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
| 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 |
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.