Dosage considerations with perindopril for systemic hypertension

  • Domenic A Sica
    Address for reprints: Domenic A. Sica, MD, Department of Clinical Pharmacology and Hypertension, Box 980160, Medical College of Virginia Station, Virginia Commonwealth University, Richmond, Virginia 23298-0160
    Department of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
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      Perindopril erbumine is a once-daily angiotensin-converting enzyme (ACE) inhibitor that effectively lowers systolic and diastolic blood pressure (BP) in patients with mild-to-moderate hypertension. Converted from the prodrug ester perindopril, the active diacid perindoprilat is distributed rapidly and extensively, primarily to tissues with high ACE activity. Its ability to lower BP is comparable to or better than that of other antihypertensive agents, both of its own class and other classes, and its trough-peak ratio is consistently between 75% and 100%, translating into 24 hours of true efficacy per dose. First-dose hypotension caused by an initial acute BP depression occurs less frequently with perindopril than with other ACE inhibitors, an advantage in volume-contracted patients and those whose BP is angiotensin II dependent, such as patients with congestive heart failure. A missed-dose study showed that most of the antihypertensive effect of perindopril remains for 24 to 48 hours after dosing, a characteristic that confers protection to patients who miss a dose. Perindopril improves the distensibility and compliance of large and small arteries, which are compromised in hypertension, and can effect vascular remodeling by a mechanism independent of BP lowering. The clinical implications of these effects are being investigated in large trials. Perindopril is well tolerated in the elderly, and combination therapy with a diuretic was shown to yield significant additional BP reduction. Perindoprilat is cleared renally; dosage should be adjusted in patients with renal impairment.
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        • Todd P.A
        • Fitton A
        Drugs. 1991; 42: 90-114
        • Zannad F
        • Bernaud C.M
        • Fay R
        • General Physicians Investigators’ Group
        Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension.
        J Hypertens. 1999; 17: 137-146
        • Yusoff K
        • Razak T.A
        • Yusof N
        • Rafee N.M
        Comparative efficacy of perindopril and enalapril once daily using 24-hour ambulatory blood pressure monitoring.
        Int J Clin Pract. 1999; 53: 277-280
        • Myers M.G
        • Perindopril Multicentre Dose-Response Study Group
        A dose-response study of perindopril in hypertension.
        Can J Cardiol. 1996; 12: 1191-1196
        • Unger T
        • Moursi M
        • Ganten D
        • Hermann K
        • Lang R.E
        Antihypertensive action of the converting enzyme inhibitor perindopril (S9490–3) in spontaneously hypertensive rats.
        J Cardiovasc Pharmacol. 1986; 8: 276-285
        • Richer C
        • Doussau M.P
        • Giudicelli J.-F
        Systemic and regional hemodynamic profile of five angiotensin I converting enzyme inhibitors in the spontaneously hypertensive rat.
        Am J Cardiol. 1987; 59: 12D-17D
        • Borghi H
        • Fillastre J.P
        • Morin J.P
        Rat and rabbit renal and tissular distributions of perindopril (S-9490-3) a new angiotensin-converting enzyme inhibitor.
        Clin Exp Hypertens. 1987; A9 ([abstract]): 1952
        • Girerd X
        • Giannattasio C
        • Moulin C
        • Safar M
        • Mancia G
        • Laurent S
        Regression of radial artery wall hypertrophy and improvement of carotid artery compliance after long-term antihypertensive treatment in elderly patients.
        J Am Coll Cardiol. 1998; 31: 1064-1073
        • Kool M.J
        • Lustermans F.A
        • Breed J.C
        • Struyker-Boudier H.A
        • Hoeks A.P
        • Van Bortel L.M
        Effect of perindopril and amiloride/hydrochlorothiazide on haemodynamics and vessel wall properties of large arteries.
        J Hypertens. 1993; 11: S362-S363
        • Thybo N.K
        • Stephens N
        • Cooper A
        • Aalkjær C
        • Heagerty A.M
        • Mulvany M.J
        Effect of antihypertensive treatment of small arteries of patients with previously untreated essential hypertension.
        Hypertension. 1995; 25: 474-481
        • Sihm I
        • Schroeder A.P
        • Aalkjær C
        • Holm M
        • Mørn B
        • Mulvany M
        • Thygessen K
        • Lederballe O
        Normalization of structural cardiovascular changes during antihypertensive treatment with a regimen based on the ACE-inhibitor perindopril.
