Chapter 7  ·  Module 3

ACE Inhibitors & Angiotensin Receptor Blockers

Mechanism, adverse effects, indications, and clinical decision framework

ACE Inhibitor — Mechanism & Key Adverse Effects

Mechanism

How ACE Inhibitors Work

  • Block angiotensin converting enzyme (zinc-containing dipeptidyl carboxypeptidase)
  • Reduce angiotensin I → angiotensin II conversion → less vasoconstriction, aldosterone, and remodeling
  • Accumulate bradykinin (normally degraded by angiotensin converting enzyme) → additional vasodilation
  • Net effect: reduced total peripheral resistance, no reflex tachycardia, reduced preload and afterload

Bradykinin-Specific Adverse Effects

Cough & Angioedema

  • Dry cough: 5–20% overall; up to 40% in Asian patients; bradykinin stimulates sensory nerve fibers in airways
  • Fix: switch to angiotensin receptor blocker (no bradykinin accumulation)
  • Angioedema: 0.1–0.5%; 3–4× higher in Black patients; bradykinin-mediated (not histamine)
  • Antihistamines and epinephrine have limited efficacy; permanently avoid all angiotensin converting enzyme inhibitors after this event

ACEi vs ARB — Head-to-Head Comparison

Class Comparison

What Differs and What Is the Same

Feature ACE Inhibitor ARB
Target Blocks angiotensin converting enzyme Blocks angiotensin II type 1 receptor directly
Bradykinin effect Accumulates bradykinin No effect on bradykinin
Dry cough Yes — 5–20% No — placebo rate
Angioedema Bradykinin-mediated Rare (~10% cross-reactivity)
Hyperkalemia Same risk Same risk
Functional acute kidney injury Same risk Same risk
Teratogenicity Contraindicated — all trimesters Contraindicated — all trimesters
Blood pressure reduction Equivalent Equivalent

Compelling Indications with Trial Evidence

When These Drugs Save Lives Beyond Blood Pressure Lowering

Outcome Trial Evidence by Indication

Indication Preferred Class Key Trial / Finding Agent
Heart failure with reduced ejection fraction ACEi first-line; ARB if intolerant CONSENSUS (1987): 40% mortality reduction with enalapril Enalapril; candesartan or valsartan if ACEi not tolerated
Post-myocardial infarction with left ventricular dysfunction ACEi first-line GISSI-3: lisinopril reduced 6-week mortality Lisinopril, ramipril
High cardiovascular risk without heart failure ACEi HOPE (2000): ramipril reduced composite events by 22% Ramipril 10 mg/day
Type 1 diabetic nephropathy ACEi Lewis 1993: captopril reduced end-stage renal disease by 50% Captopril
Type 2 diabetic nephropathy ARB IDNT (irbesartan), RENAAL (losartan): renoprotection Irbesartan, losartan
Hypertension with left ventricular hypertrophy ARB LIFE (2002): losartan superior to atenolol; 25% stroke reduction Losartan

Dual Blockade Warning & Monitoring

Do Not Combine ACEi + ARB

ONTARGET (2008): combination offered no cardiovascular benefit over monotherapy but caused twice the rate of acute kidney injury and more hyperkalemia and hypotension. VA NEPHRON-D (2013): dual blockade in diabetic nephropathy terminated early — excess acute kidney injury, no renal benefit. Combining these classes increases harm without adding benefit.

Monitoring After Initiation

What to Check and When

  • Creatinine: check at 1–2 weeks; rise up to 30% acceptable; above 30%: reduce dose; above 50%: hold
  • Potassium: check at 1–2 weeks; above 5.5 mEq/L: hold drug
  • Sick-day rule: hold angiotensin converting enzyme inhibitor or angiotensin receptor blocker (and diuretics) during vomiting, diarrhea, or fever to prevent acute kidney injury