exploring electrode is kept at the third point.

49
 ◇ aVR-PD between right arm and leftarm + Left foot.
◇ aVL-PD between left arm and right arm+ Left foot.
◇ aVF PD between left foot and right arm + Left arm .
The limb leads reflect the electrical activity of the heart in frontal plane.

c) Unipolar chest leads:

● Six chest leads V1-V6 are used routinely.
● The indifferent electrode is formed by Wilson’s common electrode.
● Active electrode is kept at any one of the six points on the precardium (V, to V).
These reflect electrical activity of the heart in the horizontal plane.
☆V1 -4th right intercostal space near sternum - Mainly right ventricular activity is recorded.
☆V2 -4th left intercostal space near the sternum
☆ V3-Midway between V2, & V4 -Mainly interventricular septal activity is recorded.
☆ V4 -5 th left intercostal space in the midclavicular line.
☆ V5 -5th left intercostal space in anterior axillary line - Mainly left ventricular activity is
recorded
☆ V6-5th left intercostal space in mid axillary line.

CLINICAL APPLICATIONS OF ECG:

It is very useful in the diagnosis, assessment of the prognosis and management of the following
conditions:
1. Myocardial infarction and ischaemia
2. Cardiac arrhythmias
3. Electrolyte imbalance
4. Myocarditis and cardiomyopathies
5. Endocrine disorders
6. Assessment of toxic effects of drugs acting on the hear
7. Conduction defects
8. Chamber hypertrophy

Cardiac monitoring: A continuous reccording of ECG is obtained by using a CRO during:

1. Cardiac surgery
2. Thoracic surgery

50
 3. In treatment of cardiac arrhythmias
4. Acute myocardial infarction
5. Postoperative intensive care
6. All emergencies

ELECTROCARDIOGRAPHIC CHANGES IN CLINICAL CONDITIONS:

1. In myocardial infarction:
● In acute myocardial infarction there is elevation of the ST segment in the leads
overlying the area of infarction.
● Leads on the opposite side of the infarction show ST segment depression. This is
due to the current flow toward electrodes over the injured area causing an
elevation of ST segment.

51
 2 .In myocardial ischaemia: ST-T changes take place. There is ST depression with "T"
inversion either in resting or after exercise.

3.In hyperkalaemia and hypokalemia: Both hyperkalaemia and hypokalaemia have

deleterious effects on the heart. Both of them bring about changes in ECG
4 .Hypokalaemia:
a) ST depression.
b) Flattened or inverted T wave
c) Prominent 'U' wave are seen.

52
5 .Hyperkalaemia: Since K efflux is responsible for repolarization, an increase in K-level in the
ECF makes the repolarization forces stronger. Hence , T wave representing repolarisation
becomes stronger.

6.Hypercalcaemia: Since calcium participates in development of pacemaker potential,

excitation-contraction coupling and myocardial contraction, hypercalcaemia facilitates all these
processes. This is reflected in ECG as shortened QT interval.

53
 FRANK STARLING’S LAW

● “The force of contraction is directly proportional to the initial length of the muscle fiber,
within the physiological limit.”
● Increase in End Diastolic Volume/pressure, increases Stroke volume

UNDERLYING PRINCIPLE

● Length-Tension relationship in cardiac muscle fibres

● Initially, as the End Diastolic Pressure [EDP] increases, the Stroke volume also increases.
● But after a point, if EDP increases, Stroke volume remains same i.e. it reached a plateau
phase.

54
CLINICAL SIGNIFICANCE

● In case of sympathetic stimulation [increased demand] , for example during exercise,

Peripheral Vascular Resistance decreases, Heart rate increases and Ionotropic effect
increases.
● The curve is shifted to left.

● In case of decreased demand [e.g. - hypoxia, acidosis etc], Heart rate and myocardial
contractility decreases and the curve shifts to the Right

55
Modification of Frank starling law by Inotropic factors:

56
 HEART SOUNDS

● S1 - ‘lub’ due to closure of av valves ; duration- 0.14 s ; occurs at beginning of systole

● S2 - ‘dub’ due to closure of semilunar valves ; duration- 0.11s ; occurs at end of systole
● S2 includes A2 - closure of aortic valve and P2 - closure of pulmonary valve
● S3 - due to rapid ventricular filling ( ventricular gallop ) Ventricles are overly compliant
; duration- 0.04 seconds; occurs at middle third of diastole ie.just after S2 ; suggestive of
systolic heart failure ( normal in pregnant women and athlete )
● S4 – due to forceful atrial contraction against stiff ventricles ( atrial gallop ) Ventricles
are non compliant; occurs just before S1 ; suggestive of hypertension, ischemic heart
disease
● Note- S4 is always abnormal
● AREAS OF AUSCULTATION
1. Aortic area- 2nd Rt ICS
2. Pulmonary area- 2nd Lt ICS
3. Tricuspid area – 4th Lt ICS
4. Mitral area – Lt 5th ICS – midclavicular line
● MURMUR – Abnormal heart sounds
● Cause- stenosis ( narrowing of valves) and regurgitation ( backward flow of blood due to
improper closure of valves)
● 1.Mid systolic murmur – Aortic stenosis
2. Early diastolic murmur– aortic regurgitation
3. Pansystolic murmur – mitral regurgitation
4. Mid diastolic murmur – mitral stenosis

