Inhalational anesthetics

Inhalational anesthetics

1. DRTR SHRESTHA, KMCTH

2. History
•Inhaled anesthetics introduced
into clinical practice with the
successful use of nitrous oxide
in 1844 for dental anesthesia
followed by recognition of the
anestheticproperties of ether
in 1846 and of chloroform in
1847.
•Modern anesthetics, beginning
with halothane, differ from
prior anesthetics in being
fluorinated and nonflammable

3. Pharmacokinetics
•Absorption from alveoli into pulmonary capillary
blood
•Distribution in the body
•Metabolism
•Elimination

4. Determinants of Alveolar Partial Pressure
▪P
AandultimatelytheP
BRAINofinhaledanesthetics
determinedby
▪Input(delivery)intoalveoliminusuptake
(loss)ofthedrugfromalveoliintoarterial
blood

5. Input of anesthetics
Input of anesthetics into alveoli depends on
1.Inhaled partial pressure (PI)
2.Alveolar ventilation
3.Characteristics of the anesthetic breathing

6. 1 Inhaled partial pressure (PI)
▪HighPIdeliveredfromanestheticmachineisrequired
duringinitialadministrationoftheanesthetic.
▪Ahighinitialinputoffsetstheimpactofuptake,
acceleratinginductionofanesthesiaasreflectedbytherate
ofriseintheP
aandthustheP
BRAIN.
▪Withtime,asuptakeintotheblooddecreases,PIshouldbe
decreasedtomatchthedecreasedanestheticuptakeand
thereforemaintainaconstantandoptimalP
BRAIN.

7. Concentration effect
▪ImpactofPIontherateofriseoftheP
aofaninhaledanesthetic
▪Impactoftheinhaledconcentrationofananestheticontherateat
whichthealveolarconcentrationincreasestowardtheinspired
▪HigherthePI,themorerapidlytheP
AapproachesthePI
▪Resultsfromconcentratingeffect&augmentationoftrachealinflow
▪Concentratingeffect:reflectsconcentrationoftheinhaledanestheticin
asmallerlungvolumeduetouptakeofallgasesinthelung
▪Anestheticinputviatrachealinflowisincreasedtofillthespace(void)
producedbyuptakeofgases

8. 2L 2L
2L
1L
50% O
2
50% N
2O
66 %O
2
33 % N
2O
2.5L
1.5L
62.5 %O
2
37.5 % N
2O
500 ml N
2O + 500 ml O
2
Augmentation of
tracheal inflow
Concentrating
effect
Inspired
After
diffusion
of N
2O
If 10% N
2Oand 90% O
2→the rise in alveolar concentration of N
2Owill be very low
5.3% by concentrating effect 5X
5.5. % by augmented inflow effect 6.8X compared to the 50:50 mixture

9. Second-Gas Effect
▪Theabilityofhigh-volumeuptakeofonegas(firstgas)toaccelerate
therateofincreaseofthePaofaconcurrentlyadministered
“companion”gas(secondgas)
▪Initiallarge-volumeuptakeofnitrousoxideacceleratestheuptakeof
companion(second)gasessuchasoxygenandvolatileanesthetics.
▪Increaseduptakeofsecondgasreflectsincreasedtrachealinflowofall
inhaledgases(firstandsecondgases)andhigherconcentrationof
secondgasorgasesinasmallerlungvolume(concentratingeffect)due
tohigh-volumeuptakeoffirstgas

10. •Concentratingeffect:Halfofnitrousoxidediffusesquicklytoblood,alveolarvolumereducesto3000ml.
Thenewalveolarconcentrationofisofluraneis40/3000~1.33%.
•Augmentedinfloworventilationeffect:Duetosubatmosphericpressurecreatedinalveoli,further1lof
mixturegasisinhaled,i.e.10mlisoflurane,490mloxygenand500mlnitrousoxide.So,thenewalveolar
concentrationis(40+10)/4000~1.25%.
50% N
2O
40 ml
1.96 L
2L
500 ml N
2O + 490 ml O
2+ 10ml Isoflurane
Inspired
After
diffusion
of N
2O
49% O2
1% Isoflurane
33.3 % N
2O
40 ml
1.96 L
1L
65.3 %O2
1.3 % Isoflurane
37.5 % N
2O
61.25 % O2
1.25% Isoflurane
4 L 4 L3 L

