Anes Inhalasi Edit

7/28/2019 Anes Inhalasi Edit

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By. dr. Ihsan Affandi

Inhaled Anesthetics


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y

1840 nitrous oxide, diethyl ether, and chloroform

1951 fluroxene, potential flammability and increasing

evidence that this drug could cause organ toxicity

1951

Halotan and introduced for clinical use in 1956 1973 Enflurrane, the next methyl ethyl ether derivative

1981 Isoflurane, the isomer of enflurane

1960Methoxyflurane, a methyl ethyl ether

1992 Desflurane, a totally fluorinated methyl ethyl ether

1994 Sevoflurane, , a totally fluorinated isopropyl ether


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Desflurane & sevoflurane

facilitate the rapid induction of anesthesia

permit precise control of anesthetic concentrations during maintenance of

anesthesia,

Favor prompt recovery at the end of anesthesia independent of the duration

of administration

reflects in large part the impact of market forces more than an improved

pharmacologic profile on various organ systems as compared will isoflurane

Inhaled Anesthetics for the Present & Future


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Commonly inorganic gas nitrous oxide and the volatile liquids isoflurane,

desflurane, and sevoflurane

Halothane and enflurane nfrequently but are included in the discussion of

the comparative pharmacology of volatile anesthetics since halothane in

particular has been studied extensively

Available but rarely the volatile liquids methoxyflurane and diethyl ether

and the cyclic hydrocarbon gas cyclopropane

Xenon is an inert gas with anesthetic properties, but its clinical use is hindered

by its high cost

CLINICALLY USEFUL INHALED ANESTHETICS


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PHYSICAL CHEMICAL PROPERTIES OF INHALED

ANASTHETICS

Nitrous

Oxide Halothane Enflurane Isoflurane Desflurane SevofluraneMolecular weightBoiling point (OC)Vapor pressure (mmHg;20OC)OdorPreservative necesarryStability in soda lime (40OC)Blood: gas partition coefficientMAC (37OC, 30 to 55years old,PB 760 mmHg) (%)

44GasSweet

NoYes0.46104

19750,2244OrganicYes

No2,540,75

18456.5172Ethernal

NoYes1.901.63

18448.5240Ethernal

NoYes1.461.17

16822.8669Ethernal

NoYes0.426.6

20058.5170Ethernal

NoNo0.691.80


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NITROUS OXIDE & HALOTAN

NITROUS OXIDE ( NO )

low-molecular-weight,

odorless to sweet-smelling

nonflammable gas of lowpotency

Poor Blood solubility (0.46)

most commonly administeredincombination with opioids or

volatile anesthetics to producegeneral anesthesia

The analgesic effects areprominent

HALOTAN

a halogenated alkane

nonflammable

The vapor of this liquid has asweet, nonpungent odor

intermediate solubility in blood

permits rapid onset & recoveryfrom anesthesia

Using alone or in combinationwith NO or injected drugs suchas opioids


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ENFLURANE and ISOFLURANE

ENFLURANE

a clear, nonflammable volatileliquid

Ethereal odor


High potency permits rapid onset& recovery

using alone or in combination

with NO or injected drugs suchas opioids.

ISOFLURANE

an isomer of enflurane

a clear, nonflammable volatileliquid

Ethereal odor


High potency permits rapidonset & recovery

using alone or in combinationwith NO or injected drugs suchas opioids


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DESFLURANE and SEVOFLURANE

DESFLURANE would boil at normal operating

room temperatures, pungent

produces airway irritation

appreciable incidence ofsalivation, coughing, orlaryngospasm

produces the highest carbonmonoxide concentrations

lower blood gas solubility more precise control over the

delivery of anesthesia and morerapid recovery from anesthesia

SEVOFLURANE Nonpungent, minimal odor

Produces bronchodilationsimilar in degree to isoflurane

least degree of airwayirritation

prompt induction ofanesthesia and recovery afterdiscontinuation of the

anestheti cannot undergo metabolism

to an acyl halide


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XENON

an inert gas, nonexplosive, nonpungent and odorless

chemically inert as reflected by absence of metabolism andlow toxicity

it is not harmful to the environment

its high cost has hindered its acceptance in anesthesiapractice

a potent hypnotic and analgesic, resulting in suppression ofhemodynamic and catecholamine responses to surgicalstimulation

