ACE Inhibitors
High-yield Verified · Oct 2026Block ACE, the enzyme that turns inactive angiotensin I into angiotensin II and also breaks down bradykinin — so vessels and the efferent arteriole relax and aldosterone falls, while bradykinin builds up (cough, angioedema).
Nursing view → administration, monitoring and patient teaching
Compare: Antihypertensives compared — mechanism and drug choice →
Drugs
Mechanism
Inhibit the angiotensin-converting enzyme, blocking conversion of angiotensin I to angiotensin II — reducing vasoconstriction and aldosterone-driven sodium/water retention. Reduced breakdown of bradykinin contributes to vasodilation (and the dry cough).
The renin–angiotensin–aldosterone cascade
The RAAS regulates blood volume, electrolytes and systemic vascular resistance, and unlike the baroreceptor reflex it adjusts pressure over both the short and the long term. Renin, stored in juxtaglomerular cells of the afferent arteriole, is released in response to four stimuli: lower renal perfusion pressure sensed by arteriolar stretch receptors; less sodium chloride reaching the macula densa; β1-receptor sympathetic activity; and humoral signals, including short-loop negative feedback from angiotensin II itself. Renin is the rate-limiting enzyme of the cascade.
Renin cleaves angiotensinogen, made by the liver, to angiotensin I, a peptide with no known biological activity. ACE, on the membranes of vascular endothelial cells — mostly in the pulmonary circulation — removes two C-terminal amino acids to make angiotensin II. ACE is not the only route: non-ACE pathways also convert angiotensin I to angiotensin II (the ARB page covers what that means for receptor blockade).
Angiotensin II acts in five ways: it constricts arteriolar smooth muscle; it drives aldosterone synthase (CYP11B2) in the zona glomerulosa; it boosts the sodium–hydrogen antiporter in the proximal tubule; it raises central sympathetic outflow; and it releases vasopressin (ADH), which increases aquaporin-2 water channels in the collecting duct. Its vasoconstriction and sodium and water retention run through the G-protein-coupled AT1 receptor (the AT1/AT2 story is on the ARB page). Aldosterone acts on mineralocorticoid receptors in collecting-duct principal cells, adding apical ENaC channels and activating the basolateral Na-K ATPase: sodium is reabsorbed and potassium is secreted into the urine.
One enzyme, two substrates
ACE is a zinc metallopeptidase also called kininase II: the same enzyme that converts angiotensin I to angiotensin II also degrades bradykinin to inactive fragments. ACE inhibitors block it competitively, so both reactions slow at once.
On the angiotensin side, less angiotensin II means less arteriolar and venous constriction, less aldosterone, less sympathetic activation and vasopressin, and less AT1-driven cardiac and vascular hypertrophy and fibrosis. Lower aldosterone lets serum potassium creep up slightly (a mean rise of about 0.1–0.2 mEq/L in the lisinopril and enalapril trials). Losing angiotensin II’s negative feedback on renin makes plasma renin activity rise.
On the bradykinin side, bradykinin that is no longer broken down releases endothelial nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor, which dilate vessels and have antiproliferative and fibrinolytic effects. The labels say it is still not settled how much bradykinin adds to the blood-pressure effect, but it does account for the cough and the angioedema.
The drugs work even in low-renin hypertension. Black patients, usually a low-renin population, have a smaller average response to monotherapy, and adding a thiazide removed that difference in the lisinopril trials.
The glomerulus: why creatinine rises and the kidney is protected
Glomerular filtration is autoregulated by angiotensin II acting between the afferent and efferent arterioles. When cardiac output falls modestly, angiotensin II constricts the efferent arteriole and holds the filtration fraction up.
ACE inhibitors relax that efferent constriction, lowering intraglomerular pressure and proteinuria — the basis of their renoprotection, which slows kidney-disease progression, particularly in type 2 diabetes. In type 1 diabetic nephropathy, captopril halved the risk of doubling serum creatinine, and of end-stage renal disease or death, by more than its blood-pressure difference alone would explain. The trade-off is a fall in filtration: a creatinine rise of up to 30% is expected.
A rise above 30% suggests the kidney was depending on efferent tone — bilateral renal artery stenosis, stenosis in a solitary kidney, or volume depletion. With unilateral stenosis the affected kidney loses function on ACE inhibition while the other kidney preserves overall function; captopril scintigraphy uses exactly this response. Across the whole kidney, renal blood flow rises on enalapril while GFR is usually unchanged.
