ACE Inhibitors Explained: Mechanism, Uses, and Side Effects

What Are ACE Inhibitors?

ACE inhibitors (angiotensin-converting enzyme inhibitors) are a class of medications that lower blood pressure and protect the heart and kidneys by blocking a key enzyme in the renin-angiotensin-aldosterone system (RAAS). They are among the most prescribed and most evidence-based drug classes in medicine, with robust data supporting their use in hypertension, heart failure, post-myocardial infarction, and diabetic nephropathy.

Common ACE inhibitors include lisinopril (Prinivil, Zestril), enalapril (Vasotec), ramipril (Altace), benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), quinapril (Accupril), and perindopril (Aceon).

How ACE Inhibitors Work: The RAAS Pathway

The renin-angiotensin-aldosterone system (RAAS) is a hormonal cascade that regulates blood pressure and fluid balance. Here is how it works — and where ACE inhibitors intervene:

1. Renin release — When blood pressure drops or sodium is low, the kidneys release renin
2. Angiotensin I formation — Renin converts angiotensinogen (from the liver) to angiotensin I
3. Angiotensin II formation — ACE (in the lungs and elsewhere) converts angiotensin I to angiotensin II ← ACE inhibitors block this step
4. Angiotensin II effects — Angiotensin II causes vasoconstriction, aldosterone release (sodium/water retention), and sympathetic activation — all of which raise blood pressure

By blocking ACE, ACE inhibitors prevent the formation of angiotensin II, causing vasodilation, reduced aldosterone secretion (less sodium and water retention), and lower blood pressure. ACE inhibitors also prevent the breakdown of bradykinin — a vasodilatory peptide — which contributes to their blood pressure-lowering effect and also causes the characteristic dry cough.

What Are ACE Inhibitors Used For?

The ACE Inhibitor Cough: Why It Happens

The most common side effect of ACE inhibitors is a dry, persistent, non-productive cough, occurring in 10–15% of patients (and up to 30–40% in Asian populations). The cough is caused by accumulation of bradykinin in the lungs — ACE normally degrades bradykinin, so when ACE is inhibited, bradykinin builds up and irritates airway sensory nerves.

The cough typically begins within the first few weeks of treatment and resolves within 1–4 weeks of stopping the ACE inhibitor. It is not dose-dependent — switching to a lower dose does not reliably eliminate the cough. Patients who develop ACE inhibitor cough should be switched to an ARB (angiotensin receptor blocker), which does not affect bradykinin metabolism and does not cause cough.

Angioedema: A Rare but Serious Side Effect

Angioedema — swelling of the face, lips, tongue, throat, or extremities — occurs in 0.1–0.7% of patients on ACE inhibitors. It is caused by bradykinin accumulation and can be life-threatening if it involves the airway. Angioedema is 3–4 times more common in Black patients than in White patients. It can occur at any time during treatment, even after years of use.

ACE inhibitor-associated angioedema is a contraindication to further ACE inhibitor use. Patients with a history of ACE inhibitor angioedema should not receive another ACE inhibitor and should use an ARB instead (ARB-associated angioedema is rare but can occur).

Other Important Side Effects

ACE Inhibitors vs ARBs: When to Use Each

ARBs (angiotensin receptor blockers) — including losartan, valsartan, irbesartan, and olmesartan — block the angiotensin II receptor directly rather than preventing angiotensin II formation. Because they do not affect bradykinin, ARBs do not cause cough or angioedema (though rare ARB-associated angioedema has been reported).

For most indications, ACE inhibitors and ARBs are clinically equivalent. ACE inhibitors are generally preferred as first-line therapy due to their longer track record and lower cost. ARBs are the preferred alternative when ACE inhibitor cough or angioedema occurs. The two classes should not be combined (dual RAAS blockade increases the risk of hyperkalemia, hypotension, and acute kidney injury without additional cardiovascular benefit — ONTARGET trial, 2008).

Drug Interactions

• Potassium-sparing diuretics and potassium supplements — Increase risk of hyperkalemia; monitor potassium closely
• NSAIDs — Reduce antihypertensive effect; increase risk of acute kidney injury
• Lithium — ACE inhibitors reduce lithium clearance; monitor lithium levels
• Aliskiren — Dual RAAS blockade; contraindicated in patients with diabetes or renal impairment
• Sacubitril/valsartan (Entresto) — Must wait 36 hours after stopping ACE inhibitor before starting sacubitril to avoid angioedema

Cost and Generic Availability

All major ACE inhibitors are available as generics at very low cost. Lisinopril is typically $4–$15/month. See our lisinopril cost guide and ACE inhibitor cost comparison for current pricing.

References

1. ALLHAT Officers. Major outcomes in high-risk hypertensive patients randomized to ACE inhibitor or calcium channel blocker vs diuretic (ALLHAT). JAMA. 2002;288(23):2981-2997.
2. Yusuf S, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients (HOPE). N Engl J Med. 2000;342(3):145-153.
3. Pfeffer MA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction (SAVE). N Engl J Med. 1992;327(10):669-677.