Opioid Analgesics

1. Opioid Analgesics Dr. Prabhakar Adake MD Asst. Professor Department of Pharmacology Yenepoya Medical College MANGALORE

2. Pain?? • Pain is an unpleasant sensation evoked by an external or internal noxious stimulus. • Affective & Nociceptive component

3. Case scenario A middle aged male patients comes to the casualty with history of severe pain abdomen, without proper diagnosis the junior doctor prescribed him inj. Morphine. After that pain started increasing. What would be the cause for increase in the pain?

5. Analgesic??????? • An agent that subdues pain by acting in the CNS or on peripheral pain mechanism.

6. Classification of Analgesics • Opioid Analgesics • Non – opioid Analgesics

7. Opioid Analgesics • The term opiate is used to describe alkaloid molecules derived from the opium poppy Papaversomniferum. • Contain 2 types of alkaloids Phenanthrene derivatives • Morphine (10% in opium), Codeine (0.5% in opium) • Thebaine (0.2% in opium), (Nonanalgesic) Benzoisoquinoline derivatives • Papaverine (1%) , Noscapine (6%) : NonanaIgeslic • The term opioid refers to all compounds which have functional properties like the opiates.

8. Classification of Opioid Analgesics

9. II.Classification Natural opium alkaloids: • Morphine • Codeine Semisynthetic opiates: • Diacetylmorphine (Heroin) • Pholcodeine Synthetic opioids: • Pethidine (Meperidine) • Fentanyl, Alfentanil, Sufentanil, Remifentanil • Methadone • Dextropropoxyphene • Tramadol

10. Pharmacological Actions [CNS] • Analgesia • Reduction in the response to a noxious (painful) stimulus. • Raises pain threshold. • Serves to alleviate anxiety. • Site:Spinal or Supraspinal • Interact with the receptors • ↑ release of inhibitory transmitters • ↓ release of nociceptive peptides

11. Opioid Receptor Transducer Mechanism Agonist binding Conformational changes in the GPCR Inhibition of adenylyl cyclase activity (,) Stimulation of K+ current (,) Inhibition of voltage-gated Ca2+ channels () Decreased release of neurotransmitter (substance-P, neurokinin A, neurokinin B, glutamate)

12. Endogenous Opioid Peptides • A number of endogenous opioid peptides having morphine like activity are found in brain, pituitary, spinal cord, GIT • β-Endorphins -  • Enkephalins -  & • Dynorphins-  • Endomorphins-  • Nociceptin- NOP receptor (nociceptin opioid peptide receptor)

13. Pharmacological Actions [CNS] Euphoria • Patients who receive morphine experience a pleasant floating sensation with lessened anxiety and distress.

14. Pharmacological Actions [CNS] Sedation • Drowsiness and Mental clouding. • Sleep is induced by opiates more frequently in the elderly

15. Pharmacological Actions [CNS] Respiratory depression • Dose-related • Suppress the respiratory centre • Death

16. Pharmacological Actions [CNS] • Cough suppression • Suppression of the cough reflex

17. Pharmacological Actions [CNS] Miosis • Stimulates the 3rd cranial nerve . • valuable in the diagnosis of opioid overdose.

18. Pharmacological Actions [CNS] • Nausea & Vomiting • Activates chemoreceptor trigger zone [CTZ]. • valuable in the diagnosis of opioid overdose.

19. Pharmacological Actions [Peripheral Effects] Cardiovascular system • no significant direct effects on the heart • Bradycardia at high dose. • Peripheral vasodilatation due to histamine release leading to Hypotension.

20. Pharmacological Actions [Peripheral Effects] • GIT • ↓ GI motility • Constipation

21. Pharmacological Actions [Peripheral Effects] • Biliary tract • constrict biliary smooth muscle  biliary colic.

22. Pharmacological Actions [Peripheral Effects] • Urinary tract Urinary retention , ↓ Urine production. • Uterus Prolong labor • Bronchial smooth muscle High dose  Constriction .

23. Pharmacological Actions • Neuroendocrine • stimulate the release of ADH, prolactin, and somatotropin • inhibit the release of luteinizing hormone.

