Aminosalicylates

The active component of all these drugs is 5-aminosalicylic acid or 5-ASA. 5-ASA's precise mechanism of action in inflammatory bowel disease is unknown but thought to include altering cytokine function.¹

Sulfasalazine (5-ASA linked to sulfapyridine) was developed in the 1930s and still has an important therapeutic role in the treatment of inflammatory bowel disease (IBD) and rheumatoid arthritis. Sulfasalazine is poorly absorbed from the small intestine but bacterial enzymes in the colon liberate the active 5-ASA.^2,3 Unfortunately, the high incidence of side-effects (occurring in 10-45% patients¹) limits sulfasalazine's therapeutic usefulness. Many of these are thought to be related to the sulfapyridine moiety and newer aminosalicylates have been developed to find alternative, better tolerated 5-ASA delivery

Given these different delivery characteristics, 5-ASA preparations cannot be assumed to be clinically interchangeable, and should not be prescribed generically in the case of mesalazine.³ Ideally the drug should be matched to the site of disease, using azo-bonded compounds for more distal disease.¹

1. Inflammatory Bowel disease¹

Treatment of acute Ulcerative colitis (UC) and Crohns Disease

This relies on use of corticosteroids and/or an aminosalicylate. Choice usually depends on the site of disease and patient preference.⁴

• Mild to moderate distal or rectal disease is treated with a local application of aminosalicylate or corticosteroid given as suppositories (for proctitis), enemas (reach to the proximal descending colon) or foam (better retained than enemas, but will only act to the distal descending colon). Rectal preparations should be given at night where possible.⁵
• Where disease is more extensive and not amenable to local therapy, oral treatment is required. Mild disease affecting the colon may be adequately treated by an aminosalicylate alone; refractory or moderate disease requires adjunctive use of an oral corticosteroid (prednisolone or modified-release budesonide).²
• Severe IBD requires hospital admission for IV corticosteroid treatment, fluid and electrolyte replacement. Specialist treatments for inducing remission in severe or refractory IBD include infliximab, methotrexate and ciclosporin.²

Maintenance of remission in UC

Sulfasalazine reduces the rate of relapse three to four times more effectively than placebo.³ Efficacy and unwanted effects are largely dose-dependent and the optimal dose in most patients is 2g sulfasalazine daily.³ All 5-ASA derivatives show comparable efficacy to sulfasalazine - choice should be influenced by tolerability (mesalazine is tolerated by 80% of those unable to tolerate sulfasalazine), dose schedule (bd dosing is associated with higher compliance) and cost.¹ Maintenance therapy with all 5-ASA drugs may reduce the risk of colorectal cancer long-term by up to 75%.^1,6

Maintenance of remission in Crohn's disease

The evidence supporting the use of aminosalicylates for this is much weaker.³ Asacol MR is licensed for the long term management of ileal disease in Crohn's.

2. Rheumatoid arthritis and psoriatic arthritis

Sulfasalazine is used as a DMARD. In this use, the sulfapyridine moiety is thought to be the active therapeutic agent. It is also used unlicensed in the treatment of juvenile idiopathic arthritis.

• Salicylate hypersensitivity - relatively common. Avoid all aminosalicylates.
• Sulphonamide hypersensitivity - avoid sulfasalazine.

  Drugs containing sulphonamide group: Sulphonamides (silver sulfadiazine or Flamazine™ Co-trimoxazole or Septrin™) Sulfasalazine Sulfonylureas (allergy rare) Thiazide diuretics (allergy rare) Loop diuretics (allergy rare) Acetazolamide Celecoxib

• Moderate to severe renal impairment: aminosalicylates are excreted via the kidneys and significant amounts of unchanged or acetylated 5-ASA is found in the urine. Renal toxicity is a risk in long term treatment, particularly to those with existing renal impairment.³
• Severe hepatic impairment
• Pregnancy and breast-feeding
• G6PD deficiency (sulfasalazine only).

Associated with 5-ASA

• Hypersensitivity reactions: rash - urticaria or more rarely Stevens-Johnson syndrome, interstitial nephritis, lupus-like syndrome.
• GI symptoms: diarrhoea, nausea, vomiting, abdominal pain, cholelithiasis, exacerbation of symptoms of colitis (rarely). Watery diarrhoea seems more common with the use of olsalazine and can sometimes be relieved by dose reduction and by taking the drug with meals.
• Myelosuppression and blood dyscrasias (agranulocytosis, aplastic anaemia, leukopenia, neutropenia, thrombocytopenia, megaloblastic anaemia, haemolytic anaemia).
• Lung complications : fibrosing alveolitis, eosinophilia
• Neurological & musculo-skeletal complications: headache, aseptic meningitis, vertigo, tinnitus, peripheral neuropathy, depression, hallucinations, myalgia, arthralgia.
• Renal dysfunction: interstitial nephritis, nephrotic syndrome.

Associated with sulfapyridine

• Oligospermia
• Increased risk of hypersensitivity reactions
• Increased risk of blood dyscrasias
• Kidney reactions (proteinuria, crystalluria, haematuria).

Adverse events and withdrawals from trials looking at the treatment of active disease are more frequent with sulfasalazine than the other 5-ASA drugs. This difference did not exist when maintenance or remission therapy was compared.⁴ Sulfasalazine's response rate is dose-related as is its toxicity - patients on maintenance therapy usually require lower doses than those with active disease. Use of a newer 5-ASA preparation avoids many of the unwanted effects of sulfasalazine (by using non-oral routes of administration, requiring lower doses of 5-ASA and avoiding the use of the sulfapyridine carrier) - consequently they are used in those unable to tolerate sulfasalazine, men concerned about their fertility and, in some centres, those starting aminosalicylates for the first time.³ However, they are also more costly than sulfasalazine.

• Cytotoxics - care is required when giving with azathioprine or mercaptopurine as increased risk of leucopaenia.

These drugs are usually initiated by secondary care specialists, however continued prescribing and monitoring may occur in the community under shared care agreements.

Many of the adverse events are reported in the first three months so close monitoring is suggested for this period.³

• FBC and LFTs prior to treatment and monthly thereafter for the first three months and then three monthly.
• Urgent FBC if patient develops bleeding, purpura, bruising, sore throat, fever or excessive tiredness.
• Renal function should be checked before treatment and annual measurement of creatinine is advocated.

Monitor efficacy with inflammatory markers (ESR, CRP) and stool frequency diary.
In primary care, do not overlook adjunctive and non-pharmacological treatment of IBD - do not forget pain management, nutritional support, treatment of malabsorption syndromes (resulting from terminal ileal disease or bowel resection), osteoporosis prevention etc.

• Report to doctor immediately if unexplained purpura, bruising, bleeding, fever, sore throat or malaise (as may indicate underlying blood dyscrasia).
• Sulfasalazine can turn tears and urine orange and stain soft contact lenses.