Inhalational Anaesthetic Agents

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Inhalational Anaesthetic Agents

Volatile and gaseous anaesthetic agents are used widely for maintenance of anaesthesia and, under some circumstances, for induction of anaesthesia. In many situations, it is appropriate to use a mixture of 66% N2O in oxygen and a small concentration of a volatile agent to maintain anaesthesia, although for reasons discussed below there are occasions when an anaesthetist might wish actively to avoid the use of nitrous oxide.

PROPERTIES OF THE IDEAL INHALATIONAL ANAESTHETIC AGENT

image It should have a pleasant odour, be non-irritant to the respiratory tract and allow pleasant and rapid induction of anaesthesia.

image It should possess a low blood/gas solubility, which permits rapid induction of and rapid recovery from anaesthesia.

image It should be chemically stable in storage and should not interact with the material of anaesthetic circuits or with soda lime.

image It should be neither flammable nor explosive.

image It should be capable of producing unconsciousness with analgesia and preferably some degree of muscle relaxation.

image It should be sufficiently potent to allow the use of high inspired oxygen concentrations when necessary.

image It should not be metabolized in the body, be non-toxic and not provoke allergic reactions.

image It should produce minimal depression of the cardiovascular and respiratory systems and should not interact with other drugs used commonly during anaesthesia, e.g. pressor agents or catecholamines.

image It should be completely inert and eliminated completely and rapidly in an unchanged form via the lungs.

image It should be easy to administer using standard vaporizers.

image It should not be epileptogenic or raise intracranial pressure.

None of the inhalational anaesthetic agents approaches the standards required of the ideal agent.

Minimum Alveolar Concentration (MAC)

MAC is the minimum alveolar concentration (in volumes per cent) of an anaesthetic at 1 atmosphere absolute (ata) which prevents movement to a standard surgical stimulus in 50% of the population. Anaesthesia is related to the partial pressure of an inhalational agent in the brain rather than its percentage concentration in alveoli, but the term MAC has gained widespread acceptance as an index of anaesthetic potency because it can be measured. It may be applied to all inhalational anaesthetics and it permits comparison of different agents. However, it represents only one point on a dose–response curve; 1 MAC of one agent is equivalent in anaesthetic potency to 1 MAC of another, but it does not follow that the agents are equipotent at 2 MAC. Nevertheless, in general terms, 0.5 MAC of one agent in combination with 0.5 MAC of another approximates to 1 MAC in total.

The MAC values for the anaesthetic agents quoted in Table 2.1 were determined experimentally in humans (volunteers) breathing a mixture of the agent in oxygen. MAC values vary under the following circumstances:

Mechanisms of Action

General anaesthetics act by the potentiation of inhibitory neurotransmitter pathways in the CNS, in particular by potentiation of GABAA and glycine receptors, and inhibition of excitatory pathways such as NMDA. Both GABAA and glycine receptors are associated with chloride channels, and binding of the ligand allows entry of chloride into the neurone causing membrane hyperpolarization. General anaesthetics (volatile agents, propofol, etomidate and thiopental) bind to the β subunit of the GABAA-chloride receptor complex. Central nicotinic acetylcholine receptors, potassium and sodium channels are also activated by clinically relevant concentrations of volatile anaesthetic agents. This can reduce presynaptic action potentials and reduce neurotransmitter release, and may also contribute to their mechanism of action.

AGENTS IN COMMON CLINICAL USE

In Western countries, it is customary to use one of the four modern volatile anaesthetic agents – isoflurane, desflurane, sevoflurane or halothane – vaporized in a mixture of nitrous oxide in oxygen or air and oxygen. The use of halothane has declined because of medicolegal pressure relating to the very rare occurrence of hepatotoxicity. The use of sevoflurane has increased rapidly, particularly in paediatric anaesthesia because of its superior quality as an inhalational induction agent. Desflurane produces rapid recovery from anaesthesia, but it is very irritant to the airway and is therefore not used as an inhalational induction agent.