24. Opioid Receptors (G Protein- coupled Receptors) • Mu (Mu1 > Mu2 -Morphine) • Mu1- Supra spinal Analgesia;Mu2 – Spinal ; • Respiratory Depression ; Constipation; Sedation; Euphoria; Miosis; Physical Dependence • Delta- Delta1, Delta2 (SPINAL) • Analgesia, GI motility • Reinforcing actions • Kappa- k1(Spinal), k2, k3(Supra Spinal) • Analgesia, Respiratory Depression , Dysphoria, Miosis, Hallucinations • Sedation, Physical dependence

27. Pharmacokinetics • Absorption • Readily absorbed • Oral route : First pass metabolism • Distribution • Distributed to all tissues • Metabolism • Conjugation : Glucuronic acid • Excretion • Urine

28. Clinical uses • PAIN • Acute pain • Post operative pain • Myocardial infarction • Fractures • Chronic Pain • Cancer pain • Pre-anesthetic medication • Cough suppressant • Diarrhea

29. Cautions & Contraindications • Don’t combine pure agonist with partial agonist – diminishing analgesia, withdrawal induction • Head injuries • Pregnancy-apnoea in foetus • Liver disorders • Elderly males • Bronchial asthma patients

30. Adverse Effects • Nausea, Vomiting • Constipation • Urinary retention • Restlessness • Pinpoint pupil • Bradycardia • Hypotension • Convulsions • Respiratory Failure • Dependence

31. Diagnosis & Treatment of Overdosage • > 50 mg of oral dose • Depressed respiration • Pin point pupil • Low body temperature • Low blood pressure • Treatment • Adequate ventilation • 0.4-0.8 mg i.V. Naloxone • Repeat when necessary

32. Diagnosis & Treatment of Physical dependence • Abnormal physiological condition in which the drug must be administered for the normal function. • Withdrawal symptoms .

33. Diagnosis & Treatment of Physical dependence

34. Diagnosis & Treatment of Physical dependence • Treatment of withdrawal Substitute with long acting orally active equivalent drug- METHADONE which can be gradually withdrawn.

35. Fentanyl • 80-100 times more potent than morphine • few cardiovascular effects • little propensity to release histamine. • Because of high lipid solubility, it enters brain rapidly and produces peak analgesia in 5 min after i. v. injection. • The duration of action is short: starts wearing off after 30-40 min due to redistribution • Transdermal fentanyl has become available for use in cancer

36. Methadone • Slow & persistent action • Sedative & subjective effects are less intense • No kick • Less abuse potential • Use- as substitute therapy for opioid dependence • 1mg methadone for 4 mg morphine.

37. Tramadol • Analgesic action mechanism • Weak affinity for -opioid receptor • norepinephrine & 5-HT reuptake Inhibition • Advantage • Less respiratory depression, nausea, vomiting, constipation • Less abuse potential • Rapid psychomotor recovery • Labour pain, injury, surgery (other short lasting pain) • Moderate pain treatment : as effective as morphine • Severe pain treatment : less effective than morphine

38. Pentazocine ( analgesic) • It has k-agonistic actions and weak mu antagonistic activity • Elicit dysphoric and psychotomimetic effects • Increase in blood pressure and heart rate Uses- • moderate to severe pain • as a preoperative medication and • as a supplement to anesthesia

39. Buprenorphine (weak  agonist & antagonist) • 25-50 times more potent than morphine • Sublingual route • Slower onset & longer duration of action • Postural hypotension is marked • Cannot be used during labour (respi dep not reversed by naloxone) Uses- • Long lasting pain- cancer • Rx of morphine dependence

40. Naloxone (, ,  antagonist) • Antagonizes all morphine actions • Sedation is less completely reversed • Blocks placebo, acupuncture, stress induced analgesia Use • Morphine poisoning • Diagnostic test for opioid addiction • Revert neonatal respiratory depression due to opioid use during labour

41. Peripherally Acting Opioid • Opioid receptor – outside central nerve system • Peripherally acting opioid agonist → analgesia without CNS side effect • Loperamide, Diphenoxylate • -opioid receptor agonist • Not cross blood-brain barrier • Relieve diarrhea

42. References 1. Tripathi K.D., Essentials of Medical Pharmacology 8th ed. Jaypee Brothers 2018. 2. Satoskar R.S. & Bhandarkar S.D., Pharmacology and Pharmacotherapeutics, 25th ed. Elsevier 2017.

43. Thank you