Inhaled Anesthetics

By. dr. Ihsan Affandi

 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 1960 Methoxyflurane, a methyl ethyl ether 1992 Desflurane, a totally fluorinated methyl ethyl ether 1994 Sevoflurane, , a totally fluorinated isopropyl ether

Inhaled Anesthetics for the Present & Future

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

CLINICALLY USEFUL INHALED ANESTHETICS

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

PHYSICAL CHEMICAL PROPERTIES OF INHALED ANASTHETICS

Nitrous Oxide Molecular weight Boiling point (OC) Vapor pressure (mmHg;20OC) Odor Preservative necesarry Stability in soda lime (40OC) Blood: gas partition coefficient MAC (37OC, 30 to 55years old, PB 760 mmHg) (%) 44 Gas Sweet No Yes 0.46 104

Halothane
197 50,2 244 Organic Yes No 2,54 0,75

Enflurane
184 56.5 172 Ethernal No Yes 1.90 1.63

Isoflurane
184 48.5 240 Ethernal No Yes 1.46 1.17

Desflura Sevoflurane ne
168 22.8 669 Ethernal No Yes 0.42 6.6 200 58.5 170 Ethernal No No 0.69 1.80

NITROUS OXIDE & HALOTAN

NITROUS OXIDE ( NO ) low-molecular-weight, odorless to sweet-smelling nonflammable gas of low potency Poor Blood solubility (0.46) most commonly administered incombination with opioids or volatile anesthetics to produce general anesthesia The analgesic effects are prominent HALOTAN a halogenated alkane nonflammable The vapor of this liquid has a sweet, nonpungent odor intermediate solubility in blood permits rapid onset & recovery from anesthesia Using alone or in combination with NO or injected drugs such as opioids

ENFLURANE and ISOFLURANE

ENFLURANE

ISOFLURANE
an isomer of enflurane a clear, nonflammable volatile liquid Ethereal odor intermediate solubility in blood High potency permits rapid onset & recovery using alone or in combination with NO or injected drugs such as opioids

a clear, nonflammable volatile liquid Ethereal odor intermediate solubility in blood High potency permits rapid onset & recovery using alone or in combination with NO or injected drugs such as opioids.

DESFLURANE and SEVOFLURANE

DESFLURANE

SEVOFLURANE

would boil at normal operating room temperatures, pungent produces airway irritation appreciable incidence of salivation, coughing, or laryngospasm produces the highest carbon monoxide concentrations lower blood gas solubility more precise control over the delivery of anesthesia and more rapid recovery from anesthesia

Nonpungent, minimal odor Produces bronchodilation similar in degree to isoflurane least degree of airway irritation prompt induction of anesthesia and recovery after discontinuation of the anestheti cannot undergo metabolism to an acyl halide

XENON

an inert gas, nonexplosive, nonpungent and odorless chemically inert as reflected by absence of metabolism and low toxicity it is not harmful to the environment its high cost has hindered its acceptance in anesthesia practice a potent hypnotic and analgesic, resulting in suppression of hemodynamic and catecholamine responses to surgical stimulation xenon does not produce hemodynamic depression in healthy adults

VARIABLE THAT INFLUENCE PHARMACOLOGIC EFFECTS OF INHALED ANESTHETICS

Anesthetic concentration Rate of increase in anesthetic concentration Spontaneous versus controlled ventilation Variations from normocapnia Surgical stimulation Patient age

Coexisting disease Concomitant drug therapy Intravascular fluid volume Preoperative medication Injected drugs to induce and/maintain anesthesia/ skeletal muscle relaxation Alterations in body temperature

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

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

Cerebral Metabolic Oxygen Requirements

produce dose-dependent decreases in cerebral metabolic oxygen requirements that are greater during the administration of isoflurane Desflurane and sevoflurane decrease cerebral metabolic oxygen requirements similar to isoflurane. Intracranial Pressure

produce increases in ICP that parallel increases in CBF enflurane must be remembered that hyperventilation of the lungs
increases the risk of seizure activity NO to increase ICP is probably less than that of volatile anesthetics, reflecting the restriction of the dose of this drug to < 1 MAC

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.

