Angiotensin-converting Enzyme Inhibitors

Synonyms: ACE inhibitors, ACEIs, ACEs

This family of drugs inhibits the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates vasoconstriction (releases aldosterone and vasopressin, stimulating salt and water retention, which raise BP) and inhibits the breakdown of bradykinin (a potent vasodilator). Angiotensin-converting enzyme inhibitors (ACE inhibitors) induce vasodilatation improving cardiac output (reduces afterload) and enhancing the renal excretion of salt and water. Most ACE inhibitors are pro-drugs which are metabolised in the liver to active metabolites. All are excreted by the kidney, and need careful titration in renal impairment; some are also metabolised by the liver.^1,2

• Hypertension: recommended first-line antihypertensive in diabetics and younger (<55 years) patients with hypertension, and second-line for other patients if BP not adequately controlled on thiazide or calcium channel blocker (or if these drugs are not tolerated or contra-indicated).³ See Management of Hypertension.
• Heart failure: (particularly in patients with left ventricular dysfunction); reduces both mortality and hospital admissions in these patients.^4,5 More recently data is emerging that ACE inhibitors are also beneficial in patients with heart failure and normal left ventricular systolic function.^6,7 See 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.⁴ There is good evidence to suggest that they should be started early.⁸
• Diabetic nephropathy: as well as lowering blood pressure, ACE inhibitors reduce the rate of albumin excretion in normotensive diabetic patients (types 1 and 2);⁹ and reduced mortality (all causes).^10,11,12
• Non-diabetic renal disease: ACE inhibitors can lower urinary protein excretion in patients with proteinuria and slow progression to renal failure (evidence for white populations only) - hence are indicated for most patients with chronic renal disease.¹³

Stroke Prevention (unlicensed indication) - evidence exists that both ramipril,¹⁴ and perindopril (the latter when in combination with diuretic indapamide)^15,16 reduces the number of strokes occurring in high risk patients whose blood pressure is not elevated.

• Pregnancy (maternal and fetal hypotension, fetal defects, oligohydramnios)^17,18,19,20 - some manufacturers say only second and third trimesters^21,22,23
• Haemodynamically significant renal artery stenosis (may cause progressive renal failure)¹⁷
• Hypersensitivity to ACE^{17,18,19,20,21,22,23}
• Hereditary and idiopathic angio-oedema²¹
• Breastfeeding^17,18,19,20

• Renal impairment, renovascular disease (beware in patients with known atherosclerosis who may have silent renal artery stenosis). Reduce and monitor frequently.
• Aortic stenosis²³
• Hyperkalaemia
• Beware very rapid fall of BP in volume depleted patients, patients with hyponatremia, on low salt diets, on dialysis or in heart failure.

Avoid the following if possible, or monitor frequently:

• 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

(For 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 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 small trial dose, and/or take tablet immediately at bedtime. Consider initiation under specialised supervision.²⁴
• Persistent dry cough (in up to 10%) - consider switching to angiotensin II receptor antagonists.

• Always check U&E and creatinine before starting.
• Assess patient for likely problems - consider whether ACE inhibitors may be better started in hospital, e.g. in patients with high risk of first-dose hypotension, hyperkalaemia or renal failure:²⁴
• If on high dose diuretics (>80 mg furosemide/day) - reduce or stop diuretics if possible a day or two before starting ACE inhibitor to reduce the risk of first-dose hypotension. If this is not possible - monitor BP for 2 hours post dose.
  
  Other higher risk patients:
  • High doses of vasodilators
  • Hypovolaemia
  • Hyponatremic (Na <130 mmol/l)
  • Hyperkalaemia
  • Hypotension (systolic <100 mmHg)
  • Unstable heart failure
  • Renal impairment (creatinine >150 μmol/l)
  • Very elderly
• Start with lowest dose at bedtime, e.g. 2.5 mg lisinopril ; (consider 6.25 mg captopril (shorter acting) for highest risk patients.
• Titrate the dose up, e.g. at weekly intervals, until maximum dose reached or BP target achieved.

• Monitor renal function, potassium and BP before starting, and regularly during treatment.
• Ideally monitor creatinine and potassium within 2 weeks of starting, sooner if high risk of renovascular disease or hyperkalaemia - then at increasing intervals until patient is stabilised on required dose, and then every 6 or 12 months thereafter.

• Worsening renal function: 20% increase in serum creatinine level is significant
• Persistent dry cough: switch to Angiotensin II Receptor Antagonists
• Hypotension
• Hyperkalaemia

• ACE Inhibitor with thiazide diuretic
• ACE Inhibitor with calcium channel blocker