RAAS: Clinical Pharmacology

The renin-angiotensin-aldosterone system (RAAS) is a key pharmacological target in hypertension, heart failure, diabetic nephropathy, and post-MI remodeling. When renal perfusion decreases, juxtaglomerular cells of the afferent arteriole release renin, which cleaves angiotensinogen (from the liver) to angiotensin I. Angiotensin-converting enzyme (ACE), primarily in pulmonary endothelium, converts angiotensin I to angiotensin II (AT-II). AT-II acts on AT1 receptors to cause: (1) potent vasoconstriction (increasing SVR and BP), (2) aldosterone secretion from the adrenal cortex (sodium/water retention, potassium excretion), (3) ADH release (water retention), (4) cardiac and vascular remodeling (fibrosis, hypertrophy), (5) sympathetic activation, and (6) efferent arteriolar constriction (maintaining GFR but increasing intraglomerular pressure and proteinuria). ACE inhibitors block AT-I → AT-II conversion AND prevent bradykinin breakdown (bradykinin accumulation causes the characteristic dry cough and rare but life-threatening angioedema). ARBs selectively block AT1 receptors without affecting bradykinin (lower cough/angioedema risk). Direct renin inhibitors (aliskiren) block the initial step. Mineralocorticoid receptor antagonists (spironolactone, eplerenone) block aldosterone effects. ARNI (sacubitril/valsartan) combines neprilysin inhibition (increases natriuretic peptides) with ARB blockade — the gold standard for HFrEF. All RAAS blockers cause hyperkalemia and are...