NMT150 PHARM Wk 9 Opioids (1).pdf

OPIOIDS Dr. Adam Gratton NMT150 MSc ND March 9, 2023 LECTURE COMPETENCIES Describe the proposed mechanism of action of opioid agonists Describe the adverse effects associated with opioid agonists Describe the mechanism of action of opioid antagonists Describe the adverse effects...

OPIOIDS Dr. Adam Gratton NMT150 MSc ND March 9, 2023 LECTURE COMPETENCIES Describe the proposed mechanism of action of opioid agonists Describe the adverse effects associated with opioid agonists Describe the mechanism of action of opioid antagonists Describe the adverse effects of opioid antagonists Describe the symptoms of opioid withdrawal OPIOIDS AND LOW BACK PAIN Not generally recommended for acute low back pain Potential increased risk of disability at 6 months when used early on Should not really be used unless there has been no benefit seen with other pain medications (NSAIDs, GABA derivatives, etc.) OPIOIDS AND LOW BACK PAIN With chronic low back pain opioids may only provide modest, short-term alleviation of pain Small doses should be used (no more than 50 morphine equivalents per day) Initial prescriptions should only be for 3 – 5 days Should not be used within the context of anxiety, depression, PTSD, history of substance abuse PATHOPHYSIOLOGY OF PAIN Enkephalins, endorphins, and dynorphins are the endogenous ligands of the opioid receptors Enkephalins are released throughout the pain axis There are three main types of opioid receptors: Mu (μ), delta (δ), and kappa (κ) Most clinically useful opioid analgesics have strong selectivity for the μ- opioid receptor PATHOPHYSIOLOGY OF PAIN μ-opioid receptors are inhibitory G-protein coupled receptors Activation leads to increased inhibitory activity via inhibition of adenylate cyclase which leads to decreased cAMP Increased potassium conductance via the opening of membrane-bound potassium channels Decreased intracellular calcium via blockage of membrane-bound calcium channels Ultimately decreased neurotransmitter release OPIOID CLASSES Full Opioid Agonists (Morphine, Codeine) Fentanyl>>Morphine>Codeine (100:1:0.15) Partial Opioid Agonists (Tramadol) Opioid Antagonists (Naloxone) OPIOID AGONISTS Opioids have a wide range of physiological effects CNS: Analgesia, euphoria, cough inhibition, miosis, dependence, respiratory depression, sedation CVS: Decreased myocardial oxygen demand, vasodilation, hypotension GI: Constipation, increased biliary sphincter tone, nausea, vomiting GU: Increased bladder sphincter tone, prolongation of labour OPIOID AGONISTS Neuroendocrine: Inhibition of LH, stimulation of ADH and prolactin Immune: Suppression of NK cell activity Skin: Flushing, pruritis, urticaria FULL VS PARTIAL AGONISTS Strong opioid agonists are generally well tolerated when given at dosages sufficient to relieve severe pain Compared to moderate opioid agonists, like codeine, that have more side effects in higher dosages. Strong opioids have a high affinity for opioid receptors which undergo a significant conformational change to produce the maximal effect Partial agonists cause less conformational change and receptor activation, however analgesic activity plateaus with higher dosages (and side effect activity does not) MORPHINE The principal alkaloid of opium poppy Well absorbed from the GI tract but extensively metabolized during first-pass Principal metabolite (~90%) is morphine-3-glucuronide which is inactive Morphine-6-glucuronide (~10%) is more active than morphine with a longer half-life and contributes to analgesic effectiveness Duration of action: 4 hours MORPHINE Primarily excreted in urine and a small amount is enterohepatically recycled from biliary excretion Standard of comparison for all other opioid analgesics Can be administered orally (but in much higher dosages) and intravenously TRAMADOL Partial μ-opioid agonist Also inhibits neuronal reuptake of serotonin and norepinephrine Relationship to analgesic effect not determined May potentiate the inhibitory effect these have on spinothalamic tract neurons Has long been incorrectly considered the “safe” opioid, due to a lower potential to cause dependence TRAMADOL Analgesic effect mediated by the M1 metabolite (O- desmethyltramadol) which is dependent on CYP2D6 CYP2D6 is highly polymorphic Given the dual nature of the drug it’s like giving morphine and venlafaxine in unknown ratio TRAMADOL Side effects include: hypoglycemia, decreases seizure threshold, orthostatic hypotension, hallucinations Interacts with antidepressants (SSRIs, TCAs) and increased risk of serotonin syndrome Duration of action: 4 hrs Half life: 6 hrs OPIOID ANTAGONISTS Competitive opioid receptor antagonists rapidly reverse the effects of opioid agonists Indicated for opioid overdose, treatment of alcohol and opioid dependences, decreasing opioid-induced constipation Bind to opioid receptors and prevents conformational change necessary for activation and agonist activity NALOXONE Administered intravenously Half life: 2 hrs Repeated administration often needed for longer-lasting opioid agonists Low bioavailability so not given orally on its own Sometimes added to oral opioid agonists to curb crushing tablets and using them intravenously Indicated for opioid overdose treatment ADVERSE EFFECTS Headache, hypertension, muscle spasms, serious allergic reactions, nasal dryness, Can cause opioid withdrawal symptoms Cardiac arrhythmias, nausea, vomiting, diarrhea, irritability, nervousness, aggressive behaviour SAMPLE QUESTION Which of the following drugs is an opioid receptor antagonist? A. Codeine B. Morphine C. Tramadol D. Naloxone