Hemodynamics and the heart
Blood pressure falls about equally supine and standing, with no compensatory tachycardia: peripheral resistance falls while cardiac output rises, with little or no change in heart rate. In heart failure, ACE inhibitors cut preload (vasodilation and natriuresis) and afterload: enalapril lowered systemic vascular resistance, pulmonary capillary wedge pressure and heart size and raised cardiac output and exercise tolerance. Lower angiotensin II and aldosterone also prevent adverse cardiac remodeling.
The effect outlasts the drug in the blood. Captopril’s antihypertensive effect persists longer than measurable inhibition of circulating ACE, and ramipril appears to act partly by inhibiting tissue as well as circulating ACE. Tight ACE binding also explains why lisinopril, enalaprilat and ramiprilat have a prolonged terminal elimination phase that does not cause accumulation.
Comparing the drugs
The four ACE inhibitors on this page
| Drug | Prodrug? | Chemical group | Food | Elimination | Half-life |
|---|---|---|---|---|---|
| Lisinopril | No — active as given | Dicarboxylate | No effect; about 25% absorbed | Not metabolized; excreted unchanged entirely in urine | Effective 12 h |
| Enalapril | Yes — hepatic CES1 hydrolysis to enalaprilat (IV form available) | Dicarboxylate | No effect; about 60% absorbed | Mainly renal, as enalaprilat and enalapril | Enalaprilat effective 11 h |
| Ramipril | Yes — ester cleavage, mainly in the liver, to ramiprilat (about 6× as active) | Dicarboxylate | Slows the rate, not the extent, of absorption | About 60% urine, 40% feces | Ramiprilat 9–18 h; terminal phase over 50 h |
| Captopril | No — active as given | Sulfhydryl | Cuts absorption 30–40% — give 1 h before meals | Urine: 40–50% unchanged, the rest as disulfides | Probably under 2 h — several doses a day |
Most ACE inhibitors are prodrugs that need hepatic esterase hydrolysis; lisinopril and captopril are the exceptions. Enalaprilat is the only parenteral ACE inhibitor. Lisinopril, enalaprilat and ramiprilat all accumulate when renal function falls.
Pharmacokinetics
- Prodrug activation — enalapril, ramipril
- Most ACE inhibitors are prodrugs that need hepatic esterase hydrolysis to the active diacid. OATP1B1 carries enalapril into hepatocytes, where carboxylesterase 1 converts it to enalaprilat — more potent, but poorly absorbed by mouth — peaking 3–4 h after the dose. Ramipril is cleaved (mainly in the liver) to ramiprilat, about 6 times as active. In hepatic impairment ramipril activation slows and plasma ramipril rises about 3-fold, though ramiprilat peaks and ACE inhibition are unchanged.
- Active as given — lisinopril, captopril
- Lisinopril and captopril need no activation, so StatPearls notes they suit patients with hepatic dysfunction. Lisinopril is hydrophilic, is not metabolized, is not bound to serum proteins and is excreted unchanged entirely in urine.
- Absorption and food
- Lisinopril is about 25% absorbed, with wide variation (6–60%); enalapril about 60%; captopril at least about 75%. Food does not change lisinopril or enalapril absorption and only slows ramipril’s, but it cuts captopril absorption by 30–40%, so captopril is given 1 hour before meals. Absolute bioavailability is 28% for ramipril and 44% for ramiprilat.
- Half-life and dosing frequency
- Effective half-lives are about 12 h for lisinopril and 11 h for enalaprilat, and 9–18 h for free ramiprilat (with a terminal phase over 50 h that reflects ACE binding), so most ACE inhibitors are taken once daily. Captopril’s half-life is probably under 2 hours, so it needs several daily doses.
- Onset
- Blood pressure starts to fall about 1 hour after a dose of lisinopril or enalapril and is lowest at about 6 h (lisinopril) or 4–6 h (enalapril); captopril’s effect peaks at 60–90 minutes. Enalaprilat, given IV, acts rapidly — useful in hypertensive emergencies.
- Renal impairment — lisinopril, enalapril, ramipril, captopril
- All four rely on the kidney. Lisinopril and enalaprilat elimination falls significantly once GFR is 30 mL/min or less, with higher peak and trough levels; at creatinine clearance under 40 mL/min/1.73 m², ramiprilat exposure (AUC) is 3–4 times normal; captopril is retained.
