Physiology

01 Overview & Scope of Physiology

Physiology is the study of how living organisms function — from the molecular events within a single ion channel to the integrated responses of the whole body during exercise, hemorrhage, or disease. It bridges the gap between the structural knowledge of anatomy and histology and the clinical reasoning required at the bedside. Understanding normal physiology is the prerequisite for understanding pathophysiology, pharmacology, and every clinical specialty.

Levels of Organization

Physiology operates at every scale: molecular (ion channels, enzyme kinetics, receptor-ligand interactions), cellular (membrane transport, signal transduction, gene expression), tissue/organ (cardiac contractility, renal filtration, neural circuits), and systems (cardiovascular regulation of blood pressure, respiratory gas exchange, endocrine feedback loops). Integration across these levels produces homeostasis — the maintenance of a stable internal environment despite constant external perturbation.

Core Disciplines Within Physiology

02 Cell Physiology & Membrane Transport

All physiologic processes begin at the cell membrane — a 7-8 nm phospholipid bilayer that separates the intracellular from the extracellular environment and controls the selective passage of ions, nutrients, and signaling molecules.

Membrane Transport Mechanisms

The Na⁺/K⁺-ATPase

The single most important membrane pump in human physiology. It transports 3 Na⁺ out and 2 K⁺ in per ATP hydrolyzed, maintaining the electrochemical gradients that drive secondary active transport, set the resting membrane potential, and regulate cell volume. It consumes approximately 30% of total body ATP at rest. It is inhibited by cardiac glycosides (digoxin, ouabain) — this increases intracellular Na⁺, which in turn reduces Ca²⁺ extrusion via the Na⁺/Ca²⁺ exchanger, increasing intracellular Ca²⁺ and enhancing cardiac contractility (the basis of digoxin's inotropic effect).

Signal Transduction Fundamentals

Cell signaling follows a general paradigm: ligand binds receptor → intracellular signal cascade → cellular response. Receptors fall into four major categories: (1) Ion channel-linked (ligand-gated ion channels — nicotinic ACh receptor, GABA-A, NMDA): fastest response, milliseconds. (2) G-protein-coupled receptors (GPCRs): the largest family (~800 in the human genome), including adrenergic, muscarinic, opioid, and most hormone receptors; response in seconds to minutes via cAMP, IP3/DAG, or ion channel modulation. (3) Enzyme-linked receptors (receptor tyrosine kinases — insulin receptor, growth factor receptors): response in minutes to hours via phosphorylation cascades (RAS-MAP kinase, PI3K-Akt). (4) Intracellular/nuclear receptors (steroid hormones, thyroid hormones, vitamin D, retinoids): slowest response, hours to days, via direct gene transcription regulation.

G-Protein Signaling Pathways

Resting Membrane Potential

The resting membrane potential of most cells is approximately -70 to -90 mV (inside negative relative to outside). It is determined primarily by the K⁺ equilibrium potential (E_K approximately -90 mV) because the resting membrane is most permeable to K⁺ through leak channels. The Nernst equation calculates the equilibrium potential for a single ion:

The Goldman-Hodgkin-Katz (GHK) equation accounts for multiple ion permeabilities simultaneously and more accurately predicts the actual resting potential, which lies between E_K and E_Na, closer to E_K because K⁺ permeability dominates at rest. During an action potential, Na⁺ permeability transiently dominates, driving the membrane toward E_Na (+61 mV).

Ion Composition: Intracellular vs Extracellular

03 Homeostasis & Feedback Systems

Homeostasis — the maintenance of a stable internal environment — is the central organizing principle of physiology. The body continuously monitors variables (temperature, pH, osmolality, blood glucose, blood pressure) and activates corrective responses through feedback loops.

Negative Feedback

The dominant regulatory mechanism in physiology. A change in a variable triggers a response that opposes the change and returns the variable toward its set point. Examples include: thermoregulation (increased body temperature triggers sweating and vasodilation to reduce temperature); blood glucose regulation (hyperglycemia stimulates insulin secretion, which lowers glucose); blood pressure regulation (baroreceptors detect elevated BP and increase vagal tone to lower heart rate and BP); thyroid axis (elevated T3/T4 suppresses TSH release from the anterior pituitary).

Positive Feedback

A change in a variable triggers a response that amplifies the change. These are inherently unstable and drive the system to completion. Physiologic examples: oxytocin during labor (uterine contractions stimulate oxytocin release, which causes stronger contractions until delivery); the LH surge in ovulation (rising estrogen triggers a positive feedback surge of LH that causes follicular rupture); the upstroke of the action potential (Na⁺ influx depolarizes the membrane, opening more Na⁺ channels); blood clotting cascade (thrombin activates more prothrombin in an amplifying cascade).

Feed-Forward Control

Anticipatory regulation that activates responses before the change occurs. The cephalic phase of gastric secretion (seeing or smelling food triggers vagal stimulation of acid and enzyme release before food reaches the stomach) and pre-exercise tachycardia (sympathetic activation increases heart rate before exercise begins) are classic examples.

Normal Physiologic Set Points

04 Cardiac Electrophysiology

The heart is a self-excitable organ. Specialized pacemaker cells generate spontaneous depolarizations that propagate through a precisely organized conduction system, ensuring coordinated atrial and ventricular contraction roughly 100,000 times per day. Understanding cardiac electrophysiology is essential for interpreting ECGs, managing arrhythmias, and understanding the mechanisms of antiarrhythmic drugs.

Electrical Properties of the Heart

The heart possesses five key electrical properties: Automaticity (ability to spontaneously depolarize — SA node, AV node, Purkinje fibers), Rhythmicity (regularity of depolarization), Conductivity (ability to propagate impulses cell-to-cell via gap junctions in intercalated discs), Excitability (ability to respond to a stimulus), and Contractility (ability to generate force). The hierarchy of pacemakers ensures a backup if the SA node fails: SA node (60-100 bpm) → AV node (40-60 bpm) → ventricular/Purkinje (20-40 bpm). If the SA node fails, the AV node takes over (junctional rhythm); if both fail, the ventricles generate an escape rhythm at 20-40 bpm — often insufficient to maintain adequate cardiac output.

The Conduction System

The SA node (right atrium, near the SVC junction) is the primary pacemaker with an intrinsic rate of 60-100 bpm. Impulses travel through atrial myocardium (internodal pathways) to the AV node (right atrial septum, near the coronary sinus) — the only normal electrical connection between atria and ventricles, with intrinsic rate 40-60 bpm. The AV node introduces a critical 0.1-second delay that allows atrial contraction to complete before ventricular systole begins (the "atrial kick"). From the AV node, the signal passes through the Bundle of His → right and left bundle branches → Purkinje fibers (intrinsic rate 20-40 bpm), which rapidly depolarize the ventricular myocardium from endocardium to epicardium.

Action Potentials

Clinical Correlations — Electrophysiology

Class I antiarrhythmics (Na⁺ channel blockers): slow phase 0 in ventricular myocytes. Class III antiarrhythmics (K⁺ channel blockers, e.g., amiodarone, sotalol): prolong phase 3, prolonging QT interval. Class IV (Ca²⁺ channel blockers, e.g., verapamil, diltiazem): slow phase 0 in pacemaker cells, useful for SVT and rate control of atrial fibrillation. Ivabradine: selectively blocks I_f current, reducing SA node firing rate without affecting contractility — used in heart failure with elevated resting heart rate.

Hyperkalemia reduces the K⁺ gradient, partially depolarizing the resting membrane potential. This initially increases excitability (peaked T waves) but progressively inactivates Na⁺ channels, slowing conduction (widened QRS) and eventually causing sine wave pattern and cardiac arrest. Calcium gluconate stabilizes the membrane; insulin/glucose and beta-agonists shift K⁺ intracellularly.

ECG Correlations to Cardiac Electrophysiology

05 The Cardiac Cycle & Pressure-Volume Loops

Phases of the Cardiac Cycle

Heart Sounds

S1: closure of mitral and tricuspid valves (beginning of systole). S2: closure of aortic and pulmonic valves (beginning of diastole). Physiologic splitting of S2: inspiration increases venous return to the right heart, delaying pulmonic valve closure — A2 then P2 heard during inspiration. Fixed splitting: ASD (constant left-to-right shunt equalizes inspiratory/expiratory volumes). Paradoxical splitting: LBBB or aortic stenosis delays aortic valve closure — P2 then A2, splitting on expiration.

