Sufentanil

[SH4:p109-p110]

 

Structure

• Thienyl analogue of fentanyl

 

Pharmacodynamics

Potency

• Analgesic potency of sufentanil is 5-10 times that of fentanyl
  * Reflects the greater affinity for receptors

Effects by systems

CNS

• Decrease in cerebral metabolic oxygen requirment (CMRO2)
• CBF is decreased or unchanged

NB:

• This decrease in CMRO2 is typical of opioids

CVS

• Bradycardia can occur with sufentanil
  * May be sufficient to reduce cardiac output
• Large doses of sufentanil (10-30 microgram/kg IV) or fentanyl (50-150 microgram/kg IV)
  --> Stable haemodynamics, provided LVF is normal
• Does NOT completely suppress sympathetic response to painful stimulus

NB:

• This CVS stability is similar to fentanyl
• Inability to completely suppress sympathetic response is also similar to fentanyl

Respiratory

• Delayed respiratory depression can occur
  * Like fentanyl

Musculoskeletal

• May cause transient skeletal muscle spasm when injected intrathecally (40microgram)
• Ridigity of chest and abdominal muscles can occur with large doses of sufentanil
  * Similar to the effect of high-dose fentanyl
  * Difficult ventilation during sufentanil-induced muscle rigidity could be due to closure of the vocal cords

Pharmacokinetics

Absorption

 

Distribution

• Vd = 123 L
• Protein-binding = 93%
  * Extensive
  * Contribute to the smaller Vd
  * Binds to alpha1-acid glycoprotein
• Rapid penetration of BBB due to high lipid-solubility
• Significant first-pass pulmonary uptake
  * Approximately 60%
  * Less than fentanyl (75%)
  * More than morphine (7%) and alfentanil (10%)

Metabolism

• High hepatic extraction ratio (???)
  * Due to high lipid solubility
  --> Clearance is sensitive to changes in hepatic blood flow

 

Rapidly metabolised to:

• N-dealkylation at piperidine nitrogen
  --> Inactive metabolites
• O-demethylation
  --> Desmethyl sufentanil
• Desmethyl sufentanil
  --> About 10% of the activity of sufentanil

Elimination

• Clearance = 900 mL/min
• <1% excreted unchanged in urine
  * High lipid solubility --> maximal renal tubular reabsorption
• Metabolites are excreted almost equally in urine and faeces
  * About 30% appear as conjugates

Action profile

• Effect-site equilibration time = 6.2 min
  * Similar to fentanyl (6.8min)
• Elimination half-time = 2.2-4.6 hours
  * Between fentanyl (3.1-6.6 hours) and alfentanil (1.4-1.5 hours)
• Context-sensitive half-time (4 hours) = 30 min

Sufentanil vs alfentanil

• Context-sensitive half-time for sufentanil (30min) is less than alfentanil (60min)
  * Despite longer elimination half-time of sufentanil (2.2-4.6 hour, vs 1.4-1.5 hours for alfentanil)
  --> Partly due to larger Vd of sufentanil
  --> More favourable recovery profile
• Alfentanil has faster effect-site equilibration time (1.4min) than sufentanil (6.2min)
  --> Easier to titrate than sufentanil

Physicochemical properties

• Weak base
• pKa = 8.0
  --> 20% nonionised at pH 7.4
• Partition coefficient (lipid solubility) = 1727
  * When morphine = 1

Pharmaceutical

Clinical

Single dose of sufentanil (0.1-0.4 microgram/kg)
--> Longer period of analgesia and less respiratory depression than fentanyl (1-4 microgram/kg)

 

Greater safety margin

1000-fold dose difference between analgesic dose of sufentanil and the dose that produce seizure in animals
* 160-fold difference for fentanil

Special considerations

Liver cirrhosis

• Elimination half-time of a single IV dose of sufentanil is not changed.

Renal failure

• Renal failure could be associated with prolonged respiratory depression from sufentanil

Elderly

• Elimination half-time is increased in elderly patients (undergoing abdominal aortic surgery)

Neonates and infants

• Decreased level of alpha1-acid glycoprotein in neonates and infants
  --> Greater free-drug fraction
  --> Increased effect in these age group

Obesity

• Vd and elimination half-time are both increased
  * Most likely due to high lipid solubility of sufentanil