RAAS Inhibitors

RAAS Inhibitors

1. Overview & rationale for RAAS inhibition

• The renin-angiotensin system (RAS / RAAS) is a coordinated endocrine, paracrine, autocrine and intracrine hormonal cascade that regulates blood pressure (BP), electrolyte (Na⁺/K⁺) balance, extracellular fluid volume and cardiovascular structural remodeling; its dysregulation drives the pathophysiology of hypertension, heart failure, MI, diabetic nephropathy and chronic kidney disease (G&G 14e Ch.30, pp.585–6).
• Angiotensin II (AngII), an octapeptide, is the principal effector; on a molar basis it is ≈40 times more potent than norepinephrine as a pressor (EC₅₀ for acutely raising BP ≈ 0.3 nM) (G&G 14e Ch.30, p.591).
• Four therapeutically exploited points of interruption exist along the cascade — renin (direct renin inhibitors), the AngI→AngII step (ACE inhibitors), the AT₁ receptor (ARBs), and the mineralocorticoid receptor (aldosterone antagonists; covered with diuretics) — plus β₁ blockers that suppress renin release (KDT 8e Ch.36, p.530).
• Because the RAS is the dominant long-term regulator of the renal pressure–natriuresis relationship, RAS-inhibiting drugs lower BP most steeply in Na⁺-depleted / high-renin states and produce a leftward shift of the pressure-natriuresis curve (G&G 14e Ch.30, pp.593, 599).
• All RAS inhibitors share a common therapeutic footprint — antihypertensive, cardioprotective in heart failure and post-MI, and renoprotective in diabetic/proteinuric nephropathy — but differ in how they perturb individual RAS components (Table 30–3) (G&G 14e Ch.30, p.596).