Pressure-Volume (PV) Loops

The PV loop is the most powerful tool for understanding cardiac mechanics. The loop plots LV pressure (y-axis) against LV volume (x-axis) over one cardiac cycle, proceeding counterclockwise. The area within the loop represents stroke work.

PV Loop Changes in Disease

06 Cardiac Output & Hemodynamics

Cardiac Output (CO)

CO = HR x SV (normal ~5 L/min at rest). Stroke volume is determined by three factors: preload (EDV, governed by venous return — Frank-Starling law), afterload (wall stress during ejection, approximated by SVR or aortic pressure), and contractility (intrinsic myocardial force generation independent of loading conditions).

Frank-Starling Law

Within physiologic limits, an increase in venous return (preload, EDV) causes increased sarcomere stretch, which increases the force of contraction and stroke volume. This allows the heart to match its output to venous return beat by beat. The curve shifts up and left with increased contractility (catecholamines, digoxin) and down and right with decreased contractility (heart failure, beta-blockers, acidosis). In severe heart failure, the heart operates on the flat portion of the Starling curve — additional fluid loading does not increase CO but does increase pulmonary congestion.

Mean Arterial Pressure (MAP)

MAP = CO x SVR (the hemodynamic equation). Also approximated as: MAP = DBP + 1/3(SBP - DBP). MAP is the primary determinant of organ perfusion; a MAP below 60-65 mmHg is generally considered inadequate for organ perfusion. MAP is regulated acutely by the baroreceptor reflex and chronically by the RAAS and renal fluid balance.

Ejection Fraction & Cardiac Performance

Ejection fraction (EF) = (SV / EDV) x 100. Normal EF is 55-70%. EF is the most commonly used clinical measure of systolic function. HFrEF (heart failure with reduced ejection fraction, EF < 40%): the ventricle dilates and cannot generate adequate force — systolic failure. HFpEF (heart failure with preserved ejection fraction, EF > 50%): the ventricle is stiff and cannot fill adequately — diastolic failure. EF is load-dependent: it increases with afterload reduction and decreases with mitral regurgitation correction (because the low-resistance "pop-off" into the LA is eliminated). For this reason, EF in MR overestimates true contractile function.

Myocardial Oxygen Demand & Supply

The heart extracts ~70-75% of delivered O₂ at rest (highest of any organ) — there is minimal extraction reserve. Therefore, increased myocardial O₂ demand can only be met by increasing coronary blood flow. Determinants of myocardial O₂ demand: heart rate (most important — tachycardia doubles demand), wall stress (= [pressure x radius] / [2 x wall thickness] — LaPlace law), and contractility. Coronary blood flow occurs predominantly during diastole (the myocardium compresses intramural coronary vessels during systole). This is why tachycardia is particularly harmful — it increases O₂ demand while reducing diastolic filling time and thus coronary perfusion. Beta-blockers reduce both heart rate and contractility, decreasing O₂ demand and increasing diastolic perfusion time — the physiologic basis for their use in angina and acute MI.

Hemodynamic Profiles

Valvular Heart Disease — Hemodynamic Consequences

07 Vascular Physiology & Blood Pressure Regulation

Vascular Structure & Function

Arteries are high-pressure, elastic vessels that dampen pulsatile flow into steady flow (Windkessel effect). Arterioles are the principal resistance vessels and the major site of blood pressure regulation — small changes in arteriolar radius cause large changes in resistance (Poiseuille's law: resistance is proportional to 1/r⁴). Capillaries are thin-walled exchange vessels with the largest total cross-sectional area and lowest flow velocity (optimizing diffusion time). Veins are high-capacitance vessels that contain approximately 60-70% of total blood volume and serve as a blood reservoir. Venoconstriction (sympathetic alpha-1) increases venous return and preload.

Starling Forces — Capillary Fluid Exchange

Edema Formation — Clinical Application of Starling Forces

Endothelial Function & Vasoactive Mediators

Blood Pressure Regulation

Autoregulation in Key Vascular Beds

Certain organs maintain constant blood flow over a range of perfusion pressures through intrinsic autoregulatory mechanisms:

Acute regulation (seconds-minutes): The baroreceptor reflex uses stretch-sensitive receptors in the carotid sinus (CN IX, glossopharyngeal) and aortic arch (CN X, vagus) to detect changes in MAP. A rise in MAP increases baroreceptor firing, which increases parasympathetic output and decreases sympathetic output — reducing heart rate, contractility, and SVR. A fall in MAP does the opposite. Baroreceptors reset over 1-2 days in chronic hypertension — explaining why rapid lowering of chronically elevated BP can cause syncope.

Intermediate regulation (minutes-hours): The renin-angiotensin system responds to decreased renal perfusion pressure, decreased NaCl delivery to the macula densa, and increased sympathetic stimulation. Angiotensin II is a potent vasoconstrictor that also stimulates aldosterone release and ADH secretion. Atrial natriuretic peptide (ANP) is released from atrial cardiomyocytes in response to stretch, promoting natriuresis and vasodilation.

Chronic regulation (hours-days): The kidneys control blood volume through sodium and water excretion. The pressure-natriuresis mechanism ensures that increased arterial pressure leads to increased Na⁺ and water excretion, reducing blood volume and returning MAP to normal. This is the ultimate long-term regulator of blood pressure.

Venous Return & Central Venous Pressure

Venous return is driven by the pressure gradient between the mean systemic filling pressure (MSFP, ~7 mmHg — the pressure in the venous system when the heart is stopped) and the right atrial pressure (RAP, ~0-4 mmHg). Venous return = (MSFP - RAP) / venous resistance. Factors that increase venous return: increased blood volume (increases MSFP), venoconstriction (increases MSFP), decreased RAP, muscular compression of veins (muscle pump), negative intrathoracic pressure during inspiration (respiratory pump). The Guyton venous return curve plotted with the Frank-Starling curve demonstrates the equilibrium point of the cardiovascular system: the intersection of the two curves determines the operating CO and RAP. Volume loading shifts the venous return curve right (increased MSFP); heart failure shifts the Starling curve down; positive inotropes shift the Starling curve up.

Microcirculation & Exchange

The capillary bed has the largest total cross-sectional area (~5000 cm²) and the slowest velocity (~0.03 cm/s) of any vascular segment — optimizing time for diffusion. Exchange occurs by three mechanisms: (1) diffusion (the most important — small lipophilic molecules cross freely; small hydrophilic molecules cross through intercellular clefts and fenestrations), (2) bulk flow/filtration (governed by Starling forces), and (3) transcytosis (vesicular transport of large proteins, particularly in the brain — contributing to the blood-brain barrier). Continuous capillaries (most tissues, tight junctions) are the least permeable; fenestrated capillaries (kidney, intestine, endocrine glands) have pores allowing small molecules; sinusoidal capillaries (liver, spleen, bone marrow) have large gaps allowing proteins and even cells to pass.

08 Pulmonary Mechanics & Ventilation

Lung Volumes & Capacities

Compliance & Surfactant

Compliance = change in volume / change in pressure (mL/cmH₂O). High compliance = easily distensible (emphysema — loss of elastic recoil from alveolar wall destruction). Low compliance = stiff lung (fibrosis, ARDS, pulmonary edema). Surfactant is produced by type II pneumocytes beginning at ~24-28 weeks gestation. It reduces alveolar surface tension, prevents alveolar collapse at end-expiration, and increases compliance. By the Law of Laplace (P = 2T/r), smaller alveoli would have higher collapsing pressure and empty into larger alveoli — surfactant prevents this by reducing surface tension more in smaller alveoli (higher concentration at lower volumes).

Surfactant deficiency causes neonatal respiratory distress syndrome (NRDS) in premature infants. Treatment: exogenous surfactant replacement. Prevention: antenatal corticosteroids (betamethasone) to accelerate surfactant production. The lecithin/sphingomyelin (L/S) ratio in amniotic fluid predicts fetal lung maturity: L/S > 2.0 indicates mature surfactant production; L/S < 1.5 indicates high risk of NRDS.

