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Goodman & Gilman's PHARMACOLOGY, 10e > Section III. Drugs Acting on the Central Nervous 

System > Chapter 14. General Anesthetics > 

Inhalational Anesthetics 

Introduction 

A wide variety of gases and volatile liquids can produce anesthesia. The first widely 

used inhalational anesthetic was diethyl ether (see Chapter 13: History and Principles 

of Anesthesiology). Subsequently, a variety of structurally unrelated compounds have 

been used as inhalational anesthetics including cyclopropane, elemental xenon, nitrous 

oxide, and more recently, short-chain halogenated alkanes and ethers. The structures 

of the currently used inhalational anesthetics are shown in Figure 14–4. One of the 

troublesome properties of the inhalational anesthetics is their low safety margin. The 

inhalational anesthetics have therapeutic indices (LD 50 /ED 50 ) that range from 2 to 4, 

making these among the most dangerous drugs in clinical use. The toxicity of these 

drugs is largely a function of their side effects, and each of the inhalational anesthetics 

has a unique side-effect profile. Hence, the selection of an inhalational anesthetic often 

is based on matching a patient's pathophysiology with drug side-effect profiles. The 

specific adverse effects of each of the inhalational anesthetics are emphasized in the 

following sections. The inhalational anesthetics also vary widely in their physical 

properties. Table 14–1 lists the important physical properties of the inhalational agents 

in clinical use. These properties are important because they govern the 

pharmacokinetics of the inhalational agents. Ideally, an inhalational agent would 

produce a rapid induction of anesthesia and a rapid recovery following discontinuation. 

The pharmacokinetics of the inhalational agents is reviewed in the following section. 

Figure 14–4. Structures of Inhalational General Anesthetics. 

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Note that all inhalational general anesthetic agents except nitrous oxide and halothane are 

ethers and that fluorine progressively replaces other halogens in the development of the 

halogenated agents. All structural differences are associated with important differences in 

pharmacological properties. 

Pharmacokinetic Principles 

The inhalational agents are some of the very few pharmacological agents administered 

as gases. The fact that these agents behave as gases rather than as liquids requires 

that different pharmacokinetic constructs be used in analyzing their uptake and 

distribution. It is essential to understand that inhalational anesthetics distribute 

between tissues (or between blood and gas) such that equilibrium is achieved when the 

partial pressure of anesthetic gas is equal in the two tissues. When a person has 

breathed an inhalational anesthetic for a sufficiently long time that all tissues are 

equilibrated with the anesthetic, the partial pressure of the anesthetic in all tissues will 

be equal to the partial pressure of the anesthetic in inspired gas. It is important to note 

that while the partial pressure of the anesthetic may be equal in all tissues, the 

concentration of anesthetic in each tissue will be different. Indeed, anesthetic partition 

coefficients are defined as the ratio of anesthetic concentration in two tissues when the 



partial pressures of anesthetic are equal in the two tissues. Blood:gas, brain:blood, and 

blood:fat partition coefficients for the various inhalational agents are listed in Table 14– 

1. These partition coefficients show that inhalational anesthetics are more soluble in 

some tissues (e.g., fat) than they are in other (e.g., blood), and that there is 

significant range in the solubility of the various inhalational agents in such tissues. 

In clinical practice, one can monitor the equilibration of a patient with anesthetic gas. 

Equilibrium is achieved when the partial pressure in inspired gas is equal to the partial 

pressure in end-tidal (alveolar) gas. This defines equilibrium, because it is the point 

when there is no net uptake of anesthetic from the alveoli into the blood. For 

inhalational agents that are not very soluble in blood or any other tissue, equilibrium is 

achieved quickly, as illustrated for nitrous oxide in Figure 14–5. If an agent is more 

soluble in a tissue such as fat, equilibrium may take many hours to reach. This occurs 

because fat represents a huge reservoir for the anesthetic, which will be filled slowly 

because of the modest blood flow to fat. This is illustrated by the slow approach of 

halothane alveolar partial pressure to inspired partial pressure in Figure 14–5. 

Figure 14–5. Uptake of Inhalational General Anesthetics. 



The rise in alveolar (F A ) anesthetic concentration toward the inspired (F I ) concentration is 

most rapid with the least soluble anesthetics, nitrous oxide and desflurane, and slowest with 

the most soluble anesthetic, halothane. All data are from human studies. (Reproduced with 

permission from Eger, 2000.) 

In considering the pharmacokinetics of anesthetics, one important parameter is the 

speed of anesthetic induction. Anesthetic induction requires that brain partial pressure 

be equal to MAC. Because the brain is well perfused, anesthetic partial pressure in 

brain becomes equal to the partial pressure in alveolar gas (and in blood) over the 

course of several minutes. Therefore, anesthesia is achieved shortly after alveolar 

partial pressure reaches MAC. While the rate of rise of alveolar partial pressure will be 

slower for anesthetics that are highly soluble in blood and other tissues, this limitation 

on speed of induction can be overcome largely by delivering higher inspired partial 

pressures of the anesthetic. 

