Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 35 General Anesthetics

MAJOR DRUG CLASSES

Inhalational anesthetics

Intravenous anesthetics

Therapeutic Overview

Modern surgical procedures would not be possible without anesthetics to block the traumatic emotional and physical pain that would otherwise be experienced by the patient. Such agents have been available since the 1840s, when diethyl ether was first used successfully to anesthetize patients undergoing surgery.

General anesthesia can be viewed as a controlled, reversible state of loss of sensation and consciousness. The ideal general anesthetic state comprises analgesia, amnesia, loss of consciousness (absence of awareness), relaxation of skeletal muscles, suppression of somatic, autonomic, and endocrine reflexes, and hemodynamic stability. Although most objectives of general anesthesia can be achieved with diethyl ether, this inhalational agent is obsolete because of its flammability and explosiveness. Other general anesthetic agents are available and are classified based on their route of administration—by inhalation or IV injection.

The induction of anesthesia produced by the IV administration of an anesthetic agent is more rapid, smoother, and more pleasant for the patient than that produced by an inhalational anesthetic agent, with its slower onset, vapors that may be unpleasant, and facemask delivery system. In addition to their use for the induction of anesthesia, hypnotic and opioid drugs are often administered IV for anesthesia management. In balanced anesthesia, which is a common practice, a combination of various anesthetic agents is used, each in small doses, to reduce the chance of significant side effects.

The safe and effective use of general anesthetics is a dynamic process that must be individualized for each patient and surgical situation. Further, the needs of both the surgical team and the patient may change during a procedure, altering anesthetic requirements. For example, there may be a need to blunt the tachycardia and hypertension that result from an intense sympathetic nervous system stimulus, produce greater relaxation of skeletal muscle, or provide additional analgesia. All interventions must be reversible, and tissue hypoxia must be prevented.

The primary therapeutic considerations are summarized in the Therapeutic Overview Box.

Abbreviations

CNS

Central nervous system

ED50

Median effective dose

GABA

γ-Aminobutyric acid

IV

Intravenous

MAC

Minimum alveolar concentration

N2O

Nitrous oxide

NMDA

N-methyl-D-aspartate

Pco2

Carbon dioxide tension (partial pressure)

Therapeutic Overview

Requirements of Anesthetic Drugs

Inhalational

Chemical stability

Minimal irritation upon inhaling

Speed of onset (time to loss of consciousness)

Ability to produce analgesia, amnesia, and muscle relaxation

Minimal side effects, especially cardiovascular and respiratory depression and toxicity to the liver

Speed and safety of emergence

Minimal metabolism

Intravenous

Chemical stability

No pain at injection site

Speed of onset

Minimal side effects

Ability to produce analgesia, amnesia, and muscle relaxation

Speed and safety of emergence

Rapid metabolism or redistribution

Mechanisms of Action

Inhalational Anesthetics

The molecular basis for the anesthetic action of inhalational agents is poorly understood. Although most inhalational anesthetics contain an ether (-O-) link and a halogen (Fig. 35-1), no obvious structure-activity relationships have been defined, suggesting that they do not exert their effects through specific cell-surface receptors, unlike most other therapeutic agents acting on the central nervous system (CNS).

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FIGURE 35–1 Chemical structure of inhalational anesthetic agents.

The potency of an inhalational anesthetic is expressed in terms of the minimum alveolar concentration (MAC), which is a concentration that prevents 50% of patients from responding to a painful stimulus, such as a skin incision. MAC is analogous to the median effective dose (ED50) and is used to express the relative potency of gaseous drugs. Meyer and Overton observed that the potencies of anesthetic agents correlate highly with their lipid solubilities, as measured by the oil:gas partition coefficient (Table 35-1Fig. 35-2). Indeed, this relationship holds not only for agents in clinical use but also for inert gases that are not used clinically, such as xenon and argon. This correlation has given rise to several theories of anesthetic action, none of which has been substantiated.

TABLE 35–1 Characteristics of Inhalational Anesthetic Agents

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FIGURE 35–2 The potency of an inhalational anesthetic agent is determined by its lipid solubility, as measured by its oil:gas partition coefficient.

According to the volume expansion theory, molecules of an anesthetic dissolve in the phospholipid bilayer of the neuronal membrane, causing it to expand and impede opening of ion channels necessary for generation and propagation of action potentials. Another hypothesis suggests that anesthetic molecules bind to specific hydrophobic regions of lipoproteins in the neuronal membrane that are part of, or close to, an ion channel. The resulting conformational change in the protein prevents effective operation of the channel. Anesthetics also have been considered to alter the fluidity of membrane lipids, which could also prevent or limit increases in ion conductance.

Alternatively, “nonspecific” effects of anesthetics may occur at specific cell-surface receptors for neurotransmitters or neuromodulators. For example, clinically relevant concentrations of halogenated inhalational anesthetics increase Cl conductance induced by γ-aminobutyric acid (GABA) in vitro neuronal preparations. Because GABA is the principal inhibitory neurotransmitter in the brain, activation or enhancement of GABA-mediated Cl conductance would inhibit neuronal activity in the CNS. Similarly, nitrous oxide (N2O) decreases cation conductance in the ion channel controlled by the N-methyl-D-aspartate (NMDA) glutamate receptor, thereby blocking the actions of the principal excitatory neurotransmitter in the brain, and all inhalational anesthetics inhibit the activity of neuronal nicotinic acetylcholine receptors. Thus, through mechanisms as yet undefined, inhalational anesthetics disrupt the function of ligand-gated ion channels, increasing inhibitory and decreasing excitatory synaptic transmission.

