Lidocaine

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Lidocaine
Lidocaine.svg
Lidocaine-from-xtal-3D-balls.png
Systematic (IUPAC) name
2-(diethylamino)-
N-(2,6-dimethylphenyl)acetamide
Clinical data
Trade names Xylocaine
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy cat. A (AU) B (US)
Legal status Prescription Only (S4) (AU) Rx Only (U.S.) (excluding 1%) (US)
Routes intravenous, subcutaneous, topical
Pharmacokinetic data
Bioavailability 35% (oral)
3% (topical)
Metabolism Hepatic, 90% CYP1A2-mediated
Half-life 1.5–2 hours
Excretion renal
Identifiers
CAS number 137-58-6 YesY
73-78-9 (hydrochloride)
ATC code C01BB01 C05AD01 D04AB01 N01BB02 R02AD02 S01HA07 S02DA01
PubChem CID 367
IUPHAR ligand 2623
DrugBank DB00281
ChemSpider 3548 YesY
UNII 98PI200987 YesY
KEGG D00358 YesY
ChEBI CHEBI:6456 YesY
ChEMBL CHEMBL79 YesY
Synonyms N-(2,6-dimethylphenyl)-N2,N2-diethylglycinamide
Chemical data
Formula C14H22N2O 
Mol. mass 234.34 g/mol
Physical data
Melt. point 68 °C (154 °F)
 YesY (what is this?)  (verify)

Lidocaine (INN) /ˈldɵkn/, xylocaine, or lignocaine (former BAN) /ˈlɪɡnɵkn/ is a common local anesthetic and class 1b antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.

History[edit]

Lidocaine, the first amino amide–type local anesthetic, was first synthesized under the name xylocaine by Swedish chemist Nils Löfgren in 1943.[1][2][3] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[1] It was first marketed in 1949.

Indications[edit]

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 are sometimes given preference for subdural and epidural anesthesias; lidocaine, on the other hand, has the advantage of a rapid onset of action. Epinephrine (aka adrenaline) vasoconstricts arteries reducing bleeding and also 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 of lidocaine makes local freezing less painful.[4]

Topical lidocaine has been shown in some patients to relieve the pain of postherpetic neuralgia (a complication of shingles), though there is not enough study evidence to recommend it as a first-line treatment.[5] IV lidocaine also has uses as a temporary fix for tinnitus. Although not completely curing the disorder, it has been shown to reduce the effects by around two thirds.[6][7]

Lidocaine is also the most important class 1B antiarrhythmic drug: it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digoxin poisoning, cardioversion or cardiac catheterization) if amiodarone is not available or contraindicated. Lidocaine should e given for this indication after defibrillation, CPR, and vasopressors have been initiated. Start with a bolus of 1-1.5mg/kg and then give 0.5-0.75mg/kg doses every 5 to 10 minutes if the arrhythmia persists to a maximum cumulative total of 3mg/kg. If normal sinus rhythm returns, switch to a continuous infusion of 1-4mg/minute.

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.

Inhaled lidocaine can be used as an antitussive (cough suppressor) acting peripherally below the larynx.[8][9]

Lidocaine along with ethanol, ammonia, and acetic acid has also been proven to be effective in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge.[10][11]

Contraindications[edit]

Absolute Contraindications for the use of lidocaine include:

Exercise caution in patients with any of the following

Adverse effects[edit]

Adverse drug reactions (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, and allergic reactions only rarely occur.[16] Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRS are listed below by system:

CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache, hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures

CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech, hypoesthesia, confusion, disorientation, loss of consciousness, respiratory depression and apnoea.

Cardiovascular: hypotension, bradycardia, arrhythmias, flushing, venous insufficiency, increased defibrillator threshold, edema, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.[17]

GI: metallic taste, nausea, vomiting

Otic: tinitis

local: thrombophlebitis

Respiratory: Bronchospasm, dyspnea, respiratory depression or arrest

Allergic

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, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia, arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.[17]

Overdosage[edit]

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 antiarrhythmic agent in critical cardiac care situations.[18] Treatment with intravenous lipid emulsions (used for parental feeding) to reverse the effects of local anaesthetic toxicity is becoming more commonplace.[19]

Insensitivity to lidocaine[edit]

Relative insensitivity to lidocaine is genetic. In hypokalemic sensory overstimulation, 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 are insensitive to lidocaine.[20]

Dosage forms[edit]

Lidocaine hydrochloride 2% epinephrine 1:80,000 solution for injection in a cartridge
Lidocaine hydrochloride 1% solution for injection
Topical lidocaine spray

Lidocaine, usually in the form of lidocaine hydrochloride, is available in various forms including:

