Perindopril

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Abstract
Perindopril is a long acting angiotensin converting enzyme (ACE) inhibitor, which displays similar pharmacodynamic properties to other agents in this class. In common with enalapril, it is also a prodrug. After absorption, perindopril is hydrolysed to the active metabolite, perindoprilat, and with once daily administration adequate 24-hour inhibition of ACE is obtained. Perindopril 4 to 8mg once daily is usually effective for blood pressure control in patients with mild to moderate essential hypertension. Those, patients who do not respond adequately to monotherapy with perindopril usually respond with the addition of a second agent, such as a thiazide diuretic. General practice trials indicate that perindopril is at least as effective and as well tolerated as usual therapeutic dosages of captopril, atenolol or hydrochlorothiazide plus amiloride in mild to moderate essential hypertension. Preliminary results indicate that perindopril may also be effective in patients with severe hypertension or congestive heart failure. Perindopril is generally well tolerated and has an adverse effect profile similar to that of other ACE inhibitors. If further clinical experience confirms initial findings, perindopril is likely to represent a useful alternative to other members of the ACE inhibitor class in all grades of hypertension and congestive heart failure. After oral administration of perindopril, potent inhibition of ACE, and consequently angiotensin II formation, is achieved in plasma and most tissues. Indeed, inhibition of angiotensin II formation, in particular in the vasculature, is the primary pharmacological action of perindopril, leading to a reduction in peripheral vascular resistance with no significant change in heart rate. The blood pressure lowering effect of perindopril has been shown in animal models of spontaneous and renovascular hypertension. Perindopril 4 to 8mg once daily significantly reduces supine and standing blood pressure in patients with essential hypertension. The maximal response is attained about 4 to 6 hours after the first dose, but with repeated once daily administration effective 24-hour control of blood pressure is maintained. The normal diurnal variation in blood pressure is unaltered. Perindopril also improves arterial structure and reduces left ventricular hypertrophy in hypertensive patients. The reduced elastic properties of the arteries and heart are furthermore restored by perindopril. Beneficial acute haemodynamic effects comprising a reduction in preload and afterload with only a slight reduction in heart rate, and increased renal blood flow are seen after oral administration of perindopril 2 to 4mg in patients with congestive heart failure. Perindopril is a prodrug ester which is hydrolysed to form the active metabolite perindoprilat, designed to allow oral administration as perindoprilat is poorly absorbed from the gastrointestinal tract. The absolute bioavailability of perindopril after oral administration varies from about 66 to 95%. Perindopril is rapidly absorbed, reaching peak plasma concentrations about 1 hour after a single oral dose, and is cleared from the circulation in about 6 hours. Perindoprilat reaches peak plasma concentrations 3 to 4 hours after administration. Only about 17 to 20% of the orally administered dose is available as perindoprilat, as extensive metabolism to other inactive metabolites occurs. Perindoprilat is widely distributed, as ACE is effectively inhibited in most tissues. About 75% and 25% of a radiolabelled dose of perindopril are recovered in the urine and faeces, respectively. The latter may represent biliary excretion or unabsorbed perindopril. Renal excretion is accounted for by perindopril, perindoprilat and other metabolites, some as glucuronide conjugates. The mean renal clearance for perindopril and perindoprilat is about 3.0 to 3.7 L/h and 6.1 to 10.3 L/h, respectively, while mean total body clearance is 31 and 41 to 46 L/h, respectively. The mean elimination half-life of perindopril is about 1.5 to 3 hours, while perindoprilat shows a biphasic elimination pattern with mean distribution (ti/2a) and elimination (t½β) phase half-lives of 5 and 25 to 30 hours, respectively. The latter half-life probably represents the strong binding of perindoprilat to ACE. Impaired renal function and increased age may decrease the excretion of perindoprilat and some other metabolites, so dosage reduction is warranted in these groups. Clinical trials with perindopril have mainly involved patients with mild to moderate essential hypertension. In this indication oral administration of perindopril 4 to 8mg once daily reduces supine and standing systolic and diastolic blood pressure by about 5 to 15%, and adequate diastolic blood pressure control (<90mm Hg) is attained in about 50 to 70% of patients with monotherapy. Addition of a second agent, in particular a thiazide diuretic, often achieves appropriate control in patients not responding adequately to monotherapy. The antihypertensive effect of perindopril is maintained during long term (1 year) administration. General practice studies indicate that perindopril is at least as effective as usual therapeutic dosages of captopril, atenolol or a combination of hydrochlorothiazide plus amiloride in mild to moderate essential hypertension. The use of perindopril in potentially at-risk hypertensive patients, such as the elderly and those with diabetes or renal impairment, has not been associated with any unfavourable metabolic changes. Limited information in patients with congestive heart failure has indicated beneficial haemodynamic effects with perindopril. Further study is therefore warranted in this therapeutic area, as well as in patients with renovascular hypertension, since these indications have been proven as viable for ACE inhibitor therapy. Perindopril has been well tolerated in clinical trials involving patients with mild to moderate essential hypertension. Adverse events have generally been mild and transient, and only rarely severe enough to necessitate withdrawal of the drug. Cumulated tolerability data are somewhat limited thus far, although one study reported 5.7% of 632 patients being withdrawn from long term treatment because of adverse events. The tolerability profile appeared similar to that of other ACE inhibitors. Large-scale clinical trials indicate that perindopril is at least as well tolerated as captopril, atenolol and hydrochlorothiazide plus amiloride in patients with essential hypertension. The usual effective dosage of perindopril is 2 to 8mg once daily in patients with mild to moderate essential hypertension. Limited experience in patients with congestive heart failure suggests that 4mg once daily is an effective dosage, and it is probably advisable to start treatment in this indication with a low dose under close medical supervision to avoid the possibility of first-dose hypotension which has been noted with other ACE inhibitors. In all indications it is advisable to start with a low daily dosage and to titrate upwards at intervals of several weeks to achieve an optimal therapeutic response. Dosage reductions are recommended in patients with renal impairment.