吸入麻醉药的临床药理学（英文）课件

1、Clinical Pharmacology of Inhaled AnestheticsDepartment of AnesthesiologyUniversity of OttawaCore Program Lecture SeriesSeptember 2003A 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 late

2、st versions of your text books.Much the material on CV and RS effects can be annoyingly inconsistent between texts and editionsFor 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

3、but the Royal College might!This stuff is relatively new and part of a broader area of research in ischemic preconditioning you know, rat stuffThanks for attending!Objectives IChemical structureStructure - function relationshipsPhysiochemical properties Mechanism of actionPharmacokinetics of Inhaled

4、 AgentsUptake and DistributionFa/Fi curves, and factors which affect them Metabolism of Inhalation Anesthetics Objectives IIDefinition of MACFactors which affect MACCardiovascular effectsPulmonary effectsCNS effectsNeuromuscular effectsHepatic effects Renal effectsUterine effects Marrow effectsThe r

5、ealityTheres an awful lot of stuff here - none of it is “new”All of it is in the textbooksBarash 4th EditionChapter 15. Inhalation Anesthesia. 377-417. Miller 5th EditionChapter 3. Mechanisms of Action. 48-73Chapter 4. Uptake and Distribution. 74-95Chapter 5a. Cardiovascular Pharmacology. 96-124Chap

6、ter 5b. Pulmonary Pharmacology. 125-146Chapter 6. Metabolism and Toxicity. 147-173Much of it requires rote memorizationSome 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) c

7、ontextExplain that which needs explaining Leave the memory work to youBe back on my porch, beer in hand, by 1730Chemical structure INitrous OxideDiethyl EtherHalothanePhysical characteristicsPlease cram the contents of the appropriate table 15.1 from Barash 4th Ed the night before the exam. Take hom

8、e 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 coefficientsRepresent the relative affinity of a gas for 2 different substances (solubility)Mea

9、sured 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 bloodBlood:gas partition coefficientsTable 15-1. Barash 4th Edition. p378. Factors infl

10、uencing deliveryAlveolar ventilationBreathing systemvolumefresh gas flowInspired partial pressure (PI)concentration effectsecond gas effectConcentration and 2nd gas effectsFactors influencing uptakeSolubility (blood:gas pc)Cardiac outputAlveolar-venous pressure gradientFor those of you who like form

11、ulae:Uptake = Q (PA-Pv)/BP FA/FI CurvesNitrous 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

12、soluble agent spreads membranes distorting 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 reall

13、y knowsMetabolism of inhaled anestheticsFairly small component of eliminationOccurs at cytochrome p450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccurs only with halothane in hypoxic conditionsThree determinants of metabolismChemical structureether bondcarbon-halogen bondHepat

14、ic enzyme activityBlood concentrationMetabolism 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 speciesa

15、dditiveMAC ValuesTable 15-1. Barash 4th Edition. p378.Factors increasing MACHyperthermiaChronic ETOH abuseHypernatremiaIncreased CNS transmittersMAOIAmphetamineCocaine EphedrineL-DOPATable 15.4. Barash 4th Edition. P389Factors decreasing MACIncreasing ageHypothermiaHyponatremiaHypotension (MAP50mmHg

16、)PregnancyHypoxemia (38 mmHg)O2 content ( 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 vasodilat

17、ors, except N2Orelax vascular smooth musclecAMP - 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

18、gkg-1 Lidocaine doubles ED50 of epinephrineChildren 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 vesselcoll

19、ateral perfusion with 90% stenosisIn practice, 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/ten

20、dons in intercostal musclesIncreased resistance 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 ventilati

21、ngED=IS=Hhypoxic drive abolished by 0.1 MACBronchial 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 H

22、PV and increase shuntShunt and PO2 appear 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 freq

23、uency - 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 flowHepatotoxicitymild, transient, postoperative increase in LFTs? due to transient hypoxia reductive metabolitesmassive hepatic