Lidocaine Hydrochloride

(BANM, rINNM)
Synonyms: Hidrocloruro de lidocaína; Lidocaïne, chlorhydrate de; Lidocaini hydrochloridum; Lidocaini Hydrochloridum Monohydricum; Lidokaiinihydrokloridi; Lidokain Hidroklorür; Lidokain-hidroklorid; Lidokain-hydrochlorid monohydrát; Lidokainhydroklorid; Lidokaino hidrochloridas; Lidokainy chlorowodorek; Lignoc. Hydrochlor.; Lignocaine Hydrochloride; Lignokain Hidroklorür.
Cyrillic synonym: Лидокаина Гидрохлорид.

💊 Chemical information

Chemical formula: C14H22N2O,HCl,H2O = 288.8.
CAS — 73-78-9 (anhydrous lidocaine hydrochloride); 6108-05-0 (lidocaine hydrochloride monohydrate).
ATC — C01BB01; C05AD01; D04AB01; N01BB02; R02AD02; S01HA07; S02DA01.
ATC Vet — QC01BB01; QC05AD01; QD04AB01; QN01BB02; QR02AD02; QS01HA07; QS02DA01.

Pharmacopoeias.

In Chin., Eur., Int., US, and Viet.

Ph. Eur. 6.2

(Lidocaine Hydrochloride). A white, or almost white, crystalline powder. M.p. 74° to 79°. Very soluble in water; freely soluble in alcohol. A 0.5% solution in water has a pH of 4.0 to 5.5. Protect from light.

USP 31

(Lidocaine Hydrochloride). A white, odourless, crystalline powder. M.p. 74° to 79°. Very soluble in water and in alcohol; soluble in chloroform; insoluble in ether.

Incompatibility.

Lidocaine hydrochloride has been reported to be incompatible in solution with amphotericin B, 1 sulfadiazine sodium, 2 methohexital sodium, 2 cefazolin sodium, 3 or phenytoin sodium. 4 Acid stable drugs such as adrenaline hydrochloride, noradrenaline acid tartrate, or isoprenaline may begin to deteriorate within several hours of admixture with lidocaine hydrochloride as lidocaine solutions may raise the pH of the final solution above the maximum pH for their stability. Such extemporaneous mixtures should be used promptly after preparation. 5 1. Whiting DA. Treatment of chromoblastomycosis with high local concentrations of amphotericin B. Br J Dermatol 1967; 79: 345–51. 2. Riley BB. Incompatibilities in intravenous solutions. J Hosp Pharm 1970; 28: 228–40. 3. Kleinberg ML, et al. Stability of antibiotics frozen and stored in disposable hypodermic syringes. Am J Hosp Pharm 1980; 37: 1087–8. 4. Kirschenbaum HL, et al. Stability and compatibility of lidocaine hydrochloride with selected large-volume parenterals and drug additives. Am J Hosp Pharm 1982; 39: 1013–15. 5. Parker EA. Xylocaine hydrochloride 2% injection. Am J Hosp Pharm 1971; 28: 805.

pH of solutions.

For the effect pH has on the surface tension and administration of lidocaine solutions by infusion, see under Administration in Uses and Administration. For its effect on the stability of local anaesthetic solutions and the pain associated with their injection.

Stability.

Although there was no decrease in the lidocaine content of lidocaine hydrochloride and adrenaline injection during transport and storage under tropical conditions, the content of adrenaline fell to almost zero in some samples after several months; supply of the injection as a dry powder and separate solvent should be considered for the tropics. 1 The lidocaine content of buffered cardioplegic solutions has been reported 2 to decrease when stored in PVC containers at ambient temperature, but not when stored at 4°. This loss appeared to result from pH-dependent sorption of lidocaine onto the plastic and did not occur when lidocaine solutions were stored in glass bottles. 1. Abu-Reid IO, et al. Stability of drugs in the tropics: a study in Sudan. Int Pharm J 1990; 4: 6–10. 2. Lackner TE, et al. Lidocaine stability in cardioplegic solution stored in glass bottles and polyvinyl chloride bags. Am J Hosp Pharm 1983; 40: 97–101.

