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Ethacrynic Acid and the Sulfa-Sensitive Patient

Ethacrynic Acid and the Sulfa-Sensitive Patient Loop diuretics are a mainstay of therapy for many patients with various disorders associated with fluid overload.1 These agents are inexpensive, effective, and well tolerated in the vast majority of patients. The 4 loop diuretics currently on the US market are furosemide, bumetanide, torsemide, and ethacrynic acid.2 Though few comparative studies have been performed, US physicians use the first 3 drugs almost exclusively, reserving ethacrynic acid (due to its ototoxic potential) for patients who have had serious hypersensitivity reactions to "sulfas" or the other loop diuretics.1,3,4 Ethacrynic acid is the only loop diuretic on the US market that does not contain a sulfonamide substituent. Unfortunately, the sole US producer of ethacrynic acid (Edecrin; Merck & Co, West Point, Pa) is currently unable to provide this drug; in fact, it has stopped production of the oral form indefinitely.5 This can present a dilemma to the clinician who has a patient requiring a loop diuretic who has a history of a serious reaction to a sulfonamide or loop diuretic. We present a case report of such a patient who was successfully treated with a graded-dose challenge to torsemide. Report of a Case A 71-year-old man with a history of coronary artery disease, type 2 diabetes, chronic renal insufficiency, atrial fibrillation, osteoporosis, obesity, obstructive sleep apnea, and congestive heart failure presented with continued symptoms of pedal edema, shortness of breath, and dyspnea on exertion despite a long history of ethacrynic acid use. The patient also had an extensive history of multiple drug reactions including a confirmed reaction of Stevens-Johnson syndrome to trimethoprim-sulfamethoxazole several years previously. He developed a rash on separate occasions when given furosemide and glyburide (both sulfonamide-containing drugs), as well as aminophylline and griseofulvin. Angiotensin-converting enzyme inhibitor use resulted in worsening renal function. The dose of ethacrynic acid prescribed was increased and the patient was sent home. Unfortunately, the pharmacy the patient used was out of ethacrynic acid and staff pharmacists discovered that a national backorder of the medication had occurred. Upon further investigation, it was determined that this drug shortage was likely to continue for the foreseeable future. With the patient's renal insufficiency (baseline serum creatinine level of approximately2.5 mg/dL [221 µmol/L]) it was believed that thiazide diuretics might be both ineffective and/or dangerous given the patient's history of reactions to sulfonamide-containing drugs. The patient's heart failure symptoms continued to worsen without any diuretic, and he returned to the clinic. Upon explaining the risks to the patient, it was believed that a graded-dose challenge of torsemide was warranted. The patient started taking 2.5 mg/d orally for 1 week, with strict instructions to call if any signs of rash, blisters, or other adverse events developed. This dose was increased slowly over the next 6 weeks to 10 mg/d orally, which he tolerated without incident. He was contacted by telephone frequently during the first 2 weeks of his graded-dose challenge to inquire about any adverse effects, which he denied. His daily diuresis improved, as did his shortness of breath and pedal edema. He was still not diuresing as much by his account as he was while taking ethacrynic acid. Thus, his dose was increased over the next month to 40 mg/d, which achieved the desired diuresis. He has not experienced rash, blisters, or any other adverse events due to torsemide treatment. His congestive heart failure symptoms have improved dramatically as well. Comment Fortunately, patients with documented, serious medication allergies are relatively rare. However, the incidence of cutaneous eruptions with sulfonamide antimicrobials may be higher than many other drugs.6 In a patient like the one described here, proper selection of medications can be challenging to the prescriber, especially when certain drugs are unavailable. We believed that we had little choice but to recommend a graded-dose challenge in an attempt to find a diuretic the patient would tolerate and find clinically effective. We chose torsemide because, even though it contains a sulfonamide molecule, its chemical structure is different from furosemide and bumetanide (Figure 1).7,8 Some evidence exists that an aromatic amine group at the N4 position of the sulfonamide molecule is critical to the development of hypersensitivity syndrome reactions and severe skin reactions such as Stevens-Johnson syndrome.9 In susceptible patients, a metabolite of this group cannot be detoxified, leading to an immunological and cytotoxic cascade, which results in these serious reactions.10 Nonaromatic amine sulfonamides, including torsemide, and all other loop diuretics, do not contain this N4 amine