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📚 GENERAL PHYSIOLOGY — Complete Study Notes

Basic → MBBS → Advanced Level | All Systems

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TABLE OF CONTENTS

1. Introduction to Physiology & Homeostasis
2. Cell Physiology
3. Membrane Transport & Resting Membrane Potential
4. Action Potential & Nerve Conduction
5. Neuromuscular Junction & Muscle Physiology
6. Cardiovascular Physiology
7. Respiratory Physiology
8. Renal Physiology & Body Fluids
9. Acid-Base Balance
10. Gastrointestinal Physiology
11. Endocrine Physiology
12. Neurophysiology & CNS
13. Special Senses
14. Blood & Immune Physiology
15. Reproductive Physiology
16. Thermoregulation & Metabolism

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SECTION 1 - INTRODUCTION TO PHYSIOLOGY & HOMEOSTASIS

1.1 What is Physiology?

1.2 Body Fluids and Internal Environment

• 60% water by weight (40 L in a 70-kg man)
• Intracellular fluid (ICF): 28 L (40% body weight)
• Extracellular fluid (ECF): 14 L (20% body weight)
  • Interstitial fluid: ~11 L
  • Plasma: ~3 L
  • Lymph, transcellular fluid: ~1 L

1.3 Homeostasis

• Body temperature: 37°C (±0.5°C)
• Blood glucose: 70-110 mg/dL (fasting)
• Arterial pH: 7.35-7.45
• Plasma osmolality: 285-295 mOsm/kg
• Arterial PO₂: 75-100 mmHg
• Arterial PCO₂: 35-45 mmHg
• Blood pressure: ~120/80 mmHg

• Negative feedback (most common): corrects deviations from set point. Examples: thermoregulation, blood pressure control, blood glucose regulation.
• Positive feedback (amplifies stimulus): childbirth (oxytocin), blood clotting (thrombin), action potential upstroke (Na⁺ channels).
• Feed-forward control: anticipatory response before disruption (e.g., salivation at sight of food).

1. Sensor / receptor
2. Afferent pathway
3. Integrating center (set point comparison)
4. Efferent pathway
5. Effector
6. Response (output that reduces error)

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SECTION 2 - CELL PHYSIOLOGY

2.1 Cell Organization

• Water: 70-85% (fat cells have less)
• Proteins: 10-20% of cell mass
• Lipids (phospholipids, cholesterol, triglycerides)
• Carbohydrates (mostly glycoproteins/glycolipids)
• Electrolytes: K⁺, Mg²⁺, HPO₄²⁻, SO₄²⁻, HCO₃⁻, small amounts of Na⁺, Cl⁻, Ca²⁺

2.2 Cell Organelles

• Inner membrane: site of electron transport chain (Complexes I-IV) and ATP synthase (Complex V)
• Outer membrane: freely permeable to small molecules
• Matrix: contains TCA cycle enzymes, mtDNA, ribosomes
• Generate 30-32 ATP per glucose molecule via oxidative phosphorylation
• Chemiosmotic theory (Mitchell): H⁺ gradient drives ATP synthase

2.3 The Cell Membrane (Plasma Membrane)

• Phospholipid bilayer: hydrophilic heads face outward, hydrophobic tails face inward
• Cholesterol: between phospholipid tails - reduces fluidity at high temp, prevents solidification at low temp; maintains membrane rigidity
• Membrane proteins:
  • Integral (transmembrane): span the bilayer; include ion channels, pumps, transporters, receptors
  • Peripheral: on inner or outer surface; enzymatic or structural roles
  • Lipid-anchored: covalently attached to membrane lipids

• Cholesterol content
• Fatty acid saturation (unsaturated = more fluid)
• Temperature

2.4 Cell Signaling

1. Ion channel receptors (ionotropic): direct gating of ion channels (e.g., nicotinic ACh receptor, GABA-A)
2. G-protein coupled receptors (GPCR): 7-transmembrane; couple to G proteins → second messengers
   • Gαs → ↑adenylyl cyclase → ↑cAMP → PKA activation
   • Gαi → ↓adenylyl cyclase → ↓cAMP
   • Gαq → ↑phospholipase C → IP₃ + DAG → Ca²⁺ release + PKC
3. Receptor tyrosine kinases (RTK): growth factors, insulin; autophosphorylation → intracellular signaling cascades
4. Nuclear receptors (intracellular): steroids, thyroid hormones, vitamin D; directly regulate gene transcription

• cAMP: formed by adenylyl cyclase, degraded by phosphodiesterase
• cGMP: formed by guanylyl cyclase (ANP, NO)
• IP₃: releases Ca²⁺ from ER
• DAG: activates PKC
• Ca²⁺: binds calmodulin → activates many enzymes

2.5 Cell Division

• Phases: Prophase → Metaphase → Anaphase → Telophase → Cytokinesis

• Meiosis I: reductional division (homologs separate)
• Meiosis II: equational division (chromatids separate)

• Cyclins + CDKs (cyclin-dependent kinases) control progression
• Checkpoints: G1/S, G2/M, spindle assembly checkpoint
• Tumor suppressor proteins (p53, Rb) apply brakes
• Proto-oncogenes (Ras, Myc) accelerate progression

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SECTION 3 - MEMBRANE TRANSPORT & RESTING MEMBRANE POTENTIAL

3.1 Membrane Transport Mechanisms

A) Passive Transport (no energy required)

• Applies to: O₂, CO₂, N₂, fatty acids, steroid hormones, small uncharged molecules
• Rate = Fick's law: J = -DA(dC/dx) where D = diffusion coefficient, A = area, dC/dx = concentration gradient
• Factors ↑diffusion: ↑concentration gradient, ↑temperature, ↓molecular weight, ↑lipid solubility

• Glucose transport into RBCs and most cells via GLUT transporters (GLUT1-4)
• Saturability, specificity, competition (like enzymes)
• Uniport: one substance, one direction

• Osmotic pressure (π): π = nCRT (van't Hoff's equation)
  • n = number of particles, C = concentration, R = gas constant, T = temperature
• Tonicity: effect of a solution on cell volume
  • Isotonic (0.9% NaCl, 5% dextrose): no change in cell volume
  • Hypotonic: cell swells (water enters)
  • Hypertonic: cell shrinks (water leaves)
• Aquaporins (AQPs): channel proteins for water transport; AQP2 in collecting duct regulated by ADH

B) Active Transport (requires energy/ATP)

• Na⁺/K⁺-ATPase (sodium pump): pumps 3 Na⁺ out and 2 K⁺ in per ATP hydrolyzed - electrogenic
  • Creates: high intracellular K⁺, low intracellular Na⁺
  • Inhibited by: ouabain, digoxin (cardiac glycosides)
• Ca²⁺-ATPase (SERCA): pumps Ca²⁺ into SR/ER
• H⁺/K⁺-ATPase: in gastric parietal cells - pumps H⁺ into stomach; inhibited by PPIs

• Cotransport (symport): Na⁺ and substrate move in same direction
  • Na⁺-glucose (SGLT1/SGLT2) in intestine/kidney
  • Na⁺-amino acid in intestine
• Countertransport (antiport): Na⁺ and substrate move in opposite directions
  • Na⁺/H⁺ exchanger (NHE3) in proximal tubule
  • Na⁺/Ca²⁺ exchanger (NCX) in cardiac muscle

• Phagocytosis: ingestion of large particles (>250 nm); used by macrophages, neutrophils
• Pinocytosis: ingestion of fluid
• Receptor-mediated endocytosis: clathrin-coated pits; e.g., LDL uptake
• Exocytosis: secretion of vesicle contents (neurotransmitters, hormones)

3.2 Resting Membrane Potential (RMP)

• Neuron RMP: -70 mV (inside negative)
• Skeletal muscle: -90 mV
• Cardiac muscle: -90 mV
• Smooth muscle: -50 to -60 mV

1. Concentration gradients maintained by Na⁺/K⁺-ATPase:
   • ICF: K⁺ = 140 mEq/L, Na⁺ = 14 mEq/L, Cl⁻ = 4 mEq/L
   • ECF: K⁺ = 4 mEq/L, Na⁺ = 142 mEq/L, Cl⁻ = 103 mEq/L
2. Differential membrane permeability: at rest, membrane is highly permeable to K⁺ (resting K⁺ channels) but poorly permeable to Na⁺
3. K⁺ diffuses out down its concentration gradient → leaves negative charges inside → creates negative potential

• E_K⁺ = -94 mV
• E_Na⁺ = +61 mV
• E_Cl⁻ = -70 mV (close to RMP)
• E_Ca²⁺ = +132 mV

• Takes into account permeability of K⁺, Na⁺, and Cl⁻
• RMP ≈ (PK × [K]out + PNa × [Na]out + PCl × [Cl]in) / (PK × [K]in + PNa × [Na]in + PCl × [Cl]out)
• At rest: PK : PNa : PCl ≈ 1 : 0.04 : 0.45

• Depolarization: membrane potential becomes less negative (moves toward 0)
• Hyperpolarization: membrane potential becomes more negative
• Threshold potential: the critical level of depolarization (~-55 mV in neurons) at which an action potential is triggered

