৪৮তম বিশেষ বিসিএস [স্বাস্থ্য] ⎯ মেডিকেল অংশ [Archived]

„ CHEMICAL MECHANISM
Chemical mechanism of regulation of respiration is
operated through the chemoreceptors. Chemoreceptors
are the sensory nerve endings, which give response to
changes in chemical constituents of blood.
Changes in Chemical Constituents of
Blood which Stimulate Chemoreceptors
1. Hypoxia (decreased pO2
)
2. Hypercapnea (increased pCO2
)
3. Increased hydrogen ion concentration.
Types of Chemoreceptors
Chemoreceptors are classified into two groups:
1. Central chemoreceptors
2. Peripheral chemoreceptors.
„ CENTRAL CHEMORECEPTORS
Central chemoreceptors are the chemoreceptors
present in the brain.
Situation
Central chemoreceptors are situated in deeper part of
medulla oblongata, close to the dorsal respiratory group
of neurons. This area is known as chemosensitive
area and the neurons are called chemoreceptors.
Chemo receptors are in close contact with blood and
cerebrospinal fluid.Mechanism of Action
Central chemoreceptors are connected with respiratory
centers, particularly the dorsal respiratory group of
neurons through synapses. These chemoreceptors
act slowly but effectively. Central chemoreceptors are
responsible for 70% to 80% of increased ventilation
through chemical regulatory mechanism.
Main stimulant for central chemoreceptors is the
increased hydrogen ion concentration. However, if
hydrogen ion concentration increases in the blood, it
cannot stimulate the central chemoreceptors because,
the hydrogen ions from blood cannot cross the bloodbrain barrier and blood-cerebrospinal fluid barrier.
On the other hand, if carbon dioxide increases in
the blood, it can easily cross the blood-brain barrier and
blood­cerebrospinal fluid barrier and enter the interstitial
fluid of brain or the cerebrospinal fluid. There, the carbon
dioxide combines with water to form carbonic acid. Since
carbonic acid is unstable, it immediately dissociates into
hydrogen ion and bicarbonate ion (Fig. 126.4).
CO2
+ H2
O → H2
CO3 → H+ + HCO3
–
Hydrogen ions stimulate the central chemoreceptors.
From chemoreceptors, the excitatory impulses are
sent to dorsal respiratory group of neurons, resulting
in increased ventilation (increased rate and force of
breathing). Because of this, excess carbon dioxide is
washed out and respiration is brought back to normal.
Lack of oxygen does not have significant effect on
the central chemoreceptors, except that it generally
depresses the overall function of brain.
„ PERIPHERAL CHEMORECEPTORS
Peripheral chemoreceptors are the chemoreceptors
present in carotid and aortic region. Refer Chapter 101
for details.
Mechanism of Action
Hypoxia is the most potent stimulant for peripheral
chemoreceptors. It is because of the presence ofoxygen sensitive potassium channels in the glomus
cells of peripheral chemoreceptors.
Hypoxia causes closure of oxygen sensitive
potassium channels and prevents potassium efflux.
This leads to depolarization of glomus cells (receptor
potential) and generation of action potentials in nerve
ending.
These impulses pass through aortic and Hering
nerves and excite the dorsal group of neurons. Dorsal
group of neurons in turn, send excitatory impulses to
respiratory muscles, resulting in increased ventilation.
This provides enough oxygen and rectifies the lack of
oxygen.
In addition to hypoxia, peripheral chemoreceptors
are also stimulated by hypercapnea and increased
hydrogen ion concentration. However, the sensitivity
of peripheral chemoreceptors to hypercapnea and
increased hydrogen ion concentration is mild.

„ INTRODUCTION
Respiration is a reflex process. But it can be controlled
voluntarily for a short period of about 40 seconds.
However, by practice, breathing can be withheld for
a long period. At the end of that period, the person is
forced to breathe.
Respiration is subjected to variation, even under
normal physiological conditions. For example, emotion
and exercise increase the rate and force of respiration. But the altered pattern of respiration is brought
back to normal, within a short time by some regulatory
mechanisms in the body.
Normally, quiet regular breathing occurs because
of two regulatory mechanisms:
1. Nervous or neural mechanism
2. Chemical mechanism.
„ NERVOUS MECHANISM
Nervous mechanism that regulates the respiration
includes:
1. Respiratory centers
2. Afferent nerves
3. Efferent nerves
„ RESPIRATORY CENTERS
Respiratory centers are group of neurons, which
control the rate, rhythm and force of respiration. These
centers are bilaterally situated in reticular formation
of the brainstem (Fig. 126.1). Depending upon the
situation in brainstem, the respiratory centers are
classified into two groups:
A. Medullary centers consisting of
1. Dorsal respiratory group of neurons
2. Ventral respiratory group of neurons
B. Pontine centers
3. Apneustic center
4. Pneumotaxic center.

„ MEDULLARY CENTERS
1. Dorsal Respiratory Group of Neurons
Situation
Dorsal respiratory group of neurons are diffusely
situated in the nucleus of tractus solitarius which is
present in the upper part of the medulla oblongata (Fig.
126.1). Usually, these neurons are collectively called
inspiratory centerAll the neurons of dorsal respiratory group are
inspiratory neurons and generate inspiratory ramp by
the virtue of their autorhythmic property (Table 126.1).
Function
Dorsal group of neurons are responsible for basic
rhythm of respiration (see below for details). 2. Ventral Respiratory Group of Neurons
Situation
Ventral respiratory group of neurons are present in
nucleus ambiguous and nucleus retroambiguous.
These two nuclei are situated in the medulla oblongata,
anterior and lateral to the nucleus of tractus solitarius.
Earlier, the ventral group neurons were collectively
called expiratory center.
Ventral respiratory group has both inspiratory and
expiratory neurons. Inspiratory neurons are found in
the central area of the group. Expiratory neurons are
in the caudal and rostral areas of the group.
Function
Normally, ventral group neurons are inactive during
quiet breathing and become active during forced breathing. During forced breathing, these neurons stimulate
both inspiratory muscles and expiratory muscles.„ PONTINE CENTERS
3. Apneustic Center
Situation
Apneustic center is situated in the reticular formation of
lower pons.
Function
Apneustic center increases depth of inspiration by
acting directly on dorsal group neurons4. Pneumotaxic Center
Situation
Pneumotaxic center is situated in the dorsolateral part
of reticular formation in upper pons. It is formed by
neurons of medial parabrachial and subparabrachial
nuclei. Subparabrachial nucleus is also called ventral
parabrachial or Kölliker-Fuse nucleus.
Function
Primary function of pneumotaxic center is to control
the medullary respiratory centers, particularly the
dorsal group neurons. It acts through apneustic center.
Pneumotaxic center inhibits the apneustic center so
that the dorsal group neurons are inhibited. Because
of this, inspiration stops and expiration starts. Thus,
pneumotaxic center influences the switching between
inspiration and expiration.
Pneumotaxic center increases respiratory rate by
reducing the duration of inspiration.„ CONNECTIONS OF RESPIRATORY CENTERS
Efferent Pathway
Nerve fibers from respiratory centers leave the brainstem and descend in anterior part of lateral columns of
spinal cord.
These nerve fibers terminate on motor neurons
in the anterior horn cells of cervical and thoracic
segments of spinal cord. From motor neurons of spinal
cord, two sets of nerve fibers arise:
1. Phrenic nerve fibers (C3 to C5), which supply the
diaphragm
2. Intercostal nerve fibers (T1 to T11), which supply
the external intercostal muscles.
Vagus nerve also contains some efferent fibers
from the respiratory centers.
Afferent Pathway
Respiratory centers receive afferent impulses from:
1. Peripheral chemoreceptors and baroreceptors via
branches of glossopharyngeal and vagus nerves
2. Stretch receptors of lungs via vagus nerve.
By receiving afferent impulses from these receptors, respiratory centers modulate the movements of
thoracic cage and lungs through efferent nerve fibers.
„ INTEGRATION OF RESPIRATORY CENTERS
Role of Medullary Centers
Rhythmic discharge of inspiratory impulses
Dorsal respiratory group of neurons are responsible
for the normal rhythm of respiration. These neurons
maintain the normal rhythm of respiration by discharging
impulses (action potentials) rhythmically. These
impulses are transmitted to respiratory muscles by
phrenic and intercostal nerves.

