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
 3.1.3.5.3.6. Sufentanil 

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