Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

William H. Barr


The primary objective of the research was to investigate the pharmacodynamics of digoxin in dogs. Initially an assay specific for digoxin in the presence of its major metabolites, viz., digoxigenin, digoxigenin mono-digitoxoside, digoxigenin bis-digitoxoside and dihydrodigoxin was developed using HPLC-RIA. Methodology for non-invasive measurement of left ventricular ejection time (LVET) and other systolic time intervals (STI) in beagle dogs were developed. This involved surgery for exteriorization of the carotid artery in the dogs and subsequent measurements of LVET and STI after recovery. STI, heart rate (HR) and digoxin levels were monitored in normal beagle dogs administered 0.05 mg/kg or 0.025 mg/kg i.v., infused uniformly over a 5 min. period. The STI did not lend itself to pharmacodynamic modelling. The LVET, QS2 and P-R interval were found to be inversely, but linearly, related to the heart rate. Therefore, the bradycardic response to digoxin was extensively investigated in beagle dogs. Pharmacodynamic models evaluated for modelling the bradycardic response to digoxin were: the pharmacokinetic model with a direct linear link, the linear model, the physiologic-pharmacokinetic model with direct linear link and the effect compartment model. The physiologic pharmacokinetic model was simulated using SPICE2 which uses network thermodynamics to simulate biological systems. Criteria for the selection of appropriate models were established. Using the established criteria, the effect compartment model was demonstrated to be the best model. The implications and applications of pharmacodynamic models in general and specifically of the pharmacodynamic model for the bradycardic response to the digoxin are discussed.


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