Intravenous Anesthetics

Most IV anesthetic agents contain ring structures (Figure 35-3), have well-documented effects at specific cell-surface receptors, and include benzodiazepines, barbiturates, opioids, and several other compounds.

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FIGURE 35–3 Structures of representative intravenous general anesthetic drugs.

The barbiturate anesthetics include thiopental and methohexital, while the benzodiazepine anesthetics include diazepam and midazolam. These agents act at two distinct recognition sites on the GABAA receptor Cl channel complex to potentiate GABA-mediated Cl conductance and neuronal inhibition (see Chapter 31).

Several opioids used for anesthesia include fentanyl and its analogs sufentanil and remifentanil. Although morphine was used for many years, these newer high-potency compounds are gradually replacing it. The depressant action of the opioids on neuronal activity is mediated by the μ opioid receptor and those of mixed-action opioids by μ and κ opioid receptors (see Chapter 36).

Ketamine appears to act by blocking neuronal excitation; it binds to the phencyclidine receptor, a site within the cation channel gated by the NMDA glutamate receptor, and inhibits cation conductance through the channel.

Propofol, the most widely used anesthetic in the United States, appears to facilitate GABAA receptor-mediated inhibition and inhibits glutamate NMDA receptor-mediated excitation. Etomidate also facilitates GABAA receptor-mediated neuronal inhibition. In addition, at clinically relevant concentrations in vitro, both drugs block the specific high-affinity neuronal uptake of GABA without affecting its release.

Pharmacokinetics

Inhalational Anesthetics

The depth of anesthesia is determined by the concentration of the anesthetic in the brain. Therefore, to produce concentrations adequate for surgery, it is necessary to deliver an appropriate amount of drug to the brain. Unlike most drugs, inhalational anesthetics are administered as gases or vapors. Therefore a specific set of physical principles applies to the delivery of these agents.

In a mixture of gases, the partial pressure of an anesthetic agent is directly proportional to its fractional concentration in the mixture (Dalton’s Law). Thus, as depicted in Figure 35-4, in a mixture of 70% N2O, 25% O2, and 5% halothane, which might be used during mask induction of anesthesia, the partial pressures of the component gases are 532, 190, and 38 mm Hg, respectively, at 1 atmosphere (760 mm Hg) of pressure.

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FIGURE 35–4 The partial pressure of a gas in a mixture of gases is directly proportional to its concentration.

When a gas is dissolved in the blood or other body tissues, its partial pressure is directly proportional to its concentration but inversely proportional to its solubility in that tissue. The concept of partial pressure is of central importance, because the partial pressure of a gas is the driving force that moves the gas from the anesthetic machine to the lungs, from the lungs to the blood, and from the blood to the brain. At theoretical equilibrium, the partial pressures are equal in all body tissues, alveoli, and the inspired gas mixture. Because solubility varies from tissue to tissue as a consequence of differences in tissue lipophilicity, the concentration of anesthetic must also vary from tissue to tissue if partial pressures are equal throughout the body. The partial pressure (or concentration) of the anesthetic in the inspired gas mixture is the factor controlled most easily by the anesthesiologist. This is accomplished by adjusting the anesthetic machine to optimize partial pressures during induction, maintenance, or both.

The rate of induction of anesthesia by inhalational agents is affected by numerous factors, including those that reduce alveolar ventilation, which represents the product of the rate of respiration and tidal volume less the pulmonary dead space (Table 35-2). Thus if a patient is administered respiratory depressants such as barbiturates or opioid analgesics preoperatively, the rate of respiration or tidal volume decreases, thereby reducing alveolar ventilation in the absence of assisted ventilation. Alveolar dead space is substantial in patients with pulmonary diseases such as emphysema and atelectasis, which result in decreased alveolar ventilation and rate of anesthesia induction.

TABLE 35–2 Factors Affecting the Rate of Induction with an Inhalational Anesthetic

Condition

Rate of Induction

Increased concentration of anesthetic in inspired gas mixture

Increased

Increased alveolar ventilation

Increased

Increased solubility of anesthetic in blood (blood:gas partition coefficient)

Decreased

Increased cardiac output

Decreased

The path followed by an inhalational anesthetic during induction of, and emergence from, anesthesia is diagrammed in Figure 35-5. Induction is facilitated by factors that maintain a high partial pressure of the anesthetic in the inspired gas mixture, alveolar space, and arterial blood to deliver as much of the gas to the brain as quickly as possible. The alveolar membrane poses no barrier to gases, permitting unhindered diffusion in both directions. Therefore, once the anesthetic gas reaches the alveolar space, it obeys the law of mass action and moves down its partial-pressure gradient into arterial blood. At the initiation of anesthetic administration, the partial pressure of the anesthetic in the alveolar space is much higher than that in blood. Thus the partial pressure gradient between the alveolar space and the arteriolar blood is high, and initially the gas moves rapidly into blood. As the partial pressure of the anesthetic agent in blood increases, the gradient between the alveolar space and blood decreases and uptake slows (Fig. 35-6).

