Narcotic and narcotic antagonist pK a's and partition coefficients and their significance in clinical practice

Abstract

The pK a's, partition coefficients and drug distribution coefficients (apparent partition coefficients) have been investigated for a number of narcotics and where possible for their congener narcotic antagonists. These studies were carried out by a novel microelectrometric titration technique as a function of temperature and pH. This method enables one to determine not only the dissociation constants to deconvolute overlapping pK a's, but also to determine the solubilities and oil-water distribution of these various drugs. The drug distribution coefficients displayed marked sensitivity to pH at values which span the range of attainable human physiological pH values. This has significant pharmacological implications for proper choice and scaling of drug dosages under various clinical situations among which are cited hyperventilation under a general anesthetic while concomitantly under a narcotic analgesic, obstetrical analgesia, and medical and anti-abuse usage of narcotic antagonists. The partition coefficients and drug distribution coefficients were noticeably different at 20 °C (where such measurements are customarily made) from those at 37 °C (body temperature). Furthermore, various drugs exhibit very non-equivalent increases in drug distribution coefficients with increasing temperature, ranging from 21% for morphine to 200% for naltrexone. This non-regularity indicates that it will not be valid to extrapolate by any constant factor the measurements made at lower temperatures. Even the true partition coefficients increase with temperature from 20 ° to 37 °C.