Pharmacology Notes

ACE inhibitors are used in the treatment of hypertension, heart failure, post–myocardial infarction with left ventricular dysfunction (left ventricular ejection fraction less than 40%), and diabetic nephropathy. ACE inhibitors are also used in the prevention of cardiovascular disease and in the prevention and treatment of renal complications of scleroderma 

The ACE inhibitors currently available in Australia are captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril. All the drugs in this class work in a similar way; however, they have different marketing indications. This does not necessarily mean a different spectrum of activity, but is based on the available clinical trial data, and on registration applications. Ramipril has marketed indications for prevention of progressive renal failure in patients with persistent proteinuria (more than 1 g/day), and to reduce the risk of myocardial infarction, stroke or cardiovascular death. It is also marketed to reduce the need for revascularisation procedures in patients 55 years of age or more with: coronary artery disease, stroke or peripheral vascular disease, or diabetes and one or more risk factors (hypertension, high total cholesterol, low HDL cholesterol, current smoker, microalbuminuria, previous vascular disease). Perindopril has a marketing indication for established coronary artery disease without heart failure to reduce risk of myocardial infarction or cardiac arrest.

Angiotensin converting enzyme is a nonspecific dipeptidase that converts inactive angiotensin I to the active angiotensin II, and inactivates bradykinin. ACE inhibitors block this enzyme, and this results in relaxation of blood vessels, reduction in the force of cardiac contraction, removal of the trophic effects of angiotensin II on cardiovascular tissues, and reduced release of aldosterone—and thus to sodium loss and potassium retention. ACE inhibitors also inhibit the breakdown of bradykinin, and the increased bradykinin levels may be partially responsible for some of these effects.

A large number of ACE inhibitors are available, and although there have been a few head to head comparisons, the importance of different properties of particular drugs to clinical practice is not definitely established. A number of ACE inhibitor preparations are available in combination with a low dose of thiazide or indapamide.

Most ACE inhibitors are excreted via the kidney and therefore accumulate in patients with renal impairment. The maintenance dose should be reduced in these patients.

The duration of action of ACE inhibitors is determined by plasma half-life and affinity for binding to tissue angiotensin converting enzyme. Satisfactory 24-hour blood pressure control can be achieved in most patients whose blood pressure is responsive to ACE inhibitors, using once-daily dosing with any of the ACE inhibitors except captopril (which must be taken more frequently).

Generally ACE inhibitors are well tolerated. There have been a few studies looking at adverse effects with different ACE inhibitors, usually comparing newer drugs with captopril or enalapril. In general, these comparisons have not shown a significant difference in the incidence or nature of adverse effects between any of the ACE inhibitors.

Apart from excessive reduction of blood pressure, the major adverse effects are cough, skin rashes and infrequent cases of angioedema. Occasionally, patients can exhibit a heightened allergic response (eg becoming newly allergic to bee sting).

ACE inhibitors are contraindicated in pregnancy because of an association with retardation of fetal development, oligohydramnios and stillbirth. Defects in skull ossification have also been reported.

Plasma potassium usually increases following commencement of ACE inhibitor therapy, particularly in patients with renal impairment, so potassium supplements or concomitant potassium-sparing diuretics are usually not required and may cause life-threatening hyperkalaemia.

Occasional patients develop severe progressive renal impairment following even small doses of an ACE inhibitor. This occurs in the context of severe parenchymal renal disease or renal artery stenosis—either bilateral or with a single functioning kidney.

Electrolytes and renal function should be checked before, and 1 to 2 weeks after, commencing ACE inhibitor therapy. These should also be reviewed after each dose increment, or if changed clinical circumstances might predispose to or indicate changes in renal function (eg dehydration, addition of a drug that can affect renal function).

The first dose of an ACE inhibitor can cause marked and often symptomatic hypotension. This is particularly likely in heart failure, dehydration or sodium depletion. Consider: ceasing, suspending or decreasing the dose of diuretics; using a small initial dose of ACE inhibitor; ceasing potassium-sparing diuretics and potassium supplements; and measuring blood pressure, serum creatinine and electrolytes.