19th May 2025

Angiotensin-Converting Enzyme (ACE)-inhibitors

Indications

Angiotensin-converting enzyme (ACE) inhibitors are used in the treatment of hypertension, heart failure, diabetic nephropathy, and coronary artery disease.

Mechanism of action

ACE-inhibitors block angiotensin-converting enzyme, which acts to convert angiotensin I to angiotensin II. Angiotensin II is responsible for:

producing vasoconstriction of precapillary arterioles and postcapillary venules
the production and release of aldosterone
inhibiting norepinephrine reuptake
stimulating the adrenal medulla to release catecholamines
the hypertrophy of smooth muscle cells within blood vessels and cardiac myocytes
reducing excretion of water and sodium within urine.

The majority of side effects produced by ACE-inhibitors are therefore a result of reduced angiotensin II production, which results in increased urinary excretion of water and sodium, reduced arterial and venous pressure, and reduced hypertrophy of vascular and cardiac musculature.

Examples

Ramipril, lisinopril, enalapril, captopril, fosinopril.

Adverse effects

Adverse drug effect	Mechanism	Comments
Dry cough	Precise mechanism unknown; postulated to be due to increased local concentrations of kinins and substance P. These substances are metabolised by ACE; concentrations are therefore increased with ACE inhibitor use. This may lead to stimulation of sensory (C-) fibres present in the upper airway. ACE inhibition may also lead to increased levels of thromboxane via activation of the arachidonic pathway, which may cause bronchoconstriction.	Usually begins 1-2 weeks of starting therapy and resolves within 1-4 days of discontinuation. Females more commonly affected than males. Patients should be switched to angiotensin II receptor blocker.
Hypotension	Reduced angiotensin II production, which results in increased urinary excretion of water and sodium and reduced arterial and venous pressure.	May manifest as dizziness, weakness or syncope. May be seen in volume-depleted patients or those with heart failure. Commencement at low dose e.g. 2.5mg enalapril BD can reduce effect.
Impaired renal function	Reduced glomerular filtration rate (GFR); more commonly seen in patients with pre-existing chronic kidney disease (CKD), bilateral renal artery stenosis, heart failure, polycystic kidney disease. Believed a result of pre-existing reduction in intrarenal perfusion pressure, with a resulting angiotensin II-induced increase in postglomerular arteriole resistance. Reduced angiotensin II will therefore lower intraglomerular pressure and reduce GFR.	Rise in serum creatinine seen 3-5 days after institution of ACE-inhibitor. Most often GFR reduces by 5-25% but can be >30%. If serum creatinine rises >30% above baseline within 6-8 weeks, ACE-inhibitor should be discontinued.
Hyperkalaemia	Aldosterone is the main hormone that stimulates urinary potassium excretion. Angiotensin II increases aldosterone production, so reduction of angiotensin II with ACE-inhibitor use increases serum potassium concentration.	Usually only mild increase in serum potassium seen in patients with normal renal function; more severe in CKD, diabetes, older patients, and simultaneous use of potassium-sparing diuretics or NSAIDs.
Anaemia	Suppression of erythropoietin production; increased risk in presence of CKD. In this setting, the accumulation of N-acetyl-seryl-aspartyl-lysyl-proline suppresses stem cell division.
Angioedema / anaphylactoid reactions	ACE is involved in the metabolism of bradykinin, its metabolite, des-Arg9-BK, and substance P. The accumulation of these three peptides during ACE-inhibition leads to an increase in secondary metabolic enzymes which predispose patients to developing angioedema.	Risk factors include history of previous angioedema, female gender, age over 65 years, concurrent aspirin/NSAID use, smoking and genetic factors.
Pancreatitis	Precise mechanism unknown; may be a result of angioedema of pancreatic duct resulting in obstruction
Complications in pregnancy	ACE-inhibitors are contraindicated during pregnancy; they cross the placenta and reduce fetal angiotensin II levels, which are normally required to maintain fetal GFR. Exposure in second and third trimesters leads to impaired renal function and can lead to oligohydramnios and renal failure after delivery. Little is known about first-trimester exposure but there is a higher risk of major congenital malformations compared with nonexposed foetuses.

Table 8: Adverse Effects

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