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

Over the last few years, we have gained increasing knowledge regarding the regulatory roles of clock genes for nearly all physiological functions in single cells, plants, animals and humans. There is no doubt that living subjects are under the control of circadian clocks. The importance of circadian rhythms is that they are anticipatory in nature, allowing a better survival in a world with continuously changing environmental conditions, such as day and night.

Over the last few decades, experimental and clinical studies have convincingly demonstrated that the cardiovascular system is also highly organized in time. In humans, the use of ambulatory blood pressure-monitoring systems clearly demonstrate that blood pressure in normotensive and in hypertensive patients are dependent on the time of day. Moreover, different forms of hypertension may exhibit different circadian patterns. In normotension, as well as in primary hypertension, there is, in general, a nightly drop in blood pressure (dippers), whereas, in secondary hypertension due to, for example, renal disease, pregnancy, diabetes mellitus or Cushing’s disease, the rhythm in blood pressure is abolished in approximately 70% of cases (nondippers) or even reversed, with the highest values at night (risers). This is of particular interest since the loss in nocturnal blood pressure fall correlates with increased end-organ damage in cardiac, cerebral, vascular and renal tissues. Moreover, pathophysiological events within the cardiovascular system do not occur at random within the 24 h of a day.

Thus, the onset of nonfatal or fatal myocardial infarction predominantly occurs around 6 a.m. to 12 p.m. A similar circadian time pattern has been shown for sudden cardiac death, stroke, ventricular arrhythmias and arterial embolism. Symptoms in coronary heart-diseased patients, such as myocardial ischemia, angina attacks or silent ischemia, are also significantly more frequent during the day than at night, whereas the onset of angina attacks in variant angina peaks at approximately 4 a.m. In a large survey of 7731 patients who were identified prospectively in the Thrombolysis In Myocardial Ischemia (TIMI) III Registry [1], further evidence was obtained for a circadian variation in the onset of cardiac pain with a peak between 6 a.m. and 12 p.m. This circadian pattern was observed both in patients with unstable angina and in those with evolving non-Q-wave acute myocardial infarction.

Can the biological rhythms present in hypertension have an impact on the timing of drug dosing? Bearing in mind the circadian time-dependent organization of blood pressure regulation, it is easy to conceive that not only must the right amount of the right substance be at the right place but this must also occur at the right time. Thus, it is easy to understand that exogenous compounds, including drugs, may challenge the individual and their rhythmic organization differently depending on the time of exposure.

Along the same lines, several clinical studies have challenged the question of whether we should consider the timing of antihypertensive drug treatment in relation to a ‘normal’ or ‘pathological’ 24-h blood pressure profile.

The antihypertensive drug treatment includes various types of drugs, such as diuretics, β- and α-adrenoceptor blockers, calcium-channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs) and AT₁-receptor blockers, which differ in their sites of action, as well as in their half-lifes, pharmaceutical formulations and, thus, dosing intervals. Despite the great number of studies published in evaluating antihypertensive drug efficacy, the time of day of drug application was rarely a specific point of investigation. Therefore, in this editorial, emphasis will be put on crossover studies (morning vs evening) with antihypertensive drugs to highlight this point more clearly.

There have been several ‘chronotherapeutics’ marketed (e.g., Corvera HS, chronotherapeutic oral drug absorption system (CODAS)-verapamil, Cardizem LA, graded release diltiazem [GRD], Innopran XL™) over the last few years. It is well documented that the compounds, propranolol, diltiazem and verapamil, are effective in lowering blood pressure in hypertensive patients. In general, sustained-release formulations were made for the morning drugs having a relatively short half-life of approximately 4 h to allow after evening dosing peak drug concentrations during the early morning hours [2–13]. Thus, these chronotherapeutics are the result of modern galenic technology with the additional aspect to be dosed in the evening. In none of these studies were the new retard formulations tested in a crossover way (i.e., morning vs evening) in order to demonstrate the superiority of one over the other. According to the aim of the producers, they were only tested after evening dosing. In some cases, a comparison was performed with nonretard formulations. This raises the question: is an antihypertensive drug with a long half-life and administered at bedtime not a chronotherapeutic?

In Tables 1 & 2, crossover studies (morning vs evening) on the 24-h blood pressure profile are presented, which were published for ACEI, CCB and AT₁-receptor blockers in dippers and nondippers. These data clearly show that CCBs (there was only one study with an AT₁-receptor antagonist) reduce the blood pressure independently from the time of drug dosing in both dippers and nondippers. Interestingly, evening dosing of CCB in nondippers not only reduces high blood pressure but also normalizes the disturbed blood pressure profile of these patients. ACEIs, on the other hand, can modify the 24-h blood pressure profile in dippers on evening dosing with a higher risk of superdipping, which may lead to reduced cerebral perfusion; no data are available for ACEIs in nondippers. Unfortunately, no such crossover studies were published for β-receptor antagonists and diuretics.

In conclusion, I would be cautious about using the term chronotherapeutic. There is no doubt that the early morning hours are the hours of highest cardiovascular risk. Whether an antihypertensive drug can cover this time span adequately is more or less a question of its half-life, duration of action or the underlying mechanisms of action, which can also be circadian phase-dependent [25]. In my mind, it is essential to preserve or to restore a ‘normal’ 24-h blood pressure profile. The term chronotherapeutic should not be used for better marketing of a drug. We should bear in mind that our bodily functions are well organized within a 24-h timeframe and that our body clocks are in synchrony. This paradigm should also be considered in the drug treatment of hypertension.

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].