Multi-Systems: Autoimmune Treatments Flashcards

1
Q

What are the (3) signals req’d for T Lymphocyte activation?

A
  1. MHC from APC w/ Antigenic Peptide presented to TCR
  2. Co-stimulatory binding of APC CD 80/86 to T-cell CD 28
  3. Self-Reception of IL-2 on T-cell
    • Stimulates activation, proliferation, and Effector function
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2
Q

What are the (2) Calcineurin Inhibitors?

A
  1. Cyclosporine
    • Cyclosporine –> Cyclophilin –> Calcineurin
  2. Tacrolimus (FK506)
    • Tacrolimus –> FKBP-12 –> Calcineurin
    • Calcineurin + Calmodulin + Ca2+ –> dephosphorylates NFAT to activated NFAT
      - -> inhibits IL-2 gene transcription
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3
Q

What is the Mechanism of Cyclosprine?

A
  • Inhibits Calcineurin - Protein phosphatase req’d for Transcription of IL-2 (T cell activator)
  • Inhibition suppresses Cell-mediated immunity
  • Normally, Calcineurin mediates Dephosphorylation of NFAT (Nuclear Factor of Activated T cells) –> NFAT nuclear translocation and IL-2 promoter binding –> Increased IL-2 exspression
  • Cyclosprine binds to Cyclophilin, complex blocks Calcineurin activity –> Decreased IL-2 expression
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4
Q

Clinical application of Cyclosporine?

A
  • Immunosuppression
  • Organ transplant recipients
  • Tx of “Graft vs. Host” Disease in Bone Marrow Transplant recipients
  • Can be used as a DMARD
  • CYP3A4 Mediated metabolism
    • CYP3A4 inhibitors (Erythromycin or Voriconazole) can dramatically elevate Cyclosporine lvls
    • –> Nephrotoxicity risk
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5
Q

SEs of Cyclosporine?

A
  • Nephrotoxicity especially when combined with Erythromycin or Voriconazole
  • HTN
  • Hirsutism
  • Gum Hyperplasia (Gingival Hyperplasia)
  • Neurotoxicity
  • Hyperlipidemia
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6
Q

Mechanism of Tacrolimus (FK506)?

A
  • Calcineurin Ihibitor for Immunospupression
  • 50x - 100x more potent than Cyclosporine
  • Less Nephrotoxicity
  • Binds to FKBP-12 –> Tacrolimus-FKBP complex –> inhibits Calcineurin and suppresses IL-2 expression
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7
Q

Clinical use of Tacrolimus (FK506)?

A
  • Immunosuppression
  • prevents Graft vs Host disease
  • Primarily used for Prophylaxis after Kidney (Renal)
    and Liver Transplants
  • Rescue therapy
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8
Q

SEs of Tacrolimus (FK506)?

A
  • Nephrotoxicity (less than Cyclosporine)
  • HTN
  • Inhibition of Pancreatic Beta-Islet cells
  • Increased risk of Lymphoma
  • Neurotoxicity
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9
Q

(3) Drugs that are Inhibitors of Cell Proliferation?

A
  1. Sirolimus
  2. Mycophenolate mofetil
  3. Azathioprine
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10
Q

Mechanism of Sirolimus?

A
  • Like Tacrolimus, binds to FKBP-12 forms complex
  • HOWEVER, it does not inhibit Cacineurin, but instead blocks IL-2 responsiveness of T cells by
  • *Inhibiting P13-kinase, mTOR kinase** (mammalian target of Rapamycine) which modulates Gene expression
  • mTOR dysregulation is a/w Neoplasia
  • mTOR inhibitors can be used in the treatment of some types of Malignancy
  • Metabolized in the Liver by CYP3A4
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11
Q

Clinical uses of Sirolimus?

A
  • Immunosuppression for Organ Transplant recipients
  • Prevention of Cardiac stent Restenosis
    • Sirolimus-eluting Coronary artery stents inhibit Neointimal hyperplasia and decrease restenosis rates
  • Kaposi Sarcoma in transplant pts. –> lesion regression
    • KS requires mTOR activity for growth
  • Tuberous sclerosis - genes mutated in this disorder (TSC1 and TSC2) is to regulate mTOR
  • Metabolized in Liver CYP3A4
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12
Q

SEs of Sirolimus?