xenon does not produce hemodynamic depression in healthyadults


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VARIABLE THAT INFLUENCE PHARMACOLOGIC EFFECTS

OF INHALED ANESTHETICS

Anesthetic concentration

Rate of increase inanesthetic concentration

Spontaneous versuscontrolled ventilation

Variations fromnormocapnia Surgicalstimulation

Patient age

Coexisting disease

Concomitant drug therapyIntravascular fluid volume

Preoperative medication Injected drugs to induce

and/maintain anesthesia/skeletal

muscle relaxation

Alterations in bodytemperature


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CENTRAL NERVOUS SYSTEM EFFECTS

Mental impairment is not detectable in volunteers breathing

1,600 ppm (0.16%) nitrous oxide or 16 ppm (0.0016%)

halothane

Volatile anesthetics do not cause retrograde amnesia or

prolonged impairment of intellectual function

Cerebral metabolic oxygen requirements are decreased in

parallel with drug-induced decreases in cerebral activity

Inhaled anesthetics cause loss of response to verbal com-mand

at MAC-awake concentrations


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Cerebral-Blood Flow (CBF)

Volatile anesthetics (VA) produce dose-dependent increases in CBF

VA administered during normocapnia in concentrations of > 0.6

MAC reduce cerebral vasodilation, decreased cerebral vascular

Sevoflurane has an intrinsic dose-dependent cerebral vasodilatory

effect but this effect is less than that of isoflurane

Desflurane and isoflurane are similar in terms of increases in CBF

and the preservation of reactivity activity to carbon dioxide

nitrous oxide may be a more potent cerebral vasodilator than an

equipotent dose of isoflurane alone in humans


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produce dose-dependent decreases in cerebral metabolic oxygenrequirements that are greater during the administration of isoflurane

Desflurane and sevoflurane decrease cerebral metabolic oxygen

requirements similar to isoflurane.

produce increases in ICP that parallel increases in CBF

enflurane must be remembered that hyperventilation of the lungs

increases the risk of seizure activityNO to increase ICP is probably less than that of volatile anesthetics,

reflecting the restriction of the dose of this drug to < 1 MAC

Cerebral Metabolic Oxygen Requirements

Intracranial Pressure


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Cerebrospinal Fluid (CSF ) Production

Enflurane increases both the rate of production and the resistance

to reabsorption of CSF

isoflurane doesnt alter production of CSF

CIRCULATORY EFFECTS

effects manifest as changes in systemic

blood pressure

heart rate

cardiac output stroke volume

right atrial pressure

systemic vascular resistance

cardiac rhythm, and coronary blood flow.


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Mean Arterial Pressure

Halothane, isoflurane, desflurane, and sevoflurane

produce similar and dose-dependent decreases in mean

arterial pressure

nitrous oxide produces either no change or modestincreases in systemic blood pressure

Heart Rate


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Coronary Blood Flow

Volatile anesthetics (VA) induce coronary vasodilation bypreferentially acting on essels

adenosine, in addition, has a pronounced impact on the

small precapillary arterioles

Isoflurane, other coronary vasodilators (adenosine,dipyridamole, nitroprusside) that preferentially dilate thesmall coronary resistance coronary vessels would be capableof redistributing blood from ischemic to nonischemic areas

coronary steal syndrome


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Neurocirculatory Responses

The solubility of desflurane a good choice to treat abruptincreases in systemic blood pressure and/or heart rate asmay occur in response to sudden changes in the intensity ofsurgical stimulation

In contrast to desflurane and isoflurane, neurocirculator

responses do not accompany abrupt increases in thedelivered concentration of sevoflurane