11. 2 Alveolar Ventilation
▪Increasedalveolarventilation,likePI,promotesinputof
anestheticstooffsetuptake
▪MorerapidrateofincreaseinthePatowardthePIand
thusinductionofanesthesia
▪Inneonates,thisratioisapproximately5:1comparedwith
only1.5:1inadults,reflectingthegreatermetabolicratein
neonatescomparedwithadults.
▪RateofincreaseofPatowardthePIandthustheinduction
ofanesthesiaismorerapidinneonatesthaninadults

12. Spontaneous vs Mechanical Ventilation
▪Inhaledanestheticsinfluencetheirownuptakebyvirtueofdose-
dependentdepressanteffectsonalveolarventilation.
▪Asanestheticinputdecreasesinparallelwithdecreasedventilation,
anestheticpresentintissuesisredistributedfromtissuesinwhichitis
presentinhighconcentrations(brain)toothertissuesinwhichitis
presentinlowconcentrations(skeletalmuscles).
▪Whentheconcentration(partialpressure)inthebraindecreasestoa
certainthreshold,ventilationincreasesanddeliveryoftheanesthetic
tothelungsincreases.
▪Aprotectivemechanism,whichisnotseeninmechanicalventilation

13. 3 Anesthetic Breathing System
▪Inductioncanbeacceleratedwiththeuseofhighinflow
rates
▪Smallerthecircuitvolume,closertheinspiredgas
concentrationwillbetothefreshgasconcentration
▪Lowerthecircuitabsorption,closertheinspiredgas
concentrationwillbetothefreshgasconcentration.
▪Inrebreathingtheinspiredgasmixturesmaybediluted
byresidualgasesinthesystem.Lowertherebreathing,
closertheinspiredgasconcentrationwillbetothefresh
gasconcentration

14. Uptake of inhaled anesthetics
Uptake of inhaled anesthetics from alveoli into the pulmonary
capillary blood depends on
▪Solubility of the anesthetic in body tissues
▪Cardiac output
▪Alveolar-to-venouspartial pressure differences

15. Solubility
▪Partitioncoefficientisadistributionratiodescribinghow
theinhaledanestheticdistributesitselfbetweentwo
phasesatequilibrium(partialpressuresequalinboth
phases).
▪Ostwald’sblood:gaspartitioncoefficientof0.5meansthat
theconcentrationofinhaledanestheticinthebloodishalf
thatpresentinthealveolargaseswhenthepartial
pressuresoftheanestheticinthesetwophasesisidentical

16. Blood:GasPartition Coefficients
▪Whenbloodsolubilityislow,minimalamountsofinhaledanestheticmustbe
dissolvedbeforeequilibrationisachieved;therefore,therateofincreaseofPa
andPa,andthusonset-of-drugeffectssuchastheinductionofanesthesia,are
rapid.
▪overpressuretechniqueandmaybeusedtospeedtheinductionofanesthesia:
increasingthePIabovethatrequiredformaintenanceofanesthesia
▪Blood:gaspartitioncoefficientsarealteredbyindividualvariationsinwater,
lipid,andproteincontentandbythehematocritofwholeblood
▪blood:gaspartitioncoefficientsareabout20%lessinbloodwithahematocrit
of21%comparedwithbloodwithahematocritof43%.Presumably,this
decreasedsolubilityreflectsthedecreaseinlipid-dissolvingsitesnormally
providedbyerythrocytes.
▪Ingestionofafattymealaltersthecompositionofblood,resultinginan
approximately20%increaseinthesolubilityofvolatileanestheticsinblood

17. Tissue: blood partition coefficients
▪Tissue:bloodpartitioncoefficientsdetermineuptakeof
anestheticintotissuesandthetimenecessaryfor
equilibrationoftissueswiththePa.

