Pharmacology and Anti-Cytokine Drugs Flashcards
What are the two major cytokines that cause inflammation?
IL-1 and TNF
What are the two major cytokines that cause T-cell growth and division?
IL-2
What is the major cytokine that cause defense against viruses?
IFN-alpha
What is the major cytokine that causes cell-mediated immunity?
IFN-gamma
What is the major cytokine that causes chemotaxis to the sites of inflammation and of cells to secondary lymphoid organs?
IL-8
What is the major cytokine that causes down-regulation of immune response and regulation of embryonic development?
TGF-Beta
What is the major cytokine that causes wound healing and synthesis of ECM?
EGF
What is the major cytokine that causes stimulation of hematopoiesis?
GM-CSF
What do DMARDs do?
Prevent proliferation of lymphocytes, reduce the inflammatory process
eg: lefluomide and methotrexate
What is the target of biologic agents as anti-rheumatic drugs?
TNF-alpha;
IL-1
RA: How does etanrecept (enbrel) work?
recombinant fusion protein consisting of 2 soluble p75 TNF receptor moeties linked to Fc portion of human IgG1
binds TNF-alpha with high affinity and neutralizes its biological activity
admin: subcutaneously;
half-life: ~115 hrs;
(as effective as methotrexate; can combine with methotrextate)
RA: How does infliximab (Remicade) work?
“Human Constant and Mouse variable part)
chimeric monoclonal antibody to TNF-alpha; Fc region of human IgG and Fab sequences of a mouse anti-TNF-alpha antibody
reduces blood level of TNF-alpha, may dislodge TNF-alpha bound to cells
admin: IV
RA: How does adalimumab (Humira) work?
“Humanized Ab”
recombinant human monoclonal Ab to TNF-alpha;
complexes with soluble TNF-alpha and prevents its interaction with p55 and p75 surface receptors
Admin: subcutaneously
How do you know a drug is chimeric?
“xi” before -mab
How do you know if a drug is humanized?
“um” before -mab
Which drug targets IL-1?
anakinra (kineret)
What does anakinra do?
blocks the cellular effects of IL-1
it’s a non-glycosylated IL-1Ra (IL-1 Receptor antagonists; endogenous protein)
admin: daily; subcutaneous
What is the pathogenesis of RA (rhematoid arthritis)?
1) activation of innate immune system
2) dendritic cells migrate to lymph node
3) present antigen to T cells
4) T cells proliferate and migrate to joint
5) T cells produce pro-inflammatory CYTOKINES
6) activated MACROPHAGES and FIBROBLASTS produce TNF-alpha
7) Further recruitment of immune and inflammatory cells to joint
How does CTLA-4 turn off T cell responses?
CTLA-4 is a TM protein on activated T cell that also binds to B7
It gets upregulated after the T cell is activated.
CTLA-4 biding to B7 prevents necessary costimulation effect of B7/CD28 binding, thus shutting down T cell response
How does abatacept work?
Costimulatory blockade
like B7 binding of CTLA-4-Ig
What drugs can treat Crohn’s disease?
- infliximab
- certolizumab
Crohn’s: How does certolizumab (cimzia) work?
PEGylated Fab fragment of humanized TNF-alpha antibody
binds soluble and membrane bound TNF-alpha;
admin: subcutaneously
Lupus: what does benlysta do/work?
monoclonal antibody to BAFF/BLSy
Wha is BAFF?
B-cell activating factor (B lymphocyte stimulator); key determinant of whether B cell will survive or die during development of tolerance;
member of TNF-alpha family of proteins
What is the pathogenesis of Lupus?
With excess BAFF, B cells proliferate and survive, leading to pro-inflammatory autoantibodies, kidney deposition, and complement activation… which causes inflammation and tissue destruction
What are contraindications to anti-cytokine therapy?
- active infection
- if TB+, treat latent TB before therapy
- pre-existing demyelinating disorders
What cytokine is targeted for psoriasis?
IL-17A (via secukinumab = cosentyx)