„ HYPOXIA
„ DEFINITION
Hypoxia is defined as reduced availability of oxygen
to the tissues. The term anoxia refers to absence of
oxygen. In olden days, the term anoxia was in use.
Since there is no possibility for total absence of oxygen
in living conditions, use of this term is abandoned.
„ CLASSIFICATION AND CAUSES
OF HYPOXIA
Four important factors which leads to hypoxia are:
1. Oxygen tension in arterial blood
2. Oxygen carrying capacity of blood
3. Velocity of blood flow
4. Utilization of oxygen by the cellsOn the basis of above factors, hypoxia is classified
into four types:
1. Hypoxic hypoxia
2. Anemic hypoxia
3. Stagnant hypoxia
4. Histotoxic hypoxia.
Each type of hypoxia may be acute or chronic.
Simultaneously, two or more types of hypoxia may be
present.
1. Hypoxic Hypoxia
Hypoxic hypoxia means decreased oxygen content in
blood. It is also called arterial hypoxia.
Characteristic features of hypoxic hypoxia
Hypoxic hypoxia is characterized by reduced oxygen
tension in arterial blood. All other features remain normal (Table 127.1

2. Anemic Hypoxia
Anemic hypoxia is the condition characterized by the
inability of blood to carry enough amount of oxygen.
Oxygen availability is normal. But the blood is not able
to take up sufficient amount of oxygen due to anemic
conditionCharacteristic features of anemic hypoxia
Anemic hypoxia is characterized by decreased oxygen
carrying capacity of blood. All other features remain
normal (Table 127.1)


3. Stagnant Hypoxia
Stagnant hypoxia is the hypoxia caused by decreased
velocity of blood flow. It is otherwise called hypokinetic
hypoxiaCharacteristic features of stagnant hypoxia
Stagnant hypoxia is characterized by decreased velocity
of blood flow. All other features remain normal (Table
127.1)
4. Histotoxic Hypoxia
Histotoxic hypoxia is the type of hypoxia produced by
the inability of tissues to utilize oxygen.
Causes for histotoxic hypoxia
Histotoxic hypoxia occurs due to cyanide or sulfide
poisoning.cellular oxidative enzymes and there is a complete
paralysis of cytochrome oxidase system. So, even if
oxygen is supplied, the tissues are not in a position to
utilize it.
Characteristic features of histotoxic hypoxia
Histotoxic hypoxia is characterized by inability of
tissues to utilize oxygen even if it is delivered. All other
features remain normal (Table 127.1)

Efficacy of Oxygen Therapy in Different
Types of Hypoxia
Oxygen therapy is the best treatment for hypoxia. But it
is not effective equally in all types of hypoxia. Value of
oxygen therapy depends upon the type of hypoxia. So,
before deciding the oxygen therapy, one should recall
the physiological basis of different types of hypoxia.
In hypoxic hypoxia, the oxygen therapy is 100%
useful. In anemic hypoxia, oxygen therapy is moderately
effective to about 70%. In stagnant hypoxia, the
effectiveness of oxygen therapy is less than 50%. In
histotoxic hypoxia, the oxygen therapy is not useful at
all. It is because, even if oxygen is delivered, the cells
cannot utilize oxygen.

„ DIGESTION OF CARBOHYDRATES
„ IN THE MOUTH
Enzymes involved in the digestion of carbohydrates
are known as amylolytic enzymes. The only amylolytic
enzyme present in saliva is the salivary amylase or
ptyalin .
„ IN THE STOMACH
Gastric juice contains a weak amylase, which plays a
minor role in digestion of carbohydrates.
„ IN THE INTESTINE
Amylolytic enzymes present in the small intestine are
derived from pancreatic juice and succus entericus
(Table 45.1).
Amylolytic Enzyme in Pancreatic Juice
Pancreatic juice contains pancreatic amylase .
Amylolytic Enzymes in Succus Entericus
Amylolytic enzymes present in succus entericus are
maltase, sucrase, lactase, dextrinase and trehalase
.

„ FINAL PRODUCTS OF
CARBOHYDRATE DIGESTION
Final products of carbohydrate digestion are monosaccharides, which are glucose, fructose and galactose.Glucose represents 80% of the final product of carbohydrate digestion. Galactose and fructose represent the
remaining 20%.

„ ABSORPTION OF CARBOHYDRATES
Carbohydrates are absorbed from the small intestine
mainly as monosaccharides, viz. glucose, galactose
and fructose.
„ ABSORPTION OF GLUCOSE
Glucose is transported from the lumen of small intestine
into the epithelial cells in the mucus membrane of small
intestine, by means of sodium cotransport. Energy for
this is obtained by the binding process of sodium ion
and glucose molecule to carrier protein.
From the epithelial cell, glucose is absorbed into the
portal vein by facilitated diffusion. However, sodium ion
moves laterally into the intercellular space. From here, it
is transported into blood by active transport, utilizing the
energy liberated by breakdown of ATP.

„ ABSORPTION OF GALACTOSE
Galactose is also absorbed from the small intestine in
the same mechanism as that of glucose.

