SULFONYLUREAS & SULFA ALLERGY

FACT OR FICTION?

DR. SUJAY IYERI YEAR POSTGRADUATE, GENERAL MEDICINE

GUIDE: PROF. DR. K JEYAPALAN

TABLE OF CONTENT

• INTRODUCTION• SULFONAMIDES• SULFONYLUREAS• SULFA ALLERGY• THE DIFFERENCE MAKER!• ACADEMIC LITERATURE• CLINICAL BOTTOM LINE• REFERENCES

INTRODUCTION

• Sulfonamide medication are drugs that contain a Sulfonamide moiety (SO2NH2).• The imprecise term ‘Sulfa Drugs’ is most often applied to

Sulfonamide antimicrobials, although it is variably used for nonantimicrobial Sulfonamides as well.• Sulfa allergy is a term that is applied for adverse reactions

& symptoms caused by antimicrobial Sulfonamide medications.• Sulfonylureas are a class of organic compounds that are

used as oral antidiabetic medications – Secretogogues.

SULFONAMIDES

• Sulfonamides are divided into two distinct groups: • Antimicrobials• Nonantimicrobials

SULFONAMIDE ANTIMICROBIALS

• First antibiotics to be used systemically.• Discovered in 1932, they were revolutionary drugs that saved the

lives of thousands of people in World War II.• Dr. Gerhard Domagk.• They are Dihydropteroate Synthase inhibitors that have

bacteriostatic action.• Most commonly used Sulfonamide is Co-Trimoxazole, a

combination of Sulfamethoxazole & Trimethoprim.• Use has decreased because of resistance and adverse reactions.

SULFONAMIDE ANTIMICROBIALSSYSTEMIC AGENTS: TOPICAL & OPHTHALMIC

AGENTS:• SULFADIAZINE• SULFADOXINE• SULFAGUANIDINE• SULFAMERAZINE• SULFAMETHIZOLE• SULFAMETHAZINE• SULFAMETHOXAZOLE• SULFAMETOPYRAZINE• SULFAMOXOLE• SULFAPYRIDINE• SULFISOXAZOLE

• MAFENIDE• SILVER SULFADIAZINE• SULFACETAMIDE• SULFANILAMIDE

SULFONAMIDE ANTIMICROBIALS: MECHANISM

• Sulfonamides act as competitive inhibitors of Dihydropteroate Synthase, which catalyses the conversion of Para-Aminobenzoate to Dihydropteroate, a key step in Folate synthesis.

SULFONAMIDE NONANTIMICROBIALS

LOOP DIURETICS:• TORSEMIDE• FUROSEMIDE• BUMETANIDE

CARBONIC ANHYDRASE INHIBITORS:• ACETAZOLAMIDE• BRINZOLAMIDE• METHAZOLAMIDE

THIAZIDE DIURETICS:• HYDROCHLOROTHIAZIDE• CHLORTHALIDONE• METALAZONE• INDAPAMIDE

ANTIRETROVIRALS: • AMPRENAVIR• FOSAMPRENAVIR• DARUNAVIR• SIMEPRIVIR

SULFONYLUREA HYPOGLYCEMICS:• GLIMIPERIDE• GLICLAZIDE• GLIPIZIDE• GLYBURIDE• CHLORPROPRAMIDE• TOLAZAMIDE

OTHERS:• CELECOXIB• PROBENECID• SOTALOL• SULFASALAZINE• SUMATRIPTAN• TIPRANAVIR• TOPIRAMATE• ZONISAMIDE

SULFONYLUREAS

• Among the most widely used drugs for the treatment of patients with Type 2 Diabetes Mellitus.• They work by stimulating Insulin secretion, so are useful

only in patients with some beta cell function.

SULFONYLUREAS: MECHANISM & CLASSIFICATION

• Sulfonylureas are Secretagogues. They bind & close the K-ATP channels in the pancreatic beta cells, which stimulates insulin secretion.• First generation are not used anymore.• They lower blood sugar by 20% and HbA1C by 1-2%.I

GENERATIONII

GENERATION• ACETOHEXAMIDE• CHLORPROPAMIDE• TOLBUTAMIDE

• GLIPIZIDE• GLICLAZIDE• GLYBURIDE • GLIMEPIRIDE

SULFONYLUREAS: MEDICAL USE

INITIAL THERAPY OF DIABETES:• Contraindications to Metformin.• In severe hyperglycemia if Insulin is not preferred.• Used in Maturity Onset Diabetes Of the Young (MODY).COMBINATION:• Used in combination with other oral antidiabetic agents or

Insulin in patients who fail initial therapy.They are used because of glucose lowering efficacy, universal

availability and low cost.

SULFA ALLERGY• The term Sulfa Drugs have contributed to the ongoing

confusion about relevant cross-reactivity among Sulfonamide drugs.• It is preferable to avoid the term ‘Sulfa Allergy’.• Antimicrobial Sulfonamides are the second most frequent

cause of allergic drug reactions.• Nonantimicrobial Sulfonamides do not cause the adverse reactions seen in the antimicrobials and there is minimal evidence of cross-reactivity.• Incidence of the allergic reactions varies:• 34 in 1000.• 8 % in hospitalized patients.

SULFONAMIDE ALLERGY: TYPES

A variety of hypersensitivity reactions can occur in response to Sulfonamides.• Isolated cutaneous reactions.• Morbiliform rash with fever and systemic symptoms.• Immediate type allergy & anaphylaxis.• Stevens-Johnson syndrome & Toxic Epidermal Necrolysis.• Other uncommon reactions:• Serum Sickness.• Hemolytic Anemia.• Aseptic Meningitis.

