Lidocaine

Absorption

In general, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin . The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream . And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism . After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues .
The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion . Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile . The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue . The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved . There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels .
Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent . Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration .
Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion .

Toxicity

Symptoms of overdose and/or acute systemic toxicity involve central nervous system toxicity that presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for neurotic behavior. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia, and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcomes. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats.

Description

Lidocaine is used topically to relieve itching, burning, and pain from skin inflammations; and it is injected as a dental or minor surgery anesthetic.

Description

Lidocaine [2-(diethylamino)-N-(2, 6-dimethylphenyl) acetamide monohydrochloride] is the most commonly used amino amide-type local anesthetic. Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, such as procaine and tetracaine. It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture that is very popular with pediatric patients. The use of lidocaine–epinephrine mixtures should be avoided, however, in areas with limited vascular supply to prevent tissue necrosis. Lidocaine also frequently is used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits sodium channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetics.
Central nervous system changes are the most frequently observed systemic toxicities of lidocaine. The initial manifestations are restlessness, vertigo, tinnitus, slurred speech, and eventually, seizures. Subsequent manifestations include CNS depression with a cessation of convulsions and the onset of unconsciousness and respiratory depression or cardiac arrest. This biphasic effect occurs because local anesthetics initially block the inhibitory GABAergic pathways, resulting in stimulation, and eventually block both inhibitory and excitatory pathways (i.e., block the sodium channels associated with the NMDA receptors, resulting in overall CNS inhibition).

Chemical properties

solid

Originator

Xylocaine,Astra,US,1949

The Uses of Lidocaine

Lidocaine (Alphacaine)is a selective inverse peripheral histamine H1-receptor agonist with an IC50 of >32 μM. [1] Histamine is responsible for many features of allergic reactions. Lidocaine (Alphacaine)is a second-generation antihistamine agent closely st

The Uses of Lidocaine

Antiarrhythmic Agents, Anesthetics；Anticonvulsant；antihypertensive

The Uses of Lidocaine

Lidocaine is used in creams and lotions to soothe areas of inflamed skin or for example in hemorrhoid preparations to reduce discomfort; used by doctors to anesthetise areas prior to surgery, often avoiding the need for a general anesthetie; used by injection after a heart attack to treat some rhythm disturbances.

Indications

Lidocaine is an anesthetic of the amide group indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks .

Background

Ever since its discovery and availability for sale and use in the late 1940s, lidocaine has become an exceptionally commonly used medication . In particular, lidocaine's principal mode of action in acting as a local anesthetic that numbs the sensations of tissues means the agent is indicated for facilitating local anesthesia for a large variety of surgical procedures . It ultimately elicits its numbing activity by blocking sodium channels so that the neurons of local tissues that have the medication applied on are transiently incapable of signaling the brain regarding sensations . In doing so, however, it can block or decrease muscle contractile, resulting in effects like vasodilation, hypotension, and irregular heart rate, among others . As a result, lidocaine is also considered a class Ib anti-arrhythmic agent . Nevertheless, lidocaine's local anesthetic action sees its use in many medical situations or circumstances that may benefit from its action, including the treatment of premature ejaculation .
Regardless, lidocaine is currently available as a relatively non-expensive generic medication that is written for in millions of prescriptions internationally on a yearly basis. It is even included in the World Health Organization's List of Essential Medicines .

What are the applications of Application

Lidocaine is a selective inverse peripheral histamine H1-receptor agonist

Definition

ChEBI: Lidocaine is the monocarboxylic acid amide resulting from the formal condensation of N,N-diethylglycine with 2,6-dimethylaniline. It has a role as a local anaesthetic, an anti-arrhythmia drug, an environmental contaminant, a xenobiotic and a drug allergen. It is a monocarboxylic acid amide, a tertiary amino compound and a member of benzenes. It derives from a glycinamide.

Indications

Experimentally, lidocaine has been found to prevent VF arising during myocardial ischemia or infarction by preventing the fragmentation of organized largewavefronts into heterogeneous wavelets. Although lidocaine is of proven benefit in preventing VF early after clinical myocardial infarction, there is no evidence that it reduces mortality. To the contrary, lidocaine may increase mortality after myocardial infarction by approximately 40% to 60%.There are no controlled studies of lidocaine in secondary prevention of recurrence of VT or VF.
Lidocaine terminates organized monomorphic spontaneous VT or induced sustained VT in only approximately 20% of cases and is less effective than many other antiarrhythmic drugs. In a blinded, randomized study of intravenous lidocaine versus intravenous amiodarone in out-of-hospital VF resistant to defibrillation, lidocaine was associated with half the likelihood of survival to hospital admission compared with amiodarone.