„ ABSORPTION OF FRUCTOSE
Fructose is absorbed into blood by means of facilitated
diffusion. Some molecules of fructose are converted
into glucose. Glucose is absorbed as described above.

„ VITAL CAPACITY
„ DEFINITION
Vital capacity is the maximum volume of air that can be
expelled out of lungs forcefully after a maximal or deep
inspiration.
„ LUNG VOLUMES INCLUDED
IN VITAL CAPACITY
Vital capacity includes inspiratory reserve volume, tidal
volume and expiratory reserve volume.

„ NORMAL VALUE
VC = IRV + TV + ERV
= 3,300 + 500 + 1,000 = 4,800 mL.

„ VARIATIONS OF VITAL CAPACITY
Physiological Variations
1. Sex: In females, vital capacity is less than in
males
2. Body built: Vital capacity is slightly more in
heavily built persons
3. Posture: Vital capacity is more in standing
position and less in lying position
4. Athletes: Vital capacity is more in athletes
5. Occupation: Vital capacity is decreased in
people with sedentary jobs. It is increased in
persons who play musical wind instruments
such as bugle and flute.

Pathological Variations

Vital capacity is decreased in the following respiratory
diseases:
1. Asthma
2. Emphysema
3. Weakness or paralysis of respiratory muscle
4. Pulmonary congestion
5. Pneumonia
6. Pneumothorax
7. Hemothorax
8. Pyothorax
9. Hydrothorax
10. Pulmonary edema
11. Pulmonary tuberculosis.

Measurement

Vital capacity is measured by spirometry. The subject is
asked to take a deep inspiration and expire forcefully.

„ FORCED VITAL CAPACITY

Forced vital capacity (FVC) is the volume of air that
can be exhaled forcefully and rapidly after a maximal or
deep inspiration. It is a dynamic lung capacity.
Normally FVC is equal to VC. However in some
pulmonary diseases, FVC is decreased


„ RESIDUAL VOLUME

Residual volume (RV) is the volume of air remaining in lungs even after forced expiration. Normally,
lungs cannot be emptied completely even by forceful
expiration. Some quantity of air always remains in the
lungs even after the forced expiration.Residual volume is significant because of two
reasons:
1. It helps to aerate the blood in between breathing
and during expiration
2. It maintains the contour of the lungs.
Normal Value
1,200 mL (1.2 L)


„ PEAK EXPIRATORY FLOW RATE
„ DEFINITION

Peak expiratory flow rate (PEFR) is the maximum rate
at which the air can be expired after a deep inspiration.

„ NORMAL VALUE
In normal persons, it is 400 L/minute.
„ MEASUREMENT

Peak expiratory flow rate is measured by using Wright
peak flow meter or a mini peak flow meter.

„ SIGNIFICANCE OF DETERMINING PEFR

Determination of PEFR rate is useful for assessing
the respiratory diseases especially to differentiate the
obstructive and restrictive diseases. Generally, PEFR
is reduced in all type of respiratory disease. However,
reduction is more significant in the obstructive diseases
than in the restrictive diseases.
Thus, in restrictive diseases, the PEFR is 200 L/minute and in obstructive diseases, it is only 100 L/min

Factors Affecting Oxygen-hemoglobin
Dissociation Curve
Oxygen-hemoglobin dissociation curve is shifted to left
or right by various factors:
1. Shift to left indicates acceptance (association) of
oxygen by hemoglobin
2. Shift to right indicates dissociation of oxygen from
hemoglobin.
1. Shift to right
Oxygen-hemoglobin dissociation curve is shifted to
right in the following conditions:
i. Decrease in partial pressure of oxygen
ii. Increase in partial pressure of carbon dioxide
(Bohr effect)
iii. Increase in hydrogen ion concentration and
decrease in pH (acidity)
iv. Increased body temperature
v. Excess of 2,3-diphosphoglycerate (DPG) in
RBC. It is also called 2,3-biphosphoglycerate
(BPG). DPG is a byproduct in Embden-Meyerhof pathway of carbohydrate metabolism. It
combines with β-chains of hemoglobin. In conditions like muscular exercise and in high attitude,
the DPG increases in RBC. So, the oxygenhemoglobin dissociation curve shifts to right to
a great extent.
2. Shift to left
Oxygen-hemoglobin dissociation curve is shifted to
left in the following conditions:
i. In fetal blood because, fetal hemoglobin has
got more affinity for oxygen than the adult
hemoglobin
ii. Decrease in hydrogen ion concentration and
increase in pH (alkalinity).

Bohr Effect
Bohr effect is the effect by which presence of carbon
dioxide decreases the affinity of hemoglobin for oxygen.
Bohr effect was postulated by Christian Bohr in 1904.
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 oxygendissociation 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.

„ DIGESTION OF LIPIDS
Lipids are digested by lipolytic enzymes.

„ IN THE MOUTH
Saliva contains lingual lipase. This enzyme is secreted
by lingual glands of mouth and swallowed along with
saliva. So, the lipid digestion does not commence in the
mouth.

„ IN THE STOMACH
Gastric lipase or tributyrase is the lipolytic enzyme
present in gastric juice .

„ IN THE INTESTINE
Almost all the lipids are digested in the small intestine
because of the availability of bile salts, pancreatic
lipolytic enzymes and intestinal lipase.

Role of Bile Salts:

Bile salts play an important role in the digestion of lipids.

Lipolytic Enzymes in Pancreatic Juice

Pancreatic lipase is the most important enzyme for the
digestion of fats. Other lipolytic enzymes of pancreatic
juice are cholesterol ester hydrolase, phospholipase A
and phospholipase B .

Lipolytic Enzyme in Succus Entericus
Intestinal lipase is the only lipolytic enzyme present in
succus entericus .

„ FINAL PRODUCTS OF FAT DIGESTION
Fatty acids, cholesterol and monoglycerides are the
final products of lipid digestion.

„ ABSORPTION OF LIPIDS
Monoglycerides, cholesterol and fatty acids from the
micelles enter the cells of intestinal mucosa by simple
diffusion.

From here, further transport occurs as follows:

1. In the mucosal cells, most of the monoglycerides
are converted into triglycerides. Triglycerides are
also formed by re-esterification of fatty acids with
more than 10 to 12 carbon atoms. Some of the
cholesterol is also esterifiedTriglycerides and cholesterol esters are coated with
a layer of protein, cholesterol and phospholipids to form
the particles called chylomicrons.
Chylomicrons cannot pass through the membrane
of the blood capillaries because of the larger size. So,
these lipid particles enter the lymph vessels and then
are transferred into blood from lymph.

