Pharmacology of IBD Agents PDF Fall 2024

PHM 736 Fall 2024 Lunawati Bennett MS, PhD; PharmD, FACN “He, your Teacher will no longer hide Himself, but your eyes will behold your Teacher. Your ears will hear a word behind you, “This is the way, walk in it, whenever you turn to the right or to the left.” - Isaiah 30:20-21  IBD-inflammato...

PHM 736 Fall 2024 Lunawati Bennett MS, PhD; PharmD, FACN “He, your Teacher will no longer hide Himself, but your eyes will behold your Teacher. Your ears will hear a word behind you, “This is the way, walk in it, whenever you turn to the right or to the left.” - Isaiah 30:20-21  IBD-inflammatory bowel disease  PABA- para aminosalicylic acid  TNF- tumor necrosis factor  HA- headache  UC- Ulcerative Colitis  CD- Crohn’s Disease  NVD- nausea, vomiting, diarrhea  COX- cyclooxygenase  CR- controlled release  PG- prostaglandin  MTX- methotrexate  LT- leukotriene  MTX PG- methotrexate polyglutamate  Th- T helper  PLA- phospholipase A  GSH- gluthathione Sulfydryl  LOX-lipooxygenase  IL- interleukin  NO- Nitric oxide  AICAR- amino-Imidazole Carboxamide  URTI- upper respiratory tract infection  6-TGN = 6TG—6-thioguanine nucleotides  Aza- Azathioprine  6 TU- 6 thiouric acid  6-MP = 6-mercaptopurine  PMN- poly morpho nuclear  6- MMP- 6 methylmercaptopurine  FPGS- folate poly glutamate syntase  DHFR- dihydrofolate reductase  FH4- tetra hydro folate= THF  TS = TYMS- thymydylate synthase  FH2- dihydro folate  HGPRT- hypoxanthine guanine  NF- nuclear factor phosphoribosyl transferase =HPRT  TPMT- thiopurine methyl transferase  GU- gastrourinary  5-ASA = 5- amino salicylic acid  GI- gastrointestinal At the end of this lecture and after studying the material, the student should be able to : 1. Differentiate UC and CD, area being affected, different in the immunologic properties being activated, and primary symptoms of the disease 2. Identify names and classes of drugs useful to treat IBD 3. Identify MOA, ADRs, active compound, supplementation needed for sulfasalazine 4. Identify MOA and ADRs of glucocorticoids 5. Identify MOA, ADRs, DDI effect on slow and fast metabolizers , and metabolites being made from thiopurines 6. Identify MOA, ADRs, use, and antidote of methotrexate at low and high dose 7. Define MOA, identify drug names, ADRs of anti-TNF  agents. Identify drug with more potency and reason of potency 8. Identify MOA, ADRs, drug names of : integrin receptor antagonist, Janus kinase inhibitor, cyclosporine, inhibitor of IL12/23, SP-1 modulator Generic Brand Drug class Methotrexate Trexall, Rheumatrex Folate antagonist, antimetabolite, Immunosuppressive Tofacitinib Xeljanz Janus kinase inhibitor 2 forms of Idiopathic IBD: ✓ Ulcerative colitis (UC): mucosal inflammation, ________________________ ✓ Crohn’s disease (CD): transmucosal inflammation, _____________________ Symptoms: ✓ bloody diarrhea, ✓ rectal urgency, ✓ tenesmus (feeling to pass stools, even when colon is empty), ✓ N,V, weight loss, ✓ fatigue https://www.youtube.com/watch?v=7nuWeubJczY Etiology Due to: ✓ Genetic ✓ Psychological ✓ Lifestyle ✓ Infectious agents like viruses, mycobacteria ✓ Immunologic: ▪ ↑↑Th1(↑ ______________ immunity, ↓ humoral mediated immunity ) in CD ▪ ↑↑ Th2 (↓ cell mediated immunity, ↑ __________________ immunity) in UC ▪ ↑ TNF → promote inflammatory cells, ↑ eicosanoids , LTB4 Active to moderate Active to severe Remission____ ↓ ↓ ↓ Aminosalicylate IV hydrocortisone Olsalazine (first-line) methylprednisolone ↓ ↓ Prednisone upon remission ↓ PO prednisone + amino salicylate If no response add Azathioprine or 6-mercaptopurine Anti diarrhea, antispasmodics, vitamins B12, vitamin D, calcium, iron, probiotics