Analgesics

1. Analgesics Narcotic Analgesics. Non Narcotic Analgesics

3. Comparison of Analgesics

4. Non Narcotic Analgesics Non Steroidal Antiinflammatory Drugs or Agents (NSAID). Non Opioid analgesics.

5. NSAID Mechanism of Action: • Inhibition of PG synthesis • Cyclooxygenase (COX) Enzyme. • Two types of COX enzyme: • COX-1 present in all parts of the body . • COX-2 locally induced by inflammation.

6. Pharmacological Actions of NSAID • Analgesic. • Antipyretic • Anticoagulant. • Antiinflammatory.

7. Pharmacological Actions of NSAID • Fluid Retention • Vasodilation • Allergenic: • Bronchial Asthma. • Anaphylaxis

8. Pharmacological Actions of NSAID • Gastric Irritation: Direct Irritation: if acidic. PG inhibition: all Variable response : according to: Individual, Dose, Agent, Severity.

9. Pharmacological Actions of NSAID • Hepatic Dysfunction: • Especially with acetaminophen overdose. • Renal Dysfunction: Analgesic Nephropathy. • Uterine relaxation, can delay labor.

10. Salicylates • Weak acids: pKa 3.5 • Protein Bound. • Distribute to all tissues • Elimination: • High doses: Zero Order • Low doses: First Order

11. ADRs & Overdose of Salicylates • Hyperventilation • Metabolic Acidosis • Hypersensitivity: Salicylism • Reye's Syndrome, in children. • Bleeding • Delays delivery • Fetal Abnormalities • Ulcerogenic

12. Acetaminophen = Paracetamol • Less plasma protein bound • Weak PG synthesis inhibitor • Actions may be through CNS activity.

13. Acetaminophen = Paracetamol • Very commonly used analgesic, effective, safe, and cheap. • Not: • Antiinflammatory • Platelets inhibitor • Ulcerogenic • Teratogenic

14. Acetaminophen = Paracetamol • Toxicity • Severe hepatotoxicity, only with high doses. Evident only after 24 hours of ingestion. • N- acetylcysteine is the antidote, should be given in the first 24hours.

15. Diclofenac • Potent, widely used. • Available for oral, local( ophthalmic, topical gel), mouth wash, rectal and parenteral administration( for renal colic).

16. Propionic Acid Derivatives • Ibuprofen • Ketoprofen • Naproxin

17. Older Analgesics • Indomethacin • Pancytopenia • Phenylbutazone • Aplastic Anemia • Mefenamic Acid

19. Cyclooxygenase II Inhibitors • Meloxicam • Rofecoxib • Celocoxib

20. Cyclooxygenase II Inhibitors • Selective for COX at inflammation sites. • Do not affect platelet function. • May increase the incidence of edema and hypertension. • Less gastroirritant. • Higher incidence of cardiovascular thrombotic events.

21. Opioid Analgesics • Opioid • Narcotic • Opium: Papaversomniferum • Morphine, Morpheus(إله النوم) , -ine • Endorphins • Enkephalins

22. Opioid Analgesics • Dependence =إعتماد (Abuse , Addiction , Habituation): Psychological (Psychic, Craving , Compulsive) Physiological (Physical , Adaptive ......) • Toleranceتحمل =. • Cross Dependence. • Cross Tolerance.

23. History of Opium Papaversemniferum 3000 BC Morphine 1806 Heroin 1898 شركة الهند الشرقية 1600 حرب الأفيون1839-1842 اختراع السيرنج 1853 Morphine Receptors 1973

24. Opioid Receptors • Mu1 • Mu2 • Kappa • Sigma • Delta • Epsilon. • Agents differ in their affinity and selectivity to these receptors. • This will produce different pharmacological actions.

25. Opiate Receptor Interactions

26. Depressant effects of Morphine • Analgesia, suppression of pain. • Drowsiness and decreased mental alertness, sedation • Decreased respiration. • Increased intracranial pressure. • Decreased myocardial oxygen demand. • Suppression of cough, antitussive.

27. Depressant effects of Morphine • Decreased peristalsis. • Inhibition of fluid and electrolyte accumulation in the intestinal lumen. • Decreased gastric acid secretion. • Slight decrease in body temperature. • Decreased release of LH and FSH

28. Stimulant effects of Morphine • Euphoria. • Miosis, constriction of pupils. • Stimulation of chemoreceptor trigger zone. • Increased tone of intestinal smooth muscle. • Increased tone of sphincter of Oddi, so, increased biliary pressure.

