Analgesics2009

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Analgesics2009

  1. 1. Pharmacology ofAnalgesia
  2. 2. Opium is anarcotic formedfrom thelatex(juice)released bylacerating theimmature seedpods (fruits) ofPapaverPapaversomniferum.somniferum.Opium contains up to 12% morphine, an opiate alkaloid,which is most frequently processed chemically toproduce heroin for the illegal drug trade.Opioid AnalgesicsOpioid Analgesics
  3. 3. Opioid AnalgesicsOpioid Analgesicsµ- receptors are most important CNS contains opioid peptides –enkephalins, endorphins, dynorphins,orphanin/nociceptin Four receptors subtypes –µ, κ, ∂, N/OFQ(Gi-coupled - AC inhibition -decrease cAMP) Presynaptic and postsynaptic inhibition
  4. 4. OpioidOpioidsspharmpharmacologyacology
  5. 5. AnalgesiaAnalgesiaAn analgesicanalgesic (alsoknown as apainkiller) is anydrug used torelieve pain(achieve analgesia)
  6. 6. Tissue injurylead toactivation ofnociceptors(pain receptors)by differrentsubstancesreleased byinjured tissues.ThermalChemicalMechanicalElectricalActivated pain receptors generateimpulses that go into spinal cordthrough primary afferent neurons.
  7. 7. Opioid ReceptorsOpioid ReceptorsOpioid agonists inhibitthe release of excitatorytransmitters from theseprimary afferents, andthey directly inhibit thedorsal horn paintransmission neuron.Thus, opioids exert apowerful analgesiceffect directly on thespinal cord.
  8. 8. It is well established thatthe analgesic effects ofopioids arise from theirability to directly inhibitthe ascendingtransmission ofnociceptive informationfrom the spinal corddorsal horn and toactivate pain controlcircuits that descendfrom the midbrain to thespinal cord dorsal horn.
  9. 9. Morphine inhibits the release of:gonadotropin-releasing hormone (GnRH)corticotropin-releasing hormone (CRH) thus decreasing circulating concentrations ofluteinizing hormone (LH), follicle-stimulating hormone(FSH), ACTH, and b-endorphin;As a result plasma concentrations of testosterone andcortisol decline.
  10. 10. Convulsions• With most opioids, convulsions occur only at dosesfar in excess of those required to produce profoundanalgesia.• High doses of morphine and related opioids produceconvulsions
  11. 11. SedationDrowsiness and clouding of mentation arecommon effects of opioids. There is little orno amnesia. Sleep is induced by opioidsmore frequently in the elderly than inyoung, healthy individuals. Ordinarily, thepatient can be easily aroused from thissleep.
  12. 12. Respiratory depressionAll of the opioidanalgesics can producesignificant respiratorydepression by inhibitingbrainstem respiratorymechanisms acting onreceptors. Therespiratory depression isdose-related. Opioid-induced respiratorydepression remains oneof the most difficultclinical challenges in thetreatment of severe pain.
  13. 13. Cardiovascular systemMost opioids haveno significant directeffects on the heartand, other thanbradycardia, nomajor effects oncardiac rhythm.
  14. 14. Smooth muscles• Longitudinal relaxes• Circular constricts:- GI: peristalsis, constipation, cramping- GU: urinary retention- Bile duct : pressure(OA contraindicated- in biliary colic)- Pupils: miosis
  15. 15. Morphineand relatedopioids alsodepress thecough reflex atleast in part by adirect effect on acough center inthe medulla.
  16. 16. When we use OA for coughsuppression? Cough is due to foreign body inthe lungs Cough is due to lung cancer Cough is due to pleura irritationby broken ribs parts after trauma
  17. 17. The opioidanalgesics canactivate thebrainstemchemoreceptortrigger zone toproduce nauseaandvomiting(actionon dopaminereceptors)
  18. 18. Histamine releaseMorphine and some other opioidsprovoke release of histamine, whichsometimes plays a large role in thehypotension.
