吸入麻醉药临床药理学英文

1、吸入麻醉药临床药理学英文A note for those at the lectureThose I was able to keep awake might notice that Ive added/modified a couple of the slides to better reflect the information in the latest versions of your text books.Much the material on CV and RS effects can be annoyingly inconsistent between texts and ed

2、itionsFor those who asked about “protection” and volatile anesthesia Ive appended a couple of recent articles “for your interest”“FYI” means that I wont examine you on this stuff but the Royal College might!This stuff is relatively new and part of a broader area of research in ischemic preconditioni

3、ng you know, rat stuffThanks for attending!Objectives IChemical structureStructure - function relationshipsPhysiochemical properties Mechanism of actionPharmacokinetics of Inhaled AgentsUptake and DistributionFa/Fi curves, and factors which affect them Metabolism of Inhalation Anesthetics Objectives

4、 IIDefinition of MACFactors which affect MACCardiovascular effectsPulmonary effectsCNS effectsNeuromuscular effectsHepatic effects Renal effectsUterine effects Marrow effectsThe realityTheres an awful lot of stuff here - none of it is “new”All of it is in the textbooksBarash 4th EditionChapter 15. I

5、nhalation Anesthesia. 377-417. Miller 5th EditionChapter 3. Mechanisms of Action. 48-73Chapter 4. Uptake and Distribution. 74-95Chapter 5a. Cardiovascular Pharmacology. 96-124Chapter 5b. Pulmonary Pharmacology. 125-146Chapter 6. Metabolism and Toxicity. 147-173Much of it requires rote memorizationSo

6、me of it useful - all of it “test-able” I cant cover all of it in 3 hoursGregs goals for this lectureInflict my view of what you should knowPut this in a clinical (read: useful) contextExplain that which needs explaining Leave the memory work to youBe back on my porch, beer in hand, by 1730Chemical

7、structure INitrous OxideDiethyl EtherHalothaneFun with chemistryHalogenation reduces flammabilityFluorination reduces solubilityTrifluorcarbon groups add stabilityAlkanes precipitate arrythmiasChemical structure IIIsofluraneSevofluraneDesfluranePhysical characteristicsPlease cram the contents of the

8、 appropriate table 15.1 from Barash 4th Ed the night before the exam. Take home points include:desflurane boils at 24 OChalothane is preserved with thymolvapor pressures are needed for some exam questionsknowledge of blood:gas partition coefficients may actually be useful Partition coefficientsRepre

9、sent the relative affinity of a gas for 2 different substances (solubility)Measured at equilibrium so partial pressures are equal, but.The amounts of gas dissolved in each substance (concentration) arent equal.We most commonly refer to blood:gas pcThe larger the number, the more soluble in bloodBloo

10、d:gas partition coefficientsTable 15-1. Barash 4th Edition. p378. The blood:gas pc is useful, really.Anesthesia is related to the partial pressure of the gas in the brain.If a drug is dissolved in blood, it isnt available as a gasMore molecules of a soluble gas are required to saturate liquid phase

11、before increasing partial pressureSpeed of onset/offset closely related to solubilityThe lower the blood:gas pc - the faster the onsetUptake and distributionAnesthesia depends upon brain partial pressureAlveolar partial pressure (PA) = PbrainThe faster PA approaches the desired level the faster the

12、patient is anesthetized PA is a balance between delivery of drug to the alveolus and uptake of that drug into the bloodTime for an analogyTo induce anesthesia the bucket (PA) must be full. Unfortunately the bucket has a leak (uptake). To fill the bucket you must either (a) pour it in faster (increas

13、e delivery) or (b) slow down the leak (decrease uptake). abFactors influencing deliveryAlveolar ventilationBreathing systemvolumefresh gas flowInspired partial pressure (PI)concentration effectsecond gas effectConcentration and 2nd gas effectsFactors influencing uptakeSolubility (blood:gas pc)Cardia

14、c outputAlveolar-venous pressure gradientFor those of you who like formulae:Uptake = Q (PA-Pv)/BP FA/FI CurvesV/Q distribution and uptakeVentilation perfusionuptake is decreased which enhances rise in FAmay speed induction for soluble agentsless difference with low solubility agents (fast anyway)Nit

