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GENERAL PHYSIOLOGY

1.Cell Membrane - Structure

Features:
Plasma membrane is a dynamic structure and its constituents are constantly renewed.
The thickness of membrane is about 7.5 nm
Semipermeable - allowing some substances to pass through while excluding others
Components:
Phospholipids
Cholesterol 40%
Proteins -------------- 55%
Carbohydrate -------- 5%
Arrangement of the components:
Explained by Fluid Mosaic Model proposed by Singer & Nicolson
- Phospholipids forms a fluid structure in which proteins and other components are
embedded to give a mosaic pattern.
- Fluidity helps the substances dissolved in lipid layer to move to different places in
the membrane
Lipid Bilayer:
- Made up of two layers of phospholipid molecules
- Each phospholipid molecule has a hydrophilic phosphate head and two hydrophobic
fatty acid chains
- These molecules are arranged in two layers in opposite direction
- The inner and outer surfaces of the lipid bilayer are hydrophilic and the interior of
the bilayer is hydrophobic
Proteins:
Two types of proteins: Peripheral & integral or transmembrane proteins
Peripheral proteins are attached to the outer and inner surfaces of membrane
Integral proteins extends through the membrane from outside to inside
Carbohydrates:
Oligosaccharide molecules are attached to the surface of membrane.
The molecules which are attached to membrane proteins are glycoproteins
The molecules which are attached to phospholipid molecules are glycolipids
These molecules form “Glycocalyx” surrounding the cell
Significance of each component:
Phospholipids - Maintains the membrane in fluid state & provides flexibility to the
membrane
Cholesterol – Provides rigidity (stiffness) to the membrane
Proteins – Critical components of membrane as it performs many functions
Glycocalyx – Helps in cell to cell recognition
Functions of cell membrane:
1. Forms a protective barrier surrounding the cells
2. Semipermeability of the membrane differentiates the concentration of ECF from ICF
3. which is responsible for development of biopotentials
4. Links adjacent cells together by intercellular connections
5. Provides anchoring sites for filaments of cytoskeleton
6. Allow cell to cell recognition – Glycocalyx
7. Provides a binding site for enzymes/hormones
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2. Cell membrane Proteins

Embedded in the fluid lipid bilayer

Peripheral proteins
Integral proteins

Types: Peripheral & integral or transmembrane proteins

1.Peripheral proteins :
• Loosely bound to the membrane
• Non-covalently bound to integral proteins
• Provides structural integrity to the cell membrane
Types
1. Intrinsic - anchored to cytoskeleton of the cell
2. Extrinsic - act as cell adhesion molecules (CAM)
2. Integral proteins (Transmembrane proteins ) :
• Covalently bond
• Penetrate lipid bilayer
Functions of integral proteins:
• Channels: Provide channels for the ions to diffuse in both directions e.g., Na+ Channels (allow
sodium ions to diffuse inside). Diffusion of ions through channels is simple diffusion
• Carriers: Transport the substances along the concentration gradient. Diffusion with the help of
carrier proteins is called facilitated diffusion. E.g., transport of glucose by a carrier protein GLUT
• Pumps: Transport the substances against the electrochemical gradient e.g., Na+-K+ ATPase
pump. The pumping of substances with the help of transport protein is called primary active
transport
• Receptors: Receive the chemical signals from outside e.g., Hormones & neurotransmitters
• Antigens: Differentiates the self from non-self e.g Human Leukocyte Antigen (HLA) & Blood
group Antigens
• Enzymes: Catalyze the reactions at surface of the membranes e.g Adenylate cyclase
• Cell Adhesion Molecules: Help to anchor the cells to neighboring cells and to the basal lamina
--------------------------------------------------------------------------------------------------------------------------
3. Glycocalyx
Glycocalyx is a coat on the external surface of the plasma membrane. This coating consists of several
carbohydrate moieties (glycolipids and glycoproteins)
Functional significance:

contribute to cell-cell recognition, communication, and intracellular adhesion

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distinguish between own healthy cells and transplanted tissues, diseased cells, or invading organisms.

--------------------------------------------------------------------------------------------------------------------

Lipid Bilayer as semipermeable membrane::

The phospholipid bilayer structure with specific membrane proteins accounts for the selective
permeability of the membrane
Small molecules and larger hydrophobic molecules move through easily. e.g. O2, CO2, N2 and alcohol
Hydrophilic molecules have lower solubility to penetrate the membrane slowly. E.g. Ions, glucose and
urea ,
Importance of Semipermeability:
Semipermeability of plasma membrane determines the concentration difference between ECF & ICF
------------------------------------------------------------------------------------------------------------------------------
Transport Across the Membrane
Membrane Transport

Passive Transport Active Transport

Passive transport mechanisms:
• Diffusion
• Facilitated Diffusion
• Osmosis
• Capillary filtration
• Bulk Flow / Solvent drag
DIFFUSION
Diffusion is the net movement of molecules (or ions) from a region of their high concentration to a
region of their lower concentration.
Characteristic features of diffusion
• The molecules move down a concentration gradient.
• Requires no energy
• Molecules move about randomly by kinetic energy
• As a result of diffusion, molecules reach equilibrium (no net movement of molecules from either
side).
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Factors Affecting Diffusion

• Cell membrane permeability
• Concentration Gradient
• Pressure gradient
• Electrical potential gradient
Cell membrane permeability depends upon:
• Solubility of the substance in the lipid bilayer
• Molecular size of the particle
• Charge of the particle
• Charge at the pore
• Surface area
• Thickness
• Number of protein channels
• Temperature
Fick’s law of Diffusion:
J = DA (C1-C2)
---------------
T
J = Rate of Diffusion T = Thickness of membrane
C1-C2 = concentration gradient D = Diffusion coefficient
A = Cross sectional area
Types of diffusion:
1. Simple diffusion
2. Facilitated diffusion

1. Simple Diffusion
Diffusion without the help of a carrier protein
Mode of Simple Diffusion

Through Lipid Bilayer Through Channels

Molecules that pass through the lipid bilayer by diffusion

• Gases (oxygen, carbon dioxide)
• Water molecules (rate is slow due to polarity)
• Lipids (steroid hormones)
• Lipid soluble molecules (hydrocarbons, alcohols, some vitamins)
• Small noncharged molecules (NH3)
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Molecules that pass through the Channels by diffusion

• Ions (Na+, K+, Cl-)
• Small water soluble molecules
• Water (faster rate)
Gating of Protein channels
Types of gated channels
1. Voltage gated channels – open when there is a change in the resting membrane potential
e.g., Na+ channels along the nerve fiber

2.Ligand gated channels – open when a chemical binds to the receptor which is attached
to the channel e.g., channels attached to the acetylcholine receptors in synapse or Neuro-
muscular junction

Mechanical gated channels – Open when there is a mechanical stretch

e.g Channels in the smooth muscle fiber
Drugs that block channels:
Sodium channels – Tetrodotoxin (TTX) & Saxitoxin
Potassium channels – TEA (Tetra Ethyl Ammonium)
Calcium channels – Verapramil (to treat hypertension)

2. Facilitated diffusion
Movement of solutes from high concentration to low concentration through the membrane
with the help of a carrier protein
Features of Facilitated Diffusion
• Occurs along the concentration gradient
• Does not require energy
• Involves carrier protein
• Carrier proteins are highly specific for molecules
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• Have saturation point. Diffusion increases with increase in concentration gradient in simple
diffusion whereas in facilitated diffusion, diffusion depends on availability of carrier proteins.
When the carrier proteins are saturated, facilitated diffusion stops
• Competitive inhibition occurs
Mechanism of Facilitated Diffusion
• Molecule binds to carrier
• Carrier changes conformation
• Molecule released on other side
• Purely passive process- stops when concentrations are equal

e.g., Glucose transport in to the cells with the help of a carrier protein GLUT (Glucose Transporter)
• Glucose molecule from interstitial fluid binds to GLUT
• GLUT changes its confirmation
• Glucose molecule is released in to the ICF

