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Chapter: Modern Pharmacology with Clinical Applications: General Anesthesia: Intravenous and Inhalational Agents

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Halogenated Hydrocarbon Anesthetics

Sevoflurane, desflurane, enflurane, isoflurane, halothane, and methoxyflurane are considered to be quite potent halogenated hydrocarbon anesthetics, since they pro-duce surgical levels of anesthesia at low inspired partial pressures.

Halogenated Hydrocarbon Anesthetics

Sevoflurane, desflurane, enflurane, isoflurane, halothane, and methoxyflurane are considered to be quite potent halogenated hydrocarbon anesthetics, since they pro-duce surgical levels of anesthesia at low inspired partial pressures. None of the halogenated hydrocarbons, how-ever, possess all of the pharmacological properties that are considered desirable for an anesthetic agent, so they are often given with other anesthetics and adjunctive drugs to provide effective and safe anesthetic manage-ment. The use of these drug combinations is referred to as balanced anesthesia.

Balanced Anesthesia with Inhalational Anesthetic Agents

An anesthetic plan based on the concept of balanced anesthesia may proceed as follows. First, since anesthetic partial pressure for an inhalational agent in the brain is not attained rapidly, patients are usually anesthetized with an IV agent. A bolus of an IV anesthetic provides unconsciousness long enough to establish the anesthetic brain tension of most of the inhalational drugs. Second, a supplemental analgesic (i.e., an opioid or the inhala-tional gas N2O) is required because halogenated hydro-carbons exhibit varying and often inadequate degrees of analgesia, so patients may respond to strongly noxious surgical manipulations with movement and reflex car-diovascular changes. 

Third, since the neuromuscular blockade provided by the halogenated hydrocarbons is incomplete, neuromuscular blocking agents, such as suc-cinylcholine or the curariform drugs, must be used to provide paralysis adequate for surgical access. Fourth, the anesthetic plan is also designed to minimize any un-desirable cardiovascular and respiratory responses to these drugs. This includes using drug combinations that minimize the dose of the halogenated hydrocarbon. For example, N2O 25 to 40%, which by itself produces mini-mal cardiovascular depression, is frequently used with about half of the MAC of a particular halogenated hy-drocarbon; this tends to preserve cardiovascular stabil-ity. Since MACs are additive, unconsciousness is ade-quate when a combination of inhalational agents is used.

Halothane

Halothane (Fluothane) depresses respiratory function, leading to decreased tidal volume and an increased rate of ventilation. Since the increased rate does not ade-quately compensate for the decrease in tidal volume, minute ventilation will be reduced; plasma PaCO2 rises, and hypoxic drive is depressed. With surgical anesthe-sia, spontaneous ventilation is inadequate, and the pa-tient’s ventilation must be controlled.

Halothane administration can result in a marked re-duction in arterial blood pressure that is due primarily to direct myocardial depression, which reduces cardiac output. The fall in pressure is not opposed by reflex sympathetic activation, however, since halothane also blunts baroreceptor and carotid reflexes. Systemic vas-cular resistance is unchanged, although blood flow to various tissues is redistributed. Halothane also sensi-tizes the heart to the arrhythmogenic effect of cate-cholamines. Thus, maintenance of the patient’s blood pressure with epinephrine must be done cautiously.

 

It is clinically significant that cerebral blood flow in-creases as a result of a direct relaxant action of halothane on cerebral vasculature. Intracranial pressure may rise to a level at which it can become dangerous in patients with intracranial pathology. Although the coronary arteries are dilated, coronary blood flow decreases because of the overall reduction in systemic blood pressure. Thus, the balance between myocardial perfusion and oxygen de-mand (which is reduced with halothane) should be taken into account for patients with cardiac disease.

Similar disturbances in intracranial pressure and coronary blood flow occur with most of the halogenated hydrocarbons. In addition, renal blood flow, filtration, and urine output decrease with the use of halothane. These changes also occur with other inhalational agents that reduce arterial blood pressure.

Halothane and all other halogenated hydrocarbons cause some relaxation of skeletal muscle. The relaxation is not adequate when muscle paralysis is a requirement of the operative procedure, but halothane’s action will potentiate the effect of neuromuscular blocking drugs, reducing their dose requirement.

Although recovery from anesthesia does not rely on metabolic factors, halothane and many of the halo-genated hydrocarbons undergo some biotransforma-tion. Halothane is oxidized in the liver to trifluoroacetic acid, Br- , and Cl- . In the absence of oxygen, reductive intermediates of halothane metabolism may form and damage liver tissue. These intermediates have been im-plicated in a controversial syndrome of halothane hep-atitis. This rare syndrome (1:35,000 anesthetics) is histo-logically indistinguishable from viral hepatitis. The likelihood of liver dysfunction increases with repeated administrations of halothane, and antibodies to hepato-cytes are obtained from patients who develop liver dys-function following halothane. It has been suggested that liver necrosis may be a hypersensitivity reaction, per-haps initiated by the reactive intermediates formed dur-ing halothane metabolism. It seems prudent to limit the use of halothane in patients with liver dysfunction that resulted from a previous exposure to the anesthetic.

