442-MT2-DMARDs

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Author:
jgiantess
ID:
142173
Filename:
442-MT2-DMARDs
Updated:
2012-03-18 17:12:25
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pharmacology
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pharmacology
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  1. Methotrexate
    • MoA:
    • - Inhibit of aminoimidazolecarboxamide (AICAR) transformylase
    • (10-formyl THF + AICAR -x-> THF + FAICAR)
    • Accum AICAR: increase adenosine release @ sites of inflammation, increase inhibition of inflammation (adenosine A2 receptors) =action in autoimmune disease.
    • - affects polymorphonuclear chemotaxis
    • - Also inhibit dihydrofolate reductase , and thymidylate synthetase (angiogenesis and affects lymphocyte/mac function)
    • - Anti-inflam: inhibits cytokine production, purine biosynthesis; stimulates adenosine release.
    • - Decreased rate of appearance of new RA erosions
    • - Improves survival (only drug CVD)
    • - 2-3 weeks onset (use NSAIDs to bridge)
    • PK:
    • A: F ~70%
    • D: 35-50% PB
    • M: hydroxylated to less active
    • Parent cpd+ metabolite
    • metab’d further into
    • polyglutamated derivs
    • intracellularly.
    • E: renal: 70-80% unchanged
    • Bile: 30%
    • T1/2: 6-9 hours  24 hours
    • (intracellular t1/2 much longer, so can dose less frequently)
    • SE:
    • HEENT: stomatitis, (+/- pain)
    • Pulm: hypersensitivity lung, fibrosis, pneumonitis
    • GI: Diarrhea, N/V, hepatotoxicity (LE), cirrhosis
    • Heme: thromobocytopeia
    • Teratogenic: CI in pregs
    • MTX is folic acid antag: can induce folic acid deficiency…
    • Supplement (controversial):Folic acid 5mg daily OR Leucovorin once weekly (24 hours after MTX)
  2. Hydroxychloroquine
    • MoA:
    • - Amtimalarial
    • - MOA unknown
    • - No effect on radiographic progression
    • PK:
    • A: “good and rapid”
    • D: “wide” PB 50%, extensively tissue-bound in melanin-containing tissues (retinas)
    • M: deaminated in liver
    • E: t1/2 up to 45 days (long)
    • SE:
    • CNS: dizz, H/A, insomnia, dreams
    • HEENT: decrease accommodation, bullseye retna,benign corneal deposits, burred vision, pre-retinopathy (Get ophthalmologist exam /yr)
    • GI: N/V, D (decreased with food)
    • Heme: hemolysis in G6PD def
    • DERM: rash, alopecia, skin pigmentation
    • May be used in pregnancy (if not already get complete absence of symptoms in pregnancy)
  3. Sulfasalazine
    • MoA:
    • - MOA unknown
    • - Sulfapyridine = antirheumatic props
    • - decrease IgA and IgM rheumatoid factor prod.
    • - Inhibit in vitro B cellproliferation
    • - Decrease radiographic progression
    • - Reduce sn/sx of RA
    • PK: Prodrug cleaved by bacteria in colon to sulfapyridine & 5-ASA
    • SE:
    • HEENT: stomatitis
    • GI: N/V/D, anorexia, increase LE
    • Heme: leucopenia
    • Oligospermia
    • Derm: alopecia, rash, urticaria, serum sickness-like reactions, skin/urine turn yellow-orange
    • Hypersensitivity to sulfa
    • Ok for pregnancy
  4. Gold
    • MoA:
    • - MOA: don’t have to know…reduce phagocytosis by macs, reduce proliferative response of lymphocytes, reduce IgA IgM RF production..etc
    • - Actually unknown.
    • - Given IM
    • - Slow onset of action
    • PK:
    • Give10mg IM x1, then 25mg IM in 2nd week, then 50mg IM weekly -> response/1g
    • If response, decrease to 50mg q2wks x 3mos, then q3wks x 3mos, then maintenance monthly dose (indefinitely).
    • Tx failure: no response after total 1g administered.
