Fentanyl

[SH4:p104-p109]

 

Usage

Analgesia

Blunt circulatory response to
* Direct laryngoscopy
* Sudden changes in sergical stimulation

Structure

• Phenylpiperidine-derivative
• Synthetic opioid agonist
• Structurally related to mepridine

Pharmacodynamics

Potency

• 75-125 times more potent than morphine

Mechanism of action

?? MOP receptor agonist

Side-effects

CNS

EEG

• Large doses of fentanyl can produce changes in somatosensory evoked potentials
  --> Does not interfere with entropy/BIS monitoring

Intracranial pressure

• Modest increase in ICP (6-9mmHg)
  * Despite normal PaCO2
  * Could be due to autoregulatory cerebrovasodilation due to decreased BP
  * Other mechanism could be possible

CVS

• No histamine-release
  * Even in large doses, fentanyl does not cause histamine release like morphine does
• Bradycardia
  * More prominent in fentanyl than in morphine
• Carotid sinus baroreceptor control of heart rate can become depressed

Respiratory

• Respiratory depression
• Reflex coughing may be associated with preinduction administration of fentanyl, sufentanil, and alfentanil

Skeletal muscle rigidity

• Opioid-induced skeletal muscle rigidity is possible
• Myoclonus secondary to depression of inhibitory neurons can also be possible

Allergy

Allergic reation is rare

Secondary peaks

Ion trapping
--> Fentanyl or morphine could become sequestrated in acidic gastric acid
--> Later on absorbed in intestine
--> Possible secondary peaks in plasma concentration of fentanyl and morphine

 

Alternative explanation
--> Restoration of VQ relationship in lung in postoperative period
--> Washout of fentanyl from the lung
--> Secondary peak in plasma concentration

Biliary spasm

• Biliary spasm effect is the greatest with fentanyl
  * Fentanyl > Morphine > Meperidine > Pentazocine
  * See [Pharmacokinetics of opioids]

Pharmacokinetics

Absorption

IV, S/C, Transdermal, Transmucosal

 

Distribution

• Vd = 335 L
  * Larger than morphine (224L)
  * Due to the greater lipid solubility
• Vd = 3-5 L/kg (steady state)
  * [RDM6:p401]
• Protein-binding = 84%
• More than 80% of the injected fentanyl leaves plasma within 5 minutes

Inactive sites

• Lung is a large inactive storage site
  --> About 75% of fentanyl dose undergoes first-pass pulmonary uptake
• Fat
• Muscles

Metabolism

• Hepatic extraction ratio = 0.8-1.0
  * [RDM6:p401]
• Fentanyl is extensively metabolised by N-demethylation
• Hepatic P450 enzyme CYP3A is involved
  --> Fentanyl is susceptible to drug interaction

Metabolites

Metabolites include:

• Norfentanyl
  * Structurally similar to normeperidine
  * Principle metabolite in human
  * Excreted by kidney
  * Still detectable in urine after 72 hours
• Hydroxyproprionyl-fentanyl
• Hydroxyproprionyl-norfentanyl

Overall,

• Fentanyl metabolites are thought to have minimal pharmacological activity

Elimination

• Clearance = 1530 L/min
• Clearance = 10-20 mL/kg/min
  * [RDM6:p401]
• < 10% of fentanyl is excreted unchanged in urine

Action profile

• More rapid onset and shorter duration than morphine
• Time lag between the peak plasma fentanyl concentration and the peak slowing on the EEG
• Elimination half-time = 3.1-6.6 hours
  * Longer than morphine (1.7-3.3 hours)
  * Due to larger Vd and similar clearance
• Effect-site (Blood/brain) equilibration time = 6.8 min
• Short duration of action is due to
  * Rapid redistribution to inactive tissues (fat and muscles)
• Duration of action = 30-60 min
  * [SS3:p154]

Context sensitive half-time

• For fentanyl, context sensitive half-time increases as inactive sites become saturated
• After 2 hours of infusion, context sensitive half-time for fentanyl is longer than that for sufentanil
• Context sensitive half-time (after 4 hours) = 260 min

Physicochemical properties

• Weak base
• pKa = 8.4
  --> 8.5% of fentanyl is non-ionised at pH 7.4
• Partition coefficient (lipid solubility) = 955
  * Morphine being 1

Overall, rapid tissue uptake due to higher lipid solubility, despite the lower non-ionised fraction.

Pharmaceuticals

Preparation

Transdermal fentanyl

• From 12.5 microgram/hr (2.1mg) to 100 microgram/hour (16.8mg)

Clinical

Administration

• Analgesia = 1-2 microgram/kg IV
• Labour analgesia
  = max 25 micrograms intrathecal
  * Maximum benefit achieved at 25 micrograms
• Reduction in sympathetic response = 1.5-3 micrograms/kg IV (5 minutes before induction)
• Surgical anaesthesia = 50-150 microgram/kg IV

 

Transmucosal fentanyl

In 2-8 years old,

• 15-20 microgram/kg, 45 min before induction
• But may cause increased incidence of PONV (not influenced by prophylactic droperidol)
  * Conflicting studies regarding PONV

 

For postoperative pain

• 1 mg of oral transmucosal fentanyl = 5 mg of IV morphine

Transdermal fentanyl

• From 12.5 microgram/hr (2.1mg) to 100 microgram/hour (16.8mg)
• Peak plasma fentanyl concentration in about 18 hours

Surgical anaesthesia

When large doses of fentanyl is used as the sole anaesthetic agent

Advantage

• Stable haemodynamic state, due to
  * Lack of direct myocardial depression
  * Absence of histamine release
  * Suppression of stress response to surgery

Disadvantage

• Failure to completely prevent sympathetic response to painful surgical stimulation
• Possible patient awareness
• Postoperative depression of ventilation

Drug interaction

• Analgesic concentrations of fentanyl could
  * Potentiate effects of midazolam
  * Reduce dose requirement of propofol
• Marked synergism between fentanyl and benzodiazepine regarding
  * Hypnosis
  * Respiratory depression

Special considerations

Elderly

In elderly,

• Elimination half-time is increased due to
  * Reduced clearance
  * Vd is unchanged

Reduced clearance could be due to

• Reduced hepatic blood flow
• Reduced microsomal enzyme activity
• Decreased albumin production
  * Fentanyl is highly protein-bound

Hepatic disease

• Hepatic cirrhosis does NOT prolong elimination half-time of fentanyl significantly

Transdermal patches

• Topical heating could increase the rate of release from the patch