吸入麻醉药的临床药理学(英文)课件.ppt

1、Clinical Pharmacology of Inhaled AnestheticsDepartment of AnesthesiologyUniversity of OttawaCore Program Lecture SeriesSeptember 2019Department of AnesthesiologyCivic CampusA note for those at the lecture Those I was able to keep awake might notice that Ive added/modified a couple of the slides to b

2、etter 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 editions For those who asked about“protection”and volatile anesthesia Ive appended a couple of recent articles“for your interest”“FYI”means

3、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 preconditioning you know,rat stuff Thanks for attending!Department of AnesthesiologyCivic CampusObjectives I Chemical structure Structure-function relatio

4、nships Physiochemical properties Mechanism of action Pharmacokinetics of Inhaled Agents Uptake and Distribution Fa/Fi curves,and factors which affect them Metabolism of Inhalation Anesthetics Department of AnesthesiologyCivic CampusObjectives II Definition of MAC Factors which affect MAC Cardiovascu

5、lar effects Pulmonary effects CNS effects Neuromuscular effects Hepatic effects Renal effects Uterine effects Marrow effectsDepartment of AnesthesiologyCivic CampusThe reality Theres an awful lot of stuff here-none of it is“new”All of it is in the textbooks Barash 4th Edition Chapter 15.Inhalation A

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

7、all of it“test-able”I cant cover all of it in 3 hoursDepartment of AnesthesiologyCivic CampusGregs goals for this lecture Inflict my view of what you should know Put this in a clinical(read:useful)context Explain that which needs explaining Leave the memory work to you Be back on my porch,beer in ha

8、nd,by 1730Department of AnesthesiologyCivic CampusChemical structure INitrous OxideDiethyl EtherHalothaneDepartment of AnesthesiologyCivic CampusFun with chemistry Halogenation reduces flammability Fluorination reduces solubility Trifluorcarbon groups add stability Alkanes precipitate arrythmiasDepa

9、rtment of AnesthesiologyCivic CampusChemical structure IIIsofluraneSevofluraneDesfluraneDepartment of AnesthesiologyCivic CampusPhysical characteristics Please 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

10、 OC halothane is preserved with thymol vapor pressures are needed for some exam questions knowledge of blood:gas partition coefficients may actually be useful Department of AnesthesiologyCivic CampusPartition coefficients Represent the relative affinity of a gas for 2 different substances(solubility

11、)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 pc The larger the number,the more soluble in bloodDepartment of AnesthesiologyCivic CampusBlood:gas partition coefficientsAnestheti

12、c Blood:Gas PC Desflurane 0.42 Nitrous oxide 0.46 Sevoflurane 0.65 Isoflurane 1.46 Enflurane 1.91 Halothane 2.50 Table 15-1.Barash 4th Edition.p378.Department of AnesthesiologyCivic CampusThe blood:gas pc is useful,really.Anesthesia is related to the partial pressure of the gas in the brain.If a dru

13、g is dissolved in blood,it isnt available as a gas More molecules of a soluble gas are required to saturate liquid phase before increasing partial pressure Speed of onset/offset closely related to solubility The lower the blood:gas pc-the faster the onsetDepartment of AnesthesiologyCivic CampusUptak

14、e and distribution Anesthesia depends upon brain partial pressure Alveolar partial pressure(PA)=Pbrain The 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 of that drug into the blood Time for an analogy

15、Department of AnesthesiologyCivic CampusTo 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).abDepartment of AnesthesiologyCivic CampusFactors infl

16、uencing delivery Alveolar ventilation Breathing system volume fresh gas flow Inspired partial pressure(PI)concentration effect second gas effectDepartment of AnesthesiologyCivic CampusConcentration and 2nd gas effectsDepartment of AnesthesiologyCivic CampusFactors influencing uptake Solubility(blood

17、:gas pc)Cardiac output Alveolar-venous pressure gradient For those of you who like formulae:Uptake=Q (PA-Pv)/BP Department of AnesthesiologyCivic CampusFA/FI CurvesDepartment of AnesthesiologyCivic CampusV/Q distribution and uptake Ventilation perfusion uptake is decreased which enhances rise in FA

18、may speed induction for soluble agents less difference with low solubility agents(fast anyway)Department of AnesthesiologyCivic CampusNitrous Oxide N20 leaves blood 34x more than N2 absorbed Sure,other agents are more soluble but we dont give them at 70%end-tidal concentration distension of closed a

19、ir spaces 70%N2O will double a pneumo in 10 minutesAgent Blood:Gas PC Nitrous Oxide 0.47 Nitrogen 0.014 Department of AnesthesiologyCivic CampusMechanism of Action Meyer-Overton Theory lipid soluble agent spreads membranes distorting membrane proteins(ie ion channels).Protein Receptor Hypothesis inh

20、aled agent binds to membrane protein and changes ion conductance Neurotransmitter Availability inhaled agent prevents breakdown of GABA Gregs Postulate if more than one theory-then no one really knowsDepartment of AnesthesiologyCivic CampusMetabolism of inhaled anesthetics Fairly small component of

21、elimination Occurs at cytochrome p450 Inducible Oxidative o-dealkylation dehalogenation epoxidation Reductive occurs only with halothane in hypoxic conditionsDepartment of AnesthesiologyCivic CampusThree determinants of metabolism Chemical structure ether bond carbon-halogen bond Hepatic enzyme acti

