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Inhaled Anesthetics (Pharmacology)

NOTE: This content is currently being rewritten by our editors, but we have included the original article from OpenAnesthesia’s encyclopedia section before our March 2023 site update.

Overview/General Principles

Figure 1. Molecular Structure of Common Inhaled General Anesthetics


Surrogate measures of pain suggest that, with the exception of nitrous oxide, inhaled anesthetics do not provide any significant analgesia. They do, however, produce immobility and amnesia. Other than nitrous oxide (which increases skeletal muscle tone), inhaled anesthetics either do not affect, or in some cases lower skeletal muscle tone.

Mechanism of Action

Inhaled anesthetics produce immobility via actions on the spinal cord [Campagna JA et al. N Engl J Med 348: 2110, 2003]. There is consensus that inhaled anesthetics produce anesthesia by enhancing inhibitory channels and attenuating excitatory channels, but whether or not this occurs through direct binding or membrane alterations is not known. [Miller]

Minimum Alveolar Concentration

The Minimum Alveolar Concentration (MAC) of an inhaled anesthetic is the alveolar (or end-expiratory) concentration at which 50% of patients will not show a motor response to a standardized surgical incision. The standard deviation of MAC is ~10%, thus 95% of patients will not respond to 1.2 MAC, and 99% will not respond to 1.3 MAC. Standard MAC values assume the absence of all other potentially sedative or hypnotic drugs. According to rat data, MAC values are additive in terms of preventing movement to incision (0.5 MAC of nitrous oxide plus 0.5 MAC of isoflurane = 1.0 MAC of any other agent) [Rampil IJ Anesthesiology 80: 606, 1994].

Table 1. Anesthetic Requirements


Partial Pressure

PA — Pa — Pbrain, thus PA is only an approximation of Pbrain. Note that sevoflurane has the highest brain-blood coefficient (1.7) and the second lowest MAC (1.85, whereas the lowest, isoflurane, has a brain-blood of 1.6 but a blood-gas of 1.46, substantially higher than sevoflurane’s 0.69).


Input depends on PI, VA, and the mechanics of the breathing system (ex. dead space). Increasing PI in order to accelerate input is known as the concentration effect, although this may only be achievable in the presence of nitrous oxide [Eger Anesthesiology 24: 153, 1963]. As the body approaches steady state, PI must be decreased in order to maintain a constant Pbrain. The “second gas effect” says that large volume intake of one gas enhances the intake of a second gas (ex. transient PaO2 increase of 10% following nitrous oxide administration), but this is probably clinically insignificant [Miller].

Complete equilibration with any tissue takes 3 time constants – time constant for isoflurane is 3-4 minutes, for sevoflurane, desflurane, or nitrous oxide is ~ 2 minutes. For all inhaled anesthetics, PI should therefore be decreased after 6-12 minutes.

Table 2. Time Constants and Brain Equilibration

Elimination and Recovery

Ventilation is the most important factor affecting the decrease in sevoflurane, desflurane, and isoflurane. The time needed for a 50% decrease in sevoflurane, desflurane, or isoflurane is < 5 minutes and essentially independent of case duration [Bailey Anesth Analg 85: 681, 1997] – the main differences between these three is in the final 20% of the elimination process.

Physiologic Effects

Circulatory System

Inhaled anesthetics all cause a dose-dependent decrease in MAP due to decreases in SVR – this can be minimized by combining them with nitrous oxide [Bailey Anesth Analg 85: 681, 1997], which has been shown to sometimes increase MAP. Inhaled anesthetics also cause increases in heart rate, although at different doses – sevoflurane is unique in that it does not appreciably increase HR until 1.5 MAC is achieved. Desflurane can actually stimulate the cardiovascular system, although this ability wanes as anesthesia is maintained. Sevoflurane, desflurane, and isoflurane all diminish baroreceptor responses. Because changes in MAP are due to SNS induced changes in SVR (and not cardiac stimulation or lack thereof), neither sevoflurane, desflurane, or isoflurane appreciably affect cardiac output in healthy volunteers [Cahalan Review Course IARS 1996: 14, 1996] – sevoflurane exhibits the most profound drop, from 100 L/min to 80 L/min as MAC goes from 0.0 to 1.0, however this increases back to 90 L/min as MAC approaches 2.0.

Table 3. MAC at which heart rate increases

Note that sudden changes in anesthetic concentration can elicit more profound cardiovascular effects. Sudden increase in desflurane from 4 to 8% can double heart rate and blood pressure (this can be attenuated with small doses of opioids, clonidine, or esmolol). This does not happen with sevoflurane [Ebert TJ et al. Anesthesiology 83: 88, 1995] Sevoflurane, desflurane, and isoflurane do not predispose the heart to ventricular dysrhythmias [Navarro R et al. Anesthesiology 80: 545, 1994], and evidence from animal studies suggests that they may even suppress dysrhythmias related to ischemia [Miller] All inhaled anesthetics prolong the QT interval (clinical significance unclear), but sevoflurane should be avoided in patients with long QT syndrome [Miller]. Treatment of LQTS is Beta-blockade, and patients with LQTS have been safely anesthetized with all modern inhaled anesthetics while being Beta-blocked.