Pulmonary Pressures & Vascular Physiology

The pulmonary circulation is a low-pressure, low-resistance system. Normal pulmonary arterial pressure is ~25/10 mmHg (mean ~15 mmHg), compared to systemic arterial ~120/80 mmHg (mean ~93 mmHg). Despite receiving the entire cardiac output, the pulmonary circulation operates at ~1/6 the pressure of the systemic circulation because of its low resistance (thin-walled, highly distensible vessels). When pulmonary blood flow increases (e.g., exercise), resistance falls further through recruitment (opening of previously closed capillaries) and distension (widening of already-open capillaries), keeping pressure low. Pulmonary hypertension (mean PAP > 20 mmHg) develops when this compensatory capacity is overwhelmed — causes include left heart disease (most common), lung disease/hypoxia, chronic PE, and primary pulmonary arterial hypertension (PAH). Chronic PH leads to right ventricular hypertrophy and eventually right heart failure (cor pulmonale).

Airway Resistance & Work of Breathing

Resistance = (P_alveolar - P_atmospheric) / airflow. By Poiseuille's law, resistance is proportional to 1/r⁴ — halving the radius increases resistance 16-fold. The medium-sized bronchi (generations 4-8) contribute the most to total resistance, not the smallest airways (which have enormous collective cross-sectional area). Factors increasing resistance: bronchospasm, mucus, mucosal edema, airway compression (tumor, dynamic compression during forced expiration). The equal pressure point (EPP) theory explains dynamic airway compression: during forced expiration, pleural pressure exceeds intraluminal pressure at the EPP, causing airway collapse — worsened in emphysema (reduced radial traction) and the basis for pursed-lip breathing (creates back-pressure to stent airways open).

Respiratory Mechanics — Pressure Relationships

Inspiration is normally an active process (diaphragm contraction generates negative intrapleural pressure, ~-5 to -8 cmH₂O, which creates a pressure gradient for airflow into the lungs). Expiration is normally passive (elastic recoil of lungs and chest wall). Intrapleural pressure is always negative during quiet breathing (prevents lung collapse). Transpulmonary pressure = alveolar pressure - intrapleural pressure (the distending pressure of the lung; always positive — if it reaches zero, the lung collapses). In pneumothorax, air enters the pleural space → intrapleural pressure becomes atmospheric or positive → transpulmonary pressure falls to zero → lung collapses. In tension pneumothorax, a one-way valve mechanism causes progressive positive intrapleural pressure → mediastinal shift → impaired venous return → cardiovascular collapse. Immediate decompression (needle thoracostomy, 2nd intercostal space, midclavicular line) is life-saving.

Oxygen Cascade — From Atmosphere to Mitochondria

Dead Space & Alveolar Ventilation

Anatomic dead space (~150 mL): conducting airways where no gas exchange occurs. Alveolar dead space: ventilated alveoli with no perfusion (V/Q = infinity). Physiologic dead space = anatomic + alveolar dead space. Alveolar ventilation (V_A) = RR x (TV - dead space). Example: RR 12, TV 500 mL: V_A = 12 x (500 - 150) = 4200 mL/min. Rapid shallow breathing (e.g., RR 20, TV 250 mL) yields: V_A = 20 x (250 - 150) = 2000 mL/min — worse alveolar ventilation despite the same minute ventilation (5000 mL/min), explaining the importance of tidal volume in effective ventilation.

09 Gas Exchange & V/Q Matching

The Alveolar Gas Equation

Causes of Hypoxemia

V/Q Matching & Zones of the Lung

The normal overall V/Q ratio is ~0.8. In the upright lung, gravity creates a gradient: the apex has high V/Q (~3.3, relatively over-ventilated, under-perfused) while the base has low V/Q (~0.6, relatively over-perfused). The West zones describe pulmonary blood flow based on the relationship between P_A (alveolar), P_a (arterial), and P_v (venous):

10 Oxygen & CO₂ Transport

Oxygen Transport

Total O₂ content of blood (CaO₂) = (1.34 x Hb x SaO₂) + (0.003 x PaO₂). At normal values: (1.34 x 15 x 0.98) + (0.003 x 100) = 19.7 + 0.3 = 20 mL O₂/dL. Dissolved O₂ contributes only ~1.5% — virtually all O₂ is carried bound to hemoglobin. O₂ delivery (DO₂) = CO x CaO₂ x 10 = 5 x 20 x 10 = ~1000 mL/min. Normal O₂ consumption (VO₂) ~250 mL/min, so the extraction ratio is ~25% — a large reserve that increases during exercise or low-output states.

The Oxyhemoglobin Dissociation Curve

The sigmoid shape reflects cooperative binding: once one O₂ molecule binds, affinity for subsequent O₂ increases (T-state to R-state transition). The P50 is the PO₂ at which Hb is 50% saturated — normally ~27 mmHg.

Chemoreceptor Control of Breathing

Central chemoreceptors (medulla): respond primarily to CSF pH (which reflects PaCO₂ — CO₂ crosses the blood-brain barrier freely and is converted to H⁺ + HCO₃^-). PaCO₂ is the strongest drive to breathe under normal conditions. A rise in PaCO₂ of just 2-3 mmHg increases ventilation by 100%. Peripheral chemoreceptors: carotid bodies (CN IX → NTS) and aortic bodies (CN X → NTS) respond to decreased PaO₂ (primarily, significant response only below ~60 mmHg), increased PaCO₂, and decreased pH. The peripheral chemoreceptors are the ONLY sensors that detect hypoxemia.

CO₂ Transport

CO₂ is transported in three forms: dissolved CO₂ (~7%), carbaminohemoglobin (~23%, bound to Hb amino groups), and bicarbonate (~70%). In the tissues: CO₂ + H₂O is converted to H₂CO₃ (via carbonic anhydrase in RBCs) then to HCO₃^- + H⁺. The HCO₃^- is exchanged for Cl^- across the RBC membrane (the chloride shift). In the lungs, this process reverses, releasing CO₂ for exhalation. The Haldane effect: deoxygenated Hb carries more CO₂ than oxygenated Hb — facilitating CO₂ loading in tissues and unloading in the lungs.

11 Glomerular Filtration & Renal Blood Flow

The kidneys receive approximately 25% of cardiac output (~1200 mL/min) despite comprising only 0.4% of body weight — reflecting their critical role in filtration, excretion, and homeostasis. Renal blood flow (RBF) is directed primarily to the cortex (90%), with only 10% to the medulla, which operates in a relatively hypoxic environment (necessary for the concentration gradient).

Glomerular Filtration Rate (GFR)

Autoregulation of Renal Blood Flow

RBF and GFR are maintained constant over a MAP range of ~80-180 mmHg through two intrinsic mechanisms: the myogenic mechanism (afferent arteriolar smooth muscle contracts in response to stretch from increased perfusion pressure) and tubuloglomerular feedback (TGF) (increased NaCl delivery to the macula densa causes afferent arteriolar constriction via adenosine, reducing GFR). These mechanisms fail below MAP ~80 mmHg, leading to decreased GFR and prerenal azotemia.

The Juxtaglomerular Apparatus

The JGA consists of three components: (1) Juxtaglomerular (JG) cells — modified smooth muscle cells in the afferent arteriole wall that synthesize, store, and release renin. They act as baroreceptors (decreased stretch → increased renin) and are innervated by sympathetic beta-1 fibers (stimulation → increased renin). (2) Macula densa — specialized epithelial cells in the TAL where it contacts the glomerulus. They sense NaCl concentration in tubular fluid via NKCC2 transport. Decreased NaCl → increased renin release (and afferent dilation via PGE2 → maintains GFR). Increased NaCl → decreased renin and afferent constriction via adenosine. (3) Extraglomerular mesangial cells (lacis cells) — function unclear, may transmit signals between macula densa and JG cells.

Regulation of GFR

Renal Clearance Concepts — Detailed

The clearance of a substance reveals its handling by the nephron relative to GFR:

The glucose transport maximum (T_m) is ~375 mg/min. At normal plasma glucose (~100 mg/dL) and GFR (125 mL/min), the filtered glucose load is ~125 mg/min — well below T_m, so all glucose is reabsorbed. When plasma glucose exceeds ~180 mg/dL, the filtered load exceeds T_m and glucose "spills" into urine (glycosuria). However, the actual threshold varies between nephrons, creating a "splay" region between ~180-350 mg/dL where some but not all nephrons are at capacity. SGLT2 inhibitors reduce the T_m, producing glycosuria at lower glucose levels.

