2006A07 Briefly outline the pharmacology of naloxone.

 

List:

·     PC

·     PK

·     PD

 

Physicochemical:

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

 

Pharmacokinetic:

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%

·  VDSS 2L/kg

Metabolism

·  Phase 2 -> naloxone-3-glucuronide

·  Rapid Cl 25mL/kg/min

·  Short t1/2β 60 mins

Excretion

·  Glucuronide metabolite -> urinated

 

Pharmacodynamics:

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