ACE Inhibitors and ARBs
ACE inhibitors and angiotensin receptor blockers target the renin-angiotensin-aldosterone system to lower blood pressure, protect the kidneys, and improve survival in heart failure.
## The Renin-Angiotensin-Aldosterone System
The RAAS is a hormonal cascade that regulates blood pressure and fluid balance. Renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II causes vasoconstriction, aldosterone release, and sympathetic activation. Blocking this pathway reduces preload, afterload, and pathological cardiac remodeling.
## ACE Inhibitors
ACE inhibitors (enalapril, lisinopril, ramipril, perindopril) block the conversion of angiotensin I to angiotensin II. They also inhibit bradykinin degradation, which contributes to vasodilation but causes the characteristic dry cough in 5-20% of patients.
**Key indications:** Hypertension (first-line), HFrEF (mortality benefit), diabetic nephropathy (slows progression), post-MI left ventricular dysfunction.
**Notable side effects:** Dry cough (bradykinin-mediated), angioedema (rare but potentially life-threatening, higher incidence in Black patients), hyperkalemia, and acute kidney injury in bilateral renal artery stenosis. Absolutely contraindicated in pregnancy (teratogenic in all trimesters).
## Angiotensin Receptor Blockers
ARBs (losartan, valsartan, candesartan, telmisartan, olmesartan) block the AT1 receptor directly, preventing angiotensin II from exerting its effects regardless of the synthesis pathway. Because they do not affect bradykinin metabolism, dry cough and angioedema are significantly less common.
ARBs are typically used when ACE inhibitors are not tolerated due to cough. In heart failure, valsartan combined with sacubitril (ARNI) has largely replaced standalone ACE inhibitor/ARB therapy for HFrEF based on the PARADIGM-HF trial.
## ACE Inhibitor vs ARB: Clinical Differences
| Feature | ACE Inhibitor | ARB |
|---------|--------------|-----|
| Cough incidence | 5-20% | ~1% |
| Angioedema risk | Higher | Lower |
| Bradykinin effect | Increased | No effect |
| Post-MI evidence | Extensive | Growing |
| Cost | Generic, inexpensive | Generic, slightly higher |
## Dual RAAS Blockade
Combining an ACE inhibitor with an ARB (dual RAAS blockade) was studied in ONTARGET and VA NEPHRON-D trials. Results showed increased hyperkalemia, hypotension, and renal dysfunction without meaningful benefit. Dual blockade is generally avoided except in specific proteinuric nephropathy cases under specialist supervision.
## Monitoring
Check serum creatinine and potassium within 1-2 weeks of initiation or dose increase. A creatinine rise of up to 30% is acceptable and expected. Rises beyond 30% warrant investigation for renal artery stenosis. Avoid concurrent potassium-sparing diuretics and potassium supplements without monitoring.
## Key Takeaways
- ACE inhibitors and ARBs both target RAAS but differ in side effect profiles.
- ACE inhibitor cough is the most common reason for switching to an ARB.
- Both classes are renoprotective in diabetic nephropathy with albuminuria.
- Avoid combining ACE inhibitors and ARBs -- hyperkalemia and renal risk outweigh benefits.