💊 Adverse Effects and Treatment

Effects on the CNS.

Suspected psychotic reactions have been reported in 6 patients given intravenous lidocaine for the treatment of cardiac disorders.1 In another case,2 2 patients developed signs of cerebral ataxia after topical use of lidocaine for endoscopy. When compared with other local anaesthetics, lidocaine may be associated with an increased risk of neurotoxic complications when used for spinal anaesthesia,.
1. Turner WM. Lidocaine and psychotic reactions. Ann Intern Med 1982; 97: 149–50
2. Perney P, et al. Transitory ataxia related to topically administered lidocaine. Ann Pharmacother 2004; 38: 828–30.

Effects on the skin.

Erythema and pigmentation of the upper lip in a child after local dental infiltration of lidocaine was attributed to a type of fixed drug eruption.1 Erythema may also occur after topical use of some lidocaine formulations, such as transdermal patches, while transient blanching of the skin is frequent after application of eutectic lidocaine/prilocaine mixtures to the skin.2 True hypersensitivity reactions, including dermatitis, are rare but can occur.3
1. Curley RK, et al. An unusual cutaneous reaction to lignocaine. Br Dent J 1987; 162: 113–14
2. Villada G, et al. Local blanching after epicutaneous application of EMLA cream: a double-blind randomized study among 50 healthy volunteers. Dermatologica 1990; 181: 38–40
3. Bircher AJ, et al. Delayed-type hypersensitivity to subcutaneous lidocaine with tolerance to articaine: confirmation by in vivo and in vitro tests. Contact Dermatitis 1996; 34: 387–9.

Overdosage.

The most serious effects of lidocaine intoxication are on the CNS and cardiovascular system and overdosage can result in severe hypotension, asystole, bradycardia, apnoea, seizures, coma, cardiac arrest, respiratory arrest, and death. Intoxication with lidocaine is relatively common and can occur as a result of acute overdosage after poor control of intravenous maintenance infusions or accidental injection of concentrated solutions. However, it more commonly results from inadvertent intravascular dosage during regional anaesthesia, or from too rapid injection of antiarrhythmic doses, particularly in patients with circulatory insufficiency, or when clearance is reduced due to heart failure, liver disease, old age, or through interaction with other drugs.1 Seizures have also been reported after excessive doses given subcutaneously.2 Although the bioavailability of lidocaine is low it may be sufficient to result in significant toxicity when swallowed1 and there have been reports of CNS effects, seizures, and death in children3-7 and adults8-10 after the ingestion of topical solutions and after the use of viscous preparations in the mouth. Death has also ensued after gargling with a 4% lidocaine solution.11 Lidocaine is absorbed from mucous membranes and serious toxicity has been reported after urethral12 or rectal13instillation of lidocaine preparations.
1. Denaro CP, Benowitz NL. Poisoning due to class 1B antiarrhythmic drugs: lignocaine, mexiletine and tocainide. Med Toxicol Adverse Drug Exp 1989; 4: 412–28
2. Pelter MA, et al. Seizure-like reaction associated with subcutaneous lidocaine injection. Clin Pharm 1989; 8: 767–8
3. Sakai RI, Lattin JE. Lidocaine ingestion. Am J Dis Child 1980; 134: 323
4. Rothstein P, et al. Prolonged seizures associated with the use of viscous lidocaine. J Pediatr 1982; 101: 461–3
5. Mofenson HC, et al. Lidocaine toxicity from topical mucosal application. Clin Pediatr (Phila) 1983; 22: 190–2
6. Giard MJ, et al. Seizures induced by oral viscous lidocaine. Clin Pharm 1983; 2: 110
7. Amitai Y, et al. Death following accidental lidocaine overdose in a child. N Engl J Med 1986; 314: 182–3
8. Parish RC, et al. Seizures following oral lidocaine for esophageal anesthesia. Drug Intell Clin Pharm 1985; 19: 199–201
9. Fruncillo RJ, et al. CNS toxicity after ingestion of topical lidocaine. N Engl J Med 1982; 306: 426–7
10. Geraets DR, et al. Toxicity potential of oral lidocaine in a patient receiving mexiletine. Ann Pharmacother 1992; 26: 1380–1
11. Zuberi BF, et al. Lidocaine toxicity in a student undergoing upper gastrointestinal endoscopy. Gut 2000; 46: 435
12. Dix VW, Tresidder GC. Collapse after use of lignocaine jelly for urethral anaesthesia. Lancet 1963; i: 890
13. Pottage A, Scott DB. Safety of "topical" lignocaine. Lancet 1988; i: 1003.

