Physiology

Introduction

Fluid Mosaic Model (singer & Nicolson, 1972)

• Membrane = a lipid bilayer in which proteins float like icebergs in a sea
• Both lipids and proteins are free to move laterally → hence "fluid"

Composition

A. Lipids

• Phospholipids — amphipathic: hydrophilic head outward, hydrophobic tail inward
• Bilayer is impermeable to water-soluble substances (ions, glucose, urea)
• Cholesterol → controls fluidity; prevents the membrane becoming too fluid or too rigid

B. Proteins

C. Carbohydrates — the glycocalyx

• Negatively charged → repels other negative ions
• Cell–cell recognition and adhesion
• Receptor sites for hormones; antigenic determinants (blood groups)

Functions of the Cell Membrane

• Selective permeability — a barrier
• Transport of substances
• Reception of signals (hormone and neurotransmitter receptors)
• Cell–cell recognition and adhesion
• Generation of membrane potential
• Immunological identity — antigens

Classification of Transport

Passive Transport

A. Simple diffusion

• Movement down a concentration gradient; no carrier
• Through the lipid bilayer → O2, CO2, N2, alcohol, steroids (lipid-soluble)
• Through protein channels → water, ions
• Fick's law — rate ∝ area × concentration gradient; ∝ 1/thickness

B. Facilitated (carrier-mediated) diffusion

• Down the gradient but requires a carrier
• Shows saturation, specificity and competition
• Examples — glucose (GLUT transporters), amino acids

C. Osmosis

• Movement of water across a semipermeable membrane from lower to higher solute concentration
• Through aquaporins

Ion Channels

Applied Aspects

• Cystic fibrosis — defective CFTR chloride channel → thick viscid secretions
• Cholera toxin — opens Cl− channels in gut → massive secretory diarrhoea
• Local anaesthetics → block voltage-gated Na+ channels
• Hereditary spherocytosis — defective spectrin → loss of membrane stability

Definition

Classification

1. Primary active transport — energy directly from ATP hydrolysis

2. Secondary active transport — energy from an ion gradient created by primary transport

3. Vesicular transport — endocytosis and exocytosis

Primary Active Transport

A. Sodium–potassium pump (Na⁺–K⁺ ATPase)

• Present in all cell membranes
• Structure — 2 α subunits (catalytic, bear the ATPase site) + 2 β subunits

3 Na+ pumped out → 2 K+ pumped IN → 1 ATP hydrolysed → Net loss of 1 positive charge from inside → electrogenic pump

Functions of the Na⁺–K⁺ pump

• Maintains low intracellular Na+ and high intracellular K+
• Contributes about −4 mV directly to the resting membrane potential
• Controls cell volume — prevents osmotic swelling
• Creates the Na+ gradient that drives all secondary active transport
• Consumes 20–30% of the cell's resting ATP (up to 70% in neurones)
• Inhibited by ouabain and digitalis

B. Other primary pumps

Characteristics of Active Transport

• Saturation — a maximum rate (Tmax) exists once all carriers are occupied
• Specificity — each carrier moves one substance or a closely related group
• Competitive inhibition — related solutes compete for the same carrier
• Temperature dependent — slows markedly with cooling
• Inhibited by metabolic poisons — cyanide, dinitrophenol, iodoacetate (all block ATP production)
• Stops in hypoxia — no ATP

Secondary Active Transport

Na+–K+ pump → Low intracellular Na+ → Steep inward Na+ gradient → Na+ re-entry drags glucose uphill → Glucose absorbed

Transcellular Transport — Glucose Absorption in the Gut

Apical membrane: SGLT-1 (secondary active, Na+-linked) → Glucose enters the enterocyte against its gradient → Basolateral membrane: GLUT-2 (facilitated diffusion) → Glucose leaves into blood down its gradient

• Na+ pumped out at the basolateral surface by the Na+–K+ pump → keeps the apical gradient going
• Same arrangement operates in the renal proximal tubule

Comparison of Transport Mechanisms

Vesicular Transport

Applied Aspects

• Digitalis → inhibits Na+–K+ ATPase → ↑ intracellular Na+ → ↓ Na+–Ca2+ exchange → ↑ intracellular Ca2+ → positive inotropic effect
• ORS in diarrhoea — works because Na+–glucose co-transport stays intact in cholera; glucose must be present for the sodium to be absorbed
• Familial hypercholesterolaemia — defective LDL receptor → failure of receptor-mediated endocytosis
• Cell swelling in hypoxia — no ATP → pump fails → Na+ and water enter the cell

Total Body Water

• Adult male — 60% of body weight (42 L in a 70 kg man)
• Adult female — 50% (more subcutaneous fat, which holds little water)
• Newborn — 75–80%
• Obese — lower; elderly — lower

Fluid Compartments

• Transcellular fluid — CSF, synovial, pleural, pericardial, peritoneal, intraocular, GI secretions

Ionic Composition

• Osmolality of both compartments = 290–300 mOsm/kg — always equal, since water moves freely
• Plasma differs from interstitial fluid only in its higher protein content

Measurement — the Dilution Principle

Properties of an ideal marker

• Distributes only in the compartment being measured
• Non-toxic, easily measured
• Not metabolised or excreted rapidly

• ICF cannot be measured directly — no marker enters all cells and stays there
• ICF = Total body water − ECF (measured by difference)
• Interstitial fluid = ECF − Plasma (also by difference)

Daily Water Balance

• Obligatory urine volume = 500 mL/day — the minimum needed to excrete the daily solute load

Regulation of Body Fluid Volume

• Thirst — hypothalamic osmoreceptors
• ADH — water retention by the collecting duct
• Aldosterone — Na+ and hence water retention
• ANP — natriuresis when the atria are stretched

Applied Aspects

• Dehydration — isotonic (haemorrhage, diarrhoea), hypertonic (water loss > salt), hypotonic (salt loss > water)
• 3rd space loss — fluid sequestered in peritoneum or bowel lumen; lost to circulation though still inside the body
• IV fluids — isotonic saline stays in ECF; 5% dextrose distributes through all compartments once the glucose is metabolised

Definition

Factors Responsible

1. Unequal ion distribution across the membrane

2. Selective permeability — membrane at rest is 50–100× more permeable to K+ than to Na+

3. Na+–K+ pump — electrogenic

4. Non-diffusible intracellular anions — proteins, phosphates

Genesis of RMP

A. Contribution of K⁺ (the main factor)

High intracellular K+ (140 mEq/L) → K+ leaks out through leak channels → Anions (protein) cannot follow → Inside becomes negative → Electrical attraction opposes further K+ exit → Equilibrium reached

• K+ equilibrium potential (EK) = −90 mV

B. Contribution of Na⁺

• Small inward leak of Na+ makes the interior slightly less negative
• ENa = +61 mV
• Shifts RMP from −90 mV to about −86 mV

