Opioid Analgesics and Antagonists PDF

Opioids 1 Dr. Theebaa Learning Objectives: Opioid Analgesics and Antagonists: 1. Classify therapeutically useful opioid analgesics based on their receptor selectivity. 2. Explain the mechanism of action of opioids. 3. Explain the pharmacological actions of morphine. 4. Lis...

Opioids 1 Dr. Theebaa Learning Objectives: Opioid Analgesics and Antagonists: 1. Classify therapeutically useful opioid analgesics based on their receptor selectivity. 2. Explain the mechanism of action of opioids. 3. Explain the pharmacological actions of morphine. 4. List pure opioid antagonists. 5. Describe the role of drugs used in opioid dependence. 6. Apply the pharmacological aspects of methadone to provide the basis for its use in the management of opioid dependence. 7. Apply the concepts of pharmacological actions of morphine to provide the basis for its therapeutic uses. 8. Apply the concepts of pharmacological actions of morphine to provide the basis for its adverse effects. 9. Apply the concepts of pharmacological actions of morphine to provide the basis for its contraindications. 10. Explain the management of acute morphine poisoning. 11. List the therapeutic uses of other opioid analgesics. 12. Select the appropriate analgesic based on the WHO analgesic (pain relief) ladder. Introduction Opioid analgesics are "opium-like analgesics." Opium is an extract obtained from unripe seed capsules of the poppy plant (Papaver somniferum). Enkephalins, endorphins, and dynorphins are peptides released within the body in response to pain and bind to opioid receptors to relieve pain. Opioid Receptors μ (Mu): Analgesia (supraspinal level), euphoria, sedation, physical dependence, miosis. μ2: Analgesia (spinal level), respiratory depression, inhibition of GI motility. κ (Kappa): Analgesia (spinal level), dysphoria, psychotomimetic effect, sedation, inhibition of GI motility. δ (Delta): Analgesia (spinal + affective component of supraspinal), respiratory depression, reinforcing action, inhibition of GI motility, proconvulsant action. Classification of Opioids Agonists at μ Receptors: Morphine, codeine, pethidine, oxycodone, dextropropoxyphene. Agonists at κ Receptors: Fentanyl. Agonists at δ Receptors: Methadone, tramadol. Mixed Agonist-Antagonists and Partial Agonists: Pentazocine (antagonist at μ receptor, agonist at κ and δ receptors), Buprenorphine (partial agonist at μ receptor, antagonist at κ and δ receptors). Opioid Antagonists Pure antagonists at μ, κ, and δ receptors include Naloxone, Naltrexone, and Nalmefene. Mechanism of Action of Opioids Opioid agonists bind to opioid receptors (G-protein coupled receptors) and produce the following actions: Inhibit adenylate cyclase → ↓ intracellular cAMP → decrease in cell excitability (through μ & δ receptors). Activation of potassium channels → increase in K+ efflux → hyperpolarization of neurons → decrease in neuronal excitability (through μ & δ receptors). Suppress N-type voltage-gated calcium channels → reduced intracellular Ca2+ → decreased release of neurotransmitters from presynaptic neurons (through κ receptors). Pharmacological Actions of Morphine Central Effects: Stimulant Effects: Analgesia, euphoria, dysphoria, sedation, respiratory depression, vasomotor center depression, cough suppression, miosis, nausea and vomiting, convulsions. Depressant Effects: Affects the cardiovascular system, gastrointestinal tract, biliary tract, urinary bladder, and bronchi. Central Pharmacological Effects Analgesic: Mediated mainly through μ, κ, and δ receptors. Reduces both the sensory and affective (emotional) components of pain. Increases pain threshold, decreases pain transmission, and decreases emotional reaction to pain. More effective against dull, continuous pain such as deep-seated visceral pain than sharp, intermittent integumentary pain. Neuropathic pain may respond poorly to opioid analgesics. Euphoria/Dysphoria: Produces a sense of well-being (μ). Distress and anxiety associated with pain are reduced. Patients in distress due to pain may complain of dysphoria (κ), characterized by restlessness and malaise. Sedation: Mediated through μ and κ receptors. Drowsiness and mental clouding of judgment can be seen. Disrupts normal REM sleep patterns. Respiratory Depression: Mediated through μ receptors. Respiratory depression is the most common cause of death in opioid poisoning. This is dose-dependent and can occur at therapeutic doses. Inhibition of the respiratory center in the medulla leads to increased pCO2, causing cerebrovascular dilation, increased blood flow, and increased intracranial pressure. Vasomotor Center Depression: Seen at higher doses, may cause bradycardia and fall in blood pressure. Cough Suppression: Causes suppression of the cough center and cough reflex at sub- analgesic doses. Stimulant Effects: Miosis: Mediated through μ and κ receptors. Pinpoint pupils due to stimulation of the Nucleus Edinger Westphal. Useful in the diagnosis of opioid poisoning. Nausea and Vomiting: Directly stimulate the chemoreceptor trigger zone (CTZ), leading to emesis. Convulsions: May be seen at high doses. Peripheral Effects of Morphine Cardiovascular System: Larger doses of morphine can cause postural hypotension and bradycardia due to the release of histamine from mast cells, depression of the vasomotor center in the medulla, and direct action decreasing the tone of blood vessels. Gastrointestinal Tract: Increases the sphincter tone and decreases GI motility, leading to constipation (μ). Biliary Tract: Contraction of biliary tract smooth muscle, which may cause biliary spasm, and increased intrabiliary pressure by increasing the tone of the sphincter of Oddi. Urinary Bladder: Constriction of the urinary sphincter can cause difficulty in urination, while contraction of the detrusor muscle causes urgency to urinate. Bronchi: Bronchospasm due to the release of histamine from mast cells. Tolerance Reduction in effect with repeated dosing (or higher dose is required to produce the same effect). Tolerance develops to analgesia, euphoria, and sedation. Tolerance to respiratory effects develops slowly. Tolerance does not develop to miosis, constipation, and convulsions. Tolerance develops due to long-term desensitization or down-regulation of receptor-effector coupling mechanisms and increased production of intracellular cAMP, decreased K+ efflux, and increased intracellular Ca2+ to counteract the mechanism of action of morphine. Opioid Dependence Psychological Dependence: The patient believes that the optimal state of well-being is achieved only through the action of the drugs. Euphoria and easing of pain during the use of opioids lead to strong emotional cravings for the drug. Physical Dependence: Continued presence of the drug is needed to maintain physiological equilibrium. Abrupt stoppage of opioids results in withdrawal symptoms such as pain, hyperventilation, cough, vomiting, diarrhea, mydriasis, dysphoria, agitation, piloerection, and drug-seeking behavior. Management of Opioid Dependence 1. Methadone: Methadone is an agonist at μ receptors and is long-acting. The opioid in use is substituted by methadone to spare the addict from undesirable withdrawal symptoms as the opioid receptors remain occupied for a longer duration. Methadone can later be withdrawn by tapering the doses over weeks. Tolerance and physical dependence develop more slowly with methadone, and the withdrawal symptoms after abrupt discontinuance are milder. Methadone is orally effective and has a longer duration of action. 2. Buprenorphine: A partial opioid agonist used as an alternative to methadone. 3. Naltrexone: A long-acting, orally effective pure opioid antagonist used in addicts who are completely withdrawn from opioids (after methadone therapy) to block pleasurable effects leading to relapse. 4. Clonidine: A centrally acting sympatholytic agent used to prevent relapse and reduce the severity of withdrawal effects of opioids.