are also helpful for UC and CD Mild to moderate Active moderate to severe Remission__ ↓ ↓ ↓ Aminosalicylate Prednisone PO or IV methyl Aminosalicylates + prednisolone Infliximab, or ↓ ↓ Azathioprine, or Add metronidazole No response, add infliximab Methotrexate, or (perianal, small ↓ ↓ 6 MP bowel type) No response, remission, ↓ ↓ add azathioprine Taper off prednisone Anti diarrhea, antispasmodics, vitamins B12, vitamin D, calcium, iron, probiotics are also helpful for UC and CD  Anti-inflammatory Drugs: Aminosalicylates: 5-ASA (azo cpd or mesalamine cpd) - ______________: Azulfidine®, Dipentum®, Colazal® - ______________: Pentasa®, Azacol ®, Rowasa®, Canasa® , Lialda® Others (Immunosuppresants): ▪ Glucocorticoids: prednisone, prednisolone, budesonide, methyl prednisone ▪ Thiopurines: azathioprine, 6-Mercaptopurine ▪ Immunosuppressants: methotrexate, cyclosporine ▪ Anti-TNF : infliximab, adalimumab, certolizumab pegol ▪ Adhesion molecule Antagonist: natalizumab, vedolizumab ▪ Interleukin receptor antagonist: Ustekinumab ▪ Janus Kinase Inhibitors: Tofacitinib ▪ SP-1 Modulator: Zeposia® MOA: anti inflammatory, 5-ASA (active moiety) work to inhibit the synthesis of PG in the colon, interferes with the production of inflammatory cytokines, and inhibit cellular functions of natural killer cells, mucosal lymphocytes and macrophages. https://www.youtube.com/watch?v=-ittHMcSbCk Azo : ▪ Sulfasalazine (Azulfidine®, Sulfazine®)- see next slide for explanation ▪ Olsalazine (Dipentum®) (ADRs: watery diarrhea (10-25%, abdominal pain) ▪ Balsalazide (best tolerated. Test renal and hepatic function periodically) Colazal®-TID, Giazo® BID for males Mesalamine : Pentasa® (time-release micro-granules that release 5-ASA in small intestine, jejunum) Asacol® (5-ASA especially coated to dissolve at pH 7 in the distal ileum and proximal colon. DDI : bioavailability of digoxin, given TID) Lialda ® (pH dependent resin, slow release throughout the colon) Rowasa® (5-ASA enema, deliver to rectum) Canasa® (5-ASA suppositories, deliver to rectum) Sulfasalazine: least expensive, have the highest ADRs ADRs: _________________, more ADRs in slow acetylators, HA, rash, NVD 40% of pts experience ADRs with sulfasalazine: nausea, GI upset, myalgia, alopecia, ______________________ (Sulfasalazine impairs folate absorption, pts need 1 g/day folic acid supplementation) Cause yellow orange discoloration of skin and urine DDI: ↓ effect of digoxin, iron, folic acid, PABA drugs ↑ effect of oral anticoagulant, MTX, oral hypoglycemic Avoid use with antacids, H2RA, PPI (interfere with absorption) Pregnancy: B, D (at term) Contraindication: pts with sulfa or salicylate allergies, GI or GU obstruction MOA: inhibit production of inflammatory cytokines (TNF-, IL-I and IL-8), inhibit phospholipase A, and nitric oxide synthase Prednisone, prednisolone: QD dosing. Pregnancy C IV methylprednisolone: for severely ill pts. Pregnancy C Hydrocortisone: enemas, foam, rectal, suppositories, Pregnancy C Advantages: maximize colonic absorption, ↓systemic absorption (15-30%), ↓systemic ADRs Budesonide: first pass metabolism by CYP3A4, low oral bioavailability. Budesonide CR (Entocort®) releases the drug in the distal ileum and colon where it is absorbed. Less effective but less ADR than prednisone or prednisolone. Pregnancy B ADRs ▪ If use longer than 2 weeks can cause: iatrogenic Cushing's syndrome, adrenal suppression ▪ Insomnia, behavioral changes (primarily hypomania) ▪ Acute peptic ulcers ▪ Protein breakdown (catabolism) ▪ Hyperglycemia ▪ Impaired wound healing ▪ Immunosuppression : lower resistance to infection ▪ Osteoporosis ▪ ↑intraocular pressure ▪ Hypertension and hypokalemia Pts treated with corticosteroids should be on high-protein and potassium-enriched diets. Use for relapse IBD that required high dose of glucocorticoids, but need to taper off the dose. Do not stop taking glucocorticoids abruptly  MAO: 6 TG, suppresses purine nucleotide metabolism and DNA synthesis → inhibit cell division and proliferation (inhibit B and T cells function) ✓ Purine Analogs= antimetabolites Not FDA indication for IBD, but use in induction and maintenance during remission http://www.medscape.com/viewarticle/445620_2  AZA and 6-MP are metabolized into 3 routes: 1. oxidative pathway: XO→6-TU, inactive 2. S-methylation TPMT →6-MMP, inactive 3. HGPRT →active nucleotide 6-TGN http://www.nzma.org.nz/journal/118-1210/1324/  AZA is metabolized to active 6MP by glutathione Sulfhydryl t1/2 of AZA and 6-MP: short t1/2 of 6-TG : days, concentrated in cells. Due to prolonged onset of 6 TG →the therapeutic effect of AZA is seen after several weeks Drugs: Azathioprine (Imuran®) 6-mercaptopurine (Purinethol®)-like AZA, with less ADRs, take on empty stomach Use: IBD, prevent transplant rejection, RA, multiple sclerosis Pts with absent of TPMT (slow metabolizer) → risk myelosuppression ( 6-TG level) Rapid metabolizer → 4x faster clearance of the drug TPMT level can be measured before therapy ▪ DDI: allopurinol (must  dose of AZA to ¼ of 1/3 due to causing leukopenia. Allopurinol is xanthine oxidase inhibitor ▪ ADRs: NV, anemia, hepatoxicity, rash BBW: lymphoma, leukopenia, thrombocytopenia ✓ Monitor: CBC, platelet count, Liver function test ✓ Pregnancy D. Cross placenta, but can be used in pregnancy ✓ Dose adjustment in renal dysfunction MOA: ✓Folate antagonist, inhibit AICAR transformylase and TYMS →  AICAR→  Adenosine → ↓ IL2, ↓ inflammation (low dose) ❖Folate antagonist, inhibit DHFR →↓ FH4 ↓FH2. Inhibit cell mediated immune rxn, ↓ PMN, ↓ inflammation (high dose) Indications: treatment of Crohn’s disease, autoimmune diseases, RA, psoriasis, SLE, dermatomyositis, anti cancer, immunosuppressant Intracellularly → Polyglutamated MTX (causing long duration of MTX action). 70% of drug are absorbed. Excretion:70% renal, 30% bile t 1/2 -6-9h; up to 24h in some patients. Need dose adjustment in renal dysfunction Formulations: intrathecal, IV, PO. Does not pass BBB Monitor: renal, Liver function test, pulmonary, neurologic seizure ✓ Teratogenic. Do not use in pregnancy (X). ✓ Pregnancy should be avoided for a minimal of 3 mo. in male even after d/c treatment ADRs: myelosuppression, severe oral ulceration/stomatitis, renal, NV, LFT pneumonitis, photosensitivity, alopecia crystalluria at high dose (need hydration and alkaline the urine to renal toxicity) In overdose or use for oncology, need to take Leucovorin an analog of FH4, can bypass the blockage of the enzyme and replenish folate pool At doses used for treatment of IBD, rarely cause bone marrow suppression. Need to maintain hydration and nutrition. Take folic acid as directed. DDI: -NSAID can prolong MTX level, - corticosteroids  uptake of MTX (separate by 12 hr) MOA: suppress cell mediated immune reaction. CsA binds to cyclophillin, formed a complex with calcineurin → NFATc are not form→ IL2→ T and B cells The drug is also called Calcineurin inhibitor Drug: Sandimmune®- low bioavailability Neoral ®, Gengraf®- modified microemulsion, better bioavailability DDI: most drugs effect CsA level. Metabolized by CYP3A4 ( inducers or inhibitors). Inhibitors: ketoconazole, verapamil, cimetidine, grapefruit juice, fluvoxamine Ketoconazole + CSA- allow up to 80% reduction in CSA dose Inducers: rifampin, phenytoin, phenobarbital, carbamazepine, isoniazid, St. John’s