First Line Drugs

Cells involved in the Body Defense

Phagocytic cells (Neutrophils, Macrophages). They are like heavy weapons. These cells kill and digest the foreign invaders (organisms)

Natural Killer Cells (NK cells). The are like soldiers. These cells kill foreign cells, and virus infected cells Complement proteins. They are like small weapons. The are present in blood plasma, they initiate inflammation and facilitate killing of microorganisms and other cells

Cytokines are like guns produced by killer cells (modulate adaptive immune system)
T- and B-Lymphocytes are responsible for cell-mediated response, produce antibodies and cytokines, are like weapon factories
T-cells differentiate into "memory" cells which retain the "memory" of the "alien"; thus, their response is faster during the next encounter.

5-amino salicylic acid (5-ASA)

It is the active moiety of a drug called Sulfasalazine, which is a drug that was originally developed for Rheumatoid Arthritis. Sulfasalazine, under enzymatic breakdown by the colonic bacteria, releases two moieties, viz. 5-ASA (also called Mesalamine) and Sulfapyridine. 5-ASA is responsible for the therapeutic effects while the latter is responsible for most of the side-effects. Sulfapyridine is required as a carrier molecule to conduct 5-ASA to the distal parts of the gastro-intestinal tract including the colon; else 5-ASA would be completely absorbed in the proximal parts of the small intestines. 5-ASA is a topically active drug which has been extensively used for treatment of UC & CD. It exerts its action by an anti-inflammatory action, limiting the formation of pro-inflammatory prostaglandins.

Various different formulations have been formulated to ensure delivery to the different afflicted parts. Some of the strategies are listed below:

  1. Diazo bonding (with Sulfapyridine or another 5-ASA molecule or 4-aminobenzoyl-ß-alanine)
  2. pH-dependent coating (with Eudragit-S, Eudragit-L)
  3. time- & pH-dependent coating with Ethylcellulose

Some of the common formulation in use and their characteristics are tabulated below (brand names have not been mentioned):

DrugStrategyRelease MechanismSite of Action
Sulfasalazine 5'-ASA + Sulfapyridine (Diazo bond) Cleavage of azo-bond by colonic bacteria Colon
Olsalazine 5'-ASA + 5'-ASA (Diazo bond) Cleavage of azo-bond by colonic bacteria Colon
Balsalazide 5'-ASA + 4-aminobenzoyl-ß-alanine (Diazo bond) Cleavage of azo-bond by colonic bacteria Colon
Mesalamine Eudragit-S coated 5'-ASA Coating dissolves at pH>7 Ileum (some), colon
Mesalamine Eudragit-L coated 5'-ASA Coating dissolves at pH>6 Ileum, Colon
Mesalamine Ethylcellulose coated 5'-ASA Time- and pH- dependent slow release Jejunum (some), Ileum, Colon


Corticosteroids are a group of highly effective drugs. The apprehensions about steroids, though not without basis, are applicable only to "indiscriminate" and "unintelligent" use of the drugs. Their appropriate use can prove to be of immense value of an IBD patient.

While steroids have a wide range of numerous action in the body, their main actions that are responsible for efficacy in IBD are:

  1. Inhibition of Interleukins (IL-1, IL-2, IL-6, IL8)
  2. Inhibition of ?-Interferon (IFN-?)
  3. Inhibition of TNF-beta

Prednisolone is the classic corticosteroid that is used and Budesonide is the more recent commonly used one. Due to its higher metabolism in the liver (and higher first-pass metabolism as well), Budesonide have fewer of the side-effects which are typically associated with chronic therapy with classical steroids. Suppression of Hypothalamo-Pituitary-Adrenal axis does, however, occur on prolonged administration, resulting in the serious side effects associated with this group of drugs Prednisolone has been subjected to a lot of investigation in clinical trials. A few are summarized here:

(a)In one placebo-controlled trial in mild-moderate CD remission rates were 50% with Budesonide when it was used in a dose of 9 g/day.

(b)In another 16 week study, comparative with Mesalamine, 9 g/day of Budesonide demonstrated a remission rate of 62% which was significantly better than the 36% with 4 g/day mesalamine.

Budesonide has been subjected to a lot of investigation in clinical trials. A few are summarized here:

(a)In one placebo-controlled trial in mild-moderate CD remission rates were 50% with Budesonide when it was used in a dose of 9 g/day.

(b)In another 16 week study, comparative with Mesalamine, 9 g/day of Budesonide demonstrated a remission rate of 62% which was significantly better than the 36% with 4 g/day mesalamine.

