Pharmacology/Anti-cytokine Drugs - Walworth 4/7/16 Flashcards Preview

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Flashcards in Pharmacology/Anti-cytokine Drugs - Walworth 4/7/16 Deck (15):
1

effects of GPCR stimulation

Gs - increase adenylate cyclase

Gi - decrease adenylate cyclase

Gq - increase PLC

2

chemical mediators of inflammation

  • vasoactive amines (histamine, 5HT)
  • neuropeptides (substance P)
  • plasma proteases (Factor XII)
  • lipid-derived arachidonic metabolites
  • platelet-activating factor
  • cytokines: IL1, TNF-alpha

3

examples of diseases resulting from chronic inflammation  for which anti-cytokine therapy is useful!

  • rheumatoid arthritis
  • inflammatory bowel disease
    • Crohn's disease
    • ulcerative colitis
  • lupus
  • psoriasis

4

major effects of IL1 and TNFalpha

acute-phase rxns

  • fever
  • incr sleep
  • decr appetite
  • incr acute-phase proteins
  • hemodynamic effects (shock)
  • neutrophilia 

endothelial effects

  • leukocyte adherence
  • PGI synthesis
  • incr procoag activity
  • decr anticoag activity
  • incr IL1, IL6, ILB PDGF

fibroblast effects (prolif, collagen synth, PGE, etc)

cytokine effects (incr cytokine secretion)

5

rheumatoid arthritis

  • pathophys
  • basic drugs: mech

pathophysiology

antigen drives lymphocyte proliferation → production of autoantibody → complement fixation, attraction of infl cells, cytokine production

  • activation of innate immune system → DCs migrate to lymph nodes, activate T cells → T cells migrate to joint → produce pro-infl cytokines
  • activated macrophages and fibroblasts → produce TNFalpha
  • more immune cells recruited to joint

drugs

DMARDs (ex. leflunomide, methotrexate)

  • prevent prolif of lymphocytes
  • reduce infl process

6

RA drugs

 

"cepts"

"TNF sponges"

etancercept: contains extracellular domain of TNFalpha-R

  • high affinity for TNFalpha → neutralization
  • indication: rheumatoid arthritis, other types of arthritis
  • admin: subcutaneous, weekly
    • often taken in combo with methotrexate

7

RA drubs

"mabs"

"TNF sponges" - antibody to TNFalpha

infliximab: chimeric antibody (part mouse, part human)

  • high affinity for TNFalpha → neutralization
  • admin: IV

adalimumab: humanized antibody

  • admin: subcutaneous

8

RA drugs:

anakinra

IL1 receptor antagonist - endogenous protein

anakinra: chimeric antibody (part mouse, part human)

  • admin: daily subcutaneous injection
    • can be given with MTX, but not TNF agents

9

RA drugs:

 

abatacept

CTLA-4-Ig

binds to B7 (aka CD80, CD86) on APC, prevents signal2 in T cell activation (B7/CD28 binding)

  • lowers serum concentration of infl mediators
  • admin: IV, 2wk, 4wk, monthly followup (shouldn't be admin with other biologics)
  •  

10

IBD

chronic inflammation can affect permeability of epithelial layer (make it more permeable than healthy) → amplifying loop of infl

 

  • Crohn's disease (entire GI tract)
  • ulcerative colitis (colon)

11

IBD drugs

 

mabs

infliximab: chimeric antibody to TNFalpha

  • admin: IV infusion for 2 hr every 2 weeks, then every 8 weeks

certolizumab: PEGylated Fab fragment of humanized TNFalpha antibody

  • admin: subcutaneous

12

BAFF

 

link to disease

B cell Activation Factor

BlyS - B lymphocyte stimulator

member of TNFalpha family

 

key determinant of whether B cells will survive/die during tolerance processes!

 

diease link: excess BAFF in lupus →

  • excess production of monoclonal antibodies
  • kidney deposition
  • complement activation

collectively, infl + tissue destruction

13

adverse effects of anti-cytokine therapy

  • injection site rxns
  • infusion rxns
  • cytopenia with anti-TNF therapy : need to monitor CBC
  • serious infections (sepsis, TB)
  • malignancies reported
  • hepatotox (infliximab)

14

contraindications to anti-cytokine therapy

active infections

  • TB+? treat latent TB first
  • pre existing demyelinating diseases

15

secukinumab

IL17 inhibitor → controls psoriasis