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ANALGESICS

ANALGESICS. Opioid/narcotic/morphine like Nonopiod /Non-narcotic /Aspirin like /Antipyretic or antiinflammatory analgesics. OPIOIDS. Opium: Pure active alkaline extract Papaver somniferum (Incision of the seed pod) :Serturner 1803 Opiates - products obtained from opium poppy

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ANALGESICS

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  1. ANALGESICS

  2. Opioid/narcotic/morphine like • Nonopiod /Non-narcotic /Aspirin like /Antipyretic or antiinflammatory analgesics

  3. OPIOIDS

  4. Opium: Pure active alkaline extract Papaver somniferum(Incision of the seed pod) :Serturner 1803 Opiates- products obtained from opium poppy Opioid – all naturally occuring, semisynthetic & synthetic drugs which has morphine like action • TWO TYPES • PHENANTHERE DERIVATIVES • MORPHINE (9-14%) • CODIENE (0.5-2%) ALKALOIDS IN OPIUM • THEBAINE (0.2-1%) • BENZOISOQUINIDINE DERIVATES • PAPAVARINE • NOSCARPINE • NARCINE

  5. OPIOID RECEPTORS(G Protein- coupled Receptors) • Mu (Mu1 > Mu2 -Morphine) • Mu1- Supra spinal Analgesia(A);Mu2 - Spinal A; • Respiratory Depression(RD); Constipation; Sedation; Euphoria; Miosis; Physical Dependence (Morphine type) • ANTAGONIST : Beta- funaltrexamine (irreversible) • Delta- Delta1, Delta2 (SPINAL) • A, RD, Affective behaviour, GI motility • Limbic area- Dependence & Reinforcing actions • ANTAGONIST : Naltrindole • Kappa- k1(Spinal), k2, k3(Supra Spinal) • Ketocyclazocine & Dynorphin A (High Affinity) • A, RD, Dysphoria, Miosis, Hallucinations • Sedation, Physical dependence (Nalorphine type) • ANTAGONIST : Norbinaltorphimine

  6. MoA at the RECEPTOR LEVEL Activation reduces cAMP formation & opens K channels or supresses voltage gated N type Ca channels =neuronal hyperpolarization & reduced availability of intracellular Ca = decreased neurotransmitter release by CNS and myenteric neurones

  7. RECEPTOR ACTIVITY OF REPRESENTATIVE OPIOID AGONISTS Mu Delta Kappa

  8. RECEPTOR ACTIVITY OF PARTIAL AGONIST- ANTAGONISTS Mu Delta Kappa

  9. ENDOGENOUS OPIOID • Released from our body in response to pain • 3 families of endogenous opioid released in body viz the enkephalines, endorphins & dynorphins

  10. Classification

  11. CNS EFFECTS • ANALGESIA • EUPHORIA • SEDATION • RESPIRATORY DEPRESSION • COUGH SUPPRESSION • MIOSIS • TRUNCAL RIGIDITY • NAUSEA & VOMITING

  12. PERIPHERAL EFFECTS • CVS • GIT • BILIARY • GUT • Urinary bladder • NEUROENDOCRINE (via Hypothalamus) • ADH, SOMATOTROPIN, PROLACTIN • LH, FSH, ACTH • MISCELLANEOUS • Histamineregic neurons • Immune Function

  13. CAUTIONS & CONTRAINDICATIONS • DON’T COMBINE PURE AGONIST WITH PARTIAL AGONIST – DIMINISHING ANALGESIA, WITHDRAWAL INDUCTION • HEADINJURIES-CO2-VASODILATION-ICP • PREGNANCY-APNOEA IN FOETUS • PULMONARY Fn IMPAIRMENT • ELDERLY MALES • ASTHMA

  14. DRUG ADMINISTRATION • MORPHINE • SC/ IM 10-15 mg q (3-5) hrs • IV 2-10 mg • Epidural injection 3-5 mg • 60 mg TOXIC • 250 mg FATAL • Half life - 2.5-3hrs ; 90% lost in 24 hrs