2. Fatty acids containing less than 10 to 12 carbon
atoms enter the portal blood from mucosal cells and
are transported as free fatty acids or unesterified
fatty acids. Most of the fats are absorbed in the
upper part of small intestine. Presence of bile is
essential for fat absorption.

„ STORAGE OF LIPIDS
Lipids are stored in adipose tissue and liver. Fat stored
in adipose tissue is called neutral fat or tissue fat.
When chylomicrons are traveling through capillaries of
adipose tissue or liver, the enzyme called lipoprotein
lipase present in the capillary endothelium hydrolyzes
triglycerides of chylomicrons into free fatty acids (FFA)
and glycerol. FFA and glycerol enter the fat cells
(adipocytes or lipocytes) of the adipose tissue or liver
cells. Then, the FFA and glycerol are again converted
into triglycerides and stored in these cells. Other contents
of chylomicrons such as cholesterol and phospholipids,
which are released into the blood combine with proteins
to form lipoproteins.

„ CYANOSIS
„ DEFINITION

Cyanosis is defined as the diffused bluish coloration
of skin and mucus membrane. It is due to the presence
of large amount of reduced hemoglobin in the blood.
Quantity of reduced hemoglobin should be at least 5 to
7 g/dL in the blood to cause cyanosis.

„ DISTRIBUTION OF CYANOSIS
When it occurs, cyanosis is distributed all over the body.
But, it is more marked in certain regions where the skin
is thin. These areas are lips, cheeks, ear lobes, nose
and fingertips above the base of the nail.

„ CONDITIONS WHEN CYANOSIS OCCURS

1. Any condition which leads to arterial hypoxia and
stagnant hypoxia. Cyanosis does not occur in
anemic hypoxia because the hemoglobin content
itself is less. It does not occur in histotoxic hypoxia
because of tissue damage.

2. Conditions when altered hemoglobin is formed.
Due to poisoning, hemoglobin is altered into
methemoglobin or sulfhemoglobin, which causes
cyanosis. The cyanotic discoloration is due to the
dark color of these compounds only and not due to
reduced hemoglobin.

3. Conditions like polycythemia when blood flow is
slow. During polycythemia, because of increased
RBC count, the viscosity of blood is increased and it
leads to sluggishness of blood flow. So the quantity
of deoxygenated blood increases, which causes
bluish discoloration of skin

Hormonal Regulation of Protein Metabolism:

Growth Hormone Increases the Synthesis of Cellular
Proteins. Growth hormone causes the tissue proteins to
increase. The precise mechanism by which this occurs is not
known, but it is believed to result mainly from increased transport of amino acids through the cell membranes, acceleration of
the DNA and RNA transcription and translation processes for
protein synthesis, and decreased oxidation of tissue proteins.

Insulin Is Necessary for Protein Synthesis.
Total lack of insulin reduces protein synthesis to almost zero. Insulin
accelerates the transport of some amino acids into cells,
which could be the stimulus to protein synthesis. Also, insulin reduces protein degradation and increases the availability
of glucose to the cells, so the need for amino acids for energy
is correspondingly reduced.

Glucocorticoids Increase Breakdown of Most Tissue
Proteins.

The glucocorticoids secreted by the adrenal cortex decrease the quantity of protein in most tissues while
increasing the amino acid concentration in the plasma, as
well as increasing both liver proteins and plasma proteins.
It is believed that the glucocorticoids act by increasing the
rate of breakdown of extrahepatic proteins, thereby making
increased quantities of amino acids available in the body fluids. This allows the liver to synthesize increased quantities of
hepatic cellular proteins and plasma proteins.


Testosterone Increases Protein Deposition in Tissues.

Testosterone, the male sex hormone, causes increased deposition of protein in tissues throughout the body, especially
the contractile proteins of the muscles (30 to 50 percent
increase). The mechanism of this effect is unknown, but it is
definitely different from the effect of growth hormone, in the
following way: Growth hormone causes tissues to continue growing almost indefinitely, whereas testosterone causes the
muscles and, to a much lesser extent, some other protein tissues to enlarge for only several months. Once the muscles
and other protein tissues have reached a maximum, despite
continued administration of testosterone, further protein
deposition ceases.

Estrogen.

Estrogen, the principal female sex hormone,
also causes some deposition of protein, but its effect is relatively insignificant in comparison with that of testosterone.

Thyroxine.
Thyroxine increases the rate of metabolism
of all cells and, as a result, indirectly affects protein metabolism. If insufficient carbohydrates and fats are available for
energy, thyroxine causes rapid degradation of proteins and
uses them for energy. Conversely, if adequate quantities of
carbohydrates and fats are available and excess amino acids
are also available in the extracellular fluid, thyroxine can actually increase the rate of protein synthesis. In growing animals
or human beings, deficiency of thyroxine causes growth to
be greatly inhibited because of lack of protein synthesis. In
essence, it is believed that thyroxine has little specific effect
on protein metabolism but does have an important general
effect by increasing the rates of both normal anabolic and
normal catabolic protein reactions.

Hormonal Regulation of Fat Utilization. 
At least seven of the hormones secreted by the endocrine glands have significant effects on fat utilization. Some important hormonal
effects on fat metabolism—in addition to insulin lack, discussed in the previous paragraph—are noted here.

Probably the most dramatic increase that occurs in fat utilization is that observed during heavy exercise. This results
almost entirely from release of epinephrine and norepinephrine by the adrenal medullae during exercise, as a result of
sympathetic stimulation. These two hormones directly activate hormone-sensitive triglyceride lipase, which is present in
abundance in the fat cells, and this causes rapid breakdown
of triglycerides and mobilization of fatty acids. Sometimes
the free fatty acid concentration in the blood of an exercising person rises as much as eightfold, and the use of these
fatty acids by the muscles for energy is correspondingly
increased. Other types of stress that activate the sympathetic
nervous system can also increase fatty acid mobilization and
utilization in a similar manner.

Stress also causes large quantities of corticotropin to be
released by the anterior pituitary gland, and this causes the
adrenal cortex to secrete extra quantities of glucocorticoids.
Both corticotropin and glucocorticoids activate either the
same hormone-sensitive triglyceride lipase as that activated
by epinephrine and norepinephrine or a similar lipase. When
corticotropin and glucocorticoids are secreted in excessive
amounts for long periods, as occurs in the endocrine condition called Cushing’s syndrome, fats are frequently mobilized to such a great extent that ketosis results. Corticotropin
and glucocorticoids are then said to have a ketogenic effect.

