ACE inhibitors: reduce angiotensin II, protect the heart and kidneys
Angiotensin-converting-enzyme (ACE) inhibitors are medicines that block the renin–angiotensin–aldosterone system (RAAS). By reducing formation of angiotensin II and slowing breakdown of bradykinin, they lower blood pressure, reduce cardiac workload and maladaptive remodelling, and can lower intraglomerular pressure in proteinuric kidney disease. They are central medicines in hypertension, heart failure with reduced ejection fraction (HFrEF), selected post-myocardial-infarction patients, and chronic kidney disease with albuminuria.
Clinical safety message: ACE inhibitors are prescription medicines. Check blood pressure, renal function and serum potassium before treatment and after starting or increasing the dose. They are contraindicated in pregnancy and must be stopped promptly if pregnancy occurs.
1. What are ACE inhibitors?
ACE inhibitors are cardiovascular medicines whose generic names usually end in -pril. They inhibit ACE, also called kininase II. ACE normally converts the relatively inactive peptide angiotensin I into the potent vasoconstrictor angiotensin II and also helps break down the vasodilator bradykinin.
Blocking this enzyme therefore produces two important effects at the same time: less angiotensin II and more bradykinin. The first effect explains most cardiovascular and renal benefits; the second contributes to vasodilation but also explains the characteristic dry cough and some cases of angioedema.
Common ACE inhibitors
Captopril
Active drug with relatively rapid onset and short duration. Usually given two or three times daily. It is especially familiar in scleroderma renal crisis; its short action can also be useful when careful dose adjustment is required. Food reduces its absorption, so it is commonly taken before meals.
Enalapril
An oral prodrug converted to active enalaprilat. Enalaprilat is the ACE inhibitor available for intravenous use in selected settings. Enalapril is commonly used in hypertension and HFrEF.
Lisinopril
An active, water-soluble medicine that is not metabolised to an active metabolite. It is usually given once daily and is cleared mainly by the kidneys; dose adjustment is needed in renal impairment.
Ramipril and perindopril
Longer-acting prodrugs commonly used for hypertension and cardiovascular risk reduction in appropriate patients. They are convenient for adherence because of once-daily dosing.
Fosinopril
A prodrug whose active metabolite has both renal and hepatic elimination. This may be useful where renal function is reduced, but dose choice must still follow the local formulary and clinical assessment.
Benazepril, quinapril, trandolapril, moexipril
These share the same class mechanism but differ in onset, duration, metabolism, availability and approved indications. Choose an agent that is available, affordable, evidence-based for the indication, and practical for the patient.
2. The RAAS: why blocking ACE lowers blood pressure
The RAAS is a hormonal system that preserves circulating volume and arterial pressure. It is helpful during haemorrhage or dehydration, but chronic overactivity contributes to hypertension, heart failure, cardiac remodelling and kidney damage.
- Renin release: reduced renal perfusion, sympathetic stimulation, or reduced sodium delivery to the macula densa stimulates juxtaglomerular cells in the kidney to release renin.
- Angiotensin I formation: renin cleaves liver-derived angiotensinogen to form angiotensin I.
- ACE action: ACE, found prominently on vascular endothelium including pulmonary circulation, converts angiotensin I to angiotensin II.
- Angiotensin II action: mainly through AT1 receptors, angiotensin II constricts arterioles, promotes aldosterone secretion, increases sodium and water retention, enhances sympathetic activity, stimulates thirst, and promotes cardiac and vascular hypertrophy/fibrosis.
- Bradykinin breakdown: ACE also degrades bradykinin. Bradykinin promotes vasodilation partly through nitric oxide and prostacyclin.
ACE inhibitor → ↓ angiotensin II + ↓ aldosterone + ↑ bradykinin → vasodilation, natriuresis, lower preload and afterload, less remodelling, and lower intraglomerular pressure.
Step-by-step mechanism of action
- Arteriolar vasodilation: less angiotensin II reduces systemic vascular resistance. This reduces afterload, so the left ventricle ejects blood against less resistance.
- Reduced aldosterone: less aldosterone reduces sodium reabsorption in the distal nephron. Water follows sodium, reducing extracellular fluid volume and preload.
- Less sympathetic and trophic stimulation: chronic angiotensin II promotes adverse myocardial and vascular hypertrophy. ACE inhibitors help limit this remodelling, particularly after MI and in HFrEF.
