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Download Opioids – anal-gesics (lol) ©2010 Mark Tuttle Mechanism of action
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Transcript
Opioids – anal-gesics (lol) Mechanism of action/Uses 1. ↓voltage-gated Ca2+ channels ↓ NT release 2. ↑K+ channel conductance Hyperpolarizes: IPSP ©2010 Mark Tuttle Drugs Pharmacodynamics Pharmacokinetics - Morphine - Analgesia: ↑ threshold & alters subjective - Well absorbed, but ↓ bioavailability - Etrophine - Sedation: qualitatively diff from other depress’s - Distribution: crosses the blood-brain barrier - Heroin (pro drug) - Mood effects: euphoria (μ) or dysphoria (κ) - Plasma t½: 2-3 hours o More potent - Respiratory depression: ↓ sensitivity to CO2 - Conjugated with glucuronic acid, and - Codeine o Usual cause of death in overdose excreted mostly in the urine, primarily as 3↓ ascending pain transmission o Selective antitussive o ↑ brain blood flow can cause edema glucuronide - Spinal cord & thalamus o CPY2D6 morphine - Neuroendocrine / hypothalamic actions o Metabolite can cause CNS stimulation - Presynaptic μ,κ,δ: Ca2+ channels - Dextromethorphan o ↑ Prolactin and vasopressin (ADH) - Morphine-6-glucuronide is also an active - Postsynaptic: κ only: K+ channels o Selective antitussive ↓ GnRH, CRH, LH, FSH, ACTH, β-endorphin opioid, about 100 times as potent as ↓ descending pain modulation - Meperidine o ↓ set-point for thermoregulation morphine. - Periaqueductal gray + medulla o Faster onset, ↓ t½ - Pupillary constriction (miosis) ↓ tolerance o Crosses the blood-brain barrier poorly, but - Disinhibit anti-pain GABA intern n. o Interaction w/ MAO I’s - Nausea and vomiting - due to stimulation of CTZ may account for some of morphine's o Seizures - Antitussive: cough reflex depressed in medulla actions μ receptors - Fentanyl - Cardiovascular actions: min effx w/usual doses Antagonists - Most effects, euphoria, sedation o “Breakthrough pain” - Relief of dyspnea: Mechanism is not known. - Naloxone (IV) κ receptors - Methadone - Morphine can release histamine from mast cells - Naltrexone (Oral) - Miosis, dysphoria, psychotic o Acute/chronic withdr. - Gastrointestinal Tract (myenteric plexus): Will precipitate abstinence (withdrawal) δ , Σ receptors o Longer t½ o ↑ tone, ↓peristalsis: constipation syndrome if addict is not weaned first - Propoxyphene o ↑biliary Tone (colic possible) Withdrawal None are better at separating o Weak agonist o Tolerance to this effect does NOT readily dvlp - Hyperactivity of autonomic nervous system analgesia from the adverse effects ↓potency, ↓ abuse - GU Tract: ↓renal function, uterus: ↑ labor - Intense craving (Psychological withdrawl) - Low PC no BBB o Can be worse than physical withdrawal Tolerance is functional not metabolic o Diphenoxylate o Loperamide Partial agonists & mixed agonist-antagonists κ agonist, μ antagonist/weak agonist Pentazocine - ↓ Analgesia & respiratory depression Nalbuphine - ↑ Dysphoria, psychomimetic from κ receptors Will precipitate abstinence - ↑ effect separation (withdrawal) syndrome if addict is not Butorphanol weaned first - ↑ effect separation Buprenorphine - ↑ t½ - Resistant to naloxone Endogenous opiopeptins: Actions of exogenously administered enkephalins and endorphins are similar to morphine, including tolerance and physical dependence - Pro-opiomelanocortin o β-endorphin, β-lipotropin, ACTH, and MSH - Proenkephalin-derived peptides o Met-enkephalin, Leu-enkephalin - Prodynorphin-derived peptides o Dynorphins A and B, and others, all of which include the leu-enkephalin sequence