Acute Porphyria Drugs

Acute Porphyria Drug Database

N01BB51 - Bupivacaine, Combinations
Propably not porphyrinogenic
PNP
Rationale
Limitations: This safety classification applies only to preparations containing a combination of the two drugs bupipivacaine and adrenaline (epinephrine). The same ATC-code (N01BB51) can in some countries be used for different combinations of bupivacaine and other drugs which in theory may be porphyrinogenic. Please refer to the classification and monograph of each individual substance. If the combination contains a substance which is not classified (NC) or has been classified as porphyrinogenic (PSP, PRP or P), the safety classification of such a combination as PNP is no longer valid. Bupivacaine: Used uneventfully in more than 53 patients with latent or active acute porphyria. By clinical criteria the local anaesthetic bupivacaine is not porphyrinogenic. One report of increased porphyrinogenic activity following an operation where bupivacaine was used in epidural anaesthesia, but causality was not established. Bupivacaine is classified NP. Adrenalin (epinephrine): Endogenous catecholamine. Metabolism is not CYP-dependent. No data pointing to CYP-interaction. Epinephrine is classified NP.
Chemical description
Bupivacaine hydrochloride is a local anaesthetic of the amide type. Bupivacaine occurs as a 50:50 racemic mixture of the R- and S-enantiomers. Epinephrine is a catecholamine added for longer duration of local anaesthesia.
Therapeutic characteristics
Local anaesthetic. Administration together with adrenalin (not porphyrinogenic) gives a slower release of the local anaesthetic, probably resulting in lower hepatic exposure / time unit and higher tolerance. There are conflicting references regarding bupivacaine but clinical experience points to of relative non- porphyrinogenicity. Recommended for first hand use.
Metabolism and pharmakokinetics
Bupivacaine is principally metabolized to pipecolylxylidine (PPX) by N-dealkylation, probably in the liver. Bupivacaine is excreted in urine as small amounts of PPX, unchanged drug (5%), and other metabolites is yet unidentified. Rendic (2002) reports that bupivacaine is a substrate of CYP3A4 (major reaction), CYP1A2, CYP2C19 and 2D6 (minor reaction). Adrenalin (epinephrine) is an endogenous compound. It is very rapidly inactivated by processes which include uptake into adrenergic neurones, diffusion, and enzymatic degradation in the liver and body tissues. Metabolism involves monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
Personal communication
Thunell, S., study to be published: 48 patients exposed to bupivacaine without porphyric adverse reaction reported. Peters: According to our experience not porphyrinogenic.
Published experience
Used uneventfully in AIP woman during delivery (Aggarwal, N., Bagga, R. et al, 2002). Used uneventfully for epidural anaesthesia during delivery by woman with latent VP (Consolo, D., Ouardirhi, Y. et al, 2005). Used uneventfully twice over two years in the same patient (one epidural and one spinal injection), an AIP woman (McNeill, M.J. & Bennet, A., 1990). Used uneventfully in epidural anaesthesia to relieve postoperative pain in AIP patient presenting with elevated PBG (Messmer, M., Gerheuser, F. et al, 2004). Used uneventfully as epidural, during surgery and post operativly in VP woman (Minoda,Y., Yoshimine, K. et al, 1997). Used uneventfully as spinal epidural in AIP woman (Sahu, M.T., Rajaram, S. et al, 2006). Used uneventfully as epidural, during surgery and post operativly, in HCP man (Yamamori, Y., Sumi, M. et al, 1996). Used uneventfully as spinal anesthesia in VP man (Bohrer, H. & Schmidt, H., 1992). Listed as safe in review by James and Hift (James, M.F. & Hift, R.J., 2000). One report of increased porphyrinogenic activity following an operation where bupivacaine was used in epidural anaesthesia, but causality was not established (Ii, C., Tanaka, N. et al, 1993).
IPNet drug reports
Bupivacaine (N01BB01): Uneventful use reported in 5 patients with acute porphyria.

References

  1. Scientific articles
  2. Aggarwal, N., Bagga, R. et al. Pregnancy with acute intermittent porphyria: A case report and review of literature. J Obstet Gynaecol Res 2002; 28(3): 160-2. #2485
  3. Bohrer, H., Schmidt, H. Regional Anesthesia as Anesthetic Technique of Choice in Acute Hepatic Porphyria. J Clin Anesth 1992; 4: 259. PMID 1610588. #4643
  4. Consolo, D.,Ouardirhi, Y. et al.[Obstetrical anaesthesia and porphyrias].Annales Françaises d’Anesthésie et de Réanimation 2005;24: 428-431. #2487
  5. 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
  6. Ii, C., Tanaka, N. et al. [Anesthetic management of a patient with acute intermittent porphyria]. Masui 1993; 42: 1849-52. #2488
  7. James,M.F., Hift,R.J. Porphyrias.Br J Anaesth 2000; 85, 143-53. PMID 10928003. #4644
  8. McNeill, MJ, Bennet, A. Use of regional anaesthesia in a patient with acute porphyria. Br J Anaesth 1990;64: 371-3. #2491
  9. Messmer, M., Gerheuser, F. et al.[Desflurane in acute intermittent porphyria.] Anaesthesist 2004; 53:244-8. DOI 10.1007/s00101-003-0615-7 #2492
  10. Minoda, Y., Yoshimine, K. et al. Anesthetic management of a patient with variegate porphyria. Anesth 1997;11:307-8. #2493
  11. 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
  12. Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. #1025
  13. Thunell, S. Evidence-based porphyrogenicity assessment of seven local anasthetics (2009, to be published). #2497
  14. Yamamori,Y., Sumi, M. et al. Safety of isoflurane and epidural anesthesia in a patient with hereditary coproporphyria. J Anesth 1996;10:80-2. #2496
  15. Drug reference publications
  16. McEvoy GK, editor. Bupivacaine Hydrochloride. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (January 2009). #2490
  17. Sweetman SC, editor. Martindale: The complete drug reference. Adrenaline. Pharmaceutical Press 2009. #1017
  18. Sweetman SC, editor. Martindale: The complete drug reference. Bupivacaine Hydrochloride. Pharmaceutical Press 2009. #2495
  19. Summary of Product Characteristics
  20. Norwegian medicines agency. Summary of Product Characteristics (SPC). Marcain-adrenalin. #2494
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