  15. INTERACTIONS WITH OTHER DRUGS • SEDATIVE – HYPNOTICS • CNS DEPRESSION ACCENTUATED • RESPIRATORY DEPRESSION • ANTIPSYCHOTIC TRANQUILIZERS • INCREASED SEDATION • CVS EFFECTS ARE INCREASED • MAO INHIBITORS • HYPERPYREXIC COMA • HYPERTENSION • RIGIDITY • EXCITATION

  16. DRUG TOXICITY & UNDESIRABLE EFFECTS • HYPOTENSION RESPIRATORY DEPRESSION • CONSTIPATION URINARY RETENTION • HYPERACTIVITY INTRACRANIAL PRESSURE • CONVULSIONS HYPOTHERMIA • TOLERANCE • PHYSICAL DEPENDENCE • PSYCHOLOGICAL DEPENDENCE

  17. DIAGNOSIS & TREATMENT OF OVERDOSAGE • DIAGNOSIS • ADDICT- NEEDLE MARKS- MIOSIS • COMATOSED (0.2-0.4 mg i.v. NALOXONE reverses coma) • TREATMENT • PRINCIPLE- ADEQUATE VENTILATION • 0.4-0.8 mg i.v. NALOXONE • REPEAT WHEN NECESSARY • NEW BORN- 5-25 ug /kg

  18. WITHDRAWAL • ABSTINENCE MANIFESTATIONS PERIOD • 6-12 hrs craving lethargy weakness • 12hrs yawning lacrimation tremors • 48 hrs fever BP HR pupil dilatation • 7-10 days insomnia back & leg pains • TREATMENT OF WITHDRAWAL • SUBSTITUTE WITH LONG ACTING ORALLY ACTIVE EQUIVALENT DRUG- METHADONE WHICH IS GRADUALLY WITHDRAWN

  19. Codeine It is methyl morphine Less potent than morphine More selective cough suppressant Analgesic action is mainly due to morphine It has good activity by oral route, acts for 4-6hrs Metabolized in liver & excreted in urine Constipation is prominent side effect Contraindicated in asthmatics

  20. Dose: 30 – 60 mg orally as analgesic 15 – 20 mg as antitussive Available as tab codeine sulfate & codeine phosphate 15-60mg

  21. Diacetylmorphine( heroin) 3 times more potent than morphine, more lipid soluble Rapidly hydrolyzed to 6-monoacetylmorphine  morphine Pharmacological action is due to 6MAM & morphine Excreted in urine as free & conjugate morphine

  22. Pethidine ( Meperidine ) • It was synthesized as an atropine substitute • Chemically unrelated to morphine, has similar action Pharmacological actions: CNS: analgesia, respiratory depression, • safer in asthmatics

  23. CVS: increases heart rate on i.v. Administration Effect on smooth muscle is less intense :miosis, constipation & urinary retention less prominant

  24. Pharmacokinetics: its absorbed by all routes, only 50%pass through first-pass metabolism, peak plasma value is reached in 1- 2 hrs 60% plasma protein bound Half time 3 hrs Metabolized mainly in liver & excreted in urine Dose: 50- 100 mg orally; children 1- 1.8 mg/ kg

  25. Side effects: similar to morphine, except that less constipating and urinary retention are less common Contraindications are same as other opioids Interactions: chlorpromazine increases therespiratory depression effects of pethidine. Phenobarbital or phenytoin increases systemic clearence With MAO inhibitors- tremors , mydriasis, delirium, convulsions

  26. Fentanyl • Its pethidine congener, 80 times more potent than morphine, both in respiratory depression & analgesia • Duration of action is short, t1/2 3-4 hrs • It is combined with droperidol as i.v anaesthetic • High doses cause muscular rigidity which can be blocked by naloxone Dose: 0.1mg

  27. Methadone Chemically dissimilar but pharmacologically similar to morphine Pharmacological action : effective analgesia, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals

  28. Pharmacokinetics: well absorbed from GIT Peak value reaches in about 4 hrs 90% plasma protein bound Metabolized in liver & excreted in urine Half life 1 to 1.5 days Side effects: long term administration produce excessive sweating, lymphocytosis &increased concentration of prolactin, albumin & globulins. Rifampin and phenytoin precipitate withdrawal symptoms