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SECTION 4 - ACTION POTENTIAL & NERVE CONDUCTION

4.1 Action Potential

Phases of Action Potential (Neuron):

• Resting/closed (can be activated): at RMP
• Open/activated: during upstroke (m gates open)
• Inactivated/closed (cannot be activated): h gate closes; requires return to RMP to recover (terodotoxin blocks these)
• Local anesthetics (lidocaine) block Na⁺ channels in inactivated state

• Delayed rectifier: opens during repolarization
• Slower activation than Na⁺ channels
• Tetraethylammonium (TEA) blocks K⁺ channels

• Absolute refractory period (ARP): Na⁺ channels inactivated; no AP possible regardless of stimulus strength. Duration ~1-2 ms
• Relative refractory period (RRP): Na⁺ channels partially recovered + K⁺ channels still open; suprathreshold stimulus can trigger AP. Duration 10-15 ms

4.2 Graded Potentials vs Action Potentials

4.3 Nerve Conduction

• Slow conduction velocity: 0.5-2 m/s
• C fibers (pain, temperature, autonomic)

• Much faster: up to 70-120 m/s
• Myelin: produced by Schwann cells (PNS) and oligodendrocytes (CNS)
• Nodes of Ranvier: 1-2 mm apart; high concentration of voltage-gated Na⁺ channels

• ↑Axon diameter → ↑velocity
• ↑Myelination → ↑velocity
• ↑Temperature → ↑velocity (to ~45°C; above that, conduction fails)

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SECTION 5 - NEUROMUSCULAR JUNCTION & MUSCLE PHYSIOLOGY

5.1 Neuromuscular Junction (NMJ)

1. AP reaches motor nerve terminal
2. Depolarization opens voltage-gated Ca²⁺ channels (N-type) at terminal
3. Ca²⁺ entry triggers acetylcholine (ACh) exocytosis from synaptic vesicles
4. ACh crosses synaptic cleft (50 nm)
5. ACh binds nicotinic ACh receptors (nAChR) - ligand-gated Na⁺/K⁺ channel (ionotropic)
6. Na⁺ influx > K⁺ efflux → end-plate potential (EPP; depolarization ~-80 → -15 mV)
7. EPP spreads, triggers AP in muscle fiber
8. ACh degraded by acetylcholinesterase (AChE) in cleft
9. Choline reuptaken by presynaptic terminal for resynthesis of ACh

• Botulinum toxin: inhibits ACh release (blocks SNARE proteins) → flaccid paralysis
• Black widow spider venom: causes massive ACh release → initially spastic then flaccid
• Curare / vecuronium (non-depolarizing blockers): competitive antagonist at nAChR → flaccid paralysis; reversed by neostigmine (AChE inhibitor)
• Succinylcholine (depolarizing blocker): mimics ACh, persistent depolarization → initial fasciculations then paralysis (Phase I/II block)
• Neostigmine / organophosphates: inhibit AChE → ↑ACh in cleft → overstimulation
• Myasthenia gravis: autoimmune antibodies against nAChR → reduced EPPs → muscle weakness; treated with pyridostigmine (AChE inhibitor)
• Lambert-Eaton myasthenic syndrome: antibodies against presynaptic voltage-gated Ca²⁺ channels → reduced ACh release

5.2 Skeletal Muscle Physiology

• Muscle fiber → myofibrils → sarcomeres (basic contractile unit)
• Sarcomere: from Z-line to Z-line (2.2 μm at rest)
  • A-band: thick filaments (myosin) + overlap region; does NOT change length during contraction
  • I-band: thin filaments (actin) only; SHORTENS during contraction
  • H-zone: thick filaments only (no actin); SHORTENS during contraction
  • M-line: center of A-band; holds thick filaments together
  • Z-line (disc): anchors thin filaments; defines sarcomere boundaries

• Myosin (thick filament): heavy meromyosin (head with ATPase + actin-binding) + light meromyosin (tail)
• Actin (thin filament): F-actin (polymer of G-actin); contains myosin-binding sites
• Tropomyosin: lies along actin groove; covers myosin-binding sites at rest
• Troponin complex:
  • TnT: binds tropomyosin
  • TnI: inhibitory; prevents actin-myosin interaction
  • TnC: binds Ca²⁺; triggers conformational change

1. ATP binds to myosin head → myosin dissociates from actin
2. ATPase hydrolyzes ATP → ADP + Pi; myosin head cocks (high-energy state, 90° orientation)
3. Myosin head attaches to actin (cross-bridge formation)
4. Power stroke: Pi released → myosin head pivots (45°) → pulls actin toward M-line
5. ADP released; rigor state (myosin firmly attached without ATP)
6. New ATP binds → cycle repeats

1. AP travels along sarcolemma and down T-tubules (transverse tubules)
2. T-tubule AP activates dihydropyridine (DHP) receptors - voltage sensors in T-tubule membrane
3. DHP receptors mechanically activate ryanodine receptors (RyR1) in SR
4. Ca²⁺ floods from SR into cytoplasm (rises from 10⁻⁷ to 10⁻⁵ M)
5. Ca²⁺ binds TnC → tropomyosin moves → actin active sites exposed → cross-bridge cycle proceeds
6. Relaxation: SERCA pumps Ca²⁺ back into SR; Ca²⁺ unbinds TnC; tropomyosin re-blocks active sites

5.3 Mechanics of Muscle Contraction

• Latent period (5 ms) → contraction (40-100 ms) → relaxation (50-200 ms)

• Temporal summation: repeated stimuli before relaxation → summed twitches
• Tetanus: high-frequency stimulation → sustained maximal contraction (unfused if wavy, fused if smooth)

• Optimal overlap of actin and myosin filaments at resting length → maximum tension
• Too short (H-zone compressed): thick filaments hit Z-lines → decreased tension
• Too long (minimal overlap): fewer cross-bridges → decreased tension
• In intact body: muscles operate near optimal length

• Inverse relationship: as load increases, velocity of shortening decreases
• At maximum load: velocity = 0 (isometric contraction)
• At zero load: maximum velocity (Vmax)

• Isometric: muscle develops tension but does not shorten (length constant)
• Isotonic (concentric): muscle shortens while developing constant tension
• Eccentric: muscle lengthens while developing tension (e.g., lowering a weight)

5.4 Smooth Muscle

• No T-tubules (sarcolemmal invaginations, caveolae)
• No organized sarcomeres (no striations)
• Actin + myosin + tropomyosin present but no troponin
• Contraction regulated by calmodulin-myosin light chain kinase (MLCK)
• Ca²⁺ sources: ECF entry (L-type Ca²⁺ channels) AND SR release (IP₃-sensitive)

1. Stimulus (nerve, hormone, stretch, local factors)
2. ↑Cytoplasmic Ca²⁺
3. Ca²⁺ binds calmodulin → Ca²⁺-calmodulin complex
4. Activates MLCK → phosphorylates myosin light chain (MLC)
5. Phospho-MLC activates myosin ATPase → cross-bridge cycling
6. Relaxation: MLCP (myosin light chain phosphatase) dephosphorylates MLC

• Unitary (single-unit / visceral): gap junctions; electrically coupled; spontaneous activity; found in GI, uterus, ureter, bladder
• Multi-unit: individual cells, separately innervated; precise control; found in ciliary muscle, iris, large blood vessels

5.5 Cardiac Muscle

• Striated like skeletal muscle
• EC coupling via Ca²⁺-induced Ca²⁺ release (CICR): DHP receptor triggers RyR2 in SR
• Depends more on ECF Ca²⁺ than skeletal muscle
• Gap junctions (intercalated discs) allow synchronized contraction
• Cannot be tetanized (ARP lasts throughout systole)

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SECTION 6 - CARDIOVASCULAR PHYSIOLOGY

6.1 Cardiac Electrophysiology

• No fast Na⁺ channels; no stable Phase 4
• Phase 4 (pacemaker potential / funny current): If (HCN channels, non-selective, Na⁺/K⁺ → slow depolarization)
• Phase 0: L-type Ca²⁺ channels (slow, no fast Na⁺)
• Fires spontaneously at 60-100 bpm
• Rate controlled by ANS:
  • Sympathetic (β₁): ↑cAMP → ↑If → faster Phase 4 slope → ↑HR (positive chronotropy)
  • Parasympathetic (ACh, M₂): ↑IKAch → hyperpolarization + slower Phase 4 → ↓HR (negative chronotropy)

• SA node: 60-100 bpm (dominant pacemaker)
• AV node: 40-60 bpm
• Bundle of His/Purkinje: 20-40 bpm

• Purkinje fibers: fastest conduction (4 m/s) → synchronous ventricular activation

6.2 ECG (Electrocardiogram)

• Hyperkalemia: peaked T waves → wide QRS → sine wave → VF
• Hypokalemia: flat/inverted T waves, prominent U waves
• Hypercalcemia: shortened QT interval
• Hypocalcemia: prolonged QT interval

6.3 The Heart as a Pump

• Isovolumetric contraction: all valves closed; pressure rises; volume constant (MV closed, AoV closed)
• Rapid ejection: aortic valve opens when LV pressure > aortic pressure; blood ejected
• Reduced ejection: slower ejection as pressures equalize

