Antidotes and Alcohols: Has Fomepizole Made Ethanol an Obsolete Therapy?

Jeffrey Brent
Toxicology Associates
University of Colorado Health Sciences Center
Denver, CO

January 1998; 1(1): 2


There is presently an intense debate being carried on via ACMTNet regarding the subject of this editorial. I will attempt to summarize the issues germane to this evolving dialogue. In November of 1997, the Federal Food and Drug Administration (FDA) gave approval for the use of 4-methylpyrazole as an antidote for ethylene glycol (EG) poisoning. Now that this substance has the status of a pharmaceutical, it is appropriate to use it's generic name, fomepizole. The approval of fomepizole has stimulated a lively discussion of the comparative benefits of this agent with our only prior alternative, ethanol. I will attempt to review the pros and cons for both of these agents in the treatment of EG and methanol poisoning.

It has been known for nearly thirty years that both pyrazole and its 4-methyl derivative inhibited alcohol dehydrogenase (ADH) in both animals and humans. (1-3) However, fomepizole appeared to be the more promising agent because it lacked the hepatotoxicity of pyrazole (4-8) and was a more potent inhibitor of ADH. (1,9)

Twenty five years ago, it was shown that administration of fomepizole to man inhibits ethanol metabolism without significant adverse effects.(7) Fomepizole's potential as an antidote for toxic alcohol poisoning became quickly apparent, and in 1974 Mundy et al demonstrated that 4MP could protect against EG poisoning in animals. (10) Clay and Murphy subsequently showed that fomepizole can prevent metabolic acidosis and glycolate formation in EG poisoned dogs and monkeys. If fomepizole was given after the EG, once a metabolic acidosis was established, then treatment with this agent caused a resolution of the metabolic acidosis and a fall in glycolate levels. (11) Glycolic acid is the major circulating metabolite of ethylene glycol, and is responsible for the metabolic acidosis. (11,13) The antidotal effect of fomepizole in animal models of EG poisoning has been repeatedly demonstrated. (10, 11, 14-16)

Simultaneous with the development of fomepizole as an antidote in animal models of EG poisoning was the development of its use in methanol toxicity. In 1975, McMartin et al showed that the metabolic acidosis induced by methanol was due to format accumulation, a process which was prevented by the administration of fomepizole. Furthermore, methanol-induced metabolic acidosis tended to reverse after fomepizole administration. (17)

Simultaneously, Pietruszko (18) demonstrated in vitro that fomepizole inhibits methanol metabolism by human liver ADH with a micromolar Ki indicating that fomepizole is a potent inhibitor of methanol metabolism.

The first clinical use of fomepizole was in 1981 when Lindros et al used this agent to inhibit ethanol metabolism in the treatment of a disulfiram reaction. (19) Subsequently, volunteer studies showed that fomepizole was safe when administered to humans.(20-22) Thus the stage was set for clinical trials with this agent as a potential antidote.

Between 1986 and 1996, there were 5 case reports describing 9 cases of EG poisoning treated with fomepizole. (23-27) A tantalizing aspect of these reports is that three of the nine patients developed renal injury. All three of these patients had abnormal serum creatinines at the time fomepizole therapy was started. The remaining six patients had normal serum creatinines at the time of initiation of therapy. None of these six developed renal injury. This observation suggested that fomepizole may be nephroprotective in EG poisoning. In 1995, the Methylpyrazole for Toxic Alcohols (META) study group was constituted. The investigators making up the META Study Group are given in Table 1. Since November 1995, a total of 30 patients with EG or methanol poisoning have been enrolled in the META Study. This was a highly protocol driven study in which patients meeting precise inclusion criteria were enrolled using a specific dosing and dialysis protocol, schedule for obtaining samples for serum and urinary metabolites of EG and methanol, and samples for fomepizole pharmacokinetics.

Table 1: META Study Group
 Cynthia Aaron  Daniel Douglas  Ken Kulig
 Jawaid Achtar   Marsha Ford  Charles McKay
 Randall Berlin  Candace Graudins  Ken McMartin
 Gregory Bogdan  Christine Hantsch  Scott Phillips
 Jeffrey Brent  Selia Hartigan  Donna Seger
 Keith K. Burkhart  Keenan Heard  Christian Tomaszewski
 Michael Burns  Judd Hollander  Kevin Wallace
 Steven Curry  William Kerns  Paul Wax
 Richard Dart  Mark Kirk  Suzanne White
 Ward Donovan  Lada Kokan

In the summer of 1997, Orphan Medical, Inc. submitted a new drug application for fomepizole to the Food and Drug Administration. This application's clinical component consisted primarily of the data from the META study, supplemented by a compilation of cases treated by Dr. Frederick Baud in Paris. In December, approval was granted.

