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).
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
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; 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:
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.