2.2 Physiology
Key Takeaways
- Cardiac output equals heart rate multiplied by stroke volume (CO = HR × SV) and is regulated by autonomic tone, preload, afterload, and contractility — the levers beta-blockers, ACE inhibitors, and diuretics manipulate in heart failure.
- The renin-angiotensin-aldosterone system raises blood volume and pressure within minutes to hours; ACE inhibitors, ARBs, and direct renin inhibitors interrupt this axis and are first-line agents for hypertension, heart failure, and diabetic kidney disease.
- Glomerular filtration rate averages 120 mL/min/1.73 m² in healthy adults and is the single most important renal parameter for drug dosing because most renally cleared drugs (vancomycin, metformin, digoxin) require adjustment when GFR falls below 60 mL/min.
- Insulin lowers blood glucose by promoting hepatic and muscle glycogen synthesis, muscle glucose uptake via GLUT4, and fat lipogenesis, while glucagon raises glucose by stimulating hepatic glycogenolysis and gluconeogenesis; the insulin-to-glucagon ratio governs fed-state versus fasting metabolism.
- Negative feedback loops dominate endocrine regulation — thyroid hormone suppresses TRH and TSH, cortisol suppresses CRH and ACTH — which is why abrupt withdrawal of exogenous steroids causes adrenal crisis because the suppressed hypothalamic-pituitary-adrenal axis cannot respond.
Physiology explains how the body maintains the internal conditions that drugs are designed to modify. Every antihypertensive, every diuretic, every hormone replacement, and every bronchodilator works by tweaking a physiological control system. Mastering physiology lets you predict a drug's effects, its adverse effects, and the rebound phenomena that occur when it is withdrawn.
Cardiovascular Physiology
The cardiac cycle consists of systole (contraction and ejection) and diastole (relaxation and filling). Cardiac output (CO) is the product of heart rate (HR) and stroke volume (SV): CO = HR × SV. Stroke volume depends on preload (venous return — the Frank-Starling mechanism), afterload (aortic resistance), and contractility (inotropic state). This equation is the framework for every cardiovascular drug: beta-blockers reduce HR and contractility, ACE inhibitors reduce afterload, and loop diuretics reduce preload.
Blood pressure = cardiac output × systemic vascular resistance (BP = CO × SVR). The autonomic nervous system modulates both: sympathetic tone raises HR, contractility, and vasoconstriction (alpha-1) while vasodilating skeletal muscle (beta-2); parasympathetic tone via the vagus nerve slows HR and atrioventricular conduction (M2 receptors).
The renin-angiotensin-aldosterone system (RAAS) is the body's long-term blood pressure regulator. When renal perfusion falls, juxtaglomerular cells release renin, which converts angiotensinogen to angiotensin I; ACE in the lungs converts angiotensin I to angiotensin II, a potent vasoconstrictor that also triggers aldosterone release from the adrenal cortex. Aldosterone increases sodium reabsorption in the collecting duct, expanding blood volume. ACE inhibitors (lisinopril), ARBs (losartan), and direct renin inhibitors (aliskiren) interrupt this cascade at different points.
Respiratory Physiology
Ventilation is the bulk flow of air in and out of the lungs; gas exchange occurs by diffusion at the alveolar-capillary membrane. V/Q matching describes the balance between ventilation (V) and perfusion (Q) in each lung unit. A shunt (perfusion without ventilation, as in pneumonia) causes hypoxemia that does not improve with supplemental oxygen; dead space (ventilation without perfusion, as in pulmonary embolism) wastes ventilation. Bronchodilators (beta-2 agonists, anticholinergics) improve ventilation; pulmonary vasodilators (sildenafil, epoprostenol) improve perfusion.
Renal Physiology
The kidney filters, reabsorbs, and secretes. Glomerular filtration rate (GFR) — about 120 mL/min/1.73 m² in healthy adults — is measured clinically as estimated GFR (eGFR) or creatinine clearance. Drugs cleared by filtration (vancomycin, digoxin, metformin) require dose adjustment when GFR falls.
Tubular reabsorption is segment-specific: the proximal tubule reabsorbs ~100% of glucose and amino acids and ~65% of sodium; the loop of Henle establishes the medullary concentration gradient via countercurrent multiplication; the distal tubule fine-tunes sodium and calcium; the collecting duct is the final site regulated by aldosterone (sodium reabsorption, potassium secretion) and ADH (water reabsorption via aquaporin-2).
The kidney regulates acid-base balance by reabsorbing filtered bicarbonate (proximal tubule) and generating new bicarbonate by excreting ammonium and titratable acids (alpha-intercalated cells of the collecting duct). It regulates electrolytes: potassium balance is governed by aldosterone, sodium by ANP and aldosterone, calcium and phosphate by PTH and calcitriol.
