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Synapse - Definition and Properties

Definition

• Presynaptic side - usually the axon terminal of the transmitting neuron
• Postsynaptic side - usually a dendrite, soma (cell body), or occasionally another axon of the receiving neuron
• Synaptic cleft - the narrow extracellular space (200-300 Angstroms wide) separating the two membranes

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Types of Synapses

1. Chemical Synapses

• Presynaptic terminal (bouton/synaptic knob): Contains synaptic vesicles (with neurotransmitter), mitochondria (ATP supply for transmitter synthesis), and voltage-gated Ca2+ channels at active zones
• Synaptic vesicles: Store and release neurotransmitter by exocytosis
• Postsynaptic membrane: Bears ionotropic (ligand-gated ion channel) or metabotropic (G protein-coupled) receptors

2. Electrical Synapses

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Steps in Chemical Synaptic Transmission

1. Neurotransmitter is packaged into vesicles and concentrated/docked at the presynaptic terminal (via SNARE proteins: synaptobrevin/v-SNARE + syntaxin + SNAP-25/t-SNAREs)
2. Presynaptic membrane depolarizes (action potential arrives)
3. Depolarization opens voltage-gated Ca2+ channels; Ca2+ enters the terminal
4. Ca2+ binds to synaptotagmin (a Ca2+-sensing protein), triggering vesicle-membrane fusion and exocytosis - transmitter release increases ~100,000-fold; each exocytosis takes only a fraction of a millisecond
5. Transmitter is released into the cleft in quantized (quantal) amounts and diffuses passively across
6. Transmitter binds to postsynaptic receptors - opens ion channels (ionotropic) or activates G protein cascades (metabotropic)
7. Transmitter is cleared by diffusion, enzymatic degradation, or reuptake into cells

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Properties of the Synapse

1. One-Way (Unidirectional) Conduction

2. Synaptic Delay

3. Summation

4. Facilitation, Augmentation, and Post-Tetanic Potentiation

5. Synaptic Fatigue

6. Effect of pH (Acidosis/Alkalosis)

• Alkalosis increases neuronal excitability - arterial pH rising from 7.4 to 7.8-8.0 can precipitate epileptic seizures
• Acidosis depresses neuronal activity - pH below 7.0 typically causes coma (as in severe diabetic ketoacidosis or uremia)

7. Effect of Hypoxia

8. Effect of Drugs

• Excitatory agents: Caffeine, theophylline (lower neuronal excitation threshold); strychnine (blocks inhibitory glycine receptors, causing tonic spasms)
• Depressant/anesthetic agents: Increase membrane threshold for excitation, decreasing synaptic transmission (often by dissolving in lipid membranes and altering their physical properties)

9. Excitation vs. Inhibition

• Excitatory neurotransmitters (e.g., glutamate) - cause depolarization (EPSP)
• Inhibitory neurotransmitters (e.g., GABA, glycine) - cause hyperpolarization (IPSP)

10. Quantal Release

11. Convergence and Divergence

• Convergence: Many presynaptic neurons synapse on one postsynaptic neuron (up to 10,000-200,000 synaptic knobs on a single motor neuron)
• Divergence: One presynaptic neuron may synapse on many postsynaptic neurons, distributing the signal widely

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Summary Table: Electrical vs. Chemical Synapses

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• Guyton and Hall Textbook of Medical Physiology, Ch. 46 - Chemical and Electrical Synapses, Special Characteristics of Synaptic Transmission
• Medical Physiology (Boron & Boulpaep) - Neuronal Synapses, Steps in Synaptic Transmission
• Costanzo Physiology, 7th Edition - Chemical Synapses, Summation, Synaptic Fatigue
• Neuroscience: Exploring the Brain, 5th Edition - The Synapse, Synaptic Integration

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Chapter 1: General Physiology - Complete Answers

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Q1. Feedback Mechanisms - Positive and Negative

Definition

Components of a Feedback System

1. Sensor/Receptor - detects a change in the controlled variable
2. Control center - processes information and determines the response
3. Effector - carries out the corrective response

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A. Negative Feedback Mechanism

• Most common type in the body
• Stabilizing - maintains homeostasis
• The system "feeds back negatively" to reduce the error

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B. Positive Feedback Mechanism

• Less common - not used for routine homeostasis
• Self-amplifying and explosive in nature
• Always moves toward a final outcome (event-driven)
• Requires an external mechanism to terminate the loop

1. Action Potential (Hodgkin Cycle):
   • Depolarization → Na+ channels open → Na+ influx → further depolarization → more Na+ channels open (self-amplifying)
   • Terminated by: Na+ channel inactivation + K+ channel opening
2. Parturition (childbirth):
   • Fetal head stretches cervix → oxytocin released → uterine contractions → more cervical stretch → more oxytocin
   • Terminated by: delivery of baby
3. Blood clotting (coagulation cascade):
   • Each step amplifies the next, producing a burst of thrombin and fibrin clot
   • Terminated by: clot formation + natural anticoagulants
4. Surge of LH at ovulation:
   • Rising estrogen (at high levels) triggers LH surge → ovulation
   • Terminated by: collapse of estrogen after ovulation

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Comparison Table

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Q2. Transport Across Cell Membrane

A. Passive Transport (no energy required)

1. Simple Diffusion

• Lipid-soluble (non-polar) substances pass directly through the lipid bilayer
• Rate depends on: concentration gradient, membrane thickness, lipid solubility (partition coefficient), surface area, molecular size
• Fick's Law: Rate of diffusion = (D × A × ΔC) / thickness
• Examples: O2, CO2, steroids, urea, ethanol, fatty acids

2. Facilitated Diffusion

• Water-soluble or charged substances cross via specific carrier proteins or channel proteins, still down their gradient (no energy needed)

• Ion channels (Na+, K+, Ca2+, Cl- channels)
• Aquaporins (water channels)
• Can be: voltage-gated, ligand-gated, mechanically gated

• Conformational change in a carrier protein shuttles the solute
• Shows: saturation kinetics, specificity, competition
• Example: GLUT transporters for glucose

3. Osmosis

• Movement of water across a semipermeable membrane from low solute concentration to high solute concentration
• Driven by osmotic pressure gradient
• Osmolarity: Number of osmoles per litre of solution
• Normal plasma osmolality = 285-295 mOsm/kg

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B. Active Transport (energy required)

1. Primary Active Transport

• Uses ATP directly
• Na+-K+ ATPase pump: Pumps 3 Na+ out, 2 K+ in per ATP cycle; electrogenic; maintains resting membrane potential
• Ca2+-ATPase pump: Removes Ca2+ from cytoplasm
• H+-K+ ATPase: In gastric parietal cells (acid secretion)

2. Secondary Active Transport

• Uses the electrochemical gradient created by the Na+-K+ pump (indirect ATP use)

• Example: SGLT (Na+-glucose cotransporter) in intestine and renal tubule; Na+-amino acid transporters

• Example: Na+-H+ exchanger, Na+-Ca2+ exchanger

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C. Vesicular Transport (for large molecules)

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Summary Table: Transport Mechanisms

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Q3. Body Fluid Compartments - Oedema - ORS

A. Body Fluid Compartments

• In a 70 kg adult man: TBW = 42 litres

Total Body Water (42 L)
├── Intracellular Fluid (ICF) = 28 L (2/3 of TBW = ~40% body weight)
└── Extracellular Fluid (ECF) = 14 L (1/3 of TBW = ~20% body weight)
    ├── Plasma = 3 L (~4.5% body weight)
    ├── Interstitial Fluid = 11 L (~15% body weight)
    └── Transcellular Fluid = ~1-2 L (synovial, CSF, peritoneal, pericardial, intraocular)

• 60% body weight = total body water
• 40% body weight = intracellular fluid
• 20% body weight = extracellular fluid

Composition:

• TBW: Tritiated water, antipyrine
• ECF: Inulin, mannitol, sucrose, sodium thiosulfate
• Plasma volume: Evans blue dye, radioactive albumin
• Blood volume = Plasma volume / (1 - haematocrit)
• ICF = TBW - ECF

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B. Oedema

Starling Forces (Govern fluid exchange at capillary)

• Pc = Capillary hydrostatic pressure (pushes fluid OUT)
• Pi = Interstitial hydrostatic pressure (pushes fluid IN)
• πc = Plasma oncotic (colloid osmotic) pressure (pulls fluid IN)
• πi = Interstitial oncotic pressure (pulls fluid OUT)

Causes of Oedema (by mechanism):

Types:

• Pitting oedema: Leaves a pit when pressed (cardiac, renal, nutritional, venous)
• Non-pitting oedema: No pitting (lymphoedema, myxoedema in hypothyroidism)

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C. ORS (Oral Rehydration Solution)

• Na+ and glucose are co-transported into enterocytes by SGLT1
• Na+ absorption drives water absorption osmotically
• Citrate/bicarbonate corrects metabolic acidosis
• K+ replaces losses from diarrhoea

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Q4. Resting Membrane Potential (RMP) and Action Potential

A. Resting Membrane Potential (RMP)

• Nerve fibers: -70 mV (Guyton & Hall)
• Skeletal muscle: -90 mV
• Cardiac muscle: -90 mV
• Smooth muscle: -50 to -55 mV

Basis of RMP

1. K+ diffusion potential: Membrane is ~100x more permeable to K+ than Na+ at rest. K+ leaks out down its concentration gradient, leaving negative charge inside. K+ equilibrium potential (Ek) = -94 mV.
2. Na+ leak: Small but slightly depolarizes. Na+ Nernst potential = +61 mV. The combined Goldman equation potential for Na+ and K+ gives -86 mV.
3. Na+-K+ ATPase pump: Electrogenic - pumps 3 Na+ out for 2 K+ in, contributing an additional -4 mV. This also actively maintains the concentration gradients.

