Pharmacology of cardiovascular chronotherapeutic agents

Abstract

Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people—both normotensive and hypertensive—blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 pm and 2 am, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustained-release pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep.