Angiotensin-converting enzyme inhibitors

Synonyms: ACE inhibitors, ACEIs, ACEs

What are angiotensin-converting enzyme inhibitors?¹

Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE). They have many uses and are generally well tolerated.

Angiotensin II has various functions including:

• Promoting vasoconstriction - through stimulation of the sympathetic nervous system, and the release of aldosterone and vasopressin.

• Renal changes - some of which are through the actions of aldosterone (with salt and water retention) and others which may be caused directly - eg, renal vasoconstriction.

• Cardiac and vascular remodelling - through the actions of growth factors and increased afterload.

This leads to hypertension and the complications of hypertension, such as left ventricular hypertrophy. ACE inhibitors induce vasodilatation which will improve cardiac output (by reducing afterload) and enhance the renal excretion of salt and water. Most ACE inhibitors are prodrugs which are metabolised in the liver to active metabolites. All are excreted by the kidney, and need careful titration in renal impairment.

Indications¹

Hypertension

An ACE inhibitor may be the most appropriate initial drug for hypertension in younger Caucasian patients.

Patients of black African or African-Caribbean origin, those aged over 55 years, and those with primary aldosteronism respond less well.

ACE inhibitors are particularly indicated for hypertension in patients with type 1 diabetes with nephropathy.

They may be used second-line for other patients if blood pressure (BP) is not adequately controlled on thiazide or a calcium-channel blocker (or if these drugs are not tolerated or are contra-indicated). See separate article Management of Hypertension.

They may reduce blood pressure very rapidly in some patients particularly in those receiving diuretic therapy.

Heart failure

ACE inhibitors are used in all grades of heart failure, usually combined with a beta-blocker.

Potassium supplements and potassium-sparing diuretics should be discontinued before introducing an ACE inhibitor because of the risk of hyperkalaemia. However, a low dose of spironolactone may be beneficial in severe heart failure and can be used with an ACE inhibitor provided serum potassium is monitored carefully.

Profound first-dose hypotension may occur when ACE inhibitors are introduced to patients with heart failure who are already taking a high dose of a loop diuretic (eg, furosemide 80 mg daily or more). Temporary withdrawal of the loop diuretic reduces the risk, but may cause severe rebound pulmonary oedema. Therefore, for patients on high doses of loop diuretics, the ACE inhibitor may need to be initiated under specialist supervision.

An ACE inhibitor can be initiated in the community in patients who are receiving a low dose of a diuretic or who are not otherwise at risk of serious hypotension; nevertheless, care is required and a very low dose of the ACE inhibitor is given initially.

See separate article Heart Failure Management.

Post-myocardial infarction (MI)

ACE inhibitors are used in the early and long-term management of patients who have had a myocardial infarction. ACE inhibitors may also have a role in preventing other cardiovascular events. ACE inhibitors reduce ischaemic events, mortality and hospital admissions (heart failure or further MI) in this group of patients.

Diabetic nephropathy

As well as lowering BP, ACE inhibitors reduce the rate of albumin excretion in normotensive patients with diabetes (types 1 and 2). There is reduced mortality (all causes).²

See also the separate article on Diabetic Nephropathy.

Contra-indications¹

• Angio-oedema.

• History of angioedema associated with prior ACE inhibitor therapy.

• Haemodynamically significant renal artery stenosis (may cause progressive renal failure).

• ACE inhibitors should be avoided in pregnancy unless essential. They may adversely affect fetal and neonatal blood pressure control and renal function. Skull defects and oligohydramnios have also been reported.

• Breastfeeding: information on the use of ACE inhibitors in breastfeeding is limited.

• The combination of an ACE inhibitor with aliskiren is contra-indicated in patients with diabetes mellitus.

• The combination of an ACE inhibitor with aliskiren (an inhibitor of renin, which converts angiotensinogen to angiotensin I) is contra-indicated in patients with an eGFR less than 60 mL/minute/1.73 m².

