Anaphylactic reactions result from the interaction of antigens with specific IgE antibodies, which have been formed by previous exposure to the antigen. Anaphylactoid reactions are clinically indistinguishable from anaphylaxis but do not result from prior exposure to a triggering agent and do not involve IgE. Intravenous anaesthetics and muscle relaxants can cause anaphylactic or anaphylactoid reactions and, rarely, they are fatal. Muscle relaxants are responsible for 70% of anaphylactic reactions during anaesthesia and suxamethonium accounts for almost half of these.

Cocaine had been suggested as a local anaesthetic for clinical use when Sigmund Freud investigated the alkaloid in Vienna in 1884 with Carl Koller. The latter had long been interested in the problem of local anaesthesia in the eye, for general anaesthesia has disadvantages in ophthalmology. Observing that numbness of the mouth occurred after taking cocaine orally he realised that this was a local anaesthetic effect. He tried cocaine on animals' eyes and introduced it into clinical ophthalmological practice, whilst Freud was on holiday. Freud had already thought of this use and discussed it but, appreciating that sex was of greater importance than surgery, he had gone to see his fiancée. The use of cocaine spread rapidly and it was soon being used to block nerve trunks. Chemists then began to search for less toxic substitutes, with the result that procaine was introduced in 1905.

Desired properties. Innumerable compounds have local anaesthetic properties, but few are suitable for clinical use. Useful substances must be water-soluble, sterilisable by heat, have a rapid onset of effect, a duration of action appropriate to the operation to be performed, be nontoxic, both locally and when absorbed into the circulation, and leave no local after-effects.

Mode of action. Local anaesthetics prevent the initiation and propagation of the nerve impulse (action potential). By reducing the passage of sodium through voltage-gated sodium ion channels they raise the threshold of excitability; in consequence, conduction is blocked at afferent nerve endings, and by sensory and motor nerve fibres. The fibres in nerve trunks are affected in order of size, the smallest (autonomic, sensory) first, probably because they have a proportionately greater surface area, and then the larger (motor) fibres. Paradoxically the effect in the central nervous system is stimulation (see below).

Pharmacokinetics. The distribution rate of a single dose of a local anaesthetic is determined by diffusion into tissues with concentrations approximately in relation to blood flow (plasma t]/2 only a few minutes). By injection or infiltration, local anaesthetics are usually effective within 5min and have a useful duration of effect of 1-1.5 h, which in some cases may be doubled by adding a vasoconstrictor (below).

Most local anaesthetics are used in the form of the acid salts, as these are both soluble and stable. The acid salt (usually HCI) dissociates in the tissues to liberate the free base, which is biologically active. This dissociation is delayed in abnormally acid, e.g. inflamed, tissues; but the risk of spreading infection makes local anaesthesia undesirable in infected areas.

Absorption from mucous membranes on topical application varies according to the compound. Those that are well absorbed are used as surface anaesthetics (cocaine, lidocaine, prilocaine). Absorption of topically applied local anaesthetic can be extremely rapid and give plasma concentrations comparable to those obtained by injection. This has led to deaths from overdosage, especially via the urethra.

For topical effect on intact skin for needling procedures a eutectic8 mixture of bases of prilocaine or lidocaine is used (EMLA — eutectic mixture of

8 A mixture of two solids that becomes a liquid because the mixture has a lower melting point than either of its components.

Local anaesthetics local anaesthetics). Absorption is very slow and a cream is applied under an occlusive dressing for at least 1 h. Tetracaine gel 4% (Ametop) is more effective than EMLA cream and allows pain free venepuncture 30 minutes after application.

Ester compounds (cocaine, procaine, tetracaine, benzocaine) are hydrolysed by liver and plasma esterases and their effects may be prolonged where there is genetic enzyme deficiency.

Amide compounds [lignocaine (lidocaine), prilo-caine, bupivacaine, levobupivacaine, ropivacaine] are dealkylated in the liver.

Impaired liver function, whether due to primary cellular insufficiency or to low liver blood flow as in cardiac failure, may both delay elimination and allow higher peak plasma concentrations of both types of local anaesthetic. This is likely to be important only with large or repeated doses or infusions. These considerations are important in the management of cardiac arrhythmias by i.v. infusion of lignocaine (lidocaine) (see p. 502).

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