• Isovolumetric relaxation: all valves closed; pressure falls; volume constant
• Rapid passive filling: mitral valve opens (LV pressure < LA pressure)
• Slow filling (diastasis): slow filling phase
• Atrial systole: "atrial kick" - contributes 20-30% of ventricular filling

• A→B: Isovolumetric contraction
• B→C: Ejection
• C→D: Isovolumetric relaxation
• D→A: Ventricular filling
• ESPVR (end-systolic pressure-volume relationship): slope = Emax = contractility index
• EDPVR: passive compliance of ventricle

• S1: Closure of mitral (M₁) + tricuspid (T₁) valves (start of systole). Best at apex. "Lub"
• S2: Closure of aortic (A₂) + pulmonary (P₂) valves (end of systole). Best at base. "Dub"
  • Normal splitting: A₂ before P₂; widens with inspiration
• S3 (ventricular gallop): early diastole, rapid filling phase; normal in children/athletes; ABNORMAL in adults (heart failure, MR)
• S4 (atrial gallop): late diastole, atrial kick against stiff ventricle; suggests reduced compliance (hypertrophy, MI)

6.4 Cardiac Output (CO)

• SV = EDV - ESV
• Normal EDV = 120-130 mL; ESV = 50-60 mL; SV = 70 mL
• Ejection fraction (EF) = SV/EDV × 100 = ~60% (normal ≥55%)

• "The heart pumps whatever comes to it"
• ↑Preload (↑EDV) → ↑stretch of cardiac myocytes → ↑force of contraction → ↑SV
• Mechanism: more optimal actin-myosin overlap + ↑Ca²⁺ sensitivity of troponin C
• Curve shifts UP with ↑contractility (sympathetics, catecholamines, digoxin)
• Curve shifts DOWN with ↓contractility (heart failure, β-blockers, acidosis)

1. Preload: ventricular filling volume (EDV); affected by venous return, heart rate, blood volume
2. Afterload: resistance against which heart pumps; related to aortic pressure (Laplace's law: T = Pr/2h)
3. Contractility (inotropy): intrinsic force of contraction independent of preload/afterload
   • ↑by: sympathetics, digitalis, ↑heart rate (Bowditch effect), ↑Ca²⁺
   • ↓by: β-blockers, Ca²⁺ channel blockers, acidosis, hypoxia, heart failure

• VO₂ = oxygen consumption (~250 mL/min at rest)
• CaO₂ = arterial O₂ content (~200 mL/L)
• CvO₂ = venous O₂ content (~150 mL/L)
• CO = 250 / (200-150) = 250/50 = 5 L/min

6.5 Blood Pressure & Vascular Physiology

• Normal: systolic 100-140 mmHg / diastolic 60-90 mmHg
• Mean arterial pressure (MAP) = DBP + 1/3(PP)
  • Or MAP = CO × TPR (total peripheral resistance)
• Pulse pressure (PP) = SBP - DBP ≈ 40 mmHg

• Q = flow rate, ΔP = pressure gradient, r = radius, η = viscosity, L = length
• Resistance (R) = 8ηL/(πr⁴)
• Radius is the dominant factor (r⁴); doubling radius → 16× increase in flow

• Systemic vessels arranged in parallel → TPR = 1/(1/R1 + 1/R2 + ... )
• Total resistance lower than any individual

• Arteries: compliance vessels, pulse dampening, elastic recoil (Windkessel)
• Arterioles: resistance vessels; main site of TPR regulation; controlled by ANS, local metabolites
• Capillaries: exchange vessels; thin walls, large surface area, slow flow

• Pc = capillary hydrostatic pressure (~32 mmHg at arterial end, ~15 at venous end)
• Pi = interstitial hydrostatic pressure (~3 mmHg)
• πc = plasma oncotic pressure (~25 mmHg, albumin main contributor)
• πi = interstitial oncotic pressure (~8 mmHg)
• Arterial end: net filtration (fluid out) ≈ +9 mmHg
• Venous end: net reabsorption (fluid in) ≈ -8 mmHg
• Remainder removed by lymphatics

• Myogenic response: ↑pressure → vessel constricts (protects capillaries)
• Metabolic autoregulation: ↑CO₂, ↓O₂, ↑adenosine, ↑K⁺, ↑H⁺ → vasodilation
• Most important in: brain, heart, kidney

• Arterial baroreceptors: carotid sinus (CN IX) and aortic arch (CN X)
• ↑BP → ↑baroreceptor firing → NTS (medulla) → ↑vagal tone + ↓sympathetic → ↓HR, ↓contractility, vasodilation → ↓BP
• ↓BP → opposite response
• Buffer against short-term BP changes; reset in chronic hypertension

• RAAS (renin-angiotensin-aldosterone system)
• ADH / vasopressin
• Atrial natriuretic peptide (ANP)
• Kidney: pressure natriuresis-diuresis (most powerful long-term regulator)

6.6 Coronary Circulation

• Left coronary artery (LAD + circumflex): supplies LV, anterior wall, septum
• Right coronary artery (RCA): supplies RV, inferior/posterior LV, SA and AV nodes
• Coronary flow mainly during diastole (LV systolic compression impedes flow)
• Coronary flow regulation: local metabolites (adenosine, CO₂, ↓O₂) → powerful vasodilation
• O₂ extraction at rest: ~70% (nearly maximal); must ↑flow to ↑O₂ delivery

6.7 Special Circulations

• Low pressure (25/8 mmHg), low resistance
• Unique: hypoxia causes VASOCONSTRICTION (opposite to systemic) → diverts blood from poorly ventilated areas
• Normal: all alveoli ventilated and perfused

• Very tight autoregulation (50-150 mmHg MAP)
• PCO₂ is most potent regulator: ↑PCO₂ → cerebral vasodilation (hypercapnia)
• Blood-brain barrier (tight junctions of endothelium + astrocyte foot processes)

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SECTION 7 - RESPIRATORY PHYSIOLOGY

7.1 Lung Volumes and Capacities

7.2 Mechanics of Breathing

• Diaphragm + external intercostals contract
• Chest wall expands → intrapleural pressure drops from -5 to -8 mmHg
• Alveolar pressure drops below atmospheric → air flows in
• Accessory muscles: scalenes, sternocleidomastoid (used in heavy breathing)

• Quiet expiration is passive (elastic recoil)
• Forced expiration is active: internal intercostals + abdominal muscles

• Normal lung compliance: 200 mL/cmH₂O
• ↑Compliance: emphysema (elastin destruction)
• ↓Compliance: pulmonary fibrosis, pulmonary edema, RDS, atelectasis

• Small alveoli: higher pressure → tend to collapse
• Surfactant (dipalmitoylphosphatidylcholine, DPPC): produced by type II pneumocytes
  • ↓Surface tension → ↑compliance → prevents collapse of small alveoli
  • Equal pressure in large and small alveoli (no pendelluft)
  • Absent in RDS of newborn (surfactant not produced until 34-36 weeks gestation)

• R = ΔP/Q = (8ηL)/(πr⁴)
• Medium bronchi: highest total resistance
• Increased by: bronchospasm (asthma), secretions, mucosal edema, emphysema (loss of elastic support)
• Decreased by: sympathetics (β₂ → bronchodilation), lung volume (↑volume → ↑airway caliber)

• Increased in restrictive diseases (more elastic work) and obstructive diseases (more resistive work)

7.3 Alveolar Ventilation & Dead Space

• Anatomical dead space: conducting airways (nose to terminal bronchioles); ~150 mL
• Alveolar dead space: unperfused alveoli (minimal in normal lungs)
• Physiological dead space = anatomical + alveolar; normal ~150 mL
  • Bohr equation: VD/VT = (PaCO₂ - PECO₂)/PaCO₂

• PiO₂ = FiO₂ × (Pb - PH₂O) = 0.21 × (760-47) = 150 mmHg
• PACO₂ ≈ PaCO₂ = 40 mmHg
• RQ (respiratory quotient) ≈ 0.8
• PAO₂ = 150 - 40/0.8 = 150 - 50 = 100 mmHg

• Normal ≤15 mmHg (breathing room air)
• Increased in: V/Q mismatch, shunt, diffusion impairment
• Normal in: hypoventilation, high altitude

7.4 Gas Exchange

• Determined by Fick's law of diffusion
• CO used for measurement (has high affinity for Hb)
• ↓DLCO: emphysema, pulmonary fibrosis, pulmonary hypertension
• ↑DLCO: polycythemia, pulmonary hemorrhage, left-to-right shunt

• Dissolved O₂: 0.003 mL/dL/mmHg (very small)
• Bound to Hb (oxyhemoglobin): 97-98% of total
  • Hb-O₂ dissociation curve: S-shaped (sigmoidal)
  • P50: PO₂ at which Hb is 50% saturated = 26.8 mmHg
  • Right shift (↑P50, ↓O₂ affinity - facilitates unloading): ↑PCO₂, ↑H⁺ (↓pH), ↑temperature, ↑2,3-DPG
  • Left shift (↓P50, ↑O₂ affinity - facilitates loading): ↓PCO₂, ↓H⁺ (↑pH), ↓temperature, ↓2,3-DPG, HbF, CO poisoning, MetHb
  • Bohr effect: CO₂/H⁺ ↓O₂ affinity in tissues → promotes O₂ unloading
  • Normal CaO₂ = (1.34 × [Hb] × SaO₂) + (0.003 × PaO₂) ≈ 20 mL/dL

