The importance of biological rhythms in drug treatment of hypertension and sex-dependent modifications

Björn Lemmer

Institute of Experimental and Clinical Pharmacology and Toxicology, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany

Abstract: The cardiovascular system is highly organized in time. Blood pressure, heart rate, peripheral resistance, pressure, and vasodilating hormones display pronounced circadian variations. New data presented here demonstrate also sex-dependent differences in vasodilating hormones, with higher NO_χ excretion in females than males and a steeper early morning rise in norepinephrine in males, whereas the 24-hour blood pressure and heart-rate profiles were not different. Various antihypertensive drugs were investigated in crossover studies – morning versus evening dosing – in hypertensive patients; however, consistent data were only described for angiotensin-converting-enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin II type 1 (AT₁) receptor blockers. Whereas in dippers ACE inhibitors had a superdipping effect when dosed at night, no difference in the blood pressure lowering effect or on the 24-hour blood pressure profile was found with calcium channel blockers after morning and evening dosing. In nondippers, the calcium channel blockers isradipine and amlodipine transformed nondippers into dippers, similar after evening dosing. The effects of AT₁-receptor blockers are similar to those of ACE inhibitors. Also, diuretics are able to normalize non dipping behavior. Moreover, a circadian phase dependency in their pharmacokinetics has been demonstrated for various cardiovascular-active drugs, such as beta blockers, calcium channel blockers, oral nitrates, and ACE inhibitors, modified by the galenic formulation. There is evidence that in hypertensive dippers, antihypertensive drugs should be given during early morning hours, whereas in non dippers it can be necessary to add an evening dose or even to apply a single evening dose in order not only to reduce high blood pressure, but also to normalize a disturbed non dipping 24-hour blood pressure profile.

Keywords: chronopharmacology, hypertension, beta-blockers, calcium channel blockers, ACE inhibitors, AT₁-receptor blockers, diuretics, chronopharmacokinetics, ABPM, circadian rhythms, urine NO_χ excretion, plasma norepinephrine, sex dependency