Nernst Equation (equilibrium potential for a single ion):

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B. Action Potential (AP)

Phases of Action Potential:

Properties of Action Potential:

1. All-or-None law: Either full AP fires or none - no partial APs
2. Propagation: Non-decremental spread along the axon
3. Absolute refractory period: Na+ channels completely inactivated; no AP possible regardless of stimulus strength (~1 ms in nerve)
4. Relative refractory period: Na+ channels partially recovered; a stronger-than-normal stimulus can evoke AP
5. Threshold: A minimum depolarization must be reached

Ionic Basis - Hodgkin & Huxley Cycle (Positive Feedback):

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• Guyton and Hall Textbook of Medical Physiology - Body fluid compartments, RMP, Action potential
• Costanzo Physiology, 7th Edition - RMP, Action potential, transport mechanisms
• Medical Physiology (Boron & Boulpaep) - Membrane transport, RMP

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Chapter 2: Blood - Complete Answers

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Q1. Plasma Proteins

Definition

Classification and Functions

Key Functions of Plasma Proteins (summary)

1. Oncotic pressure (colloid osmotic pressure): ~25 mmHg - prevents fluid leaking from capillaries; albumin contributes most
2. Transport: Bind and carry hormones (thyroxine, cortisol), lipids, drugs, bilirubin, metals
3. Coagulation: Fibrinogen, prothrombin, clotting factors
4. Immunity: Immunoglobulins (antibodies), complement
5. Buffering: 15% of blood buffering capacity (via -COOH and -NH2 groups)
6. Acute phase response: CRP, fibrinogen, α1-antitrypsin rise during inflammation
7. Nutritional reserve: Amino acid pool

Hypoproteinaemia - Causes and Effects

• Causes: Malnutrition/starvation, liver disease (decreased synthesis), nephrotic syndrome (urinary loss), protein-losing enteropathy
• Effect: Decreased oncotic pressure → oedema

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Q2. Haemoglobin, Erythropoiesis, Polycythemia

A. Haemoglobin (Hb)

• Molecular weight: 64,500 Da
• 4 subunits: each has a globin chain + haem group
• Haem = protoporphyrin ring + Fe²⁺ (ferrous iron)
• Each haem binds ONE O2 molecule → one Hb molecule carries 4 O2 molecules
• Adult Hb (HbA1): 2α + 2β chains (major fraction, 97%)
• HbA2: 2α + 2δ (2.5%)
• HbF (Foetal): 2α + 2γ - higher O2 affinity than HbA (lower 2,3-DPG binding)

• Adult male: 13.5–17.5 g/dL
• Adult female: 12–16 g/dL
• Newborn: ~19 g/dL

1. O2 transport (oxyhaemoglobin)
2. CO2 transport (carbaminohaemoglobin - ~23% of CO2)
3. Buffering (Haldane effect)
4. Carries NO (nitric oxide)

• Sigmoid (S-shaped) due to cooperative binding (allosteric effect)
• Right shift (↓ affinity, ↑ O2 release): ↑ CO2, ↑ H+ (↓ pH), ↑ temperature, ↑ 2,3-DPG (Bohr effect)
• Left shift (↑ affinity, ↓ O2 release): ↓ CO2, ↓ H+, ↓ temperature, ↓ 2,3-DPG, HbF, CO poisoning, methaemoglobin

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B. Erythropoiesis

• Foetal: Yolk sac (0-2 months) → Liver & Spleen (2-7 months) → Bone marrow (from 5 months onward)
• After birth: Red bone marrow (sternum, vertebrae, ribs, pelvis, skull, proximal long bones)

Pluripotent Stem Cell
        ↓
CFU-GEMM (Mixed myeloid progenitor)
        ↓
BFU-E (Burst-forming unit - erythroid)
        ↓
CFU-E (Colony-forming unit - erythroid)
        ↓
Pronormoblast (Proerythroblast)
        ↓
Early Normoblast (Basophilic erythroblast) - active Hb synthesis begins
        ↓
Intermediate Normoblast (Polychromatic erythroblast)
        ↓
Late Normoblast (Orthochromatic erythroblast) - nucleus extruded
        ↓
Reticulocyte (still has ribosomes + mRNA, can synthesize Hb)
        ↓ (1-2 days in circulation, matures in spleen)
Mature RBC (biconcave disc, no nucleus, no organelles)

• Produced mainly by peritubular cells of the kidney (90%) and liver (10%)
• Stimulus: Tissue hypoxia (↓ pO2, anaemia, ↑ altitude, reduced blood flow)
• Action: Stimulates BFU-E → CFU-E differentiation, accelerates maturation, increases reticulocyte release
• Negative feedback: When Hb rises and oxygenation improves, EPO production drops

• Male: 4.5–5.5 million/μL
• Female: 3.8–5.0 million/μL
• Life span: ~120 days
• Destruction: By macrophages in spleen, liver, bone marrow (reticuloendothelial system)

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C. Polycythemia

• Raised Hb, haematocrit, RBC count
• Splenomegaly
• Plethoric facies, hypertension
• Thrombotic tendency (stroke, DVT, PE)
• Pruritus after hot bath (histamine from basophils)
• Bleeding tendency (abnormal platelet function)

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Q3. Anaemia and Jaundice

A. Anaemia

• Male: Hb < 13.5 g/dL
• Female: Hb < 12.0 g/dL
• Children: Hb < 11 g/dL

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B. Jaundice (Icterus)

1. Haemoglobin broken down by RES → Haem → Biliverdin → Unconjugated bilirubin (indirect, water-insoluble, albumin-bound)
2. Transported to liver → conjugated with glucuronic acid by UDP-glucuronyl transferase → Conjugated bilirubin (direct, water-soluble)
3. Excreted in bile → gut → Urobilinogen (some reabsorbed - enterohepatic circulation) → Urobilin (stool colour) + Stercobilin

• Pre-hepatic: Haemolytic anaemias, malaria, transfusion reaction
• Hepatic: Hepatitis, cirrhosis, Gilbert's syndrome, Crigler-Najjar
• Post-hepatic: Gallstones, carcinoma head of pancreas, cholangiocarcinoma

• Physiological: Days 2-3 to day 10 due to high foetal Hb breakdown + immature liver glucuronyl transferase
• Pathological: Rh/ABO incompatibility, G6PD, congenital infections
• Kernicterus: Unconjugated bilirubin crosses BBB → deposits in basal ganglia → brain damage

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Q4. Functions of WBC (White Blood Cells)

• Leukocytosis: ↑ WBCs - infection, inflammation, leukaemia
• Leukopenia: ↓ WBCs - viral infections, aplastic anaemia, chemotherapy
• Shift to left: Increased band (immature) neutrophils - severe bacterial infection

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Q5. Immunity - Classification, Humoral and Cell-Mediated

Classification of Immunity

Immunity
├── Innate (Non-specific, Natural)
│   ├── Physical barriers (skin, mucous membranes)
│   ├── Chemical barriers (lysozyme, acids, complement)
│   └── Cellular (neutrophils, macrophages, NK cells)
└── Adaptive (Specific, Acquired)
    ├── Active
    │   ├── Natural (after infection)
    │   └── Artificial (vaccination)
    └── Passive
        ├── Natural (maternal IgG via placenta; IgA via breast milk)
        └── Artificial (antiserum injection)

Humoral Immunity (B-cell mediated)

• Mediated by: B lymphocytes → Plasma cells → Antibodies (immunoglobulins)
• Antigen recognition: B cells recognize soluble antigens directly via B-cell receptor (BCR)
• Process:
  1. Antigen → recognized by B cell → T helper cell (CD4+) provides co-stimulation
  2. B cell proliferates → plasma cells (antibody secretion) + memory B cells
  3. Antibodies circulate and neutralize antigen
• Antibody Classes: IgG (most abundant; crosses placenta), IgA (secretory, in saliva/milk), IgM (first produced; pentamer; activates complement), IgE (allergy/parasites), IgD (B-cell surface receptor)
• Effective against: Extracellular bacteria, toxins, viruses (before cell entry)

Cell-Mediated Immunity (T-cell mediated)

• Mediated by: T lymphocytes (T cells)
• Types:
  • CD4+ T helper (Th) cells: Recognize antigen on MHC class II; activate B cells, CD8+ T cells, macrophages; produce cytokines
    • Th1 (IL-2, IFN-γ): Activates macrophages and cytotoxic T cells
    • Th2 (IL-4, IL-5): Activates B cells, eosinophils; antibody production
  • CD8+ Cytotoxic T cells (CTL): Recognize antigen on MHC class I; directly kill virus-infected cells and tumour cells via perforin/granzyme
  • Regulatory T cells (Treg): Suppress immune responses; prevent autoimmunity
• Effective against: Intracellular pathogens (viruses, mycobacteria, fungi), tumour cells, transplant rejection, delayed hypersensitivity

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Q6. Functions of Platelets, Mechanism of Blood Coagulation (Intrinsic and Extrinsic)

A. Functions of Platelets

1. Vascular repair - adhesion: Platelets adhere to exposed collagen (via vWF and GPIb receptor) when endothelium is damaged
2. Platelet plug formation: Platelets aggregate to seal small vessel breaks (primary haemostasis)
3. Activation and release reaction: ADP, thromboxane A2, serotonin released → amplify aggregation; TXA2 causes vasoconstriction
4. Support coagulation: Platelet phospholipids (platelet factor 3 / PF3) provide surface for coagulation factor complexes (intrinsic tenase, prothrombinase)
5. Clot retraction: Platelet thrombostenin (actin-myosin) contracts the clot
6. Platelet-derived growth factor (PDGF): Promotes vascular wall repair
7. Vasoconstriction: Via thromboxane A2 and serotonin release

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B. Mechanism of Blood Coagulation

Extrinsic Pathway (Tissue Factor Pathway - FAST):

• Trigger: Tissue damage → Tissue Factor (Factor III) released
• TF + Factor VII → TF-VIIa complex
• Activates Factor X → Xa (with Ca2+ and Factor V)
• Time: 15 seconds | Measured by: PT (Prothrombin Time)

Intrinsic Pathway (Contact Activation - SLOW):

• Trigger: Contact of Factor XII with exposed subendothelial collagen
• XII → XIIa → XI → XIa → IX → IXa → (with VIII, Ca2+, PF3) → X → Xa
• Time: 1-6 minutes | Measured by: aPTT (activated Partial Thromboplastin Time)

Common Pathway:

Xa + Va + Ca2+ + Phospholipid (Prothrombinase complex)
                    ↓
           Prothrombin (II) → Thrombin (IIa)
                    ↓
           Fibrinogen (I) → Fibrin monomer
                    ↓ (Factor XIIIa + Ca2+)
           Cross-linked Fibrin clot (stable)

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Q7. Anticoagulants - Natural and Artificial

A. Natural Anticoagulants

B. Artificial (Clinical) Anticoagulants

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Q8. Blood Groups - Landsteiner's Law, ABO, Rh System, HDN

A. Landsteiner's Law

• These naturally occurring antibodies (isohemagglutinins) are IgM and appear without prior exposure (formed from gut bacterial antigens that share structure with blood group antigens)

B. ABO Blood Group System

• Donor O → can give to O, A, B, AB
• Donor A → can give to A, AB
• Donor B → can give to B, AB
• Donor AB → can only give to AB

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C. Rh Blood Group System

• Rh antigen (D antigen) is the most important: present on RBC surface
• Rh positive: D antigen present (~85% of population)
• Rh negative: D antigen absent (~15% of population)
• Key difference from ABO: Anti-D antibodies do NOT occur naturally - they are only produced after exposure to Rh-positive blood (transfusion or pregnancy)
• Anti-D is IgG (can cross placenta, unlike ABO IgM)

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D. Rh Incompatibility / Haemolytic Disease of the Newborn (HDN / Erythroblastosis Fetalis)

1. Rh-negative mother carries Rh-positive foetus (father Rh+)
2. During delivery (or miscarriage/amniocentesis), foetal Rh+ RBCs leak into maternal circulation
3. Mother produces anti-D IgG antibodies (sensitization - usually no problem in 1st pregnancy)
4. In subsequent Rh+ pregnancies, anti-D IgG crosses placenta → attaches to foetal RBCs → haemolysis
5. Consequences: Foetal anaemia, jaundice, oedema (hydrops fetalis), cardiac failure, kernicterus (bilirubin deposits in brain)

• Given to Rh-negative mother at 28 weeks and within 72 hours of delivery
• Masks fetal Rh antigens that entered maternal circulation → prevents sensitization

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Q9. Blood Transfusion - Matched and Mismatched Reaction

Cross-matching

1. ABO and Rh typing of donor and recipient
2. Cross-match test:
   • Major cross-match: Donor RBC + recipient serum (most important)
   • Minor cross-match: Donor serum + recipient RBC
3. Coombs test (DAT/IAT): Detects antibodies on RBC surface

Matched Transfusion

• Compatible blood given → smooth transfusion, no adverse reaction
• Patient monitored for first 15 minutes (most reactions occur early)

Mismatched (Incompatible) Transfusion Reaction

• Usually ABO incompatibility (clerical error is most common cause)
• Anti-A or anti-B antibodies + transfused RBC antigens → intravascular haemolysis
• Features (occur within minutes):
  • Fever, chills, rigors
  • Severe backache/loin pain (renal involvement)
  • Haemoglobinuria (dark/red urine)
  • Hypotension, shock
  • DIC (disseminated intravascular coagulation)
  • Acute renal failure
• Management: Stop transfusion immediately; IV fluids, maintain urine output; treat DIC; check blood bank for error

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Chapter 3: Nerve Muscle Physiology

Legend: 🔵 LQ = Long Question (10-15 marks) | 🟡 SQ = Short Question (5 marks)

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Q1. 🔵 LQ - Structure and Functions of a Neuron

Structure of a Neuron

1. Cell Body (Soma / Perikaryon)

• Contains the nucleus (large, vesicular, prominent nucleolus)
• Nissl bodies (rough ER + ribosomes) - site of protein synthesis; dispersed in axon hillock
• Golgi apparatus, mitochondria, neurofilaments, microtubules
• Axon hillock: cone-shaped origin of axon; lowest threshold for AP generation (spike-initiation zone)

2. Dendrites

• Multiple short, branching processes arising from the soma
• Increase receptive surface area
• Contain Nissl bodies and organelles
• Receive incoming signals (afferent input) from other neurons
• Site of most synaptic inputs; integrate signals through EPSPs and IPSPs
• May have dendritic spines (increase surface area for synaptic contacts)

3. Axon

• Single, long process arising from the axon hillock
• Conducts impulses away from soma (efferent output) - orthodromic direction
• Myelin sheath (in myelinated fibres) produced by Schwann cells (PNS) or oligodendrocytes (CNS)
• Nodes of Ranvier: gaps in myelin (~1-2 μm); site of AP regeneration in saltatory conduction
• Axon terminals (boutons/synaptic knobs): contain synaptic vesicles + mitochondria
• No Nissl bodies → cannot synthesize proteins locally (depends on axonal transport)
• Branching at terminal end = telodendria

Types of Neurons by Structure:

Functions of a Neuron:

1. Sensory (afferent): Receive stimuli from periphery, transmit to CNS
2. Motor (efferent): Transmit commands from CNS to effectors (muscles, glands)
3. Interneurons: Connect sensory and motor neurons; integration, modulation
4. Integration: Sum up excitatory and inhibitory inputs at soma to decide firing
5. Secretion: Neurosecretory neurons release hormones (hypothalamic neurons)

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Q2. 🟡 SQ - Neuroglia

CNS Neuroglia (4 types):

PNS Neuroglia:

• Schwann cells: Myelin formation and maintenance in PNS; guide nerve regeneration
• Satellite cells: Surround neuron cell bodies in sensory ganglia

Key Functions of Neuroglia:

1. Structural support and scaffolding for neurons
2. Myelin formation (saltatory conduction)
3. Nutrient supply to neurons
4. Regulate the extracellular environment (K+, neurotransmitters)
5. Blood-brain barrier (astrocyte end-feet)
6. Immune defense (microglia)
7. CSF production and circulation (ependymal)
8. Repair and regeneration guidance

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Q3. 🔵 LQ - Types, Functions, and Properties of Nerve Fibres

Classification by Erlanger and Gasser (Based on conduction velocity):

Mnemonic: Thicker = Faster; Myelinated > Unmyelinated

Lloyd's Classification (Based on sensory afferents only):

Properties of Nerve Fibres:

1. All-or-None law: A nerve fibre either fires fully or not at all
2. Threshold: Minimum stimulus to trigger an AP
3. Refractory period: Absolute (no AP possible) and relative (stronger stimulus needed)
4. Conductivity: Ability to transmit impulse along its length
5. Excitability: Ability to respond to stimuli
6. Accommodation: When a slowly rising stimulus is applied, the threshold rises so that the fibre does not fire - due to slow Na+ channel inactivation
7. Conduction velocity depends on: fibre diameter, myelination, temperature
8. Fatigue: Does not fatigue under physiological conditions (unlike synapses)
9. Bidirectional conduction (though normal conduction is orthodromic)
10. Metabolic dependency: Requires O2; blocked by hypoxia, ischaemia

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Q4. 🟡 SQ - Degeneration and Regeneration in Peripheral Nerves

Classification of Nerve Injury (Seddon):

Wallerian Degeneration (after axon is cut):

1. Axon and myelin degenerate within 24-48 hours
2. Schwann cells proliferate, phagocytose myelin debris (form bands of Büngner)
3. Macrophages invade and clear debris
4. Endoneurial tubes persist as regeneration guides

1. Brief retrograde degeneration to nearest node
2. Cell body undergoes chromatolysis (Nissl substance disperses, nucleus moves to periphery) - indicates injury + increased protein synthesis for regeneration

Regeneration:

1. Sprouting from proximal axon stump begins within days
2. Axon grows along Schwann cell tubes (bands of Büngner) at 1-3 mm/day (~ 1 inch/month)
3. Remyelination occurs as axon grows
4. Target reinnervation - motor and sensory reinnervation
5. Recovery better when endoneurial tubes intact (axonotmesis > neurotmesis)

• Distance to target
• Age (younger = better)
• Nutritional status
• Type of injury
• Surgical repair quality

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Q5. 🟡 SQ - Saltatory Conduction

Basis:

• Myelin sheath acts as electrical insulator (high resistance, low capacitance)
• Voltage-gated Na+ channels are concentrated only at nodes of Ranvier (essentially absent under myelin)
• During AP: strong inward Na+ current at one node generates local circuit currents that jump to the next node, depolarising it to threshold
• The impulse effectively "leaps" from node to node (internodal distance: 0.2-2 mm)

Advantages over continuous conduction:

1. Much faster: 70-120 m/s vs 0.5-2 m/s in unmyelinated fibres
2. Energy efficient: Na+-K+ pump only needs to restore ion gradients at nodes (small area), not entire membrane
3. Space efficient: Same conduction speed in a much thinner myelinated fibre than needed for an unmyelinated fibre

Clinical relevance:

• Multiple sclerosis (MS): Demyelination → loss of saltatory conduction → slowed or blocked conduction → neurological deficits
• Guillain-Barré syndrome: Acute demyelinating polyneuropathy

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Q6. 🟡 SQ - Axonal Transport

Types:

Clinical relevance:

• Retrograde transport used by rabies virus, herpes simplex virus, tetanus toxin to reach CNS
• Disrupted axonal transport → neurodegeneration (Alzheimer's, ALS)
• Nerve growth factor (NGF) reaches soma by retrograde transport → signals neuron survival

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Q7. 🔵 LQ - Structure of Neuromuscular Junction (NMJ)

Structural Components:

• Large myelinated axon (Aα fibre) loses myelin and branches
• Axon terminal: swollen knob-like ending lying in a groove on muscle surface
• Contains:
  • ~300,000 synaptic vesicles (each ~50 nm diameter) filled with acetylcholine (ACh)
  • Mitochondria (ATP for ACh synthesis)
  • Active zones: linear dense bars where vesicles dock; flanked by voltage-gated Ca2+ channels
• Covered by Schwann cell cap

• Width: 20-30 nm (narrower than CNS synapses)
• Contains acetylcholinesterase (AChE) - destroys ACh rapidly

• Muscle membrane (sarcolemma) folded into junctional folds / subneural clefts (increase surface area)
• Mouths of folds contain high density of nicotinic ACh receptors (nAChR) - pentameric structure (2α + β + δ + ε)
• Deeper in folds: voltage-gated Na+ channels (trigger action potential)
• After denervation: nAChRs spread over whole muscle surface (supersensitivity)

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Q8. 🔵 LQ - Neuromuscular Transmission

Sequence of Events:

• ~125 vesicles released per action potential

• EPP is always suprathreshold (safety factor ~5) → always generates muscle AP

Drugs affecting NMJ:

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Q9. 🟡 SQ - Myasthenia Gravis

Pathophysiology:

• Autoantibodies against nAChRs (mainly directed at the α-subunit's main immunogenic region - MIR) in 85% of cases
• Also anti-MuSK antibodies (muscle-specific kinase) in 15%
• Antibodies + complement → receptor destruction + loss of junctional folds → reduced EPP amplitude → fails to reach threshold → muscle weakness
• Thymus plays key role: thymic hyperplasia (young women) or thymoma (older men); thymic myoid cells express nAChR → site of sensitisation

Clinical Features:

• Muscle weakness that worsens with activity, improves with rest (fatigability)
• Ptosis and diplopia (most common initial symptoms - extraocular muscles most vulnerable)
• Dysphagia, dysarthria (bulbar symptoms)
• Limb weakness (proximal > distal)
• Respiratory muscle involvement → myasthenic crisis (respiratory failure - medical emergency)
• Bimodal peak: Young women (20s) + older men (60s)

Diagnosis:

• Tensilon (edrophonium) test: Short-acting AChE inhibitor → dramatic but brief improvement
• Anti-AChR antibody titre
• Single-fibre EMG (most sensitive)
• CT chest (thymoma)
• Repetitive nerve stimulation → decremental response

Treatment:

1. Pyridostigmine (AChE inhibitor) - symptomatic
2. Immunosuppression: Corticosteroids, azathioprine, mycophenolate
3. Thymectomy (especially in thymoma; improves 75%)
4. Plasmapheresis / IVIG - acute crises

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Q10. 🔵 LQ - Molecular Basis of Muscle Contraction in Skeletal and Smooth Muscle

A. Skeletal Muscle Contraction (Sliding Filament Theory - Huxley & Hanson)

• Thick filaments: Myosin (heavy chains + light chains); myosin heads have ATPase activity and actin-binding sites
• Thin filaments: Actin (F-actin) + Tropomyosin (blocks myosin binding sites at rest) + Troponin complex (TnT - binds tropomyosin; TnI - inhibitory; TnC - binds Ca2+)
• Z lines: Anchor thin filaments
• M line: Anchor thick filaments
• Titin: Elastic protein, connects M line to Z line; gives passive elasticity

Steps in Skeletal Muscle Contraction (Cross-Bridge Cycle):

1. AP → T-tubule → SR → Ca2+ release (via ryanodine receptor RyR1)
2. Ca2+ binds TnC → conformational change in troponin → tropomyosin moves away → exposes myosin-binding sites on actin
3. Myosin head (with ADP+Pi) attaches to actin → cross-bridge formed
4. Power stroke: Pi released → myosin head pivots (rotates ~45°) → pulls actin toward M-line → thin filaments slide → sarcomere shortens; ADP released
5. ATP binds myosin → cross-bridge detaches (if no ATP → rigor mortis)
6. ATP hydrolysis by myosin ATPase → myosin head returns to cocked (high-energy) position → ready for next cycle
7. Relaxation: Ca2+ pumped back into SR by Ca2+-ATPase (SERCA) → TnC releases Ca2+ → tropomyosin re-covers binding sites

B. Smooth Muscle Contraction

• No troponin; regulation via calmodulin
• Thin filaments lack troponin-tropomyosin system