- Distribution and dialysis
- Enalapril crosses the blood–brain barrier poorly, if at all, and enalaprilat not at all. Captopril is 25–30% protein-bound. Lisinopril and enalaprilat are removed by hemodialysis, and captopril can be removed from adult circulation the same way.
Uses & drug choice
- Hypertension
- Heart failure & post-MI (cardioprotective)
- Diabetic nephropathy / chronic kidney disease (renal protection)
Adverse effects
- Dry cough
- Bradykinin, substance P and prostaglandins accumulate in the bronchial epithelium and sensitize the cough reflex through C fibers. It affects 5–20% of patients (more often women, Asian patients and nonsmokers), usually begins 1–6 months into treatment and clears 1–4 weeks after stopping. ARBs do not inhibit kininase II, so cough recurs rarely on them (cross-reactivity under 3%).
- Angioedema
- Bradykinin that is not degraded increases submucosal vascular permeability — a bradykinin-mediated angioedema, without urticaria or itching, unlike histamine-mediated swelling. That is why it often resists epinephrine, glucocorticoids and antihistamines, and why icatibant (a bradykinin-receptor antagonist) or C1-esterase inhibitor concentrate are considered in severe cases. It occurs in 0.1–0.7% of patients, about 4 times as often in Black patients, and can appear at any time (median onset 1–2 years). DPP-4 also degrades bradykinin.
- Hyperkalemia
- It follows directly from the mechanism: without angiotensin II there is less aldosterone, so the collecting duct secretes less potassium. Reduced kidney function or potassium-retaining drugs add to it.
- First-dose hypotension and dizziness
- When blood pressure is being held up by angiotensin II — high baseline renin, volume depletion, high-dose or newly started diuretics, salt restriction or dialysis — removing it drops pressure sharply, usually within the first hour of the first captopril dose. Dizziness eases when volume is maintained and diuretics are avoided.
- Rising creatinine and acute kidney injury
- Relaxing the efferent arteriole lowers intraglomerular pressure. A creatinine rise of up to 30% is expected; more than that means filtration depended on efferent tone, as in bilateral renal artery stenosis or volume depletion.
- Fetal toxicity (boxed warning)
- Fetal renal hemodynamics are low-pressure and depend on angiotensin II. Blocking it lowers fetal renal pressure and GFR, so urine output fails: oligohydramnios and anuria follow, with renal tubular dysplasia, lung and skull hypoplasia and skeletal deformations. The labels tie the harm mainly to the second and third trimesters, and StatPearls also describes an association between first-trimester exposure and major malformations.
- Captopril neutropenia, taste loss and rash
- Captopril neutropenia is marrow suppression: bone-marrow examinations consistently showed myeloid hypoplasia, often with erythroid hypoplasia and fewer megakaryocytes. Risk tracks the patient’s condition and dose — captopril is retained when renal function falls, the high-risk renal-impairment patients were taking relatively high doses for their kidney function, and collagen vascular disease adds to the risk; among heart-failure patients who developed it after the trials, more than three-quarters were also taking procainamide. Taste loss and rash likewise vary with renal status and dose.
Toxicity & antidote
Overdose mainly causes hypotension, sometimes with hyperkalemia and acute kidney injury. It usually responds to IV crystalloid and Trendelenburg positioning; refractory cases need vasopressors. Synthetic angiotensin II (Giapreza) restores the missing hormone directly and is described as a physiological antidote for vasodilatory shock refractory to conventional vasopressors.
Naloxone has reversed ACE-inhibitor hypotension in a few case reports. The proposed mechanism is that ACE inhibitors also inhibit enkephalinase, so endogenous opioids (enkephalins) accumulate. Lisinopril, enalaprilat and captopril can be removed by hemodialysis.
Interactions
Contraindications
- Prior angioedema (from any ACE inhibitor, hereditary, or idiopathic) — Re-exposure can trigger recurrent, potentially fatal airway swelling driven by bradykinin.
- Pregnancy — Fetal renal toxicity, oligohydramnios, and death (the boxed warning). Stop immediately if pregnancy occurs.
- Within 36 hours of a neprilysin inhibitor (sacubitril / ARNI) — Both raise bradykinin; overlapping them sharply increases the risk of angioedema.
- Bilateral renal artery stenosis — These kidneys depend on angiotensin II to maintain filtration pressure — blocking it precipitates acute kidney injury.