 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 modest increases in systemic blood pressure Heart Rate

Coronary Blood Flow

Volatile anesthetics (VA) induce coronary vasodilation by preferentially 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 the small coronary resistance coronary vessels would be capable of redistributing blood from ischemic to nonischemic areas coronary steal syndrome

Neurocirculatory Responses

The solubility of desflurane a good choice to treat abrupt increases in systemic blood pressure and/or heart rate as may occur in response to sudden changes in the intensity of surgical stimulation In contrast to desflurane and isoflurane, neurocirculator responses do not accompany abrupt increases in the delivered concentration of sevoflurane Fentanyl (1.5 to 4.5 g/kg IV administered 5 minutes before the 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 transient cardiovascular responses to rapid increases in desflurane concentration

Fentanyl may be the most clinically useful of these drugs because it blunts the increase in heart rate and blood pressure, has minimal cardiovascular depressant effects, and imposes little postanesthetic sedation Alfentanil, 10 jig/kg IV, in conjunction wins the induction of anesthesia, also blunts the hemodynamic responses to an abrupt increase in fire delivered concentration of desflurane The increase irs plasma norepinephrine concentrations that accompany the abrupt increase in desflurane concentration are not predictably prevented by the prior administration of opioids

Preexisting Diseases and Drug Therapy

VA decrease myocardial contractility of normal and failing cardiac muscle by similar amounts, but the significance is greater in diseased cardiac muscle Neurocirculatory responses evoked by abrupt increases in the concentration of desflurane may be undesirable in coronary artery disease (CAD) CAD administration of 40% NO produces evidence of myocardial depression antihypertensives, beta adrenergic antagonists influence the magnitude of circulatory effects produced by VA Calcium entry blockers decrease myocardial contractility & thus render the heart more vulnerable to direct depressant effects of inhaled anesthetics

Cardiac Protection (Anesthetic reconditioning)

The preconditioning effects of VA may be beneficial in patients who are susceptible to myocardial infarction during and 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 24 postoperative hours than patients receiving propofol Cardiac output was improved in patients receiving sevoflurane but not propofol suggesting better maintenance of myocardial function.

VENTILATION EFFECTS

Inhaled anesthetics produce dose dependent and drug specific effects on the : pattern of breathing, ventilatory response 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 pulmonary vasoconstriction as a mechanism for this decrease in oxygenation has not been confirmed during one lung ventilation in patients breathing halothane or isoflurane Changes in intraoperative PaO2 and the incidence of postoperative pulmonary complications are not different with halothane, enflurane, or isoflurane

Pattern of Breathing

Inhaled anesthetics, except for isoflurane, produce dose dependent increases in the frequency of breathing Isoflurane increases frequency of breathing similarly to other inhaled anesthetics up to a dose of 1 MAC. if concentration of isoflurane > I MAC, it doesn,t NO increases frequency of breathing more than other inhaled anesthetics at concentrations of > 1 MAC The effect of inhaled anesthetics on the frequency of breathing presumably reflects CNS stimulation Tidal volume is decreased in association with anesthetic induced increases in the frequency of breathing

Ventilatory Response to Carbon Dioxide

VA produce dose dependent depression of ventilation characterized by decreases in the ventilatory response to carbon dioxide and increases in the PaO2 Desflurane and sevoflurane depress ventilation, producing profound decreases in ventilation leading to apnea between 1.5 and 2.0 MAC, increase PaO2 and decrease the ventilatory response to carbon dioxide Depression of ventilation produced by anesthetic concentrations up to 1.24 MAC desflurane are similar to the depression produced by isoflurane NO does,nt increase the PaCO2 NO combined with a volatile anesthetic produces less depression of ventilation an increase in PaCO2 than the volatile drug alone

Surgical Stimulation increases minute ventilation by about 40% because of increases in tidal volume and frequency of breathing Duration of Administration After about 5 hours of administration, the increase in PaCO2 produced by a VA is less than that present during administration of the same concentration for 1 hour Mechanism of Depression by increases in the PaCO2, direct depressant effects on the medullary ventilatory center additional mechanism to selectively interfere with intercostal muscle function loss of chest wall stabilization chest to collapse inward during inspiration, contributing to decreases in lung volumes, particularly the functional residual capacity

Management of Ventilatory Depression

The predictable ventilatory depressant effects of volatile anesthetics are most often managed by institution of mechanical (controlled) ventilation of the patient's lungs Assisted ventilation of the lungs is a guestionibly effective method for offsetting the ventilator depressant effects of volatile anesthetics Ventilatory Response to Hypoxemia All inhaled anesthetics, including nitrous oxide, profoundly depress the ventilatory response to hypoxemia that is normally mediated by the carotid bodies

Airway Resistance and Irritability

Risk factors for developing bronhospasm during anesthetic, include young age (<10 years), perioperative respiratory infection, endotracheal incubation and the presence of chronic obstructive pulmonary disease (COPD) isoflurane and sevoflurane produce bronchodilation in patients with COPD Bronchoconstriction produced by desflurane is most likely to occur in patients who smoke Administration of fentanyl I g/kg IV or morphine 100 g/kg IV prior to inhalation induction with desflurane and nitrous oxide significantly decreases airway irritability associated with desflurane

