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