Question 16

Compare and contrast the pharmacology of morphine, fentanyl and remifentanil.

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College Answer

The question asked for a comparison of the pharmacology (pharmacokinetics and pharmacodynamics) of three commonly used opiates. Better answers made use of a well constructed table with headings including chemistry, protein binding, lipid solubility, half-lives, context sensitive half-time, volume of distribution, metabolism, active metabolites, oral bioavailability, and clearance. A distinction should have been clearly drawn between onset, peak, and duration of effect. CNS stimulant effects as well as depressant effects, were expected to be listed.
Syllabus: G2d, 2d
Recommended sources: Anaesthesia, Miller Chp 11 and Pharmacological Basis of
Therapeutics, Goodman and Gillman, Chp 21

Discussion

Name Morphine Fentanyl Remifentanil
Class Opioid Opioid Opioid
Chemistry Natural phenanthrene alkaloid 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 Oral, IV, epidural, intrathecal, transdermal, subcutaneous, IM Subcutaneous, IM, IV, epidural, intrathecal, transdermal IV, intranasal
Absorption Well absorbed orally, 30% bioavailability 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 8.0, 23% is unionised at pH 7.4; octanol-water partition coefficient ~ 1.42 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 = 1-6L/kg; 20-35% protein-bound 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) mu-opiate receptor (pre-synaptic G-protein coupled receptor)
Metabolism Hepatic metabolism; notable metabolites include morphine 6-glucuronide, an active metabolite 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 Minimal unchanged drug cleared renally, but most of the metabolites rely on renal excretion 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 Slow onset, half-life 2-4 hrs 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.
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 Hyperpolarisation of cell membrane by increasing potassium conductance; reduced production of cAMP and closure of voltage-gated calcium channels
Clinical effects Analgesia, respiratory depression, constipation, miosis, urinary retention. Also has a cardiovascular effect, by inducing a non-immune histamine release (which produces vasodilation) 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 Crow et al (2021) Smith et al (2016), p.146 Smith et al (2016), p.338

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.