        Blood Press. 1995; 4: 241-248
        • Chalmers J
        • Neal B
        • MacMahon S
        • PROGRESS Management Committee
        PROGRESS (Perindopril Protection Against Recurrent Stroke Study).
        J Hypertens. 2000; 18: S13-S19
        • Fox K.M
        • Henderson J.R
        • Bertrand M.E
        • Ferrari R
        • Remme W.J
        • Simoons M.L
        The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA).
        Eur Heart J. 1998; 19: J52-J55
        • Lecocq B
        • Funck-Brentano C
        • Lecocq V
        • Ferry A
        • Gardin M.-E
        • Devissaguet M
        • Jaillon P
        Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.
        Clin Pharmacol Ther. 1990; 47: 397-402
        • Louis W.J
        • Workman B.S
        • Conway E.L
        • Worland P
        • Rowley K
        • Drummer O
        • McNeil J.J
        • Harris G
        • Jarrott B
        Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.
        J Cardiovasc Pharmacol. 1992; 20: 505-511
        • Lees K.R
        • Green S.T
        • Reid J.L
        Influence of age on the pharmacokinetics and pharmacodynamics of perindopril.
        Clin Pharmacol Ther. 1988; 44: 418-425
        • Devissaguet J.P
        • Ammoury N
        • Devissaguet M
        • Perret L
        Pharmacokinetics of perindopril and its metabolites in healthy volunteers.
        Fundam Clin Pharmacol. 1990; 4: 175-189
        • Lees K.R
        Clinical pharmacology of perindopril.
        J Hum Hypertens. 1990; 4: 7-11
        • Bree F
        • Nguyen P
        • Urien S
        • Resplandy G
        • Tillement J.P
        Specific and high affinity binding of perindoprilat, but not of perindopril to blood ACE.
        Int J Clin Pharmacol Ther Toxicol. 1992; 30: 325-330
        • Funck-Brentano C
        • Lecocq B
        • Jaillon P
        • Devissaguet M
        Effects of food on the pharmacokinetics and ACE-inhibition of perindopril in healthy volunteers.
        in: Velasco M Israel A Romero E Silva H Recent Advances in Pharmacology and Therapeutics. Elsevier Science Publishers BV, Amsterdam1989: 277-280
        • Sennesael J
        • Ali A
        • Sweny P
        • Vandenburg M
        • Slovic D
        • Dratwa M
        • Resplandy G
        • Genissel P
        • Desche P
        The pharmacokinetics of perindopril and its effects on serum angiotensin converting enzyme activity in patients with chronic renal failure.
        Br J Clin Pharmacol. 1992; 33: 93-99
        • Verpooten G.A
        • Genissel P.M
        • Thomas J.R
        • DeBroe M.E
        Single dose pharmacokinetics of perindopril and its metabolites in hypertensive patients with various degrees of renal insufficiency.
        Br J Clin Pharmacol. 1991; 32: 187-192
        • Guerrin A
        • Resplandy G
        • Marchais S
        • Taillard F
        • London G
        The effect of haemodialysis on the pharmacokinetics of perindoprilat after long-term perindopril.
        Eur J Clin Pharmacol. 1993; 44: 183-187
        • Sica D.A
        • Gehr T.W.B
        • Fernandez A
        Risk-benefit ratio of angiotensin antagonists versus ACE inhibitors in end-stage renal disease.
        Drug Safety. 2000; 22: 350-360
        • Thiollet M
        • Funck-Brentano C
        • Grange J.-D
        • Midavaine M
        • Respkandy G
        • Jaillon P
        The pharmacokinetics of perindopril in patients with liver cirrhosis.
        Br J Clin Pharmacol. 1992; 33: 326-328
        • Sica D.A
        Kinetics of angiotensin-converting enzyme inhibitors in renal failure.
        J Cardiovasc Pharmacol. 1992; 20: S13-S20
        • Hurst M
        • Jarvis B
        Drugs. 2001; 61: 867-896
        • Agabiti-Rosei E
        • Ambrosioni E
        • Finardi G
        • Folino P
        • Gambassi G
        • Malini P
        • Marchesi E
        • Muiesan M.L
        • Semplicini A
        • Pessina A.C
        Perindopril versus captopril.
        Am J Med. 1992; 92: 79S-83S
        • Grandi A.M
        • Venco A
        • Barzizza F
        • Petrucci E
        • Scalise F
        • Perani G
        • Marchesi E
        • Folino P
        • Finardi G
        Double-blind comparison of perindopril and captopril in hypertension.
