GI Drugs for IBD Treatment PDF

GI Medications Treatment of Inflammatory Bowel Disease Debra Forzese, Pharm. D. Inflammatory Bowel Disease (IBD) Goals of drug therapy for IBD o Suppress inflammation o Induce remission o Maintain disease remission IBD Drug Therapy 5-Aminosalicylates (Sulfasalazine, Mesalamine) Corticosteroids (Bude...

GI Medications Treatment of Inflammatory Bowel Disease Debra Forzese, Pharm. D. Inflammatory Bowel Disease (IBD) Goals of drug therapy for IBD o Suppress inflammation o Induce remission o Maintain disease remission IBD Drug Therapy 5-Aminosalicylates (Sulfasalazine, Mesalamine) Corticosteroids (Budesonide, Prednisone) Immunomodulators (azathioprine, mercaptopurine) Immunosuppressives (cyclosporine, tacrolimus) TNF- ⍺ inhibitors (Adalimumab, Certolizumab) ⍺4-Integrin inhibitors (Natalizumab, Vedolizumab) Anti-Interleukin 12/23 (Ustekinumab) Janus Kinase Inhibitors (Tofacitinib) Goal of IBD Treatment Treat early in the disease course Treat aggressively with biologics Administer dual therapy with immunomodulators and biologics in appropriate patients Aim for deep remission (endoscopic and histologic remission) Patients who respond to biologic therapies enjoy an improvement in clinical symptoms, have better quality of life, have less disability, fatigue, and depression, and have fewer surgeries and hospitalizations Aminosalicylates (5-ASA) Aminosalicylate Agents Azo Compounds(prodrugs) o Sulfasalazine (Azulfadine) o Balsalazide (Colazal) o Olsalazine (Dipentum) Mesalamine Compounds o Mesalamine (Pentasa, Lialda) o Mesalamine enema o Mesalamine suppository Sulfasalazine Indication o Treatment of mild to moderate ulcerative colitis o Adjunctive therapy in severe ulcerative colitis o Prolongation of remission period between acute attacks of ulcerative colitis Off label – Crohn disease Sulfasalazine Dosing Adult – initiate with low dose to reduce GI intolerance Pediatric Renal impairment – limited data on safety with preexisting kidney disease, if possible, avoid use o if necessary, use caution with lowest effective dose and monitor kidney function frequently Hepatic impairment – use with extreme caution, no dose adjustments provided by manufacturer Sulfasalazine Mechanism of action Specific mechanism of action unknown Inhibit production of chemical mediators of inflammatory response Free radical scavenger or inhibitor of tumor necrosis factor Local effects on GI mucosa rather than systemic activity Sulfasalazine Pharmacokinetic/Pharmacodynamic Factors Onset of action for ulcerative colitis 3-4 weeks Slow acetylators – prolonged half life Sulfasalazine Adverse Effects Anorexia, nausea, vomiting, gastric distress Headache Blood dyscrasias Hepatotoxicity Hypersensitivity –anaphylaxis, skin rash Nephrotoxicity (rare) Male infertility (reversible) Sulfasalazine Drug Interactions Covid-19 vaccines – sulfasalazine can reduce therapeutic effect of Covid vaccines Methenamine – may increase adverse effects of sulfasalazine NSAIDs – can enhance nephrotoxic effect of sulfasalazine Folic Acid – sulfasalazine can reduce folic acid levels Sulfasalazine Warnings Folate deficiency – can reduce folic acid absorption Infections – severe infections, sometimes fatal sepsis and pneumonia Sulfasalazine Pregnancy – may be continued at maintenance doses, not preferred drug in this class for use in pregnant women Breastfeeding – manufacturer recommends caution when administering sulfasalazine to breastfeeding women; considered compatible for use in females with IBD who are breastfeeding; however, sulfasalazine not the preferred drug in this class for lactating women Glucocorticoids Glucocorticoids Glucocorticoids FDA approved for treatment of IBD (moderate to severe) o Prednisone o Prednisolone o Methylprednisolone o Budesonide o Triamcinolone Glucocorticoids induce a reduction in the inflammatory response and symptomatic remission in most patients with Crohn’s disease, with improvement generally occurring within 5 days of initiating treatment; however, some patients require treatment for several weeks before remission occurs Glucocorticoids Used commonly in moderate to severe active IBD Inhibit production of inflammatory cytokines, reduce inflammatory cell adhesion molecules Once patient responds, usually within 2 weeks, dosage is tapered to minimize adverse effects Can be administered IV in severe cases Active cases of IBD in the rectum and sigmoid colon treated with hydrocortisone enemas, foam, suppositories to maximize colonic effects while minimizing systemic absorption Despite efficacy of glucocorticoids, they have several serious side effects including osteoporosis, hyperglycemia, gastric ulcers, increased susceptibility to infections Maintenance treatment with systemic glucocorticoids is not recommended Glucocorticoids Budesonide – synthetic analog of prednisolone, released entirely in the colon Has significant first pass hepatic metabolism, resulting in low oral bioavailability Slightly less effective than