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Flashcards in Multi-Systems: Autoimmune Treatments Deck (53)
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1

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

  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

2

What are the (2) Calcineurin Inhibitors?

  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

3

What is the Mechanism of Cyclosprine?

  • 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

4

Clinical application of Cyclosporine?

  • 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

5

SEs of Cyclosporine?

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

6

Mechanism of Tacrolimus (FK506)?

  • 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

7

Clinical use of Tacrolimus (FK506)?

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

8

SEs of Tacrolimus (FK506)?

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

9

(3) Drugs that are Inhibitors of Cell Proliferation?

  1. Sirolimus
  2. Mycophenolate mofetil
  3. Azathioprine

10

Mechanism of Sirolimus?

  • 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

11

Clinical uses of Sirolimus?

  • 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

12

SEs of Sirolimus?

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

13

Mechanism of Mycophenolate Mofetil?

  • Active metabolite --> Mycophenolic acid
    -->
     Inhibitor of IMP dehydrogenase, the rate-limigting step in the de 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

14

Clinical use of Mycophenolate Mofetil?

  • 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

15

SEs of Mycophenolate Mofetil?

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

16

Mechanism of Azathioprine?

  • 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

17

Clincial use of Azathioprine?

  • Immunosuppression of Solid Organ Transplantation
  • RA, Psoriasis, SLE, IBD

18

SEs of Azathioprine?

  • Leukopenia
  • Diarrhea

19

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

"MS CLPT"

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

20

Mechanism of Methotrexate?

  • 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

21

Clinical use of Methotrexate?

  • 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

22

SEs of Methotrexate?

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

23

Mechanism of Sulfasalazine>

  • 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

Clinical use of Sulfasalazine?

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

25

SE of Sulfasalazine?

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

26

Mechanism of Penicillamine and USE?

  • 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

SEs of Penicillamine?

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

28

Mechanims of Hydroxychloroquine (Chloroquine)?

  • 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

Clinical use of Hydroxychloroquine?

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

30

SEs of Hydroxychloroquine?

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