57
 CEREBRAL BLOOD FLOW

● CIRCLE OF WILLIS Brain is supplied by 2 internal carotid arteries and 2 vertebral

arteries ( forms basilar artery)
●
● Cerebral blood flow is 750 ml/ min or 50-60 ml/ min/ 100 g
● CPP = MAP- ICP
( Cerebral perfusion pressure= Mean arterial pressure – intracranial pressure)
● Factors affecting cerebral blood flow

58
 1) PCO2
2) PO2
3) H+ ion concentration
4) Substances from astrocytes
Slight Fall in PO2- causes vasodilation- increases cerebral blood flow
Moderate- severe fall in PO2- vasoconstriction – decreases cerebral blood flow
Increase in PCO2 – vasodilation – increase cerebral blood flow

AUTOREGULATION
● Autoregulation of cerebral blood flow occurs between arterial pressures 60-140 mmHg
● When arterial pressure <60 mmHg – cerebral blood flow decreases
● When arterial pressure rises – role of sympathetic system – vasoconstriction- decreases
cerebral blood flow. This prevents hemorrhage and stroke

59
 TRIPLE RESPONSE
● When the skin is stroked firmly with a pointed object, the response to the injury manifests
as triple response.
● Triple response is a three-part response, consisting of the red reaction, wheal and flare.

RED REACTION :
● Red line which appears at the site of injury in about 10 seconds.
● Dilation of the precapillary sphincters is produced by histamine,bradykinin released from
the damaged skin.
● Pressure is also responsible for dilation of capillaries.
● Anaesthesia of the skin does not prevent the red reaction because it is not mediated by the
nervous system.

WHEAL :
● The swelling (local edema) is called wheal.
● Occurs within a few minutes following red reaction.
● Occurs due to increased capillary permeability with consequent extravasation of fluid
mediated by histamine,Substance P,CGRP
FLARE :
● Diffusely spreading and irregularly outlined redness of the skin surrounding the red line
that occurs after a few minutes of the appearance of red line.
● Occurs due to the dilation of the arterioles and precapillary sphincters.
● Dilation of the arteriole increases local blood flow.
● Arteriolar dilation occurs by activation of Axon reflex ( an example of antidromic
conduction of the impulse):
From the site of injury, the impulse is conducted in the afferent fibers ---->
sensory neurons give branches to the blood vessels ---> impulse is also relayed
antidromically to the blood vessels---> endings of sensory fibers on the blood vessels release
substance P and CGRP that produce arteriolar dilation.
Dermatographia refers to striking triple response that occurs as an unusual reaction in some
individuals probably due to excessive release of the histamine from the involved skin area.

60
 FETAL CIRCULATION
● Circulation in fetus (before birth)
● Differs significantly from circulation in postnatal life.
● Fetal lungs are functionally inactive and the fetus derives oxygen and nutrients from the
placenta.

PATTERN OF CIRCULATION :
Fetus receives blood supply from the placenta through umbilical veins which are only 80%
saturated with oxygen as the placenta has extracted some of its oxygen.

SPECIAL FEATURES :

● Right ventricle pumps blood into pulmonary artery against higher resistance as the
pulmonary vascular resistance is very high.
● Most part of the right ventricular output enters directly into the aorta through ductus
arteriosus.
● The right ventricle receives blood from the placenta and pumps into the aorta from where
about 60% of the blood goes to the placenta for oxygenation and only 40% is distributed
to the different parts of the body.This occurs because peripheral resistance of the fetal
vessels is high.
● About 50% of the blood from the right atrium directly enters into the left atrium via
foramen ovale.
● Oxygen saturation of the fetal arterial blood is much lower than that of the
adults.However fetal tissues are highly resistant to the effect of hypoxia. The fetal
hemoglobin also has higher affinity to the oxygen.

61
 CHANGES AT BIRTH :
● Closure of the umbilical vessel ceases blood flow through the umbilical veins.This results
in the closure of ductus venosus.
● Clamping of umbilical vessels immediately after birth causes asphyxia that activates the
respiratory center. Respiratory signal is generated. This results in expansion of the lungs.
As the lung fills with air, the pulmonary vascular resistance decreases significantly.
● Closure of the umbilical vessels increases the total peripheral resistance and blood
pressure. The left atrial reserve is raised above the volume of blood present in inferior
vena cava and right atrium.
● Pulmonary arterial pressure decreases significantly due to decreased pulmonary vascular
resistance. This along with increased aortic pressure reverses the flow of blood through
the ductus arteriosus.
● Constriction of ductus arteriosus begins within a few minutes and is completely closed
within 1–2 days after birth.
● Before birth, the thickness of both ventricles is equal.After birth, thickness of the right
ventricular wall decreases, whereas left ventricular thickness increases.

