Diurnal Rhythms, the Renin-Angiotensin System and Antihypertensive Therapy

Michael Schachter


Br J Cardiol. 2004;11(4) 

In This Article

Implications for Antihypertensive Therapy - Chronotherapeutics

There is no controversy about the need for sustained blood pressure control throughout the day and night.[14] Any antihypertensive drug is assessed for its ability to provide this control, which may be quantitated in a number of ways. The best known is still the trough:peak ratio, while the smoothness index has also been advocated in some studies. Many trials now measure the effects of missing one dose of the medication to be tested.[15] At the same time, all the impetus has been towards the development of once-daily drugs, since this is likely to encourage adherence to treatment. There are now drugs in almost all the major therapeutic classes which will provide 24-hour blood pressure control as measured by the technique mentioned above, but this does not fully address the problem of the morning blood pressure surge. If once-daily medication is taken soon after waking, blood pressure control may be adequate about 24 hours later before the next dose is due, but in fact it needs to be better than adequate: rather it should be at its maximum, providing greatest protection at a time of increased risk. There may be three ways to achieve this:

  • To abandon the once-daily approach and to take an additional drug late in the evening to ensure blood pressure control 6-8 hours later.

  • To use formulations which may be taken once daily but with delayed release of drug timed for optimal effect.

  • To use a drug with high efficacy and a trough:peak ratio close to one.

The term chronotherapeutics has been applied to studies on the optimisation of the timing of drug delivery to produce the greatest possible efficacy and safety.[16] It is not surprising in view of previous comments that this area of research has been very much focused on hypertension. How then can we apply the three approaches mentioned? Furthermore, how, if at all, do these approaches fit with our knowledge of the rhythms of the sympathetic and renin-angiotensin systems?

The evidence is not as comprehensive as one might like but a considerable amount does exist. To take the above points one by one:

  • The alpha1-selective blocker doxazosin may be taken at bedtime and there is evidence that the subsequent morning blood pressure surge is blunted.[17] This complicates the treatment regime but may be particularly useful in patients with prostatic hypertrophy and nocturia. There seems to be little problem with nocturnal hypotension.

  • The calcium channel blocker verapamil has seen the greatest research effort with novel formulations. The controlled onset extended release preparation (COER), again taken at bedtime, has been shown to reduce morning rises in both heart rate and blood pressure[18] but an outcome trial was stopped prematurely in somewhat controversial circumstances.[19] It is not clear whether this preparation will be marketed in the near future, or at all.

  • Some of the newer angiotensin II receptor blockers (ARBs) have a very prolonged duration of action. Of these, telmisartan is probably the longest acting, and has a half-life of about 24 hours. It may be particularly relevant that there appears to be a biphasic pattern in the elimination of this drug, possibly reflecting secondary release from tissue-binding sites. In comparison with another ARB, losartan, and with the long-acting calcium channel blocker amlodipine, telmisartan (40-120 mg given once daily in the morning) produced greater reductions in blood pressure the following morning.[20,21] Although the differences were small (approximately 3/1.5 mmHg) they were nonetheless statistically significant and would be expected to have a clinically significant impact on risk reduction.