The cell membrane is a phospholipid bilayer ~7.5 nm thick that serves as a selective permeability barrier. Simple diffusion allows small nonpolar molecules (O&bdq;, CO&bdq;, N&bdq;) and lipid-soluble substances (steroids, ethanol) to cross directly through the membrane down their concentration gradient. Fick's law of diffusion states that the rate of diffusion is proportional to the surface area, concentration gradient, and membrane permeability, and inversely proportional to membrane thickness. Facilitated diffusion utilizes carrier proteins (GLUT transporters for glucose) or channel proteins (ion channels) to move substances down their electrochemical gradient without energy expenditure. Osmosis is the net diffusion of water across a semipermeable membrane, driven by osmotic pressure gradients; body fluids are maintained at an osmolality of ~285–295 mOsm/kg. Active transport requires ATP hydrolysis to move substances against their electrochemical gradient; primary active transport includes the Na+/K+ ATPase (3 Na+ out, 2 K+ in per ATP) and Ca2+ ATPase. Secondary active transport uses the Na+ gradient established by Na+/K+ ATPase to drive cotransport (SGLT, Na+/K+/2Cl−) or countertransport (Na+/H+ exchanger, Na+/Ca2+ exchanger). Endocytosis (pinocytosis, receptor-mediated, phagocytosis) and exocytosis transport large molecules and particles across the membrane via vesicle formation and fusion.

Ion channels are transmembrane proteins that form aqueous pores permitting rapid ion flow down electrochemical gradients. They exhibit three essential properties: selectivity (permit only certain ions based on size and charge), gating (voltage-gated, ligand-gated, mechanically gated, or constitutively open), and conductance (rate of ion flow, measured in picosiemens). Voltage-gated Na+ channels have two gates: an activation gate (opens with depolarization, m-gate) and an inactivation gate (closes with sustained depolarization, h-gate). Voltage-gated K+ channels have a single delay rectifier gate that opens slowly with depolarization. Ligand-gated ion channels (nicotinic ACh receptor, GABA-A receptor, NMDA receptor) directly couple neurotransmitter binding to ion flux. The Na+/K+ ATPase is the single most important ion pump, consuming ~20–40% of cellular ATP; it electrogenically transports 3 Na+ out for 2 K+ in per cycle, contributing −4 to −10 mV directly to the resting membrane potential. The Ca2+ ATPase (PMCA) and the SERCA pump (sarco/endoplasmic reticulum) maintain cytosolic Ca2+ at extremely low levels (~100 nM). The H+/K+ ATPase in gastric parietal cells secretes HCl into the stomach lumen. The Na+/Ca2+ exchanger (NCX) is electrogenic (3 Na+ in, 1 Ca2+ out) and plays a major role in cardiac muscle relaxation.

The resting membrane potential (RMP) of most excitable cells ranges from −70 to −90 mV. The Nernst equation calculates the equilibrium potential for a single ion: E = (RT/zF) × ln([X]out/[X]in). At 37°C, this simplifies to E = 61/z × log([X]out/[X]in). For K+, EK = −94 mV; for Na+, ENa = +60 mV; for Ca2+, ECa = +132 mV; for Cl−, ECl = −70 mV. The Goldman-Hodgkin-Katz (GHK) equation incorporates the relative membrane permeabilities of multiple ions to calculate the actual RMP; because the membrane at rest is 50–100 times more permeable to K+ than Na+, the RMP is closest to EK. The action potential is an all-or-none regenerative depolarization. In neurons and skeletal muscle, it follows the sequence: (1) stimulus depolarizes membrane to threshold (−55 mV); (2) rapid opening of voltage-gated Na+ channels produces the upstroke (phase 0); (3) Na+ channels inactivate and delayed rectifier K+ channels open, producing repolarization (phase 3); (4) hyperpolarization occurs as K+ conductance briefly exceeds the resting value, followed by return to RMP. The absolute refractory period corresponds to the time when Na+ channels are inactivated and no stimulus can elicit another action potential; the relative refractory period follows, when a stronger-than-normal stimulus can generate an action potential. Saltatory conduction in myelinated fibers achieves conduction velocities up to 120 m/s by restricting depolarization to the nodes of Ranvier.

Cell signaling can be autocrine (same cell), paracrine (local diffusion), endocrine (hormones via blood), or juxtacrine (direct contact). Receptors are classified as: (1) ion channel-coupled (ionotropic) — fast synaptic transmission; (2) G protein-coupled (metabotropic) — seven transmembrane domain receptors activating heterotrimeric G proteins (Gs → ↑cAMP, Gi → ↓cAMP, Gq → ↑IP3/DAG, G12/13 → Rho); (3) enzyme-linked receptors — receptor tyrosine kinases (RTKs, e.g., insulin, EGF, PDGF) dimerize and autophosphorylate, activating MAPK, PI3K, and JAK-STAT pathways; (4) nuclear receptors — steroid/thyroid hormone receptors that act as transcription factors. Second messengers amplify signals: cAMP activates PKA which phosphorylates target proteins; IP3 triggers Ca2+ release from endoplasmic reticulum; DAG activates PKC; cGMP activates PKG (important in smooth muscle relaxation). Ca2+ as a second messenger is regulated by calmodulin, which activates CaM kinases, calcineurin, and MLCK. The cAMP pathway is terminated by phosphodiesterases (PDEs), which are targets of drugs like theophylline and sildenafil. Signal amplification is enormous: a single activated β-adrenergic receptor can activate hundreds of Gs proteins, each activating adenylyl cyclase to produce thousands of cAMP molecules.

Channelopathies are diseases caused by ion channel dysfunction. Long QT syndrome results from defective K+ channels (LQT1: KCNQ1/KvLQT1; LQT2: KCNH2/HERG) or Na+ channels (LQT3: SCN5A/NaV1.5 gain-of-function), predisposing to torsades de pointes. Brugada syndrome (SCN5A loss-of-function) causes ST-elevation in V1–V3 and ventricular fibrillation. Cystic fibrosis results from CFTR Cl− channel mutation (F508del most common) → impaired Cl− secretion and increased Na+ absorption in airway epithelium → thick mucus, chronic infections. Familial hypokalemic periodic paralysis involves mutations in CaV1.1 or NaV1.4 channels → episodic weakness with hypokalemia. Malignant hyperthermia involves ryanodine receptor (RyR1) mutation → uncontrolled Ca2+ release from SR → hyperthermia, rigidity, rhabdomyolysis. Digitalis (cardiac glycosides) inhibits Na+/K+ ATPase → intracellular Na+ rises → NCX reverses → intracellular Ca2+ rises → increased inotropy (positive inotropic effect). Local anesthetics (lidocaine, bupivacaine) block voltage-gated Na+ channels, preventing action potential propagation in sensory neurons.

Cardiac action potentials differ between pacemaker cells (SA node, AV node) and working myocytes (atrial, ventricular, Purkinje). Fast-response action potentials (ventricular myocytes, Purkinje fibers) have 5 phases: Phase 0 — rapid depolarization via voltage-gated Na+ channels (NaV1.5); Phase 1 — early repolarization from transient outward K+ current (Ito); Phase 2 — plateau from L-type Ca2+ channels (CaV1.2) balancing delayed rectifier K+ currents (IKr, IKs); Phase 3 — repolarization as Ca2+ channels inactivate and K+ efflux dominates; Phase 4 — resting potential maintained by IK1 (inward rectifier). Slow-response action potentials (SA node, AV node) lack Na+ channel-dependent phase 0 and have spontaneous phase 4 depolarization (pacemaker potential) driven by funny current (If, HCN channels carrying Na+/K+), T-type Ca2+ current (ICaT), and decaying IKr; the upstroke is mediated by L-type Ca2+ channels. The SA node normally depolarizes fastest (60–100 bpm), setting heart rate; AV node (40–60 bpm) and Purkinje fibers (15–40 bpm) are latent pacemakers. Autonomic modulation: sympathetic (norepinephrine → β1 → ↑If, ↑ICaL → ↑HR, ↑contractility); parasympathetic (ACh → M2 → ↓If, ↑IKACh → ↓HR, ↓AV conduction).

