Calcium antagonist drugs are efficacious in the management of many cardiovascular diseases including coronary artery disease, cardiac arrhythmias, and hypertension. Since their release in the U.S., they have become among the most commonly prescribed cardiovascular drugs. There are both potential advantages and disadvantages of the use of these drugs over other available drugs (such as the beta-adrenergic receptor blocking drugs) in the ever-expanding population of geriatric patients. However, the clinical profile of these drugs in the elderly is currently unknown since premarketing metabolic and efficacy trials excluded the geriatric group. Pilot studies with calcium antagonist drugs in man suggest differences in both pharmacokinetic and pharmacodynamic responses between elderly and young hypertensive men. For this reason, it is proposed that there is both altered metabolism of the calcium antagonist drugs in the elderly and altered responses of the slow calcium channel-mediated activities of the sinus and atrioventricular nodes with aging.
The aims of this proposal are to determine the pharmacokinetics of three major calcium antagonists in physiologically aged individuals and elderly hypertensive patients and, contrast these parameters to data from young and middle-aged healthy and hypertensive individuals. Pharmacodynamic responses of the sinus node, atrioventricular node and blood pressure will also be studied in man and related to the altered kinetics of the calcium antagonists as will responses to parasympathetically-mediated and sympathetically-mediated stimuli during Ca++ antagonist infusions. The role of autonomic activity in the responses seen will also be evaluated by performing calcium antagonist infusion experiments in the presence and absence of autonomic blockade in the adult and senescent beagle. Elimination of systemic effects will be achieved by experiments: (1) with direct SA + AV nodal infusions of the drugs in dogs and, (2) by concentration-response studies in nonworking spontaneously beating right atrial preparations and in isolated perfused hearts from adult and senescent animals. The results of the proposed studies will provide important information regarding the metabolism and proper dosing of these drugs in the elderly and data regarding the altered sinus and AV nodal response profiles in the elderly. The studies will also explore the mechanisms underlying age-related differences in responses.
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