1. Ca2+ enters via voltage-gated channels (or released from SR via IP3-gated channels)
2. Ca2+ binds calmodulin (4 Ca2+ per calmodulin)
3. Ca2+-calmodulin activates myosin light chain kinase (MLCK)
4. MLCK phosphorylates myosin light chain (MLC) → activates myosin ATPase
5. Phosphorylated myosin cross-bridges with actin → contraction
6. Relaxation: MLCK inactivated (when Ca2+ falls) + myosin light chain phosphatase (MLCP) dephosphorylates MLC → relaxation

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Q11. 🟡 SQ - Differences Between Isometric and Isotonic Muscle Contraction

• Concentric: Muscle shortens while generating force (lifting)
• Eccentric: Muscle lengthens while generating force (lowering weight slowly)

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Q12. 🟡 SQ - Strength Duration Curve

Key Terms:

The Curve:

• As stimulus duration increases, the threshold intensity (strength) decreases
• At very short durations: very high intensity needed
• At longer durations: only rheobase intensity needed (curve becomes flat = asymptote)
• The curve is hyperbolic in shape

Strength (I)
    |
  2xRheobase -----*
    |             |
  Rheobase -------+-----------___________
    |             |
    |             |
    +-------------+-----> Duration (t)
                 Chronaxie

Clinical Applications:

1. Chronaxie of nerve (0.1-0.3 ms) < Chronaxie of muscle (1-10 ms) → At short durations, nerves are more excitable than muscles
2. Denervated muscle: curve shifts right (higher chronaxie) - used to diagnose denervation
3. Used in electrodiagnosis of nerve/muscle injury
4. Basis of electrical stimulation protocols in physiotherapy
5. Determines pacemaker pulse parameters

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Chapter 4: Digestive System

Legend: 🔵 LQ = Long Question (10-15 marks) | 🟡 SQ = Short Question (5 marks)

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Q1. 🔵 LQ - Composition, Functions and Regulation of Saliva, Gastric, Pancreatic, and Bile Secretion

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A. Saliva

• Water (99.5%), electrolytes (Na+, K+, Cl-, HCO3-)
• Salivary amylase (ptyalin): Begins starch digestion (cleaves α-1,4 glycosidic bonds)
• Mucin (mucus): Lubrication, bolus formation
• Lysozyme + IgA: Antibacterial protection
• Lingual lipase: Minor fat digestion
• pH: 6.2-7.4

1. Lubrication for chewing and swallowing (mucin)
2. Initiates carbohydrate digestion (amylase)
3. Dissolves food substances to enable taste
4. Antimicrobial (lysozyme, IgA, lactoferrin)
5. Dental hygiene (HCO3- neutralises acids, fluoride)
6. Speech facilitation
7. Excretion of urea, drugs (e.g., iodine, mercury)

• Neural (only) - no hormonal regulation
• Parasympathetic (dominant): Via chorda tympani (CN VII) and glossopharyngeal (CN IX) → ACh → muscarinic receptors → profuse watery saliva
• Sympathetic: Via cervical ganglia → NA → α receptors → thick, mucus-rich saliva
• Stimuli: Taste, smell, sight of food (conditioned reflex), chewing, nausea; inhibited by dehydration, sleep, fear

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B. Gastric Secretion

• H+/K+-ATPase (proton pump) on apical membrane → pumps H+ into lumen in exchange for K+
• Stimulated by: Histamine (H2 receptors → cAMP), Gastrin (CCK-B receptors → Ca2+), ACh (M3 receptors → Ca2+)
• These three are synergistic → blocking one (e.g., H2 blocker) greatly reduces secretion

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C. Pancreatic Secretion

• Water + Electrolytes: High HCO3- (113 mEq/L vs 24 mEq/L plasma) - neutralises gastric acid in duodenum
• Enzymes (in zymogen granules):

• Enzymes secreted as zymogens (inactive)
• Trypsin inhibitor secreted with juice
• Enterokinase (not in pancreas) activates trypsinogen only in duodenum
• In acute pancreatitis: premature activation of enzymes → autodigestion

• Secretin (S cells of duodenum; stimulus: low pH < 4.5 in duodenum) → ↑ HCO3- and water secretion (ductal cells)
• CCK (I cells of duodenum; stimulus: fatty acids, amino acids) → ↑ enzyme secretion (acinar cells)
• Vagus nerve (ACh): Stimulates both components (cephalic phase)

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D. Bile Secretion

• 95% of bile salts reabsorbed in terminal ileum → portal vein → liver → re-secreted
• Only 5% lost in faeces → replaced by new synthesis from cholesterol
• Total bile salt pool: ~3 g, circulates 6-10 times/day

• CCK: Released by fat and proteins in duodenum → contracts gallbladder + relaxes sphincter of Oddi → bile flows into duodenum
• Secretin: Increases HCO3- secretion from bile ducts
• Vagus nerve: Stimulates gallbladder contraction
• Fasting: Sphincter of Oddi closed → bile stored in gallbladder

1. Emulsification of dietary fats (essential for fat digestion and absorption)
2. Micellar solubilisation → absorption of fat-soluble vitamins (A, D, E, K)
3. Excretion of bilirubin, cholesterol, heavy metals, drugs
4. Neutralisation of gastric acid
5. Bacteriostatic effect

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Q2. 🟡 SQ - Movements of Small Intestine and Large Intestine

Small Intestinal Movements:

Large Intestinal Movements:

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Q3. 🟡 SQ - Deglutition (Swallowing) and Defaecation Reflex

A. Deglutition (Swallowing)

• Food chewed, mixed with saliva → bolus formed
• Tongue pushes bolus backward against hard palate into pharynx
• Voluntary, under conscious control

• Swallowing centre in medulla oblongata activated
• Coordinated reflexes in <1 second:
  • Soft palate elevates (closes nasopharynx)
  • Larynx elevates and epiglottis closes (prevents aspiration)
  • Vocal cords adduct (close glottis)
  • Respiration momentarily inhibited
  • Upper oesophageal sphincter relaxes
  • Peristaltic wave carries bolus into oesophagus
• Involuntary, cannot be stopped once initiated
• Cranial nerves involved: V, VII, IX, X, XII

• Primary peristalsis: Continuation of pharyngeal wave pushes bolus down oesophagus
• Secondary peristalsis: Triggered by distension if bolus remains; clears residue
• Lower oesophageal sphincter (LOS) relaxes to allow bolus into stomach
• Duration: ~8-10 seconds for solids; faster for liquids

B. Defaecation Reflex

1. Mass movements push faeces into rectum
2. Rectal wall distension → stretch receptors activated
3. Intrinsic reflex (via myenteric plexus): Peristaltic waves in descending colon + internal anal sphincter relaxes
4. Parasympathetic reflex (via S2-S4 sacral cord): Amplifies peristalsis, further relaxes internal anal sphincter
5. If conditions appropriate: voluntary relaxation of external anal sphincter (under somatic control via pudendal nerve) → defaecation
6. Valsalva manoeuvre: Closure of glottis + contraction of abdominal muscles → raises intra-abdominal pressure → assists defaecation

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Q4. 🔵 LQ - Digestion and Absorption of Nutrients

A. Carbohydrates

• Mouth: Salivary amylase → cleaves starch at α-1,4 bonds → dextrins, maltose (inactivated by gastric acid)
• Small intestine: Pancreatic amylase → oligosaccharides, disaccharides
• Brush border enzymes: Maltase, sucrase, lactase → monosaccharides (glucose, fructose, galactose)

• Glucose and galactose: SGLT1 (Na+-glucose cotransporter) - active, secondary active transport
• Fructose: GLUT5 (facilitated diffusion)
• All exit basolateral membrane via GLUT2 into portal blood

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B. Proteins

• Stomach: Pepsin (activated from pepsinogen by HCl; pH < 2) → polypeptides + some amino acids
• Small intestine: Trypsin, chymotrypsin, elastase, carboxypeptidase → oligopeptides + amino acids

• Amino acids: Carrier-mediated active transport (Na+-amino acid cotransporters) at brush border
• Di- and tri-peptides: PepT1 transporter → hydrolysed inside enterocytes
• Exit basolateral membrane via facilitated diffusion → portal blood

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C. Fats (Lipids)

• Lingual + gastric lipase: minor initial hydrolysis
• Emulsification by bile salts: Large fat globules → tiny droplets (increases surface area)
• Pancreatic lipase + co-lipase: Hydrolyses triglycerides → monoglycerides + free fatty acids (FFAs)
• Micelle formation: Bile salts wrap around monoglycerides + FFAs → mixed micelles

• Micelles carry lipids to brush border membrane
• Monoglycerides + FFAs diffuse passively into enterocytes
• Inside enterocytes: re-esterified to triglycerides → combined with phospholipids + cholesterol + apolipoproteins → chylomicrons
• Chylomicrons secreted by exocytosis → lacteals (lymph) → thoracic duct → subclavian vein → systemic circulation

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D. Water and Electrolytes

• ~9 litres enters GI tract daily (food + secretions); only ~100-200 mL excreted in stool
• Most water absorbed in small intestine (osmotically following solute absorption)
• Na+ absorbed by: Na+-glucose/amino acid cotransport; Na+-H+ exchange; electrogenic Na+ channels (colon)
• Cl- absorbed by Cl--HCO3- exchange
• Iron: Absorbed as Fe2+ in duodenum; regulated by hepcidin; transferrin carries it in blood
• Calcium: Absorbed actively in duodenum (calbindin, vitamin D-regulated) and passively throughout
• Vitamin B12: Binds intrinsic factor (from parietal cells) → absorbed in terminal ileum

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Q5. 🟡 SQ - GI Hormones and Their Actions

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Q6. 🟡 SQ - Gut-Brain Axis

Components:

1. Central Nervous System (CNS): Brain + spinal cord; processes emotions, stress, cognition
2. Enteric Nervous System (ENS): "Second brain" - 200-500 million neurons in Meissner (submucosal) and Auerbach (myenteric) plexuses; functions independently but communicates with CNS
3. Autonomic Nervous System: Vagus nerve (80% afferent) is the main highway; sympathetic fibres
4. HPA Axis (Hypothalamic-Pituitary-Adrenal): Stress hormones (cortisol) affect gut permeability and microbiome
5. Gut Microbiome: Trillions of bacteria produce neurotransmitters (GABA, serotonin, short-chain fatty acids) that signal to brain
6. Enteroendocrine cells: Release hormones (serotonin, CCK, GLP-1) that signal via vagus to brain

Key Signalling Molecules:

• Serotonin (5-HT): 95% of body's serotonin made in gut (enterochromaffin cells); regulates motility and mood
• Short-chain fatty acids (SCFAs): Made by gut bacteria; influence BBB integrity, glial function, neuroinflammation
• GABA: Produced by Lactobacillus; may reduce anxiety

Clinical Significance:

• IBS (Irritable Bowel Syndrome): Bidirectional dysfunction; stress worsens symptoms
• Depression/Anxiety: Gut dysbiosis linked to mental health disorders
• Parkinson's disease: α-synuclein pathology may start in ENS before brain
• Autism Spectrum Disorder: GI symptoms common; microbiome differences noted
• Probiotics targeting gut-brain axis being studied for psychiatric conditions

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Q7. 🟡 SQ - Functions of Liver and Gallbladder

Functions of the Liver:

• Carbohydrate: Glycogen synthesis (glycogenesis), breakdown (glycogenolysis), gluconeogenesis; maintains blood glucose
• Protein: Synthesis of all plasma proteins except immunoglobulins (albumin, globulins, fibrinogen, coagulation factors, complement); urea synthesis (detoxifies NH3)
• Fat: Fatty acid oxidation (β-oxidation); ketone body synthesis; lipoprotein synthesis (VLDL, HDL); cholesterol synthesis and conversion to bile acids

• Bile secretion (500-1000 mL/day)
• Bilirubin conjugation and excretion
• Excretion of drugs, heavy metals, hormones

• Drug metabolism (CYP450 enzymes - Phase I: oxidation, reduction; Phase II: conjugation)
• Detoxification of ammonia → urea (urea cycle)
• Inactivation of hormones (oestrogen, aldosterone, insulin)
• Kupffer cells (liver macrophages): phagocytose bacteria from portal blood

• Synthesis of coagulation factors (I, II, V, VII, IX, X, XI, XII) and anticoagulants (Protein C, S, antithrombin)
• Site of foetal haemopoiesis
• Stores iron, vitamin B12, fat-soluble vitamins (A, D, E, K), copper

• Kupffer cells: phagocytose antigens from gut
• Synthesis of complement proteins and acute phase proteins

• Produces IGF-1 (in response to GH)
• Converts T4 → T3
• Activates vitamin D (25-hydroxylation)
• Degrades hormones

Functions of the Gallbladder:

1. Storage of bile (40-70 mL capacity)
2. Concentration of bile (5-20 times) - absorbs water, Na+, Cl-
3. Controlled release via CCK → gallbladder contraction + sphincter of Oddi relaxation
4. Acidification of bile → precipitates calcium salts (prevents bile duct stones)
5. Mucus secretion protects gallbladder wall

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Q8. 🔵 LQ - Pathophysiology: Peptic Ulcer, GORD, Vomiting, Diarrhoea, Adynamic Ileus, Hirschsprung's Disease

A. Peptic Ulcer Disease (PUD)

• H. pylori (70-80% of duodenal ulcers; 60% gastric) - disrupts mucus barrier
• NSAIDs - inhibit COX-1 → ↓ prostaglandins → ↓ mucus + HCO3- + mucosal blood flow
• Zollinger-Ellison syndrome - gastrinoma → massive hypersecretion of HCl

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B. Gastro-Oesophageal Reflux Disease (GORD)

• LOS normally maintained at 15-25 mmHg above gastric pressure
• Causes of LOS failure: fatty meals, alcohol, smoking, hiatus hernia, obesity, pregnancy, drugs (nitrates, CCBs)
• Repeated exposure to acid → oesophagitis → Barrett's oesophagus (metaplastic columnar epithelium replaces squamous) → risk of adenocarcinoma

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C. Vomiting

• Chemoreceptor Trigger Zone (CTZ): Area postrema (floor of 4th ventricle), outside BBB → detects toxins, drugs (morphine, chemotherapy), metabolic disturbances
• Vestibular apparatus (CN VIII): Motion sickness
• GI vagal afferents: Distension, irritants, gastroenteritis
• Higher CNS: Emotional, visual, olfactory triggers

1. Nausea → hypersalivation (alkaline saliva neutralises acid)
2. Deep inspiration → glottis closes
3. Pylorus contracts, LOS relaxes
4. Violent contraction of diaphragm + abdominal muscles → ↑ intragastric pressure → gastric contents expelled

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D. Diarrhoea

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E. Adynamic (Paralytic) Ileus

• Post-operative (most common) - handling of bowel triggers reflex inhibition
• Electrolyte imbalance (especially hypokalaemia)
• Retroperitoneal haematoma/inflammation (pancreatitis)
• Peritonitis, sepsis
• Drugs (opioids, anticholinergics)
• Spinal cord injury

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F. Hirschsprung's Disease (Congenital Megacolon)

• Failure of neural crest cell migration during embryonic development
• Aganglionic segment (always includes internal anal sphincter, extends proximally variable distance) → cannot relax → functional obstruction
• Proximal colon distends → megacolon

• Failure to pass meconium within 48 hours of birth (cardinal feature)
• Abdominal distension, bilious vomiting
• Explosive passage of faeces when PR exam performed (classic sign)
• Can present in older children as chronic constipation

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Chapter 5: Cardiovascular System

Legend: 🔵 LQ = Long Question (10-15 marks) | 🟡 SQ = Short Question (5 marks)

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Q1. 🔵 LQ - Conducting System of the Heart

Components (in order of impulse travel):

1. Sinoatrial Node (SA Node) - The Pacemaker

• Location: Posterior wall of right atrium, near opening of superior vena cava, in the sulcus terminalis (Keith-Flack node)
• Size: ~10 mm long, spindle-shaped
• Intrinsic rate: 60-100 beats/min (dominant pacemaker)
• Function: Generates the cardiac impulse; sets heart rate
• Cell type: Nodal cells with unstable resting potential (pacemaker potential - "funny current" If); spontaneous diastolic depolarisation via slow Na+ influx then Ca2+ influx
• Blood supply: SA nodal artery (from RCA in 60%, LCX in 40%)

2. Internodal Pathways (Atrial Conduction)

• Three bundles transmit impulse from SA node to AV node:
  • Anterior internodal tract (Bachmann's bundle) - also conducts to left atrium
  • Middle internodal tract (Wenckebach)
  • Posterior internodal tract (Thorel)
• Conduction velocity: ~1 m/s through atrial myocardium
• Causes P wave on ECG

3. Atrioventricular Node (AV Node)

• Location: Inferior interatrial septum, above coronary sinus opening, between tricuspid valve and coronary sinus (Aschoff-Tawara node)
• Size: ~5 mm long
• Intrinsic rate: 40-60 beats/min
• KEY FUNCTION: Introduces a delay of ~0.1 second between atrial and ventricular contraction (allows ventricles to fill completely before contracting)
• Conduction velocity: 0.05 m/s (slowest in the conducting system)
• Responsible for PR interval on ECG (0.12-0.20 s)
• Blood supply: AV nodal artery (from RCA in 90%)
• Site of AV block pathology

4. Bundle of His (Atrioventricular Bundle)

• Originates at AV node; penetrates fibrous skeleton of heart
• Only electrical connection between atria and ventricles (fibrous skeleton normally insulates them)
• Divides into right and left bundle branches at top of interventricular septum

5. Right and Left Bundle Branches

• Travel subendocardially down both sides of interventricular septum
• Right bundle branch: Single compact bundle to right ventricle
• Left bundle branch: Fans out into anterior and posterior fascicles to left ventricle
• Bundle branch block produces wide QRS complex on ECG

6. Purkinje Fibres (Subendocardial branches)

• Location: Spread throughout subendocardial surface of both ventricles
• Intrinsic rate: 25-40 beats/min (lowest; ventricular escape rhythm)
• Fastest conduction: 2-4 m/s
• Stimulate ventricular myocardium from apex upward → coordinated contraction ("wringing" motion)
• Responsible for QRS complex on ECG

Summary Table:

Clinical Correlations:

• SA node disease: Sick sinus syndrome, sinus bradycardia/tachycardia
• 1st degree AV block: Prolonged PR interval (> 0.20 s)
• 2nd degree AV block: Some P waves not conducted (Mobitz I - Wenckebach; Mobitz II)
• 3rd degree (complete) AV block: No P waves conducted to ventricles; ventricular escape rhythm
• Bundle branch block: Wide QRS (> 0.12 s) - LBBB or RBBB

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Q2. 🟡 SQ - Properties of Cardiac Muscle

1. Autorhythmicity (Automaticity)

• Cardiac muscle generates its own impulses without external neural input
• Due to unstable resting membrane potential (pacemaker potential) in nodal cells
• "Funny current" (If) - slow Na+ influx → gradual depolarisation → threshold → spontaneous AP
• SA node dominates due to highest intrinsic rate (overdrive suppression of lower centres)

2. Conductivity

• Impulse spreads rapidly across cardiac muscle via gap junctions (intercalated discs)
• Intercalated discs contain: desmosomes (structural) + gap junctions/connexons (electrical coupling)
• Heart behaves as a functional syncytium (all-or-none contraction of the whole heart)

3. Contractility (Inotropy)

• Strength of contraction depends on intracellular Ca2+ concentration
• Regulated by: SNS (↑), PSNS (↓ in atria), Frank-Starling mechanism, drugs (digoxin ↑, β-blockers ↓)
• Cardiac muscle cannot go onto descending limb of length-tension curve under physiological conditions

4. Rhythmicity

• Heart beats regularly and rhythmically under SA node control
• Rhythm is maintained precisely; arrhythmias = abnormal rhythms

5. Excitability

• Responds to adequate stimulation with an AP
• Absolute refractory period is very long (250-300 ms) - nearly as long as the contraction itself
• This prevents tetanic contraction (which would be fatal)
• All-or-None Law: Cardiac muscle either contracts fully or not at all (for a given physiological state)

6. Tonicity (Tonus)

• Heart maintains slight resting tone; never completely relaxes (unlike smooth muscle)

Cardiac AP vs Skeletal Muscle AP:

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Q3. 🔵 LQ - Cardiac Cycle

Phases of the Cardiac Cycle:

Phase 1 - Ventricular Filling (Diastole) - 0.5 sec

• AV valves (mitral, tricuspid) open → blood rushes from atria into relaxed ventricles
• Accounts for ~70% of ventricular filling
• Produces S3 sound in some conditions (pathological in adults >40)

• Continued gradual filling; pressures equalise
• ECG: P wave begins at end of this phase

• Atria contract (P wave on ECG) → final 20-30% of ventricular filling
• End-Diastolic Volume (EDV) = 120-130 mL
• Loss of atrial kick (e.g., AF) reduces CO by up to 30%

Phase 2 - Isovolumetric Contraction (0.05 sec)

• Ventricles start contracting (QRS on ECG)
• AV valves close → S1 heart sound ("lub")
• Ventricular pressure rises rapidly but all valves closed → no change in volume
• This phase ends when ventricular pressure exceeds aortic/pulmonary pressure → semilunar valves open

Phase 3 - Ventricular Ejection (0.3 sec)

• Aortic and pulmonary valves open; blood ejected rapidly
• Peak ventricular pressure: left ~120 mmHg, right ~25 mmHg

• Ventricular volume decreases; ejection continues
• End-Systolic Volume (ESV) = ~50 mL
• Stroke Volume = EDV - ESV = 120 - 50 = 70 mL
• Ejection Fraction (EF) = SV/EDV = 70/120 = ~58% (normal >55%)

Phase 4 - Isovolumetric Relaxation (0.08 sec)

• Ventricles relax → pressure falls below aortic/pulmonary → semilunar valves close → S2 heart sound ("dub")
• All valves closed → ventricular pressure falls rapidly with no change in volume
• Ends when ventricular pressure falls below atrial pressure → AV valves open → new cycle begins

Summary of Cardiac Cycle:

Diastole (filling) → Isovolumetric Contraction → Ejection (Systole) → Isovolumetric Relaxation
         S1 (AV closes)                                    S2 (Semilunar closes)

Wiggers Diagram (pressure-volume events at a glance):

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Q4. 🔵 LQ - Electrocardiogram (ECG)

Standard ECG Waves and Intervals:

Note: Atrial repolarisation (Ta) is hidden within the QRS complex.

