Ramipril

Abstract

Ramipril is a long acting angiotensin converting enzyme (ACE) inhibitor, which exhibits similar pharmacodynamic properties to captopril and enalapril. Like enalapril it is a prodrug, which is hydrolysed after absorption to form the active metabolite ramiprilat which has a long elimination half-life, permitting once daily administration. In hypertensive patients daily doses in the range 2.5 to 20mg are usually effective in reducing high blood pressure and maintaining satisfactory control during long term treatment. Patients who do not respond adequately to monotherapy with ramipril usually respond with the addition of a diuretic such as hydrochlorothiazide or piretanide. Ramipril 5 to 10mg once daily shows comparable antihypertensive efficacy to usual therapeutic dosages of captopril, enalapril and atenolol in patients with mild to moderate essential hypertension. Preliminary data indicate that ramipril may be effective in indications such as severe essential hypertension and renal hypertension. It has also displayed beneficial effects in patients with moderate to severe congestive heart failure. Ramipril has been well tolerated and exhibits an adverse effect profile typical of ACE inhibitors as a class. In conclusion, ramipril will likely represent a useful alternative ACE inhibitor for use in patients with hypertension or congestive heart failure. Ramipril is a prodrug which is hydrolysed after absorption to form the active angiotensin converting enzyme (ACE) inhibitor ramiprilat. Ramiprilat decreases plasma levels of angiotensin II and aldosterone and potentiates the effects of bradykinin. Most data support the hypothesis that the beneficial haemodynamic effects of ramipril are caused by ACE inhibition and the consequent reduction in angiotensin II, which either directly or indirectly results in dilatation of peripheral vessels and reduces vascular resistance. Cumulating evidence suggests that tissue ACE, particularly in the vasculature, rather than circulating ACE, is the primary target determining the haemodynamic effects. Ramipril is effective in lowering blood pressure in animal models of hypertension which are both renin-dependent and independent. The drug had little or no effect on blood pressure or heart rate in healthy human subjects. In patients with essential hypertension, single oral doses of ramipril 10 to 20mg reduced both supine and standing systolic and diastolic blood pressure maximally by 15 to 20% after about 4 hours, and the effects lasted for up to 48 hours. Heart rate was not significantly changed by single-dose or long term administration of ramipril in patients with hypertension. Prolonged treatment with ramipril caused a reversal of left ventricular hypertrophy in hypertensive patients without any deterioration of pump function. Animal studies have shown that ramipril improves cardiac function and metabolism, and exerts beneficial haemodynamic changes (improved preload and afterload) in acuteischaemic left ventricular failure. Beneficial acute haemodynamic effects were seen after oral administration of ramipril 5 to 20mg in patients with congestive heart failure. There was a reduction in peripheral resistance and mean arterial pressure, associated with a reduction in filling pressure (measured as pulmonary capillary wedge pressure and pulmonary artery pressure), and accompanied by increased cardiac output. There was only a slight effect on heart rate. Severe first-dose hypotension may occur with high doses. In healthy subjects and patients with hypertension single or repeated doses of ramipril had no significant effect on the excretion and plasma levels of sodium, potassium, urea and creatinine, but renal plasma flow was increased. Ramipril was designed as a prodrug to improve the systemic availability of the active ACE inhibitor ramiprilat, which is poorly absorbed in humans. About 60% of an oral dose of ramipril. is absorbed in healthy subjects, and peak serum concentrations of ramipril are reached in about 1 hour. Ramipril undergoes de-esterification in the liver to form ramiprilat, which reaches peak serum concentrations about 3 hours after ramipril administration. Studies have shown the maximum serum concentration of ramiprilat to be directly related to dose, and absorption of the drug unaffected by coadministration with food. Ramipril and ramiprilat were shown to be about 73% and 56% protein bound, respectively. About 60% and 40% of a dose of radiolabelled ramipril were recovered in urine and faeces, respectively. The latter may represent both biliary excretion of metabolites and unabsorbed ramipril. The majority of renal excretion is accounted for by ramiprilat and its glucuronide conjugate. However, both ramipril and ramiprilat are metabolised to inactive diketopiperazine derivatives which are excreted in significant quantities in urine. The respective mean renal clearances of ramipril and ramiprilat were about 10 and 100 ml/min. Ramiprilat had polyphasic elimination kinetics: the half-life during the major distribution/elimination phase ranged between 1.1 and 4.5 hours. A prolonged terminal phase of elimination measured in days probably represents tight, saturable binding of ramiprilat to circulating ACE. Increased age and impaired renal function may decrease the urinary excretion of ramipril and its metabolites. Impaired hepatic function appears to result in increased maximum plasma ramipril concentrations and no change in those of ramiprilat, apart from a delay in reaching this parameter. Dose-finding and placebo-controlled studies in patients with mild to moderate essential hypertension show that oral administration of ramipril 1.25 to 10mg once daily reduces supine or standing systolic and diastolic blood pressure by about 5 to 15%, with an adequate pressure control being achieved in about 50 to 70% of patients. The drug’s efficacy is well maintained during 2 years of therapy at maintenance dosages of 2.5 or 5mg daily in the majority of...