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Drug Monograph of Cilazapril

Paper Type: Free Essay Subject: Chemistry
Wordcount: 4583 words Published: 23rd Sep 2019

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Drug Monograph of Cilazapril

Drug Monograph


Introduction………………………………………………………… page 2

Mechanism of action……………………………………………… page 3

Therapeutic use and efficacy……………………………………. Page 4

Pharmacokinetics………………………………………………….. page 5

Adverse drug reactions…………………………………………… page 6

Drug interactions………………………………………………….. page 6

Contraindications………………………………………………….. page 7

Conclusion…………………………………………………………… page 7

References…………………………………………………………… page 8

Appendices………………………………………………………….. page 10











Name: Cilazapril

Type of drug: new non-sulphur containing prodrug4, part of the angiotensin converting enzyme (ACE) inhibitors.

Use: treats high blood pressure, chronic heart failure and diabetic kidney failure.

Estimated year of introduction: 1987-88 in Europe and 1990 in USA.

Brand name: Vascace1 (also available as Dynorm, Inhibace, Inibace, Justor and Vascase)

Manufacturer: F. Hoffmann – La Roche Ltd.

Pharmaceutical form: film-coated tablets, for oral use.

IUPAC: 9(S)-[1(S)-(ethoxycarbonyl-1)-3-phenylpropylamino]-octahydro-10-oxo-6H-pyridazo [1,2-a]-[1,2] diazepine-1(S)-carboxylic acid monohydrate.30

Chemical formula: C22H31N3O5

Molecular weight: 435.5

Appearance: white, crystalline powder33 (

Solubility: freely soluble in methanol and dichloromethane, slight solubility in water.

pH: 4.9

Figure 12 shows the chemical structure of cilazapril.

Mechanism of action of the drug

Angiotensin converting enzyme inhibitors are a class of cardiovascular drugs, recently discovered, whose main role is the treatment of hypertension and heart failure. They apply their hemodynamic effect by inhibiting the renin-angiotensin system (RAS);3 they also adjust sympathetic nervous system activity and increase prostaglandin synthesis. ACE inhibitors cause vasodilation and mild natriuresis without affecting heart rate and contractility.3

Cilazapril is successful in reducing blood pressure in hypertensive patients as it is part of the ACE inhibitors class of drugs.4

Angiotensin II is a hormone that regulates the renal activity on top of acting as a vasoconstrictor for the control of blood pressure and its inhibition is the preferred treatment for heart failure and hypertension. ACE inhibitors act by restricting angiotensin II synthesis from angiotensin I.32

Systemic hypertension is when the heart rate goes above 140/90mmHg; the cause is unknown, but it is suspected to be between genetic and environmental influences.

Its regulatory systems are the autonomic nervous system which is normally responsible for immediate regulation in changes of blood pressure detected by baroreceptors and the ‘renin-angiotensin-aldosterone system’ which is a slower mechanism that reduces blood pressure when renin-protease is released by kidneys.

Figure 25 shows the effects of ACE inhibitors and how they reduce angiotensin II levels.

ACE inhibitors provide a restriction of the RAS by breaking down the vasoactive hormone bradykinin and reducing peripheral resistance and blood volume with minimum to nil effect on the heart rate.6

Cilazaprilat competitively binds to the ACE kininase II and inhibits its function, blocking the conversion of angiotensin I to angiotensin II, therefore inhibiting further angiotensin II production, which leads aldosterone to decrease Na+ and water absorption and hence decreasing vasoconstriction which prevents its potent vasoconstrictive actions, increasing vasodilation.

Cilazapril has no acute effect on cardiovascular reflexes and increases effective renal plasma flow while keeping the glomerular filtration rate unaltered.7 A close positive correlation was found between the cilazaprilat plasma concentration and the amount of ACE inhibition,7 showing that high levels of bioavailability of cilazaprilat after being administered have little effect on the plasma ACE inhibition.