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FIGURE 35–5 Pathway of an inhalational anesthetic agent during induction of (red arrows) and emergence from (blue arrows) anesthesia. The large arrows indicate the direction of net movement.

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FIGURE 35–6 Rate of rise of partial pressure of an inhalational anesthetic agent in arterial blood is determined by its solubility in blood (blood:gas partition coefficient).

Another important factor in the rate of rise of the arterial partial pressure of an anesthetic gas is its solubility in blood. This relationship is expressed as the blood:gas partition coefficient. The higher the solubility is of an anesthetic gas in blood, the more must be dissolved to produce a change in partial pressure (because partial pressure is inversely proportional to solubility). This relationship is illustrated for N2O and halothane in Figure 35-7.

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FIGURE 35–7 The solubility of an inhalational anesthetic in blood determines how rapidly its partial pressure rises in blood and brain with a change in partial pressure in the inspired gas mixture. If the alveolar space and blood were a closed system and N2O and halothane were allowed to equilibrate between the two, there would be 0.47 parts of N2O in blood for every 1 part in alveoli, and 2.3 parts of halothane in blood for every 1 part in alveoli. An increase in the partial pressure of N2O in the inspired gas mixture results in an almost fivefold larger increase in its partial pressure in blood than would a similar increase in the partial pressure of halothane in the inspired gas mixture, driving N2O into the brain more rapidly.

Nitrous oxide has a blood:gas partition coefficient of 0.47, so relatively little must be dissolved in blood for its partial pressure in blood to rise. This also is true for desflurane and sevoflurane. In contrast, blood serves as a large reservoir for halothane, retaining at equilibrium 2.3 parts for every 1 part in the alveolar space. Induction therefore depends not on dissolving the anesthetic in blood but on raising arterial partial pressure to drive the gas from blood to brain. Therefore the rate of rise of arterial partial pressure and speed of induction are fastest for gases that are least soluble in blood (see Fig. 35-6). The blood:gas partition coefficients of inhalational anesthetics are listed in Table 35-1.

Because cardiac output is the primary determinant of the rate of pulmonary blood flow, it would seem that an increase in cardiac output, and thus an increase in pulmonary blood flow, would accelerate induction of anesthesia. However, the opposite is true. The rate of anesthetic induction decreases with increasing cardiac output. An increased pulmonary blood flow means that the same volume of gas from the alveoli diffuses into a larger volume of blood per unit of time. The initial consequence is a reduced concentration of anesthetic (and partial pressure) in blood. In addition, increases in cardiac output typically increase perfusion of tissues other than brain, such as muscle, thereby increasing the apparent volume of distribution of the anesthetic. In a patient with heart failure, blood loss, or other conditions resulting in decreased cardiac output, the volume of distribution of an anesthetic is reduced, and the rate of induction is increased.

The transfer of an anesthetic from arterial blood to brain depends on factors analogous to those involved in movement of gas from alveoli to arterial blood. These include the partial pressure gradient between blood and brain, the solubility of the anesthetic in brain, and cerebral blood flow. The brain is part of the vessel-rich group of tissues that compose 9% of body mass but receive 75% of cardiac output. The anesthetic uptake curve levels off (see Fig. 35-6), reflecting attainment of equilibrium by the vessel-rich group of tissues. In contrast, the muscle group constitutes 50% of body mass but receives only 18% of cardiac output. Fat represents 19% of body mass and receives 5% of cardiac output, whereas the vessel-poor group including bone and tendon, accounts for 22% of body mass yet receives less than 2% of cardiac output. Thus approximately 41% of total body mass receives a mere 7% of cardiac output. As a consequence, in most surgical procedures, poorly perfused tissues do not contribute meaningfully to the apparent volume of distribution of the inhalational anesthetic, and true total equilibration does not occur. The importance of tissue perfusion as a factor determining the uptake of an anesthetic is illustrated for halothane in Figure 35-8.

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FIGURE 35–8 The rate at which an inhalational anesthetic agent is taken up by a tissue depends on the fraction of the cardiac output (CO) that the tissue receives. The approximate time for halothane to equilibrate between blood and tissues is indicated next to the arrows; the percentage of body mass that the tissue represents is shown in the boxes. The numbers in parentheses represent the relative percentage of CO received by each tissue group.

When administration of an anesthetic is terminated, the anesthetic gas flows from the venous blood to the alveolar space (see Fig. 35-5). Factors that affect the rate of elimination of an inhalational anesthetic are analogous to those that determine its rate of uptake. Therefore the rate of loss of an anesthetic gas during emergence from anesthesia is directly proportional to its rate of uptake, and emergence is a mirror image of induction.