OSMOSIS
The diffusion of water from an area of high concentration of water molecules (high water potential) to an
area of low concentration of water (low water potential) across a partially permeable membrane.
Osmosis occurs through water channels called “Aquaporins”
Osmotic pressure
The minimum pressure which when applied on the side of higher solute concentration prevents osmosis
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Colloidal osmotic pressure

• The osmotic pressure exerted by colloidal substances in the body is colloidal osmotic pressure
• The colloidal osmotic pressure of blood due to plasma proteins is called ONCOTIC PRESSURE
• Oncotic pressure or colloidal osmotic pressure of blood is normally 25 – 30 mmHg
• 80% of the oncotic pressure is determined by albumin
• colloidal osmotic pressure of blood is one of the factors influencing the capillary filtration
• colloidal osmotic pressure of blood opposes filtration and thereby prevents edema
• A decrease in colloidal osmotic pressure due to hypoproteinemia increases capillary filtration
and causes development of edema. E.g., Malnutrition, Liver cirrhosis and nephrotic syndrome
Osmolarity
• Number of osmotically active substances per Liter of a solution is called osmolarity
• Normal osmolarity of body fluid is 290 milliosmoles / liter
• Osmolarity of body fluid is mainly determined by sodium, Chloride and bicarbonate
• Osmolarity is also influenced to some extent by glucose, urea, plasma proteins etc.,
Tonicity
The effective osmotic pressure of a solution relative to the plasma is called tonicity
Isotonic solutions:
Solutions having same osmolarity as that of plasma ie., 290 milliosmoles/lt
Examples of isotonic solution:
• 0.9% sodium chloride solution (isotonic saline)
• 5% glucose solution
• 20% urea solution
• 10% mannitol solution
Significance of isotonic solution:
Isotonic solutions (0.9% NaCl / 5% glucose / 20% urea) can be infused in case of dehydration to
restore the body fluid volume without upsetting the osmotic equilibrium of the cells
Hypertonic solutions:
Fluids whose osmolarity is greater to that of plasma ie., > 290 milliosmoles/lt
Hypotonic solutions
Fluids whose osmolarity is lesser to that of plasma ie., < 290 milliosmoles/lt
CAPILLARY FILTRATION
• It is a process by which a fluid is forced through a membrane due to variation in the hydrostatic
pressure
• Major route of transport between blood and interstitial space.
• Filtration is determined by difference in various pressures of blood & interstitial space.
• The normal rate of net filtration in the entire body is only about 2ml/min.
• This fluid is drained by the lymphatics from the interstitial space.
Starling’s hypothesis:
• At any capillary bed the rate of filtration is determined by forces acting across the capillary
membrane.
• Any imbalance in these forces may lead to edema (accumulation of fluid in tissue spaces) or
dehydration (fluid loss from the body)
Starling’s Forces: The forces acting on the capillary membrane and influencing the rate of capillary
filtration are called Starling’s forces.
The forces are:
• Capillary hydrostatic pressure – favours filtration
• Capillary osmotic pressure – oppose filtration
• Interstitial fluid hydrostatic pressure – oppose filtration
• Interstitial fluid osmotic pressure – favours filtration
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At arterial end
Hydrostatic pressure of blood = 30 mmHg
Oncotic pressure of blood = 28 mmHg
Interstitial hydrostatic pressure = - 3 mmHg
Osmotic pressure of interstitial fluid = 8 mmHg
OUTWARD FORCES - INWARD FORCE = 30 + 8 – (-3) +28
= 30 + 8 + 3 – 28
= 13 mmHg (net filtration pressure)
At venous end
Hydrostatic pressure of blood = 10 mmHg
Oncotic pressure of blood = 28 mmHg
Interstitial hydrostatic pressure = - 3 mmHg
Osmotic pressure of interstitial fluid = 8 mmHg
OUTWARD FORCES = 10 + 8 + 3 = 21 mmHg
INWARD FORCE = 28 mmHg
28 – 21 = 7 mmHg (net absorption pressure)

SOLVENT DRAG
Transfer of solutes by being carried along with the water flow driven by osmotic gradients across cell
membranes.
Example: Transfer of fluid along with its constituents across the intestinal wall & Capillary
ACTIVE TRANSPORT
• Substances are transported against the chemical or electrical gradient (from the region of low
concentration to the region of high concentration)
• Utilizes energy from ATP
• Up-hill process
• Utilizes a transport protein (pump)

Pump
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Types of Active Transport

1) Primary
2) Secondary
3) Bulk/Vesicular Transport
a) Exocytosis
b) Endocytosis
i) Phagocytosis
ii) Pinocytosis
iii) Receptor-Mediated endocytosis
1.Primary active transport
The energy is derived directly from the breakdown of ATP or some high- energy phosphate compound.
Examples:
• Sodium-potassium ATPase pump
• Calcium ATPase pump
• Hydrogen ATPase pump
Sodium-potassium pump (a specific case of active transport)
Structure
α Subunit (100, 000 MW)
β Subunit (55000 MW)
3 Intracellular sites:
1. Sodium binding site
2. ATP binding site
3. Phosphorylation site
2 Extracellular sites
1. Potassium binding site
2. Ouabin binding site

Mechanism of the pump:

• Cytoplasmic Na+ binds to the sodium-potassium pump.
• Na+ binding stimulates phosphorylation by ATP.
• Phosphorylation causes the protein to change its shape. Na+ is expelled to the outside.
• K+ binds on the extracellular side and triggers release of the phosphate group
• Loss of the phosphate (dephosphorylation) restores the protein’s original shape.
• K+ is released, and the cycle repeats
• Three sodium ions are pumped outside where as two potassium ions are pumped inside
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Functions of Na+ -K+ Pump

1. Maintains Na+ & K+ gradients across the membrane essential for genesis of RMP (Resting
Membrane Potential).
2. Maintains Cell volume: If the pump is paralyzed, sodium ions which enter the cell remain
inside & water follows, causing swelling and rupture of cells.
3. Important role in secondary active transport.
4. Maintains high intracellular K+ which is important for protein synthesis
2. Secondary active transport
The energy is derived secondarily (indirectly) from the energy which has been stored in the form of
ionic concentration differences, created in by primary active transport. In other words the downhill
energy (energy of diffusion) of one substance is utilized for uphill movement (active transport) of
another substance
Types:
• Co-transport (symport)
• Counter transport (Antiport)
Co – transport: Both the substances are transported in the same direction
e.g., Sodium – Glucose Co-transport & Sodium-Amino acid Co-transport
Counter transport: Two substances are transported. One substance is transported in opposite
direction to the other substance
e.g., Sodium-Hydrogen counter transport & Sodium- Calcium counter transport

Sodium - Glucose co-transport:

• An example for secondary active transport
• Sodium and glucose are transported together from ECF to ICF through the cell membrane by a
transport protein
• The transport protein is SGLT (Sodium Dependent Glucose Transporter)
• This occurs secondary to Na+-K+ ATPase pump (secondary active transport) which maintains the
concentration gradient of sodium
• The diffusion energy of sodium is utilized by glucose for its active transport
• As this transport does not utilize energy directly, this is secondary active transport
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Sites of Sodium - Glucose co-transport