A
  • Anemia
  • Leukopenia
  • Thrombocytopenia
  • Hyperlipidemia (Increased Cholesterol and Triglycerides)
  • Increased risk of Lymphocele in Transplant pts.
    • Contraindicated in Liver and Lung pts.
  • Diarrhea, Nausea, Constipation
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13
Q

Mechanism of Mycophenolate Mofetil?

A
  • Active metabolite –> Mycophenolic acid
    –>
    Inhibitor ofIMP dehydrogenase, the rate-limigting step in thede novo synthesis of GMP
    (Inosine monophoshate dehydrogenase, IMP dehyd.)

    –> Inhibition is particulary toxic to B and T lymphocytes which rely on de novo synthesis of Purine biosynthesis
  • Mycophenolic acid also binds to Type II IMP dehydrogenase isoform expressed in Lymphocytes
    –> Impaired Lymphocyte proliferation
    –> Immunosuppresion
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14
Q

Clinical use of Mycophenolate Mofetil?

A
  • Immunosuppresion of Solid Organ Transplants
  • -> used w/ low dose Cyclosporine/Tacrolimus
  • Recommended following Renal and Heart Transplant
  • -> Should NOT be administered w/ Antacids (decreased absorption)
  • Treats RA, Psoriasis, SLE, Inflammatory Bowel disease
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15
Q

SEs of Mycophenolate Mofetil?

A
  • Myelosuppression (Bone Marrow Suppression cells)
    • ​Leukopenia (WBCs)
  • GI symptoms
    • Nausea
    • Cramping
    • Diarrhea
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16
Q

Mechanism of Azathioprine?

A
  • Active Metabolite is **6-mercaptopurine (6-MP)
  • -> acts as a IMP dehydrogenase inhibitor
  • -> Also Inhibits PRPP** an enzyme that catalyses the rate-limiting step in de novo Purine Synthesis
  • Purine analog that Disrupts de novo Purine Biosynthesis (Both GMP and AMP)
  • -> Inhibits DNA replication
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17
Q

Clincial use of Azathioprine?

A
  • Immunosuppression of Solid Organ Transplantation
  • RA, Psoriasis, SLE, IBD
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18
Q

SEs of Azathioprine?

A
  • Leukopenia
  • Diarrhea
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19
Q

(6) Disease-Modifying Anti-Rheumatic Drugs (DMARDs)?

“MS CLPT”

A
  1. Methotrexate
  2. Sulfasaline
  3. Chloroquine
  4. Leflunamide
  5. Penicillamine
  6. Tofacitinib
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20
Q

Mechanism of Methotrexate?

A
  • Folic acid analog –> Antagonist
  • Inhibits Dihydrofolate reductase (DHFR) and prevents Folate recycling –> Decreased Synthesis of Purine Nucleotides Metabolism and Adenosine accumulation
  • Impaired Nucleic Acid synthesis
  • -> Disproportionately affects rapidly dividing cells
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21
Q

Clinical use of Methotrexate?

A
  • Immunosuppression - First-line therapy
    • Sever RA
    • Psoriasis
  • Ankylosing Spondylitis
  • Polymyositis
  • Dermatomyositis
  • SLE
  • Wegener’s Vasculitis
  • Antineoplastic - Used in combination w/ Chemotherapy for many Malignancies
  • Ectopic Pregnancies
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22
Q

SEs of Methotrexate?

A
  • Myelosuppression
    • Leukopenia / Anemia
  • GI hemorrhagic enteritis
  • Ulcerative Stomatitis
  • Contraindicated in Pregnancy
  • Arachnoiditis
  • Neurotixicity
  • Pneumonitis
  • Hepatic Toxicity
  • Alopecia
23
Q

Mechanism of Sulfasalazine>

A
  • In the Colon, bacteria break the AZO bond and free the Salicylate Derivative
  • -> Acts locally as an Anti-inflammatory agent
  • Prodrug - Mechanism unknown - thought to work by Scavenging of ROS produced by Neutrophils
  • Induces Remission in Active RA and Crohn’s Disease
24
Q

Clinical use of Sulfasalazine?

A
  • Rheumatoid Arthritis (RA)
  • Polyarticular Juvenile Rheumatoid Arthritis (JRA)
  • Inflammatory Bowel Disease (IBD)
    • Acute flares
    • Maintenance of Remission
25
Q

SE of Sulfasalazine?

