Uses, Administration, Adverse Effects and Treatment ACE Inhibitors

Uses and Administration

ACE inhibitors are antihypertensive drugs that act as vasodilators and reduce peripheral resistance. They inhibit angiotensin-converting enzyme (ACE), which is involved in the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a potent direct vasoconstrictor effect. ACE is identical to bradykininase (kininase II) and ACE inhibitors also reduce the degradation of bradykinin, which is a direct vasodilator and is also involved in the generation of prostaglandins. The pharmacological actions of ACE inhibitors are thought to be primarily due to the inhibition of the renin-angiotensin-aldosterone system, but since they also effectively reduce blood pressure in patients with low renin concentrations other mechanisms are probably also involved. ACE inhibitors produce a reduction in both preload and afterload in patients with heart failure. They also reduce left ventricular remodelling, a process that sometimes follows myocardial infarction. Normally, renal blood flow is increased without a change in glomerular filtration rate. ACE inhibitors also reduce proteinuria associated with glomerular kidney disease. ACE inhibitors are used in the treatment of hypertension and heart failure and are given to improve survival after myocardial infarction and for the prophylaxis of cardiovascular events in patients with certain risk factors. They are also used in the treatment of diabetic nephropathy. They are generally given orally. In some hypertensive patients there may be a precipitous fall in blood pressure when starting therapy with an ACE inhibitor and the first dose should preferably be given at bedtime; if possible, any diuretic therapy should be stopped a few days beforehand and resumed later if necessary. In patients with heart failure taking loop diuretics, severe first-dose hypotension is common on introduction of an ACE inhibitor, but temporary withdrawal of the diuretic may cause rebound pulmonary oedema. Thus treatment should start with a low dose under close medical supervision (Sweetman).

Adverse Effects and Treatment

Many of the adverse effects of ACE inhibitors relate to their pharmacological action and all therefore have a similar spectrum of adverse effects. Some effects, such as taste disturbances and skin reactions, were at one time attributed to the presence of a sulfhydryl group (as in captopril) but have now also been reported with other ACE inhibitors; however, they may be more common with captopril. The most common adverse effects are due to the vascular effects of ACE inhibitors and include hypotension, dizziness, fatigue, headache, and nausea and other gastrointestinal disturbances. Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume-depleted patients (for example, those given previous diuretic therapy). Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain. Deterioration in renal function, including increasing blood concentrations of urea and creatinine, may occur, and reversible acute renal failure has been reported. Renal effects are most common in patients with existing renal or renovascular dysfunction or heart failure, in whom vasodilatation reduces renal perfusion pressure; it may be aggravated by hypovolaemia. Proteinuria has also occurred and in some patients has progressed to nephrotic syndrome. Hyperkalaemia and hyponatraemia may develop due to decreased aldosterone secretion. Other adverse effects include persistent dry cough and other upper respiratory tract symptoms, and angioedema; these may be related to effects on bradykinin or prostaglandin metabolism. Skin rashes (including erythema multiforme and toxic epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions have also been reported. Blood disorders have been reported with ACE inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and in those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and anaemias. Other less common adverse effects reported with ACEinhibitors include stomatitis, abdominal pain, pancreatitis, hepatocellular injury or cholestatic jaundice, muscle cramps, paraesthesias, mood and sleep disturbances, and impotence. ACE inhibitors have been associated with fetal toxicity. Most of the adverse effects of ACE inhibitors are reversible on withdrawing therapy. Symptomatic hypotension, including that after overdosage, generally responds to volume expansion with an intravenous infusion of sodium chloride 0.9%  (Sweetman).