        Am J Hypertens. 1991; 4: 516-520
        • Lees K.R
        • Reid J.L
        • Scott M.G.B
        • Hosie J
        • Herpin D
        • Santon J.-P
        Captopril versus perindopril.
        J Hum Hypertens. 1989; 3: 17-22
        • Alcocer L
        • Campos C
        • Bahena J.H
        • Nacaud A
        • Parra Carillo J
        • Calvo C
        • Weber C
        • Lerebours G
        • Mickalonis L
        • Villahermosa M.T
        Clinical acceptability of ACE inhibitor therapy in mild to moderate hypertension, a comparison between perindopril and enalapril.
        Cardiovasc Drugs Ther. 1995; 9: 431-436
        • Nedogoda S.V
        • Petrov V.I
        The differences between ACE inhibitors trough to peak ratios at 24-hour ambulatory monitoring (cross-over study).
        J Hypertens. 1998; 16 ([abstract]): 247
        • Polónia J
        • Pego M
        • Calaça J
        • Feligardo A
        • Santos A
        • Calaço I
        • Martins Correia J
        A double-blind comparison of perindopril and enalapril on 24-h control of blood pressure in hypertensive patients.
        Am J Hypertens. 1996; 9 ([abstract]): 162A
        • Anderson A
        • Morgan O
        • Morgan T
        Effectiveness of blood pressure control with once daily administration of enalapril and perindopril.
        Am J Hypertens. 1994; 7: 371-373
        • Agabiti R.E
        • Corea L
        • Leonetti G
        A double-blind assessment, perindopril vs verapamil of the effects on office and 24 HR ambulatory blood pressure and on left ventricular morphology.
        Hypertension. 1995; 162 ([abstract])
        • Canadian Study Group on Perindopril
        Once daily perindopril versus slow release diltiazem in the treatment of mild to moderate essential hypertension.
        Can J Cardiol. 1994; 10: 8D-12D
        • Grandi A.M
        • Bignotti M
        • Gaudio G
        • Zanzi P
        • Guasti L
        • Venco A
        Ambulatory blood pressure and left ventricular changes during antihypertensive treatment.
        J Cardiovasc Pharmacol. 1995; 26: 737-741
        • Hui Y
        • Dai Z
        • Chen X
        • Wang W
        Effect of perindopril and metoprolol on left ventricular hypertrophy and performance in essential hypertension.
        Chin Med J. 1995; 108: 678-681
        • Giuntoli F
        • Gabbani S
        • Natali A
        • Galeone F
        • Saba P
        Effects of perindopril on carbohydrate and lipoprotein metabolism in essential hypertension.
        Am J Med. 1992; 92: 95S-97S
        • Thurston H
        • Mimran A
        • Zanchetti A
        • Creytens G
        • Rorive G
        • Brown C.L
        • Santoni JPh
        A double-blind comparison of perindopril and atenolol in essential hypertension.
        J Hum Hypertens. 1990; 4: 547-552
        • Andrejak M
        • Santoni J.P
        • Carre A
        • Deruyttere M
        • Magometschnigg D
        • Gotzen R
        • Stumpe K.O
        A double-blind comparison of perindopril and hydrochlorothiazide-amiloride in mild to moderate essential hypertension.
        Fundam Clin Pharmacol. 1991; 5: 185-192
        • Sica D.A
        Renal considerations in the use of angiotensin converting enzyme inhibitors in the treatment of congestive heart failure.
        Clin Cardiol. 1997; 20: 20-23
        • MacFadyen R.J
        • Lees K.R
        • Reid J.L
        Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure.
        Br Heart J. 1991; 66: 206-211
        • Reid J.L
        • MacFadyen R.J
        • Squire I.B
        • Lees K.R
        Angiotensin-converting enzyme inhibitors in heart failure.
        Am Heart J. 1993; 126: 794-797
        • Vitovec J
        • Spinar J
        • Czech and Slovak Investigator Group
        First-dose hypotension after angiotensin-converting enzyme (ACE) inhibitors in chronic heart failure.
        Eur J Heart Fail. 2000; 2: 299-304
        • Navookarasu N.T
        • Rahman A
        • Abdullah I
        First-dose response to angiotensin-converting enzyme inhibition in congestive cardiac failure.
        Int J Clin Pract. 1999; 53: 25-30
        • Haı̈at R
        • Piot O
        • Gallois H
        • Hanania G
        • French General Hospitals National College of Cardiologists
        Blood pressure response to the first 36 hours of heart failure therapy with perindopril versus captopril.
