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Lidocaine

Lidocaine

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Lidocaine (icon), Xylocaine, or lignocaine (former BAN
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...

) (icon) is a common local anesthetic
Local anesthetic
A local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...

 and antiarrhythmic
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....

 drug. Lidocaine is used topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

ly to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.

History


Lidocaine, the first amino amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...

-type local anesthetic, was first synthesized under the name Xylocaine by Swedish chemist Nils Löfgren
Nils Löfgren
Nils Löfgren, born 1913, died 1967, was a Swedish chemist who developed the anaesthetic Lidocaine in 1943. At this time, he had recently finished his licentiate degree, and was teaching organic chemistry at the University of Stockholm...

 in 1943. His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself. It was first marketed in 1949.
Etymology: from one of its many chemical names - [alpha-Diethylamino-2,6-dimethylacetani- ] - lide + ~ocaine.

Indications


The efficacy profile of lidocaine as a local anesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block and surface anesthesia. Longer-acting substances such as bupivacaine
Bupivacaine
Bupivacaine is a local anaesthetic drug belonging to the amino amide group. AstraZeneca commonly markets it under various trade names, including Marcain, Marcaine, Sensorcaine and Vivacaine.-Indications:...

 are sometimes given preference for spinal and peridural anesthesias; lidocaine, on the other hand, has the advantage of a rapid onset of action. Epinephrine vasoconstricts arteries and hence delays the resorption of Lidocaine, almost doubling the duration of anaesthesia. For surface anesthesia several formulations are available that can be used e.g. for endoscopies, before intubations etc. Buffering the pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 of lidocaine makes local freezing less painful.

Topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

 lidocaine has been shown to relieve postherpetic neuralgia
Postherpetic neuralgia
Postherpetic neuralgia is a neuralgia caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin and follows an outbreak of herpes zoster in that same dermatomic area...

 (arising, for example, from shingles) in some patients, though there is not enough study evidence to recommend it as a first-line treatment. It also has uses as a temporary fix for tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

. Although not completely curing the illness, it has been shown to reduce the effects by around two thirds.

Lidocaine is also the most important class 1B antiarrhythmic drug: it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digitalis poisoning, cardioversion
Cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle...

 or cardiac catheterization
Cardiac catheterization
Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. This is done for both investigational and interventional purposes...

). However, a routine prophylactic administration is no longer recommended for acute cardiac infarction; the overall benefit of this measure is not convincing.

Lidocaine has also been efficient in refractory cases of status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...

.

Inhaled lidocaine can be used as an antitussive (cough suppressor) acting peripherally below the larynx.

Lidocaine has also proved effective in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge

Contraindications


Contraindications for the use of lidocaine include:
  • Heart block
    Heart block
    A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....

    , second or third degree (without pacemaker)
  • Severe sinoatrial block
    Sinoatrial block
    A sinoatrial block is a disease which involves an impairment of conduction at the sinoatrial node. An absent P wave on an ECG can indicate sinoatrial block....

     (without pacemaker)
  • Serious adverse drug reaction
    Adverse drug reaction
    An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

     to lidocaine or amide local anaesthetics
  • Concurrent treatment with quinidine
    Quinidine
    Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

    , flecainide
    Flecainide
    Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...

    , disopyramide
    Disopyramide
    Disopyramide is an antiarrhythmic medication. It is a Class Ia antiarrhythmic used in the treatment of ventricular tachycardias...

    , procainamide
    Procainamide
    Procainamide INN is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.-History:...

     (Class I antiarrhythmic agents)
  • Prior use of Amiodarone hydrochloride
  • Hypotension
    Hypotension
    In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

     not due to Arrhythmia
  • Bradycardia
    Bradycardia
    Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

  • Accelerated idioventricular rhythm
    Accelerated idioventricular rhythm
    In accelerated idioventricular rhythm, the rate of cardiac contraction is determined by the intrinsic rate of depolarisation of the cardiac cells.It can be present at birth.-Pathophysiology:...

  • Pacemaker
    Pacemaker
    An artificial pacemaker is a medical device that uses electrical impulses to regulate the beating of the heart.Pacemaker may also refer to:-Medicine:...

  • Porphyria
    Porphyria
    Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...

    , especially acute porphyria (AIP)
    Acute intermittent porphyria
    Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common...

    ; lidocaine is known to be porphyrogenic although similar drugs (e.g. bupivacaine
    Bupivacaine
    Bupivacaine is a local anaesthetic drug belonging to the amino amide group. AstraZeneca commonly markets it under various trade names, including Marcain, Marcaine, Sensorcaine and Vivacaine.-Indications:...

    , tetracaine
    Tetracaine
    Tetracaine is a potent local anesthetic of the ester group...

    ) are known to be safe.

Adverse effects


Adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, but allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

 reactions only rarely occur.

Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth (also known as circumoral paraesthesia), tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

, tremor, dizziness, blurred vision, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s) followed by depression, and with increasingly heavier exposure: drowsiness, loss of consciousness, respiratory depression and apnoea). Cardiovascular effects include hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

, arrhythmias, and/or cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...

 – some of which may be due to hypoxemia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

 secondary to respiratory depression.

ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/minute). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

, arrhythmias, cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...

, muscle twitching, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

, and/or respiratory depression.