• Dissolved CO₂: 5-10%
• As bicarbonate (HCO₃⁻): 70% (most important)
  • CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻ (catalyzed by carbonic anhydrase in RBCs)
  • HCO₃⁻ exits RBC via Cl⁻/HCO₃⁻ exchanger (chloride shift / Hamburger shift)
• Carbamino compounds (CO₂ + Hb, proteins): 20-25%
• Haldane effect: deoxygenated Hb has higher CO₂-carrying capacity (lungs: oxygenation ↑ CO₂ release)

7.5 Ventilation-Perfusion (V/Q) Matching

• Ventilation: 4.2 L/min
• Perfusion: 5 L/min

• Apex: high V/Q (~3.3) - well ventilated, underperfused → alveolar dead space
  • Preferential site for TB (high O₂)
• Base: low V/Q (~0.6) - better perfused, relatively underventilated

• V/Q = 0 (shunt): alveolus perfused but not ventilated; blood bypasses gas exchange; does NOT respond to supplemental O₂ (e.g., atelectasis, pneumonia, ARDS, intracardiac R→L shunt)
• V/Q = ∞ (dead space): alveolus ventilated but not perfused; no gas exchange (e.g., PE, emphysema)

• Zone 1 (apex): PA > Pa > Pv - alveolar pressure collapses capillaries (dead space); only in positive pressure ventilation
• Zone 2 (middle): Pa > PA > Pv - flow determined by arterial-alveolar gradient
• Zone 3 (base): Pa > Pv > PA - flow determined by arterial-venous gradient (maximal flow)

7.6 Control of Breathing

• Pre-Bötzinger complex (medulla): generates rhythmic breathing pattern
• Dorsal respiratory group (DRG, nucleus tractus solitarius): inspiration
• Ventral respiratory group (VRG): expiration + inspiration (active)
• Pneumotaxic center (pontine respiratory group): fine-tunes rhythm, limits inspiration
• Apneustic center (lower pons): promotes sustained inspiration (normally inhibited)

• Central chemoreceptors (medulla): respond to ↑PCO₂ / ↑H⁺ in CSF (most powerful stimulus for ventilation)
  • CO₂ crosses BBB easily; H⁺ does not
• Peripheral chemoreceptors (carotid bodies / aortic bodies):
  • Carotid bodies (CN IX): primary peripheral chemoreceptors; respond to ↓PaO₂ (<60 mmHg), ↑PaCO₂, ↑H⁺
  • Aortic bodies (CN X): less important in humans
  • In chronic hypercapnia: central response blunted; hypoxia becomes primary drive (COPD "blue bloaters")

1. CO₂/H⁺ (most powerful normal stimulus)
2. O₂ (stimulus only when PaO₂ <60 mmHg)
3. Cortical override (voluntary breath-holding, speech)

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SECTION 8 - RENAL PHYSIOLOGY & BODY FLUIDS

8.1 Overview of Kidney Functions

1. Filtration + excretion of metabolic wastes (urea, creatinine, uric acid)
2. Regulation of body fluid volume and composition
3. Maintenance of acid-base balance
4. Hormone production: erythropoietin (EPO), renin, 1,25-dihydroxyvitamin D (calcitriol)
5. Gluconeogenesis (during prolonged fasting)
6. Drug/toxin excretion

8.2 Renal Anatomy & Nephron

• Cortex: glomeruli, proximal tubules, distal tubules
• Outer medulla: loop of Henle (thick ascending limb)
• Inner medulla: loop of Henle (thin limbs), collecting ducts
• Papilla: tip of pyramid; collecting ducts drain into calyces

• Cortical nephrons (85%): short loops, don't reach inner medulla
• Juxtamedullary nephrons (15%): long loops, key for concentrating urine; vasa recta

8.3 Glomerular Filtration

• Normal: ~125 mL/min (180 L/day filtered; ~1.5 L/day excreted)

1. Glomerular endothelium (fenestrated, 70-100 nm pores)
2. Glomerular basement membrane (GBM, type IV collagen, laminin)
3. Slit diaphragm of podocyte foot processes (nephrin, podocin)

• Barrier: size-selective (~<8 nm; excludes albumin, large proteins) AND charge-selective (negative charge of GBM repels anionic proteins)

• PGC = glomerular capillary hydrostatic pressure ≈ 55 mmHg (pro-filtration)
• PBS = Bowman's space hydrostatic pressure ≈ 15 mmHg (anti-filtration)
• πGC = glomerular oncotic pressure ≈ 30 mmHg (anti-filtration)
• πBS = Bowman's space oncotic pressure ≈ 0 (no proteins normally)
• Net = (55-15) - (30-0) = 40 - 30 = +10 mmHg (net filtration)

• Tubuloglomerular feedback (TGF): macula densa senses ↑NaCl delivery → signals afferent arteriole to constrict → ↓GFR (autoregulation)
• Afferent arteriole constriction (angiotensin II, sympathetics): ↓GFR
• Efferent arteriole constriction (angiotensin II): ↑GFR (preferentially)
• ACE inhibitors: block angiotensin II → efferent dilation > afferent → ↓GFR (important in renal artery stenosis)

• C_x = (U_x × V̇) / P_x
• Inulin clearance = GFR (freely filtered, neither secreted nor reabsorbed) = 125 mL/min
• Creatinine clearance ≈ GFR (slightly overestimates due to secretion)
• PAH clearance = renal plasma flow (RPF) ≈ 625 mL/min (completely cleared by filtration + secretion)

8.4 Tubular Transport

• Na⁺: cotransport with glucose (SGLT2), amino acids, phosphate; Na⁺/H⁺ exchange (NHE3)
• Glucose: entirely reabsorbed (Tm = 375 mg/min; threshold ≈ 180 mg/dL plasma glucose)
• HCO₃⁻: 80-90% reabsorbed (via carbonic anhydrase)
• Urea: passive reabsorption (50%)
• Water: follows Na⁺ (obligatory reabsorption via AQP1); isosmotic reabsorption
• Secretion: H⁺, organic acids and bases (drugs like penicillin, PAH, uric acid)

• Descending limb: permeable to water; impermeable to solutes → water leaves → tubular fluid becomes hyperosmotic
• Ascending limb (thin): impermeable to water; permeable to NaCl (passive reabsorption)
• Thick ascending limb (TAL): impermeable to water; active Na⁺/K⁺/2Cl⁻ cotransport (NKCC2) → dilutes tubular fluid
  • Furosemide (loop diuretic) blocks NKCC2
  • Creates medullary hyperosmolarity (countercurrent multiplication)

• Na⁺/Cl⁻ cotransporter (NCC): blocked by thiazide diuretics
• Ca²⁺ reabsorption regulated by PTH and vitamin D
• Mg²⁺ reabsorption
• Fluid entering DCT is hypoosmotic (~100 mOsm/kg)

• Principal cells (Na⁺ reabsorption, K⁺ secretion): aldosterone → ↑ENaC (epithelial Na channels) + basolateral Na⁺/K⁺-ATPase
  • Spironolactone/eplerenone (K⁺-sparing): block aldosterone receptor
  • Amiloride/triamterene (K⁺-sparing): block ENaC directly
• ADH (vasopressin): acts on V2 receptors → ↑cAMP → inserts AQP2 into apical membrane → water reabsorption → concentrated urine
• Alpha-intercalated cells: H⁺ secretion (acid-base balance)
• Beta-intercalated cells: HCO₃⁻ secretion

8.5 Urine Concentration/Dilution

• Descending limb loses water; ascending limb extrudes salt → creates medullary gradient (300 → 1200 mOsm/kg from cortex to papilla)

• Maintains medullary gradient without washing it out
• Blood flows down (equilibrates with hyperosmotic medulla) then up (equilibrates back with interstitium)

• Osmoreceptors in hypothalamus: ↑plasma osmolality → ↑ADH release from posterior pituitary
• Baroreceptors: ↓blood volume/pressure → ↑ADH release (less sensitive but overwhelms osmotic signal in severe hemorrhage)
• Alcohol → ↓ADH → diuresis
• Diabetes insipidus (DI): Central DI (↓ADH production) vs. Nephrogenic DI (↓renal response to ADH)

8.6 Regulation of Na⁺ Balance and Blood Volume

• Aldosterone (adrenal cortex): principal regulator; ↑Na⁺ reabsorption in collecting duct
  • Stimulated by: ↑angiotensin II, ↑K⁺, ↓Na⁺ (indirect)
• ANP (atrial natriuretic peptide): released from atria with ↑stretch (↑blood volume); ↑GFR, ↓aldosterone, ↓Na⁺ reabsorption → natriuresis