29. Stimulant effects of Morphine • Increased tone of detrusor muscle. • Increased tone of vesical sphincter. • Increased release of prolactin and antidiuretic hormone. • Proconvulsant in overdose.

30. Pharmacokinetics • Highly lipid soluble, so easily absorbed and widely distributed. • Metabolized in the liver. • Great first-pass effect(75%).

31. Therapeutic Uses • Severe Acute pain of temporary nature. • Chronic Pain: Pain of terminal cancer Try nonopiates first. Try weaker opiates first. Use regular fixed schedule. • Obstetric Anesthesia. • Preanesthetic medication. • Pulmonary Edema: Relieve anxiety. Cause peripheral blood pooling • Severe diarrhea and dry cough.

32. Adverse Effects • Bradycardia. • Urinary retention. • Dry mouth, nausea, vomiting. • Allergic reactions. • Constipation. • Sedation, confusion, nightmares, hallucinations. • Dependence and withdrawal reactions. • Respiratory depression and death.

33. Diagnostic Sign of Toxicity • Pinpoint pupils….. No tolerance

34. Contraindications • Head Injury. • Shock and decreased blood volume. • Chronic hypoxic conditions.

35. Tolerance to Opioids • Tolerance develops to almost all actions of opioids, EXCEPT: Miosis( diagnostic sign of overdose and tolerance). Constipation. Convulsions.

36. Tolerance to Opioids Tolerance to opioids is homeostatic. Factors Affecting Development of Tolerance: • Rate of Administration • Dose • Agent used.

38. Homeostatic Mechanism of Tolerance.

39. Opioid Withdrawal • 6-12 hr: • Drug seeking (purposive) behavior, non purposive signs, such as restlessness, lacrimation, rhinorrhea, sweating, yawning. • 12-24hr: • Restless sleep for several hours (yen) and feeling more miserable than before after awakening; irritability, tremor, dilated pupils, anorexia, gooseflesh skin.

40. Opioid Withdrawal • 24-72hr: • Increased intensity of previous signs plus weakness, depression, nausea, vomiting, intestinal cramps, diarrhea, alternate chills and flushes, various aches and pains, increased heart rate and blood pressure, involuntary movements of arms and legs, dehydration and possible electrolyte imbalances.

41. Opioid Withdrawal • Later: • Above symptoms of autonomic hyperactivity alternate with brief periods of restless sleep and gradually decrease in intensity until addict feels better in 7-10 days but may still exhibit strong craving for the drug. • Some mild signs may be detectable for up to 6 months. • Delayed growth and development of infants born to addicted mothers may be detected for up to one year.

42. Treatment of Opioid Dependence • Suppression of Withdrawal Syndrome Morphine Heroin • Opioid Substitution: Methadone • Detoxification: Gradually decreasing the dose of methadone. Naloxone • Narcotic Antagonists: Naltrexone for 2-6 months following detoxification.

43. Opioid Agonists • Morphine • Prototype. • Codeine: • Mild analgesic(1/7 th of morphine) • Heroin: • 6-acyl morphine, modified morphine. • More potent, very lipid soluble, enters CNS very rapidly.

44. Opioid Agonists • Meperidine (Pethidine): • Less powerful than morphine. • Less dependence. • Less effect on cough and respiratory center. • Can be used in head injury. • Was widely used for labor, but replaced by epidural analgesia. • Action lasts for 2-3 hours. • Can be given orally, sc, im, iv. • Methadone & L  Acetyl Methadone (LAAM): • Same as morphine but has little of morphine’s euphoria. • Can substitute for morphine in the treatment of withdrawal reactions.

45. Opioid Agonists • d- Propoxyphene: • Weak analgesic. • Usually combined with paracetamole. • Slightly addictive. • Fentanyl: • Short acting. • Used IV for anesthetic induction. • Also used as a patch for terminal pain. • Tramadol: • New analgesic. • As powerful as meperidine. • Action extends for 6 hours. • Given orally and parenterally. • Addiction potential is low.

46. Opioid Antagonists • Naloxone: • No analgesic action. • Used for morphine poisoning. • Rapid and short action. • So, repeated doses may be needed. • Naltrexone: • Longer acting. • Used for treatment of dependence.