A. Classification and Pharmacokinetics
The agents currently used in inhalation anesthesia are nitrous oxide (a gas) and several easily vaporized liquid halogenated hydrocarbons, including halothane, desflurane, enflurane, isoflurane, sevoflurane, and methoxyflurane. They are administered as gases; their partial pressure, or “tension,” in the inhaled air or in blood or other tissue is a measure of their concentration. Because the standard pressure of the total inhaled mixture is atmospheric pressure (760 mm Hg at sea level), the partial pressure may also be expressed as a percentage. Thus, 50% nitrous oxide in the inhaled air would have a partial pressure of 380 mm Hg. The speed of induction of anesthetic effects depends on several factors, discussed next.
The more rapidly a drug equilibrates with the blood, the more quickly the drug passes into the brain to produce anesthetic effects. Drugs with a low blood:gas partition coefficient (eg, nitrous oxide) equilibrate more rapidly than those with a higher blood solubility (eg, halothane), as illustrated in Figure 25–1. Partition coefficients for inhalation anesthetics are shown in Table 25–1.
Why induction of anesthesia is slower with more soluble anesthetic gases and faster with less soluble ones. In this schematic diagram, solubility is represented by the size of the blood compartment (the more soluble the gas, the larger is the compartment). For a given concentration or partial pressure of the 2 anesthetic gases in the inspired air, it will take much longer with halothane than with nitrous oxide for the blood partial pressure to rise to the same partial pressure as in the alveoli. Because the concentration in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be much slower with halothane than with nitrous oxide. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 25–3.)
TABLE 25–1Properties of inhalation anesthetics.
2. Inspired gas partial pressure
A high partial pressure of the gas in the lungs results in more rapid achievement of anesthetic levels in the blood. This effect can be taken advantage of by the initial administration of gas concentrations higher than those required for maintenance of anesthesia.
The greater the ventilation, the more rapid is the rise in alveolar and blood partial pressure of the agent and the onset of anesthesia (Figure 25–2). This effect is taken advantage of in the induction of the anesthetic state.
Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2 L/min) has a much greater effect on equilibration of halothane than nitrous oxide. FA/FI, ratio of alveolar drug concentration to inhaled concentration. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 25–5.)
At high pulmonary blood flows, the gas partial pressure rises at a slower rate; thus, the speed of onset of anesthesia is reduced. At low flow rates, onset is faster. In circulatory shock, this effect may accelerate the rate of onset of anesthesia with agents of high blood solubility.
5. Arteriovenous concentration gradient
Uptake of soluble anesthetics into highly perfused tissues may decrease gas tension in mixed venous blood. This can influence the rate of onset of anesthesia because achievement of equilibrium is dependent on the difference in anesthetic tension between arterial and venous blood.
Inhaled anesthesia is terminated by redistribution of the drug from the brain to the blood and elimination of the drug through the lungs. The rate of recovery from anesthesia using agents with low blood:gas partition coefficients is faster than that of anesthetics with high blood solubility. This important property has led to the introduction of several newer inhaled anesthetics (eg, desflurane, sevoflurane), which, because of their low blood solubility, are characterized by recovery times that are considerably shorter than is the case with older agents. Halothane and methoxyflurane are metabolized by liver enzymes to a significant extent (Table 25–1). Metabolism of halothane and methoxyflurane has only a minor influence on the speed of recovery from their anesthetic effect but does play a role in potential toxicity of these anesthetics.
C. Minimum Alveolar Anesthetic Concentration
The potency of inhaled anesthetics is best measured by the minimum alveolar anesthetic concentration (MAC), defined as the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients. Each anesthetic has a defined MAC (Table 25–1), but this value may vary among patients depending on age, cardiovascular status, and use of adjuvant drugs. Estimations of MAC value suggest a relatively “steep” dose–response relationship for inhaled anesthetics. MACs for infants and elderly patients are lower than those for adolescents and young adults. When several anesthetic agents are used simultaneously, their MAC values are additive.
D. Effects of Inhaled Anesthetics
Inhaled anesthetics decrease brain metabolic rate. They reduce vascular resistance and thus increase cerebral blood flow. This may lead to an increase in intracranial pressure. High concentrations of enflurane may cause spike-and-wave activity and muscle twitching, but this effect is unique to this drug. Although nitrous oxide has low anesthetic potency (ie, a high MAC), it exerts marked analgesic and amnestic actions.
2. Cardiovascular effects
Most inhaled anesthetics decrease arterial blood pressure moderately. Enflurane and halothane are myocardial depressants that decrease cardiac output, whereas isoflurane, desflurane and sevoflurane cause peripheral vasodilation. Nitrous oxide is less likely to lower blood pressure than are other inhaled anesthetics. Blood flow to the liver and kidney is decreased by most inhaled agents. Inhaled anesthetics depress myocardial function—nitrous oxide least. Halothane, and to a lesser degree isoflurane, may sensitize the myocardium to the arrhythmogenic effects of catecholamines.
Although the rate of respiration may be increased, all inhaled anesthetics cause a dose-dependent decrease in tidal volume and minute ventilation, leading to an increase in arterial CO2 tension. Inhaled anesthetics decrease ventilatory response to hypoxia even at subanesthetic concentrations (eg, during recovery). Nitrous oxide has the smallest effect on respiration. Most inhaled anesthetics are bronchodilators, but desflurane is a pulmonary irritant and may cause bronchospasm. The pungency of enflurane causes breath-holding, which limits its use in anesthesia induction.
Postoperative hepatitis has occurred (rarely) after halothane anesthesia in patients experiencing hypovolemic shock or other severe stress. The mechanism of hepatotoxicity is unclear but may involve formation of reactive metabolites that cause direct toxicity or initiate immune-mediated responses. Fluoride released by metabolism of methoxyflurane (and possibly enflurane and sevoflurane) may cause renal insufficiency after prolonged anesthesia. Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anemia. Susceptible patients may develop malignant hyperthermia when anesthetics are used together with neuromuscular blockers (especially succinylcholine). This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor (RyR1). Other chromosomal loci for malignant hyperthermia include mutant alleles of the gene-encoding skeletal muscle L-type calcium channels. The uncontrolled release of calcium by the sarcoplasmic reticulum of skeletal muscle leads to muscle spasm, hyperthermia, and autonomic lability (Table 16-2). Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.