Fentanyl (1.5 to 4.5 g/kg IV administered 5 minutes beforethe abrupt increase in desflurane concentration), esmolol(0.75 mg/kg IV 1.5 minutes before), and donidine

(4.3 g/kg orally 90 minutes before) blunt the transientcardiovascular responses to rapid increases in desfluraneconcentration


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Fentanyl may be the most clinically useful of these drugsbecause it blunts the increase in heart rate and bloodpressure, has minimal cardiovascular depressant effects, andimposes little postanesthetic sedation

Alfentanil, 10 jig/kg IV, in conjunction wins the induction ofanesthesia, also blunts the hemodynamic responses to anabrupt increase in fire delivered concentration of desflurane

The increase irs plasma norepinephrine concentrations thataccompany the abrupt increase in desflurane concentration

are not predictably prevented by the prior administration ofopioids


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Preexisting Diseases and Drug Therapy

VA decrease myocardial contractility of normal and failingcardiac muscle by similar amounts, but the significance isgreater in diseased cardiac muscle

Neurocirculatory responses evoked by abrupt increases inthe concentration of desflurane may be undesirable in

coronary artery disease (CAD)

CAD administration of 40% NO produces evidence ofmyocardial depression

antihypertensives, beta adrenergic antagonists influencethe magnitude of circulatory effects produced by VA

Calcium entry blockers decrease myocardial contractility &thus render the heart more vulnerable to direct depressanteffects of inhaled anesthetics


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The preconditioning effects of VA may be beneficial inpatients who are susceptible to myocardial infarction duringand following surgery

patients receiving sevoflurane for cardiac surgery (off bypass

or cardiopulmonary bypass) had less myocardial injury(lower release of troponin 1) during the first 24postoperative hours than patients receiving propofol

Cardiac output was improved in patients receivingsevoflurane but not propofol suggesting better maintenance

of myocardial function.

Cardiac Protection (Anesthetic reconditioning)


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VENTILATION EFFECTS

Inhaled anesthetics produce dose dependent and drugspecific effects on the : pattern of breathing, ventilatoryresponse to CO2, ventilatory response to arterial hypoxemia,and airway resistance

The PaO2, predictably declines during administration of

inhaled anesthetics in the absence of supplemental oxygen

Drug-induced inhibition of hypoxic pulmonaryvasoconstriction as a mechanism for this decrease inoxygenation has not been confirmed during one lungventilation in patients breathing halothane or isoflurane

Changes in intraoperative PaO2 and the incidence ofpostoperative pulmonary complications are not different withhalothane, enflurane, or isoflurane


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Pattern of Breathing

Inhaled anesthetics, except for isoflurane, produce dosedependent increases in the frequency of breathing

Isoflurane increases frequency of breathing similarly to otherinhaled anesthetics up to a dose of 1 MAC. if concentrationof isoflurane > I MAC, it doesn,t

NO increases frequency of breathing more than other inhaledanesthetics at concentrations of > 1 MAC

The effect of inhaled anesthetics on the frequency ofbreathing presumably reflects CNS stimulation

Tidal volume is decreased in association with anestheticinduced increases in the frequency of breathing


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Ventilatory Response to Carbon Dioxide

VA produce dose dependent depression of ventilationcharacterized by decreases in the ventilatory response tocarbon dioxide and increases in the PaO2

Desflurane and sevoflurane depress ventilation, producingprofound decreases in ventilation leading to apnea between

1.5 and 2.0 MAC, increase PaO2 and decrease the ventilatoryresponse to carbon dioxide

Depression of ventilation produced by anestheticconcentrations up to 1.24 MAC desflurane are similar to thedepression produced by isoflurane

NO does,nt increase the PaCO2 NO combined with avolatile anesthetic produces less depression of ventilation anincrease in PaCO2 than the volatile drug alone


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Surgical Stimulation increases minute ventilation by about40% because of increases in tidal volume and frequency ofbreathing