The following account of these agents, with a comparison of their pharmacological properties, may tend to exaggerate the differences between them. However, an equally satisfactory anaesthetic may be administered in the majority of patients with any of the four agents.

Isoflurane

Isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) is an isomer of enflurane and was synthesized in 1965. Clinical studies were undertaken in 1970, but because of early laboratory reports of carcinogenesis (which were not confirmed subsequently) it was not approved by the Food and Drug Administration in the United States until 1980.

Uptake and Distribution

Isoflurane has a low blood/gas solubility of 1.4 and thus alveolar concentrations equilibrate fairly rapidly with inspired concentrations. The alveolar (or arterial) partial pressure of isoflurane increases to 50% of the inspired partial pressure within 4–8 min, and to 60% by 15 min (Fig. 2.2). However, the rate of induction is limited by the pungency of the vapour and in clinical practice may be no faster than that achieved with halothane. The incidence of coughing or breath-holding on induction is significantly greater with isoflurane than with halothane. It is not an ideal agent to use for inhalational induction. The rate of recovery is slower than that associated with desflurane or sevoflurane, but more rapid than after administration of halothane (Fig. 2.3).

Cardiovascular System

In vitro, isoflurane is a myocardial depressant, but in clinical use there is less depression of cardiac output than with halothane or enflurane (Fig. 2.5). Systemic hypotension occurs predominantly as a result of a reduction in systemic vascular resistance (Figs 2.6, 2.7). Arrhythmias are uncommon and there is little sensitization of the myocardium to catecholamines (Fig. 2.8).

In addition to dilating systemic arterioles, isoflurane causes coronary vasodilatation. In the past there has been some controversy regarding the safety of isoflurane in patients with coronary artery disease because of the possibility that the coronary steal syndrome may be induced; dilatation in normal coronary arteries offers a low resistance to flow and may reduce perfusion through stenosed neighbouring vessels. It has been shown that isoflurane affects small arterioles (which makes coronary steal a theoretical possibility), but this does not appear to be of any clinical significance. Production of myocardial ischaemia in clinical practice may be a result of many factors in addition to coronary vasodilatation, including tachycardia, hypotension, increase in left ventricular end-diastolic pressure and reduced ventricular compliance. Attention should be directed to these factors before a diagnosis of isoflurane- induced coronary steal is considered.

Desflurane

Between 1959 and 1966, Terrell and his associates at Ohio Medical Products synthesized more than 700 compounds to try to produce improved inhalational anaesthetic agents. Two of these products were the halogenated methyl ethyl ethers, isoflurane and enflurane, which became widely used. Some of the original 700 products were re-examined many years later. Many were discarded for a variety of reasons. One of these (the 653rd) was difficult to synthesize because of a potentially explosive step using elemental fluorine and it had a vapour pressure close to 1 atmosphere. However, because it was predicted to have a low solubility in blood and hence would allow rapid recovery, it was re-examined with heightened interest. This product became known as desflurane. Desflurane was first used in humans in 1988 and it became available for general clinical use in the UK in 1993. Its structure (CHF2–O–CHF–CF3) differs from that of isoflurane (CHF2–O–CHCl–CF3) only in the substitution of fluorine for chlorine.

Uptake and Distribution

Desflurane has a blood/gas partition coefficient of 0.42, almost the same as that of nitrous oxide. The rate of equilibration of alveolar with inspired concentrations of desflurane is virtually identical to that for nitrous oxide (Fig. 2.2). Induction of anaesthesia is therefore extremely rapid in theory but limited somewhat by its pungent nature. However, it is possible to alter the depth of anaesthesia very rapidly and the rate of recovery of anaesthesia is faster than that following any other volatile anaesthetic agent (Fig. 2.3).

