Calcium antagonist drugs are efficacious in the management of hypertension, coronary artery disease, and supraventricular arrhythmias. These diseases are among the most frequent in the elderly and calcium antagonists have potential advantages (vasodilation, bronchodilation, lack of CNS effects) over other available drugs for use in the geriatric patient. However, the elimination kinetics and pharmacodynamics of these drugs in the elderly were largely unknown at the time of their release. It was postulated that both 1) drug elimination and 2) dynamic responses to these drugs would be altered in the elderly. Both hypotheses have been confirmed. Racemic verapamil elimination is prolonged in healthy elderly while elimination of diltiazem as a single isomer does not differ markedly in elderly vs younger hypertensives.
An aim of this proposal is to determine whether aging alters stereoselective elimination of verapamil by determining the pharmacokinetics of verapamil isomers in healthy young and elderly. Current pilot data suggest verapamil elimination is prolonged to an even greater extent in elderly patients with coronary artery disease vs. healthy elderly. A goal is to determine kinetics and dynamics of verapamil and nifedipine in elderly cardiac patients since this is the group who will be consuming the drug. In studying responses of sinus and atrioventricular (AV) nodes to verapamil, striking differences in heart rate variation and AV conduction were seen in elderly vs younger or middle-aged subjects in the absence of drugs. Data suggest increases in sympathetic and parasympathetic influences with aging. Changes in heart rate and AV conduction with senescence were also seen in beagles after pharmacologic autonomic blockade, and in isolated right atria and Langendorff-perfused hearts from Fischer 344 rats. These findings suggest both the intrinsic function of the sinus and AV nodes, and, autonomic influences on their function are altered with aging. Long-term objectives are to determine potential age-related differences in autonomic regulation of heart rate and AV conduction and function vs. potential age-related changes in activity of the sinus and AV nodal cells. In man, autonomic factors will be evaluated by analyzing heart rate variation and AV conduction before and after beta-adrenergic and parasympathetic blockade, and beta-adrenergic and dopaminergic stimulation. Potential age-related alterations in responses to substances known to directly influence sinus node and AV nodal cell activity (calcium, calcium channel agonists, acetylcholine, cadmium, nickel, Mg++, adenosine) will be studied in the absence of autonomic influences in Langendorff-perfused rat hearts. Potential age-related changes in beta-adrenergic and calcium receptors within the AV node will be studied with quantitative autoradiography of the rat AV node.
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