Opioids 1 PDF

Opioids 1 Dr Theebaa Learning objectives Opioids Analgesics and Antagonists Classify therapeutically useful opioid analgesics based on their receptor selectivity. *** (Opioids 1) Explain the mechanism of action of opioids. *** (Opioids 1) Explain the pharmacological actions of morphine. *** (Opioids...

Opioids 1 Dr Theebaa Learning objectives Opioids Analgesics and Antagonists Classify therapeutically useful opioid analgesics based on their receptor selectivity. *** (Opioids 1) Explain the mechanism of action of opioids. *** (Opioids 1) Explain the pharmacological actions of morphine. *** (Opioids 1) List pure opioid antagonists. *** (Opioids 1) Tell the role of drugs used in opioid dependence. *** (Opioids 1) Apply the pharmacological aspects of methadone to provide basis for its use in the management of opioid dependence. ** (Opioids 1) Apply the concepts of pharmacological actions of morphine to provide basis for its therapeutic uses. *** (Opioids 2) Apply the concepts of pharmacological actions of morphine to provide basis for its adverse effects.*** (Opioids 2) Apply the concepts of pharmacological actions of morphine to provide basis for its contraindications. *** (Opioids 2) Explain the management of acute morphine poisoning. *** (Opioids 2) List the therapeutic uses of other opioid analgesics. *** (Opioids 2) Select the appropriate analgesic based on WHO analgesic (pain relief) ladder. *** (Opioids 2) 2 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. These peptides are released within the body in response to pain and bind to opioid receptors to relieve pain. 3 Opioids receptors and their mediated effects Opioids receptors κ (Kappa) μ (Mu) μ1 Analgesia (supraspinal level) Euphoria Sedation Physical dependence Miosis μ2 Analgesia (spinal level) Respiratory depression Inhibition of GI motility 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 4 Classification of opioids 1. μ (Mu) κ (Kappa) 𝛿 (Delta) Agonist at Morphine, codeine, pethidine, oxycodone, dextropropoxyphene 2. μ (Mu) Agonist at Fentanyl 3. μ (Mu) Agonist at Methadone, tramadol 4. 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 𝛿 (Delta) 5 Opioids antagonist Pure antagonists at mu (μ), kappa (κ) and delta (δ) receptors include Naloxone Naltrexone Nalmefene 6 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) 7 Pharmacological actions of morphine Pharmacological actions of morphine Central effects Depressant effects Analgesia Euphoria, dysphoria Sedation Respiratory depression Vasomotor centre depression Cough suppression Stimulant effects Miosis Nausea and Vomiting Convulsions Peripheral effects Tolerance Dependence On: CVS Gastrointestinal tract Biliary tract Urinary bladder Bronchi 10 Central pharmacological effects Morphine depressant effects 1. Analgesic Mediated mainly through mu (μ), kappa (κ) and delta (δ) receptors Reduce both the sensory as well as the affective (emotional) components of the pain Increases pain threshold, ↓ pain transmission, ↓ emotional reaction to pain More effective against dull, continuous pain such as deep-seated visceral pain than a sharp intermittent integumentary pain Neuropathic pain may respond poorly to opioid analgesics 2. 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 11 Central pharmacological effects Morphine depressant effects 3. Sedation Mediated through μ and κ receptors Drowsiness and mental clouding of judgement can be seen Disrupts normal REM sleep pattern 4. 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 → ↑pCO2 Causes suppression of neurogenic, hypercapnoeic and later hypoxic drives to the respiratory center The increased pCO2 → causes cerebrovascular dilation → ↑ blood flow → increased intracranial pressure 12 Central pharmacological effects Morphine depressant effects 5. Vasomotor center depression: Seen at higher doses, may cause bradycardia and fall in BP. 6. Cough suppression: Causes suppression of cough center and cough reflex at sub-analgesic doses Stimulation of cough center in medulla Afferent impulses Efferent impulses Airway mucosa Expiratory muscles Irritants Cough 13 Central pharmacological effects Morphine stimulant effects 1. Miosis Mediated through μ and κ receptors Pinpoint pupil due to stimulation of Nucleus Edinger Westphal Useful in diagnosis of opioid poisoning 2. Nausea and Vomiting Directly stimulate the CTZ → emesis 3. Convulsions May be seen in high doses 14 Peripheral effects of morphine 1. CVS: larger dose of morphine can cause postural hypotension & bradycardia. This is due to: Release of histamine from mast cells and histamine will cause vasodilatation Depression of vasomotor centre in the medulla. Vasomotor centre regulates blood pressure and depression of vasomotor centre causes the loss of vasomotor tone of blood vessels, resulting in vasodilatation → hypotension Direct action decreasing tone of blood vessels 2. Gastrointestinal Tract: ↑ the sphincter tone and ↓ GI motility – constipation (μ) 15 Peripheral effects of morphine 3. Biliary tract: Contraction of biliary tract smooth muscle (which may cause biliary spasm) ↑ intrabiliary pressure by increasing the tone of sphincter of oddi. 4. Urinary Bladder: Constriction of the urinary sphincter can cause difficulty in urination While contraction of detrusor muscle causes urgency to urinate 5. Bronchi: Bronchospasm due to release of histamine from mast cells 16 Tolerance Reduction in effect with repeated dosing (or higher dose is required to produce same effect) Tolerance develops to - analgesia, euphoria, sedation. Tolerance to respiratory effects develops slowly. Tolerance does not develop to miosis, constipation and convulsions. Tolerance develops due to (i) Long-term desensitization or down-regulation of receptor-effector coupling mechanisms. (ii) Due to increased production of intracellular cAMP; decrease in K+ efflux; increased intracellular Ca2+ → counteracts the mechanism of action of morphine. Neurons over-synthesize cAMP to compensate expected decrease due to opioids Higher dose of opioids needed to compensate the compensatory increase in cAMP → leading to TOLERANCE 15 Opioid dependence Opioids dependence is mediated through μ receptors. Psychological dependence Physical dependence The patient believes that optimal state of well being is achieved only through the action of the drugs. Continued presence of drug needed to maintain physiological equilibrium. The euphoria that individuals feel and the easing of pain during use of opioids. Abrupt stoppage of opioid results in withdrawal symptoms. Presence of strong emotional cravings to the drug. Pain, hyperventilation, cough, vomiting, diarrhoea, mydriasis, dysphoria, agitation, piloerection and drug seeking behaviour. 16 Management of opioids dependence 1. Methadone Methadone is an agonist at μ receptor and is long acting. Therefore, the opioid in use is substituted by methadone. This will spare the addict from undesirable withdrawal symptoms because the opioid receptors remain occupied for a longer duration. Later methadone can be withdrawn by tapering the doses over a period of weeks. Methadone is preferred because Tolerance and physical dependence develop more slowly with methadone The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder It has longer duration of action It is orally effective 17 Management of opioids dependence 2. Buprenorphine It is a partial opioid agonist used as an alternative to methadone. 3. Naltrexone It is a long acting, orally effective pure opioid antagonist. Used in addicts who are completely withdrawn from opioid (after methadone therapy) Used to block pleasurable effects leading to relapse 4. Clonidine It is a centrally acting sympatholytic agent To prevent relapse Reduces the severity of withdrawal effects of opioids 18