CALCIUM ANTAGONISTS, AGING, AND HYPERTENSION

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Calcium antagonist drugs have been associated with a number of pharmacodynamic effects that may be deleterious in the elderly. These include in vivo activities (negative inotropic effects, vascular smooth muscle relaxation, selective impairment of cardiac conduction, changes in baroreflex activity) which significantly interact with the impaired homeostasis of aging (impaired baroreflex activity, decreased distensibility in peripheral vasculature, decreased sensitivity to adrenergic stimuli). Preliminary studies indicate verapamil and diltiazem administration to elderly hypertensive patients results in increased hypotensive effect without reflex tachycardia, however decreased impairment in A-V nodal conduction. We hypothesize these age- related changes in pharmacodynamics are (1) associated with both altered vascular reactivity and altered autonomic homeostatic reflex mechanisms; (2) only in part explained by a pharmacokinetic mechanism which may be stereospecific; (3) different among these 3 chemically unrelated compounds in relation to their different degrees of functional and specific adrenergic antagonism. Specific Aims: 1. Determination of in vivo peripheral vascular mechanisms of response to calcium antagonists. 2. Comparison of these mechanisms between young and elderly hypertensive patients and their contribution to the altered pharmacodynamic outcome. 3. Relating pharmacodynamics to pharmacokinetics in acute versus chronic calcium antagonist exposure in young and elderly patients to establish the contribution of altered pharmacokinetics to pharmacodynamic outcome. 4. Explore role of increased negative inotropic effect and impaired baroreflex function in the greater hypotensive response to calcium antagonists in aged hypertensive and normotensive individuals. Methods: Normotensive and hypertensive patients in 3 groups, young (aged 20-45 years), middle-aged (46-64 years), and elderly (>65 years) will be studied. Drugs studied will be (+)-verapamil, d-cis diltiazem, and nifedipine. Acute and chronic drug exposure will be used to test the hypotheses. In vivo peripheral vascular mechanisms, baroreflex function, cardiac output, and pharmacodynamic-pharmacokinetic relationships will be established to probe age-related changes in calcium antagonist effect. These studies will establish in vivo mechanisms of altered calcium antagonist pharmacodynamics and will probe in vivo age-related changes in direct drug effect and homeostatic responses for these important cardiovascular drugs. Furthermore an understanding of the pharmacodynamic uniqueness of each of the drugs as it relates to aging and hypertension will be developed.