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    Opioids 100613013235-phpapp02 Opioids 100613013235-phpapp02 Presentation Transcript

    • OPIOIDSDR CHANDRA SEKHAR BEHERAPG 2ND YEAR ANAESTHESIOLOGYThe Magic within The Flower of JoyOpium poppies are white flowers that thrive inthe dry, warmclimate of southern Asia. This field was grownforpharmaceutical purposes.Saturday, June 15, 2013 1DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OPIUMSource plant(s) Papaver somniferumPart(s) of plant sapGeographic origin Indochina RegionActive ingredients Morphine, CodeineMain producers Afghanistan (primary), Northern India, Thailand, Laos, Myanmar, Mexico, Colombia, HungaryMain consumers worldwide (#1: U.S.)Wholesale price $3,000 per kilogramRetail price $16,000 per kilogramSaturday, June 15, 2013 2DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HISTORYfirst undisputed reference to "poppy juice" is found in the writings of Theophrastus in thethird century B.C.opium derived from the Greek word for "juice"obtained from the poppy Papaver sominiferumArabian physicians were well versed in its uses and introduced the plant to the OrientParacelsus, circa 1500, repopularised the drug in Europe, where it had fallen out of favordue to toxicity18th century opium smoking became popular in the Orient and its availability in Europe ledto considerable abuseSaturday, June 15, 2013 3DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HISTORYopium containsmore than 20alkaloids1806, Sertürnerisolated a puresubstance inopium, which henamed morphine•after Morpheus, theGreek god of dreamsisolation of otheralkaloids soonfollowed•codeine in 1832 andpapaverine in 1848by the middle of the19th century, use ofthe pure alkaloidsrather than crudeopium wasbecomingwidespreadSaturday, June 15, 2013 4DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HISTORYproblems of widespread addiction ledto the search for a morphine antagonistin 1951 nalorphine was used in the RX ofmorphine overdoseat the same time, the analgesic effectsstimulated the development of anumber of new drugs; includingnaloxone, pentazocine, butorphanol etc.Saturday, June 15, 2013 5DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HISTORYresearchers concluded that the interactions and differences between morphine and itsderivatives could only be explained by the existence of more than one receptor type® receptor dualism(Martin 1967)1973 : 3 groups of workers described saturable, stereospecific binding sites (followingwork by Goldstein)1975 : the enkephalins were isolated from pig brainsince then researchers have shown that there are three distinct families of endogenousopioid peptides and multiple categories of opioid receptorsSaturday, June 15, 2013 6DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • INTRODUCTIONAll natural and semi synthetic opium alkaloid derivativessynthetic agents and other drug whose upload-like effects areblocked by naloxone-non selective opioid receptor antagonistSOURCE-Opium poppyCONSTITUENTS-Analgesic components-Morhine,codeine,ThebaineNonanalgesic component-papaverineSaturday, June 15, 2013 7DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CLASSIFICATIONSClassificationNatural Alkaloids of Opiumphenanthrenes morphine, codeine, thebainebenzylisoquinolines papaverine, noscapineSemi-synthetic Derivatives diacetylmorphine (heroin)hydromorphone, oxymorphonehydrocodone, oxycodoneSynthetic Derivativesphenylpiperidines pethidine, fentanyl, alfentanyl, sufentnylbenzmorphans pentazocine, phenazocine, cyclazocinepropionanilides methadonemorphinans levorphanolSaturday, June 15, 2013 8DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ENDOGENOUS OPIOIDSEndogenous OpioidsEndogenousPeptidesMet-enkephalinLeu-enkephalin- EndorphinDynorphin A ??Dynorphin B ??-Neoendorphin ??Saturday, June 15, 2013 9DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ENDORPHINShighest concentrations of b-endorphin occurin• pituitary gland• basal, medial, and arcuate regions of the hypothalamus• long axoned neurons which synapse in theseptum, periaqueductal grey and thalamic regions ofthe midbrainunclear whether b-endorphin existsfunctionally in the spinal cord