1. ↓BP / ↓Na⁺ delivery to macula densa / ↑sympathetics → Juxtaglomerular (JG) cells secrete renin
2. Renin cleaves angiotensinogen (from liver) → Angiotensin I
3. ACE (in lungs/endothelium) converts Ang I → Angiotensin II
4. Angiotensin II: vasoconstriction (↑TPR), aldosterone secretion, ↑ADH release, ↑thirst, direct tubular Na⁺/H₂O reabsorption
5. Aldosterone → ↑Na⁺ reabsorption → ↑blood volume → ↑BP

8.7 K⁺ Balance

• Aldosterone: ↑K⁺ secretion in collecting duct (principal cells)
• Insulin + catecholamines: drive K⁺ into cells (↓plasma K⁺)
• Acid-base status: acidosis → K⁺ exits cells (↑plasma K⁺); alkalosis → K⁺ enters cells (↓plasma K⁺)

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SECTION 9 - ACID-BASE BALANCE

9.1 Buffer Systems

1. Bicarbonate-carbonate system (most important ECF buffer; pKa 6.1): HCO₃⁻/CO₂
2. Phosphate system (important in urine): H₂PO₄⁻/HPO₄²⁻ (pKa 6.8)
3. Protein/hemoglobin (important ICF buffer): histidine residues
4. Ammonia/ammonium (urine buffer, especially in chronic acidosis)

• pH: 7.35-7.45
• PaCO₂: 35-45 mmHg
• HCO₃⁻: 22-26 mEq/L
• PaO₂: 75-100 mmHg
• Base excess: -2 to +2

9.2 Acid-Base Disorders

• Normal: 8-12 mEq/L (accounts for unmeasured anions: albumin, phosphate, sulfate, organic acids)
• High AG metabolic acidosis (MUDPILES): Methanol, Uremia, Diabetic ketoacidosis, Propylene glycol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates
• Normal AG metabolic acidosis (hyperchloremic): Diarrhea (loss of HCO₃⁻), RTA (types I, II, IV), acetazolamide

• Normal: <10 mOsm/kg; elevated in: methanol, ethylene glycol, isopropanol intoxication

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SECTION 10 - GASTROINTESTINAL PHYSIOLOGY

10.1 GI Motility

• Slow waves (basic electrical rhythm, BER) - set by interstitial cells of Cajal
• Stomach: 3/min; duodenum: 12/min; ileum: 8-9/min
• Slow waves do not directly cause contractions; if amplitude reaches threshold + excitatory input → AP → contraction

• Peristalsis: coordinated wave of contraction behind bolus
• Lower esophageal sphincter (LES): high-pressure zone; relaxed by VIP, NO; contracted by ACh, gastrin

• Reservoir + churning (antrum) function
• Rate-limiting step of gastric emptying: antrum-pylorus interaction
• Slowed by: lipids, protein, acid, hyperosmolar solutions (enterogastric reflex + hormones: CCK, secretin, GIP)

• Segmentation: mixing movements; regulated by BER
• Migrating motor complex (MMC): "housekeeper" contractions between meals; motilin-stimulated (erythromycin mimics motilin)

• Haustral contractions: mixing
• Mass movements: 1-3×/day, propel contents to rectum; triggered by gastrocolic reflex (food in stomach)
• Defecation reflex: distension of rectum → sacral parasympathetics → contract rectum + relax internal anal sphincter; external anal sphincter = voluntary

10.2 GI Secretion

• 1-1.5 L/day; amylase (carbohydrate digestion), mucus, lysozyme, IgA
• Stimulated by parasympathetics (CN VII, IX); primary secretion isotonic → secondary: Na⁺ reabsorbed, K⁺ secreted → hypotonic (unlike sweat glands)

• H⁺/K⁺-ATPase (proton pump) at apical membrane
• Cl⁻ exits via apical Cl⁻ channel
• CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻ (carbonic anhydrase)
• HCO₃⁻ exits basolaterally via Cl⁻/HCO₃⁻ exchanger → alkaline tide in blood

1. Cephalic phase (30%): sight/smell/taste/chewing of food → vagal → ACh → parietal cells (direct) + G cells (GRP)
2. Gastric phase (60%): food in stomach → distension + protein → gastrin + vagal reflexes → HCl
3. Intestinal phase (10%): food in duodenum; initially stimulatory; then inhibitory (secretin, CCK, GIP)

• Exocrine: 1-2 L/day alkaline juice (HCO₃⁻, pH 8) + enzymes
  • Secretin → ↑HCO₃⁻ (ductal cells via CFTR)
  • CCK → ↑enzyme secretion (from acinar cells): trypsinogen (→trypsin by enterokinase), chymotrypsinogen, lipase, amylase, elastase
  • Trypsin activates other zymogens; inhibited by trypsin inhibitor in pancreatic juice
• Endocrine: islets of Langerhans (discussed in Section 11)

• ~500-1000 mL/day; stored + concentrated in gallbladder
• Primary bile acids: cholic + chenodeoxycholic (from cholesterol)
• Secondary bile acids: deoxycholic + lithocholic (from bacterial action in colon)
• Bile salts (conjugated with glycine or taurine): emulsify fats
• CCK → gallbladder contraction + sphincter of Oddi relaxation → bile release
• Enterohepatic circulation: 95% of bile salts reabsorbed in terminal ileum; circulate 6-10x/day

10.3 Digestion and Absorption

• Digestion: salivary amylase (mouth) → pancreatic amylase (lumen) → brush border enzymes (maltase, sucrase, lactase, isomaltase)
• Absorption: SGLT1 (Na⁺-glucose cotransport), GLUT5 (fructose, passive), GLUT2 (basolateral exit)

• Digestion: pepsin (stomach) → trypsin, chymotrypsin, elastase, carboxypeptidase (pancreas) → brush border peptidases
• Absorption: di/tripeptides via PepT1 (H⁺-coupled cotransporter); amino acids via specific transporters

• Digestion: lingual + gastric lipase → pancreatic lipase (+ colipase) → 2-monoglycerides + fatty acids
• Emulsification by bile salts → micelles → fatty acids diffuse into enterocytes
• In enterocytes: resynthesis of triglycerides → chylomicrons (with apoB-48) → exocytosis into lacteals → thoracic duct → blood
• Fat-soluble vitamins (A, D, E, K): absorbed with fat (requires bile salts)

• Requires intrinsic factor (IF) from parietal cells; IF-B12 complex absorbed in terminal ileum by cubilin receptors
• Deficiency: pernicious anemia (lack of IF, anti-parietal cell or anti-IF antibodies), terminal ileum resection

• Absorbed as ferrous iron (Fe²⁺) by DMT1 (divalent metal transporter) in duodenum
• ↑Absorption: vitamin C (reduces Fe³⁺ to Fe²⁺), acidic pH, ↓iron stores
• ↓Absorption: phytates (grains), tea/coffee (tannins), calcium, elevated hepcidin

• Active transport in duodenum (via calbindin, regulated by 1,25-(OH)₂-Vitamin D)
• Passive in jejunum/ileum

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SECTION 11 - ENDOCRINE PHYSIOLOGY

11.1 Overview of Hormones

11.2 Thyroid Hormone

1. Iodide trapping: Na⁺/I⁻ symporter (NIS) at basolateral membrane - stimulated by TSH; inhibited by perchlorate
2. Oxidation of I⁻ → I₂ by thyroid peroxidase (TPO)
3. Organification: iodination of tyrosine residues on thyroglobulin → MIT, DIT
4. Coupling: MIT + DIT → T3; DIT + DIT → T4 (by TPO)
5. Secretion: pinocytosis of colloid → lysosomal proteolysis → T3 + T4 released

• T4 (thyroxine) is main secretory product; T3 is more active (converted by 5'-deiodinase in periphery)
• Most T3/T4 is bound to thyroxine-binding globulin (TBG) - only free (unbound) hormone is active

• Stimulate basal metabolic rate (BMR): ↑Na⁺/K⁺-ATPase expression → ↑O₂ consumption → thermogenesis
• ↑β-adrenergic receptors → potentiate sympathetic effects on heart (↑HR, ↑contractility)
• Essential for brain development (congenital hypothyroidism → cretinism if untreated)
• Required for normal growth (↑GH + IGF-1 effects)
• ↑Gut motility, ↑bone turnover, ↑erythropoiesis

• Negative feedback: T3 inhibits TRH and TSH

11.3 Adrenal Gland

• Zona Glomerulosa: mineralocorticoids (aldosterone) - regulated by RAAS, K⁺
• Zona Fasciculata: glucocorticoids (cortisol) - regulated by ACTH
• Zona Reticularis: androgens (DHEA, androstenedione) - regulated by ACTH

• Metabolic: ↑gluconeogenesis, ↑proteolysis, ↑lipolysis, ↑blood glucose; "anti-insulin"
• Anti-inflammatory/immunosuppressive: ↓phospholipase A2 → ↓arachidonic acid → ↓prostaglandins/leukotrienes; inhibits NF-κB
• Permissive effects: required for catecholamines to cause vasoconstriction
• ↑Bone resorption, ↓bone formation (chronic excess → osteoporosis)
• ↑Gastric acid secretion (ulcers)
• Negative feedback on CRH and ACTH

• Epi: β₁ (↑HR, ↑contractility) > β₂ (vasodilation, bronchodilation) > α₁ (vasoconstriction)
• NE: α₁ > α₂ > β₁; primarily vasoconstriction
• Synthesis: Tyrosine → DOPA → Dopamine → NE → Epi (requires PNMT, induced by cortisol from adrenal cortex)