In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to achieve low levels of blood pressure.8

As hypertension is associated with impaired endothelial function in both animals and humans, the target to achieve efficient antihypertensive therapy should include restoration of the normal endothelial functions and therefore, the goal of this study was to test whether in vivo treatment of spontaneously hypertensive rats (SHRs) with cilazapril improved endothelial function in their isolated thoracic aorta. Injecting SHRs with cilazapril produced a significant decrease in their blood pressure and normalization of endothelium-dependent relaxation evoked by acetylcholine (ACh) and adenosine diphosphate (ADP). However, cilazapril treatment had no substantial effect on the endothelium-dependent contractions evoked by 5-hydroxytryptamine (serotonin) and prostaglandin F2α (PGF2α). On the other hand, in vitro treatment of isolated thoracic aortas with indomethacin normalized endothelium-dependent relaxations as well as inhibiting endothelium-dependent contractions to serotonin and PGF2α. These outcomes suggested that cilazapril increases the synthesis and release of endothelium-derived relaxing factors (EDRFs). However, the exact mechanism of action of ACE inhibitors on endothelial dysfunction is yet to be established.9

Therapeutic use and efficacy

Cilazapril is converted into cilazaprilat after being orally administered. The effects can be observed within one hour of a single dose and the maximum effect is reached after 3 to 7 hours, depending on the individuals.

In some patients it is best to start with the first dose before their bedtime, when starting the ACE inhibitor therapy.



Type of therapy




2.5mg once daily

Concomitant Diuretic Therapy

0.5mg once daily

Elderly patients (>65 Years)

Start at 1.25mg once daily

Renal impairment

0.25mg to 5mg once daily, based on patient’s creatinine clearance levels

Hepatic impairment

0.5mg daily

Congestive heart failure

As adjunctive with diuretics

0.5mg once daily

Table 110describes the amount of cilazapril that should be administered to patients with various additional conditions.

When using cilazapril contemporarily with diuretics, the diuretic should be stopped 2 to 3 days before starting the therapy and resumed later if completely necessary.

As the effects and safety of this drug have not been tested on children, it is recommended not to administer cilazapril to them.11

Daily doses of 2.5 to 5mg of cilazapril are clinically and statistically significantly more effective than placebo.12 However, a lower starting dose of 0.5 mg is advised for hypertensive patients with an exceedingly active renin-angiotensin-aldosterone system as they may experience extreme drops in their blood pressure.14

In systemic hypertension, hemodynamic changes in systolic and diastolic functions can lead left ventricular hypertrophy. Both of these cardiac functions were detected and measured using echocardiography and measured in a study of 23 hypertensive patients treated with 2.5‐5 mg of cilazapril daily for 6 months and as a result a decline in the left ventricular mass occurred alongside an improvement in early diastolic filling pattern.13


The prodrug Cilazapril is well absorbed and is converted to its active metabolite cilazaprilat in the liver, and then eliminated through filtration in the kidneys4. Cilazaprilat has a bioavailability of 60%, in the liver where Its peak plasma concentration is reached within 2 hours of administration, which is then eliminated by the kidneys, unchanged, after approximately 30hours in urine15 however, in renal impairment, low levels of cilazaprilat are removed.16

Study 1:

The pharmacokinetics and dose proportionality of cilazapril were investigated in a study with 24 volunteers (gender not specified), using the 0.5 to 5 mg dose range intended for therapeutic use. Plasma concentrations of cilazapril and of its active metabolite cilazaprilat together with plasma ACE activity were determined by radio‐enzymatic assay. All doses produced significant inhibition of ACE and the higher the doses the longer the duration of maximal effect lasted.17

Study 2:

The pharmacokinetics of cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two of the different doses. A 2-week interval was left between treatments and plasma levels of cilazaprilat were observed and recorded for up to 3 days after the drug was administered. Peak plasma levels were shown to be directly proportional to dose, and the half-life (t1/2) during the first 8 hours after dosing was 1.5 hours. However, after 24 hours, there was a prolonged terminal phase with a t1/2 bordering 50 hours, and slight dose-dependency was present in this phase. The data suggested that the distribution and absorption of cilazapril in the body is nonlinear.18