    • ENKEPHALLINSwidely distributed throughout the CNS,• limbic system (amygdaloid & septal nuclei)• medial thalamic nuclei• periaqueductal grey matter & midline reticular formation in the midbrain• the periventricular grey areas in the medulla• laminae I, II & IV of the spinal cord (substantia gelatinosa)• the area postrema (CTZ)NB: all of which are involved in the reception of afferentnociceptive informationSaturday, June 15, 2013 11DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • STRUCTURE ACTIVITYcomplex structures usually with a number of opticalisomers, of which only the l-isomer is most activestructural similarities within this class include,• structure conforms to a "T-shape"• a tertiary, positively charged basic nitrogen• a quaternary carbon, C13 in morphine,• separated from the basic N by an ethane (-CH2-CH2-) chain• attached to a phenyl group (phenol, ketone)• presence of an aromatic ring• centre is 0.455 nm from the nitrogen atomSaturday, June 15, 2013 12DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • Structure - TSaturday, June 15, 2013 13DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • MORPHINESaturday, June 15, 2013 14DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • Schematic of Presynaptic OpiateactionSaturday, June 15, 2013 15DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RECEPTORSType Effects Agonist Antagonist1SupraspinalanalgesiaMiosisEuphoriaAbusepotentialMorphineNaloxonePentazocinenaltrexone2BradycardiaRespiratorydepressionGIT motilityAs above As aboveSaturday, June 15, 2013 16DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RECEPTORSReceptorsType Effects Agonist AntagonistKappaSpinalanalgesiaPentazocine NaloxoneSedation ketacycline NaloxoneDeltaSpinalanalgesiaPentazocine NaloxoneDysphoria D-leu-enkephalin ?Sigma Mydriasis ?ketamine ?HallucinationsN-allylnormethazocine?Saturday, June 15, 2013 17DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OPIOID RECEPTORSMu (morphine) MOP OP3Delta DOP OP1Kappa KOP OP2Nociceptin orphaninFQ NOP orphanSaturday, June 15, 2013 18DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RECEPTOR ACTIVITYthe actions of opioids are generally described withreference to only 3 types of receptors• ® µ, k, & don the basis of these receptors, drugs can bedivided into 4 groups,• agonists• antagonists• agonist-antagonists• partial agonistsSaturday, June 15, 2013 19DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • TERMINOLOGYPURE AGONIST-Hasaffinity for binding plusefficacyPURE ANTAGONIST-Hasaffinity for binding butno efficacy blocks actionof exogenous andendogenous ligandsMIXED AGONIST-ANTAGONIST-Producesagonist effect at onereceptor and antagonisteffect on anotherPARTIAL AGONIST-Hasaffinity for binding butlow efficacySaturday, June 15, 2013 20DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CLASSIFICATIONAGONISTmorphinePARTIALAGONISTbuprenorphinePUREANTAGONISTnaloxoneMIXED AGONISTANTAGONISTnalbuphineSaturday, June 15, 2013 21DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PARTIAL AGONISTSdrugs that produce a less thanmaximal responseand, therefore, have a lowintrinsic activity are called partialagoniststhese display certainpharmacological features,•the slope of the dose-response curve isless than that of a full agonist•the dose response curve exhibits a ceilingwith the maximal response below thatobtainable by a full agonist•partial agonists are able to antagonisethe effects of large doses of full agonistsSaturday, June 15, 2013 22DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PARTIAL AGONISTSNB: this is aschematicrepresentation toillustrate thedifferential effects ofvarious opioid agents;the actual interactionsresponsible foragonist / partialagonist activity areuncertainSaturday, June 15, 2013 23DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • AGONISTSSaturday, June 15, 2013 24DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ANTAGONISTSSaturday, June 15, 2013 25DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • AGONISTS - ANTAGONISTSSaturday, June 15, 2013 26DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ANALGESIAµ-receptors are located on the terminal axons of primaryafferents within laminae I & II (substantia gelatinosa) of thespinal cord (+ spinal nucleus of the trigeminal nerve)• decrease the presynaptic release of neurotransmitters, predominantlysubstance Penkephalinergic interneurones in the dorsal horn arepredominantly inhibitory to the soma of cells in the deeperlaminae IV & V• morphine is inactive at these sites• met-ENK, a d-receptor agonist inhibits neuronal firing• both µ & d receptors inhibit spinal transmission of painSaturday, June 