02-20 Anti-Inflammatory PHARM Flashcards

Question

Pharmacologic Strategies for Tx of Chronic Inflamm

Answer 1

* Class = DMARD * MoA * Inhibits folate metabolism which leads to decreased DNA synthesis. * Alleviates acute inflammation by acting as an immunosuppressive drug. * Uses * Low-dose methotrexate is now first-line Rx for the tx of RA * * Side-effects * Though MTX for autoimm dzs is taken in lower doses than for cancer, ADRs e.g. hair loss, nausea, h/a, and skin pigmentation are still common * _Common_: GI distress, oral ulcerations, and progressive dose-related hepatotoxicity. * _Rare_: pulm fibrosis, hepatic fibrosis, severe hypersensitive pneumonitis in pre-existing lung dz. * Contra-indications * Contraindicated in pregnancy, lactation, alcoholism, blood disorders, immunodeficiency. * Drug-drug interactions *

Answer 2

* Class: DMARD Immunosuppressive drug that is orally active. * MoA * Metabolite, A77 1726, is the active compound and has long half life. * Major action is inhibition of dihydroorotate dehydrogenase and blockade of pyrimidine biosynthesis. * Prevents histamine release and COX-2 expression. * Uses * Similar efficacy for Rheumatoid Arthritis patients as methotrexate. * Side Effects * Similar GI side effects as Methotrexate. * Slightly more common hepatic side effects than Methotrexate

Answer 3

* Class = DMARD * Prodrug combo of sulfapyridine and 5-aminosalicylic acid (mesalamine). * MoA * Colonic bacteria metabolize prodrug → allows accum of mesalamine w/o GI complications. * **mesalamine** inhib of arach. acid metab in bowel mucosa by inhib of COX. * also inhibits leukotriene synthesis, possibly thru inhib of lipoxygenase * **Sulfapyridine** is more active metabolite in joints * functions as a free radical scavenger. * Reduces tissue damage * blocks immune-modulatory signaling. * Uses * UC & Crohn's most commonly * Alternative for juvenile RA or women of child bearing age. * RA to reduce bone deterioration. * Side-effects * More toxic than MTX or leflunomide * rashes, n/v, dizziness, and h/a * occasionally: leukopenia. * Contra-ind * Not given to patients with sulfa drug or salicylate allergies. * Drug-Drugs Interactions * You _can_ give this w/ NSAIDS

Answer 4

* MoA * inhibs WBC infiltration at the site * interferes w/ inflamm mediator fxn * suppresses humoral immune responses. * Inhib COX2 expression * reduction in edema or scar tissue * general suppression in immune response. * anti-inflam action thought to involve phospholipase A2 inhib proteins, or "lipocortins" * Lipocortins control biosynthesis of prostaglandins and leukotrienes by inhib arachidonic acid (their precursor) * Uses * * Side-effects * Cushing Syndrome (hypercorticism) * physiological dependence due to HPA suppression * exert neg feedback on pit, inhibs ACTH * results in ‪↓‬ synth of endogen corticosteroids and androgens * Metab effects: Protein catab and diversion of AAs to glucose metab * increased need for insulin. * thus weight gain, visceral fat, muscle wasting and hyperglycemia. * cortisone and hydrocortisone → sodium and fluid retention, **hypokalemia** * **ulcers** * hypomania or acute **psychosis**, depression * Hyperhidrosis * Telangeictasia * Contra-indications * Peptic ulcer * Heart dz or HTN w/ CHF * Infections (especially HSV), DM, osteoporosis * Psychoses * Hepatic dysfunction

Answer 5

TNF-α = central cytokine in mediating the chronic inflam * signaling mediated by cell surface receptors TNFR1 and TNFR2. * TNF-α is produced in M0s and stimulates activation of T-lymphocytes and other pro-inflammatory events. 1. Induces pro-inflam cytokines (e.g. IL-1 & IL-6) 2. Enhances leukocyte migration. 3. Increases endothelial layer permeability 4. Increases synth of endothelial and WBC adhesion molecules 5. Activates PMNs and eos. 6. Stimulates prolif of synovial fibroblasts. 7. ↑ Synthesis of prostaglandins. 8. ↑s expression & release of extracellular proteases → tissue destruction and remodeling. * This is the sx that leads to the highest degree of long-term suffering and debilitation in RA patients.

Answer 6

**Class** * Both are anti-TNF-α * Similar drugs; main difference is that: * infliximab is composed of human constant and _murine_ variable regions whilst * adalimumab is recombinant human antibody (more thoroughly humanized → greater stability of the antibody and improved clinical tolerance) * Pts treated w/ infliximab may develop human anti-chimeric Abs (HACA). * This is less likely with adalilumab. **MoA** * TNF-α is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. * Activated M0s release TNF-α, which acts on chondrocytes, fibroblasts, and osteoclasts to release metalloproteinases (MMP) and other effector molecules that induce the migration of PMNs. * Both infliximab and adalimumab neutralize TNF-α by binding to it and blocking its interaction with the p55 and p75 cell surface TNF receptors. * ↑ [TNF-α] is found in synovial fluid of pts w/ RA * plays important role in both pathologic inflam and joint destruction **Pharmacokinetics** * Infliximab is administered **IV** * predom distrib w/in vasc compartment. * may also enter site of inflam * Adalimumab is admin **SC** **Uses** * Used alone or in combo w/ MTX * Infliximab * ankylosing spondylitis  * Juvenile RA * Psoriasis * Psoriatic arthritis * RA * **Bechet’s Syndrome** * **Crohn's** * **unique to inflix** * Single infliximab infusion induces a clinical response or remission in 65% of pts w/ mod-to-severe tx-resistant Crohn's! * Adalimumab * ankylosing spondylitis *  Juvenile RA * Psoriasis * Psoriatic arthritis * RA **Contra-indicaitons** * Caution should be used for patients who have recently received vaccines. **Drug-Drug** * On-going trial to determine effects of combination with anti-inflammatory steroids. **Cost** * 100 mg vial: $600.00—699.99/ea. Annual costs approach $15,000 for a patient with rheumatoid arthritis.

Answer 7

Class * Anti-TNF-α Structure * Recombinant fusion prot: consisting of the human IgG1 heavy chain fused to the extracellular domain of TNFR1 (no light chains!) * Favored over Infliximab of Adalimumab for treatment of chronic pain due to a longer half-life. MoA * Pharmacokinetics * Administered SC or IV Uses * Used alone or with methotrexate to manage mod-to-severe chronic inflam: * ankylosing spondylitis  * Juvenile RA * Psoriasis * Psoriatic arthritis * Rheumaoid arthritis Contra-indications * Caution when prescribing Etanercept w/ myelosuppressive anti-rheumatic agents e.g. azathioprine, cyclophosphamide, leflunomide, or methotrexate. * These combos have been assoc'd w/ pancytopenia, incl aplastic anemia * Caution should be used for patients who have recently received vaccines. Drug-drug interactions Cost * Annual cost: $10,400 to 15,600 * NOTE: Anti-etanercept antibodies have been noted in ~16% of patients, but do not seem to interfere with efficacy or alter toxicity profile.*

Answer 8

* Infliximab can tx * classically characterized as a triad: 1. Recurring crops of **mouth ulcers** (aphthous ulcers), 2. **Genital ulcer**s 3. Inflammation of the uvea (area of eye around pupil) a.ka. **uveitis**.