18. Oil: gas partition coefficients
▪Oil:gaspartitioncoefficientsparallelanesthetic
requirements
▪EstimatedMAC=150dividedbytheoil:gaspartition
coefficient
▪150,istheaveragevalueoftheproductofoil:gassolubility
andMACforseveralinhaledanestheticswithwidely
divergentlipidsolubilities

19. Cardiac output
▪Cardiacoutput(pulmonarybloodflow)influencesuptake
▪AndP
Abycarryingawayeithermoreorlessanesthetic
fromthealveoli
▪Anincreasedcardiacoutputresultsinmorerapiduptake,
→rateofincreaseintheP
A→slowinductionofanesthesia

20. Alveolar–venous partial pressure gradient
▪Thedifferencebetweenalveolarandvenouspartial
pressuresisduetotissueuptakeofinhalationagents.
▪Braintissueequilibratesquicklybecauseitishighly
perfusedwithblood.Leantissue(muscle)hasroughlythe
sameaffinityforanaestheticagentsasblood(bloodtissue
coefficient1:1),butperfusionismuchlowerthanbrain
tissue;therefore,equilibrationisslower.Fat–blood
coefficientsaresignificantly>1.
▪Suchhighaffinityoffattissueforanaestheticanditslow
perfusionlevelsresultinaverylongequilibrationtime.

21. Pharmacodynamics
▪MACofaninhaledanestheticisdefinedasthatconcentrationat1
atmospherethatpreventsskeletalmusclemovementinresponsetoa
supramaximalpainfulstimulus(surgicalskinincision)in50%of
patients
▪MAC
awake,theconcentrationofanestheticthatpreventsconsciousness
in50%ofpersons,-abouthalfofMAC.
▪MAC
memory,theconcentrationofanestheticthatisassociatedwith
amnesiain50%ofpatients,0.25MAC
▪MAC
bar,topreventadrenergicresponsetonoxiousstimuli-1.5MAC
▪MACintubation1.3MAC

22. MAC of Inhaled Anesthetics
▪Nitrous oxide 104
▪Halothane 0.75
▪Enflurane 1.63
▪Isoflurane 1.17
▪Desflurane 6.6
▪Sevoflurane 1.80
▪Xenon 70

23. Increase in MAC
▪Hyperthermia
▪Excess pheomelaninproduction (red hair)
▪Drug-induced increases in central nervous system
catecholamine levels
▪Cyclosporine
▪Hypernatremia

24. Decrease in MAC
▪Hypothermia
▪Increasing age
▪Preoperative medication
▪Drug-induced decreases in
central nervous system
catecholamine levels
▪a-2 agonists
▪Acute alcohol ingestion
▪Pregnancy
▪Postpartum (till 24–72 hours)
▪Lithium
▪Lidocaine
▪Neuraxial opioids (?)
▪PaO
2<38 mm Hg
▪Mean blood pressure<40
mmHg
▪Cardiopulmonary bypass
▪Hyponatremia

25. Mechanisms of Anesthetic Action
Meyer-OvertonTheory
(HansHorstMeyer1899,CharlesErnestOverton1901)
▪Correlationbetweenthelipidsolubilityofinhaled
anesthetics(oliveoil:gaspartitioncoefficient)and
anestheticpotency
▪Greaterthelipidsolubility→greateritsanaesthetic
potency
▪Inhaledanestheticsdisruptsthestructureordynamic
propertiesofthelipidportionsofnervemembranes.

26. ▪Linear relationship
between potency and
partition coefficient for
many types of
anaesthetics
▪Anaesthetic concentration
required to induce
anaesthesia in 50% of a
population of animals (the
EC
50) was independent of
the means by which the
anaesthetic was delivered,
i.e., the gas or aqueous
phase

27. Criticalvolumehypothesis(Miller&Smith1973)
▪Anestheticbindingtohydrophobic/lipophilicsites
inthephospholipidbilayer
▪Expandthebilayerbeyondacriticalamount,
alteringmembranefunction
▪Distortionofchannelsnecessaryforionfluxandthe
subsequentdevelopmentofactionpotentials
neededforsynaptictransmission

28. Bulky and hydrophobic
anaesthetic molecules
accumulate inside the
neuronal cell membrane
causing its distortion and
expansion (thickening) due
to volume displacement.
Membranethickeningreversiblyaltersfunctionofmembraneionchannelsthus
providinganaestheticeffect.
Actualchemicalstructureoftheanaestheticagentpersewasnotimportant.
Butitsmolecularvolumeplaysthemajorrole:themorespacewithinmembrane
isoccupiedbyanaesthetic-thegreateristheanaestheticeffect.