A
  • GI distress
  • Leukopenia
  • Allergic reaction to Sulfa Moiety (Anaphylaxis)
    • Rash
    • Fever
    • Stevens-Johnson Syndrome
    • Hepatitis
    • Nephritis
    • Bone marrow suppression
26
Q

Mechanism of Penicillamine and USE?

A
  • Produced by Hydrolysis of Penicillin
  • Anti-Rheumatoid activity in ~75% of Patients
    • Perhaps connected to Decreased IL-1 Production and Collagen maturation
  • Metal Chelator (Wilson’s disease / Heavy Metal Poison)
    • NOT w/ Gold Compounds
27
Q

SEs of Penicillamine?

A
  • Rashes
  • Stomatitis
  • GI distress
  • Proteinuria
  • Leukopenia
  • Thombocytopenia
  • Contraindicated w/ Renal Disease and Pregnancy
28
Q

Mechanims of Hydroxychloroquine (Chloroquine)?

A
  • Antirheumatic - Inhibitory effects on Processing of Peptide Antigens and their Assembly into MHC complexes by Macrophages
    • Similar effecs on Posttranslationional processing of Proteins may account fot he Observed effects on Release of Cytokines
      • TNF-α
      • IL-1
      • IFN-γ
  • Antimalarial
29
Q

Clinical use of Hydroxychloroquine?

A
  • Rheumatoid arthritis (RA)
  • Juvenile Inflammatory Arthritis
  • SLE
  • Discoid Lupus
  • Sjogren’s Syndrome (Salivary gland swelling and extraglandular features)
30
Q

SEs of Hydroxychloroquine?

A
  • Retinopathy (Ocular Toxicity)
    • decreased visual acuitiy, scotomata, pigmented changes in Retina, Corneal deposits
  • Maculopapular Rash
  • Myopathy / Cardiomyopathy (Rare)
31
Q

Mechanism of Leflunamide?

A
  • Prodrug whose Metabolie inhibits Dihydroorotate dehydrogenase - essential Mitochondrial enzyme in
    de novo Pyrimidine Synthesis
  • Prevents Expansion of Activated Lymphocytes
32
Q

Clinical use of Leflunamide?

A
  • Rheumatoid Arthritis
33
Q

SEs of Leflunamide?

A
  • Infrequent but Severe Hepatotoxicity
  • Diarrhea
  • Nausea
  • Myelosuppression
34
Q

Mechanism of Tofacitinib?

A
  • 1st approved Inhibitor of Janus-Kinases
  • Inhibits JAK/STAT signaling a/w Multiple Cytokines
  • Blocks T cell Differentiation and Production of Pro-inflammatory mediators
  • Approved for pts who have FAILED MTX therapy
35
Q

SEs of Tofacitinib?

A
  • Increased infections
  • Lymphoma
  • Neutropenia / Anemia
  • Elevated LDLs
36
Q

Chimeric Abs?

A
  • Binds to the Fc region in Human
  • The Antigen binding site is from a Mouse
37
Q

Humanized Abs?

A
  • Binds the Entire Ab is Human in origin
  • EXCEPT for the CDR region
  • Responsible for the Ability of the Antigen Binding site to Bind to a Target Antigen
38
Q

Daclizumab?

A
  • Chimeric monoclonal Ab
  • Against CD 25 Alpha chain of the IL-2 receptor
  • Inhibits IL-2 mediated T cell activation
  • Reduces Acute rejection when used w/ Cyclosporine in Kidney and Cardiac transplant
39
Q

Basiliximab?

A
  • Chimeric
  • Against CD 25 Alpha Chain of IL-2
  • Inhibits IL-2 mediated T-cell activation
  • Prophylaxis and Tx for Acute Rejection
  • BUT has Acute HSN reactions
40
Q

Infliximab?

A
  • Chimeric monoclonal Ab
  • Against TNF-α (soluble and transmembrane forms)
  • Crohn’s disease
  • Ulcerative colitis
  • RA
  • Psoriatic arthritis
  • Increased Susceptibility to Infection, esp. Tuberculosis
  • Reactivation of Hep B and Malignancies, Hepatotoxicity
  • Significant incidence of Anti-Infliximab Antibodies
41
Q

Etanercept?

