ACE inhibitors

Quick revision

ACE inhibitors competitively block the conversion of angiotensin I to angiotensin II, so vasoconstriction and aldosterone secretion both fall — and because the same enzyme also degrades bradykinin, the cough and the angio-oedema come from the mechanism rather than from an allergy.

• Mechanism: competitive inhibition of angiotensin-converting enzyme, which blocks conversion of angiotensin I to angiotensin II and reduces aldosterone secretion. (1)
• Core approved roles are hypertension, heart failure with reduced ejection fraction, chronic kidney disease with albuminuria, and the period after ST-elevation myocardial infarction. (1)
• Dry cough is reported in 10% to 20% of patients and reflects accumulation of kinins in the lung, not hypersensitivity. (1)
• Angio-oedema is rare but potentially life-threatening, is also attributed to bradykinin accumulation, and rules the class out permanently once it has happened. (1)
• Hyperkalaemia (2% to 6%) follows directly from the loss of aldosterone-driven potassium secretion. (1)
• A slight fall in glomerular filtration rate on starting is expected; a further large fall points to poor renal perfusion and mandates stopping. (1)
• Contraindicated in the second and third trimesters of pregnancy because of a well-documented fetopathy. (1)
• Lisinopril and captopril are the only members that are not prodrugs, so they need no hepatic activation. (1)
• Monitoring means renal function and serum potassium, checked before starting and again when the dose changes. (4)

Overview

ACE inhibitors are used to treat and manage hypertension and a range of related cardiovascular conditions, including heart failure with reduced ejection fraction, chronic kidney disease, coronary artery disease and myocardial infarction. Captopril was the first member approved for clinical use, in 1981, and the class is now large enough that most members share a recognisable name ending. (1)

Their target sits in the middle of the renin-angiotensin-aldosterone system. Juxtaglomerular cells release renin, renin cleaves liver-derived angiotensinogen to angiotensin I, and angiotensin-converting enzyme — expressed on vascular endothelium and concentrated in the pulmonary circulation — removes two amino acids to generate angiotensin II. Angiotensin II is the principal effector: it constricts arterioles, stimulates aldosterone release from the zona glomerulosa, increases proximal tubular sodium reabsorption, raises sympathetic outflow and triggers vasopressin release. (2)

Blocking that one enzyme therefore does two useful things at once. Less angiotensin II means vasodilation and a lower blood pressure; less aldosterone means less sodium and water retention. Because chronic exposure to angiotensin II and aldosterone drives adverse cardiac remodelling, reducing both is also what gives the class its prognostic role rather than a purely haemodynamic one. (1)

What defines the class at the bedside is a small set of predictable problems. Dry cough is reported in 10% to 20% of patients, dizziness in 12% to 19%, hypotension in 7% to 11%, raised blood urea nitrogen and creatinine in 2% to 11%, syncope in 5% to 7% and hyperkalaemia in 2% to 6%. Angio-oedema is far rarer but potentially life-threatening, and pregnancy is an absolute bar. (1)

Classification and drug examples

The conventional division is by chemical structure — the group attached to the molecule that binds the zinc site of the enzyme — because that grouping also tracks the pharmacokinetic differences students are asked about.

Mechanism of action

ACE inhibitors are competitive inhibitors of angiotensin-converting enzyme. Blocking the enzyme reduces the formation of angiotensin II, which lowers vasoconstriction and aldosterone secretion; because the same enzyme also degrades bradykinin, kinins accumulate, and that second consequence explains the cough and the angio-oedema.