- Efferent arteriolar dilation: angiotensin II normally constricts the efferent glomerular arteriole. ACE inhibition dilates it, reducing intraglomerular pressure and protein leakage. This is renoprotective in many proteinuric kidney diseases, but it can lower filtration pressure too much when renal perfusion is critically dependent on angiotensin II.
- Bradykinin accumulation: increased bradykinin contributes to vasodilation, dry persistent cough and, rarely, potentially fatal angioedema.
- Feedback response: plasma renin activity rises because the usual negative feedback from angiotensin II is removed. This does not mean the medicine has failed.
3. Major pharmacological effects
| System | Effect of ACE inhibition | Why it matters clinically |
|---|---|---|
| Arterioles | Vasodilation and reduced systemic vascular resistance | Lowers blood pressure and cardiac afterload |
| Veins / volume | Reduced aldosterone-mediated sodium and water retention | Reduces congestion and preload; assists heart-failure control |
| Heart | Reduces sympathetic/angiotensin-driven hypertrophy and fibrosis | Improves long-term outcomes in eligible HFrEF and post-MI patients |
| Glomerulus | Dilates efferent arteriole and lowers intraglomerular pressure | Can reduce albuminuria and slow kidney damage, but may increase creatinine in low-perfusion states |
| Potassium balance | Less aldosterone means less potassium excretion | Risk of hyperkalaemia; monitor serum potassium |
| Airway / skin | Bradykinin accumulation | Explains dry cough and angioedema |
4. Therapeutic uses
Hypertension
ACE inhibitors are effective antihypertensives. They are especially valuable when hypertension occurs with albuminuric chronic kidney disease, diabetes with albuminuria, HFrEF, previous myocardial infarction, or left-ventricular dysfunction. Many adults need combination treatment; an ACE inhibitor may be combined with a thiazide/thiazide-like diuretic or a dihydropyridine calcium-channel blocker when appropriate.
Important: do not routinely combine an ACE inhibitor with an ARB or direct renin inhibitor simply to obtain more RAAS blockade. The extra risk of hypotension, hyperkalaemia and acute kidney injury outweighs benefit in most patients.
Heart failure with reduced ejection fraction (HFrEF)
In symptomatic HFrEF, ACE inhibitors reduce afterload and preload and help counter harmful neurohormonal activation. They have a well-established mortality and morbidity benefit when used with other guideline-directed therapy. Where an ARNI (angiotensin receptor–neprilysin inhibitor) is indicated and tolerated, local guidelines may prefer it instead; an ACE inhibitor and an ARNI must never overlap. A 36-hour washout is required when changing from an ACE inhibitor to sacubitril/valsartan because of angioedema risk.
After myocardial infarction and left-ventricular dysfunction
ACE inhibitors are used after MI in appropriate stable patients, particularly where there is left-ventricular systolic dysfunction, heart failure, diabetes, hypertension or high cardiovascular risk. They reduce adverse ventricular remodelling and may improve survival. Start only after haemodynamic stability has been established; do not give during cardiogenic shock or significant hypotension.
Chronic kidney disease with albuminuria
By lowering intraglomerular pressure, ACE inhibitors reduce albuminuria and may slow progression of proteinuric CKD. A small early reduction in eGFR or rise in creatinine can occur from the intended haemodynamic effect. A substantial or progressive deterioration should trigger assessment for volume depletion, NSAID use, renal-artery stenosis, excessive diuresis, intercurrent illness or another cause of acute kidney injury.
Other important indications
- Diabetic kidney disease: particularly when hypertension and albuminuria are present.
- Non-diabetic proteinuric CKD: where clinically appropriate and carefully monitored.
- Scleroderma renal crisis: captopril is classically used because prompt ACE inhibition is life-saving.
- Selected high cardiovascular-risk patients: some agents have evidence in particular populations; use national/local guidance.