Excitation-contraction (EC) coupling links the action potential to myocyte contraction. The action potential travels along the sarcolemma and down T-tubules (invaginations of the cell membrane). L-type Ca2+ channels (dihydropyridine receptors, DHPR) on the T-tubule open during the plateau, allowing Ca2+ influx that triggers Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2). The resulting increase in cytosolic Ca2+ (from ~100 nM to ~1 μM) binds troponin C, causing a conformational change that moves tropomyosin away from the myosin-binding sites on actin, allowing cross-bridge cycling. Relaxation occurs when Ca2+ is pumped back into the SR by SERCA2a (regulated by phospholamban; PKA phosphorylation of phospholamban removes inhibition, accelerating relaxation — lusitropic effect), and extruded from the cell by the Na+/Ca2+ exchanger (NCX) and the PMCA. The amount of Ca2+ released is proportional to the SR Ca2+ load and the L-type Ca2+ current, making EC coupling a graded process. Factors that increase SR Ca2+ load (e.g., digoxin, β-adrenergic stimulation) increase contractility (positive inotropy).

The Frank-Starling mechanism states that stroke volume (SV) increases with increased preload (ventricular end-diastolic volume), up to a point. This is due to length-dependent activation: greater sarcomere stretch optimizes actin-myosin overlap and increases Ca2+ sensitivity. Preload is determined by venous return, which is influenced by total blood volume, body position, intrathoracic pressure, and atrial contraction (atrial kick provides ~20% of ventricular filling). Afterload is the force the ventricle must overcome to eject blood — primarily determined by aortic pressure and peripheral resistance. Increased afterload reduces SV and increases myocardial O&bdq; demand. The cardiac cycle consists of: (1) atrial systole (ECG P wave); (2) isovolumetric ventricular contraction (ECG QRS, all valves closed, rapid pressure rise); (3) rapid ejection (aortic valve opens, LV pressure rises briefly then falls); (4) reduced ejection; (5) isovolumetric relaxation (aortic valve closes, all valves closed, pressure falls); (6) rapid ventricular filling (mitral valve opens); (7) reduced filling (diastasis). The Wiggers diagram correlates ECG, heart sounds, pressures, and volumes throughout the cycle. S1 = mitral + tricuspid closure (start of systole); S2 = aortic + pulmonic closure (start of diastole); S3 = rapid ventricular filling (may be normal in young); S4 = atrial contraction against stiff ventricle (pathologic).

The pressure-volume (PV) loop plots LV pressure against LV volume for one cardiac cycle. The loop consists of four phases: (A) isovolumetric contraction (ab); (B) ejection (bc); (C) isovolumetric relaxation (cd); (D) filling (da). The area within the loop is stroke work. The end-systolic pressure-volume relationship (ESPVR) is a linear relationship reflecting contractility; increased contractility shifts the slope upward and leftward. The end-diastolic pressure-volume relationship (EDPVR) reflects ventricular compliance; stiffer ventricles (HFpEF) have a steeper EDPVR. Cardiac output (CO = HR × SV) is normally 4–8 L/min. SV is determined by preload (venous return, distending pressure), afterload (arterial pressure), and contractility (β-adrenergic state, Ca2+ availability). The cardiac function curve (CO vs. right atrial pressure) shows the effect of preload on CO; the vascular function curve (venous return vs. right atrial pressure) shows the effect of resistance and mean circulatory filling pressure. The intersection of these curves determines the equilibrium point. Ejection fraction (EF = SV/EDV) is the most commonly used clinical measure of systolic function (normal ≥55%). Myocardial O&bdq; demand is determined by wall tension (LaPlace's law: tension = pressure × radius / wall thickness), heart rate, and contractility; supply is determined by coronary perfusion pressure (aortic diastolic pressure − LV pressure) and diastolic time.

Cardiac output increases during exercise via four mechanisms: (1) increased HR (β1-adrenergic), (2) increased contractility (β1-adrenergic increased Ca2+ influx), (3) increased preload (enhanced venous return from skeletal muscle pump and respiratory pump), (4) decreased afterload (peripheral vasodilation in exercising muscle). In heart failure with reduced ejection fraction (HFrEF), the response to increased preload is blunted because the ventricle operates on a flattened Frank-Starling curve. Compensatory mechanisms include increased sympathetic tone, RAAS activation, and ventricular remodeling, which ultimately worsen function (vicious cycle). In heart failure with preserved ejection fraction (HFpEF), the ventricle has increased stiffness (steeper EDPVR), causing elevated filling pressures and pulmonary congestion despite normal EF. Arrhythmia mechanisms include: (1) abnormal automaticity (enhanced phase 4 depolarization); (2) triggered activity (early afterdepolarizations in long QT, delayed afterdepolarizations from Ca2+ overload); (3) re-entry (circus movement around scar, accessory pathway in WPW). Antiarrhythmic drugs are classified by the Vaughan Williams system: Class I (Na+ channel blockers), Class II (β-blockers), Class III (K+ channel blockers), Class IV (Ca2+ channel blockers).

Poiseuille's law describes laminar flow through a cylindrical tube: Q = (ΔP × πr⁴) / (8ηL), where Q is flow, ΔP is pressure gradient, r is radius, η is viscosity, and L is length. The critical factor is radius raised to the fourth power. Vascular resistance is calculated by R = 8ηL/πr⁴; systemic vascular resistance (SVR) = (MAP − CVP) / CO, normally 800–1200 dyn·s/cm⁵. Series resistances add, parallel resistances add in reciprocal. LaPlace's law (wall tension = transmural pressure × radius) applies to vessels and the heart. In dilated cardiomyopathy, increased LV radius increases wall tension, increasing O₂ demand. Blood viscosity depends primarily on hematocrit; polycythemia increases resistance, anemia decreases it. Reynolds number predicts turbulent flow (>2000) which produces murmurs and bruits.

Mean arterial pressure (MAP) = diastolic pressure + 1/3(pulse pressure); normally 70–105 mmHg. Short-term regulation (seconds-minutes) is primarily via the baroreceptor reflex. Arterial baroreceptors (carotid sinus, CN IX; aortic arch, CN X) sense stretch; increased BP → increased afferent firing → NTS in medulla → increased parasympathetic outflow (↓HR) and decreased sympathetic outflow (↓vasoconstriction) → BP falls. Baroreceptors reset in chronic HTN. The chemoreflex responds to hypoxia, hypercapnia, and acidosis. Intermediate-term regulation involves RAAS: decreased renal perfusion → renin → angiotensin II (vasoconstrictor, aldosterone secretion, ADH release, thirst). Long-term regulation involves renal pressure-natriuresis. Atrial natriuretic peptide (ANP) and BNP promote Na+ and water excretion, vasodilation, and inhibit RAAS. The renal-body fluid system for long-term BP control operates through the relationship between BP and urinary output (pressure-natriuresis curve).

Capillary fluid exchange is governed by Starling forces: net filtration = Kf [(Pc + πi) − (Pi + πc)], where Kf is filtration coefficient, Pc is capillary hydrostatic pressure (~35 mmHg arterial, ~15 mmHg venous), Pi is interstitial hydrostatic pressure (~1–3 mmHg), πc is capillary oncotic pressure (~25 mmHg, primarily albumin), and πi is interstitial oncotic pressure (~1–5 mmHg). At the arterial end, net filtration pressure is ~13 mmHg outward; at the venous end, net pressure is ~−7 mmHg (reabsorption). About 90% of filtered fluid is reabsorbed; the rest returns via lymphatics. Edema occurs from increased Pc (heart failure, venous obstruction), decreased πc (hypoalbuminemia), increased capillary permeability (inflammation, burns), or lymphatic obstruction (lymphedema). The lymphatic system returns ~2–4 L/day of interstitial fluid and transports absorbed fats and immune cells.

The microcirculation includes arterioles (resistance vessels), capillaries (exchange vessels), and venules (capacitance vessels). Local metabolic control matches flow to demand: increased metabolism → increased adenosine, K+, H+, CO₂, lactate → vasodilation (functional hyperemia). Autoregulation maintains constant flow over MAP 60–140 mmHg via myogenic response (stretch-induced vasoconstriction) and metabolic mechanisms. The endothelium produces vasodilators (NO, prostacyclin, EDHF) and vasoconstrictors (endothelin-1, thromboxane A₂). NO is synthesized by eNOS from L-arginine, diffuses to smooth muscle, activates guanylyl cyclase → cGMP → vasodilation. Shear stress is the primary stimulus for NO release. Endothelial dysfunction (impaired NO bioavailability) is a hallmark of HTN, diabetes, and atherosclerosis. The coronary, cerebral, and renal circulations have the most robust autoregulation.