Absorption in Intestine
Reabsorption in Kidney
Clinical use of secondary active transport:
This is used in oral rehydration therapy which helps to restore the volume of body fluid which is lost
in dehydration
ORS (Oral Rehydration Solution)
• simple treatment for dehydration
• It consists of a solution of salts and sugars which is taken by mouth.
• As both substances are osmotically active particles, they increase the absorption of water. This
will restore the body fluid effectively
3.VESICULAR TRANSPORT
• Vesicular transport is an active process in which materials move into or out of the cell enclosed as
vesicles.
• Vesicles are small membrane sacs. They can form at the cell membrane or can fuse with the
membrane.
• Transports macromolecules like protein and even cells like bacteria
• There are two basic types of vesicular transport-endocytosis and exocytosis.
Exocytosis:
A process by which the contents of secretory vesicles move out of the cell and into the
extracellular space.
Mechanism of exocytosis:
intracellular vesicle moves to the plasma membrane
↓
fusion of the vesicular membrane and plasma membrane
↓
Rupture of membrane and release of contents outside
Examples
secretion of proteins like enzymes, peptide hormones and antibodies from cells, release of
neurotransmitter from presynaptic neurons
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Endocytosis
Process by which the macromolecules are transported in to the cells
Types:
1. Pinocytosis
2. Phagocytosis
3. Receptor mediated endocytosis
1. Pinocytosis
• Process in which the cell takes in surrounding fluids, including all solutes present.
• Pinocytosis is nonspecific in the substances that it transports.
• Also called as “cell drinking”
Mechanism of pinocytosis:
• Cell forms an invagination
• Vesicles are formed within the cell
• These pinocytic vesicles subsequently fuse with lysosomes to hydrolyze (break down) the
particles.
Example:
Absorption of antibodies in the intestine of baby from mother’s milk

2. Phagocytosis
Process by which microorganisms like bacteria and other particulate materials are engulfed in to the
Cell. Also called as “cell eating”
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Mechanism of Phagocytosis:

Example: Engulfing of bacteria by phagocytes (Neutrophils & Macrophages)

3. Receptor mediated endocytosis

This type of endocytosis is triggered by various ligands binding to the receptors on the cell surface
Mechanism:
• Binding of chemical molecules to the receptors in the clathrin-coated pits
• Contraction of clathrin
• The pit is then pinched off forming a coated vesicle
• The vesicle then becomes endosome
Example: Uptake of cholesterol
Transport of iron
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CELL JUNCTIONS
The cell membranes of adjoining cells are connected with one another through intercellular junctions.
Types
• Tight junctions
• Anchoring junction
- Desmosomes
- Hemidesmosomes
- Adherence junction
Focal adhesion
• Gap junction
1.Tight junctions (Zona Occludens or occluding zone):
• The cell membranes of two adjacent cells fuse with each other
• Obliteration of the space between them.
E.g: blood brain barrier, Intestinal epithelial cells
Functions:
• Form strong union between neighboring cells which provides strength & stability to the cells
• Barrier to the movement of ions and other solutes from one cell to other (Useful in Blood brain
barrier & Blood testis barrier)
• Prevents lateral movement of proteins → maintains polarity of cells
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2.Anchoring junction:
• Provide firm structural attachment between two cells or between a cell and the extracellular
matrix
• The attachment is provided by either actin or intermediate filaments
Desmosomes
• Cell membrane of adjacent cells is separated by 200A gap.
• A part of the gap is occupied by a solid structure which provides a strong union between the cells
• The proteins involved are Cadherins
• Seen in skin and neck of uterus
Hemidesmosomes:
• Appears like half desmosomes
• Anchor cells to the basement membrane
• The proteins involved are integrins
Adherence junctions
• Connect actin filaments of one cell to those of another cell
• The membranes of the adjacent cells are held together by transmembrane proteins called
cadherins
• Present at the basal regions of tight junction in cardiac muscle and epidermis of skin
Focal adhesions:
• Attach cells to basal lamina
• Also connect the actin filaments of the cell to the extracellular matrix
• The transmembrane proteins involved are integrins
• Seen in epithelia of various organs
3. Gap junction:
• Cell membrane of adjacent cells is separated by a gap of 2-3 nm
• The gap is connected by protein cannels
• One half of the protein cannel is contributed by one cell and the other half from the adjacent cell
• The protein channel contributed by each cell is called connexon and is made up of six subunits
enclosing a channel of about 2 nm
• Present in cardiac muscle, smooth muscle & astrocytes
Functions of Gap junctions
• Allow two way transmission of low molecular weight substances like glucose, aminoacids &
other ions
• Direct movement of ions between cells helps in rapid propagation (conduction) of impulses
• Synchronize the activity of neurons or muscle fibers in an all or none manner
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• In astrocytes, play an active role in signaling in the brain through chemical messengers
Importance of gap junctions in cardiac muscle:
By synchronizing the activity of cardiac muscle fibers, make the heart to function as a syncytium
(single cell). Direct ionic movement and rapid propagation of electrical impulses through the fibers
play an important role in this

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HOMEOSTASIS
Definition:
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MUSCLE PHYSIOLOGY
10 marks
1. NEUROMUSCULAR JUNCTION
Neuro Muscular Junction is the junction between a motor nerve ending and a
muscle fiber
Physiologic Anatomy
- Terminal buttons – Divisions at the end of motor neuron
- Synaptic gutter - the depression on the skeletal muscle fiber
- Motor end plate - the thickened part of the sarcolemma
- Junctional folds - folds of motor end plate
- Presynaptic membrane – membrane of the nerve terminal
- Postsynaptic membrane - muscle membrane
- Synaptic cleft - The space between the two membranes
- Synaptic vesicles – Vesicles containing the neurotransmitter Acetyl choline
at presynaptic nerve terminal
- Ach receptors – Receptors found on the post synaptic membrane

Synaptic gutter

Motor End plate

Events in transmission

Arrival of nerve impulse at the presynaptic nerve terminal

↓
Depolarisation of the presynaptic nerve terminal
↓
Opening up of the Ca++ channel and entry of calcium into the presynaptic membrane
↓
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Release of the neurotransmitter (Ach) from vesicles into the synaptic cleft
↓
Fusion of the synaptic vesicle with the presynaptic membrane
↓
Rupture of vesicles & release of Ach into the synaptic cleft
↓
Binding of the Ach with the receptors on the post synaptic membrane
↓
Permeability of post synaptic membrane to Na+ increases
↓
Depolarisation of the post synaptic membrane-generation of End Plate Potential
↓
End Plate Potential reaches threshold & an action potential is produced which is
propagated.
DRUGS ACTING ON NMJ
1. Neuro Muscular Blockers
a) Botulinum toxin –
A bacterial toxin which inhibits the synthesis or release of Ach
b) Tubocurarine
By competitive inhibition.
c)  Bungarotoxin
By irreversible combination with the receptor
2. Drugs that stimulate Transmission
a) Neostigmine, Physostigmine
By inactivating Anticholinesterase → Prolonged depolarisation
Used in treating Myasthenia gravis
----------------------------------------------------------------------------------------------------------
2.EXCITATION-CONTRACTION COUPLING

DEFINITION:
The process in which depolarization of the muscle fiber initiates its
contraction is called excitation-contraction coupling.
i.e electrical phenomenon is converted in to mechanical phenomenon.
Nerve Action Potential
↓ Neuromuscular transmission
Muscle Action Potential
↓ Excitation contraction coupling
Muscular contraction
EVENTS

• Release of Acetylcholine from nerve terminal

• Binding of acetylcholine to the receptors present on the motor end plate
• Increased Na+ and K+ conductance in end- plate membrane
• Generation of end plate potential
• When the end plate potential reaches the firing level → generation of action
potential in muscle fibers.
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• Spread of depolarization along T tubules to interior of the muscle fiber

• Change in configuration of DHP receptors in membrane of “T” tubule → opens
ryanodine receptors (Ca2+ channels) of cisternae→ release of calcium into the
cytosol
• Ca2+ diffuses to thick and thin filaments.
• Thin actin filaments slide over the thick myosin filaments
• Z lines come closure → Shortening of sarcomere →Muscle contraction

Action potential

Motor end plate

Cisternae

3. MOLECULAR MECHANISM OF MUSCULAR

CONTRACTION/ SLIDING FILAMENT THEORY
EVENTS DURING MUSCULAR CONTRACTION
• Electrical events
• Mechanical events
• Chemical events
• Thermal events
ELECTRICAL EVENTS
• Transmission of nerve impulse to muscle across NMJ
• Excitation of muscle → development of muscle action potential
• Transmission of muscle action potential through “T” tubules to interior of muscle fiber
• release of calcium into the cytosol
MECHANICAL OR MOLECULAR EVENTS
• Explained by sliding filament theory-proposed by Huxley and Huxley in
1969. Most accepted theory
 4

