吸入麻醉药的临床药理学(英文)精选课件

1、Clinical Pharmacology of Inhaled AnestheticsDepartment of AnesthesiologyUniversity of OttawaCore Program Lecture SeriesSeptember 2019Clinical Pharmacology of InhaA 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 reflec

2、t 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 editionsFor those who asked about “protection” and volatile anesthesia Ive appended a couple of recent articles “for your interest”“FYI” means that I wo

3、nt 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 preconditioning you know, rat stuffThanks for attending!A note for those at the lecturObjectives IChemical structureStructure - function relationshipsPhysiochemica

4、l properties Mechanism of actionPharmacokinetics of Inhaled AgentsUptake and DistributionFa/Fi curves, and factors which affect them Metabolism of Inhalation Anesthetics Objectives IChemical structureObjectives IIDefinition of MACFactors which affect MACCardiovascular effectsPulmonary effectsCNS eff

5、ectsNeuromuscular effectsHepatic effects Renal effectsUterine effects Marrow effectsObjectives IIDefinition of MACThe realityTheres 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.

6、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 memorizationSome of it useful - all of it “test-able” I cant cover all of

7、it in 3 hoursThe realityTheres an awful loGregs 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 1730Gregs goals for this lectureIChemical st

8、ructure INitrous OxideDiethyl EtherHalothaneChemical structure INitrous OxFun with chemistryHalogenation reduces flammabilityFluorination reduces solubilityTrifluorcarbon groups add stabilityAlkanes precipitate arrythmiasFun with chemistryHalogenationChemical structure IIIsofluraneSevofluraneDesflur

9、aneChemical structure IIIsofluranPhysical characteristicsPlease cram the contents of the 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 questionsknowledg

10、e of blood:gas partition coefficients may actually be useful Physical characteristicsPleasePartition coefficientsRepresent 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

11、(concentration) arent equal.We most commonly refer to blood:gas pcThe larger the number, the more soluble in bloodPartition coefficientsRepresenBlood:gas partition coefficientsTable 15-1. Barash 4th Edition. p378. Blood:gas partition coefficienThe blood:gas pc is useful, really.Anesthesia is related

12、 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 before increasing partial pressureSpeed of onset/offset closely related to solubilityThe lower the blood:gas pc - the fast

13、er the onsetThe blood:gas pc is useful, reUptake and distributionAnesthesia depends upon brain partial pressureAlveolar partial pressure (PA) = PbrainThe faster PA approaches the desired level the faster the patient is anesthetized PA is a balance between delivery of drug to the alveolus and uptake

14、of that drug into the bloodTime for an analogyUptake and distributionAnestheTo 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 (increase delivery) or (b) slow down the leak (decrease uptake). abTo

15、induce anesthesia the buckeFactors influencing deliveryAlveolar ventilationBreathing systemvolumefresh gas flowInspired partial pressure (PI)concentration effectsecond gas effectFactors influencing deliveryAlConcentration and 2nd gas effectsConcentration and 2nd gas effeFactors influencing uptakeSol

16、ubility (blood:gas pc)Cardiac outputAlveolar-venous pressure gradientFor those of you who like formulae:Uptake = Q (PA-Pv)/BP Factors influencing uptakeSoluFA/FI CurvesFA/FI CurvesV/Q distribution and uptakeVentilation perfusionuptake is decreased which enhances rise in FAmay speed induction for sol

17、uble agentsless difference with low solubility agents (fast anyway)V/Q distribution and uptakeVenNitrous 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

18、in 10 minutesNitrous OxideN20 leaves blood Mechanism of ActionMeyer-Overton Theorylipid soluble agent spreads membranes distorting membrane proteins (ie ion channels).Protein Receptor Hypothesisinhaled agent binds to membrane protein and changes ion conductanceNeurotransmitter Availabilityinhaled ag