  19. 19. Morphine pharmacokinetics• Glucoronidation• Morphine-6-glucuronide is highly active• Caution in renal dysfunction
  20. 20. Type Drug name PropertiesFull agonist MepiridineMethadoneMorphineFentanyl subgroupLevorphanolAntimuscarinic action(atropine-like action), no miosis,tachycardia, no spasm of smooth muscles.Long half-life, use for maintenance of opiate addictsPartialagonistsCodeinePropoxypheneHydrocodoneAntitussiveAnalgesic in combination with NSAIDsand other drugs (Solpadeine)
  21. 21. Type Drug name PropertiesMixed opioidagonist-antagonistsNalbuphine k-agonist – spinal analgesia,dysphoriam – antagonist – precipitation ofwithdrawalAntagonists NaltrexoneNaloxoneNalmefeneIV, reversal of respiratorydepression, used in opiate addiction
  22. 22. Problems with opioid therapyProblems with opioid therapy1.1. Acute toxicity(classic triad):Acute toxicity(classic triad):- ComaComa- Pinpoint pupilsPinpoint pupils- Respiratory depressionRespiratory depressionManagement of acute toxicity:Management of acute toxicity:- SupportiveSupportive- IV naloxoneIV naloxone2.Tolerance(pharmakodynamic)2.Tolerance(pharmakodynamic) – decrease of drug efficiency over time withmultiple administrations. This is due to increased cAMP production in cells.Tolerance can be overcome by dose increasing . Marked tolerance may develop tothe analgesic, sedating, and respiratory depressant effects, but not to the miotic,convulsant, and constipating actions.3.Dependence3.Dependence(psychological and physical symptoms on withdrawal)
  23. 23. 4.Withdrawal:4.Withdrawal: sweating, lacrimation, rhinorrhea,anxiety, restlessness, insomnia, dilated pupils,tachycardia, hypertension, nausea/vomiting,abdominal pain, diarrhea,muscle aches.Opioid withdrawal is not life threatening. Emergenceof withdrawal symptoms varies with half-life of theparticular opioid; within 6-12 hours after the last doseof morphine/hydromorphone/oxycodone or 72-96hours following methadone. Duration and intensity ofwithdrawal symptoms can be variable and are relatedto clearance of the drug; withdrawal from morphine isshort (5-10 days) but more protracted withmethadone.
  24. 24. Management of withdrawal•Supportive•Clonidine•Methadone
  25. 25. Drug with specific actionLoperamide (Imodium) – antidiarrheal agentDextromethorphan – antitussive agentBoth are over-the-counter (OTC) drugs
  26. 26. NSAIDs• Non-steroidal anti-inflammatory drugs• NAIDs have analgesic, antipyretic and, in higher doses, anti-inflammatory effects• Term "non-steroidal" is used to distinguish these drugs fromsteroids, which have a similar anti-inflammatory action• NSAIDs are non-narcotic analgesics
  27. 27. BurnsChemical irritantsFrostbiteToxinsInfection by pathogensPhysical injuryImmune reactionsIonizing radiationForeign bodiesTissueInjuryActivation of thearachidonic acid cascadethrough membrane boundphospholipase A2 (PA2).
  28. 28. o Arachidonic acid is a polyunsaturated fatty acid that ispresent in the phospholipids of membranes of the bodyscells.o Enzyme phospholipase A2 (PLA2) release arachidonic acidfrom a phospholipid moleculePLA2Arachidonicacid
  29. 29. NSAIDsInhibition-vasoconstrictor- plateletaggregation.- inhibit plateletaggregation-vasodilation- gastric acid secretion↓- gastric mucus↑secretion- hyperalgesia- pyrogenic
  30. 30. COX-1 is expressed in most tissues including platelets andGICOX-2 is inducible; is expressed in brain, kidney and in sitesof inflamation.COX-1 generates prostanoids for "housekeeping" such asgastric epithelial cytoprotection,COX-2 is the major source of prostanoids in inflammationand cancer.This distinction is overly simplistic, however; thereare both physiologic and pathophysiologic processes inwhich each enzyme is uniquely involved and others in whichthey function coordinately. For example, endothelial COX-2is the primary source of vascular prostacyclin (PGI2),whereas renal COX-2-derived prostanoids are important fornormal renal development and maintenance of function.
