Thread by @pfehlers

1/
Sulfa allergy - the second most common I see behind PCNs. Sulfonamides run the gamut from sumatriptan to furosemide to everyone's favorite, sulfamethoxazole (SMX). Is an allergy to one really a contraindication to the rest? My first #tweetorial! @tony_breu @medicalignorome

2/
First, we have to know what a sulfonamide IS. Basically, it's any drug containing the sulfonamide moiety R-SO2-N-R'R". See below for the generic structure.

3/
SMX, half of our beloved Bactrim/Septra/Cotrimoxazole, appears below. We already know about the sulfonamide structure, but there are two other critically important groups to note: a primary N4 arylamine (in blue) and an N1 heterocyclic ring (in red).

4/
Sulfa allergies come in two broad flavors: IgE-mediated (type 1 hypersensitivity) and non-IgE-mediated (type 2, cytotoxic; type 3, immune-complex; type 4, cell-mediated). Starting with type 1, which portion of the molecule is specifically recognized by IgE (the "epitope")?

5/
It's the heterocyclic ring at the N1 position. This was demonstrated by taking sera from patients with anaphylaxis (a type 1 allergy) to SMX and performing inhibition assays to the culprit IgE with sulfonamides. Those w/ methylated ring at N1 provoked response.

PMID: 3237218

6/
SMX & related antibiotics are the only sulfonamide drugs we use that have this N1 heterocyclic ring. Other sulfonamides (e.g., furosemide, reproduced below) lack it and therefore lack any potential for type 1 allergy cross-reactivity.

7/
The non-type-1-hypersensitivities, however, are typically of more concern with SMX. These includes dermatopathies like SJS/TEN or systemic syndromes like serum sickness or DRESS. They are mediated not by IgE but either by IgG/IgM-complexes or T-cells.

8/
Which moiety on SMX is responsible for non-IgE hypersensitivities?

9/
The arylamine is necessary for these reactions to occur. It's not the parent SMX: it's downstream metabolites, particularly a reactive [-nitroso] intermediate. 20% of SMX is oxidized by CYP2C9 at N4 (green). This hydroxylamine can autooxidize to a nitrososulfonamide (blue).

9/
You can see in the above figure that the nitroso-SMX is shown as a protein adduct (red). It tends to haptenate (bind to proteins) to generate novel immunogens, which then cause the worrisome drug reactions like SJS or DRESS.

PMID: 15303450

10/
Nitroso-SMX was shown to be the reactive metabolite by incubating agranulocytes with hydroxylamine-SMX. The SMX-HA autooxidized to reactive nitroso-SMX, resulting in superoxide radical generation (fig 6) and required detoxification by glutathione conjugation (fig 9).

11/
What can we say about sulfonamide allergy? Well, it's not actually about the sulfonamide moiety at all. It's about the other 2 functional groups. We can look at a third common sulfonamide, HCTZ, and see that it too lacks the N1 ring or the N4 arylamine.

12/
Do we have any clinical evidence to support using sulfonamide nonantibiotics in patients with a sulfa allergy? The best came out of @NEJM in 2003. A large cohort study of all UK outpatients, it compares those with and without sulfa allergy.

13/
Those with allergy were more likely than those without allergy to react to a sulfa nonabx. However, they were even MORE likely to react to a penicillin - and those with a PCN allergy were even more likely react to a sulfonamide nonabx than those with a sulfa allergy were.

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This indicates that there is likely, as the authors put it, a "general predisposition to allergic reactions among certain patients, rather than a specific cross-reactivity with drugs containing the sulfa moiety." The pharmacology matches our reality.

15/
So the next time you are faced with a patient that needs diuresis but has "sulfa allergy" in their chart, feel free to load 'em with furosemide! No ethacrynic acid needed. For more in-depth look at this topic, see my blog post below.

wp.me/saywSO-sulfa