Standard Leads:

• Bipolar: I (RA-LA), II (RA-LF), III (LA-LF)
• Augmented unipolar: aVR, aVL, aVF
• Einthoven's triangle: Leads I, II, III form a triangle; Lead I + aVF used for axis determination

• V1-V6: right to left across precordium

Clinical Applications:

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Q5. 🔵 LQ - Blood Pressure: Definition, Factors Regulating It, Hypertension, Hypotension

Definition

• Systolic BP (SBP): Peak pressure during ventricular systole. Normal: 100-120 mmHg
• Diastolic BP (DBP): Lowest pressure during ventricular diastole. Normal: 60-80 mmHg
• Pulse pressure = SBP - DBP = ~40 mmHg
• Mean Arterial Pressure (MAP) = DBP + 1/3 pulse pressure ≈ 93 mmHg

Factors Regulating Blood Pressure:

A. Short-term Regulation (seconds to minutes):

• Location: Carotid sinus (CN IX) + Aortic arch (CN X)
• ↑ BP → stretch baroreceptors → ↑ firing → vasomotor centre in medulla → ↓ sympathetic + ↑ parasympathetic → ↓ HR + ↓ SVR → BP falls back
• ↓ BP → reverse (baroreceptors inhibited → sympathetic activation)
• Reset upward in hypertension (baroreceptor "resetting")

• Peripheral (carotid + aortic bodies): ↓ pO2, ↑ pCO2, ↓ pH → vasoconstriction + ↑ HR
• Central (medullary): ↑ CO2/H+ → ↑ sympathetic → ↑ BP

• Extreme ↑ intracranial pressure → brain ischaemia → massive sympathetic discharge → severe hypertension (last-resort BP defence)

B. Intermediate Regulation (minutes to hours):

• ↓ BP/renal perfusion → juxtaglomerular cells release renin → angiotensinogen → angiotensin I → ACE → angiotensin II → vasoconstriction + stimulates aldosterone
• Aldosterone (adrenal cortex) → ↑ Na+ and water reabsorption → ↑ blood volume → ↑ BP

• Released by posterior pituitary in response to ↑ osmolality or ↓ BP
• Vasoconstriction (V1 receptors) + water reabsorption (V2 receptors) → ↑ blood volume → ↑ BP

• ↓ BP → capillary hydrostatic pressure falls → interstitial fluid absorbed into blood → expands plasma volume

C. Long-term Regulation:

• ↑ BP → ↑ GFR + ↓ tubular Na+ reabsorption → ↑ Na+ and water excretion → ↓ blood volume → ↓ BP
• Kidney sets the "long-term set point" for BP; chronic hypertension requires a shift in this curve

Hypertension

• Essential (Primary) hypertension (90-95%): No identifiable cause; multifactorial (genetics, salt intake, obesity, stress, sedentary lifestyle)
• Secondary hypertension (5-10%): Identifiable cause
  • Renal: Chronic kidney disease, renal artery stenosis
  • Endocrine: Hyperaldosteronism (Conn's), phaeochromocytoma, Cushing's, hyperthyroidism
  • Drugs: OCPs, NSAIDs, steroids, sympathomimetics

• Cardiac: LVH, angina, MI, heart failure
• Hypertensive encephalopathy, stroke, cerebral haemorrhage
• Aorta: Aortic dissection, aneurysm
• Dementia
• Stroke + renal damage (nephrosclerosis, proteinuria, CKD)

Hypotension

• Orthostatic (postural) hypotension: ≥ 20 mmHg fall in SBP on standing; causes: dehydration, autonomic neuropathy (diabetes, Parkinson's), antihypertensives, prolonged bed rest
• Neurally mediated (vasovagal) syncope: Paradoxical bradycardia + vasodilation; triggered by pain, emotion, prolonged standing

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Q6. 🔵 LQ - Cardiac Output: Definition, Factors Regulating It, Methods to Measure

Definition

Factors Regulating Cardiac Output:

1. Heart Rate (Chronotropy)

• ↑ HR → ↑ CO (up to ~150-160 bpm; above this, diastolic filling time too short → SV falls)
• Increased by: Sympathetic (β1), adrenaline, fever, hypoxia, exercise, anxiety, hyperthyroidism
• Decreased by: Parasympathetic (M2, via vagus), β-blockers, complete heart block, hypothyroidism

2. Stroke Volume (determined by 3 factors):

• = Force stretching the ventricle before contraction = EDV
• ↑ Preload → ↑ fibre length → ↑ force of contraction → ↑ SV (Frank-Starling Law)
• Frank-Starling Law: "The energy of contraction is proportional to the initial length of the cardiac muscle fibre"
• Increased by: ↑ venous return, bradycardia (more filling time), recumbent position, fluid loading
• Decreased by: haemorrhage, dehydration, venodilators (nitrates), tachycardia

• = Aortic diastolic pressure / Total Peripheral Resistance (TPR) for LV
• ↑ Afterload → ↑ wall tension → ventricle works harder → ↑ O2 consumption; in healthy heart, slight ↑; in failing heart, ↑ afterload → ↓ SV
• Increased by: hypertension, aortic stenosis, vasoconstriction
• Decreased by: vasodilators, aortic regurgitation

• Independent of preload and afterload; reflects myocardial Ca2+ availability
• Positive inotropes (↑ contractility): Sympathetic/catecholamines (β1 → ↑ cAMP → ↑ Ca2+), digoxin (inhibits Na+-K+ ATPase → ↑ intracellular Na+ → ↑ Ca2+ via NCX), exercise
• Negative inotropes (↓ contractility): β-blockers, CCBs (verapamil, diltiazem), acidosis, hypoxia, heart failure

Methods to Measure Cardiac Output:

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Q7. 🟡 SQ - Heart Sounds

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Q8. 🟡 SQ - Coronary Circulation

• Right coronary artery (RCA): Supplies SA node (60%), AV node (90%), right ventricle, inferior/posterior LV, posterior interventricular septum
• Left coronary artery (LCA):
  • Left anterior descending (LAD): Anterior LV wall, anterior IV septum (bundle branches), apex - "artery of sudden death"
  • Left circumflex (LCx): Lateral and posterior LV; SA node (40%)
• Dominance: RCA dominant in ~80% (supplies posterior descending artery); LCA dominant in ~10%; co-dominant 10%

• Total flow: ~250 mL/min at rest (~5% of CO)
• Flow occurs mainly during diastole (LV compresses vessels during systole)
• Highest O2 extraction of any organ (~75%; can only ↑ flow, not extraction, during ↑ demand)
• Autoregulation: 60-140 mmHg perfusion pressure range; vasodilator reserve (adenosine, NO, prostacyclin)
• Angina = demand > supply; coronary steal (vasodilators divert blood)

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Q9. 🟡 SQ - Cardiac Failure

Types:

• Left heart failure: ↓ CO + pulmonary congestion → breathlessness, orthopnoea, PND, basal crepitations
• Right heart failure: Systemic venous congestion → peripheral oedema, raised JVP, hepatomegaly
• Congestive cardiac failure (CCF): Both sides involved
• Systolic failure: ↓ EF (< 40%); dilated, weak ventricle; HFrEF
• Diastolic failure: Normal EF but stiff ventricle (impaired filling); HFpEF; e.g., LVH, restrictive cardiomyopathy

Compensatory Mechanisms (initially helpful, later harmful):

1. Frank-Starling mechanism: ↑ EDV → ↑ SV (limited; eventually ventricle dilates)
2. Tachycardia: ↑ HR → maintains CO
3. RAAS activation: ↑ Angiotensin II + Aldosterone → Na+ and water retention → ↑ blood volume → ↑ preload
4. Sympathetic activation: ↑ HR + contractility + vasoconstriction
5. Ventricular hypertrophy/remodelling: Initially maintains CO; eventually fibrosis + dysfunction

Clinical Features:

• Left failure: Dyspnoea on exertion → orthopnoea → PND → pulmonary oedema; S3 gallop, basal crepitations
• Right failure: Peripheral pitting oedema, ↑ JVP, hepatomegaly, ascites
• Both: Fatigue, reduced exercise tolerance, cool peripheries

Treatment:

• Diuretics (↓ preload/congestion), ACE inhibitors/ARBs (↓ afterload + RAAS), β-blockers (reduce remodelling), aldosterone antagonists (spironolactone), SGLT2 inhibitors, sacubitril-valsartan; CRT, ICD, transplant in severe cases

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Q10. 🟡 SQ - Shock

Classification:

Stages of Shock:

1. Compensated (early): Compensatory mechanisms maintain BP; tachycardia, peripheral vasoconstriction, cool clammy skin
2. Decompensated (progressive): Mechanisms fail; ↓ BP, confusion, oliguria
3. Irreversible (terminal): Multi-organ failure; cell death irreversible despite treatment

Septic Shock:

• Endotoxins → systemic inflammatory response → vasodilation (↓ SVR) → maldistribution of flow → cellular hypoxia despite normal or high CO
• Features: ↑ CO, ↓ SVR, warm peripheries (early), fever/hypothermia, DIC

Treatment Principles:

• Restore tissue perfusion: IV fluids (hypovolemic), vasopressors (noradrenaline in septic/distributive), treat cause
• Monitor: MAP ≥ 65 mmHg, urine output ≥ 0.5 mL/kg/hr, serum lactate

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Chapter 6: Respiratory System

Legend: 🔵 LQ = Long Question (10-15 marks) | 🟡 SQ = Short Question (5 marks)

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Q1. 🔵 LQ - Lung Volumes and Capacities

A. Lung Volumes (4 primary, non-overlapping):

B. Lung Capacities (combinations of volumes):

Note: RV, FRC, and TLC cannot be measured by spirometry alone (need helium dilution or body plethysmograph)

C. Spirometric Measurements:

Pattern Recognition:

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Q2. 🔵 LQ - Mechanics of Breathing, Surfactant, and Compliance

A. Mechanics of Breathing

1. Diaphragm contracts (descends 1-10 cm) - primary muscle of inspiration (innervated by phrenic nerve C3,4,5)
2. External intercostal muscles contract → ribs elevated + outward (bucket-handle movement)
3. Thoracic volume increases → intrathoracic pressure falls below atmospheric → air flows IN
4. Pleural pressure: -5 cmH2O at rest → -8 cmH2O during inspiration

• Diaphragm + intercostals relax
• Elastic recoil of lungs + chest wall drives air out
• No active muscle contraction needed

• Internal intercostals contract
• Abdominal muscles contract (rectus abdominis, obliques) → increases intra-abdominal pressure → forces diaphragm upward

• Scalene muscles (raise first 2 ribs)
• Sternocleidomastoid (raises sternum)
• Used in severe dyspnoea / respiratory distress

• Internal intercostals
• Abdominal muscles (rectus abdominis, external/internal obliques, transversus)

B. Surfactant

• Surfactant reduces surface tension of alveolar fluid
• This is critical because small alveoli (small radius r) would otherwise have very high collapsing pressure
• Without surfactant: small alveoli collapse (atelectasis) + large alveoli overdistend
• Surfactant increases compliance, reduces work of breathing, and stabilises alveoli of different sizes by reducing surface tension more in smaller alveoli (where molecules are closer together)

• Neonatal Respiratory Distress Syndrome (NRDS / Hyaline Membrane Disease): Premature infants lack surfactant (adequate surfactant production requires 34-36 weeks gestation; induced by cortisol) → alveolar collapse at birth → severe respiratory distress
  • Prevention: Antenatal corticosteroids to mother; postnatal surfactant replacement therapy
• Surfactant also has immune functions via SP-A and SP-D (opsonisation, innate immunity)