Growth hormone has an effect similar to but weaker than that
of corticotropin and glucocorticoids in activating hormone sensitive lipase. Therefore, growth hormone can also have
a mild ketogenic effect.
Finally, thyroid hormone causes rapid mobilization of fat,
which is believed to result indirectly from an increased over all rate of energy metabolism in all cells of the body under the
influence of this hormone. The resulting reduction in acetylCoA and other intermediates of both fat and carbohydrate
metabolism in the cells is a stimulus to fat mobilization.

„ TRANSPORT OF CARBON DIOXIDE
Carbon dioxide is transported by the blood from cells
to the alveoli.
Carbon dioxide is transported in the blood in four
ways:
1. As dissolved form (7%)
2. As carbonic acid (negligible)
3. As bicarbonate (63%)
4. As carbamino compounds (30%).
„ AS DISSOLVED FORM
Carbon dioxide diffuses into blood and dissolves in the
fluid of plasma forming a simple solution. Only about
3 mL/100 mL of plasma of carbon dioxide is transported
as dissolved state. It is about 7% of total carbon
dioxide in the blood.
„ AS CARBONIC ACID
Part of dissolved carbon dioxide in plasma combines
with the water to form carbonic acid. Transport of
carbon dioxide in this form is negligible.
„ AS BICARBONATE
About 63% of carbon dioxide is transported as bicarbonate. From plasma, carbon dioxide enters the
RBCs. In the RBCs, carbon dioxide combines with
water to form carbonic acid. The reaction inside RBCs
is very rapid because of the presence of carbonic
anhydrase. This enzyme accelerates the reaction.
Carbonic anhydrase is present only inside the RBCs
and not in plasma. That is why carbonic acid formation
is at least 200 to 300 times more in RBCs than in
plasma.
Carbonic acid is very unstable. Almost all carbonic
acid (99.9%) formed in red blood corpuscles, dissociates
into bicarbonate and hydrogen ions. Concentration of
bicarbonate ions in the cell increases more and more.
Due to high concentration, bicarbonate ions diffuse
through the cell membrane into plasma.
714 Section 9 t Respiratory System and Environmental Physiology
Chloride Shift or Hamburger Phenomenon
Chloride shift or Hamburger phenomenon is the exchange of a chloride ion for a bicarbonate ion across
RBC membrane. It was discovered by Hartog Jakob
Hamburger in 1892.
Chloride shift occurs when carbon dioxide enters the
blood from tissues. In plasma, plenty of sodium chloride
is present. It dissociates into sodium and chloride ions
(Fig. 125.2). When the negatively charged bicarbonate
ions move out of RBC into the plasma, the negatively
charged chloride ions move into the RBC in order to
maintain the electrolyte equilibrium (ionic balance).
Anion exchanger 1 (band 3 protein), which acts
like antiport pump in RBC membrane is responsible
for the exchange of bicarbonate ions and chloride
ions. Bicarbonate ions combine with sodium ions in
the plasma and form sodium bicarbonate. In this form,
it is transported in the blood.
Hydrogen ions dissociated from carbonic acid are
buffered by hemoglobin inside the cell.
Reverse Chloride Shift
Reverse chloride shift is the process by which chloride
ions are moved back into plasma from RBC shift. It
occurs in lungs. It helps in elimination of carbon
dioxide from the blood. Bicarbonate is converted back
into carbon dioxide, which has to be expelled out. It
takes place by the following mechanism:
When blood reaches the alveoli, sodium bicarbonate in plasma dissociates into sodium and bicarbonate
ions. Bicarbonate ion moves into the RBC. It makes
chloride ion to move out of the RBC into the plasma, where
it combines with sodium and forms sodium chloride.
Bicarbonate ion inside the RBC combines with
hydrogen ion forms carbonic acid, which dissociates
into water and carbon dioxide. Carbon dioxide is then
expelled out.


Haldane Effect
Haldane effect is the effect by which combination of
oxygen with hemoglobin displaces carbon dioxide from
hemoglobin. It was first described by John Scott Haldane
in 1860. Excess of oxygen content in blood causes shift
of the carbon dioxide dissociation curve to right.
Causes for Haldane effect
Due to the combination with oxygen, hemoglobin becomes strongly acidic. It causes displacement of carbon dioxide from hemoglobin in two ways:

1. Highly acidic hemoglobin has low tendency to
combine with carbon dioxide. So, carbon dioxide is
displaced from blood.
2. Because of the acidity, hydrogen ions are released
in excess. Hydrogen ions bind with bicarbonate
ions to form carbonic acid. Carbonic acid in turn
dissociates into water and carbon dioxide. Carbon
dioxide is released from blood into alveoli.
Significance of Haldane effect
Haldane effect is essential for:
1. Release of carbon dioxide from blood into the
alveoli of lungs
2. Uptake of oxygen by the blood

