ANESTÉSICOS ANESTÉSICOS INALATÓRIOSINALATÓRIOS

Carlos Darcy A. BersotCarlos Darcy A. Bersot

Anestesiologia - Dados HistóricosAnestesiologia - Dados Históricos

18461842

PK InalatóriaPK Inalatória

PK InalatóriaPK Inalatória

CaptaçãoCaptação FAFA FIFI FA/FIFA/FI

Dalton’s law: Dalton’s law:

partial pressure of each component gas is partial pressure of each component gas is directly related to its concentrationdirectly related to its concentration

P total = P1 + P2 + P3 + .......Pn P total = P1 + P2 + P3 + .......Pn The Partial Pressure is defined as the The Partial Pressure is defined as the

pressure of a single gas in the mixture as pressure of a single gas in the mixture as if that gas alone occupied the containerif that gas alone occupied the container

Henry’s law:Henry’s law:

The quantity of gas that will dissolve in a The quantity of gas that will dissolve in a liquid is proportional to the partial liquid is proportional to the partial pressure of that gas in contact with the pressure of that gas in contact with the liquid, or the partial pressure of the gas in liquid, or the partial pressure of the gas in the gas phasethe gas phase

Partition coefficient:Partition coefficient: An expression of the relative An expression of the relative

solubility of a substance in two solubility of a substance in two immiscible phases. It compares the immiscible phases. It compares the amount of gas present in the first amount of gas present in the first phase when one part dissolves in phase when one part dissolves in the second phase.the second phase.

Partition coefficient:Partition coefficient: An expression of the relative An expression of the relative

solubility of a substance in two solubility of a substance in two immiscible phases. It compares the immiscible phases. It compares the amount of gas present in the first amount of gas present in the first phase when one part dissolves in phase when one part dissolves in the second phase.the second phase.

PK InalatóriaPK Inalatória

PK InalatóriaPK Inalatória

PK InalatóriaPK Inalatória

PK InalatóriaPK Inalatória

INDUCTION

Te

mp

o(s

eg

)

0

50

100

150

200

250

300

IsofluraneEnfluraneHalothane

RECOVERY

Bersot,CD UFRJ 2006 in mice

Concentration/Second Concentration/Second Gas EffectsGas Effects

As you anesthetic concentration, you alveolar concentration.

As you 1st anesthetic concentration, you alveolar concentration of 2nd anesthetic .

AA 1% of

second gas

BB 1.7 % of second

gas

19 % O231.7 % O2

Uptake of half of the N2O 66.7 % N2O

80% N2O

Minimum alveolar Minimum alveolar concentration (MAC)concentration (MAC)

Alveolar concentrationAlveolar concentration required to required to prevent movement in 50% of subjectsprevent movement in 50% of subjects

standard stimulus – originally incisionstandard stimulus – originally incision represents +/- brain concentrationrepresents +/- brain concentration

additiveadditive

MAC Values (%)MAC Values (%)

PROPRIEDADES FISICOQUÍNICAS DOS ANESTÉSICOS INALATÓRIOS

  Sevoflurano Desflurano Isoflurano Enflurano Halotano N2O

Ponto de ebulição (°C) 59 24 49 57 50 –88

Pressão de vapor a 20°C (mm Hg) 157 669 238 172 243 38.770

Peso molecular (g) 200 168 184 184 197 44

Coeficiente de partição óleo:gás 47 19 91 97 224 1.4

Coeficiente de partição sangue:gás 0,65 0,42 1,46 1,9 2,50 0,46

Solubilidade cérebro:sangue 1,7 1,3 1,6 1,4 1,9 1,1

Solubilidade gordura:sangue 47,5 27,2 44,9 36 51,1 2,3

Solubilidade músculo:sangue 3,1 2,0 2,9 1,7 3,4 1,2

CAM em O2, 30-60 a, 37°C PB760 (%) 1,8 6,6 1,17 1,63 0,75 104

CAM em 60–70% N2O (%) 0,66 2,38 0,56 0,57 0,29  

CAM >65 a (%) 1,45 5,17 1,0 1,55 0,64 —

Preservativo Não Não Não Não Timol Não

Estável em absorvedor CO2 úmido Não Sim Sim Sim Não Sim

Inflamabilidade (%) (N2O/O2 70/30%) 10 17 7 5,8 4,8  

Recuperado como metabólitos(%) 2–5 0,02 0,2 2,4 20  

NEUROSCIENCE OF NEUROSCIENCE OF GENERAL GENERAL

ANAESTHESIAANAESTHESIA

Molecular Mechanism of Molecular Mechanism of Action: Two IdeasAction: Two Ideas

1.1. Meyer-Overton TheoryMeyer-Overton Theorylipid soluble drug increases volume of lipid soluble drug increases volume of

lipid membranes which, in turn, lipid membranes which, in turn, distorts membrane proteins distorts membrane proteins

