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Pharmacotherapeutic Group: Local anaesthetic. ATC Code: N01BB02.
Pharmacology: Pharmacological Description: Xylocaine 2% jelly provides prompt and profound anaesthesia of mucous membranes and lubrication which reduces friction. Its water-miscible base, characterized by high viscosity and low surface tension, brings the anaesthetic into intimate and prolonged contact with the tissue, giving effective anaesthesia of long duration (approx. 20-30 min). Anaesthesia usually occurs rapidly (within 5 min, depending upon the area of application).
Pharmacodynamics: Lidocaine like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the nerve membrane. Local anaesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.
Local anaesthetic drugs may also have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating from the central nervous and cardiovascular systems.
Central nervous system toxicity (see Overdosage) usually precedes the cardiovascular effects as it occurs at lower plasma concentrations. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and possibly cardiac arrest.
Pharmacokinetics: Lidocaine is absorbed following topical administration to mucous membranes, its rate and extent of absorption being dependent upon concentration and the total dose administered, the specific site of application, and the duration of exposure. In general, the rate of absorption of local anaesthetic agents following topical application is most rapid after intratracheal and bronchial administration. Lidocaine is also well-absorbed from the gastrointestinal tract, although little intact drug appears in the circulation because of biotransformation in the liver.
Normally about 65% of the lidocaine is bound to plasma proteins. Amide local anaesthetics are mainly bound to alpha-1-acid glycoprotein but also to albumin. Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion.
The main elimination pathway of lidocaine is by liver metabolism. The primary route of lidocaine in human is N-dealkylation to monoethylglycine xylidine (MEGX), followed by hydrolysis to 2,6-xylidine and hydroxylation to 4-hydroxy-2,6-xylidine. MEGX can also be further dealkylated to glycine xylidine (GX). The pharmacological/toxicological actions of MEGX and GX are similar to, but less potent than, those of lidocaine. GX has a longer half-life (about 10h) than lidocaine and may accumulate during long-term administration. Approximately 90% of the lidocaine administrated intravenously is excreted in the form of various metabolites, and less than 10% is excreted unchanged in the urine. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-xylidine, accounting for about 70-80% of the dose excreted in the urine.
The elimination half-life of lidocaine following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.
Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 μg free base per mL.
Toxicology: Preclinical Safety Data: Reproduction Toxicology: In studies of embryonal/foetal development in rat and rabbit no teratogenic effects where seen after dosing lidocaine during organogenesis. Embryonal toxicity was seen in rabbit at mother-toxic dose. The offspring of rats treated with mother-toxic dose during late pregnancy and lactation showed decreased post-natal survival.
Genotoxicity and Carcinogenicity: Genotoxicity studies with lidocaine were negative. The carcinogenicity of lidocaine has not been studied. The metabolite 2,6-xylidine has genotoxic potential in vitro. In a cancer study on rat with exposure to 2,6-xylidine in utero, post natally and during the whole life-time, tumours in the nasal cavity, subcutaneously and in the liver were observed. The clinical relevance of these tumour findings after short-term/intermittent use is unknown.
