Question 5

Compare and contrast the pharmacokinetics and pharmacodynamics of IV fentanyl and IV remifentanil (60% of marks). Discuss the concept of context sensitive half-time using these drugs as examples (40% of marks).

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College Answer

Well-constructed answers were presented in a table to compare pharmacokinetics and
pharmacodynamics with a separate paragraph to discuss the concept of context sensitive halftime.
Important pharmacokinetic points included: the differences in lipid solubility, ionised
fractions and onset, and differences in metabolism. Marks were awarded for a definition of
context-sensitive half-time. A discussion of these two drugs’ context-sensitive half-times should
have included the differences in re-distribution into other compartments and rates of elimination

Discussion

If a comparison table is called for, then one can be easily generated:

Name Fentanyl Remifentanil
Class Opioid Opioid
Chemistry Synthetic opiate; a derivative of 4-anilinopiperidine. IV presentation is a clear colourless solution. Synthetic opiate; phenylpiperidine derivative of fentanyl. IV presentation is a lyophilised power with glycine buffer, making it unsuitable for intrathecal or epidural administration
Routes of administration Subcutaneous, IM, IV, epidural, intrathecal, transdermal IV, intranasal
Absorption Orally, bioavailability is 33%. Mucosal absorption is poor. Transdermal absorption is slow. Oral bioavailability is poor- thought to be near 0%. Mucosal absorption is relatively rapid and it can be used intranasally
Solubility pKa 8.4; only 9% is ionised at pH 7.4. Highly lipid soluble: octanol:water partition coefficient is 717 pka 7.26; 42% is ionised at pH 7.4. Highly lipid soluble: octanol:water partition coefficient is 17.9
Distribution VOD is 6L/kg. Highly protein-bound (81-94%). VOD is 0.1L/kg, highly protein bound (70%).
Target receptor mu-opiate receptor (pre-synaptic G-protein coupled receptor) mu-opiate receptor (pre-synaptic G-protein coupled receptor)
Mechanism of action Hyperpolarisation of cell membrane by increasing potassium conductance; reduced production of cAMP and closure of voltage-gated calcium channels Hyperpolarisation of cell membrane by increasing potassium conductance; reduced production of cAMP and closure of voltage-gated calcium channels
Metabolism Hepatic metabolism, as well as in the intestine: CYP450 3A4: N-dealkylation to norfentanyl - then hydroxylation (all metabolites are inactive). Rapid ester hydrolysis by plasma esterases; the metabolite is inactive
Elimination 10% unchanged in the urine. Slow hepatic clearance: half life ranges from 2 to 12 hours Elimination is independent of renal or hepatic function, and is very rapid. Elimination half-life is 5-14 minutes.
Time course of action Rapid onset (2-5 minutes to peak effect); small dose acts for 30-60 minutes, but high doses are effective for 4-6 hours. Offset of effect is due to redistribution into fat and muscle. Rapid onset of effect - peak effect within 1-3 minutes; rapid offset of effect within 5-10 minutes, which is predictable and independent of the duration of infusion or dose.
Clinical effects Vagal bradycardia; blunted cardiovascular reflexes and decreased sympathetic response to intubation; respiratory depression; chest wall rigidity; potent analgesic effect (50-80 times more potent than morphine); miosis; decreased gastrointestinal activity; increased detrusor tone; nausea; vomiting Vagal bradycardia and hypotension (MAP decreased by 20%); respiratory deoression, chest wall rigidity; potent analgesic (similar to fentanyl); miosis; decreased gastrointestinal motility. Minimal nausea or vomiting.
Single best reference for further information Scarth et al (2016), p.146 Scarth et al (2016), p.338

No, a separate paragraph to discuss the concept of context sensitive halftime:

  • Context-sensitive half time (CSHT) is the time required for a 50% decrease in the central compartment drug concentration after an infusion of the drug is ceased; where the "context" is the prior duration of drug infusion.
  • It is used to preduct redistribution and elimination kinetics in drugs which have extensive tissue distribution, and which do not undergo tissue metabolism
  • A drug with a high tissue distribution and no tissue metabolism (eg. fentanyl) will have a different context-sensitive half time depending on the duration of infusion: 
    • A short infusion (i.e. bolus) will have a short CSHT (30-60 minutes)
    • A long infusion (several hours) will have a long CSHT (
  • A drug with a high tissue distribution and extensive tissue metabolism (eg. reminfentanil) will have a CSHT which is independent of the duration of infusion

References

Scarth, Edward, and Susan Smith. Drugs in anaesthesia and intensive care. Oxford University Press, 2016.

Beers, Richard, and Enrico Camporesi. "Remifentanil update." CNS drugs 18.15 (2004): 1085-1104.