Although inhaled anesthetics are cleared from the body largely via the lung, most undergo some degree of hepatic metabolism, and several metabolites have been implicated in organ toxicity. The extensive metabolism of methoxyflurane, 50% to 60% of an administered dose, results in the release of fluoride ions, which can reach nephrotoxic concentrations during long surgical procedures; therefore methoxyflurane is no longer used. The extent of biotransformation of other inhalational anesthetics ranges from approximately 15% for halothane to negligible amounts for N2O (see Table 35-1). Inhalational anesthetics that are not appreciably metabolized generally exhibit less-toxic sequelae.

Intravenous Anesthetics

When IV anesthetics are administered, movement of drug from blood to brain determines its onset of action. A good IV anesthetic drug should be effective within one “arm-to-brain blood circulation.” The short-acting compounds propofol and etomidate are the fastest to induce anesthesia, that is, 30 to 50 seconds from injection to loss of the eyelash reflex, or one arm-to-brain circulation. On the other hand, a benzodiazepine requires several minutes to induce a similar response. Because blood flow to the brain is also important, the onset of action may be delayed in a patient with extremely low cardiac output and therefore a relatively low blood flow to the brain.

The duration of effect of a single induction dose of an IV anesthetic is determined by its rate of redistribution or metabolism. Redistribution from the brain into less-well-perfused tissues (i.e., abdominal viscera, skeletal muscle) is the predominant mechanism responsible for termination of action. Redistribution can occur within minutes of induction of anesthesia with a single dose of anesthetic, resulting in recovery of reflex activity and consciousness. The IV induction agents have varying speeds of onset, durations of action, and rates of redistribution. The pharmacokinetic and physicochemical characteristics of the ideal IV anesthetic are listed in Box 35-1.

BOX 35–1 Characteristics of an Ideal Intravenous Anesthetic Drug

Physicochemical

H2O soluble

Stable on shelf and to light exposure

Lipophilic

Small injection volume

Pharmacokinetic

Rapid onset of action

Short duration of action

Nontoxic metabolites

Pharmacodynamic

Wide margin of safety

No interpatient variability in effects

Nonallergenic

Nontoxic to tissues

Thiopental has been used widely for IV induction because of its rapid and smooth onset and its short duration of action. It is highly lipid soluble, rapidly crosses the blood-brain barrier, and is rapidly redistributed from brain to other body tissues. These pharmacokinetic characteristics preclude its use as a maintenance agent for lengthy procedures. However, because of its long terminal elimination half-life (Table 35-3), thiopental accumulates in the body, and its duration of action increases with repeated administration, causing some patients to remain unconscious after surgery is completed. Thiopental is metabolized primarily in the liver to H2O-soluble metabolites that are excreted in the urine. The pharmacokinetic properties of other barbiturates used as IV anesthetics, such as methohexital, are generally similar to those of thiopental.

TABLE 35–3 Comparison of Intravenous Anesthetics in Healthy Adults

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Induction of anesthesia with the benzodiazepine diazepam is relatively slow, often taking several minutes. It has a long redistribution half-life (30 to 60 minutes), a long duration of action, and a long terminal elimination half-life (see Table 35-3). It is metabolized by the microsomal enzyme system in liver, and most of its metabolites are pharmacologically active and have long half-lives (see Chapter 31). Midazolam is an H2O-soluble benzodiazepine twice as potent as diazepam. It takes midazolam 2 to 3 minutes to induce anesthesia, which is faster than diazepam but slower than thiopental.

Morphine, the prototypical opioid analgesic, is given subcutaneously or intramuscularly in doses of 8 to 15 mg to allay anxiety and ease pain before, during, and after surgery. It is administered IV in substantially higher doses in combination with an inhalational or IV anesthetic for the induction and maintenance of anesthesia, especially for cardiac or other major surgery. Because of its low lipophilicity, morphine crosses the blood-brain barrier slowly, and plasma concentrations may not accurately reflect those in brain. Morphine is metabolized in the liver, primarily to morphine-6-glucuronide, which retains considerable morphine-like activity but has limited access to the CNS.

Remifentanil, the newest potent and ultrashort-acting μ opioid receptor agonist, has a rapid onset of action, is metabolized rapidly by plasma and tissue esterases, and has a terminal elimination half-life of 10 to 15 minutes. It is often one of the components in “balanced-anesthesia,” where it is given as a continuous infusion, titrating to the desired effect. Because remifentanil is so short-acting, patients should be given a longer-acting opioid or other analgesic 10 to 15 minutes before emergence from anesthesia. Other opioids commonly used in anesthesia differ from morphine in their potency, rate of onset, and duration of action but are generally similar in their pharmacological activity (see Table 35-3 and Chapter 36).

Propofol is twice as potent as thiopental. Loss of consciousness occurs within one arm-to-brain circulation time. The induction dose is much lower in the elderly and slightly higher in younger children. Propofol can be used for both induction and maintenance of anesthesia. The duration of sleep after administration of a single dose is 5 to 10 minutes. To achieve a more sustained effect after induction, the patient should be given another bolus dose within 5 minutes or receive a continuous infusion; the latter is preferred to ensure smooth maintenance and constant plasma concentrations. The redistribution half-life of propofol is 5 to 10 minutes, and a long terminal-elimination half-life suggests that propofol may accumulate in tissues after prolonged use.

