Clinical Pharmacokinetics of Narcotic Agonist-Antagonist Drugs
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Narcotic agonist-antagonist drugs are able specifically to reverse the effects of morphine and other opiate agonists in some pharmacological preparations. They also have some agonist properties which in some cases may be extensive and provide useful clinical properties such as analgesia, or may be minimal. Thus pentazocine, buprenorphine, nalbuphine and butorphanol all demonstrate definite analgesic properties. Naltrexone, in contrast, has only limited agonist action, as shown for example in pupil constriction, and is perhaps better regarded as an antagonist.
After intravenous administration of buprenorphine there is an initially rapid early distribution phase with a half-life of about 2 minutes. Studies on butorphanol and pentazocine had insufficient early samples to allow accurate analysis of this phase. Otherwise, the intravenous pharmacokinetics for all these drugs show bi- or tri-exponential decay with terminal half-lives of between 3 and 5 hours, plasma clearances of between 1200 and 2800 ml/min, and apparent volumes of distribution of 200 to 400L. These values for plasma clearance and terminal half-life have been confirmed in oral and intramuscular studies.
There is only limited information about the rate or extent of absorption after intramuscular administration. For buprenorphine peak plasma concentrations are reached between 2 and 5 minutes; for pentazocine and butorphanol the peak is later, at between 15 and 60 minutes for pentazocine and 45 minutes for butorphanol. Systemic availability of intramuscular buprenorphine is in the range of 40 to 100%, but is generally greater than 90%. Availability of intramuscular butorphanol has been reported to be complete.
Oral systemic availability for drugs with a high plasma clearance is predictably low because of a significant first-pass effect through the liver. The oral availabilities of pentazocine and nalbuphine have been calculated to be about 20%, and although there are no pharmacokinetic data, some evidence of clinical efficacy suggests a similar figure for butorphanol and buprenorphine. For naltrexone however, the available data suggest that this drug is completely absorbed after oral administration.
Only buprenorphine has been studied by the sublingual route. The systemic availability was variable (16 to 94%), but on average it was 55% in a study of long duration; the absorption half-life from the buccal cavity was estimated to be 76 minutes. Over a limited dose range there appeared to be linear increases in the maximum rise in plasma concentration and AUC with buprenorphine administered by this route. There have been no pharmacokinetic studies of the narcotic agonist-antagonist drugs by other routes of administration, such as after intrathecal or extradural administration, or rectally or transcutaneously.
Pharmacodynamic data for these drugs are incomplete. Analgesia in man appears to be dose-related for pentazocine, butorphanol, buprenorphine and nalbuphine; morphine antagonism is dose-related for naltrexone. The appearance of opiate side effects (nausea and drowsiness) is reported to be dose-related for pentazocine, butorphanol and buprenorphine.
‘Ceiling’ effects on respiratory depression in man are found for pentazocine, butorphanol, buprenorphine and nalbuphine. For pupillary effects, there is evidence for a ceiling effect for nalbuphine and naltrexone, but dose-related effects for buprenorphine. Some of the neuroendocrine effects of buprenorphine and butorphanol appear to be dose-related, but there has been little work done in this area.
KeywordsMorphine Buprenorphine Naltrexone Hepatic Blood Flow Pentazocine
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