12 Tubular Transport & Nephron Function

Proximal Convoluted Tubule (PCT)

The workhorse of the nephron — reabsorbs ~65% of filtered Na⁺, water, K⁺, HCO₃^-, glucose, amino acids, phosphate, and urea. All glucose and amino acid reabsorption occurs here via Na⁺-coupled secondary active transport (SGLT2 for glucose in the early PCT, SGLT1 in the late PCT). The PCT has a high transport maximum (T_m) for glucose (~375 mg/min); when plasma glucose exceeds ~180 mg/dL (renal threshold), glucose appears in the urine (glycosuria). SGLT2 inhibitors (empagliflozin, dapagliflozin) lower the T_m, causing glycosuria at lower glucose levels — the basis for their use in diabetes and heart failure.

Bicarbonate reabsorption in the PCT is mediated by carbonic anhydrase (luminal CA IV and intracellular CA II). The Na⁺/H⁺ exchanger (NHE3) on the luminal membrane secretes H⁺, which combines with filtered HCO₃^- to form CO₂ + H₂O (via CA IV). CO₂ diffuses into the cell, where CA II regenerates HCO₃^-, which exits basolaterally. Acetazolamide inhibits CA, causing bicarbonaturia and metabolic acidosis — used for altitude sickness and idiopathic intracranial hypertension.

Loop of Henle

The thin descending limb is permeable to water but not NaCl (concentrates tubular fluid as it descends into the hyperosmolar medulla). The thick ascending limb (TAL) is impermeable to water but actively reabsorbs ~25% of filtered NaCl via the Na⁺/K⁺/2Cl^- cotransporter (NKCC2). This is the target of loop diuretics (furosemide, bumetanide). The TAL is the "diluting segment" — it makes the tubular fluid hypotonic while making the medullary interstitium hypertonic. The TAL also reabsorbs Mg²⁺ and Ca²⁺ paracellularly, driven by the lumen-positive voltage created by K⁺ recycling through ROMK channels. Loop diuretics abolish this voltage, causing renal Ca²⁺ and Mg²⁺ wasting.

Distal Convoluted Tubule (DCT)

Reabsorbs ~5% of filtered NaCl via the Na⁺/Cl^- cotransporter (NCC) — target of thiazide diuretics. The DCT is also a site of active Ca²⁺ reabsorption (stimulated by PTH and enhanced by thiazides — hence thiazides reduce urinary Ca²⁺ and are used for recurrent calcium nephrolithiasis).

Collecting Duct

Principal cells: respond to aldosterone (increases ENaC Na⁺ channels and ROMK K⁺ channels → Na⁺ reabsorption and K⁺ secretion) and ADH (inserts AQP-2 water channels → water reabsorption). Intercalated cells: Type A secrete H⁺ (acid excretion) and reabsorb HCO₃^-; Type B secrete HCO₃^- and reabsorb H⁺. K⁺-sparing diuretics act here: spironolactone/eplerenone block mineralocorticoid receptor; amiloride/triamterene directly block ENaC.

Nephron Segment Summary

13 Water Balance, ADH & Concentration Mechanisms

Antidiuretic Hormone (ADH / Vasopressin)

ADH is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus, stored in and released from the posterior pituitary. The primary stimulus for ADH release is increased plasma osmolality (detected by osmoreceptors in the hypothalamus; threshold ~280 mOsm/kg). Secondary stimuli include decreased blood volume/pressure (detected by baroreceptors — a less sensitive but more powerful stimulus), pain, nausea, and stress. ADH acts on V2 receptors in the collecting duct, inserting AQP-2 water channels via cAMP-mediated exocytosis, allowing water reabsorption and urine concentration. ADH also acts on V1 receptors on vascular smooth muscle, causing vasoconstriction (hence "vasopressin").

The Countercurrent Multiplier & Exchanger

The medullary osmotic gradient (300 mOsm at the cortex to 1200 mOsm at the papillary tip) is created by the countercurrent multiplier (loop of Henle) and maintained by the countercurrent exchanger (vasa recta). The TAL actively pumps NaCl into the interstitium without water (impermeability), creating a "single effect" of ~200 mOsm at each horizontal level. The countercurrent flow arrangement multiplies this effect along the axis of the medulla. Urea recycling (ADH stimulates urea transporters in the inner medullary collecting duct) contributes ~50% of the medullary osmotic gradient.

Free Water Clearance

Free water clearance (C_H2O) = V - C_osm, where C_osm = (U_osm x V) / P_osm. Positive C_H2O = dilute urine (water excretion exceeds solute clearance). Negative C_H2O (also called T_cH₂O) = concentrated urine (water is being conserved). In SIADH, C_H2O is negative (excessive water retention). In DI, C_H2O is positive (excessive water excretion).

Hyponatremia — Physiologic Framework

Hyponatremia (Na⁺ < 135 mEq/L) is the most common electrolyte disorder. The approach uses serum osmolality, volume status, and urine studies:

14 RAAS & Sodium/Potassium Homeostasis

The Renin-Angiotensin-Aldosterone System

Renin is released by juxtaglomerular (JG) cells of the afferent arteriole in response to: (1) decreased renal perfusion pressure, (2) decreased NaCl delivery to the macula densa, (3) increased sympathetic stimulation (beta-1 receptors on JG cells). Renin converts angiotensinogen (from the liver) to angiotensin I. ACE (primarily in the pulmonary vasculature) converts angiotensin I to angiotensin II (Ang II). ACE also degrades bradykinin — ACE inhibitor-induced cough is attributed to bradykinin accumulation.

Actions of Angiotensin II

Aldosterone

Released from the zona glomerulosa in response to Ang II, hyperkalemia, and ACTH. It acts on mineralocorticoid receptors in the collecting duct principal cells to increase expression of ENaC (Na⁺ reabsorption) and ROMK (K⁺ secretion). Net effect: Na⁺ retention, K⁺ excretion, H⁺ excretion (via increased lumen-negative voltage driving H⁺ secretion by intercalated cells). Hyperaldosteronism (Conn syndrome): hypertension + hypokalemia + metabolic alkalosis. Hypoaldosteronism (Addison disease, type IV RTA): hypotension + hyperkalemia + metabolic acidosis.

Potassium Homeostasis

98% of total body K⁺ is intracellular (~140 mEq/L ICF vs ~4 mEq/L ECF). This steep gradient is maintained by the Na⁺/K⁺-ATPase and is critical for the resting membrane potential, cardiac conduction, and neuromuscular function. Small changes in serum K⁺ have profound effects on cardiac electrophysiology — both hypokalemia and hyperkalemia are potentially lethal. Serum K⁺ is maintained at 3.5-5.0 mEq/L by two mechanisms: internal balance (shifts between ICF and ECF — rapid, minute-to-minute regulation) and external balance (renal excretion, ~90%; GI excretion, ~10% — slower, over hours).

Magnesium & Phosphate

Magnesium (normal 1.5-2.5 mg/dL): 60% in bone, 39% intracellular, 1% ECF. Essential for enzymatic reactions (kinase activity, DNA/RNA synthesis), neuromuscular function, and maintaining K⁺ and Ca²⁺ homeostasis. Hypomagnesemia causes refractory hypokalemia (Mg²⁺ is needed to close ROMK channels in the collecting duct — without it, K⁺ wasting continues despite supplementation) and refractory hypocalcemia (Mg²⁺ is needed for PTH secretion and action). Always check and correct Mg²⁺ when treating hypokalemia or hypocalcemia. Phosphate (normal 2.5-4.5 mg/dL): primarily intracellular, essential for ATP, 2,3-DPG, nucleic acids, bone minerite. Regulated by PTH (phosphaturic) and vitamin D (increases GI absorption). Severe hypophosphatemia (< 1 mg/dL) causes rhabdomyolysis, respiratory failure (diaphragm weakness), hemolytic anemia (decreased RBC ATP and 2,3-DPG), and cardiac dysfunction. Refeeding syndrome in malnourished patients can cause precipitous hypophosphatemia as insulin drives phosphate intracellularly.

15 Acid-Base Fundamentals & Buffer Systems

The Henderson-Hasselbalch Equation

Buffer Systems

The body uses three buffer systems to resist pH changes: (1) Bicarbonate buffer (CO₂/HCO₃^- system — the most important ECF buffer because both components are independently regulated: CO₂ by lungs, HCO₃^- by kidneys). (2) Hemoglobin buffer (the main ICF buffer in blood — deoxyhemoglobin binds H⁺ more readily than oxyhemoglobin). (3) Phosphate buffer (HPO₄^2-/H₂PO₄^- — important intracellularly and in renal tubular fluid). Proteins serve as buffers through their amino acid side chains (histidine residues are particularly effective at physiologic pH).