  • Injected local anesthetic (sometimes combined with epinephrine to reduce bleeding)
  • Dermal patch (sometimes combined with prilocaine)
  • Intravenous injection
  • Intravenous infusion
  • Nasal instillation/spray (combined with phenylephrine)
  • Oral gel (often referred to as "viscous lidocaine" or abbreviated "lidocaine visc" or "lidocaine hcl visc" in pharmacology; used as teething gel)
  • Oral liquid
  • Oral and topical ointments, with and without flavoring, respectively[21][22]
  • Topical gel (as with Aloe vera gels that include lidocaine)[23]
  • Topical liquid
  • Lidocaine HCl 2% Jelly, combined with hypromellose, to anesthetize and lubricate the urethra, etc., for inserting a catheter or instrument
  • Topical patch (lidocaine 5%), marketed since 1999 in the US by Endo Pharmaceuticals[24] as "Lidoderm" - and since 2007 in the UK by Grünenthal as "Versatis"
  • Topical ointment (lidocaine 5%) as a temporary reliever of discomfort associated anorectal disorders, such as hemorrhoids, marketed as an over-the-counter product in the US as "RectiCare" since 2012 by Ferndale Healthcare, Inc.
  • Topical aerosol spray
  • Inhaled via a nebulizer
  • As a component of a GI cocktail used in emergency rooms

Adulterant in cocaine[edit]

Lidocaine is often added to cocaine as a diluent.[25] Cocaine numbs the gums when applied, and since lidocaine causes stronger numbness,[26] a user gets the impression of high-quality cocaine when in actuality, the user is receiving a diluted product.[27]

Preparation[edit]

Lidocaine may be prepared in two steps by the reaction of 2,6-xylidine with chloroacetyl chloride, followed by the reaction with diethylamine:[28][29]

Synthesis of lidocaine.png

Pharmacokinetics[edit]

Lidocaine is approximately 95% metabolized (dealkylated) in the liver by CYP3A4 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.[30]

The elimination half-life of lidocaine is approximately 90–120 minutes in most patients. This may be prolonged in patients with hepatic impairment (average 343 minutes) or congestive heart failure (average 136 minutes).[31]

Pharmacodynamics[edit]

Anaesthesia[edit]

Lidocaine alters signal conduction in neurons by blocking the fast voltage gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation.[32] With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential. 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 use[edit]

Lidocaine is not currently listed by the World Anti-Doping Agency as an illegal substance.[33] Lidocaine is used as an adjuvant, adulterant, and diluent to street drugs such as cocaine and heroin.[34]

Compendial status[edit]

See also[edit]

Notes and references[edit]