The physicochemical properties of some IV anesthetic drugs render them insoluble in H2O at physiological pH, necessitating use of solvents or adjusting the pH of the injectate (see Table 35-3), either of which can lead to problems. The alkaline pH of a 2.5% solution of thiopental makes it unsuitable for mixing with acidic drugs, especially opioids and muscle relaxants. Thiopental solutions also cause tissue damage if injected intraarterially or extravascularly. Acidic etomidate solutions can cause pain and thrombophlebitis after intravascular injection. All alcohol-based solvents and buffers are venous irritants, causing pain when injected IV. Thus a diazepam solution is sometimes mixed with a solution of the local anesthetic lidocaine to make the injection less painful. Midazolam, in contrast, is H2O soluble and poses no special problems for IV administration. Propofol emulsion causes pain on injection, a problem that may be resolved by newer formulations.

Relationship of Mechanisms of Action to Clinical Response

Inhalational Anesthetics

As indicated, the MAC is used to express the relative potency of gaseous drugs and is the concentration that prevents 50% of patients from responding to a painful stimulus. Clearly, an inhalational anesthetic should be administered at a concentration higher than 1.0 MAC to achieve an acceptable level of surgical anesthesia in which there is no movement in 100% of patients. Thus, although 1.0 MAC defines the ED50, a level of anesthesia satisfactory for most surgical procedures is achieved at an alveolar gas concentration of 1.3 MAC, which is equal to or greater than the ED99, the concentration that prevents greater than 99% of patients from responding to a painful stimulus.

Because doses of inhalational anesthetics are additive, a 0.5 MAC of compound “A” can be combined with a 0.5 MAC of compound “B” to give an inspired-gas mixture that has a MAC of 1.0. For example, 1.0 MAC of halothane is 0.75% (5.7 mm Hg, or 5.7 torr at 1.0 atmosphere of pressure), and 1.0 MAC of isoflurane is 1.15% (8.7 mm Hg). Therefore an inspired gas mixture containing 0.375% halothane and 0.575% isoflurane has a MAC of 1.0.

Except for N2O, all inhalational anesthetics in clinical use are sufficiently potent to produce surgical anesthesia when administered in a mixture containing at least 25% O2. Although MAC is not a prime factor in determining the inhalational anesthetic selected, it does provide a convenient point of reference for comparing their properties. For example, it can be useful to compare the extent of hypotension or relaxation of skeletal muscle produced by two different anesthetic agents administered at a MAC of 1.0.

The MAC is independent of the duration of the surgical procedure, remaining unchanged with time, and is unaffected by the sex of the patient. It also is relatively independent of the type of noxious stimulus applied (e.g., pressure versus heat). Indeed, increasing the intensity of the noxious stimulus, within limits, has little effect on MAC, although higher anesthetic concentrations are required for some traumatic surgical manipulations. MAC is also relatively unaffected by the acid-base status of the patient and is independent of the patient’s body mass. However, at a fixed alveolar concentration, it takes longer to anesthetize a larger patient because of differences in the apparent volume of distribution. Although the MAC of an anesthetic is relatively independent of many patient and surgical variables, it is affected by age. The anesthetic requirement is higher in infants and lower in geriatric patients.

The general health of the patient also affects the anesthetic requirement. Not surprisingly, it is lower in debilitated patients than in otherwise healthy ones. Another consideration is the presence of other drugs. In general, the MAC of an inhalational anesthetic is reduced in patients receiving other CNS depressants. In surgical patients these drugs are commonly opioid analgesics, antianxiety agents, sedatives, or IV anesthetics used for induction. Indeed, CNS depressants are frequently administered preoperatively or intraoperatively to lower the MAC for an inhalational anesthetic.

Nitrous oxide, which cannot be used safely by itself to produce surgical levels of anesthesia, is a common component of anesthetic-gas mixtures. A concentration of 70% N2O in an inspired gas mixture lowers the MAC of the halogenated agent by one half to two thirds. Alcoholic patients who have acquired a tolerance to the CNS depressant effects of ethanol often have an increased anesthetic requirement, as do patients who are tolerant to barbiturates and benzodiazepines. CNS stimulants also cause the anesthetic requirement to be increased. Although a stimulant is unlikely to be administered to a hospitalized patient, the widespread abuse of stimulants increases the probability of encountering patients undergoing emergency surgery with appreciable tissue concentrations of cocaine or amphetamine.

Intravenous Anesthetics

The onset of anesthesia induction with IV agents is determined by administering a single dose and monitoring for a loss of reflex, for example, the lash or cough reflex. Factors that alter the apparent volume of distribution, including protein binding, alter the amount of drug required to obtund body reflexes. An insufficient dose of a single IV agent may lead to transient excitation, which varies for different agents. Excitation may be manifest as hiccups with methohexital, myoclonic twitches with etomidate, and nonpurposeful movements with propofol and thiopental. Thiopental may cause laryngeal spasm in an asthmatic patient, especially if the dose is insufficient or the patient is inadequately premedicated.

