Date of Award
Doctor of Philosophy
Amiodarone, a cardiac antiarrhythmic agent, provides greater efficacy, more convenient dosing, and produces fewer acute adverse effects than most other antiarrhythmic agents. Toxic effects do occur during chronic therapy, of which pulmonary fibrosis is the most serious. Relationships between adverse effects, serum drug concentrations and administered dose are not yet well understood. Lamellar inclusions observed in the lung with amiodarone pulmonary toxicity resemble those from damage by superoxide free radicals in paraquat-induced pulmonary fibrosis. Observation of superoxide dismutase (SOD) activity in patients receiving amiodarone was considered a possible source of preliminary evidence that amiodarone alters free radical metabolism. A liquid chromatographic method was developed for measuring serum amiodarone and desethylamiodarone (DEA) concentrations and access to an assay of SOD activity was attained. Thirty-one patients completed a one year prospective study to evaluate relationships between serum drug concentrations, drug effects, drug dose and erythrocyte SOD activity. Effects observed were: 6 cases of subclinical pulmonary toxicity with sustained falls in pulmonary diffusion capacity, one of which progressed to overt pulmonary toxicity after completing the study, 8 cases of enzyme elevations diagnostic of mild hepatitis, and 17 cases of abnormalities in thyroid biochemistry. Concentration response curves for the study population revealed correlations between log serum DEA concentrations, QT interval, corneal microdeposits, serum transaminases, and serum creatinine. Mean DEA concentrations were closely related to mean amiodarone concentrations and to accumulated dose of amiodarone during the one year study. Elimination half-lives of amiodarone and DEA were estimated to be 56 and 129 days respectively. SOD activity declined in the group of patients with subclinical pulmonary toxicity and fell 27% from baseline in the patient who later developed overt pulmonary toxicity.;Results suggest that relationships exist between serum drug concentrations, accumulated dose of amiodarone, and several drug effects. Records of QT interval, corneal microdeposits and total accumulated dose may be useful aids in the clinical assessment of the adequacy of therapy and risk for adverse effects and may complement therapeutic drug monitoring. Elimination constants for amiodarone and DEA may be estimated in individual patients without stopping therapy by serial measurement of drug concentrations during the extended accumulation phase. (Abstract shortened with permission of author.)
Pollak, Paul Timothy, "Amiodarone Toxicity: Relationships To Cumulative Dose And Serum Drug Concentrations With Preliminary Observations Of Changes In Superoxide Dismutase Activity" (1988). Digitized Theses. 1764.