11.4 Pancreatic Hormones

• β-cells (~65%): insulin
• α-cells (~20%): glucagon
• δ-cells (~5%): somatostatin (inhibits both insulin and glucagon)
• PP cells: pancreatic polypeptide

• Stimulus for secretion: ↑blood glucose (main), amino acids (leucine, arginine), GLP-1, GIP, CCK, vagal (ACh)
• Mechanism of insulin secretion by β-cell (KATP channel model):
  1. Glucose enters β-cell via GLUT2 (non-saturable)
  2. Glucose metabolized → ↑ATP/ADP ratio
  3. ↑ATP closes ATP-sensitive K⁺ channel (KATP) → membrane depolarizes
  4. Voltage-gated Ca²⁺ channels open → Ca²⁺ enters → insulin exocytosis
  • Sulfonylureas (glipizide, glyburide) block KATP → always stimulate insulin
• Actions:
  • Anabolic, glucose-lowering hormone
  • ↑Glucose uptake (GLUT4 in muscle and fat - only insulin-sensitive GLUT)
  • ↑Glycogen synthesis (glycogen synthase)
  • ↑Fatty acid synthesis, ↓lipolysis
  • ↑Protein synthesis, ↓proteolysis
  • ↑K⁺ uptake into cells

• Stimulus: ↓blood glucose, amino acids (especially alanine/arginine), sympathetics
• Actions (via Gs → ↑cAMP in liver):
  • ↑Glycogenolysis (↑glucose output)
  • ↑Gluconeogenesis
  • ↑Ketogenesis (↑fatty acid oxidation)
  • Essentially opposes insulin
• Inhibited by: ↑glucose, insulin, somatostatin

11.5 Parathyroid Hormone & Calcium Regulation

• Ionized Ca²⁺ (free, physiologically active): 4.5-5 mg/dL (~50%)
• Protein-bound (albumin): ~40%
• Complexed (citrate, phosphate): ~10%

• Stimulus: ↓ionized Ca²⁺, ↑phosphate, ↓Mg²⁺
• Actions:
  • Kidney: ↑Ca²⁺ reabsorption (DCT), ↑phosphate excretion (proximal tubule), ↑1α-hydroxylase (converts 25-OH-Vit D → active 1,25-(OH)₂-Vit D)
  • Bone: ↑osteoclast activity (via RANK-L) → ↑Ca²⁺ + ↑phosphate release (acute); chronic low-dose PTH → ↑bone formation (teriparatide)
  • Net effect: ↑plasma Ca²⁺, ↓plasma phosphate

• Source: skin (sunlight converts 7-dehydrocholesterol → cholecalciferol) → liver (25-hydroxylation) → kidney (1α-hydroxylation)
• Actions: ↑Ca²⁺ and phosphate absorption from gut (↑calbindin), ↑renal reabsorption, ↑bone mineralization

• Stimulus: ↑Ca²⁺
• Actions: ↓osteoclast activity → ↓serum Ca²⁺; ↓renal Ca²⁺ reabsorption
• Relatively minor role in adults (much more important in fish/animals)

11.6 Growth Hormone (GH)

• Secreted by somatotroph cells of anterior pituitary; pulsatile release
• Peak secretion: deep sleep (slow-wave sleep)
• Stimulated by: GHRH, sleep, fasting, hypoglycemia, exercise, amino acids
• Inhibited by: somatostatin, hyperglycemia, IGF-1 (negative feedback), obesity

• Direct effects (anti-insulin/diabetogenic): ↑lipolysis, ↑blood glucose (↓glucose uptake)
• Indirect effects (via IGF-1 from liver): ↑linear growth (epiphyseal plate), ↑protein synthesis, ↑lean body mass, ↑organ growth
• GH deficiency in children: short stature; GH excess: gigantism (before epiphyseal fusion), acromegaly (after)

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SECTION 12 - NEUROPHYSIOLOGY & CNS

12.1 Synapse Physiology

• Chemical synapse: neurotransmitter released; major type; slower (~1 ms delay); amplifiable; one-directional
• Electrical synapse (gap junctions): direct ionic flow; fast; bidirectional; cardiac muscle, smooth muscle, some brain regions

1. AP reaches presynaptic terminal
2. Depolarization → opens voltage-gated Ca²⁺ channels (N or P/Q type)
3. Ca²⁺ triggers SNARE complex assembly → vesicle fusion → NT release
4. NT diffuses across cleft (20-40 nm)
5. NT binds postsynaptic receptors
6. Postsynaptic potential generated (EPSP or IPSP)
7. NT removed: reuptake (main), enzymatic degradation (AChE, MAO, COMT), diffusion

• Temporal summation: multiple EPSPs from same synapse in rapid succession
• Spatial summation: simultaneous EPSPs from multiple synapses

• Requires simultaneous glutamate binding AND membrane depolarization (to remove Mg²⁺ block)
• Permeable to Ca²⁺, Na⁺, K⁺
• Role in long-term potentiation (LTP) - synaptic basis of learning/memory
• Also: coincidence detector

12.2 Autonomic Nervous System (ANS)

• Sympathetic: T1-L2 (thoracolumbar); short preganglionic, long postganglionic
  • Preganglionic: ACh → nAChR (nicotinic)
  • Postganglionic: NE → adrenergic receptors (mostly; exception: sweat glands, some blood vessels = ACh → muscarinic)
  • Adrenal medulla: directly innervated by long preganglionic; secretes Epi + NE into blood
• Parasympathetic: CN III, VII, IX, X; S2-S4 (craniosacral); long preganglionic, short postganglionic
  • Both pre- and postganglionic: ACh
  • Preganglionic → nicotinic; postganglionic → muscarinic (M1-M5)

• Heart: ↑HR (β₁), ↑contractility (β₁)
• Blood vessels: mostly constriction (α₁); skeletal muscle vasodilation (β₂)
• Bronchi: dilation (β₂)
• GI: ↓motility, ↓secretion; contracts sphincters
• Bladder: ↓detrusor tone (β₃); contracts trigone/sphincter (α₁)
• Eye: mydriasis (dilator pupillae, α₁); ciliary muscle relaxation (β - far vision)
• Liver: glycogenolysis (β₂, α₁)
• Pancreas: ↓insulin, ↑glucagon (α₂)

• Heart: ↓HR (M₂)
• Bronchi: constriction (M₃)
• GI: ↑motility, ↑secretion; relaxes sphincters
• Bladder: ↑detrusor (M₃); relax sphincter
• Eye: miosis (sphincter pupillae, M₃); ciliary contraction (near vision, accommodation, M₃)
• Salivary glands: ↑watery secretion (M₃)
• Lacrimal glands: ↑secretion (M₃)

12.3 Sensory Physiology

• Mechanoreceptors (touch, pressure, vibration, proprioception)
• Thermoreceptors (Krause's end-bulbs: cold; Ruffini corpuscles: warm)
• Nociceptors (free nerve endings: pain)
• Photoreceptors (rods, cones)
• Chemoreceptors (olfaction, taste, carotid body)
• Proprioceptors (muscle spindles, Golgi tendon organs)

• Slowly adapting: sustained response (Merkel's discs, Ruffini, pain)
• Rapidly adapting (phasic): respond to change/onset/offset (Pacinian, Meissner's)

• Aδ fibers: fast, sharp, localized (first pain) via neospinothalamic tract → VPL thalamus → somatosensory cortex
• C fibers: slow, burning, diffuse (second pain) via paleospinothalamic tract → reticular formation, thalamus (intralaminar), anterior cingulate cortex
• Gate control theory (Melzack & Wall): large-diameter Aβ fibers activate interneurons in dorsal horn that inhibit pain transmission (substantia gelatinosa)
• Endogenous opioid system: β-endorphin, enkephalins, dynorphins → μ, δ, κ receptors → inhibit pain

• Located in postcentral gyrus
• Somatotopic organization (homunculus): lips, hands, and tongue have largest representation

• 1st order: dorsal column (ipsilateral) → nucleus gracilis/cuneatus (medulla)
• 2nd order: decussates in medulla → medial lemniscus → VPL thalamus
• 3rd order: internal capsule → postcentral gyrus

• 1st order: enter spinal cord → synapse in Rexed lamina I, II, V
• 2nd order: decussates at same or 1-2 levels above entry → contralateral anterolateral column → VPL/VPM thalamus
• 3rd order: postcentral gyrus

12.4 Motor System

• Primary motor cortex (M1): precentral gyrus; executes voluntary movement
• Premotor cortex + SMA: planning and programming of movement
• Prefrontal cortex: intention and decision

• Upper motor neuron (UMN): M1 → corona radiata → internal capsule (posterior limb) → cerebral peduncle → pyramids → decussate at medullary-spinal junction (85%) → lateral corticospinal tract
• Lower motor neuron (LMN): anterior horn cells → peripheral nerve → neuromuscular junction → muscle
• UMN signs: spasticity, hyperreflexia, extensor plantar (Babinski), no atrophy (clonus)
• LMN signs: flaccidity, hyporeflexia, fasciculations, muscle atrophy

