Toxicology Agents
Opiate antagonists

Description: Naloxone is a semisynthetic opiate-receptor antagonist. It is the n-allyl derivative of oxymorphone. Classically, it is used to reverse the clinical effects of opiate analgesics, but recognition of the presence of endorphins and enkephalins has led to diverse claims about its uses. Besides treatment of opiate overdose, it has been used to reverse the effects of ethanol and benzodiazepines, to reverse hypotension associated with spinal injury, to improve neurologic recovery after ischemic stroke, and to treat hypercapnic COPD, although response in these conditions is not as dramatic or predictable as when reversing the effects of opiates. Preliminary controlled data suggest the drug may also have utility for constipation-predominant irritable bowel syndrome (IBS) and for addressing opiate-induced constipation. Naloxone was approved by the FDA in 1971.

Mechanism of Action: Naloxone, unlike the older narcotic antagonists levallorphan and nalorphine, is essentially a pure antagonist with little or no agonistic activity. (Levallorphan and nalorphine have since been removed from the market.) In patients who have not recently received opioid drugs, naloxone shows little or no pharmacological effects, even at high doses. Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Mu receptors are responsible for analgesia, euphoria, respiratory depression, and miosis; kappa-receptors are responsible for analgesia, dysphoria, some psychomimetic effects (i.e., disorientation and/or depersonalization), and sedation; and delta-receptors mediate analgesia, sedation, and possibly hormonal and neurotransmitter release. Naloxone is thought to antagonize mu-, kappa-, and delta-receptors. This antagonism is competitive and short-lived. Thus, repeat doses of naloxone may be required when long-acting opiates are involved. Naloxone itself produces no physical or psychological dependence and will not worsen respiratory depression if administered for non-opiate overdose.

Naloxone antagonizes both the toxic and clinical effects of opiates. Thus, not only are respiratory depression, hypotension, and sedation reversed but so is analgesia. Clinicians should use discretion when considering administering naloxone to patients who are sedated from opiates but do not exhibit respiratory depression. Reversal of analgesia is undesirable in patients known to be in severe pain. Naloxone should not be used for drowsiness unless opiate-induced respiratory depression coexists.

Finally, because endorphins and enkephalins (endogenous substances with opiate-like activity) are known to exist in higher concentrations in certain disease states, naloxone has been considered a therapeutic agent for conditions other than opiate overdose. Various respiratory diseases have been associated with elevated circulating concentrations of endorphins, and naloxone has been studied in patients with COPD,[165] obesity-hypoventilation syndrome,[166] and high-altitude pulmonary edema.[167]

Pharmacokinetics: Naloxone is administered intravenously, intramuscularly, intraosseously, or subcutaneously. Naloxone is ineffective orally unless extremely large doses are administered. Oral doses of 1000—2500 mg have produced clinical effects.[97] Oral naloxone is 1/50 as potent as parenteral naloxone due to a significant first-pass effect in the liver. Onset of action is 1—2 minutes after IV administration. Onset is 2—5 minutes after SC or IM administration, although action can be delayed in hypotensive patients. The duration of action is dependent on the dose and administration route; duration of action is more prolonged after IM administration than after IV administration. Following parenteral administration, distribution is rapid. Naloxone achieves a brain-to-serum ratio 12—15 times greater than morphine.

Metabolism takes place rapidly in the liver, mainly by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. In adults, the plasma half-life ranges from 30—81 minutes; in neonates, the half-life is about 3 hours. Excretion of the metabolites in the urine indicates that 60—70% of an oral or IV dose is excreted within 72 hours.

97. Handal KA, Schauben JL, Salamone FR. Naloxone. Ann Emerg Med 1983;12:438—45.

165. Santiago TV, Sheft SA, Khan AU et al. Effect of naloxone on the respiratory responses to hypoxia in chronic obstructive pulmonary disease. Am Rev Resp Dis 1984;130:183—6.

166. Orlowski JP, Herrell DW, Moodie DS. Narcotic antagonist therapy of the obesity hypoventilation syndrome. Crit Care Med 1982;10:604—7.

167. Bar-Or D et al. Naloxone, beta-endorphins, and high-altitude pulmonary edema. Ann Intern Med 1982;96:684—5.

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