Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE). The converting enzyme, or kininase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Bisoprolol has no significant negative inotropic effects.
Bisoprolol reaches its maximum effects 3-4 hours after administration. Due to the half-life of 10-12 hours, bisoprolol acts for 24 hours.
The maximum blood-pressure-lowering effects of bisoprolol are generally reached after 2 weeks.
In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases. The decrease in plasma renin activity is proposed as a mechanism of action underlying the antihypertensive effect of beta-blockers.
Bisoprolol reduces the sympatho-adrenergic response by blocking cardiac beta-adrenergic receptors. This results in a decrease in heart rate and contractility, causing a reduction in oxygen consumption by the myocardium, which is the desired effect in the case of angina associated with underlying coronary heart disease.
Perindopril is active in all grades of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.
Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate.
Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.
Perindopril reduces cardiac work by a decrease in pre-load and after-load.
The rate and extent of absorption of bisoprolol and perindopril from bisoprolol/perindopril fixed-dose combination are not significantly different, respectively, from the rate and extent of absorption of bisoprolol and perindopril when taken alone as monotherapy.
Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract and, because of its small hepatic first-pass metabolism (approximately 10%), it has a bioavailability of approximately 90% after oral administration.
The distribution volume is 3.5 l/kg. The plasma protein binding of bisoprolol is about 30%.
Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Total clearance is approximately 15 l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.
The kinetics of bisoprolol are linear and independent of age.
Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with chronic heart failure and with impaired liver or renal function has not been studied. In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours.
After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour.
The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to ACE, but is concentration-dependent.
Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure. Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance). Dialysis clearance of perindoprilat is equal to 70 ml/min.
Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. In reproductive toxicology studies, bisoprolol had no effect on fertility or other general results of reproduction.
Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.
In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage. No mutagenicity has been observed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. However, ACE inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been observed. Fertility was not impaired either in male or in female rats
No carcinogenicity has been observed in long term studies in rats and mice.
Bisoprolol/perindopril fixed-dose combination will be prescribed as a direct replacement for individual doses of bisoprolol and perindopril, so there will be no increase in the environmental exposure.
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