Drug Monograph
Lisinopril
Zestril, Prinivil — lysine analog of enalaprilat
Pharmacokinetic Profile
Half-Life
~12 h (effective accumulation); ~40 h (terminal)
Metabolism
None — not a prodrug; excreted unchanged in urine
Protein Binding
Does not bind to serum proteins (other than ACE)
Bioavailability
~25% (6–60% inter-patient variability); ~16% in NYHA II–IV HF
Volume of Distribution
Slightly smaller in HF; not extensively distributed beyond plasma
Clinical Information
Drug Class
Angiotensin-Converting Enzyme (ACE) Inhibitor
Available Doses
2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg (tablets); oral solution available
Route
Oral (once daily)
Renal Adjustment
CrCl 10–30: half starting dose; CrCl <10 or HD: 2.5 mg daily
Hepatic Adjustment
None required (not hepatically metabolised)
Pregnancy
Contraindicated — FDA Boxed Warning (fetal injury/death)
Lactation
Unknown excretion; manufacturer recommends against use
Schedule / Legal Status
Rx only
Generic Available
Yes (widely available)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypertension | Adults and paediatric ≥6 years | Monotherapy or combination | FDA Approved |
| Heart failure (systolic, HFrEF) | Adults | Adjunctive (with diuretics ± digitalis) | FDA Approved |
| Acute myocardial infarction (haemodynamically stable, within 24 h) | Adults | Monotherapy or combination | FDA Approved |
Lisinopril is one of the most widely prescribed ACE inhibitors globally and a cornerstone of cardiovascular pharmacotherapy. Unlike enalapril and most other ACE inhibitors, lisinopril is not a prodrug: it is the active moiety itself, requiring no hepatic conversion. This makes it suitable for patients with significant liver disease. Its long effective half-life supports once-daily dosing across all indications. The GISSI-3 trial established its mortality benefit in acute MI, while the ATLAS trial demonstrated that higher doses (32.5–35 mg) reduce combined death and hospitalisation compared with low doses (2.5–5 mg) in heart failure.
Off-Label Uses
Diabetic nephropathy / proteinuria reduction: The ADA recommends ACE inhibitors as first-line agents in hypertensive patients with diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Lisinopril reduces proteinuria and slows progression of diabetic kidney disease. Evidence: High
Migraine prophylaxis: Limited data suggest lisinopril 10–20 mg daily may reduce migraine frequency and severity. Evidence: Moderate
Scleroderma renal crisis: ACE inhibitors are first-line treatment per EULAR recommendations. Evidence: Moderate
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — not on diuretic | 10 mg once daily | 20–40 mg once daily | 80 mg/day | Onset ~1 h; peak effect ~6 h; antihypertensive effect may diminish at end of dosing interval with ≤10 mg Doses above 40 mg may not provide additional BP reduction |
| Hypertension — on concomitant diuretic | 5 mg once daily | 20–40 mg once daily | 80 mg/day | Discontinue diuretic 2–3 days before starting if possible; if cannot discontinue, supervise for ≥2 h after first dose Risk of first-dose hypotension in volume-depleted patients |
| Heart failure (HFrEF) — adjunctive therapy | 5 mg once daily (2.5 mg if Na<130 mEq/L) | 20–40 mg once daily | 40 mg/day | Use with diuretics ± digitalis; titrate by ≤10 mg at ≥2-week intervals ATLAS trial: high-dose (32.5–35 mg) reduced death + hospitalisation by 12% vs low-dose (2.5–5 mg) |
| Acute MI — haemodynamically stable, within 24 h | 5 mg within 24 h of symptom onset | 5 mg at 24 h, then 10 mg at 48 h, then 10 mg once daily | 10 mg/day | Continue for ≥6 weeks; SBP 100–120 mmHg: start 2.5 mg; SBP ≤100 mmHg: maintenance 5 mg (temporary 2.5 mg if needed); SBP <90 for >1 h: discontinue GISSI-3: 11% reduction in 6-week mortality (6.4% vs 7.2%, 2p=0.04) |
Paediatric and Renal Dose Adjustments
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Paediatric hypertension (≥6 years, GFR >30) | 0.07 mg/kg once daily (up to 5 mg) | Adjust per BP response | 0.61 mg/kg (up to 40 mg) | Not recommended if GFR <30 or age <6 years Oral solution available for paediatric dosing |
| CrCl 10–30 mL/min (all indications) | Half the usual starting dose (HTN: 5 mg; HF/MI: 2.5 mg) | Titrate per response | 40 mg/day | Reduced renal clearance prolongs elimination Monitor renal function and potassium closely during titration |
| CrCl <10 mL/min or haemodialysis | 2.5 mg once daily | Titrate per response | 40 mg/day | Lisinopril is dialysable; supplement after haemodialysis if needed AUC and Cmax approximately doubled in elderly patients |
Clinical Pearl: Not a Prodrug
Unlike enalapril, ramipril, and most other ACE inhibitors, lisinopril is not a prodrug and requires no hepatic conversion to its active form. It is already the active moiety (the lysine analog of enalaprilat). This means its onset, efficacy, and duration are unaffected by liver function, making it a suitable choice for patients with hepatic impairment or cirrhosis. No hepatic dose adjustment is required for any degree of liver disease.
