Drugs

, Volume 41, Issue 5, pp 799–820 | Cite as

Cilazapril

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Cardiovascular Disease
  • Felicitas Deget
  • Rex N. Brogden
Drug Evaluation

Summary

Synopsis

Cilazapril is an orally active angiotensin converting enzyme (ACE) inhibitor which lowers peripheral vascular resistance without affecting heart rate. Like enalapril and ramipril it is a prodrug, and is hydrolysed after absorption to cilazaprilat, which has a long terminal phase elimination half-life permitting once daily administration. Given once daily at doses between 2.5 and 5mg, cilazapril reduces arterial blood pressure in patients with mild to moderate essential and renal hypertension. Patients who do not respond adequately to cilazapril monotherapy usually respond with the addition of a diuretic such as hydrochlorothiazide. Preliminary data suggest that cilazapril is of comparable antihypertensive efficacy to usual therapeutic dosages of hydrochlorothiazide, slow release propranolol, nitrendipine, captopril and enalapril. In small studies cilazapril has produced sustained beneficial haemodynamic effects in patients with congestive heart failure. Cilazapril has been well tolerated and exhibits tolerability typical of ACE inhibitors as a class, including their lack of detrimental effect on glucose or lipid metabolism. Cilazapril should provide an effective alternative in the treatment of hypertension and, if preliminary data are confirmed, in congestive heart failure.

Pharmacodynamic Properties

Cilazapril is a prodrug which is hydrolysed to the active angiotensin converting enzyme (ACE) inhibitor cilazaprilat after absorption. Cilazapril causes an increase in plasma renin activity and a decrease in plasma angiotensin II and aldosterone concentrations. Most data support the hypothesis that the beneficial haemodynamic effects of cilazapril result from ACE inhibition and the consequent reduction of angiotensin II levels, which either directly or indirectly causes dilatation of peripheral vessels and reduction of vascular resistance. The contribution of the decreased degradation of bradykinins, if any, is unknown.

In vitro, cilazapril was a highly specific and more potent inhibitor of ACE than enalapril and captopril. Similarly in animal studies, compared to equal doses of enalapril, cilazapril 0.25mg produced more pronounced inhibition of ACE (96% vs 76%) and had a longer duration of action. The rate of recovery of ACE activity was slower after administration of cilazapril (5 to 6%/h) than after enalapril (10%/h).

In humans, the maximum degree of ACE inhibition exceeded 90%, even after low doses of cilazapril (1.25mg) and was apparent about 2 to 3 hours after administration. ACE activity remained below baseline values for up to 72 hours after a single dose. Despite the long terminal phase elimination half-life of 40 to 50 hours, drug accumulation did not usually occur over 2 weeks’ administration, although some accumulation was noted in patients with congestive heart failure. Additionally, cilazapril effectively antagonised the pressor response to angiotensin I infusions, showing high potency in Schild-plot analysis (apparent Ki dose of 0.6mg), and abolished the induced venoconstriction and attenuated the angiotensin I-dependent increase of splanchnic vascular resistance in normal volunteers.

In animal models single doses of cilazapril elicited a significant reduction of blood pressure which lasted about 6 hours. The antihypertensive effect was maximal 3 to 7 days after starting daily treatment. In humans, the onset of antihypertensive action was noted within 1 to 2 hours of administration and peak effects occurred after 4 to 10 hours. In a rat model with carotid artery injury caused by endothelial removal, administration of cilazapril before and after injury prevented the myointimal proliferation that occurred in untreated controls.

During therapy with cilazapril, neither heart rate nor left and right ventricular ejection fraction significantly changed and baroreceptor activity was also unaffected. However, cilazapril has been shown to improve left ventricular diastolic function in patients with left ventricular hypertrophy after single doses and during long term administration. In patients with congestive heart failure, a single dose of cilazapril 0.5 to 2.5mg caused a decrease in arterial blood pressure, pulmonary wedge pressure and systemic vascular resistance, and an increase in cardiac output. Oral administration of cilazapril 2.5 to 5mg to patients with renal disease, or of 10mg plus hydrochlorbthiazide to patients with severe hypertension, reduced renal vascular resistance without affecting renal plasma flow, glomerular filtration rate or renal blood flow. In healthy volunteers, however, a single 5mg dose increased glomerular filtration rate and rerial plasma flow.