C. Contribution of the Na⁺–K⁺ pump

• 3 Na+ out : 2 K+ in → net loss of positive charge
• Adds a further −4 mV → final RMP −90 mV

Quantitative Contribution to RMP

Measurement of RMP

• Two electrodes — one inside the cell, one outside
• Intracellular electrode = glass microelectrode, tip < 1 µm, filled with 3M KCl
• Connected to a cathode ray oscilloscope through an amplifier
• First recorded by Hodgkin and Huxley in the giant axon of the squid

Nernst Equation

• Gives the equilibrium potential for a single ion
• Goldman–Hodgkin–Katz equation accounts for all permeant ions and their relative permeabilities

Ionic Basis Summarised

Terms Related to Membrane Potential

Applied Aspects

• Hyperkalaemia → ↑ extracellular K+ → RMP becomes less negative (depolarised) → initial hyperexcitability, then inactivation of Na+ channels → cardiac arrest in diastole
• Hypokalaemia → RMP more negative (hyperpolarised) → muscle weakness, paralysis
• Hypocalcaemia → ↑ Na+ permeability → hyperexcitability → tetany
• Ouabain / digitalis → pump inhibition → gradual loss of RMP

Definition

Variables Kept Constant

Components of a Control System

Stimulus → Sensor (receptor) → Integrating centre → Effector → Response → Feedback to sensor

• Set point — the value the system defends
• Error signal — the difference between actual and set point
• Gain — effectiveness of the system = correction ÷ remaining error

Negative Feedback

Examples

Positive Feedback

Physiological (useful) examples

• Parturition — head stretches cervix → oxytocin → stronger contraction → more stretch (Ferguson reflex)
• Blood clotting — thrombin activates factors V and VIII → more thrombin
• Action potential — depolarisation opens Na+ channels → more depolarisation
• LH surge before ovulation
• Milk ejection reflex

Pathological (vicious cycle) examples

• Circulatory shock → ↓ BP → ↓ coronary flow → weaker heart → further ↓ BP
• Heart failure → ↓ cardiac output → salt and water retention → more overload

Organ Systems Contributing to Homeostasis

Gain of a Control System

• Example — baroreceptor system: a stimulus that would raise BP by 175 mmHg actually raises it by only 25 mmHg
• Correction = 150; remaining error = 25 → gain = −6
• Higher gain = more effective control

Feed-forward Control

• Anticipatory — correction begins before the variable changes
• Examples — cephalic phase of gastric secretion; hyperventilation at the start of exercise

Applied Aspects

• Disease = failure of homeostasis. Diabetes mellitus is failed glucose homeostasis; heart failure is failed circulatory homeostasis
• Ageing → reduced gain of control systems → poor tolerance of heat, cold and fluid shifts
• Positive feedback becoming uncontrolled is the basis of shock irreversibility

Definition

Sites

Stages of Development

Pluripotent stem cell → CFU-E → Proerythroblast → Early (basophilic) normoblast → Intermediate (polychromatophilic) normoblast → Late (orthochromatic) normoblast → Reticulocyte → Mature RBC

Changes during maturation

• Total time about 7 days
• Reticulocyte spends 1–2 days in marrow, 1 day in blood
• Normal reticulocyte count 0.5–1.5%

Factors Necessary for Erythropoiesis

A. Growth factor

• Erythropoietin — a glycoprotein hormone

– 90% from the kidney — peritubular interstitial cells

– 10% from the liver

– Stimulus: tissue hypoxia

– Acts on CFU-E → ↑ proliferation and differentiation

B. Maturation factors

Regulation

↓ Tissue O2 (anaemia, hypoxia, haemorrhage, altitude) → Renal peritubular cells sense hypoxia → ↑ Erythropoietin → ↑ Erythropoiesis in marrow → ↑ RBC count → ↑ O2 delivery → Negative feedback switches EPO off

Fate of RBC

• Lifespan 120 days
• Destroyed in the reticuloendothelial system — spleen (the "graveyard of RBC"), liver, bone marrow
• Iron is recycled; globin returns to the amino acid pool; haem → bilirubin

Normal Values Related to RBC

• Biconcave shape → ↑ surface area for gas exchange, and flexibility to pass through 3 µm capillaries
• No nucleus and no mitochondria → energy from anaerobic glycolysis only

Applied Aspects

• Chronic renal failure → ↓ erythropoietin → normocytic normochromic anaemia; treated with recombinant EPO
• Pernicious anaemia — autoimmune loss of intrinsic factor; needs parenteral B12, oral is useless
• Polycythaemia — primary (vera, a myeloproliferative disorder, EPO low) vs secondary (altitude, cyanotic heart disease, EPO high)
• EPO abuse in endurance athletes → ↑ haematocrit → thrombosis
• Reticulocyte count is the best index of marrow response to therapy

Definition

Stages of Haemostasis

1. Vascular spasm — immediate local vasoconstriction

2. Platelet plug formation — temporary (primary) haemostatic plug

3. Blood coagulation — definitive (secondary) plug

4. Fibrous organisation or lysis of the clot

Coagulation Factors

• Factor VI does not exist — it was activated factor V
• Vitamin K dependent: II, VII, IX, X (mnemonic 1972) plus proteins C and S
• All synthesised in the liver except III, IV and VIII

Extrinsic Pathway

Tissue injury → Tissue factor (III) released → III + VII + Ca2+ → Activates Factor X

• Rapid — 15 seconds
• Tested by Prothrombin Time (PT), normal 11–16 s
• Standardised as INR; monitors warfarin therapy

Intrinsic Pathway

Contact with collagen / glass → XII → XIIa → XI → XIa → IX → IXa → IXa + VIIIa + Ca2+ + platelet phospholipid → Activates Factor X

• Slower — 2 to 6 minutes
• Tested by Activated Partial Thromboplastin Time (APTT), normal 30–40 s; monitors heparin therapy

Common Pathway

Xa + Va + Ca2+ + phospholipid = Prothrombin activator → Prothrombin (II) → thrombin → Fibrinogen (I) → Fibrin monomer → Fibrin polymer → Factor XIIIa cross-links → stable fibrin clot

• Thrombin also activates factors V, VIII, XI and XIII → a positive feedback loop

Natural Anticoagulant Mechanisms

• Smooth intact endothelium + negative surface charge
• Antithrombin III — inactivates thrombin, IXa, Xa, XIa, XIIa; action accelerated 1000× by heparin
• Heparin — from mast cells and basophils
• Protein C and S — inactivate factors Va and VIIIa; vitamin K dependent
• Thrombomodulin on endothelium — activates protein C
• Prostacyclin (PGI2) and NO — inhibit platelet aggregation