Veins are capacitance vessels containing ~60–70% of total blood volume. Venous return depends on: (1) pressure gradient from peripheral veins (mean systemic filling pressure, ~7 mmHg) to right atrium (CVP, ~0–5 mmHg); (2) resistance; (3) skeletal muscle pump; (4) respiratory pump (inspiration decreases intrathoracic pressure, increasing venous return); (5) venoconstriction (α1-adrenergic). Mean circulatory filling pressure (MCFP) reflects blood volume and vascular compliance. CVP reflects RV preload; elevated CVP indicates RV failure, volume overload, or increased intrathoracic pressure. The pressure gradient for venous return is MCFP − CVP. During exercise, α1 venoconstriction translocates blood from splanchnic and cutaneous beds to central circulation. Orthostatic stress pools blood in lower extremities; the baroreflex compensates with tachycardia and vasoconstriction. The skeletal muscle and respiratory pumps are critical for maintaining venous return during upright exercise.

Hypertension is BP ≥130/80 mmHg (ACC/AHA). Primary HTN (>90%) involves increased SVR from RAAS dysregulation, sympathetic overactivity, endothelial dysfunction, and vascular remodeling. Secondary causes include renal artery stenosis, primary aldosteronism, pheochromocytoma, Cushing, and sleep apnea. HTN increases afterload, promoting LV hypertrophy and accelerating atherosclerosis (leading to stroke, CAD, CKD). Shock is inadequate tissue perfusion (MAP <65, lactate ≥2) with four types: hypovolemic, cardiogenic, distributive (sepsis, anaphylaxis, neurogenic), and obstructive (PE, tamponade, tension pneumothorax). Early compensation involves baroreflex and RAAS; decompensation causes worsening acidosis, vasodilation, and multi-organ failure. Septic shock features vasoplegia treated with norepinephrine and fluids. Edema: pitting (high Pc or low oncotic) vs non-pitting (lymphedema, myxedema).

Lung volumes are measured by spirometry. Tidal volume (TV) is the volume inspired/expired with each breath (~500 mL). Inspiratory reserve volume (IRV) is the extra volume beyond TV (~3000 mL). Expiratory reserve volume (ERV) is the volume expired below TV (~1200 mL). Residual volume (RV) is the volume remaining after maximal expiration (~1200 mL); RV is measured by helium dilution or body plethysmography. Lung capacities: inspiratory capacity (IC = TV + IRV, ~3500 mL); functional residual capacity (FRC = ERV + RV, ~2400 mL); vital capacity (VC = TV + IRV + ERV, ~4700 mL); total lung capacity (TLC = VC + RV, ~6000 mL). FRC is the equilibrium volume at which chest wall outward recoil equals lung inward recoil. Spirometry measures FVC and FEV1. Normal FEV1/FVC ≥ 0.70. Obstructive: ↓FEV1/FVC (<0.70), ↓FEV1, normal/↑TLC (air trapping). Restrictive: normal/↑FEV1/FVC (>0.80), ↓VC, ↓TLC. Flow-volume loops show a scooped expiratory limb in COPD; flattened loop in fixed upper airway obstruction.

In an upright lung, both ventilation (V) and perfusion (Q) increase from apex to base, but Q increases more steeply. West zones: Zone 1 (apex): PA > Pa > Pv → no perfusion (alveolar dead space); Zone 2: Pa > PA > Pv → intermittent perfusion (waterfall effect); Zone 3 (base): Pa > Pv > PA → continuous perfusion. Overall V/Q ratio is ~0.8–1.0. Low V/Q units (shunt-like) at bases; high V/Q units (dead space-like) at apices. Hypoxic pulmonary vasoconstriction (HPV) diverts blood from hypoxic regions; it is blunted by vasodilators and sepsis. Pathologic shunts cause hypoxemia refractory to 100% O₂ (e.g., ARDS, pulmonary AVM, R→L shunt). Dead space: anatomical (~150 mL) + alveolar (unperfused alveoli); VD/VT normally ~0.2–0.4, increased in PE, COPD, ARDS. The A-a gradient (PAO₂ − PaO₂) is normally <10–20 mmHg; widened in V/Q mismatch, shunt, and diffusion impairment; normal in hypoventilation.

Oxygen is transported dissolved (PaO₂ × 0.003 mL O₂/dL/mmHg, ~2%) and bound to hemoglobin (Hb × 1.34 × SaO₂, ~98%). Total O₂ content = (Hb × 1.34 × SaO₂) + (PaO₂ × 0.003), normally ~20 mL O₂/dL. The oxyhemoglobin dissociation curve is sigmoidal (cooperative binding); P50 is normally ~26 mmHg. Right shift (↓affinity, ↑P50) with ↑temperature, ↑H+ (Bohr effect), ↑CO₂ (Haldane effect), ↑2,3-BPG; facilitates O₂ unloading. Left shift (↑affinity, ↓P50) with alkalosis, hypothermia, decreased CO₂, decreased 2,3-BPG (stored blood); impairs O₂ unloading. The Bohr effect: increased H+ from metabolically active tissues decreases Hb affinity for O₂. The Haldane effect: deoxygenated Hb has higher affinity for CO₂ and H+, enhancing CO₂ loading in tissues and unloading in lungs. CO binds Hb with ~250× O₂ affinity (COHb, left shift). Methemoglobin (Fe3+) cannot bind O₂; treated with methylene blue. HbF has higher O₂ affinity (left shift) for transplacental transfer.

CO₂ is transported dissolved (PaCO₂ × 0.03 mmol/L/mmHg, ~5–10%), as bicarbonate (HCO₃−) via carbonic anhydrase in RBCs: CO₂ + H₂O ↔ H₂CO₃ ↔ H+ + HCO₃− (~60–70%), and as carbamino compounds on Hb (~20–30%). Henderson-Hasselbalch: pH = 6.1 + log([HCO₃−] / (0.03 × PaCO₂)). Normal: pH 7.35–7.45, PaCO₂ 35–45 mmHg, HCO₃− 22–26 mEq/L. For metabolic acidosis, Winter's formula: PaCO₂ = (1.5 × HCO₃) + 8 ± 2. Anion gap = Na − Cl − HCO₃ (normal 8–12). AG metabolic acidosis (MUDPILES: methanol, uremia, DKA, propylene glycol, isoniazid, lactic acidosis, ethylene glycol, salicylates) vs non-AG (hyperchloremic: diarrhea, RTA, acetazolamide). Delta gap (ΔAG/ΔHCO₃): <1 = combined AG + non-AG acidosis; >2 = concurrent metabolic alkalosis. Respiratory acidosis: acute compensation (cellular H+ buffering, ↑HCO₃ 1 per 10 mmHg ↑PaCO₂); chronic compensation (renal, ↑HCO₃ 3.5 per 10 mmHg).

The respiratory center in the medulla oblongata includes the dorsal respiratory group (DRG, processing sensory input) and the ventral respiratory group (VRG, containing the pre-Bötzinger complex for rhythm generation). Central chemoreceptors (ventrolateral medulla) sense CO₂ via CSF H+ changes (~70% of ventilatory response). Peripheral chemoreceptors (carotid bodies, CN IX; aortic bodies, CN X) sense O₂, CO₂, and pH; the carotid bodies provide hypoxic drive (response to PaO₂ <60 mmHg). Hypercapnia is normally a stronger stimulus than hypoxemia; in chronic CO₂ retention (COPD), central chemoreceptors become desensitized and hypoxic drive becomes primary (caution with O₂ therapy). Hypoxia types: hypoxic (low PaO₂: altitude, hypoventilation, V/Q mismatch, shunt), anemic (normal PaO₂, low O₂ content), stagnant (low CO), histotoxic (cyanide, sepsis — impaired utilization). Respiratory failure: Type I (hypoxemic, PaO₂ <60, normal/low PaCO₂) — V/Q mismatch, shunt, PE; Type II (hypercapnic, PaCO₂ >50, ± hypoxemia) — hypoventilation, COPD, neuromuscular disease, opioid overdose.

Glomerular filtration rate (GFR) is the volume filtered per minute, normally ~125 mL/min (180 L/day). GFR = Kf [(Pgc − Pbs) − (πgc − πbs)], where Kf is filtration coefficient, Pgc is glomerular capillary hydrostatic pressure (~60 mmHg), Pbs is Bowman's space pressure (~18 mmHg), πgc is capillary oncotic pressure (~32 mmHg), and πbs is Bowman's space oncotic pressure (~0). Net filtration pressure is ~10 mmHg. The filtration barrier includes fenestrated endothelium, GBM, and podocyte slit diaphragms. Renal blood flow is ~1200 mL/min (20–25% of CO); filtration fraction (FF = GFR/RPF) is ~0.20. Autoregulation maintains GFR and RBF across MAP 80–180 mmHg via myogenic response (afferent arteriolar constriction with stretch) and tubuloglomerular feedback (TGF: macula densa senses NaCl, signals afferent constriction). The juxtaglomerular apparatus includes macula densa, JG cells (renin), and mesangial cells. Sympathetic (β1 on JG cells) stimulates renin release. Loss of autoregulation contributes to hyperfiltration injury in CKD.