wort MOA of CsA ( 2 of 3) In Goodman and Gillman’s, 2023 ADRs: nephrotoxic (do not give with aminoglycosides, some NSAIDs, or cimetidine), neurotoxic (tremors, HA, peripheral neuropathy), hepatotoxic ,  risk of lymphoma,  risk infection , HTN, hirsutism hyperkalemia, hyperlipidemia, gingival hyperplasia, glucose intolerance,  TG Indications: treatment of severe RA, IBD, and prevent transplant rejection BBW: renal impairment (with high dose) causing  risk of lymphoma,  risk infection, HTN Monitor: BP, renal, electrolytes, CBC, signs of infection. Maintenance levels: trough or 2 hr after dosing TNF is produced by: a. innate immunity (macrophage, dendrite cells), b. adaptive immune system ( especially Th1), c. non-immune cells (fibroblast, smooth muscle cells) TNF can lead to production of multiple cytokines such as IL (interleukin -1, -6), and increase inflammation  TNF exists as: soluble and membrane bound TNF bind to TNF receptor→ causing activation of NF-B →  proinflammatory cytokines, activation and proliferation of T cell, leukocyte migration, and apoptosis ✓ Due to its ADRs of monoclonal Ab, all patients must undergo purified protein derivative (PPD) testing; and prophylactic treatment to test possible latent tuberculosis activation. Development of antibodies to antibody (ATA)/ Human Anti-Mouse Antibodies (HAMA) commonly o Occurs in 3-10% pts. ✓ The ATA can eliminate desired clinical response or can increase the likelihood of developing acute or delayed injection reactions ❖ For mild and self-limiting ATA, patients can be prophylaxis with APAP, diphenhydramine, corticosteroids. Antibodies produced by the human immune system in response to exposure to mouse-derived proteins MOA: inhibit soluble and membrane bound TNF that are pro inflammatories, inhibit T-cell and macrophages function→  cytokine release http://www.crohnsdiseasefocus.com/articles/crohns-disease- treatment/crohns-disease-treatment-anti-tnf.php Drugs Additional info 1. Infliximab (Remicade®) ADRs: risk of infections,  reactivation of latent tuberculosis,  risk of hepatitis B,  risk of lymphoma, HF, hematologic, hepatoxicity 2. Adalimumab (Humira®) leukopenia, pain at site injection, demyelinating disease 3.Certolizumab pegol (Cimzia®) Infliximab: q 2 month, IV 4. Golimumab (Simponi® Adalimumab: q 2 week, SubQ Certolizumab: q 2 week, SubQ Golimumab: q month, SubQ Pregnancy B. Use only if benefit outweigh the risk to the fetus. t ½ of 4 agents range from 8- 20 days Infliximab and Adalimumab- IgG1. Fc portion bind to membrane bound TNF → activates complement pathway→ potency Certolizumab- Fab fragment attached to PEG (lack Fc portion), conjugated to PEG MOA: humanized -4 integrin inhibitor that binds to cell surface receptors of vascular endothelium of GI →block migration of lymphocytes into the tissues. It can also be called integrin receptor antagonist. Drug: Natalizumab (Tysabri ®) Indications: treatment of moderate to severe CD and multiple sclerosis ADRs: infusion reaction, headache, fatigue (see other ADRs)  Also Increased risk of opportunistic brain viral infection (progressive multifocal leukoencephalopathy, PML) that can cause death and severe disability and liver damage. Only can prescribed through TOUCH Prescribing program Given as IV every 4 weeks If no therapeutic benefit by 12 weeks, treatment should be discontinued MOA: bind to 47 integrin and blocks interaction of 47 integrin with mucosal adhesion on cell adhesion molecule 1 (MadCAM-1).  