C. Compliance

• Normal lung compliance: ~200 mL/cmH2O

• Static compliance: Measured when no airflow; reflects elastic properties alone
• Dynamic compliance: Measured during airflow; affected by airway resistance

• Emphysema (destruction of elastic tissue)
• Aging
• Surfactant

• Pulmonary fibrosis (increased collagen)
• NRDS (surfactant deficiency)
• Pulmonary oedema
• Atelectasis

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Q3. 🟡 SQ - Dead Space and Alveolar Ventilation

• Anatomic dead space: Conducting airways (nose → bronchioles, no gas exchange) = 150 mL
• Physiologic dead space: Anatomic + functional (alveoli ventilated but not perfused; e.g., pulmonary embolism); in healthy lungs ≈ anatomic dead space
• Bohr equation for physiologic dead space: VD = VT × (PaCO2 - PECO2) / PaCO2

Only alveolar ventilation participates in gas exchange; dead space ventilation is wasted

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Q4. 🔵 LQ - Gas Exchange and Transport of O2 and CO2

A. Gas Exchange at Alveoli and Tissues

• pO2 in atmosphere: 160 mmHg (21% of 760)
• pO2 in alveoli (PAO2): ~100 mmHg (diluted by CO2 + water vapour)
• pCO2 in alveoli (PACO2): ~40 mmHg

• Large surface area of alveoli (~70 m2) + thin membrane (0.3-0.5 μm) → rapid diffusion
• CO2 diffuses ~20x faster than O2 (despite lower partial pressure gradient) due to higher solubility

B. Oxygen Transport

• Each gram of Hb carries 1.34 mL O2 when fully saturated
• At Hb 15 g/dL: O2 carrying capacity = 15 × 1.34 = 20.1 mL/100 mL blood
• O2 Content (CaO2) = (Hb × 1.34 × SaO2) + (0.003 × PaO2)

• Sigmoid due to cooperative binding (allosteric mechanism)
• P50 = partial pressure at which Hb is 50% saturated = 26-27 mmHg

• ↑ CO2 (↑ H+, acidosis), ↑ temperature, ↑ 2,3-DPG
• Beneficial in exercising tissues (unloads more O2)

• ↓ CO2, alkalosis, ↓ temperature, ↓ 2,3-DPG, HbF (foetal Hb - facilitates O2 transfer from mother to foetus), CO poisoning

C. Carbon Dioxide Transport

• H+ buffered by deoxyhaemoglobin (Haldane effect)
• HCO3- exits RBC in exchange for Cl- (chloride shift / Hamburger phenomenon)

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Q5. 🟡 SQ - Ventilation/Perfusion (V/Q) Ratio

• Apex: V/Q > 0.8 (high) - both ventilation and perfusion are lower but perfusion reduced more; apex relatively over-ventilated
• Base: V/Q < 0.8 (low) - both higher but perfusion increases more than ventilation; base relatively over-perfused

V/Q Mismatch (Causes of Hypoxaemia):

• V/Q mismatch: Correctable by giving supplemental O2 (↑ PAO2 corrects hypoxaemia)
• True shunt: NOT correctable by supplemental O2 alone (deoxygenated blood bypasses ventilated alveoli)

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Q6. 🔵 LQ - Control of Respiration

A. Respiratory Centres (in brainstem):

• Dorsal Respiratory Group (DRG) - nucleus tractus solitarius: primarily inspiratory neurons; sets basic rhythm; receives afferents from peripheral chemoreceptors + vagus
• Ventral Respiratory Group (VRG) - contains pre-Bötzinger complex (rhythm generator) + Bötzinger complex (expiratory); mainly expiratory but recruits during forced breathing

• Pontine Respiratory Group (PRG) / Pneumotaxic centre - upper pons: controls rate and depth; inhibits inspiration → smooth cycling; lesion = apneusis (prolonged inspiration)
• Apneustic centre - lower pons: stimulates and prolongs inspiration; normally inhibited by pneumotaxic centre

B. Chemical Control (most important):

• Location: Ventral surface of medulla (separate from respiratory centres)
• Stimulus: ↑ H+ (↓ pH) in CSF - indirectly from ↑ PaCO2 (CO2 crosses BBB, forms H+ in CSF via carbonic anhydrase)
• Response: CO2 ↑ by 1 mmHg → VE increases by ~2 L/min
• NOT directly sensitive to PaO2

• Location: Carotid bodies (main; CN IX) + Aortic bodies (CN X)
• Stimulus: ↓ PaO2 (below 60 mmHg - dominant stimulus), ↑ PaCO2, ↓ pH
• Respond rapidly (within seconds) to hypoxaemia
• In chronic hypercapnia (COPD), central receptors desensitise → patient depends on hypoxic drive via peripheral chemoreceptors (danger of giving high-flow O2)

C. Other Afferent Inputs:

• Lung stretch receptors (slowly adapting) in airways → via vagus to DRG → inhibit inspiration when lungs fully inflated
• Prevents over-inflation; important in neonates; minor role in adults at tidal volumes

• Located near pulmonary capillaries; stimulated by pulmonary oedema, emboli, chemicals
• Cause rapid shallow breathing, cough, bronchoconstriction

• In airway epithelium; stimulated by dust, smoke, noxious gases → cough, bronchoconstriction

• Stimulate ventilation during exercise (fast response before blood gas changes occur)

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Q7. 🟡 SQ - Hypoxia: Types and Classification

Classification:

• Demand hypoxia: Excessive tissue demand exceeds delivery (e.g., sepsis, hyperthyroidism)
• Affinity hypoxia: Hb has such high O2 affinity it won't release O2 to tissues (carbon monoxide - left shift)

Cyanosis

• Central cyanosis: Affects tongue + mucous membranes + periphery; due to arterial hypoxaemia (V/Q mismatch, hypoventilation, shunt, lung disease, high altitude)
• Peripheral cyanosis: Affects extremities only; tongue normal; due to ↑ O2 extraction in cold/slow-moving blood (cold exposure, heart failure, Raynaud's)

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Q8. 🔵 LQ - Pulmonary Function Tests and Respiratory Diseases

A. Pulmonary Function Tests (PFTs)

• FVC, FEV1, FEV1/FVC, PEFR, FEF 25-75% (see Q1 for values)
• Obstructive pattern (FEV1/FVC < 70%): COPD, asthma, bronchiectasis
• Restrictive pattern (FVC ↓, FEV1/FVC normal/↑): pulmonary fibrosis, pleural effusion, chest wall deformity

• Obstructive: Scooped-out (concave) expiratory limb
• Restrictive: Small loop (reduced volumes), normal shape

• Measures gas transfer across alveolar-capillary membrane
• ↓ DLCO: Emphysema (↓ surface area), pulmonary fibrosis (thickened membrane), pulmonary oedema
• ↑ DLCO: Pulmonary haemorrhage (extra Hb available), polycythaemia, post-exercise

• Cheap, portable monitoring of obstructive disease
• Used for asthma monitoring and severity classification

B. Asthma

• Trigger (allergen, exercise, cold air, aspirin) → mast cell degranulation → histamine, leukotrienes, prostaglandins
• Bronchospasm: Smooth muscle contraction → airway narrowing
• Mucus hypersecretion → plugging
• Inflammation + oedema → airway wall thickening
• Chronic changes: Airway remodelling (smooth muscle hypertrophy, goblet cell hyperplasia, fibrosis)

C. COPD (Chronic Obstructive Pulmonary Disease)

• Chronic Bronchitis: "Blue bloater" - productive cough >3 months/year for >2 consecutive years; ↑ mucus glands (Reid index > 0.5), mucus hypersecretion; hypoxaemia + hypercapnia; cyanosis + oedema
• Emphysema: "Pink puffer" - permanent destructive enlargement of air spaces distal to terminal bronchioles; ↓ elastic recoil; barrel chest; hyperinflation; pursed-lip breathing; mainly hypoxic but retain CO2 less

D. Respiratory Failure

• Mechanism: V/Q mismatch, shunt, diffusion impairment
• Causes: Pneumonia, pulmonary oedema, ARDS, PE, asthma attack
• Treatment: Supplemental O2 (responds well)

• Mechanism: Alveolar hypoventilation (pump failure)
• Causes: COPD exacerbation, respiratory muscle weakness (MG, GBS), CNS depression (opioids), chest wall deformity
• Treatment: Treat cause; NIV (BiPAP); controlled O2 (avoid hypercapnia); intubation if severe

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Q9. 🟡 SQ - Oxygen Dissociation Curve (Summary)

• At PaO2 = 100 mmHg (arterial blood): SaO2 = 98% (plateau region - loading in lungs)
• At PO2 = 40 mmHg (mixed venous): SaO2 = 75% (steep region - unloading in tissues)
• At P50 = 26-27 mmHg: SaO2 = 50%

• Flat upper portion: Loading of O2 in lungs is maintained even if PaO2 drops to ~60 mmHg (SaO2 still 90%) - provides safety margin at altitude/lung disease
• Steep lower portion: Small drop in tissue PO2 → large O2 unloading → tissues can extract more O2 during exercise

• ↑ CO2, ↑ H+ (↓ pH) = Bohr effect
• ↑ Temperature
• ↑ 2,3-DPG (produced by RBCs in chronic hypoxia, anaemia, high altitude)

• ↓ CO2, ↓ H+ (↑ pH)
• ↓ Temperature
• ↓ 2,3-DPG
• Foetal Hb (HbF) - binds 2,3-DPG less; allows placental O2 transfer
• Carboxyhaemoglobin (COHb) - CO binds Hb 250x more avidly than O2; also causes left shift; cherry-red colour; treated with 100% O2

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Chapter 7: Renal System

Legend: 🔵 LQ = Long Question (10-15 marks) | 🟡 SQ = Short Question (5 marks)

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Q1. 🟡 SQ - Functions of the Kidney

Excretory Functions:

• Excretion of metabolic waste products: Urea (protein catabolism), creatinine (muscle metabolism), uric acid (purine catabolism), bilirubin metabolites
• Excretion of foreign chemicals: Drugs, toxins, food additives, pesticides

Regulatory Functions:

• Water and osmolality regulation: Adjusts urine osmolality between 50-1200 mOsm/kg to maintain plasma osmolality ~290 mOsm/kg
• Electrolyte balance: Regulates Na+, K+, Cl-, HCO3-, Ca2+, Mg2+, PO4-
• Acid-base balance: Excretes H+ and regenerates HCO3-; maintains arterial pH 7.35-7.45
• Blood pressure regulation: Via sodium balance, volume status, and RAAS (renin-angiotensin-aldosterone system)

Endocrine Functions:

• Erythropoietin (EPO): Secreted by interstitial cells of cortex in response to hypoxia → stimulates RBC production in bone marrow
• Renin: Secreted by juxtaglomerular cells of afferent arteriole → activates RAAS → angiotensin II → vasoconstriction + aldosterone release
• 1,25-Dihydroxycholecalciferol (Calcitriol / Active Vitamin D): Kidney converts 25-OH-D3 → 1,25-(OH)2-D3 via 1α-hydroxylase → promotes intestinal Ca2+ absorption
• Prostaglandins: Vasodilatory PGE2 and PGI2 locally regulate glomerular blood flow

Gluconeogenesis:

• Kidneys contribute ~20% of total gluconeogenesis (especially during prolonged fasting)

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Q2. 🔵 LQ - Glomerular Filtration and GFR

A. The Nephron (Functional Unit)

• Renal corpuscle = glomerulus + Bowman's capsule
• Proximal convoluted tubule (PCT)
• Loop of Henle (descending thin limb, ascending thin limb, thick ascending limb)
• Distal convoluted tubule (DCT)
• Collecting duct (CD) - connects to renal pelvis

B. Glomerular Filtration

• Normal: 125 mL/min (~180 L/day); only ~1.5 L excreted as urine
• Filtration fraction = GFR / Renal plasma flow = 125/625 = ~20%

1. Glomerular capillary endothelium (fenestrated, pores 60-100 nm) - charge + size barrier
2. Glomerular basement membrane (GBM) - negative charge barrier (type IV collagen, laminin, heparan sulphate)
3. Podocyte foot processes with slit diaphragms (nephrin, podocin) - final size barrier

• Freely filtered: Water, glucose, amino acids, urea, creatinine, uric acid, electrolytes (MW < 7,000)
• Partially restricted: Albumin (MW 69,000; negative charge repelled by GBM)
• Not filtered: RBCs, WBCs, platelets, large plasma proteins

C. Measurement of GFR

• U = urine concentration of substance (mg/mL)
• V = urine flow rate (mL/min)
• P = plasma concentration (mg/mL)

• GFR = Uinulin × V / Pinulin = 125 mL/min

• Normal: 90-130 mL/min/1.73 m2

• ERPF = CPAH = UPAH × V / PPAH = 625 mL/min

D. Regulation of GFR

• Myogenic mechanism: ↑ BP → stretch of afferent arteriole wall → vasoconstriction → maintained GFR
• Tubuloglomerular feedback (TGF): ↑ NaCl delivery to macula densa cells of juxtaglomerular apparatus → release of adenosine (and TXA2) → constrict afferent arteriole → ↓ GFR (negative feedback)

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Q3. 🔵 LQ - Tubular Reabsorption and Secretion

A. Overview

• PCT reabsorbs ~65-67% of filtered Na+, water, glucose, amino acids, HCO3-
• Loop of Henle: ~25% Na+ reabsorption
• DCT and CD: Fine-tuning of Na+, K+, water, acid-base balance

B. Proximal Convoluted Tubule (PCT)

• Na+ enters cell via Na+-glucose cotransporter (SGLT2), Na+-amino acid cotransporter, Na+/H+ exchanger (NHE3) on apical membrane
• Na+ exits basolaterally via Na+/K+-ATPase (primary active transport)
• Water follows osmotically through aquaporin 1 (AQP1) channels (iso-osmotic reabsorption)
• Glucose: reabsorbed by SGLT2 (PCT) and SGLT1 (late PCT); transport maximum (Tm) = 375 mg/min; threshold ~200 mg/dL; glucosuria above this
• HCO3-: reabsorbed as CO2 (not directly); Na+/H+ exchanger secretes H+ → H+ + HCO3- → H2CO3 → CO2 + H2O (carbonic anhydrase) → CO2 diffuses in → reformed to HCO3- intracellularly

• Organic acids: uric acid, bile salts, prostaglandins, creatinine (small amount)
• Organic bases: choline, histamine
• Drugs: penicillin, salicylates, PAH, thiazides, furosemide, probenecid (secreted via OAT transporters)

C. Loop of Henle

• Impermeable to water
• Active NaCl reabsorption via Na+-K+-2Cl- (NKCC2) cotransporter on apical membrane - site of action of loop diuretics
• K+ recycled back into lumen (generating lumen-positive potential driving paracellular Ca2+, Mg2+ reabsorption)
• Dilutes tubular fluid → generates hypotonic fluid entering DCT (~100 mOsm)

D. Distal Convoluted Tubule (DCT)

• Reabsorbs Na+ via NCC (Na+-Cl- cotransporter) - site of action of thiazide diuretics
• Reabsorbs Ca2+ (regulated by PTH and calcitriol) via TRPV5 channel
• Reabsorbs Mg2+
• Aldosterone stimulates Na+ reabsorption here and in cortical collecting duct

E. Collecting Duct (CD)

• Na+ reabsorption via ENaC (epithelial Na+ channel) - regulated by aldosterone (increases ENaC expression + Na+/K+-ATPase activity)
• K+ secretion into lumen (via ROMK channel) - explains aldosterone → hypokalaemia
• Water reabsorption via AQP2 - regulated by ADH/AVP

• Type A (α): Secrete H+ (H+-ATPase) + reabsorb HCO3-; active in acidosis
• Type B (β): Secrete HCO3-, reabsorb H+; active in alkalosis

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Q4. 🔵 LQ - Concentration and Dilution of Urine (Countercurrent Mechanism)

A. Overview

B. Countercurrent Multiplier (Loop of Henle)

1. Thick ascending limb (TAL) actively pumps NaCl into medullary interstitium (via NKCC2) BUT is impermeable to water → solute accumulates in interstitium
2. This creates a hyperosmotic interstitium → draws water OUT of the thin descending limb (which is water-permeable, solute-impermeable) → descending tubular fluid becomes concentrated
3. Concentrated fluid turns the hairpin bend and enters the ascending limb, which pumps more NaCl out
4. Each cycle multiplies the osmotic gradient → tip of loop reaches ~1200 mOsm
5. Urea recycling: In the presence of ADH, inner medullary collecting duct (IMCD) is permeable to urea → urea moves out into medulla → urea enters thin descending limb of loop → recycled → contributes ~400 mOsm to papillary tip gradient

C. Countercurrent Exchanger (Vasa Recta)

• Vasa recta = hairpin-shaped capillaries that parallel loop of Henle
• Blood entering descending vasa recta gains solute (NaCl, urea) as it descends into hypertonic medulla; loses water
• Blood leaving ascending vasa recta loses solute, gains water back
• Net effect: Solutes remain trapped in medulla; medullary interstitium osmolarity maintained
• Without vasa recta countercurrent exchange, the gradient would be washed out by blood flow

D. Role of ADH (Antidiuretic Hormone / Arginine Vasopressin - AVP)

• ↑ plasma osmolality (>280 mOsm) detected by osmoreceptors in hypothalamus
• ↓ blood volume/pressure detected by baroreceptors (carotid sinus, aortic arch, atria)
• Nausea, pain, stress, nicotine → ↑ ADH
• Alcohol, ANP → suppress ADH

• ADH binds V2 receptors on basolateral membrane of collecting duct principal cells
• → Gs protein → ↑ cAMP → PKA activation → phosphorylation → insertion of AQP2 water channels into apical membrane
• → Water reabsorption from collecting duct lumen into hypertonic medullary interstitium → concentrated urine

• Central DI: ↓ ADH production (head injury, tumour, surgery) → dilute polyuria; treated with desmopressin (DDAVP)
• Nephrogenic DI: Kidney unresponsive to ADH (V2 receptor or AQP2 mutation, hypercalcaemia, lithium toxicity) → treated with thiazides + low-salt diet

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Q5. 🔵 LQ - Renal Regulation of Acid-Base Balance

A. Normal Blood Gas Values:

• Arterial pH: 7.35-7.45
• PaCO2: 35-45 mmHg
• HCO3-: 22-26 mEq/L
• Henderson-Hasselbalch equation: pH = 6.1 + log ([HCO3-] / 0.03 × PaCO2)

B. Renal Mechanisms for H+ Excretion:

• H+ secreted by NHE3 → combines with filtered HCO3- → H2CO3 → CO2 + H2O (carbonic anhydrase IV on brush border) → CO2 diffuses into PCT cells → carbonic anhydrase II converts back to H+ + HCO3- → H+ recycled, HCO3- exits into blood via NBC (Na+/HCO3- cotransporter)
• This process "reabsorbs" HCO3- (doesn't actually secrete net H+)

• H+ pumped into tubular lumen by H+-ATPase (type A intercalated cells) combines with HPO4²- (dibasic phosphate, pKa 6.8) → H2PO4- (monobasic phosphate) excreted
• Phosphate acts as a "buffer" for H+ → each H2PO4- excreted represents one new HCO3- generated

• Glutamine enters PCT → glutaminase → NH4+ + HCO3- regenerated
• NH4+ secreted into tubular lumen (substitutes for K+ on NKCC2 in TAL, reabsorbed then secreted again)
• In acidosis, NH3 diffusion trapping: NH3 diffuses into collecting duct lumen → H+ + NH3 → NH4+ trapped (lipid-insoluble) → excreted
• Each NH4+ excreted = one new HCO3- entering blood
• NH4+ excretion increases 10-fold in chronic acidosis (major compensation)

C. Acid-Base Disorders:

• High anion gap metabolic acidosis (MUDPILES): Methanol, Uraemia, DKA, Paraldehyde, Isoniazid, Lactic acidosis, Ethylene glycol, Salicylates
• Normal anion gap (hyperchloraemic) acidosis: Diarrhoea, renal tubular acidosis, IV saline

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Q6. 🟡 SQ - Micturition Reflex

Anatomy:

• Detrusor muscle: Smooth muscle of bladder wall (parasympathetic, S2-S4 → contract = voiding)
• Internal urethral sphincter: Smooth muscle; sympathetic (L1-L2) keeps closed during storage
• External urethral sphincter: Skeletal muscle; voluntary (pudendal nerve, S2-S4 → contracts = continence)

Storage Phase:

• Sympathetic (L1-L2): Relaxes detrusor (β3-AR), contracts internal sphincter (α-AR) → urine stored
• External sphincter voluntarily contracted
• First urge to void: ~150 mL; fullness sensation: 400-500 mL
• Cortical/supraspinal centres continuously inhibit the voiding reflex

Voiding Phase:

1. Voluntary decision → cortex releases inhibition → pontine micturition centre (PMC) activated
2. PMC inhibits external sphincter (Onuf's nucleus) → external sphincter relaxes
3. PMC activates sacral parasympathetic (S2-S4) → pelvic nerve → acetylcholine on M3 receptors → detrusor contracts
4. Internal sphincter relaxes passively (coordinated with detrusor)
5. Urine enters posterior urethra → stretch receptors → positive feedback → sustained voiding

Neurological lesions:

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Q7. 🔵 LQ - Renal Failure and Diuretics

A. Acute Kidney Injury (AKI)

• Phases: Initiation → Oliguric (↓ urine < 400 mL/day; ↑ K+, ↑ urea, ↑ creatinine) → Polyuric (tubules recover, urine ↑ but can't concentrate) → Recovery
• Mechanism: Ischaemia or nephrotoxins (contrast, aminoglycosides, cisplatin) → tubular cell necrosis → cast formation → tubular obstruction + backleak

B. Chronic Kidney Disease (CKD)

• ↑ urea, creatinine → uraemia (encephalopathy, pericarditis, platelet dysfunction)
• ↓ EPO → normocytic anaemia
• ↓ 1α-hydroxylase → ↓ calcitriol → ↓ Ca2+ absorption → hypocalcaemia → ↑ PTH → renal osteodystrophy
• ↑ K+ → hyperkalaemia (cardiac arrhythmias)
• ↓ H+ excretion → metabolic acidosis
• Na+/water retention → hypertension + oedema
• ↑ phosphate → hyperphosphataemia → ectopic calcification

C. Diuretics

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