Proximal tubule (PT) reabsorbs ~65% of filtered Na+, 60–70% of water, 80–90% of HCO₃−, essentially all glucose and amino acids, and most Ca2+, PO₄³−, and urate. PT uses Na+ cotransporters (SGLT2 for glucose, Na+/PO₄, Na+/amino acid) and Na+/H+ exchanger (NHE3) for HCO₃ reclamation. Carbonic anhydrase (CA) is essential. Loop of Henle reabsorbs ~25% of Na+; thick ascending limb (TAL) uses NKCC2 (blocked by loop diuretics), is water-impermeable, and establishes the medullary gradient. DCT reabsorbs ~5–8% of Na+ via NCC (blocked by thiazides) and is Ca2+ reabsorption site (PTH-regulated). Collecting duct: principal cells reabsorb Na+ (ENaC, blocked by amiloride) and secrete K+ (ROMK), regulated by aldosterone; water reabsorption via AQP2 (ADH-regulated). α-Intercalated cells secrete H+ (H+-ATPase); β-intercalated cells secrete HCO₃−. The PT also secretes organic anions and cations (drugs, toxins, urate).

The countercurrent multiplier establishes a corticopapillary gradient (300 mOsm cortex to 1200–1400 mOsm papilla). The TAL actively transports NaCl out (NKCC2) but is water-impermeable, creating dilute tubular fluid and concentrating the medullary interstitium. The descending LOH is water-permeable but not NaCl-permeable, allowing water to be drawn out. Urea recycling contributes ~40–50% of the gradient via UT-A1, UT-A2, and UT-B transporters. Vasa recta countercurrent exchange preserves the gradient. ADH (vasopressin) binds V2 receptors → PKA → AQP2 insertion → water reabsorption → concentrated urine. Without ADH (diabetes insipidus), collecting duct is water-impermeable, producing dilute urine (as low as 50 mOsm). Maximal concentrating ability is 800–1400 mOsm/kg; diluting ability ~50 mOsm/kg. Free water clearance: CH₂O = V − Cosm (positive in water diuresis, negative in antidiuresis).

The kidney regulates acid-base via: (1) HCO₃ reclamation (PT, ~4500 mEq/day); (2) titratable acid excretion (~30–40 mEq/day, phosphate buffer); (3) NH₄+ (ammonium) excretion — the major adaptive mechanism, up to 300–400 mEq/day in chronic acidosis. In PT, glutamine metabolism generates NH₃ (diffuses into lumen) and HCO₃− (returned to blood). In the collecting duct, α-intercalated cells secrete H+ via H+-ATPase; NH₃ + H+ → NH₄+ (ion trapping). Urine pH can fall to 4.4. RTA types: Type 1 (distal) — impaired H+ secretion → hyperchloremic acidosis, hypokalemia, nephrolithiasis; Type 2 (proximal) — impaired HCO₃ reclamation → hyperchloremic acidosis, hypokalemia, Fanconi syndrome; Type 4 (hyporeninemic hypoaldosteronism) → hyperkalemic hyperchloremic acidosis (common in DM, CKD).

Total body water (TBW) is ~60% of weight. ICF (2/3), ECF (1/3: interstitial 3/4, plasma 1/4). Major ECF cation Na+ (135–145 mEq/L); major ICF cation K+ (140–150 mEq/L). Na+ balance regulated by aldosterone, ANP, and pressure-natriuresis. Water balance regulated by ADH and thirst. Hyponatremia (Na <135): SIADH, hypothyroidism, adrenal insufficiency, CHF, cirrhosis, thiazides. Hypernatremia (Na >145): DI, insensible losses. K+ balance: 98% intracellular; distribution by insulin (↑uptake), β2-agonists (↑uptake), acidosis (↓uptake). Hypokalemia: diuretics, diarrhea, hyperaldosteronism, vomiting. Hyperkalemia: renal failure, K+-sparing diuretics, ACEi/ARB, adrenal insufficiency, tumor lysis, rhabdomyolysis. Ca2+ and PO₄ regulated by PTH, vitamin D, calcitonin. Mg2+ reabsorbed in TAL; hypomagnesemia causes hypocalcemia (impaired PTH) and hypokalemia (ROMK dysfunction).

Diuretics: osmotic (mannitol, PT/LOH), CA inhibitors (acetazolamide, PT), loop diuretics (furosemide, NKCC2 in TAL, ~25% Na+ reabsorption), thiazides (HCTZ, NCC in DCT, Ca2+ retention), K+-sparing (spironolactone/eplerenone — aldosterone antagonists; amiloride/triamterene — ENaC blockers). AKI: pre-renal (BUN:Cr >20, FeNa <1%, FeUrea <35%, urine osm >500); intrinsic ATN (FeNa >2%, muddy brown casts); AIN (WBC casts, eosinophiluria); GN (RBC casts). Post-renal (hydronephrosis). CKD: eGFR <60 for ≥3 months; complications: hyperkalemia, acidosis, anemia, renal osteodystrophy, uremia. RRT indications: AEIOU (Acidosis pH <7.15, Electrolytes K >6.5, Ingestion, Overload pulmonary edema, Uremia).

GI motility is controlled by the enteric nervous system (~500 million neurons): myenteric (Auerbach) plexus controls motility; submucosal (Meissner) plexus controls secretion and blood flow. The ENS operates autonomously, modulated by the ANS. Interstitial cells of Cajal (ICC) generate slow waves (stomach ~3/min, duodenum ~12/min, ileum ~8–9/min, colon ~3/min). Peristalsis: ascending contraction (ACh/substance P) + descending relaxation (NO/VIP). Segmentation mixes chyme. The migrating motor complex (MMC cycles every 90–120 min during fasting, sweeping debris to colon (\"housekeeper\" function). Gastric emptying delayed by fats and proteins (CCK, GIP, secretin). The gastrocolic reflex promotes mass movement after eating. Defecation reflex: rectal distention → internal anal sphincter relaxation (smooth muscle, involuntary) + external sphincter (skeletal muscle, voluntary control).

Salivary (1–1.5 L/day): parasympathetic (ACh, watery), sympathetic (mucous). Contains α-amylase, lipase, mucins, lysozyme, IgA. Gastric (2–3 L/day): cephalic (vagus → gastrin + ACh), gastric (distention, amino acids → gastrin), intestinal (feedback inhibition). Parietal cells: HCl (H+/K+ ATPase) + intrinsic factor. Chief cells: pepsinogen. G cells: gastrin. ECL cells: histamine. Pancreatic (1.5–2 L/day): secretin → HCO₃−-rich; CCK → enzyme-rich (trypsinogen, chymotrypsinogen, amylase, lipase, colipase, nucleases). Biliary (0.5–1 L/day): bile salts from cholesterol, conjugated to glycine/taurine, emulsify fats, form micelles; >95% reabsorbed in terminal ileum (enterohepatic circulation, 12–24 g/day cycling). Gallbladder concentrates bile 5–10×, contracts with CCK. Bile contains bilirubin, phospholipids, HCO₃−.

Carbohydrates: α-amylase (mouth, pancreas) → disaccharides → brush border enzymes (sucrase-isomaltase, lactase, maltase) → monosaccharides. Glucose and galactose via SGLT1; fructose via GLUT5; exit via GLUT2. Lactose intolerance: lactase deficiency (primary in non-Europeans, secondary from gut injury). Proteins: pepsin (stomach) → trypsin, chymotrypsin, carboxypeptidase, elastase (pancreas) → brush border peptidases → amino acids, di/tripeptides (PEPT1). Fats: bile salt micelles emulsify triglycerides; pancreatic lipase + colipase → 2-monoglycerides + free fatty acids → enterocyte → re-esterification → chylomicrons (apoB-48) → lacteals. MCTs absorbed directly into portal blood. Vitamin B12: intrinsic factor (parietal cells) + terminal ileum. Iron: DcytB reduces Fe3+ to Fe2+, DMT1 imports, ferroportin exports (regulated by hepcidin). Calcium: TRPV6, calbindin (regulated by calcitriol). Fat-soluble vitamins (A, D, E, K) incorporated into micelles and chylomicrons.

