INHALATIONALAGENT-俞卫锋ppt课件

1、INHALATIONAL AGENT Weifeng YuDept of Anesthesia, EHBHHistorical Development of inhalational agentPharmacology of inhalational agent3. Mechanisms of inhalational agent4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Anaethetics5. Sevoflurane is Best Volatile Anesthetic ever developedH

2、istorical Developmentunlucky;rough 充溢坎坷intense emotion充溢热情joys and sorrows，partings and reunions-vicissitndes of life悲欢离合To finish operationPressing patientShortening timeDrinking alcoholic beveragesBleedingBoxing lower jaw 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当年截肢手术时运用的工具Dec. 10th, 1844Laughing, Sing, Danc

3、e, Speak or Fight 当天晚会上发生的一件事触动了牙医Horace Wells ( 1815 - 1848)Sam Cooley在笑气的作用下受伤了John M Riggs协助Wells拔掉了龋齿Wells清醒后的第一句话是：A new era in tooth pulling!Wells兴冲冲找到John C. WarrenJan. 10th, 1845病人与其他人一样发出尖叫人们永远无法忘记回荡在麻省总院圆顶演示手术室内“Humbug的叫喊面对Wells的失败，人们不由想起几年前著名的外科医生Velpeau的“著名结论：Eviter la douleur dans les o

4、perations 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 necessairement admettre Iassociation 外科手术必然伴随着疼痛，任何寻觅处理外科手术疼痛的努力均是徒劳的不久，

5、 Velpeau的预言就被突破了 突破Velpeau预言的是另一位牙科医生，他的名字曾经被永久地载入了世界医学开展史WilliamT.G. Morton Oct,16,1846 William Thomas Green Morton Ether Demonstrating Massachusetts General HospitalInhalation Anesthetics DevelopedDIETHYL ETHERDIVINYL ETHER ETHYL VINYL ETHERETHYL CHLORIDECYCLOPROPANETRICHLORETHYLENEFLUROXENEMETHOX

6、YFLURANENITROUS OXIDEHALOTHANEENFLURANEISOFLURANEDESFLURANESEVOFLURANEHistorical DevelopmentETHER 1540 Synthesized by Valerius Cordus 1846 Demonstrated by William Thomas Green Morton HALOTHANE 1951 Synthesized by Sukling 1956 Pharmacological researched by Raventos 1956 Clinical used by JohnstoneMETH

7、OXYFLURANE 1956 Synthesized by Artusio and van Poznak 1959 Clinical usedHistorical DevelopmentENFLURANE 1963 Synthesized by Terrell 1963 Animal experimented by Krantz 1973 Clinical usedISOFLURANE 1965 Synthesized by Terrell 1975 Animal experimented by Dobkin,Byles, Stevens and Eger 1981 Clinical use

8、dHistorical DevelopmentDESFLURANE 1959-1966: Synthesized by Terrell 1990: Clinical used by John SEVOFLURANE 1968: Synthesized by Regan 1975: Wallin described pharmacologic and toxicological properties 1975:Cook/Mazze described renal and metabolic effects in animals. 1981: Holaday published phase-1cl

9、inical study 1984:Maruishi Pharmaceuticals purchased drug FDA approval 1994; widely available in US in 1995 Historical Development of inhalational agentPharmacology of inhalational agent3. Mechanisms of inhalational agent4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Anaethetics5.

10、Sevoflurane is Best Volatile Anesthetic ever developedIdeal Properties of Volatile AgentsPleasant odour, non-irritant to the airwayLow blood gas solubilityChemically stable in storageNo interaction with the anaesthetic circuits or soda limeNeither flammable nor explosiveProducing unconciousness with

11、 analgesia, preferably with some degree of muscle relaxationIdeal Properties of Volatile AgentsPotentShould not be metabolised in the body, non toxicNo allergic reactionMinimal depression of CVS and RSShould not interact with other drugsCompletely inert, eliminated completely and rapidly in unchange

12、d form via the lungsStructure and Functional RelationshipHalogenation of hydrocarbon and ethersAnaesthetic potencyCardiac arrhythmia F Cl Br IEffect of increased fluorine substitutionWeak anaestheticReduced flammability?increased stabilityStructure and Functional RelationshipIncreased halogen to eth

13、ers leads toIncreased convulsant activityHalogenation methyl ethyl ethersLead to more stable and better anaestheticsPharmacokinetics of volatile agentsPrincipal objective a constant and optimal brain partial pressure of the inhaled anaesthetics. Equilibrium PA -Pa-PbrResult the PA is the indirect me

