Drugs acting on RAAS
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Drugs acting on RAAS
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Here is a complete, organized overview of drugs acting on the RAAS system.
Drugs Acting on the Renin-Angiotensin-Aldosterone System (RAAS)
The RAAS Pathway
The RAAS cascade: Angiotensinogen (hepatic α₂-globulin) → Renin → Angiotensin I → ACE → Angiotensin II → acts on AT₁ receptors → vasoconstriction + aldosterone release → sodium/water retention → ↑ BP
Classification of RAAS Drugs
1. Renin Inhibitors (Direct Renin Inhibitors - DRIs)
Mechanism: Block the earliest step - renin cannot convert angiotensinogen to Angiotensin I.
| Drug | Dose | Notes |
|---|---|---|
| Aliskiren | 150-300 mg/day orally | Only approved oral DRI |
- Binds the active site of renin with 10,000-fold higher affinity than other aspartic peptidases (IC50 ~0.6 nM)
- Reduces Ang I, Ang II, and plasma aldosterone; increases plasma renin concentration (loss of AngII negative feedback)
- Bioavailability ~2.5%; t½ = 20-45 h; minimal hepatic metabolism; excreted mainly in feces
- ADRs: Diarrhea (dose-related), cough, angioedema (less than ACEi)
- Contraindicated in pregnancy; avoid with ACEi or ARB (additive risk without extra benefit)
- Substrate for P-glycoprotein; fatty meals reduce absorption; metabolized by CYP3A4
2. ACE Inhibitors (ACEIs)
Mechanism: Block ACE, which prevents conversion of Ang I → Ang II AND inhibits bradykinin degradation (→ ↑ NO, ↑ prostacyclin → vasodilation).
Suffix: "-pril"
| Drug | Special Feature |
|---|---|
| Captopril | Shortest acting; active drug (no prodrug conversion needed) |
| Enalapril | Prodrug → enalaprilat; only ACEI available IV (enalaprilat) |
| Lisinopril | Active drug; no hepatic conversion needed |
| Ramipril | Prodrug; preferred in high CV risk patients (HOPE trial) |
| Fosinopril | Only ACEI with dual renal + hepatic elimination - no dose adjustment in renal impairment |
| Perindopril | Prodrug; long-acting |
| Quinapril, Benazepril, Trandolapril, Moexipril | Prodrugs; renally eliminated |
Therapeutic uses:
- Hypertension (first-line with diabetes, CKD, post-MI, HFrEF)
- Heart failure (reduces preload and afterload)
- Post-MI ventricular remodeling
- Diabetic nephropathy (reduces efferent arteriolar resistance → ↓ intraglomerular pressure → ↓ proteinuria)
- Chronic kidney disease
Adverse effects:
- Dry cough (up to 10%) - due to ↑ bradykinin and substance P in pulmonary tree
- Angioedema (rare but potentially life-threatening) - also bradykinin-mediated
- Hyperkalemia (↓ aldosterone → ↓ K⁺ excretion)
- First-dose hypotension
- Fetotoxicity / teratogenicity - contraindicated in pregnancy (causes fetal renal agenesis)
- Altered taste (captopril - contains sulfhydryl group)
- Captopril specifically: rash, taste disturbance due to sulfhydryl group
Pharmacokinetics key point: All except captopril and lisinopril are prodrugs requiring hepatic conversion - captopril/lisinopril preferred in severe hepatic impairment.
3. Angiotensin II Receptor Blockers (ARBs)
Mechanism: Selectively block AT₁ receptors - prevent all actions of Ang II (vasoconstriction, aldosterone release, sympathetic facilitation) regardless of how Ang II was formed (not only ACE-generated).
Advantage over ACEi: More complete Ang II blockade (chymase can also form Ang II); no bradykinin accumulation → no cough, much less angioedema.
