MECHANISM OF ACTION FACTORS INFLUENCING ACTIVITY Molecular weight Lipid solubility pKa pH
Systemic effects TOXICITY
Factors affecting local anaesthetic toxicity ESTER-LINKED AGENTS
Bupivacaine Lidocaine (lignocaine) Prilocaine Ropivacaine ADDITIVES Glucose
Additives with analgesic activity
Bupivacaine hydrochloride Lidocaine hydrochloride Prilocaine hydrochloride Ropivacaine hydrochloride
Local anaesthetic agents are used directly to block neuronal transmission. They also stabilize other electrically excitable membranes, and some examples, such as lignocaine, have clinically useful anti-arrhythmic activity.
Local anaesthetic agents comprise a lipophilic tertiary amine group linked to a hydrophilic aromatic group. They are divided into esters and amides based on the linking group. Figure LA.1 shows examples of these two types of local anaesthetic agent. Protonation of the highlighted amine nitrogen atom confers activity on the molecule once it is inside the cell.
Local anaesthetic agents exist in two states, acid (protonated) and basic (non ionized) in equilibrium according to their pKa and ambient pH, as determined by the Henderson-Hasselbach equation (Figure LA.2).
Local anaesthetic agents are weak bases. At physiological pH, there exists a mixture of non ionized and ionized drug. This is important as only the non ionized drug passes through the membrane, yet it is only the ionized drug that is active. Small changes in pH have marked effects on the proportion of drug that is ionized and, therefore, markedly influence the effect.
Injectable local anaesthetics must be soluble and stable in water, which is achieved by creating hydrochlorides of the drug. These drugs exist within ampoules in acid solution with a high degree of ionization that maintains solubility.
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