Pharmacology/Anti-cytokine Drugs - Walworth 4/7/16 Flashcards
(15 cards)
effects of GPCR stimulation
Gs - increase adenylate cyclase
Gi - decrease adenylate cyclase
Gq - increase PLC
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
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
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)
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
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
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
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
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)
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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)
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
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
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)
contraindications to anti-cytokine therapy
active infections
- TB+? treat latent TB first
- pre existing demyelinating diseases
secukinumab
IL17 inhibitor → controls psoriasis