CLINICAL ASPECTS :
● Atrial septal defect (patent foramen ovale) : Opening between the two atria (foramen
ovale) does not close after birth. Oxygen supply decreases to the tissues due to left to
right shunt.
● Patent ductus arteriosus : Failure of the closure of ductus arteriosus results in flow of
blood from the aorta to the pulmonary artery, as the pressure in the aorta is more. Also an
example of left to right shunt. Oxygenation of the tissues of the body decreases in this
condition.
● Tetralogy of Fallot : Consists of four cardiovascular defects namely Ventricular septal
defect, Pulmonary stenosis, Right ventricular hypertrophy, and Overriding of the aorta.
Oxygenation of blood is grossly reduced. Therefore, tissues suffer from severe hypoxia,
and cyanosis develops.

62
 PACEMAKER POTENTIAL
● Pacemaker of the heart (SA node) discharges rhythmically and automatically.
● Automaticity is possible due to spontaneous diastolic depolarization of the membrane
potential following completion of each action potential.
● Resting (diastolic) membrane potential that depolarizes is called the prepotential as it
brings the membrane potential to the threshold level, which then triggers the action
potential. The prepotential is known as pacemaker potential.

IONIC BASIS :

❖ In the Initial Part :

● Repolarization is due to efflux of potassium ions.
● At the peak of each action potential, potassium conductance (Ik) begins.
● Towards the end of repolarization, the Ik declines (potassium decay).
● At this moment,“f” channels or funny channels open (If or Ih current) and Ih
increases. (Funny current)
● These events allow the membrane to depolarize.
❖ In the Later Part :
● The later part of pacemaker potential due to the opening of transient calcium
channels.
● The entry of calcium through the T-channels completes the pacemaker potential
and takes the membrane potential to the threshold level, which then fires to form
the action potential.
● The upstroke of action potential occurs due to opening of the long-lasting
calcium channels.

63
OTHER IONS :
● Calcium sparks (release of calcium locally from sarcoplasmic reticulum) also contribute
to the pacemaker potential.
● Pacemaker potential is largely due to decay of the potassium efflux and Ih (the initial
part), and influx of calcium (the later part).
● Contribution of sodium ion is linked to the Ih.

● In pacemaking tissues there is no resting membrane potential, rather the pacemaker

potential is the restless membrane potential.
● Pacemaker potential can also be produced by AV node and other tissues of the heart
(latent pacemakers) when SA node fails to generate impulse adequately.
● The rate of impulse generation depends on the slope of pacemaker potential.

Sympathetic Stimulation :
Sympathetic stimulation makes the slope steeper and increases the heart rate.
Norepinephrine binds to beta 1 receptors, which increases the intracellular cAMP that in turn
increases the opening of calcium channels.
Parasympathetic Stimulation :
Parasympathetic stimulation makes the slope flat and decreases the heart rate.Ach
acts on M2 muscarinic receptors. This ultimately counters the decay of K+,decreases the
concentration of cyclic AMP and calcium influx hence decreases the force of contraction.
However, vagal stimulation mainly affects the rate rather than the force of contraction, because
ventricles have sparse vagal innervation.

64
 CORONARY CIRCULATION
● It refers to the blood flow to the heart.
● About 250ml/min flows through the entire heart

SPECIAL FEATURES OF CORONARY CIRCULATION

● Heart is the only organ to generate its own perfusion pressure
● Coronary blood flow fluctuates during different phases of cardiac cycle. During
systole CBF is minimum and during diastole it is maximum.
● Regional variation: Left ventricle receives blood flow twice to that of right
ventricle. From endocardium to epicardium there is gradual increase in blood
flow.
● Coronary arteries are end arteries and do not show proper anastomosis. Abrupt
occlusion of a coronary artery leads to ischaemic necrosis (death) of the
myocardium supplied by the occluded vessel. However, if a coronary artery
narrows slowly over a period of days or weeks collateral vessels develop between
occluded and non-occluded arteries and provide sufficient blood to the ischaemic
myocardium and either relieve or reduce the extent of ischaemia.
● Myocardium depends largely on aerobic metabolism.
● The resting AV difference of O2 content is very high. Coefficient of O2 utilization
is 70% in myocardium while in other tissues it is only 25%.
● Metabolic factors (hypoxia) are important and more powerful and are responsible
for autoregulation of coronary blood flow. Neural factors are less important in
regulating the coronary blood flow.
● Capillary density per square millimetre is relatively more, i.e., 1:1.
● Blood flow through both the arteries is not same. Left coronary blood flow is
more and supply nearly 70-80% of myocardial mass.

