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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.
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.
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.
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.
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.
KeywordsAngiotensin Converting Enzyme Captopril Enalapril Angiotensin Converting Enzyme Inhibition Hydrochlorothiazide
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- Bailey RR, Swainson CP, Walker RJ. Effects of cilazapril on renal function and hormones in hypertensive patients with renal disease. New Zealand Medical Journal 103: 221–223, 1990Google Scholar
- Belz GG, Essig J, Erb K, Breithaupt K, Hoogkamer JFW, et al. Pharmacokinetic and pharmacodynamic interactions between the ACE inhibitor cilazapril and β-adrenoceptor antagonist propranolol in healthy subjects and in hypertensive patients. British Journal of Clinical Pharmacology 27: 317S-322S, 1989bCrossRefGoogle Scholar
- Belz GG, Essig J, Kleinbloesem CH, Hoogkamer JFW, Wiegand UW. Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose-effect curves and baroreceptor reflex. British Journal of Clinical Pharmacology 26: 547–556, 1988aPubMedCrossRefGoogle Scholar
- Brunner HR, Waeber B, Nussberger J. Angiotensin-converting enzyme inhibition versus blockade of the renin-angiotensin system. American Journal of Medicine 87 (Suppl. 6B): 15–18, 1989Google Scholar
- Carlsen JE, Hansen FM, Jensen HA. Efficacy and safety of cilazapril in hypertensive patients with moderate to severe renal impairment. American Journal of Medicine 87 (Suppl. 6B): 79–82, 1989Google Scholar
- Chin AS, Lombard JT, Tsoi DK, Lee AP, Struver GP, et al. Improved ventricular function with cilazapril therapy in normotensive congestive heart failure, Clinical Science 35: 267A, 1987Google Scholar
- Clozel J-P, Kuhn H, Hefti F. Decreases of vascular hypertrophy in four different types of arteries in spontaneously hypertensive rats. American Journal of Medicine 87 (Suppl. 6B): 93–95, 1989bGoogle Scholar
- Ellis SG, Roubin GS, Wilentz J, Lin S, Douglas Jr JS, et al. Results of a randomized trial of heparin and aspirin vs aspirin alone for prevention of acute closure (AC) and restenosis (R) after angioplasty (PTCA). Abstract 0848. Circulation 76 (Suppl. 2): IV–213, 1987Google Scholar
- Erb KA, Breithaupt K, Kleinbloesem CH, Wolf GK, Belz GG. Does the combination of cilazapril and propranolol lower blood pressure at rest and during exercise more pronouncedly than either of the two components alone? Clinical Physiology and Biochemistry 8 (Suppl. 2): 32–45, 1990Google Scholar
- Fassanella d’Amore T, Bussien JP, Nussberger J, Waeber B, Turini GA, et al. Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers. Journal of Cardiovascular Pharmacology 9: 26–31, 1987Google Scholar
- Folkow B. Physiological aspects of primary hypertension. Physiological Reviews 62: 437–504, 1982Google Scholar
- Fong A, Dunton A, LeJemtel T, Ribner H, Massin E, et al. Acute hemodynamic response to oral cilazapril in congestive heart failure. Clinical Pharmacology and Therapeutics 41: 197, 1987Google Scholar
- Francis RJ, Brown AN, Kler L, Fasanella d’Amore T, Nussberger J, et al. Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model. Journal of Cardiovascular Pharmacology 9: 32–38, 1987PubMedGoogle Scholar
- Gasic S, Heinz GH, Kleinbloesem C, Korn A. Effects of ACE-inhibition with cilazapril on splanchnic and systemic hemodynamics in man. European Heart Journal 9 (Suppl. A): P198, 1988Google Scholar
- Goldszer RC, Lilly LS, Solomon HS. Prevalence of cough during angiotensin-converting enzyme inhibitor therapy. American. Journal of Medicine 85: 887, 1988aGoogle Scholar