2.2. Protein Receptor HypothesisProtein Receptor Hypothesisinhaled agent binds directly to inhaled agent binds directly to

hydrophobic part of membrane hydrophobic part of membrane proteinprotein

The GABA/Cl channel complex

GABAA / GABAB

GABA effects vs direct Cl- action

Channel open-time Bicuculline = GABAA

antagonist (NB bicuculline doesn’t reverse general anaesthesia!!!)

Subcortical vs Cortical

Cortex is more sensitive than thalamus/reticular activating system (Steriade, Electro Clin Neurophys 1994;90:1), (Tomoda, BJA 1993;71:383), (Angel, Exp Phys 1991;76:1), (Dougherty, J. Neurophys 1997;77:1375)

The Pathways of MAC/Rousability

Actual State

Potential response

“Functional Disconnection of cortico-thalamic circuits” White & Alkire, Neuroimage 2003;19:402

Halothane and K+ Channels (IKAn) (Winegar -Anesth 1996;85:889)

Hyperpolarization is minor and NOT proportional to Spike Rate (MacIvor & Kendig, Anesthesiology, 1991;74:83)

May be important in EEG phenomena of Deep Anaesthesia

Nitrous OxideNitrous Oxide

Simple linear Simple linear compoundcompound

Not metabolizedNot metabolized Only anesthetic Only anesthetic

agent that is agent that is inorganicinorganic

Nitrous OxideNitrous Oxide

Low potencyLow potency MAC value is 105%MAC value is 105% Weak anesthetic, powerful analgesicWeak anesthetic, powerful analgesic Needs other agents for surgical Needs other agents for surgical

anesthesiaanesthesia Low blood solubility (quick recovery)Low blood solubility (quick recovery)

Nitrous Oxide Systemic EffectsNitrous Oxide Systemic Effects

Minimal effects on heart rate and Minimal effects on heart rate and blood pressureblood pressure

May cause myocardial depressionMay cause myocardial depression Little effect on respirationLittle effect on respiration Safe, efficacious agentSafe, efficacious agent

Nitrous Oxide Side EffectsNitrous Oxide Side Effects

Beginning of case: second gas effectBeginning of case: second gas effect End of case: diffusion hypoxiaEnd of case: diffusion hypoxia Diffusion into closed spacesDiffusion into closed spaces

Nitrous Oxide Side EffectsNitrous Oxide Side Effects

Inhibits methionine synthetase Inhibits methionine synthetase (precursor to DNA synthesis)(precursor to DNA synthesis)

Inhibits vitamin B-12 metabolismInhibits vitamin B-12 metabolism Dentists, OR personnel, abusers at riskDentists, OR personnel, abusers at risk

HalothaneHalothane

Synthesized in Synthesized in 1956 by Suckling1956 by Suckling

Halogen Halogen substituted ethanesubstituted ethane

Volatile liquid Volatile liquid easily vaporized, easily vaporized, stable, and stable, and nonflammablenonflammable

HalothaneHalothane

Most potent inhalational anestheticMost potent inhalational anesthetic MAC of 0.75%MAC of 0.75% Efficacious in depressing Efficacious in depressing

consciousnessconsciousness Very soluble in blood and adiposeVery soluble in blood and adipose Prolonged emergenceProlonged emergence

Halothane Systemic EffectsHalothane Systemic Effects

Inhibits sympathetic response to Inhibits sympathetic response to painful stimulipainful stimuli

Inhibits sympathetic driven Inhibits sympathetic driven baroreflex response (hypovolemia)baroreflex response (hypovolemia)

Sensitizes myocardium to effects of Sensitizes myocardium to effects of exogenous catecholamines-- exogenous catecholamines-- ventricular arrhythmiasventricular arrhythmias

Halothane Systemic EffectsHalothane Systemic Effects

Decreases respiratory drive-- central Decreases respiratory drive-- central response to COresponse to CO22 and peripheral to O and peripheral to O22

Depresses myocardium-- lowers BP Depresses myocardium-- lowers BP and slows conductionand slows conduction

Mild peripheral vasodilationMild peripheral vasodilation

Halothane Side EffectsHalothane Side Effects

““Halothane Hepatitis” -- 1/10,000 Halothane Hepatitis” -- 1/10,000 casescases fever, hepatic necrosis, deathfever, hepatic necrosis, death metabolic breakdown products are metabolic breakdown products are

hapten-protein conjugateshapten-protein conjugates immunologically mediated assaultimmunologically mediated assault exposure dependentexposure dependent

