Pharmacology · Cardiovascular

ACE Inhibitors & Angiotensin Receptor Blockers

Mechanism, adverse effects, indications, and clinical decision framework

Angiotensin converting enzyme is a zinc-containing enzyme with two substrates, and ACE inhibitors block both at once — reducing angiotensin II conversion, which is the antihypertensive and organ-protective mechanism, while preventing bradykinin degradation, which supplies additional vasodilation but also produces the two adverse effects that define the class.
Dry cough (5 to 20 percent overall, up to 40 percent in patients of Asian descent) and angioedema (0.1 to 0.5 percent, three to four times higher in Black patients) are both bradykinin-mediated rather than histamine-mediated — which is why antihistamines and epinephrine have limited efficacy, and why every ACE inhibitor must be permanently avoided after an angioedema event.
Angiotensin receptor blockers antagonize the angiotensin II type 1 receptor directly without touching angiotensin converting enzyme, so bradykinin never accumulates and cough rates match placebo — making them the definitive switch for ACE inhibitor cough and the best-tolerated major antihypertensive class.
Compelling indications are outcome benefits independent of blood pressure lowering, and trial evidence divides the two classes: ACE inhibitors for heart failure with reduced ejection fraction, post-myocardial infarction left ventricular dysfunction, high cardiovascular risk, and type 1 diabetic nephropathy; angiotensin receptor blockers for type 2 diabetic nephropathy and hypertension with left ventricular hypertrophy.
Both classes share every effect arising from angiotensin II type 1 receptor blockade itself — hyperkalemia, functional acute kidney injury, first-dose hypotension, and teratogenicity in all trimesters — and must never be combined, since dual blockade adds acute kidney injury and hyperkalemia without any cardiovascular or renal benefit.

Abbreviations: ACE = angiotensin converting enzyme · ACEi = angiotensin converting enzyme inhibitor · ARB = angiotensin receptor blocker · mEq/L = milliequivalents per liter

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

ARB Mechanism & Agent-Specific Selection

Mechanism

How ARBs Work

Selective competitive antagonists at the angiotensin II type 1 receptor: block vasoconstriction, aldosterone release, sodium retention, sympathetic facilitation, and remodeling
Angiotensin converting enzyme is untouched → no bradykinin accumulation → no cough, no bradykinin angioedema
Loss of type 1 receptor feedback raises circulating angiotensin II, which preferentially stimulates type 2 receptors (counterregulatory vasodilation, anti-fibrotic)
Net hemodynamic profile essentially identical to angiotensin converting enzyme inhibitors

ACE Inhibitor Agent Selection

Which Agent and Why

Most are prodrugs requiring hepatic activation; captopril and lisinopril are active as administered
Lisinopril: water-soluble, renally excreted unchanged — preferred when hepatic function is impaired
Fosinopril: dual renal and hepatic elimination — preferred in advanced chronic kidney disease
Ramipril: broadest outcome trial evidence base across indications

ARB Agent Selection

Distinguishing Properties

Losartan: only ARB with a meaningful uricosuric effect (inhibits urate transporter 1) — preferred with coexisting gout or hyperuricemia
Telmisartan: biliary elimination, no dose adjustment in advanced chronic kidney disease; longest half-life (~24 hours)
Irbesartan: approved specifically for renoprotection in type 2 diabetic nephropathy
Olmesartan: rare sprue-like enteropathy with villous atrophy; resolves on discontinuation

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

Suggested References

Author / Organization	Title	Source
Katzung BG, ed.	Basic and Clinical Pharmacology. 15th ed.	McGraw-Hill; 2021
Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed.	McGraw-Hill; 2023
Whelton PK, Carey RM, Aronow WS, et al.	2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults	J Am Coll Cardiol. 2018;71(19):e127–e248
Mancia G, Kreutz R, Brunstrom M, et al.	2023 ESH guidelines for the management of arterial hypertension	J Hypertens. 2023;41(12):1874–2071
Ferrario CM	Role of angiotensin II in cardiovascular disease — therapeutic implications of more than a century of research	J Renin Angiotensin Aldosterone Syst. 2006;7(1):3–14
The CONSENSUS Trial Study Group	Effects of enalapril on mortality in severe congestive heart failure	N Engl J Med. 1987;316(23):1429–1435
GISSI-3 Investigators	Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction	Lancet. 1994;343(8906):1115–1122
Yusuf S, Sleight P, Pogue J, et al.	Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients (HOPE trial)	N Engl J Med. 2000;342(3):145–153
Fox KM; EUROPA Investigators	Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease (EUROPA)	Lancet. 2003;362(9386):782–788
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD	The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy	N Engl J Med. 1993;329(20):1456–1462
Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN)	Randomised placebo-controlled trial of effect of ramipril on decline in GFR and risk of terminal renal failure in proteinuric, non-diabetic nephropathy (REIN trial)	Lancet. 1997;349(9069):1857–1863
Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD	Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists	Hypertension. 2012;60(2):444–450
Dahlof B, Devereux RB, Kjeldsen SE, et al.	Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE)	Lancet. 2002;359(9311):995–1003
Brenner BM, Cooper ME, de Zeeuw D, et al.	Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy (RENAAL)	N Engl J Med. 2001;345(12):861–869
Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators	A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure (Val-HeFT)	N Engl J Med. 2001;345(23):1667–1675
Lewis EJ, Hunsicker LG, Clarke WR, et al.	Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes (IDNT)	N Engl J Med. 2001;345(12):851–860
Parving HH, Lehnert H, Brochner-Mortensen J, et al.	The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes (IRMA-2)	N Engl J Med. 2001;345(12):870–878
Granger CB, McMurray JJ, Yusuf S, et al.	Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to ACE inhibitors (CHARM-Alternative)	Lancet. 2003;362(9386):772–776
Yusuf S, Teo KK, Pogue J, et al.	Telmisartan, ramipril, or both in patients at high risk for vascular events (ONTARGET)	N Engl J Med. 2008;358(15):1547–1559
Fried LF, Emanuele N, Zhang JH, et al.	Combined angiotensin inhibition for the treatment of diabetic nephropathy (VA NEPHRON-D)	N Engl J Med. 2013;369(20):1892–1903
Parving HH, Brenner BM, McMurray JJ, et al.	Cardiorenal end points in a trial of aliskiren for type 2 diabetes (ALTITUDE)	N Engl J Med. 2012;367(23):2204–2213