• States that muscular contraction is due to sliding of actin filaments over the
myosin filaments.
• Involves two important sequences:
• Exposure of myosin binding sites of actin molecules
• Cross bridge cycle
Exposure of myosin binding sites of actin molecules
• Binding of calcium to troponin C
• Conformational change of troponin C.
• Lateral movement of tropomyosin – troponin complex from actin filaments
• Exposure of myosin binding sites of actin molecules
Cross bridge cycle
1. Activation of myosin ATPase enzyme
2. Hydrolysis of an ATP molecule → release of energy → activation of myosin crossbridges
3. Binding of crossbridges to the actin filaments
4. Bending of myosin head when ADP and P are released from the crossbridges → pulls the
actin filament towards the centre of sarcomere (powerstroke)
5. Binding of another ATP molecule → detachment of crossbridges from actin filaments
6. Binding of another ATP molecule → Attachment of crossbridge to another distal actin
molecule
CROSSBRIDGE CYCLE
Attachment – Swivel (power stroke) – detachment – attachment again.
RELAXATION OF MUSCLE
• reuptake of Ca2+ into sarcoplasmic reticulum (SR)
• Troponin-tropomyosin move back to their position and cover the active sites of actin
filaments.
▪ Interaction between the actin & myosin ceases
▪ The muscle relaxes

CHEMICAL EVENTS
• Energy is provided by hydrolysis of ATP & creatine phosphate
Contraction-Relaxation Steps Requiring ATP
• For binding of myosin crossbridges to actin filaments
• Detachment of crossbridges from actin filaments
• Active transport (Pumping) of Ca2+ back into sarcoplasmic reticulum

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5 & 3 marks

1.SARCOMERE
• Sarcomere is the contractile unit of the muscle fiber.
• It is the distance between two “Z” lines.
• It consists of “A” band at the center and half of the “I” band at the sides.
• “A” band is made up of thick myosin filaments and “I” band is made up of thin
actin filaments.
The length of sarcomere at rest is about 2.5 µm. During muscle contraction the length of
sarcomere reduces to 1.5 µm. During stretching it increases in length to 3.5µm.
 5

2. MOTOR UNIT
Definition: A single motor neuron with all its axonic terminals and the muscle fibers
supplied by it
Size principle:
The size of the type I motor unit is larger i.e., the number of muscle fibers supplied
by a single motor neuron is high. Type I motor unit controls the gross movements & the
muscle fibers involved are slow red muscle fibers.
The size of the type II motor unit is smaller i.e., the number of muscle fibers
supplied by a single motor neuron is low. Type II motor unit controls the fine skilled
movements & the muscle fibers involved are fast white muscle fibers.

3.SMOOTH MUSCLE CONTRACTION/ ROLE OF CALMODULIN

Steps involved:

1. Depolarisation of smooth muscle fibers

2. Release of calcium from sarcoplasmic reticulum
3. Calcium bind to “Calmodulin”(calcium binding protein in smooth
muscle fibers)
4. This calcium- calmodulin complex activates myosin light chain
kinase
5. The enzyme light chain kinase causes phosphorylation of myosin
6. Sliding of actin over myosin
4. SMOOTH MUSCLE PROPERTIES
 6

APPLIED
MUSCLE PHYSIOLOGY Applied
1. What is the physiological basis of administration of Neostigmine to a patient with
myasthenia gravis?
Neostigmine inhibits the action of acetylcholine esterase enzyme → prolonged depolarization
→ increase in the degree of contraction
2. Name the drugs that interfere with neuro-muscular transmission
Drugs that block Transmission
Botulinum toxin – a bacterial toxin, Tubocurarine, Suxamethonium &  Bungarotoxin
Drugs that stimulate Transmission
• Neostigmine & Physostigmine
3. Explain the basis of the use of curare form of drugs as muscle relaxants and the
use of anticholinestrases in treatment of myasthenia gravis
- Curare form of drugs block the neuromuscular transmission by competitive inhibition
- Anticholinestrases inhibit the action of acetylcholine esterase enzyme
4. What is rigors mortis? What is its clinical significance?
Rigidity after death is called rigor mortis. Clinical significance – to find out the time
of death
5. A man after prolonged illness died. Several hours after death, his body becomes
rigid.
What is that phenomenon called?
Why rigidity occurs after death?
i) Rigor mortis
ii) Unavailability of ATP . The non availability of ATP after the muscle had started to
shorten will not allow the muscle to relax. So the muscle will remain rigid.
6. Explain the medicolegal importance of “Rigor Mortis”
Rigor mortis is development of rigidity of body after death. Rigidity develops 4-5
hours after death and disappears within 24 hours. This is useful in finding out the time of
death
7. Explain the pathophysiology of myasthenia gravis
Myasthenia gravis is an autoimmune disorder characterized by inability of
neuromuscular junction to transmit signals from nerve fiber to muscle
Cause: Antibodies against acetylcholine receptors on motor end plate
Features:
- Paralysis of skeletal muscles
- Muscle strength is greatest in the morning and least in the evening
- EMG recorded on continuous effort shows a gradual decline in the
amplitude of potentials
Treatment:
a) Neostigmine & Physostigmine (anticholinesterase) – destroys acetylcholine
esterase & potentiates the effect of acetylcholine on the end plate
b) Steriods – destroy lymphocytes & there by reduce the antibody titre
11. A female patient of 40 yrs. age complains of drooping of eye lid and general
weakness and fatigue that aggravates towards evening, but improves after
rest or sleep. What could be your provisional diagnosis and what is the
nature of dysfunction? Give the physiological basis of use of a drug in this
condition.
Diagnosis : Myasthenia gravis .
Drug: Neostigmine (anticholinesterase) – destroys acetylcholine esterase &
potentiates the effect of acetylcholine on the end plate
 1

NERVE PHYSIOLOGY

1. ACTION POTENTIAL
Definition: Transient change in the resting membrane potential when the membrane is excited by a
threshold stimulus
Genesis of action potential
• depolarization –decrease in electronegativity of the interior of the resting cell
• repolarization – return of RMP to negative value
• depolarization beyond threshold leads to action potential

depolarization exceeds threshold

↓
sodium channels open
↓
sodium ions rush in
↓
membrane potential reverses
↓
shifts from -70 mv to +60 mv
↓
as membrane potential reaches +40mv , the
sodium channels close and are inactivated
↓
potassium channels open
↓
Potassium ions diffuse out
↓
membrane repolarizes
↓
Membrane potential returns to negative value (-70mv)

5 7

4 8

-55 mv
1 3
-70 mv 9
2

PHASES OF ACTION POTENTIAL

1. Stimulus artifact
 2

2. Latent period
3. Slow depolarization
4. Firing level
5. Rapid depolarization
6. Spike potential
7. Rapid repolarisation
8. Slow repolarisation
9. Hyperpolarisation
IONIC BASIS OF ACTION POTENTIAL
Stimulus artifact – A brief irregular deflection of the baseline at the beginning of
recorded AP. It marks the point of stimulus
Latent period – the period between the application of stimulus and the beginning of
action potential. This is the time taken by the impulse to travel along the axon.
Slow depolarization – This is due to Na+ influx through the sodium leakage channels
Firing level – The point at which the rate of depolarization increases
Rapid depolarization – This is due to rapid entry of Na+ through voltage gated Na+
Channels
Spike potential – The sharp rise and rapid fall are the spike potential of the axon
Rapid repolarization – This is due to rapid exit of K+ through the voltage gated K+ channels
After depolarization – a slower fall of potential at the end of repolarisation. This is due
to slow exit of K+
After Hyperpolarization – Overshooting of tracing in the hyperpolarizing direction. This is
due to continuous efflux of K+ through slow K+ channels