15, 2013 27DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ANALGESIAstimulation of pain fibres activates enkephalinergic neurones inthe spinal cord, which play a role in the "gating" of pain and inmediating the effect of descending medullary analgesic pathwaysfurther modulation of nociception involves the periventricular andperiaqueductal grey matter• direct microinjections of morphine, or electrical stimulation produce analgesiawhich can be blocked by naloxone• stimulation at this level results in barrages of impulses travelling in descendingpathways to the dorsal horns of the spinal cordSaturday, June 15, 2013 28DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • AGE EFFECTSradioligand-receptor studies have shown amarked and widespread reduction in mu anddelta receptor densities with agethis work supports clinical studies whichshow a far greater correlation between doserequirements and age, cf. body weightthis is a specific effect, as similar studiesshow an increase in benzodiazepinereceptorsSaturday, June 15, 2013 29DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PHARMACODYNAMICS“What the drug does to the body”This means:• Receptor and cellular levelAnd..• Organ system effects• Such as• CVS• CNS• Resp• GIT• Genitourinary• Placenta/Foetus• etcSaturday, June 15, 2013 30DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CNSEEGSSEP’SPUPILSCTZCEREBRALMETABOLICRATEMUSCLERIGIDITYSaturday, June 15, 2013 31DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CNSEEG•High voltage,slow deltawavesSSEP’s• velocityandamplitudePupils•MiosisCTZ•N & V withhelp fromvestibularnucleusSaturday, June 15, 2013 32DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CNS•10-25% reduction•Little change toCBFCMRSaturday, June 15, 2013 33DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CNSPruritisSaturday, June 15, 2013 34DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OTHER CNS EFFECTS•nausea & vomiting•direct stimulation of the CTZ in the area postrema of themedulla•also stimulated by apomorphine, a dopaminergic agonist•may RX with phenothiazines which posses a dominantdopamine-blocking action•up to 15-40% of ambulatory patients, may be a vestibularcomponent•miosis•caused by most mu & kappa receptor agonists•stimulation of the Edinger-Westphal nucleus•pinpoint pupils being pathognomic of opioid overdose2importantexcitatoryeffectsinclude,Saturday, June 15, 2013 35DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • MUSCLE RIGIDITYhigh doses may produce rigidity, characterised by increasingmuscle tone progressing to severe stiffness, particularly inthe thoracic and abdominal musclesappears to be a higher incidence with• large boluses and rapid infusions• the elderly• concomitant use of N2O• with alfentanylSaturday, June 15, 2013 36DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CEREBRAL BLOOD FLOWthe opioids generally produce a modest (~ 10-15%)decrease in CMRO2 and ICPin contrast to the volatile agents they are cerebralvasoconstrictorsthis occurs even in the presence of nitrous oxideGuy Ludbrook thinks they uncouple CBF & CMRO2Saturday, June 15, 2013 37DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CEREBRAL BLOOD FLOWmorphine 1-3 mg/kg + 70% N2O• insignificant changes in CBF and CMRO2fentanyl 100 µg/kg + 70% N2O• dose related decreases in,• CBF to a maximum of 50%• CMRO2 to a maximum of 35%similar changes seen with sufentanyl and alfentanylall of these agents decrease CSF formation while not affecting reabsorptionSaturday, June 15, 2013 38DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CVSHYPOTENSIONBRADYCARDIASaturday, June 15, 2013 39DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CVS EFFECTSmorphine & related opioids produce minimaleffects in normal supine subjectshowever they do produce,• peripheral vascular dilation• reduced peripheral resistance• depression of the baroreceptor reflexes® postural hypotension in erect subjectsSaturday, June 15, 2013 40DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CVS EFFECTSthese effects are produced by a numberof mechanisms,• release of histamine• a direct centrally mediated reduction insympathetic tone - reversed by naloxone• a vagal induced bradycardia• direct and indirect (PaCO2) mediated vasodilatation• splanchnic sequestration of bloodSaturday, June 15, 2013 41DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • CVS:BRADYCARDIAall µ-receptor agonists (except pethidine) HRrisk of bradycardia / asystole on induction,• Ca++-channel, or b-adrenergic blockers• concomitant use of benzodiazepines• muscle relaxants without vagolytic properties (vecuronium)• muscle relaxants with vagotonic properties (succinylcholine)• vagal stimuli (laryngoscopy)• rapid administration of the opioidSaturday, June 15, 2013 42DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RESPIRATORYCO2 RESPONSE CURVEHYPOXIC DRIVECOUGHSaturday, June 15, 2013 43DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RESPIRATORYall µ-receptor agonistsdose dependent depressionof respiration,• brainstem sensitivity to CO2• slope of the CO2-ventilation response curve• apnoeic threshold• hypoxic drive to respiration•carotid body chemoreception is virtuallyabolished• pontine & medullary centres involved inrhythmic respirationthey do not affect hypoxic pulmonaryvasoconstrictionSaturday, June 15, 2013 44DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • RESPIRATORYdelayed respiratory depression has been reported withmost of the opioids• morphine, pethidine, fentanyl, alfentanyl, and sufentanylexact cause is unclear, possibly• secondary plasma drug peaks• sequestration of ~ 20% of fentanyl in the stomach• large peripheral storage compartments (skeletal muscle)• supplemental analgesics and other medications• lack of nociceptive stimulationSaturday, June 15, 2013 45DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • FACTORS INCREASING RESPIRATORYDEPRESSIONFactors Increasing Opioid Respiratory DepressionIncreasing doseIntermittent bolus vs. continuous infusionIncreased brain penetration, or drug deliverydecreased distribution, low COincreased unionised fraction (respiratory alkalosis)Decreased reuptake from the brain (respiratory alkalosis)Decreased drug clearancedecreased liver blood flow (abdominal surgery)intrinsic liver diseaseSecondary plasma drug peaksperipheral storage compartments, lung, fat, musclesequestration in the stomachIncreased ionised fraction at the receptor site (respiratory acidosis)SleepIncreasing age ( 60 yrs) and neonatesMetabolic alkalosisFactors Increasing Opioid Respiratory DepressionIncreasing doseIntermittent bolus vs. continuous infusionIncreased brain penetration, or drug deliverydecreased distribution, low COincreased unionised fraction (respiratory alkalosis)Decreased reuptake from the brain (respiratory alkalosis)Decreased drug clearancedecreased liver blood flow (abdominal surgery)intrinsic liver diseaseSecondary plasma drug peaksperipheral storage compartments, lung, fat, musclesequestration in the stomachIncreased ionised fraction at the receptor site (respiratory acidosis)SleepIncreasing age ( 60 yrs) and neonatesMetabolic alkalosisSaturday, June 15, 2013 46DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • GITSTOMACHSMALL INTESTINELARGE INTESTINEthe net effect is to decrease motilitySaturday, June 15, 2013 47DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • GUTINCREASED TONEURINARY RETENTIONSaturday, June 15, 2013 48DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • NEUROENDOCRINEGenerally decreses the responsivness of the hypothalamuscausing Decrese in tempDecrease relese of GnRHIncrese in GH & ProlactinMay give rise to mild drug induced SIADHSaturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE49
    • Toleranceresult from uncoupling of the drug-receptor effect• decrease in the number of receptors• reduction of their affinity for a given agonist, and• subcellular uncoupling of the receptor and second messengerthere is little cross-tolerance between different receptorgroupshigh affinity agonists, ie. those with the greatestreceptor reserve, produce least toleranceSaturday, June 15, 2013 50DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • TOLERANCE TO OPIOIDSComponents of different types of tolerance may be presentSome effects of opioids are more susceptible to tolerance thanothers:Rapidly occurring:• Nausea and vomiting• Sedation• Euphoria• Respiratory depressionLess affected by tolerance:• Constipation• MiosisSaturday, June 15, 2013 51DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PHARMACOKINETICSRemember this means:• Absorption• Bioavailability• Distribution• Protein Binding• Metabolism• t½• Metabolites• ExcretionSaturday, June 15, 2013 52DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • IMPORTENCE OF KINETICS INOPIOIDSQuestions regarding infusions, repeat