Halothane Side EffectsHalothane Side Effects

Malignant Hyperthermia-- 1/60,000 Malignant Hyperthermia-- 1/60,000 with succinylcholine to 1/260,000 with succinylcholine to 1/260,000 withoutwithout halothane in 60%, succinylcholine in halothane in 60%, succinylcholine in

77%77% Classic-- rapid rise in body Classic-- rapid rise in body

temperature, muscle rigidity, temperature, muscle rigidity, tachycardia, rhabdomyolysis, acidosis, tachycardia, rhabdomyolysis, acidosis, hyperkalemia, DIChyperkalemia, DIC

EnfluraneEnflurane

Developed in 1963 Developed in 1963 by Terrell, by Terrell, released for use in released for use in 19721972

Stable, Stable, nonflammable nonflammable liquidliquid

Pungent odorPungent odor MAC 1.68%MAC 1.68%

Enflurane Systemic EffectsEnflurane Systemic Effects

Potent inotropic and chronotropic Potent inotropic and chronotropic depressant and decreases systemic depressant and decreases systemic vascular resistance-- lowers blood vascular resistance-- lowers blood pressure and conduction dramaticallypressure and conduction dramatically

Inhibits sympathetic baroreflex Inhibits sympathetic baroreflex responseresponse

Sensitizes myocardium to effects of Sensitizes myocardium to effects of exogenous catecholamines-- exogenous catecholamines-- arrhythmiasarrhythmias

Enflurane Side EffectsEnflurane Side Effects

Metabolism one-tenth that of Metabolism one-tenth that of halothane-- does not release quantity halothane-- does not release quantity of hepatotoxic metabolitesof hepatotoxic metabolites

Metabolism releases fluoride ion-- Metabolism releases fluoride ion-- renal toxicityrenal toxicity

Epileptiform EEG patternsEpileptiform EEG patterns

IsofluraneIsoflurane

Synthesized in 1965 Synthesized in 1965 by Terrell, by Terrell, introduced into introduced into practice in 1984practice in 1984

Not carcinogenicNot carcinogenic Nonflammable,pungeNonflammable,punge

ntnt Less soluble than Less soluble than

halothane or halothane or enfluraneenflurane

MAC of 1.30 %MAC of 1.30 %

Isoflurane Systemic EffectsIsoflurane Systemic Effects

Depresses respiratory drive and Depresses respiratory drive and ventilatory responses-- less than ventilatory responses-- less than enfluraneenflurane

Myocardial depressant-- less than Myocardial depressant-- less than enfluraneenflurane

Inhibits sympathetic baroreflex Inhibits sympathetic baroreflex response-- less than enfluraneresponse-- less than enflurane

Sensitizes myocardium to catecholamines Sensitizes myocardium to catecholamines -- less than halothane or enflurane-- less than halothane or enflurane

Isoflurane Systemic EffectsIsoflurane Systemic Effects

Produces most significant reduction Produces most significant reduction in systemic vascular resistance-- in systemic vascular resistance-- coronary steal syndrome, increased coronary steal syndrome, increased ICPICP

Excellent muscle relaxant-- Excellent muscle relaxant-- potentiates effects of neuromuscular potentiates effects of neuromuscular blockersblockers

Isoflurane Side EffectsIsoflurane Side Effects

Little metabolism (0.2%) -- low Little metabolism (0.2%) -- low potential of organotoxic metabolitespotential of organotoxic metabolites

Bronchoirritating, laryngospasmBronchoirritating, laryngospasm

Sevoflurane and DesfluraneSevoflurane and Desflurane

Low solubility in blood-- produces Low solubility in blood-- produces rapid induction and emergencerapid induction and emergence

Minimal systemic effects-- mild Minimal systemic effects-- mild respiratory and cardiac suppressionrespiratory and cardiac suppression

Few side effectsFew side effects ExpensiveExpensive DifferencesDifferences

Sistema Nervoso Central

Silêncio ao EEG:Iso, Sevo e Desflurano: em torno de 2 CAMHalotano: acima de 3,5 CAMEnflurano: não há silêncio

