Medical Physiology

• 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) x ln([X]out/[X]in).
• At 37 degrees C, this simplifies to E = 61/z x 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)
• (3) rapid ejection (aortic valve opens, LV pressure rises briefly then falls)
• (4) reduced ejection
• (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 x 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 x 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 x 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 x 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 = 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. 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 x 0. 003 mL O₂/dL/mmHg, ~2%) and bound to hemoglobin (Hb x 1. 34 x SaO₂, ~98%).
• Total O₂ content = (Hb x 1. 34 x SaO₂) + (PaO₂ x 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 x 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 x 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 x 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 x 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): 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 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 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 500); intrinsic ATN (FeNa > 2%, muddy brown casts); AIN (WBC casts, eosinophiluria); GN (RBC casts).
• Post-renal (hydronephrosis).
• CKD: eGFR = 3 months; complications: hyperkalemia, acidosis, anemia, renal osteodystrophy, uremia. RRT indications: AEIOU (Acidosis pH 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 x, 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 x 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 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 x (from ~5 to 20 - 25 L/min) via increased HR (2 - 3 x) and SV (1. 5 x).
• 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 x; splanchnic, renal, skin flow decrease. Fick principle: VO₂ = CO x (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 degrees C +/- 0. 5 degrees 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 ( 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 x 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 x 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 degrees C, CNS dysfunction, anhidrosis (classic) or continued sweating (exertional); treatment: rapid cooling (evaporative, ice packs, cold IV fluids).
• Hypothermia: core temp < 35 degrees 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.