14、asurement of anaesthetic partial pressure at the brain. Partial Rebreathing SystemGA MACHINE FGF BREATHING CIRCUIT Fi FA F a BRAINFactors affecting FiThe concentration set on the vaporizerThe fresh gas flow rate The volume of the breathing circuitThe amount of absorption by the anaesthetic machine a

15、nd breathing system AlveolusUptakeInputbalanceFactors affecting FAFiFaFAFactors affecting FAInput 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 delive

16、ry of anaesthetic to the alveolusHypocarbia reduced decrease CBF and reduced delivery of agent to brainThe respiratory depressant effect of inhaled agent act as a negative feedbackFactors affecting FAUptake depends on:Blood gas solubilityThe higher the blood gas partition coefficient the greater its

17、 uptake by the pulmonary circulation. Thus the rise of FA/FI is slower, so does the speed of induction 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 a

18、naesthetic agent thus slow the rise of FA/FI and inductionMyocardial depressant effect of the 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 lB/G x Q x t -1/2 (ml/min)Brody FormulaSevering

19、haus FormulaLowe FormulaCalculation of total gas uptakeFactors affecting FAPartial pressure difference between alveolar gas and venous bloodThe gradient depends on tissue uptakeDetermined by three factors:Tissue solubilityTissue blood flowPartial pressure difference between arterial blood and tissue

20、 (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. 2001;11:623;Cork et al. Anesthesiology. 1981;54:310; T

21、orri et al. Minerva Anestesiol, 2002; 68:523. *Vessel-rich group: brain, heart, liver, kidney, endocrine glands.Factors affecting Fa Ventilation perfusion mismatchMore affected if agents are poorly solubleThus an endobronchial intubation or right to left intracardiac shunt will slow the rate of indu

22、ction with nitrous oxide more than with halothaneMinimun Alveolar Concentration (MAC)Definition:The alveolar concentration of an inhaled anaesthetic, at 1 atm pressure, in 100% O2, at equiblibrium that produce immobility in 50% of those subjects exposed to a standardized noxious stimuli MAC continue

23、It represants an anaesthetic 50% effective dose (ED50). 1.3 MAC would prevent95% of subjects from moving and is roughly equal to ED95Relatively constant within species and between speciesMAC continueDetermination of MACFor human :surgical skin incision; in animal :usually produced by clamping the ta

24、il or by passing electric current Response to stimulus must be positive, gross and purposeful muscular movement,For 15 minutes to achieve equiblibration between end tidal , alveolar, arterial and brain anaesthetic partial pressureMAC continueMAC awake Minimun alveolar concentration of anaesthetics t

25、hat would allow opening of eyes on verbal command during emergence from anaesthesia Roughly about 0.3 0.4 MACMAC intubation Minimum alveolar concentration of anaesthetic that would inhibit movement and coughing during endotracheal intubation ( 1.3 MAC)MAC continueMAC BARMinimum alveolar concentratio

26、n of anaesthetics necessary to prevent adrenergic response to skin incision (1.5 MAC)When different inhaled anaesthetic are compared, the ratio of MAC skin incision to MAC intubation or MAC awake is relatively constant.Factors affecting MACDecrease in MACHypothermia (from 41 C 26 C )HyponatraemiaHyp

27、oxia ( PaO2 95 mmHg )Hypotension (MAP40 mmHg )Anaemia ( 38 mmHgPaCO2 15 95 mmHgIsovolaemic anaemiaBlood pressure 40 mmHgHypothyroidism Historical Development of inhalational agentPharmacology of inhalational agent3. Mechanisms of inhalational agent4. Hepatotoxicity and Nephrotoxicity of Halogenated

28、Inhalational Anaethetics5. Sevoflurane is Best Volatile Anesthetic ever developedHistory of Mechanisms of Anesthesia1846 Morton demonstrates anesthesia1900 Meyer and Overton Hypothesis; focus on lipids1980 Franks, Lieb, White; focus on proteins, specifically ligand and voltage-gated channels Meyer-O

29、verton HypothesisAnesthetic potency correlates with anesthetic affinity to a lipid phaseMAC for Conventional Anesthetics Correlates Inversely with LipophilicityAffinity to Saline (Water) Doesnot Appear to Affect PotencyMeyer-Overton HypothesisLipophilicity, alone, does not predict anesthetic potency

30、Hydrophilicity is also essentialSuggests that anesthetics act at a site that has both polar and nonpolar characteristicsIonophores or Receptors that Might Mediate Inhaled Anesthetic Actions Inhibitory:Alpha-2 AdrenergicGABAAGlycineOpioidPotassium Excitatory: Acetylcholine Calcium Glutamate Serotonin