Elimination of inhalational anesthetics is largely the reverse process of uptake. For 

agents with low blood and tissue solubility, recovery from anesthesia should mirror 

anesthetic induction, regardless of the duration of anesthetic administration. For 

inhalational agents with high blood and tissue solubility, recovery will be a function of 

the duration of anesthetic administration. This occurs because the accumulated 

amounts of anesthetic in the fat reservoir will prevent blood (and therefore alveolar) 

partial pressures from falling rapidly. Patients will be arousable when alveolar partial 

pressure reaches MAC awake , a partial pressure somewhat lower than MAC (see Table 

14–1). 

Halothane 

Chemistry and Formulation 

Halothane (FLUOTHANE) is 2-bromo-2-chloro-1,1,1-trifluoroethane (see Figure 14–4). 

Halothane is a volatile liquid at room temperature and must be stored in a sealed 

container. Because halothane is a light-sensitive compound that also is subject to 

spontaneous breakdown, it is marketed in amber bottles with thymol added as a 

preservative. Mixtures of halothane with oxygen or air are neither flammable nor 

explosive. 

Pharmacokinetic 

Halothane has a relatively high blood:gas partition coefficient and high blood:fat 



partition coefficient (see Table 14–1). Induction with halothane therefore is relatively 

slow, and the alveolar halothane concentration remains substantially lower than the 

inspired halothane concentration for many hours of administration. Because halothane 

is soluble in fat and other body tissues, it will accumulate during prolonged 

administration. Therefore, the speed of recovery from halothane is lengthened as a 

function of duration of administration (Stoelting and Eger, 1969). 

Approximately 60% to 80% of halothane taken up by the body is eliminated 

unchanged via the lungs in the first 24 hours after its administration. A substantial 

amount of the halothane not eliminated in exhaled gas is biotransformed in the liver by 

cytochrome P450 enzymes. The major metabolite of halothane is trifluoroacetic acid, 

which is formed by removal of bromine and chlorine ions (Gruenke et al., 1988). 

Trifluoroacetic acid, bromine, and chlorine all can be detected in the urine. 

Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, can 

trifluoroacetylate covalently several proteins in the liver. An immune reaction to these 

altered proteins may be responsible for the rare cases of fulminant halothane-induced 

hepatic necrosis (Kenna et al., 1988). There also is a minor reductive pathway 

accounting for approximately 1% of halothane metabolism and generally observed only 

under hypoxic conditions (Van Dyke et al., 1988). 

Clinical Use 

Halothane, introduced in 1956, was the first of the modern, halogenated inhalational 

anesthetics used in clinical practice. It is a potent agent that usually is used for 

maintenance of anesthesia. It is not pungent and is therefore well tolerated for 

inhalation induction of anesthesia. This is most commonly done in children, where 

preoperative placement of an intravenous catheter can be difficult. Anesthesia is 

produced by halothane at end-tidal concentrations of 0.7% to 1.0% halothane. The 

end-tidal concentration of halothane required to produce anesthesia is substantially 

reduced when it is coadministered with nitrous oxide. The use of halothane in the 

United States has diminished substantially in the past decade because of the 

introduction of newer inhalational agents with better pharmacokinetic and side-effect 

profiles. Halothane continues to be extensively used in children because it is well 

tolerated for inhalation induction and because the serious side effects appear to be 

diminished in children. Halothane has a low cost and is therefore still widely used in 

developing countries. 



Side Effects 

Cardiovascular System 

The most predictable side effect of halothane is a dose-dependent reduction in arterial 

blood pressure. Mean arterial pressure decreases about 20% to 25% at MAC 

concentrations of halothane. This reduction in blood pressure primarily is the result of 

direct myocardial depression leading to reduced cardiac output (see Figure 14–6). 

Myocardial depression is thought to result from attenuation of depolarization-induced 

intracellular calcium transients (Lynch, 1997). Halothane-induced hypotension usually 

is accompanied by either bradycardia or a normal heart rate. This absence of a 

tachycardic (or contractile) response to reduced blood pressure is thought to be due to 

an inability of the heart to respond to the effector arm of the baroceptor reflex. Heart 

rate can be increased during halothane anesthesia by exogenous catecholamine or by 

sympathoadrenal stimulation. Halothane-induced reductions in blood pressure and 

heart rate generally disappear after several hours of constant halothane 

administration. This is thought to occur because of progressive sympathetic stimulation 

(Eger et al., 1970). 

Figure 14–6. Influence of Inhalational General Anesthetics on the 

Systemic Circulation. 



While all of the inhalational anesthetics reduce systemic blood pressure in a dose-related 

manner (top), the lower figure shows that cardiac output is well preserved with isoflurane 

and desflurane and, therefore, that the causes of hypotension vary with the agent. (Data are 

from human studies except for sevoflurane, where data are from swine: Bahlman et al., 

1972; Cromwell et al., 1971; Weiskopf et al., 1991; Calverley et al., 1978; Stevens et al., 

1971; Eger et al., 1970; Weiskopf et al., 1988). 