2. RESTING MEMBRANE POTENTIAL ( RMP)

Definition : The potential difference existing across the cell membrane when the cell is at rest is
called resting membrane potential
RMP of different cells:
Nerve fibers = -70 mv
Skeletal muscle fiber = -90 mv
Smooth muscle fiber = -50 mv
Cardiac muscle fiber = -90 mv
Genesis of RMP:
a) K+ Efflux: K+ is mainly responsible for the development of RMP (- 94 mv)
b) Na+ influx: Na+ that enters in to the cell may neutralize up to 8 mv
c) Na+- K+ Pump:
Direct role – Pumps 3Na+ out and 2k+ in creating a negativity inside (- 4 mv)
Summary of net effect:
K+ diffusion to outside = - 94 mv
+
Na diffusion to inside = + 8 mv
Na+ - K+ Pump = - 4 mv
Net effect = +90 mv
 3

3. CONDUCTION OF NERVE IMPULSE

CONDUCTION IN UNMYELINATED FIBERS
• Explained by LOCAL CIRCUIT THEORY
• Conduction is by spread of +ve curent to adjacent area of membrane interiorly
• Exteriorly the circuit is completed
• Thus, by local circuit current flow, an active region stimulates the adjacent inactive regions to
the threshold.
• The impulse is conducted in both directions at constant speed

CONDUCTION IN MYELINATED NERVE FIBRES (SALTATORY CONDUCTION)

• The myelin sheath acts as an insulator. It does not allow passage of any ions through the
membrane. So the conduction of impulse is not continuous as in unmyelinated fiber
• The nerve impulse is conducted from one node of Ranvier to the next node of Ranvier
• The action potential “jumps” from one node to the next. Hence called saltatory conduction
• Local circuit current flows between active and inactive node

Advantages of saltatory conduction

• helps in faster conduction of impulses
• Energy is saved as sodium potassium pumps are only required at specific points along the axon.
 4

4. Erlanger gasser classification

Fibre type Function Diameter (µm) Conduction

velocity(m / s)
A-α Proprioception, 12 – 20 70 – 120
Somatomotor
A-β Touch, Pressure 5 – 12 30 – 70

A-γ Motor to spindle 3–6 15 – 30

A-δ Pain, temperature, touch 2–5 12 – 30

B Preganglionic autonomic 3 3–5

C Dorsol root pain 0.4 – 1.2 0.5 – 2

5.COMPOUND ACTION POTENTIAL

Compound action potential is a multipeak potential recorded from a nerve trunk.
Basis of compound action potential:
A nerve trunk is made up of different group of fibers.
Each group of nerve fibers has different conduction velocity. Hence the
impulses reach the recording electrode at different times. The first peak belongs to
fast conducting fibers & the last peak belongs to slow conducting fibers

APPLIED
1. Why regeneration does not occur in the central nervous system?
Absence of Neurolemma, the outermost layer surrounding the myelin sheath of an axon

2. Describe the degenerative changes in a peripheral nerve after cut injury. Or describe Wallerian
degeneration
Changes in proximal and distal stumps:
Functional changes:
– Decrease in the conduction velocity
– Failure in the conduction of nerve impulse
Physical changes:
 5

- Breaking up of axon cylinder into fragments

- Myelin sheath disintegrates into fat droplets

Changes in cell body:

– Nissle granules disintegrates into fragments - chromotolysis
– Golgi apparatus, mitochondria & neurofibrils disappear
– Cell body swells due to accumulation of fluid and becomes round.
– Nucleus is pushed to the periphery.
----------------------------------------------------------------------------------------------------------------------------- -
3. Saturday night palsy
- Saturday night palsy is due to the effect of mechanical pressure or compression on
Radial nerve.
- Type A fibers are most affected fibers → muscle weakness
- Type B fibers are moderately affected → diminished sense of touch & pressure
- Type C fibers are the least affected fibers → intact pain sensation

Susceptibility Most Intermediate Least susceptible

for: susceptible
Hypoxia B A C
Pressure A B C
Local C A B
anesthetics
 1

BLOOD
1. ERYTHROPOIESIS
* Refers to the process of production and maturation of Red Blood
Cells (erythrocytes)
* Site of production – Red bone marrow of all the bones upto 20
years of life. After 20 years, only flat bones produce RBCs.
Stages of Erythropoiesis :
1. Hemocytoblast
2. BFU –E, Blast Forming Unit – E
3. CFU-E, Colony Forming Unit – E
4. Proerythroblast
5. Early normoblast
6. Intermediate normoblast
7. Late normoblast
8. Recticulocyte
9. Mature erythrocyte
1. Hemocytoblast:
- 18 – 23 um in diameter
- Large Nucleus
- Thin rim of basophilic cytoplasm
- Pleuripotent stem cells
2. Blast Forming Unit – E:
- Unipotent progenitor cell.
- Less Sensitive to Erythropoietin
3. CFU (E) – Colony Forming Unit
- Matured unipotent progenitor cell
- Highly sensitive to erythropoietin
4. Proerythroblast:
- 14-19 µm in diameter.
- Large nucleus with distinct nucleoli
- Basophilic cytoplasm.
- Vit B12 & Folic acid are required for the conversion of this stage into next stage.
5. Early normoblast;
- 11-17 µm in diameter.
- Dense nucleus
- Basophilic cytoplasm.
6. Intermediate normoblast:
- 10-12 µm in diameter
- more condensed nucleus
- Hb (Hemoglobin) is formed
- Polychromatophilic cytoplasm.
7. Late normoblast:
- 8-12 µm in diameter.
- Dense nucleus (Pyknotic)
- Nucleus extrudes after this stage & disintegrates
- Acidophilic cytoplasm.
8. Reticulocyte:
- Almost of the same size of matured RBC
- A small reticulum is seen in the cytoplasm.
10. Mature Erythrocyte:
- About 7.2 um in diameter.
- No nucleus
- Acidophilic cytoplasm
 2

Regulation of Erythropoiesis

1. Erythropoietin a hormone secreted by kidneys

- Stimulates the bone marrow tissue to produce more RBCs.

2. Hypoxia: Lack of O2 is the main condition which stimulates erythropoietin secretion.

Lack of O2 (Hypoxia)

Kidneys

Erythropoietin

Red Bone marrow

RBC Production

Restoration of O2 Supply
 3

3. Nutrients:
a) Proteins for synthesis of Hb.
b) Minerals:
i) Iron : for synthesis of heme part of Hb.
ii) Copper: for synthesis of Hb.
4. Vitamins:

a) Vitamins B12 & Folic Acid: Required for synthesis of DNA. These factors are called
maturation factors.
b) Vitamin C is also required.

5. Hormones:
Thyroxine stimulate erythropoietin
Glucocorticoids
Testosterone
Growth hormone RBC Production

Normal Count of RBC:

- Male 5-6 million/cu mm of blood
- Female 4.5 – 5.5 millions/cu mm of blood.
---------------------------------------------------------------------------------------------------------------------
2.WBC – White Blood Cells
Leucocytes (anucleated, colourless)

Granulocytes Agranulocyte

Neutrophils (50 - 70%) Monocyte (2-8%)

Eosinophils (1-4%)
Basophils (0-1%) Lymphocyte (20-40)

Cell Type Size Nucleus Cytoplasm

Neutrophil 10-14 u Multilobed Fine granules
(1-5 lobed) Purple coloured
Eosinophil 10-14 u Bilobed, Spectacle, Coarse granules brick
shaped red coloured
Basophil 10-14 u Bilobed ‘S’ shaped Thick granules, Blue
coloured , obscure or
mask the nucleus
Monocyte 15-20 u Kidney shaped, Abundant cytoplasm,
eccentric (towards no granules
periphery)
Lymphocyte 7-10 u Round Nucleus A Thin rim of
(Small) filling the cells cytoplasm

Large 12-16 u Large Round Nucleus Abundant cytoplasm.

 4

Functions of WBCs:

1. Neutrophils: Phagocytosis

Process of Phagocytosis:

a. Margination The neutrophils slow down in the circulation and get attached to
the wall of capillary endothelium.

b. Diapedesis - Neutrophils squeeze through the pores of capillary wall and

enter the tissue.

c. Chemotaxis – Neutrophils are attracted towards the infected site by the

chemicals released from the site.

d. Phagocytosis – Neutrophils, when comes in contact with bacteria ,the

membrane invaginates & enclose around the bacteria.

