Opioid Antagonists
Minor changes in the structure of an opioid agonist can convert the drug into an opioid antagonist at one or more of the opioid receptor sites (Fig. 7-22).189 Th most common change is substitution of an alkyl group for a methyl group on an opioid agonist. For example, naloxone is the N-alkyl derivative of oxymorphone (see Fig. 7-21). Naloxone, naltrexone, and nalmefene are pure m opioid receptor antagonists with no agonist activity. The high affinity for opioid receptors characteristic of pure opioid antagonists results in displacement of the opioid agonist from m receptors. After this displacement, the binding of the pure antagonist does not activate m receptors and antagonism occurs.
Naloxone
Naloxone is a nonselective antagonist at all three opioid receptors. Naloxone is selective when used to (a) treat opioid-induced depression of ventilation as may be present in the postoperative period, (b) treat opioid-induced depression of ventilation in the neonate due to maternal administration of an opioid, (c) facilitate treatment of deliberate opioid overdose, and (d) detect suspected physical dependence. Naloxone, 1 to 4 mg/kg IV, promptly reverses opioid-induced analgesia and depression of ventilation. The short duration of action of naloxone (30 to 45 minutes) is presumed to be due to its rapid removal from the brain. This emphasizes that supplemental doses of naloxone will likely be necessary for sustained antagonism of opioid agonists. In this regard, a continuous infusion of naloxone, 5 mg/kg/ hour, prevents depression of ventilation without altering analgesia produced by neuraxial opioids.190 Naloxone is metabolized primarily in the liver by
conjugation with glucuronic acid to form naloxone-3-glucuronide. The elimination half-time is 60 to 90 minutes. Naloxone is absorbed orally, but metabolism during its first pass through the liver renders it only one-fifth as potent as when administered parenterally.
Side Effects
Antagonism of opioid-induced depression of ventilation is accompanied by an inevitable reversal of analgesia. It may be possible, however, to titrate the dose of naloxone such that depression of ventilation is partially but acceptably antagonized to also maintain partial analgesia. Nausea and vomiting appear to be closely related to the
dose and speed of injection of naloxone. Administration of naloxone slowly over 2 to 3 minutes rather than as a bolus seems to decrease the incidence of nausea and vomiting. Awakening occurs either before or simultaneously with vomiting, which ensures that the patient’s protective upper airway reflexes have returned and the likelihood of pulmonary aspiration is minimized. Cardiovascular stimulation after administration of
naloxone manifests as increased sympathetic nervous system activity, presumably reflecting the abrupt reversal of analgesia and the sudden perception of pain. This increased sympathetic nervous system activity may manifest as tachycardia, hypertension, pulmonary edema, and cardiac dysrhythmias.191 Even ventricular fibrillation has occurred after the IV administration of naloxone and the associated sudden increase in sympathetic nervous system activity.192 Naloxone can easily cross the placenta. For this reason, administration of naloxone to an opioid-dependent parturient may produce acute withdrawal in the neonate.
Role in Treatment of Shock
Naloxone produces dose-related improvement in myocardial contractility and survival in animals subjected to hypovolemic shock and, to a lesser extent, in those sub- jected to septic shock.193 The beneficial effects of naloxone in the treatment of shock occur only with doses .1 mg/ kg IV, suggesting that the beneficial effects of this drug are not opioid receptor–mediated or, alternatively, are mediated by opioid receptors other than m receptors—possibly d and k receptors.
Antagonism of General Anesthesia The occasional observation that high doses of naloxone seem to antagonize the depressant effect of inhaled anesthetics may represent drug-induced activation of the cholinergic arousal system in the brain, independent of any interaction with opioid receptors.194 A role of endorphins in the production of general anesthesia is not supported by data demonstrating a failure of naloxone to alter anesthetic requirements (MAC) in animals.