Question 9

Pass rate
31%
Other SAQs in this paper:
Other SAQs in this topic:

(a) Describe the pharmacokinetics of intravenous fentanyl and intravenous remifentanil (40% of marks).

(b) Explain how these features create contrasts between the two drugs (20% of marks).

(c) Discuss the concept of context sensitive half-time using these drugs as examples (40% of marks)

 

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College Answer

This question is essentially a compare and contrast question. It was worded specifically to encourage candidates to describe the pharmacokinetics of the drugs in question (in particular the relative lipid solubilities, volume of distribution, pka/ionisation, plasma protein binding, and metabolism) and then use these features to discuss the clinically relevant implications. In part (c) a brief definition of what is meant by the context sensitive half time followed by how these pharmacokinetic differences influence the CSHT of each was required.

Discussion

a) Pharmacokinetics:

Name Fentanyl Remifentanil
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; 9% is unionised at pH 7.4. Highly lipid soluble: octanol:water partition coefficient is 717

pka 7.26; 42% is unionised 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%).
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.

b) "clinically relevant implications", in the primary?? Well, ok...

  • Both drugs have a rapid offset of effect when used in short term sedation and analgesia.
  • Fentanyl offset is due to redistribution. Thus:
    • Infusions continuing for many days will result in the accumulation of the drug and a gradual redistribution from the fat compartment, resulting in a prolonged post-infusion effect.
    • This increases the risk of delirium and reduces the validity of the neurological assessment, but maintains analgesia.
  • Remifentanil has a rapid offset of effect due to plasma esterase metabolism. Thus:
    • Irrespective of the duration of infusion, the offset time remains the same.
    • This means the patient's level of consciousness is rapidly restored, but at the cost of the loss of the analgesic effect and the risk of acute withdrawal if the infusion was prolonged.

c) feels like it would have been easier to bundle with b), but:.

Context-sensitive half time is the time required for a 50% decrease in the central compartment drug concentration after drug administration has ceased; where the "context" is the duration of a “BET” (bolus, elimination, transfer) infusion that maintained a steady concentration in the central compartment.

  • Fentanyl is widely and rapidly distributed, accumulating in tissues with sustained infusion
  • Because of tissue compartment distribution, context-sensitive half time for fentanyl is markedly prolonged following a long course of use
  • Remifentanil is metabolised rapidly by plasma esterases and is not distributed, and so has no appreciable CSHT 

References

Zöllner, C., and C. Stein. "Opioids." Handbook of Experimental Pharmacology (2006): 31-63.

Crow, Jessica R., Stephanie L. Davis, and Andrew S. Jarrell. "Pharmacology and Pharmacokinetics of Opioids in the ICU." Opioid Use in Critical Care. Springer, Cham, 2021. 31-64.

Cata, Juan P., and Shreyas P. Bhavsar. "Pharmacology of opioids." Basic Sciences in Anesthesia. Springer, Cham, 2018. 123-137.

Armenian, Patil, et al. "Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review." Neuropharmacology 134 (2018): 121-132.

Hughes, Michael A., Peter S. Glass, and James R. Jacobs. "Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs." Anesthesiology 76.3 (1992): 334-341.

Shafer, Steven L., and John R. Varvel. "Pharmacokinetics, pharmacodynamics, and rational opioid selection." Anesthesiology74.1 (1991): 53-63.

Bailey, James M. "Context-sensitive half-times." Clinical pharmacokinetics 41.11 (2002): 793-799.

Schnider, Thomas W., et al. "The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers." Anesthesiology: The Journal of the American Society of Anesthesiologists 88.5 (1998): 1170-1182.

Youngs, Elizabeth J., and Steven L. Shafer. "Pharmacokinetic parameters relevant to recovery from opioids." Anesthesiology81.4 (1994): 833-842.

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