Then the enclosed vesicle is pinched off from the membrane. This forms a phagosome.
This combines with lysosomes. Lysosome releases lytic enzymes which digest the contents of
phagosome.
 5

Examples:
- Phagocytosis of bacteria.
- Phagocytosis of dead cells.
- Phagocytosis of antigen - antibody complex
- Phagocytosis of foreign particles like carbon particles, sodium urate crystals.
2. Eosinophil:
a. Anti-allergic – Eosinophils contain anti – inflammatory histaminase which
inactivate histamine.

b. Anti-Parasitic – Eosinophils contain a basic protein which destroys larval

parasites.

c. clot lysis – Eosinophils produce prefibrinolysin when activated, lyse the clot.

d. Phagocytosis – Engulf antigen – antibody complexes.

e. Detoxification: Certain foreign proteins are detoxified.

3. Basophil:

a) Release histamine which takes part in allergic reactions.

b) Release heparin which takes part in prevention of intravascular clotting.

4. Monocyte:
a. Enter the tissues & form tissue macrophages.
b. The main function of monocytes in circulation & tissues is phagocytosis.
c. Macrophages also co operate with B & T cymphocytes in both hormonal &
cell mediated immunity.

5. Lymphocytes:
B- Lymphocytes and T- Lymphocytes

B Lymphocytes: Take part in humoral immunity on exposure to antigens

B- Lymphocytes.

Plasma cells.
 6

Secretion of antibodies
T. Lymphocytes: Take part in cell-mediated immunity
i) Rejection of foreign grafts
ii) Destruction of cancer cells
iii) T helper cells take part in humoral immunity.
iv) T Suppressor cells prevent auto immunity.
v) Major defence against bacterial, Viral & fungal infections.
--------------------------------------------------------------------------------------------------------------------
3. IMMUNITY

Definition: The resistance of the body to the diseases caused by micro organisms (infectious
diseases) is called immunity.

Classification:

Immunity

Innate immunity (inherent) Acquired immunity

(Skin, mucous, membrane, (after exposure to micro-
GIT secretions, Micro & Macrophages, organisms.)
Natural killer cells etc.)

Natural Artificial

Passive Active Passive Active

Transfer of antibodies - Clinical Injection of Vaccination
Through placenta to fetus Disease activated
& through colostrums - Sub clinical lymphocytes
infection & Serum with
antibodies

Humoral immunity Cell-mediated

Activation of B Lymphocytes Activation of ‘T’ Lymphocyte

Plasma cells Formation of 4 Types of T cells

Antibodies a) Cytotoxic ‘T’ cells

b)T helper
c)T Suppressor
d)T Memory cells
 7

HUMORAL IMMUNITY

- B Lymphocytes participate in humoral immunity.

- on exposure to antigens → activation of B- lymphocytes to plasma cells → produce
specific antibodies against foreign antigens.
Mechanism pf Humoral immunity
- Antigen is fragmented by macrophages.
- A fragment of antigen binds to MHC Class II protein in the cell membrane of macrophages
and forms a complex.
- this complex is presented to the B cell by macrophages ( Antigen Presenting cell).
- Macrophage also secretes interleukin 1 which activates both T-Helper cells and B-
Lymphocytes.
- ‘T’ helper cells secrete IL2, IL4, IL5, IL6 (cytokines).
- these cytokines act on ‘B’ lymphocytes.
- ‘B’ Lymphocytes undergo proliferation & differentiation
- ‘B’ lymphocytes form plasma cells.
- Plasma cells produce specific antibodies.
Antibodies: Types Ig G, Ig A, Ig M, Ig D, Ig E.
1. Ig G antibodies:
- 75% of the total antibodies in the body.
- can cross the placenta.
- secreted into colostrum
- role in immunity in the fetus & the new – born.
2. Ig A Antibodies:
- 20% of total antibodies.
- present in mucosal secretions.
- protect the mucosal surface from infections.
3. Ig M antibodies:
- Mostly intra vascular.
- Destroy the organisms that enter the circulation.
4. Ig D antibodies
- Present in the surface of immature B- lymphocytes.
- help in the functional maturation of B- Lymphocytes.
5. Ig E antibodies:
- Present mainly on the surface of mast cells and basophils.
- Responsible for hypersensitive immune reactions (Allergy)
Functions of Antibodies:

1. Neutralisation of Antigen : - Antibodies neutralise the toxic effect of some bacterial

toxins.
2. Immobilization of bacteria: Immobilise the cilia or flagella of motile bacteria.
This limits the spread of disease.
3. Enhancement of phagocytosis: (Opsonisation):
- Ig G antibodies form an attachment to the antigen and enhances the phagocytic
activity of neutrophils and macrophages.
4. Antibody dependant cellular cytotoxicity:
- Antibodies link the target cells with Natural killer cells which kill the targets
secreting toxic chemicals.
5. Agglutination & Precipitation of antigen:
By cross linking antibodies make the pathogens to clump together (agglutination) &
the soluble antigens to form precipitation. This helps in easy phagocytosis.
6. Activation of complement:
- Antibodies bound to antigens activate a group of proteins in the plasma called
complement proteins. They facilitate the exudation of phagocytes towards the site
of infection.
 8

7. Provide fetal & newborn immunity:

- By the transfer of antibodies from mother through placenta & colostrums, the
fetus & newborn acquire immunity.
Cell – Mediated Immunity
- T Lymphocytes are involved in cell mediated immunity.
- They are produced in the bone marrow.
- They attain functional maturity in ‘Thymus’ under the influence of a hormone called
‘Thymopoietin” secreted from Thymus.
- They are 4 types of ‘T’ cells.
a) T helper cells (CD 4)
b) T Killer/Cytotoxic T Cells (CD 8)
c) T Suppressor cells.
d) T memory cells.
a) Activation of T Helper cells:

Antigen binds to MHC class II protein on the surface of Macrophage (Antigen presenting cell)

Forms a complex

secretion of IL-1

Presentation to “T” cell “

Activation of “T” Helper cells

B) Activation of cytotoxic ‘T’ Cells:

i) Antigen in virus infected cells, cancer cells & foreign grafts.

Processing of antigen to peptide fragments

Peptide fragments of processed antigen bind to MHC class I protein & forms a complex.

Presented to cytotoxic ‘T’ cells.

Activation of cytotoxic ‘T’ Cells.

-------------------------------------------------------------------------------------------------------------------
ii) Another way of activation of cytotoxic ‘T’ Cells

Antigen + MHC class II protein on the surface of macrophages (APC)

Interleukin – 1

Activation of ‘T’ helper cells.

Production of IL-2 by ‘T’ helper cells.

 9

Activation of cytotoxic ‘T’ cells.

Function of Activated cytotoxic ‘T” Cells;

Activated cytotoxic ‘T’ Cells

Perforin lymphotoxin

Forms holes in the Activates damaging

Plasma membrane of enzymes in the target cell
Target cells - Entry of ECF-

Swelling & burst of cell Destruction of DNA

Cell death Cell death

Examples: Death of virus infected cells, Tumour cells & foreign graft cells.

a) Function of ‘T’ helper cells:

Take place in both humoral & cell mediated immunity
i) Role in humoral immunity:

T- helper cells(TH2)

Interleukin – 2,4,5 & 6 (cytokines)

Activation of B Cells

Plasma cell

Secretion of antibodies
(ii) Role in cell-mediated immunity:
T- helper cells (TH1)

Interleukin – 2

Activation of cytotoxic ‘T’ Cells

Release of perferins & lymphotoxins

Death of target cells

b) Function of cytotoxic ‘T’ Cells:
- Destruction of Virus infected cells.
- Destruction of cancer cells.
- Rejection of foreign grafts.
- Major defence against viral, fungal & bacterial infection.
c) Functions of ‘T’ Suppressor cells:
- Suppress the production of antibodies against the own tissue.
- this prevents the auto immune diseases like Rheumatoid arthritis etc.
d) Function of ‘T’ Memory cell:
- Facilitates the activation of ‘T’ lymphocytes faster during secondary response.
 10