Inhibit migration of memory T lymphocyte across the endothelium into the inflamed GI tissue  It does not bind or inhibit function of 41 and E7 Drug: Vedolizumab (Entyvio®) ADRs: nasophyngitis, HA, N, arthralgia, respiratory infection, risk of PML Indications: UC (moderate to severe), CD (moderate to severe) who are intolerant or not responsive to TNF  blocker or immunomodulator. Patients should NOT receive live vaccines  Dose: 300 mg IV, give on 0, 2, 6 weeks and every 8 weeks after https://www.youtube.com/watch?v=9zLYxr2Tv7I MOA: interfere with IL-12 and IL 23 overt expression →  T cells activation, disrupt immune cell that cause inflammation Drugs: Ustekinumab (Stelara®) Risankizumab (Skyrizi®)- only IL 23 Indication: IBD, psoriasis arthritis, plaque psoriasis ADR: pneumonia,  risk of tuberculosis,  risk of developing cancer, infusion reaction (can premeds with Benadryl, Tylenol, slow infusion or use methyl prednisone) A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. https://www.youtube.com/watch?v=KWHUwVdVICM  MOA: Inhibitor of Janus kinase enzymes that stimulating immune cell functions Drug: Tofacitinib (Xeljanz®) Indications: IBD, RA (rheumatoid arthritis) ADRs:  LFT,  lipids, infusion rxn, infection, neutropenia DDI: Cyp 3A4 and 2C19 BW: risk of tuberculosis, fungal, viral, bacterial infections, lymphoma and cancer Pregnancy C MOA: Blocks lymphocytes' ability to emerge from lymph nodes→  lymphocytes availability to go to CNS or intestine →  inflammation Immune modulator Drug: Ozanimod (Zeposia®) Use: for relapsing forms of multiple sclerosis (MS) and ulcerative colitis BBW: MI, angina, stroke, HF, AV block, sleep apnea, MOA Inhibitors ADRs: Macular edema, URI, UTI,  BP, Slowed heart rate, orthostatic hypotension,  infection DDI: gemfibrozil, MAO inhibitors, live vaccine CY2C8 inhibitor or inducers, BB or CCB, drugs cause QT prolongation 1. Crohn’s disease is due to increase in _____cell immunologic reaction, Ulcerative colitis is due to increase in _____ humoral reaction 2. Sulfasalazine (Azulfidine ®) can cause :_____________, need _________ supplement. It work by __________, _______, ______ Active drug is __________________ 3. Purine analog works by ________,________ can cause _________ in slow metabolizer. It is NOT useful as anti-inflammatory agent 4. Drug belongs to anti TNF agent are _____, _____. These drugs can cause_____________, __________, _______ 5. IBD patient who is _____ may be given prednisone. ___________ is as ADR of excess prednisone 6) Stelera works as________ and ________antagonist. It is also indicated for ________, ________.  Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition Editors: Brunton, Hilal-Dandan, Knollmann. Publisher: McGraw-Hill, 2023 Katzung BG et al. Basic & Clinical Pharmacology. 15th ed. 2021 Husser, DA. New Therapeutic agents marketed in the first half of 2009: part 1. Pharmacy Today, September 2009. Various internet source as cited  Amino salicylates (4 of 4) Generic Name Trade Name Formulation Site of Action Max Dosage Sulfasalazine Azulfidine® Sulfapyridine carrier Colon Up to 6 g/d Mesalamine Asacol® pH dependent Terminal ileum, Up to 4.8 g/d colon Mesalamine Pentasa® Ethylcellulose covering Duodenum, Up to 4 g/d individually coated jejunum, ileum, microgranules colon Mesalamine Lialda® Multi-Matrix System Colon Up to 4.8 g/d Mesalamine Rowasa® Liquid enema Below the splenic Up to 4 g/d flexure Olsalazine Dipentum® Two molecules of Colon Up to 3 g/d mesalamine Balsalazide Colazal® 4-aminobenzoyl-b- Colon Up to 6.75 g/d alanine carrier Mab= monab=monoclonal antibody Letter before mab indicate the source of antibody O= mouse U= human xi= chimeric Internal letter identifies the therapeutic use of the antibody “Tu”= tumor “vi”= virus “ci”= circulation  Rituximab = chimeric human murine- monoclonal antibody