3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.5. Opioids
                      3.1.3.5.3. Opioid agonists
 3.1.3.5.3.7. Alfentanil 

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