Cilazapril

Cilazapril is a specific, long-acting angiotensin-converting enzyme (ACE) inhibitor which suppresses the renin-angiotensin-aldosterone system and thereby the conversion of the inactive angiotensin I to angiotensin II, which is a potent vasoconstrictor. At recommended doses, the effect of cilazapril in hypertensive patients and in patients with congestive heart failure is maintained for up to 24 hours.

Absorption

Cilazapril is efficiently absorbed and rapidly converted to the active form, cilazaprilat. Ingestion of food immediately prior to cilazapril administration delays and reduces absorption to a minor extent which, however, is therapeutically irrelevant. The bioavailability of cilazaprilat from oral cilazapril approximates 60%, based on urinary recovery data. Maximum plasma concentrations are reached within 2 hours after administration and are directly related to dosage.

Elimination

Cilazaprilat is eliminated unchanged by the kidneys, with an effective half-life of 9 hours after oncedaily dosing with cilazapril.

Special populations

Renal impairment

In patients with renal impairment, higher plasma concentrations of cilazaprilat are observed than in patients with normal renal function, since drug clearance is reduced when creatinine clearance is lower. There is no elimination in patients with complete renal failure, but haemodialysis reduces concentrations of both cilazapril and cilazaprilat to a limited extent.

Elderly patients

In elderly patients whose renal function is normal for age, plasma concentrations of cilazaprilat may be up to 40% higher, and clearance 20% lower, than in younger patients. Similar changes in the pharmacokinetics occur in patients with moderate to severe liver cirrhosis.

Congestive heart failure

In patients with congestive heart failure, clearance of cilazaprilat is correlated with creatinine clearance. Thus, dosage adjustments beyond those recommended for patients with impaired renal function should not be necessary.

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.