Drugs For Inflammatory Bowel Disease Flashcards
Pathogenesis of IBD and target sites for treatment in CD and UC (3)
- TH1 and TH17 pathways predominate in CD: TH1 activates TNF-alpha, which activated macrophages
- TH2 and TH17 pathways predominate in UC: IL-4 induces TH2 differentiation
- Balance of pro-inflammatory and anti-inflammatory events are regulated by TH17 and TReg cells, which limit immune and inflammatory responses
Goals of IBD Pharmacotherapy (5)
- Induction of clinical remission
- Maintenance of remission
- Improvement of quality of life
- Avoidance of surgery
- Prevention of complications
IBD Treatment Pyramid (mild to severe)
Mild: 5-ASAs, Antibiotics (less use nowadays), topical corticosteroids (proctitis), budesonide (ileitis)
Moderate: Azathropine/6-mercaptopurine, methotrexate, oral corticosteroids, TNF antagonists
Severe: IV corticosteroids, TNF antagonists, Cyclosporine, Natalizumab, Surgery
5-Aminosalycilates (agents, general, MOA, PK, pregnancy, indications)
Agents: mesalamine, sulfasalazine, olsalazine, balsalazide
General: prodrugs (sulfasalazine, olsalazine, balsalazide) and formulations that have been created to be delivered to the distal GI tract. Efficacy is due to topical effect on the GI mucosa and not by systemic effects. Drugs work best when high concentrations are achieved at the site of disease.
MOA: Improvement in inflammation may occur due to blockage of COX-2 and prostaglandin synthesis in the colon. Inhibits production of IL-1 and TNF-alpha. Inhibits NK cells, mucosal lymphocytes, and macrophages.
PK: t1/2: 5-10 hours
Pregnancy: B
Indications: UC and CD
Different formulations of 5-ASAs and their targets (8)
- Mesalamine enema suspension (left colon + rectum)
- Mesalamine suppository (rectum)
- Mesalamine delayed-release tablets (colon +/- distal ileum)
- Mesalamine controlled release tablets (entire small bowel + colon)
- Mesalamine capsules with delayed release granules (colon)
- Sulfasalazine 5-ASA azo-bound to sulfapyridine (colon)
- Olsalazine 5-ASA dimer linked by azo bond (colon)
- Balsalazide 5-ASA azo-bound to inert carrier (colon)
Azo compounds of 5-ASA (3)
- Azo compounds decrease absorption in small intestine.
- Bacteria cleave azo bond in terminal ileum and colon (azoreductase enzyme)
- Sulfasalazine, olsalazine, and balsalazide are 5-ASAs bound by an azo bond to another compound (colon targets ONLY!)
Caveat with sulfasalazine
Is a sulfa drug and may induce a reaction in patients with sulfa allergies. Should be avoided in these patients.
Metabolites of 5-ASA drugs (4)
- All prodrugs and mesalamine create N-acetyl-5-ASA metabolite; formed by N-acetyltransferase
- Other metabolite of sulfasalazine: sulfapyridine
- Other metabolite of balsalazide: 4-ABA
- *Olsalazine does not have another metabolite as it is a 5-ASA dimer
5-Aminosalicylates (ADRs, DDIs, and considerations)
ADRs: Common- headache, nausea, diarrhea, interstitial nephritis
Sulfasalazine- high incidence of ADRs due to sulfapyridine. 40% of patients cannot tolerate. May cause allergic reactions, hemolytic anemia, leukopenia, hepatitis. Slow acetylators experience more ADRs and fast acetylators experience fewer ADRs.
DDIs: Concurrent use with azathropine or mercaptopurine and mesalamine may result in increased risk of myelosuppression. Abx reduce availability of active moiety due to decreased levels of azoreductase enzyme (decreases prodrug efficacy). Lactulose lowers pH of intestine and decrease release of pH dependent formulations. Antacids, H2 antagonists, PPIs may cause premature release of delayed or extended-release products because they raise pH. Renal or liver impairment patients need dose adjustment.
Considerations: sulfasalazine should not be used in patients with sulfa allergy. Folic acid needs to be co-administered with sulfasalazine.
