Blood pressure treatment based on daily body rhythm?

Summarized by Robert W. Griffith, MD
December 15, 2000 (Reviewed: February 16, 2003)

Our lives are influenced by many natural rhythms, some of which affect our bodily functions. Women are more aware of this than men, because of their monthly hormonal cycles controlling menstruation. However, there are more subtle rhythmic effects, such as the increased likelihood of depression in the winter months.

The day-night cycle is the dominant daily, or circadian, rhythm, and there are a number of diseases that show a relation to this. For instance, allergic rhinitis, asthma, rheumatoid arthritis, osteoarthritis, and peptic ulcer are all worse at different specific times of the day. Some heart conditions, too, show this daily rhythm, to a greater or lesser extent. Angina pectoris, heart attack (myocardial infarction, or MI), sudden death due to an irregular heartbeat, and stroke are all more common in the morning after waking up. Knowledge of the underlying changes in the function of the heart and blood vessels during the day has led to attempts to design medication that allow more exact treatment, taking this daily rhythm into account.

The blood pressure and heart rate in normal people are usually highest in the early morning. This is exaggerated in people with high blood pressure. After waking up, someone with high blood pressure may increase their blood pressure by 2 to 3 mmHg every hour for the next 4 to 6 hours. After that, the blood pressure goes down, reaching its lowest levels between midnight and 3AM. These changes seem to be related to the activity of the sympathetic nervous system; the output from the adrenal glands is lessened during sleep, and then increases on awakening.

This cycle of changes in blood pressure and heart rate are of little significance in healthy people. However, for those with high blood pressure, they can have more serious consequences. There are several possibilities: the rhythm can disappear, so that the blood pressure remains high throughout the 24 hours, or the peaks and troughs of the cycle can increase in size, so that blood pressure is much higher in the morning and much lower during the night.

People with high blood pressure whose blood pressure at night drops below their daytime pressure are called "dippers". If their blood pressure doesn't drop at night ("non-dippers"), they are at a greater risk of having a heart attack. African Americans and patients with high blood pressure who are salt-sensitive are more likely to be non-dippers.

Heart attacks and cardiac arrest occur more often in the morning than in the late evening. In some circumstances this problem is the even more apparent - in those taking a beta-blocker blood pressure drug, in those without chest pain, and on weekdays! Scientists think that possible triggers for these events are the increase in physical and mental activity on waking up, which causes release of chemicals into the blood stream, putting increased strain on the heart muscle. At the same time, blood-clotting mechanisms are more active, increasing the risk of thrombosis in a coronary artery.

Although irregularities of the heart rhythm have been studied less than the changes in blood pressure and blood flow to the heart muscle, it can be shown that such irregularities are greatest in people around 9AM. There is less likelihood of cardiac irregularity during sleep.

Stroke, too, has been shown to occur more often in the first few hours after waking up. This has been confirmed for all three types of stroke - thrombosis in a brain artery, transient ischemic attacks (TIAs), and cerebral hemorrhage. The latter - bleeding into the brain tissue or on the brain surface - is probably related to the morning increases in blood pressure. The occurrence of thrombosis in the brain vessels was found in studies to be more common in high blood pressure patients who were "dippers" having a more than 20% fall in pressure at night. Dippers taking blood pressure medication are at particular risk of cerebral thrombosis, compared with non-dippers.

What are the practical consequences of this knowledge? Some studies have been done of the rhythms and blood pressure changes during the day in people taking once-a-day blood pressure medication. It was found that, whether they took the medication in the morning or in the evening, there was no change in the height of their blood pressure during the day. Taking the medication in the evening, however, resulted in a greater reduction in blood pressure at night, which might be serious for the elderly (with relatively inelastic arteries) or those who had already had a stroke.

A new approach has been developed. One form of high blood pressure medication - a calcium channel blocker called verapamil - has been put into a formulation that delays its release for about 4 to 5 hours, and then releases slowly for up to 18 hours. If this drug is taken at bedtime, the delivery system provides good drug concentrations in the blood between 4AM and noon, just the period of higher blood pressure and increased risk of a heart attack or stroke that requires handling.

So far, this ingenious dosage formulation has not been studied enough to show clear effects on actual daily rates of heart attacks and stroke. Until this information is available, it seems unlikely that it will be widely used, as although the underlying theory is good, evidence of increased survival is really what's needed. In the meantime, 'chronotherapeutics' remains simply an interesting prospect.

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

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