A
  • Recombinant Chimera of soluble p57-TNF receptor
    Type II and Fc portion
    ofhuman IgG
    • ​Each molecule of Etanercept can bind to and inactivate two TNF molecules
    • Inhibiting the Inflammatory cascade downstream of this key cytokine
  • Thought to act by Neutralizing free TNF
  • A/w increased incidence of Demyelinating Diseases / Multiple Sclerosis and can Reactivate Tuberculosis and Atypical Mycobacterial infections, prediscposes to Opportunistic Infections
42
Q

Adalimumab?

A
  • Human Chimeric monoclonal Ab (Infliximab)
  • Against TNF-α (soluble and transmembrane forms)
  • Crohn’s disease
  • Ulcerative colitis
  • RA
  • Psoriatic arthritis
  • Increased Susceptibility to Infection, esp. Tuberculosis
  • Reactivation of Hep B and Malignancies, Hepatotoxicity
43
Q

Abatacept?

A
  • Recombinant Chimeric of the Extracellular domain of
  • *CTLA-4** and the Fc Portion of Human IgG used for RA
  • Binds to CD80 and CD 86 to block binding to CD 28 and Prevent T-cell activation
  • CTLA4 binds to CD80 and CD86 molecules on APCs
  • -> Blocking their ability to Co-stimulate (Primary stimulus being MHC - TCR), thus Blocking T cell activation
  • Used for Refractory Rheumatoid Arthritis
44
Q

Muromonab?

A
  • Mouse Monoclonal Ab
  • Against CD3 Surface protein of T cells
  • Blocks engagement of T cell receptor - previously indicated for Reversal of Acute rejection
  • Can non-specifically Activate T cells upon infusion, resulting in Cytokine release **syndrome
  • -> adverese, systemic inflammatory response**, HSN
  • Voluntarily withdrawn from market
45
Q

Anakinra?

A
  • Nonglycosylated analog of Human IL-1 Receptor Antagonist
  • Used for Anti-TNF-α - refractory RA
    • It poses a significant Increased risk of Infection** when used in **Combination w/ an Anti-TNF-α ​agent
  • Approved for the treatment of RA
46
Q

Tocilizumab?

A
  • a Humanized monoclonal Ab
  • Against B lymphocyte stimulator (BAFF) - a member of the TNF family
  • Increased risk of Infection
47
Q

Rituximab?

A
  • Recominant Chimeric
  • Anti-CD20 monoclonal Ab that promotes Complement mediated Lysis of CD20-positive B cells
  • RA, Non-Hodgkin’s Lymphoma, Chronic Lymphocytic Leukemia
48
Q

Omalizumab?

A
  • Humanized monoclonal Ab
  • against IgE that is found on the Surfae of Mast cells and Basophils
  • Drug blocks IgE-mediated Mast cell and Basophil Activation
  • Used in the face of Allergic reactions
  • Moderate to severe Allergic Asthma that is Unresponsive to Inhaled Corticosteroids
49
Q

Alemtuzumab?

A
  • Monoclonal Ab
  • Against CD52 Panlymphocyte (B and T cells) antigen
  • Used to treat CLL
  • Used to Prevent Acute Rejection
50
Q

Fingolimod?

A
  • Blocks the Migration of Lymphocytes out of Lymph Nodes
  • Rx for MS
  • A/w Fatal infections
51
Q

Natalizumab?

A
  • Humanized monoclonal Ab
  • Against A4 subunit of A4b1-integrin
  • Results in the Inhibition of Lymphocyte migration through the Endothelial cell sites of Inflammation
  • Rx for Crohn’s Disease and MS
  • A/w increased risk of JC virus-induced Progressive Multifocal Lekoencephalopathy
52
Q

IFN-β

A
  • Beta Interferon is a Type I interferon that Induces a Potent Antiviral State in Target cells
  • Single Cystein to Serine substitution
  • Rx for MS
  • IFN-β decreases relapse frequency in the Relapsing/Remitting form of this disease
  • Flu-like symptoms
    • Fever, Myalgias, Malaise
  • Neutropenia, Thrombocytopenia
  • Exacerbation of Depression and Suicidality
53
Q

(3) Colony Stimulating Factors that promote Hematopoeisis?

A
  1. Epoetin α
    • Recombinant Erythropoeitin analogue –> RBCs in anemic pts.
  2. Darbepoeitn α
    • ​​longer half life –> RBCs in anemic pts.
    • Possible stimulation of Tumor cell proliferation
    • Increased risk of CV events
  3. Filgastrim
    • ​​Stimulates Neutrophil proliferation and Maturation as well as Migration.