HEPATIC EFFECTS

Hepatic Blood Flow

In patients receiving 1.5% end-tidal isoflurane, total hepatic blood flow and hepatic artery blood flow was maintained while portal vein blood flow was increased confirming that isoflurane was a vasodilator of the hepatic circulation plioviding beneficial effects on hepatic oxygen delivery (Gatecel et al., 2003). In contrast, halothane acts is a vasoconstrictor on the hepatic circulation hepatocyte hypoxia is a significant mechanism in the multifactorial etiology of postoperative hepatic dysfunction.

Drug Clearance
Volatile anesthetics may interfere with clearance of drugs from the plasma as a result of decreases in hepatic blood flow 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 hepatocelular injury)

Hepatotoxicity
Postoperative liver dysfunction has been associated with most volatile anesthetics, with halothane receiving the most attention It is likely that inadequate hepatocyte oxygenation

Halothane

halothane hepatitis is estimated to occur in 1 in 10,000 to t in 30,000 adult selflimited postoperative hepatotoxicity that is characterized by nausea, lethargy-, fever, and minor increases in plasma concentrations of liver transaminase enzymes patients receiving halothane and may lead to mass hepatic necrosis and death

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 been covalently modified by the reactive oxidative trifluoroacetyl halide metabolite of halothane to neoantigens the subsequent antigen-antibody interaction is responsible for the liver injury

Enflurane, Isciflurane, and Desflurane

enflurane, isoflurane, and desflurane could produce hepatotoxicity by a mechanism similar to that of halothane but at a lower incidence oxidatively metabolized by liver cytochrome P-450 enzymes to form acetylated liver protein the incidence of anesthetic-induced hepatitis would be greatest with halothane, intermediate with enflurane, and rare with isoflurane Desflurane is metabolized even less than isoflurane, and from the standpoint of immune-mediated hepatotoxicity, desflurane should be very safe because it would have the lowest level of adduct formation

Sevoflurane

The chemical structure unlike that of other fluorinated votatile anesthetics, dictates metabolism does not result in the formation of trifluoroacetylated liver proteins and cannot stimulate the formation of antitriffluoroacetylated protein antibodies sevoflurane differs from halothane, enflurane, and desflurane, all of which are metabolized to reactive acetyl halide metabolites sevoflurane, would not be expected to produce immune mediated hepatotoxicity or to cause crosssensitivity in patients previously exposed to halothane

RENAL EFFECTS

Volatile anesthetics produce similar dose-related decreases in renal blood flow, glomerular filtration rate, and urine output

Fluoride-induced Nephrotoxicity polyuria, hypematremia, hyperosmolarity, increased plasma creatinine, inability to concentrate urine was first recognized in patients after the administration of metlioxyflurane, 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 indicator that renal toxicity may occur from other volatile anesthetics

Sevoflurane

Sevoflurane is metabolized to inorganic fluoride, and peak plasma fluoride concentrations consistently exceed those peak levels that occur after a comparable dose of enflurane 2 patients receiving enflurane developed transient impairment of renal concentrating ability despite lower peak plasma fluoride concentrations than receiving sevoflurane intrarenal production of inorganic fluorideimportant factor for nephrotoxicity than hepatic metabolism that causes increased plasma fluoride concentrations patients with increased plasma concentrations of fluoride after administration of sevofluraneless renal dysfunction than patients receiving enflurane

Vinyl Halide Nephrotoxicity

CO2 absorbents containing K and NaOH react with sevoflurane and eliminate hydrogen fluoride degradation product produced in greatest amounts is fluorometliyl - 2,2diflurol-(trifluoromethyl)vinyl ether (compound A) Mechanism in animals for nephrotoxicity via the beta-lyase pathway to a reactive thiol but humans have less than one tenth of the enzymatic activityless vulnerable to injury utilizing at least a 2 liters/minute fresh gas flow rate when administering sevoflurane In children, sevoflurane lasting 4 hours using total fresh gas flows of 2 liters per minute produced compound A of < 15 ppm, and there was no vidence of renal dysfunction

SKELETAL MUSCLE EFFECTS

Neuromuscular Junction Ether derivative fluorinated volatile anesthetics produce skeletal muscle relaxation that is about twofold greater than that 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