Respiratory Compensation

The lungs respond to metabolic acid-base disturbances within minutes to hours. In metabolic acidosis, peripheral and central chemoreceptors detect low pH, stimulating hyperventilation to lower PaCO₂ (Kussmaul breathing in DKA is a classic example). In metabolic alkalosis, hypoventilation raises PaCO₂, but this is limited by the hypoxic drive — respiratory compensation for metabolic alkalosis is less effective than for metabolic acidosis.

Renal Compensation

The kidneys respond to respiratory acid-base disturbances over 3-5 days. In respiratory acidosis (elevated PaCO₂), the kidneys increase HCO₃^- reabsorption and H⁺ excretion (via increased ammoniagenesis and titratable acid). In respiratory alkalosis (low PaCO₂), the kidneys decrease HCO₃^- reabsorption, allowing bicarbonaturia. The renal compensation is slow but powerful and can nearly normalize pH over days.

Renal Acid Excretion

The kidneys excrete approximately 70 mEq of H⁺ per day (the daily acid load from metabolism). This is accomplished through: (1) HCO₃^- reabsorption (~4320 mEq/day of filtered HCO₃^- is reclaimed, primarily in the PCT), (2) titratable acid excretion (~30 mEq/day — H⁺ buffered by phosphate in tubular fluid: HPO₄^2- + H⁺ → H₂PO₄^-), and (3) ammonium excretion (~40 mEq/day — NH₃ produced in the PCT from glutamine, combines with H⁺ to form NH₄⁺, which is trapped in the tubular lumen). Ammonium excretion is the primary adaptive response to chronic acid loads and can increase 10-fold in chronic metabolic acidosis.

Urine Anion Gap

Urine anion gap (UAG) = U_Na + U_K - U_Cl. This estimates urinary ammonium (NH₄⁺) excretion. In a normal AG metabolic acidosis: a negative UAG (Cl^- > Na⁺ + K⁺) indicates appropriate renal NH₄⁺ excretion → the acidosis is GI in origin (diarrhea). A positive UAG indicates impaired renal acid excretion → renal tubular acidosis. Remember: "nega-GI-ve" — negative UAG points to GI cause.

16 Acid-Base Disorders & Compensation

Primary Acid-Base Disorders

Anion Gap

Anion gap (AG) = Na⁺ - (Cl^- + HCO₃^-). Normal = 12 +/- 2 mEq/L (or 8-10 with modern assays). An elevated AG indicates the presence of unmeasured anions — the mnemonic MUDPILES: Methanol, Uremia, DKA, Propylene glycol, INH/Iron, Lactic acidosis, Ethylene glycol, Salicylates. A normal AG (hyperchloremic) metabolic acidosis results from HCO₃^- loss (diarrhea, RTA types 1, 2, and 4) or failure to excrete H⁺.

Delta-Delta Analysis

The delta-delta (delta ratio) compares the change in AG to the change in HCO₃^-: Delta ratio = (AG - 12) / (24 - HCO₃^-). If ratio is less than 1: concurrent non-AG metabolic acidosis (HCO₃^- fell more than expected from the AG elevation alone). If ratio is greater than 2: concurrent metabolic alkalosis (HCO₃^- did not fall as much as expected). If ratio is 1-2: pure AG metabolic acidosis.

Renal Tubular Acidosis (RTA)

Osmolar Gap

Osmolar gap = measured osmolality - calculated osmolality. Calculated osmolality = 2(Na⁺) + glucose/18 + BUN/2.8. Normal osmolar gap is less than 10 mOsm/kg. An elevated osmolar gap with an elevated anion gap metabolic acidosis strongly suggests toxic alcohol ingestion: methanol (→ formic acid, causes blindness), ethylene glycol (→ oxalic acid, causes renal failure with calcium oxalate crystals), or isopropyl alcohol (elevated osmolar gap WITHOUT acidosis — metabolized to acetone, not an acid).

17 GI Motility & Secretion

GI Motility

The GI tract has intrinsic motility generated by the interstitial cells of Cajal (ICC) — the pacemaker cells that generate slow waves (basic electrical rhythm). Slow wave frequency varies by location: stomach ~3/min, duodenum ~12/min, ileum ~8/min. Slow waves set the maximum frequency of contraction, but contraction only occurs when slow waves are depolarized above threshold by excitatory stimuli (acetylcholine, substance P). The migrating motor complex (MMC) occurs during fasting, sweeping undigested material and bacteria from the small intestine in ~90-minute cycles. It is mediated by motilin and disrupted by feeding. Erythromycin acts as a motilin agonist, promoting gastric emptying.

Gastric Acid Secretion

Parietal cells secrete HCl via the H⁺/K⁺-ATPase (proton pump) on the luminal surface. Three stimulatory pathways converge on the parietal cell: (1) Acetylcholine (vagal, via M3 receptors — blocked by atropine), (2) Histamine (from ECL cells, via H2 receptors — blocked by H2 blockers such as famotidine), (3) Gastrin (from G cells, via CCK-B receptors). PPIs (omeprazole, pantoprazole) irreversibly inhibit the H⁺/K⁺-ATPase — the most potent acid-suppressing agents.

Acid secretion is inhibited by: somatostatin (from D cells — inhibits gastrin, histamine, and acid directly), secretin (from S cells, released by acid in the duodenum), GIP, and prostaglandins (PGE2 — protective; NSAIDs block PGE2 synthesis, promoting ulceration).

Pancreatic & Biliary Secretion

Secretin (released by duodenal S cells in response to acid) stimulates pancreatic ductal cells to secrete HCO₃^--rich fluid, neutralizing gastric acid. CCK (released by duodenal I cells in response to fatty acids and amino acids) stimulates pancreatic acinar cells to secrete digestive enzymes (trypsinogen, lipase, amylase) and causes gallbladder contraction and sphincter of Oddi relaxation. Bile is produced by hepatocytes, stored and concentrated in the gallbladder, and released into the duodenum for fat emulsification. Bile salts are recycled via the enterohepatic circulation (95% reabsorbed in the terminal ileum via ASBT transporter — this is why terminal ileum resection causes bile salt malabsorption, fat malabsorption, and steatorrhea).

18 Digestion, Absorption & Hepatobiliary Function

Carbohydrate Digestion & Absorption

Salivary amylase begins starch digestion (inactivated by gastric acid). Pancreatic amylase continues digestion to oligosaccharides in the duodenum. Brush border enzymes (maltase, sucrase, isomaltase, lactase) cleave oligosaccharides and disaccharides into monosaccharides. Glucose and galactose are absorbed via SGLT1 (Na⁺-coupled active transport) on the luminal surface and exit basolaterally via GLUT2. Fructose is absorbed via GLUT5 (facilitated diffusion). Lactase deficiency is the most common disaccharidase deficiency — undigested lactose is fermented by colonic bacteria, producing gas, bloating, and osmotic diarrhea.

Protein Digestion & Absorption

Pepsin (from pepsinogen, activated by gastric acid) begins protein digestion in the stomach. Pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases) continue digestion in the duodenum. Enterokinase (brush border enzyme in the duodenum) converts trypsinogen to trypsin, which then activates all other pancreatic zymogens — the key regulatory step. Amino acids are absorbed via Na⁺-coupled transporters. Di- and tripeptides are absorbed via the PepT1 H⁺-coupled cotransporter.

Fat Digestion & Absorption

Lingual and gastric lipases begin triglyceride hydrolysis. Pancreatic lipase (with colipase) is the principal enzyme, cleaving triglycerides at the sn-1 and sn-3 positions to yield 2-monoacylglycerol and free fatty acids. These are incorporated into mixed micelles (with bile salts, cholesterol, and fat-soluble vitamins) for transport across the unstirred water layer. At the brush border, micelle components are absorbed; bile salts remain in the lumen for reabsorption in the terminal ileum. Inside enterocytes, long-chain fatty acids are re-esterified to triglycerides and packaged into chylomicrons, which enter the lymphatics (lacteals) and eventually the bloodstream via the thoracic duct. Short- and medium-chain fatty acids enter the portal blood directly.