The liver has >500 functions. Hepatocytes arranged in lobules with portal triads (hepatic artery, portal vein, bile duct). Sinusoids lined by endothelial cells and Kupffer cells. Acinus zones: zone 1 (periportal, oxidative, gluconeogenesis); zone 3 (centrilobular, CYP450, susceptible to toxins). Bilirubin: heme → biliverdin → unconjugated bilirubin (albumin-bound) → hepatocyte uptake (OATP) → conjugation (UGT1A1) → conjugated bilirubin → bile. Gut bacteria deconjugate to urobilinogen (partial reabsorption, urine/stool excretion). Jaundice: >2–2.5 mg/dL bilirubin. Drug metabolism: Phase I (CYP3A4, CYP2D6, CYP2C9) + Phase II (conjugation). First-pass metabolism reduces oral drug bioavailability. The liver synthesizes albumin (3.5–5.0 g/dL), clotting factors (except vWF, FVIII), complement, acute-phase proteins, and angiotensinogen. Glucose homeostasis: glycogen storage, gluconeogenesis, glycolysis. Lipid metabolism: VLDL, HDL, cholesterol synthesis, β-oxidation.

The gut-brain axis involves bidirectional communication via vagal afferents, sympathetic efferents, neuroendocrine signals, and the microbiome. The microbiome (~10¹⁴ bacteria, 500–1000 species, Firmicutes, Bacteroidetes) contributes to SCFA production (butyrate, propionate, acetate), vitamin synthesis (K, B12, biotin), immune modulation, and metabolism. Dysbiosis implicated in IBS, IBD, metabolic syndrome, and CNS disorders. Emesis center in medulla integrates input from CTZ (area postrema, D₂, 5-HT₃, M1, H1, NK1), vestibular system, GI (5-HT₃), and higher centers. Antiemetics: 5-HT₃ antagonists (ondansetron), NK1 antagonists (aprepitant), D₂ antagonists (metoclopramide), H1 (meclizine), M1 (scopolamine). Diarrhea: osmotic, secretory, inflammatory, motility-related. Constipation: decreased motility, prolonged transit; management: fiber, PEG, lactulose, stimulants (bisacodyl), secretagogues (lubiprostone, linaclotide).

The hypothalamic-pituitary axis is the master regulator. Hypothalamus secretes releasing/inhibiting hormones into the hypothalamic-hypophyseal portal system connecting the median eminence to the anterior pituitary. TRH → TSH; CRH → ACTH; GHRH → GH; GnRH → LH, FSH; dopamine (PIF) → ↓prolactin. Anterior pituitary: TSH, ACTH, GH, LH, FSH, prolactin. Each under negative feedback. Posterior pituitary stores ADH (supraoptic nucleus, V2 receptors → water reabsorption, V1 → vasoconstriction) and oxytocin (paraventricular nucleus, uterine contraction, milk ejection). GH acts directly (lipolysis, anti-insulin) and indirectly via IGF-1 (liver). Prolactin tonically inhibited by dopamine; stalk section or dopamine antagonists cause hyperprolactinemia → galactorrhea, hypogonadism. Hypopituitarism: loss of GH first, then LH/FSH, TSH, ACTH; treatment involves hormone replacement.

Thyroid hormone synthesis: (1) NIS traps iodide; (2) TPO oxidizes I- to reactive iodine; (3) organification: iodination of Tg tyrosine residues → MIT, DIT; (4) coupling: TPO links MIT+DIT → T₃, DIT+DIT → T₄; (5) endocytosis, proteolysis → T₃/T₄ release; (6) MIT/DIT deiodination and recycling. Secretion: T₄ (90%), T₃ (10%). Peripheral conversion: T₄ → T₃ by D1/D2 (~80% of T₃). D3 inactivates T₄ → rT₃. Transport: TBG (~70%), transthyretin, albumin. Free hormones are active. T₃ binds nuclear TRα/TRβ. Effects: ↑metabolic rate, thermogenesis (UCPs), ↑HR, ↑contractility, ↑GI motility, ↑CNS excitability, ↑bone turnover, ↑gluconeogenesis/glycolysis, ↑lipolysis. The Wolff-Chaikoff effect: excess iodide inhibits organification (transient, ~10–14 days escape). Jod-Basedow: iodide causes hyperthyroidism in autonomous tissue. TSH regulates via TRH (+) and T₃ feedback.

Zona glomerulosa (aldosterone, mineralocorticoid), zona fasciculata (cortisol, glucocorticoid), zona reticularis (DHEA, androstenedione). Steroidogenesis: cholesterol → pregnenolone (CYP11A1). Cortisol: 17-OH-pregnenolone → 11-deoxycortisol → cortisol (CYP21A2, CYP11B1). Circadian: peak ~8 AM, nadir ~midnight. Actions: gluconeogenesis, lipolysis, protein catabolism, anti-inflammatory, permissive for catecholamines, decreased bone formation. Transported by CBG and albumin. 11β-HSD2 in kidney protects MR; licorice inhibits it (apparent mineralocorticoid excess). Aldosterone: progesterone → DOC → corticosterone → aldosterone (CYP11B2). Stimulated by AngII and K+. Actions: ENaC, ROMK, H+ secretion. Adrenal androgens: DHEA, DHEA-S (most abundant), androstenedione; precursors for peripheral testosterone/estradiol. DHEA-S is a marker of adrenal androgen production; declines with age (adrenopause).

β-cells (60–70%): insulin + amylin. α-cells (20–25%): glucagon. δ-cells (5–10%): somatostatin. PP-cells: pancreatic polypeptide. Insulin: preproinsulin → proinsulin (C-peptide) → insulin + C-peptide. Secretion stimulated by glucose (GLUT2 → ATP → KATP closes → depolarization → Ca2+ influx → exocytosis), amino acids, GLP-1, ACh. Inhibited by somatostatin, α2-adrenergic, low glucose. Insulin receptor (RTK) → IRS → PI3K → Akt → GLUT4 translocation, glycogenesis, lipogenesis, protein synthesis, ↓gluconeogenesis. Glucagon (Gs → ↑cAMP) → glycogenolysis, gluconeogenesis, ketogenesis, lipolysis. Stimulated by hypoglycemia, amino acids, β-adrenergic. Incretin effect: oral glucose > insulin than IV (GLP-1, GIP). DPP-4 degrades GLP-1. Insulin-to-glucagon ratio determines fed (anabolic) vs fasting (catabolic) state. Amylin delays gastric emptying, suppresses glucagon. Somatostatin paracrine inhibits both insulin and glucagon.

PTH (chief cells, CaSR senses low Ca2+) → bone resorption (RANKL), renal Ca2+ reabsorption, PO₄ excretion, 1α-hydroxylase activation. PTH raises Ca2+, lowers PO₄. Vitamin D: diet + skin (7-dehydrocholesterol + UVB) → liver (25-hydroxylase) to 25-(OH)-D₃ → kidney (1α-hydroxylase, stimulated by PTH, low Ca2+/PO₄) to 1,25-(OH)₂D₃ (calcitriol). Calcitriol: ↑intestinal Ca2+/PO₄ absorption (TRPV6, calbindin, NaPi2b), ↑bone mineralization, ↓PTH. CYP24A1 inactivates vitamin D. Calcitonin (parafollicular C-cells, high Ca2+) → ↓osteoclast activity. FGF23 (osteocytes) → ↓renal PO₄ reabsorption, ↓1α-hydroxylase; elevated in X-linked hypophosphatemia, CKD. CaSR mutations: gain-of-function → hypocalcemia (autosomal dominant hypocalcemia); loss-of-function → hypercalcemia (familial hypocalciuric hypercalcemia, FHH).

DM: Type 1 (autoimmune, DKA) vs Type 2 (insulin resistance, HHS). DKA: acidosis, ketones; HHS: hyperosmolality. Cushing: ACTH-dependent (pituitary, ectopic) vs independent (adrenal). Diagnosis: 1mg DST, midnight cortisol, 24h UFC. Thyroid: Graves (TSI, diffuse goiter, exophthalmos, pretibial myxedema) vs Hashimoto (TPO antibodies, atrophic goiter). Hyperparathyroidism: primary (high Ca, high PTH, low PO₄) vs secondary (high PTH, normal/low Ca, low vitamin D). SIADH: euvolemic hyponatremia, low uric acid, high urine Na; water restriction, tolvaptan. DI: central (ADH deficient, responds to DDAVP) vs nephrogenic (ADH resistant, thiazides). Pheochromocytoma: paroxysmal HTN, palpitations, headache; plasma metanephrines; treatment: α-blockade first, then β-blockade, then surgery. MEN syndromes: MEN1 (parathyroid, pituitary, pancreas), MEN2A (MTC, pheo, parathyroid), MEN2B (MTC, pheo, neuromas).

