Imidapril

The hypotensive effect of imidapril in hypertension appears to result primarily from the suppression of the plasma renin-angiotensin-aldosterone system. Renin is an endogenous enzyme synthesised by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme, a peptidylpeptidase, to angiotensin II. Angiotensin II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion.

Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.

Another function of the converting enzyme is to degrade the potent vasodepressive kinin peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin system which may contribute to peripheral vasodilation by activating the prostaglandin system. Possibly this mechanism is involved in the hypotensive effect of ACE inhibitors and is responsible for certain side effects.

Pharmacodynamic effects

Administration of imidapril to hypertensive patients results in a reduction of sitting, supine and standing blood pressure to about the same extent with no compensatory in-crease of the heart rate. The peak hypotensive effect was observed 6-8 hours after drug intake.

Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term treatment. Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure.

There is an increase in renal blood flow and glomerular filtration rate is usually unchanged.

Absorption

Following oral administration imidapril is rapidly absorbed from the gastrointestinal tract and reaches its maximum plasma concentration within 2 hours. Plasma concentrations decline monophasically with a half-life of about 2 hours. Its absorption is about 70%. A fat-rich meal significantly reduces the absorption of imidapril.

Distribution

The protein binding of imidapril and imidaprilat is moderate (85% and 53%, respectively).

Biotransformation, Elimination

Imidapril is mainly hydrolysed to its pharmacologically active metabolite, imidaprilat. Maximum plasma concentrations of imidaprilat are reached within 7 hours. Plasma concentrations of imidaprilat decline biphasically with an initial half-life of about 7-9 hours and a terminal half-life of more than 24 hours. The absolute bioavailability of imidaprilat is about 42%. After oral administration of the radiolabelled compound about 40% of total radioactivity is excreted in urine and about 50% in the faeces.

Linearity

Oral absorption of imidapril after single oral dosing appeared linear from at least 10 mg up to 240 mg imidapril based on plasma and urinary excretion data.

Renal impairment

After multiple dosing steady state concentrations of imidaprilat are reached after the first administration of imidapril after about 5 days. Increased plasma levels and AUC values of imidapril and imidaprilat were observed in patients with renal impairment. There was a two fold increase in the AUC of imidaprilat in patients with a creatinine clearance 30-80 ml/min and an almost tenfold increase in patients with a creatinine clearance 10-29 ml/min. The experience in all grades of renal impairment is very limited. There is no experience with the 20 mg dose in renal impairment.

Hepatic impairment

In patients with hepatic impairment the AUC of imidapril and imidaprilat were slightly higher than in normal subjects while the tmax for both was similar in the two groups. Furthermore the t_1/2 of imidaprilat, but not that of imidapril, was significantly increased in the hepatically impaired patients.

There were no specific effects from either short studies (including mutagenicity studies) or long term toxicity studies (including carcinogenicity studies) which provide any additional relevant data to that available from the use in man.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

In animal reproduction studies imidapril did not show clear evidence of foetotoxicity though prenatal growth retardation and reduced body weight gain were seen in rat pups at 1500 mg/kg. Male and female fertility in rats was not impaired. Teratogenicity studies in rats and rabbits did not reveal any teratogenic potential.