Alfentanil

Usage

 

Structure

Analogue of fentanyl

 

 

Pharmacodynamics

Potency

Less potent than fentanyl
* About 1/10 to 1/5 the potency as fentanyl
* About 1/3 the duration as fentanyl

Effects

PONV

At equipotent doses of alfentanil, sufentanil, and fentanyl,
* Alfentanil is associated with lower incidence of PONV compared to sufentanil and fentanyl

Biliary spasm

Similar increase in biliary tract pressures as that produced by fentanyl
* But shorter in duration

Pharmacokinetics

 

Absorption

Distribution

• Vd
  = 27 L [SH4:p93]
  = 0.4-1.0 L/kg [RDM6:p401]
• Protein-binding
  = 92% [SH4:p93; RDM6:p401]
  * Principally bound to alpha1-acid glycoprotein (level is not altered by liver disease)
• Alfentanil has smaller Vd than fentanyl (3-5L/kg) because
  * Lower lipid solubility (129 vs 955), AND
  * Higher protein-binding (92% vs 84%)

Metabolism

• Hepatic extraction ratio
  = 0.3 - 0.5 [RDM6:p401]

 

Metabolism is mainly by two independent pathways

1. Piperidine N-dealkylation
   --> Noralfentanil
2. Amide N-dealkylation
   --> N-phenylpropionamide

• Noralfentanil is the major metabolite recovered in urine
• Metabolism of alfentanil is mainly by CYP450 3A4
  * Alfentanil is a sensitive probe for CYP3A activity

Elimination

• Clearance
  = 4 - 9 mL/kg/min [RDM6:p401]
• <0.5% of alfentanil is excreted unchanged in urine.
• 96% of alfentanil is cleared from plasma within 60 minutes

Action profile

• Effect-site equilibration time = 1.4 min
  * c.f. fentanyl (6.8min) and sufentanil (6.2min)
  * Fast equilibration time is due to low pKa (6.5), and thus high proportion (90%) is unionised, despite lower lipid solubility
• Elimination half-time = 1.4-1.5 hours
  * c.f. fentanyl (3.1-6.6 hours) and sufentanil (2.2-4.6 hours)
• Context sensitive half-time after 4 hours of infusion = 60 min
  * c.f. sufentanil (30 min)
  * CSHT for alfentanil is fairly constant after 4 hours [???]
• Duration of action = 5-10 min
  * [SS3:p10]

Alfentanil vs sufentanil

Alfentanil has smaller Vd than sufentanil
--> Vd of alfentanil equilibrates more quickly than sufentanil
--> Peripheral distribution is not a significant contributor to decreases in plasma concentration of alfentanil
--> Even though alfentanil has shorter half-life than sufentanil, but after 4 hours of infusion, half-time becomes longer than sufentanil

Physicochemical properties

• Weak base
• pKa = 6.5
  --> 89% non-ionised at pH 7.4
  * Lowest pK of opioids
• Partition coefficient = 129
  * When morphine = 1
  * c.f. Sufentanil (1727) and fentanil (955)

Pharmaceutics

Clinical

Administration

Intubation

• Alfentanil 15 microgram/kg about 90 seconds before laryngoscopy
  --> Blunts the systemic BP and HR response to intubation

Induction of anaesthesia

• Alfentanil 150-300 microgram/kg
  --> Unconsciousness in 45 seconds

 

Interaction

• Erythromycin inhibits alfentanil metabolism by its action on CYP450 enzymes

Caution

Untreated Parkinson's disease

• Alfentanil may cause acute dystonia in patients with untreated Parkinson's diease
• Alfentanil may decrease central dopaminergic transmission

 

Special considerations

Hepatic impairment

• Liver cirrhosis prolongs the elimination half-time of alfentanil
• Cholestatic disease does NOT prolong the elimination half-time

 

Renal impairment

• Renal failure does NOT alter the clearance or elimination half-time of alfentanil

 

Paediatrics

• In children, alfentanil has shorter elimination half-time
  * Smaller Vd in children, thus faster elimination
  * Smaller Vd due to smaller percentage of adipose tissues