29. ▪Stereoisomersofananaestheticdrughaveverydifferentanaesthetic
potencywhereastheiroil/gaspartitioncoefficientsaresimilar
▪Certaindrugsthatarehighlysolubleinlipids,andthereforeexpected
toactasanaesthetics,exertconvulsiveeffectinstead
(callednonimmobilizers.[Flurothyl(Indoklon)volatileliquiddrug
fromhalogenatedetherfamily]
▪Asmallincreaseinbodytemperatureaffectsmembranedensityand
fluidityasmuchasgeneralanaesthetics,yetitdoesnotcause
anaesthesia.
▪Increasingthechainlengthinahomologousseriesofstraight-chain
alcoholsoralkanesincreasestheirlipidsolubility,buttheiranaesthetic
potencystopsincreasingbeyondacertaincutofflength.
Objections to lipid hypotheses

30. Macroscopic
▪Atthespinalcordlevel,inhalationanaestheticsdecreasetransmissionofnoxious
afferentinformationascendingfromthespinalcordtothecerebralcortexviathe
thalamus,therebydecreasingsupraspinalarousal.
▪Thereisalsoinhibitionofspinalefferentneuronalactivityreducingmovementresponse
topain.
▪Hypnosisandamnesia,ontheotherhand,aremediatedatthesupraspinallevel.
▪Inhalationagentsgloballydepresscerebralbloodflowandglucosemetabolism.
▪Tomographicassessmentofregionaluptakeofglucoseinanaesthetizedvolunteers
indicatesthatthethalamusandmidbrainreticularformationsaremoredepressed
thanotherregions.
▪Electroencephalographicchangesincludinggeneralizedslowing,increasedamplitude,
anduncouplingofcoherentanteroposteriorandinterhemisphericalactivityoccurduring
anaesthetic-inducedunconsciousness

31. Synaptic
▪Theactionsofinhalationagentsonionchannelsofneuronal
tissuecaninfluenceeitherthepresynapticreleaseof
neurotransmitters,alterthepost-synapticresponsethresholdto
neurotransmitters,orboth.
▪Inhaledanaestheticsarebelievedtoinhibitexcitatory
presynapticchannelactivitymediatedbyneuronalnicotinic,
serotonergic,andglutaminergicreceptors,whilealso
augmentingtheinhibitorypost-synapticchannelactivity
mediatedbyGABA
Aandglycinereceptors.
▪Thecombinedeffectistoreduceneuronalandsynaptic
transmission.

32. Molecular
▪Effectsofinhalationagentsona-subunitsoftheGABA
A
transmembranereceptorcomplexarelikelytobeimportant.
▪GABAbindingtoitsreceptorleadstoopeningofachloride
channelleadingtoincreasedCl
2-
ionconductanceand
hyperpolarizationofthecellmembrane,therebyincreasingthe
depolarizationthreshold.
▪InhalationanaestheticsprolongtheGABA
Areceptor-mediated
inhibitoryCl
2-
current,therebyinhibitingpost-synapticneuronal
excitability
▪N
2OandxenonareNMDAantagonists