Duration of Administration After about 5 hours ofadministration, the increase in PaCO2 produced by a VA is

less than that present during administration of the sameconcentration for 1 hour

Mechanism of Depression

by increases in the PaCO2, direct depressant effects on themedullary ventilatory center

additional mechanism to selectively interfere with intercostalmuscle function loss of chest wall stabilization chest tocollapse inward during inspiration, contributing to decreasesin lung volumes, particularly the functional residual capacity


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Management of Ventilatory Depression

The predictable ventilatory depressant effects of volatileanesthetics are most often managed by institution ofmechanical (controlled) ventilation of the patient's lungs

Assisted ventilation of the lungs is a guestionibly effectivemethod for offsetting the ventilator depressant effects of

volatile anesthetics

Ventilatory Response to Hypoxemia

All inhaled anesthetics, including nitrous oxide, profoundlydepress the ventilatory response to hypoxemia that isnormally mediated by the carotid bodies


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Airway Resistance and Irritability

Risk factors for developing bronhospasm during anesthetic,include young age (


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HEPATIC EFFECTS

Hepatic Blood Flow In patients receiving 1.5% end-tidal isoflurane, total hepatic

blood flow and hepatic artery blood flow was maintainedwhile portal vein blood flow was increased confirming thatisoflurane was a vasodilator of the hepatic circulationplioviding beneficial effects on hepatic oxygen delivery(Gatecel et al., 2003). In contrast, halothane acts is avasoconstrictor on the hepatic circulation

hepatocyte hypoxia is a significant mechanism in themultifactorial etiology of postoperative hepatic dysfunction.


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Drug Clearance Volatile anesthetics may interfere with clearance of drugs

from the plasma as a result of decreases in hepatic bloodflow or inhibition of drug metabolizing enzymes

Liver Function Tests Transient increases in the plasma alanine aminotransferase

activity follow administration of enflurane and desflurane,but not isoflurane administration, to human volunteers.Transient increases in plasma concentrations of alpha

glutathione transferase (sensitive indicator of hepatocelularinjury)


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Hepatotoxicity Postoperative liver dysfunction has been associated with

most volatile anesthetics, with halothane receiving the mostattention

It is likely that inadequate hepatocyte oxygenation Halothane

halothane hepatitis is estimated to occur in 1 in 10,000 to t in30,000 adult

selflimited postoperative hepatotoxicity that is characterized

by nausea, lethargy-, fever, and minor increases in plasmaconcentrations of liver transaminase enzymes

patients receiving halothane and may lead to mass hepaticnecrosis and death


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Halothane Hepatitis Manifestations of halothane hepatitis include eosinophilia,

fever, rash, arthralgia, & prior exposure to halothane

the presence of circulatory Ig G antibodies in at least 70% of

those patients with the diagnosis of halothane hepatitis These antibodies are directed against liver microsomal

proteins on the surface of hepatocytes that have beencovalently modified by the reactive oxidative trifluoroacetylhalide metabolite of halothane to neoantigens

the subsequent antigen-antibody interaction is responsiblefor the liver injury


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Enflurane, Isciflurane, and Desflurane enflurane, isoflurane, and desflurane could produce

hepatotoxicity by a mechanism similar to that of halothanebut at a lower incidence oxidatively metabolized by livercytochrome P-450 enzymes to form acetylated liver protein

the incidence of anesthetic-induced hepatitis would begreatest with halothane, intermediate with enflurane, andrare with isoflurane

Desflurane is metabolized even less than isoflurane, andfrom the standpoint of immune-mediated hepatotoxicity,desflurane should be very safe because it would have thelowest level of adduct formation


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Sevoflurane

The chemical structure unlike that of other fluorinatedvotatile anesthetics, dictates metabolism does not result inthe formation of trifluoroacetylated liver proteins and cannot stimulate the formation of antitriffluoroacetylatedprotein antibodies

sevoflurane differs from halothane, enflurane, anddesflurane, all of which are metabolized to reactive acetylhalide metabolites sevoflurane, would not be expected to

produce immune mediated hepatotoxicity or to cause cross-sensitivity in patients previously exposed to halothane