Intestinal Fluid & Electrolyte Transport

The GI tract handles approximately 9 L of fluid daily (2 L ingested + 7 L of secretions from salivary glands, stomach, pancreas, bile, and intestine). The small intestine reabsorbs ~7.5 L, the colon ~1.3 L, leaving only ~100-200 mL in stool. Disruption of this balance causes diarrhea. Secretory diarrhea: active secretion of Cl^-/water into the lumen (cholera toxin → cAMP → CFTR Cl^- channel activation; large volume, persists during fasting, no osmotic gap). Osmotic diarrhea: unabsorbed solutes draw water into the lumen (lactose intolerance, sorbitol, magnesium-containing antacids; stops during fasting, positive osmotic gap: stool osmolality - 2[stool Na⁺ + stool K⁺] > 50 mOsm). Oral rehydration solution (ORS) exploits the Na⁺/glucose cotransporter (SGLT1) — glucose facilitates Na⁺ absorption, and water follows osmotically. This is why ORS contains both glucose and sodium and has saved millions of lives from cholera and infectious diarrhea worldwide.

Absorption Sites

Vitamin Absorption & Deficiency Syndromes

Hepatic Function

The liver performs over 500 functions including: bile synthesis, bilirubin conjugation and excretion, albumin synthesis (major determinant of plasma oncotic pressure), coagulation factor synthesis (I, II, V, VII, IX, X, XI, XII, XIII), drug metabolism (phase I: CYP450 oxidation; phase II: conjugation), ammonia metabolism (urea cycle), glycogen storage and gluconeogenesis, cholesterol and lipoprotein metabolism, and detoxification. Hepatic blood flow (~1500 mL/min) arrives via the portal vein (~75%, deoxygenated, nutrient-rich) and the hepatic artery (~25%, oxygenated).

Bilirubin Metabolism

Bilirubin is the breakdown product of heme (from senescent RBCs, ~80%). The pathway: heme → biliverdin (by heme oxygenase) → unconjugated (indirect) bilirubin (water-insoluble, albumin-bound in blood, NOT filtered by kidneys). In hepatocytes: unconjugated bilirubin is conjugated with glucuronic acid by UDP-glucuronyl transferase (UGT1A1) → conjugated (direct) bilirubin (water-soluble) → excreted into bile → intestinal bacteria convert it to urobilinogen → most excreted in stool as stercobilin (brown color); ~10-20% reabsorbed (enterohepatic circulation) → some excreted by kidney as urobilin (yellow urine color).

GI Hormones Summary

19 Neuronal Signaling & Synaptic Transmission

The Action Potential

Neurons communicate via action potentials — all-or-none electrical events that propagate along axons. At rest, the membrane is at approximately -70 mV (K⁺ leak channels dominate). When a stimulus depolarizes the membrane to threshold (~-55 mV), voltage-gated Na⁺ channels open rapidly, causing a positive feedback loop of depolarization (phase 0, rising to ~+30 mV). Na⁺ channels then inactivate (refractory period) while voltage-gated K⁺ channels open, repolarizing the membrane (phase 3). A brief hyperpolarization (undershoot) occurs as K⁺ channels close slowly. The absolute refractory period (Na⁺ channels inactivated — no AP possible regardless of stimulus) ensures unidirectional propagation. The relative refractory period (some Na⁺ channels recovered — AP possible with stronger-than-normal stimulus) allows frequency coding of stimulus intensity.

Conduction Velocity

AP propagation speed depends on axon diameter (larger = faster) and myelination. Myelinated axons conduct via saltatory conduction — APs "jump" between nodes of Ranvier, where Na⁺ channels are concentrated. This increases velocity from ~1 m/s (unmyelinated C fibers, pain) to ~120 m/s (large myelinated A-alpha fibers, proprioception). Demyelinating diseases (multiple sclerosis, Guillain-Barre) slow or block conduction, causing neurologic deficits.

Nerve Fiber Classification

Synaptic Transmission

At chemical synapses: AP arrival at the presynaptic terminal opens voltage-gated Ca²⁺ channels → Ca²⁺ influx triggers vesicle fusion (SNARE complex: synaptobrevin, SNAP-25, syntaxin) → neurotransmitter release into the synaptic cleft → binding to postsynaptic receptors. Neurotransmitter is then removed by reuptake (monoamine transporters — target of SSRIs, SNRIs, TCAs, cocaine), enzymatic degradation (AChE breaks down ACh; MAO degrades monoamines), or diffusion.

Major Neurotransmitters

Neuromuscular Junction Physiology

The NMJ is the synapse between a motor neuron and skeletal muscle. An AP arriving at the motor nerve terminal opens voltage-gated Ca²⁺ channels → Ca²⁺ influx triggers ACh vesicle release → ACh crosses the synaptic cleft and binds nicotinic ACh receptors (ligand-gated Na⁺/K⁺ channels) on the motor end plate → end-plate potential → if threshold is reached, a muscle fiber AP is generated → contraction. ACh is rapidly hydrolyzed by acetylcholinesterase (AChE) in the synaptic cleft, terminating the signal.

20 Autonomic Nervous System

Sympathetic vs Parasympathetic

Adrenergic Receptor Subtypes

21 Sensory & Motor Systems

Spinal Cord Lesion Syndromes

Sensory Pathways

Motor Pathways

The corticospinal (pyramidal) tract is the primary voluntary motor pathway. Upper motor neurons (UMN) originate in the primary motor cortex (precentral gyrus), descend through the internal capsule and cerebral peduncles, and 85-90% decussate at the pyramidal decussation in the medulla (forming the lateral corticospinal tract). They synapse on lower motor neurons (LMN) in the ventral horn of the spinal cord, which project to skeletal muscle via the ventral root.

Cerebellum

The cerebellum coordinates movement, balance, and motor learning. Lesions cause ipsilateral deficits (cerebellar hemispheres control ipsilateral limbs because of double-crossing: corticopontocerebellar pathway crosses once, cerebellothalamocortical pathway crosses back). Signs: DANISH — Dysdiadochokinesia, Ataxia, Nystagmus, Intention tremor, Scanning speech, Hypotonia. Midline (vermis) lesions cause truncal ataxia and wide-based gait; lateral (hemisphere) lesions cause limb ataxia and dysmetria.

Basal Ganglia

The basal ganglia modulate movement through two parallel pathways: the direct pathway (facilitates movement: cortex → striatum [D1 receptors, excitatory] → inhibits GPi/SNr → disinhibits thalamus → increases cortical motor output) and the indirect pathway (inhibits movement: cortex → striatum [D2 receptors, inhibitory] → less inhibition of GPe → more inhibition of STN → less excitation of GPi/SNr → more inhibition of thalamus → decreased cortical output). Dopamine from the substantia nigra pars compacta (SNc) activates the direct pathway (D1) and inhibits the indirect pathway (D2) — net effect: facilitates movement. In Parkinson disease, loss of dopaminergic neurons in the SNc leads to reduced direct pathway activity and increased indirect pathway activity → bradykinesia, rigidity, resting tremor. In Huntington disease, degeneration of striatal neurons (indirect pathway first) → excessive movement (chorea).

Special Senses — Vision

Phototransduction occurs in rods (dim light, peripheral vision, rhodopsin pigment) and cones (color vision, central vision — three types: S/blue, M/green, L/red). In the dark, retinal photoreceptors are depolarized (cGMP opens Na⁺ channels — "dark current") and continuously release glutamate. Light activates rhodopsin → transducin (G_t) → phosphodiesterase (PDE) → decreases cGMP → Na⁺ channels close → hyperpolarization → decreased glutamate release. This is a unique case where the stimulus (light) causes hyperpolarization, not depolarization. Sildenafil (Viagra) inhibits PDE5 (vascular smooth muscle) but can cross-inhibit retinal PDE6, causing blue-tinged vision (cyanopsia).

Special Senses — Hearing

Sound waves vibrate the tympanic membrane → ossicular chain (malleus, incus, stapes — amplifies pressure 20-fold by concentrating force from the large TM to the small oval window) → perilymph waves in the cochlea → basilar membrane vibration → deflection of stereocilia on inner hair cells → mechanotransduction channels open (K⁺ influx from K⁺-rich endolymph) → depolarization → glutamate release → CN VIII firing. The basilar membrane is tonotopically organized: base (narrow, stiff) encodes high frequencies; apex (wide, flexible) encodes low frequencies. Conductive hearing loss: middle ear pathology (otitis media, otosclerosis); Weber lateralizes to affected ear, Rinne shows bone > air. Sensorineural hearing loss: inner ear or CN VIII pathology (presbycusis, acoustic neuroma, ototoxic drugs); Weber lateralizes to unaffected ear, Rinne shows air > bone bilaterally.