dosing, context sensitive half-life, onset times, etc relate to the individual drugs and their kineticsLipid solubility allows access across biological membranes (includingBBB). Tends to result in faster effect-site equilibration.pKa important – opioids are weak bases. A lower pKa means a higherproportion of drug is unionised (or in its lipid soluble form)High plasma protein binding restricts volume of distributionSaturday, June 15, 2013 53DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • IDEAL KINETICS FOR OPIOIDINFUSIONIdeal properties:•Short elimination half life•Offset by metabolism or excretion, notredistribution•No active metabolites•Tight concentration – effect relationshipSaturday, June 15, 2013 54DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PHARMACOKINETIC PROPERTIES OFOPIOIDSPharmacokinetic DataAgent Morphine Pethidine Fentanyl Alfentanyl SufentanylpKa 8.0 8.5 8.4 6.5 8.0% Unionized 23% < 10% < 10% 90% 20%Octanol:H2O1.4 39 813 145 1778t½(min) 1.0-2.5 1-2 1-3 1-2t½(min) 10-20 5-15 10-30 4-17 15-20t½(hrs) 2-4 3-5 2-4 1-2 2-3VdSS(l/kg) 3-5 3-5 3-5 0.4-1.0 2.5-3.0Cl (ml/kg/m) 15-30 8-18 10-20 4-9 10-15ER 0.8-1.0 0.7-0.9 0.8-1.0 0.3-0.5 0.7-0.9Saturday, June 15, 2013 55DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • MORPHINESaturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE56
    • MORPHINE• Poor lipid solubility and vd-3-5l/kg• Conversion of phamacologicaly activemetabolite m6g• Slow onset and prolong duration• Pka-8.0 ,• % unionised at pH-7.4-23• %plasma protein binding-35• Clearance-15-30ml/min/kgSaturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE57
    • INDICATIONS• Morphine can be used as an analgesic in hospital settings to relieve:– pain in myocardial infarction– pain in sickle cell crisis– pain associated with surgical conditions, pre- and postoperatively– pain associated with trauma– severe chronic pain, e.g., cancer– pain from kidney stones (renal colic, ureterolithiasis)– severe back pain• Morphine can also be used:– as an adjunct to general anesthesia– in epidural anesthesia or intrathecal analgesia– for palliative care (i.e., to alleviate pain without curing the underlying reason for it, usuallybecause the latter is found impossible)– as an antitussive for severe cough– as an antidiarrheal in chronic conditions (e.g., for diarrhea associated with AIDS, althoughloperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioidfor diarrhea).Saturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE58
    • CONTRADICTIONS• The following conditions are relative contraindications formorphine:• acute respiratory depression• renal failure (due to accumulation of the metabolitesmorphine-3-glucuronide and morphine-6-glucuronide)• chemical toxicity (potentially lethal in low tolerancesubjects)• raised intracranial pressure, including head injury (risk ofworsening respiratory depression)• Biliary colic.• Although it has previously been thought that morphine wascontraindicated in acute pancreatitis, a review of theliterature shows no evidence for this.Saturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE59
    • CODEINEAbout1/10th thepotency ofmorphinelowerefficacy thanmorphineabout 10%converted tomorphine byCYP450 2D610% ofpatients donot possessthis enzymeSaturday, June 15, 2013 60DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HEROINCrosses blood-brain barriermore rapidly than morphine2-4 X greater potency thanmorphineConverted to morphineSaturday, June 15, 2013 61DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HYDROMORPHONEAbout 8-10X potency ofmorphineSlightly shorter durationthan morphineavailable as suppositorySaturday, June 15, 2013 62DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OXYMORPHONESame ashydromorphoneSaturday, June 15, 2013 63DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OXYCODEINEAbout 10X potency of codeineAlso metabolized by CYP450-2D6Controlled release formulation(OxyContin)Saturday, June 15, 2013 64DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • HYDROCODONE ANDDIHYDROCODEINESame as oxycodoneSaturday, June 15, 2013 65DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PARTIAL AGONIST-BUPRENORPHINEPartial agonist atmu receptorsPartial agonist atkappa3 receptorsAntagonist atkappa1 receptorsLower efficacyanalgesic thanmorphineSlow dissociationfrom receptorhence naloxoneresistentSaturday, June 15, 2013 66DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • SYNTHETIC