Hypertension: do we need to consider the biological clock in drug dosing?

Figures & data

Table 1. Effects of calcium-channel blockers on the 24-h pattern of blood pressure in dippers, nondippers and normotension.

Drug	Patients (n)	Dose (mg)	Duration (weeks)	Dosing time	Lowering of blood pressure			Ref.
					Day	Night	24 h profile
Primary hypertension (dipper)
Amlodipine	20	5	4	Morning Evening	↓↓ ↓↓	↓↓ ↓↓	Preserved Preserved	[14]
Amlodipine	12	5	3	8 a.m. 8 p.m.	↓ ↓	↓ ↓	Preserved Preserved	[15]
Isradipine	18	5	4	7 a.m. 7 p.m.	↓↓ ↓↓	↓↓ ↓↓	Preserved Preserved	[16]
Lacidipine	33	4	6	Morning Evening	↓↓ ↓	↓ ↓-↓↓	Preserved Preserved?	[17]
Nifedipine GITS	10	30	1-2	10 a.m. 10 a.m.	↓↓ ↓↓	↓↓ ↓↓	Preserved Preserved	[18]
Nisoldipine ER	39	20	4	7-9 a.m. 9-11 p.m.	↓↓ ↓↓	↓(↓) ↓↓	Preserved Preserved	[19]
Nitrendipine	41	20	4	6 a.m. 6 p.m.	↓ ↓	↓ ↓	Preserved Preserved	[20]
Nitrendipine	6	10	0.5	6 a.m. 6 p.m.	↓↓ ↓	↓↓ ↓↓	Preserved Changed	[21]
Secondary hypertension (nondipper)
Amlodipine	39	5	3	8 a.m. 8 p.m.	↓ ↓	↓↓ ↓↓	Normalized Normalized	[22]
Isradipine	16	5	3	8 a.m. 8 p.m.	↓↓ ↓	↓↓ ↓↓↓	Disturbed Normalized	[23]
Nisoldipine ER	36	20	4	7-9 a.m. 9-11 p.m.	↓↓ ↓↓	↓↓↓ ↓↓↓	Normalized Normalized	[19]
Normotension
Nifedipine IR	10	12	Single dose	8 a.m. 7 p.m.	↓ ↓	↓↓ ↓	Preserved Preserved	[24]

Only data obtained in crossover studies are considered. Drug dose, duration of blood pressure profile, treatment, circadian time of drug application, number of patients and the diagnoses, as well as the effect on the blood pressure profile, are given.

ER: Extended release; GITS: Gastrointestinal therapeutic system; IR: Immediate release.

Reproduced from [25].

Table 2. Effect of angiotensin-converting enzyme inhibitors and AT₁-receptor blockers on blood pressure profile in dippers, crossover studies.

Drug	Patients (n)	Dose (mg)	Duration	Dosing time	Lowering of blood pressure			Ref.
					Day	Night	24 h profile
ACE-inhibitors
Benazepril	10	10	1 day	9 a.m. 9 p.m.	↓↓↓ ↓	↓↓ ↓↓	Preserved Changed	[26]
Enalapril	10	10	1 day	8 a.m. 7 p.m.	↓↓ ↓↓	↓ ↓↓↓	Preserved Changed	[27]
Enalapril	10	10	3 weeks	8 a.m. 7 p.m.	↓↓ ↓	↓ ↓↓	Preserved Changed	[27]
Perindopril	18	2	4 weeks	7 a.m. 9 p.m.	↓↓ ↓	↓ ↓↓	Preserved Changed	[28]
Quinapril	18	20	4 weeks	8 a.m. 10 p.m.	↓↓ ↓↓	↓ ↓↓	Preserved Preserved	[29]
Lamipril	33	2.5	4 weeks	8 a.m. 8 p.m.	↓ (↓)	(↓) ↓	Preserved Preserved	[30]
Trandolapril	30	1-2	8 weeks	Morning Bedtime	↓↓ ↓↓	↓↓ ↓↓	No profiles Shown	[31]
AT1-receptor-blockers
Valsartan	90	160	3 months	Awalking Bedtime	↓↓ ↓↓	↓↓ ↓↓	Preserved Preserved	[32] (parallel group design)

Drug dose, duration of blood pressure profile, treatment, circadian time of drug application, number of patients, diagnosis, as well as the effect on the blood pressure profile, are given.

ACE: Angiotensin-converting enzyme.

Reproduced from [25].

Mengden T, Binswanger B, Gruene S, Spühler T, Weisser B, Vetter W. Dynamics of drug compliance and 24-hour blood pressure control of once daily morning vs evening amlodipine. J. Hypertens.10(Suppl. 4), S136(P103) (1992).