Respiratory System

Desflurane causes respiratory depression to a degree similar to that of isoflurane up to a MAC of 1.5. It increases PaCO2 (Fig. 2.4) and decreases the ventilatory response to imposed increases in PaCO2. It is irritant to the upper respiratory tract, particularly at concentrations greater than 6%. It is therefore not recommended for gaseous induction of anaesthesia because it causes coughing, breath-holding and laryngospasm.

Cardiovascular Effects

Desflurane appears to have two distinct actions on the cardiovascular system. Firstly, its main actions are those which are similar to isoflurane: dose-related decreases in systemic vascular resistance, myocardial contractility and mean arterial pressure (Figs 2.52.7). Heart rate is unchanged at lower steady-state concentrations, but increases with higher concentrations (Fig. 2.9). Addition of nitrous oxide maintains heart rate unchanged. Cardiac output tends to be maintained as with isoflurane. The second cardiovascular action occurs when its inspired concentration is increased rapidly to greater than 1 MAC. In the absence of premedicant drugs, this increases sympathetic activity, leading to increased heart rate and arterial pressure. Experimental studies in animals have not detected a coronary steal phenomenon. Desflurane, in common with isoflurane and sevoflurane, does not sensitize the myocardium to catecholamines (Fig. 2.8).

Musculoskeletal System

Desflurane causes muscle relaxation in a dose-related manner. Concentrations exceeding 1 MAC produce fade in response to tetanic stimulation of the ulnar nerve. It enhances the effect of muscle relaxants. Studies in susceptible swine indicate that desflurane may trigger malignant hyperthermia.

Therefore, in summary, desflurane offers some advantages over other agents:

However, it has some significant drawbacks:

Sevoflurane

Sevoflurane (fluoromethyl-2,2,2-trifluoro-1-ethyl ether) was first synthesized in 1968 and its clinical use reported in 1971. The initial development was slow because of some apparent toxic effects, which were found later to be caused by flawed experimental design. After its first use in volunteers in 1981, further work was delayed again because of problems of biotransformation and stability with soda lime. The drug has been available for general clinical use since 1990.

Metabolism

Approximately 5% of the absorbed dose is metabolized in the liver to two main metabolites. The major breakdown product is hexafluoroisopropanol, an organic fluoride molecule which is excreted in the urine as a glucuronide conjugate. Although this molecule is potentially hepatotoxic, conjugation of hexafluoroisopropanol occurs so rapidly that clinically significant liver damage seems theoretically impossible. The second breakdown product is inorganic fluoride ion. The mean peak fluoride ion concentration after 60 min of anaesthesia at 1 MAC is 22 μmol L–1, which is significantly higher than that after an equivalent dose of isoflurane. The metabolism of sevoflurane is catalysed by the 2E1 isoform of cytochrome P450 which may be induced by phenobarbital, isoniazid and ethanol and inhibited by disulfiram.

Respiratory System

The drug is non-irritant to the upper respiratory tract. It produces dose-dependent ventilatory depression, reduces respiratory drive in response to hypoxaemia and increases carbon dioxide partial pressure to a similar degree to other volatile agents (Fig. 2.4). The ventilatory depression associated with sevoflurane may result from a combination of central depression of medullary respiratory neurones and depression of diaphragmatic function and contractility. It relaxes bronchial smooth muscle but not as effectively as halothane.

Cardiovascular System

The properties of sevoflurane are similar to those of isoflurane, with slightly smaller effects on heart rate (Fig. 2.9) and less coronary vasodilatation. It decreases arterial pressure (Fig. 2.7) mainly by reducing peripheral vascular resistance (Fig. 2.6), but cardiac output is well maintained over the normal anaesthetic maintenance doses (Fig. 2.5). There is mild myocardial depression resulting from its effect on calcium channels. Sevoflurane does not differ from isoflurane in its sensitization of the myocardium to exogenous catecholamines (Fig. 2.8). It is a less potent coronary arteriolar dilator and does not appear to cause coronary steal. Sevoflurane is associated with a lower heart rate and therefore helps to reduce myocardial oxygen consumption.

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