inhalationalagent.ppt

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1、inhalational agent Historical Development of inhalational agent Pharmacology of inhalational agent 3. Mechanisms of inhalational agent 4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Anaethetics 5. Sevoflurane is Best Volatile Anesthetic ever developedHistorical Developmentnunlucky;

2、rough 充满坎坷充满坎坷nintense emotion充满激情充满激情njoys and sorrows，partings and reunions-vicissitndes of life悲欢离合悲欢离合To finish operation Pressing patient Shortening time Drinking alcoholic beverages Bleeding Boxing lower jaw 外科手术犹如酷刑，因此病人宁愿去死，也不外科手术犹如酷刑，因此病人宁愿去死，也不愿接受外科手术治疗愿接受外科手术治疗当年截肢手术时使用的工具当年截肢手术时使用的工具Dec.

3、 10th, 1844Laughing, Sing, Dance, Speak or Fight当天晚会上发生的一件事触动了牙医当天晚会上发生的一件事触动了牙医Horace Wells ( 1815 - 1848)Sam Cooley在笑气的作用在笑气的作用下受伤了下受伤了John M Riggs帮助帮助Wells拔掉了龋齿拔掉了龋齿Wells清醒后的第一句话是：清醒后的第一句话是：A new era in tooth pulling!Wells兴冲冲找到兴冲冲找到John C. WarrenJan. 10th, 1845面对面对Wells的失败，人们不禁想起的失败，人们不禁想起几年前著名的外

4、科医生几年前著名的外科医生Velpeau的的“著名著名”论断：论断：Eviter la douleur dans les operations est une chimere quil nest pas permis de poursuivre aujourdhui. Instruments trachants et douleur, en medecine operatoire, sont deux mots qui ne se presentent point Iun sans Iautre a Iesprit des malades, et dont il faut necessaire

5、ment admettre Iassociation 外科手术必然伴随着疼痛，任何寻找外科手术必然伴随着疼痛，任何寻找解决外科手术疼痛的努力均是徒劳的解决外科手术疼痛的努力均是徒劳的不久，不久， Velpeau的预言就被打破了的预言就被打破了打破打破Velpeau预言的预言的是另一位牙科医生，他是另一位牙科医生，他的名字已经被永久地载的名字已经被永久地载入了世界医学发展史入了世界医学发展史WilliamT.G. Morton Oct,16,1846 William Thomas Green Morton Ether Demonstrating Massachusetts General Hos

6、pitalInhalation Anesthetics DevelopednDIETHYL ETHERnDIVINYL ETHER nETHYL VINYL ETHERnETHYL CHLORIDEnCYCLOPROPANEnTRICHLORETHYLENEnFLUROXENEnMETHOXYFLURANEnNITROUS OXIDEnHALOTHANEnENFLURANEnISOFLURANEnDESFLURANEnSEVOFLURANEHistorical DevelopmentnETHER 1540 Synthesized by Valerius Cordus 1846 Demonstr

7、ated by William Thomas Green Morton nHALOTHANE 1951 Synthesized by Sukling 1956 Pharmacological researched by Raventos 1956 Clinical used by JohnstonenMETHOXYFLURANE 1956 Synthesized by Artusio and van Poznak 1959 Clinical usedHistorical DevelopmentnENFLURANE 1963 Synthesized by Terrell 1963 Animal

8、experimented by Krantz 1973 Clinical usednISOFLURANE 1965 Synthesized by Terrell 1975 Animal experimented by Dobkin,Byles, Stevens and Eger 1981 Clinical usedHistorical DevelopmentDESFLURANE 1959-1966: Synthesized by Terrell 1990: Clinical used by John SEVOFLURANE 1968: Synthesized by Regan 1975: Wa

9、llin described pharmacologic and toxicological properties 1975:Cook/Mazze described renal and metabolic effects in animals. 1981: Holaday published phase-1clinical study 1984:Maruishi Pharmaceuticals purchased drug FDA approval 1994; widely available in US in 1995 Historical Development of inhalatio

10、nal agent Pharmacology of inhalational agent 3. Mechanisms of inhalational agent 4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Anaethetics 5. Sevoflurane is Best Volatile Anesthetic ever developedIdeal Properties of Volatile AgentsnPleasant odour, non-irritant to the airwaynLow bl

11、ood gas solubilitynChemically stable in storagenNo interaction with the anaesthetic circuits or soda limenNeither flammable nor explosivenProducing unconciousness with analgesia, preferably with some degree of muscle relaxationIdeal Properties of Volatile AgentsnPotentnShould not be metabolised in t