Methoxyflurane

Methoxyflurane (Penthrane) is the most potent inhala-tional agent available, but its high solubility in tissues lim-its its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myo-cardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better main-tained.Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride con-centrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane.

Enflurane

Enflurane (Ethrane) depresses myocardial contractility and lowers systemic vascular resistance. In contrast to halothane, it does not block sympathetic reflexes, and therefore, its administration results in tachycardia. However, the increased heart rate is not sufficient to op-pose enflurane’s other cardiovascular actions, so cardiac output and blood pressure fall. In addition, enflurane sensitizes the myocardium to catecholamine-induced arrhythmias, although to a lesser extent than with halothane. Enflurane depresses respiration through mechanisms similar to halothane’s and requires that the patient’s ventilation be assisted.

Neuromuscular transmission is depressed by enflu-rane, resulting in some skeletal muscle paralysis.Although muscle relaxation is inadequate for many surgical proce-dures, the anesthetic enhances the action of neuromuscu-lar blocking agents, thereby lowering the dose of the par-alytic agent needed and minimizing side effects.

Deep anesthesia with enflurane is associated with the appearance of seizurelike electroencephalographic (EEG) changes. Occasionally frank tonic–clonic sei-zures are observed. Consequently, other inhalational agents are usually given to patients with preexisting seizure disorders.

Another concern associated with the use of enflu-rane is its biotransformation, which leads to increased plasma fluoride. Following lengthy procedures in healthy patients, fluoride may reach levels that result in a mild reduction in renal concentrating ability. Thus, en-flurane should be used cautiously in patients with clini-cally significant renal disease.

Isoflurane

Isoflurane (Forane) is a structural isomer of enflurane and produces similar pharmacological properties: some analgesia, some neuromuscular blockade, and depressed respiration. In contrast, however, isoflurane is consid-ered a particularly safe anesthetic in patients with isch-emic heart disease, since cardiac output is maintained, the coronary arteries are dilated, and the myocardium does not appear to be sensitized to the effects of cate-cholamines. Also, blood pressure falls as a result of va-sodilation, which preserves tissue blood flow. Isoflurane causes transient and mild tachycardia by direct sympa-thetic stimulation; this is particularly important in the management of patients with myocardial ischemia.

Unlike enflurane, isoflurane does not produce a seizurelike EEG pattern. Furthermore, the metabolic transformation of isoflurane is only one-tenth that of enflurane, so fluoride production is quite low. Among the halogenated hydrocarbons, isoflurane is one of the most popular, since it preserves cardiovascular stability and causes a low incidence of untoward effects.

Desflurane

Desflurane (Suprane) shares most of the pharmacologi-cal properties of isoflurane. Desflurane has low tissue and blood solubility compared with other halogenated hydrocarbons, and its anesthetic partial pressure is thus established more rapidly. Recovery is similarly prompt when the patient is switched to room air or oxygen. Desflurane’s popularity for outpatient procedures stems from its rapid onset and prompt elimination from the body by exhalation. A disadvantage is that desflurane ir-ritates the respiratory tract; thus, it is not preferred for induction of anesthesia using an inhalational technique. However, desflurane may be used to maintain anesthe-sia after induction with an alternative IV or inhalational agent, preserving the advantage of rapid recovery.

Desflurane, like other halogenated hydrocarbon anesthetics, causes a decrease in blood pressure. The re-duced pressure occurs primarily as a consequence of decreased vascular resistance, and since cardiac output is well maintained, tissue perfusion is preserved.

Desflurane stimulates the sympathetic nervous system and causes abrupt transient tachycardia during induc-tion or as the concentration of the agent is raised to meet the patient’s changing needs.

Desflurane causes an increase in the rate of ventila-tion, a decrease in tidal volume, and a decrease in minute volume as inspired concentrations only slightly exceed 1 MAC. Thus should anesthesiologists require desflurane to be administered near or above MAC lev-els, patients are likely to have marked reductions in PCO2.

Sevoflurane

Sevoflurane (Ultane) is the most recently introduced in-halation anesthetic. It has low tissue and blood solubil-ity, which allows for rapid induction and emergence and makes it useful for outpatient and ambulatory proce-dures. It has the advantage of not being pungent, a char-acteristic that permits a smooth inhalation induction, and is particularly useful in pediatric anesthesia.

Hypotension is produced by sevoflurane as systemic vasodilation occurs and cardiac output decreases. Since it does not directly produce tachycardia, it is a useful al-ternative to consider in patients with myocardial isch-emia. However, a concern for reflex-induced tachycar-dia remains.

Sevoflurane undergoes hepatic biotransformation (about 3% of the inhaled dose), and it is somewhat de-graded by conventional CO2 absorbents. The degrada-tion product from the absorbent has been reported to be nephrotoxic, although the report is controversial and not substantiated by more recent studies. Sevoflurane’s actions on skeletal muscle and on vascular regulation within the CNS are similar to those described for the other halogenated hydrocarbon anesthetics.

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