moiety. Thus, they would not be expected to cross-react with sulfonamide antimicrobials to cause Stevens-Johnson syndrome.11 Interestingly, the N1 substituent on the aromatic ring is thought to be necessary for the development of IgE-mediated type I reactions.12 Again, nonaromatic amine sulfonamides do not contain this substituent.11 Data compiled from the pharmacovigilance networks of several European countries suggest that the risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis from a medication is highest in the first 2 months of use.13 This same case-control study did find an increased risk of developing these syndromes with trimethoprim-sulfamethoxazole (and other sulfonamide antimicrobials), but not with sulfonylureas, thiazide diuretics, or furosemide. This highlights the contradictory evidence for cross-reactivity between sulfonamide antimicrobials and other agents that also contain a sulfonamide molecule. Though the medical literature contains case reports implicating a wide variety of medications that cause these severe reactions, authors have suggested that a causal relationship has not been confirmed in many instances.11,14 A recent review found as many reported cases of clinical cross-reactivity with sulfonamide-containing compounds as cases where no cross-reactivity was demonstrated.11 View LargeDownload Chemical structures of the loop diuretics. Graphic structures of torsemide (A), furosemide (B), bumetanide (C), and ethacrynic acid (D). We are certainly not downplaying the seriousness of either Stevens-Johnson syndrome or toxic epidermal necrolysis. The former is fatal in 5% of cases, while the latter is fatal 30% of the time.15 With such a risk of serious complications, extreme caution should be exercised by the clinician who must prescribe medications implicated in causing these syndromes. However, the evidence demonstrating that a reaction with a sulfonamide antibiotic increases the risk of a similar reaction with other drugs with a sulfonamide molecule is lacking. In the rare patient, such as ours, who had a serious reaction to trimethoprim-sulfamethoxazole, glyburide, and furosemide, yet required a diuretic for his heart failure symptoms, we suggest that a thorough allergy history be taken by the health care provider to confirm the nature and severity of the reaction. If this history is positive for a reaction such as a hypersensitivity syndrome or Stevens-Johnson syndrome with a sulfonamide antimicrobial, we suggest that torsemide be used in a graded-dose challenge as described herein until (or if) ethacrynic acid becomes available again. If a rash was the reported reaction to another diuretic with a sulfonamide molecule, we also believe that torsemide as dosed herein is a reasonable alternative. References 1. Brater DC Diuretic therapy. N Engl J Med. 1998;339387- 395Google ScholarCrossref 2. Hebel SKed Drug Facts and Comparisons 2002. St Louis, Mo Facts & Comparisons Inc2002; 3. Brater DC Pharmacology of diuretics. Am J Med Sci. 2000;31938- 50Google ScholarCrossref 4. Rybak LP Ototoxicity of ethacrynic acid (a persistent clinical problem). J Laryngol Otol. 1988;102518- 520Google ScholarCrossref 5. American Society of Health-System Pharmacists, Drug Product Shortages Management Resource Center: Diuretics. Available At:Http://Www.Ashp.Org/Shortage/Diuretics.Cfm?Cfid=15939151&Cftoken=72491520. Accessed January 30, 2002. 6. Boxer MBDykewicz MSPatterson RGreenberger PAKelly JF The management of patients with sulfonamide allergy. N Engl Reg Allergy Proc. 1988;9219- 223Google ScholarCrossref 7. Gilman AGRall TWNies ASTaylor Peds Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY Pergamon Press1990;721- 725 8. Blose JSAdams KFPatterson JH Torsemide: a pyridine-sulfonylurea loop diuretic. Ann Pharmacother. 1995;29396- 402Google Scholar 9. Naisbitt DJHough SJGill HJPirmohamed MKitteringham NRPark BK Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity. Br J Pharmacol. 1999;1261393- 1407Google ScholarCrossref 10. Shear NHSpielberg SPGrant DMTang BKKalow W Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986;105179- 184Google ScholarCrossref 11. Knowles SShapiro LShear NH Should Celecoxib be contraindicated in patients who are allergic to sulfonamides? revisiting the meaning of "sulfa" allergy. Drug Saf. 2001;24239- 247Google ScholarCrossref 12. Harle DBaldo BWells J Drugs as allergens: detection and combing site specificities of IgE antibodies to sulfamethoxazole. Mol Immunol. 1988;251347- 1354Google ScholarCrossref 13. Roujeau JCKelly JPNaldi L et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;3331600- 1607Google ScholarCrossref 14. Bianchine JRAlexander MSAndresen BDNg KJ The aspirin/Reye's syndrome link. Lancet. 1982;21333Google ScholarCrossref 15. Wolkenstein PRevuz J Drug-induced severe skin reactions: incidence, management, and prevention. Drug Saf. 1995;1356- 68Google ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Ethacrynic Acid and the Sulfa-Sensitive Patient

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Publisher