Suffix: "-sartan"
| Drug | Notes |
|---|---|
| Losartan | First approved ARB; also lowers uric acid (uricosuric) |
| Valsartan | Used post-MI; component of sacubitril/valsartan (Entresto) |
| Irbesartan | Good evidence in diabetic nephropathy |
| Candesartan | Potent; used in heart failure |
| Olmesartan | Longest-acting |
| Telmisartan | Longest t½; also activates PPAR-γ (metabolic benefit) |
| Eprosartan, Azilsartan | Second-generation |
Uses: Same as ACEi; preferred when ACEi cough is intolerable; first-line in diabetic nephropathy, HFrEF, post-MI, hypertension.
Adverse effects: Similar to ACEi but no cough, very rare angioedema; hyperkalemia; teratogenic (contraindicated in pregnancy).
Do NOT combine ACEi + ARB - increased risk of hypotension, hyperkalemia, and renal failure without additional cardiovascular benefit.
4. Aldosterone Receptor Antagonists (Mineralocorticoid Receptor Antagonists - MRAs)
Mechanism: Competitively block mineralocorticoid receptors in the collecting duct → prevent Na⁺/water retention and K⁺ excretion; also block cardiac fibrosis mediated by aldosterone.
4a. Steroidal MRAs
| Drug | Selectivity | Key Uses | Notes |
|---|---|---|---|
| Spironolactone | Non-selective (also blocks androgen + progesterone receptors) | HFrEF, primary hyperaldosteronism, resistant HTN, ascites | ADRs: gynecomastia, impotence, menstrual irregularity |
| Eplerenone | Selective for mineralocorticoid receptor | Post-MI heart failure, HFrEF, hypertension | Fewer endocrine ADRs; more expensive |
4b. Non-steroidal MRA (New Generation)
| Drug | Notes |
|---|---|
| Finerenone | FDA approved 2021; indicated for CKD with type 2 diabetes; reduces cardiovascular events and CKD progression; fewer hyperkalemia than steroidal MRAs |
Class ADRs: Hyperkalemia (most important), hyponatremia. Spironolactone-specific: gynecomastia, menstrual irregularity, decreased libido (anti-androgenic).
5. Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
Mechanism: Combined AT₁ receptor blockade + neprilysin inhibition (↑ natriuretic peptides ANP/BNP).
| Drug | Components | Indication |
|---|---|---|
| Sacubitril/Valsartan (Entresto) | Neprilysin inhibitor + ARB | HFrEF (NYHA II-IV); superior to enalapril in PARADIGM-HF trial |
- Neprilysin degrades natriuretic peptides; inhibiting it raises ANP/BNP levels → natriuresis, vasodilation, anti-fibrosis
- Must NOT be combined with ACEi (high risk of angioedema; 36-hour washout required when switching from ACEi)
- Also approved for hypertension in some guidelines
Summary Classification Table
| Class | Drug(s) | Site of Action | Key Indication |
|---|---|---|---|
| Direct Renin Inhibitor | Aliskiren | Renin (blocks Ang I formation) | Hypertension |
| ACE Inhibitors | Captopril, Enalapril, Lisinopril, Ramipril, etc. | ACE (blocks Ang II formation + bradykinin degradation) | HTN, HF, CKD, post-MI |
| ARBs | Losartan, Valsartan, Irbesartan, Candesartan, etc. | AT₁ receptor (blocks Ang II action) | HTN, HF, CKD, post-MI |
| Steroidal MRAs | Spironolactone, Eplerenone | Mineralocorticoid receptor | HF, hyperaldosteronism, resistant HTN |
| Non-steroidal MRA | Finerenone | Mineralocorticoid receptor | CKD + T2DM |
| ARNI | Sacubitril/Valsartan | AT₁ receptor + neprilysin | HFrEF |
Key Contraindications Across All RAAS Drugs
- Pregnancy - all RAAS drugs are teratogenic (fetal renal agenesis)
- Bilateral renal artery stenosis - ACEi/ARBs cause acute renal failure
- Hyperkalemia - all RAAS drugs increase serum K⁺
- History of angioedema with ACEi - use ARB instead (not ARNI)
Sources: Lippincott Illustrated Reviews Pharmacology, 7th Ed.; Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung's Basic & Clinical Pharmacology, 16th Ed.
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