CATHEJELL Jelly in collapsible syringe Ref.[27542] Active ingredients: Lidocaine

Mechanism of Action

Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. Local anesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.

Pharmacodynamics

Onset of Action

Anesthesia is achieved within 5 minutes, depending on the area of application. Duration of anesthesia is approximately 20–30 minutes. Cathejell (lidocaine hydrochloride) is ineffective when applied to intact skin.

Hemodynamics

Lidocaine, like other local anesthetics, may also have effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach 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 since it occurs at lower plasma concentrations. Direct effects of local anesthetics on the heart include slow conduction, negative inotropism, and eventually cardiac arrest.

Pharmacokinetics

Absorption

The rate and extent of absorption depends upon concentration and total dose administered, the specific site of application and duration of exposure. In general, the rate of absorption of local anesthetic agents following topical application to wound surfaces and mucous membranes is high and occurs most rapidly after intratracheal and bronchial administration. The absorption of lidocaine jelly from the nasopharynx is usually lower than with other lidocaine products. Blood concentrations of lidocaine after instillation of the jelly in the intact urethra and bladder in doses up to 800 mg are fairly low and below toxic levels. Lidocaine is also well absorbed from the gastrointestinal tract, although little intact drug may appear in the circulation because of biotransformation in the liver.

Distribution

Lidocaine has a total plasma clearance of 0.95 L/min and a volume of distribution at steady state of 91 L.

Lidocaine readily crosses the placenta, and equilibrium in regard to free, unbound drug will be reached. Because the degree of plasma protein binding in the fetus is less than in the mother, the total plasma concentration will be greater in the mother, but the free concentrations will be the same.

The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 µg of free base per mL, 60% to 80% of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine crosses the bloodbrain and placental barriers, presumably by passive diffusion.

Metabolism

Lidocaine is metabolized rapidly by the liver, and its metabolites and the unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. Only 2% of lidocaine is excreted unchanged. Most of it is metabolized first to monoethylglycinexylidide (MEGX) and then to glycinexylidide (GX) and 2,6-dimethylaniline. Up to 70% appears in the urine as 4-hydroxy-2,6-dimethylaniline. 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 10 h) than lidocaine and may accumulate during long-term administration.

Excretion

Lidocaine has an elimination half-life of 1.6 h and an estimated hepatic extraction ratio of 0.65. The clearance of lidocaine is almost entirely due to liver metabolism and depends both on liver blood flow and the activity of metabolizing enzymes. 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-dimethylaniline, accounting for about 70% to 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 hours. The elimination half-life in neonates (3.2 hours) is approximately twice that of adults. 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.

Special Populations and Conditions

Acidosis increases the systemic toxicity of lidocaine while the use of CNS depressants may increase the levels of lidocaine required to produce overt CNS effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 µg free base per mL.

Carcinogenesis and Mutagenesis

Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-dimethylaniline, showed weak evidence of activity in some genotoxicity tests. A chronic oral toxicity study of the metabolite 2,6-dimethylaniline (0, 14, 45, 135 mg/kg) administered and fed to rats showed that there was a significantly greater incidence of nasal cavity tumors in male and female animals that had daily oral exposure to the highest dose of 2,6-dimethylaniline for 2 years. The lowest tumour-inducing dose tested in animals (135 mg/kg) corresponds to approximately 50 times the amount of 2,6-dimethylaniline to which a 50 kg subject would be exposed to following the application of 20 g of lidocaine jelly 2% for 24 hours on the mucosa, assuming the highest theoretical extent of absorption of 100% and 80% conversion to 2,6-dimethylaniline. Based on a yearly exposure (once daily dosing with 2,6-dimethylaniline in animals and 5 treatment sessions with 20 g lidocaine jelly 2% in humans), the safety margins would be approximately 3400 times when comparing the exposure in animals to man.