• Function: coordination, timing, smooth movement, balance, motor learning
• Spinocerebellum (vermis + intermediate): receives proprioceptive + motor info; corrects ongoing movement
• Cerebrocerebellum (lateral hemispheres): motor planning, timing
• Vestibulocerebellum (flocculonodular lobe): balance, eye movements
• Pure ipsilateral deficits (cerebellum does NOT cross)
• Signs: ataxia, dysmetria (past-pointing), dysdiadochokinesia, intention tremor, nystagmus, dysarthria

• Structures: striatum (caudate + putamen), globus pallidus (GPi/GPe), subthalamic nucleus (STN), substantia nigra pars reticulata (SNr) and pars compacta (SNc)
• Direct pathway: cortex → striatum → GPi/SNr → thalamus → cortex (facilitates movement; EXCITATORY net effect)
• Indirect pathway: cortex → striatum → GPe → STN → GPi/SNr → thalamus → cortex (inhibits movement; INHIBITORY net effect)
• Dopamine from SNc acts on D1 receptors (facilitates direct) and D2 receptors (inhibits indirect) → net = facilitates movement
• Parkinson's disease: ↓dopamine from SNc → ↑inhibition of movement → bradykinesia, rigidity, resting tremor (4-6 Hz)
• Huntington's disease: degeneration of striatum (especially caudate), loss of indirect pathway → excessive movement (chorea)

12.5 Sleep Physiology

• NREM Stage 1: theta waves (4-7 Hz); drowsiness
• NREM Stage 2: sleep spindles (12-14 Hz) + K-complexes; light sleep
• NREM Stage 3 (slow-wave/deep sleep): delta waves (<2 Hz, >75 μV); growth hormone released; most restful; harder to wake
• REM sleep: EEG similar to waking (low-voltage, mixed frequency); PGO waves; dreams; atonia; ↑sympathetic; penile/clitoral engorgement

• Early night: more deep NREM; later night: more REM
• REM duration increases with each cycle

• Wakefulness: norepinephrine (locus ceruleus), serotonin (raphe), acetylcholine (BF), histamine (tuberomammillary nucleus), orexin/hypocretin (lateral hypothalamus)
• NREM: GABA (VLPO - ventrolateral preoptic area)
• REM: ACh (LDT/PPT), ↓NE and 5-HT
• Narcolepsy: loss of orexin/hypocretin neurons → cataplexy, sleep attacks, sleep paralysis

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SECTION 13 - SPECIAL SENSES

13.1 Vision

• Cornea (70% of refraction) + Lens (fine-tuning/accommodation)
• Aqueous humor: anterior chamber; produced by ciliary body; drained by Canal of Schlemm
• Vitreous humor: posterior cavity; gel
• Retina: contains photoreceptors

• Rods: 120 million; peripheral retina; scotopic (dim light) vision; monochromatic; contain rhodopsin (opsin + 11-cis retinal)
• Cones: 6 million; central (fovea); photopic (bright light) vision; color; three types (S=blue, M=green, L=red opsins)
• Fovea centralis: highest acuity; only cones, densest packing; no rods; no blood vessels overlying

1. Dark: Na⁺ channels open (cGMP-gated); "dark current" → rod partly depolarized (~-40 mV) → tonic glutamate release
2. Light: rhodopsin (11-cis retinal → all-trans retinal → activates opsin)
3. Opsin activates transducin (G-protein) → activates phosphodiesterase (PDE)
4. PDE hydrolyzes cGMP → ↓cGMP → Na⁺ channels close
5. Rod hyperpolarizes → ↓glutamate release → bipolar cell / ganglion cell response → visual signal

• Nasal retinal fibers (temporal visual field) → optic chiasm → cross → contralateral optic tract
• Temporal retinal fibers (nasal visual field) → optic chiasm → do NOT cross → ipsilateral optic tract
• Optic tract → lateral geniculate nucleus (LGN) → optic radiation → primary visual cortex (V1, calcarine cortex)

• Optic nerve lesion: monocular blindness (ipsilateral)
• Optic chiasm lesion: bitemporal hemianopia (pituitary tumor, craniopharyngioma)
• Optic tract lesion: contralateral homonymous hemianopia
• Meyer's loop lesion (temporal): contralateral superior quadrantanopia ("pie in the sky")
• Parietal optic radiation: contralateral inferior quadrantanopia ("pie on the floor")
• Occipital cortex lesion: contralateral homonymous hemianopia with macular sparing

13.2 Hearing

• Sound waves → tympanic membrane → ossicles (malleus, incus, stapes) → oval window → cochlea
• Ossicular chain amplifies sound ~22× (overcomes impedance mismatch between air and fluid)
• Stapes movement → perilymph (scala vestibuli) → basilar membrane displacement
• Tonotopy: base of basilar membrane: stiff, narrow → high frequencies; apex: flexible, wide → low frequencies
• Basilar membrane movement → deflects stereocilia of inner hair cells (IHC)
• Stereocilia tip links: stretch opens mechanosensitive K⁺/Ca²⁺ channels → IHC depolarizes
• ↑Ca²⁺ → neurotransmitter (glutamate) release → spiral ganglion (CN VIII) → cochlear nucleus → superior olive (binaural processing, sound localization) → inferior colliculus → medial geniculate nucleus (MGN, thalamus) → primary auditory cortex (A1, Heschl's gyrus)
• Conductive hearing loss: problem with outer/middle ear; better with bone conduction (Weber test: lateralizes to affected side; Rinne: BC > AC)
• Sensorineural hearing loss: problem with cochlea/auditory nerve; bone and air conduction equally reduced (Weber: lateralizes to unaffected side; Rinne: AC > BC but both reduced)

13.3 Vestibular System

• Semicircular canals (3 pairs): detect angular acceleration; ampullae contain cupula + hair cells; endolymph deflects cupula
• Utricle and saccule: detect linear acceleration and gravity; contain maculae with otoliths (heavy crystals)
• Signal → vestibular ganglion (Scarpa's) → CN VIII → vestibular nuclei → vestibulocerebellum + spinal cord + oculomotor nuclei
• Nystagmus: involuntary eye movements; fast phase names the direction; "slow phase away, fast phase toward lesion" (Alexander's Law)

13.4 Taste and Smell

• 5 basic tastes: sweet, salty, sour, bitter, umami (glutamate)
• Taste cells on tongue papillae → CN VII (anterior 2/3), IX (posterior 1/3), X (epiglottis) → nucleus tractus solitarius (NTS) → VPM thalamus → insular cortex

• Olfactory receptor neurons (ORNs) in nasal epithelium → olfactory filaments → cribriform plate → olfactory bulb → olfactory tract
• Unique: only sense that does NOT relay through thalamus first
• Projects directly to piriform cortex (primary olfactory cortex), entorhinal cortex, amygdala

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SECTION 14 - BLOOD & IMMUNE PHYSIOLOGY

14.1 Blood Composition

• Whole blood: plasma (55%) + formed elements (45% = hematocrit)
• Plasma proteins: albumin (50%, maintains oncotic pressure, carrier), globulins (antibodies), fibrinogen (clotting)
• Normal blood volume: 5 L (70 mL/kg)

14.2 Red Blood Cells (Erythrocytes)

• 4.5-5.5 million/μL (men), 4-5 million/μL (women)
• Hb: 13-17 g/dL (men), 12-15 g/dL (women); Hematocrit: 42-52% (men), 36-48% (women)
• No nucleus, no mitochondria (anaerobic glucose metabolism via glycolysis)
• Biconcave disc: ↑surface area to volume ratio → efficient gas exchange
• Life span: 120 days; removed by macrophages in spleen/liver

• Regulated by erythropoietin (EPO) from renal interstitial cells (peritubular cells)
• Stimulus for EPO: ↓PaO₂ (hypoxia), ↓Hb, ↑2,3-DPG
• Requires: iron, B12, folate, vitamin C, intrinsic factor

• Adult Hb (HbA): α₂β₂ (97%)
• HbA₂: α₂δ₂ (2.5%)
• HbF: α₂γ₂ (fetal hemoglobin; ↑affinity for O₂, ↓P50)
• HbS (sickle cell): β⁶ Glu → Val substitution

14.3 White Blood Cells (Leukocytes)

• Total WBC: 4,500-11,000/μL

14.4 Platelet Physiology & Hemostasis

1. Vascular injury → collagen exposed + endothelium damaged
2. vWF binds exposed collagen; vWF binds platelet GpIb receptor → platelet adhesion
3. Platelet activation: shape change, granule release (ADP, TXA₂, serotonin)
4. ADP activates more platelets (P2Y12 - blocked by clopidogrel)
5. TXA₂ causes vasoconstriction + more platelet activation (inhibited by aspirin/COX-1 inhibition)
6. GpIIb/IIIa receptor activated → binds fibrinogen → platelet aggregation

• Extrinsic pathway: tissue factor (TF) + Factor VII → VIIa → activates X
• Intrinsic pathway: Factor XII activation → XI → IX → X (+ VIIIa)
• Common pathway: X + V (prothrombinase complex) → prothrombin → thrombin → fibrinogen → fibrin; XIII cross-links fibrin