31、 Dopamine Norepinephrine 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 ImmobilityBut Blockade of GAB

32、AA Receptors with Intrathecal Picrotoxin Does not Increase MAC in Proportion to the Capacity of the Anesthetic to Enhance Receptor Activity;Thus, GABAA Receptors Do not Mediate ImmobilityGlycine Receptors May, But GABAA Receptors Do Not, Mediate ImmobilityOpioid Receptors Do not Mediate the Immobili

33、zation Produced by Inhaled Anesthetics a-2 Adrenergic Blockers Do not Increase MAC Eger et al.Anesth Analg 96:1661-4, 2003But Intrathecal vs. Intravenous Administration to Rats of the Potassium Channel Activator Riluzole Equally Affects MACAnd MAC Is Not Increased in Mice Lacking the KCNK5 Potassium

34、 ChannelConclusion Glycine Receptors May, But GABAA, Opioid, a-2 adrenergic Receptors and potassium channels do not, mediate the capacity of inhaled anesthetics to produce immobility What About Excitatory Ionophores and Channels?But Blockade of Muscarinic and/or Nicotinic Acetylcholine Receptors Doe

35、s not Change MACEger et al.Anesth Analg94:1500-4, 2002lamineNMDA Receptors May Mediate Immobility Produced by Some Aromatic Compounds but not by Conventional AnestheticsEger et al. UnpublishedDataOndanstron Administration Does Not Decrease MACDepletion of CNS Catecholamines, Including Dopamine and N

36、orepinephrine, Has a Small Effect on MACConclusion Acetylcholine ,NMDA ,Serotonin receptors do not mediate the immobility produced by inhaled anesthetics. Central nervous system catecholamine receptors may or may not mediate a small fraction of the capacity of inhaled anesthetics to produce immobili

37、ty. Summary Regarding MACVarious ligand- or voltage-gated channels have been proposed as plausible targetsWe now question the relevance of GABAA, acetylcholine, serotonin, a-2-adrenergic, NMDA, or opioid receptors, or potassium channels Perhaps 1 or 2 (e.g., maybe glycine) underlie a small part of a

38、nesthesia, but even these cannot explain anesthesia and, furthermore, may not be important for some inhaled anestheticsHistorical Development of inhalational agentPharmacology of inhalational agent3. Mechanisms of inhalational agent4. Hepatotoxicity and Nephrotoxicity of Halogenated Inhalational Ana

39、ethetics5. Sevoflurane is Best Volatile Anesthetic ever developedThe toxic potential is derived from their hepatic or renal metabolism. Interact with components of carbon dioxide absorbents may lead to formation of toxic potential degradation products. Introduction Metabolism of halogenated anaesthe

40、ticsMetabolism of halogenated oxidatively anaestheticsTrifluoroacetyl chloride Metabolism of sevoflurane Rates of metabolism of volatile anaestheticsReaction with carbon dioxide absorbentsAll halogenated anaesthetic agents potentially react with ingredients of carbon dioxide (CO2) absorbents. Potass

41、ium hydroxide (KOH) and sodium hydroxide (NaOH) have been identified as the main reactive components. High temperature of the absorbent and desiccation enhance the breakdown reactions Carbon monoxide formationToxic concentrations of carbon monoxide (CO) have been reported following contact of desflu

42、rane with desiccated absorbents containing NaOH or KOH. Elevated concentrations of CO have also been reported for isoflurane, enflurane or halothane but the peak concentrations are far less than those observed with desflurane.Compound A formationCompound A, a fluoromethy!-2,2-difluoro-l-(trifluorome

43、thyl)-vinyl-ether, originates from chemical reactions of sevoflurane with KOH, NaOH of CO2 absorbents. The formation and accumulation of compound A in re-breathing anaesthesia circuits is increased with low fresh gas flows. HepatotoxicityReductive metabolic hepatotoxicity The mild form of hepatic in

44、jury Oxidative immune-mediated hepatitisA fulminant severe fatal hepatic injury Predisposing factors Incidence of 1:35 000 for fatal hepatic necrosis after halothane anaesthesia.Increased risk after repeated administrations. Severe hepatic toxicity is higher in obese patients and in females. The ant

45、ibodies generated by one anaesthetic can apparently cross-react with antigens generated by a different one. Reductive metabolic hepatotoxicity the mild form of hepatic injury SymptomTransient elevation of liver enzymes Decrease in protein synthesis and secretion of intracellular proteins are early m

