Analgesics Lecture 2: Opioids PDF

Analgesics Lecture 2: Opioids Prof. David Finn Pharmacology and Therapeutics [email protected] Pharmacological effects (CNS and periphery) Classification Learning objectives Mechanism of action Adverse drug reactions Morphine as an example opioid Other opioid drugs History of opioids...

Analgesics Lecture 2: Opioids Prof. David Finn Pharmacology and Therapeutics [email protected] Pharmacological effects (CNS and periphery) Classification Learning objectives Mechanism of action Adverse drug reactions Morphine as an example opioid Other opioid drugs History of opioids Opium is extracted from poppy seeds (Papaver somniferum)​ Used for thousands of years to produce:​ o Euphoria​ o Analgesia​ o Sedation​ o Relief from diarrhoea o Cough suppression History of opioids In Greek and Roman times opium and laudanum (opium combined with alcohol) were used to treat almost all known diseases​ Morphine was isolated from opium in the early 1800s and since then it has been the most effective treatment for severe pain​ Chemical structure of morphine At present… Morphine remains the gold standard with which every new opioid analgesic has been compared ​ Opioid analgesics are the most effective class of drugs available for the management of severe pain Classification of opioid analgesics Natural opium alkaloids Morphine Codeine Semisynthetic opiates Heroin (Diacetylmorphine) Hydrocodone Oxycodone Synthetic opiates Pethidine Fentanyl Tramadol Methadone Dextropropoxyphene Opioid receptors All opioid bind to specific opioid receptors They are classified as: o Mu (µ, MOP) o Kappa (κ, KOP) o Delta (δ, DOP) o Nociceptin/Orphanin FQ (NOP) Opioid receptors All opioid receptors are G-protein-coupled receptors (GPCRs) µ receptors: responsible for most of the analgesic effects of opioids o Also, responsible for the additional effects of opioids Κ receptors: responsible for analgesia at the spinal level​ δ receptors: more important in the periphery extracellular plasma membrane intracellular Endogenous opioid peptides These are peptides with opiate-like pharmacological effects There are four types of EOPs ​ o Leu-Enkephalin ​ o Met-Enkephalin​ o Dynorphin​ o β-Endorphin​ Opioids and descending inhibition Mechanism of action Opioid receptors and peptides Mechanism of action of opioids In the periphery and CNS Morphine: Pharmacological effects (1) In the CNS: 1. Analgesia: Pain has multiple components, including sensory and emotional components​ o Opioids are unique in that they relieve both components of pain 2. Euphoria: especially patients who are on i.v. morphine experience a pleasant floating sensation and lessened anxiety and distress​ (“high”) Morphine: Pharmacological effects (2) In the CNS: 3. Sedation: drowsiness is a frequent concomitant of opioid action​ o There is little or no amnesia​ 4. Respiratory Depression​: All opioid analgesics depress respiration by acting directly on the respiratory center​ Morphine: Pharmacological effects (3) In the CNS: 5. Nausea and vomiting o Opioid receptors are present in the chemoreceptor trigger zone (CTZ) and are simulated by opioid analgesics o This leads to vomiting and symptoms of nausea​ Morphine: Pharmacological effects (4) In the periphery: o Morphine releases histamine from mast cell  itching/urticaria/bronchoconstriction o Bradycardia – due to action on medulla o Hypotension and may lead to reflex tachycardia (also linked with histamine release) Morphine: Pharmacological effects (5) In the periphery: o In the gastrointestinal tract (GIT)  Constipation  Spasm of pyloric, ileocaecal sphincters​  Decrease in all intestinal secretions​  People with substance abuse disorder remain chronically constipated​ Morphine: Pharmacological effects (6) Other effects: o Cough suppression​  Opioids have a very good cough suppressant (antitussive) action​  Codeine is used for this purpose​ o Constriction of pupils is seen with virtually all opioids Morphine: Pharmacological effects (7) Other effects: o Truncal rigidity​​  An intensification of tone in the large trunk muscle​  This interferes with ventilation​  Effect is most apparent with high doses of highly lipid soluble opioids​  E.g. fentanyl, sulfentanil Morphine: Pharmacokinetics Oral absorption: unreliable (high first pass metabolism)​ Widely distributed​ o Enters the brain but slowly​ o Rapidly enters the placental barrier​ Morphine-6-glucuronide is the active metabolite Most morphine is excreted in 24 h​ Morphine: Adverse drug reactions Respiratory depression​ Sedation, mental clouding, lethargy​ Vomiting​ Urinary retention, constipation​ Hypotension/ Bradycardia​ Morphine poisoning: acute lethal dose in humans is 250 mg, but 50 mg produce severe toxicity​ Treatment in case of ADR Respiratory support​ Maintenance of blood pressure Gastric lavage​ Specific antidote: Naloxone (opioid receptor antagonist) 0.4-0.8 mg i.v. every 2-3 minutes until respiration picks up​ Tolerance and dependence​ Tolerance: More needed to produce the same effect​ Dependence: Physical (withdrawal phenomenon) and psychological (craving)​ High degree of tolerance and dependence is noted with morphine​ Individuals with substance abuse disorder tolerate morphine in grams​ Morphine produces both physiological and psychological dependence​ Other opioids - Codeine​ It is methyl morphine, occurs naturally in opium Partly converted into morphine​ after administration It is less potent than morphine​ Selective cough suppressant​ Has good oral bioavailability​ Codeine: Case study (1) A 26-year-old patient has knee surgery​ Codeine is prescribed for post-op pain​ Patient reports no relief with up to 360 mg/24 hours​ After switching to morphine, pain is easily controlled with 10 mg/24 hours​ Codeine: Case study (2) Lesson: o Codeine is a pro-drug requiring metabolic activation by O-demethylation to morphine by CYP2D6​ o Approx. 5-10% Europeans are homozygous for inactive variant CYP2D6 alleles and experience no analgesic effect with codeine​ Other opioids – Pethidine (Meperidine)​ Pethidine was synthesized as an atropine substitute in 1939​ Chemically unrelated to morphine but has similar actions​ Has a very good analgesic action​ Poor cough suppressant action​ Given i.m. and onset of action is very rapid​ Used for postoperative pain relief and during labour Pethidine: ADR Similar to morphine​ Overdose of pethidine causes many excitatory effects​ Tremors, mydriasis, hyperreflexia, delirium, myoclonus, and convulsions​ This is due to accumulation of its metabolite norpethidine​ Other opioids – Fentanyl​ 80-100 times more potent than morphine​ Short duration of action​ Given IV, IT, transdermal​ Used in anaesthesia with droperidol (antiemetic/antipsychotic)​ Other opioids – Hydrocodone​ Semi-synthetic derivative of codeine Mu-opioid receptor agonist Commonly used in combination with paracetamol or aspirin or ibuprofen to treat moderate to severe pain Combination drug products e.g. Co-codamol and others Acute pain/injury, post-surgical pain Oral tablets, capsules, liquid solutions​ Analgesic and antitussive actions Other opioids Tramadol​: Weak opioid used in post-operative pain​ Buprenorphine: Acute/chronic pain treatment, longacting, ~12 h half-life​ Methadone: Long-acting/Chronic pain/maintenance of addicts​ Uses of opioids Analgesic: opioid analgesia is indicated in moderate to severe pain; they only provide symptomatic relief​ Visceral pain Post-surgical pain Palliative care Pre-anaesthetic medication​ Act by providing analgesia and relieving apprehension ​ Opioids – future The aim is to develop better opioids that provide analgesia without side effects​ Local application: avoid CNS side effects o Intrathecal​ o Epidural​ Opioids – future κ receptor agonists?​ o Moderately good analgesics​ o Not addictive​ o No respiratory depression​ o BUT they cause dysphoria and hallucinations δ receptor agonists may also have potential o Weaker analgesics than µ agonists but fewer side effects Co-administration with other analgesics - synergism​ Key points  Opioids are strong analgesics used to relieve severe pain  All opioids act by suppressing neuronal activity (via opioid receptors)  Opioids act at peripheral, spinal, and supra-spinal sites  Adverse effects include respiratory depression, sedation, vomiting, constipation, and hypotension/bradycardia Adjuvant Analgesics + Defined as drugs with other indications that may be analgesic in specific circumstances + Numerous drugs in diverse classes + Multipurpose or specific for neuropathic pain Multipurpose Adjuvant Analgesics Class Examples Antidepressants amitriptyline, desipramine, nortriptyline, duloxetine, venlafaxine, paroxetine, Alpha-2 adrenergic agonists tizanidine, clonidine Corticosteroids dexamethasone prednisone, Adjuvant Analgesics for Neuropathic Pain Class Examples Anticonvulsants gabapentin, pregabalin, valproate, lamotrigine phenytoin, carbamazepine, clonazepam, topiramate, tiagabine, levetiracetam oxcarbazepine, Local anesthetics mexiletine, tocainide Model of alpha(2)-delta ligand action Primary afferent nerve terminal 2nd order pain Transmission neurone Recommended reading + Rang and Dale’s Pharmacology 10th Edition Chapter 43 (analgesics), 50 (drugs of abuse)​ + Golan’s Principles of Pharmacology 4th Edition​ Pharmacology of Analgesia (Chapter 18)​ Pharmacology of Drugs of abuse (Chapter 19)​