Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients.
1 In a placebo-controlled double-blind cross-over study lasting 6 weeks, twenty patients with essential hypertension were treated with placebo for 2 weeks followed by oral cilazapril 2.5 mg once a day or oral indomethacin 50 mg twice daily for 2 weeks. Afterwards they received the combination of both drugs for a further 2 weeks. 2 Cilazapril significantly lowered systolic and diastolic blood pressure for a period of 24 h post administration. 3 Indomethacin significantly attenuated the antihypertensive activity of cilazapril. This was more pronounced in those patients who were treated for the initial 2 weeks with indomethacin plus placebo (and subsequently with cilazapril in addition) than in the subjects who first received cilazapril plus placebo and then the combination. 4 Correspondingly the decrease of plasma renin activity (PRA) and urinary prostaglandin excretion (PGE2) was more pronounced in those patients treated initially with indomethacin. 5 The effect of indomethacin on the antihypertensive effect of cilazapril appears to depend upon the sequence of drug administration.
1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day‐1), cilazapril (2, 5 mg day‐1), and a combination of both in a double‐blind cross‐over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose‐effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose‐ effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin‐stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found.
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