SULFA ALLERGY: PATHOPHYSIOLOGY

Sulfonamide Antibiotic allergy is multifactorial:• Metabolism of sulfonamide antimicrobials to reactive

metabolites that act as Haptens and link with protein complexes to initiate an immunologic reaction.• Some intermediate metabolites can be directly

cytotoxic.• Interaction between T cell receptors and unmetabolized

antimicrobials.

THE DIFFERENCE MAKER!

• Antimicrobial Sulfonamides share two essential functional groups:• An Arylamine at N4.• An Aromatic Heterocyclic Ring at N1.

• The presence of both moieties is essential to their antimicrobial action and is also believed to be central to the pathogenesis of hypersensitive reactions.• The Nonantimicrobial Sulfonamdies do not contain an Arylamine group or a substituted aromatic heterocyclic ring.

LITERATURE

SULFONAMIDE ALLERGIES & OUTCOMES RELATED TO USE OF POTENTIALLY CROSS-REACTIVE DRUGS IN HOSPITALISED PATIENTS• Pharmacotherapy (April 2006) • B A Hemstreet et al.• 94 patients• Conclusion: No adverse effects were reported or documented

with outpatient or inpatient Sulfonamide Nonantibiotic use, even among patients with histories of life-threatening reactions to Sulfonamides.

LITERATUREABSENCE OF CROSS-REACTIVITY BETWEEN SULFONAMIDE ANTIBIOTICS & NONANTIBIOTICS• New England Journal of Medicine (October 2003)• B L Strom et al.• Largest study• Conclusion: There is an association, but this association

appears to be due to a predisposition to allergic reaction rather than to cross-reactivity with Sulfonamide-based drugs.• Odds ratio of sulfonylureas was lower than that of loop

diuretics.

LITERATURE

LITERATURE

SULFONAMIDE CROSS-REACTIVITY: IS THERE EVIDENCE TO SUPPORT BROAD CROSS-ALLERGENICITY?• American Journal of Health System Pharmacy (September 2013)• N R Wulf• From 1966 to 2011. Literature research.• Conclusion: A review of the professional literature and

manufacturer-provided data did not find convincing evidence of broad cross-reactivity between Antibacterial and Nonantibacterial Sulfonamide agents.

LITERATURELIKELIHOOD & MECHANISM OF CROSS-ALLERGENICITY BETWEEN SULFONAMIDE ANTIBIOTICS & OTHER DRUGS CONTAINING A SULFONAMIDE GROUP• Pharmacotherapy (July 2004)• C Brackett et al• Conclusion: Formation of metabolites is a stereospecific

process that occurs at the N4 amino nitrogen of the Sulfonamide Antibiotics, a structure not found on any Nonantibiotic Sulfonamide drugs. The stereospecificity of these reactions implies that cross-reactivity with Nonantibiotic Sulfonamide-containing drugs is highly unlikely; this assertion is supported by recent literature.

LITERATURE

SULFONAMIDE HYPERSENSITIVITY• Immunology & Allergy Clinics of North America (August

2004)• C Slatore et al.• Conclusion: The preponderance of available evidence

suggests that Sulfonamide Antibiotics probably do not cross-react with Sulfonamide Nonantibiotics.

LITERATURE

METABOLIC RATIONALE FOR LACK OF CROSS-REACTIVITY BETWEEN SULFONAMIDE ANTIBIOTICS & OTHER SULFONAMIDE CONTAINING DRUGS• Drug Metabolism Letters (June 2012)• D F Lehman et al• Conclusion: As other drugs containing Sulfonamide group

do not contain arylamine group, no reactive intermediates are formed and therefore there is no cross-reactivity.

LITERATURE

MEDICATION USE AND RISK OF STEVENS-JOHNSON SYNDROME OR TOXIC EPIDERMAL NECROLYSIS.• New England Journal of Medicine (December 1995)• J C Roujeau et al.• Conclusion: Sulfonamide use increases risk of Toxic

Epidermal Necrolysis/Stevens-Johnson Syndrome. Thiazide diuretics and Sulfonylureas were not associated with increased risk of TEN/SJS.

LITERATURE

APPROACH TO MANAGING PATIENTS WITH SULFA ALLERGY• Canadian Family Physician (November 2006)• D Ponka et al.• Conclusion: Cross-reactivity between Sulfa Antibiotics and

Nonantibiotics is rare, but on occasion it can affect the management of patients with sulfa allergy.

LITERATURE

SULFONAMIDE CROSS-REACTIVITY: FACT OR FICTION?• Annals of Pharmacotherapy (2005)• K K Johnson. Critical review from 1966 to 2004.• Conclusion: After a thorough critique of the literature, it

appears that the dogma of sulfonylarylamine cross-reactivity with non-sulfonylarylamines is not supported by the data. While many of the case reports on the surface support the concept of cross-reactivity, on closer examination the level of evidence in many of the cases does not conclusively support either a connection or an association between the observed cause and effect.

CLINICAL BOTTOM LINE

• Sulfonylureas are secretogogues, they increase Insulin secretion from beta cells. They are important Oral Antidiabetic Medications.• Sulfonylureas are structurally distinct from Sulfonamide

Antibiotics.• Recent evidence suggests cross-reactivity is uncommon

and patients who are allergic to Sulfonamide antibiotics may safely receive Sulfonamide Nonantibiotics.• It is imperative that Sulfonylureas are not contraindicated

in Diabetic patients with Sulfonamide Antibiotic allergy.

REFERENCES

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