Proteção cerebral:Isoflurano: semelhante ao tiopental, até silêncio

Atividade convulsivante:Enflurano > 2 CAM

Fluxo Sangüíneo Cerebral

Stoelting

Isoflurano preserva auto-regulaçãoHalotano não preserva

Liquor

ProduçãProduçãoo

AbsorçAbsorçãoão

Efeito na Efeito na PICPIC

EnfluranEnfluranoo

++ -- ++

IsofluraIsofluranono == ++

NN22OO ==

Barash

Stoelting

Sistema Nervoso Autônomo

Índice Cardíaco, PVC, RVS

RVS

ContrContra-a-

tilidatilidadede

RVSRVS PAPA

HalotHalot -- ++ --

I, S, I, S, DD

== -- --

Freqüência Cardíaca e Pressão ArterialPressão Arterial

HH --

I,S,I,S,DD

++

FC:

Mecanismos: depressão de reflexo baro-r, depressão NSA

Arritmias

Parâmetros Respiratórios

Barash

Mecanismo da depressão:depressão dos centros

medularesalteração da função dos

músculos intercostais

Resposta Ventilatória ao CO2

Stoelting

Resposta à hipoxemia0,1 CAM diminui 50-70%

Broncodilatação

Barash

É difícil demonstrar efeito broncodilatador na ausência de broncoconstricção

Vasoconstricção Hipóxica

Barash

A inibição da vasoconstricçãopulmonar hipóxica pelosanestésicos inalatórios nãoprejudica a oxigenação naventilação monopulmonar.

Músculos EsqueléticosHipertermia Maligna

Todos os halogenados podem desencadear

Aumento das contraturas induzidas por cafeínano sartório do sapo

NN22OO IsoIso EnflEnfl HalHal

1,31,3 33 44 1111

Contratilidade Uterina

Metabolismo dosAnestésicos Inalatórios

Metabolismo dos Anestésicos InalatóriosDegradação pelos absorvedores de CO2

Monóxido de Carbono – COComposto A

MetabolismoOxidativo

FluoretosTrifluoracetato

Redutivo

O metabolismo dos halogenados pode:gerar produtos tóxicos ao fígado, aos rins e órgãos reprodutoresinfluenciar na eliminação do anestésico (metoxiflurano)

Composto A

Produção maior com:fluxos baixos de gasestemperaturas altasumidade baixaabsorvedor baritado

O composto A em si não é tóxico.

A biodegradação para conjugados de cisteína e a ação da enzimarenal beta-liase resulta na produção de tiol potencialmente tóxico.

O metabolismo pela via da beta liase é menos extenso em humanosque em ratos

Fluxo Sangüíneo Hepático

Stoelting

A ação do Desflurano é semelhante à do Isoflurano

HepatotoxicidadeOs testes de função hepática ficam alterados transitoriamente com

quase todos os anestésicos, exceto isoflurano, em voluntáriosHipóxia e baixa perfusão agravam as alterações no pós-operatórioIndução enzimática aumenta necessidade de oxigênio

Barash

Pacientes com lesão hepáticatêm alterações maiores

HepatotoxicidadeAs alterações no pós-operatório são mais evidentes com o Halotano:

20% têm quadro benigno e auto-limitado:náusea, letargia, febre, aumento de transaminases

Produtos do metabolismo redutivo não são tóxicos

Hepatite por Halogenados

Eosinofilia, febre, alterações cutâneas, artralgia, exposição prévia

Há suscetibilidade genética

1:10.000 a 1:30.000 de pacientes que recebem HalotanoOcorre também com enflurano, isoflurano e desflurano

incidência é menor que com halotano, em proporção comsolubilidade e metabolização oxidativa

há sensibilização cruzada entre anestésicos

Hepatite por Halogenados

TFA é produto do metabolismo oxidativo

Proteínas trifluoracetiladasevocam resposta imune

Do Sevoflurano não seforma trifluoracetato

EosinofiliaFebreRashArtralgiaExposição prévia

MulherMeia idadeExposições múltiplas

Hepatite por Halogenados

Quadro Clínico

Fatores Predisponentes

Rins

Todos os halogenados, pela queda da PA e do DC, diminuem:FSRTFGDiurese

A hidratação pré-operatória abole ou diminui essas alterações

Nefrotoxicidade por fluoretos

Incapacidade de concentrar urinaPoliúriaHipernatremiaHiperosmolaridadeAumento da creatinina sérica

Observada primeiro com Metoxiflurano:Fluoretos: < 40 m/L sem efeitos

50 – 80 m/L toxicidade subclínica> 80 m/L toxicidade clínica

Os níveis não são iguais para outros anestésicosprodução intra-renal?

Sevoflurano e Função Renal

Netrotoxicidade por haletos vinílicos(Composto A)

Composto A é fatal para 50% de ratos expostos a400 ppm por 3 horas.

Circuito fechado > 5h: < 20ppm