Basic pharmacology of local anaesthetics

Abstract

Describe the basic structure of local anaesthetic agents. Illustrate the relationships between the structure, function and toxicity of local anaesthetic agents. Identify the pharmacological profiles of commonly used local anaesthetics.

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“…The alpha subunit is comprised of four domains, each containing six segments that wrap round to form a bell-shaped central channel. The channel itself is formed by the S5 and S6 segments and the short loops of amino acids that link them (Taylor and McLeod, 2019). First described by Hodgkin and Huxley (1952), three conformational states of the channel exist: resting, open, and inactivated.…”

“…First described by Hodgkin and Huxley (1952), three conformational states of the channel exist: resting, open, and inactivated. The membrane potential is approximately -70 mV in the resting state: this charge is generated by the movement of positively charged potassium ions from outside the neuron (to the inside) via the sodium-potassium pump and the negatively charged anions that remain within the cell (Taylor and McLeod, 2019). After a stimulus, the sodium channels open during depolarisation, allowing a rapid influx of sodium ions down the electrical and chemical gradient which leads to channel inactivation.…”

“…The local anaesthetic molecule consists of 3 components: a lipophilic aromatic ring, an intermediate ester or amide chain, and a terminal hydrophilic amine (Columb and MacLennan, 2007;Taylor and McLeod, 2019). Each of these contribute distinct properties to the molecule (see fig 1).…”

“…Figure 1: basic structure a local anaesthetic (Metcalfe and Reilly, 2010) For the local anaesthetic base to be stable in solution, it is formulated as a (water-soluble) hydrochloride (acid) salt. This is represented by: B (base LA) + H + (hydrochloride salt) ⇋ BH + (protonated form) Following the diffusion of the non-ionised base through the neural (cell) membrane into the axoplasm, it re-protonates and enters the voltage-gated sodium channels to suppress action potentials by inhibiting the influx of sodium ions, preventing the ion channel from assuming an active or ''open'' state (Becker, 2006;Taylor and McLeod, 2019). The quaternary form of a LA will not penetrate the neuron and therefore the time for onset of anaesthesia is predicated on the proportion of molecules that convert to the tertiary, lipid-soluble structure when exposed to physiologic pH (7.4) (Becker 2006).…”

“…The order of peak plasma concentration after a single dose is: intrapleural > intercostal > lumbar epidural > brachial plexus > subcutaneous > sciatic > femoral. (Taylor and McLeod, 2019). The implication from the literature is that pedal blocks -being even more distal -have slower systemic uptake and reduced potential for acute overdosage.…”