PharmacologyIntravenous anaesthetic agents
Section snippets
The ideal intravenous anaesthetic agent
Table 1 summarizes most of the desirable properties of an intravenous anaesthetic agent. Note that all of these properties may be unachievable in a single agent, and some are contradictory (e.g. a rapidly-acting drug is likely to be lipid soluble and so is unlikely to be equally water soluble). The properties of the agents discussed below should be assessed against these ideal properties.
Propofol
Propofol (2,6-diisopropylphenol) (Figure 1a) is arguably the most frequently used intravenous induction agent in the Western world. It is presented as a white oil-in-water emulsion containing 1% (weight-by-volume; or more recently 2%) propofol in soya bean oil (10%), egg phosphatidate (1.2%) and glycerol (2.25%). The solution has a pH of around 7.0 and is stable at room temperature and is not sensitive to light. The induction dose is around 1.5–2.0 mg/kg. Propofol is 98% protein bound and
Barbiturates
Barbituric acid (2,4,6-trioxohexahydropyrimidine), is formed by the condensation of malonic acid and urea (Figure 1b). Barbiturates undergo keto–enol isomerization (Figure 1c); the keto form is favoured in alkaline solutions and substitution of the sodium ion (Na+) for the hydrogen atom of the keto form results in water soluble salts.
Barbituric acid lacks central depressant activity, but the presence of alkyl or aryl groups at position C5 (i.e. at CH2 position in Figure 1b) confers
Thiopental
Thiopental (Figure 1d) is presented as a sodium salt (0.5 g pale yellow powder) to promote dissolution of the drug in 20 ml water (to form a 2.5% solution). The powder also contains 30 mg anhydrous sodium carbonate, and the ampoule is filled with nitrogen (80 kPa; to prevent precipitation of insoluble free acid by atmospheric carbon dioxide). When prepared, the solution is not stable and should be used within 24–48 hours, but can be kept up to a week in a refrigerator. The solution has a pH of
Methohexital
Methohexital is an oxybarbiturate with a methyl group at the 1-N terminal (Figure 1e). It is a racemic mixture of two isomers, and is about three times more potent than thiopental. It is presented as a white powder mixed with 6% sodium carbonate to ensure stabilization, and is stable for up to 6 weeks after preparation. The prepared solution is 1% with a pH of about 10–11 (similar to thiopental). It is highly lipid soluble, 75% non-ionized at pH 7.4, and is 70–80% protein bound (i.e. has
Ketamine
Ketamine is an arylcyclohexylamine and structurally related to phencyclidine (Figure 1f). It has two isomers. The d-isomer is more potent than the l-isomer, but the parenteral solution is a racemic mixture. Ketamine hydrochloride is a white crystalline solid, which is soluble in water. It is supplied as 1, 5, and 10% solutions, which are stable at room temperature (benzethonium chloride is added as a preservative). The solution has a pH of about 3.5–5.5. Ketamine has a pKa (acid dissociation
Etomidate
Etomidate is an imidazole derivative and exists as two isomers (only the (+)isomer is active) (Figure 1g). It is presented in 10 ml ampoules containing 2 mg/ml dissolved in water with 35% propylene glycol. The solution has a pH of about 8.1 and an osmolality of 4640 mOsmole/litre. It is highly lipid soluble and protein binding is about 75%. Etomidate is therefore susceptible to factors that affect protein binding. The clearance rate is about six times that of thiopental. Etomidate is
Other agents and techniques of intravenous anaesthesia
Benzodiazepines are rarely used for intravenous induction of anaesthesia as sole agents, but are often used for premedication, as adjuncts to induction, or for sedation. The term benzodiazepine refers to the portion of the structure composed of a benzene ring, fused to a seven-member diazepine ring (Figure 1h). Because the important members of the benzodiazepine group contain a 5-aryl substituent and a 1,4-diazepine ring, the term has come to refer to the 5-aryl-1,4-benzodiazepines. The 5-aryl
Dexmedetomidine
This is a α2-adrenoceptor agonist, incorporating an imidazoline structure (Figure 2), and is the pharmacologically active d-enantiomer of medetomidine (which has been long established as a sedative and analgesic in veterinary medicine). Compared with clonidine, dexmedetomidine is more specific for α2-receptors, is a full agonist. The distribution half-life is rapid (∼6 minutes) and elimination half-life is ∼2 hours. It can be used as a total intravenous anaesthetic in doses up to 10 μg/kg/hour
Magnesium (Mg2+)
Mg2+ (usually administered intravenously as dissolved sulphate) is well established to reduce the minimum alveolar concentration of volatile anaesthetics. It acts as a natural calcium antagonist, regulating calcium access into the cell. This (and its effect in catecholamine release from the adrenal medulla and adrenergic nerve endings) induces vascular smooth muscle relaxation. This effect also reduces acetylcholine release from the motor nerve terminals, leading to muscle weakness (i.e.
Remimazolam
Remimazolam (CNS-7056) is a short-acting GABA(A) agonist currently in phase III testing. The incorporation of a carboxylic ester moiety (Figure 3) into its structure renders it susceptible to metabolism by tissue esterases. Given the abundance of these enzymes, the degradation of remimazolam to its inactive metabolite is rapid, with the offset of clinical effect similarly fast (approximately 25% of the time to recovery from an equieffective dose of midazolam).
Infusion kinetics
Whereas bolus delivered drugs' duration of action is influenced predominately by distribution, the offset of action of an infusion is more complex. Many intravenous agents are used as infusions and all have at some point in their history been used as in this way. When an infusion has been running at steady-state (infusion rate equals clearance), the time taken for the plasma concentration to halve (context-sensitive half time, Figure 4) is dependent on the length of time that the infusion has
Summary
Table 2 summarizes the salient features of the intravenous anaesthetic agents. Each agent has particular properties and for effective use in clinical practice, these are best tailored to each patient's condition and the requirements of the surgery. Whichever agent is used to induce anaesthesia, it is important to carefully titrate its action, especially with respect to cardiorespiratory and airway effects.