„ TRANSPORT OF OXYGEN
Oxygen is transported from alveoli to the tissue by
blood in two forms:
1. As simple physical solution
2. In combination with hemoglobin.
„ AS SIMPLE SOLUTION
Oxygen dissolves in water of plasma and is transported
in this physical form. Amount of oxygen transported in
this way is very negligible. It is only 0.3 mL/100 mL
of plasma. It forms only about 3% of total oxygen in
blood. It is because of poor solubility of oxygen in
water content of plasma. Still, transport of oxygen in
this form becomes important during the conditions
like muscular exercise to meet the excess demand of
oxygen by the tissues.
„ IN COMBINATION WITH HEMOGLOBIN
Oxygen combines with hemoglobin in blood and is
transported as oxyhemoglobin. Transport of oxygen
in this form is important because, maximum amount
(97%) of oxygen is transported by this method.
Oxygenation of Hemoglobin
Oxygen combines with hemoglobin only as a physical combination. It is only oxygenation and not
oxidation. This type of combination of oxygen with
hemoglobin has got some advantages. Oxygen can be
readily released from hemoglobin when it is needed. Hemoglobin accepts oxygen readily whenever the partial
pressure of oxygen in the blood is more. Hemoglobin
gives out oxygen whenever the partial pressure of
oxygen in the blood is less.
Oxygen combines with the iron in heme part of
hemoglobin. Each molecule of hemoglobin contains 4
atoms of iron. Iron of the hemoglobin is present in ferrous
form. Each iron atom combines with one molecule of
oxygen. After combination, iron remains in ferrous
form only. That is why the combination of oxygen with
hemoglobin is called oxygenation and not oxidation.
Oxygen Carrying Capacity of Hemoglobin
Oxygen carrying capacity of hemoglobin is the amount
of oxygen transported by 1 gram of hemoglobin. It is
1.34 mL/g.
Oxygen Carrying Capacity of Blood
Oxygen carrying capacity of blood refers to the amount
of oxygen transported by blood. Normal hemoglobin
content in blood is 15 g%.
Since oxygen carrying capacity of hemoglobin is
1.34 mL/g, blood with 15 g% of hemoglobin should carry
20.1 mL% of oxygen, i.e. 20.1 mL of oxygen in 100 mL
of blood.
But, blood with 15 g% of hemoglobin carries only 19
mL% of oxygen, i.e. 19 mL of oxygen is carried by 100
mL of blood (Table 125.1). Oxygen carrying capacity of
blood is only 19 mL% because the hemoglobin is not
fully saturated with oxygen. It is saturated only for about
95%.
Saturation of Hemoglobin with Oxygen
Saturation is the state or condition when hemoglobin
is unable to hold or carry any more oxygen. Saturation
of hemoglobin with oxygen depends upon partial
pressure of oxygen. And it is explained by oxygenhemoglobin dissociation curve.
„ OXYGEN-HEMOGLOBIN
DISSOCIATION CURVE
Oxygen-hemoglobin dissociation curve is the curve
that demonstrates the relationship between partial
pressure of oxygen and the percentage saturation
of hemoglobin with oxygen. It explains hemoglobin’s
affinity for oxygen.
Normally in the blood, hemoglobin is saturated
with oxygen only up to 95%. 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.
Method to Plot Oxygen-hemoglobin
Dissociation Curve
Ten flasks or tonometers are taken. Each one is
filled with a known quantity of blood with known
concentration of hemoglobin. Blood in each tonometer
is exposed to oxygen at different partial pressures.
Tonometer is rotated at a constant temperature till the
blood takes as much of oxygen as it can. Then, blood
is analyzed to measure the percentage saturation of
hemoglobin with oxygen. Partial pressure of oxygen
and saturation of hemoglobin are plotted to obtain the
oxygen-hemoglobin dissociation curve.
Normal Oxygen-hemoglobin Dissociation Curve
Under normal conditions, oxygen-hemoglobin dissociation curve is ‘S’ shaped or sigmoid shaped (Fig.125.1).
Lower part of the curve indicates dissociation of oxygen
from hemoglobin. Upper part of the curve indicates
the uptake of oxygen by hemoglobin depending upon
partial pressure of oxygen.
P50
P50 is the partial pressure of oxygen at which hemoglobin
saturation with oxygen is 50%. When the partial pressure of oxygen is 25 to 27 mm Hg, the hemoglobin issaturated to about 50%. That is, the blood contains 50%
of oxygen. At 40 mm Hg of partial pressure of oxygen,
the saturation is 75%. It becomes 95% when the partial
pressure of oxygen is 100 mm Hg.

DIGESTION OF PROTEINS

Enzymes responsible for the digestion of proteins are
called proteolytic enzymes.

IN THE MOUTH
Digestion of proteins does not occur in mouth, since
saliva does not contain any proteolytic enzymes. So, the
digestion of proteins starts only in stomach .

IN THE STOMACH
Pepsin is the only proteolytic enzyme in gastric juice
. Rennin is also present in gastric juice. But
it is absent in human.

IN THE SMALL INTESTINE
Most of the proteins are digested in the duodenum and
jejunum by the proteolytic enzymes of the pancreatic
juice and succus entericus.

Proteolytic Enzymes in Pancreatic Juice:

Pancreatic juice contains trypsin, chymotrypsin and
carboxypeptidases. Trypsin and chymotrypsin are
called endopeptidases, as these two enzymes break the
interior bonds of the protein molecules 

Proteolytic Enzymes in Succus Entericus:

Final digestion of proteins is by the proteolytic
enzymes present in the succus entericus. It contains dipeptidases, tripeptidases and aminopeptidases

FINAL PRODUCTS OF PROTEIN DIGESTION

Final products of protein digestion are the amino acids,
which are absorbed into blood from intestine.

ABSORPTION OF PROTEINS

Proteins are absorbed in the form of amino acids from
small intestine. The levo amino acids are actively
absorbed by means of sodium cotransport, whereas,
the dextro amino acids are absorbed by means of
facilitated diffusion.
Absorption of amino acids is faster in duodenum
and jejunum and slower in ileum.

„ VELOCITY OF BLOOD FLOW
„ DEFINITION
Velocity of blood flow is the rate at which blood flows
through a particular region of the body. It mainly
depends upon the diameter or cross-sectional area of
blood vessel.

„ MEAN VELOCITY OF BLOOD FLOW
IN DIFFERENT VESSELS
Mean velocity (cm/second) of blood flow in different
blood vessels:
Large arteries : 50.00
Small arteries : 5.00
Arterioles : 0.50
Capillaries : 0.05
Venules : 0.10
Small veins : 1.00
Large veins : 2.00

„ METHODS OF STUDY
1. By Using Flowmeters

2. By Hemodromography
Hemodromography is a technique

„ FACTORS MAINTAINING VELOCITY
Three factors are responsible for the maintenance of
the velocity of blood flow:
1. Cardiac output
2. Cross-sectional area of the blood vessel
3. Viscosity of the blood.

1. Cardiac Output:

Velocity of blood flow is directly proportional to cardiac
output. Increase in cardiac output leads to increase in
the velocity of blood flow in all parts of the circulation.

2. Cross-sectional Area of Blood Vessels:

Velocity of blood flow is inversely proportional to the total
cross-sectional area of the vascular bed, through which
the blood circulates. Cross-sectional area increases
progressively as the arteries ramify. Cross-sectional
area of each branch is smaller, but the sum of the crosssectional areas of all the branches is always greater than
that of the parent vessel. So, velocity of blood flow is
decreased as the distance from the heart is increased.

3. Viscosity of Blood:

Velocity of blood flow is inversely proportional to the
viscosity of blood. If viscosity is more, the velocity
of blood flow is reduced (See in Factors maintaining
volume of blood flow). It is because of the friction of
blood against arterial wall, which is more when viscosity
of blood is increased