Pharmacology
Mechanism of Action
Lisinopril competitively inhibits angiotensin-converting enzyme (ACE), which catalyses two critical reactions: the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, and the degradation of the vasodilator bradykinin. By blocking both pathways, lisinopril reduces systemic vascular resistance and aldosterone secretion (lowering blood pressure and sodium retention) while increasing circulating bradykinin (contributing to vasodilation but also accounting for the class-associated dry cough and angioedema risk). The resulting suppression of the renin-angiotensin-aldosterone system (RAAS) reduces cardiac preload and afterload, which is the basis for its benefit in heart failure and post-MI remodelling. Lisinopril also increases serum renin activity through removal of angiotensin II negative feedback.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~25% (range 6–60%); reduced to ~16% in NYHA II–IV heart failure; Tmax ~7 h; not affected by food | Large inter-patient variability necessitates dose titration to clinical response rather than relying on a fixed dose; food does not need to be considered for timing |
| Distribution | Does not bind to serum proteins other than ACE; Vd slightly smaller in heart failure patients; in rat studies, radioactivity found in the placenta but not in the foetuses | Absence of significant protein binding means drug-displacement interactions are not a concern; foetal toxicity from ACE inhibitors is due to pharmacological RAAS blockade (causing foetal renal dysfunction) rather than direct drug transfer — FDA Boxed Warning applies regardless |
| Metabolism | Not metabolised — lisinopril is already the active compound (not a prodrug); no hepatic biotransformation; does not inhibit CYP enzymes | Liver disease does not affect efficacy or clearance; no dose adjustment required for any degree of hepatic impairment; drug-drug interactions via CYP metabolism are not expected |
| Elimination | Excreted entirely unchanged in urine via glomerular filtration, tubular secretion, and reabsorption; effective accumulation t½ ~12 h; terminal t½ ~40 h (saturable ACE binding); steady state after 2–3 daily doses | Renal impairment directly prolongs elimination — dose reduction required at CrCl ≤30; the 12 h effective half-life supports once-daily dosing; the 40 h terminal half-life reflects slow dissociation from tissue ACE and does not contribute to drug accumulation at standard intervals |
Side Effects
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypotension (persistent, SBP <90 for >1 h) | 9.0% (GISSI-3, MI); 3.8% excess (HF trials) | Most common in acute MI and HF settings; risk increased in volume-depleted or diuretic-treated patients; start low and titrate slowly; hold diuretic 2–3 days before initiation if possible |
| Cough (dry, persistent) | 3–10% | Class effect due to bradykinin accumulation; occurs weeks to months after initiation; resolves within 1–4 weeks of discontinuation; switch to ARB if intolerable |
| Headache | 5.7% | Usually self-limiting; more common early in therapy; 3.8% excess over placebo in hypertension trials |
| Dizziness | 5.4% | Related to blood pressure lowering; 3.5% excess over placebo; more frequent in elderly and volume-depleted patients |
| Hypotension (in hypertension) | 1–4% | Symptomatic postural hypotension usually not observed at recommended starting doses; anticipated in volume/salt-depleted patients |
| Hyperkalaemia (K>5.7 mEq/L) | 2.2% (HTN); 4.8% (HF) | Risk increased with renal impairment, diabetes, K-sparing diuretics, or potassium supplements; monitor potassium within 1–2 weeks of initiation |
| Fatigue / asthenia | 1–3% | Usually mild; may improve with continued therapy |
| Diarrhoea | 1–3% | Gastrointestinal effects generally mild |
| Serum creatinine elevation | 1–2% | Benign increase common at initiation; expected rise up to 30% is acceptable; significant or progressive elevation warrants discontinuation or evaluation for renal artery stenosis |
Serious
Serious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Angioedema | 0.1–0.2% | Usually within first 3 months (can occur any time) | Discontinue lisinopril immediately and permanently; manage airway emergently; administer epinephrine if laryngeal involvement; document ACE inhibitor allergy in records; Black patients have 2–4× higher risk |