Most IV anesthetics do not have muscle relaxant effects, and with the exception of the opioids and ketamine, have no analgesic properties. Ketamine may produce hypnotic (dissociative), amnestic, and analgesic effects. Because it does not reduce cardiac output or blood pressure, ketamine is a useful induction agent in hypovolemic patients. However, ketamine often causes “bad dreams,” especially in adults, unless it is combined with a small dose of a benzodiazepine.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Clinical problems associated with the use of both the inhalational and intravenous anesthetics are summarized in the Clinical Problems Box.

Inhalational Anesthetics

Respiratory and Cardiovascular Effects

All inhalational anesthetics reduce spontaneous respiration in a concentration-dependent manner by depressing medullary centers in the brainstem. They decrease the responsiveness of chemoreceptors in respiratory centers to elevations in carbon dioxide tension (Pco2) in blood and cerebrospinal fluid, which normally serve as a potent stimulus for increasing minute ventilation. The result is a shift to the right and flattening of the Pco2 ventilation-response curve (Fig. 35-9). Thus the ventilatory response to hypercapnia is attenuated. Opioids also reduce the responsiveness of brainstem chemoreceptors to elevations in Pco2 and shift the Pco2 ventilation-response curve in a similar manner. When an opioid is given concurrently with an inhalational anesthetic, the effects of the two on respiration are additive and often synergistic, as shown in Figure 35-9. CO2 exerts a local effect on the cerebral vasculature by dilating small vessels. The resultant increase in intracranial pressure is a cause for concern in patients with head trauma.

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FIGURE 35–9 Anesthetic agents reduce the ventilatory response to increases in the arterial carbon dioxide tension (Pco2) in blood and cerebrospinal fluid. This effect is exacerbated by opioid analgesics.

All inhalational anesthetics depress the force of myocardial contraction in a concentration-dependent manner in isolated heart preparations. In patients, the effects on myocardial function varies depending on the agent, the concentration needed for surgical anesthesia, and the drug’s effects on the sympathetic nervous system. Nitrous oxide has minimal effects on cardiovascular function, whereas halothane significantly depresses most cardiovascular variables. The cardiovascular effects of other anesthetics fall between those of N2O and halothane.

In addition to directly depressing myocardial contractility and reducing cardiac output, halothane depresses the central outflow of the sympathetic nervous system, depresses the baroreceptor reflex, and relaxes peripheral vascular smooth muscle, the latter attributable to a direct action and to the elevated blood concentrations of CO2 resulting from depression of brainstem respiratory centers. The overall effect is hypotension and decreased organ perfusion. Halothane also sensitizes the myocardium to dysrhythmias induced by catecholamines, an action shared to a lesser extent with enflurane. Therefore caution must be exercised when pressor drugs are administered to counteract the hypotension induced by these anesthetics.

Hepatic and Renal Effects

The liver and kidney are the most prominent targets of undesirable effects of anesthetics. Generally, metabolites of the anesthetics are implicated in organ toxicity, but it is often difficult to determine which toxic effects are attributable to the anesthetic itself or to its metabolites. Some adverse effects are caused by the anesthetic-induced decrease in cardiac output and blood flow to the liver or may result from blood transfusions administered during surgery. Halothane hepatitis occurs in 1 in 10,000 to 1 in 20,000 patients, with fatal hepatic necrosis occurring in approximately half. A metabolite of halothane is postulated to form a hapten that triggers an immune response. Liver function tests commonly show abnormalities for 1 or more days after administration of inhalational anesthetics. Although halothane has been administered safely countless times, it is now used less frequently, particularly in the United States, in favor of newer halogenated agents, because of the specter of hepatic toxicity.

Renal blood flow and glomerular filtration rate are decreased during general anesthesia, resulting in decreased urine formation. Enflurane and sevoflurane undergo some metabolism in the liver and release free fluoride ions, which can be nephrotoxic in sufficiently high concentrations during lengthy surgical procedures. It is best not to use either agent in patients with impaired renal function. Halothane, though metabolized to an appreciable extent (see Table 35-1), does not release significant amounts of free fluoride.

Malignant Hyperthermia

Halogenated inhalational anesthetics, and halothane in particular, can precipitate malignant hyperthermia in genetically susceptible patients. Depolarizing neuromuscular blocking agents, notably succinylcholine (see Chapter 12), can also trigger this reaction, which is manifest as a sustained contraction of the musculature with a dramatic increase in O2 consumption and an increased body temperature. The syndrome results from a failure of the sarcoplasmic reticulum to re-sequester Ca++, preventing the dissociation of actin and myosin filaments of muscle. The resultant hyperthermia is an emergency requiring prompt treatment, including rapid cooling and administration of the skeletal muscle relaxant dantrolene (see Chapter 12). Overall, malignant hyperthermia occurs in 1 in 15,000 to 1 in 50,000 cases. The combined use of halothane and succinylcholine is associated with the highest incidence, and the combined use of a halogenated anesthetic other than halothane and a non-depolarizing muscle relaxant is associated with the lowest incidence.

