MECHANISM OF ACTION OF LOCAL ANAESTHETICS

The primary target of local anaesthetics, the voltage- activated Na⁺ channel (VASC) is one of numerous membrane proteins which reside in the phospholipid bilayers encapsulating neurones (Fig. 4.1). VASCs provide selective permeability to Na⁺ when the cell becomes depolarized from the resting potential (approximately − 70 mV), which is maintained in quiescent neurones by the tonic activity of potassium ion (K⁺) channels. Local anaesthetics applied either topically to the skin or by infiltration inhibit action potentials in primary afferent nociceptive neurones, the pain-sensing neurones which transmit to the dorsal horn of the spinal cord (Fig. 4.2).

Pain transmission begins as a depolarization in the nerve ending of the primary afferent neurone initiated by the activation of cation channels. When the depolarization reaches the threshold for activation of VASCs (approximately − 45 mV), action potentials are generated, resulting in rapid depolarization to approximately + 20 mV (Fig. 4.3). Each action potential is brief (approximately 2 ms) because VASCs rapidly inactivate, leading to closure of their inactivation gates, and at the same time voltage-activated K⁺ channels activate, leading to an increase in the permeability of the cell membrane to K⁺. As a result, the membrane potential travels rapidly back towards the K⁺ equilibrium potential and this period is known as the after-hyperpolarization, a phenomenon which contributes to the refractory period during which it is unlikely that another action potential will be generated (Fig. 4.3).

THE VOLTAGE-ACTIVATED Na⁺ CHANNEL

Local anaesthetics gain access to their binding site within the inner lumen of the VASC when the activation gate opens in response to depolarization. The VASC is formed by a large protein (the α-subunit) consisting of 24 membrane-spanning segments arranged in four repetitive motifs (Fig. 4.1). The fourth segment of each motif is a voltage sensor, a series of positively charged amino acids (arginine and lysine residues) lying within the membrane. Depolarization causes electrostatic repulsion of the voltage sensors, providing the energy required to open the activation gate (Fig. 4.3). Na⁺ ions, selected by the filter formed by the four pore loops (between the 5th and 6th segments) lining the outer vestibule of the channel, are then free to pass down their concentration gradient into the cell, generating a depolarizing electrical current. However, Na⁺ current is inhibited by local anaesthetic bound within the inner vestibule of the channel. The inactivation gate, formed by intracellular components of the channel, closes rapidly following depolarization (Fig. 4.3) and local anaesthetics stabilize the inactivated state.

There are multiple subtypes of VASCs, named after the identity of their α-subunit (Na_V1.1–Na_V1.9) encoded by one of nine different genes (SCN1A–SCN5A, SCN8A–SCN11A) which are differentially expressed in tissues throughout the body and which have differing pharmacological and biophysical properties. This heterogeneity provides the potential (to date unmet) for selectively targeting VASCs in pain-sensing neurones. Nociceptive neurones predominantly express Na_V1.7, Na_V1.8 and/or Na_V1.9 α-subunits. Mutations in the SCN9A gene, which encodes Na_V1.7, are associated with several pain pathologies. Aspects of systemic toxicity relate to the ability of local anaesthetics to block VASCs outside the pain pathway. Cardiac VASCs are of the Na_V1.5 subtype and local anaesthetics such as ropivacaine and levobupivacaine are thought to have less systemic toxicity due to their lower affinity for cardiac channels. Additional VASC heterogeneity is conferred by four genes which encode ancillary β-subunits.

PAIN FIBRES

Different peripheral nerve fibres have differing sensitivities to block by local anaesthetics and are classified as A, B and C according to their conduction velocities, A being the fastest conductors and C the slowest. Aδ and C fibres both conduct pain (Fig. 4.2). Other subtypes of A fibre supply skeletal muscles (α and γ) and conduct tactile sensation (β), while type B are preganglionic autonomic fibres. Aδ fibres are heavily myelinated and rapidly conduct acute stabbing pain. Myelination enables a remarkably high velocity of transmission (approximately 20 m s^− 1) through a mechanism known as saltatory conduction. VASCs are segregated within the neuronal membrane of Aδ fibres at gaps in the myelin sheaths (nodes of Ranvier), enabling action potentials effectively to ‘jump’ from one node to the next. Aδ fibres are of small diameter and therefore have little ability to conduct changes in membrane potential once VASC activity has been inhibited. This makes them particularly sensitive to local anaesthetic block. Unlike Aδ fibres, C fibres are unmyelinated and their velocity of conduction from the skin to the spinal cord is relatively slow (approximately 1 m s^− 1). Local anaesthetics effectively block the transmission of dull, aching pain mediated by C fibres. The fibre diameter is very small (approximately 1 μm) and therefore there is little passive conduction, making transmission reliant on the activity of VASCs. C fibres are activated by inflammatory mediators and therefore the pain resulting from their stimulation can also be treated by anti-inflammatory agents.

LOCAL ANAESTHETIC STRUCTURE

Local anaesthetics of the amide and ester classes share three structural moieties: an aromatic portion, an intermediate chain and an amine group (Fig. 4.4