Immune Modulating Drugs: These drugs interfere with the natural immune system of the body and blocks them. This category includes Azathioprine (AZA), 6-Mercaptopurine (6-MP) and Methotrexate. These drugs are considered in:

  1. Patients with active CD who do not respond adequately to the first-line therapy
  2. Patients in whom steroids cannot be tapered
  3. Patients who have fistulas and cannot tolerate the first-line drugs
  4. Patients requiring post-surgical prophylaxis

Azathioprine and 6-Marcaptopurine

The two are related i.e. AZA is a precursor of 6-MERCAPTOPURINE. 6-MERCAPTOPURINE is metabolized by 3 competing enzymes and one of them, Thiopurine Methyltransferase (TPMT,converts 6-MERCAPTOPURINE to 6-methyl-mercaptopurine. This reaction is a safety valve for patients receiving 6-MERCAPTOPURINE. Under normal situations, some 6-MERCAPTOPURINE is metabolized,while some is converted to its active derivative 6-thioguanine, which in turn inhibits cell multiplication and contributes to the therapeutic action. However,in individuals who are deficient in this converting enzyme most or all of the 6-MERCAPTOPURINE is metabolized to 6-thioguanine,resulting in high levels of 6-thioguanine causinfg side-effects such as leukopenia and bone marrow suppression, which are life threatening.

The doses at which AZA and 6-MERCAPTOPURINE are usually used are 2-3 mg/kg/day and 1-1.5 mg/kg/day respectively. Some clinicians prefer to gradually increase the dose over a period of time to better acclimatize the body to these drugs and improve the tolerability.

Precautions: While on these drugs patients should undergo regular complete blood count according to the following schedule: Weekly for 4 weeks, once in 2 weeks for 4 weeks, once in 1-3 months for the entire duration of the therapy. In addition, periodic checks on the liver function are also advised.


Methotrexate is an analog (structurally related) to dihydrofolic acid - an essential vitamine for the normal function of the body. At higher doses methotrexate inhibits multiplication of cells, while at lower doses it has demonstrated significant anti-inflammatory actions. Specifically, it can inhibit TNF-alpha in macrophages - kind of white blood cells. Originally it was used for diseases such as Psoriasis and Rheumatoid Arthritis.

Methotrexate is a good drug for inducing remission as well as maintaining remission. It is used more commonly in CD and is preferred for those patients who have shown intolerance to 6-MERCAPTOPURINE. Depending on the need in the patient, it may be administered intramuscularly, subcutaneously or orally. Methotrexate acts by:

  1. Anti-proliferative action (prevents cell multiplication) by virtue of its folate antagonistic action
  2. Immunosuppressive action by induction of adenosine - a component of genes
  3. Immuno-modulating and Anti-inflammatory action by its inhibition of IL-1, IL-2, IL6, IL-8

Methotrexate has been investigated in CD in clinical trials. A few representative results are summarized here:

a.In one randomized, placebo-controlled trial in chronic CD (at least 3 months of steroid and failure to taper) 39.4% patients on Methotrexate achieved remission compared to 19.1% in placebo-treated patients by 8 weeks. The dose used was a weekly intramuscular dose of 25mg.

b.In another randomized study, patients who experienced remission with weekly intramuscular doses of 25mg, were administered weekly intramuscular doses of 15mg or placebo and studied for maintenance of remission. At 40 weeks, 65% of patients on Methotrexate were on remission compared to 39% on placebo.


  1. As with AZA and 6-MERCAPTOPURINE, regular complete blood cell count should be done every 1-2 months.
  2. As with AZA and 6-MERCAPTOPURINE, integrity of the liver function should also be tested for every 1-2 months.
  3. Besides the above mentioned tests, oral folic acid supplementation should be administered in dose of 1-2 mg/day to prevent nausea and inflammation and ulcers in the mouth.


  1. Stomatitis (inflammation and ulcers in the mouth)
  2. Nausea, Vomiting
  3. Hair Loss
  4. Leukopenia (decrease in white blood cells)
  5. Increase in liver enzyme (indicates mild functional abnormality of liver function)

Cyclosporine A:

Cyclosporine A is an immunosuppressant drug which is primarily used in organ transplants,such as of kidney and heart,to prevent rejection of the transplanted organ.Its immunosuppressant action has found application in management of severe cases of ulcerative colitis.The following are the specific scenarios that may warrant the deployment of cyclosporine A:

  1. Cases that do not respond adequately to corticosteroids.
  2. Cases resistant to corticosteroid and not willing to undergo surgery.

As "bridge-therapy" until effects of AZA or 6-MERCAPTOPURINE begin. The drug has the potential to maintain remission for long periods.It,however,has its share of side-effects that can limit its use (fever,nausea,vomiting diarrhea,peptic ulcers,gingival hyperplasia,convulsions,etc.)