RAAS System Pharmacology

## Overview

The renin-angiotensin-aldosterone system (RAAS) is a hormonal cascade that regulates blood pressure, fluid balance, and electrolyte homeostasis. Chronic RAAS overactivation drives hypertension, cardiac remodeling, renal fibrosis, and vascular damage. Multiple drug classes target different points in this cascade.

## The RAAS Cascade

Renin (released from juxtaglomerular cells in response to low perfusion, sympathetic stimulation, or low sodium) cleaves angiotensinogen to angiotensin I. ACE converts angiotensin I to angiotensin II. Angiotensin II acts on AT1 receptors to cause vasoconstriction, aldosterone release, sympathetic facilitation, and pro-fibrotic signaling. Aldosterone promotes sodium retention and potassium excretion.

## ACE Inhibitors

Lisinopril, enalapril, and ramipril competitively inhibit ACE, reducing angiotensin II and aldosterone while increasing bradykinin. Bradykinin accumulation mediates vasodilatory benefit and the dry cough (5-20%). First-line for hypertension with CKD, diabetes, or HF. Contraindicated in pregnancy. Hyperkalemia risk requires monitoring with MRAs or CKD.

## Angiotensin Receptor Blockers

Losartan, valsartan, and candesartan selectively block AT1 receptors. They do not increase bradykinin, avoiding cough and reducing angioedema risk. Outcome evidence is comparable to ACE inhibitors. ARBs are preferred in ACE inhibitor-intolerant patients. Dual ACE/ARB therapy is not recommended (ONTARGET showed no added benefit with more adverse effects).

## Direct Renin Inhibitors

Aliskiren directly inhibits renin, the rate-limiting step. It reduces angiotensin I, II, and aldosterone. The ALTITUDE trial showed harm when combined with ACE inhibitors or ARBs in diabetic patients. Rarely used in practice; never combine with other RAAS blockers in diabetes or CKD.

## Mineralocorticoid Receptor Antagonists

Spironolactone and eplerenone block aldosterone receptors in the distal nephron, collecting duct, heart, and vasculature. Beyond potassium-sparing diuresis, they reduce myocardial fibrosis and vascular stiffness. Mortality benefit is proven in HFrEF (RALES, EMPHASIS-HF) and resistant hypertension (PATHWAY-2). Spironolactone causes gynecomastia through progesterone and androgen receptor cross-reactivity; eplerenone is more selective. Finerenone is a non-steroidal MRA with proven cardiorenal benefits in diabetic kidney disease (FIDELIO-DKD, FIGARO-DKD).

## ARNI: Sacubitril/Valsartan

Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides, bradykinin, and adrenomedullin. Combined with valsartan (ARB), it simultaneously enhances protective neurohormonal pathways while blocking RAAS. PARADIGM-HF demonstrated superiority over enalapril in HFrEF. A 36-hour washout from ACE inhibitors is mandatory before starting to prevent angioedema.

## Key Takeaways

- RAAS drugs target five distinct points: renin, ACE, AT1 receptor, aldosterone receptor, neprilysin
- ACE inhibitors and ARBs are first-line for hypertension with CKD, diabetes, or HF
- Dual RAAS blockade (ACEi + ARB) is harmful and not recommended
- ARNI (sacubitril/valsartan) is preferred over ACE inhibitors in HFrEF