Fibrinolysis

Plasminogen (in the clot) → tPA / urokinase / streptokinase → plasmin → Digests fibrin → FDPs and D-dimer

Bleeding and Clotting Time

Applied Aspects

• Haemophilia A — factor VIII deficiency; X-linked recessive; ↑ APTT with normal PT and bleeding time
• Vitamin K deficiency → ↑ PT; haemorrhagic disease of the newborn (prevented by 1 mg vitamin K at birth)
• Liver disease → all factors ↓ → both PT and APTT prolonged
• DIC — widespread clotting then consumption of factors → bleeding; ↑ D-dimer
• Warfarin blocks vitamin K epoxide reductase; effect takes 2–3 days; reversed by vitamin K. Heparin acts immediately; reversed by protamine

Introduction

• Over 30 systems known; ABO and Rh are clinically the most important
• ABO discovered by Karl Landsteiner (1901)

Abo System

• Antibodies are naturally occurring IgM — do not cross the placenta
• Appear by 2–8 months of age; peak at 8–10 years
• Antigens are glycoproteins; the precursor is the H antigen
• Bombay phenotype (Oh) — no H antigen → tests as O but cannot receive O blood

Inheritance

• Three alleles — IA, IB, i
• IA and IB are co-dominant; i is recessive
• Group A = IAIA or IAi; Group O = ii only

RH System

• Discovered in the Rhesus monkey by Landsteiner and Wiener
• Antigens — C, D, E, c, e; D is the most antigenic
• Rh positive = D antigen present; 85% of Indians are Rh positive
• Anti-D is not naturally occurring — forms only after exposure
• Anti-D is IgG → crosses the placenta

Transfusion — Donor Compatibility

Mismatched Transfusion Reaction

Incompatible RBC transfused → Recipient antibody binds donor RBC → Agglutination + complement activation → Intravascular haemolysis → Free Hb in plasma → haemoglobinuria → Acute tubular necrosis → renal failure

Features

• Fever with rigors, loin and chest pain, restlessness
• Hypotension and shock
• Jaundice, haemoglobinuria (dark urine)
• Acute renal failure — the chief cause of death
• DIC in severe cases

Erythroblastosis Fetalis (haemolytic Disease of the Newborn)

Rh-negative mother + Rh-positive fetus → Fetal RBC enter maternal circulation at delivery → Mother forms anti-D (IgG) → Next Rh-positive pregnancy → IgG crosses placenta → Haemolysis of fetal RBC

• First child usually escapes; risk rises with each pregnancy
• Features — anaemia, jaundice within 24 h, hepatosplenomegaly, hydrops fetalis, kernicterus
• Prevention — anti-D immunoglobulin 300 µg IM to the mother within 72 hours of delivery, abortion or amniocentesis
• Treatment — phototherapy, exchange transfusion, intrauterine transfusion

Other Blood Group Systems and Blood Banking

• Other systems — MNS, Lewis, Kell, Duffy, Kidd, Lutheran, P
• Stored at 4 °C in CPD-A (citrate-phosphate-dextrose-adenine)
• Shelf life 35–42 days
• Storage lesion — ↓ 2,3-BPG, ↓ ATP, ↑ K+, ↑ ammonia, ↑ RBC fragility
• Component therapy preferred — packed cells, platelets, FFP, cryoprecipitate

Applied Aspects

• Cross-matching — major (donor cells + recipient serum) and minor (recipient cells + donor serum)
• Coombs test — direct detects antibody already on RBC (newborn); indirect detects free antibody in serum (mother)
• Medicolegal — blood groups can exclude but never prove paternity
• Massive transfusion complications — citrate toxicity (hypocalcaemia), hyperkalaemia, hypothermia, dilutional coagulopathy
• Autologous transfusion — the patient's own blood; avoids all incompatibility and infection risk

Normal Values

Classification

Neutrophils

• Lifespan — 6–8 hours in blood, 4–5 days in tissue
• First cell to reach the site of acute inflammation
• Functions — phagocytosis, the body's first line of cellular defence

Margination → Diapedesis (squeeze between endothelial cells) → Chemotaxis → Opsonisation (IgG, C3b) → Phagocytosis → Killing — respiratory burst (H2O2, superoxide) + lysosomal enzymes

• Arneth count — classifies by nuclear lobes

– Shift to left — more immature (fewer lobes) → acute infection

– Shift to right — more hypersegmented → megaloblastic anaemia

Other Leucocytes

Leucopoiesis

Pluripotent stem cell → Myeloid or lymphoid stem cell → Myeloblast / lymphoblast → Promyelocyte → myelocyte → metamyelocyte → Band form → Mature granulocyte

• Regulated by colony stimulating factors — G-CSF, M-CSF, GM-CSF, and interleukins
• Granulocytes take 7–10 days to develop
• Marrow holds a reserve pool about 20× the circulating number

Immunity

Acquired immunity — two arms

• IgG — most abundant; only one that crosses the placenta
• IgM — largest; first antibody in a primary response
• IgA — secretory; in milk, saliva, tears, gut
• IgE — allergy and parasites

Applied Aspects

• Leukaemia — malignant proliferation of WBC; acute (blast cells) vs chronic
• Agranulocytosis — neutrophils < 500/µL → severe infection; caused by chloramphenicol, carbimazole, cytotoxics
• AIDS — HIV destroys CD4 T cells → failure of cell-mediated immunity → opportunistic infection
• Leucocyte adhesion deficiency → failure of margination
• Chronic granulomatous disease → defective respiratory burst → phagocytosis without killing

Definition and Normal Values

Structure

• Molecular weight 64,458
• Consists of haem (4%) + globin (96%)
• Haem = protoporphyrin IX + Fe2+ (ferrous). Iron in the ferrous state alone can bind O2
• Globin = 4 polypeptide chains, each bound to one haem
• One Hb molecule therefore binds 4 O2 molecules

Types of Haemoglobin

• HbF has higher O2 affinity (P50 19 mmHg) — it binds 2,3-BPG poorly → allows placental O2 extraction

Synthesis of Haem

Succinyl CoA + Glycine → ala synthase (rate-limiting; needs vit B6) → δ-aminolaevulinic acid → Porphobilinogen → Uroporphyrinogen → Coproporphyrinogen → Protoporphyrin IX → + Fe2+ (ferrochelatase) → haem

• Occurs in mitochondria and cytosol of the normoblast
• Haem inhibits ala synthase — negative feedback
• Lead inhibits ala dehydratase and ferrochelatase → basophilic stippling, ↑ ala in urine

Fate of Haemoglobin

RBC lives 120 days → Destroyed in res (spleen, liver, marrow) → Hb → haem + globin → Globin → amino acid pool → Haem → haem oxygenase → iron released (recycled) + biliverdin → Biliverdin reductase → Unconjugated bilirubin

