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Theoretic Significance of pH Dependence of Narcotics and Narcotic Antagonists in Clinical Anesthesia

DONALD W. BENSON, MD, PhD^*, JOYCE J. KAUFMAN, PhD, and WALTER S. KOSKI, PhD

*Professor and Chairman, Department of Anesthesiology, University of Chicago Hospitals, Chicago, Illinois 60637. B. N. Baker Professor, Department of Chemistry, The Johns Hopkins University, 21218. Associate Professor, Department of Anesthesiology, and Principal Research Scientist, Department of Chemistry, The Johns Hopkins University, 21218. B. N. Baker Professor, Department of Chemistry, The Johns Hopkins University, 21218. B. N. Baker Professor, Department of Chemistry, The Johns Hopkins University, 21218. Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

Abstract

Determination of the effect of pH and temperature on pK_a partition, and drug distribution coefficients in a series of common narcotics and their antagonists has shown that within the range of blood pH (7.1 to 7.7) encountered in the practice of anesthesiology, marked differences of distribution of the drugs between a model lipid (octanol) and water can occur. When these data are considered in the light of clinical experience with narcotics used in patients undergoing or recovering from surgical procedures, a correlation between the depth and duration of narcosis or the efficacy of narcotic antidotes and ventilatory status is seen. This correlation can be explained in part if the influence of blood pH on the probable CNS/blood distribution of a given drug is taken into consideration. Support is given to this proposal by representative studies in the literature. The very different drug distribution coefficients of two closely related narcotic antagonists, naloxone and naltrexone, correctly predicted the faster onset and shorter duration of the former, which was confirmed by reported clinical observations.