Chemical synaptic transmission is the fundamental mechanism of interneuronal communication. An action potential opens presynaptic voltage-gated Ca2+ channels (P/Q-type, N-type), triggering vesicle docking (SNARE proteins: syntaxin, SNAP-25, synaptobrevin) and exocytosis of neurotransmitter (NT). NTs bind postsynaptic receptors. Ionotropic receptors (ligand-gated ion channels) mediate fast transmission: AMPA/NMDA (glutamate, excitatory), GABA-A (Cl− influx, inhibitory), glycine, nicotinic ACh. Metabotropic (GPCRs) mediate slow modulatory effects: GABA-B, mGluR, muscarinic ACh, D1/D2, 5-HT, adrenergic. EPSPs depolarize; IPSPs hyperpolarize. Summation determines threshold. Major NTs: glutamate (excitatory, LTP), GABA (inhibitory, from GAD), ACh (NMJ, autonomic ganglia, CNS), dopamine (motor, reward), norepinephrine (arousal, locus coeruleus), serotonin (mood, raphe), histamine (arousal). NT inactivation: enzymatic (AChE), reuptake (DAT, SERT, NET), diffusion. Presynaptic inhibition (GABA-B) and facilitation (β-adrenergic) modulate release. Long-term potentiation (LTP) in hippocampus: NMDA activation (glutamate + depolarization) → Ca2+ influx → CaMKII → AMPA upregulation.

Dorsal column-medial lemniscus (DCML): discriminative touch, vibration, proprioception. First-order neurons (Aβ) ascend ipsilaterally in dorsal columns (gracilis, cuneatus) to medulla; second-order decussate (internal arcuate fibers) and ascend as medial lemniscus to VPL thalamus; third-order to primary somatosensory cortex (postcentral gyrus). Spinothalamic tract (STT): pain and temperature. First-order (Aδ [sharp], C [burning]) synapse in dorsal horn; second-order decussate (anterior commissure) and ascend to VPL + medial thalamus (emotional aspect). Trigeminal system: face sensation via CN V (main sensory nucleus → touch; spinal trigeminal nucleus → pain/temperature). Gate control: Aβ fibers inhibit C fiber transmission in dorsal horn (TENS, rubbing). Descending pain modulation: PAG → RVM → dorsal horn (endogenous opioids, serotonin, NE). Hyperalgesia (increased pain) and allodynia (pain from non-painful stimulus): central sensitization (wind-up, NMDA) and peripheral sensitization (inflammatory mediators). Referred pain: visceral and somatic afferents converge on same spinal segments (e.g., cardiac pain → left arm).

Corticospinal tract (CST): upper motor neurons (Betz cells, layer V) descend through internal capsule, cerebral peduncle, medullary pyramids (80–90% decussate), to lower motor neurons (α-motor neurons, ventral horn). UMN lesion: spasticity, hyperreflexia, Babinski, weakness (pyramidal distribution). LMN lesion: flaccid, hyporeflexia, atrophy, fasciculations. Basal ganglia (caudate, putamen, GPi, GPe, STN, SNc, SNr): direct pathway (D1, striatum → GPi/SNr → thalamus) facilitates movement; indirect pathway (D2, striatum → GPe → STN → GPi/SNr) suppresses movement. SNc dopamine: D1 excites direct, D2 inhibits indirect. Dopamine loss (Parkinson's) → indirect dominance → bradykinesia, rigidity, tremor. Cerebellum: vestibulocerebellum (balance), spinocerebellum (proprioception), cerebrocerebellum (motor planning). Purkinje cells (GABAergic) inhibit deep cerebellar nuclei. Cerebellar lesion: ipsilateral dysmetria, intention tremor, dysdiadochokinesia, ataxia, hypotonia, nystagmus. The motor cortex includes primary motor (M1, area 4), premotor (PM), and supplementary motor area (SMA), which code movement parameters and sequence planning.

Sympathetic (SNS, T1–L2): preganglionic ACh (short) → paravertebral/prevertebral ganglia → postganglionic NE (most) or ACh (sweat glands). Adrenal medulla: epinephrine (80%) + NE (20%) into blood. Effects: ↑HR (β1), ↑contractility (β1), bronchodilation (β2), vasoconstriction (α1, skin/gut/kidney), vasodilation muscle (β2), ↓GI motility (α2, β2), mydriasis (α1), ejaculation (α1), lipolysis (β1/3), glycogenolysis (β2, α1). Parasympathetic (PSNS, CN III, VII, IX, X, S2–4): preganglionic ACh (long) → terminal ganglia near target → postganglionic ACh (muscarinic M2, M3). Vagal (CN X) supplies ~75% of PSNS outflow. Effects: ↓HR (M2), bronchodilation reversed (M3 → bronchoconstriction), ↑GI motility/secretion (M3), miosis (M3), bladder contraction (M3), erection (M3, NO). Enteric nervous system: autonomous but modulated by ANS. Autonomic reflexes: baroreflex, chemoreflex, pupillary light, micturition, defecation. Sympathetic and parasympathetic systems exhibit tonic activity (autonomic tone); often opposing but complementary (dynamic antagonism).

Memory: sensory (ms), short-term/working (prefrontal cortex, ~7 items), long-term (hippocampus, MTL). Explicit (semantic, episodic) → hippocampus; implicit (procedural, conditioning) → striatum, cerebellum, amygdala. LTP: NMDA → CaMKII → AMPA upregulation. Language: left hemisphere dominant. Broca (BA 44/45, inferior frontal) → expressive aphasia (non-fluent). Wernicke (BA 22, posterior superior temporal) → receptive aphasia (fluent, poor comprehension). Arcuate fasciculus connecting them → conduction aphasia (poor repetition). Global aphasia = both Broca + Wernicke. Sleep: NREM (75–80%, N1–N3) and REM (dreaming, atonia) cycle ~90 min. VLPO (GABA) promotes sleep; locus coeruleus, raphe, TMN promote arousal. SCN generates circadian rhythm entrained by light (melanopsin RGCs → retinohypothalamic tract). Parkinson's: SNc dopamine loss, Lewy bodies. Triad: resting tremor, rigidity, bradykinesia. Treatment: carbidopa/levodopa, DBS. Stroke: ischemic (80%) vs hemorrhagic. MCA: contralateral hemiparesis/hemisensory, homonymous hemianopia, aphasia (dominant), neglect (non-dominant). Lacunar: pure motor, pure sensory, ataxic hemiparesis, dysarthria/clumsy hand.

Skeletal muscle is organized as: whole muscle → fascicles → fibers (multinucleated) → myofibrils → sarcomeres (Z-disk to Z-disk). The sarcomere contains: A-band (myosin + overlapping actin), H-zone (myosin only, center of A-band), I-band (actin only), M-line (myosin cross-linking). Thin filaments: F-actin (globular G-actin polymerized), tropomyosin, troponin (TnC [Ca2+ binding], TnI [inhibitory], TnT [tropomyosin binding]). Thick filaments: myosin II (two heavy chains + four light chains, globular heads with ATPase and actin-binding domains). Sliding filament theory: myosin heads bind actin, undergo power stroke (conformational change), pulling thin filaments toward M-line. A-band constant; I-band and H-zone shorten. Cross-bridge cycle: (1) ATP binds myosin (dissociates from actin); (2) ATP hydrolysis cocks head (ADP+Pi, high-energy); (3) myosin binds actin (strong binding); (4) power stroke (Pi released, head pivots, ADP released, filament slides ~10 nm); (5) ATP binds again, cycle repeats. Fiber types: Type I (slow oxidative, fatigue-resistant, myosin ATPase slow), Type IIa (fast oxidative-glycolytic), Type IIb (fast glycolytic, fatigue quickly). Velocity of shortening maximal at zero load (Vmax). Force-length relationship: optimal overlap at ~2.0–2.2 μm sarcomere length.