Pregnancy.

Serious adverse effects of epidural anaesthesia are rare but lidocaine may have transient effects on the neonatal auditory system.1
1. Bozynski MEA, et al. Effect of prenatal lignocaine on auditory brain stem evoked response. Arch Dis Child 1989; 64: 934–8.

💊 Precautions

In general lidocaine should not be given to patients with hypovolaemia, heart block or other conduction disturbances, and should be used with caution in patients with congestive heart failure, bradycardia, or respiratory depression. Lidocaine is metabolised in the liver and must be given with caution to patients with hepatic impairment. The plasma half-life of lidocaine may be prolonged in conditions that reduce hepatic blood flow such as cardiac and circulatory failure. Metabolites of lidocaine may accumulate in patients with renal impairment. The intramuscular injection of lidocaine may increase creatine phosphokinase concentrations that can interfere with the diagnosis of acute myocardial infarction.

Breast feeding.

No adverse effects have been seen in breastfed infants whose mothers were receiving lidocaine, and the American Academy of Pediatrics1 considers that it is therefore usually compatible with breast feeding.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 02/06/04)

Cerebrovascular disorders.

Lidocaine 5 mg/kg by intravenous infusion over 30 minutes was associated with a 12% reduction in cerebral blood flow in healthy subjects although this returned to normal within 60 minutes.1 Cerebral blood flow in patients with diabetes was lower than in healthy subjects, but was unaffected by lidocaine infusion, indicating reduced cerebrovascular reactivity.
1. Kastrup J, et al. Intravenous lidocaine and cerebral blood flow: impaired microvascular reactivity in diabetic patients. J Clin Pharmacol 1990; 30: 318–23.

Porphyria.

Lidocaine is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Renal impairment.

The pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide appear to be unaffected in patients with renal failure except that accumulation of the metabolite glycinexylidide may occur during infusions of 12 hours or more.1 Data to predict the amount of lidocaine and glycinexylidide removed during haemodialysis have been provided.2,3 Lidocaine does not appear to be removed during haemofiltration.4
1. Collinsworth KA, et al. Pharmacokinetics and metabolism of lidocaine in patients with renal failure. Clin Pharmacol Ther 1975; 18: 59–64
2. Gibson TP, Nelson HA. Drug kinetics and artificial kidneys. Clin Pharmacokinet 1977; 2: 403–26
3. Lee CC, Marbury TC. Drug therapy in patients undergoing haemodialysis: clinical pharmacokinetic considerations. Clin Pharmacokinet 1984; 9: 42–66
4. Saima S, et al. Negligible removal of lidocaine during arteriovenous hemofiltration. Ther Drug Monit 1990; 12: 154–6.

Smoking.

The effects of smoking on lidocaine therapy are unclear. Studies in a limited number of patients have found reduced systemic bioavailability suggestive of induction of drugmetabolising activity1 and an inconsistent effect on protein binding.2,3
1. Huet P-M, Lelorier J. Effects of smoking and chronic hepatitis B on lidocaine and indocyanine green kinetics. Clin Pharmacol Ther 1980; 28: 208–15
2. McNamara PJ, et al. Effect of smoking on binding of lidocaine to human serum proteins. J Pharm Sci 1980; 69: 749–51
3. Davis D, et al. The effects of age and smoking on the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol 1985; 19: 261–5.

