Opioid Analgesics & Antagonists

1. Opioid Analgesics & Antagonists By Bohlooli S. PhD School of Medicine, Ardabil University of Medical Sciences

2. Introduction • Opium poppy is the source of crude opium • Sertürner in 1803 isolated morphine • Naming it after Morpheus, the Greek god of dreams • Opioid analgesics is a widely used term for: • Natural, semi-synthetic, synthetic • Endogenous peptides

3. Basic Pharmacology of the Opioid Analgesics

4. Source • Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album • Opium contains many alkaloids, the principle one being morphine, which is present in a concentration of about 10%

5. Classification & Chemistry • Opioid drugs include: • Full agonists • Morphine • Partial agonists • Codeine • Antagonists • Naloxone

6. Chemical structure

7. Chemistry • Phenanthrenes • Morphine, hydromorphone, and oxymorphone • Codeine,oxycodone, dihydrocodeine, and hydrocodone • Phenylheptylamines • Methadone • Propoxyphene • Phenylpiperidines • Fentanyl, sufentanil, alfentanil, and remifentanil • Diphenoxylate and its metabolite, difenoxin • Loperamide • Morphinans

8. Chemistry; Opioids with Mixed Receptor Actions • Phenanthrenes • Nalbuphine , Buprenorphine • Morphinans • Butorphanol • Benzomorphans • Pentazocine • Miscellaneous • Tramadol, Tapentadol

9. Opioid Receptor Subtypes, Their Functions, and Their Endogenous Peptide Affinities

10. Endogenous Opioid Peptides • Endorphins • Drived from: prepro-opiomelanocortin • Enkephalins • met-enkephalin • leu-enkephalin • Drived from: preproenkephalin • Dynorphins • Drived from: preprodynorphin • Endomorphins • Nociceptin / Orphanin FQ • Orphanin opioid-receptor-like subtype 1 (ORL1)

11. Pharmacokinetics

12. Pharmacokinetics

13. Pharmacokinetics • Absorption • Distribution • Metabolism • Excretion

14. Absorption • Well absorbed • Variable first-pass metabolism • Subcutaneous, intramuscular, and oral routes- other routes: • Nasal insufflation • Oral mucosa via lozenges • Transdermal patches

15. Metabolism • Converted to polar metabolites • Morphine • morphine-3-glucuronide ::neuroexcitatory • morphine-6-glucuronide ::potency four to six times • Accumulation can produce unexpected results • Hydromorphone like morphine • H3G has CNS excitatory properties • Esters (eg, heroin, remifentanil) are rapidly hydrolyzed • Hepatic oxidative metabolism for phenylpiperidine opioids • meperidine, fentanyl, alfentanil, sufentanil • Normeperidine cause seizures in renal failure • Polymorphism of CYP2D6 • Codeine :: no significant analgesic effect or an exaggerated response

16. Pharmacodynamics

17. Mechanism of Action

18. Receptor Types • Based on pharmacologic criteria • 1, 2 • 1, 2 • 1, 2, 3 • Genetically one subtype from each of the ,  and  receptor families

19. Cellular Actions • Closing voltage-gated Ca2+ channels on presynaptic nerve terminals • Inhibit release of • Glutamate, acetylcholine, norepinephrine, serotonin, and substance P • Hyperpolarizing and thus inhibiting postsynaptic neurons by opening K+ channels

20. Relation of Physiologic Effects to Receptor Type • Opioid analgesics act primarily at the  -opioid receptor • Analgesia, euphoria, respiratory depression, and physical dependence • Butorphanol and nalbuphine • Preference for  opioid receptors • Greater analgesia in women

21. Receptor Distribution and Neural Mechanisms of Analgesia: Transmission

22. Receptor Distribution and Neural Mechanisms of Analgesia: Modulation

23. Ion Channels & Novel Analgesic Targets: chronic Pain • Capsaicin receptor, TRPV1 and TRPA1 • P2X : purines receptor • Tetrodotoxin-resistant voltage-gated sodium channel (Nav1.8)-PN3/SNS channel • Lidocaine and mexiletine • Ziconotide,  a blocker of voltage-gated N-type calcium channels • Related to marine snail toxin -conotoxin • Gabapentin/Pregabalin : analogs of GABA • Ketamine: NMDA antagonists • Nicotine •  9-tetrahydrocannabinol