Ethanol has been used as an antidote for EG and methanol poisoning since 1946. (28) Thus we have a long history of experience with this agent. Those of us who have used it frequently have developed a facility with this tricky antidote. Ethanol's major advantages are that it is inexpensive and, in the absence of a pharmaceutically prepared preparation,can even be administered orally in selected patients. The latter can be done with commercial alcoholic beverages. A comparison of the advantages and disadvantages of ethanol as an antidote is given in Table 2.

 

Table 2: Ethanol Treatment of Ethylene Glycol or Methanol Poisoning -
Pros and Cons

 PRO

  1. Inexpensive
  2. Long history of use
  3. Available in many forms, including oral spirits

CON

  1. Non-FDA approved
  2. Parenteral forms often not available
  3. Requires frequent checks of levels
  4. Unpredictable kinetics
  5. Requires infusion pump
  6. Oral treatment unreliable
  7. Causes intoxication
  8. Causes depressed mental status
  9. Often unpleasant for patient
  10. Requires an intensive care unit.
  11. Degree to which it inhibits metabolism has not been
    well studied
  12. May cause hepatotoxicity
  13. Errors in its use common
  14. General reluctance to use presumptively in metabolic
    acidosis of unknown etiology
  15. May cause hypoglycemia

Ethanol is not approved as an antidote for EG or methanol poisoning. Although commercial 10% ethanol solutions are manufactured, they are frequently not available. Thus hospitals must often resort to a 5% solution, or to compounding from absolute ethanol. Using the more dilute solution requires large volumes to be administered, which is potentially a serious problem for both pediatric patients and those with cardiac or renal insufficiency. Compounding an ethanol solution de novo can cause delays in treatment. As all of us who have experience with this antidote know, ethanol is difficult to use. Most of the information regarding the difficulty of the use of ethanol derives from case reports, other kinds of anecdotes, and personal experience. Although there is an accumulated tribal wisdom of clinical toxicologists that ethanol is difficult to use, this has never been systemically demonstrated.

In order to use ethanol effectively, one has to be cognizant of its unpredictable kinetics, and therefore frequent levels must be obtained. I personally obtain these levels every one to two hours unless I am sure that these have been stable for a long period of time. The latter, however, is an unusual circumstance. Because any unplanned alterations in the infusion rate can have major consequences by virtue of either causing ethanol levels to become subtherapeutic or causing them to rise to unwanted high concentrations, it is necessary to closely watch the infusion and have it administered through an infusion pump. Patients who are maintained on an ethanol infusion may develop alterations in mental status, initially being intoxicated, subsequent to which their mental status may deteriorate, thus increasing the risk of aspiration. Patients treated with ethanol must be in an intensive care unit and may require intubation. Although we know that ethanol has the ability to competitively inhibit the metabolism of EG and methanol, the degree to which it inhibits the formation of metabolites in poisoned patients has not been well studied. The therapeutic efficacy of ethanol remains unvalidated. Patients who are treated with ethanol are at risk for developing hypo-glycemia, a problem which is particularly prevalent in both pediatric and malnourished populations. Because ethanol treatment may last for several days, patients need to be monitored for the development of elevated liver enzymes. Given the challenges associated with the therapeutic use of ethanol, there are legitimate questions regarding its reliability in the hands of those less experienced in it's use than amedical toxicologist.

In the META trial, patients were allowed to be entered into the trial if they were transferred from another hospital after being loaded with ethanol. It was our experience that most of these patients were inappropriately treated with ethanol, resulting in subtherapeutic levels. The majority of patients diagnosed with EG or methanol poisoning have metabolic acidosis as their initial presentation. Frequently there is a time delay between the time that these diagnoses are considered and the time that they are verified by a serum level. In the interim, presumptive therapeutic maneuvers could be taken. However, because of the problems related to the use of ethanol, patients are frequently not treated in a presumptive manner. Therapy may thus be delayed until as a definitive diagnosis is made. Because of the difficulties in obtaining EG and methanol levels, this delay can be substantial. Lastly, although one can use oral loading of ethanol emergently, this route of administration is associated with unpredictable concentrations initially, and even greater difficulty in maintaining target levels.

Fomepizole is an alternative to ethanol therapy without the disadvantages of the latter. Although approved for the treatment of EG poisoning, like ethanol it is not FDA approved for the treatment of methanol intoxication. It is anticipated that an application for this indication will be filed shortly, largely based on the methanol arm of the META trial. The cost of fomepizole makes it considerably more expensive to purchase than ethanol. As reviewed above, there is a long history of clinical experience with ethanol that we do not yet have with fomepizole, although the latter has been more systematically studied in intoxicated patients. A comparison of the pros and cons associated with fomepizole therapy is given in Table 3.