    • Onset: 4-6 mo or after 1g
    • SE: Often lead to D/C
    • HEENT: stomatitis
    • GI: mucositis
    • GU: proteinuria -> gold-ind’d membranous glomerulonephropathy -> nephritic syndrome; microscopic hematuria
    • HEME: immune thrombocytopenia, granulocytopenia, aplastic anemia
    • DERM: rash (pruritic erythematous -> severe exfoliative dermatitis); chrysiasis
    • Inj rxns: nitritoid reaction (flush, dizz, faint)
    • Monitoring:
    • If mild mucocutaneous eruption, d/c tx.
    • If eruption better, restart at 10-15mg/wk, increase to 50mg/wk.
    • Chrysiasis- skin bluish gray forever.
    • Not safe in pregs
  5. Leflunomide
    • MoA:
    • - Indirectly inhibits protein synthesis
    • - Competitive inhibitor of pyrimidine synth (enzyme DHODH)   lymphocyte prolif + modulation of inflammation
    • - Arrests activated lymphocytes in G1
    • - Slows radiographic progression of joint damage
    • - Prevents new joint erosions in 80% of patients over 2 year period
    • - Similar efficacy to MTX
    • PK:
    • D:extensive PB
    • E: urine, bile, t1/2 14-16 d
    • Onset of action: 4-8 weeks
    • SE:
    • GI: reversible increase LE >3x ULN (esp w/ MTX)
    • Diarrhea, GI upset
    • DERM: alopecia
    • Teratogenic - Adequate birth control (x2)
    • If want to get pregs:
    • - cholestyramine 8gtid x11d
    • - 2x leflunomide levels drawn 14 days apart
    • - Sr[] <0.02mg/L prior to conception
  6. Cyclosporine
    • MoA:
    • - Immunosuppressive agent, calcineurin antagonist
    • - Inhibits T cell fxn by inhibiting transcription of IL-2 (big contributor to RA)
    • SE: Infection, Renal insufficiency, Hirsuitism
  7. Etanercept(Enebrel)
    • Soluble TNFR (recomb fusion protein)
    • -structure: human p75 extracellular TNF receptor + human IgGI
    • -mimics p75, takes up TNF in circulatin and inactivates them
    • -onset: 1-4 weeks (v fast)
    • -25mg SC twice weekly
    • PK:
    • A: 58% abs SC
    • D: 0.11 L/kg
    • M: neg
    • E: renal – negligible
    • Cl 0.02ml/min/kg
    • T1/2: 4 days (IV 70 hrs, SC 92 hrs)
    • Target: TNF/Lymphotoxin-alpha (both cytokines)
    • SE:
    • CNS: demyelinating syndromes (Do not give for pts with MS)
    • Infections: increase Upper RTI, serious/opportunistic infections i.e. TB
    • Heme: pancytopenia, neutropenia, blood dyscrasias
    • Others: injection site rxns 37% (mild)
    • 1% pts develop anti-etanercept Ab but non-neutralizing.
    • Can activate latent TB…just treat concomitantly with INH?
  8. Infliximab(Remicade)
    • TNF MAb (chimeric): high affinity/spec.
    • -stucture: mouse TNF binding site + human IgGI
    • -binds TNF from macs in joints and circ, +inactivates them(px int’n with receptors on surface of inflamm cells)
    • -onset: days to weeks
    • -3-10mg/kg IV w/ MTX q4-8wks T1/2: 8-10 days
    • Target: TNF
    • SE:
    • Infusion related:
    • - “cytokine release syndrome” (fever, chills,h/a)…usually with first infusion and decreases w/ time
    • Anti-infliximab Ab (10-30%) (MUST be used with MTX (blocks Ab that sucks up infliximab)
    • Anti-DS DNA Ab
    • Systemic lupus erythematosus (SLE)
    • Sepsis and disseminated TB and other opportunistic infections
    • Slow infusion rate.