Halothane does not cause a significant change in systemic vascular resistance. 

Nonetheless, it causes changes in the resistance and autoregulation of specific vascular 

beds leading to redistribution of blood flow. The vascular beds of the skin and brain are 



dilated directly by halothane, leading to increased cerebral blood flow and skin 

perfusion. Conversely, autoregulation of renal, splanchnic, and cerebral blood flow is 

inhibited by halothane, leading to reduced perfusion of these organs in the face of 

reduced blood pressure. Coronary autoregulation is largely preserved during halothane 

anesthesia. Finally, halothane does inhibit hypoxic pulmonary vasoconstriction, which 

leads to increased perfusion to poorly ventilated regions of the lung and an increased 

alveolar:arterial oxygen gradient. 

Halothane also has significant effects on cardiac rhythm. Sinus bradycardia and 

atrioventricular rhythms occur frequently during halothane anesthesia but are usually 

benign. These rhythms result mainly from a direct depressive effect of halothane on 

sinoatrial node discharge. Halothane also can sensitize the myocardium to the 

arrythmogenic effects of epinephrine (Sumikawa et al., 1983). Premature ventricular 

contractions and sustained ventricular tachycardia can be observed during halothane 

anesthesia when exogenous administration or endogenous adrenal production elevates 

plasma epinephrine levels. Epinephrine-induced arrhythmias during halothane 

anesthesia are thought to be mediated by a synergistic effect on 1 - and 1 -adrenergic 

receptors (Hayashi et al., 1988). 

Respiratory System 

Spontaneous respiration is rapid and shallow during halothane anesthesia. This 

produces a decrease in alveolar ventilation resulting in an elevation in arterial carbon 

dioxide tension from 40 mm Hg to >50 mm Hg at 1 MAC (see Figure 14–7). The 

elevated carbon dioxide does not provoke a compensatory increase in ventilation, 

because halothane causes a concentration-dependent inhibition of the ventilatory 

response to carbon dioxide (Knill and Gelb, 1978). This action of halothane is thought 

to be mediated by depression of central chemoceptor mechanisms. Halothane also 

inhibits peripheral chemoceptor responses to arterial hypoxemia. Thus, neither 

hemodynamic (tachycardia, hypertension) nor ventilatory responses to hypoxemia are 

observed during halothane anesthesia, making it prudent to monitor arterial 

oxygenation directly. Halothane also is an effective bronchodilator, producing direct 

relaxation of bronchial smooth muscle (Yamakage, 1992) and has been effectively used 

as a treatment of last resort in patients with status asthmaticus (Gold and Helrich, 

1970). 



Figure 14–7. Respiratory Effects of Inhalational Anesthetics. 

Spontaneous ventilation with all of the halogenated inhalational anesthetics reduces minute 

volume of ventilation in a dose-dependent manner (lower panel). This results in an increased 

arterial carbon dioxide tension (top panel). Differences among agents are modest. (Data are 

from Doi and Ikeda, 1987; Lockhart et al., 1991; Munson et al., 1966; Calverley et al., 1978; 

Fourcade et al., 1971.) 

Nervous System 

Halothane dilates the cerebral vasculature, increasing cerebral blood flow under most 

conditions. This increase in blood flow can increase intracranial pressure in patients 

with space-occupying intracranial masses, brain edema, or preexisting intracranial 



hypertension. For this reason, halothane is relatively contraindicated in patients at risk 

for elevated intracranial pressure. Halothane also attenuates autoregulation of cerebral 

blood flow. For this reason, cerebral blood flow can decrease when arterial blood 

pressure is markedly decreased. Modest decreases in cerebral blood flow generally are 

well tolerated, because halothane also reduces cerebral metabolic consumption of 

oxygen. 

Muscle 

Halothane causes some relaxation of skeletal muscle via its central-depressant effects. 

Halothane also potentiates the actions of nondepolarizing muscle relaxants (curariform 

drugs; see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic 

Ganglia), increasing both their duration of action and the magnitude of their effect. 

Halothane also is one of the triggering agents for malignant hyperthermia, a syndrome 

characterized by severe muscle contraction, rapid development of hyperthermia, and a 

massive increase in metabolic rate in genetically susceptible patients. This syndrome 

frequently is fatal and is treated by immediate discontinuation of the anesthetic and 

administration of dantrolene. 

Uterine smooth muscle is relaxed by halothane. This is a useful property for 

manipulation of the fetus (version) in the prenatal period and for delivery of retained 

placenta postnatally. Halothane, however, does inhibit uterine contractions during 

parturition, prolonging labor and increasing blood loss. Halothane therefore is not used 

as an analgesic or anesthetic for labor and vaginal delivery. 

Kidney 

Patients anesthetized with halothane usually produce a small volume of concentrated 

urine. This is the consequence of halothane-induced reduction of renal blood flow and 

glomerular filtration rate; these parameters may be reduced by 40% to 50% at 1 MAC. 