- Gordon JB, Berk BC, Bettman MA, Selwyn AP, Rennke H, et al. Vascular smooth muscle proliferation following balloon injury is synergistically inhibited by low molecular weight heparin and hydrocortisone. Abstract 0846. Circulation 76 (Suppl. 2): IV–213, 1987Google Scholar
- Grigg LE, Kay T, Manolas EG, Hunt D, Valentine PA. Does max-EPA lower the risk of restenosis after PTCA: a prospective randomized trial. Abstract 0850. Circulation 76 (Suppl. 4): IV–214, 1987Google Scholar
- Gross V, Schölmerich J, Treher E, Wiegand UW, Neis W, et al. Altered kinetics of cilazapril (Ro 31-2548) and cilazaprilat (Ro 31-3113) in patients with liver cirrhosis. Hepatology 8: 1382, 1988Google Scholar
- HolmesJr DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA registry of the National Heart, Lung, and Blood Institute. American Journal of Cardiology 53 (Suppl.): 77C–81C, 1984PubMedCrossRefGoogle Scholar
- Kobrin I, Ben-Ishay D, Bompari R, Dixon R, Hoverman RJ, et al. Efficacy and safety of cilazapril in elderly patients with essential hypertension. American Journal of Medicine 87 (Suppl. 6B); 33–36, 1989Google Scholar
- Kögler P. Cilazapril: a new non-thiol-containing angiotensin-converting enzyme inhibitor: worldwide clinical experience in hypertension. American Journal of Medicine 87 (Suppl. 6B): 51–55, 1989Google Scholar
- Kohno M, Yasunari K, Murakawa K, Yokokawa K, Takeda T. Cilazapril: acute effects of cilazapril on hemodynamic and endocrine responses during exercise in patients with essential hypertension. Rinsho Iyaku 17: 723–731, 1989Google Scholar
- Lernhardt EB, Ziegler MG. Cilazapril-induced cough. Clinical Research 35: 377A, 1987Google Scholar
- Marmor A, Green T, Krakner J, Szucs T, Schneeweiss A. A single dose of cilazapril improves diastolic function in hypertensive patients. American Journal of Medicine 87 (Suppl. 6B): 61–63, 1989Google Scholar
- Milner MR, Gallino RA, Leffingwell A, Pichard AD, Rosenberg J, et al. High dose omega-3 fatty acid supplementation reduces clinical restenosis after coronary angioplasty. Abstract 2527. Circulation 78 (Suppl. II): 11–634, 1988Google Scholar
- Morgan TO. Efficacy of cilazapril compared with hydrochlorothiazide in the treatment of mild to moderate essential hypertension. American Journal of Medicine 87 (Suppl. 6B): 37–41, 1989Google Scholar
- Nakashima M, Kanamaru M. Cilazapril (Ro 31-2848): tolerance, pharmacokinetics and pharmacodynamics of single doses of cilazapril in normal volunteers. Rinsho Iyaku 4: 2221–2247, 1988Google Scholar
- Natoff IL, Redshaw S. Angiotensin-converting enzyme inhibitors - cilazapril and other bicyclic hexahydropyridazines. Drugs of the Future 12: 475–483, 1987Google Scholar
- Nilsen OG, Sellevold OFM, Romfo OS, Smedsrud A, Grynne B, et al. Pharmacokinetics and effects on renal function following cilazapril and hydrochlorothiazide alone and in combination in healthy subjects and hypertensive patients. British Journal of Clinical Pharmacology 27: 323S–328S, 1989PubMedCrossRefGoogle Scholar
- Passmore AP, Kondowe GB, Johnston GD. Effect of cilazapril, a new angiotensin converting enzyme inhibitor, on renal hemodynamics, prostaglandin and electrolyte excretion. Clinical Pharmacology and Therapeutics 43: 198, 1988Google Scholar
- Raizner A, Hollman J, Demke D, Wakefield L, Ciprostene Investigators. Beneficial effects of ciprostene in PTCA: A multicenter, randomized, controlled trial. Abstract 1158. Circulation 78 (Suppl. 2): 11–290, 1988Google Scholar
- Reis GJ, Sipperly ME, Boucher TM, McCabe CH, Bairn DS, et al. Results of a randomized, double-blind placebo-controlled trial of fish oil for prevention of restenosis after PTCA. Abstract 1159. Circulation 78 (Suppl. 2): 11–291, 1988Google Scholar
- Ribner HS, Zucker MJ, Stasior C, Molteni A, Fong A, et al. Acute hemodynamic and hormonal effects of cilazapril, a new, longacting angiotensin converting enzyme inhibitor, in congestive heart failure. Clinical Research 35: 319A, 1987Google Scholar
