Inhibition of angiotensin II formation, particularly in the vasculature is the primary pharmacological action of perindopril. It produces vasodilation in arterioles, small and large arteries, the elastic properties of which it restores. The usual effective dosage giving 24 hours antihypertensive cover, for mild to moderate hypertension is a single dose of 4 mg daily. The fall in blood pressure (BP) is rapidly obtained; in responders BP is normalized in 1 month and thereafter there is no fading of the effect. There is no rebound effect on stoppage of treatment. In the arteries and myocardium, perindopril reduces parietal hypertrophy and hypertrophy of the smooth muscle cells and improves the elastin/collagen ratio. It also reduces left ventricular hypertrophy. 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 2 to 4 mg daily, of perindopril in patients with congestive heart failure.

Perindopril is a prodrug ester, which is hydrolysed to form the active metabolite perindoprilat.
Absorption:
Administered orally, perindopril is rapidly absorbed from the gut and plasma-peak concentration is reached in 1 hour. Perindoprilat reaches plasma-peak concentrations in 3 to 4 hours after administration.
Distribution
The distribution volumes of perindopril and perindoprilat are small owing to the weak lipophilic nature of the compounds. Binding to plasma proteins is weak making drug interactions very unlikely, except with active principles that bind to ACE.
Metabolism
Only 17 to 20% of the orally administered dose of perindopril is available as perindoprilat. Conversion into the latter is slow with peak concentration occurring after 3 to 4 hours. In addition to perindoprilat, 5 other metabolites are formed, all of which are inactive.
Elimination
All metabolites are rapidly excreted in the urine and are not detectable 8 hours after oral administration. About 75% and 25% of a radio-labelled dose of perindopril is recovered in urine and faeces, respectively. Plasma half- life of perindopril is 1 hour. Perindoprilat shows a biphasic elimination pattern because of all ACEI. It has a strong affinity for the enzyme but a low binding capacity. The plasma half-life of the free fraction is 1 hour and of the bound fraction is 24 hours the latter being a good indicator of the duration of its pharmacological activity. The two half-lives are independent of the dose administered. Steady state of perindopril is achieved in 4 days.

Rare and mild side effects are sometimes observed at the start of the treatment. Cough, fatigue, asthenia, headache, disturbances of mood and/or sleep have been reported. Less frequently reported side effects include taste impairment, epigastric discomfort, nausea, abdominal pain and rash. Reversible increases in blood urea and creatinine may be observed. Proteinuria has occurred in some patients. Rarely angioneurotic oedema and decrease in haemoglobin, red cells and platelets have been reported.

Dosage: Essential hypertension
COVERSYL 4 mg tablet in the morning as a single oral dose. This may be increased to 8 mg after 1 month of treatment.
In the elderly, treatment should be started with 2 mg and this may be doubled if necessary, after 1 month’s treatment.

Congestive heart failure
COVERSYL treatment should start under close medical supervision. Initial dose of 2 mg as a single, oral dose in the morning increased to the effective dosage of 4 mg after 1 to 2 weeks, once BP acceptability has been demonstrated (SBP >= 100 mm Hg).

Prevention of recurrent stroke
In patients with history of cerebrovascular disease, COVERSYL should be introduced at a dose of 2mg daily for 2 weeks, then increase to 4 mg daily for further 2 weeks before introducing indapamide. Treatment can be initiated at any time from 2 weeks up to several years after the initial stroke episode.