(Mazze et al., 1963). Halothane-induced changes in renal function are fully reversible 

and are not associated with long-term nephrotoxicity. 

Liver and Gastrointestinal Tract 

Halothane reduces splanchnic and hepatic blood flow as a consequence of reduced 

perfusion pressure, as discussed above. This reduced blood flow has not been shown to 

produce detrimental effects on hepatic or gastrointestinal function. 

Halothane can produce fulminant hepatic necrosis in a small number of patients. This 



syndrome generally is characterized by fever, anorexia, nausea, and vomiting 

developing several days after anesthesia and can be accompanied by a rash and 

peripheral eosinophilia. There is a rapid progression to hepatic failure, with a fatality 

rate of approximately 50%. This syndrome occurs in about 1 in 10,000 patients 

receiving halothane and is referred to as halothane hepatitis (Subcommittee on the 

National Halothane Study, 1966). Current thinking is that halothane hepatitis is the 

result of an immune response to trifluoracetylated proteins on hepatocytes 

(see"Pharmacokinetics," above). 

Isoflurane 

Chemistry and Physical Properties 

Isoflurane (FORANE) is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (see Figure 14– 

4). It is a volatile liquid at room temperature and is neither flammable nor explosive in 

mixtures of air or oxygen. 

Pharmacokinetics 

Isoflurane has a blood:gas partition coefficient substantially lower than that of 

halothane or enflurane (see Table 14–1). Consequently, induction with isoflurane and 

recovery from isoflurane are relatively rapid. Changes in anesthetic depth also can be 

achieved more rapidly with isoflurane than with halothane or enflurane. More than 99% 

of inhaled isoflurane is excreted unchanged via the lungs. Approximately 0.2% of 

absorbed isoflurane is oxidatively metabolized by cytochrome P450 2E1 (Kharasch et 

al., 1993). The small amount of isoflurane degradation products produced are 

insufficient to produce any renal, hepatic, or other organ toxicity. Isoflurane does not 

appear to be a mutagen, teratogen, or carcinogen (Eger et al., 1978). 

Clinical Use 

Isoflurane is the most commonly used inhalational anesthetic in the United States. 

Induction of anesthesia can be achieved in less than 10 minutes with an inhaled 

concentration of 3% isoflurane in oxygen; this concentration is reduced to 1.5% to 

2.5% for maintenance of anesthesia. The use of other drugs such as opioids or nitrous 

oxide reduces the concentration of isoflurane required for surgical anesthesia. 

Side Effects 




Isoflurane produces a concentration-dependent decrease in arterial blood pressure. 

Unlike halothane, cardiac output is well maintained with isoflurane, and hypotension is 

the result of decreased systemic vascular resistance (see Figure 14–6). Isoflurane 

produces vasodilation in most vascular beds, with particularly pronounced effects in 

skin and muscle. Isoflurane is a potent coronary vasodilator, simultaneously producing 

increased coronary blood flow and decreased myocardial oxygen consumption. In 

theory, this makes isoflurane a particularly safe anesthetic to use for patients with 

ischemic heart disease. However, concern has been raised that isoflurane may produce 

myocardial ischemia by inducing "coronary steal" (i.e., the diversion of blood flow from 

poorly perfused to well-perfused areas) (Buffington et al., 1988). This concern has not 

been substantiated in subsequent animal and human studies. Patients anesthetized 

with isoflurane generally have mildly elevated heart rates, and rapid changes in 

isoflurane concentration can produce transient tachycardia and hypertension. This is 

the result of direct isoflurane-induced sympathetic stimulation. 


Isoflurane produces concentration-dependent depression of ventilation. Patients 

spontaneously breathing isoflurane have a normal rate of respiration but a reduced 

tidal volume, resulting in a marked reduction in alveolar ventilation and an increase in 

arterial carbon dioxide tension (see Figure 14–7). Isoflurane is particularly effective at 

depressing the ventilatory response to hypercapnia and hypoxia (Hirshman et al., 

1977). While isoflurane is an effective bronchodilator, it also is an airway irritant and 

can stimulate airway reflexes during induction of anesthesia, producing coughing and 

laryngospasm. 


Isoflurane, like halothane, dilates the cerebral vasculature, producing increased 

cerebral blood flow and the risk of increased intracranial pressure. Isoflurane also 

reduces cerebral metabolic oxygen consumption. Isoflurane causes less cerebral 

vasodilation than do either enflurane or halothane, making it a preferred agent for 

neurosurgical procedures (Drummond et al., 1983). The modest effects of isoflurane on 

cerebral blood flow can be reversed readily by hyperventilation (McPherson et al., 

1989). 

Muscle 



Isoflurane produces some relaxation of skeletal muscle via its central effects. It also 

enhances the effects of both depolarizing and nondepolarizing muscle relaxants. 

Isoflurane is more potent than halothane in its potentiation of neuromuscular blocking 

agents. Isoflurane, like other halogenated inhalational anesthetics, relaxes uterine 

smooth muscle and is not recommended for analgesia or anesthesia for labor and 

vaginal delivery. 

