Ramipril

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Abstract
Ramipril is a second generation angiotensin converting enzyme (ACE) inhibitor. Like enalapril, it is a prodrug and is hydrolysed in vivo to release the active metabolite, ramiprilat, which has a long elimination half-life, permitting once-daily administration. The antihypertensive efficacy of ramipril has been confirmed in large-scale noncomparative studies conducted in general practice as well as in more rigorously controlled clinical trials. In the former, approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with ramipril 2.5 or 5 mg/day, while comparative trials indicate that the antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and the β-adrenoceptor antagonist atenolol. As expected, the response rate to ramipril monotherapy is lower in patients with severe hypertension (around 40%), although the blood pressure lowering effect can be enhanced with the addition of a diuretic such as hydrochlorothiazide or piretanide. The antihypertensive efficacy of ramipril is maintained in patients with diabetes mellitus and preliminary data indicate that the drug has the beneficial effect of decreasing urinary albumin excretion in diabetic patients with nephropathy. Ramipril is superior to atenolol in causing regression of left ventricular hypertrophy, although the clinical significance of this effect per se remains to be established. The large-scale Acute Infarction Ramipril Efficacy (AIRE) study demonstrated that ramipril 5 or 10 mg/day significantly decreased the risk of all-cause mortality by 27% in patients with clinical evidence of heart failure after acute myocardial infarction, even if transient. The beneficial effect of ramipril was apparent by 30 days of treatment and appeared to be greatest in patients with more severe ventricular damage after infarction. Ramipril is well tolerated in general practice, with 5% or fewer patients discontinuing therapy because of drug intolerance. The data available suggest that ramipril shares a similar tolerability profile to that of other established ACE inhibitors. Thus, clinical data confirm ramipril as a useful alternative ACE inhibitor for the treatment of patients with mild to moderate hypertension, and indicate a beneficial effect of the drug inpatients with clinical evidence of heart failure after acute myocardial infarction. It is also reasonable to assume that ramipril will be of value in the treatment of patients with more established heart failure or asymptomatic left ventricular dysfunction. Ramipril is a prodrug designed to improve the systemic bioavailability of the active angiotensin converting enzyme (ACE) inhibitor, ramiprilat. Most data support the hypothesis that the beneficial haemodynamic effects of ramiprilat result from decreased angiotensin II formation, which, in turn, decreases vasopressor activity and peripheral vascular resistance. Moreover, evidence is accumulating that local inhibition of ACE and angiotensin II formation in specific target tissues such as the vascular wall may in some way be involved in the haemodynamic effects of ramipril. ACE inhibition potentiates endogenous bradykinin levels, which may contribute to 2 potentially beneficial cardiac effects observed with these agents, namely regression of left ventricular hypertrophy and a cardioprotective effect on the ischaemic myocardium. When administered to patients with essential hypertension, a single oral dose of ramipril 2.5 to 20mg decreased systolic and diastolic blood pressure in a dose-dependent manner without affecting the normal circadian variation in blood pressure or heart rate. The antihypertensive response was maximal at 4 to 8 hours and was still apparent at 24 hours after dosing. In patients with moderate to severe congestive heart failure, a single oral dose of ramipril 5 or 10mg had the beneficial effect of decreasing preload and afterload with a reflex increase in cardiac output. The effect of ramipril on renal blood flow in hypertensive patients with normal kidney function has been variable, but with no indication of a negative effect. Like other ACE inhibitors, ramipril has the beneficial action of reducing the urinary albumin excretion rate in diabetic patients with nephropathy. Short term, significant improvements in glucose tolerance and insulin sensitivity have been documented in elderly insulin-resistant patients with mild hypertension treated with ramipril. More than 55% of an oral dose of ramipril is absorbed and bioavailability is unaffected by the presence of food. Once absorbed, ramipril is rapidly de-esterified to form the active metabolite ramiprilat; peak plasma concentrations of the parent drug and ramiprilat are reached in about 1 and 3 hours, respectively. De-esterification takes place primarily in the liver. Ramiprilat has an extended terminal elimination phase lasting 110 hours which is due to slow dissociation from its binding site on ACE. However, significant accumulation of the parent drug or ramiprilat has not been observed after 2 weeks’ administration of therapeutic dosages of ramipril in healthy volunteers. Renal excretion is the main route of elimination of the parent drug and ramiprilat and their respective metabolites. Approximately 60% of a single oral dose of ramipril is recovered in the urine, while the remaining 40% is recovered in the faeces and includes biliary excretion. Plasma concentrations of ramiprilat are increased in the elderly and patients with renal or heart failure, while those of the parent drug are potentiated in patients with hepatic impairment. Accordingly, low initial dosages and/or dosage reductions of ramipril are likely to be necessary in these special patient populations. In noncomparative studies conducted in general practice, approximately 