💊 Interactions

For interactions associated with local anaesthetics. The clearance of lidocaine may be reduced by propranolol and cimetidine (see below). The cardiac depressant effects of lidocaine are additive with those of beta blockers and of other antiarrhythmics. Additive cardiac effects may also occur when lidocaine is given with intravenous phenytoin; however, the long-term use of phenytoin and other enzyme-inducers may increase dosage requirements of lidocaine (see Antiepileptics, below). Hypokalaemia produced by acetazolamide, loop diuretics, and thiazides antagonises the effect of lidocaine.

Antiarrhythmics.

Lidocaine toxicity, arising from the use of an oral preparation containing lidocaine, has been reported1 in a patient who was receiving mexiletine. There are individual reports of seizures or heart failure and cardiac arrest in patients who received intravenous lidocaine with ajmaline,2 amiodarone,3,4 or tocainide.5 Delirium has been reported in a patient who received lidocaine with procainamide.6
1. Geraets DR, et al. Toxicity potential of oral lidocaine in a patient receiving mexiletine. Ann Pharmacother 1992; 26: 1380–1
2. Bleifeld W. Side effects of antiarrhythmic drugs. Naunyn Schmiedebergs Arch Pharmacol 1971; 269: 282–97
3. Siegmund JB, et al. Amiodarone interaction with lidocaine. J Cardiovasc Pharmacol 1993; 21: 513–15
4. Keidar S, et al. Sinoatrial arrest due to lidocaine injection in sick sinus syndrome during amiodarone administration. Am Heart J 1982; 104: 1384–5
5. Forrence E, et al. A seizure induced by concurrent lidocaine-tocainide therapy—is it just a case of additive toxicity? Drug Intell Clin Pharm 1986; 20: 56–9
6. Ilyas M, et al. Delirium induced by a combination of anti-arrhythmic drugs. Lancet 1969; ii: 1368–9.

Antiepileptics.

Studies in healthy subjects and patients with epilepsy1,2 suggest that long-term use of drugs such as phenytoin or barbiturates may increase dosage requirements for lidocaine due to induction of drug-metabolising microsomal enzymes. Phenytoin can also increase plasma concentrations of α1-acid glycoprotein and thereby reduce the free fraction of lidocaine in plasma.3 The cardiac depressant effects of lidocaine may be dangerously enhanced by intravenous phenytoin.4
1. Heinonen J, et al. Plasma lidocaine levels in patients treated with potential inducers of microsomal enzymes. Acta Anaesthesiol Scand 1970; 14: 89–95
2. Perucca E, Richens A. Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients. Br J Clin Pharmacol 1979; 8: 21–31
3. Routledge PA, et al. Lignocaine disposition in blood in epilepsy. Br J Clin Pharmacol 1981; 12: 663–6
4. Wood RA. Sinoatrial arrest: an interaction between phenytoin and lignocaine. BMJ 1971; 1: 645.

Beta blockers.