 Google Scholar

Nold G, Strobel G, Lemmer B. Morning versus evening amlodipine: effect on circadian blood pressure profile in essential hypertensive patients. Blood Press. Monit.3, 17–25 (1998).

 PubMedGoogle Scholar

Fogari R, Malacco E, Tettamanti F, Gnemmi AE, Milani M. Evening vs morning isradipine sustained release in essential hypertension – a double-blind study with 24-h ambulatory monitoring. Br. J. Clin. Pharmacol.35, 51–54 (1993).

 PubMed Web of Science ®Google Scholar

van Montfrans GA, Schelling A, Buurke EJ, Schut N, Houben JJ. Dosing time of lacidipine and the circadian blood pressure curve: the MOTIME study. J. Hypertens.16(Suppl. 9), S15–S19 (1998).

 PubMed Web of Science ®Google Scholar

Greminger P, Suter PM, Holm D, Kobelt R, Vetter W. Morning versus evening administration of nifedipine gastrointestinal therapeutic system in the management of essential hypertension. Clin. Investig.72, 864–869 (1994).

 PubMedGoogle Scholar

White WB, Mansoor GA, Pickering TG et al. Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate. Am. J. Hypertens.12, 806–814 (1999).

 PubMed Web of Science ®Google Scholar

Meilhac B, Mallion JM, Carre A et al. Antihypertensive effect and tolerance of nitrendipine administered either in the morning or in the evening of office and ambulatory blood pressure. Therapie47, 205–210 (1992).

 PubMed Web of Science ®Google Scholar

Umeda T, Naomi S, Iwaoka T et al. Timing for administration of an antihypertensive drug in the treatment of essential hypertension. Hypertension23(Suppl. 1), I211–I214 (1994).

 Google Scholar

Lemmer B, Luders S, Nold G, Schrader J, Manfredini R, Portaluppi F. Normalisation of non-dipping blood pressure profile by amlodipine after single morning or evening dosing. Am. J. Hypertens.15, 109A (2002).

 Google Scholar

Portaluppi F, Vergnani L, Manfredini R, degli Uberti EC, Fersini C. Time-dependent effect of isradipine on the nocturnal hypertension of chronic renal failure. Am. J. Hypertens.8, 719–726 (1995).

 PubMed Web of Science ®Google Scholar

Lemmer B, Nold G, Behne S, Kaiser R. Chronopharmacokinetics and cardiovascular effects of nifedipine. Chronobiol. Int.8, 485–494 (1991).

 PubMed Web of Science ®Google Scholar

Lemmer B. The importance of circadian rhythms on drug response in hypertension and coronary heart disease – from mice and man. Pharmacol. Ther.111, 629–651 (2006).

 PubMed Web of Science ®Google Scholar

Palatini P, Mos L, Motolese M et al. Effect of evening versus morning benazepril on 24-hour blood pressure – a comparative study with continuous intraarterial monitoring. Int. J. Clin. Pharmacol. Ther. Toxicol.31, 295–300 (1993).

 PubMed Web of Science ®Google Scholar

Witte K, Weisser K, Neubeck M et al. Cardiovascular effects, pharmacokinetics, and converting enzyme inhibition of enalapril after morning versus evening administration. Clin. Pharmacol. Ther.54, 177–186 (1993).

 PubMed Web of Science ®Google Scholar

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.15, 205–211 (1997).

 PubMed Web of Science ®Google Scholar

Palatini P, Racioppa A, Raule G, Zaninotto M, Penzo M, Pessina AC. Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril. Clin. Pharmacol. Ther.52, 378–383 (1992).

 PubMed Web of Science ®Google Scholar

Myburgh DP, Verho M, Botes JH, Erasmus TP, Luus HG. 24-hour blood pressure control with ramipril: comparison of once-daily morning and evening administration. Curr. Ther. Res. Clin. Exp.56, 1298–1306 (1995).

 Web of Science ®Google Scholar

Koroda T, Kario K, Hoshide S et al. Effects of bedtime vs. morning administration of the long-acting lipophilic angiotensin-converting enzyme inhibitor trandolapril on morning blood pressure in hypertensive patients. Hypertens. Res.27, 15–20 (2004).

 PubMed Web of Science ®Google Scholar

Hermida RC, Calvo C, Ayala DE et al. Administration time-dependent effects of valsartan on ambulatory blood pressure in hypertensive subjects. Hypertension42, 283–290 (2003).

 PubMed Web of Science ®Google Scholar