Kidney 

Isoflurane reduces renal blood flow and glomerular filtration rate. This results in a 

small volume of concentrated urine. Changes in renal function observed during 

isoflurane anesthesia are rapidly reversed, and there are no long-term renal sequelae 

or toxicity associated with isoflurane. 


Splanchnic (and hepatic) blood flow is reduced with increasing doses of isoflurane, as 

systemic arterial pressure decreases. Liver function tests are minimally affected by 

isoflurane, and there is no described incidence of hepatic toxicity with isoflurane. 

Enflurane 

Chemical and Physical Properties 

Enflurane (ETHRANE) is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether (see Figure 14– 

4). It is a clear colorless liquid at room temperature with a mild, sweet odor. Like other 

inhalational anesthetics, it is volatile and must be stored in a sealed bottle. It is 

nonflammable and nonexplosive in mixtures of air or oxygen. 


Because of its relatively high blood:gas partition coefficient, induction of anesthesia 

and recovery from enflurane are relatively slow (see Table 14–1). Enflurane is 

metabolized to a modest extent, with 2% to 8% of absorbed enflurane undergoing 

oxidative metabolism in the liver by cytochrome P450 2E1 (Kharasch et al., 1994). 

Fluoride ions are a by-product of enflurane metabolism, but plasma fluoride levels are 

low and nontoxic. Patients taking isoniazid exhibit enhanced metabolism of enflurane 

with significantly elevated serum fluoride concentrations (Mazze et al., 1982). 

Clinical Use 

Surgical anesthesia can be induced with enflurane in less than 10 minutes with an 



inhaled concentration of 4% in oxygen. Anesthesia can be maintained with 

concentrations from 1.5% to 3%. As with other anesthetics, the enflurane 

concentrations required to produce anesthesia are reduced when it is coadministered 

with nitrous oxide or opioids. Use of enflurane has decreased substantially in recent 

years with the introduction of newer inhalational agents with preferable 

pharmacokinetic and side-effect profiles. 

Side Effects 


Enflurane causes a concentration-dependent decrease in arterial blood pressure. 

Hypotension is due, in part, to depression of myocardial contractility with some 

contribution from peripheral vasodilation (see Figure 14–6). Enflurane has minimal 

effects on heart rate and produces neither the bradycardia seen with halothane nor the 

tachycardia seen with isoflurane. 


The respiratory effects of enflurane are similar to those of halothane. Spontaneous 

ventilation with enflurane produces a pattern of rapid, shallow breathing. Minute 

ventilation is markedly decreased, and a Pa CO2 of 60 mm Hg is seen with 1 MAC of 

enflurane (see Figure 14–7). Enflurane produces a greater depression of the ventilatory 

responses to hypoxia and hypercarbia than do either halothane or isoflurane (Hirshman 

et al., 1977). Enflurane, like other inhalational anesthetics, is an effective 

bronchodilator. 


Enflurane is a cerebral vasodilator and thus can increase intracranial pressure in some 

patients. Like other inhalational anesthetics, enflurane reduces cerebral metabolic 

oxygen consumption. Enflurane has an unusual property of producing electrical seizure 

activity. High concentrations of enflurane or profound hypocarbia during enflurane 

anesthesia result in a characteristic high-voltage, high-frequency 

electroencephalographic (EEG) pattern, which progresses to spike-and-dome 

complexes. The spike-and-dome pattern can be punctuated by frank seizure activity, 

which may or may not be accompanied by peripheral motor manifestations of seizure 

activity. The seizures are self-limited and are not thought to produce permanent 

damage. Enflurane is not thought to precipitate seizures in epileptic patients. 



Nonetheless, enflurane is generally not used in patients with seizure disorders. 

Muscle 

Enflurane produces significant skeletal muscle relaxation in the absence of muscle 

relaxants. It also significantly enhances the effects of nondepolarizing muscle 

relaxants. As with other inhalational agents, enflurane relaxes uterine smooth muscle. 

It thus is not widely used for obstetrical anesthesia. 

Kidney 

Like other inhalational anesthetics, enflurane reduces renal blood flow, glomerular 

filtration rate, and urinary output. These effects are rapidly reversed with 

discontinuation of the drug. Enflurane metabolism produces significant plasma levels of 

fluoride ions (20 to 40 M) and can produce transient urinary-concentrating defects 

following prolonged administration (Mazze et al., 1977). There is scant evidence of 

long-term nephrotoxicity following enflurane use, and it is safe to use in patients with 

renal impairment, provided that the depth of enflurane anesthesia and the duration of 

administration are not excessive. 


Enflurane reduces splanchnic and hepatic blood flow in proportion to reduced arterial 

blood pressure. Enflurane does not appear to alter liver function or to be hepatoxic. 

Desflurane 


Desflurane (SUPRANE) is difluoromethyl 1-fluoro-2,2,2-trifluoromethyl ether (see Figure 

14–4). It is a highly volatile liquid at room temperature (vapor pressure = 681 mm Hg) 

and thus must be stored in tightly sealed bottles. Delivery of a precise concentration of 

desflurane requires the use of a specially heated vaporizer that delivers pure vapor 

that is then diluted appropriately with other gases (oxygen, air, nitrous oxide). 

