2006A07 Briefly outline the pharmacology of naloxone.

Structure/class

·   Phenanthrene nucleus with substitution on amine group conferring antagonism

·   Presented enantiopure (L-naloxone active, D-naloxone inactive) (?)

Presentation

·   Aqueous solution in glass ampoule

Administration

·   Mild narcosis: 1-4mcg/kg q2mins

·   Life-threatening: 1mg

·   IM if prolonged effect required

Time course

·   Onset: <2 mins

·   Peak: 10mins

·   Duration: 30mins IV, 1-2 hours IM

o Note shorter than many opioids, risk of re-sedation

Absorption

·   Oral bioav 2% (cf. naltrexone)

Distribution

·   Highly lipid soluble, crosses placenta

·   Weak base, pKa 8, 23% unionised at pH 7.4

·   Plasma protein binding 50%

·   V_DSS 2L/kg

Metabolism

·   Phase 2 -> naloxone-3-glucuronide

·   Rapid Cl 25mL/kg/min

·   Short t_1/2β 60 mins

Excretion

·   Glucuronide metabolite -> urinated

Mechanism

·   MOP:KOP:DOP = 3:2:2

·   Prevents activation of inhibitory G-protein coupled receptor

·   ↑guanylyl cyclase activity -> ↑cAMP

·   ↑activity of VDCC

·   ↓K⁺ efflux -> facilitate depolarisation

Effects

·   Reversal of opioid toxicity i.e. sedation, respiratory depression, apnoea

Toxicity

·   Overdose -> withdrawal features:

·   CNS: pain, anxiety, agitation, seizure

·   CVS: ↑SNS output, ↑HR, ↑mAP, arrhythmia, APO