24 - DMARDS Flashcards
TNFR1 Function
(TNF-Receptor 1)
ALL CELLS HAVE THIS
TNF-a Binds
VVV
APOPTOSIS
TRADD -> death domain
MethoTrexate MoA
2nd Target
MTX-PG
VV–down regulates–VV
Thymidylate Synthase = TS
VVV
disrupts PYRIMIDINE SYNTHESIS
VVV
disrupts Proliferation of Anti-inflammatory cells
Abatacept = Orencia
MoA / Target
IgG domain - Fused to CTLA4
V targets V
CD80/86
which blocks the interaction with
CD28
Action:
- *Dampents T-Cell CO-STIMULATION**
- inhibits the production of:*
- *TNFa / INF-y / IL-2**
TNF-a
Functions
Multifuncitional Pro-inflammatory Mediator
A) Induction of further Cytokine Production
B) Activation / Expression of ADHESION molecules
C) Growth Stimulation
Key roles in:
Acute+Chronic Inflammation
Anti-Tumor Response
Infection
TNFR2 Function
TNF-a Receptor 2
- *found ONLY in IMMUNE CELLS**
- no death domain –> does NOT induce apoptosis*
Recruitment of TRAF2
VVV
Activation of NFkB Pathway
VVV
cytokines / inhibitors of apoptosis
- *more TNF-A // IL-1**
- *Adhesion molecules**
Which DMARD?
- weakly inhibits pro-inflammatory effects of:*
- *Arachidonic Acid Cascade**
inhibits: ATIC & DHFR
resulting in ↑ADENOSINE release
downregulates Neutrophil:
activation / chemotaxis / migration / degranulation
- *Immunomodulatory:
- inhibits* T-Lymphocyte proliferation//NK-Cell Activity**
- *B-cell activation**
SULFASALAZINE
Uses GUT/COLONIC BACTERIA
to breakdown SSZ
VV
5-ASA & Sulfapyridine
Antiinflammatory & Antibiotic
HydroxyChloroQuine
Indication
Relatively Safe & Well Tolerated
Anti-Malarial
limited ability to prevent joint damage on THEIR OWN
SLOWEST onset of action, equal or less efficacy
Suited for:
Early / Mild RA
Usually a part of:
TRIPLE THERAPY
w/ MTX + SSZ
Most Important
ANTI-RHEUMATIC DRUG
MTX
Methotrexate
MethoTrexate
PK
- *Wide Range of Bioavailability** for PO
- worsens with INCREASED dose*
MTX half life = 6 hours
Most is excreted via URINE –> Consider Creatinine Clearance
we DONT measure SERUM MTX
MTX-PG half life = 60 DAYS
POLYGLUTAMATED MTX –> stays inside cell
we measure MTX-PG in RBC to monitor for MTX
Which DMARD?
Blocks DiHydroOrotate DeHydrogenase = DHODH
VVV
↓ PYRIMIDINE SYNTHESIS
Primarily in:
Mitogen-Stimulated T-cells
in the MITOCHONDIRA
LEFLUNOMIDE
Arava
Prodrug
rapidly & completely converted to
Active Metabolite @ MITOCHONDRIA
CATEGORY X
HT & HYPERcholesteremia & Weight Loss
3 Drug Strategies for
Inhibition of Cytokine Action
in RA
Neutrolization of Cytokines
mABs = Remicade / Humira
soluble Receptor = Enbrel
Receptor Blockade
Recept Antagonist = Kineret
Activation of Anti-Inflammatory Pathways
What do these drugs target?
REMICADE
HUMIRA
ENBREL
CIMZIA
TNF-A
Which DMARD?
Weak base that can INCREASE pH
within cytoplasmic vesicles –> immunoregulatory effects
- *Attenuates AntiGen Processing & Presentation**
- macrophages / monocytes require PRECISE pH –> digestion*
- Inhibits proinflammatory cytokines:*
- *IL-1 / IL-6 / INF-y**
HydroxyChloroQuine
HCQ
Retinal/Ocular Toxicity
Large VD / 40-50 day half life
Most excreted in:
Unchanged in Urine
Which Drug may be the best choice for WOMEN
Of CHILD BEARING age?