Central Nervous System Effects

As indicated, N2O lacks sufficient potency to produce surgical levels of anesthesia safely by itself. It can produce analgesia comparable to that produced by a therapeutic dose of morphine at concentrations of 20% and can cause amnesia at concentrations of 60%. At a concentration of 40%, N2O can induce a state of behavioral disinhibition and raucousness in patients not receiving other drugs. It is this action of N2O that has given the agent the name “laughing gas.” Most often, N2O is administered in combination with a halogenated anesthetic to lower the anesthetic requirement for the latter and to promote rapid induction (see Fig. 35-6).

Concentrations of enflurane above its MAC, especially during hypocapnia, can cause a characteristic seizure activity on an electroencephalogram, coupled with increased motor activity in the nonmedicated patient. This excitatory effect of enflurane has minimal or no adverse consequences to the patient. Nevertheless, it may be a consideration in patients with known seizure disorders. Isoflurane, a structural isomer of enflurane, does not evoke seizures. In fact, it suppresses electrical activity of the brain and can, in combination with thiopental, provide some protection against hypoxic injury.

Other Effects

Nitrous oxide diffuses into enclosed air-filled cavities in the body, where it exchanges with nitrogen. Because of a difference in their blood:gas partition coefficients, blood can carry much more N2O than nitrogen. Nitrous oxide diffuses out of blood and into air-filled cavities approximately 35 times faster than nitrogen leaves those cavities and enters the blood. This results in an increase in pressure and distention of enclosed air-filled, nitrogen-containing spaces. This situation might be encountered in patients with an occlusion of the middle ear, pneumothorax, obstructed intestine, or air emboli in the bloodstream, or after a pneumoencephalogram. These conditions, if not absolute contraindications to the use of N2O, are at least signals for caution.

Nitrous oxide also oxidizes components of vitamin B12, which decreases the availability of this vitamin and inhibits the activity of methionine synthetase, a vitamin B12-dependent enzyme. This results in a decrease in protein and nucleic acid synthesis, megaloblastic anemia, and other signs of vitamin B12 deficiency. Inhalation of N2O for as little as 2 hours can result in a detectable decrease in methionine synthetase activity, and megaloblastic anemia has been observed in severely ill patients several days after exposure. Generally, clinical problems do not occur unless exposure is lengthened from hours to days. However, long-term exposure to low concentrations of N2O has been linked to neuropathies stemming from vitamin B12 deficiency. There is also some evidence that ongoing occupational exposure to N2O reduces fertility in women.

Intravenous Anesthetics

General side effects, clinical problems, and toxicities associated with the use of the benzodiazepines and opioids are presented in Chapter 31 and Chapter 36, respectively.

Respiratory and Cardiovascular Effects

The benzodiazepines, barbiturates, and opioids are well-known respiratory and cardiovascular depressants and should be used only in a setting in which instrumentation is available to provide assisted ventilation. Thiopental decreases myocardial contractile force and dilates peripheral vessels and thus is contraindicated in patients with cardiovascular instability, such as in shock. Midazolam depresses cardiovascular function to the same extent as thiopental. However, a smaller dose of midazolam given incrementally does not cause myocardial depression, and because of its prominent amnestic effect, can produce a pleasant induction in patients with severe hypovolemia. Propofol also depresses both the respiratory and cardiovascular systems.

The effects of etomidate on the cardiovascular and respiratory systems are relatively benign; however, small increases in heart rate and dysrhythmias have been reported. In addition, ketamine has well-documented cardiovascular stimulant actions.

Central Nervous System Effects

Ketamine is related structurally to phencyclidine, and both drugs have many pharmacological actions in common. At appropriate doses the patient may appear to be awake but is unresponsive to or dissociated from the environment (hence the term dissociative anesthesia). The usefulness of ketamine for maintenance of anesthesia is limited by the high incidence of unpleasant dreams and other dysphoric episodes occurring in patients during emergence from anesthesia. This is one reason why ketamine is used primarily as an induction agent in patients for brief painful procedures, such as changing burn dressings, where its analgesic and amnestic effects are advantageous. A benzodiazepine is often coadministered with ketamine to minimize postoperative psychotomimetic reactions.

Other Effects

The barbiturates are contraindicated in patients who may be allergic or have a familial history of acute intermittent porphyria, and propofol is contraindicated in any person with hypersensitivity to the drug.

Etomidate is not suitable for IV infusion for maintenance of anesthesia, because it causes pain on injection, myoclonus, and thrombophlebitis at the injection site. Its propensity to cause nausea and vomiting postoperatively limits its use in an outpatient setting. Etomidate has also been shown to suppress the synthesis and release of corticosteroids.

Postoperative nausea and vomiting are common side effects with opioids. The rapid IV administration of morphine can evoke histamine release from mast cells, which in turn causes arterial and venous dilatation and hypotension. This effect can be prevented by pretreatment with H1 and H2 receptor blockers, such as diphenhydramine and cimetidine, respectively (see Chapter 14).

Treatment of Acute Intoxication

Specific receptor antagonists are available to reverse the respiratory and sedative effects of the benzodiazepines and opioids (see Chapter 31 and Chapter 36, respectively).