Multiple studies in patients at risk for CAD or undergoing CABG have failed to demonstrate an outcome difference between inhalational and intravenous techniques or between various inhaled anesthetics [Grundman U et al. Acta Anaesthesiol Scand 40: 1101, 1996, Miller].

All inhaled anesthetics prolong the QT interval (clinical significance unclear), but sevoflurane should be avoided in patients with long QT syndrome [Miller]. In fact, all inhaled anesthetics exert a protective effect on the heart in a mechanism independent of alterations in the oxygen supply-demand ratio – this is called anesthetic preconditioning. For instance – sevoflurane and/or desflurane at 0.2 to 1.0 MAC produces lower levels of cardiac enzymes then administration of propofol to patients undergoing CABG [DeHert SG et al. Anesthesiology 99: 314, 2003]. Similarly, entire duration sevoflurane results in lower incidence of MI than pre or post-bypass, alone, and pre or post-bypass sevoflurane results in lower MI incidence than no sevoflurane (propofol alone) [DeHert SG et al. Anesthesiology 101: 299, 2004]

Ischemic preconditioning occurs in two phases – the first takes place 1-2 hours after the conditioning episode, the second takes place 24-72 hours later and is dependent on ATP-sensitive mitochondrial K+ channels – this second mechanism is fundamental to anesthetic agents’ ability to enhance ischemic preconditioning and/or provide myocardial protection [Zaugg M et al. Anesthesiology 97: 4, 2002]

Pulmonary System

Inhaled anesthetics decrease tidal volume and increase frequency, leading to greater dead space ventilation, thus PaCO2 increases proportionately [Eger EI. Desflurane: A Compendium and Reference, p: 1-11, 1993]. Substituting 60% nitrous oxide for volatile anesthetic may reduce the increase in PaCO2 [Miller]. Volatile anesthetics blunt the body’s response to increased CO2 and decreased O2 [Sjogren: Anesth Analg 86: 403, 1998], although the former may be attenuated by surgical stimulation [Eger EI. Desflurane: A Compendium and Reference, p: 1-11, 1993]. Enhanced respiratory activity (cephalad diaphragm, inward displacement of rib cage) leads to a reduction in FRC. Atelectasis is increased as compared to spontaneous ventilation.

Pulmonary blood flow is altered, but hypoxic pulmonary vasoconstriction is essentially unchanged. Inhaled anesthetics cause bronchodilation but unless a patient has preexisting bronchoconstriction, the effects are minimal.

Sevoflurane and nitrous oxide are non-pungent, however isoflurane and desflurane are pungent and can irritate airways at levels > 1.0 MAC (esp. in the absence of IV medications).

Neurologic System

Nitrous oxide causes cerebral vasodilation and increases CBF in the absence of volatile anesthetics. Additionally, CMRO2 is mildly increased, however coadministration of opiates, barbiturates, or propofol (but not ketamine) attenuates these effects [Petersen KD et al. Anesthesiology 98: 329, 2003] Sevoflurane, desflurane, and isoflurane decrease CMRO2. They all vasodilate above 0.6 MAC and produce a biphasic effect on cerebral blood flow – at 0.5 MAC, CMRO2 decreases, and counteracts the vasodilatory effects (ie CBF does not change); above 1.0 MAC, vasodilatory effects become more prominent, and actually increase CBF.

Table 4. CNS Effects of Anesthetics

ICP increases for all inhaled agents at MAC 1.0, and autoregulation is impaired at levels below that. 1.0 MAC of isoflurane or desflurane decreases CBF during craniotomy for supratentorial tumors [Fraga M et al. Anesthesiology 98: 1085, 2003] but does not affect ICP. In contrast, 1.0 MAC of iso/des will decrease CBF and raise ICP in pituitary resections, and subjective measures of brain relaxation suggest that 50% NO plus 0.5 MAC of iso/des provide better relaxation [Miller].

All volatile anesthetics reduce evoked potential and can abolish them at 1.0 MAC (or 0.5 MAC with 50% nitrous oxide). 0.2-0.3 MAC can reduce the reliability of evoked potential monitoring [Lotto ML et al. J Neurosurg Anesth 16: 32, 2004].

EEG effects of inhaled anesthetics include an initial increase in amplitude and synchrony, followed by periods of electrical silence as doses increase. Between MAC 1.5 and 2.0, an isoelectric pattern emerges. Sevoflurane and enflurane may be associated with epileptic activity on the EEG.


Severe hepatic injury can occur with isoflurane, sevoflurane, or desflurane. The mechanism for this massive hepatic necrosis is immunologic, and requires prior exposure to a volatile anesthetic. Isoflurane and desflurane are oxidated by P450 to form trifluoroacetate, which can bind to liver proteins and act as a hapten (similarly, sevoflurane is degraded to Compound A by the CO2 absorbent, and may also produce a hapten when in contact with liver proteins).


Volatile anesthetics produce dose-dependent relaxation of skeletal muscles and enhance SCh and non-depolarizing neuromuscular drugs (especially desflurane).

Malignant Hyperthermia

Animal studies suggest that there is less risk with desflurane and sevoflurane (and possibly isoflurane) as compared to halothane; however, all potent volatile agents should be avoided in the MH-susceptible patient.