| Acute renal failure | Rare; higher risk with bilateral renal artery stenosis | Days to weeks after initiation | Assess renal function before and after initiation; discontinue if progressive rise in creatinine (>30% above baseline); screen for renal artery stenosis in patients with unexplained renal decline |
| Severe hyperkalaemia (K>6.0 mEq/L) | ~1% (higher in HF and CKD) | Days to weeks | ECG monitoring; discontinue K-sparing agents; administer calcium, insulin/dextrose, sodium bicarbonate, or sodium polystyrene as clinically indicated; discontinue lisinopril if refractory |
| Hepatotoxicity (cholestatic jaundice progressing to hepatic necrosis) | Rare (case reports) | Weeks to months | Discontinue immediately if jaundice or marked transaminase elevation; provide supportive care; ACE inhibitor-related hepatotoxicity can be fatal if not recognised early |
| Foetal toxicity | High risk (2nd & 3rd trimester) | In utero exposure | FDA Boxed Warning: discontinue as soon as pregnancy detected; causes oligohydramnios, foetal renal failure, skull hypoplasia, limb contractures, and neonatal death; counsel all women of childbearing potential |
Discontinuation
Discontinuation Rates
Hypertension Trials
5.7% discontinued due to adverse events
Top reasons: Headache (3.8% excess), dizziness (3.5% excess), cough (2.5% excess)
Heart Failure (Up to 4 Years)
11% discontinued due to adverse events
Top reasons: Hypotension (3.8% excess), chest pain (2.1% excess), renal dysfunction (1.3% excess)
ACE Inhibitor Cough: Management Strategy
Dry cough occurs in 3–10% of patients taking ACE inhibitors due to accumulation of bradykinin and substance P in the bronchial mucosa. It is more common in women, non-smokers, and patients of East Asian descent. The cough is nonproductive, persistent, and typically worsens at night or when supine. After ACE inhibitor discontinuation, cough resolves within 1–4 weeks. If BP or HF therapy must continue, switching to an ARB (e.g., losartan, valsartan) eliminates the cough in the majority of patients, as ARBs do not affect bradykinin metabolism.
Drug Interactions
Lisinopril is not metabolised by CYP enzymes and does not bind significantly to plasma proteins, so pharmacokinetic drug interactions are minimal. The primary interaction concerns are pharmacodynamic: drugs affecting RAAS, potassium homeostasis, or renal function can amplify lisinopril’s effects or cause dangerous hyperkalaemia or hypotension.
MajorSacubitril / Neprilysin Inhibitors (Entresto)
MechanismDual inhibition of neprilysin and ACE markedly increases bradykinin
EffectLife-threatening angioedema risk
ManagementContraindicated; allow 36-hour washout after stopping lisinopril before starting sacubitril/valsartan (and vice versa)
FDA PIMajorAliskiren (in diabetes or CrCl <60)
MechanismDual RAAS blockade (direct renin inhibitor + ACE inhibitor)
EffectIncreased risk of hyperkalaemia, hypotension, and renal impairment
ManagementContraindicated in patients with diabetes; avoid in patients with CrCl <60 mL/min
FDA PIMajorPotassium-Sparing Diuretics / K+ Supplements
MechanismACE inhibitors reduce aldosterone, decreasing renal potassium excretion
EffectSevere hyperkalaemia, potentially fatal cardiac arrhythmias
ManagementIf concurrent use essential, monitor potassium frequently; avoid routine K+ supplementation; use with extreme caution in renal impairment
FDA PIModerateNSAIDs (ibuprofen, naproxen, ketorolac)
MechanismNSAIDs reduce prostaglandin-mediated renal blood flow and oppose ACE inhibitor antihypertensive effect
EffectAttenuated BP lowering; increased risk of acute kidney injury, especially in elderly, dehydrated, or CKD patients
ManagementMonitor renal function and BP when starting or stopping NSAIDs; use paracetamol as alternative analgesic when possible
FDA PIModerateLithium
MechanismACE inhibitors reduce lithium renal clearance
EffectIncreased serum lithium levels; risk of lithium toxicity
ManagementMonitor lithium levels closely after initiation, dose change, or discontinuation of lisinopril; concurrent use with diuretics further increases risk
FDA PIMinorDiuretics (thiazides, loop)
MechanismAdditive BP lowering; volume depletion activates RAAS, amplifying ACE inhibitor effect
EffectFirst-dose hypotension (especially if volume-depleted); therapeutic combination for refractory hypertension
ManagementExpected combination; temporarily hold diuretic 2–3 days before starting or start lisinopril at reduced dose (5 mg); no PK interaction with furosemide confirmed
FDA PIMonitoring
- Blood PressureEach visit; 2–4 weeks after dose changes
