Derm/Otolary/Rheum (Week 2 Quiz): Meds

_________

• Can increase BP → cause water retention

• When combined with ACE-I → increase acute renal failure risk

• MOA: Afferent arteriole → locally produced PGs → cause vasodilation

• When inhibited → blood vessels constrict → decreases filtration + urine output

• NSAIDs inhibit prostaglandin synthesis → vasoconstriction

Ibuprofen

_________

• MOA: COX inhibitor only in the CNS → reduces fever + pain BUT no anti-inflammatory effects (no inhibition in the peripheral tissues)

• Inhibits COX-1 centrally and PGs play a role in amplifying pain signals in the spinal cord (analgesic effect)

• Acts on the hypothalamus to regulate temperature (antipyretic effect)

Acetaminophen (Tylenol)

_________

• Topical NSAID option

• Provide anti-inflammatory effects while avoiding systemic exposure

• NSAID + ACE-1 = Risk of increased BP and renal failure with NSAIDs → higher in older patients as they are not hemodynamically flexible + may already be hypertensive

Voltaren Cream (Diclofenac)

_________

• Intra-articular therapy for OA

• Hyaluronic acid (HA) in the viscosupplement preparations is derived from avian, bacterial, or synthetic sources

• HA treatment → pain alleviation (may be related to anti-inflammatory effect of HA)

• Perform arthrocentesis before injecting HA

Viscosupplements (Synvisc, Euflexxa, Hyalgan, Orthovisc, Supartz)

_________

• Viscosupplement for OA

• Allergy warning: drug derived from avian sources (birds)

• Avoid in patients with: egg or avian allergy

• Frequency: every 3-6 months

Supartz

_________

• Preferred choice for knee flares

• Lipophilicity: highly lipophilic + formulated as a suspension

• Extended Duration: very slow release (slow dissolution) → stays in joint for 21 days

Triamcinolone Hexaacetonide (Kenalog)

Triamcinolone _________:

• 7-day duration

Diacetate

Triamcinolone _________:

• 14-day duration

Acetonide

_________

• These drugs can alter the course of the disease (cause disease remission) and simply used to manage disease Sxs

• Any medication ending in “-cept”

  • Decoy receptor based on a receptor naturally found in the body

• NSAIDs + Corticosteroids are NOT DMARDs (control pain + inflammation)

DMARDs

_________

• Anti-TNF-alpha Drug

• contribute to immune stimulation + inflammation

• Immune suppression = infection risk

• Chimeric Monoclonal AB

• 1st monoclonal AB that got approved

• Mouse in fragment antigen binding (FAB)

• 75% human

• Xi = chimeric

• Half-Life: 8-10 days

Infliximab

_________

• IV

  • Subcutaneous injection = allergic reaction or skin damage

  • Skin is packed w/immune cells that would recognize the mouse (chimeric) fragments and trigger a localized attack

Infliximab

_________

• Anti-TNF-alpha Drug

• contribute to immune stimulation + inflammation

• Immune suppression = infection risk

• Has the advanatage

• Most widely used

• 100% human

• Subcutaneous

• Half-Life: 10-20 days

Adalimumab

_________

• Anti-TNF-alpha Drug

• contribute to immune stimulation + inflammation

• Immune suppression = infection risk

• Human Recombiant Ab

• 95% human

• FAB fragment attached to PEG = makes it more stable + reduce immune response

• Lacks Fc portion = cannot trigger cell lysis (ADCC/CDC)

• Subcutaneous

• PEG shields 5% mouse = subcutaneous injection

• Half-Life: 14 days

Certolizumab Pegol

_________

• Neutralized soluble TNF + membrane-bound TNF

• DOES NOT induce apoptosis of cells expressing membrane-bound TNF

• DOES NOT complement-mediated cytotoxicity of cells expressing membrane-bound TNF

Certolizumab Pegol

_________

• Anti-TNF-alpha Drug

• contribute to immune stimulation + inflammation

• Immune suppression = infection risk

Golimumab

Full Antibodies (_________)

• More effective than decoy receptors (Etanercept = only neutralize the cytokine) because they destroy immune cells via ADCC/CDC

• Possess the Fc (fixed) component of a full Ab

• Neutralize soluble TNF-alpha

• Recruit other immune cells to destroy cells expressing TNF-alpha on their surface

  • This happens via Antibody-Dependent Cell Cytotoxicity, Complement-Dependent Cytotoxicity, and induction of apoptosis

  • Leads to more profound immunosuppression = highly effect but requiring strict screening for TB + opportunistic infections

Infliximab, Adalimumab

_________ (IV) + _________ (Gold Standard =. long half-life + easy self-administration at home) (only achieved with full analog)

• Neutralized soluble TNF + membrane-bound TNF

• Induces Apoptosis of cells expressing membrane-bound TNF

• Complement-Mediated Cytotoxicity of cells expressing membrane-bound TNF

Infliximab, Adalimumab

_________

• Soluble decoy TNF-alpha for SQ infection for RA

• Lacks the full Ab structure

• Does NOT destroy cells (no ADCC/CDC)