• About 6 g of Hb is destroyed daily, yielding 300 mg of bilirubin
• Carbon monoxide is released — the body's only endogenous source
• Iron is conserved — only about 1 mg/day is lost

Functions of Haemoglobin

• Transport of O2 — 1 g Hb carries 1.34 mL O2; 97% of blood oxygen
• Transport of CO2 — as carbaminohaemoglobin (23% of total CO2)
• Buffering — the most important buffer of the blood after bicarbonate; reduced Hb is a better buffer than oxyhaemoglobin
• Contributes to blood viscosity

Iron Metabolism (in Brief)

• Total body iron 3–4 g; 65–70% in haemoglobin
• Absorbed in the duodenum as Fe2+; vitamin C aids absorption, phytates and tea hinder it
• Transported as transferrin; stored as ferritin and haemosiderin in liver, spleen and marrow
• Daily requirement — 1 mg male, 2–3 mg female, 3–4 mg in pregnancy
• Loss about 1 mg/day; there is no active excretory mechanism for iron

Abnormal Haemoglobins and Derivatives

Applied Aspects

• Thalassaemia — reduced synthesis of α or β chains; ↑ HbA2 and HbF in β-thalassaemia trait
• Sickle cell disease — abnormal structure; HbS polymerises when deoxygenated → sickling → vaso-occlusive crises
• Haemoglobinuria — when free plasma Hb exceeds the binding capacity of haptoglobin (about 100 mg/dL)
• Anaemia — graded by Hb: mild 10–12, moderate 7–10, severe < 7 g/dL
• Hb electrophoresis — the definitive test for thalassaemia and sickle cell disease
• HbA1c — glycated Hb; reflects the average blood glucose over the preceding 8–12 weeks
• Lead poisoning → blocks haem synthesis → basophilic stippling, ↑ urinary ala, microcytic anaemia

Definition

Phases

Ionic Basis

Stimulus → Membrane depolarises to firing level (−55 mV) → Voltage-gated Na+ channels open → Na+ influx → further depolarisation → positive feedback → spike to +35 mV → Na+ channels inactivate; K+ channels open → K+ efflux → repolarisation

• Na+ channel has two gates — an activation gate (outer, opens fast) and an inactivation gate (inner, closes slowly). This explains the refractory period
• Total duration in nerve 1–2 ms; in skeletal muscle 2–4 ms; in cardiac muscle 200–300 ms
• Actual ion movement is minute — 1 in 100,000 ions; the Na+–K+ pump restores it later

Properties of Action Potential

• All-or-none law — a subthreshold stimulus produces no response; at or above threshold the response is maximal and of constant amplitude, regardless of stimulus strength
• Propagated without decrement — amplitude does not fall along the fibre
• Self-propagating — local circuit currents depolarise the adjacent segment
• Refractory period follows
• Stimulus strength is coded by frequency, not amplitude

Refractory Period

• Significance — limits the maximum firing frequency (about 2500/s in nerve) and ensures one-way conduction
• In cardiac muscle the long refractory period prevents tetanus — essential for the pumping action

Electrotonic Potential and Local Response

• Subthreshold stimulus → local, graded, non-propagated change
• Catelectrotonus — depolarisation at the cathode → ↑ excitability
• Anelectrotonus — hyperpolarisation at the anode → ↓ excitability
• Local response — at 7–15% below threshold; graded and can summate

Strength–duration Curve

• Chronaxie is inversely proportional to excitability — a short chronaxie means a highly excitable tissue
• Chronaxie values — nerve 0.0001–0.001 s; skeletal muscle 0.001–0.01 s; cardiac muscle 0.001–0.003 s
• Denervated muscle has a greatly prolonged chronaxie — used to detect denervation

Compound Action Potential

• Recorded from a whole nerve trunk, not a single fibre
• Does not obey the all-or-none law — amplitude increases with stimulus strength as more fibres are recruited
• Shows multiple peaks (A, B, C waves) because fibres conduct at different velocities

Applied Aspects

• Local anaesthetics (lignocaine) → block voltage-gated Na+ channels from within → no action potential → loss of sensation. Small unmyelinated pain fibres are blocked first
• Tetrodotoxin (puffer fish) → blocks Na+ channels; tetraethylammonium blocks K+ channels
• Hypocalcaemia → ↑ Na+ permeability → firing level approaches RMP → spontaneous discharge → tetany
• Hyperkalaemia → sustained depolarisation → Na+ channels inactivated → cardiac arrest
• Multiple sclerosis → demyelination → conduction block or slowing → visual and motor deficits
• Epilepsy → abnormal synchronous high-frequency discharge of cortical neurones; phenytoin acts by prolonging Na+ channel inactivation
• Hyperventilation → alkalosis → ↓ ionised calcium → tetany with carpopedal spasm

Definition

Structure

• Presynaptic terminal — unmyelinated axon ending; contains synaptic vesicles of acetylcholine (about 10,000 molecules per vesicle) and many mitochondria
• Synaptic cleft — 20–50 nm wide; contains acetylcholinesterase in the basal lamina
• Postsynaptic membrane (end plate) — thrown into junctional folds to ↑ surface area; bears nicotinic (NM) receptors at the crests

Steps of Neuromuscular Transmission

Nerve action potential reaches terminal → Voltage-gated Ca2+ channels open → Ca2+ influx → vesicles fuse with membrane → ACh released by exocytosis (about 125 vesicles) → ACh binds nicotinic receptor → Na+ influx → End Plate Potential → EPP reaches threshold → Muscle action potential → contraction

End Plate Potential (epp)

• MEPP (miniature end plate potential) — 0.5 mV; produced by spontaneous release of a single quantum (one vesicle)
• Normal EPP is about 3–4× larger than needed to reach threshold — the safety factor of transmission

Fate of Acetylcholine

ACh in cleft → Acetylcholinesterase → Choline + acetate → Choline reuptake into nerve terminal (rate-limiting) → Recombined with acetyl CoA by choline acetyltransferase → ACh resynthesised

• Hydrolysis is complete in 1 millisecond → permits rapid repetitive transmission

Quantal Release of Acetylcholine

• Quantum = the contents of one synaptic vesicle, about 10,000 ACh molecules
• At rest, single quanta are released spontaneously → MEPPs of 0.5 mV
• One nerve impulse releases about 125–300 quanta simultaneously → a full EPP of 50–75 mV
• Release is strictly Ca2+ dependent — no Ca2+, no release
• Mg2+ competitively inhibits Ca2+ → hypermagnesaemia causes weakness

Properties of Neuromuscular Transmission

• One-way (unidirectional) conduction
• Synaptic delay — 0.5–1 ms, mainly the time for Ca2+-triggered exocytosis
• Fatigue on prolonged high-frequency stimulation — ACh stores deplete
• Susceptible to hypoxia and drugs
• 1:1 transmission — each nerve impulse normally produces one muscle impulse