COMPOUNDMeperidineFentanyl, Sufentanyl, AlfentanylRemifentanylMethadone ,tramadol L-α-acetyl-methadol: LAAMSaturday, June 15, 2013 67DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • MEPERIDINEAbout 1/8th potency of morphineshorter durationfewer smooth muscle spasms thanmorphineNo meiosisbiotransformed to a toxic metabolitethat builds up and can cause seizures.Synergistic with Gila monster venomSaturday, June 15, 2013 68DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • FENTANYL80 - 100 xpotency ofmorphinefastonset, shortdurationused i.v. foranesthesiaavailable aspatchavailable asoral slowreleasedevice.Saturday, June 15, 2013 69DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • USES• Extensivly used for anaesthesia and analgesia inboth operating room and ICUsettings• Used with benzodiazepines and midazolam inendoscopic procedure,cardiaccatheterisation, oral surgeries• Widely used as tansdermal patches to alleviatepain like in cancer• Fentanyl given in intrathecaly as spinalanaesthesia and epiduraly as epidural anaesthsiaand anagesiaSaturday, June 15, 2013DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE70
    • SULFENTANILExteremly lipid soluble-rapid effect site equilibration andrapid redistribution of the drug leading to termination ofeffectHigh plasma protein binding lead to less Vd than fentanylAccumulate in prolong infusion become longer thanalfentnyl at 8 hrsSaturday, June 15, 2013 71DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ALFENTNILLow pKa-very fast equilibaration time with CNS because bulk ofdrug in unionised form &cross BBB even though not lipid solubleas other fentanyl congenersLow Vd-due to low lipid solubility and high proteinbinding.Redistribution is not a significant in offset-requiresmetabolism.this explains longer CSHT than sulfentanil until 8 hrsMetabolised by cyt p450 3A4-Inducible and explains variabilityseenSaturday, June 15, 2013 72DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • REMIFENTANILHighly unionised-rapid onset of effectRapid clearance and small Vd-effect terminated by eliminationMetabolite GR90291 has only 1/4600 th activity –unlikely to produceeffect after infusionTight concentration-effect relationshipVery well suited for infusionSaturday, June 15, 2013 73DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • METHADONEPotency similar to morphine for i.v.administration, but 4 x more potentorallylong plasma half-lifeused in treatment of narcoticdependenceDuration of action increases withrepeated useSaturday, June 15, 2013 74DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • LAAMExtremely long plasmahalf-life (>72 hr)Suppresses opiatewithdrawal for 4-5 daysSaturday, June 15, 2013 75DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • TRAMADOLThese actionsare synergisticfor analgesiaα-2adrenoceptoragonistNE and 5-HTreuptakeblocker(antidepressant)Opioid receptoragonist (mu anddelta)Saturday, June 15, 2013 76DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ANTAGONISTSNaloxone Naltrexone NalmefeneSaturday, June 15, 2013 77DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • SIGNS OF OVERDOSEStuporousor incomaRespiratoryrateextremelylowpinpointpupilslow bodytemperatureflacid skeletalmuscles, jawrelaxedSaturday, June 15, 2013 78DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • NALOXONEno analgesic activity at allcompetitive antagonist at mu, kappa, and sigma receptordisplaces morphine and other OPIOID from receptor sitereverses all actions of the OPIOID and does it rather quicklyit will precipitate withdrawalincreased blood pressuremetabolized same as morphine through glucuronic acid and excreted throughkidney
    • NALTREXONELong half-lifeeffectiveorally orinjectedavailable inoral formonlyused fortreatment ofdependenceSaturday, June 15, 2013 80DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • NALMEFENEIntermediateduration (4-6 hr)orally activeno hepatotoxicitywith long term useSaturday, June 15, 2013 81DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • MIXED AGONIST ANTAGONISTNalorphine andcyclazocinePentazocine:Talwin NXButorphanolNalbuphineSaturday, June 15, 2013 82DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • NALORPHIN AND CYCLOZOCINEKappa3 receptoragonistsMu receptorantagonistsproducepsychotomimeticeffectsproducedysphoriaSaturday, June 15, 2013 83DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PENTAZOCINEKappa