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
aLidocaine = 1, NA = not applicable (not used in solution), ? = information not available.
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 pKa of the local anaesthetic:
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.