Local anaesthetics
Local anaesthetics are drugs used primarily to inhibit pain by preventing impulse conduction along sensory nerves. They achieve this by blocking voltage-sensitive sodium ion (Na + ) channels in the cell membrane. Local anaesthetics are also used as antidysrhythmics (see Chapter 14 ) and in epilepsy (see Chapter 12 ).
The basic electrophysiology of neurons
Sodium channels ( Figs. 26.1 and 26.2 ) can exist in three states: resting (i.e. closed), activated (i.e. open) and inactivated (i.e. blocked; explained below).
The resting cell
The action of the Na + pump in cell membranes normally maintains a high level of potassium ion (K + ) and a low level of Na + within the cell (see Chapter 4 ). In the resting cell, the membrane is more permeable to K + than to Na + . The efflux of K + makes the cell interior negative with respect to the outside, giving a membrane potential between -60 and -90 mV. In the resting cell, the Na + channels are closed .
Activation – the action potential
When a nerve cell is stimulated locally (e.g. by noxious stimuli acting on a pain fibre or by neurotransmitter action on a receptor linked to a cation channel) the Na + channel opens, leading to a local increase in the membrane permeability to Na + . The resultant increased influx of positive Na + causes membrane depolarization and an action potential is generated. This is a regenerative process, as the action potential itself causes more Na + channels to open, allowing its propagation along the nerve.
Inactivation
Within 5 ms the Na + channels are inactivated (i.e. they close and are transiently refractory to being opened again) allowing the cell to repolarize. (The delayed opening of K + channels in response to the membrane depolarization also contributes to repolarization.) The rapidity of the sequence of events means that repetitive firing can proceed at high frequency.
Local anaesthetics
Important examples are lidocaine (lignocaine), tetracaine (amethocaine), bupivacaine, procaine and prilocaine. Cocaine was the first local anaesthetic to be used but has few clinical applications now.
Mechanism of action
Local anaesthetics are nearly all weak bases (p K a 8–9) and have similar chemical structures ( Fig. 26.3 ). They act by blocking Na + channels and stopping the propagation of action potentials in nerve. ( Figs. 26.1 and 26.4 ). Local anaesthetics gain access to their binding site either from the cell interior or by lateral diffusion in the cell membrane. In both cases, it is essential for the drug to adopt its lipid-soluble, uncharged form to gain access ( Fig. 26.4 ). This of course depends on pH and can explain the reduced activity of local anaesthetics in inflamed tissue, where the lower pH increases ionization. Many local anaesthetics show use-dependence , that is they are more effective in blocking channels once these have been activated. This may be because the drug’s binding site is within the channel and accessible only when the channel opens, or it may result from greater affinity for the inactivated state of the channel.
Local anaesthetics usually block small diameter fibres at lower concentrations than large fibres. Accordingly, pain sensation is blocked before other sensory inputs, but it is not usually possible to achieve local anaesthesia without loss of other sensory modalities or local paralysis.
Pharmacokinetics
The plasma half-life of most local anaesthetics is 1–2 h, but their action persists for longer due to retention at the site of administration. The duration of action can be increased by the concomitant administration of a vasoconstrictor in the same formulation (epinephrine (adrenaline) or felypressin). The esters (tetracaine, benzocaine, procaine, cocaine) are hydrolysed rapidly by plasma esterases once they reach the bloodstream, whereas most amides (prilocaine, bupivacaine) are relatively resistant to plasma esterases and are subject to N-dealkylation and hydrolysis in the liver at a slower rate.
The variable lipid solubility of local anaesthetics determines the rate at which they penetrate tissues to cause nerve block and thus their suitability for action on mucous membranes.
Table 26.1 summarizes the properties of three local anaesthetics. Cocaine and lidocaine penetrate membranes readily; procaine does so poorly. Benzocaine differs from other local anaesthetics in lacking the basic amine side-chain; this results in increased lipophilicity and allows rapid entry into tissues, a fast onset and long duration of action.
| LA | Onset of action | Duration of action | Metabolism |
|---|---|---|---|
| Lidocaine | Rapid | Moderate | Amide-linked LAs are degraded in the liver |
| Bupivacaine | Slow | Long | |
| Tetracaine | Slow | Long | Ester-linked LA, hydrolysed by plasma esterases |
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