Question 12

Compare and contrast the pharmacokinetics and adverse effects of morphine and fentanyl.

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College Answer

This question is best answered in a tabular form, comparing absorption, distribution, metabolism, excretion and the adverse effects. Common omissions were lack of details on distribution, and not relating lipid solubility to effect.  A description of the relative adverse effects was expected, e.g., more histamine release, less  bradycardia, rather than listing similar adverse effects, e.g. respiratory depression. Comparisons of pharmaceutics and pharmacodynamics did not attract any additional marks.


Name Morphine Fentanyl
Class Opioid Opioid
Chemistry Natural phenanthrene Synthetic opiate; a derivative of 4-anilinopiperidine. IV presentation is a clear colourless solution.
Routes of administration Oral, IV, epidural, intrathecal, transdermal, subcutaneous, IM Subcutaneous, IM, IV, epidural, intrathecal, transdermal
Absorption Well absorbed orally, 30% bioavailability Orally, bioavailability is 33%. Mucosal absorption is poor. Transdermal absorption is slow.
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
Distribution VOD = 1-6L/kg; 20-35% protein-bound VOD is 6L/kg. Highly protein-bound (81-94%).
Target 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).
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
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.
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
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
Single best reference for further information Crow et al (2021) Smith et al (2016), p.146


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.