PHAR: Rheumatoid Arthritis Flashcards
What are the two therapeutic goals for rheumatoid arthritis treatment?
- Preserve function.
- Prevent pain.
Immune cells associated with RA.
- Macrophages.
- T and B lymphocytes.
- Endothelial layer of blood vessels.
- Fibroblasts.
What are the three DMARDs that inhibit T cell proliferation and function?
- Methotrexate (MTX)
- Leflunomide
- Glucocorticoids
Name two drugs that have an unknown method of action.
- Sulfasalazine.
- Hydroxychloroquine.
What immune cell produces TNFa?
Macrophages.
What immune cell stimulates macrophages to produce TNFa?
T lymphocyte.
- What are two examples of potent glucocorticoids?
- What molecule is modified to make these glucocorticoids?
- Prednisolone. (potent glucocorticoid).
- Dexamethasone. (very potent glucocorticoid).
- Hydrocortisone (cortisol)
What are some adverse effects of MTX?
- Neutropenia.
- Thrombocytopenia.
- Mouth ulcers.
- GI upset.
- Teratogenicity risk.
- Hepatotoxicity.
- Pulmonary fibrosis.
Which class of RA medication are TNF-alpha inhibitors?
Name 2 examples.
Biologicals
Infliximab and Adalimumab
What are adverse effects of TNF-alpha inhibition?
- Immune suppression
- Increased infection rate
- Dorman tuberculosis reactivation
- Increased rate of some malignancies?
How does MTX prevent T-cell proliferation?
Folate antagonist (has v similar structure). Folate delivers building blocks for DNA through conversion from tetrohydrofolate (FH4) to folate. DHFR is the enzyme which converts folate back to FH4.
- Inhibits Dihydrofolate Reductase (DHFR) enzyme
- Prevents conversion folic acid to terahydrofolic acid
- Prevents nucleic acid synthesis
- Prevents T-cell proliferation.
How is MTX excreted? (and hence, what function needs to be checked beforehand)
Really excreted, renal function
How does leflunomide prevent T-cell proliferation?
- Blocks dihydroorotate deyhdrogenase
- Prevents pyrimidine synthesis
How do non-steroidal anti-inflammatory drugs (NSAIDS) work?
Do they prevent disease progression?
- Inhibit prostaglandin production, suppressing signs of inflammation (inc. pain)
- Do not prevent disease progression.
What are DMARDs?
Disease Modifying Anti-Rheumatoid Drugs
What are the 3 main targets/mechanisms/classes of DMARDs?
- Targeting T-cells
- Targeting macrophages
- Unknown mechanism
Which drugs target macrophage action?
- TNFa inhibitors
- Anti-IL6
- Glucocorticoids
What is the mechanism of action of glucocorticoid?
- Enter cytosol & bind to a receptor
- translocate to nucleus
- Bind to GRE (glucocorticoid responsive element) promoter gene, stimulating transcription of anti-inflammatory proteins.
What is the effect of glucocorticoids on inflammatory cells?
T-cells: decrease recruitment & proliferation
B-cells: decrease antibody production
Macrophages: decrease cytokine production, including TNFa. Also decreases it’s other pro-inflammatory functions.
What are the adverse effects of glucocorticoids?
How are these avoided?
- metabolic effects (changing metabolism, developing diabetes)
- mineralocorticoid effects (salt & water retention)
Avoided by giving locally (long acting joint injections for RA, asthma puffers, creams)
Why should leflunomide be avoided in young women?
Even more teratogenic than MTX.
Very long half-life.
Are glucocorticoids DMARDs?
No, while they blunt the immune reaction they are insufficient to slow progression of the disease
(some evidence they may have DMARD effects in early stages)
What is the typical order/choice of drugs?
- MTX
- leflunomide
- add sulfasalazine or hydroxychloroquine
- add biologic (ie Infliximab or Adilimumab)
- supplement with NSAIDs for pain relief
- glucocorticoids low-dose systemic in early treatment or locally via injection for acute flare ups.