Drugs and Toxins Acting at the NMJ

Comparison — Neuromuscular Junction VS Neuronal Synapse

Applied Aspects

• Myasthenia gravis — autoantibodies against nicotinic receptors → ↓ receptor number → fatigable weakness; improves with neostigmine
• Lambert–Eaton syndrome — antibodies against presynaptic Ca2+ channels → ↓ ACh release; strength improves with repeated activity (opposite of myasthenia)
• Tetanus toxin — blocks inhibitory glycine release in the cord → spastic paralysis (contrast with botulinum)
• Organophosphate poisoning — sludge features (salivation, lacrimation, urination, defaecation, GI upset, emesis) with muscle fasciculation; treat with atropine and pralidoxime before ageing of the enzyme occurs
• Aminoglycosides → ↓ ACh release → may unmask or worsen myasthenia

Structure of the Sarcomere

Contractile Proteins

• Myosin (thick) — head has actin-binding site + ATPase
• Actin (thin) — F-actin double helix with myosin-binding sites
• Tropomyosin — lies in the actin groove; covers the binding sites at rest
• Troponin — three subunits: troponin C (binds Ca2+), troponin I (inhibitory), troponin T (binds tropomyosin)
• Titin — elasticity; nebulin, dystrophin — structural

Excitation–contraction Coupling

Muscle action potential → Spreads along T-tubule → Activates dihydropyridine (DHP) receptor — a voltage sensor → Opens ryanodine receptor on sarcoplasmic reticulum → Ca2+ released from terminal cisternae → Ca2+ binds troponin C → Tropomyosin moves aside → Actin binding sites exposed

• Triad = one T-tubule + two terminal cisternae; at the A–I junction in mammalian muscle
• Cytosolic Ca2+ rises from 10−7 to 10−5 M

Sliding Filament Mechanism (huxley, 1954)

The cross-bridge cycle

1. Attachment — energised myosin head binds the exposed actin site

2. Power stroke — head tilts 45°, pulling actin toward the centre; ADP + Pi released

3. Detachment — a fresh ATP binds the myosin head → it releases actin

4. Re-energisation — ATP hydrolysed by myosin ATPase → head recocked to 90°

• The cycle repeats as long as Ca2+ and ATP are present
• Each cycle shortens the sarcomere by about 1%

Relaxation

Stimulus stops → Ca2+ pumped back into SR by SERCA (Ca2+-ATPase) → Ca2+ stored bound to calsequestrin → Ca2+ leaves troponin C → Tropomyosin re-covers binding sites → relaxation

• Relaxation also requires ATP — both for the pump and to detach the cross-bridges

Simple Muscle Twitch

• Total duration about 0.1 s
• Relaxation is longer than contraction

Summation and Tetanus

Repeated stimuli before relaxation is complete → Successive contractions summate → Partial fusion → incomplete (clonic) tetanus → Complete fusion → complete (tonic) tetanus

• Tetanus develops 3–4× more tension than a single twitch, because Ca2+ accumulates in the sarcoplasm
• Cardiac muscle cannot be tetanised — its refractory period lasts almost the whole contraction
• Treppe (staircase) — progressive increase in force over the first few contractions, due to accumulating Ca2+

Energy Sources for Contraction

Applied Aspects

• Rigor mortis — after death ATP is exhausted → myosin heads cannot detach from actin → persistent stiffness
• Duchenne muscular dystrophy — absent dystrophin → membrane fragility → progressive weakness; ↑↑ serum CPK
• Malignant hyperthermia — mutated ryanodine receptor → uncontrolled Ca2+ release on halothane or succinylcholine → rigidity and hyperthermia; treated with dantrolene
• Troponin I and T are the most specific serum markers of myocardial infarction
• Tetany — hypocalcaemia lowers the firing threshold of nerve, not of muscle; the muscle itself is normal
• Botulinum toxin is used therapeutically in blepharospasm, achalasia and spasticity, by preventing ACh release

Structure of a Neurone

• Cell body (soma) — contains Nissl granules (rough ER), the site of protein synthesis
• Dendrites — receive impulses; conduct toward the soma
• Axon — conducts away; arises from the axon hillock, which has the lowest threshold and is the site of impulse initiation
• Myelin sheath — by Schwann cells in the periphery and oligodendrocytes in the CNS
• Nodes of Ranvier — gaps in myelin, 1 mm apart; rich in Na+ channels

Classification BY Erlanger and Gasser

• Sensory classification — Ia (annulospiral), Ib (Golgi tendon), II (flower spray, touch), III (pain, cold), IV (unmyelinated, pain)

Properties of Nerve Fibres

• Excitability — the ability to respond to a stimulus
• Conductivity — transmission of the impulse
• All-or-none law — applies to a single fibre, not to a whole nerve trunk
• Refractory period
• Accommodation — a slowly rising stimulus fails to excite
• Summation — of subthreshold stimuli
• Indefatigability — nerve does not fatigue easily (unlike the synapse)

Conduction of the Impulse

A. In unmyelinated fibres — continuous conduction

Active region depolarised → Local circuit current flows to adjacent region → Adjacent region reaches threshold → Action potential regenerated → Process repeats point to point

B. In myelinated fibres — saltatory conduction

• Myelin is a good insulator → current cannot flow across the internode
• The impulse therefore jumps from node to node (Latin saltare, to leap)

Factors Affecting Conduction Velocity

• Diameter — velocity ∝ diameter (∝ √diameter in unmyelinated fibres)
• Myelination — the single greatest factor
• Temperature — cooling slows conduction; a nerve block occurs at about 8 °C
• Internodal distance — longer internodes conduct faster

Degeneration and Regeneration

• Wallerian degeneration — the segment distal to injury degenerates within 3–4 days; axon and myelin break up and are removed by macrophages
• Retrograde degeneration — proximal stump degenerates back one or two nodes
• Chromatolysis — in the cell body; Nissl granules disperse and the nucleus moves peripherally
• Regeneration — occurs in peripheral nerves only, at about 1 mm/day, guided by Schwann cell tubes (bands of Büngner)
• CNS axons do not regenerate — oligodendrocytes release inhibitory factors and glial scarring occurs

Axoplasmic Transport

• Retrograde transport carries tetanus toxin, rabies and herpes virus from the periphery to the CNS

Applied Aspects

• Demyelinating disease — multiple sclerosis (CNS), Guillain–Barré syndrome (peripheral) → slowed or blocked conduction
• Nerve conduction velocity studies — demyelination slows velocity; axonal loss reduces amplitude
• Pressure block — large fibres are affected first (order: motor, touch, pain); local anaesthetics block small fibres first (order: pain, temperature, touch, motor)
• Hypoxia affects fibres in the order B > A > C; this is why autonomic function fails early in ischaemia