RoutineMeasure sitting and standing; peak antihypertensive effect occurs ~6 h post-dose; trough effect (just before next dose) should be measured to confirm 24-hour coverage, especially at doses ≤10 mg - Serum PotassiumBaseline; 1–2 weeks after initiation or dose change; periodic
RoutineHyperkalaemia (K>5.7) occurred in 2.2% of hypertension and 4.8% of heart failure patients in clinical trials; risk increased with renal impairment, diabetes, concurrent K-sparing agents - Renal Function (BUN/Creatinine)Baseline; 1–2 weeks after initiation; periodic
RoutineUp to 30% rise in creatinine is expected and acceptable at initiation; progressive or >30% rise warrants evaluation for renal artery stenosis or volume depletion; higher risk of renal dysfunction in HF (1.3% excess vs placebo) - Pregnancy StatusBefore initiation; ongoing in women of childbearing potential
RoutineFDA Boxed Warning: discontinue as soon as pregnancy is detected; lisinopril causes foetal renal failure, oligohydramnios, and death when used in 2nd–3rd trimester; counsel contraception - Angioedema SignsEvery assessment (especially first 3 months)
Trigger-basedAsymmetric swelling of face, lips, tongue, or airway without urticaria; can occur at any time but most common within first 3 months; higher incidence in Black patients (2–4× relative risk); permanently discontinue if occurs - Hepatic FunctionIf jaundice or symptoms suggestive of hepatic injury occur
Trigger-basedRare cholestatic jaundice progressing to hepatic necrosis has been reported with ACE inhibitors; discontinue lisinopril and investigate if marked transaminase elevation or jaundice develops
Contraindications & Cautions
Absolute Contraindications
- History of angioedema related to prior ACE inhibitor use: Risk of recurrence is high; permanently contraindicates the entire ACE inhibitor class
- Hereditary or idiopathic angioedema: ACE inhibitors may precipitate or worsen episodes
- Concurrent use with neprilysin inhibitors (sacubitril): Requires 36-hour washout period between agents due to severe angioedema risk
- Concurrent use with aliskiren in patients with diabetes: Increased risk of hyperkalaemia, hypotension, and renal impairment
- Pregnancy (2nd and 3rd trimester): FDA Boxed Warning — causes foetal injury and death
Relative Contraindications (Specialist Input Recommended)
- Bilateral renal artery stenosis (or unilateral in solitary kidney): ACE inhibitors can precipitate acute renal failure by abolishing efferent arteriolar tone needed to maintain GFR
- Severe aortic stenosis or hypertrophic cardiomyopathy with outflow obstruction: Afterload reduction may cause haemodynamic compromise
- Hyperkalaemia (K>5.5 mEq/L): ACE inhibitors further reduce potassium excretion
Use with Caution
- Renal impairment (CrCl <30 mL/min): Reduce starting dose; monitor creatinine and potassium closely
- Volume/salt depletion: At high risk of first-dose hypotension; correct volume status or start at lower dose with supervision
- Elderly: Cmax and AUC approximately doubled; start at lowest dose; assess renal function
- Black patients: Higher incidence of angioedema (2–4×) and reduced antihypertensive response to ACE inhibitor monotherapy; combination with thiazide or CCB often needed
FDA Boxed Warning
Foetal Toxicity
When pregnancy is detected, discontinue lisinopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing foetus. In the second and third trimesters, ACE inhibitors cause oligohydramnios resulting from decreased foetal renal function, which can lead to foetal limb contractures, skull hypoplasia, pulmonary hypoplasia, and neonatal death. Counsel all women of childbearing potential about the risks and the need for effective contraception while taking lisinopril.
Patient Counselling
Purpose of Therapy
Explain that lisinopril is a once-daily tablet that relaxes blood vessels and reduces the workload on the heart. It is used to treat high blood pressure, help the heart pump more effectively in heart failure, and reduce the risk of death after a heart attack. It works by blocking a chemical (angiotensin II) that narrows blood vessels and causes salt and water retention.
How to Take
Take lisinopril at approximately the same time each day with or without food. Do not stop taking it suddenly without consulting your prescriber, even if you feel well, as high blood pressure often has no symptoms. If you miss a dose, take it as soon as you remember unless it is close to your next dose, in which case skip the missed dose.