22 Endocrine Physiology & Hormone Signaling

Hormone Classification by Mechanism

Second Messenger Systems

cAMP pathway (G_s activates adenylyl cyclase → cAMP → PKA): hormones using this pathway include ACTH, TSH, LH, FSH, ADH (V2), PTH, glucagon, beta-adrenergic agonists. G_i inhibits adenylyl cyclase (alpha-2, M2). IP3/DAG pathway (G_q activates PLC → IP3 releases Ca²⁺ from ER; DAG activates PKC): hormones include Ang II, ADH (V1), oxytocin, GnRH, TRH, alpha-1 adrenergic. Receptor tyrosine kinase (RTK): insulin, IGF-1, EGF, PDGF — receptor autophosphorylation activates MAP kinase and PI3K/Akt pathways. JAK-STAT: GH, prolactin, erythropoietin, cytokines.

The Hypothalamic-Pituitary Axes

Insulin & Glucagon — Glucose Homeostasis

Insulin (from pancreatic beta cells) is the primary anabolic hormone. It is released in response to elevated blood glucose (glucose enters beta cells via GLUT2 → glycolysis → increased ATP → closes K_ATP channels → depolarization → Ca²⁺ influx → insulin vesicle exocytosis). Insulin promotes glucose uptake (via GLUT4 translocation in muscle and adipose), glycogenesis, lipogenesis, and protein synthesis. It suppresses gluconeogenesis, glycogenolysis, lipolysis, and proteolysis. Insulin signals through a receptor tyrosine kinase (RTK) → IRS-1 → PI3K/Akt pathway → GLUT4 insertion and metabolic effects.

Glucagon (from pancreatic alpha cells) is the counterregulatory hormone, released during hypoglycemia. It acts via G_s-coupled receptors → cAMP → PKA in hepatocytes to promote glycogenolysis and gluconeogenesis, raising blood glucose. Other counterregulatory hormones include epinephrine, cortisol, and GH — all are "diabetogenic" (raise glucose). In type 1 diabetes, loss of insulin AND impaired glucagon response to hypoglycemia (from loss of paracrine insulin signaling to alpha cells) creates "hypoglycemia unawareness" — a dangerous complication.

23 Thyroid, Adrenal & Calcium Homeostasis

Thyroid Physiology

The thyroid gland synthesizes T4 (thyroxine, ~90% of output, relatively inactive) and T3 (triiodothyronine, ~10% of output, 3-5x more active). Peripheral conversion of T4 to T3 by 5'-deiodinase (type 1 and 2) produces most circulating T3. Type 3 deiodinase converts T4 to reverse T3 (rT3), which is inactive — increased in critical illness ("sick euthyroid" or "euthyroid sick syndrome"). Thyroid hormones are lipophilic and travel in blood mostly bound to TBG (thyroxine-binding globulin); only the free fraction is biologically active.

Thyroid hormones increase basal metabolic rate, oxygen consumption, heat production, heart rate and contractility (upregulate beta-1 receptors), and are essential for CNS development in neonates (cretinism if deficient). Wolff-Chaikoff effect: excess iodine transiently inhibits thyroid hormone synthesis (used acutely in thyroid storm). Jod-Basedow effect: excess iodine triggers hyperthyroidism in patients with underlying thyroid autonomy (toxic nodular goiter).

Thyroid Function Tests — Interpretation

Adrenal Physiology

The adrenal cortex produces steroids in three zones (mnemonic: "GFR — Salt, Sugar, Sex"): zona Glomerulosa (aldosterone — mineralocorticoid, regulated by Ang II and K⁺), zona Fasciculata (cortisol — glucocorticoid, regulated by ACTH), zona Reticularis (DHEA/androgens, regulated by ACTH). The adrenal medulla produces catecholamines (epinephrine 80%, norepinephrine 20%).

Cortisol actions: increased gluconeogenesis, lipolysis, proteolysis (catabolic); anti-inflammatory and immunosuppressive; maintains vascular tone (permissive effect on catecholamines); inhibits bone formation. Cortisol follows a diurnal rhythm (peak 6-8 AM, nadir at midnight). Chronic cortisol excess (Cushing syndrome) causes central obesity, striae, hyperglycemia, osteoporosis, proximal myopathy, and immunosuppression.

Adrenal Insufficiency & Stress Response

The adrenal cortex is essential for the stress response. Primary adrenal insufficiency (Addison disease): destruction of the adrenal cortex (autoimmune most common in developed countries, TB worldwide) → deficiency of cortisol AND aldosterone. Presents with hypotension, hyperkalemia, metabolic acidosis, hyperpigmentation (increased ACTH from loss of negative feedback → ACTH is cleaved from POMC, which also yields MSH). Secondary adrenal insufficiency: decreased ACTH (most commonly from chronic exogenous glucocorticoid use → hypothalamic-pituitary suppression → adrenal atrophy). No hyperpigmentation (ACTH is low). Aldosterone is usually preserved (regulated mainly by RAAS and K⁺, not ACTH). Adrenal crisis is a life-threatening emergency precipitated by physiologic stress (surgery, infection) in a patient with unrecognized adrenal insufficiency or abrupt steroid withdrawal. Treatment: IV hydrocortisone (stress dose = 100 mg bolus then 50 mg q8h) + aggressive fluid resuscitation.

Calcium Homeostasis

24 Muscle Physiology & Excitation-Contraction Coupling

Skeletal Muscle Contraction

The sliding filament theory: muscle contraction occurs when actin thin filaments slide past myosin thick filaments, shortening the sarcomere. The sequence: (1) AP at the NMJ → ACh release → nicotinic receptor activation → end-plate potential → muscle fiber AP, (2) AP propagates along the sarcolemma and down T-tubules, (3) voltage change in T-tubules activates the dihydropyridine receptor (DHPR), which is mechanically coupled to the ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR), (4) Ca²⁺ release from SR binds troponin C → conformational change moves tropomyosin off the actin binding sites → myosin cross-bridge cycling begins (requires ATP), (5) relaxation occurs when Ca²⁺ is pumped back into the SR by SERCA (SR Ca²⁺-ATPase).

Muscle Fiber Types

Cardiac vs Skeletal vs Smooth Muscle

Length-Tension & Force-Velocity Relationships

The length-tension relationship describes how muscle force varies with sarcomere length. Maximum active tension is generated at optimal sarcomere length (~2.2 micrometers) where actin-myosin overlap is maximal. Stretching beyond optimal length reduces overlap and force (descending limb). Excessive shortening causes thin filament overlap and reduced force (ascending limb). In the heart, the ascending limb of this curve is the physiologic basis of the Frank-Starling mechanism — increased ventricular filling (preload) stretches sarcomeres toward optimal length, increasing contractile force.

The force-velocity relationship shows that as afterload (force) increases, shortening velocity decreases. At maximum isometric force (very high afterload), velocity is zero (isovolumetric contraction). At zero load, velocity is maximum (unloaded shortening — V_max). V_max reflects intrinsic contractility independent of loading conditions. Positive inotropes (catecholamines, digoxin) increase V_max; heart failure decreases V_max.

Smooth Muscle Contraction

Unlike skeletal and cardiac muscle (which use troponin-tropomyosin), smooth muscle contraction is regulated by calmodulin-MLCK. When Ca²⁺ rises (from IP3-mediated release from SR or extracellular influx through L-type Ca²⁺ channels), it binds calmodulin → activates myosin light chain kinase (MLCK) → phosphorylates myosin light chain → allows actin-myosin cross-bridge cycling → contraction. Relaxation occurs when Ca²⁺ falls and myosin light chain phosphatase (MLCP) dephosphorylates myosin. NO (nitric oxide) causes smooth muscle relaxation by activating guanylyl cyclase → increased cGMP → activates PKG → decreases intracellular Ca²⁺ and activates MLCP. This is the mechanism of nitroglycerin-mediated vasodilation. PDE5 inhibitors (sildenafil) prevent cGMP degradation, prolonging the vasodilatory effect — used for erectile dysfunction and pulmonary hypertension.