Classification of Muscle

Types of Skeletal Muscle Fibre

Smooth Muscle — Types

Mechanism of Smooth Muscle Contraction

Stimulus → Ca2+ enters mainly from ECF → Ca2+ binds calmodulin → Activates myosin light chain kinase → Phosphorylates myosin light chain → Cross-bridge cycling → contraction

• Relaxation — myosin light chain phosphatase dephosphorylates the head
• Latch bridge mechanism — cross-bridges detach very slowly → sustained tension at very low energy cost; essential for sphincters and blood vessels
• Smooth muscle uses only about 1/300th the energy of skeletal muscle for the same tension

Properties of Cardiac Muscle

• Rhythmicity (autorhythmicity) — from the SA node
• All-or-none law applies to the whole heart, not to a single fibre, because it is a functional syncytium
• Long refractory period (250–300 ms) → tetanus impossible
• Staircase (Treppe) phenomenon
• Obeys Starling's law

Special Properties of Smooth Muscle

• Plasticity (stress relaxation) — tension falls back toward normal after sustained stretch. Allows the bladder and stomach to fill without a rise in pressure
• Rhythmicity — slow waves and spike potentials generated by the interstitial cells of Cajal, the pacemaker of the gut
• Tone — maintained partial contraction, as in sphincters and arterioles
• Response to stretch — stretch itself causes contraction (myogenic response); basis of autoregulation of blood flow
• Sensitive to chemical agents — hormones, local metabolites, pH, O2; contracts even when denervated

Applied Aspects

• Training — endurance training increases type I capacity; strength training hypertrophies type II fibres
• Cardiac muscle cannot regenerate → infarcted myocardium heals by fibrous scar, never by new muscle
• Smooth muscle hyperplasia — the uterus in pregnancy grows by both hypertrophy and hyperplasia
• Calcium channel blockers act chiefly on smooth and cardiac muscle, since these depend on extracellular Ca2+; skeletal muscle is spared because it uses SR calcium
• Denervation hypersensitivity — denervated smooth muscle becomes supersensitive to circulating transmitter, as receptors spread over the whole membrane
• Hirschsprung disease — absent ganglion cells → loss of coordinated smooth muscle activity → functional obstruction

Definition

Phases of the Cardiac Cycle

A. Atrial systole (0.11 s)

• Contributes only 20–30% of ventricular filling — the "atrial kick"
• 70–80% of filling has already occurred passively
• Produces the a wave of the JVP and the fourth heart sound
• Its loss (as in atrial fibrillation) is well tolerated at rest but limits exercise

B. Isovolumetric (isometric) contraction (0.05 s)

Ventricle contracts → AV valves close → first heart sound → All four valves shut → Pressure rises steeply; volume unchanged → Ends when LV pressure exceeds aortic pressure (80 mmHg)

C. Ejection phase (0.22 s)

• Rapid ejection (0.11 s) — 70% of stroke volume expelled; LV pressure peaks at 120 mmHg
• Reduced ejection (0.11 s) — remaining 30%; pressure begins to fall

D. Protodiastole (0.04 s)

• Ventricular pressure falls below aortic pressure
• Semilunar valves close → second heart sound
• Produces the incisura (dicrotic notch) on the aortic pressure curve

E. Isovolumetric relaxation (0.08 s)

• All valves closed again; volume constant at ESV = 50 mL
• Pressure falls rapidly to below atrial pressure

F. Ventricular filling (0.5 s)

• Rapid filling (0.11 s) — AV valves open; produces the third heart sound
• Slow filling / diastasis (0.19 s) — the phase most shortened by tachycardia
• Last rapid filling — the next atrial systole

Volume Changes

Pressure Changes

Jugular Venous Pulse

Applied Aspects

• Tachycardia shortens diastole more than systole → less filling time and less coronary perfusion time → poorly tolerated in mitral stenosis and ischaemic heart disease
• Mitral stenosis → obstructed filling → ↑ left atrial pressure → pulmonary congestion
• Aortic stenosis → ↑ afterload → LV hypertrophy
• Atrial fibrillation → loss of atrial kick → about 20% fall in cardiac output; absent a wave in JVP
• Cannon a waves — atrium contracts against a closed tricuspid valve; seen in complete heart block and ventricular tachycardia

Definitions and Normal Values

Determinants of Stroke Volume

A. Preload — Frank–Starling mechanism

• Starling's law — force of contraction is directly proportional to the initial length of the muscle fibre, within physiological limits
• Basis — the length–tension relationship; stretch moves sarcomeres toward the optimal 2.2 µm
• Also ↑ sensitivity of troponin C to Ca2+
• Preload ↑ by — venous return, blood volume, venoconstriction, muscle pump, lying down, bradycardia

B. Afterload

• The resistance against which the ventricle must eject — effectively aortic pressure and peripheral resistance
• ↑ Afterload → ↓ stroke volume
• ↑ in hypertension and aortic stenosis

C. Contractility (inotropic state)

Factors Affecting Cardiac Output

Regulation of Cardiac Output

• Intrinsic (heterometric) — Starling's law: matches output to venous return beat by beat, and equalises right and left ventricular output
• Intrinsic (homometric) — Anrep effect: ↑ contractility on sudden ↑ afterload; Bowditch (Treppe) effect: ↑ contractility with ↑ heart rate
• Extrinsic — nervous: sympathetic → ↑ rate and force; vagus → ↓ rate
• Extrinsic — humoral: adrenaline, thyroxine, glucagon

Measurement of Cardiac Output

A. Fick principle

• Requires mixed venous blood from the pulmonary artery — hence cardiac catheterisation

B. Other methods

Cardiac Work and Efficiency

• External (stroke) work = Stroke volume × Mean arterial pressure
• Volume work — the greater part is spent overcoming pressure, not moving volume
• Kinetic energy component is only about 1% normally, but rises to 50% in aortic stenosis
• Left ventricular work is about 6–7× that of the right
• Cardiac efficiency = 20–25%; the rest appears as heat
• Myocardial O2 consumption is determined chiefly by heart rate, wall tension and contractility — not by the work done

Applied Aspects

• Heart failure → the heart operates on the descending limb of the Starling curve → further dilatation reduces output
• Ejection fraction < 40% defines systolic heart failure
• High-output failure — anaemia, thyrotoxicosis, beri-beri, arteriovenous fistula, Paget disease
• Cardiac tamponade → restricted filling → ↓ preload → ↓ CO despite normal contractility

Definitions and Normal Values

Classification of Regulatory Mechanisms

Rapid — Nervous Mechanisms

A. Baroreceptor reflex (marey reflex)

• Receptors — carotid sinus and aortic arch; stretch receptors
• Afferent — carotid sinus via Hering nerve → glossopharyngeal (IX); aortic via vagus (X)
• Centre — nucleus tractus solitarius in the medulla