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RENAL EFFECTS

Volatile anesthetics produce similar dose-related decreasesin renal blood flow, glomerular filtration rate, and urineoutput

Fluoride-induced Nephrotoxicity

polyuria, hypematremia, hyperosmolarity, increased plasmacreatinine, inability to concentrate urine was firstrecognized in patients after the administration ofmetlioxyflurane, which undergoes extensive metabolism(70% of the absorbed dose) to inorganic fluoride, which acts

as a renal toxin

a plasma fluoride concentration of 30 m/liter indicatorthat renal toxicity may occur from other volatile anesthetics


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Sevoflurane Sevoflurane is metabolized to inorganic fluoride, and peak

plasma fluoride concentrations consistently exceed thosepeak levels that occur after a comparable dose of enflurane

2 patients receiving enflurane developed transientimpairment of renal concentrating ability despite lower peakplasma fluoride concentrations than receiving sevoflurane

intrarenal production of inorganic fluorideimportant factorfor nephrotoxicity than hepatic metabolism that causesincreased plasma fluoride concentrations

patients with increased plasma concentrations of fluorideafter administration of sevofluraneless renal dysfunctionthan patients receiving enflurane


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Vinyl Halide Nephrotoxicity CO2 absorbents containing K and NaOH react with

sevoflurane and eliminate hydrogen fluoride degradationproduct produced in greatest amounts is fluorometliyl - 2,2-diflurol-(trifluoromethyl)vinyl ether (compound A)

Mechanism in animals for nephrotoxicity via the beta-lyasepathway to a reactive thiol but humans have less than onetenth of the enzymatic activityless vulnerable to injury

utilizing at least a 2 liters/minute fresh gas flow rate whenadministering sevoflurane In children, sevoflurane lasting 4

hours using total fresh gas flows of 2 liters per minuteproduced compound A of < 15 ppm, and there was novidence of renal dysfunction


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SKELETAL MUSCLE EFFECTS

Neuromuscular Junction

Ether derivative fluorinated volatile anesthetics produceskeletal muscle relaxation that is about twofold greater thanthat associated with comparable dose of halothane

NO doesnt relax skeletal muscles, and in doses of > 1 MAC

produce skeletal muscle rigidity

Malignant Hyperthermia

desflurane and sevoflurane can trigger malignant

hyperthermia in genetically susceptible patients halothane is the most potent trigger and NO is a weak

trigger for malignant hyper thermia


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Volatile anesthetics produce similar & dose dependentdecreases in uterine smooth muscle contractility and blood

These changes are modest at 0.5 MAC (analgesicconcentrations) & become substantial at > 1 MAC

NO doesnt alter uterine contractility in doses used to provideanalgesia during vaginal delivery

uterine relaxation produced by volatile anesthetics maycontribute to blood loss due to uterine atony

blood loss during therapeutic abortion is greater in patients

anesthetized with a volatile anesthetic compared with that inpatients receiving nitrous oxide barbiturate opioid anesthesia

OBSTETRIC EFFECTS


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Figure Impact of volatile anesthetics on contractility of uterine smooth muscle


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RESISTANCE TO INFECTION decreased resistance to bacterial infection due to inhaled

anesthetics unlikely considering the duration ofadministration and dose of these drugs

GENETIC EFFECTS

The Ames test, which identifies chemicals that act asmutagens and carcinogens, is negative for enflurane,isoflurane, desflurane, sevoflurane, and NO

BONE MARROW FUNCTION

Megaloblastic changes are consistently found in patients whohave been exposed to concentrations of NO for 24 hours

Exposure to NO lasting 4 days or longer results inagranulocytosis


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PERIPHERAL NEUROPATHY Humans who chronically inhale NO for nonmedical purposes

may develop a neuropathy characterized by sensorimotorpolyneuropathy

TOTAL BODY OXYGEN REQUIREMENTS are decreased by similar amounts by volatile anesthetic