        J Cardiovasc Pharmacol. 1999; 33: 953-959
        • Neutel J.M
        The importance of 24-h blood pressure control.
        Blood Press Monit. 2001; 6: 9-16
        • Sica D.A
        Impact of antihypertensive therapy on the rate-pressure product.
        Eur Heart J. 1999; 1: B24-B33
        • Fenichel R.R
        • Lipicky R.J
        On the trough-to-peak ratio of drug effect in antihypertensive trials.
        Am J Hypertens. 1996; 9: 105S-107S
        • Zannad F
        • Matzinger A
        • Larche J
        Trough/peak ratios of once daily angiotensin converting enzyme inhibitors and calcium antagonists.
        Am J Hypertens. 1996; 9: 633-643
        • Tan K.W
        • Leenen F.H.H
        Persistence of anti-hypertensive effect after missed dose of perindopril.
        Br J Clin Pharmacol. 1999; 48: 628-630
        • Vaur L
        • Bobrie G
        • Dutrey-Dupagne C
        • Dubroca I
        • Vaisse B
        • d’Yvoire M.B
        • Elkik F
        • Chatellier G
        • Menard J
        Short-term effects of withdrawing angiotensin converting enzyme inhibitor therapy on home self-measured blood pressure in hypertensive patients.
        Am J Hypertens. 1998; 11: 165-173
        • Rudd P
        Medication compliance for antihypertensive therapy.
        in: Oparil S Weber M Hypertension A Companion to Brenner and Rector’s—The Kidney. WB Saunders, Philadelphia2000: 419-431
        • Morgan T
        • Anderson A
        • Jones E
        The effect on 24 h blood pressure control of an angiotensin converting enzyme inhibitor (perindopril) administered in the morning or at night.
        J Hypertens. 1997; 15: 205-211
        • Sica D.A
        • Gehr T.W.B
        Circadian variation in blood pressure.
        Cong Heart Fail. 1998; 4: 44-48
        • Gehr T.W.B
        • Sica D.A
        Dose-response relationships in antihypertensive treatment.
        in: Oparil S Weber M Hypertension A Companion to Brenner and Rector’s—The Kidney. WB Saunders, Philadelphia2000: 492-496
        • Lees K.R
        The dose-response relationship with angiotensin converting enzyme inhibitors.
        J Hypertens. 1992; 10: S3-S11
        • Chrysant S.G
        • McDonald R.H
        • Wright J.T
        • Barden P.L
        • Weiss R.J
        • Perindopril Study Group
        Perindopril as monotherapy in hypertension.
        Clin Pharmacol Ther. 1993; 53: 479-484
        • Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
        Arch Intern Med. 1997; 157: 2413-2446
        • Sica D.A
        Fixed-dose combination therapy.
        Cardiovasc Rev Rep. 1997; 9: 28-46
        • McClellan K.J
        • Markham A
        Perindopril 2 mg/indapamide 0.625 mg.
        Drugs. 1999; 58: 297-302
        • Myers M.G
        • Asmar R
        • Leenen F.H.H
        • Safar M
        Fixed low-dose combination therapy in hypertension.
        J Hypertens. 2000; 18: 317-325
        • Castaigne A
        • Chalmers J
        • Morgan T
        • Chastang C
        • Feldmann L
        • Guez D
        Efficacy and safety of an oral fixed low-dose perindopril 2 mg/indapamide 0.625 mg combination.
        Clin Exp Hypertens. 1999; 21: 1097-1110
        • Chalmers J
        • Castaigne A
        • Morgan T
        • Chastang C
        Long-term efficacy of a new, fixed, very-low-dose angiotensin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients.
        J Hypertens. 2000; 18: 327-337
        • Brown C.L
        • Backhouse C.I
        • Grippat J.C
        • Santoni JPh
        The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects.
        Eur J Clin Pharmacol. 1990; 39: 327-332
        • Luccioni R
        • Sever P.S
        • Di Perri T
        • Redon J
        • Laurandia I
        • Brault Y
        • Chastang C
        • Guez D
        • European Coordination Group
        An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.
        J Hypertens. 1995; 13: 1847-1851
        • Mallion J.-M
        • Chastang C
        • Unger P
        Efficacy and safety of a fixed low-dose perindopril/indapamide combination in essential hypertension.
        Clin Exp Hypertens. 2000; 22: 23-32