Local Anaesthetic Agents

Local anaesthetics are analgesic drugs that suppress action potentials by blocking voltage-activated sodium ion (Na⁺) channels in excitable tissues. Examples include the anaesthetic amides (e.g. lidocaine, bupivacaine, ropivacaine) and esters (e.g. cocaine and procaine) (Table 4.1). Other drugs which can inhibit voltage-activated Na⁺ channels, such as diphenhydramine (a first-generation histamine H1 receptor antagonist) and amitriptyline (a tricyclic antidepressant) also have local anaesthetic properties. The blockade of voltage-activated Na⁺ channels accounts for both their analgesic effects, mediated through inhibition of action potentials in nociceptive neurones, and their systemic effects. The inhibition of action potentials in the heart contributes to local anaesthetic toxicity and also accounts for the antiarrhythmic actions of intravenous lidocaine (a class 1b antiarrhythmic). Unlike general anaesthetics (the pharmacology of which is described in Chs 1 and 2), local anaesthetics do not diminish consciousness when administered correctly.

TABLE 4.1

The Features of Individual Local Anaesthetic Drugs

NB: Published figures vary. Strichartz, G.R., Sanchez, V., Arthur, G.R., et al. 1990. Fundamental properties of local anesthetics. II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs. Anesth. Analg. 71, 158–170.

^a Lidocaine = 1, NA = not applicable (not used in solution), ? = information not available.

Local anaesthetics block sensation at the site of administration by inhibiting action potentials in all nociceptive fibres and therefore do not discriminate between pain modalities, unlike other analgesic drugs, such as the anti-inflammatory agents and opioids. Opioid analgesics (morphine, fentanyl, hydrocodone, etc.) and other central analgesic drugs such as the α₂-adrenergic agents (clonidine, dexmedetomidine) activate metabotropic (G protein-coupled) receptors within the membranes of specific neurones located within the pain pathway. A component of the actions of these drugs is centrally mediated (as described in Ch 5).

This chapter describes the pharmacology of local anaesthetics: their molecular mechanism of action, pharmacokinetics, systemic toxicity and recent developments which may improve their efficacy and safety.

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).

FIGURE 4.1 The topology of the VASC α-subunit. (A) The subunit has 24 membrane-spanning segments arranged in four domains with positively charged amino acid residues in the fourth segment of each domain providing voltage-sensitivity. Pore loops between segments five and six line the channel and have negatively charged amino acids which attract Na⁺ into the channel’s outer vestibule. The intracellular loop between domains three and four contains the inactivation gate (or h gate). (B) The four domains come together to form a channel. The ancillary β-subunits, which modulate channel function, are not shown.

FIGURE 4.2 The ascending pain pathway. (A) Peripheral nociceptors in the skin are activated by painful stimuli. Rapid stabbing pain is transmitted by myelinated Aδ fibres. Unmyelinated C fibres, activated by inflammatory mediators (e.g. bradykinin (BK), serotonin (5-HT), prostoglandins (PG) and histamine (H)) transmit aching pain more slowly. These fibres express TRPV1 channels activated by both noxious heat and capsaicin. (B) Primary afferent fibres synapse on neurones in the dorsal horn of the spinal cord, which transmit pain stimuli to the thalamus. Thalamic neurones project to the cortex.

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).

FIGURE 4.3 Most VASCs are closed at resting membrane potential (− 70 mV). Depolarization activates VASCs once the threshold potential is reached. Open VASCs enable greater depolarization until channels become inactivated and no longer support Na⁺ influx due to closure of the h-gate. Voltage-activated K⁺ channels (not shown) enable K⁺ efflux leading to hyperpolarization.

Mechanism of Local Anaesthetic Inhibition of the Voltage-Activated Na⁺ Channel

Local anaesthetics inhibit VASC activity by gaining access to the open channel from the inside of the cell and binding to specific amino acids lining the channel lumen (Fig. 4.1). They bind preferentially to the open channel and are therefore said to be use-dependent (or open channel) blockers. First, the local anaesthetic must cross the cell membrane, a passage which requires lipid solubility. The molecule must then diffuse into the aqueous environment within the ion channel. Amide and ester local anaesthetics posses both lipophilic and hydrophilic properties and are described as amphipathic (Fig. 4.4). They exist in basic (uncharged) and cationic (charged) forms and the relative proportion of each (determined using the Henderson–Hasselbalch equation) is dependent upon the pH of the solution and the pK_a of the local anaesthetic:

FIGURE 4.4 General formula for local anaesthetic drugs.

Local anaesthetics are weak bases and most have a pK_a of approximately 8.5. Therefore there is approximately 10-fold more charged than uncharged molecule at physiological pH (~ 7.5):

An alkaline solution speeds the onset of analgesia by increasing the proportion of uncharged local anaesthetic on the outside of the nerve, resulting in more rapid access to the inside of the cell where the balance of isoforms re-establishes on the basis of the intracellular pH. By contrast, infected and inflamed tissue has a relatively low (acidic) pH leading to an increase in the proportion of the membrane-impermeant cationic local anaesthetic component and the requirement for higher doses to achieve analgesia.

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.