  29. Uses: To relief of pain, as substitution therapy for opioid dependence Dose: 2.5 to 10 mg oral or i.m. DOLOPHINE HCl Available as tab 5 & 10 mg

  30. Dextropropoxyphene It is chemically related to methadone but similar to codeine in analgesic and side effects, except less constipating It is nearly ½ as potent as codeine Metabolized in liver T ½ 4—12hrs The demethylated metabolite of propoxyphene is cardio toxic Acute intoxication produce respiratory and CNS depression It has been used as mild analgesic(60—120mg)

  31. Dose: 65mg DARVON, DOLENE Available as 32- 65mg capsules

  32. Tramadol:it is centrally acting analgesic • it inhibit reuptake of nor adrenaline and 5 HT and thus activate monoaminergic inhibition of pain . • oral bioavailability is good t ½ is 3 – 5 hours.it causes less respiratory depressions , sedation, constipation ,urinary retention and rise in intra-Biliary pressure than morphine. • Side effects: Dizziness, nausea, sleepiness,dry mouth, sweating and heamodynamic effects are minimal. • Indication: medium intensity short lasting pain. • Dosage : 50-100 mg oral or IM or slow IV infusion, • children 1-2 mg/kg

  33. CLINICAL USE • ANALGESIA • Severe cancer pain • Obstetric labour • ANAESTHESIA (Fentanyl) • Pre-medication & Neuroleptic (with Droperidol) • ACUTE LEFT VENTRICULAR FAILURE Reduced preload & afterload • COUGH • DIARRHOEA- diphenoxylate, loperamide • PREANAESTHETIC MEDICATION

  34. Agonists- antagonists nalorphine ,pentazocine, butorphanol • Partial /weak agonist buprenorphine • Pure antagonists naloxone, naltrexone, nalmefene

  35. PENTAZOCINE • It is a k receptor agonist& µ antagonist .20mg pentazocine=10mg morphine • Euphoria in low doses • Higher doses(>60mg –dysphoria may occur due to k receptor stimulation

  36. Inc bp& heart rate. • Dose:50-100mg oral,30-60mg IM • Postoperative & in burns, trauma, fracture ,cancer… • Adverse effects: • Sedation,seating,dizziness,nausea,dysphoria

  37. Buprenorphine • Lipid soluble, 25 times more potent than morphine • Slow onset & longer duration of action • Cancer pain, postoperative pain, MI, premedicatin

  38. OPIOID ANTAGONISM Naloxone • no analgesic activity • competitive antagonist at mu, kappa, and sigma receptor • displaces morphine and other OPIOID from receptor site • metabolized same as morphine through glucuronic acid and excreted through kidney • Morphine poisoning & for reversing neonatal asphyxia

  39. Naltrexone • More potent than naloxone • long duration of activity • single dose block action of heroin effects for 24 hours • patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement) • approved for use by the FDA • also used for treatment of alcoholism 

  40. DIAGNOSIS & TREATMENT OF OVERDOSAGE • DIAGNOSIS • ADDICT- NEEDLE MARKS- MIOSIS • COMATOSED (0.2-0.4 mg i.v. NALOXONE reverses coma) • TREATMENT • PRINCIPLE- ADEQUATE VENTILATION • 0.4-0.8 mg i.v. NALOXONE every 2-3min • REPEAT WHEN NECESSARY • NEW BORN- 5-25 ug /kg

  41. WITHDRAWAL • ABSTINENCE MANIFESTATIONS PERIOD • 6-12 hrs craving lethargy weakness • 12hrs yawning lacrimation tremors • 48 hrs fever BP HR pupil dilatation • 7-10 days insomnia back & leg pains • TREATMENT OF WITHDRAWAL • SUBSTITUTE WITH LONG ACTING ORALLY ACTIVE EQUIVALENT DRUG- METHADONE WHICH IS GRADUALLY WITHDRAWN

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