12、he body, non toxicnNo allergic reactionnMinimal depression of CVS and RSnShould not interact with other drugsnCompletely inert, eliminated completely and rapidly in unchanged form via the lungsStructure and Functional RelationshipqHalogenation of hydrocarbon and ethersAnaesthetic potencyCardiac arrh

13、ythmia F Cl Br IqEffect of increased fluorine substitutionnWeak anaestheticReduced flammability?increased stabilityStructure and Functional RelationshipqIncreased halogen to ethers leads toIncreased convulsant activityqHalogenation methyl ethyl ethersLead to more stable and better anaestheticsPharma

14、cokinetics of volatile agentsnPrincipal objective a constant and optimal brain partial pressure of the inhaled anaesthetics.n Equilibrium PA -Pa-PbrnResult the PA is the indirect measurement of anaesthetic partial pressure at the brain. lu n gfre s h g a sC Oa b s o rb e r2Partial Rebreathing System

15、GA MACHINE FGF BREATHING CIRCUIT Fi FA F a BRAINFactors affecting FinThe concentration set on the vaporizernThe fresh gas flow rate nThe volume of the breathing circuitnThe amount of absorption by the anaesthetic machine and breathing system AlveolusFactors affecting FAFiFaFAFactors affecting FAqInp

16、ut depends on: 1.Inspired concentration The higher the concentration the faster the rise of FA/FIConcentration effectSecond gas effectFactors affecting FA 2.VentilationIncreased VA will increase the delivery of anaesthetic to the alveolusHypocarbia reduced decrease CBF and reduced delivery of agent

17、to brainThe respiratory depressant effect of inhaled agent act as a negative feedbackFactors affecting FAqUptake depends on:Blood gas solubilityThe higher the blood gas partition coefficient the greater its uptake by the pulmonary circulation. Thus the rise of FA/FI is slower, so does the speed of i

18、nduction and recovery.Factors affecting FAAlveolar blood flow (ie. Cardiac output)In the absence of pulmonary shunting is essentially equal to cardiac outputIncrease cardiac output will increase uptake of anaesthetic agent thus slow the rise of FA/FI and inductionMyocardial depressant effect of the

19、inhaled anaesthetic will act as a positive feedbackCalculation of total gas uptakeVO2 = 10 x BW (kg)3/4 (ml/min)VN20 = 1000 x t -1/2 (ml/min) VA N = f x MAC x l lB/G x Q x t -1/2 (ml/min)Brody FormulaSeveringhaus FormulaLowe FormulaCalculation of total gas uptakeTotal gas uptakemL/minCalculation of

20、total gas uptake for a patient weighing 75 kg.N2Isoflurane2140012001000800600400200153045607590105min0Factors affecting FAPartial pressure difference between alveolar gas and venous bloodnThe gradient depends on tissue uptakenDetermined by three factors:nTissue solubilitynTissue blood flownPartial p

21、ressure difference between arterial blood and tissue (vessel rich group, muscle group, fat group, vessel poor group)Does Fat Solubility Affect Recovery From Anesthesia?Eger. In: Anesthesia, 5th ed. 2000:74; Philip. Gas Man. 2002; Roizen In: Anesthesia. 5th ed. 2000:903; Sollazzi et al. Obes Surg. 20

22、01;11:623;Cork et al. Anesthesiology. 1981;54:310; Torri et al. Minerva Anestesiol, 2002; 68:523. *Vessel-rich group: brain, heart, liver, kidney, endocrine glands.Factors affecting Faq Ventilation perfusion mismatchnMore affected if agents are poorly solublenThus an endobronchial intubation or righ

23、t to left intracardiac shunt will slow the rate of induction with nitrous oxide more than with halothaneMinimun Alveolar Concentration (MAC)qDefinition:nThe alveolar concentration of an inhaled anaesthetic, at 1 atm pressure, in 100% O2, at equiblibrium that produce immobility in 50% of those subjec

24、ts exposed to a standardized noxious stimuli MAC continuenIt represants an anaesthetic 50% effective dose (ED50). n1.3 MAC would prevent95% of subjects from moving and is roughly equal to ED95nRelatively constant within species and between speciesMAC continueqDetermination of MACnFor human :surgical

25、 skin incision; in animal :usually produced by clamping the tail or by passing electric current nResponse to stimulus must be positive, gross and purposeful muscular movement,nFor 15 minutes to achieve equiblibration between end tidal , alveolar, arterial and brain anaesthetic partial pressureMAC co

