Lidocaine toxicity from

Mofenson HC, Caraccio TR, Miller H, Greensher J. Lidocaine toxicity from topical mucosal application. With a review of the clinical pharmacology of lidocaine. CUn Pediatr (Phila) 1983 22(3) 190-2. 

MEXILETINE LIDOCAINE Mexiletine t lidocaine levels (with cases of toxicity when lidocaine is given intravenously) Mexiletine displaces lidocaine from its tissue-binding sites it also seems to l its clearance but the exact mechanism is uncertain at present Watch for the early symptoms and signs of lidocaine toxicity (perioral paraesthesia, T muscle tone)... 

The cardiovascular system is more resistant to the toxic effects of local anesthetics than the nervous system. Mild circulatory depression can precede nervous system toxicity, but seizures are more likely to occur before circulatory collapse. The intravenous dose of lidocaine required to produce cardiovascular coUapse is seven times that which causes seizures. The safety margin for racemic bupivacaine is much lower. The stereospecific levorotatory isomers levobupivacaine and ropivacaine are less cardiotoxic, and have a higher safety margin than bupivacaine, but not lidocaine in the case of ropivacaine this may be at the expense of reduced anesthetic potency (14,15). Toxicity from anesthetic combinations is additive. 

Gold MS, Reichling DB, Hampl KF, Drasner K, Levine JD 1998 Lidocaine toxicity in primary afferent neurons from the rat. J Pharmacol Exp Ther 285 413-421... 

Toxicity from local anesthetics (other than cocaine) is usually caused by therapeutic overdosage (ie, excessive doses for local nerve blocks), inadvertent acceleration of intravenous infusions (lidocaine), or accidental injection of products meant for dilution (eg, 20% lidocaine) instead of those formulated for direct administration (2% solution). Acute injection of lidocaine has also been used as a method of homicide. 

A study in 6 healthy subjects receiving 30-hour infusions of lidocaine at a rate of 2 mg/minute found that pretreatment with propranolol 80 mg every 8 hours for 3 days raised the steady-state plasma lidocaine levels by 19% (from 2.1 to 2.5 micrograms/mL) and reduced the plasma clearance by 16%. Other similar studies have found a 22.5 to 30% increase in steady-state serum lidocaine levels and a 14.7 to 46% fall in plasma clearance due to the concurrent use of propranolol. Two cases of lidocaine toxicity attributed to a lidocaine-propranolol interaction were revealed by a search of the FDA adverse drug reaction file in 1981. A further case of lidocaine toxicity (seizures) has been described in a man on propranolol after accidental oral ingestion of lidocaine for oesophageal anaesthesia. High serum levels of lidocaine were detected. ... 

Nervous system Systemic lidocaine toxicity has been described from the simultaneous use of transdermal patches and a heating pad [69 ]. 

Central nervous system toxicity from local anesthetics has previously been described. Lidocaine is usually considered to be safe up to a total intravenous dose of 3 mg/kg. However, although the total dose of the local anesthetic is important, lidocaine injected directly into the arterial circulation close to the central nervous system can produce toxicity in small doses [77 ]. 

Lldoc ine. Lidocaine hydrochloride, an anilide, was originally introduced as a local anesthetic in 1943 and found to be a potent antiarrhythmic in 1960. The compound is a reverse amide of procainamide. Lidocaine is generally considered to be the dmg of choice in the treatment of ventricular arrhythmias and those originating from digitalis glycoside toxicity (1,2,15—17). 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

The most commonly used vasoconstrictors, the sympathomimetic drugs, are often added to local anesthetics to delay absorption of the anesthetic from its injection site. By slowing absorption, these drugs reduce the anesthetic s systemic toxicity and keep it in contact with nerve fibers longer, thereby increasing the drug s duration of action. Administration of lidocaine 1% with epinephrine results in the same degree of blockade as that produced by lidocaine 2% without the vasoconstrictor. 

This is a class IB drug used primarily for the emergency treatment of ventricular arrhythmias. It has little effect on sinus node automaticity but depresses normal and abnormal forms of automaticity in Purkinje fibres. It is generally ineffective against supraventricular and accessory pathway-induced (e.g. WPW syndrome) arrhythmias. Lidocaine is relatively safe and free from adverse cardiovascular side effects. It causes minimal cardiodepression, although high doses can cause heart block. The most common side effect is a dose-related CNS toxicity. It is given intravenously as a bolus of 1 mg-kg-1 followed by an infusion of 20-50 pg-kg-l-min-1. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Fatty acid esters would be predicted to have little irritation or toxic effects. Ex vivo permeability studies conducted in porcine buccal mucosa showed significant permeation enhancement of an enkephalin from liquid crystalline phases of glycerine monooleate [32]. These were reported to enhance peptide absorption by a cotransport mechanism. Diethylene glycol monoethyl ether was reported to enhance the permeation of essential oil components of Salvia desoleana through porcine buccal mucosa from a topical microemulsion gel formulation [33]. Some sucrose fatty acid esters, namely, sucrose laurate, sucrose oleate, sucrose palmitate, and sucrose stearate, were investigated on the permeation of lidocaine hydrochloride [34], with 1.5% w/v sucrose laurate showing a 22-fold increase in the enhancement ratio. 

The effect of a local anaesthetic is terminated by its removal from the site of application. Anything that delays its absorption into the circulation will prolong its local action and can reduce its systemic toxicity where large doses are used. Most local anaesthetics, with the exception of cocaine, cause vascular dilation. The addition of a vasoconstrictor such as adrenaline (epinephrine) reduces local blood flow, slows the rate of absorption of the local anaesthetic, and prolongs its effect the duration of action of lidocaine is doubled from one to two hours. Normally, the final concentration of adrenaline (epinephrine) should be 1 in 200 000, although dentists use up to 1 in 80 000. 

The pharmacokinetics and safety of the 5% lidocaine patches have been studied in 20 healthy volunteers, who applied four patches to the skin either every 24 hours or every 12 hours for 3 days (67). Mean steady-state plasma concentrations were 186 and 225 ng/ml respectively, well below those required for an antidysrhythmic effect (1500 ng/ml) or a risk of toxicity (5000 ng/ml). The patches were well tolerated, with no major cutaneous adverse effects. This is in line with data from postmarketing surveillance studies, which have shown that since the availability of lidocaine patches in 1999, no adverse cardiac or other serious adverse events have been reported (68). 

Pfeifer HJ, Greenblatt DJ, Koch-Weser J. Clinical use and toxicity of intravenous lidocaine. A report from the Boston Collaborative Drug Surveillance Program. Am Heart J 1976 92(2) 168-73. 

Methemoglobinemia has been reported with benzocaine, Cetacaine (a mixture of benzocaine, butyl aminobenzo-ate, and tetracaine), cocaine, lidocaine, novocaine, and prUocaine. Acquired methemoglobinemia can result from exposure to chemicals that contain an aniline group, such as benzocaine and procaine, or to those that are transformed to metabolites that contain an aniline group, such as lidocaine and prilocaine. Toxic blood concentrations of local anesthetics, aberrant hemoglobin, and NADH-methemoglobin reductase deficiency are critical... 

Allergic reactions, including anaphylaxis, have been reported to local anesthetics. This is much more common for amide than ester-containing anesthetics. Local tissue, especially nerve fiber, toxicity can occur. This was most dramatically noted with the advent of microbore intrathecal catheters used to inject high-concentration (5%) lidocaine. It is thought this resulted in high local tissue concentrations and produced a number of cases of cauda equine syndrome and radiculopathy. As a result of these incidents, microbore catheters were removed from the market in 1993. 

---