- Hyperkalemia use caution — ACE inhibitors raise potassium; starting one with an already-high level risks dangerous arrhythmias.
- Taking aliskiren, in a patient with diabetes — Every ACE-inhibitor label on this page says not to co-administer aliskiren in patients with diabetes; combining RAS blockers raises the risk of hypotension, hyperkalemia and changes in renal function, including acute renal failure.
- Taking an ARB (dual RAS blockade) — StatPearls lists an ACE inhibitor plus an ARB as contraindicated: in the ONTARGET trial the combination added no benefit and caused more hypotension, syncope and renal dysfunction. The labels likewise say to avoid combined RAS blockade.
High-yield
- A — Angiotensin II falls: vessels and the efferent arteriole relax, aldosterone falls and potassium rises
- B — Bradykinin builds up: dry cough and angioedema
- C — Creatinine creeps up (up to 30% is expected); more suggests bilateral renal artery stenosis
A and C are the angiotensin side of the enzyme; B is the kininase II side.
- Li — lisinopril: active as given, not metabolized, excreted unchanged in urine
- C — captopril: active as given (sulfhydryl), but its half-life is under 2 hours
Every other ACE inhibitor on this page is a prodrug that needs hepatic ester hydrolysis — enalapril to enalaprilat, ramipril to ramiprilat.
Practice questions
Q1A 52-year-old Black man started lisinopril 18 months ago. He arrives with marked swelling of the lips and tongue but no hives or itching. Diphenhydramine and IV methylprednisolone do not reduce the swelling.
Which mechanism best explains this reaction?
- A.IgE-mediated mast-cell degranulation releasing histamine
- B.Reduced degradation of bradykinin, increasing submucosal vascular permeability
- C.Inherited deficiency of C1-esterase inhibitor
- D.Excess angiotensin II acting on AT1 receptors in the airway
- E.Blockade of AT1 receptors by lisinopril
Show answer
B. Reduced degradation of bradykinin, increasing submucosal vascular permeability — ACE (kininase II) degrades bradykinin, so ACE inhibition lets bradykinin accumulate and raise submucosal vascular permeability. Bradykinin-mediated angioedema lacks urticaria and itching and often resists antihistamines, glucocorticoids and epinephrine — unlike histamine-mediated swelling. It can appear at any time (median onset 1–2 years) and is about 4 times as common in Black patients. Hereditary C1-inhibitor deficiency is a different, excess-production form of bradykinin angioedema; ACE inhibitors lower angiotensin II rather than raise it; and lisinopril inhibits ACE — AT1-receptor blockade is how ARBs work.
Q2A 71-year-old man with resistant hypertension, diffuse atherosclerosis and an abdominal bruit starts an ACE inhibitor. Two weeks later his serum creatinine has risen 70% from baseline.
Which mechanism best explains the rise in creatinine?
- A.Loss of angiotensin II–mediated efferent arteriolar constriction that was maintaining GFR
- B.Increased aldosterone secretion causing sodium retention
- C.Bradykinin-induced constriction of the afferent arteriole
- D.Increased angiotensin II formation within the kidney
- E.Suppression of renin release from juxtaglomerular cells
Show answer
A. Loss of angiotensin II–mediated efferent arteriolar constriction that was maintaining GFR — In bilateral renal artery stenosis, filtration depends on angiotensin II constricting the efferent arteriole. ACE inhibition removes that tone, intraglomerular pressure falls, and GFR drops; a creatinine rise above 30% should prompt a search for bilateral stenosis or volume depletion. ACE inhibitors lower aldosterone and angiotensin II rather than raise them. Bradykinin dilates vessels rather than constricting them. Losing angiotensin II feedback raises plasma renin activity instead of suppressing renin.
Q3In a pharmacokinetic study, volunteers take oral enalapril. The ACE-inhibiting compound measured in plasma peaks 3–4 hours after the dose, later than enalapril itself.
How is the active compound formed?
- A.Oxidation by hepatic CYP2D6
- B.Hydrolysis by red-cell cytosolic esterases
- C.Hydrolysis by hepatic carboxylesterase 1 after OATP1B1 uptake into hepatocytes
- D.Glucuronidation in the liver
- E.Tubular secretion and activation in the kidney
Show answer
C. Hydrolysis by hepatic carboxylesterase 1 after OATP1B1 uptake into hepatocytes — Enalapril is a prodrug: OATP1B1 transports it into hepatocytes, where carboxylesterase 1 hydrolyzes it to enalaprilat, the active and more potent inhibitor, which peaks 3–4 hours after an oral dose. Most ACE inhibitors are activated this way by hepatic esterases; lisinopril and captopril need no activation. The kidney excretes enalaprilat rather than activating it.