DETERMINATION OF CORONARY BLOOD FLOW

Direct method: Flow metres are connected directly to coronary artires of experimental
animals and blood flow is estimated
Indirect method:
● Kety’s Method. Principle: amount of substance taken by an organ in a unit
time is equal to AV difference of its concentration times the blood flow
● Radionuclide’s utilization method
● Coronary angiography

65
DETERMINANTS OF CBF
1) Mean pressure in the aorta: CBF is directly proportional to Mean pressure in aorta
2) Coronary vascular resistance: vascular resistance depends on diameter of
coronary vessels. Auto regulatory mechanism in heart alter the CBF depending on
the need by altering the diameter of coronary vessels
3) Extra coronary vascular pressure: during systole CBF is reduced because of
throttling effect of contracting myocardium over the coronary vessels.
4) During diastole ventricles are relaxing and throttling effect is absent and hence
blood flow increases. This is called as phasic flow. Left CBF is affected more as
left ventricular myocardium is thicker and stronger. Right CBF is least affected as
right ventricular myocardium is thinner.
Phasic flow:
● During systole:
Isovolumetric contraction: left CBF is zero due to compression of
coronary vessels
Ejection phase:
Maximum ejection: increase in CBF due to maximum pressure in
the aorta
Reduced ejection: decrease in blood flow due to reduced pressure
gradient
● During diastole:
Proto diastole and isovolumetric relaxation: CBF reaches peak because of
maximum pressure gradient and absence of extra coronary vascular
pressure.
During rest of diastole: CBF remains at higher level

66
REGULATION OF CORONARY BLOOD FLOW
1. Auto regulation of coronary blood flow

Direct effect:
Decreased myocardial o2

Intracellular acidosis

Calcium binding less

Vascular smooth muscle relaxes

Increased diameter of coronary vessels

Increased CBF

Berne’s hypothesis:
Hypoxia

ATP converted to Adenosine

Vasodilation

Blood flow increases

No hypoxia

Adenosine wash off

Restoration of blood vessel diameter

2. Neural regulatory mechanism

Sympathetic nervous system: CBF decreases by stimulation of α receptor.

CBF increases by stimulation of β receptor

67
 Parasympathetic nervous system: does not influence

3. Hormonal regulation:

● Catecholamines: same as sympathetic

● Ach: same as para sympathetic
● Angiotensin: causes vasoconstriction and decreases blood flow
● Thyroxine: increases CBF
4. Myogenic mechanism

APPLIED ASPECT:
● Coronary thrombosis
● Myocardial Ischemia
● Myocardial infraction
● Angina pectoris

68
 CUSHING REFLEX (CNS ISCHAEMIC RESPONSE)

● Last ditch effort

Decrease in BP <40mm Hg / increase in intracranial pressure

Chemicals (hypoxia, asphyxia, hypercapnia, acidosis)

Direct effect

Vasomotor centre

Sympathetic nerve fibres

Vasoconstriction

Increased BP

69
 BARORECEPTOR REFLEX
Baroreceptor reflex regulates blood pressure within seconds. It is the most important reflex
mechanism involved in short term regulation of blood pressure.
It is also called as Sinoaortic reflex.

70
Pressure range for baroreflex regulation:

Physiological significance of baroreceptor reflex:

● It is the first and foremost reflex for regulation of blood pressure which operates within a
few seconds to correct it.
● It regulates blood pressure when pressure change is within the range of 500 to 200
mmHg. Hence it constitutes a feedback mechanism to stabilize blood pressure over a
wide range of fluctuation in pressure.
● Baroreceptor reflex explains the physiological basis for Marey's law which states that
they heart rate is inversely proportional to the blood pressure but not the vice versa.
● Baroreceptor resetting occurs in chronic hypertension.

71
 JVP AND ITS SIGNIFICANCE

-Atrial pressure is directly transmitted to Internal Jugular Pressure hence JVP is indirect
estimation of atrial pressure.
-It has three positive (a, c, v) and two negative waves (x,y).
a wave:
-It is due to atrial systole. Pressure in the jugular vein also increases as some blood regurgitates
during atrial systole.
c wave:
-It is due to bulging of the tricuspid valve into right atrium during isovolumetric contraction.
x wave:
- It is the 1st negative wave.
- It is caused by a fall of right atrial pressure due to relaxation of the right atrium.
v wave:
-It is due to passive increase in pressure in right atrium due to venous return while the tricuspid
valve remains closed.
y wave:
-Due to emptying of atria as tricuspid valve opens.

CLINICAL SIGNIFICANCE:

72