26、ntinuenMAC awake Minimun alveolar concentration of anaesthetics that would allow opening of eyes on verbal command during emergence from anaesthesia Roughly about 0.3 0.4 MACnMAC intubation Minimum alveolar concentration of anaesthetic that would inhibit movement and coughing during endotracheal int

27、ubation ( 1.3 MAC)MAC continuenMAC BARnMinimum alveolar concentration of anaesthetics necessary to prevent adrenergic response to skin incision (1.5 MAC)nWhen different inhaled anaesthetic are compared, the ratio of MAC skin incision to MAC intubation or MAC awake is relatively constant.Factors affe

28、cting MACqDecrease in MACnHypothermia (from 41 C 26 C )nHyponatraemianHypoxia ( PaO2 95 mmHg )nHypotension (MAP40 mmHg )nAnaemia ( 38 mmHgnPaCO2 15 95 mmHgnIsovolaemic anaemianBlood pressure 40 mmHgnHypothyroidism Historical Development of inhalational agent Pharmacology of inhalational agent 3. Mec

29、hanisms of inhalational agent 4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Anaethetics 5. Sevoflurane is Best Volatile Anesthetic ever developedHistory of Mechanisms of Anesthesia1846 Morton demonstrates anesthesia1900 Meyer and Overton Hypothesis; focus on lipids1980 Franks, Lie

30、b, White; focus on proteins, specifically ligand and voltage-gated channels Meyer-Overton HypothesisAnesthetic potency correlates with anesthetic affinity to a lipid phase0.0010.010.111101001000Conventional AnestheticsMAC(ata)Oil/Gas Partition CoefficientMAC for Conventional Anesthetics Correlates I

31、nversely with Lipophilicity0.11100.11Meyer-OvertonConstant(MAC XO/G p.c.)(atm)Saline/Gas Partition CoefficientConventional AnestheticsAffinity to Saline (Water) Doesnot Appear to Affect PotencyMeyer-Overton HypothesisnLipophilicity, alone, does not predict anesthetic potencynHydrophilicity is also e

32、ssentialnSuggests that anesthetics act at a site that has both polar and nonpolar characteristicsIonophores or Receptors that Might Mediate Inhaled Anesthetic Actions Inhibitory:nAlpha-2 AdrenergicnGABAAnGlycinenOpioidnPotassium Excitatory:n Acetylcholinen Calcium n Glutamaten Serotoninn Dopaminen N

33、orepinephrinen SodiumDo Inhibitory Ionophores & Channels Explain Anesthesia?Blockade of Glycine Receptors with Intrathecal Strychnine Increases MAC in Proportion to the Capacity of the Anesthetic to Enhance Receptor Activity;Thus, Glycine Receptors May Mediate Immobility0501000100200% Increasein MAC

34、 withIntrathecalInfusions of12 and 24 g*kg-1*min-1Strychnine% Potentiation of Glycine ReceptorsZhang et al.Anesth Analg96:97-101, 2003Cyclo-propaneIsofluraneHalothaneBut Blockade of GABAA Receptors with Intrathecal Picrotoxin Does not Increase MAC in Proportion to the Capacity of the Anesthetic to E

35、nhance Receptor Activity;Thus, GABAA Receptors Do not Mediate Immobility0501000200400600% Increasein MAC withIntrathecalInfusion of0.6 and 2.4 g*kg-1*min-1Picrotoxin% Potentiation of GABAA ReceptorsCyclo-propaneXenonHalothaneZhang et al.Anesth Analg99:85-90, 2004Glycine Receptors May, But GABAA Rece

36、ptors Do Not, Mediate Immobility05010010100PercentIncreasein MAC(In Vivo)withIncreasingReceptorEnhancement(In Vitro)Percent Receptor EnhancementCyclo-propaneHalo-thaneIso-fluraneGlycine10100Cyclo-propaneXenonIso-fluraneGABAOpioid Receptors Do not Mediate the Immobilization Produced by Inhaled Anesth

37、etics -20-1001020021050250PercentChange inHalothaneMAC in RatsProduced byNaloxoneInjection(mean, SE)Naloxone (mg/kg)Harper et al.Anesthesiology49:3-5, 1978a-2 Adrenergic Blockers Do not Increase MAC 00.51110Treatment MACDivided byControl MAC(mean, SD;*p 9 MAC-h) sevoflurane anaesthesia Bito H,et al