Q4A 31-year-old woman with chronic hypertension treated with lisinopril is found at 26 weeks’ gestation to have severe oligohydramnios.
Which mechanism best explains the fetal finding?
- A.Fetal hyperkalemia causing polyuria
- B.Reduced fetal glomerular filtration because fetal renal perfusion pressure depends on angiotensin II
- C.Maternal hyperaldosteronism caused by the drug
- D.Bradykinin-mediated leak of amniotic fluid
- E.Direct fetal β1-receptor blockade
Show answer
B. Reduced fetal glomerular filtration because fetal renal perfusion pressure depends on angiotensin II — The fetal kidney works at low pressure and depends on angiotensin II. RAS blockade in the second and third trimesters lowers fetal renal pressure and GFR, causing oligohydramnios and anuria, with risks of renal tubular dysplasia, lung and skull hypoplasia, renal failure and death. Oligohydramnios means less fetal urine, not polyuria. ACE inhibitors lower aldosterone rather than raise it, and their mechanism is ACE inhibition, not β blockade.
Q5A 58-year-old woman with hypertension and type 2 diabetes with albuminuria has had a persistent dry, tickling cough since starting an ACE inhibitor 3 months ago. Her chest radiograph is normal.
Which change best keeps renin–angiotensin protection while removing the cause of the cough?
- A.Switch to enalapril
- B.Switch to captopril
- C.Switch to losartan (an ARB)
- D.Add aliskiren to the current ACE inhibitor
- E.Add an ARB to the current ACE inhibitor
Show answer
C. Switch to losartan (an ARB) — ACE-inhibitor cough comes from bradykinin, substance P and prostaglandins that build up because kininase II is inhibited. Every ACE inhibitor does this, so switching within the class does not help. ARBs do not inhibit kininase II or raise bradykinin, so their cough rate is 1–4% and cross-reactivity is under 3%. Dual RAS blockade — an ARB or aliskiren added to an ACE inhibitor — increases hyperkalemia, hypotension and renal dysfunction without added benefit, and aliskiren with an ACE inhibitor is contraindicated in diabetes.
Sources
- ACE Inhibitors — mechanism, angioedema, contraindications — StatPearls (NCBI)
- Zestril (lisinopril) — boxed warning (fetal toxicity), angioedema, hyperkalemia, interactions (FDA label) — FDA / DailyMed
- Vasotec (enalapril maleate) — FDA label — FDA / DailyMed
- Ramipril capsules — current FDA label (boxed warning: fetal toxicity) — FDA / DailyMed
- Physiology, Renin Angiotensin System — renin triggers, ACE in the lungs, angiotensin II actions — StatPearls (NCBI)
- Antihypertensive Medications — ACE inhibitors: efferent arteriole, bradykinin, cough and angioedema rates, creatinine ≤ 30% rule — StatPearls (NCBI)
- Renal Artery Stenosis — angiotensin II and efferent-arteriole dependence of GFR — StatPearls (NCBI)
- Prerenal Kidney Failure — efferent arteriole; severe hyperkalemia and arrhythmia risk — StatPearls (NCBI)
- The use of stems in the selection of International Nonproprietary Names (-pril) — World Health Organization
- StatPearls: Ramipril — postural hypotension and fall risk at treatment start — StatPearls (NCBI)
- Captopril tablets (Ajanta) — FDA label: boxed warning (fetal toxicity), neutropenia/agranulocytosis, proteinuria, take 1 hour before meals — FDA / DailyMed
- Captopril — active (non-prodrug) ACE inhibitor, pharmacokinetics, adverse effects, monitoring — StatPearls (NCBI)
- Lisinopril — hydrophilic, not hepatically metabolized — StatPearls (NCBI)
- Enalapril — OATP1B1 uptake and carboxylesterase 1 activation — StatPearls (NCBI)
- Angioedema — bradykinin- vs histamine-mediated, treatment resistance, DPP-4 — StatPearls (NCBI)
- Angiotensin II Receptor Blockers — angiotensin I converted by ACE and non-ACE pathways — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.