INHALATIONALAGENT-俞卫锋.ppt

INHALATIONAL AGENT,Weifeng Yu Dept of Anesthesia, EHBH,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 developed,Historical Development,unlucky;rough 充满坎坷 intense emotion充满激情 joys and sorrows，partings and reunions-vicissitndes of life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，也不愿接受外科手术治疗,当年截肢手术时使用的工具,Dec. 10th, 1844,Laughing, Sing, Dance, 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帮助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. Warren,Jan. 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，人们不禁想起,几年前著名的外科医生Velpeau的“著名”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 necessairement admettre Iassociation 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,不久， Velpeau的预言就被打破了,打破Velpeau预言的是另一位牙科医生，他的名字已经被永久地载入了世界医学发展史 WilliamT.G. Morton,Oct,16,1846 William Thomas Green Morton Ether Demonstrating Massachusetts General Hospital,Inhalation Anesthetics Developed,DIETHYL ETHER DIVINYL ETHER ETHYL VINYL ETHER ETHYL CHLORIDE CYCLOPROPANE TRICHLORETHYLENE FLUROXENE METHOXYFLURANE,NITROUS OXIDE HALOTHANE ENFLURANE ISOFLURANE DESFLURANE SEVOFLURANE,Historical Development,ETHER 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 Johnstone METHOXYFLURANE 1956 Synthesized by Artusio and van Poznak 1959 Clinical used,Historical Development,ENFLURANE 1963 Synthesized by Terrell 1963 Animal experimented by Krantz 1973 Clinical used ISOFLURANE 1965 Synthesized by Terrell 1975 Animal experimented by Dobkin,Byles, Stevens and Eger 1981 Clinical used,Historical Development,DESFLURANE 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-1clinical study 1984:Maruishi Pharmaceuticals purchased drug FDA approval 1994; widely available in US in 1995,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 developed,Ideal Properties of Volatile Agents,Pleasant odour, non-irritant to the airway Low blood gas solubility Chemically stable in storage No interaction with the anaesthetic circuits or soda lime Neither flammable nor explosive Producing unconciousness with analgesia, preferably with some degree of muscle relaxation,Ideal Properties of Volatile Agents,Potent Should not be metabolised in the body, non toxic No allergic reaction Minimal depression of CVS and RS Should not interact with other drugs Completely inert, eliminated completely and rapidly in unchanged form via the lungs,Structure and Functional Relationship,Halogenation of hydrocarbon and ethers Anaesthetic potency Cardiac arrhythmia F Cl Br I Effect of increased fluorine substitution Weak anaesthetic Reduced flammability ?increased stability,Structure and Functional Relationship,Increased halogen to ethers leads to Increased convulsant activity Halogenation methyl ethyl ethers Lead to more stable and better anaesthetics,Pharmacokinetics of volatile agents,Principal objective a constant and optimal brain partial pressure of the inhaled anaesthetics. Equilibrium PA -Pa-Pbr Result the PA is the indirect measurement of anaesthetic partial pressure at the brain.,Partial Rebreathing System,GA MACHINE FGF BREATHING CIRCUIT Fi FA F a BRAIN,Factors affecting Fi,The concentration set on the vaporizer The fresh gas flow rate The volume of the breathing circuit The amount of absorption by the anaesthetic machine and breathing system,Alveolus,Uptake,Input,balance,Factors affecting FA,Fi,Fa,FA,Factors affecting FA,Input depends on: 1.Inspired concentration The higher the concentration the faster the rise of FA/FI Concentration effect Second gas effect,Factors affecting FA,2.Ventilation Increased VA will increase the delivery of anaesthetic to the alveolus Hypocarbia reduced decrease CBF and reduced delivery of agent to brain The respiratory depressant effect of inhaled agent act as a negative feedback,Factors affecting FA,Uptake depends on: Blood gas solubility The 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 induction and recovery.,Factors affecting FA,Alveolar blood flow (ie. Cardiac output) In the absence of pulmonary shunting is essentially equal to cardiac output Increase cardiac output will increase uptake of anaesthetic agent thus slow the rise of FA/FI and induction Myocardial depressant effect of the inhaled anaesthetic will act as a positive feedback,Calculation of total gas uptake,VO2 = 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 Formula,Severinghaus Formula,Lowe Formula,Calculation of total gas uptake,Factors affecting FA,Partial pressure difference between alveolar gas and venous blood The gradient depends on tissue uptake Determined by three factors: Tissue solubility Tissue blood flow Partial pressure 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. 2001;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 Fa,Ventilation perfusion mismatch More affected if agents are poorly soluble Thus an endobronchial intubation or right to left intracardiac shunt will slow the rate of induction with nitrous oxide more than with halothane,Minimun 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,It represants an anaesthetic 50% effective dose (ED50). 1.3 MAC would prevent95% of subjects from moving and is roughly equal to ED95 Relatively constant within species and between species,MAC continue,Determination of MAC For human :surgical skin incision; in animal :usually produced by clamping the tail 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 pressure,MAC continue,MAC 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 MAC MAC intubation Minimum alveolar concentration of anaesthetic that would inhibit movement and coughing during endotracheal intubation ( 1.3 MAC),MAC continue,MAC BAR Minimum alveolar concentration 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 MAC,Decrease in MAC Hypothermia (from 41 C 26 C ) Hyponatraemia Hypoxia ( PaO2 95 mmHg ) Hypotension (MAP40 mmHg ) Anaemia ( 4.3 ml O2/dl blood ) Drug induced decreases in CNS cathecolamines store (Reserpine,Methyldopa,Clonidine) Acute alcohol ingestion,Chronic administration of ampethamine Cardiopulmonary bypass Increasing age (maximun at 6 month old ) Calcium channel blockers (verapamil , nimodipine ) Benzodiazepine Nitrous oxide i.v. local anaesthetics Ketamine Opiod,Factors affecting MAC,Increase in MAC Hyperthermia Hypernatraemia (due to increase in Na in CSF) Hyperthyroidism Alcoholism Drug induced elevation in CNS cathecolamines store Epidrine Cocain Acute administration of dextroamphetamine,Factors affecting MAC,No change in MAC Gender Duration of anaesthesia Hyperkalaemia Hypokalaemia Metabolic acid base status PaO2 38 mmHg PaCO2 15 95 mmHg Isovolaemic anaemia Blood pressure 40 mmHg Hypothyroidism,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 developed,History of Mechanisms of Anesthesia,1846 Morton demonstrates anesthesia 1900 Meyer and Overton Hypothesis; focus on lipids 1980 Franks, Lieb, White; focus on proteins, specifically ligand and voltage-gated channels,Meyer-Overton Hypothesis,Anesthetic potency correlates with anesthetic affinity to a lipid phase,MAC for Conventional Anesthetics Correlates Inversely with Lipophilicity,Affinity to Saline (Water) Does not Appear to Affect Potency,Meyer-Overton Hypothesis,Lipophilicity, alone, does not predict anesthetic potency Hydrophilicity is also essential Suggests that anesthetics act at a site that has both polar and nonpolar characteristics,Ionophores or Receptors that Might Mediate Inhaled Anesthetic Actions,Inhibitory: Alpha-2 Adrenergic GABAA Glycine Opioid Potassium,Excitatory: Acetylcholine Calcium Glutamate Serotonin Dopamine Norepinephrine Sodium,Do 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 Immobility,But Blockade of GABAA 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 Immobility,Glycine Receptors May, But GABAA Receptors Do Not, Mediate Immobility,Opioid Receptors Do not Mediate the Immobilization Produced by Inhaled Anesthetics,a-2 Adrenergic Blockers Do not Increase MAC,Eger et al. Anesth Analg 96:1661-4, 2003,But Intrathecal vs. Intravenous Administration to Rats of the Potassium Channel Activator Riluzole Equally Affects MAC,And MAC Is Not Increased in Mice Lacking the KCNK5 Potassium Channel,Conclusion,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 Does not Change MAC,Eger et al. Anesth Analg 94:1500-4, 2002,lamine,NMDA Receptors May Mediate Immobility Produced by Some Aromatic Compounds but not by Conventional Anesthetics,Eger et al. Unpublished Data,Ondanstron Administration Does Not Decrease MAC,Depletion of CNS Catecholamines, Including Dopamine and Norepinephrine, Has a Small Effect on MAC,Conclusion,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 immobility.,Summary Regarding MAC,Various ligand- or voltage-gated channels have been proposed as plausible targets We 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 anesthesia, but even these cannot explain anesthesia and, furthermore, may not be important for some inhaled anesthetics,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 developed,The 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 anaesthetics,Metabolism of halogenated oxidatively anaesthetics,Trifluoroacetyl chloride,Metabolism of sevoflurane,Rates of metabolism of volatile anaesthetics,Reaction with carbon dioxide absorbents,All halogenated anaesthetic agents potentially react with ingredients of carbon dioxide (CO2) absorbents. Potassium 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 formation,Toxic concentrations of carbon monoxide (CO) have been reported following contact of desflurane 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 formation,Compound A, a fluoromethy!-2,2-difluoro-l-(trifluoromethyl)-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.,Hepatotoxicity,Reductive metabolic hepatotoxicity The mild form of hepatic injury Oxidative immune-mediated hepatitis A 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 antibodies generated by one anaesthetic can apparently cross-react with antigens generated by a different one.,Reductive metabolic hepatotoxicity the mild form of hepatic injury,Symptom Transient elevation of liver enzymes Decrease in protein synthesis and secretion of intracellular proteins are early markers 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 change Ultrastructural changes consisting of vacuolation, disappearance of ribosomes, mitochondrial swelling and fragmentation of smooth endoplasmic reticulum,Reductive metabolic hepatotoxicity the mild form of hepatic injury,Mechanism Free radical intermediates of reductive metabolism generates lipid peroxidation Reductive halothane metabolism is common in surgical patients even under normoxic conditions.,Age: too young / too old to use PCA Mental state: able to comprehend and understand the instructions to use PCA Psychiatric disorder Effort Press the PCA Button,Immune-mediated hepatitis A fulminant severe fatal hepatic injury,Symptom,Immune-mediated hepatitis A fulminant severe fatal hepatic injury,Mechanism-oxidative metabolism An 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 hepatitis A fulminant severe fatal hepatic injury,Immunochemical 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 glutathione as well as cytochrome P450 2E1-specific inhibitors,Immune-mediated hepatitis A fulminant severe fatal hepatic injury,Diagnostic methods Those antibodies can be detected by enzyme-linked immunoabsorbent assay (ELISA) using purified trifluoroacetylated liver microsomal proteins (100, 76 and 57 kDa). Published 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 cytosolic free Ca2+ uptake of calcium from extracellular medium,Ca2+ cytochemistry,Ca2+ cytochemistry,Nephrotoxicity,Inorganic fluoride,Concentrations of inorganic fluoride above a critical threshold of 50 uM were associated with clinically significant renal injury.,Nephrotoxicity,Laboratory studies Serum inorganic 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 fluoride 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 anaesthesia,Nephrotoxicity,More 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,Nephrotoxicity,Conclusion Nephrotoxicicy after methoxyflurane follows a different pathomechanism that the methoxyflurane experience cannot be transfer