Compare and contrast the mechanism of action, pharmacokinetics and central nervous system
effects of morphine and tramadol.
In general candidates either lacked a depth of knowledge, or a deep enough understanding of the drugs so as to apply their knowledge specifically to the central nervous system (CNS). Mechanism of action and pharmacokinetics for morphine was better understood, in comparison to tramadol. Mention of the non-CNS effects of morphine and tramadol, was not expected, did not score marks, and would have wasted valuable exam time.
|Chemistry||Natural phenanthrene||Synthetic phenylpropylamine opioid|
|Routes of administration||Oral, IV, epidural, intrathecal, transdermal, subcutaneous, IM||Oral, IV|
|Absorption||Well absorbed orally, 30% bioavailability||100% absorbed orally, 70% oral bioavailability, but increases to 90-100% with sustained dosing because of hepatic enzyme saturation|
|Solubility||pKa 8.0, 23% is unionised at pH 7.4; octanol-water partition coefficient ~ 1.42||pKa 9.41, highly lipophilic|
|Distribution||VOD = 1-6L/kg; 20-35% protein-bound||VOD = 2.6-2.9L/kg; 20% protein-bound|
|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; notable metabolites include O-desmethyltramadol, an active metabolite|
|Elimination||Minimal unchanged drug cleared renally, but most of the metabolites rely on renal excretion||Minimal unchanged drug cleared renally, but most of the metabolites rely on renal excretion|
|Time course of action||Slow onset, half-life 2-4 hrs||Half life = 6 hours|
|Mechanism of action||Basis of its analgesic effect is the hyperpolarisation of presynaptic cell membrane by increasing potassium conductance; reduced production of cAMP and closure of voltage-gated calcium channels. The result is decreased neurotransmitter release from primary pain afferent finbres||Hyperpolarisation of cell membrane by increasing potassium conductance; reduced production of cAMP and closure of voltage-gated calcium channels. Also acts as as a serotonin and noradrenaline reuptake inhibitor|
|Clinical effects||Analgesia, respiratory depression, constipation, miosis, urinary retention. Also has a cardiovascular effect, by inducing a non-immune histamine release (which produces vasodilation)||Analgesia, constipation, miosis, urinary retention. Lowers seizure threshold, interacts with serotonergic drugs to increase risk of serotonin syndrome. Less respiratory depression than morphine.|
|Single best reference for further information||Crow et al (2021)||Crow et al (2021)|
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.
Inturrisi, Charles E. "Clinical pharmacology of opioids for pain." The Clinical journal of pain 18.4 (2002): S3-S13.