The NMJ: motor neuron AP → P/Q-type Ca2+ channels → ACh release (quantal, ~5000–10000 molecules/vesicle) → nAChR on motor end plate → Na+ influx → end-plate potential (EPP, ~70 mV, normally suprathreshold → safety factor). AChE rapidly hydrolyzes ACh, terminating transmission. Muscle AP propagates along sarcolemma and into T-tubules (at A-I junctions). The DHPR (CaV1.1) on T-tubule mechanically couples to RyR1 on SR terminal cisternae (triads). DHPR activation → RyR1 opens → Ca2+ release from SR → Ca2+ binds TnC → contraction. (Unlike cardiac muscle, skeletal does not require Ca2+ influx.) Relaxation: SERCA1 pumps Ca2+ back into SR. Myasthenia gravis: IgG against nAChR → decreased nAChR number → reduced EPP amplitude → transmission failure → fatigable weakness. Repetitive nerve stimulation shows decremental response. Lambert-Eaton: anti-P/Q Ca2+ channel antibodies → decreased ACh release → weakness that improves with activity (incremental response).

Smooth muscle lacks sarcomeres and troponin. Actin attaches to dense bodies (containing α-actinin). Myosin forms only when phosphorylated. Two types: multi-unit (iris, large airways, independently innervated) and single-unit/visceral (GI tract, uterus, ureter, electrically coupled via gap junctions, spontaneous pacemaker activity). EC coupling: Ca2+ enters from ECF (L-type voltage-gated, ligand-gated, receptor-operated) and SR (IP3 receptors, RyR). Ca2+ binds calmodulin → MLCK activation → MLC20 phosphorylation → myosin ATPase → contraction. Relaxation: MLCP dephosphorylates MLC. Latch mechanism: sustained tension with very low ATP consumption (important in sphincters, blood vessels). Regulation: Gq/11-PLC-IP3/Ca2+ (contraction); Gs-cAMP-PKA (↓Ca2+, ↓MLCK) → relaxation; NO-GC-cGMP-PKG → relaxation (↓Ca2+). Drugs: β2 agonists (bronchodilation, tocolysis), CCBs (vasodilation), nitrates (NO donors), PDE5 inhibitors (sildenafil → ↑cGMP).

Cardiac muscle: striated, intercalated disks (gap junctions: connexin 43; desmosomes), functional syncytium. Differences from skeletal: (1) cannot tetanize (long refractory period); (2) pacemaker cells (automaticity); (3) CICR via DHPR (CaV1.2) → RyR2; (4) plateau phase; (5) oxidative metabolism (mitochondria ~30% of cell volume); (6) SERCA2a (phospholamban-regulated); (7) β1-adrenergic regulation (PKA phosphorylates DHPR, RyR2, PLB, TnI, MyBP-C). Force-frequency (Bowditch): ↑HR → ↑contractility (more Ca2+ entry). Skeletal muscle energy: immediate (CrP + ADP → Cr + ATP, ~5–10 sec), short-term (anaerobic glycolysis, ~1–2 min), long-term (oxidative phosphorylation). CrP is 4–5× resting ATP. Training: endurance → ↑oxidative enzymes, capillaries, mitochondria; resistance → hypertrophy (mTOR). Clinical: malignant hyperthermia (RyR1 mutation → uncontrolled Ca2+ release → dantrolene). Duchenne MD (dystrophin deficiency, X-linked, elevated CK, Gower sign, calf pseudohypertrophy, dilated cardiomyopathy). Rhabdomyolysis (CK >5000, myoglobinuria, AKI → aggressive IVF, alkalinize urine).

Hematopoiesis produces all blood cells from hematopoietic stem cells (HSCs) in bone marrow. HSCs are multipotent and self-renewing. Myeloid lineage (CFU-GEMM): erythrocytes (CFU-E, EPO-dependent), megakaryocytes (TPO-dependent), granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages, dendritic cells, mast cells. Lymphoid lineage (CLP): T-cells (thymus), B-cells (bone marrow), NK cells, dendritic cells. Growth factors: EPO (kidney peritubular cells, stimulated by HIF in hypoxia), TPO (liver), G-CSF, GM-CSF, M-CSF, SCF, interleukins (IL-3, IL-5, IL-7, IL-11). Bone marrow niche: stromal cells, osteoblasts, endothelial cells, adipocytes. Fetal: yolk sac → liver → bone marrow. At birth, red marrow throughout bones; with age, fatty marrow in long bones; extramedullary hematopoiesis (liver, spleen) in severe anemia or marrow infiltration. The marrow produces ~2.5 billion RBCs, ~2.5 billion platelets, and ~1 billion neutrophils per kg per day.

RBCs are anucleate biconcave disks (~7.5 μm) with ~270 million Hb molecules each. Lifespan ~120 days; senescent RBCs removed by splenic macrophages (extravascular hemolysis). EPO is the primary regulator of erythropoiesis; produced in response to tissue hypoxia (HIF-1α stabilization). Reticulocyte count normally ~1%; increases in hemolysis or blood loss. Anemia: microcytic (Fe deficiency: low ferritin, high TIBC; thalassemia: microcytosis out of proportion; ACD: high ferritin, low TIBC), normocytic (ACD, hemolytic, acute blood loss, CKD, marrow failure), macrocytic (B12 deficiency: neurologic + anemia; folate: anemia only; MDS; alcohol; hypothyroidism). Hemolysis: intravascular (G6PD, MAHA, transfusion reaction, PNH) → free Hb, hemoglobinuria, decreased haptoglobin; extravascular (spherocytosis, AIHA, SCD) → splenic sequestration, increased indirect bilirubin, LDH. 2,3-BPG from Rapoport-Luebering shunt regulates Hb O₂ affinity; increases in hypoxia, anemia, high altitude. HbA (α₂β₂, adult), HbA₂ (α₂δ₂, 2–3%), HbF (α₂γ₂, fetal, <1% in adults, higher in hereditary persistence and some hemoglobinopathies).

Primary hemostasis: endothelial injury → vWF (from Weibel-Palade bodies) binds exposed collagen → platelet adhesion (GP1b-vWF), activation (shape change, granule release: ADP, TXA2, serotonin), aggregation (GPIIb/IIIa-fibrinogen bridging). Secondary hemostasis (coagulation cascade): extrinsic pathway (tissue factor + FVIIa → FX activation) and intrinsic pathway (FXII → FXI → FIX → FVIIIa) converge at common pathway (FXa + FVa → prothrombin → thrombin → fibrinogen → fibrin). Thrombin also activates FV, FVIII, FXI, FXIII, platelets. FXIII cross-links fibrin. PT: tests extrinsic + common (VII, X, V, II, fibrinogen). PTT: tests intrinsic + common (XII, XI, IX, VIII, X, V, II, fibrinogen). Natural anticoagulants: antithrombin III (inhibits thrombin, FXa, FIXa; enhanced by heparin), protein C (activated by thrombin-thrombomodulin, inactivates FVa, FVIIIa), protein S (cofactor), TFPI (inhibits TF-FVIIa-FXa). Fibrinolysis: tPA/urokinase → plasminogen → plasmin → fibrin degradation; D-dimer specific for cross-linked fibrin. VWD: quantitative/qualitative VWF deficiency (most common inherited bleeding disorder). Hemophilia A (FVIII deficiency, X-linked) and B (FIX deficiency). DIC: systemic coagulation activation with factor consumption. TTP: ADAMTS13 deficiency → uncleaved VWF multimers → microthrombi (MAHA + thrombocytopenia).

Innate immunity (rapid, non-specific): barriers (skin, mucosa), humoral (complement, defensins, collectins), cellular (neutrophils, macrophages, NK cells, dendritic cells, mast cells, eosinophils, basophils). PRRs (TLRs, NLRs, RLRs, CLRs) recognize PAMPs and DAMPs. TLR4 recognizes LPS. NLRP3 inflammasome → IL-1β, IL-18. NK cells kill infected/tumor cells via perforin/granzyme and ADCC (CD16). Adaptive immunity (slow, specific, memory): T-cells mature in thymus; B-cells in bone marrow. CD4+ helper T-cells: Th1 (IFN-γ, macrophages), Th2 (IL-4, IL-5, B-cells/eosinophils), Th17 (IL-17, neutrophils), Treg (TGF-β, IL-10, suppression), Tfh (B-cell help). CD8+ cytotoxic T-cells kill via perforin/granzyme, FasL. MHC I (all nucleated cells, endogenous Ag → CD8). MHC II (APCs: DC, macrophages, B-cells, exogenous Ag → CD4). B-cells: BCR (surface Ig), with T-cell help undergo class switching, affinity maturation, differentiation to plasma cells (Ig-secreting) and memory B-cells. Antibodies: IgG (most abundant, opsonization, ADCC, placental transfer, neutralization), IgM (primary response, complement), IgA (mucosal, dimer), IgE (mast cell sensitization, parasite defense, allergy), IgD (BCR).