Dizziness and Low Blood Pressure
Tell patientYou may feel lightheaded or dizzy, especially when standing up quickly or when starting the medication. Rise slowly from sitting or lying positions. Drink adequate fluids unless your doctor has restricted your fluid intake. Dizziness usually improves as your body adjusts to the medication.
Call prescriberContact your prescriber if dizziness is severe, persistent, or accompanied by fainting, as your dose may need adjustment.
Dry Cough
Tell patientA dry, persistent cough is a known side effect of this class of medication and occurs in up to 1 in 10 patients. It is not dangerous but can be bothersome. The cough goes away within a few weeks of stopping the medication. There are alternative medications available that do not cause cough.
Call prescriberReport the cough to your prescriber; they may switch you to a different type of blood pressure medication (ARB) that does not cause this side effect.
Swelling of Face, Lips, or Tongue (Angioedema)
Tell patientIn rare cases, this medication can cause swelling of the face, lips, tongue, or throat. This is a serious allergic reaction that can make it difficult to breathe or swallow. It can happen at any time, even if you have been taking the medication for months or years.
Call prescriberSeek emergency medical help immediately if you develop any swelling of the face, lips, tongue, or throat, or if you have difficulty breathing or swallowing. Do not take another dose of this medication.
Pregnancy Warning
Tell patientLisinopril can cause serious harm or death to an unborn baby, especially during the second and third trimesters of pregnancy. If you are planning to become pregnant or think you might be pregnant, you must discuss this with your prescriber before conception so a safer alternative can be arranged.
Call prescriberNotify your prescriber immediately if you become pregnant or suspect you may be pregnant. Do not wait for your next scheduled appointment.
Potassium Levels
Tell patientThis medication can increase potassium levels in your blood. Avoid using salt substitutes containing potassium (e.g., Lo-Salt) and avoid taking potassium supplements unless specifically directed by your prescriber. Eat a balanced diet without excessive potassium-rich foods.
Call prescriberReport any muscle weakness, irregular heartbeat, tingling, or numbness, as these may be signs of high potassium.
Sources
Regulatory (PI / SmPC)
- Zestril (lisinopril) Prescribing Information. AstraZeneca; FDA-approved label, revised 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019777s060lbl.pdfPrimary FDA label for lisinopril (Zestril) with complete prescribing information including dosing, GISSI-3 and ATLAS trial data, adverse reactions, and pharmacokinetics.
- Prinivil (lisinopril) Prescribing Information. Merck; FDA-approved label, revised 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019558s060lbl.pdfAlternate brand label with paediatric dosing data, dose-response studies, and heart failure clinical trial summaries.
Key Clinical Trials
- Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3: 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. doi:10.1016/S0140-6736(94)90232-1Landmark trial (n=19,394) showing 11% reduction in 6-week mortality with lisinopril (6.4% vs 7.2%, 2p=0.04) when initiated within 24 hours of acute MI.
- Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting-enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure (ATLAS). Circulation. 1999;100(23):2312–2318. doi:10.1161/01.CIR.100.23.2312RCT (n=3,164) comparing high-dose (32.5–35 mg) vs low-dose (2.5–5 mg) lisinopril in chronic HF; high dose reduced combined death and hospitalisation by 12%.
Guidelines
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895–e1032. doi:10.1161/CIR.0000000000001063Current AHA/ACC heart failure guideline recommending ACE inhibitors (including lisinopril) for HFrEF as part of guideline-directed medical therapy.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 2018;71(6):e13–e115. doi:10.1161/HYP.0000000000000065ACC/AHA hypertension guideline with ACE inhibitor positioning as first-line therapy, particularly in patients with diabetes, CKD, or heart failure.
- ElSayed NA, Aleppo G, Aroda VR, et al. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1):S179–S218. doi:10.2337/dc24-S010ADA Standards of Care recommending ACE inhibitors as first-line antihypertensive agents in patients with diabetes and albuminuria (UACR ≥30 mg/g).
Mechanistic / Basic Science
- Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998;97(14):1411–1420. doi:10.1161/01.CIR.97.14.1411Comprehensive review of ACE inhibitor pharmacology including bradykinin potentiation, RAAS suppression, and the mechanistic basis for cough and angioedema.
Pharmacokinetics / Special Populations
- Lisinopril. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK482230/Comprehensive clinical pharmacology review with dosing by indication, renal adjustments, adverse effects, and drug interactions.
- Beermann B. Pharmacokinetics of lisinopril. Am J Med. 1988;85(3B):25–30. doi:10.1016/0002-9343(88)90346-4Definitive PK study establishing lisinopril’s 25% oral bioavailability, 12.6 h accumulation half-life, lack of metabolism, and renal elimination.