Clinical Pharmacodynamics of Cardiovascular Agents: Focus on Sudden Cardiac Death
Sudden death due to ventricular tachyarrhythmias is common in patients with advanced coronary artery disease. Three strategies might be useful: slowing progression of coronary atherosclerosis (e.g. antihypertensive or lipid-lowering agents); antiarrhythmic therapy; or elimination of transient factors which trigger fatal arrhythmias (e.g. antiplatelet drugs or ß-blockers). For each of these classes of compounds, an easily measured response variable, such as heart rate, blood pressure, ECG interval, frequency of ambient arrhythmia, or bleeding time, is available and the links between drug concentrations and response are readily determined. However, the common extrapolation that these responses are necessarily accompanied by a decrease in sudden death is unfounded. In addition, patients who are at risk for sudden death have an underlying cardiac substrate which can fluctuate over seconds to years, resulting in both loss of drug efficacy and increased drug toxicity. Thus evaluation of interventions designed to reduce sudden death must be performed in patients at risk, using death as the study end-point. This approach also permits assessment of compounds whose only therapeutic action might be to reduce sudden death.
KeywordsSudden Death Parent Drug Antiarrhythmic Drug Poor Metabolizers Antiarrhythmic Therapy
Unable to display preview. Download preview PDF.
- Barbey, J. T., K. A. Thompson, D. S. Echt, R. L. Woosley, and D. M. Roden (1988). Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites 0-desmethyl encainide and 3- methoxy-O-desmethyl encainide in man. Circulation, 77, 380–391.PubMedCrossRefGoogle Scholar
- Bigger J. T., Jr., J. L. Fleiss, R. Kleiger, J. P. Miller, L. M. Rolintzky, and Multicenter Post-Infarction Research Group (1984). The relationship among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation, 69, 250–258.Google Scholar
- Birgersdotter, U. M., J. Turgeon, W. Wong, and D. M. Roden (1990). Stereoselective genetically-determined interaction of flecainide and quinidine. Clin. Res.,38, 339A.Google Scholar
- Echt, D. S., P. R. Liebson, B. Mitchell, R. W. Peters, D. Obias-Manno, A. H. Barker, A. Arensberg, A. Baker, L. Friedman, H. L. Greene, M. L. Huther, D. W. Richardson, and the CAST Investigators (1991). Mortality and morbidity in patients receiving encainide, flecainide, or placebo: The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med., 324, 781–788.PubMedCrossRefGoogle Scholar
- Roden, D. M. (1988). Encainide and related antiarrhythmic drugs. ISI Atlas of Science 374–380.Google Scholar
- Thompson, K. A., D. H. S. Iansmith, L. A. Siddoway, R. L. Woosley, and D. M. Roden (1988a). Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers. J. Pharmacol. Exp. Ther.,244, 950–955.Google Scholar
- Wong, W., H. N. Pavlou, and D. M. Roden (1989). Pharmacology of sematilide, a class III procainamide analog, in man. 62nd Annual Scientific Sessions, American Heart Association. Circulation, 80, SII-326.Google Scholar