5. Choosing an ACE inhibitor: useful differences
| Feature | Captopril | Enalapril | Lisinopril | Ramipril / Perindopril |
|---|---|---|---|---|
| Active drug or prodrug | Active | Prodrug → enalaprilat | Active | Prodrugs |
| Usual duration | Shorter; often 2–3 times daily | Longer; often once or twice daily | Long; usually once daily | Long; usually once daily |
| Food effect | Absorption reduced by food | Minimal practical effect | Minimal practical effect | Check product-specific guidance |
| Special point | Scleroderma renal crisis; taste disturbance/rash more associated with sulfhydryl group | IV enalaprilat exists | Common once-daily option; renal elimination | Convenient long-acting choices |
Illustrative adult doses: always check the local formulary
Exact dose selection depends on diagnosis, age, blood pressure, renal function, potassium, concurrent diuretics and local protocol. The figures below are common adult oral ranges for study purposes—not an individual prescription.
| Medicine | Common starting dose | Common usual range / maximum | Practical notes |
|---|---|---|---|
| Captopril | 6.25–12.5 mg two or three times daily | Often titrated to 25–50 mg two or three times daily | Start very low in HFrEF, frailty, volume depletion or renal impairment; give before meals |
| Enalapril | 2.5–5 mg once or twice daily | Usually 10–20 mg/day; HFrEF targets may be higher in selected patients | Oral prodrug; dose-adjust in renal impairment |
| Lisinopril | 2.5–10 mg once daily | Usually 10–40 mg once daily | Renally cleared; reduce starting dose when eGFR is low |
| Ramipril | 1.25–2.5 mg once daily | Often 5–10 mg once daily | Titrate gradually; use lower initial dose in HFrEF or renal impairment |
| Perindopril | 2–4 mg once daily | Usually 4–8 mg once daily | Product salt/formulation may alter stated strength; check local product |
6. Adverse effects and their mechanisms
Dry, persistent cough
Usually non-productive and troublesome, often developing days to months after starting therapy. It is linked to increased bradykinin and substance P in the airways. Exclude infection, asthma, reflux and heart failure; if clearly drug related and intolerable, a clinician may change to an ARB.
Hypotension and dizziness
Most likely after the first dose or a dose increase in patients who are volume depleted, taking high-dose diuretics, have severe heart failure, diarrhoea/vomiting, low dietary salt or hyponatraemia. Assess for postural symptoms and falls risk.
Hyperkalaemia
Reduced aldosterone means reduced renal potassium excretion. Risk rises with CKD, diabetes, dehydration, potassium supplements, potassium-sparing diuretics, trimethoprim, NSAIDs and dual RAAS blockade.
Rise in creatinine / acute kidney injury
A modest early creatinine rise may occur because efferent arteriolar dilation lowers filtration pressure. Marked or progressive deterioration is dangerous and requires prompt review for dehydration, renal artery stenosis, NSAIDs, sepsis, excessive diuresis or obstruction.
Angioedema
Sudden swelling of lips, tongue, face, throat or bowel can occur at any time and may obstruct the airway. Stop the ACE inhibitor and seek urgent emergency care immediately. Prior ACE-inhibitor angioedema is a contraindication to future ACE inhibitor use.
Other effects
Headache, fatigue, nausea, rash, taste disturbance (especially captopril), rare neutropenia/agranulocytosis, proteinuria, cholestatic/hepatocellular injury and rare severe skin reactions may occur. Investigate persistent or severe symptoms rather than assuming they are benign.
Angioedema: act immediately
Any tongue, mouth or throat swelling, voice change, stridor, dyspnoea, difficulty swallowing, or rapidly progressive facial swelling in a patient taking an ACE inhibitor is a potential airway emergency. Stop the medicine, activate emergency assessment, protect the airway and document the reaction clearly. Do not rechallenge with an ACE inhibitor.
7. Contraindications and major cautions
Do not use ACE inhibitors in the following situations
- Pregnancy: ACE inhibitors can cause fetal renal injury, oligohydramnios, skull hypoplasia, pulmonary hypoplasia, neonatal renal failure and death, especially after the first trimester. Stop immediately when pregnancy is recognised and arrange urgent clinician review for an alternative.
- Previous ACE-inhibitor-related angioedema: also avoid in hereditary or idiopathic angioedema unless a specialist specifically directs otherwise.
- Known hypersensitivity to the medicine.
- Concomitant neprilysin inhibitor use: never administer with sacubitril/valsartan; allow a 36-hour washout when switching from an ACE inhibitor to an ARNI.
- Concomitant aliskiren in diabetes: this combination is contraindicated in many product labels because of renal, potassium and hypotension risk.