and delta agonistNon addictive and non euphoricHas ceilling effectSaturday, June 15, 2013 84DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • BUTORPHANOLKappa receptor agonistMu receptorantagonistAvailable as nasal sprayanalgesic eq tobuprenorhine andnalbuphine5 X morepotent inwomen thanmenSaturday, June 15, 2013 85DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • NALBUPHINEKappareceptoragonistMu receptorantagonistLittledysphoriacompared tonalorphineLess abusepotentialthanmorphineSaturday, June 15, 2013 86DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • DEPENDENCE AND ADDICTIONDependence: The propensityto experience an abstinencesyndrome afterdiscontinuation of a drug, oradministration of anantagonist drug. May beginto develop from 1-2 weekswith several doses/day.Addiction: A chroniccondition, characterised bythe compulsive use of asubstance resultant in harm(physical, psychological orsocial) and continued usedespite that harmSaturday, June 15, 2013 87DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • WITHDRAWALThe time course is a function of the elimination half-life of the opioidSymptoms will appear within 6 to 12 hours and reach a peak at 24 to72 hours following cessation of a short half-life drug such asmorphine36 to 48 hours with methadone, a long half-life drug.The daily dose required to prevent withdrawal, when ceasing isapproximately one fourth of the previous dose.Saturday, June 15, 2013 88DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • WITHDRAWALThe onset is characterized by feelings of anxiety, nervousness and irritabilitychills and hot flushes."wetness" including salivation, lacrimation, rhinorrhea and diaphoresispiloerection.At the peak, nausea, vomiting, abdominal cramps, insomniaand, rarely, multifocal myoclonus.
    • OPIOID ANAESTHESIAconsiderable debate as to whether opioids in their own rightproduce anaesthesiato date there is no study showing that opioids alone, withoutmuscle relaxants or other supplementation, will reliablyproduce anaesthesia in humansmost studies assess the reductions in volatile MAC in animalmodels, demonstrating a ceiling effect which issubanaestheticSaturday, June 15, 2013 90DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OPIOID ANAESTHESIAthe problems with these studies include,• the profile of action of opioids varies considerably withanimal species, thus extrapolation to humans is not readilyachieved• as inhibition of motor responses occur at deeper levels ofanaesthesia than unconsciousness, amnesia and analgesia,methods requiring motor responses, eg. tail clampstudies, underestimate opioid effect• volatile agents inhibit descending inhibitory pain pathwaysactivated by the opioids, therefore may decrease theeffectiveness of the opioidsSaturday, June 15, 2013 91DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • ANAESTHESIApresumed specific action of the opioids would not be expected toproduce anaesthesiapostulated that the analgesia produced at subanaestheticconcentrations and the unconsciousness produced at higher levelsmay be mediated by different processesdual mechanism hypothesis requires that in addition to thereceptor mediated effects, an opioid must be lipid soluble enoughto act as a general anaesthetic• a biphasic response has been noted for fentanyl and sufentanyl
    • ANAESTHETIC TECNIQUES USINGOPIOIDSANALGESIASEDATIONBALANCED ANAESTHESIANEUROLEPTANALGESIA-NEUROLEPTANAESTHESIATIVAOPIOID BASED ANAESTHESIA IN CARDIAC SURGERIESSaturday, June 15, 2013 93DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PCADrug Age Lockout Concentration18-40 yrs 40-70 yrs >70 yrs (mins)Morphine 1.5-2 mgs 1 mg 0.5mgs 5 1 mg/mlPethidine 15-20 mgs 10 mgs 5 mgs 5 10 mg/mlFentanyl 15-20mcgs10 mcgs 5 mcgs 5 10 mgs/mlTramadol 15-20mcgs10 mgs 5 mgs 5 10 mgs/mlSaturday, June 15, 2013 94DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PCANausea 40-90%Vomiting 8-40%PruritisSedationSaturday, June 15, 2013 95DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • PCARespiratory depressionUrinary retentionMyoclonus (high doses)ConstipationSaturday, June 15, 2013 96DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • OPIOID PATHWAYopioid paininhibitionoccurs atmultiple levels• spinal cord• brain-stem• thalamusSaturday, June 15, 2013 97DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE
    • Saturday, June 15, 2013 98DEPT OF ANAESTHESIA MKCG MEDICALCOLLEGE