Naloxone

[SH4:p120-121]

Structure

• Naloxone is the N-alkyl derivative of oxymorphone
• Nonselective antagonist at all 3 classic opioid receptors
• Compared with morphine, naloxone has
  * Oxygen (instead of hydroxyl group) at carbon 6
  * Single bond (instead of double) between carbon 7 and 8
  * Hydroxyl group (instead of hydrogen) at carbon 14
  * Two more carbon (an ethene) attached to the methyl group at the N at position 17

NB:

• Antagonist action is due to substitution at N at position 17 [???]

Pharmacodynamics

Effects

• Antagonism at the opioid receptors
• Reversal of general anesthesia
  * Could be due to activation of cholinergic arousal system in the brain, independent of any interaction with opioid receptors

NB:

• When administered in doses >1mg/kg IV
  --> Improvement in myocardial contractility
  * Probably not opioid receptor mediated

Side effects

• Reversal of analgesia
• N&V
  * Related to dose and speed of injection
  * Large dose and fast injection increases incidence of N&V
  * Awakening often occurs before or simultaneously with vomiting
• Increased sympathetic activity
  --> CVS stimulation
  * Probably due to sudden preception of pain
  * Manifest as tachycardia, hypertension, pulmonary oedema, and cardiac dysrhythmias

Pharmacokinetics

Absorption

• PO --> Bioavailability = 20%
• IV

Metabolism

• Metabolised primarily in the liver by conjugation with glucuronic acid
  --> Naloxone-3-glucuronide

Action profile

• Duration of action = 30-45 min
  * Due to rapid removal from brain
• Elimination half-time = 60-90 min

Clinical

Administration

• Naloxone 1-4 microgram/kg IV
  --> Reverses opioid-induced analgesia and depression of ventilation
• Continuous infusion of naloxone 5 microgram/kg/hour
  --> Prevents respiratory depression without altering analgesia produced by neuraxial opioids

Special considerations

Maternal-foetal

Naloxone easily crosses placenta
--> Potentially could cause acute withdrawal in the neonate