Gastrointestinal Physiology
The GI tract digests and absorbs nutrients, motes them through peristalsis (mediated by enteric nervous system), and hosts the gut microbiome (~10¹³ organisms). The stomach's parietal cells secrete HCl (pH 1–2) — proton pump inhibitors block the H⁺/K⁺ ATPase. Gastric emptying governs oral drug onset: prokinetics (metoclopramide) accelerate it, opioids and anticholinergics delay it. Most absorption occurs in the small intestine, where the slightly alkaline pH (6–7) favors absorption of weak acids.
Endocrine Physiology
The hypothalamic-pituitary axes control five endocrine glands: the HPA axis (CRH → ACTH → cortisol), HPT axis (TRH → TSH → T3/T4), HPG axis (GnRH → FSH/LH → gonadal steroids), GH axis (GHRH → GH → IGF-1), and prolactin (mostly under tonic dopamine inhibition). Each axis is governed by negative feedback: thyroid hormone feeds back on the hypothalamus and pituitary, cortisol feeds back on CRH and ACTH.
The pancreatic endocrine system regulates glucose. Insulin (secreted by beta cells in response to glucose) lowers blood glucose by promoting muscle glucose uptake (GLUT4), glycogen synthesis, and lipogenesis. Glucagon (alpha cells, secreted during fasting) raises glucose via hepatic glycogenolysis and gluconeogenesis. Somatostatin (delta cells) inhibits both. Sulfonylureas stimulate insulin secretion; metformin inhibits hepatic gluconeogenesis; SGLT2 inhibitors block renal glucose reabsorption; GLP-1 agonists amplify glucose-dependent insulin secretion.
Nervous System Physiology and Autonomic Control
Neurons communicate at synapses via neurotransmitters binding receptors on the postsynaptic membrane. Action potentials are all-or-nothing depolarizations driven by voltage-gated sodium channels; local anesthetics block these channels from the inside.
The autonomic nervous system has two opposing branches that innervate most visceral organs. The sympathetic branch (thoracolumbar origin, short preganglionic fibers releasing acetylcholine onto nicotinic receptors in ganglia, long postganglionic fibers releasing norepinephrine onto adrenergic receptors) drives the fight-or-flight response. The parasympathetic branch (craniosacral origin, long preganglionic fibers, short postganglionic fibers releasing acetylcholine onto muscarinic receptors) drives rest-and-digest function.
Homeostasis and Feedback Loops
Homeostasis is maintained largely by negative feedback: a sensor detects a change, a control center responds, an effector corrects the change. Examples include thermoregulation, blood glucose, calcium balance, and the HPA axis. Positive feedback amplifies a change until an endpoint is reached — ovulation (LH surge), blood clotting, and parturition (oxytocin-driven uterine contractions). Drugs that mimic or block feedback signals can cause paradoxical effects: chronic exogenous glucocorticoids suppress the HPA axis, and abrupt cessation triggers adrenal crisis because the atrophic adrenal cortex cannot respond to ACTH. Recognizing the feedback loop helps you anticipate this and taper steroids slowly.
Sympathetic vs Parasympathetic Effects on Major Organs
| Organ | Sympathetic Effect | Parasympathetic Effect |
|---|---|---|
| Heart (SA node) | β1 → ↑ heart rate | M2 → ↓ heart rate |
| Heart (contractility) | β1 → ↑ contractility | Minimal effect |
| Bronchi | β2 → bronchodilation | M3 → bronchoconstriction, ↑ secretions |
| Eye (pupil) | α1 → mydriasis (dilation) | M3 → miosis (constriction) |
| GI motility | β2, α2 → decreased | M3 → increased |
| GI secretions | Decreased | M3 → increased |
| Bladder (detrusor) | β2 → relaxed | M3 → contracted (voiding) |
| Bladder (sphincter) | α1 → contracted (retention) | M3 → relaxed (voiding) |
| Blood vessels (skin/splanchnic) | α1 → vasoconstriction | Minimal direct innervation |
| Blood vessels (skeletal muscle) | β2 → vasodilation | Minimal |
| Sweat glands | ACh (sympathetic cholinergic) → increased | Minimal |
| Salivary glands | α1 → thick, viscous saliva | M3 → profuse watery saliva |
| Liver | β2 → glycogenolysis, gluconeogenesis | Minimal |
This table is the master key to autonomic pharmacology. Sympathomimetics (epinephrine, albuterol) reproduce the left column; parasympathomimetics (bethanechol, neostigmine) reproduce the right. Blockers reverse the column: beta-blockers antagonize the sympathetic cardiac effects; anticholinergics (atropine, oxybutynin) block parasympathetic effects.
A patient on long-term prednisone for rheumatoid arthritis stops the drug abruptly and within 24 hours develops hypotension, fatigue, abdominal pain, and vomiting. Which physiological mechanism best explains this presentation?
Which renal physiological parameter is most directly used to adjust the dose of vancomycin and most other renally cleared drugs?