Glucocorticoids vs. Mineralcorticoids (clinical indications and delivery site) [5]
- Glucocorticoids produce an anti-inflammatory effect
- Mineralcorticoids cause Na+ and H2O retention (unwanted effects)
- Budesonide (oral controlled release/rectal), prednisone (oral), and methylprednisolone (IV) all have greater glucocorticoid potency than mineralcorticoid potency.
- These drugs are indicated in the treatment of Acute UC and CD
5 *Hydrocortisone has an equal ratio of glucocorticoid and mineralcorticoid, but is used for UC and CD topically (rectal) or IV (less common of use)
Glucocorticoids (agents, MOA, PK, pregnancy, indications)
Agents: budesonide, prednisone, methylprednisolone
MOA: anti-inflammatory corticosteroids with potent glucocorticoid and weak mineralcorticoid activity. Broad range of active inhibition against multiple cell types and mediators involved in inflammation.
PK: t1/2: 2-3.5 hours. Use with caution in patients with renal disease
Pregnancy: may be used cautiously for induction of remission in pregnant women with IBD. Use only if potential benefit justifies potential risk to fetus. Monitor infants born to mothers receiving glucocorticoids during pregnancy for signs and symptoms of hypoadrenalism.
Indications: UC and CD
Glucocorticoids (ADRs, DDIs, Considerations)
ADRs: Common- infections, osteopenia, osteoporosis, adrenal insufficiency, avascular necrosis, weight gain, insomnia, mood changes, delirium, cataracts, glaucoma, striae, delayed wound healing
DDIs: Concurrent use with fluoroquinolones may result in an increased risk of tendon rupture. Concurrent use with aminoglycoside antibiotics may increase ototoxicity.
Considerations: May decrease hypoglycemic effects in DM patients; cause hyperglycemia. May cause hypotension in patients being treated for HTN.
Immunosuppressant agents - Thiopurines (agents, MOA, PK, pregnancy, indications)
Agents: 6-mercaptopurine, azathioprine (prodrug of 6-mercaptopurine)
MOA: Impairs purine biosynthesis and inhibits cell proliferation, which impacts T and B cells.
PK: Mercaptopurine has 50% bioavailability. Azathioprine has 80% bioavailability. Azathioprine is non-enzymatically converted to 6-mercaptopurine. 6-mercaptopurine is converted to its inactive metabolite 6-methyl-mercaptopurine (6-MMP) by TPMT.
Pregnancy: D
Indications: UC and CD
Immunosuppressant agents - Thiopurines (ADRs and DDIs)
ADRs: Common- gastritis, nausea, vomiting, fever, hepatic encephalopathy, pancreatitis. BLACK BOX WARNING- long-term immunosuppression with this drug increases risk of NEOPLASIA.
Pharmacogenomics- Thiopurine methyltransferase (TMPT): poor metabolizers (reduced levels of TMPT) are at increased risk for developing severe, life-threatening MYELOTOXICITY
DDIs: use with live vaccines may result in an increased risk of INFECTION
Immunosuppressant agents - Antimetabolite (Methotrexate) [MOA, PK, pregnancy, indications)
MOA: Inhibits dihydrofolate reductase. Interferes with inflammatory actions of IL-1 and stimulates apoptosis of activated T lymphocytes.
PK: t1/2: 3-10 hours
Pregnancy: X. Do not use in women of childbearing age.
Indications: CD
Immunosuppressant agents - Antimetabolite (Methotrexate) [ADRs and DDIs]
ADRs: Common- alopecia, photosensitivity, rash, diarrhea, anorexia, nausea, vomiting, stomatitis, leukopenia, pneumonitis. BLACK BOX WARNING- fibrosis and cirrhosis with prolonged use, malignant lymphoma, fetal death and congenital abnormalities, hepatotoxicity
DDIs: Use with live vaccines may increase risk of INFECTION. Oral abx may decrease absorption of methotrexate (decreased efficacy)
Immunosupprssant agents - Calcineurin inhibitors (agents, MOA, PK, Pregnancy, indications)
Agents: cyclosporine and tacrolimus
MOA: inhibits the cytoplasmic phosphatase calcineurin. Calcineurin is essential for T cell activation and multiplication.
PK: t1/2: 23-46 hours
Pregnancy: N/A. Use only if benefit > risk to fetus. Drug is present in breast milk.