  1. ^ a b Löfgren N (1948). Studies on local anesthetics: Xylocaine: a new synthetic drug (Inaugural dissertation). Stockholm, Sweden: Ivar Heggstroms. OCLC 646046738. [page needed]
  2. ^ Löfgren N, Lundqvist B (1946). "Studies on local anaesthetics II". Svensk Kemisk Tidskrift 58: 206–17. 
  3. ^ Wildsmith JAW (2011). "Lidocaine: A more complex story than 'simple' chemistry suggests". The Proceedings of the History of Anaesthesia Society 43: 9–16. 
  4. ^ Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R (2010). "Adjusting the pH of lidocaine for reducing pain on injection". Cochrane Database Syst Rev (12): CD006581. doi:10.1002/14651858.CD006581.pub2. PMID 21154371. 
  5. ^ Khaliq W, Alam S, Puri N (2007). "Topical lidocaine for the treatment of postherpetic neuralgia". Cochrane Database Syst Rev (2): CD004846. doi:10.1002/14651858.CD004846.pub2. PMID 17443559. 
  6. ^ "New hope for tinnitus sufferers". BBC News. 9 January 2008. 
  7. ^ Kalcioglu MT, Bayindir T, Erdem T, Ozturan O. (2005). "Objective evaluation of the effects of intravenous lidocaine on tinnitus.". Hearing Research. 
  8. ^ Adcock JJ, Douglas GJ, Garabette M, Gascoigne M, Beatch G, Walker M, Page CP (February 2003). "RSD931, a novel anti-tussive agent acting on airway sensory nerves". Br. J. Pharmacol. 138 (3): 407–16. doi:10.1038/sj.bjp.0705056. PMC 1573683. PMID 12569065. 
  9. ^ Biller JA (2007). "Airway obstruction, bronchospasm, and cough". In Berger AM, Shuster JL, Von Roenn JH. Principles and practice of palliative care and supportive oncology. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 297–307. ISBN 978-0-7817-9595-1. "Inhaled lidocaine is used to suppress cough during bronchoscopy. Animal studies and a few human studies suggest that lidocaine has an antitussive effect…" 
  10. ^ Birsa LM, Verity PG, Lee RF (May 2010). "Evaluation of the effects of various chemicals on discharge of and pain caused by jellyfish nematocysts". Comp. Biochem. Physiol. C Toxicol. Pharmacol. 151 (4): 426–30. doi:10.1016/j.cbpc.2010.01.007. PMID 20116454. 
  11. ^ http://www.ncbi.nlm.nih.gov/pubmed/24637105
  12. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm342035.htm
  13. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm342035.htm
  14. ^ "Table 96–4. Drugs and Porphyria". Merck Manual. Merck & Company, Inc. 2011. 
  15. ^ "Lidocaine - N01BB02". Drug porphyrinogenicity monograph. The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. "strong clinical evidence points to lidocaine as probably not porphyrinogenic" 
  16. ^ Jackson D, Chen AH, Bennett CR (October 1994). "Identifying true lidocaine allergy". J Am Dent Assoc 125 (10): 1362–6. PMID 7844301. 
  17. ^ a b Australian Medicines Handbook. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. 2006. ISBN 0-9757919-2-3. [page needed]
  18. ^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 840–4. ISBN 0-9626523-7-7. 
  19. ^ Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W (February 2009). "Guidelines and the adoption of 'lipid rescue' therapy for local anaesthetic toxicity". Anaesthesia 64 (2): 122–5. doi:10.1111/j.1365-2044.2008.05816.x. PMID 19143686. 
  20. ^ Hakim AJ, Grahame R, Norris P, Hopper C (February 2005). "Local anaesthetic failure in joint hypermobility syndrome". J R Soc Med 98 (2): 84–5. doi:10.1258/jrsm.98.2.84. PMC 1079398. PMID 15684369. 
  21. ^ "Product information for lidocaine ointment, USP 5%, spearmint flavored". Product Insert. Taro Pharmaceutical Industries Ltd. Retrieved July 27, 2009. 
  22. ^ "Lidocaine Ointment Prescribing Information". Drugs.com. Retrieved January 22, 2012. 
  23. ^ "Solarcaine". Schering-Plough Healthcare Products, Inc. Retrieved July 27, 2009. 
  24. ^ "Lidoderm (Lidocaine Patch 5%)". Our Products. Endo Pharmaceuticals. Retrieved 18 October 2012. 
  25. ^ Bernardo NP, Siqueira MEPB, De Paiva MJN, Maia PP (2003). "Caffeine and other adulterants in seizures of street cocaine in Brazil". International Journal of Drug Policy 14 (4): 331–4. doi:10.1016/S0955-3959(03)00083-5. 
  26. ^ Kimberly H (1997-12-15). "Take a big-picture approach when dealing with corneal sensation". Retrieved 2009-04-23. "Lidocaine is more potent, with rapid diffusion and penetration." 
  27. ^ "UNITED STATES of America, Plaintiff-Appellee, v. Luis A. CUELLO, Alvaro Bastides-Benitez, John Doe, a/k/a Hugo Hurtado, and Alvaro Carvajal, Defendants-Appellants". Docket No. 78-5314. United States Court of Appeals, Fifth Circuit. 1979-07-25. 
  28. ^ Reilly TJ (1999). "The Preparation of Lidocaine". Journal of Chemical Education 76 (11): 1557. doi:10.1021/ed076p1557. 
  29. ^ US patent 2441498, Bengt JL, Niels, ML, "Alkyl glycinanilides", issued 1948-05-11, assigned to Astra Apotekarnes Kem FAB 
  30. ^ Lewin NA, Nelson LH (2006). "Chapter 61: Antidysrhythmics". In Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA, Nelson LH. Goldfrank's Toxicologic Emergencies (8th ed.). New York: McGraw-Hill. pp. 963–4. ISBN 0-07-143763-0. 
  31. ^ Thomson PD, Melmon KL, Richardson JA, Cohn K, Steinbrunn W, Cudihee R, Rowland M (April 1973). "Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans". Ann. Intern. Med. 78 (4): 499–508. doi:10.7326/0003-4819-78-4-499. PMID 4694036. 
  32. ^ Carterall, William A. (2001). "Molecular Mechanisms of Gating and Drug Block of Sodium Channels". Sodium Channels and Neuronal Hyperexcitability. Novartis Foundation Symposia 241. p. 206. doi:10.1002/0470846682.ch14. ISBN 9780470846681. 
  33. ^ "The 2010 Prohibited List International Standard". The World Anti-Doping Code. World Anti-Doping Agency (WADA). 19 September 2009. 
  34. ^ "New York Drug Threat Assessment". National Drug Intelligence Center. November 2002. 
  35. ^ "Revision Bulletin: Lidocaine and Prilocaine Cream–Revision to Related Compounds Test". The United States Pharmacopeial Convention. November 30, 2007. 
  36. ^ Lim TK, Macleod BA, Ries CR, Schwarz SK (2007). "The quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animal models in vivo.". Anesthesiology 107 (2): 305–11. 

External links[edit]