Pharmacokinetic Properties

Maximum plasma concentrations of unchanged cilazapril occur within about 1 hour whereas peak plasma concentrations of cilazaprilat occur up to 3 hours after oral administration, in a dose proportional manner. Bioavailability estimates of cilazapril based on AUC and urinary recovery data were 57% and 77%, respectively. Cilazaprilat is excreted almost exclusively by the kidney and no further metabolism occurs. The renal clearance amounts to 14 to 15 L/h. The elimination kinetics of cilazaprilat are polyphasic with a rapid elimination of the unbound drug within the first 8 hours giving an initial phase half-life of 1.5 to 1.8 hours. Terminal half-life is prolonged, with a terminal phase half-life of 40 to 50 hours being reported, interpreted as reflecting the high affinity of cilazaprilat for ACE.

In elderly subjects and patients with renal dysfunction renal clearance may be reduced but initial phase half-life is substantially increased only when creatinine clearance is less than 40 ml/ min.

Therapeutic Efficacy

Noncomparative and placebo-controlled published therapeutic studies, usually involving small numbers of patients, showed that cilazapril reduced systolic and diastolic blood pressure in patients with mild to moderate essential hypertension. Dosages of between 1.25 and 20mg (usually 2.5 to 5mg) per day were administered once daily, and controlled blood pressure for 24 hours. No changes in diurnal variability of blood pressure were observed. In patients in whom cilazapril alone failed to lower blood pressure sufficiently, the coadministration of hydrochlorothiazide was usually effective. When given in combination with hydrochlorothiazide, cilazapril increased the diuretic effects and attenuated hypokalaemia induced by hydrochlorothiazide. The antihypertensive efficacy of cilazapril did not diminish during long term therapy up to 1 year. Preliminary studies comparing the antihypertensive efficacy of cilazapril with that of other antihypertensive agents suggest that cilazapril 2.5mg to 5mg once daily is comparable with hydrochlorothiazide 25 to 50mg daily, slow-release propranolol 80 to 160mg once daily, captopril 25 to 50mg twice daily, atenolol 50 to 100mg once daily or enalapril 10 to 20mg once daily. Cilazapril 2.5mg daily was similar in efficacy to propranolol slow release 120mg while cilazapril 1.25 to 2.5mg and nitrendipine 10mg were also comparable.

Initial noncomparative and placebo-controlled clinical studies in patients with congestive heart failure indicated a favourable influence of cilazapril on haemodynamics which persisted over an observation period of up to 3 months. Additionally, a prolongation of exercise duration and improvement in New York Heart Association functional classification occurred in 78 to 85% of patients after 2 to 3 months of treatment.

Tolerability

The type and incidence of adverse effects observed with cilazapril were similar to those observed with other ACE inhibitors and placebo.

Cough and nonspecific side effects such as dizziness, fatigue and headache have been reported most frequently during treatment with cilazapril. The majority of these adverse reactions were mild and usually disappeared without discontinuation of cilazapril therapy. In an overview of tolerability of cilazapril monotherapy in over 3700 patients, adverse effects with a reported incidence in excess of 1% included headache (4.5%), dizziness (3.3%), fatigue (1.7%) and cough (1.6%).

Dosage and Administration

In patients with essential hypertension, therapy with cilazapril should be initiated with a daily dosage of 1.25mg, and in patients with congestive heart failure a starting dose of 0.5mg should be administered. In the elderly, initial dosage should not exceed 1.25mg once daily. Due to an increased risk of hypotension, low initial doses should be given to all patients with volume depletion.

Depending on the blood pressure response, the dosage of cilazapril can gradually be increased up to 5mg once daily. In order to improve efficacy in patients who fail to respond adequately to cilazapril alone, hydrochlorothiazide or a similar non-potassium-sparing diuretic may be added. Dosage of cilazapril should be reduced in patients with renal failure, with initial dosages of lmg and 0.5mg when creatinine clearance is greater than 40 ml/min and between 10 and 40 ml/min, respectively. Recommended maximum maintenance dosages are 5 and 2.5mg, respectively.

Keywords

Angiotensin Converting Enzyme Captopril Enalapril Angiotensin Converting Enzyme Inhibition Hydrochlorothiazide 

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Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Felicitas Deget
    • 1
  • Rex N. Brogden
    • 1
  1. 1.Adis Drug Information servicesAucklandNew Zealand

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