A chronotherapeutic approach to the management of hypertension

Patients with hypertension have a characteristic circadian pattern of blood pressure (BP) variability in a 24-h period, characterized by a wide range while awake and active, and a narrower range during sleep and inactivity. Blood pressure in the untreated hypertensive individual declines by approximately 10% to 20% during sleep compared with the mean awake BP values. Early in the morning (assuming a typical day-night activity cycle), the BP rises sharply on awakening, when physical and mental activities increase. Antihypertensive therapy has been traditionally dosed in the morning after awakening, and in recent years most of the newly developed antihypertensive agents have been once-daily, long-acting preparations. However, theoretically, this pattern of drug dosing may be suboptimal since pharmacodynamic activity is attenuated at the end of the dosing period, when a large rise in BP may occur. Presently, only a few studies have been performed to evaluate the effects of nocturnal dosing of standard long-acting drugs. Consequently, we undertook an assessment of the effects of a new formulation of verapamil--controlled onset extended release verapamil HCl (COER-24)--that is dosed nocturnally and has a controlled onset of delivery (4 to 5 h postdose) and an extended release for the remainder of the dosing period. Through ambulatory BP monitoring, evaluation revealed that this verapamil formulation produced changes in BP that followed the circadian rhythm of BP: lower reductions during sleep, when the BP is intrinsically lowest, and appropriately larger reductions during the early morning and daytime hours, when ambulatory BP values accelerate and plateau to their highest levels. These data demonstrate that it is possible to design antihypertensive therapy for once-nightly dosing, thereby providing a chronotherapeutic regimen for patients with hypertension.