Significant increases in plasma-lidocaine concentrations have occurred with propranolol,1-4 owing to a reduction in the clearance of lidocaine from plasma. A similar interaction has occurred with nadolol3 and metoprolol,2 although in another study5 metoprolol did not alter the pharmacokinetics of lidocaine. The hepatic metabolism of lidocaine may be reduced as a result of a fall in hepatic blood flow associated with reduced cardiac output or it may be caused by direct inhibition of hepatic microsomal enzymes.6 Significant impairment of lidocaine clearance would therefore be most likely to occur with those drugs that lack intrinsic sympathomimetic activity and have a greater effect on cardiac output or with the more lipid-soluble drugs that have greater effects on microsomal oxygenases. The reduction in clearance produced by propranolol seems to be mainly by direct inhibition of metabolism rather than by lowering of hepatic blood flow.4
1. Ochs HR, et al. Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol. N Engl J Med 1980; 303: 373–7
2. Conrad KA, et al. Lidocaine elimination: effects of metoprolol and of propranolol. Clin Pharmacol Ther 1983; 33: 133–8
3. Schneck DW, et al. Effects of nadolol and propranolol on plasma lidocaine clearance. Clin Pharmacol Ther 1984; 36: 584–7
4. Bax NDS, et al. The impairment of lignocaine clearance by propranolol—major contribution from enzyme inhibition. Br J Clin Pharmacol 1985; 19: 597–603
5. Miners JO, et al. Failure of ‘therapeutic’ doses of β-adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine. Br J Clin Pharmacol 1984; 18: 853–60
6. Tucker GT, et al. Effects of β-adrenoceptor antagonists on the pharmacokinetics of lignocaine. Br J Clin Pharmacol 1984; 17 (suppl 1): 21S–28S.

H2-antagonists.

There have been numerous studies1-4 of the interaction between cimetidine and lidocaine but differences between the studies make interpretation of the overall clinical significance of the results difficult. Cimetidine appears to reduce the hepatic metabolism of lidocaine; it may also reduce its clearance by decreasing hepatic blood flow. Significant increases in plasma-lidocaine concentrations have been reported. Changes in protein binding are not generally important but patients with myocardial infarction who have increased levels of α1-acid glycoprotein may be partially protected from increases in concentrations of free lidocaine.5 Since it is not possible to identify those patients at risk all patients receiving both drugs should be closely monitored for signs of toxicity. The use of other H2-antagonists may be preferable. In studies in healthy subjects ranitidine either had no effect on lidocaine kinetics6 or produced changes consistent with small reductions in hepatic blood flow.7
1. Feely J, et al. Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med 1982; 96: 592–4
2. Knapp AB, et al. The cimetidine-lidocaine interaction. Ann Intern Med 1983; 98: 174–7
3. Patterson JH, et al. Influence of a continuous cimetidine infusion on lidocaine plasma concentrations in patients. J Clin Pharmacol 1985; 25: 607–9
4. Bauer LA, et al. Cimetidine-induced decrease in lidocaine metabolism. Am Heart J 1984; 108: 413–15
5. Berk SI, et al. The effect of oral cimetidine on total and unbound serum lidocaine concentrations in patients with suspected myocardial infarction. Int J Cardiol 1987; 14: 91–4
6. Feely J, Guy E. Lack of effect of ranitidine on the disposition of lignocaine. Br J Clin Pharmacol 1983; 15: 378–9
7. Robson RA, et al. The effect of ranitidine on the disposition of lignocaine. Br J Clin Pharmacol 1985; 20: 170–3.

Local anaesthetics.

Although a number of drugs were shown to reduce the amount of lidocaine bound to α1-acid glycoprotein only the displacement produced by bupivacaine was considered to be of possible clinical significance.1 There is concern about the use of lidocaine to treat cocaineinduced arrhythmias as lidocaine may enhance toxicity.2
1. Goolkasian DL, et al. Displacement of lidocaine from serum α acid glycoprotein binding sites by basic drugs. Eur J Clin Pharmacol 1983; 25: 413–17
2. Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995; 333: 1267–72.

Neuromuscular blockers.

The possible interaction between neuromuscular blockers and antiarrhythmics including lidocaine is discussed under Atracurium.

Oral contraceptives.

For mention of the effect of oral contraceptives on the protein binding of lidocaine, see under Protein Binding in Pharmacokinetics, below.

💊 Pharmacokinetics

Lidocaine is readily absorbed from the gastrointestinal tract, from mucous membranes, and through damaged skin. Absorption through intact skin is poor. It is rapidly absorbed from injection sites including muscle. After an intravenous dose lidocaine is rapidly and widely distributed into highly perfused tissues followed by redistribution into skeletal muscle and adipose tissue. Lidocaine is bound to plasma proteins, including
Published November 16, 2018.