„ JAUNDICE OR ICTERUS
Jaundice or icterus is the condition characterized by
yellow coloration of the skin, mucous membrane and
deeper tissues due to increased bilirubin level in blood.
The word jaundice is derived from the French word
‘jaune’ meaning yellow.
The normal serum bilirubin level is 0.5 to 1.5 mg/dL.
Jaundice occurs when bilirubin level exceeds 2 mg/dL.
Types of Jaundice
Jaundice is classified into three types:
1. Prehepatic or hemolytic jaundice
2. Hepatic or hepatocellular jaundice
3. Posthepatic or obstructive jaundice.
1. Prehepatic or Hemolytic Jaundice
Hemolytic jaundice is the type of jaundice that occurs
because of excessive destruction of RBCs resulting in
increased blood level of free (unconjugated) bilirubin. In
this condition, the excretory function of liver is normal.
But the quantity of bilirubin increases enormously. The
liver cells cannot excrete that much excess bilirubin
rapidly. Unconjugated bilirubin is insoluble in water and
is not excreted in urine. So, it accumulates in the blood
resulting in jaundice.
Formation of urobilinogen also increases resulting in
the excretion of more amount of urobilinogen in urine.
Causes
Any condition that causes hemolytic anemia can lead to
hemolytic jaundice.
Common causes of hemolytic jaundice are:
i. Renal disorder
ii. Hypersplenism
iii. Burns
iv. Infections such as malaria
v. Hemoglobin abnormalities such as sickle cell
anemia or thalassemia
vi. Drugs or chemical substances causing red cell
damage
vii. Autoimmune diseases.
2. Hepatic or Hepatocellular or
Cholestatic Jaundice
Hepatic jaundice is the type of jaundice that occurs due
to the damage of hepatic cells. Because of the damage,
the conjugated bilirubin from liver cannot be excreted
and it returns to blood.
Causes
i. Infection (infective jaundice) by virus, resulting
in hepatitis (viral hepatitis)
ii. Alcoholic hepatitis
iii. Cirrhosis of liver
iv. Exposure to toxic materials.
3. Posthepatic or Obstructive or
Extrahepatic Jaundice
Posthepatic type of jaundice occurs because of the
obstruc tion of bile flow at any level of the biliary system.
The bile cannot be excreted into small intestine. So, bile
salts and bile pigments enter the circulation. The blood
contains more amount of conjugated bilirubin (Table
40.2).
Causes
i. Gallstones
ii. Cancer of biliary system or pancreas.

„ FACTORS DETERMINING VOLUME
OF BLOOD FLOW:

Volume of blood flow is determined by five factors:
1. Pressure gradient
2. Resistance to blood flow
3. Viscosity of blood
4. Diameter of blood vessels
5. Velocity of blood flow.

1. Pressure Gradient
Volume of blood flowing through any blood vessel is
directly proportional to the pressure gradient. Pressure
gradient is the pressure difference between the two
ends of the blood vessel

2. Resistance to Blood Flow
(Peripheral Resistance)
Volume of blood flow is inversely proportional to
the resistance. Resistance is the friction, tension or
hindrance, against which the blood has to flow. Peripheral
resistance means the resistance offered to blood flow
in peripheral blood vessels. Though resistance exists in
all the blood vessels to some extent, it is remarkable in
the peripheral vessels, particularly the arterioles.
Determinants of peripheral resistance
i. Radius of blood vessels
ii. Pressure gradient
iii. Viscosity of blood.
Peripheral resistance is inversely related to radius
of the blood vessel, i.e. lesser the radius, more will be
the resistance. Radius of the arterioles is very less. It is
because the arterioles remain partially constricted all the
time due to sympathetic tone. So, the resistance is more.
Hence, the arterioles are called resistant vessels

3. Viscosity of Blood
Volume of blood flow is inversely proportional to the
viscosity of blood. Viscosity is the friction of blood against
the wall of the blood vessel. Isaac Newton described
viscosity as the internal friction or lack of slipperiness.
Viscosity influences the blood flow through resistance.
Factors determining viscosity
RBC count is the main factor which determines the
viscosity of the blood. Another factor determining
viscosity is plasma protein, mainly albumin.
When hemoconcentration occurs as in case of
burns or in polycythemia, the viscosity increases and
the velocity of blood flow decreases, so the volume of
blood reaching the organ is decreased.

4. Diameter of Blood Vessels
Volume of blood flow is directly proportional to the
diameter of the blood vessels. When the diameter of a
segment of blood vessel is considered, the aorta has the
maximum diameter and capillary has got the minimum
diameter. But, in circulation, the diameter of the vessel
is considered in relation to the cross-sectional area
through which the blood flows. Cross-sectional area is progressively increased as
the arteries ramify and as the distance from the heart
is increased. Cross-sectional area of each branch is
smaller, but the sum of the cross-sectional areas of all
the branches is always greater than that of the parent
vessel. In this way, the aorta has got less cross-sectional
area of 4 cm2
, compared to that of capillaries, which is
2,500 cm2
.
But, the cross-sectional area is subjected to variations
under physiological and pathological conditions. Diameter of the aorta depends upon the elasticity of the
wall and its recoiling tendency helps in maintaining the
flow and pressure. Diameter of the arterioles depends
upon the sympathetic tone.

5. Velocity of Blood Flow
Volume of blood flow is directly proportional to the
velocity of blood flow. Velocity of blood flow is the rate
at which blood flows through a particular region. It is
described later in this chapter

„ HEART RATE
„ NORMAL HEART RATE
Normal heart rate is 72/minute. It ranges between 60
and 80 per minute.
„ TACHYCARDIA
Tachycardia is the increase in heart rate above 100/
minute.
Physiological Conditions when
Tachycardia Occurs
1. Childhood
2. Exercise
3. Pregnancy
4. Emotional conditions such as anxiety.
Pathological Conditions when
Tachycardia Occurs
1. Fever
2. Anemia
3. Hypoxia
4. Hyperthyroidism
5. Hypersecretion of catecholamines
6. Cardiomyopathy
7. Diseases of heart valves


„ BRADYCARDIA
Bradycardia is the decrease in heart rate below 60/
minute.
Physiological Conditions when
Bradycardia Occurs
1. Sleep
2. Athletes.
Pathological Conditions when
Bradycardia Occurs
1. Hypothermia
2. Hypothyroidism
3. Heart attack
4. Congenital heart disease
5. Degenerative process of aging
6. Obstructive jaundice
7. Increased intracranial pressure.
Drugs which Induce Bradycardia
1. Beta blockers
2. Channel blockers
3. Digitalis and other antiarrhythmic drugs.

„ FACTORS MAINTAINING CARDIAC OUTPUT

Cardiac output is maintained (determined) by four
factors:
1. Venous return
2. Force of contraction
3. Heart rate
4. Peripheral resistance.

„ 1. VENOUS RETURN

Venous return is the amount of blood which is returned to
heart from different parts of the body. When it increases,
the ventricular filling and cardiac output are increased.
Thus, cardiac output is directly proportional to venous
return, provided the other factors (force of contraction,
heart rate and peripheral resistance) remain constant.
Venous return in turn, depends upon five factors:
i. Respiratory pump
ii. Muscle pump
iii. Gravity
iv. Venous pressure
v. Sympathetic tone.

„ 2. FORCE OF CONTRACTION

Cardiac output is directly proportional to the force of
contraction, provided the other three factors remain
constant. According to Frank-Starling law, force of
contraction of heart is directly proportional to the initial
length of muscle fibers, before the onset of contraction.
Force of contraction depends upon preload and
afterload.