Use only with careful assessment, monitoring or specialist input
- Suspected bilateral renal-artery stenosis or stenosis in a solitary functioning kidney: glomerular filtration may depend heavily on angiotensin-II-mediated efferent constriction.
- Existing hyperkalaemia or conditions strongly predisposing to it.
- Severe renal impairment, acute kidney injury or rapidly changing renal function.
- Marked volume depletion: correct dehydration, vomiting, diarrhoea or over-diuresis first where possible.
- Severe aortic stenosis, hypertrophic obstructive cardiomyopathy or other fixed-outflow states: vasodilation may be poorly tolerated.
- Dialysis with certain high-flux membranes or LDL apheresis: rare anaphylactoid reactions have been reported; check the service protocol.
8. Clinically important interactions
| Interacting medicine / situation | What may happen | Safe response |
|---|---|---|
| Potassium supplements or salt substitutes containing potassium | Hyperkalaemia | Avoid unless specifically prescribed; monitor potassium |
| Spironolactone, eplerenone, amiloride, triamterene | Marked potassium rise, especially with CKD | Use only when indicated with close monitoring |
| NSAIDs | Reduced antihypertensive effect and increased acute kidney injury risk | Avoid unnecessary NSAIDs; assess hydration and renal function |
| Diuretic + ACE inhibitor + NSAID | The “triple whammy”: higher risk of acute kidney injury | Educate patient; check renal function promptly if unwell |
| ARB or aliskiren | Dual RAAS blockade: hypotension, hyperkalaemia and renal harm | Do not combine routinely |
| Sacubitril/valsartan | Increased angioedema risk | Never overlap; maintain the required 36-hour washout from ACE inhibitor |
| Lithium | Reduced lithium clearance and lithium toxicity | Avoid where possible or monitor lithium level closely |
| Trimethoprim / co-trimoxazole | May contribute to hyperkalaemia | Review risk, particularly in older adults and CKD |
9. Monitoring before and during treatment
Baseline assessment
- Confirm the indication and check whether an ACE inhibitor is the appropriate RAAS medicine.
- Record blood pressure; include sitting/standing measurement if dizziness, frailty or volume depletion is possible.
- Check serum creatinine/eGFR and potassium.
- Review pregnancy status and contraception where relevant; counsel clearly about fetal risk.
- Review current medicines, especially NSAIDs, diuretics, potassium products, ARBs, aliskiren, lithium and mineralocorticoid receptor antagonists.
- Assess fluid status, heart-failure congestion, dehydration and recent vomiting/diarrhoea.
After starting or changing the dose
- Recheck blood pressure, creatinine/eGFR and potassium within approximately 1–2 weeks of initiation or dose increase, sooner in high-risk patients or according to the local protocol.
- Ask about dizziness, syncope, cough, reduced urine output, muscle weakness/palpitations, facial swelling and adherence.
- Once stable, repeat renal function and potassium periodically and whenever intercurrent illness, dehydration, a new interacting medicine, or dose adjustment occurs.
- A creatinine rise around 30% or more from baseline, significant potassium elevation, symptomatic hypotension or a rapidly falling eGFR needs clinical review rather than automatic continuation.
Vomiting, diarrhoea, fever, or poor fluid intake can make ACE inhibition unsafe
Patients who become significantly dehydrated may develop hypotension or acute kidney injury. They should seek advice promptly; local “sick-day” plans may advise temporary withholding of an ACE inhibitor during severe dehydrating illness and restarting only after recovery and clinical advice. This must be individualised—patients with heart failure should not make prolonged changes without guidance.
10. Nursing considerations
Assessment and administration
- Check the prescription, indication, current BP, apical pulse where relevant, fluid status, renal function and potassium before administration.
- For a first dose or dose escalation in a vulnerable patient, monitor for postural hypotension. Encourage slow position changes and falls precautions.
- Do not administer an ACE inhibitor automatically to a patient with severe hypotension, shock, active significant dehydration, acute kidney injury, marked hyperkalaemia or suspected angioedema—escalate to the prescriber.
- Document baseline and follow-up clinical findings, laboratory values, patient education and any adverse reaction.
- In a heart-failure patient, assess weight, oedema, lung signs, dyspnoea, exercise tolerance and diuretic response alongside BP and renal data.
Patient education
- Take the medicine at the same time each day. Do not double a missed dose; follow the product or clinician advice.
