Digitalis intoxication has been reported to occur in as many as 20 percent of hospitalized patients receiving a cardiac glycoside. There is overlap in serum glycoside concentrations in patients with and without toxicity, indicating a narrow margin of safety of these drugs, and also patient-to-patient variation in drug sensitivity which limits the usefulness of a target concentration strategy. Old age, acute myocardial infarction or ischemia, hypoxemia, hypokalemia and several other conditions reduce the tolerance of the patient to the digitalis glycosieds. Thus, the mechanisms by which the glycoside sensitivity of the heart is altered by old age, ischemic heart disease or other drugs will be studied using animal models. Digitalis sensitivity of the heart may be altered at three levels, i.e., changes in pharmacokinetics, receptor kinetics and events that follow drug binding to the receptor. The proposed project primarily focuses on alterations in drug-receptor interactions. Experiments in aged animals an drug-interaction studies will be performed in rats, hamsters, guinea pigs and dogs. The interaction of cardiac glycosides with their putative pharmacological and toxic receptor, the Na,K-ATPase enzyme system, is markedly affected by intracellular sodium and extracellular potassium. This enzyme system is intimately related to the membrane sodium pump, and therefore the interaction of the glycoside with this system in turn results in an alteration in the movement of sodium and potassium across the cell membrane. Thus, whether the aging process causes alterations in transmembrane sodium movement, properties or tissue concentration of Na,K-ATPase, the reserve capacity of the sodium pump, and other factors which can alter sodium pump activity will be examined. Furthermore, whether the changes in transmembrane ion movement brough about by aging, ischemia, anoxia, quinidine, lidocaine or beta adrenergic blocking agents effect the glycoside sensitivity of cardiac muscle will be studied. Results of these studies will help us understand the mechanisms of action of these drugs as well as providing a rational basis for identifying hypersensitive patients as a group, and to set a lower target concentration suitable for those individuals.
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