38、Long-term ( 10 hour) low-flow anaesthesia with sevoflurane. Munday IT,et al A comparable protocol in healthy volunteers, prolonged sevoflurane or enflurane anaesthesiaNephrotoxicityMore sensitive indicators for renal damage.nN-acetyl-D-glucosaminidase(NAG)n gamma-glutamyl-transferasen 2microglobulin

39、 Tsukamoto N,et al No difference in excretion of these indicators after sevoflurane or isoflurane anaesthesia in patients with creatinine clearances between 10 and 55 ml/minute NephrotoxicityConclusionn Nephrotoxicicy after methoxyflurane follows a different pathomechanism nthat the methoxyflurane e

40、xperience cannot be transferred to other halogenated anaestheticsNephrotoxicityMethoxyflurane and sevofluranenSevoflurane was metabolized by liver cytochrome P450 2E 1 nMethoxyflurane is metabolized by a number of subtypes of cytochrome P450 1A2,2C9/10 and 2D6 in kidney microsomesNephrotoxicity- com

41、pound A nAnimal studies:Histological signs of renal injury compound A 50 p.p.m. 3-hour 200 p.p.m. l-hour nIn clinical practice: average peak concentrations of compound A : 20-30 p.p.mnTo date, there is almost no evidence that compound A has the potential to produce renal injury in humans SummarySumm

42、ary -SevofluraneNo HepatotoxicityNo NephrotoxicityFree radical intermediatesTrifluoroacetyl chloride Inorganic fluoride other agentsnAt 2 MAC (4%) causes both systemic vasodilatation and myocardial depressionnEasily reversed by decreasing inspired concentrationPHARMACOLOGICAL PROPERTIES nCirculatory

43、 EffectsnDoes not stimulate catecholamine releasenDoes not predispose heart to arrhythmias when exogenous catecholamine drugs administerednProtects heart from ischemia in animals and manPHARMACOLOGICAL PROPERTIES nMechanism(s)nCoronary vasodilatationnActivating adenosine triphosphate-regulated KATP

44、channelsnSuppressing mitochondrial respiratory functionPHARMACOLOGICAL PROPERTIES nProlongs Q-T interval in some patientsnIncidence no greater that with halothane or isofluranenOccurs with other commonly used drugs: thiopental, propofol, succinylcholine, neostigmine, droperidolnSignificance unknownn

45、Hard to disprove the existence of EvilsBlood Pressure and Heart Rate Similarly Affected During Maintenance with Sevoflurane versus Isoflurane80100120SystolicBloodPressure(mm Hg)or HeartRate(bpm)(mean, SE)Awake2 MinutesSurgery15 MinutesSurgery60 MinutesSurgery5 Minutesto EndSevofluraneSevofluraneIsof

46、luraneIsofluraneSystolicBloodPresureHeartRate*Frink et al.Anesth Analg1992;74:241-5BP and HR Similarly Affected During Maintenance with Sevoflurane versus Propofol, Each with Epidural Anesthesia60708090100MeanArterialBloodPressure(mm Hg)or HeartRate(bpm)(mean, SE)Awake2 MinutesSurgery30 MinutesSurge

47、ry60 MinutesSurgery10 Minutesto EndSevofluraneSevofluranePropofolPropofolMeanArterialBloodPresureHeartRateTsushima et al.J Anesth12:57-61, 1998An Acute Increase in Sevoflurane Concentration Does Not Stimulate the Circulation on Induction of Anesthesia90100048Percent ofHeart Rate inVolunteersat 1 MAC

48、Sevoflurane(mean, SD)Minutes after Sevoflurane VaporizerSetting Increased from 1 MAC to 1.5 MACEbert et al.Anesthesiology83: 88-95, 1995An Acute Increase in Isoflurane Concentration Stimulates the Circulation on Induction of Anesthesia608010001020HeartRateBPM;mean,SD)Minutes after Isoflurane Increas

49、edfrom 0.55 MAC TO 1.67 MACWeiskopf et al.Anesthesiology80:1035-45, 1994PHARMACOLOGICAL PROPERTIES nRespiratory EffectsnDose dependent decrease in VtnNo appreciable change in fnDose dependent decrease in ventilatory response to CO2PHARMACOLOGICAL PROPERTIES nRespiratory EffectsnMinimal effect on hyp

50、oxic pulmonary vasoconstrictor responsenCauses bronchodilatation; useful in asthmatic patientsnNO AIRWAY IRRITABILITY; excellent for inhalation inductions; laryngospasm rare on induction/emergencePotent Inhaled Anesthetics Dilate Constricted Bronchi0100200012Percent ofControl AirwayResistance inRats