The O2 requirements of the heart decrease more than thoseof other organs, associ-ated with decreases in systemicblood pressure and myocardial contractility protect tissues

from ischemia that might result from decreased oxygendelivery due to drug induced decreases in perfusion pressure


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METABOLISM

Assessment of the magnitude of metabolism is by :(a) measurement of metabolites

(b) comparison of the total amount of anesthetic recovered inthe exhaled gases with the amount taken up duringadministration (mass balance)

alveolar ventilation is principally responsible for theelimination of enflurane and isoflurane (presumably alsodesflurane and sevoflu-rane) equally important forelimination of halothane & methoxyflurane

Determinants of Metabolism chemical structure,hepatic Enzyme activity, blood concentration of theanesthetic, and genetic factors


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METABOLISM OF VOLATILE ANESTHETICS AS ASSESEDBY METEBOLITE RECOVERY VERSUS MASS BALANCE

STUDIES

Magnitude of MetabolismAnesthetic MetaboliteRecovery (%)

MassBalance (%)

Nitrous oxideHalothaneEnfluraneIsofluraneDesfluraneSevoflurane

0.00415-1230.20.025

46.18.50*


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Chemical Structure The ether bond & carbon halogenbond susceptible to oxidative metabolism

Hepatic Enzyme ActivityThe activity of hepaticcytochrome P-450 enzymes

Blood Concentration

Inhaled anesthetics that are not highly soluble in blood andtissues (NO, enflurane, isoflurane, desflurane, sevofluane)tend to be exhaled rapidly via the lungs at the conclusion ofan anesthetic

Genetic Factors the most important determinant of drugmetabolizing enzyme activity


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Metabolism of Inhaled Anesthetics

Nitrous Oxide There is no evidence that NO under goes oxidative

metabolism in the liver

Halothane

uniquely metabolized undergoes oxidation by cytochromeP-450 enzymes when ample oxygen is present but reductivemetabolism when hepatocyte PO2 decreases

The principal oxidative metabolites resulting frommetabolism by cytochrome P-450 enzymes are trifluoroaceticacid, chloride, and bromide

In genetically susceptible patients, a reactive trifluoroacetylhalide oxidative metabolite of halothane may interact with(acetylate) hepatic microsomal proteins (neoantigens) tostimulate the formation of antibodies


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Enflurane 3% of absorbed enflurane oxidative metabolism by

cytochrome P-450 enzymes to form inorganic fluoride andorganic fluoride compounds

Like halothane, enflurane which may cause the formation of

neoantigens in susceptible patients

Isoflurane

0.2% of absorbed isoflurane oxidative metabolism bycytochrome P-450 enzymes the metabolism of isofluranemuch less than with enflurane

Desflurane

0.02% of absorbed desflurane oxidative metabolism bycytochrome P-450 enzymes


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Carbon Monoxide Toxicity

Carbonmonoxidereflects the degradation of volatileanesthetics that contain a CHF (desflurane, enflurane, andisoflurane) by the strong bases present in desiccated CO2absorbents

Desflurane produces the highest carbon monoxide

concentration followed by enflurane and isoflurane Halothane and sevoflurane do not possess a vinyl group

(CHF) and thus carbon monoxide production on exposure toCO2 absorbents unlikely

But, carbon monoxide formation is a risk of sevoflurane

administration in the presence of desiccated CO2 absorbent

Precautions to insure CO2 absorbents that contain strongbased havent become desiccated is important for preventing


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Sevoflurane 5% of absorbed sevoflurane oxidative metabolism by

cytochrome P-450 enzymes to form organic and inorganicfluoride metabolites

sevoflurane does not undergo metabolism to acetyl halidethat result of trifluoatated liver proteins cannot stimulate

protein antibodies leading to hepatotoxicity

hepatic production of fluoride may be less of a nephrotoxicrisk than is intrarenal production of fluoride from enflurane

Sevoflurane is absorbed and degraded by desiccated CO2absorbents, especially when the temperature of theabsorbent is increased compound A production


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