SSZ
sulfasalazine
Category B / C for pregnancy
REDUCED FERTILITY
In MALES
Which DMARD requires COLONIC BACTERIA
SSZ
sulfasalazine
Colonic bacteria –> 5-asa + Sulfapyridine
Antinflammatory:
Inhibits ATIC / DHFR / AA cacade / neutrophils
Immunomodulatory:
inhibits T-lymphocytes / NK cells / B-cells
Two Forms of TNF-a
Membrane Bound TNF-a
Soluble TNF-a
converted by TACE (TNFa Converting Enzyme)
MethoTrexate MoA
1st Target
MTX-PG
VV–*INHIBITS–VV
**ATIC**
–> **↑*ADENOSINE↑**
source of anti-inflammatory effects, modulates cytokines
SUPPRESSES PRO-inflammatory mediators
IL-2 / INF-y / IL-12 / TNF-a / IL-6 / IL-8 / NO
- *ENHANCES** production of ANTI-Inflammatory mediators
- *IL-4** / IL-10 / IL-1 receptor antagonist
Glucocorticoids for RA
One of the MOST effective:
Anti-Inflammatory**&**IMS therapies
Cornerstone for:
SLE / Vasculitis / Polymyalgia Rheumatica / Myostis
Joint Sparing Effect is based on:
- *INHIBITION of Pro-Inflammatory Cytokines**
- *IL-1 & TNF-a**
Sulfasalazine
PK
BioAvailability of SZA = 10%
Most undergoes EnteroHepatic Circulation
& is secreted unchanged in BILE
Sulfapyridine (biproduct)
extensively metabolized in LIVER
excreted in URINE
CATEGORY B / C for Pregnancy
may be best choice for women of child bearing age
but Reduced fertility in men
Treatment of Rheumatoid Diseases target WHAT?
Cycle of:
Proinflammatory Cytokines
Autoantibody Production
Tissue Damage
Autoaggresive T-cells
MethoTrexate MoA
3 Targets & 3 Results
MTX enters cells via:
RFC (reduced folate carrier) or FR (Folate Receptor)
tries to leave via ABC but…
FPGSynthase makes …, to also prevent it from leaving
VVV
–> POLYGLUTAMATED METHOTREXATE ( MTX - PG )
which inhibits 3 targets:
ATIC –> MORE ADENOSINE
TS –> reduce PYRIMIDINE synthesis
DHFR –> inhibits TRANSMETHYLATION reactions
Anti-Inflammatory Cytokines
in RA
In RA, we have a lack of these things:
want to INCREASE to balance out the Pro-Inflammatory Cytokines
IL-10
TGF-B
IL-1 receptor antagonist
sTNF-R = soluble TNF-receptor
Infliximab = Remicade
MoA / Targets
CHIMERIC monoclonal AB
Binds & Neutralizes:
BOTH TNF-A’s
soluble & membrane bound
Tocilizumab
MoA / Target
IL-6 RECEPTOR
approved for Arthritis
EULAR Recommendations
for DMARD progression
3 Phases
wait 3-6 months BETWEEN each
Phase 1
MTX + short term Glucocorticoid
VV if 50% improvement not seen VV
Phase 2
Add SECOND DMARD or Biologic / JAK-Inhibitor
VV if 50% improvement not seen VV
Phase 3
Change or ADD - Biologic / JAK-inihbitor
MethoTrexate MoA
1st Target
MTX-PG
VV–I**NHIBITS–VV
DiHydroFolate Reductase = DHFR
VVV
Methylation of RNA & DNA
VVV
disrupts
DNA Synthesis & Proliferation of Anti-Inflammatory Cells
