Sulfasalazine
From DrugPedia: A Wikipedia for Drug discovery
Sulfasalazine (brand name Azulfidine in the United States, Salazopyrin in Europe) is a sulfa drug, a derivative of Mesalazine (5-aminosalicylic acid abbreviated as 5-ASA), used primarily as an anti-inflammatory agent in the treatment of inflammatory bowel disease as well as for rheumatoid arthritis. It is not a pain killer.
[edit] Indications
Sulfasalazine is mainly used for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is also effective in several types of arthritis, particularly rheumatoid arthritis.
However, in recent British research involving animal studies, and more recently, human trials for the treatment of chronic alcoholics, sulfasalazine has been found to reverse the scarring associated with cirrhosis of the liver. Apparently, cells called myofibroblasts, that cause scar tissue to form in a diseased liver, also give off proteins that prevent the breakdown of the scar tissue. Sulfasalazine appears to retard the secretion of these proteins.
According to the findings of a case series published in BMC Musculoskeletal Disorders, the use of sulfasalazine in the treatment of inflammatory arthritis can result in serious hepatotoxicity - an adverse effect which appears to be ‘under-appreciated’ in practice.
The results are from a local reporting system, which was set up in 2000 to look further into adverse drug reactions (ADRs) associated with disease-modifying antirheumatic drugs (DMARDs). The authors describe a series of 10 patients who developed serious hepatotoxicity whilst taking sulfasalazine. All had normal liver function tests (LFTs) prior to initiation of sulfasalazine, and none started any other new medications at the time of starting sulfasalazine. All patients however were using other drugs when sulfasalazine was started; in some cases this included other potentially hepatotoxic drugs.
Eight of the ten patients were hospitalised; three were admitted to the regional liver unit, including two with hepatic failure who received liver transplants. One case was fatal. Other causes of hepatitis were considered and investigated but exhaustive investigations were not done in all cases. All but one event occurred within 6 weeks of starting treatment. Likelihood of drug-related hepatotoxicity was judged highly probable in 7; probable in 1; and possible in 2 cases by two senior clinicians.
The authors note that 5 of the 10 patients were Black British of African or Caribbean descent. Using a series of assumptions, they estimated that the frequency of serious hepatotoxicity with sulfasalazine in their local population was 0.4% (6/1400). As 12% of their population are of a Black British background, they conclude that the risk of hepatotoxicity is significantly higher in this ethnic group.
The authors say that their experiences “indicate that such toxicity is likely to be missed by current national recommendations for monitoring…although this risk frequency is regarded by convention as uncommon the potential severity of reactions seen may make some patients and practitioners wary of sulfasalazine”.
It is usually not given to children under 2 years of age.
The use of sulfasalazine has declined due mainly to the fact that it yields the metabolite sulfapyridine which gives rise to side-effects such as agranulocytosis and hypospermia. However, the other metabolite of sulfasalazine, 5-aminosalicylic acid (5-ASA) is attributed to the drug's therapeutic effect. Therefore, 5-ASA and other derivatives of 5-ASA, are now usually preferred and given alone (as mesalazine), despite their increased cost, due to their more favourable side-effect profile.
[edit] Mode of action
Sulfasalazine, and its metabolite 5-ASA, are poorly absorbed. Its main mode of action is therefore believed to be inside the intestine. In Crohn's disease and ulcerative colitis, it is thought to be an antinflammatory drug that is essentially providing topical relief inside the intestine. It does this via a number of mechanisms such as reducing the synthesis of inflammatory mediators known as eicosanoids and inflammatory cytokines. However, unlike glucocorticoids (another class of drug used in the treatment in inflammatory bowel disease), sulfasalazine has no immunosuppressant action.
When treatment for arthritis is successful, pain, joint swelling and stiffness will be reduced and this may slow down or stop the development of joint damage. The precise reasons why sulfasalazine is effective in various forms of arthritis is not clearly understood.
Because sulfasalazine and its metabolite 5-ASA are poorly absorbed into the bloodstream, it is surprising that the drug is effective against symptoms outside of the intestine. One possible explanation is that, given that ulcerative colitis produces arthritic symptoms, it is possible that, in some cases, the arthritic symptoms are actually a product of unrecognized ulcerative colitis, which is effectively treated with sulfazalazine.
Talk to your doctor if you have ulcerative colitis, as some patients that have both sets of symptoms of ulcerative colitis and arthritis may have ankylosing spondylitis, which is a genetic condition, often associated with the antigen HLA-B27. This is a genetic marker, and there is a test available for it. Sulfasalazine is also good for this.
The other metabolite, sulfapyridine, is absorbed into the blood, and is believed to be the source of the side-effects discussed below. It is possible that the sulfapyridine is responsible for some of the anti-arthritic effects of sulfasalazine.
[edit] Side effects
The most common side effect is nausea but often this can be controlled by a reduction in dose. Sometimes other medications may be needed. Occasionally mouth ulcers, a sore mouth or loose bowel motions may occur. Certain patients may develop a headache or slight dizziness but adjusting the dosage may bring things under control.
A rash may develop which may be itchy, but usually resolves quite quickly once the drug is stopped. Sulfasalazine can in rare cases cause a drop in the numbers of white blood cells which are needed to fight infection. If the blood count is monitored closely, it is unusual for this to be serious. Sulfasalazine can decrease the numbers of platelets, cells which help to stop bleeding, but again it is rare for this to actually cause problems. If however you develop a sore mouth, mouth ulcers, easy bruising, nosebleeds or bleeding gums, your doctor should be notified immediately.
The other potential problem is that sulfasalazine can cause a type of hepatitis (liver inflammation). This is most commonly minor and does not cause symptoms. Most often we find that some of the blood tests which reflect liver function may become a little abnormal but these soon return to normal if the treatment is stopped. A study at University of Newcastle found that the drug may also act to aid the healing of cirrhosis of the liver.[1]
Sulfasalazine always causes some orange discolouration of the urine and your perspiration may be a little orange-tinged. This will generally wash out of clothes, but will damage some nylon fabrics. Contact lenses, particularly extended-wear soft lenses may be permanently stained. It can also cause semen to turn orange.
Sulfasalazine in rare cases can cause severe depression in young males.
Lastly, sulfasalazine may cause a decrease in the sperm count in men which may result in temporary infertility. This reverses when the drug is stopped. Temporary infertility may also occur in women. Sulfasalazine is considered to be safe in pregnancy, but should you wish to become pregnant, you should discuss this with your rheumatologist.
Sulfsalazine metabolizes to sulfapyridine. Serum levels should monitored every three months, and more frequently at the outset. Serum levels above 50 micrograms/L are associated with side effects.