↑ BP → Baroreceptors stretched → ↑ Afferent firing → Inhibits vasomotor centre; stimulates vagal centre → ↓ Sympathetic, ↑ parasympathetic → ↓ HR, ↓ contractility, vasodilatation → BP falls

• Most sensitive between 60–180 mmHg
• Resets in 1–2 days to a new level → therefore useless for long-term regulation
• Chief function — buffering sudden changes, especially on standing

B. Chemoreceptor reflex

• Carotid and aortic bodies; stimulated by ↓ PO2, ↑ PCO2, ↑ H+
• Operates only when BP falls below 80 mmHg → vasoconstriction

C. CNS ischaemic response

• The most powerful of all sympathetic activators
• Operates when BP falls below 60 mmHg; maximal at 15–20 mmHg
• Cushing reflex — raised intracranial pressure → medullary ischaemia → ↑ BP + bradycardia + irregular respiration
• A "last-ditch" mechanism to preserve cerebral perfusion

Intermediate Mechanisms

• Renin–angiotensin system — onset in minutes; see below
• Capillary fluid shift — ↓ BP → ↓ capillary hydrostatic pressure → fluid drawn from interstitium into blood
• Stress relaxation of vessels — vessels gradually accommodate a changed volume
• Vasopressin (ADH) — vasoconstriction at high concentration

Long-term — Renal Body Fluid Mechanism

↑ BP → Pressure diuresis and natriuresis → ↑ Renal excretion of salt and water → ↓ ECF volume → ↓ Venous return → ↓ cardiac output → BP returns TO normal

• This system has infinite gain — it continues to act until BP is exactly restored
• Therefore the kidney is the ultimate long-term regulator of blood pressure

Renin–angiotensin–aldosterone system

↓ Renal perfusion / ↓ Na+ / sympathetic stimulation → renin from juxtaglomerular cells → Angiotensinogen → Angiotensin I → ACE (chiefly in lung) → angiotensin II → Vasoconstriction + aldosterone + ADH + thirst → BP rises

Peripheral Resistance and Poiseuille’s Law

• Halving the radius increases resistance 16-fold
• Arterioles are the chief resistance vessels — the "stopcocks" of the circulation; they account for about 50% of total peripheral resistance
• Viscosity also matters — ↑ in polycythaemia, ↓ in anaemia
• Laminar flow is silent; turbulent flow produces sound, which is the basis of Korotkoff sounds and murmurs
• Reynolds number > 2000 predicts turbulence

Applied Aspects

• Carotid sinus syncope — a tight collar or neck massage stimulates the sinus → bradycardia and hypotension → fainting
• Postural hypotension — failure of the baroreceptor reflex, as in autonomic neuropathy of diabetes
• Antihypertensives act on these mechanisms — ACE inhibitors and ARBs on the RAAS, diuretics on the renal mechanism, β-blockers on cardiac output
• Essential hypertension — the renal pressure–natriuresis curve is reset to the right, so a higher pressure is needed to excrete the same sodium load
• Cushing reflex — a rising BP with bradycardia in a head-injured patient is an ominous sign of raised intracranial pressure
• Renal artery stenosis → persistent renin release → secondary hypertension, correctable by angioplasty

Components of the Conducting System

• The SA node is the pacemaker because it has the fastest rate of spontaneous depolarisation and therefore reaches threshold first — it overdrive-suppresses the rest
• Blood supply — SA node from the right coronary artery in 60%; AV node from the right coronary in 90%

Conduction Velocities

AV nodal delay

• Duration 0.09–0.13 second
• Cause — small fibre diameter, fewer gap junctions, low RMP (−60 mV)
• Significance — allows the atria to complete their contraction and empty into the ventricles before ventricular systole begins

Pacemaker Potential (sa Node)

• RMP is unstable — only −55 to −60 mV
• Slow spontaneous depolarisation is called the prepotential or pacemaker potential

If ("funny") current — slow Na+ influx → T-type Ca2+ channels open → Threshold (−40 mV) reached → L-type Ca2+ influx → upstroke → K+ efflux → repolarisation

• The SA node upstroke is due to Ca2+, not Na+ → slow, no overshoot
• Sympathetic → ↑ slope of prepotential → tachycardia
• Vagus → ↑ K+ permeability → hyperpolarisation → bradycardia

Ventricular Action Potential

• Duration 250–300 ms — far longer than in skeletal muscle
• The plateau prolongs the refractory period so that it lasts almost the whole contraction → tetanus is impossible → the heart must relax and refill between beats

Properties of Cardiac Muscle

• Rhythmicity (autorhythmicity) — beats without any nerve supply; the denervated and even the excised heart continues to beat
• Conductivity — spreads as a functional syncytium via intercalated discs
• Excitability — with a long refractory period
• Contractility — obeys the all-or-none law as a whole
• Staircase (Treppe) phenomenon — force increases over the first few beats
• Refractory period 250–300 ms — the longest in the body

Applied Aspects

• Heart block

– First degree — PR interval > 0.2 s

– Second degree — some P waves not conducted (Mobitz I and II)

– Third degree (complete) — atria and ventricles beat independently; ventricular rate 30–40/min → Stokes–Adams attacks

• Ectopic pacemaker — when a focus fires faster than the SA node, or when SA conduction is blocked
• Sick sinus syndrome → requires an artificial pacemaker
• Digitalis slows AV conduction → used to control ventricular rate in atrial fibrillation
• Hyperkalaemia → depresses conduction → widened QRS → cardiac arrest
• Wolff–Parkinson–White syndrome — an accessory bundle of Kent bypasses the AV node → short PR interval with a delta wave → re-entrant tachycardia
• Vagal manoeuvres (carotid massage, Valsalva) slow AV conduction and can terminate supraventricular tachycardia
• Artificial pacemaker — indicated in complete heart block and sick sinus syndrome

Definition

• Recorded at a paper speed of 25 mm/s and a sensitivity of 1 mV = 10 mm
• Therefore 1 small square = 0.04 s and 1 large square = 0.2 s

Leads

• Lead I = left arm − right arm; Lead II = left leg − right arm; Lead III = left leg − left arm
• Einthoven's law — Lead II = Lead I + Lead III
• AVR is normally negative in all its deflections

Regional correlation

Waves and Intervals

• Atrial repolarisation is not seen — it is buried within the QRS complex
• T wave is upright although it is repolarisation, because repolarisation proceeds from epicardium to endocardium, the reverse of depolarisation

Determination of Heart Rate and Axis

• Rate = 300 ÷ number of large squares between two R waves
• Or 1500 ÷ number of small squares
• Normal QRS axis = −30° to +90°
• Left axis deviation — LVH, left anterior hemiblock; right axis deviation — RVH, pulmonary embolism