• Heparin: activates antithrombin III → inactivates thrombin + Xa; monitored by aPTT
• Warfarin: inhibits Vitamin K-dependent factors (II, VII, IX, X, protein C, S); monitored by PT/INR
• Newer agents: rivaroxaban (anti-Xa), apixaban (anti-Xa), dabigatran (anti-IIa)

• Plasminogen → plasmin (by t-PA, urokinase)
• Plasmin degrades fibrin → D-dimers (elevated in PE, DVT, DIC)
• Inhibited by: α₂-antiplasmin, PAI-1

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SECTION 15 - REPRODUCTIVE PHYSIOLOGY

15.1 Male Reproductive Physiology

• Leydig cells (interstitial): produce testosterone (stimulated by LH)
• Sertoli cells (tubular): support spermatogenesis; produce inhibin (feedback ↓FSH) + androgen-binding protein (ABP)
• Blood-testis barrier formed by tight junctions between Sertoli cells

• Stimulated by LH → activates cAMP → testosterone synthesis
• Actions: virilization, spermatogenesis (with FSH), ↑muscle/bone mass, ↑RBC production
• Converted to: dihydrotestosterone (DHT) by 5α-reductase (prostate, skin, hair follicles; more potent)
• Converted to: estradiol by aromatase (adipose tissue, brain)

• Spermatogonia → primary spermatocyte → secondary spermatocyte → spermatid → spermatozoa
• Takes ~74 days; FSH + testosterone required
• Temperature-sensitive (requires 2-3°C below body temperature, hence testes in scrotum)

15.2 Female Reproductive Physiology

• Menses (days 1-5): endometrial shedding due to ↓progesterone + ↓estrogen
• FSH ↑ → recruits cohort of follicles → one dominant follicle
• Dominant follicle produces ↑estrogen → endometrial proliferation
• ↑Estrogen → positive feedback on LH → LH surge

• LH surge triggers ovulation (~36 hours after peak LH)
• Increased LH → rupture of follicle → oocyte released

• Corpus luteum forms from ruptured follicle → secretes progesterone + estrogen
• Progesterone: secretory transformation of endometrium, ↑basal body temperature, ↓LH/FSH
• If no fertilization: corpus luteum degenerates (luteolysis) → ↓progesterone → menses

• Estrogen (granulosa cells): ↑LH receptors, ↑endometrial growth, cervical mucus (watery), feedback
• Progesterone (corpus luteum): prepares endometrium for implantation, ↑basal body temperature, ↑viscous cervical mucus, maintains pregnancy
• Inhibin: from granulosa cells → ↓FSH specifically

• Fertilization in fallopian tube (ampullary region)
• Zona reaction prevents polyspermy
• Implantation ~6-10 days post-fertilization
• Trophoblast → syncytiotrophoblast → secretes β-hCG → maintains corpus luteum → ↑progesterone
• β-hCG detectable in urine ~8 days post-fertilization; basis of pregnancy test

15.3 Pregnancy Physiology

• Cardiovascular: ↑CO (40-50%), ↑blood volume (50%), ↓SVR (↑progesterone → vasodilation), ↓BP (first trimester)
• Respiratory: ↑TV (tidal volume), ↑RR, ↑minute ventilation; ↓FRC, ↓RV (diaphragm pushed up); mild respiratory alkalosis (PCO₂ 30 mmHg)
• Renal: ↑GFR (50%), ↑RPF; ↓plasma creatinine and BUN; ↑aldosterone, ↑ADH
• Hematological: ↑plasma volume > ↑RBC mass → dilutional ("physiologic") anemia; ↑WBC; ↑clotting factors
• GI: ↓LES tone → GERD; ↓gastric motility → constipation; ↑progesterone relaxes smooth muscle

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SECTION 16 - THERMOREGULATION & METABOLISM

16.1 Body Temperature Regulation

• Basal metabolic rate (BMR): ~70 kcal/hr at rest
• Muscle activity (shivering thermogenesis): most powerful heat producer
• Non-shivering thermogenesis: brown adipose tissue (BAT); uncoupling protein 1 (UCP1) = thermogenin; uncouples oxidative phosphorylation → heat instead of ATP

• Radiation: ~60% at rest; heat radiated as infrared
• Evaporation: sweating (~25%); most important in heat
• Conduction: direct contact
• Convection: moving air/water

• Posterior hypothalamus: heat conservation + generation (shivering, vasoconstriction)
• Anterior hypothalamus: heat dissipation (sweating, vasodilation)

• Pyrogens (bacteria, IL-1, IL-6, TNF-α) → COX-2 in hypothalamic endothelium → prostaglandin E₂ (PGE₂) → ↑set point
• Fever is different from hyperthermia: in fever, set point is raised; in hyperthermia, mechanisms are overwhelmed

16.2 Energy Metabolism

• Carbohydrates: 4 kcal/g; glucose → 30-32 ATP (aerobic); 2 ATP (anaerobic)
• Proteins: 4 kcal/g
• Fats: 9 kcal/g; most energy-dense; complete oxidation = 130 ATP (palmitate)
• Alcohol: 7 kcal/g (non-nutritive)

• Fed state: ↑insulin; glucose storage as glycogen (liver, muscle); triglyceride synthesis; protein synthesis
• Fasted state (hours): ↑glucagon; glycogenolysis → glucose; then gluconeogenesis (from amino acids, glycerol, lactate)
• Starvation (days): ↑lipolysis → FFAs → liver → ketone bodies (acetoacetate, β-hydroxybutyrate); ketones used by brain, muscle, heart; glucose preserved for obligate glucose users (RBCs, inner medulla, brain partially)

• Pure carbohydrate: RQ = 1.0
• Pure fat: RQ = 0.7
• Pure protein: RQ ≈ 0.8
• Mixed diet: RQ ≈ 0.8
• Ketoacidosis/hyperventilation: RQ > 1 (CO₂ produced > O₂ consumed)

• ↑ by: thyroid hormones (most potent), sympathetics/catecholamines, fever, growth hormone, testosterone
• ↓ by: starvation, hypothyroidism, sleep, aging

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CLINICAL CORRELATIONS & HIGH-YIELD MBBS TOPICS

Key Equations Summary

Clinically Important Reflexes

Key Hormone Disorders - MBBS Summary

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ADVANCED PHYSIOLOGY TOPICS

Molecular Mechanisms of Learning & Memory

• LTP (Long-term potentiation): NMDA receptor-dependent; increased AMPA receptor insertion; structural synaptic changes; hippocampus
• LTD (Long-term depression): NMDA-dependent (low-frequency); AMPA receptor removal from synapse
• Memory consolidation: hippocampus (short to long-term transfer during sleep); basal ganglia (procedural); amygdala (emotional)
• Hebbian plasticity: "neurons that fire together, wire together"

Electrophysiology of Cardiac Arrhythmias

• Re-entry: requires unidirectional block + slow conduction; basis of AF, flutter, SVT, VT
• Triggered activity: delayed/early afterdepolarizations; DAD (digoxin toxicity, ↑Ca²⁺); EAD (long QT, ↓K⁺)
• Enhanced automaticity: ↑sympathetics, ↓K⁺, ischemia

Microcirculation & Nitric Oxide

• Endothelium-derived relaxing factor (EDRF) = Nitric Oxide (NO):
  • Synthesized by eNOS (endothelial NO synthase) from L-arginine + O₂
  • ACh, shear stress, bradykinin → ↑Ca²⁺ in endothelium → ↑eNOS → NO
  • NO diffuses to smooth muscle → activates soluble guanylyl cyclase → ↑cGMP → PKG → MLCK inactivation → vasodilation
  • Sildenafil (Viagra): inhibits PDE5 → ↑cGMP → vasodilation (penile, pulmonary)

Advanced Renal: Tubuloglomerular Feedback & Macula Densa

• Macula densa cells sense luminal Na⁺Cl⁻ via NKCC2
• ↑NaCl → ↑adenosine → constricts afferent arteriole → ↓GFR
• Also: ↑NaCl → ↓renin release (negative feedback on RAAS)

Osmoregulation & Thirst

• Osmoreceptors: anterior hypothalamus (OVLT, SFO - circumventricular organs outside BBB)
• ↑Osmolality → ↑ADH + ↑thirst
• Volume depletion → ↑ADH (via baroreceptors) + ↑thirst + ↑RAAS
• Thirst mechanism > ADH in volume depletion (behavioral response crucial)

Oxygen Free Radicals & Mitochondrial Physiology

• Reactive oxygen species (ROS): O₂⁻ (superoxide), H₂O₂, OH• (hydroxyl radical)
• Generated by: ETC leak, NADPH oxidase, xanthine oxidase
• Detoxified by: SOD (superoxide dismutase), catalase, glutathione peroxidase
• Role in: ischemia-reperfusion injury, aging, oxidative stress diseases

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What's Covered (Summary)

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• Guyton & Hall Textbook of Medical Physiology (14th Ed.)
• Ganong's Review of Medical Physiology (26th Ed.)
• Costanzo Physiology (7th Ed.)
• Medical Physiology - Boron & Boulpaep
• Kandel's Principles of Neural Science (6th Ed.)