ACE Inhibitors and ARBs

The renin-angiotensin-aldosterone system (RAAS) works synergistically with the ANS to regulate blood pressure and fluid balance. Renin is released from juxtaglomerular cells in response to: sympathetic stimulation of renal beta-1 receptors; low [Na+] in the distal convoluted tubule (sensed by macula densa cells); and low renal blood pressure (sensed by baroreceptors). Renin cleaves angiotensinogen (a plasma globulin produced by the liver) to form angiotensin I (Ang I), a peptide with low biological activity.

Angiotensin-converting enzyme (ACE), found on vascular endothelial surfaces and in soluble form in tissues, cleaves Ang I to form angiotensin II (Ang II). Ang II is the primary effector of RAAS. It activates two receptor subtypes: AT1R (responsible for pathological hypertensive effects — vasoconstriction, fibrosis, hypertrophy, Na+ and water retention, increased sympathetic outflow) and AT2R (considered beneficial — promotes vasodilation, anti-fibrotic, inhibits cell proliferation).

ACE also degrades bradykinin (BK). ACE inhibitors (ACE-Is) therefore both reduce Ang II and increase BK. Bradykinin → BK receptor → increased NO synthesis → vasodilation.

ACE inhibitors (the "-pril" drugs, e.g. enalapril): reduce Ang II → vasodilation (arteries and veins) → decreased preload and afterload; reduce aldosterone secretion → natriuresis and diuresis → decreased plasma volume → lower BP; reduce sympathetic activation; inhibit cardiac and vascular hypertrophy and fibrosis. Enalapril is an oral prodrug converted hepatically to enalaprilat (active form); renally cleared. First-line for hypertension and chronic heart failure.

ACE inhibitor ADRs: persistent dry cough (bradykinin accumulation); angioedema (up to 25% of angioedema cases); initial hypotension; rash; dysgeusia. Contraindicated in pregnancy (teratogenic; crosses placenta) and in patients with prior hypersensitivity or hereditary angioedema.

ARBs (the "-sartan" drugs, e.g. candesartan, losartan) directly block AT1R, preventing all Ang II effects at AT1R regardless of how Ang II is formed (ACE or chymase). They allow Ang II to act on beneficial AT2Rs. Unlike ACE-Is, ARBs do not affect bradykinin levels — no increase in dry cough or angioedema risk, but also no additional bradykinin-mediated vasodilation. Indications are the same as ACE-Is; used when patients cannot tolerate ACE-Is. Key ADRs: hyperkalaemia (inhibited aldosterone → K+ retention), hypotension. Major contraindication: pregnancy.