Desflurane is nonflammable and nonexplosive in mixtures of air or oxygen. 


Desflurane has a very low blood:gas partition coefficient (0.42) and also is not very 

soluble in fat or other peripheral tissues (see Table 14–1). For this reason, the alveolar 

(and blood) concentration rapidly rises to the level of inspired concentration. Indeed, 

within five minutes of administration, the alveolar concentration reaches 80% of the 



inspired concentration. This provides for a very rapid induction of anesthesia and for 

rapid changes in depth of anesthesia following changes in the inspired concentration. 

Emergence from anesthesia also is very rapid with desflurane. The time to awakening 

following desflurane is half as long as with halothane or sevoflurane and usually does 

not exceed 5 to 10 minutes (Smiley et al., 1991). 

Desflurane is metabolized to a minimal extent, and more than 99% of absorbed 

desflurane is eliminated unchanged via the lungs. A small amount of absorbed 

desflurane is oxidatively metabolized by hepatic cytochrome P450 enzymes. Virtually 

no serum fluoride ions are detectable in serum after desflurane administration, but low 

concentrations of trifluoroacetic acid are detectable in serum and urine (Koblin et al., 

1988). 

Clinical Use 

Desflurane is a widely used anesthetic for outpatient surgery because of its rapid onset 

of action and rapid recovery. Desflurane is irritating to the airway in awake patients 

and can provoke coughing, salivation, and bronchospasm. Anesthesia therefore usually 

is induced with an intravenous agent, with desflurane subsequently administered for 

maintenance of anesthesia. Maintenance of anesthesia usually requires inhaled 

concentrations of 6% to 8%. Lower concentrations of desflurane are required if it is 

coadministered with nitrous oxide or opioids. 

Side Effects 


Desflurane, like all inhalational anesthetics, causes a concentration-dependent 

decrease in blood pressure. Desflurane has a very modest negative inotropic effect and 

produces hypotension primarily by decreasing systemic vascular resistance (Eger, 

1994) (see Figure 14–6). Cardiac output thus is well preserved during desflurane 

anesthesia, as is blood flow to the major organ beds (splanchnic, renal, cerebral, 

coronary). Marked increases in heart rate often are noted during induction of 

desflurane anesthesia and during abrupt increases in the delivered concentration of 

desflurane. This tachycardia is transient and is the result of desflurane-induced 

stimulation of the sympathetic nervous system (Ebert and Muzi, 1993). While the 

hypotensive effects of some inhalational anesthetics are attenuated as a function of 

duration of administration, this is not the case with desflurane (Weiskopf et al., 1991). 




Similar to halothane and enflurane, desflurane causes a concentration-dependent 

increase in respiratory rate and a decrease in tidal volume. At low concentrations (less 

than 1 MAC) the net effect is to preserve minute ventilation. At desflurane 

concentrations greater than 1 MAC, minute ventilation is markedly depressed, resulting 

in elevated arterial carbon dioxide tension (see Figure 14–7) (Lockhart et al., 1991). 

Patients spontaneously breathing desflurane at concentrationsgreater than 1.5 MAC will 

have extreme elevations of arterial carbon dioxide tension and may become apneic. 

Desflurane, like other inhalational agents, is a bronchodilator. It is also a strong airway 

irritant, however, and can cause coughing, breath-holding, laryngospasm, and 

excessive respiratory secretions. Because of its irritant properties, desflurane is not 

used for induction of anesthesia. 


Desflurane decreases cerebral vascular resistance and cerebral metabolic oxygen 

consumption. Under conditions of normocapnia and normotension, desflurane produces 

an increase in cerebral blood flow and can increase intracranial pressure in patients 

with poor intracranial compliance. The vasoconstrictive response to hypocapnia is 

preserved during desflurane anesthesia, and increases in intracranial pressure thus can 

be prevented by hyperventilation. 

Muscle 

Desflurane produces direct skeletal muscle relaxation as well as enhancing the effects 

of nondepolarizing and depolarizing neuromuscular blocking agents (Caldwell et al., 

1991). 

Kidney 

Desflurane has no reported nephrotoxicity. This is consistent with its minimal metabolic 

degradation. 


Desflurane is not known to affect liver function tests or to cause hepatotoxicity. 

Sevoflurane 


Sevoflurane (ULTANE) is fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl]ethyl ether (see 



Figure 14–4). It is a clear, colorless, volatile liquid at room temperature and must be 

stored in a sealed bottle. It is nonflammable and nonexplosive in mixtures of air or 

oxygen. 


The low solubility of sevoflurane in blood and other tissues provides for rapid induction 

of anesthesia, rapid changes in anesthetic depth following changes in delivered 

concentration, and rapid emergence following discontinuation of administration (see 

Table 14–1). Approximately 3% of absorbed sevoflurane is biotransformed. 