American Medical Association
Copyright
Copyright © 2003 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.163.1.116
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Abstract

Loop diuretics are a mainstay of therapy for many patients with various disorders associated with fluid overload.1 These agents are inexpensive, effective, and well tolerated in the vast majority of patients. The 4 loop diuretics currently on the US market are furosemide, bumetanide, torsemide, and ethacrynic acid.2 Though few comparative studies have been performed, US physicians use the first 3 drugs almost exclusively, reserving ethacrynic acid (due to its ototoxic potential) for patients who have had serious hypersensitivity reactions to "sulfas" or the other loop diuretics.1,3,4 Ethacrynic acid is the only loop diuretic on the US market that does not contain a sulfonamide substituent. Unfortunately, the sole US producer of ethacrynic acid (Edecrin; Merck & Co, West Point, Pa) is currently unable to provide this drug; in fact, it has stopped production of the oral form indefinitely.5 This can present a dilemma to the clinician who has a patient requiring a loop diuretic who has a history of a serious reaction to a sulfonamide or loop diuretic. We present a case report of such a patient who was successfully treated with a graded-dose challenge to torsemide. Report of a Case A 71-year-old man with a history of coronary artery disease, type 2 diabetes, chronic renal insufficiency, atrial fibrillation, osteoporosis, obesity, obstructive sleep apnea, and congestive heart failure presented with continued symptoms of pedal edema, shortness of breath, and dyspnea on exertion despite a long history of ethacrynic acid use. The patient also had an extensive history of multiple drug reactions including a confirmed reaction of Stevens-Johnson syndrome to trimethoprim-sulfamethoxazole several years previously. He developed a rash on separate occasions when given furosemide and glyburide (both sulfonamide-containing drugs), as well as aminophylline and griseofulvin. Angiotensin-converting enzyme inhibitor use resulted in worsening renal function. The dose of ethacrynic acid prescribed was increased and the patient was sent home. Unfortunately, the pharmacy the patient used was out of ethacrynic acid and staff pharmacists discovered that a national backorder of the medication had occurred. Upon further investigation, it was determined that this drug shortage was likely to continue for the foreseeable future. With the patient's renal insufficiency (baseline serum creatinine level of approximately2.5 mg/dL [221 µmol/L]) it was believed that thiazide diuretics might be both ineffective and/or dangerous given the patient's history of reactions to sulfonamide-containing drugs. The patient's heart failure symptoms continued to worsen without any diuretic, and he returned to the clinic. Upon explaining the risks to the patient, it was believed that a graded-dose challenge of torsemide was warranted. The patient started taking 2.5 mg/d orally for 1 week, with strict instructions to call if any signs of rash, blisters, or other adverse events developed. This dose was increased slowly over the next 6 weeks to 10 mg/d orally, which he tolerated without incident. He was contacted by telephone frequently during the first 2 weeks of his graded-dose challenge to inquire about any adverse effects, which he denied. His daily diuresis improved, as did his shortness of breath and pedal edema. He was still not diuresing as much by his account as he was while taking ethacrynic acid. Thus, his dose was increased over the next month to 40 mg/d, which achieved the desired diuresis. He has not experienced rash, blisters, or any other adverse events due to torsemide treatment. His congestive heart failure symptoms have improved dramatically as well. Comment Fortunately, patients with documented, serious medication allergies are relatively rare. However, the incidence of cutaneous eruptions with sulfonamide antimicrobials may be higher than many other drugs.6 In a patient like the one described here, proper selection of medications can be challenging to the prescriber, especially when certain drugs are unavailable. We believed that we had little choice but to recommend a graded-dose challenge in an attempt to find a diuretic the patient would tolerate and find clinically effective. We chose torsemide because, even though it contains a sulfonamide molecule, its chemical structure is different from furosemide and bumetanide (Figure 1).7,8 Some evidence exists that an aromatic amine group at the N4 position of the sulfonamide molecule is critical to the development of hypersensitivity syndrome reactions and severe skin reactions such as Stevens-Johnson syndrome.9 In susceptible patients, a metabolite of this group cannot be detoxified, leading to an immunological and cytotoxic cascade, which results in these serious reactions.10 Nonaromatic amine sulfonamides, including torsemide, and all other loop diuretics, do