Cilazapril - Non- sulfhydryl- containg ACE inhibitor- Investigational drugs
Drug Name:Cilazapril - Non- sulfhydryl- containg ACE inhibitor- Investigational drugs
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Pharmacology/ Pharmacokinetics
Drug Interaction:
Drug interactions-
Indomethicin (eg. Indocin) considerably atentuates the antihypertensive activity of cilazapril.
This attenuation was most pronounced when cilazapril was added to indomethicin, while the
addition of indomethicin to a stable clizapril regimen resulted in a degree of attentuation
of effect which was cosidered to be clinically significant.
Thus the significance of this interaction appears to be on the order of drug administration.
Indication:
Hypertension
Summary-
Cilazapril is a long-acting potent ACE inhibitor. It appears to be well tolerated, while offering
the advantage of once-daily dosing. This property may make it usful ddition to a class of
drugs whose safety and efficacy continued to be confirmed in a variety of disease states.
An NDA for cilazapril was filed in September 1989 for hypertension. Roche and Glaxo will
comarket cilazapril as Inhibace. On August 13,1992, the FDA classified cilazapril as
- approvable-
Adverse Reaction:
Side effects-
Clizapril appears to be well tolerated in controled trials of cilazapril monotherapy in
> 3500 patients. The most frequently reported side effects were-
Headache -4.5%, dizziness 3.3%, fatigue 1.7%, cough 1.6%, chest pain 0.8%,
rash, somnolence 0.6%
In patients > 65 years of age, cough, dizziness, palpitations, and somlolence ocurred
slighly more frequently than in younger patients.
The addition of HCTZ in an additional 1000 patients resulted in a slightly higher incidence
of dizziness, cough and somnolence, while the incidence of other side effects were
comparable to cilzapril monotherapy
Pharmacology/ Pharmacokinetics:
Pharmacology-
Cilazapril is a potent , structurally new non-sulfhydryl- containing active angiotensin -
converting enzyme (ACE) inhibitor prodrug under investigation for use in patients with
hypertension and CHF.
Following oral admin , cilazapril is de-esterified in the liver and other tissues to the active
diacid form , cilazarilat. Cilazaprilat, is app 10 times more potent than captopril (Captoten)
and 5 times more potent than enalapilat, the active form of enalapril (Vasotec).
ACE inhibitors block the enzyamatic conversion of angiotensin I to the potent vasoconstrictor angiotensin II, While this inhibition also results in reduced metabolism of braycardin, alteration in prostaglandin system and the reduction in plasma aldosterone in the prostaglandin system and reduction in plasma aldosterone and antidiuertic hormone,
these responses do not appear to be responsible for the primary therapeutic effects of
these agents.
Blockade of angiotensin II prodution reduces supine and standing pressure in hypertensive
patients. In patients with CHF, the vasodilatory response reduces the overload, leading to
an increase in cardiac ouput.
After admin of cilazapril , ACE activity, angiotensin II and plasma aldostreone concentrations,total peripheral resistence , blood pressure(systolic, diasystolic and mean ) and the response to exogenous angiotensin I are all reduced, while the heart rate , baroreceptor reflux sensitivity,cardiovascular reflexes and glomerular filtrations rare are usually unchanged.
Pharmacokinetics-
Cilazapril is rapidly absorbed after oral admin. with peak levels of parent compound acheived ay app 1 hour. Convertion to cilazaprilat the active form, is rapid and extensive, with peak levels attained at app 1.8 hours with 57% absolute bioavailability of the active compound.In contrast to some other ACEIs the bioavailability not significantly reduced by food.
The elimination ofcilazapril is biphasic with an initial half-life of 1 - 2 hours controlled by the
rate of conversion to this active form, followed by prolonged terminal elimination half-life
of 30 to 50 hours.
Clinical trials-
Clinical trials in > 4500 hypertensive patients have evaluated the efficacy of clizapril.
Single daily dose of 2.5 to 5mg areas effective as single daily doses of Hydrocchlorothiazide (HCTZ eg Esidrex) 25 to 50mg , atenolol (Tenormin) 50 to 100mg, sustained release propranol eg Inderal LA) 80 to 160mg, and enalapril 10 to 20mg in patients with mild to moderate hypertension.
A 5mg cilazapril dose produces a maximal effect , which can be enhanced by the addition of 12.5 to 25mg HCTZ. In patients with severe hypetension, including patients with left ventricular hypertrophy the mean effective dose was 10mg in combination with 12.5 to 25mg HCTZ daily