33. Effects on Respiratory system
▪Depressventilationbyreducingtidalvolume
▪Increaseinrespiratoryratedoesnotcompensateforthereducedalveolarventilation,asitprimarily
resultsinincreaseddead-spaceventilation.
▪Consequently,PaCO
2increases
▪Increasethethreshold(⬇sensitivity)ofrespiratorycentrestoCO
2
▪Hypoxicdrive(theventilatoryresponsetoarterialhypoxia)thatismediatedbyperipheral
chemoreceptorsinthecarotidbodies:depressedbyN
2O,Halothane
▪Halothane:apotentbronchodilator,reversesasthma-inducedbronchospasm
▪Halothaneattenuatesairwayreflexesandrelaxesbronchialsmoothmusclebyinhibitingintracellular
calciummobilization.Halothanealsodepressesclearanceofmucusfromtherespiratorytract
(mucociliaryfunction),promotingpostoperativehypoxiaandatelectasis
▪Isofluraneandsevofluranedecreaseairwayresistance.
▪Desflurane:pungent,airwayirritation-manifestedbysalivation,breath-holding,coughing,and
laryngospasm.Airwayresistancemayincreaseinchildrenwithreactiveairwaysusceptibility.→poor
choiceforinhalationinduction.

34. N
2OHalothaneIsofluraneDesfluraneSevoflurane
Tidal
volume
⬇ ⬇⬇ ⬇⬇ ⬇ ⬇
Respiratory
Rate
⬆ ⬆⬆ ⬆ ⬆ ⬆
Effects on Respiratory system

35. CVS
▪N
2O stimulates Sympathetic NS→catecholamine stimulation
▪So, even though N
2O causes myocardial depression, BP, CO, HR unchanged
▪Reduction of arterial BP mainly due to myocardial depression
▪Reduction in mean arterial pressure by desflurane, sevoflurane, and isoflurane is primarily
determined by the reduction in systemic vascular resistance.
▪Normally, hypotension inhibits baroreceptors in the aortic arch and carotid bifurcation, causing a
decrease in vagal stimulation and a compensatory rise in heart rate. Halothane blunts this reflex.
▪Cardiac output maintained with isoflurane due to preservation of carotid baroreflexes.
▪Halothane sensitizes heart to arrthymogeniceffects of epinephrine→doseabove 1.5mcg/kg avoided
▪Isoflurane: Dilation of normal coronary arteries can divert blood away from fixed stenotic lesions
(Coronary steal)
▪Sevoflurane may prolong the QT interval, manifest 60 min following emergence in infants
•Ischaemicpreconditioning with inhalation anaesthetics may reduce perioperative myocardial
injury: K
ATPchannel activity increased→decrease in the voltage gradient, decrease in calcium ion
accumulation, the cardiac action potential shortens, negative inotropic action and remarkable
protection against subsequentmsustainedischemic

36. N
2OHalothaneIsofluraneDesfluraneSevoflurane
Blood
pressure
⬌ ⬇⬇ ⬇⬇ ⬇⬇ ⬇
Heart rate⬌ ⬇ ⬆ ⬆⬌ ⬌
SVR ⬌ ⬌ ⬇⬇ ⬇⬇ ⬇
Cardiac
output
⬌ ⬇ ⬌ ⬆⬌ ⬇
CVS

37. Central nervous system
▪⬆CBFandCerebralbloodvolume→⬆ICP
▪N
2O:⬆CMRO
2→lessattractiveforneuroanesthesia
▪Decreasecerebralmetabolicrateandoxygenconsumption
▪Vasodilatationofcerebralvessels→⬇cerebralvascularresistance,⬆CBF,⬆ICP
(MorepronouncedwithHalothane)
▪Hyperventilationpriortohalothaneadministration→prevent⬆ICP
▪Hyperventilation→⬇PaCO2→arterialvasoconstriction→⬇CBF,cerebralbloodvolume,ICP
▪LesswithIsoflurane;hyperventilationnotneededtoprevent⬆ICP
▪However,thesereduceMAP→decreasedCPP
▪ElectricallysilentEEG
▪Burstsuppressionathigherconcentrationwithdesflurane

38. N
2OHalothaneIsofluraneDesfluraneSevoflurane
Blood
flow
⬆ ⬆⬆ ⬆ ⬆ ⬆
ICP ⬆ ⬆⬆ ⬆ ⬆ ⬆
CMR ⬆ ⬇ ⬇⬇ ⬇⬇ ⬇⬇
Seizure ⬇ ⬇ ⬇ ⬇ ⬇
Central nervous system

39. Neuromuscular
▪N
2Odoesnotprovidesignificantmusclerelaxation.Athigh
concentrations→skeletalmusclerigidity
▪Halothanerelaxesskeletalmuscleandpotentiatesnon-
depolarizingneuromuscular-blockingagents.
▪Volatileanesthetics:triggeringagentofmalignant
hyperthermia
▪Desfluraneisassociatedwithadose-dependentdecrease
intheresponsetotrain-of-fourandtetanicperipheral
nervestimulation.