Overdosage


Overdosage with lidocaine can be a result of excessive administration via topical or parenteral routes, accidental oral ingestion of topical preparations by children, accidental intravenous (rather than subcutaneous, intrathecal or paracervical) injection or prolonged use of subcutaneous infiltration anesthesia during cosmetic surgical procedures. These occurrences have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma or serum to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. It is important in the interpretation of analytical results to recognize that lidocaine is often routinely administered intravenously as an antiarrhthymic agent in critical cardiac care situations. Treatment with intravenous lipid emulsions (used for parental feeding) to reverse the effects of local anaesthetic toxicity is becoming more common place.

Insensitivity to lidocaine


Relative insensitivity to lidocaine is genetic. In hypokalemic sensory overstimulation
Hypokalemic sensory overstimulation
Hypokalemic sensory overstimulation is a form of attention deficit hyperactivity disorder that has several similarities to disorders of ion channels, in particular to the muscle disorder hypokalemic periodic paralysis.-Characterization of the disorder:...

, relative insensitivity to lidocaine has been described in people who also have attention deficit hyperactivity disorder. In dental anesthesia, a relative insensitivity to lidocaine can occur for anatomical reasons due to unexpected positions of nerves. Some people with Ehlers-Danlos syndrome
Ehlers-Danlos syndrome
Ehlers–Danlos syndrome is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen . The collagen in connective tissue helps tissues to resist deformation...

 are insensitive to lidocaine.

Dosage forms



Lidocaine, usually in the form of lidocaine hydrochloride, is available in various forms including:
  • Injected local anesthetic (sometimes combined with epinephrine
    Epinephrine
    Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

     to reduce bleeding)
  • Dermal patch (sometimes combined with prilocaine
    Prilocaine
    Prilocaine is a local anesthetic of the amino amide type first prepared by Claes Tegner and Nils Lofgren. In its injectable form , it is often used in dentistry. It is also often combined with lidocaine as a preparation for dermal anesthesia , for treatment of conditions like paresthesia...

    )
  • Intravenous injection (sometimes combined with epinephrine to reduce bleeding)
  • Intravenous infusion
  • Nasal instillation/spray (combined with phenylephrine
    Phenylephrine
    Phenylephrine is a selective α1-adrenergic receptor agonist used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure...

    )
  • Oral gel (often referred to as "viscous lidocaine" or abbreviated "lidocaine visc" or "lidocaine hcl visc" in pharmacology; used as teething gel)
  • Oral liquid
  • Topical gel (as with Aloe vera
    Aloe vera
    Aloe vera, pronounced , also known as the true aloe or medicinal aloe, is a species of succulent plant in the genus Aloe that is believed to have originated in the Sudan. Aloe vera grows in arid climates and is widely distributed in Africa, India, Nepal and other arid areas.The species is...

     gels that include lidocaine)
  • Topical liquid
  • Topical patch (lidocaine 5% patch is marketed as "Lidoderm" in the US (since 1999) and "Versatis" in the UK (since 2007 by Grünenthal))
  • Topical aerosol spray
  • Inhaled via a nebulizer

Adulterant in cocaine


Lidocaine is often added to cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 as a diluent
Diluent
A diluent is a diluting agent.Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other. This can be problematic, because it might not be economically feasible to transport such fluids in this state.To ease this restricted movement, diluents...

. Cocaine numbs the gums when applied, and since lidocaine causes stronger numbness, a user gets the impression of high-quality cocaine when in actuality, the user is receiving a diluted product.

Preparation


Lidocaine may be prepared in two steps by the reaction of 2,6-xylidine
2,6-Xylidine
2,6-Xylidine is a aromatic amine with the chemical formula 2C6H3NH2. It is an isomer of 2,4-xylidine and 3,4-xylidine. It is a clear to yellow-red liquid which darkens upon exposure to air and light.2,6-Xylidine may be used to synthesize lidocaine:...

 with chloroacetyl chloride
Chloroacetyl chloride
Chloroacetyl chloride is a chlorinated acyl chloride. It is a bifunctional compound, making it a useful building block chemical.-Production:Industrially, it is produced by the carbonylation of methylene chloride, oxidation of vinylidene chloride, or the addition of chlorine to ketene...

, followed by the reaction with diethylamine
Diethylamine
Diethylamine is a secondary amine with the molecular structure CH3CH2NHCH2CH3. It is a flammable, strongly alkaline liquid. It is miscible with water and ethanol. It is a colorless liquid which often appears brown due to impurities...

:

Pharmacokinetics


Lidocaine is approximately 95% metabolized (dealkylated) in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 by CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

 to the pharmacologically-active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half life than lidocaine but also is a less potent sodium channel blocker.

The elimination half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 of lidocaine is approximately 90–120 minutes in most patients. This may be prolonged in patients with hepatic impairment
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...

 (average 343 minutes) or congestive heart failure (average 136 minutes).

Anesthesia


Lidocaine alters signal conduction in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s by blocking the fast voltage gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation. With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

. This creates the anaesthetic effect by not merely preventing pain signals from propagating to the brain but by stopping them before they begin. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations will also affect other modalities of neuron signaling.

Illegal uses


Lidocaine is not currently listed by the World Anti-Doping Agency
World Anti-Doping Agency
The World Anti-Doping Agency , , is an independent foundation created through a collective initiative led by the International Olympic Committee . It was set up on November 10, 1999 in Lausanne, Switzerland, as a result of what was called the "Declaration of Lausanne", to promote, coordinate and...

as an illegal substance. Lidocaine is used as an adjuvant, adulterant, mimic and diluent to illegal street drugs (e.g. cocaine). (See U.S. DEA web site).

Use as a gag reflex reducer.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC459418/pdf/thorax00202-0029.pdf

External links