Study Title:

Lidocaine Toxicity Summary Report

Study Abstract

Toxicity Summary:
IDENTIFICATION AND USE: Lidocaine is a white or slightly yellow, crystalline powder or needle with a characteristic odor. It is commonly used as a medication including for local anesthetics, anti-arrhythmia agent, or as a voltage-gated sodium channel blocker. Lidocaine may also be used in the treatment of hypertensive emergencies, or acute coronary syndrome associated with the toxicity of various stimulants and antiarrhythmic agents. A lidocaine transdermal patch is used for relief of pain associated with postherpetic neuralgia. An oral patch is available for application to accessible mucous membranes of the mouth prior to superficial dental procedures. The combination of lidocaine (2.5%) and prilocaine (2.5%) in an occlusive dressing is used as an anesthetic prior to venipuncture, skin graft harvesting, and infiltration of anesthetics into genitalia. Lidocaine in combination with tetracaine in a formulation that generates a "peel" is approved for topical local analgesia prior to superficial dermatological procedures. HUMAN EXPOSURE AND TOXICITY: Adverse effects of the drug mainly involve the CNS because of its rapid entry in the brain. Adverse CNS reactions may be manifested by drowsiness; dizziness; disorientation; confusion; lightheadedness; tremulousness; psychosis; nervousness; apprehension; agitation; euphoria; tinnitus; visual disturbances including blurred or double vision; nausea; vomiting; paresthesia; sensations of neat, cold or numbness; difficulty swallowing; dyspnea; and slurred speech. Muscle twitching or tremors, seizures, unconsciousness, coma, and respiratory depression and arrest may also occur. Shortly following the CNS effects, patients with lidocaine toxicity may also experience cardiovascular effects. If the patient is supported through this period, the drug rapidly distributes away from the heart, and spontaneous cardiac function returns. Lidocaine, when administered to a baby may induce convulsions. Lidocaine intoxication in the neonate, occurring as a result of inadvertent injection into the fetal scalp or cranium during local anesthesia (caudal or paracervical block or episiotomy), produces apnea, hypotonia, and seizures. Dilated pupils and loss of the oculocephalic reflex may also be observed. The more severe of these effects develop when serum lidocaine concentrations exceed 5 ug/mL and are often preceded by paresthesias or somnolence. Continuous application for 72 hours of four lidocaine patches 5%, changed every 12 or 24 hours, produced mild application-site erythema in most patients, but no systemic adverse reactions. No loss in sensation at the application site was reported. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. In human SH-SY5Y neuroblastoma cells, local anesthesia caused rapid cell death, which was primarily due to necrosis. Lidocaine can trigger apoptosis with either increased time of exposure or increased concentration. ANIMAL STUDIES: In rats persistent functional impairment and histologic damage in the nerve roots and the spinal cord was less severe after epidural lidocaine than after intrathecal lidocaine. In 8 New Zealand Rabbits receiving 0.2 mL 1% lidocaine hydrochloride applied intracamerally to the lenses, had morphological abnormalities in both cornea and iris of the lidocaine injected eyes. Another experiment in rabbits with 2% lidocaine HCl applied intracamerally on the corneal endothelium found that lidocaine caused statistically significant corneal thickening and clinically significant corneal opacification. Lidocaine injection into the dorsal root ganglion of rats produced hyperalgesia, possibly due to activation of resident satellite glial cells. One-hour exposure of primary rabbit urothelial cells (PRUC) culture to 0.5 or 1.0% lidocaine decreased cell viability. Lidocaine rapidly crosses the placenta in pregnant guinea pigs. High concentrations are found in the fetal liver, heart, and brain. High myocardial levels of drug in the fetus may possibly account for marked depressant effects that local anesthetics produce. In another study, no significant effects were observed in offspring of rats administered lidocaine at by constant infusion for 2 weeks before mating and throughout pregnancy. Additionally, pregnancy did not enhance the CNS and cardiovascular toxic effects of lidocaine when studied in pregnant sheep receiving continuous IV drug infusion and compared to data from nonpregnant ewes. Lidocaine did not induce genotoxicity in the wing somatic mutation and recombination test in Drosophila melanogaster, which detects point and chromosomal mutations as well as recombination induced by the activity of genotoxins of direct and indirect action. Lidocaine 0.25% did decrease cell viability and caused DNA degradation in murine fibroblasts 3T6. Lidocaine was not oncogenic when administered topically weekly to the dorsal skin of mice for 26 weeks.

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