Sevoflurane is metabolized in the liver by cytochrome P450 2E1, with the predominant 

product being hexafluoroisopropanol (Kharasch et al., 1995). Hepatic metabolism of 

sevoflurane also produces inorganic fluoride. Serum fluoride concentrations reach a 

peak shortly after surgery and decline rapidly. Interaction of sevoflurane with soda lime 

also produces decomposition products. The major product of interest is referred to as 

compound A and is pentafluoroisopropenyl fluoromethyl ether (see"Side 

Effects"—"Kidney," below) (Hanaki et al., 1987). 

Clinical Use 

Sevoflurane has been widely used in Japan for a number of years and is enjoying 

increasing use in the United States. Sevoflurane is widely used for outpatient 

anesthesia because of its rapid recovery profile. It also is a useful drug for inhalation 

induction of anesthesia (particularly in children), because it is not irritating to the 

airway. Induction of anesthesia is rapidly achieved using inhaled concentrations of 2% 

to 4% sevoflurane. 

Side Effects 


Sevoflurane, like all other halogenated inhalational anesthetics, produces a 

concentration-dependent decrease in arterial blood pressure. This hypotensive effect 

primarily is due to systemic vasodilation, although sevoflurane also produces a 

concentration-dependent decrease in cardiac output (see Figure 14–6). Unlike 

isoflurane or desflurane, sevoflurane does not produce tachycardia and thus may be a 

preferable agent in patients prone to myocardial ischemia. 




Sevoflurane produces a concen-tration-dependent reduction in tidal volume and 

increase in respiratory rate in spontaneously breathing patients. The increased 

respiratory frequency is not adequate to compensate for reduced tidal volume, with the 

net effect being a reduction in minute ventilation and an increase in arterial carbon 

dioxide tension (Doi and Ikeda, 1987) (see Figure 14–7). Sevoflurane is not irritating 

to the airway and is a potent bronchodilator. Because of this combination of properties, 

sevoflurane is the most effective clinical bronchodilator of the inhalational anesthetics 

(Rooke et al., 1997). 


Sevoflurane produces effects on cerebral vascular resistance, cerebral metabolic 

oxygen consumption, and cerebral blood flow that are very similar to those produced 

by isoflurane and desflurane. While sevoflurane thus can increase intracranial pressure 

in patients with poor intracranial compliance, the response to hypocapnia is preserved 

during sevoflurane anesthesia, and increases in intracranial pressure thus can be 

prevented by hyperventilation. 

Muscle 

Sevoflurane produces direct skeletal muscle relaxation as well as enhancing the effects 

of nondepolarizing and depolarizing neuromuscular blocking agents. Its effects are 

similar to those of other halogenated inhalational anesthetics. 

Kidney 

Controversy has surrounded the potential nephrotoxicity of compound A, the 

degradation product produced by interaction of sevoflurane with the carbon dioxide 

absorbant soda lime. There has been a report showing transient biochemical evidence 

of renal injury in studies with human volunteers but no evidence of permanent renal 

injury (Eger et al., 1997). Large clinical studies have showed no evidence of increased 

serum creatinine, blood urea nitrogen, or any other evidence of renal impairment 

following sevoflurane administration (Mazze et al., 2000). The current recommendation 

of the U.S. Food and Drug Administration is that sevoflurane be administered with 

fresh gas flows of at least 2 liters/minute to minimize accumulation of compound A. 


Sevoflurane is not known to cause hepatotoxicity or alterations of hepatic function 

tests. 



Nitrous Oxide 

Chemical and Physical Properties 

Nitrous oxide (dinitrogen monoxide; N 2 O) is a colorless, odorless gas at room 

temperature (see Figure 14–4). It is sold in steel cylinders and must be delivered 

through calibrated flow meters provided on all anesthesia machines. Nitrous oxide is 

neither flammable nor explosive, but it does support combustion as actively as oxygen 

does when it is present in proper concentration with a flammable anesthetic or material. 


Nitrous oxide is very insoluble in blood and other tissues (see Table 14–1). This results 

in rapid equilibration between delivered and alveolar anesthetic concentrations and 

provides for rapid induction of anesthesia and rapid emergence following 

discontinuation of administration. The rapid uptake of nitrous oxide from alveolar gas 

serves to concentrate coadministered halogenated anesthetics; this effect (the "second 

gas effect") speeds induction of anesthesia. On discontinuation of nitrous oxide 

administration, nitrous oxide gas can diffuse from blood to the alveoli, diluting oxygen 

in the lung. This can produce an effect called diffusional hypoxia. To avoid hypoxia, 

100% oxygen rather than air should be administered when nitrous oxide is 

discontinued. 

Nitrous oxide is almost completely eliminated by the lungs, with some minimal 

diffusion through the skin. Nitrous oxide is not biotransformed by enzymatic action in 

human tissue, and 99.9% of absorbed nitrous oxide is eliminated unchanged. Nitrous 

oxide can be degraded by interaction with vitamin B12 in intestinal bacteria. This 

results in inactivation of methionine synthesis and can produce signs of vitamin B 12 

deficiency (megaloblastic anemia, peripheral neuropathy) following long-term nitrous 

oxide administration (O'Sullivan et al., 1981). For this reason, nitrous oxide is not used 

as a chronic analgesic or as a sedative in critical care settings. 

