The story of local anaesthesia begins in 1884 when the naturally occurring alkaloid cocaine was used by Carl Koller in his search for a topically effective anaesthetic for eye surgery. Operating conditions were much superior to those provided by contemporary general anaesthesia and surgeons were quick to appreciate the advantages of local methods. Injections of cocaine, either by local infiltration or more centrally, soon brought an appreciation of agent toxicity and unwanted effects. The search for less toxic drugs followed and procaine was synthesised in 1905. Numerous examples have followed; a major advance was the Swedish discovery of the stable amide lignocaine in 1948 by Lofgren.

Some knowledge of the following topics is necessary to understand how local anaesthetics produce their effects:
1. physiology of neural conduction,
2. differing neuron types,
3. anatomy of neural tissues,
4. physico-chemical properties, and
5. formulation of local anaesthetic drugs.

1. Physiology of Neural Conduction and Effects of Local Anaesthetics
Neural tissue is fundamentally excitable in an electrical sense and is capable of responding in an ordered way to perturbations of the resting ionic gradients which normally exist across the axon membrane. The so-called resting potential is about 70mV negative (inside relative to the outside) (1). The resting potential is generated as a result of the activity of a sodium-potassium pump which continually pumps sodium to the outside of the membrane in exchange for potassium which is pumped in. As a result of this pump activity, marked concentration gradients for these two cations are developed across the membrane. The respective extracellular and intracellular concentrations of the ions are:

Na+ (Outside)		145 mMol/L
Na+ (Inside)		15 mMol/L
K+ (Outside)		5 mMol/L
K+ (Inside)		140 mMol/L

Membrane depolarisation is triggered by the sudden opening of sodium-specific channels which is followed by a massive influx of Na+ passing down its concentration gradient. This produces a transient rise in membrane potential to around 40mV positive (inside relative to outside). As the intracellular potential rises, the voltage change leads to a slower opening of potassium specific channels.

Repolarisation occurs as a result of closure of the sodium channels in the presence of the continued efflux of potassium down its own concentration gradient through the still-open potassium channel. As the intracellular potential falls back to the resting level, the potassium channel closes and potassium conductance returns to the basal state. These phenomena can be demonstrated in appropriate physiological preparations (eg. giant squid axon) and are illustrated in Figure 53.1.

The depolarisation wave is propagated in neighbouring areas of the axon membrane by the serial repetition of this sequence. This wave travelling along the axon constitutes the transmitted impulse. If a nerve is myelinated, neural transmission by the process of saltatory conduction occurs. This form of transmission involves depolarisation only at the nodes of Ranvier and is much more rapid and energy efficient than transmission in unmyelinated nerves.

Local anaesthetic agents occupy Na+ channels and inhibit the rapid passage of Na+ ions and the propagation of the wave. These events are complex and not fully understood. Suffice to say that nerve block by local anaesthetics is not an 'all or none' phenomenon and that the degree of impedance of neuronal traffic will depend on numerous interrelated factors (Chapter 95).

2. Differing Neurone Types Axons differ widely in structure and function. The three major classes of nerve fibres in decreasing diameter are:
1. 'A' fibres: myelinated somatic nerves,
2. 'B' fibres: myelinated preganglionic autonomic nerves, and
3. 'C' fibres: fine non-myelinated axons.

'A' fibres are further divided into alpha, beta, gamma and delta fibres, of decreasing diameter.

Myelinated fibres propagate impulses more rapidly that non-myelinated and are more resistant to blockade.

The degree of myelination, speed of conduction and size of the fibre determine the sensitivity of the neurone to various local anaesthetic agents and to different concentrations of the same drug (Chapter 4). The differing sensitivities of the neurone types explain the phenomenon known as 'differential neural blockade' which is responsible for 'sensory-motor split' (Chapter 88).

3. Anatomy of Neural Tissue
There is considerable variation in neural anatomy. For example, the sciatic nerve is heavily invested with fibrous and connective tissue, epidural nerve roots considerably less so, and nerve roots in the subarachnoid space hardly at all. It can be readily appreciated that access to neuronal tissue by diffusion of local anaesthetic can vary widely in different situations.

4. Physico-chemical Properties and Formulation of Local Anaesthetics
In pure form, weakly basic local anaesthetics are largely non-ionised and, therefore, poorly water soluble. Formulation as HCI salts at a pH of 4.0 to 7.0 greatly increases the ionised fraction which then equilibrates, in aqueous solution, with a small amount of free base. Upon injection into the body, physiological buffers raise the pH so that the non-ionised fraction increases.

It is as the lipophilic, non-ionised form that the drug diffuses across the axon membrane. The acidic intracellular conditions drive the equilibrium back towards the ionised fraction. It is in this form that the drug finally exerts its blocking action.

Summary
Local anaesthetics act at the axonal membrane to inhibit the transmission of impulses along the nerve cell. The pharmaco-dynamics and -kinetics are complex and the complete picture is not yet elucidated.

Reference:
1. deJong RH Clinical Physiology of Local Anesthetic Action. In: Cousins MJ, Bridenbaugh PO (eds). Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd ed, JB Lippincott Co, Philadelphia,1988. p 21-44