Discuss the pharmacology of aminosalicylates?

  • Sulphasalazine consists of a sulfapyridine moiety attached to 5- aminosalicylic acid (5-ASA). It is broken down in the colon by the azoreductase bacterial enzyme to its individual components. 5-ASA is anti-inflammatory whereas sulfapyridine has antiarthritic and antibacterial properties. Sulfapyridine is also responsible for most of the side effects of Sulphasalazine. Sulfapyridine is rapidly absorbed from the colon, whereas 5-ASA is poorly absorbed from the colon.
  • A number of 5-ASA products have been developed with similar efficacy to sulphasalazine but with better tolerance and side effect profile. Oral 5-ASA undergoes rapid absorption in the jejunum and will thus have limited efficacy in distal small and colonic disease. To bypass proximal small bowel absorption, delayed release formulations have been developed. This include topical formulations of mesalazine as enemas, suppositories or foams; oral mesalazine coated with various pH dependent polymers (asacol, salofalk); oral mesalazine encapsulated into ethylcellulose microgranules (Pentasa); or alternative azo bond derivatives that combine two 5- ASA moieties into a dimer (olsalazine, dipentum®); or attach 5-ASA to an alternative inert carrier (balsalazide, Colazide®). Olsalazine and balsalazide are mainly active in colon as they require colonic bacteria to cleave the azo bond and release the 5-ASA moiety. pH dependent polymers dissolve in pH greater than 7 and so releases the drug to the distal small bowel and colon.
  • Recently a once a day formulation of mesalazine (Mezavant XL ®) has been released. It has a multimatrix system(MMX) that incorporates mesalazine into a lipophilic matrix within a hydrophilic matrix encapsulated in a polymer resistant to disintegration at a pH lower than 7 to delay release throughout the colon.
  • Unencapsulated mesalazine granules (salofalk® granules) are also used.

Discuss the mechanism of action of aminosalicylates?

The exact mechanism is still unknown. However, their action is thought to be predominantly topical at the site of inflammation. Mesalazine have favourable anti-inflammatory effects in in vitro studies by reducing prostaglandin and leukotriene production, inhibiting bacteria induced chemotaxis and scavenging of free radicles.

Discuss the uses of aminosalicylates?

  • Treatment and maintenance of remission in UC.
    • An effective dose (2 to 6 g/day) induces a remission in 50 to 80 percent of patients. The drug acts within 2-4 weeks. Sulphasalazine and 5-ASA drugs have similar efficacy but 5-ASA drugs have a better side effect profile.
    • Topical therapies (enemas, suppositories, foams) deliver mesalazine directly to the distal colon.  Topical therapies provide quicker response and are hence considered the treatment of choice for patients with distal colitis. The choice of formulation depends upon the extent of disease and patient preference. Suppositories are only effective in the rectum (about 10 cm), whereas enemas can reach the splenic flexure. However, enemas are more difficult to administer.
    • Combined oral and topical 5-ASA therapy is more effective than oral therapy or topical therapy alone in patients with more extensive mild to moderate UC.
    • 5-ASA also has a protective effect in prevention in colon cancer in UC.
  • Use in Crohn’s disease
    • 5-ASA agents are used commonly for the treatment of mild to moderately active Crohn’s disease and for maintenance of remission. However their efficacy is not established in either role and some experts recommend that 5-ASA drugs should not be used in the treatment of Crohn’s disease for either induction or maintenance of remission. Others argue that 5-ASA should be used in patients with mild Crohn’s disease based upon their excellent safety profile.

Discuss the side effects of aminosalicylates?

  • Sulfasalazine
    • Common side effects include nausea, headache, fever, rash, and male infertility. These problems are dose related.
    • Folic acid (1 mg/day) supplementation is recommended as sulphasalazine can affect folate metabolism.
    • Agranulocytosis is a rare side effect of Sulphasalazine. This typically occurs within the first two months of therapy and is almost invariably accompanied by fever and rash. Agranulocytosis may be fatal, although bone marrow recovery occurs in the majority of patients within one to two weeks of drug discontinuation.
    • Patients with sulpha allergies should not be given Sulphasalazine.
  • Mesalazine
    • Headaches and gastrointestinal upset (nausea, abdominal pain) are the common side effects with mesalazine.
    • Diarrhea can occur with all mesalazine and 5-ASA preparations, especially those with a dia-azo bond, including olsalazine and balsalazide. Diarrhoea is due to increased ileal secretion and improves within a few weeks time due to colonic adaptation. In addition, mesalazine can rarely cause a paradoxical worsening of colitis symptoms.  This may be masked when patients are receiving concurrent steroids and may appear as refractory colitis. It is recommended that patients who are unable to taper steroids despite high dose mesalazine be given a trial off mesalazine to rule out unanticipated hypersensitivity colitis.
    • Renal impairment (including interstitial nephritis and nephrotic syndrome) is rare and idiosyncratic. All aminosalicylates have been associated with nephrotoxicity, which appears both to be idiosyncratic and in part dose related. Reactions are rare, but patients with pre-existing renal disease are at higher risk. Occasional (perhaps annual) measurement of creatinine is sensible, although there is no evidence that monitoring is necessary or effective. Aminosalicylates should be stopped if renal function deteriorates
  • Hypersensitivity reactions to both Sulphasalazine and aminosalicylates can occasionally result in pancreatitis and pneumonitis. These responses are likely to recur; thus, the drug should not be resumed in these patients.

Discuss the safety of aminosalicylates in pregnancy?

Sulphasalazine is safe during pregnancy and nursing. There is less experience with the newer 5-ASA agents in pregnancy, however current evidence suggests that both topical and oral agents are safe in pregnancy

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