IBD: GC, purine analogs and MTX Domina Petric, MD Inflammatory Bowel Disease Pharmacology

Glucocorticoids (GC) In gastrointestinal practice, prednisone and prednisolone are the most commonly used oral GC. These drugs have an intermediate duration of biologic activity: once-daily dosing.

Glucocorticoids (GC) Hydrocortisone enemas, foam and suppositories are used to maximize colonic tissue effects and minimize systemic absorption via topical tratment of active inflammatory bowel disease in the rectum and sigmoid colon. Absorption of hydrocortisone is reduced with rectal administration. 15-30% of the administered dosage is still absorbed.

Budesonide It is potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor. It is a subject to rapid first-pass hepatic metabolism (in part by CYP3A4). That results in low oral bioavailability.

Budesonide A controlled-release oral formulation of budesonide (Entocort) releases the drug in the distal ileum and colon. The bioavailability of controlled-release budesonide capsule is approximately 10%.

Glucocorticoids: inhibit production of inflammatory cytokines (TNF-α, IL-1) and chemokines (IL-8) reduce expression of inflammatory cell adhesion molecules inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2 and NF-κB

Clinical uses GC are commonly used in the treatment of patients with moderate to severe active inflammatory bowel disease. Active disease is treated with an initial oral dosage of 40-60 mg/d of prednisone or prednisolone.

Clinical uses Once a patient responds to initial therapy (usually within 1-2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously.

Clinical uses For IBD involving the rectum or sigmoid colon, rectally administered GC are preffered (lower systemic absorption). Oral controlled-release budesonide 9 mg/d is used in the treatment of mild to moderate Crohn´s disease involving the ileum and proximal colon.

Clinical uses GC are not useful for maintaining disease remission. Aminosalicylates or immunosupressive agents are used for this purpose.

Most common side effects sodium and fluid retention in the body weight gain swelling of the legs (edema) high blood pressure loss of potassium headache muscle weakness

Most common side effects puffiness of the face (moon face) facial hair growth thinning and easy bruising of the skin slow wound healing glaucoma, cataract ulcers in the stomach and duodenum osteoporosis

Most common side effects loss of diabetes control menstrual irregularity buffalo hump (rounding of the upper back) obesity, diabetes depression, euphoria, insomnia mood swings

Purine analogs: azathioprine, 6-mercaptopurine

Pharmacokinetics Azathioprine and 6-mercaptopurine (6-MP) are purine antimetabolites with immunosuppressive properties. The bioavailability of azathioprine (80%) is superior to 6-MP (50%). After absorption azathioprine is rapidly converted by a non-enzymatic process to 6-MP.

Pharmacokinetics 6-MP undergoes a complex biotransformation via competing catabolic enzymes: xanthine oxidase, thiopurine methyltransferase. These enzymes produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides.

Pharmacokinetics Azathioprine and 6-MP have a serum half-life of less than 2 hours. The active 6-thioguanine nucleotides are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from orally administered purine analogs.

Clinical uses Purine analogs are important agents in the induction and maintenance of remission of IBD. Most patients with normal thiopurine-S-methyltransferase (TPMT) activity are treated with 1-1,5 mg/kg/d of 6-MP and 2-2,5 mg/kg/day of azathioprine.

Clinical uses After 3-6 months of treatment, 50-60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Purine analogs allow dose reduction or elimination of GC in most of the patients.

Adverse effects Dose-related toxicities of purine analogs are nausea, vomiting, bone marrow depression and hepatic toxicity. Bone marrow depression leads to leukopenia, macrocytosis, anemia and thrombocytopenia.

Adverse effects Routine laboratory monitoring of complete blood count and liver function tests is required in all patients. Leukopenia and elevations in liver chemistries usually respond to medication dose reduction.

Adverse effects Severe leukopenia may predispose to opportunistic infections. Leukopenia may respond to therapy with granulocyte stimulating factor.

Adverse effects Catabolism of 6-MP by TPMT is low in 11% and absent in 0,3% of the population. In those patients there is increased production of active 6-thioguanine metabolites and increased risk of bone marrow depression.

Adverse effects TPMT levels can be measured before initiating therapy. These drugs should not be administered to patients with no TPMT activity. For the patients with intermediate activity lower doses are needed.

Adverse effects Hypersensitivity reactions to purine analogs occur in 5% of patients: fever rash pancreatitis diarrhea hepatitis

Adverse effects There may be increased risk of lymphoma in patients taking purine analogs. Although these drugs cross the placenta, risk of teratogenicity appears to be small.

Drug interactions That may lead to severe leukopenia. Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides. That may lead to severe leukopenia. Allopurinol should be avoided in patients taking purine analogs, except in carefully monitored situations and if necessary.

Methotrexate (MTX)

Pharmacokinetics MTX is antimetabolite used in IBD. It may be given orally, subcutaneously or intramuscularly. Reported oral bioavailability is 50-90% at doses used in chronic inflammatory diseases.

Pharmacodynamics The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, MTX inhibits cellular proliferation.

Pharmacodynamics At low doses used in the treatment of IBD (12-25 mg/weak), the antiproliferative effects may not be evident. MTX may interfere with the inflammatory actions of IL-1.

Pharmacodynamics It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. MTX may also stimulate apoptosis and death of activated T lymphocytes.

Clinical uses MTX is used to induce and maintain remission in patients with Crohn´s disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, MTX is given once weekly 15-25 mg sc.

Clinical uses If a satisfactory response is achieved within 8-12 weeks, the dose is reduced to 15 mg/wk.

Adverse effects At higher dosage, MTX may cause bone marrow depression, megaloblastic anemia, alopecia and mucositis. At lower doses used in IBD these side effects are less common. Folate supplementation is recommended.

Adverse effects In patients with psoriasis treated with MTX, hepatic damage is common. Among patients with IBD and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology. www.medicinenet.com