  9. Adalimumab (Humira)
    • TNF MAb (recombinant)
    • -structure: human TNF binding site + human IgGI
    • 40mg SC qoweek T1/2: 10-20 days
    • Target: TNF
  10. Anakinra
    • IL-1 blocker : human recombinant
    • - IL-1 is immune and pro-inflammatory cytokine, autoinduction regulates own expression; mediates disease activity and progression of joint destruction, correlates with plasma/synovial fluid levels of IL-1.
    • - IL-1ra is endogenous R antag.
    • - Blocks IL-1 from binding to IL-1R by binding with same affinity.
    • - Onset: 2-4 weeks Rapid onset of action…but not work well.
    • SE:
    • Injection site reactions (66%): mild erythema, itching, discomfort that reslves over 1-2 mo
    • Infection: increased risk of serious ifxn (shutting down immune system...DO NOT use 2 biologics at same time. Combo increase risk of death from infection)
    • Heme: neutropenia.
    • Comboanakinra/etanercept: 3% severe neutr
    • Neutralizing Abs rare: do not appear to correlate with clinical response or adverse events.
  11. Abatacept
    • - Selective T-cell co-stimulation modulator; recombinant human fusion protein:
    • - EC human CTLA4 (cytotoxic T-lymphocyte-associated antigen-4) + Fc domain of human IgG1.
    • - Normally, T-cell activation needs binding of CD28 and TCR to an APC; but CTLA-4 can displac binding of CD28 to CD80/86, therefore Tcell activation inhibition.
    • - Abatacept acts like the CLTA4.
    • - Onset: within 2-12 weeks. T1/2: 14.7 days
    • Admin: silicone-free syr; IV 30min infusion once, then at week 2, 4, and every 4 weeks thereafter.
    • Blocks not just TNF-alpha (macs), aso blocks IL-6 and MMPs from fibroblasts, and autoantibodies (RF) from b-cells…but response rate === other biologics (50-60%)
  12. Rituximab
    • - B-cell depletion
    • - B-cells important in RA, and CD20 Ag is expressed on B-cells -> target!
    • - Synthetic CD20 monoclonal Ab, selectively depletes CD20+ B cells
    • - Chimeric murine/human MAb: mouse variable region (CD20 binding site) + human IgG1 constant region.
    • - Onset: 2 months
    • - Target: binds to CD20 antigen T1/2: 19.7 days
    • Admin: 1000mg IV days 1-15 (50mg/h up to 400mg/h)
    • Can go without dosng for up to 1.5 years! (mostppl need reinfuson after 6mo -1yr)
    • Other drugs: risk of lymphoma…but rituximab can be used to treat lymphoma!
    • *Depletes B cells w/o compromising immune
    • Lethal brain condition…not much experience. Black box warning.
    • Binds CD20 on pre to mature B cells (hematopoietic stem cells, pro-B cells, plasma cells, and other normal tissuesdo not have CD20 antigen)
  13. Tocilizumab
    • - Anti-IL-6 receptor antibody
    • - IL-6 activates T-cells, B cells, induction of RF, differentiation of monocytes to macs, activation of osteoclasts…etc
    • - 95% human, 5% mice, monoclonal recombinant humanized anti-IL-6 receptor Ab (murine binding site for IL-6 , human IgG1)
    • - Binds directly to IL-6 receptor and prevents Il-6 from binding/activating
    • - Onset: assessed at 12 weeks T1/2: 10 days
    • Admin: 4-8mg/kg IV q4 wks
  14. Tofacitinib
    • - NOT a biological: just small molec
    • - Designed based on congenital JAC3 deficiency -> immunodef. By blocking JAK, block inflamm cascade (many in pathogenesis of RA: IL-6,7.10…)
    • - Efficacy===biologics
    • - Orally active immunosuppressant
    • - Inhibits janus activated kinase 3 (JAK3) Once daily dosing 20mg effective for tx RA. Anemia, diarrhea, increase nasopharyngitis infxns
    • Interacts with fluconazole (increaseAUC and Cmax of tofacitinib)
    • Safe for combo w/ MTX

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