Download - ANESTÉSICOS GERAIS INALATÓRIOS
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