not contain this N4 amine moiety. Thus, they would not be expected to cross-react with sulfonamide antimicrobials to cause Stevens-Johnson syndrome.11 Interestingly, the N1 substituent on the aromatic ring is thought to be necessary for the development of IgE-mediated type I reactions.12 Again, nonaromatic amine sulfonamides do not contain this substituent.11 Data compiled from the pharmacovigilance networks of several European countries suggest that the risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis from a medication is highest in the first 2 months of use.13 This same case-control study did find an increased risk of developing these syndromes with trimethoprim-sulfamethoxazole (and other sulfonamide antimicrobials), but not with sulfonylureas, thiazide diuretics, or furosemide. This highlights the contradictory evidence for cross-reactivity between sulfonamide antimicrobials and other agents that also contain a sulfonamide molecule. Though the medical literature contains case reports implicating a wide variety of medications that cause these severe reactions, authors have suggested that a causal relationship has not been confirmed in many instances.11,14 A recent review found as many reported cases of clinical cross-reactivity with sulfonamide-containing compounds as cases where no cross-reactivity was demonstrated.11 View LargeDownload Chemical structures of the loop diuretics. Graphic structures of torsemide (A), furosemide (B), bumetanide (C), and ethacrynic acid (D). We are certainly not downplaying the seriousness of either Stevens-Johnson syndrome or toxic epidermal necrolysis. The former is fatal in 5% of cases, while the latter is fatal 30% of the time.15 With such a risk of serious complications, extreme caution should be exercised by the clinician who must prescribe medications implicated in causing these syndromes. However, the evidence demonstrating that a reaction with a sulfonamide antibiotic increases the risk of a similar reaction with other drugs with a sulfonamide molecule is lacking. In the rare patient, such as ours, who had a serious reaction to trimethoprim-sulfamethoxazole, glyburide, and furosemide, yet required a diuretic for his heart failure symptoms, we suggest that a thorough allergy history be taken by the health care provider to confirm the nature and severity of the reaction. If this history is positive for a reaction such as a hypersensitivity syndrome or Stevens-Johnson syndrome with a sulfonamide antimicrobial, we suggest that torsemide be used in a graded-dose challenge as described herein until (or if) ethacrynic acid becomes available again. If a rash was the reported reaction to another diuretic with a sulfonamide molecule, we also believe that torsemide as dosed herein is a reasonable alternative. References 1. Brater DC Diuretic therapy. N Engl J Med. 1998;339387- 395Google ScholarCrossref 2. Hebel SKed Drug Facts and Comparisons 2002. St Louis, Mo Facts & Comparisons Inc2002; 3. Brater DC Pharmacology of diuretics. Am J Med Sci. 2000;31938- 50Google ScholarCrossref 4. Rybak LP Ototoxicity of ethacrynic acid (a persistent clinical problem). J Laryngol Otol. 1988;102518- 520Google ScholarCrossref 5. American Society of Health-System Pharmacists, Drug Product Shortages Management Resource Center: Diuretics. Available At:Http://Www.Ashp.Org/Shortage/Diuretics.Cfm?Cfid=15939151&Cftoken=72491520. Accessed January 30, 2002. 6. Boxer MBDykewicz MSPatterson RGreenberger PAKelly JF The management of patients with sulfonamide allergy. N Engl Reg Allergy Proc. 1988;9219- 223Google ScholarCrossref 7. Gilman AGRall TWNies ASTaylor Peds Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY Pergamon Press1990;721- 725 8. Blose JSAdams KFPatterson JH Torsemide: a pyridine-sulfonylurea loop diuretic. Ann Pharmacother. 1995;29396- 402Google Scholar 9. Naisbitt DJHough SJGill HJPirmohamed MKitteringham NRPark BK Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity. Br J Pharmacol. 1999;1261393- 1407Google ScholarCrossref 10. Shear NHSpielberg SPGrant DMTang BKKalow W Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986;105179- 184Google ScholarCrossref 11. Knowles SShapiro LShear NH Should Celecoxib be contraindicated in patients who are allergic to sulfonamides? revisiting the meaning of "sulfa" allergy. Drug Saf. 2001;24239- 247Google ScholarCrossref 12. Harle DBaldo BWells J Drugs as allergens: detection and combing site specificities of IgE antibodies to sulfamethoxazole. Mol Immunol. 1988;251347- 1354Google ScholarCrossref 13. Roujeau JCKelly JPNaldi L et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;3331600- 1607Google ScholarCrossref 14. Bianchine JRAlexander MSAndresen BDNg KJ The aspirin/Reye's syndrome link. Lancet. 1982;21333Google ScholarCrossref 15. Wolkenstein PRevuz J Drug-induced severe skin reactions: incidence, management, and prevention. Drug Saf. 1995;1356- 68Google ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jan 13, 2003

Keywords: ethacrynic acid,sulfonamides

References