Angiotensin-converting Enzyme Inhibitors

Synonyms: ACE inhibitors, ACEIs, ACEs

This family of drugs inhibits the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE). 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.^[1]Under normal circumstances, ACE also inactivates bradykinin; thus, ACE inhibition is associated with increased levels of bradykinin and this is thought to underly the ACE inhibitor-associated cough.

Indications^[2]

• Hypertension: recommended first-line antihypertensive in those with diabetes and in younger (<55 years) patients with hypertension, and 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.
• Heart failure: (particularly in patients with left ventricular dysfunction); reduces both mortality and hospital admissions in these patients. More recently data are emerging that ACE inhibitors are also beneficial in patients with heart failure and normal left ventricular systolic function. See separate article Heart Failure Management.
• Post-myocardial infarction (MI): ACE inhibitors reduce ischaemic events, mortality and hospital admissions (heart failure or further MI) in this group of patients. There is good evidence to suggest that they should be started early.
• 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).^[3]
• Non-diabetic renal disease: ACE inhibitors can lower urinary protein excretion in patients with proteinuria and slow progression to chronic kidney disease (evidence for white populations only) - hence, they are indicated for most patients with chronic kidney disease.^[4]

Stroke prevention (unlicensed indication) - evidence exists that the number of strokes occurring in high-risk patients whose BP is not elevated can be reduced with both:

• Ramipril.^[5]
• Peridopril (when in combination with diuretic indapamide).^{[6, 7]}

Contra-indications^[2]

• Pregnancy (maternal and fetal hypotension, fetal defects, oligohydramnios). Some manufacturers say only second and third trimesters.
• Haemodynamically significant renal artery stenosis (may cause progressive renal failure).
• Hypersensitivity to ACE.
• Hereditary and idiopathic angio-oedema.
• Breast-feeding.

Cautions

• Renal impairment, renovascular disease (beware in patients with known atherosclerosis who may have silent renal artery stenosis). Reduce and monitor frequently.
• Aortic stenosis.^[8]
• 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 interactions

Avoid the following if possible, or monitor frequently:

• Non-steroidal anti-inflammatory drugs (NSAIDs) - increased risk of renal failure.
• Heparin, potassium-saving diuretics or potassium supplements, ciclosporin, and epoetin - increased risk of hyperkalaemia.
• Lithium - increased serum levels of lithium.

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.^[9]
• Persistent dry cough (in up to 10%) - consider switching to angiotensin-II receptor antagonists.

Initiation

• Always check U&E and creatinine before starting.
• Assess the patient for likely problems - consider whether ACE inhibitors may be better started in hospital - eg, in patients with high risk of first-dose hypotension, hyperkalaemia or renal failure:^[9]
• If on high-dose diuretics (>80 mg furosemide/day) - reduce or stop diuretics, if possible a day or two before starting an ACE inhibitor, to reduce the risk of first-dose hypotension. If this is not possible - monitor BP for two hours post-dose.
  
  Other higher-risk patients:
  • High doses of vasodilators.
  • Hypovolaemia.
  • Hyponatraemic (Na <130 mmol/L).
  • Hyperkalaemia.
  • Hypotension (systolic <100 mm Hg).
  • Unstable heart failure.
  • Renal impairment (creatinine >150 μmol/L).
  • Very elderly.
• Start with the lowest dose at bedtime - eg, 2.5 mg lisinopril; (consider 6.25 mg captopril (shorter-acting) for highest-risk patients.
• Titrate the dose up (eg, at weekly intervals) until a maximum dose is reached or BP target is achieved.

Monitoring

• Monitor renal function, potassium and BP before starting, and regularly during treatment.
• Ideally, monitor creatinine until the required dosage is reached, and then every six or twelve months thereafter.

Common reasons to stop angiotensin-converting enzyme inhibitors

• Worsening renal function: 20% increase in the serum creatinine level is significant.
• Persistent dry cough: switch to angiotensin-II receptor antagonists.
• Hypotension.
• Hyperkalaemia.

Combination products available

• ACE inhibitor with thiazide diuretic.
• ACE inhibitor with calcium-channel blocker.