4.HEMOSTASIS
Definition:
Prevention of blood loss by arrest of bleeding
Stages:
Vasoconstriction
Platelet plug formation
Blood coagulation
Clot retraction
Fibrinolysis
Growth of fibrous tissue to repair the ruptured/damaged vessel permanently
a. Vasoconstriction:
Ruptured blood vessel
↓
Vasoconstriction
↓
Reduction in bleeding
-vasoconstriction due to Nervous reflexes, Local myogenic spasm & local humoral
factors (e.g Serotonin from platelets)
b. Platelet plug formation:
Platelets circulate in a resting, inactive state
↓
When blood vessel wall is injured
↓
Platelets adhere to collagen, laminin and von –
Willibrand factor in the vessel wall.
↓
Platelet activation
(Activated platelets change shape, release ADP & stick to each other →platelet
aggregation.Platelet activating factor (PAF) secreted by neutrophil, monocytes &
platelets increase aggregation)
Thromboxane A2 increases platelet aggregation; helps in formation of temporary
hemostatic plug
c. Blood clotting or coagulation:
Damage to the tissues of Damage to the blood
blood vessel wall

EXTRINSIC INTRINSIC
PATHWAY PATHWAY

Formation of Prothrombin Activator Complex

↓
Prothrombin Thrombin
↓
Fibrinogen Fibrin (clot)

d. Clot retraction:
Definition:
Reduction in the size of clot
 11

Mechanism:
Fibrin stabilizing factor & thrombosthenin produced by platelets cause
strong contraction of platelets which are attached to fibrin
↓
Reduction of clot into smaller mass

9.Fibrinolysis (lysis of clot):

Damaged vascular endothelium
↓
Releases Thrombomodulin
↓
Thrombomodulin + Thrombin complex
↓
Activates protein c

Inactivates factors V &VIII Inhibits the inhibitor of Tissue

Plasminogen Activator
↓
Activation of tPA ( Tissue Plasminogen Activator)
↓
Plasminogen → Plasmin(lysis of clot)

5. BLOOD COAGULATION/ CLOTTING

Introduction:
When blood comes out of the blood vessel, it looses 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
 12

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

Extrinsic mechanism of clotting:

Triggered by tissue injury
Injured tissues release factor III (tissue factor)

VII VIIa
PF3
Ca2 + & III

X Xa
Va Prothrombin
Ca2+ Activator
tissue phospholipids Complex

Intrinsic mechanism of clotting:

Contact of blood with collagen, HMW kininogen, kallikrein
↓
Release of platelet phospholipids
&
activation of factor XII XIIa
↓
XI XI a
↓
IX IXa
PL
Ca2+
VIIIa

X Xa
Va Prothrombin
Ca2+ Activator
Platelet phospholipids Complex
 13

common pathway:
Both intrinsic and extrinsic pathways activate
Factor X Xa
PF3
Ca2+
V

Prothrombin (II) thrombin

XIIIa
stabilization

fibrinogen(I) fibrin (clot)

Clot: A meshwork of fibrin threads entrapping the blood cells and a fluid called serum
6. BLOOD GROUPS
Discovered by Landsteiner
Awarded Nobel Prize
Blood group systems:
ABO system
Rh System
Lewis System
MN system
Luthern System
ABO system
Grouping depends on presence/absence of Antigens/Agglutinogens
Antigens –A & B
Blood groups are A(A1&A2), B, AB(A1B & A2B) & O
Antibodies/Agglutinins Are in plasma
Landsteiner’s Law:
- If an agglutinogen is present on the RBC, corresponding agglutinin will be
absent in the plasma
- If an agglutinogen is absent corresponding agglutinin will be present
[Exception to the 2nd part is Rh System - Rh-ve people will not have Rh
Antibodies]
Rh Blood Group:
Discovered by Landsteiner & Weiner
The Rh Antigens are C, D, E. The common antigen is D antigen
People having ‘D’ antigen are called Rh +ve (85%)
People not having ‘D’ antigen are called Rh-ve (15%)
There are no naturally occurring antibodies
Blood Group Agglutinogen and Agglutinin:
Genotype Blood Group Agglutinogen Agglutinin
(RBC) (plasma)

AA, AO A A Anti B
BB, BO B B Anti A
AB AB AB Nil
OO O Nil Anti A
Anti B
 14

Determination of Blood Group:

Cells (R.B.C)
Anti A serum Anti B serum
A + --

B -- +

AB + +

O -- --

+ Agglutination -- No Agglutination
Uses of Blood Grouping:
In Blood Transfusion
In Pregnancy
In Disputed Paternity
Infertility and Early Fetal loss
Disease Relation e.g O group have twice incidence of Duodenal ulcer than A or B
In forensic science
In Anthropological studies
Blood Transfusion:
Transferring blood from one person to another person
Cross matching :
Major cross matching
Recipient’s Serum + Donor’s RBC
Minor Cross matching
Recipient’s RBC + Donor’s Serum
Universal Donor - O group persons have no agglutinogen and so can give blood to
anyone.
Universal Recipient - AB group persons have no agglutinins and so can receive any
type of blood
The above are no longer valid as complications can be produced by Rh and other
sub groups. But in case of extreme emergency O-ve blood can be used
ABO incompatibility:
- ABO incompatibility rarely produces hemolytic disease of newborn
- Anti A & Anti B antibodies are of IgM
- Cannot cross the placenta
Rh Incompatibility:
When 2nd time Rh +ve blood is transfused into negative blood–severe reactions occur
In women – during pregnancy incompatibility leads to ERYTHROBLASTOSIS
FOETALIS – a hemolytic disease of new born
 15

BLOOD – 5 MARKS
1.Functions of plasma proteins
Important plasma proteins are Albumin, Globulin & Fibrinogen
Normal Albumin/Globulin ratio = 1.7 : 1
a. Colloidal osmotic pressure: Albumin is mainly responsible for the development of
colloidal osmotic pressure. The normal colloidal osmotic pressure of blood is 25-30
mmHg. This is mainly responsible for the passage of fluid across the capillary
membrane
b. Viscosity of blood: Globulin maintains the viscosity of blood to some extent.
Viscosity is one of factors that influence blood pressure
c. Immunity: Antibodies (Immunoglobulins) belong to gammaglobulins. Antibodies
neutralize the antigen
d. Coagulation: Both prothrombin & fibrinogen take part in clotting process
Prothrombin activator

Prothrombin Thrombin

Fibrinogen Fibrin (clot)

e. Transport:
i) CO2 is transported by carbamino proteins
ii) Transferrin – transports iron
iii) Ceruloplasmin – transports copper
iv) TBG – Thyroxine Bound Globulin
v) CBG – Cortisol Bound Globulin
f. Acid-Base Balance – Plasma proteins act as buffers & neutralize any change in
blood pH
g. Protein reserve – Serve as storehouse of protein. Provides proteins to tissues during
starvation
h. ESR : Fibrinogen & Globulin increase the ESR. Albumin decreases the ESR
i. Haptoglobin: Forms the complex with hemoglobin & prevent its filtration into the
kidney
2. ANTICOAGULANTS
Anticoagulants are the substances that prevent clotting
a. Natural anticoagulants:
Heparin – produced by mast cells & basophils
Mechanism of action: facilitates antithrombin – III which inhibits the clotting
factors II, IX, XI & XII
b. Anticoagulants used in blood bank:
Acid Citrate Dextrose (ACD): Calcium chelating agent
Mechanism of action: forms a complex with calcium ions and decreases ionic
calcium level
c. Anticoagulants used in the laboratories:
Sodium citrate – Forms double salt with calcium ions
Double oxalate (Oxalates of K+ & NH4) - Precipitation of calcium
EDTA- Ethylene Diamine tetra acetate – Preparation of calcium ions
d. Therapeutic anti coagulants:
Dicoumarol – prevents the synthesis of blood clotting factors II, VII, IX, X by
competitive inhibition with vitamin .K.
------------------------------------------------------------------------------------------------------------
---------
 16

