1、Clinical Pharmacology of Inhaled AnestheticsDepartment of AnesthesiologyUniversity of OttawaCore Program Lecture SeriesSeptember 2019A 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 better reflect the information in the lat
2、est 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 that I wont examine you on this stuff bu
3、t 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!Objectives I Chemical structure Structure-function relationships Physiochemical properties Mechanism of action Pharmacokinetics of Inhaled
4、 Agents Uptake and Distribution Fa/Fi curves,and factors which affect them Metabolism of Inhalation Anesthetics Objectives II Definition of MAC Factors which affect MAC Cardiovascular effects Pulmonary effects CNS effects Neuromuscular effects Hepatic effects Renal effects Uterine effects Marrow eff
5、ectsThe 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 Anesthesia.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
6、Chapter 5b.Pulmonary Pharmacology.125-146 Chapter 6.Metabolism and Toxicity.147-173 Much of it requires rote memorization Some of it useful-all of it“test-able”I cant cover all of it in 3 hoursGregs goals for this lecture Inflict my view of what you should know Put this in a clinical(read:useful)con
7、text Explain that which needs explaining Leave the memory work to you Be back on my porch,beer in hand,by 1730Chemical structure INitrous OxideDiethyl EtherHalothaneFun with chemistry Halogenation reduces flammability Fluorination reduces solubility Trifluorcarbon groups add stability Alkanes precip
8、itate arrythmiasChemical structure IIIsofluraneSevofluraneDesfluranePhysical 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 OC halothane is preserved with thymol vapor pressures are n
9、eeded for some exam questions knowledge of blood:gas partition coefficients may actually be useful Partition coefficients Represent 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 sub
10、stance(concentration)arent equal.We most commonly refer to blood:gas pc The larger the number,the more soluble in bloodBlood:gas partition coefficientsAnesthetic 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 Editi
11、on.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 gas More molecules of a soluble gas are required to saturate liquid phase before increasing partial pressure Speed of onset/offset cl
12、osely related to solubility The lower the blood:gas pc-the faster the onsetUptake 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
13、 drug to the alveolus and uptake of that drug into the blood Time 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(increase delivery)or(b)slow down the leak(decrease uptake).abFactors infl
14、uencing delivery Alveolar ventilation Breathing system volume fresh gas flow Inspired partial pressure(PI)concentration effect second gas effectConcentration and 2nd gas effectsFactors influencing uptake Solubility(blood:gas pc)Cardiac output Alveolar-venous pressure gradient For those of you who li
15、ke formulae:Uptake=Q (PA-Pv)/BP FA/FI CurvesV/Q distribution and uptake Ventilation perfusion uptake is decreased which enhances rise in FA may speed induction for soluble agents less difference with low solubility agents(fast anyway)Nitrous Oxide N20 leaves blood 34x more than N2 absorbed Sure,othe
16、r agents are more soluble but we dont give them at 70%end-tidal concentration distension of closed air spaces 70%N2O will double a pneumo in 10 minutesAgent Blood:Gas PC Nitrous Oxide 0.47 Nitrogen 0.014 Mechanism of Action Meyer-Overton Theory lipid soluble agent spreads membranes distorting membra
17、ne proteins(ie ion channels).Protein Receptor Hypothesis inhaled 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 knowsMetabolism of inhaled anesthetics Fairly
18、 small component of elimination Occurs at cytochrome p450 Inducible Oxidative o-dealkylation dehalogenation epoxidation Reductive occurs only with halothane in hypoxic conditionsThree determinants of metabolism Chemical structure ether bond carbon-halogen bond Hepatic enzyme activity Blood concentra
19、tionMetabolism 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.BreakMinimum alveolar concentration Alveolar concentration required to prevent movement in 50%of subjects standar
20、d stimulus represents brain concentration consistent within and between species additiveMAC ValuesAgent MAC Nitrous oxide 104 Desflurane 6.6 Sevoflurane 1.8 Enflurane 1.63 Isoflurane 1.17 Halothane 0.75 Table 15-1.Barash 4th Edition.p378.Factors increasing MAC Hyperthermia Chronic ETOH abuse Hyperna
21、tremia Increased CNS transmitters MAOI Amphetamine Cocaine Ephedrine L-DOPATable 15.4.Barash 4th Edition.P389Factors decreasing MAC Increasing age Hypothermia Hyponatremia Hypotension(MAP50mmHg)Pregnancy Hypoxemia(38 mmHg)O2 content(I=D=S.Cardiac output Despite myocardial depression cardiac output i
22、s well-maintained with isoflurane and desflurane preservation of heart rate greater reduction in SVR preservation of baroreceptor reflexesSystemic vascular resistance All are direct vasodilators,except N2O relax vascular smooth muscle cAMP-Ca2+and or nitric oxide involved variable effects on individ
23、ual vascular bedsDysrhytmias 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 ED50 of epinephrine Children somewhat more resistantCoronary blood flow Isoflura
24、ne 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 coronary vessel collateral perfusion with 90%stenosis In practice,doesnt seem to be a problemRespiratory pattern Increa
25、sed frequency Decreased tidal volume Decreased minute ventilation Attributed(in cats)to sensitization of pulmonary stretch receptors-not supported in humansMechanoreceptors Sense tension in muscles/tendons in intercostal muscles Increased resistance detected and increased respiratory effort recruite
26、d Responses to inspiratory and expiratory loads diminished Further inhibition in patients with COPDChemoreceptors Apneic threshold raised Response to PCO2 blunted PCO2 increased while spontaneously ventilating ED=IS=H hypoxic drive abolished by 0.1 MACBronchial musculature Reduce vagal tone Direct r
27、elaxation increased cAMP(but not via adrenoreceptor mediated)When bronchospastic,a dose dependent reduction in Raw occurs with most agents Hypoxic pulmonary vasoconstriction Inhaled anesthetics appear to blunt HPV and increase shunt Shunt and PO2 appear unchanged in studies of inhaled anesthetics du
28、ring one lung ventilation Intrinsic changes in HPV confounded by changes in cardiac output pulmonary artery pressure positionCentral nervous system Increase cerebral blood flow Increase ICP Decreased CMRO2 Decreased frequency-increased voltage on EEG 2 MAC enflurane increases seizure activity Decrea
29、sed amplitude-increased latency on SSEPNeuromuscular function Skeletal muscle relaxation Potentiate NDMR Trigger MHHepatic Hepatic arterial blood flow decreased by halothane Clearance of drugs decreased in keeping with reductions in hepatic blood flow Hepatotoxicity mild,transient,postoperative incr
30、ease in LFTs?due to transient hypoxia reductive metabolites massive hepatic necrosis oxidative metabolite binds to hepatocyte repeat exposure leads to immune-mediated necrosisRenal Dose-dependent decreases in renal blood flow glomerular filtration rate urine output Related to changes in CO and BP no
31、t ADH Fluoride nephrotoxicity at serum conc.50 mol/l F-opposes ADH leading to polyuria methoxyflurane 2.5 MAC-hours enflurane 9.6 MAC-hours Obstetrical N2O has no effect Halogenated volatiles lead to dose-dependent uterine relaxation reductions in uterine blood flowMiscellaneous 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