Molecular target

Angiotensin-converting enzyme on vascular endothelium, expressed predominantly in the pulmonary circulation

1. Renin sets the cascade running

   Juxtaglomerular cells in the afferent arteriole release renin in response to reduced renal perfusion, reduced sodium and chloride delivery to the macula densa, beta-1 adrenergic stimulation and humoral signals. Renin then cleaves liver-derived angiotensinogen to angiotensin I, a peptide with no known biological activity of its own. (2)

2. ACE converts angiotensin I to angiotensin II

   Angiotensin-converting enzyme, expressed on the plasma membranes of vascular endothelial cells and concentrated in the pulmonary circulation, removes two amino acids from the C-terminus of angiotensin I to generate the active peptide. (2)

3. Competitive inhibition reduces angiotensin II formation

   The drug competes with angiotensin I for the enzyme, so less angiotensin II is produced. Angiotensin II is a potent vasoconstrictor, and removing it dilates vessels and lowers blood pressure. (1)

4. Aldosterone falls with it

   Angiotensin II normally stimulates the adrenal cortex to produce aldosterone, which drives sodium and therefore water reabsorption while potassium and protons are secreted into the urine. Less angiotensin II means less aldosterone, less sodium and water retention — and less urinary potassium loss, which is where the hyperkalaemia comes from. (1)

5. Remodelling slows

   The combined actions of angiotensin II and aldosterone lead to adverse cardiac remodelling. By reducing the concentrations of both, ACE inhibitors prevent that remodelling, which is the basis of their prognostic rather than merely symptomatic benefit. (1)

6. Bradykinin accumulates as a side consequence

   Angiotensin-converting enzyme also metabolises bradykinin and other local molecules. Inhibiting the enzyme raises kinin concentrations, and bradykinin induces prominent vasodilation and plasma extravasation into local tissue — the accepted explanation for both the dry cough and, in susceptible individuals, angio-oedema. (1)

Major clinical uses

Pharmacokinetics

• The single most useful pharmacokinetic split in this class is prodrug status. Lisinopril and captopril are active as administered; enalapril, fosinopril, benazepril, quinapril and moexipril must be converted in the liver, which is why a non-prodrug is preferable when hepatic function is impaired. (1)
• Most members can be given once daily. Captopril needs several doses a day, and benazepril, quinapril and moexipril may need more frequent dosing because of a lower trough-to-peak ratio. (1)
• Blood tests are taken before starting and again when the dose changes, to check kidney function and potassium. Intercurrent illness with severe diarrhoea or vomiting is a recognised trigger for temporarily withholding the drug, and is a point patients are specifically counselled on. (4)
• Withholding renin-angiotensin system inhibitors before non-cardiac surgery has been reported to reduce intraoperative hypotension and acute kidney injury, with non-significant effects on mortality and major adverse cardiovascular events. (1)
• This page gives no dose regimens by design. Doses depend on indication, renal function, volume status, age and the other drugs in use, and belong in a prescribing reference used by the treating clinician.

Adverse effects

Common

• Dry cough: Reported in 10% to 20% of patients, typically beginning between one week and six months after initiation. Resolution usually follows 1 to 4 days after stopping but can take up to a month. There is also an increased propensity to bronchospasm. (1)
• Dizziness: Reported in 12% to 19% of patients, and mitigated by maintaining adequate volume status and avoiding concomitant diuretic therapy. The first dose is the most likely to provoke it. (1) (4)
• Hypotension: Reported in 7% to 11% of patients and more common where baseline renin concentrations are high. Repleting fluids and stopping a diuretic before starting therapy minimises hypotensive episodes. (1)
• Raised blood urea nitrogen and creatinine: Reported in 2% to 11% of patients. A slight reduction in glomerular filtration rate is common on initiation and is not by itself a reason to stop. (1)
• Syncope: Reported in 5% to 7% of patients, and part of the same haemodynamic picture as the dizziness and hypotension. (1)
• Hyperkalaemia: Reported in 2% to 6% of patients. Comorbidities that reduce kidney function, and medications that cause potassium retention, both increase the risk. (1)