• Slightly less immunosuppressive + potentially less effective than full Abs

• Extracellular domain of the TNR-alpha receptor + that’s bound Fc fragment

• Decreased activation of immune cells with RA patients = better Ab

Etanercept

_________

• 2nd pro-inflammatory cytokine

• Anti-IL-1

• Similar to Atanercept

• IB-1-Beta receptor with Fc portion

• If used in combos (anti-TNF-alpha + anti-IL-1), higher risk of immunosuppression that outweighs the benefits

Rilonacept

_________

• 2nd pro-inflammatory cytokine

• Anti-IL-1

• Monoclonal Ab that binds to IL-1

• If used in combos (anti-TNF-alpha + anti-IL-1), higher risk of immunosuppression that outweighs the benefits

Canakinumab

_________

• Anti-IL-6 receptor Mab

• Ab is against the receptor (not the cytokine)

• IL-6 receptor enters into the cell membrane (membrane-bound) or present in soluble form

• Soluble receptor can bind the cytokine → translocate to the membrane → activate inflammation (targets both forms)

• MOA: binds to and neutralizes IL-6 receptors (2 types = transmembrane + soluble)

• Gp130 is a membrane glycoprotein that is required for IL-6 receptor function

• Results in a strong immunosuppressive effect

Tocilizamab

_________

• B cell target, specifically CD20 (surface marker found on mature plasma cells)

• MOA: Binding of this drug (chimeric) to CD20 results in a host of effects including: apoptosis, ADCC (macrophages = cell lysis), and CDC (complement activation)

• Result: depletion of peripheral blood B cells

Rituximab

_________

• T cell costimulation inhibitor

• Decoy receptor that inhibits T cells

• T cell costimulation is important in regulation of immune tolerance, immune response, and autoimmunity

• Activated = interaction with APC

• T cell activation requires 2 signals:

  • Engagement of MHC on APC + T cell receptor

  • Engagement of CD28 (T cell) with B7 or APC

Abatacept

_________

• _________ is a natural function antagonist of CD28

  • Translocates to the surface of T cells (_________ → CD28)

  • CTLA4 binds to _________ → forces T-lymphocytes into inhibitory state

  • SE: profound immune suppression (no T-lymphocyte response)

  • Redistribution of CTLA4 to cell surface results in engaging _________ on APC

  • _________ has a higher binding affinity to B7 compared to the binding affinity of CD28 to B7

• This drug is a fusion protein composed of the extracellular domain of _________ + _________1 Fc

• MOA: competitive inhibition of CD28 → _________

  • Increases threshold for T-cell activation

Abatacept, CTLA4, B7, B7, B7, CTLA4, CTLA4, IgG, B7

_________

• Oral DMARDs

• Anti-cancer drug or anti-folate

• Produces an immunosuppressive effect → prevents immune system from proliferating

• If not working → Injectable DMARD!

• Antagonizes folic acid → less B + T cells, macrophages, and monocytes (they all require proliferation/replication)

• Given once a week (QD = death)

• RA patients take methotrexate + folic acid (protects immune system form harmful effects of methotrexate)

  • Dose is 1 or 2 mg

Methotrexate

_________

• MOA:

  • Structurally-similar to enzyme co-factor: Folic Acid (prevents immune system from proliferating/replicating cells = synthesize DNA then split)

  • Thus can compete with folic acid on binding to enzymes that require folic acid as a co-factor.

  • Folic acid carries a methylene group that it can transfer to a substrate e.g. dUMP to generate dTMP (deoxythymidine monophosphate)

  • Inhibits DNA replication + ability to synthesize purine + pyrimidine → No adenine, guanine, cytosine, and thymine → immune cells cannot replicate

Methotrexate

_________

• Oral JAK inhibitor (oral DMARD)

• JAK is a family of non-receptor TKs

• Originally developed for cancer, but repurposed for RA

• Part of the JAK-STAT (Signal Transducer + Activator of Transcription) Pathway

• Has a affinity for JAK1 + JAK3 compared to JAK2 + TYK2

  • Inhibits JK → inhibits IL-6 signaling

• IL-6 is a cytokines that plays a role in RA pathogenesis. Signaling through IL-6 receptor is mediated by the JAK-STAT pathway

• Consequence: downregulates the production of cytokines → more immunosuppression → increased infection risk

Tofacitinib

_________

• JAK Inhibitor Treatment

• More immunosuppression → increases infection risk

Upadacitinib (Rinvoq)

_________

• Oral DMARD

• Immunosuppressive drug that reduces immune cell proliferation

Lefluonamide

_________

• Oral DMARD

• Anti-malarial drug that has the ability to interfere with antigen processing + has anti-rheumatic properties

Hydroxychloroquine (Plaquinil)

_________

• Oral DMARD

• Prodrug converted into an active metabolite that has immunosuppressive properties

Azathioprine

_________

• Oral DMARD

• Immunosuppressive drug used in prevention of organ transplant rejection

Cyclosporine