Manufacturing Process

One mol of 2,6-xylidine is dissolved in 800 ml glacial acetic acid. The mixture is cooled to 10°C, after which 1.1 mol chloracetyl chloride is added at one time. The mixture is stirred vigorously during a few moments after which 1,000 ml half-saturated sodium acetate solution, or other buffering or alkalizing substance, is added at one time. The reaction mixture is shaken during half an hour. The precipitate formed which consists of ω-chloro-2,6- dimethyl-acetanilide is filtered off, washed with water and dried. The product is sufficiently pure for further treatment. The yield amounts to 70 to 80% of the theoretical amount.
One mole of the chloracetyl xylidide thus prepared and 2.5 to 3 mols diethyl amine are dissolved in 1,000 ml dry benzene. The mixture is refluxed for 4 to 5 hours. The separated diethyl amine hydrochloride is filtered off. The benzene solution is shaken out two times with 3N hydrochloric acid, the first time with 800 ml and the second time with 400 ml acid. To the combined acid extracts is added an approximately 30% solution of sodium hydroxide until the precipitate does not increase.
The precipitate, which sometimes is an oil, is taken up in ether. The ether solution is dried with anhydrous potassium carbonate after which the ether is driven off. The remaining crude substance is purified by vacuum distillation. During the distillation practically the entire quantity of the substance is carried over within a temperature interval of 1° to 2°C. The yield approaches the theoretical amount. MP 68° to 69°C. BP 180° to 182°C at 4 mm Hg; 159° to 160°C at 2 mm Hg. (Procedure is from US Patent 2,441,498.)

brand name

Alphacaine (Carlisle); Lidoderm (Teikoku); Xylocaine (AstraZeneca）.

Therapeutic Function

Local anesthetic, Antiarrhythmic

General Description

Lidocaine was the first amino amide synthesized in 1948and has become the most widely used local anesthetic. Thetertiary amine has a pKa of 7.8 and it is formulated as thehydrochloride salt with a pH between 5.0 and 5.5. When lidocaineis formulated premixed with epinephrine the pH ofthe solution is adjusted to between 2.0 and 2.5 to prevent the hydrolysis of the epinephrine. Lidocaine is also availablewith or without preservatives. Some formulations of lidocainecontain a methylparaben preservative that maycause allergic reactions in PABA-sensitive individuals. Thelow pKa and medium water solubility provide intermediateduration of topical anesthesia of mucous membranes.Lidocaine can also be used for infiltration, peripheral nerveand plexus blockade, and epidural anesthesia.

Biological Activity

Anasthetic and class Ib antiarrhythmic agent.? Blocks voltage-gated sodium channels in the inactivated state.

Contact allergens

Lidocaine is an anesthetic of the amide group, like articaine or bupivacaine. Immediate-type IgE-dependent reactions are rare, and delayed-type contact dermatitis is exceptional. Cross-reactivity between the different amide anesthetics is not systematic.

Biochem/physiol Actions

Na+ channel blocker; class IB antiarrhythmic that is rapidly absorbed after parenteral administration.

Pharmacology

Lidocaine is the most widely used local anaesthetic. It has a rapid onset and short duration of action. Lidocaine is rapidly and extensively metabolised in the liver and is safe at recommended doses. Efficacy is enhanced markedly and duration of action prolonged by addition of adrenaline. Lidocaine is less toxic than bupivacaine; a testament to this relative safety is that lidocaine is used intravenously as a class 1b antiarrhythmic and as an i.v. infusion to treat refractory chronic pain. Lidocaine solutions for injection are available in concentrations of 1% and 2%, with or without adrenaline. It is also available as a spray (4% or 10%), cream (2% or 4%), ointment or medicated plaster (both 5%) for topical application.

Pharmacokinetics

Lidocaine is administered intravenously because extensive first-pass transformation by the liver prevents clinically effective plasma concentrations orally. The drug is dealkylated and eliminated almost entirely by the liver; therefore, dosage adjustments are necessary in the presence of hepatic disease or dysfunction. Lidocaine clearance exhibits the time dependency common to high-clearance agents. With a continuous infusion lasting more than 24 hours, there is a decrease in total lidocaine clearance and an increase in elimination half-life compared with a single dose. Lidocaine free plasma levels can vary in certain patients owing to binding with albumin and the acutephase reactant a1-acid glycoprotein. Levels of a1-acid glycoprotein are increased in patients after surgery or acute myocardial infarction, whereas levels of both a1-acid glycoprotein and serum albumin are decreased in chronic hepatic disease or heart failure and in those who are malnourished. This is an essential consideration because it is the unbound fraction that is pharmacologically active.

Pharmacokinetics

Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure . With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present . The net effect is normally a modest hypotension when the recommended dosages are not exceeded .
In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction . Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse .
Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base . As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values . This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection . The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection .
Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation . This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels .

Clinical Use

The metabolism of lidocaine is typical of the amino amideanesthetics . The liver is responsiblefor most of the metabolism of lidocaine and any decreasein liver function will decrease metabolism. Lidocaineis primarily metabolized by de-ethylation of the tertiary nitrogento form monoethylglycinexylidide (MEGX). At lowlidocaine concentrations, CYP1A2 is the enzyme responsiblefor most MEGX formation. At high lidocaine concentrations,both CYP1A2 and CYP3A4 are responsible for the formationof MEGX.

Side Effects

Central nervous system side effects such as drowsiness, slurred speech, paresthesias, agitation, and confusion predominate. These symptoms may progress to convulsions and respiratory arrest with higher plasma concentrations. A rare adverse effect is malignant hyperthermia.
Cimetidine significantly reduces the systemic clearance of lidocaine as well as the volume of distribution at steady state and the degree of plasma protein binding. Beta blockers also reduce lidocaine clearance owing to a decrease in hepatic blood flow. For the same reason, clearance is reduced in congestive heart failure or low-output states.
Amiodarone may also influence the pharmacokinetics of lidocaine. In patients receiving amiodarone, single doses of intravenous lidocaine do not influence the pharmacokinetics of either agent. When amiodarone treatment is started in patients who are already receiving lidocaine infusion, there is a decrease in lidocaine clearance, which can result in toxic lidocaine levels.

Safety Profile

Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Human systemic effects: blood pressure lowering, changes in heart rate, coma, convulsions, dlstorted perceptions, dyspnea, excitement, hallucinations, muscle contraction or spasticity, pulse rate, respiratory depression, toxic psychosis. An experimental teratogen. Other experimental reproductive effects. A local anesthetic. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (2.2.2), is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives |á-chloro-2,6-dimethylacetanilide (2.1.1), and its subsequent reaction with diethylamine [11].

Synthesis of Lidocaine

Veterinary Drugs and Treatments

Besides its use as a local and topical anesthetic agent, lidocaine is used to treat ventricular arrhythmias, principally ventricular tachycardia and ventricular premature complexes in all species. Cats may be more sensitive to the drug and some clinicians feel that it should not be used in this species as an antiarrhythmic, but this remains controversial. In horses, lidocaine may be useful to prevent postoperative ileus and reperfusion injury.

Electrophysiologic Effects

Experimentally, lidocaine has been found to prevent VF arising during myocardial ischemia or infarction by preventing the fragmentation of organized largewavefronts into heterogeneous wavelets. Although lidocaine is of proven benefit in preventing VF early after clinical myocardial infarction, there is no evidence that it reduces mortality. To the contrary, lidocaine may increase mortality after myocardial infarction by approximately 40% to 60%.There are no controlled studies of lidocaine in secondary prevention of recurrence of VT or VF.
Lidocaine terminates organized monomorphic spontaneous VT or induced sustained VT in only approximately 20% of cases and is less effective than many other antiarrhythmic drugs. In a blinded, randomized study of intravenous lidocaine versus intravenous amiodarone in out-of-hospital VF resistant to defibrillation, lidocaine was associated with half the likelihood of survival to hospital admission compared with amiodarone.

Drug interactions

The concurrent administration of lidocaine with cimetidine but not ranitidine may cause an increase (15%) in the plasma concentration of lidocaine. This effect is a manifestation of cimetidine reducing the clearance and volume of distribution of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration.

Pregnancy toxicity

Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks. Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The fetus appears to be capable of metabolizing lidocaine at term. The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult. Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery. Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia, or respiratory depression may occur. Local anesthetics rapidly cross the placenta and, when used for epidural, paracervical, pudendal, or caudal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman.

Metabolism

Lidocaine is metabolized predominantly and rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys . Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation . N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide . The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine HCl . Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged . The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline .

Metabolism

Lidocaine is extensively metabolized in the liver by N-dealkylation and aromatic hydroxylations catalyzed by CYP1A2 isozymes. Lidocaine also possesses a weak inhibitory activity toward the CYP1A2 isozymes and, therefore, may interfere with metabolism of other medications.

storage

Store at RT

Toxicity evaluation

The potency of lidocaine depends on various factors including age of the subject, weight, physique including obesity, vascularity of the site, and indication for use, as this would determine the absorption and excretion rate. Physiologically, lidocaine blocks neuronal transmission by interfering with the flow of sodium across excitable membranes. A single lidocaine molecule binds to a single voltage-gated sodium channel impeding the movement of sodium ions across neuronal membranes. Consequently repolarization is prevented and further depolarization is not possible. Toxicity is dose related and results from excessive quantities of lidocaine.

Precautions

Contraindications include hypersensitivity to local anesthetics of the amide type (a very rare occurrence), severe hepatic dysfunction, a history of grand mal seizures due to lidocaine, and age 70 or older. Lidocaine is contraindicated in the presence of second- or thirddegree heart block, since it may increase the degree of block and can abolish the idioventricular pacemaker responsible for maintaining the cardiac rhythm.