Serious adverse effects

• Angio-oedema: A rare but potentially life-threatening reaction with episodic swelling of the face, lips and upper airway. Excessive accumulation of bradykinin in susceptible individuals is the proposed mechanism, and variants near the bradykinin receptor B2 gene have been associated with it. The primary treatment is discontinuation of ACE inhibitor therapy; airway compromise can require endotracheal intubation, and the class is avoided afterwards. (1)
• Marked decline in renal function: Patients with heart failure, chronic kidney disease or bilateral renal artery stenosis and poor renal perfusion can suffer a further reduction in glomerular filtration rate beyond the expected small fall. This pattern mandates discontinuation of ACE inhibitor therapy rather than dose reduction. (1)
• Fetal toxicity: Drugs inhibiting the renin-angiotensin system correlate with oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia and death. The fetal kidney is the site of the problem: low-pressure fetal haemodynamics are easily disrupted when angiotensin II falls. The class is contraindicated in pregnancy, and pregnancy status is checked before and during therapy. (1)
• Rare haematological reactions: Anaemia, neutropenia, agranulocytosis and thrombocytopenia are described as rare adverse effects of the class. A full blood count with differential is used to look for them where the clinical picture suggests it. (1)

Drug-specific effects

• Captopril: The only ACE inhibitor to penetrate the blood-brain barrier, with confusion and lethargy as the corresponding features in toxicity. (1)
• ACE inhibitors as a class: Post-marketing surveillance reports significant adverse events in fewer than one percent of patients, including anaphylactoid reactions, eosinophilic pneumonitis, hyponatraemia, intestinal angio-oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis. (1)

Contraindications, precautions and interactions

Contraindications

• Pregnancy, because of teratogenic effects including oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia and death. (1)
• Angio-oedema related to previous ACE inhibitor treatment, and idiopathic or hereditary angio-oedema. (1)
• Hypersensitivity to any ACE inhibitor or to a component of the formulation, with cross-reactivity between members to be considered. (1)
• Current use of aliskiren in a patient with diabetes mellitus. (1)

Precautions

• Abnormal renal function. Where renal function is abnormal but stable, close monitoring is required; if it starts to decline, the clinician should discontinue the ACE inhibitor. (1)
• Aortic valve stenosis, where afterload reduction can lead to severe hypotension. (1)
• Hypovolaemia and dehydration, which these drugs can worsen; initiation is also avoided in an older patient who is dehydrated. (1)
• Heart failure already treated with a high dose of a loop diuretic, where profound first-dose hypotension may occur. (1)
• Sarcoidosis, where the drug lowers peripheral ACE concentrations and makes that measurement uninterpretable. (1)
• Intercurrent illness with severe watery diarrhoea or vomiting, which is a recognised reason for a temporary interruption decided by the prescriber. (4)

Drug interactions

• Aliskiren: Two levels of restriction that are easy to conflate. Co-administration with an ACE inhibitor is CONTRAINDICATED in a patient with diabetes; separately, the labels direct that the combination be AVOIDED in renal impairment, taking a glomerular filtration rate below about 60 mL/min as the threshold. The second is an avoidance, not a contraindication. (5)
• Lithium: ACE inhibitors reduce renal lithium clearance, raising the risk of lithium toxicity; lithium concentrations and clinical signs are checked frequently during co-administration. (1)
• Potassium-sparing diuretics, NSAIDs, ciclosporin and anticoagulants: Combination increases hyperkalaemia, hypotension and renal failure risk, and calls for particular precaution. (1)
• Sulfonylureas: Combination in a patient with diabetes may increase the risk of hypoglycaemia, so blood glucose is monitored regularly. (1)
• Azathioprine: Associated with bone marrow suppression including anaemia and leukopenia; full blood counts are monitored for early myelosuppression. (1)
• Allopurinol: Concurrent use may raise the risk of hypersensitivity reactions, so skin rashes and systemic allergic symptoms are watched for. (1)
• Other antihypertensive agents: Toxicity is rare at therapeutic doses but becomes more likely in combination, with hyperkalaemia, hypotension and renal failure the effects that compound. (1)

