PHRM 736 Drug Action II IBD PDF

PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material 1. Differentiate between ulcerative colitis (UC) and Crohn’s disease (CD), areas being affected, differences in immunologic properties being activated, and primary symptoms of the disease....

PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material 1. Differentiate between ulcerative colitis (UC) and Crohn’s disease (CD), areas being affected, differences in immunologic properties being activated, and primary symptoms of the disease. two types of idiopathic inflammatory bowel disease: o ulcerative colitis = mucosal inflammation, affecting the rectum and colon § humoral mediated immunity; B cells o Crohn’s disease = transmucosal inflammation, affecting any part of body § cell mediated immunity; T cells symptoms: bloody diarrhea 2. Identify names and classes of drugs used to treat IBD. anti-inflammatory drugs: aminosalicylates; 5-ASA (5-aminosalicyclic acid) o azo: Azulfidine, Dipentum, Colazal o mesalamine (5-ASA): Pentasa, Azacol, Rowasa, Canasa, Lialda others: o glucocorticoids: prednisone, prednisolone, budesonide, methylprednisone o thiopurines: azathioprine, 6-mercaptopurine o immunosuppressives: methotrexate, cyclosporine o anti-TNF ∝: infliximab, adalimumab, certolizumab pegol, natalizumab o IL-receptor antagonist: ustekinumab o janus kinase inhibitors: tofacitinib 3. Identify MOA, ADRs, active compounds, and supplementation of sulfasalazine. MOA inhibits synthesis of prostaglandins (anti-inflammatory); azo (N=N) is broken down to 5-ASA (active compound) side effects sulfa allergy, headache, rash, n/v/d, bone marrow suppression, yellow-orange discoloration of skin/urine active compounds mesalamine = 5-ASA DDI folic acid (may need supplementation – 1 g/day) Þ has the most side effects but is the least expensive!! Þ bone marrow suppression due to depletion of folate  PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material 4. Identify MOA and ADRs of glucocorticoids. MOA inhibit production of cytokines cushing’s syndrome, adrenal suppression, insomnia, behavior side effects changes, peptic ulcers, hyperglycemia, impaired wound healing, immunosuppression, osteoporosis, increase intraocular pressure, hypertension, hypokalemia Þ all are pregnancy category C, EXCEPT budesonide (pregnancy category B) Þ patients need to be on high protein and potassium-rich diets (due to hypokalemia) Þ avoid abrupt discontinuation Þ patients who are unresponsive to glucocorticoids, cannot take them!! Þ patients who are dependent on glucocorticoids, must take a small dose for life 5. Identify MOA, ADRs, and DDI effects of thiopurines. 6-TG (active compound) suppresses purine nucleotide metabolism MOA and DNA synthesis à inhibits cell division and proliferation inhibits B and T cell function side effects n/v, hepatotoxicity, lymphoma, leukopenia, thrombocytopenia boxed warning lymphoma, leukopenia, thrombocytopenia DDIs: allopurinol Þ must monitor CBC and LFTs Þ if a patient has both gout and IBD, a high dose of allopurinol is still needed, so you must decrease dose of 6-TGN (azathioprine) o allopurinol = xanthine oxidase inhibitor 6. Identify metabolites being made and slow/fast metabolizers of thiopurines. 6-mercaptopurine (6- MP) must be taken on an empty stomach!! Þ azathioprine and 6-MP are metabolized 3 different ways: o oxidative pathway: XO à 6-TU = inactive o s-methylation: TPMT à 6-MMP = inactive o HGPRT à active nucleotide 6-TGN § must decrease dose in poor metabolizers (patients who don’t have TPMT) due to increased risk of bone marrow suppression § must increase dose in rapid metabolizers PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material 7. Identify MOA, ADRs, use, & antidote of methotrexate at a low and high dose. MOA low dose: inhibits AICAR à inhibits IL-2 à decreases inflammation high dose: inhibits cell-mediated immunity à decreases inflammation 4 cancer uses Crohn’s disease, autoimmune diseases, rheumatoid arthritis, psoriasis, lupus, dermatomyositis, cancers, immunosuppressant side effects myelosuppression, oral ulceration/stomatitis, renal effects, n/v, increased LFTs, pneumonitis, photosensitivity, alopecia, crystalluria (high dose) antidote leucovorin Þ must monitor LFTs Þ stay hydrated and make urine basic (using bicarb) to prevent renal toxicity 8. Define MOA, identify drug names, and ADRs of anti-TNF-alpha agents. MOA inhibit TNF à decrease cytokine release drug names infliximab, adalimumab, certolizumab, golimumab side effects ↑infections, reactivation of latent TB, hep B, lymphoma Þ should not be given to immunocompromised patients Þ how to name monoclonal antibodies: o -mab or -monab = monoclonal antibody o the letter before mab indicates the source of antibody § o = mouse | u = human | xi = chimeric o the internal letter indicates therapeutic use § “tu” = tumor | “vi” = virus | “ci” = circulation o ex: rituximab à chimeric human murine-monoclonal antibody PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material 9. Identify drugs with more potency and the reason for potency of anti-TNF- alpha agents. infliximab and adalimumab are more potent because they contain an Fc portion that activates the complement pathway o Fc portion binds to membrane bound NTF à activates complement pathway à increases potency certolizumab is less potent because it lacks the Fc portion 10. Identify MOA, ADRs, and drug names of integrin receptor antagonist, janus kinase inhibitor, cyclosporine, and inhibitors of IL-12/23. integrin receptor antagonist; adhesion molecule antagonist humanized mab à blocks migration of lymphocytes natalizumab side effects: infusion reactions, headache, fatigue, brain infection (PML) binds to alpha-4-beta-7 integrin à blocks interaction of integrin with MadCAM-1 à inhibits migration of memory vedolizumab T cells into inflamed GI tissue side effects: nasopharyngitis, headache, arthralgia, brain infection (PML) Þ for infusion reactions, take Tylenol or benadryl!! o if an allergic reaction, STOP TAKING Þ if there is no therapeutic benefit in 12 weeks, d/c treatment for natalizumab!! janus kinase inhibitor MOA inhibits janus kinase à inhibits immune cell functions drug names tofacitinib (Xeljanz) side effects increased LFTs, increases lipids, infusion reactions, infections Þ not a monoclonal antibody but a small molecule that can be taken PO Þ mostly used for rheumatoid arthritis but shows benefits in IBD PHRM 736 | Drug Action II | Pharmacology of Drugs to Treat IBD Dr. Bennett | Objectives | Exam 1 Material cyclosporine (CsA) suppresses cell mediated immune reactions MOA binds to cyclophilin to prevent formation of IL-2 calcineurin inhibitor drug names Sandimmune à low bioavailability (PO) Neoral; Gengraf à better bioavailability side effects nephrotoxic, neurotoxic (tremors), hepatotoxic, increased risk of lymphoma, infections, HTN, gingival hyperplasia DDIs ketoconazole, grapefruit juice boxed warning renal impairment, lymphoma, infections, HTN Þ most effective immunosuppressive drug o lymphoma and infection risk are common with immunosuppressive agents IL-12/23 inhibitors MOA decrease IL-12/23 à disrupt immune cells that cause inflammation drug names ustekinumab (Stelara) side effects pneumonia, increases risk of TB, cancers, infusion reactions Þ also used for psoriasis Þ these are biologic monoclonal antibodies Þ watch youtube video on this!!