19、ent prevents breakdown of GABAGregs Postulateif more than one theory - then no one really knowsMechanism of ActionMeyer-OvertMetabolism of inhaled anestheticsFairly small component of eliminationOccurs at cytochrome p450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccurs only wi

20、th halothane in hypoxic conditionsMetabolism of inhaled anesthetThree determinants of metabolismChemical structureether bondcarbon-halogen bondHepatic enzyme activityBlood concentrationThree determinants of metaboliMetabolism of inhaled anesthetics IITable 15-1. Barash 4th Edition. p378.Metabolism o

21、f inhaled anesthetBreakBreakMinimum alveolar concentrationAlveolar concentration required to prevent movement in 50% of subjectsstandard stimulusrepresents brain concentrationconsistent within and between speciesadditiveMinimum alveolar concentrationMAC ValuesTable 15-1. Barash 4th Edition. p378.MAC

22、 ValuesTable 15-1. Barash 4Factors increasing MACHyperthermiaChronic ETOH abuseHypernatremiaIncreased CNS transmittersMAOIAmphetamineCocaine EphedrineL-DOPATable 15.4. Barash 4th Edition. P389Factors increasing MACHypertheFactors decreasing MACIncreasing ageHypothermiaHyponatremiaHypotension (MAP50m

23、mHg)PregnancyHypoxemia (38 mmHg)O2 content ( I = D = S. Myocardial contractilityAll voCardiac outputDespite myocardial depression cardiac output is well-maintained with isoflurane and desfluranepreservation of heart rategreater reduction in SVRpreservation of baroreceptor reflexesCardiac outputDespi

24、te myocardiSystemic vascular resistanceAll are direct vasodilators, except N2Orelax vascular smooth musclecAMP - Ca2+and or nitric oxide involvedvariable effects on individual vascular bedsSystemic vascular resistanceAlDysrhytmiasHalothane potentiates catecholamine-related dysrhythmiasED50 of epineh

25、rine producing dysrhythmias at 1.25 MAChalothane 2.1 gkg-1isoflurane 6.9 gkg-1enflurane 10.9 gkg-1 Lidocaine doubles ED50 of epinephrineChildren somewhat more resistantDysrhytmiasHalothane potentiatCoronary blood flowIsoflurane is a potent coronary vasodilatorIn theory, dilation of normal coronary v

26、essels can direct blood flow away from stenotic coronariesSteal-prone anatomytotal occlusion of 1 major coronary vesselcollateral perfusion with 90% stenosisIn practice, doesnt seem to be a problemCoronary blood flowIsoflurane Respiratory patternIncreased frequencyDecreased tidal volumeDecreased min

27、ute ventilationAttributed (in cats) to sensitization of pulmonary stretch receptors - not supported in humansRespiratory patternIncreased fMechanoreceptorsSense tension in muscles/tendons in intercostal musclesIncreased resistance detected and increased respiratory effort recruitedResponses to inspi

28、ratory and expiratory loads diminishedFurther inhibition in patients with COPDMechanoreceptorsSense tension ChemoreceptorsApneic threshold raisedResponse to PCO2 bluntedPCO2 increased while spontaneously ventilatingED=IS=Hhypoxic drive abolished by 0.1 MACChemoreceptorsApneic thresholdBronchial musc

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

30、and PO2 appear unchanged in studies of inhaled anesthetics during one lung ventilationIntrinsic changes in HPV confounded bychanges in cardiac outputpulmonary artery pressurepositionHypoxic pulmonary vasoconstricCentral nervous systemIncrease cerebral blood flowIncrease ICPDecreased CMRO2Decreased f

31、requency - increased voltage on EEG2 MAC enflurane increases seizure activityDecreased amplitude - increased latency on SSEPCentral nervous systemIncreaseNeuromuscular functionSkeletal muscle relaxationPotentiate NDMRTrigger MHNeuromuscular functionSkeletalHepaticHepatic arterial blood flow decreased by halothaneClearance of drugs decreased in keeping with reductions in hep