Comparison tables

High-yield exam pearls

• The cough is bradykinin, not allergy. (1) Angiotensin-converting enzyme also metabolises bradykinin and other local mediators, so inhibiting it in the lung raises kinin concentrations and irritates the bronchi. That is why an angiotensin receptor blocker, which does not raise bradykinin, is the usual substitute.
• Only two members of the class are not prodrugs. (1) Lisinopril and captopril are active as given, whereas enalapril, fosinopril, benazepril, quinapril and moexipril require hepatic conversion to enalaprilat, fosinoprilat, benazeprilat, quinaprilat and moexiprilat. A non-prodrug is preferable where liver function is impaired.
• Enalapril is the one with an intravenous form. (1) Enalaprilat is the only intravenous ACE inhibitor and has a rapid onset of action, which is what makes it useful in hypertensive emergencies; every other member is oral only.
• Fosinopril is the one that leaves by two routes. (1) It is eliminated both renally and hepatically, so it can be used without dose adjustment in renal impairment — the exception that the rest of the class does not share.
• Captopril is the one that reaches the brain. (1) It is the only ACE inhibitor described as penetrating the blood-brain barrier, and confusion and lethargy are the corresponding features in toxicity.
• First-dose hypotension is worst on top of a high-dose loop diuretic. (1) Profound first-dose hypotension may occur when an ACE inhibitor is introduced to a patient with heart failure who is already on a high dose of a loop diuretic, which is why volume repletion beforehand matters.
• An ACE inhibitor makes the serum ACE level in sarcoidosis uninterpretable. (1) The drug lowers ACE concentrations in peripheral blood, so the result cannot be read as a marker of disease activity in a patient taking one.

Common exam traps

• Trap: "An ACE inhibitor cough means the patient is allergic to the drug." Actually: It is a pharmacological consequence of reduced bradykinin breakdown, not hypersensitivity. It typically appears between one week and six months after starting and usually settles 1 to 4 days after stopping, although it can persist for up to a month. (1)
• Trap: "Any rise in creatinine after starting means the drug must be stopped." Actually: A slight reduction in glomerular filtration rate is common on initiation. It is the further, larger fall seen with heart failure, chronic kidney disease or bilateral renal artery stenosis and poor renal perfusion that mandates discontinuation. (1)
• Trap: "A low dose is acceptable in pregnancy." Actually: Drugs that inhibit the renin-angiotensin system are linked to oligohydramnios, reduced fetal renal function, anuria, renal failure, skull hypoplasia and death. They are contraindicated in the second and third trimesters, and a strong association with major malformations has been described for first-trimester exposure. (1)
• Trap: "Angio-oedema on an ACE inhibitor can be handled by reducing the dose." Actually: The primary treatment is discontinuation of ACE inhibitor therapy, and the class is avoided thereafter. Swelling of the face, lips and upper airway can be severe enough to require endotracheal intubation to secure the airway. (1)
• Trap: "Hyperkalaemia on an ACE inhibitor is an idiosyncratic reaction." Actually: It is a direct result of the mechanism: blocking angiotensin II removes the stimulus to aldosterone, and without aldosterone-driven secretion potassium accumulates. Reduced kidney function or a potassium-retaining co-prescription raises the risk further. (1)
• Trap: "ACE inhibitors are the preferred first antihypertensive for every patient." Actually: In the Black population with diabetes mellitus and without chronic kidney disease, initial antihypertensive therapy is described as a thiazide diuretic or a calcium channel blocker rather than an ACE inhibitor or an angiotensin receptor blocker. (1)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. Which enzymatic step do ACE inhibitors block?

   • Cleavage of angiotensinogen to angiotensin I by renin
   • Conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme
   • Binding of aldosterone to the mineralocorticoid receptor in the collecting duct
   • Degradation of natriuretic peptides by neprilysin
   Show answer

   Answer: Conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme

   ACE inhibitors are competitive inhibitors of angiotensin-converting enzyme and prevent the conversion of angiotensin I to angiotensin II. Renin cleaves angiotensinogen upstream of that step, and the mineralocorticoid receptor and neprilysin are the targets of entirely different classes. (1) (2)

2. Why do ACE inhibitors cause a dry cough in a substantial minority of patients?

   • They deposit in bronchial epithelium and cause direct chemical irritation
   • They trigger an IgE-mediated hypersensitivity response in the airway
   • The same enzyme also degrades bradykinin, so inhibiting it raises kinin concentrations in the lung
   • They increase angiotensin II at the AT2 receptor, which stimulates the cough reflex
   Show answer

   Answer: The same enzyme also degrades bradykinin, so inhibiting it raises kinin concentrations in the lung