prednisolone in producing clinical remission but much less systemic side effects Glucocorticoids No proven efficacy in maintaining remission in IBD and should not be used for this Risk of significant side effects from use of glucocorticoids increases with prolonged use and therefore alternative treatments should be considered if patients require repeat course of glucocorticoids within 3 months Alternative treatments include immunomodulators or biologics Purine Analogs Purine Analog Agents Azathioprine 6-Mercaptopurine Purine Analogs Indications Off label use in IBD Prolonged half life (days) Onset of therapeutic benefit in IBD – up to 17 weeks Play important role in inducing and maintaining remission of IBD Used in combination with anti-TNF therapy with moderate to severe IBD o Synergistic anti-inflammatory activity o Reduced clearance of anti-TNF agent o Reduced neutralizing antibodies against anti-TNF agent Sometimes used as monotherapy to allow reduction or elimination of corticosteroids Purine Analogs Adverse Effects Pancreatitis Nausea, vomiting Bone marrow depression – increased risk of infections, monitor blood counts Hepatotoxicity – monitor liver function Hypersensitivity – fever, rash, pancreatitis, hepatitis T-cell lymphoma – long term use Drug Interactions Allopurinol – significant increased levels of purine analogs that can lead to leukopenia Anti-Tumor Necrosis Factor Therapy (Anti-TNF) Anti-TNF Agents Infliximab (Remicade) Adalimumab (Humira) Golimumab (Simponi) Certolizumab (Cimzia) Infliximab Administered by IV infusion Higher efficacy in Crohn’s disease – given as 3 infusions then every 8 weeks for maintenance of remission Approved for acute and chronic treatment of moderate to severe Crohn disease, with inadequate response to conventional therapies Use in patients with steroid dependence and inability to taper or steroid refractory disease Median time to clinical response is 2 weeks With chronic administration clinical response can be maintained and may have disease remission One third of patients may lose response to therapy Other agents in this class less effective Screen for coexistent infection with perianal and abdominal abscess High rate of disease flare when infliximab stopped, even with prolonged remission Anti-Integrin Therapy Anti-Integrin Agents Natalizumab (Tysabri) Vedolizumab (Entyvio) Anti-Integrin Anti-integrin agents inhibit interactions between leukocytes and intestinal vasculature, preventing influx of inflammatory cells, which mediate the inflammatory process in IBD, into intestinal lesions Leukocyte trafficking to the gut is central to the pathogenesis of IBD, its inhibition is recognized as an important goal in development of anti-IBD drugs Ant-Integrin therapy blocks action of integrins, suppressing the recruitment of inflammatory cells to intestinal lesions Vedolizumab (VDZ) More specific activity, inhibits lymphocyte trafficking selectively in the intestine Takes time to reach maximal effects of VDZ but has sustained effects VDZ more effective than anti-TNF therapy in maintenance phase Little systemic immunosuppression because VDZ acts selectively in intestine Half life 25 days Administered as IV infusion Before initiating treatment, all patients should be brought up to date with all immunizations Vedolizumab (VDZ) Adverse effects – nasopharyngitis headache arthralgia nausea fatigue Increased risk for developing infections Elevated liver enzymes, may lead to severe liver injury Hypersensitivity reactions - anaphylaxis Anti-IL-12/23 Therapy Ustekinumab Human monoclonal antibody that binds to cytokines Blocks cell signaling, cytokine production, gene activation which results in inhibition of cell mediated responses believed important in inflammation of Crohn’s disease Second line treatment for patients with moderate to severe Crohn’s Disease who have failed other therapies Half life 15-45 days Initial dose as weight based IV infusion then SQ dose every 8 weeks Well tolerated, low risk of serious adverse effects – most common upper respiratory infection Janus Kinase Inhibitors Tofacitinib (Xeljanz) Tofacitinib is approved for treatment of moderate to severe ulcerative colitis Taken orally, rapidly absorbed Short half life 3 hours Renal excretion and hepatic metabolism – dose reduction with renal or hepatic impairment Interrupts signaling pathway that influences production of several interleukins involved in mucosal inflammation Discontinue if no response by 16 weeks Should not be taken with other immunosuppressants Tofacitinib (Xeljanz) Adverse Reactions Immunosuppressive agent – increases risk of infections Increased risk of herpes zoster reactivation – vaccinate with Shingrix 3-4 weeks prior to treatment if possible May increase total cholesterol, HDL, LDL – check lipids 8 weeks after initiation of treatment NOT recommended for use in children – safety not established Black Box Warning per FDA in 2019 – increased risk of thrombosis, pulmonary embolism, death with higher doses