Indications: CD
Immunosuppressant agents - Calcineurin inhibitors (ADRs, DDIs, and considerations)
ADRs: Common- HTN, hypertrichosis, nephrotoxicity, hyperkalemia, infection, lymphoma, skin cancer, hepatitis, seizures. Tacrolimus may cause DM. BLACK BOX WARNING- increased risk of developing infections and malignancies.
DDIs: Concurrent use of tacrolimus and mesoridazine or fluconazole may prolong QT interval
Considerations: Glucose levels may increase during tx. Inform lactose-intolerant patients that oral formulation contains lactose.
Anti-TNF Antibodies (agents, MOA, PK, pregnancy, indications)
Agents: infliximab, adalimumab, golimumab, certolizumab, etanercept
MOA: TNF-alpha inhibitor. Results in interference in the production of downstream inflammatory mediators, including IL-1, prostaglandins, platelet activating factor, and nitric oxide
PK: t1/2: varies by formulation (golimumab 2 weeks; adalimumab 10-20 days)
Pregnancy: N/A. Use only if benefits > risk to fetus.
Indications: CD
Anti-TNF Antibodies (ADRs, DDIs, Considerations)
ADRs: Common- infusion/injection site reaction, infection, melanoma, reactivation of latent TB and hepatitis B, drug-induced lupus, demyelination disease, psoriasiform reactions, worsening of CHF
DDIs: No clinical signification interactions
Considerations: TNF-alpha can be identified in the stool of patients with CD. Concentration of TNF-alpha may be correlated to disease severity. Drugs may reactivate latent TB or hepatitis B, so patients should be tested before starting therapy.
Adhesion Molecular Inhibitors (agents, MOA, PK, pregnancy, indications)
Agents: vedolizumab and natalizumab
MOA: Specifically binds to the integrin receptor expressed on T cells and blocks interaction with mucosal cell adhesion molecules. Inhibits movement of memory T cells across the endothelium into inflamed GI tissue.
PK: t1/2: 3-17 days
Pregnancy: N/A. Use only if benefits > risks to fetus
Indications: CD an UC
Adhesion Molecular Inhibitors (ADRs, DDIs, Considerations)
ADRs: Common- infusion/injection site reaction, infection
DDIs: no clinical signification interactions
Considerations: Used in patients with inadequate response to, loss of response to, or intolerance to TNF-alpha inhibitors or immunomodulators
Anti-interleukin 12/23p40 Antibody (ustekinumab) [MOA, PK, pregnancy, indications]
MOA: human IgG-kappa monoclonal antibody that binds to p40 subunits of the interleukin (IL)-12 and IL-23 cytokines, which are involved in inflammatory and immune responses. Disrupts the IL-12 and IL-23 cytokine responses that have been linked to the chronic inflammation in CD by TH1 and TH17.
PK: t1/2: 10-126 days
Pregnancy: N/A. Use only if benefits > risks to fetus.
Indications: CD
Anti-interleukin 12/23p40 Antibody (ustekinumab) [ADRs, DDIs, and Considerations]
ADRs: infusion/injection site reaction, infection
DDIs: Echinacea may decrease therapeutic effect
Considerations: avoid live vaccines
General first line treatment for mild to moderate extensive UC
Oral 5-ASAs with oral glucocorticoids
General treatment of acute UC or CD
Systemic corticosteroids. Duration of use should be minimized and the dose should be gradually tapered over 3-4 weeks.
General treatment of moderate to severe active UC or UC patients who are corticosteroid dependetnt
Anti-TNF antibodies
General treatment for maintenence or remission in UC as an alternative to or in combination with TNF-alpha inhibitors, in patients failing 5-ASAs, or with corticosteroid dependency.
Thiopurines
General treatment for UC patients failing TNF-alpha inhibitors
Adhesion molecule inhibitors
General treatment for maintenance and prevention of recurrence of acute UC
5-ASA agents; corticosteroids are ineffective for this purpose
General treatment at induction and maintenance for CD patients with moderate to severe disease or fistulizing disease
Anti-TNF inhibitors
General treatment in CD patients with inadequate response to reduced steroid dosage in combination with TNF-alpha inhibitors
Thiopurines and methotrexate
General treatment for CD patients failing anti-TNF inhibitors
Adhesion molecular inhibitors
General treatment for CD patients with refractory disease
Calcineurin inhibitors
