Acute Porphyria Drugs

Acute Porphyria Drug Database

C01BB01 - Lidocaine
Propably not porphyrinogenic
PNP
Rationale
Lidocaine should be used with some caution in repeated high dosing because of lacking pharmacokinetic information during long term treatment. When used as a continuous infusion, it may be beneficial to administer lidocaine in a glucose solution, if appropriate, because of the anti-porphyrinogenic effect of glucose. Lidocaine is metabolized by CYP1A2, with only a minor contribution from CYP 3A4. Lidocaine is not listed as an inducer or as a mechanism-based inhibitor of Cyp enzymes, nor is there any evidence of lidocaine capacity for Cyp-inhibition in clinical use. Lidocaine is reported as used uneventfully by 68 patients, and thus strong clinical evidence points to lidocaine as probably not porphyrinogenic. There are two reports of possible activation of the disorder following the use of lidocaine, but the reports are poorly documented and are therefore not taken into account in the judgement of the porphyrinogenicity of lidocaine.
Chemical description
Lidocaine hydrochloride is an amide derivative of diethyl amino acetic acid. Lidocaine has a lipophilic aromatic ring attached to a hydrophilic amino group by an amide linkage.
Therapeutic characteristics
Lidocaine is an antiarrytmic used in the prevention and therapy after ventricular tachyarrhythmia of different origins. It is administered as an IV bolus injection followed by infusions. Adverse effects are usually of short duration, and are dose related. Adverse reactions of lidocaine that can be confused with an acute porphyric attack are nausea, vomiting, confusion, paresthesia, tremors, seizures, numbness and respiratory depression.
Hepatic exposure
Therapeutic plasma concentration is 5 - 20 uM. The elimination half-life of lidocaine is 1 to 2 hours but may be prolonged if infusions are given for longer than 24 hours or if hepatic blood flow is reduced.
Metabolism and pharmakokinetics
The primary metabolic pathway of lidocaine is CYP1A2 and, to a minor extent, CYP3A4 mediated N-deethylation to the active monoethylglycinexylidide (MEGX). MEGX is further de-ethylated to 2,6-xylidine and glycinexylidide. 2,6-xylidine is hydrolysed by CYP 2A6 to 4-hydroxy-xylidine, which is the major metabolite found in urine. In vitro studies suggest that CYP 3A4 may be an important contributor to the N-deethylation of lidocaine in high concentrations (above therapeutic concentrations) (Wang 2000). Found to be a week inhibitor of CYP 1A2 (Kobayashi 1998), and suggested as a competitive inhibitor of CYP1A2 by Wei (1999). In another study lidocaine was found to competitively inhibit N-monodesethylation of amioderone (with Ki = 120 µM) (Kobayashi 1998). Rendic (2002) reports that lidocaine is a substrate and an inhibitor of CYP1A2, a substrate for CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP3A4 and an inhibitor and a substrate of CYP2D6. There is no evidence of lidocaine capacity for Cyp-inhibition in clinical use. Some studies have shown an accumulation of lidocaine or/and MEGX in continued administration of lidocaine (Miyabe 1999, Thomson 1987, Bauer 1982, Ngo 1997). One study report signs of CYP 3A4 TDI in rodent microsome experiments (Bensoussan 1994), but this has not been confirmed in human studies.
Preclinical data
Lidocaine was found to increase the activity of delta-aminolaevulinic acid synthase in a rat liver model (Parikh, R.K. & Moore, M.R., 1978). Lidocaine was found to induce delta-aminolaevulinic acid synthase and to cause accumulation of porphyrins and cytochrom P450 in chick embryo livers in ovo (de Verneuil, H., Deybach, J.C. et al, 1982).
Personal communication
Thunell, S., study to be published: Uneventfully used (mainly in dental procedures) by 45 patients. After the completion of the study, one instance of possible activation of the disorder following the use of lidocaine for dental surgery in a middle-aged male carrier of AIP was reported (other precipitating factors can not be excluded).
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria. One report of an attack of acute porphyria following the use of lidocaine (N02BB02) in a male with active AIP, but the attack is poorly documented. Uneventful use is also reported after use of lidocaine under other ATC codes; N02BB01 used in 9 patients, N02BB52 used in 9 patients, D04AB01 used in 3 patients and R02AD02 used in 1 patient.

References

  1. Scientific articles
  2. de Verneuil,H., Deybach,J.C. et al. Study of anaesthetic agents for their ability to elicit porphyrin biosynthesis in chick embryo liver. Biochem Pharmacol 1982; 32: 1011-18. #1192
  3. Miyabe M, Kakiuchi Y, et al, The plasma concentration of lidocaines principal metabolite increases during continuous epidural anesthesia in infants and children. Anesth Analg. 1998 Nov;87(5):1056-7. #1195
  4. Ngo LY, Tam YK, et al Effects of intravenous infusion of lidocaine on its pharmacokinetics in conscious instrumented dogs. J Pharm Sci. 1997 Aug;86(8):944-52. #1196
  5. Parikh, RK, Moore, MR. Effect of certain anaesthetic agents on the activity of rat hepatic delta-aminolaevulinate synthase. Br J Anaesth 1978; 50:1099-1103. PMID 718778. #4376
  6. Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. #1025
  7. Thunell, S. Evidence-based porphyrogenicity assessment of seven local anasthetics (2011, to be published). #1202
  8. Bargetzi MJ, Aoyama T et al. Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. Clin Pharmacol Ther 1989; 46(5):521-7. PMID 2582709. #1190
  9. Bensoussan M, delaforge M,et al. Particular ability of cytochromes P450 3A to form inhibitory P450-iron-metabolite complexes upon metabolic oxidation of aminodrugs. Biochem Pharmacol 1995; 49(5):591-502. PMID 7887973. #4374
  10. Kobayashi K, Nakajima M, et al. Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2. Br J Clin Pharmacol. 1998 Apr;45(4):361-8. PMID 9578183. #4375
  11. Orlando R, Piccoli P et al. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function.Clin Pharmacol Ther 2004;75(1):80-8. #1197
  12. Thomson AH, Kelman AW, et al. Changes in lignocaine disposition during long-term infusion in patients with acute ventricular arrhythmias. Ther Drug Monit. 1987 Sep;9(3):283-91. PMID 3672571. #4377
  13. Wang B, Zhou SF. Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. PMID 19754423. #1203
  14. Wang JS, Backman JT, et al. Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab Dispos. 2000 Aug;28(8):959-65. PMID 10901707. #4378
  15. Wei X, Dai R, et al. Inhibition of human liver cytochrome P450 1A2 by the class IB antiarrhythmics mexiletine, lidocaine, and tocainide. J Pharmacol Exsperim Ther 1999 May;289(2):853-8 #1205
  16. Drug reference publications
  17. McEvoy GK, editor. Lidocaine Hydrochloride (antiarrhythmic) The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (September 2011). #1194
  18. Sweetman SC, editor. Martindale: The complete drug reference. Lidocaine Hydrochloride. Pharmaceutical Press 2009. #1199
  19. Summary of Product Characteristics
  20. Swedish medicines agency. Summary of Product Characteristics (SPC) Xylocard. #1200
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