22、vity Blood concentrationDepartment of AnesthesiologyCivic CampusMetabolism of inhaled anesthetics IIAgent%metabolized Halothane 20 Sevoflurane 2-5 Enflurane 2.4 Isoflurane 0.2 Desflurane 0.02 Nitrous Oxide 0.004 Table 15-1.Barash 4th Edition.p378.Department of AnesthesiologyCivic CampusBreakDepartme

23、nt of AnesthesiologyCivic CampusMinimum alveolar concentration Alveolar concentration required to prevent movement in 50%of subjects standard stimulus represents brain concentration consistent within and between species additiveDepartment of AnesthesiologyCivic CampusMAC ValuesAgent MAC Nitrous oxid

24、e 104 Desflurane 6.6 Sevoflurane 1.8 Enflurane 1.63 Isoflurane 1.17 Halothane 0.75 Table 15-1.Barash 4th Edition.p378.Department of AnesthesiologyCivic CampusFactors increasing MAC Hyperthermia Chronic ETOH abuse Hypernatremia Increased CNS transmitters MAOI Amphetamine Cocaine Ephedrine L-DOPATable

25、 15.4.Barash 4th Edition.P389Department of AnesthesiologyCivic CampusFactors decreasing MAC Increasing age Hypothermia Hyponatremia Hypotension(MAP50mmHg)Pregnancy Hypoxemia(38 mmHg)O2 content(I=D=S.Department of AnesthesiologyCivic CampusCardiac output Despite myocardial depression cardiac output i

26、s well-maintained with isoflurane and desflurane preservation of heart rate greater reduction in SVR preservation of baroreceptor reflexesDepartment of AnesthesiologyCivic CampusSystemic vascular resistance All are direct vasodilators,except N2O relax vascular smooth muscle cAMP-Ca2+and or nitric ox

27、ide involved variable effects on individual vascular bedsDepartment of AnesthesiologyCivic CampusDysrhytmias Halothane potentiates catecholamine-related dysrhythmias ED50 of epinehrine producing dysrhythmias at 1.25 MAC halothane 2.1 gkg-1 isoflurane 6.9 gkg-1 enflurane 10.9 gkg-1 Lidocaine doubles

28、ED50 of epinephrine Children somewhat more resistantDepartment of AnesthesiologyCivic CampusCoronary blood flow Isoflurane is a potent coronary vasodilator In theory,dilation of normal coronary vessels can direct blood flow away from stenotic coronaries Steal-prone anatomy total occlusion of 1 major

29、 coronary vessel collateral perfusion with 90%stenosis In practice,doesnt seem to be a problemDepartment of AnesthesiologyCivic CampusRespiratory pattern Increased frequency Decreased tidal volume Decreased minute ventilation Attributed(in cats)to sensitization of pulmonary stretch receptors-not sup

30、ported in humansDepartment of AnesthesiologyCivic CampusMechanoreceptors Sense tension in muscles/tendons in intercostal muscles Increased resistance detected and increased respiratory effort recruited Responses to inspiratory and expiratory loads diminished Further inhibition in patients with COPDD

31、epartment of AnesthesiologyCivic CampusChemoreceptors Apneic threshold raised Response to PCO2 blunted PCO2 increased while spontaneously ventilating ED=IS=H hypoxic drive abolished by 0.1 MACDepartment of AnesthesiologyCivic CampusBronchial musculature Reduce vagal tone Direct relaxation increased

32、cAMP(but not via adrenoreceptor mediated)When bronchospastic,a dose dependent reduction in Raw occurs with most agents Department of AnesthesiologyCivic CampusHypoxic pulmonary vasoconstriction Inhaled anesthetics appear to blunt HPV and increase shunt Shunt and PO2 appear unchanged in studies of in

33、haled anesthetics during one lung ventilation Intrinsic changes in HPV confounded by changes in cardiac output pulmonary artery pressure positionDepartment of AnesthesiologyCivic CampusCentral nervous system Increase cerebral blood flow Increase ICP Decreased CMRO2 Decreased frequency-increased volt

34、age on EEG 2 MAC enflurane increases seizure activity Decreased amplitude-increased latency on SSEPDepartment of AnesthesiologyCivic CampusNeuromuscular function Skeletal muscle relaxation Potentiate NDMR Trigger MHDepartment of AnesthesiologyCivic CampusHepatic Hepatic arterial blood flow decreased

35、 by halothane Clearance of drugs decreased in keeping with reductions in hepatic blood flow Hepatotoxicity mild,transient,postoperative increase in LFTs?due to transient hypoxia reductive metabolites massive hepatic necrosis oxidative metabolite binds to hepatocyte repeat exposure leads to immune-me

36、diated necrosisDepartment of AnesthesiologyCivic CampusRenal Dose-dependent decreases in renal blood flow glomerular filtration rate urine output Related to changes in CO and BP not ADH Fluoride nephrotoxicity at serum conc.50 mol/l F-opposes ADH leading to polyuria methoxyflurane 2.5 MAC-hours enfl

37、urane 9.6 MAC-hours Department of AnesthesiologyCivic CampusObstetrical N2O has no effect Halogenated volatiles lead to dose-dependent uterine relaxation reductions in uterine blood flowDepartment of AnesthesiologyCivic CampusMiscellaneous N2O-related myelosupression if 12 hr exposure inhibition of methionine-synthetase megaloblastic anemia Inhaled anesthetics,N2O in particular,decrease leukocyte function Teratogenesis with prolonged exposure in rats Increased risk(RR=1.3)of spontaneous abortion with chronic exposure to N20