Cautions¹

• Renal impairment: hyperkalaemia and other side-effects of ACE inhibitors are more common in those with impaired renal function.

• Aortic stenosis.

• Hyperkalaemia.

• Beware a very rapid fall of BP in volume-depleted patients, in patients with hyponatraemia, on low-salt diets, on dialysis or in heart failure.

Important interactions¹

Avoid the following if possible, or monitor frequently:

• Concomitant treatment with NSAIDs increases the risk of renal damage.

• Potassium-sparing diuretics (or potassium-containing salt substitutes) increase the risk of hyperkalaemia.

• Heparin, ciclosporin, and epoetin also increase the risk of hyperkalaemia.

• Lithium - increased serum levels of lithium.

ACE inhibitors can cause a very rapid fall in blood pressure in volume-depleted patients. Therefore, treatment should be initiated with very low doses. If the dose of diuretic is greater than 80 mg furosemide or equivalent, the ACE inhibitor should be initiated under close supervision and in some patients the diuretic dose may need to be reduced or the diuretic discontinued at least 24 hours beforehand (this may not be possible in view of the risk of pulmonary oedema). If high-dose diuretic therapy cannot be stopped, close observation is recommended after administration of the first dose of ACE inhibitor, for at least 2 hours or until the blood pressure has stabilised (but see indications for initiation under specialist supervision below).

Combination therapy with two drugs affecting the renin-angiotensin system (ACE inhibitors, angiotensin-II receptor antagonists, and aliskiren) is not recommended due to an increased risk of hyperkalaemia, hypotension, and renal impairment, compared to use of a single drug. Patients with diabetic nephropathy are particularly susceptible to developing hyperkalaemia and should not be given an ACE inhibitor with an angiotensin-II receptor antagonist.

Common problems

(For a full list of side-effects see individual drugs).

• Impaired renal function - especially in patients with already poor renal function or renal artery stenosis - ensure regular monitoring (see 'Monitoring', below).

• Hyperkalaemia (stop or reduce potassium supplements and potassium-saving diuretics before starting ACE inhibitors).

• First-dose hypotension - minimise this by stopping or reducing loop diuretics for 24 hours before starting and give a small trial dose, and/or take tablet immediately at bedtime. Consider initiation under specialised supervision.

• Persistent dry cough (in up to 10%) - consider switching to angiotensin-II receptor antagonists.

Initiation¹

Always check U&E and creatinine before starting. Assess the patient for likely problems and consider whether ACE inhibitors may be better started in hospital - eg, in patients with high risk of first-dose hypotension, hyperkalaemia or renal failure:

Start with the lowest dose at bedtime and titrate up slowly. Always check appropriate dosages, such as referring to the BNF.

ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in those with:

• Multiple or high-dose diuretic therapy (eg, more than 80 mg of furosemide daily or equivalent).

• Concomitant angiotensin-II receptor antagonist or aliskiren.

• Hypovolaemia.

• Hyponatraemia (plasma sodium concentration below 130 mmol/L).

• Hypotension (systolic blood pressure below 90 mmHg).

• Unstable or severe heart failure.

• Haemodynamically significant left ventricular inflow or outflow impediment (eg, stenosis of the aortic or mitral valve) receiving high-dose vasodilator therapy.

• Known renovascular disease.

Monitoring

Monitor renal function, potassium and BP before starting, and regularly during treatment.

Renal function and electrolytes should be checked before starting ACE inhibitors (or increasing the dose) and monitored during treatment (more frequently if features mentioned below present).

Hyperkalaemia and other side-effects of ACE inhibitors are more common in those with impaired renal function and the dose may need to be reduced. A specialist should be involved if renal function is significantly reduced as a result of treatment with an ACE inhibitor.

Common reasons to stop angiotensin-converting enzyme inhibitors

• Worsening renal function.

• Persistent dry cough: switch to angiotensin-II receptor antagonists.

• Hypotension.

• Hyperkalaemia.