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Title: Studies on the mode of action of cardioactive drugs in animals and man
Author: Campbell, Terry J.
ISNI:       0000 0001 3518 0708
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1982
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Part.l of this thesis deals with the characterization, by electrophysiological and other means (in vivo and in vitro), of a putative steroidal antiarrhythmic agent CCI 22277. This compound is shown to act predominantly by reducing fast inward sodium current and is thus classified as Vaughan Williams Class I. In Part 2, the rate- and voltage-dependence of depression of ̇vmax by seven class 1 antiarrhythmic agents Cincluding CCI 22277) is studied in guinea-pig ventricle, using standard microelectrode techniques. All drugs were shown to produce enhanced depression of ̇vmax at increased driving rates and/or reduced resting potentials. The rates of onset and offset of the rate-dependent effects varied greatly from drug to drug and in general, fast onset and offset kinetics were associated with low molecular weight and high lipophilicity. It is concluded (in Part 4) that these findings are consistent with the "modulated receptor" model of the interaction of the sodium channel with class I drugs, although molecular weight appears to be of more importance and lipophilicity of less importance, to these interactions than previously thought. In Part 3 the hypothesis that drugs with faster rates of onset of rate-dependent depression of ̇vmax will produce greater prolongation of refractoriness than "slower" drugs, was tested experimentally using 11 class I drugs. The results were consistent with this hypothesis. Taken together with the relative effects of the various drugs on action potential duration, they provide a theoretical basis for the proposed subclassification of class I drugs into groups IA, IB and 1C.
Supervisor: Vaughan Williams, E. M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Myocardial depressants ; Drug lipophilicity