   Angiotensin-converting enzyme metabolises bradykinin and other local molecules as well as angiotensin I. Inhibiting the enzyme in the lung increases kinin concentrations and causes bronchial irritation, which is why the cough is a mechanism effect rather than an allergy, and why it is reported in roughly 10% to 20% of patients. (1)

3. Which two ACE inhibitors are active as administered and require no hepatic conversion?

   • Enalapril and ramipril
   • Lisinopril and captopril
   • Quinapril and benazepril
   • Fosinopril and moexipril
   Show answer

   Answer: Lisinopril and captopril

   Lisinopril and captopril are not prodrugs. Enalapril, fosinopril, benazepril, quinapril and moexipril all require hepatic conversion to their active forms, which is why a non-prodrug is preferred in a patient with underlying liver disease. (1)

4. A patient starting an ACE inhibitor develops a rise in serum potassium. What is the mechanistic explanation?

   • The drug directly blocks the epithelial sodium channel in the collecting duct
   • Reduced angiotensin II means reduced aldosterone, and without aldosterone less potassium is secreted into the urine
   • The drug inhibits the sodium-potassium ATPase in skeletal muscle, releasing intracellular potassium
   • Increased bradykinin drives potassium out of cells into the plasma
   Show answer

   Answer: Reduced angiotensin II means reduced aldosterone, and without aldosterone less potassium is secreted into the urine

   Blocking angiotensin II removes the downstream stimulus to aldosterone secretion. Aldosterone normally drives sodium reabsorption with secretion of potassium and protons into the urine, so its loss allows potassium to accumulate. Reduced kidney function or a potassium-retaining co-prescription increases the risk. (1) (2)

5. Which ACE inhibitor is available in an intravenous formulation?

   • Captopril
   • Ramipril
   • Enalapril, given intravenously as enalaprilat
   • Perindopril
   Show answer

   Answer: Enalapril, given intravenously as enalaprilat

   All ACE inhibitors are prescribed orally except enalapril, which can also be given intravenously. Enalaprilat is the only intravenous member of the class and has a rapid onset of action, which is what makes it useful in a hypertensive emergency. (1)

6. Which statement about ACE inhibitors in pregnancy is correct?

   • They are contraindicated in the second and third trimesters because of a documented fetopathy
   • They are the preferred antihypertensive throughout pregnancy
   • They are safe at any stage provided renal function is normal
   • They are contraindicated only in the first trimester
   Show answer

   Answer: They are contraindicated in the second and third trimesters because of a documented fetopathy

   ACE inhibitors are contraindicated during the second and third trimesters because of a well-documented fetopathy. Reported effects include oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia and death, and a strong association with major cardiovascular and neurological malformations has also been described after first-trimester exposure. (1)

7. Why is the serum ACE concentration unhelpful in a patient with suspected sarcoidosis who is already taking an ACE inhibitor?

   • The drug raises serum ACE, producing a falsely positive result
   • The drug lowers ACE concentrations in peripheral blood, so the result cannot be interpreted accurately
   • Sarcoidosis does not affect serum ACE at all
   • The assay cross-reacts with the drug and always fails
   Show answer

   Answer: The drug lowers ACE concentrations in peripheral blood, so the result cannot be interpreted accurately

   ACE inhibitors potentially lead to low ACE concentrations in peripheral blood samples, so the clinical interpretation of that measurement in a patient with sarcoidosis receiving one of these drugs is not accurate. (1)

Frequently asked questions

References

1. ACE Inhibitors (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2025
2. Physiology, Renin Angiotensin System (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2026
3. Angiotensin II Receptor Blockers (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2025
4. About ramipril (NHS) National Health Service (UK), 2026
5. LISINOPRIL tablet — prescribing information DailyMed, U.S. National Library of Medicine
6. Captopril tablet — prescribing information DailyMed, U.S. National Library of Medicine

Related drug classes

• Angiotensin receptor blockers
• Mineralocorticoid receptor antagonists
• Angiotensin receptor–neprilysin inhibitors

Back to the Cardiovascular drugs classification · Pharmacology Study Corner