Local anaesthetics are weak bases and exist predominantly in the ionised form at physiological pH, as their pKa exceeds 7.4. They fall into one of two chemical groupings, ester or amide, which describes the linkage between the aromatic lipophilic group and the hydrophilic group that each possess. Esters are comparatively unstable in solution, unlike amides that have a shelf-life of up to 2 years. See the table below for examples.
The individual structures confer different physicochemical and clinical characteristics.
All local anaesthetic agents are weak bases, meaning that they exist in two forms: ionised (BH+) and unionised (B). The pKa of local anaesthetics determines the pH at which both forms exist in equal amounts. As the pH of tissues differs from the pKa of specific drugs, more of the drug exists in either the ionised or unionised form. This is expressed in the Henderson-Hasselbalch equation:
pKa – pH = log [BH+] / [B]
where [B] is the concentration of unionised and [BH+] the concentration of ionised drug.
Bupivacaine, with a higher pKa of 8.1, has a greater fraction present in the ionised form, which is unable to penetrate the phospholipid membrane, resulting in a slower onset of action. Conversely, lidocaine has a lower pKa of 7.9, a higher fraction present in the unionised form and, therefore, a faster onset of action, as more is available to cross the phospholipid membrane.
Potency is correlated to lipid solubility in vitro, but less so in vivo. Other factors, such as vasodilator properties and tissue distribution, determine the amount of local anaesthetic that is available at the nerve.
The duration of action is associated with the extent of protein binding. Local anaesthetics with limited protein binding have a short duration of action, and, conversely, those with more extensive protein binding have a longer duration of action.
The intrinsic vasodilator activity varies between drugs and influences potency and duration of action. In general, local anaesthetics cause vasodilatation at low concentration (prilocaine>lidocaine>bupivacaine>ropivacaine) and vasoconstriction at higher concentrations. However, cocaine has solely vasoconstrictor actions by inhibiting neuronal uptake of catecholamines (uptake 1) and inhibiting monoamine oxidase (MAO). However, total dose and concentration of administered local anaesthetic will also have a significant effect on a given clinical situation.
Local anaesthetics are generally ineffective when used to anaesthetise infected tissue. The acidic environment further reduces the unionised fraction of drug available to diffuse into and block the nerve. There may also be increased local vascularity, which increases removal of drug from the site.
Central nervous system
Local anaesthetics penetrate the CNS rapidly and have a bi-phasic effect. Inhibitory interneurones are blocked first with initial excitatory phenomena, resulting in circumoral tingling, visual disturbance, tremors and dizziness. This is followed by convulsions. Finally, all central neurones are depressed, leading to apnoea and coma.
Local anaesthetic drugs block cardiac Na+ channels and decrease the maximum rate of increase of phase 0 of the cardiac action potential. They also have direct myocardial depressant properties. Lidocaine may be used to obtund the autonomic response to laryngoscopy. It is also widely used to treat ventricular arrhythmias, while bupivacaine is not, as it is 10 times slower at dissociating from the Na+ channels, resulting in persistent depression. This may lead to re-entrant arrhythmias and ventricular fibrillation. In addition, tachycardia may enhance frequency-dependent blockade by bupivacaine, which adds to its cardiac toxicity. Life-threatening arrhythmias may also reflect disruption of Ca++ and K+ channels.
When used in spinals and epidurals, local anaesthetics may block sympathetic outflow to a varying degree. This can result in hypotension requiring vasopressor support. If the cardioaccelerator fibres are blocked, bradycardia may ensue.
IV administration of lidocaine suppresses the cough reflex during laryngoscopy, endotracheal intubation, extubation and bronchoscopy.