Local anaesthetics

Local anaesthetics (LAs) are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block generation and conduction of nerve impulse at any part of the neurone with which they come in contact, without causing any structural damage. Thus, not only sensory but also motor impulses are interrupted when a local anaesthetics is applied to a mixed nerve, resulting in muscular paralysis and loss of autonomic control as well.

The local anaesthetics block nerve conduction by decreasing the entry of sodium ions during upstroke of action potential (AP). As the concentration of the local anaesthetics is increased, the rate of rise of action potential and maximum depolarization decreases causing slowing of conduction. Finally, local depolarization fails to reach the threshold potential and conduction block ensues.

The local anaesthetics interact with a receptor situated within the voltage sensitive sodium channel and raise the threshold of channel opening: sodium permeability fails to increase in response to an impulse or stimulus. Impulse conduction is interrupted when the sodium channels over a critical length of the fibre (2-3 nodes of Ranvier in case of myelinated fibres) are blocked. At physiological pH, the local anaesthetics molecule is partly ionized. The equilibrium between the unionized base form (B) and the ionized cationic form (BH) depends on the pKa of the local anaesthetics.

Potency of a local anaesthetics generally corresponds to the lipid solubility of its base form (B), because it is this form which penetrates the axon. However, the predominant active species is the cationic form of the local anaesthetics which is able to approach its receptor easily when the channel is open at the inner face, and it binds more avidly to the activated and inactivated states of the channel, than to the resting state. Binding of the local anaesthetics prolongs the inactivated state, so that the channel takes longer to recover.

The clinically used local anaesthetics have no/minimal local irritant action and block sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic synapse and receptors (non-selectively), i.e. those structures which function through increased Na permeability. They also reduce release of acetylcholine from motor nerve endings. Injected around a mixed nerve they cause anaesthesia of skin and paralysis of the voluntary muscle supplied by that nerve.

Sensory and motor fibres are inherently equally sensitive, but some local anaesthetics do exhibit unequal ability to block them, e.g. epidural bupivacaine produces sensory block at much lower concentration than that needed for motor block. The differential sensory blockade is greatly advantageous for pain relief in normal labour by enabling the mother to actively push the foetus down during uterine contractions. Similarly, in continuous epidural analgesia for postoperative pain relief (e.g. after knee replacement) absence of motor block is helpful in early ambulation and performance of exercises. Because local anaesthetics act near their site of administration, pharmacokinetic characteristics are not important determinants of their efficacy, but markedly influence their systemic effects and toxicity.

Soluble surface anaesthetics (lidocaine, tetracaine) are rapidly absorbed from mucous membranes and abraded areas, but absorption from intact skin is minimal. Procaine does not significantly penetrate mucous membranes. Rate of absorption depends on the blood flow to the area of application or injection, e.g. absorption and blood levels are higher after intercostal block than after sciatic block. The absorbed local anaesthetics being lipophilic, is widely distributed; rapidly enters highly perfused brain, heart, liver, and kidney, followed by muscle and other viscera.

Any local anaesthetics injected or applied locally is ultimately absorbed and can produce systemic effects depending on the concentration attained in the plasma and tissues. All local anesthesias are capable of producing a sequence of stimulation followed by depression. Cocaine is a powerful CNS stimulant causing in sequence euphoria excitement, mental confusion restlessness tremor and twitching of muscles convulsions unconsciousness respiratory depression death, in a dose dependent manner.

The synthetic local anesthesias are much less potent in this regard. At safe clinical doses, they produce little apparent CNS effects. Higher dose or accidental intravenous injection produces CNS stimulation followed by depression. The early neurological symptoms of overdose with lidocaine and other clinically used local anesthesias are circumoral numbness, abnormal sensation in the tongue, dizziness, blurred vision, tinnitus followed by drowsiness, dysphoria and lethargy. Still higher doses produce excitation, restlessness, agitation, muscle twitching, seizures and finally unconsciousness. 

Local anesthesias are cardiac depressants, but no significant effects are observed at conventional doses. At high doses (2-3 times the doses producing CNS effects) or on inadvertent intravenous injection, they decrease automaticity, excitability, contractility, conductivity and prolong effective refractory period (ERP). They have a quinidine like antiarrhythmic action. While procaine is not used clinically as antiarrhythmic because of short duration of action and propensity to produce CNS effects, its amide derivative procainamide is a class IA antiarrhythmic. Electrophysiological properties of heart may be markedly altered at high plasma concentrations of local anesthesias: QTc interval is prolonged and local anesthesias can themselves induce cardiac arrhythmias. Bupivacaine is relatively more cardiotoxic and has produced ventricular tachycardia, fibrillation and arrest. Lidocaine has little effect on contractility and conductivity; it abbreviates ERP and has minimal proarrhythmic potential. It is used as an antiarrhythmic.

Blood vessels local anesthesias tend to produce fall in blood pressure. This is primarily due to sympathetic blockade, but high concentrations, as obtained locally at the site of injection, do cause direct relaxation of arteriolar smooth muscle. Bupivacaine is more vasodilatory than lidocaine, while prilocaine is the least vasodilatory. Toxic doses of local anesthesias produce cardiovascular collapse. Cocaine has sympathomimetic property; increases sympathetic tone, causes local vasoconstriction, marked rise in blood pressure and tachycardia.

Published : Oct 15 2023