Sulfasalazine toxicity

Meyboom RHB (1975) Heavy metal antagonists. In Dukes MNG (ed) Meyler s side effects of drugs, 8. Excerpta Medica, Amsterdam London New York, pp 529-542 Mihas AA, Goldenberg DJ, Slaughter RL (1978) Sulfasalazine toxic reactions. Hepatitis, fever and skin rash with hypocomplementemia and immune complexes. JAMA 239 2590-2591... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

In addition to relying on safety and efficacy data, the initial DMARD choice depends on disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician experience with the medication.1,7 Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease. Patients with early, mild disease may receive monotherapy with sulfasalazine or hydroxychloroquine. Agents such as azathioprine, D-penicillamine, and gold salts are used rarely today because of concerns about toxicity and reduced efficacy.1,15... 

Ricart, E., Taylor, W. R., Loftus, E. V., et al. (2002) iV-Acetyltransferase 1 and 2 genotypes do not predict response or toxicity to treatment with mesalamine and sulfasalazine in patients with ulcerative colitis. Am. J. Gastroenterol. 97, 1763-1768. 

Peppercorn MA (1984) Sulfasalazine - pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med 101(3) 377-386... 

Deaths Deaths associated with the administration of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and liver damage, irreversible neuromuscular and CNS changes, and fibrosing alveolitis. If toxic or hypersensitivity reactions occur, discontinue sulfasalazine immediately. 

Sulfasalazine has been used for the management of RA and ankylosing spondylitis with apparently similar effectiveness as penicillamine and with less toxicity. While 5-aminosalicylic acid is the active agent in inflammatory bowel disease, it is believed that sulfapyridine is mostly responsible for the antirheumatoid effects. Gastrointestinal complaints, dizziness and photosensitivity are the most frequently observed adverse events. With levamisole and also with sulfasalazine and olsalazine a delay of 2-3 months is to be expected before positive responses will be observed. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

The most recent treatment paradigm calls for earher, more aggressive treatment of rheumatoid arthritis. DMARDs are frequently employed along with NSAIDs in the initial treatment of the disease. The COX-2 inhibitors are often used because they are less likely to cause serious GI toxicity than are the nonspecihc COX inhibitors. The usual DMARD of choice for patients with mild rheumatoid arthritis is hydroxychloroquine or sulfasalazine methotrexate is used for those with moderate to serious disease. Other DMARDs are used if these agents are poorly tolerated or do not produce suf-hcient response. Combination therapy of methotrexate and another agent is also used to treat disease that is not responsive to individual DMARDs. 

Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemoglobinemia also occur, but rarely. Neutropenia occurs in 1-5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic. 

Aminosalicylates, eg, mesalamine in many formulations Mechanism uncertain t may be inhibition of eicosanoid inflammatory mediators Topical therapeutic action systemic absorption may cause toxicity Mild to moderately severe Crohn s disease and ulcerative colitis Sulfasalazine causes sulfonamide toxicity and may cause GI upset, myalgias, arthralgias, myelosuppression other aminosalicylates much less toxic... 

Sulfasalazine Azulfidine Oral 0.5-1.0 g/d for the first week dose can be increased by 500 mg each week up to a maximum daily dose of 2-3 g/d. Relatively high toxicity may produce serious hypersensitivity reactions and blood dyscrasias. 

Penicillamine (Cuprimine), a derivative of penicillin, is officially classified as a chelating agent that is often used in the treatment of heavy metal intoxication (e.g., lead poisoning). In addition, this drug has been used in patients with severe rheumatoid arthritis, and seems to be as effective as other DMARDs such as methotrexate, sulfasalazine, and gold therapy.68 98 Penicillamine, however, tends to be substantially more toxic than other DMARDs, and is therefore used rarely in the treatment of specific patients with rheumatoid arthritis.68... 

Metabolism The sulfas are acetylated at N4, primarily in the liver. The product is devoid of antimicrobial activity, but it retains the toxic potential to precipitate at neutral or acidic pH, causing crys-talluria ( stone formation ) and therefore potential damage to the kidney (Figure 29.4). Sulfasalazine is effective in the treatment of inflammatory bowel disease because local intestinal flora split the drug into sulfapyridine and 5-aminosalicylate. The latter exerts the antiinflammatory effect. Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators. 

Slow acetylator Isoniazid Hydralazine, procainamide Phenelzine, sulfasalazine Increased incidence of peripheral neuropathy SLE-like syndrome and more prone to phenytoin toxicity Increased incidence of SLE-like syndrome More prone to side effects... 

Simple rashes are not uncommon in patients taking sulfasalazine, including maculopapular rash, pruritus, urticaria, angioedema, eczematous dermatitis, photosensitivity, skin discoloration, and oral ulceration. Raynaud s phenomenon and toxic epidermal necrolysis associated with erythroid hypoplasia and agranulocytosis have occurred in one case of toxic epidermal necrolysis there was marked immunosuppression (SEDA-18, 375). 

Spermatozoa a-Chlorohydrin directly affects spermatozoa with a resultant diminution in motility. Since this direct effect is reversible, a-chlorohydrin was once considered a candidate for male contraception. However, because irreversible toxicity was found in the epididymis, the potential for drug development of a-chlorohydrin was not explored further. The sulfonamide drug sulfasalazine may affect mature spermatozoa in the epididymis, resulting in decreased fertility. However, historical data on... 

Note Sulfasalazine is a sulfonamide and can be absorbed systemically. Sulfonamides can produce severe, possibly fatal, reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome... 

Although leukopenia is associated with Felty s syndrome, it also may result from toxicity of gold, sulfasalazine, penicillamine, immunosuppressive drugs, and biologic agents. Leukocytosis is seen commonly as a result of corticosteroid treatment. 

Toxic effects of sulfasalazine include gastrointestinal disturbances, skin rash and leukopenia. 

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