Table 3: Fomepizole Treatment of Ethylene Glycol or Methanol Poisoning - Pros and Cons

 PRO

  1. FDA approved for ethylene glycol poisoning
  2. Reliable pharmacokinetics
  3. No need to check levels
  4. No need to use infusion pump
  5. Dosing regimen standardized and validated
  6. Documented inhibition of toxic metabolite production in patients
  7. Documented nephroprotection in ethylene glycol poisoned patients
  8. Documented visual protection in methanol treated patients
  9. No effect on mental status
  10. Do not need intensive care unit treatment in uncomplicated patients
  11. Does not cause hypoglycemia
  12. Few adverse effects
  13. Better studied in poisoned patients than ethanol

 CON

  1. Not FDA approved for methanol poisoning
  2. Expensive
  3. Less clinical experience than with ethanol

Fomepizole is presently the only FDA approved antidote for the treatment of EG poisoning. Unlike ethanol, fomepizole has been demonstrated to have very reliable pharmacokinetics. (22, 29) Patients treated with the dosing regimen that was used in the META study were shown to reliably have plasma fomepizole levels above the presumed 10 micromolar target. This concentration was chosen based on animal studies.(17, 30) Most patients had plasma levels considerably above that target. However, there was some variation in the levels attained, perhaps indicating a metabolic polymorphism, which caused some patients to have levels relatively close to the 10 micromolar target. Lower doses are therefore not recommended. Because of the reliable attainment of therapeutic plasma levels in the META trial, it is unnecessary to measure fomepizole levels during therapy, or adjust the dosage in ways other than the standard dosing protocol. The therapeutic efficacy of the dosing protocol has been validated by both the nephroprotective effect and the inhibition of metabolite formation. Because the drug is administered by an intermittent bolus regimen, there is no need to use an infusion pump and the difficulties in attaining a therapeutic levels seen with ethanol should not occur, even in inexperienced hands.

Unlike ethanol, the inhibition of the formation of metabolites of ethylene glycol or methanol in poisoned patients treated with fomepizole has been demonstrated. (31, 32) Similarly, there are no adverse effects on the mental status of patients treated with fomepizole. Thus, patients treated with this fomepizole may be placed in non intensive care settings unless other aspects of their poisonings require a higher level of treatment.

Hypoglycemia is not seen with fomepizole therapy and adverse effects of any kind appear to be both rare and minor. In patients who have EG poisoning, treatment with fomepizole has been shown to inhibit metabolite formation and protect against renal injury. (31) In patients with methanol poisoning, treatment with fomepizole has been shown to inhibit formic acid production and protect against visual injury.(32, 33) Similar validation with ethanol does not exist. As described above, many patients with methanol or EG poisoning present with metabolic acidosis. Because of the benign nature of treatment with fomepizole, there should be little concern about potential adverse effects
associated with its early use in patients whose metabolic acidosis is still under investigation. Because of the lack of requirement for frequent checking of ethanol levels, probable decreased morbidity, and the possibility of treatment outside of intensive care unit settings, it is likely that some of the additional cost associated with the use of fomepizole will be offset. It is even conceivable that patients with low levels of EG or methanol poisoning, for example levels in the 20-30mg/dL range, in the absence of metabolic acidosis, could be treated as outpatients.

Dr. Brent has received research support from Orphan Medical, Inc. for the META study.

References

1. Theorell H, Yonetani T. On the effects of some heterocyclic compounds on the enzymatic activity of liver alcohol dehydrogenase. Acta Chem Scand 1969; 23: 255-260.

2. Li T-K, Theorell H. Human lever alcohol ehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand 1969; 23: 892-902.

3. Goldberg L, Rydberg U. Inhibition of ethanol Metabolism in vivo by administration of pyrazole. Biochem Pharmacol 1969; 18: 1749-62.

4. Wilson WL, Bottiglieri NG. Phase I studies with pyrazole. Cancer Chemother Rep 1962; 21: 137-141.

5. Lelbach WK. Liver cell necrosis in rats after prolonged ethanol ingestion under the influence of an alcohol dehydrogenase inhibitor. Experientia 1969; 25: 816-818.

6. Lieber CS, Rubin E, De Carli LM et al. Effects of pyrazole on hepatic function and structure. Lab Invest 1970; 22: 615-621.

7. Blomstrand R, Theorell H. Inhibitory effect on ethanol oxidation in man after administration of 4-Methylpyrazole. Life Sci 1970; 631-640.

8. Magnusson G, Nyberg JA, Bodin NO et al. Toxicity of pyrazole and 4-Methylpyrazole in mice and rats. Experientia 1972; 28: 1198-1200.

