Local anaesthetics are organic (weak) bases and defined as pharmacological agents that are capable of producing a loss of sensation in a circumscribed area of the body. (Drasner, 2012). Almost all the local anaesthetics are composed of hydrophobic (lipophilic) component and hydrophilic component separated by an intermediate chain (Walton et al. , 1994). The linkage between hydrophilic and hydrophobic groups that each possesses determines which chemical groups, ester, or amides, they fall into.
Amides, which are now more commonly used, as esters are comparatively unstable in solutions and amides have longer shelf life of up to 2 years (French & Sharp, 2012). Structural alteration in the molecule produces physicochemical change that can alter anaesthetic potency, duration, and onset of action (Covino, 1986). Potency and duration is mainly reflected by lipid solubility, protein binding, and vasodilator activity while onset of action is influenced by ionization, partition coefficient and dissociation constant (pKa values).
As local anaesthetics are weak bases, they exist partly in a unionized form and partly in an ionized form, the proportion of each depending upon the pKa values of a particular drug. Both the unionized and ionized forms are important in producing local anaesthetics (Drasner, 2012). The unionized form is able to cross the fatty sheath of nerves and gain ready access inside the nerve fibers and the ionized form blocks conduction. These two forms are in equilibrium, as soon as some unionized molecules arrive inside the cell, some will become ionized.
Amides have a lower pKa than the Esther types and pKa coefficient measures lipid solubility of an agent in fat and water. The more fat soluble and the less water soluble a compound is, the higher the pKa value (Tucker et al. , 1970). Potency is positively correlated with lipid solubility. The greater the solubility is the greater the penetration of nerve membranes, resulting in an increased rate of onset (Covino, 1986). It is determined by partition coefficient measurements (pKa values) and highly lipid soluble local anaesthetics are the most potent and have a longer duration of action. (Tucker et al., 1970).
However, local anaesthetics with limited protein binding have a shorter duration of action. Protein binding is a simple reversible process, which increases in the proportion of the number of side chains of the molecules. The degree of protein binding is related to the duration of action (French & Sharp, 2012). It is possible to classify the clinically useful local anaesthetics compounds into 3 categaries based on the difference in anaestheic potency and duration of action. Therefore, pharmacological properties of local anaesthetic agents are related to their physicochemical properties.
References Drasner,K. et al. ,2012, Basic and clinical pharmacology, local anaesthetics, Chap26, 12 edn. French J and Sharp LM, 2012, Peri-operative care series, local anaesthetics, Nottingham University Hospitals NHS Trust, UK. Covim BG, 1986, Pltarmecology of LA AGENTS, vol 58, pp. 701-716. Tucker, Geoffery T. , 1970, Binding of Anilide-type L as in Huron plasma: I. relationships between Binding, P Propertion and A Activity, Vol. 33-issue 3. John G Walton. et. al, 1994, Textbook of Dental Pharmacology and the Therapeutics, 2nd edn, Oxford Uni Press.