Locomotor RA drugs Flashcards
Methotrexate MoA
DMARD
Folate Acid Antagonist
• Enters cell -> polyglutamated.
• Prevents proliferation during cell mitosis by inhibiting dihydrofolate reductase (purine metabolism) and prevents DNA/RNA metabolism by inhibiting thymidylate synthase.
• Stops production of pro-inflammatory cytokines and of any additional fibroblasts.
• Prevents binding of IL1b to surface of cells.
Methotrexate Side Effects
Due to indiscriminate to dividing cells:
• Can cause liver problems
• Can affect blood count.
Methotrexate Administration
- Oral
- Subcutaneous/intramuscular
Loading dose: 50mg a week
Maintenance dose: 2.5mg tablet.
(!) 3-12 weeks before benefit seen.
Sulfasalazine MoA
DMARD Old sulfur antibiotic • Moa not well understood. • Not well absorbed across gut. ~ 15% of parent drug. Converted to 5-ASA • 5-ASA: treats UC and relieves arthritis symptoms (believes to have some sort of role in the gut).
Normally cells in the gut produce IL-6, IL-17 and TNFa, that get can into the blood stream and lead to inflammation
• Modulating immune system in gut: modulates distant sites of cytokine travel.
Sulfasalazine Administration
Start 500mg daily, then gradually increase over 4 weeks to 1g twice a day.
(!) 12 weeks before benefit seen.
Hydrochloroquine MoA
Anti-Malarial
• MoA not well understood.
• Accumulates in lysosomes: increases pH, which decreases protein modification.
o Cytokines often secreted with precursors that need to be modified.
• Block TLR9: recognises DNA containing immune complexes decreases activation of dendritic cells.
Hydrochloroquine Side Effects
Can get a rash from taking it.
Hydrochloroquine Administration
Start 400mg daily
Reduced to 2-3 times a week.
Leflunomide MoA
DMARD
• Moa not well understood
• Inhibits DNA and RNA synthesis though a different pathways vs methotrexate.
• Inhibits pyrimidine synthesis.
Leflunomide Administration
10-20mg a day (1st 3 days higher dose than 100mg a day).
Gold Salts MoA
DMARD
• Moa not well understood
People experience very different effects.
Gold Salts Administration
Intramuscular injections
10-20mg a day.
Etanercept MoA
TNF Alpha Blocker
Fusion protein between TNF receptor 2 and FC human IgG1
• Extracellular receptor stuck to human FC.
• Finds free TNFa alpha in the system.
Etanercept Administration
Subcutaneous injection
50mg once per week.
(!) 1-4 week for effect.
Progressive improvement over 3-6m.
Infliximab MoA
TNF Alpha Blocker
Monoclonal antibody vs TNF alpha.
• Design against mouse binding site of TNFa. .
• Remains 75% human IgG.
Adalimumab MoA
TNF Alpha Blocker
Human TNF alpha monoclonal antibody
• Binds to TNFa both soluble and bound.
Adalimumab Administration
Subcutaneous injection
100mg once a week
(!) 2-4 weeks for effect.
Anankinra MoA
IL-1 Blocker
Human recombinant IL-1 receptor antagonist.
• Different from normal IL-1 by addition of methionine to the N-terminal.
Canakinumab MoA
IL-1 Blocker
Human monoclonal antibody IL-1 beta.
• Approved for some rare autoimmune syndromes
• Trials for COPD and gout
Rinalocept MoA
IL-1 Blocker
Dimeric fusion protein extracellular domain of IL1R1 and Fc human IgG
• Used more for acute gout.
Rituximab MoA
B-Cell Blocker
(For patients who fail to respond to one or more anti-TNF alpha agents).
• Chimeric monoclonal antibody against CD20 primarily found on surface of B-cells.
Destroys both normal and malignant B-cells
• In combination with methotrexate
Rituximab Administration
• Single course of 2 infusions of 1000mg given 2 weeks apart Depletes B-cells for up to 6 months and possibly 1 year
(!) Effects seen around 3 months after infusions
Abatacept MoA
T-Cell Blocker
Fusion protein IgG fused to extracellular domain of CTLA-4.
• Activating negative switch of signal (CTLA-4) stops T-cell.
similar reports of clinical symptom improvement compared to TNF alpha but radiological results are not as good.
Advantage: slower onset for TNF alpha inhibits
Disadvantage: fewer adverse events.
> Abatacept Administration
- i.v. infusion over 30mins to 1hr once a month
- Dosage dependent on body weight.
(!) Response around 3 months