46、arkers of hepatic cell injury. Reductive metabolic hepatotoxicity the mild form of hepatic injury Morphological change Concentration- and/or dose-dependent centrilobular degeneration and necrosis together with vacuolar changeUltrastructural changes consisting of vacuolation, disappearance of ribosom

47、es, mitochondrial swelling and fragmentation of smooth endoplasmic reticulumReductive metabolic hepatotoxicity the mild form of hepatic injury MechanismFree radical intermediates of reductive metabolism generates lipid peroxidation Reductive halothane metabolism is common in surgical patients even u

48、nder normoxic conditions.Age: too young / too old to use PCAMental state:able to comprehend and understand the instructions to use PCAPsychiatric disorderEffortPress the PCA ButtonImmune-mediated hepatitisA fulminant severe fatal hepatic injurySymptomImmune-mediated hepatitisA fulminant severe fatal

49、 hepatic injuryMechanism-oxidative metabolismAn immune response against neo-antigens following acetylation of hepatocellular molecules. Trifluoroacecylated endoplasmatic reticulum proteins were identified as targets for antibodies formed shortly after halothane exposure. Immune-mediated hepatitisA f

50、ulminant severe fatal hepatic injuryImmunochemical analyses of the livers showed tissue acetylation after exposure to halothane, enflurane and isoflurane. Tissue acetylation after desflurane was very low. Neo-antigen formation can be inhibited by several substances for example, cysteine or glutathio

51、ne as well as cytochrome P450 2E1-specific inhibitorsImmune-mediated hepatitisA fulminant severe fatal hepatic injuryDiagnostic methods Those antibodies can be detected by enzyme-linked immunoabsorbent assay (ELISA) using purified trifluoroacetylated liver microsomal proteins (100, 76 and 57 kDa). P

52、ublished data report a sensitivity of 79% for this technique for differentiating the aetiology if anaesthetic-induced damage is suspected. Hepatotoxicity hepatic calcium hemeostasis Halothane can elevate cytosolic free Ca2+ by release of calcium from internal calcium stores Halothane can elevate cyt

53、osolic free Ca2+ uptake of calcium from extracellular medium Ca2+ cytochemistryCa2+ cytochemistryNephrotoxicityInorganic fluoride Concentrations of inorganic fluoride above a critical threshold of 50 uM were associated with clinically significant renal injury. NephrotoxicityLaboratory studiesSerum i

54、norganic fluoride concentrations following sevoflurane anaesthesia were about half of those after methoxyflurane. However, urinary fluoride excretion after sevoflurane was only one-third to one-fourth of that after methoxyflurane Nephrotoxicity Clinical studiesthere Elevated plasma inorganic fluorid

55、e but renal concentrating ability was not impaired Frink EJ,et al. prolonged (9 MAC-h) sevoflurane anaesthesia Bito H,et al Long-term ( 10 hour) low-flow anaesthesia with sevoflurane. Munday IT,et al A comparable protocol in healthy volunteers, prolonged sevoflurane or enflurane anaesthesiaNephrotox

56、icityMore sensitive indicators for renal damage.N-acetyl-D-glucosaminidase(NAG) gamma-glutamyl-transferase 2microglobulin 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 Ne

57、phrotoxicityConclusion Nephrotoxicicy after methoxyflurane follows a different pathomechanism that the methoxyflurane experience cannot be transferred to other halogenated anaestheticsNephrotoxicityMethoxyflurane and sevofluraneSevoflurane was metabolized by liver cytochrome P450 2E 1 Methoxyflurane

58、 is metabolized by a number of subtypes of cytochrome P450 1A2,2C9/10 and 2D6 in kidney microsomesNephrotoxicity- compound A Animal studies:Histological signs of renal injury compound A 50 p.p.m. 3-hour 200 p.p.m. l-hour In clinical practice: average peak concentrations of compound A : 20-30 p.p.mTo

59、 date, there is almost no evidence that compound A has the potential to produce renal injury in humans SummarySummary -SevofluraneNo HepatotoxicityNo NephrotoxicityFree radical intermediatesTrifluoroacetyl chloride Inorganic fluoride other agentsAt 2 MAC (4%) causes both systemic vasodilatation and

60、myocardial depressionEasily reversed by decreasing inspired concentrationPHARMACOLOGICAL PROPERTIES Circulatory EffectsDoes not stimulate catecholamine releaseDoes not predispose heart to arrhythmias when exogenous catecholamine drugs administeredProtects heart from ischemia in animals and manPHARMA