9. Makar AB, Tephly TR. Inhibition of monkey liver alcohol dehydrogenase by 4-Methylpyrazole. Biochem Med 1975; 13: 334-342.

10. Mundy RL, Hall LM, Teague RS. Pyrazole as an antidote for ethylene glycol poisoning. Toxicol Appl Pharmacol 1974; 28: 320-322.

11. Clay KL, Murphy RC. On the metabolic acidosis of ethylene glycol intoxication. Toxicol Appl Pharmacol 1977; 39: 39-49.

12. Jacobsen D, Ovrebo S, Ostborg J et al. Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Acta Med Scand 1984; 216: 409-416.

13. Hewlett TP, McMartin KE, Lauro AJ et al. Ethylene glycol poisoning. The value of glycolic acid determinations for diagnosis and treatment. J Toxicol Clin Toxicol 1986; 24: 389-402.

14. Van Stee EW, Harris AM, Horton ML et al. The treatment of ethylene glycol toxicosis with pyrazole. J Pharmacol Exp Ther 1975; 192: 251-259.

15. Chou JY, Richardson KE. The effect of pyrazole on ethylene glycol toxicity and metabolism in the rat. Toxicol Appl Pharmacol 1978; 43: 33-44.

16. Grauer GF, Thrall MAH, Henre BA et al. Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog. Toxicol Lett 1987; 35: 307-314.

17. McMartin KE, Makar AB, Martin-Amat G. Methanol poisoning. I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole. Biochem Med 1975; 13: 319-333.

18. Pietruszko R. Human liver alcohol dehydrogenase: inhibition of methanol activity by pyrazole, 4-methylpyrazole, 4-hydroxymethylpyrazole and 4-carboxypyrazole. Biochem Pharmacol 1975; 24: 1603-1607.

19. Lindros KO, Stowell A, Pikkarainen P et al. The disulfiram (antabuse)-alcohol reaction in male alcoholics: its efficient management by 4-methylpyrazole. Alcoholism: Clin Exper Res 1981; 5: 528-530.

20. McMartin KE, Jacobsen D, Sebastian S et al. Safety and metabolism of 4-methylpyrazole in human subjects. Vet Hum Toxicol 1987; 29: 471.

21. Jacobsen D, Sebastian CS, Barron SK et al. Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med 1990; 8: 455-461.

22. Jacobsen D, Barron SK, Sebastian CS et al. Non linear-kinetics of 4-MP in healthy human subjects. Eur J Clin Pharmacol 1989; 37: 599-604.

23. Baud FJ, Bismuth C, Garnier R et al. 4-methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. Clin Tox 1986-87; 24: 463-483.

24. Baud FJ, Galliot M, Astier A et al. Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. New England J Med 1988; 319: 97-100.

25. Harry P, Turcant A, Bouachour G et al. Efficacy of 4-methylpyrazole in ethylene glycol poisoning: clinical and toxicokinetic aspects. Human Experiment Tox 1994; 13: 61-64.

26. Faessel H, Houze P, Baud FJ et al. 4-methylpyrazole monitoring during haemodialysis of ethylene glycol intoxicated patients. J Clin Pharmacol 1995; 49: 211-213.

27. Jobard E, Harry P, Turcant A et al. 4-methylpyrazole and hemodialysis in ethylene glycol poisoning. Clin Tox 1996; 34: 373-377.

28. Roe O. Methanol poisoning: its clinical course, pathogenesis and treatment. Acta Med Scand 1946; 126: 1-253.

29. McMartin KE, Burns MJ, Brent J. Kinetics of fomepizole (4-methylpyrazole) in poisoned patients. Presented at the European Association of Poisons Centres and Clinical Toxicologists Annual Meeting, Oslo, Norway 1997.

30. McMartin KE, Hedstrom KG, Tolf BR et al. Studies on the metabolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model. Arch Biochem Biophys 1980; 199: 606-614.

31. Brent J, et al. 4-methylpyrazole (fomepizole) therapy of ethylene glycol poisoning: preliminary results of the meta trial. J Toxicol Clin Toxicol 1997; 35: 507.

32. Brent J, et al. 4-methylpyrazole (fomepizole) therapy of methanol poisoning: preliminary results of the meta trial. J Toxicol Clin Toxicol 1997; 35: 507.

33. Burns M et al. Treatment of methanol poisoning with intravenous 4-methylpyrozole. Ann Em Med 1997; 30: 829-832.



January 1998; 1(1): 2

This article is located at http://www.ijmt.net/ijmt/1_1/1_1_2.html

Quick Survey
Please rate this article:
1 2 3 4 5
(5 is best)
Comments?



IJMT Home | Current Issue | Past Issues | Search | Technical Support | Send Comments to ACMTNet

Copyright 1999-2003, American College of Medical Toxicology.