Circadian rhythm and antihypertensive treatment

Summarized by Robert W. Griffith, MD
November 23, 2000 (Reviewed: February 16, 2003)

Introduction

The biology and physiology of the human organism is affected by many cyclical rhythms. We are most familiar with annual and lunar cycles that influence metabolism, endocrine and neuroendocrine systems. Although circadian rhythms have been known for many years, interest in them have largely centered on the obvious sleep-wakefulness cycle. However, there are a number of diseases that show circadian differences in severity: allergic rhinitis, asthma, rheumatoid and osteoarthritis, and peptic ulcer. Cardiovascular conditions with a circadian rhythm in their rates of manifestation include angina pectoris, myocardial infarction (MI), sudden cardiac death (related to ventricular tachycardia) and stroke; these conditions are all more common in the early morning hours.

Only recently have attempts been made to dose therapeutic medications to achieve optimal results by providing high blood levels at the time of maximum risk. This discipline is called chronotherapeutics. The review by Drs Sica and White considers the role of chronotherapy in treating hypertension and the prevention of cardiovascular events.

Circadian cardiovascular rhythyms

There are a number of hemodynamic, environmental and hematologic changes associated with waking up that can trigger MI and stroke in the early morning hours. For instance, values for blood pressure and heart rate typically peak in the early morning. Most hypertensive subjects have quite a marked rise in blood pressure upon awakening - called 'the morning surge' - that can be 3 mm Hg/hour (systolic) and 2 mm Hg/hour (diastolic) for the first four to six hours after waking up. The blood pressure in such subjects declines from mid-afternoon onwards, reaching its lowest levels between midnight and 3AM. These changes typically track sympathetic nervous system activity; epinephrine concentrations are diminished during sleep and increased on awakening. In addition, however, there may be exaggerated end-organ responsiveness to norepinephrine during the early morning hours.

The amplitude of the cardiovascular circadian rhythm in healthy people is of little clinical significance. However, disease states disturb these cyclical changes. In hypertension, the amplitude is usually increased, although the rhythm can be obliterated, and in some cases of secondary hypertension there may even be a reversal - the nocturnal blood pressure is higher than daytime values.

Hypertensive 'dippers' and 'non-dippers"

Hypertensive patients are sometimes characterized as 'dippers' if their nocturnal blood pressure drops below their daytime pressure. Non-dipping patients appear to be at an increased risk of cardiovascular morbidity. Causes of non-dipping include autonomic dysfunction syndromes, diabetes (with neuropathy and/or nephropathy), renal insufficiency, pheochromocytoma, Cushing's syndrome, primary-aldosteronism, some drugs, as well as severe systolic hypertension in the elderly. There have been reports that African Americans with hypertension are more prone to be non-dippers. Also, hypertensive subjects who are salt-sensitive are more likely to be non-dippers.

Cardiovascular events

Both acute MI and ventricular arrhythmia have been shown to occur more frequently in the morning than in the late evening. Indeed, MI can be 3 times more common in the morning. In one big study (TIMI II)¹there were 3 subgroups with considerably higher rates of morning infarctions - those taking a beta-blocker within the preceding 24 hours, those who had no chest pain in the preceding 48 hours, and those who sustained their infarction on a weekday. Myocardial ischemia can be demonstrated more often in the first four to six hours after awakening, using Holter monitoring of ST segments.

The possible trigger for morning events include the increase in physical and mental activity on waking, with release of catecholamine, increased plasma cortisone levels, both increasing demands upon the myocardial. Simultaneously, there are increases in platelet aggregability, vascular tone and plasma volume.

A circadian pattern of cardiac arrhythmias is less well characterized than the changes in blood pressure and coronary ischemia already described. Ventricular tachycardia has been shown to peak at 9AM in subjects wearing a Holter monitor, as well as in those implanted with a defibrillator. This pattern is independent of the use of anti-arrhythmic medication. Moreover, there is a trough of arrhythmogenesis during sleep. The likely causes of the circadian pattern of ventricular arrhythmias are similar to those for other cardiovascular changes (hypertension, MI, stroke), with an emphasis on changes in catecholamine concentrations.

Stroke

The onset of stroke has been shown to occur more frequently in the first few hours after awakening. This applies to all three pathologic subgroups -- cerebral infarction, transient ischemic attacks and cerebral hemorrhage (both subarachnoid and intracerebral).

While the rhythm observed for hemorrhagic stroke is probably related to the circadian changes in blood pressure, the occurrence of silent cerebrovascular lesions - lacunar infarction etc. - was found to be more common in hypertensive 'dippers' with a greater than 20% decline in nocturnal blood pressure; thus 'dippers' taking antihypertensive medication are more likely to sustain asymptomatic or silent stroke than have a hemorrhagic stroke.

Chronotherapy for cardiovascular conditions

The aim of chronotherapy is to deliver a drug at the higher concentrations during the time of greatest need. In the case of cardiovascular diseases this represents the early morning post-awakening period. The effect of different times of dosing a conventional antihypertensive agent on circadian blood pressure patterns has been studied.

A once-a-day ACE inhibitor was given either in the morning or the evening to different groups of hypertensives. It could be shown that nocturnal dosing resulted in a greater effect on nocturnal pressure than morning dosing, but there was no significant difference in daytime blood pressures. As indicated above, the greater decline in nocturnal pressure (i.e. an increase in dipping) could be detrimental in the elderly or those who have had a cerebrovascular event.

In studies with a beta-blocker and a calcium channel blocker there were no differential effects on blood pressure when dosing was in the morning or the evening. Again, nocturnal medication generally reduced sleeping blood pressure more than morning dosing of the same drug.

A new approach

In order to deal with the circadian blood pressure changes in hypertension, a special delayed- release dosage form of verapamil (a calcium channel blocker) has been developed. When taken in the evening, there is delayed release for approximately 4 - 5 hours, followed by extended release for up to 18 hours. Thus, taken at bedtime, the delivery system provides adequate drug concentrations between 4AM and noon - the period of higher blood pressure and increased risk of a cardiovascular event. This formulation clearly has theoretical advantages over conventional long-acting antihypertensives, especially if these are given in the evening, where there is a risk of increasing nocturnal dipping and hence provoking cerebrovascular ischemia. (An exception to this is the drug doxazosin - an alpha-adrenergic inhibitor -, which has a slow rate of absorption and does not excessively reduce asleep blood pressures.)

Comment

The delayed-release verapamil dosage form described in this paper is the first medication specifically designed to meet the problems posed by cardiovascular circadian rhythms. The theory behind the design is clear, and the effects on diurnal blood pressures have been demonstrated, but so far there are no results of well-controlled clinical trials evaluating beneficial effects on hard end-points - for example MI, cerebral thrombosis, and silent ischemia. Until such data are available, chronotherapy may remain a choice that is not often exercised.

Source

• Chronotherapeutics and its role in the treatment of hypertension and cardiovascular disease. DA. Sica, W. White, J Clin Hypertens, 2000, vol. 2, pp. 279--286

Footnotes
1. Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombosis and Myocardial Infarction Phase II (TIMI II) Study Group. GH Tofler, JE Muller, PH Stone, J Am Coll Cardiol, 1992, vol. 20, pp. 1049--1055

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