  31. 31. COX-1- selective Non-selectiveCOX-1,2COX-2- selective- Low-doseaspirin- (up to 325 mgper day),- 75 mg astherapeuticagent for MIpreventionAll other:-Indomethacin-Ibuprophen-Naproxen-Diclofenac-Ketorolac-Piroxicam-MeloxicamCOXIBs:-rofecoxib-celecoxib-lumaricoxib-parecoxib-valdecoxib-etoricoxibNimesulide
  32. 32. 1)Antipyretic2)Analgesic3)Anti-inflammatoryAll NSAIDs, including selective COX-2 inhibitors, are antipyretic,analgesic, and antiinflammatory, with the exception ofacetaminophen(paracetamol), which is antipyretic and analgesic but is largelydevoid of antiinflammatory activity.
  33. 33. • Alleviate pain of low-to-moderate activity• Have no opioid-like effects on CNS• Pain arising from inflammation is controlled particularly well byNSAIDs• Effective for menstrual pain• Lower body temperature by inhibiting PGE2 synthesis inhypothalamic thermo regulating centers• Do not lower normal body temperature
  34. 34. Antiplatelet action Most notable for aspirin.Unlike other agents Aspirin isirreversible inhibitor ofCOX(COX should beresynthesized)No nucleus– no new COXsynthesis – no newTXA2- no plateletactivation- no thrombusformation
  35. 35. Acetaminophen(Tylenol,Panadol)• No inhibition of COX in peripheral tissues• Lack of significant anti-inflammatory action• Analgesic and antipyretic activity due to COX inhibition in CNS• No antiplatelet action• Not increase bleeding• Not cause Reye syndrime• Minimal GI distressAdverse effectsHepatotoxicity in high dose
  36. 36. Adverse effects are generallyquite similar for all of theNSAIDs:Central nervous system: Headaches, tinnitus(aspirin), and dizziness.Cardiovascular: Fluid retention hypertension, edema, and rarely,congestive heart failure.Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, andulcers or bleeding.(2,5% incidence in clinical trials)Hematologic: Rare thrombocytopenia, neutropenia, or even aplasticanemia.Hepatic: Abnormal liver function tests and rare liver failure.Pulmonary: Asthma.Rashes: All types, pruritus.Renal: Renal insufficiency, renal failure, hyperkalemia, andproteinuria.
  37. 37. Coxibs controversy• Rofecoxib and valdecoxib was withdrawn from themarket because of increased cardiovascularmortality in chronic drug users• Overall mortality was higher in patients on coxibs inclinical trials
  38. 38. NSAIDs cannot be used (arecontraindicated) in the followingcases:• Allergy to aspirin or any NSAID• Aspirin should not be used under the age of 16 years (associatedwith Reye syndrome)• During pregnancy• During breast feeding• On blood thinning agents (anticoagulants)• Suffering from a defect of the blood clotting system (coagulation)• Active peptic ulcer
  39. 39. 1)Salicylates Salicylic acidAspirin(ASA)Methyl salicylateSalsalateDiflunisalOlsalazineSulfasalazine.5)Heteroayl acetic acidderivativesTolmetinKetorolacDiclofenac2)Para-aminophenolderivativesAcetaminophen(paracetamol)6)Propionic acidderivativesIbuprofenNaproxenFenoprofenFlurbiprofenKetoprofen3)Acetic acidderivatesIndomethacinSulindacEtodolac6)Enolic acid derivates(oxicams)PiroxicamMeloxicamLornoxicamothers4)Fenamates Mefenamic acidFlufanamic acidMeclofenamic acid7)Pyrazolon derivatives AnalgineAntipyrinePhenybutazone

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