Flumazenil is a competitive antagonist at the benzodiazepine binding site of the GABAA receptor complex and can reverse the residual sedative effects of benzodiazepine agonists. Because of its receptor selectivity, flumazenil does not antagonize the depressant effects of drugs other than benzodiazepines. Flumazenil may not reverse the respiratory depressant effects of benzodiazepines completely and cannot replace equipment for airway management

CLINICAL PROBLEMS

Inhalational Agents

Depressed respiratory drive because of lower response to CO2 or to hypoxia

Depressed cardiovascular drive

Enlarged gaseous space (N2O)

Malignant hyperthermia

Intravenous Agents

Depressed respiratory drive because of lower response to CO2 or to hypoxia

Depressed cardiovascular drive

Muscular rigidity (opioids, ketamine)

Hallucinations and emergence delirium (ketamine)

Inhibited steroidogenesis (etomidate)

Reduced pain threshold (thiopental)

and resuscitation. Although flumazenil acts rapidly, within one arm-to-brain circulation time, its duration is short. Therefore re-sedation may occur after reversal (so-called residual sedation), especially in patients receiving a large dose of a long-acting benzodiazepine, requiring additional doses of flumazenil. Flumazenil can precipitate a withdrawal syndrome in patients who are physically dependent on a benzodiazepine.

The specific opioid antagonist naloxone can be administered postoperatively to reverse any respiratory depression produced by opioid analgesics and to arouse a patient. However, because it reverses all effects of opioids, including analgesia, it should not be used routinely for this purpose. The duration of action of naloxone is short, necessitating repeated administration. Because of its exquisite selectivity, naloxone will not reverse depressant effects of drugs other than opioids.

New Horizons

Efforts to reduce the rising cost of healthcare in the United States may result in 70% to 75% of all surgical procedures being performed in ambulatory surgical facilities. Surgery in hospitals will be reserved for patients requiring the most intensive medical care. This trend has important implications in terms of drug development. Because most surgical patients are discharged within hours of their surgery, the effects of anesthetic drugs have to be dissipated rapidly and completely, enabling the patient to have a clear sensorium and no residual postoperative nausea or impairment of motor function, judgment, or memory. This requires inhalational anesthetic agents that have a fast onset and offset of action like propofol. Therefore IV drugs that are inactivated rapidly by simple mechanisms (such as plasma esterase activity) will be relied on more heavily for general anesthesia, because their effects disappear within moments of terminating drug administration. Newer drugs should possess the characteristics of the ideal agent listed in Box 35-1.

Inhalational agents will still be used widely. They should have good potency and low solubility in blood for rapid onset and offset of effects, and they should undergo minimal biotransformation, because the metabolites of inhalational anesthetics are responsible for some undesirable side effects.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Inhalational Anesthetics

Desflurane (Suprane)

Enflurane (Ethrane)

Halothane (Fluothane)

Isoflurane (Forane)

N2O

Sevoflurane (Ultane)

Intravenous Anesthetics

Alfentanil (Alfenta)

Diazepam (Valium)

Droperidol (Inapsine)

Etomidate (Amidate)

Fentanyl (Sublimaze)

Ketamine (Ketalar)

Meperidine (Demerol)

Methohexital (Brevital)

Midazolam (Versed)

Propofol (Diprivan)

Remifentanil (Ultiva)

Sufentanil (Sufenta)

Thiopental (Pentothal)

Receptor Antagonists

Flumazenil (Mazicon, Romazicon)

Naloxone (Narcan)

FURTHER READING

Bovill JG. Inhalation anaesthesia: From diethyl ether to xenon. Handb Exp Pharmacol. 2008;182:121-142.

Campagna JA, Miller KW, Forman A. Mechanisms of actions of inhaled anesthetics. N Engl J Med. 2003;348:2110-2124.

Hendrickx JF, DeWolf A. Special aspects of pharmacokinetics of inhalation anesthesia. Handb Exp Pharmacol. 2008;182:159-186.

Henthorn TK. The effects of altered physiological states on intravenous anesthetics. Handb Exp Pharmacol. 2008;182:363-377.

Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;182:335-360.

Vanlersberghe C, Camu F. Propofol. Handb Exp Pharmacol. 2008;182:227-252.

SELF-ASSESSMENT QUESTIONS

1. Cardiac output and blood pressure are reduced most by:

A. Nitrous oxide (N2O).

B. Halothane.

C. Ketamine.

D. Isoflurane.

E. Fentanyl.

2. The ventilatory response to CO2 is blunted during anesthesia with:

A. Halothane.

B. Morphine.

C. Enflurane.

D. Isoflurane.

E. All of the above.

3. The MAC of an inhalational anesthetic is higher:

A. In an obese patient than in a patient of average body weight.

B. During a long surgical procedure than during a short surgical procedure.

C. In an infant than in an elderly patient.

D. In a patient pretreated with morphine than in an otherwise drug-free patient.

E. In males than in females.

4. A competitive receptor antagonist is available for reversing the undesirable postoperative effects of:

A. Thiopental.

B. Halothane.

C. Propofol.

D. Midazolam.

E. Isoflurane.

5. Potential advantages of fentanyl over morphine for the induction or maintenance of anesthesia include:

A. Superior relaxation of skeletal muscles.

B. Absence of postoperative nausea and vomiting.

C. Lack of depressant effect on spontaneous respiration.

D. All of the above.

E. None of the above.