3. PHAGOCYTOSIS (Neutrophil response during inflammation)

Definition: The process of engulfing of macromolecules like bacteria, dead cells & particulate
matter by neutrophils, monocytes & tissue macrophages is called phagocytosis.
Steps involved in the process
Margination: Neutrophils slow down in the circulation & get attached to the capillary wall. The
cell adhesion molecules adherin, Integrin & selectin are involved.
Diapedesis: Neutrophils squeeze through the pores in the capillary wall into the tissues.
Chemotaxis : Neutrophils are attracted towards the site of damage ( infection & inflammation)
by the chemicals released at the site of damage.
Engulfing :
Microbes are coated with complement & antibodies (opsonization)
↓
Neutrophil membrane invaginates enclosing the microbe
↓
Formation of vacuole
↓
Vacuole fusing with lysosome
↓
Lysosomes release hydrolyzing enzymes & bactericidal agents like hydrogen peroxide,
mycloperoxidase etc
↓
Killing & digestion of the microbe.
---------------------------------------------------------------------------------------------------------------------

4. ANTICLOTTING MECHANISMS (Factors that prevent intravascular

coagulation)
1. Physical characteristics of the endothelium (e.g) Smoothness of vascular endothelium
Atherosclerotic (deposit of fat) plague in the vascular endothelium gives a rough surface which
activates platelets & initiate clotting.
2. High blood flow rates: Increased velocity of blood flow prevents clotting.
3.Presence of natural anticoagulants: Anticoagulants like heparin, anti thrombin III & α2macro
globulin are some of the natural anti coagulants present in the circulation and prevent the intra
vascular clotting .
4. Fibrinolytic system: When small clots are formed in the vessels they are immediately lysed by
the system.
Tissue Plasminogen Activator (tPA)
↓
Plasminogen → Plasmin (digests the fibrin into soluble fragments dissolving the clot)
---------------------------------------------------------------------------------------------------------------
5. COMPOSITION & FUNCTIONS OF LYMPH
Composition of Lymph
Electrolytes – same as that of plasma
Minerals – Ca₂₊ & phosphorous are lower than plasma
Protein – lower than that of plasma
Aminoacids – same as that plasma
Urea & creatinine – same as that of plasma
Glucose & chlorides – more than that of plasma
Cells – Lymphocytes & plasma cells are present
Clotting factor and antibodies are present.
Functions of Lymph
• Returns protein, electrolytes and water to the blood from the tissue spaces
• Removes the bacteria and particulate matter
• Fat absorption in the intestine by the lacteals
 17

• The lymphocytes and antibodies present in the lymph take part in body defence against
infectious diseases
• Helps in the redistribution of body water
• Transport antibiotics and other drugs injected intramuscularly
---------------------------------------------------------------------------------------------------------------------
6. FIBRINOLYTIC SYSTEM
Fibrinolysis refers to the process of dissolution of fibrin. Fibrinolytic system refers to the
substances taking part in fibrinolysis.
The important components of fibrinolytic system:
Protein C, tissue plasminogen activator & plasmin or fibrinolysin which is present in an inactive
form (plasminogen)
Protein C → Activated protein C

Inactivates clotting Inactivates inhibitor of tissue plasminogen activator

Factors V a & VIIIa ↓
Activation of tissue plasminogen activator
↓
Plasminogen Plasmin (fibrinolysis)
Fibrinolysin lyses fibrin into soluble fragments called as fibrin degradation products which inhibit
thrombin
Plasminogen Activaor system
Intrinsic: Factor XIIa and Kallikrein
Extrinsic: Tissue plasminogen activator, Streptokinase and staphylokinase
Physiological role of fibrinolytic system
• Cleans the minute clots of tiny vessels
• Promotes normal healing process
• Dissolution of menstrual clot
• Dissolution of sperms in the epididymis
Therapeutic role of fibrinolytic system
Streptokinase and staphylokinase are bacterial enzymes that activate plasminogen to
plasmin. So they are used in the treatment of early myocardial infarction.
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7.HAZARDS OF BLOOD TRANFUSION
Complications of whole blood transfusion
1. Hemolytic reaction due to red cell incompatibility
2. Transmission of certain diseases like hepatitis malaria, AIDS, Syphilis etc.,
3. Transient hyperkalemia followed by hypokalemia
4. Hypocalcemia
5. Volume overload
6. Bacterial contamination
7. Thrombophlebitis
8. Air embolismEffect of mismatched blood transfusion

Mismatching refers to transfusion of incompatible blood groups

a. Mild hemolytic reaction
Aggultination
↓
Hemolysis
↓
Bilirubin
↓
Jaundice
 18

b. Severe immediate hemolytic reaction

Wide spread agglutination leads to development of following signs and symptoms.
1. Chill and rigors
2. Fever and headache
3. Breathlessness
4. Chest pain and abdominal pain
5. Nausea and vomiting
6. Joint pain
7. Circulatory shock (due to release of histamine and other vasodilators)
Feathers of post shock phase
8. Hemolysis of agglutinated cells
9. Release of hemoglobin and its excretion into the urine
10. Jaundice
11. Anemia
12. Renal shut down due to precipitation of Hb in the renal tubules
13. Hyperkalemia and uraemia
c. Delayed hemolytic reaction:
1. Occurs 3days to 3weeks after transfusion only as 1 in 3200 transfusions
2. Antibodies that develop against donor cells cause agglutination and hemolysis
3. Symptoms are often mild or absent.
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8. FUNCTIONS OF PLATELETS
Platelets/Thrombocytes are biconvex discs produced by bone marrow
Size: 2 to 4μ
Normal count: 1.5 to 4 lakhs/cumm of blood
Granules of platelets: α granules and dense granules
α granules : consists of factor V, Fibrinogen, Von williebrand Factor, Platelet
factor IV, PGDF
Dense granules: Consists of ADP, Calcium, serotonin

Functions of Platelets
1. Primary hemostasis – Arrest of bleeding by temporary platelet plug formation is
referred as primary hemostasis.
Injury to wall of blood vessel
↓
Exposure of collagen
↓

Platelet adherence to damaged vessel wall

↓

Release of ADP and Thromboxane A2

↓
Activation of more platelets
↓
Aggregation and adherence of platelets (enhanced by platelet activation
factor produced by platelets and macrophages)
 19

↓
Temporary platelet plug

2. Secondary Hemostasis: Arrest of bleeding by the definite clot formation is called

secondary hemostasis
Platelet phospholipids and platelet activation factor III are the factors which are
involved in clotting.
3. Clot retraction: Contraction of contractile proteins (actin, myosin and
thrombosthenin) present in the platelets play an important role in clot retraction
4. Repair of capillary endothelium: Platelets adhere to the von – willebrand factor in
the wall of damaged blood vessels and release platelet derived growth factor
(PDGF). This factor plays an role in the repair of endothelium
5. Vasoconstriction: Platelets release serotonin which is a vasoconstrictor.
6. Defense /Phagocytosis: Platelets are helpful in phagocytosis of carbon particles,
viruses and immune complexes
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9.Oral Anticoagulants
Refers to anticoagulants which are used as drugs. These substances are given through
mouth to prevent clotting.
The substances which are used as oral anticoagulants - coumarin derivatives (Dicoumarol
and warfarin)
Dicoumarol
- It is a synthetic product
- It resembles vitamin K in structure

Mechanism of action
- Vitamin K is required for synthesis of clotting factors II, VII, IX, X protein C and
Protein S
- By competitive inhibition with Vitamin K, dicoumarol inhibits the synthesis of the
above factors from liver

Other Vitamin K antagonists

Warfarin, Phenindione, Nicoumalone
Therapeutic use:
Patient with hypercoagulability (increased tendency of blood to clot) are given
these oral anticoagulants for preventing the formation of thrombus
Oral anticoagulants are not effective invitro as they are vitamin K competitive
inhibitor and can act only inside the body