25 Reproductive Physiology

Growth Hormone & Prolactin

Growth hormone (GH) is released from anterior pituitary somatotrophs in a pulsatile fashion (peak during deep sleep). It is stimulated by GHRH and ghrelin, inhibited by somatostatin and IGF-1. GH acts directly (lipolysis, insulin resistance, gluconeogenesis) and indirectly via IGF-1 (produced by the liver — promotes linear growth at epiphyseal plates, protein synthesis, and cell proliferation). GH excess before epiphyseal closure → gigantism; after closure → acromegaly (enlarged hands, feet, jaw, visceral organs, carpal tunnel, diabetes). GH deficiency in children → short stature; in adults → decreased lean mass, increased fat, fatigue.

Prolactin is the only anterior pituitary hormone under predominantly inhibitory control (by dopamine from the hypothalamus via the tuberoinfundibular pathway). Prolactin stimulates breast milk production. It is increased by: pregnancy, breastfeeding (suckling reflex), prolactinomas, dopamine antagonists (antipsychotics, metoclopramide), hypothyroidism (TRH stimulates prolactin release). High prolactin inhibits GnRH → hypogonadism (amenorrhea, infertility, decreased libido). Treatment of prolactinoma: dopamine agonists (cabergoline, bromocriptine) — first-line even for macroprolactinomas; surgery is rarely needed.

Fetal Physiology & Transitional Circulation

In utero, gas exchange occurs at the placenta (not the lungs). Fetal circulation features three shunts: (1) ductus venosus (bypasses the liver, shunting oxygenated blood from the umbilical vein to the IVC), (2) foramen ovale (right-to-left shunt from RA to LA, bypassing the lungs), (3) ductus arteriosus (right-to-left shunt from pulmonary artery to aorta, bypassing the lungs). These shunts exist because fetal pulmonary vascular resistance is very high (fluid-filled lungs, hypoxic vasoconstriction). At birth: first breath expands lungs → decreased pulmonary resistance → increased pulmonary blood flow → increased LA pressure → functional closure of foramen ovale. Rising PaO₂ + falling prostaglandins → closure of ductus arteriosus (indomethacin accelerates closure; PGE1 keeps it open in ductal-dependent congenital heart disease).

Male Reproductive Physiology

The hypothalamic-pituitary-gonadal (HPG) axis drives spermatogenesis and testosterone production. GnRH (pulsatile) stimulates LH and FSH from anterior pituitary gonadotrophs. LH acts on Leydig cells to produce testosterone. FSH acts on Sertoli cells to support spermatogenesis (Sertoli cells also produce inhibin B, which provides negative feedback on FSH, and androgen-binding protein, which maintains high local testosterone). Testosterone is converted to DHT (by 5-alpha-reductase — more potent androgen responsible for external genitalia development, prostate growth, male-pattern hair) and to estradiol (by aromatase — bone epiphyseal closure, feedback on HPG axis). Spermatogenesis takes ~74 days and requires the lower scrotal temperature (~2-3 degrees C below core body temperature).

Female Reproductive Physiology — The Menstrual Cycle

The average menstrual cycle is 28 days. Follicular phase (days 1-14): FSH stimulates follicular growth; granulosa cells produce estradiol; one dominant follicle emerges. Rising estradiol initially has negative feedback on GnRH/LH/FSH. When estradiol reaches a sustained high threshold (greater than 200 pg/mL for more than 36 hours), it switches to positive feedback, triggering the LH surge (~day 12). Ovulation occurs ~36 hours after the LH surge. Luteal phase (days 14-28): the corpus luteum produces progesterone (and estradiol), which stabilizes the endometrium for implantation, raises basal body temperature, and provides negative feedback on LH/FSH. If no implantation occurs, the corpus luteum degenerates → progesterone drops → endometrial shedding (menses). If implantation occurs, hCG from the trophoblast maintains the corpus luteum until the placenta takes over steroid production (~8-10 weeks).

Pregnancy Hormones

26 Clinical Correlates & Integrative Physiology

Fluid Compartments & Body Water Distribution

Total body water (TBW) = ~60% of body weight in a 70 kg male (~42 L). Distribution: intracellular fluid (ICF) = 2/3 of TBW (~28 L); extracellular fluid (ECF) = 1/3 of TBW (~14 L). ECF is further divided into interstitial fluid (3/4 of ECF, ~10.5 L) and plasma (1/4 of ECF, ~3.5 L). Measurement: TBW = tritiated water or deuterium oxide distribution; ECF = inulin or mannitol distribution; plasma volume = radiolabeled albumin or Evans blue dye; ICF = TBW - ECF (calculated).

Exercise Physiology

During exercise, the integrated cardiovascular, respiratory, and metabolic responses include: increased sympathetic tone → increased HR, contractility, and venous return → increased CO (up to 5-fold). SVR decreases (beta-2 vasodilation in skeletal muscle outweighs alpha-1 vasoconstriction in splanchnic/renal beds). SBP increases; DBP stays constant or slightly decreases. Minute ventilation increases (up to 20-fold) through both rate and depth. The oxygen-hemoglobin dissociation curve right-shifts (increased temperature, CO₂, 2,3-DPG, and lactic acid) to enhance O₂ delivery. At the anaerobic threshold, lactate production exceeds clearance, causing metabolic acidosis and increased ventilatory drive.

Shock Classification — Integrative Physiology

Response to Hemorrhage

Acute blood loss triggers a coordinated compensatory response: (1) Baroreceptor reflex (seconds): decreased carotid sinus/aortic arch stretch → decreased parasympathetic, increased sympathetic tone → tachycardia, vasoconstriction, increased contractility. (2) Chemoreceptor activation (minutes): decreased O₂ delivery stimulates peripheral chemoreceptors → increased ventilation. (3) RAAS activation (minutes-hours): decreased renal perfusion → renin → angiotensin II → vasoconstriction + aldosterone → Na⁺/water retention. (4) ADH release (minutes): hypovolemia is a potent non-osmotic stimulus. (5) Fluid shifts (hours): decreased capillary hydrostatic pressure → interstitial fluid moves into the vascular space (transcapillary refill). (6) Erythropoietin (days): renal hypoxia stimulates EPO production → increased RBC production.

Aging & Physiologic Changes

Cardiovascular Changes in Pregnancy

Temperature Regulation

The hypothalamus (preoptic/anterior region) is the thermoregulatory center. Responses to heat: vasodilation (increased skin blood flow via sympathetic withdrawal), sweating (cholinergic sympathetic fibers), behavioral changes. Responses to cold: vasoconstriction (alpha-1 in skin), shivering (involuntary muscle contraction generating heat), non-shivering thermogenesis (UCP1 in brown fat — important in neonates), piloerection. Fever results from pyrogens (IL-1, IL-6, TNF, PGE2) raising the hypothalamic set point. Antipyretics (acetaminophen, NSAIDs) work by inhibiting COX → reducing PGE2 synthesis in the hypothalamus.

High-Altitude Physiology

At altitude, barometric pressure decreases → lower inspired PO₂ → hypoxemia. Acute acclimatization (hours-days): peripheral chemoreceptors detect hypoxemia → hyperventilation → respiratory alkalosis → renal compensation (bicarbonaturia via decreased HCO₃^- reabsorption). Acetazolamide (CA inhibitor) accelerates renal compensation by causing metabolic acidosis, which drives further hyperventilation. Chronic acclimatization (weeks): increased EPO → polycythemia (increased O₂-carrying capacity); increased 2,3-DPG → right-shifted O₂-Hb curve (enhanced tissue O₂ delivery); pulmonary vascular remodeling (increased pulmonary artery pressure). Acute mountain sickness: headache, nausea, fatigue at >2500 m. HAPE (high-altitude pulmonary edema): noncardiogenic pulmonary edema from exaggerated HPV; treatment = descent + supplemental O₂ + nifedipine. HACE (high-altitude cerebral edema): vasogenic brain edema causing ataxia, altered mentation; treatment = immediate descent + dexamethasone.

Diving Physiology & Gas Laws

27 High-Yield Review & Key Equations

Essential Equations

High-Yield Physiology Concepts by System

Physiologic Responses — Summary of Key Reflexes

Commonly Tested Comparisons

Rapid-Fire Physiology Facts