85% of patients with mild to moderate essential hypertension responded successfully to 6 to 8 weeks’ treatment with ramipril 2.5 or 5 mg/day; that is, diastolic blood pressure was controlled at ≤90 to 95mm Hg or reduced by >10mm Hg from baseline. The response rate declined with increasing severity of hypertension, although it was similar in men and women, as well as in young and older (>65 years) patients. After 2 years, ramipril monotherapy continued to be effective in more than 90% of patients who responded successfully to short term treatment with the drug. Large-scale double-blind multicentre studies have demonstrated that the antihypertensive efficacy of ramipril is comparable to that of enalapril, Captopril, lisinopril and atenolol, while combination therapy with ramipril plus hydrochlorothiazide or piretanide was generally superior to monotherapy with either agent alone at the same dose. In terms of providing blood pressure reduction, the optimum combinations evaluated have been ramipril 5mg/hydrochlorothiazide 25mg and ramipril 5mg/piretanide 6mg. In placebo-controlled studies, once daily administration of ramipril 2.5 to 20mg for 3 months achieved target blood pressure in over 50% of diabetic patients with mild to moderate hypertension, without adversely affecting plasma glucose and lipid levels. Moreover, the drug significantly decreased the urinary albumin excretion rate in diabetic patients with nephropathy. Ramipril reduced left ventricular hypertrophy to a greater extent than atenolol, although the clinical significance of this effect per se remains to be determined. Available data suggest that ramipril effectively lowers blood pressure in patients with renal insufficiency, although drug dosage should be modified in accordance with the degree of renal impairment. Ramipril increases exercise duration and improves the status of patients with established congestive heart failure. In the large-scale Acute Infarction Ramipril Efficacy (AIRE) study, patients with clinical evidence of heart failure after acute myocardial infarction (MI), even if transient, were randomised to receive ramipril 5 or 10 mg/day or placebo (n = 1986). Ramipril was initiated between day 3 and day 10 after MI and continued for ≥6 (mean 15) months. An intention-to-treat analysis revealed that ramipril significantly decreased the risk of all-cause mortality by 27% and the combined incidence of prespecified secondary outcomes (i.e. first validated event in an individual patient, namely death, progression to severe/resistant heart failure, reinfarction or stroke) by 19% compared with placebo. A near-significant 29% reduction in the risk of all-cause mortality was apparent within 30 days of initiating ramipril therapy. Most patients benefited from treatment with ramipril, although the effect was less pronounced in younger patients (>65 years) and those not receiving concomitant diuretic therapy. Ramipril has been well tolerated by hypertensive patients during short term treatment and maintenance therapy for up to 2 years. Adverse events are usually mild and transient and only rarely severe enough to necessitate withdrawal of ramipril in general practice (≤5% of patients). In the AIRE study, the number of patients with heart failure after MI who withdrew because of drug intolerance was higher for ramipril than for placebo (12.5 vs 7%). Adverse events, regardless of causality to ramipril, have been reported in 9% of patients with essential hypertension enrolled in a large-scale general practice study based in Austria (n = 5193). Dry cough occurred in fewer than 1% of patients, while the other most commonly reported adverse events included headache and dizziness/vertigo which are expected to occur in a small proportion of patients taking oral medication. Ramipril appears to be equally well tolerated by young and elderly patients (>65 years) with mild to moderate essential hypertension. Moreover, the drug has little effect on standard laboratory test values and can be administered to diabetic patients without adversely affecting the cardiovascular risk profile. As for all ACE inhibitors, caution is advised if ramipril is to be used in combination with a potassium-sparing diuretic, since hyperkalaemia may result. Available data suggest that the tolerability profile of ramipril is similar to that of other available ACE inhibitors, although the impact of the drug on quality of life in patients with hypertension remains to be established. In the treatment of mild to moderate essential hypertension, the initial recommended oral dose of ramipril is normally 2.5mg once daily. However, a lower dosage of 1.25 mg/day should be initiated in patients already receiving a diuretic, thereby reducing the risk of symptomatic hypotension. The dosage should be titrated according to the blood pressure response, and the usual maintenance dosage is 2.5 or 5 mg/day (maximum 10 mg/day). Twice daily administration is advised for patients in whom it is suspected that the antihypertensive effect of ramipril diminishes towards the end of a once daily dosage interval. The recommended starting dose in patients with renal impairment (creatinine clearance >3 L/h/1.73m ) is 1.25mg, titrated up to a maximum of 5 mg/day. Dosages at the lower end of the therapeutic spectrum are also likely to be required in elderly patients and those with hepatic impairment. Patients with clinical evidence of heart failure following acute MI should receive an initial dosage of ramipril 2.5 mg/day titrated upwards to 5 or 10 mg/day, regardless of whether they are already receiving diuretics. In the event of poor tolerability, a lower dosage of 2.5 mg/day can be given for 2 days, followed by re-titration upwards if appropriate.

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