- Rosenthal E, Curry P. Atrial natriuretic peptide release is suppressed by therapeutic ACE inhibition in patients with congestive heart failure. Abstract 1038. European Heart Journal 11 (Suppl.): 202, 1990Google Scholar
- Rosenthal E, Curry PVL. Cilazapril: a new converting enzyme inhibitor with sustained benefit in congestive heart failure. Cardiovascular Drugs and Therapy 1: 283, 1987Google Scholar
- Sanchez RA, Traballi CA, Barclay CA, Gilbert HB, Muscará M, et al. Antihypertensive, enzymatic, and hormonal activity of cilazapril, a new angiotensin-converting enzyme inhibitor in patients with mild to moderate essential hypertension. Journal of Cardiovascular Pharmacology 11: 230–234, 1988PubMedGoogle Scholar
- Sánchez RA, Traballi CA, Marco EJ, Cianciulli T, Giannone CA, et al. Antihypertensive effect of cilazapril in severe hypertension, long-term assessment of left ventricular and renal function. American Journal of Hypertension 2: 110A, 1989aGoogle Scholar
- Sánchez RA, Traballi CA, Marco EJ, Cranciulli T, Giannone CA, et al. Long term evaluation of cilazapril in severe hypertension. Assessment of left ventricular and renal function. American Journal of Medicine 87 (Suppl. 6B): 56–63, 1989bGoogle Scholar
- Schneeweiss A, Green T, Krakuer J, Goldhamer E, Marmor A. The effect of cilazapril on systolic and diastolic cardiac function in hypertensive patients. European Heart Journal 10 (Suppl.): 189, 1989Google Scholar
- Swainson CP, Walker RJ, Bailey RR. Effects of cilazapril on renal function and hormones in hypertensive patients with renal disease. American Journal of Medicine 87 (Suppl. 6B): 83–87, 1989Google Scholar
- Tsukiyama H, Otsuka K. Effects of cilazapril, a novel angiotensin-converting enzyme inhibitor on haemodynamics in patients with essential hypertension. Yakuri To Chiryo 17: 3577–3583, 1989Google Scholar
- White CW, Knudsen M, Schmidt D, Chisholm RJ, Vandormael M. Neither ticlopidine nor aspirin-dipyridamole prevents restenosis post PTCA: Results from a randomized placebo-controlled multicenter trial. Abstract 0849. Circulation 76 (Suppl. 2): IV–213, 1987Google Scholar
- White WB, McCabe EJ. Effects of once daily ACE inhibition with cilazapril on casual, ambulatory, and exercise blood pressure. Presented at the 89th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Diego, California, March 1988Google Scholar
- Yoshinaga K, Abe K, Kaneko Y, Arakawa K, Iimura O, et al. Efficacy and safety of cilazapril (Ro 31-2848) in hypertensive patients with renal impairment. Rinsho Iyaku 5: 577–596, 1989aGoogle Scholar
- Yoshinaga K, Arakawa K, Sasaguri M, Kaneko Y, Iimura O, et al. Effect of cilazapril, a novel angiotensin-converting enzyme inhibitor, on the diurnal blood pressure variation in patients with essential hypertension. Rinsho Iyaku 5: 237–250, 1989eGoogle Scholar
- Yoshinaga K, Kaneko Y, Shionoiri H, Arakawa K, Iimura O, et al. Initial evaluation of efficacy and safety of cilazapril, a novel angiotensin-converting enzyme inhibitor, in patients with essential hypertension. Rinsho Iyaku 5: 251–274, 1989dGoogle Scholar
- Yoshinaga K, Kumahara Y, Ogihara T, Kaneko Y, Arakawa K, et al. Efficacy Yoshinaga K, Arakawa K, Sasaguri M, Kaneko Y, Iimura O, et al. Effect of cilazapril, a novel angiotensinconverting enzyme inhibitor, on the and safety of cilazapril, an inhibitor of angiotensin-converting enzyme in patients with severe hypertension. Rinsho Iyaku 5: 592–613, 1989bGoogle Scholar
- Yoshinaga K, Soruta T, Kaneko Y, Arakawa K, Iimura O, et al. Clinical evaluation of cilazapril (Ro 31-2848) on essential hypertension in monotherapy. Multicentre cooperative open study. Rinsho Iyaku 5: 983–1009, 1989cGoogle Scholar
- Yoshinaga K, Soruta T, Kaneko Y, Arakawa K, Iimura O, et al. Clinical evaluation of cilazapril in the long term treatment of essential hypertension. Rinsho Iyaku 5: 1479–1508, 1989fGoogle Scholar