Study 3:

The pharmacokinetics of cilazapril were investigated in 12 healthy male volunteers within the age range of 19 to 38 years. Single 2.5 mg oral doses of cilazapril, and equivalent oral and intravenous doses of cilazaprilat were administered to the fasted subjects, with an interval of 1 week between each treatment. Cilazapril and cilazaprilat concentrations in plasma and urine were measured by radioenzymatic methods. Urinary recovery of cilazaprilat averaged to 91% of the dose indicating an absolute bioavailability.19

Adverse drug reactions

In controlled trials of patients treated with cilazapril only few adverse reactions were reported at an incidence of 1%, which occurred at a similar frequency to treatments with placebo.

The dosages in the table 1 must be followed strictly as symptoms associated with overdose of ACE inhibitors including hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough can manifest. The recommended treatment, for cilazapril overdose, is intravenous infusion of sodium chloride or removal from the general circulation by haemodialysis.21

As ACE inhibitors can be taken by diabetic patients to protect from kidney damage, if diuretics are taken in addition to cilazapril it is best to avoid anti-inflammatory pain relief medicines (NSAIDs) to lower risk of harm to the kidneys.31

Drug interactions

Patients who do not react to cilazapril monotherapy usually need the addition of a diuretic such as hydrochlorothiazide.22

Cilazapril was studied in multiple-dose trials that included more than 4,500 hypertensive patients worldwide. 450 patients received cilazapril monotherapy for one year and another 430 patients were administered with cilazapril in a combination with hydrochlorothiazide for six months. After observing the completion of the treatments, daily doses of 2.5 to 5 mg of cilazapril seemed to be better endured than hydrochlorothiazide.23

The effects of hydrochlorothiazide on sodium and chloride excretion were led by its interactions with cilazapril.24 while decreasing angiotensin II concentrations and leading to an increase of water and sodium outflow.

The influence of how food affected the pharmacokinetics ACE inhibitory was investigated by treating 16 volunteers with 5 mg doses of oral cilazapril. Plasma and urine concentrations of cilazaprilat and plasma ACE activity were determined by a radio‐enzymatic method; resulting with an onset delay of ACE inhibition by approximately 30 minutes, but the amount and length of action were unaffected, therefore there was no relevant interaction of cilazapril with food at cellular level.25


It is not recommended the use cilazapril in pregnant and breastfeeding women, especially not in the latter six months of pregnancy as the precise effects are not known and therefore it should be administered with caution strictly following medical advice.26

Cilazapril should not be used in patients who are hypersensitive to the drug or to any other ACE inhibitors as they can have allergic reactions. It must not be used in patients with angioedema.

It is recommended by the CHMP that in patients with liver cirrhosis (but without ascites), cilazapril should be initiated at a lower dose since significant hypotension could occur, and in patients with ascites, cilazapril should not be recommended.27


With the high levels of efficacy and relatively low adverse reactions, cilazapril and other ACE inhibitors have been considered as first-line therapy for hypertension28.

Investigations have revealed from recent studies that cilazapril, in addition to its abilities of a in vivo antihypertensive, can moderate the proliferative response of vessels after vascular injury caused by surgical procedures such as ballooning. Further studies to verify and confirm these findings are ongoing.29


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  1. Rubanyi GM Kauser K Gräser T .  Effect of cilazapril and indomethacin on endothelial dysfunction in the aortas of spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology [01 Jan 1993, 22 Suppl. 5: S23-30]


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  1. Massarella JW, DeFeo TM, Brown AN, Lin A, Wills RJ. The influence of food on the pharmacokinetics and ACE inhibition of cilazapril. British journal of clinical pharmacology. 1989, 27 Suppl. 2, 205S‐209S. 31 January 1998


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Appendix I – Gantt Chart


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