OBSTETRIC EFFECTS
Volatile anesthetics produce similar & dose dependent decreases in uterine smooth muscle contractility and blood These changes are modest at 0.5 MAC (analgesic concentrations) & become substantial at > 1 MAC NO doesnt alter uterine contractility in doses used to provide analgesia during vaginal delivery uterine relaxation produced by volatile anesthetics may contribute to blood loss due to uterine atony blood loss during therapeutic abortion is greater in patients anesthetized with a volatile anesthetic compared with that in patients receiving nitrous oxide barbiturate opioid anesthesia

Figure Impact of volatile anesthetics on contractility of uterine smooth muscle

RESISTANCE TO INFECTION decreased resistance to bacterial infection due to inhaled anesthetics unlikely considering the duration of administration and dose of these drugs GENETIC EFFECTS The Ames test, which identifies chemicals that act as mutagens and carcinogens, is negative for enflurane, isoflurane, desflurane, sevoflurane, and NO BONE MARROW FUNCTION Megaloblastic changes are consistently found in patients who have been exposed to concentrations of NO for 24 hours Exposure to NO lasting 4 days or longer results in agranulocytosis

PERIPHERAL NEUROPATHY Humans who chronically inhale NO for nonmedical purposes may develop a neuropathy characterized by sensorimotor polyneuropathy TOTAL BODY OXYGEN REQUIREMENTS are decreased by similar amounts by volatile anesthetic The O2 requirements of the heart decrease more than those of other organs, associ-ated with decreases in systemic blood pressure and myocardial contractility protect tissues from ischemia that might result from decreased oxygen delivery due to drug induced decreases in perfusion pressure

METABOLISM
Assessment of the magnitude of metabolism is by : (a) measurement of metabolites (b) comparison of the total amount of anesthetic recovered in the exhaled gases with the amount taken up during administration (mass balance) alveolar ventilation is principally responsible for the elimination of enflurane and isoflurane (presumably also desflurane and sevoflu-rane) equally important for elimination of halothane & methoxyflurane Determinants of Metabolism chemical structure, hepatic Enzyme activity, blood concentration of the anesthetic, and genetic factors

METABOLISM OF VOLATILE ANESTHETICS AS ASSESED BY METEBOLITE RECOVERY VERSUS MASS BALANCE STUDIES

Magnitude of Metabolism
Anesthetic Nitrous oxide Halothane Enflurane Isoflurane Desflurane Sevoflurane Metabolite Recovery (%) 0.004 15-12 3 0.2 0.02 5 Mass Balance (%)

46.1 8.5 0*

Chemical Structure The ether bond & carbon halogen bond susceptible to oxidative metabolism Hepatic Enzyme Activity The activity of hepatic cytochrome P-450 enzymes Blood Concentration Inhaled anesthetics that are not highly soluble in blood and tissues (NO, enflurane, isoflurane, desflurane, sevofluane) tend to be exhaled rapidly via the lungs at the conclusion of an anesthetic Genetic Factors the most important determinant of drug metabolizing enzyme activity

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 cytochrome P-450 enzymes when ample oxygen is present but reductive metabolism when hepatocyte PO2 decreases The principal oxidative metabolites resulting from metabolism by cytochrome P-450 enzymes are trifluoroacetic acid, chloride, and bromide In genetically susceptible patients, a reactive trifluoroacetyl halide oxidative metabolite of halothane may interact with (acetylate) hepatic microsomal proteins (neoantigens) to stimulate the formation of antibodies

Enflurane 3% of absorbed enflurane oxidative metabolism by cytochrome P-450 enzymes to form inorganic fluoride and organic fluoride compounds Like halothane, enflurane which may cause the formation of neoantigens in susceptible patients Isoflurane 0.2% of absorbed isoflurane oxidative metabolism by cytochrome P-450 enzymes the metabolism of isoflurane much less than with enflurane Desflurane 0.02% of absorbed desflurane oxidative metabolism by cytochrome P-450 enzymes

Carbon Monoxide Toxicity

Carbonmonoxidereflects the degradation of volatile anesthetics that contain a CHF (desflurane, enflurane, and isoflurane) by the strong bases present in desiccated CO2 absorbents 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 to CO2 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 strong based havent become desiccated is important for preventing

Sevoflurane

5% of absorbed sevoflurane oxidative metabolism by cytochrome P-450 enzymes to form organic and inorganic fluoride metabolites sevoflurane does not undergo metabolism to acetyl halide that result of trifluoatated liver proteins cannot stimulate protein antibodies leading to hepatotoxicity hepatic production of fluoride may be less of a nephrotoxic risk than is intrarenal production of fluoride from enflurane Sevoflurane is absorbed and degraded by desiccated CO2 absorbents, especially when the temperature of the absorbent is increased compound A production