Einthoven’s Triangle and the Cardiac Vector

• The three bipolar limb leads form an equilateral triangle with the heart at its centre
• The heart is regarded as a dipole in a volume conductor
• Cardiac vector — the resultant of all the instantaneous electrical forces in the heart, having magnitude and direction
• A wave is upright when depolarisation moves toward the positive electrode, and inverted when it moves away
• Mean electrical axis is calculated from leads I and aVF, or from the isoelectric lead

Uses of ECG

• Diagnosis of arrhythmias and heart block
• Diagnosis and localisation of myocardial infarction
• Detection of chamber hypertrophy
• Detection of electrolyte disturbances
• Assessing drug effects and toxicity (digitalis, antiarrhythmics)
• Determination of heart rate and electrical axis

Applied Aspects

• The ECG records electrical, not mechanical activity — a normal ECG can occur in a heart that is not pumping (pulseless electrical activity)

Definition

Muscles of Respiration

A. Quiet inspiration — active

• Diaphragm — chief muscle. Nerve supply: phrenic (C3, C4, C5)

– Contracts → dome flattens → descends 1.5 cm

– ↑ vertical diameter of thorax

– Responsible for 75% of tidal volume

• External intercostals — Nerve supply: intercostal nerves

– Elevate the ribs

– Upper ribs → "pump-handle" movement → ↑ anteroposterior diameter

– Lower ribs → "bucket-handle" movement → ↑ transverse diameter

B. Forced inspiration — accessory muscles

• Sternocleidomastoid → elevates sternum
• Scalenes → elevate 1st and 2nd ribs
• Serratus anterior, pectoralis major and minor
• Alae nasi → nasal flaring
• Diaphragm descends up to 10 cm

C. Quiet expiration — passive

• No muscular contraction
• Due entirely to elastic recoil of lung and chest wall

D. Forced expiration — active

• Anterior abdominal muscles (rectus abdominis, obliques, transversus) → ↑ intra-abdominal pressure → push diaphragm up
• Internal intercostals → pull ribs down and in

Mechanism of Inspiration

Inspiratory muscles contract → ↑ thoracic volume (all 3 diameters) → ↑ negativity of intrapleural pressure → Lung expands → ↓ intra-alveolar pressure (−1 cm H2O) → air enters

Mechanism of Expiration

Muscles relax → Elastic recoil of lung → ↓ thoracic volume → ↑ intra-alveolar pressure (+1 cm H2O) → air leaves

Pressure Changes in One Respiratory Cycle

WHY Is Intrapleural Pressure Negative?

• Two opposing elastic forces act across the pleural cavity:

– Lung → recoils inwards (elastic tissue + surface tension)

– Chest wall → springs outwards

• Pleural cavity is a closed space with only a thin fluid film
• Net effect → subatmospheric (negative) pressure

Importance

• Keeps the lung expanded against its own recoil
• Aids venous return — the respiratory pump
• Becomes positive only in forced expiration (cough, Valsalva)

Compliance

• Lungs alone — 200 mL/cm H2O
• Lungs + chest wall — 110 mL/cm H2O
• Determined by: (a) elastic tissue of lung, (b) alveolar surface tension — lowered by surfactant

Work of Breathing

• Compliance (elastic) work — about 65%
• Tissue resistance work
• Airway resistance work
• Normally only 2–3% of total body energy expenditure

Applied Aspects

• Pneumothorax — air enters pleural cavity → intrapleural pressure = atmospheric → transpulmonary pressure = 0 → lung collapses
• Emphysema — loss of elastic tissue → ↑ compliance → poor recoil → air trapping → barrel chest; expiration becomes active
• Pulmonary fibrosis — ↓ compliance → ↑ work of breathing → rapid shallow breathing
• RDS of newborn — surfactant deficiency → ↑ surface tension → ↓ compliance → atelectasis

Forms of Oxygen Transport

• Dissolved fraction obeys Henry's law; small, but it generates the PO2 that loads Hb
• Hüfner's constant — 1 g Hb binds 1.34 mL O2
• O2 capacity = 15 × 1.34 = 20.1 mL/dL
• Arterial O2 content 20 mL/dL; venous 15 mL/dL
• Extracted at rest = 5 mL/dL; utilisation coefficient = 25%

Oxygen–haemoglobin Dissociation Curve

• X-axis — PO2 (mmHg); Y-axis — % saturation of Hb
• Shape — sigmoid (S-shaped)
• Cause of sigmoid shape — co-operative binding: binding of one O2 ↑ affinity of remaining haem groups

Points on the curve

Significance of the two limbs

• Upper flat part (PO2 60–100) → saturation stays > 90% despite fall in alveolar PO2 → safety margin for loading
• Lower steep part (PO2 10–40) → small fall in tissue PO2 releases large amount of O2 → favours unloading

Factors Shifting the Curve

Bohr Effect

Active tissue → ↑ CO2, ↑ H+, ↑ temperature → Curve shifts right → ↓ affinity of Hb for O2 → More O2 released to tissues

• Reverse occurs in the pulmonary capillary → favours loading

Oxygen Flux (delivery to Tissues)

• Consumption at rest (VO2) = 250 mL/min
• Therefore a 4-fold reserve exists at rest
• In exercise, VO2 may rise to 3000 mL/min; utilisation coefficient rises from 25% to 75–85%

Comparison with Myoglobin

Factors Affecting O₂ Diffusion Across the Respiratory Membrane

• Thickness of the membrane (0.2–0.6 µm) — ↑ in oedema, fibrosis → ↓ diffusion
• Surface area (70 m2) — ↓ in emphysema, pneumonectomy
• Pressure gradient — alveolar PO2 104 vs venous 40 mmHg
• Diffusion coefficient — CO2 diffuses 20× faster than O2
• Contact time — 0.75 s at rest; equilibration complete in 0.25 s

Applied Aspects

• CO poisoning — affinity of Hb for CO is 210× that for O2; also shifts curve left → bound O2 not released. PaO2 and pulse oximetry falsely normal. Skin cherry-red
• Stored blood — ↓ 2,3-BPG → left shift → poor unloading for several hours after transfusion
• Fetal Hb — binds 2,3-BPG poorly → left shift → P50 = 19 mmHg → extracts O2 from maternal blood across placenta
• High altitude — ↑ 2,3-BPG → right shift → better tissue unloading
• Anaemia — PaO2 and saturation normal; content reduced → pulse oximetry is normal and therefore misleading
• Cyanide — O2 delivered but not used → ↓ arteriovenous O2 difference; venous blood bright red

Introduction

A. Nervous Regulation — Respiratory Centres

(i) Medullary centres

(ii) Pontine centres

• Voluntary control — cerebral cortex → corticospinal tract → respiratory motor neurones (breath-holding, speech, singing)

B. Chemical Regulation — Chemoreceptors