40. Renal
▪Productionofinorganicfluoridebythemetabolismof
halogenatedagentsmaycausedirectnephrotoxicity.
▪⬇Bloodflow,GFR,urineoutput⬇
(dueto⬆Renalvascularresistance,⬇arterialBPandCO)
▪Isofluraneismoreresistanttodefluorinationandcanbe
usedforprolongedperiodswithoutsignificantincreasesin
serumfluoridelevels
▪Preoperativehydrationlimitsthesechangesinrenal
function

41. Gastrointestinal
▪N
2O increases the risk of postoperative nausea and vomiting
▪Activation of chemoreceptor trigger zone and vomiting center in the
medulla

42. Metabolism and toxicity
▪N
2O:eliminatedbyexhalation
▪Smallamountdiffusesoutthroughskin
▪<0.01%undergoesreductivemetabolisminGItractbyanaerobicbacteria
▪Oxidizescobalt(vitaminB12)→inhibitsvitaminB-12dependentenzymes
▪Methioninesynthetase(myelinformation)→peripheralneuropathies,
neurotoxicity
▪Thymidylatesynthetase(DNAsynthesis)→teratogenecity
▪Bonemarrowdepression(megaloblasticanemia)
▪Alterimmunologicalresponsetoinfectionbyaffectingchemotaxisandmotility
ofpolymorphonuclearleukocytes

43. ▪Extremely rare (1 per 35,000 cases)
–HalothaneoxidizedintheliverbyCYP2EI→principalmetabolite,trifluoroaceticacid
–Thismetabolismcanbeinhibitedbypretreatmentwithdisulfiram
▪Exposure to multiple halothane anesthetics at short intervals
▪Middle-aged obese women
▪Familial predisposition to halothane toxicity
▪Personal history of toxicity
▪Signs(are mostly related to hepatic injury)
▪increased serum alanine and aspartate transferase, elevated bilirubin (leading to
jaundice), and encephalopathy
▪Centrilobularnecrosis
▪Signs indicating an allergic reaction (eosinophilia, rash, fever) and do not
appear until a few days after exposure
Halothane hepatitis

44. Carbon monoxide poisoning
•DesfluraneisdegradedbydesiccatedCO
2
absorbent(bariumhydroxidelime,butalso
sodiumandpotassiumhydroxide)intocarbon
monoxide
•DifficulttodiagnoseunderGA
•CarboxyhemoglobinmaybedetectablebyABG
analysis,lowerthanexpectedSpO
2

45. Compound A
•Sodalimeorbariumhydroxidelime(butnotcalcium
hydroxide)candegradesevoflurane→CompoundA
•Fluoromethyl-2,2-difluoro-1-[trifluoromethyl]vinylether
•Nephrotoxic
•Accumulationincreaseswithincreasedrespiratorygas
temperature,lowflowanesthesia,drybariumhydroxide
absorbent,highsevofluraneconcentrations,and
anestheticsoflongduration.

46. Xenon
▪Inert (probably nontoxic with no metabolism)
▪Minimal CVS effects
▪TV increase, RR decrese
▪Low blood solubility (B:G coeff0.115)
▪Rapid induction and recovery
▪Does not trigger malignant hyperthermia
▪Environmentally friendly
▪Nonexplosive
▪High cost, Low potency (MAC = 70%)

47. References
▪Morgan & Mikhail’s Clinical Anesthesiology,
5th edn
▪Stoelting’sPharmacology and Physiology in
Anesthetic Practice, 5th edn
▪Khan KS, Hayes I, Buggy DJ. Pharmacology of
anaesthetic agents II: inhalation anaesthetic
agents.Continuing Education in Anaesthesia
Critical Care & Pain. 2014;14(3):106-11.