Clinical Use 

Nitrous oxide is a weak anesthetic agent and produces reliable surgical anesthesia only 

under hyperbaric conditions. It does produce significant analgesia at concentrations as 

low as 20% and usually produces sedation in concentrations between 30% and 80%. It 

is used frequently in concentrations of approximately 50% to provide analgesia and 

sedation in outpatient dentistry. Nitrous oxide cannot be used at concentrations above 



80%, because this limits the delivery of an adequate amount of oxygen. Because of 

this limitation, nitrous oxide is used primarily as an adjunct to other inhalational or 

intravenous anesthetics. Nitrous oxide substantially reduces the requirement for 

inhalational anesthetics. For example, at 70% nitrous oxide, MAC for other inhalational 

agents is reduced by about 60%, allowing for lower concentrations of halogenated 

anesthetics and a lesser degree of side effects. 

One major problem with nitrous oxide is that it will exchange with nitrogen in any air- 

containing cavity in the body. Moreover, nitrous oxide will enter the cavity faster than 

nitrogen escapes, thereby increasing the volume and/or pressure in this cavity. 

Examples of air collections that can be expanded by nitrous oxide include a 

pneumothorax, an obstructed middle ear, an air embolus, an obstructed loop of bowel, 

an intraocular air bubble, a pulmonary bulla, and intracranial air. Nitrous oxide should 

be avoided in these clinical settings. 

Side Effects 


Although nitrous oxide produces a negative inotropic effect on heart muscle in vitro, 

depressant effects on cardiac function generally are not observed in patients. This is 

because of the stimulatory effects of nitrous oxide on the sympathetic nervous system. 

The cardiovascular effects of nitrous oxide also are heavily influenced by the 

concomitant administration of other anesthetic agents. When nitrous oxide is 

coadministered with halogenated inhalational anesthetics, it generally produces an 

increase in heart rate, arterial blood pressure, and cardiac output. In contrast, when 

nitrous oxide is coadministered with an opioid, it generally decreases arterial blood 

pressure and cardiac output. Nitrous oxide also increases venous tone in both the 

peripheral and pulmonary vasculature. The effects of nitrous oxide on pulmonary 

vascular resistance can be exaggerated in patients with preexisting pulmonary 

hypertension (Schulte-Sasse et al., 1982). Nitrous oxide, therefore, is not generally 

used in patients with pulmonary hypertension. 


Nitrous oxide causes modest increases in respiratory rate and decreases in tidal 

volume in spontaneously breathing patients. The net effect is that minute ventilation is 

not significantly changed and arterial carbon dioxide tension remains normal. However, 



even modest concentrations of nitrous oxide markedly depress the ventilatory response 

to hypoxia (Yacoub et al., 1975). Thus it is prudent to monitor arterial oxygen 

saturation directly in patients receiving or recovering from nitrous oxide. 


When nitrous oxide is administered alone, it can produce significant increases in 

cerebral blood flow and intracranial pressure. When nitrous oxide is coadministered 

with intravenous anesthetic agents, increases in cerebral blood flow are attenuated or 

abolished. When nitrous oxide is added to a halogenated inhalational anesthetic, its 

vasodilatory effect on the cerebral vasculature is slightly reduced. 

Muscle 

Nitrous oxide does not relax skeletal muscle and does not enhance the effects of 

neuromuscular blocking drugs. Unlike the halogenated anesthetics, nitrous oxide is not 

a triggering agent for malignant hyperthermia. 

Kidney, Liver, and Gastrointestinal Tract 

Nitrous oxide is not known to produce any changes in renal or hepatic function and is 

neither nephrotoxic nor hepatotoxic. 

Xenon 

Xenon is an inert gas that was first identified as an anesthetic agent in 1951 (Cullen 

and Gross, 1951). It is not approved for use in the United States and is unlikely to 

enjoy widespread use, because it is a rare gas that cannot be manufactured and must 

be extracted from air. This limits the quantities of available xenon gas and renders 

xenon a very expensive agent. Despite these shortcomings, xenon has properties that 

make it a virtually ideal anesthetic gas that ultimately may be used in critical situations 

(Lynch et al., 2000). 

Xenon is extremely insoluble in blood and other tissues, providing for rapid induction 

and emergence from anesthesia (see Table 14–1). It is sufficiently potent to produce 

surgical anesthesia when administered with 30% oxygen. Most importantly, xenon has 

minimal side effects. It has no effects on cardiac output or cardiac rhythm and is not 

thought to have a significant effect on systemic vascular resistance. It also does not 

affect pulmonary function and is not known to have any hepatic or renal toxicity. 

Finally, xenon is not metabolized at all in the human body. Xenon is an anesthetic that 

may be available in the future if limitations on its availability and its high cost can be 



overcome. 

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