- Report persistent dry cough, fainting, severe dizziness, reduced urine, marked weakness, palpitations or muscle cramps.
- Seek emergency help immediately for swelling of lips, tongue, face or throat, breathing difficulty or voice change.
- Avoid over-the-counter NSAIDs such as ibuprofen or diclofenac unless a clinician/pharmacist says they are safe.
- Avoid potassium supplements and potassium-containing salt substitutes unless specifically prescribed.
- Tell every clinician and pharmacist about the ACE inhibitor, especially before new diuretics, antibiotics, lithium or cardiovascular medicines are added.
- Pregnancy must be reported immediately. Discuss reliable contraception and safer antihypertensive alternatives with the prescriber where pregnancy is possible or planned.
11. ACE inhibitors versus ARBs
| Feature | ACE inhibitors | ARBs |
|---|---|---|
| Site of action | Inhibit conversion of angiotensin I to angiotensin II and reduce bradykinin breakdown | Block AT1 receptors, preventing most angiotensin-II actions at that receptor |
| Bradykinin | Increases bradykinin | Does not directly increase bradykinin to the same extent |
| Cough | More characteristic | Less common; ARB is often considered if ACE-inhibitor cough is intolerable |
| Angioedema | Recognised rare but serious risk | Less frequent but can still occur; decision after ACE-inhibitor angioedema needs clinician judgement |
| Pregnancy / renal / potassium risks | Important risks | Also important risks |
12. Applied clinical scenarios
Hypertension + diabetes + albuminuria
An ACE inhibitor may be particularly helpful because it lowers BP and reduces intraglomerular pressure/proteinuria. Baseline creatinine, eGFR and potassium are essential; arrange early follow-up after starting or titrating.
HFrEF patient on furosemide
Start low and titrate gradually. The patient may be prone to first-dose hypotension because of diuresis and low effective circulating volume. Monitor BP, symptoms, renal function and potassium carefully; do not confuse a small expected creatinine rise with automatic treatment failure.
New dry cough after enalapril
Exclude other causes. If the cough is persistent and troublesome and linked to the ACE inhibitor, the prescriber may replace it with an ARB. Do not treat the cough simply by adding another medicine without reviewing the cause.
ACE inhibitor + spironolactone + potassium supplement
This combination can cause dangerous hyperkalaemia, particularly with CKD. Review the indication for each medicine, stop non-essential potassium exposure and obtain urgent potassium/renal testing where clinically indicated.
Facial swelling and hoarse voice
Assume potential angioedema. Stop the ACE inhibitor and initiate emergency airway assessment. This is not a routine allergy complaint to “watch at home.”
Pregnancy test becomes positive
Stop ACE inhibitor treatment promptly and arrange urgent clinician review for alternative BP management and obstetric assessment. Document the exposure and provide clear counselling.
13. High-yield examination points
- ACE inhibitors block angiotensin I → angiotensin II conversion and reduce bradykinin degradation.
- They reduce aldosterone, so they may cause hyperkalaemia.
- The classic adverse effect is a dry persistent cough due to bradykinin/substance-P accumulation.
- Angioedema is uncommon but can be life-threatening because of airway obstruction.
- ACE inhibitors dilate the efferent glomerular arteriole, lowering intraglomerular pressure and albuminuria.
- A rise in creatinine after initiation can occur; a substantial or progressive rise requires assessment for renal hypoperfusion, NSAIDs, dehydration or renal-artery stenosis.
- They are contraindicated in pregnancy and after previous ACE-inhibitor angioedema.
- Do not combine routinely with an ARB or aliskiren; never overlap with sacubitril/valsartan.
- Captopril and lisinopril are active drugs; many other ACE inhibitors are prodrugs.
- Enalaprilat is the intravenous ACE inhibitor.
- Check blood pressure, creatinine/eGFR and potassium before treatment and after initiation or dose escalation.
Can you answer these without looking back?
- Why do ACE inhibitors lower blood pressure and cause cough?
- Which glomerular arteriole do they dilate, and why can this reduce albuminuria?
- Name four situations in which hyperkalaemia risk is increased.
- What symptoms make ACE-inhibitor angioedema an emergency?
- Why must an ACE inhibitor never overlap with sacubitril/valsartan?
- Which three measurements or investigations are most important before and shortly after starting treatment?