Preload:

Preload is the stretching of the cardiac muscle fibers
at the end of diastole, just before contraction. It is due
to increase in ventricular pressure caused by filling
of blood during diastole. Stretching of muscle fibers
increases their length, which increases the force of
contraction and cardiac output.
Thus, force of contraction of heart and cardiac
output are directly proportional to preload.

Afterload:

Afterload is the force against which ventricles must
contract and eject the blood. Force is determined by
the arterial pressure. At the end of isometric contraction
period, semilunar valves are opened and blood is ejected
into the aorta and pulmonary artery. So, the pressure
increases in these two vessels. Now, the ventricles have
to work against this pressure for further ejection. Thus,
the afterload for left ventricle is determined by aortic
pressure and afterload for right ventricular pressure is
determined by pressure in pulmonary artery.
Force of contraction of heart and cardiac output are
inversely proportional to afterload.

„ 3. HEART RATE:

Cardiac output is directly proportional to heart rate
provided, the other three factors remain constant.
Moderate change in heart rate does not alter the
cardiac output. If there is a marked increase in heart
rate, cardiac output is increased.
If there is marked decrease in heart rate, cardiac
output is decreased.

„ 4. PERIPHERAL RESISTANCE:

Peripheral resistance is the resistance offered to
blood flow at the peripheral blood vessels. Peripheral
resistance is the resistance or load against which the
heart has to pump the blood. So, the cardiac output is
inversely proportional to peripheral resistance.
Resistance is offered at arterioles so, the arterioles
are called resistant vessels. In the body, maximum
peripheral resistance is offered at the splanchnic
region. 

TESTS FOR BLOOD CLOTTING:

Blood clotting tests are used to diagnose blood disorders.Some tests are also used to monitor the patients treated with anticoagulant drugs such as heparin and warfarin.
1. Bleeding time
2. Clotting time
3. Prothrombin time
4. Partial prothrombin time
5. International normalized ratio
6. Thrombin time.

„ BLEEDING TIME:

Bleeding time (BT) is the time interval from oozing of blood after a cut or injury till arrest of bleeding. Usually, it is determined by Duke method using blotting paper or filter paper method. Its normal duration is 3 to 6 minutes.
It is prolonged in purpura(thromocytopenia),DIC,vWD.

„ CLOTTING TIME:

Clotting time (CT) is the time interval from oozing of blood after a cut or injury till the formation of clot. It is usually determined by capillary tube method. Its normal
duration is 3 to 8 minutes. It is prolonged in hemophilia,DIC,vWD.

„ PROTHROMBIN TIME:

Prothrombin time (PT) is the time taken by blood to
clot after adding tissue thromboplastin to it. Blood is collected and oxalated so that, the calcium is precipitated and prothrombin is not converted into thrombin. Thus, the blood clotting is prevented. Then a large quantity
of tissue thromboplastin with calcium is added to this blood. Calcium nullifies the effect of oxalate. The tissue thromboplastin activates prothrombin and blood clotting
occurs. During this procedure, the time taken by blood to clot after adding tissue thromboplastin is determined.
Prothrombin time indicates the total quantity of prothrombin present in the blood. Normal duration of prothrombin time is 10 to 12
seconds. It is prolonged in deficiency of prothrombin and other factors like factors I, V, VII and X. However, it is normal in hemophilia.

„ PARTIAL PROTHROMBIN TIME OR
ACTIVATED PROTHROMBIN TIME:

Partial prothrombin time (PPT) is the time taken for the blood to clot after adding an activator such as phospholipid, along with calcium to it. It is also called activated
partial prothrombin time (APTT). This test is useful in monitoring the patients taking anticoagulant drugs. Normal duration of partial prothrombin time is 30 to 45
seconds. It is prolonged in heparin therapy
(since heparin inhibit clotting) and deficiency
or inhibition of factors II, V, VIII, IX, X, XI and XII.

„ INTERNATIONAL NORMALIZED RATIO:
International normalized ratio (INR) is the rating of a patient’s prothrombin time when compared to an average. It measures extrinsic clotting pathway system. INR is useful in monitoring impact of anticoagulant
drugs such as warfarin and to adjust the dosage of anticoagulants. Patients with atrial fibrillation are usually treated with warfarin to protect against blood clot, which may cause strokes. These patients should have regular blood tests to know their INR in order to adjust warfarin dosage. Blood takes longer time to clot if INR is higher.

Normal INR is about 1. In patients taking anticoagulant therapy for atrial fibrillation, INR should be between 2 and 3. For patients with heart valve disorders, INR should be between 3 and 4. But, INR greater than 4 indicates that blood is clotting too slowly and there is a risk of uncontrolled blood clotting.

„ THROMBIN TIME:

Thrombin time (TT) is the time taken for the blood to clot after adding thrombin to it. It is done to investigate the presence of heparin in plasma or to detect fibrinogen abnormalities. This test involves observation
of clotting time after adding thrombin to patient’s plasma. Normal duration of thrombin time is 12 to 20 seconds. It is prolonged in heparin therapy and during dysfibrinogenimia (abnormal function of fibrinogen with normal fibrinogen level).

FIBRINOLYSIS:

Lysis of blood clot inside the blood vessel is called fibrinolysis. It helps to remove the clot from lumen of the blood vessel. This process requires a substance called plasmin or fibrinolysin.

Formation of Plasmin:

Plasmin is formed from inactivated glycoprotein called plasminogen. Plasminogen is synthesized in liver
and it is incorporated with other proteins in the blood clot. Plasminogen is converted into plasmin by tissue plasminogen activator (t-PA), lysosomal enzymes and thrombin. The t-PA and lysosomal enzymes are released
from damaged tissues and damaged endothelium. Thrombin is derived from blood. The t-PA is always inhibited by a substance called t-PA inhibitor. It is also inhibited by factors V and VIII. Besides t-PA, there is another plasminogen activator
called urokinase plasminogen activator (u-PA). It is derived from blood.

Sequence of Events Involved in the
Activation of Plasminogen:

1. During intravascular clotting, the endothelium of the blood vessel secretes a thrombin-binding protein, the thrombomodulin. It is secreted by the endothelium of all the blood vessels, except the minute vessels
of brain

2. Thrombomodulin combines with thrombin and forms a thrombomodulin-thrombin complex
3. Thrombomodulin-thrombin complex activates protein C
4. Activated protein C inactivates factor V and VIII in the presence of a cofactor called protein S
5. Protein C also inactivates the t-PA inhibitor
6. Now, the t-PA becomes active
7. Activated t-PA and lysosomal enzymes activate plasminogen to form plasmin. Plasminogen is also activated by thrombin and u-PA.