24. Tolerance and Physical Dependence • Tolerance • Physical dependence • Withdrawal or abstinence syndrome • Mechanism • receptor recycling • receptor uncoupling

25. Organ System Effects of Morphine • Central Nervous System Effects • Cardiovascular System • Gastrointestinal Tract • Biliary Tract • Renal • Uterus • Neuroendocrine • Pruritus

26. Central Nervous System Effects

27. Central Nervous System Effects • Analgesia • Sensory • Affective (emotional) • Nonsteroidal anti-inflammatory analgesic drugs • Has no effect on emotional part • Euphoria • Pleasant floating sensation • Lessened anxiety and distress • Dysphoria may occure • Sedation • are common effects • no amnesia • Sleep is in the elderly • Occurs more frequently phenanthrenederivatives

28. Central Nervous System Effects • Respiratory Depression • Significant respiratory depression • Sepressedresponse to a carbon dioxide challenge • Influenced significantly by the degree of sensory input • Most difficult clinical challenges • Cough Suppression • Codeine • May allow accumulation of secretions • Miosis • Mediated by parasympathetic pathways • Truncal Rigidity • Intensification of tone in the large trunk muscles • Nausea and Vomiting • Activate the brainstem chemoreceptor trigger zone • Temperature • -opioid receptor agonists  hyperthermia •  -opioid receptor agonists  hypothermia

29. Cardiovascular System • Bradycardia • Meperidine antimuscarinic action  tachycardia • Hypotension may occur • Peripheral arterial and venous dilation • Release of histamine • Central depression of vasomotor-stabilizing mechanisms • Caution in patients with decreased blood volume

30. Gastrointestinal Tract • Constipation • the stomach • Motility decrease • Tone increase • Gastric secretion of hydrochloric acid is decreased • Biliary Tract • Contract biliary smooth muscle • biliary colic • Sphincter of Oddi may constrict

31. Other Peripheral Effects • Renal • Antidiuretic effect • Enhanced renal tubular sodium reabsorption • Increased ureteral and bladder tone • Uterus • May prolong labor • Neuroendocrine • stimulate the release of ADH, prolactin, and somatotropin • inhibit the release of luteinizing hormone

32. Clinical Pharmacology of the Opioid Analgesics Clinical Use of Opioid Analgesics Toxicity & Undesired Effects

33. Alternative Routes of Administration • Rectal suppositories • morphine and hydromorphone • Transdermal patch • Fentanyl • Intranasal • Butorphanol • Buccal transmucosal • Fentanyl citrate lozenge • Patient-controlled analgesia (PCA) • infusion device

34. Toxicity & Undesired Effects • Behavioral restlessness, tremulousness, hyperactivity (in dysphoric reactions) • Respiratory depression • Nausea and vomiting • Increased intracranial pressure • Postural hypotension accentuated by hypovolemia • Constipation • Urinary retention • Itching around nose, urticaria (more frequent with parenteral and spinal administration)

35. Tolerance and Dependence • Does not become clinically manifest until after 2–3 weeks • Tolerance to methadone develops more slowly • Cross-tolerance is an extremely important • Butoften be partial or incomplete • Opioid rotation • Recoupling opioid receptor  ketamine

36. Physical Dependence • Signs and symptoms • Rhinorrhea • Lacrimation • Yawning • Chills • Gooseflesh (piloerection) • Hyperventilation • Hyperthermia • Mydriasis • Muscular aches • Vomiting • Diarrhea • Anxiety, and hostility

37. Physical Dependence • time of onset, intensity, and duration of abstinence syndrome depend on • biologic half-life • morphine or heroin, usually start within 6–10 hours • methadone required several days

38. Psychologic Dependence • Euphoria, indifference to stimuli, and sedation • Abdominal effects that have been likened to an intense sexual orgasm • Reinforced by the development of physical dependence

39. The Opioid Antagonists • Naloxone,naltrexone, and nalmefene • Methylnaltrexone bromide • Alvimopan