15、rous OxideN20 leaves blood 34x more than N2 absorbedSure, other agents are more soluble but we dont give them at 70% end-tidal concentrationdistension of closed air spaces70% N2O will double a pneumo in 10 minutesMechanism of ActionMeyer-Overton Theorylipid soluble agent spreads membranes distorting

16、 membrane proteins (ie ion channels).Protein Receptor Hypothesisinhaled agent binds to membrane protein and changes ion conductanceNeurotransmitter Availabilityinhaled agent prevents breakdown of GABAGregs Postulateif more than one theory - then no one really knowsMetabolism of inhaled anestheticsFa

17、irly small component of eliminationOccurs at cytochrome p450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccurs only with halothane in hypoxic conditionsThree determinants of metabolismChemical structureether bondcarbon-halogen bondHepatic enzyme activityBlood concentrationMetab

18、olism of inhaled anesthetics IITable 15-1. Barash 4th Edition. p378.BreakMinimum alveolar concentrationAlveolar concentration required to prevent movement in 50% of subjectsstandard stimulusrepresents brain concentrationconsistent within and between speciesadditiveMAC ValuesTable 15-1. Barash 4th Ed

19、ition. p378.Factors increasing MACHyperthermiaChronic ETOH abuseHypernatremiaIncreased CNS transmittersMAOIAmphetamineCocaine EphedrineL-DOPATable 15.4. Barash 4th Edition. P389Factors decreasing MACIncreasing ageHypothermiaHyponatremiaHypotension (MAP50mmHg)PregnancyHypoxemia (38 mmHg)O2 content (

20、I = D = S. Cardiac outputDespite myocardial depression cardiac output is well-maintained with isoflurane and desfluranepreservation of heart rategreater reduction in SVRpreservation of baroreceptor reflexesSystemic vascular resistanceAll are direct vasodilators, except N2Orelax vascular smooth muscl

21、ecAMP - Ca2+and or nitric oxide involvedvariable effects on individual vascular bedsDysrhytmiasHalothane potentiates catecholamine-related dysrhythmiasED50 of epinehrine producing dysrhythmias at 1.25 MAChalothane 2.1 gkg-1isoflurane 6.9 gkg-1enflurane 10.9 gkg-1 Lidocaine doubles ED50 of epinephrin

22、eChildren somewhat more resistantCoronary blood flowIsoflurane is a potent coronary vasodilatorIn theory, dilation of normal coronary vessels can direct blood flow away from stenotic coronariesSteal-prone anatomytotal occlusion of 1 major coronary vesselcollateral perfusion with 90% stenosisIn pract

23、ice, doesnt seem to be a problemRespiratory patternIncreased frequencyDecreased tidal volumeDecreased minute ventilationAttributed (in cats) to sensitization of pulmonary stretch receptors - not supported in humansMechanoreceptorsSense tension in muscles/tendons in intercostal musclesIncreased resis

24、tance detected and increased respiratory effort recruitedResponses to inspiratory and expiratory loads diminishedFurther inhibition in patients with COPDChemoreceptorsApneic threshold raisedResponse to PCO2 bluntedPCO2 increased while spontaneously ventilatingED=IS=Hhypoxic drive abolished by 0.1 MA

25、CBronchial musculatureReduce vagal toneDirect relaxationincreased cAMP (but not via adrenoreceptor mediated)When bronchospastic, a dose dependent reduction in Raw occurs with most agents Hypoxic pulmonary vasoconstrictionInhaled anesthetics appear to blunt HPV and increase shuntShunt and PO2 appear

26、unchanged in studies of inhaled anesthetics during one lung ventilationIntrinsic changes in HPV confounded bychanges in cardiac outputpulmonary artery pressurepositionCentral nervous systemIncrease cerebral blood flowIncrease ICPDecreased CMRO2Decreased frequency - increased voltage on EEG2 MAC enflurane increases seizure activityDecreased amplitude - increased latency on SSEPNeuromuscular functionSkeletal muscle relaxationPotentiate NDMRTrigger MHHepaticHepatic arterial blood flow decreased by halothaneClearance of drugs decreased in keeping with reductions in hepatic blood flowHepatotox