Complement cascade converges at C3. Classical pathway: IgG/IgM immune complexes → C1q → C1r → C1s → C4 + C2 → C3 convertase (C4b2a). Lectin pathway: MBL/ficolins bind microbial carbohydrates → MASP-1/MASP-2 → same C3 convertase. Alternative pathway: spontaneous C3 hydrolysis (C3(H2O)) + factor B + factor D → C3 convertase (C3bBb); properdin stabilizes. C3 convertase → C3a (anaphylatoxin, chemotaxis) + C3b (opsonin). C5 convertase (C4b2a3b or C3bBb3b) → C5a (potent anaphylatoxin) + C5b → MAC (C5b-9, pore-forming lysis). Regulation: C1-INH (C1 inhibitor), DAF (CD55), MCP (CD46), factor H, factor I, CD59 (protectin). Deficiencies: C1-INH → hereditary angioedema; MAC → recurrent Neisseria; C3 → severe infections.

Iron deficiency: microcytic, low ferritin, high TIBC, responsive to oral Fe. ACD: normocytic, high ferritin, low TIBC (hepcidin-mediated). B12 deficiency: macrocytic, neurologic (subacute combined degeneration, dorsal column + corticospinal tract), elevated MMA and homocysteine. Hemolytic: reticulocytosis, LDH, indirect bilirubin, decreased haptoglobin. DAT+ = AIHA (warm: IgG, cold: IgM). SCD: HbS polymerization, vaso-occlusive crises, acute chest syndrome, stroke; HU, transfusion, crizanlizumab. Hemophilia: factor VIII/IX concentrates; emicizumab (bispecific Ab) for hemophilia A. VWD: DDAVP (type 1), VWF concentrates (type 2/3). DIC: treat cause; platelets, cryo, FFP. TTP: ADAMTS13 <10%, PLEX + steroids + rituximab; avoid platelets. HIT: platelets 5–10 days after heparin, stop heparin, direct thrombin inhibitor. CVID: low IgG, recurrent sinopulmonary infections, IVIG. SCID: infant, severe infections, HSCT. CGD: NADPH oxidase defect, catalase+ infections (S. aureus, Serratia, Aspergillus), TMP-SMX ppx, IFN-γ, HSCT. HIV: CD4 depletion → AIDS; ART (INSTI + 2 NRTIs); U=U; OI prophylaxis per CD4.

Exercise challenges multiple homeostatic systems. VO₂ max is the gold standard of cardiorespiratory fitness (normally 30–50 mL/kg/min; elite athletes >80 mL/kg/min). During exercise, CO increases 4–5× (from ~5 to 20–25 L/min) via increased HR (2–3×) and SV (1.5×). O₂ extraction increases from ~25% to ~75% (wider a−vO₂ difference). Cardiovascular response: parasympathetic withdrawal + sympathetic activation → ↑HR, ↑contractility, ↑venoconstriction (preload), vasodilation in exercising muscle (functional sympatholysis, local metabolites dominate). Regional redistribution: muscle blood flow increases 10–20×; splanchnic, renal, skin flow decrease. Fick principle: VO₂ = CO × (CaO₂ − CvO₂). Anaerobic threshold: exercise intensity where lactate production exceeds clearance (metabolic acidosis). Oxygen debt (EPOC): repays O₂ deficit, clears lactate (Cori cycle), restores CrP and ATP, replenishes myoglobin O₂. Lactate half-life ~15–20 min with active recovery. Cardiac drift: HR increases during constant-load exercise due to decreased SV from dehydration and increased skin blood flow. Sex differences: females have lower VO₂ max (lower Hb, blood volume, higher body fat).

Core body temperature regulated at ~37°C ±0.5°C by the preoptic anterior hypothalamus (POAH). Heat-sensitive neurons initiate heat loss (vasodilation, sweating); cold-sensitive neurons initiate heat conservation (vasoconstriction, shivering, nonshivering thermogenesis). Heat loss: radiation (60% at rest), conduction (<3%), convection (~15%), evaporation (~22% at rest, primary during exercise). Sweat glands (2–4 million, eccrine, cholinergic sympathetic); sweat up to 1–2 L/h (10–12 L/day with acclimatization). Sweat is hypotonic (Na+ 20–80 mEq/L). Heat acclimatization: increased sweat rate, decreased Na+ loss (aldosterone), expanded plasma volume, increased skin blood flow at lower temperature. Nonshivering thermogenesis: BAT/UCP1 (neonates, small mammals; limited in adults). Shivering: 3–5× metabolic rate increase. Thermoneutral zone: ~28°C for nude subjects. Fever: elevated set point from pyrogens → PGE₂ → POAH (antipyretics block COX-2). Hyperthermia: uncontrolled temperature rise exceeding set point (heat stroke).

At altitude >2500 m, hypobaric hypoxia occurs (inspired PO₂ at 4000 m ~85 mmHg vs 150 mmHg sea level). Acute responses: ↑ventilation (hypoxic ventilatory response via carotid body, → respiratory alkalosis), ↑HR and CO (sympathetic), ↑2,3-BPG (right-shift O₂ curve), ↑Hb (hemoconcentration then EPO). Chronic acclimatization: ↑ventilation (renal compensation of alkalosis), ↑Hb (up to 18–20 g/dL), ↑capillary density, ↑oxidative enzymes, ↑mitochondrial density. AMS: headache, nausea, fatigue, dizziness at >2500 m; prevention: graded ascent, acetazolamide (stimulates ventilation). HACE: AMS + ataxia, papilledema, AMS → descent, dexamethasone, O₂. HAPE: non-cardiogenic pulmonary edema (exaggerated HPV, uneven V/Q) → descent, O₂, nifedipine. Chronic mountain sickness: excessive polycythemia (Hb >21), pulmonary HTN, right HF; phlebotomy, descent. Native adaptations: Tibetans (higher ventilation, lower Hb, higher NO), Andeans (higher Hb, stronger HPV).

Ambient pressure increases by 1 atm per 10 m seawater. Boyle's law (P×V = constant): descent compresses gas-filled spaces (sinuses, middle ear, lungs); ascent expands them. Barotrauma: middle ear squeeze (descent), sinus squeeze, pulmonary barotrauma (ascent with breath-holding → pneumothorax, arterial gas embolism [AGE]). Decompression sickness (DCS, \"the bends\"): N₂ supersaturation in tissues during rapid ascent → N₂ bubble formation in joints, CNS, skin, lungs. Type I: joint pain, skin rash. Type II: CNS (spinal cord, brain), pulmonary (chokes), vestibular. Treatment: 100% O₂, recompression in hyperbaric chamber (US Navy treatment tables). Prevention: no-fly after diving (12–24h depending on dive profile), controlled ascent, decompression stops. Henry's law: gas solubility in tissue proportional to partial pressure. N₂ narcosis (rapture of the deep): inert gas effect on CNS at depth >30 m; reversible with ascent. O₂ toxicity: CNS (convulsions at >1.6 ATA, limiting PO₂ in diving and hyperbaric O₂ therapy) and pulmonary (tracheobronchitis, ARDS with prolonged exposure).

Circadian rhythms are endogenous ~24h cycles generated by the SCN (suprachiasmatic nucleus). Entrained by light via melanopsin-containing retinal ganglion cells (intrinsically photosensitive RGCs) projecting through the retinohypothalamic tract. The SCN signals the pineal gland to secrete melatonin (~10× higher at night). Clock genes: CLOCK, BMAL1, PER, CRY form transcription-translation feedback loops. Circadian variation: cortisol peak ~8 AM, growth hormone during slow-wave sleep, core temperature lowest ~4 AM, highest ~4–6 PM. Shift work disorder: misalignment between internal clock and sleep-wake schedule; increased CV risk, metabolic syndrome, cancer risk. Jet lag: transient desynchrony after crossing time zones; managed with timed light exposure, melatonin. Sleep disorders: insomnia (difficulty initiating/maintaining sleep), sleep apnea (OSA, central), narcolepsy (hypocretin/Orexin deficiency → excessive daytime sleepiness, cataplexy), restless legs syndrome (dopamine dysfunction, iron deficiency). Heat stroke: core temp >40°C, CNS dysfunction, anhidrosis (classic) or continued sweating (exertional); treatment: rapid cooling (evaporative, ice packs, cold IV fluids). Hypothermia: core temp <35°C; mild (32–35): shivering, confusion; moderate (28–32): no shivering, AMS, bradycardia; severe (<28): hypotension, ventricular fibrillation, asystole; treatment: passive/active rewarming, warm IV fluids, ECMO for severe.