Drugs for rheumatoid arthritis Flashcards
1
Q
Glucocorticoid (GCC) mechanism of action
A
- They indirectly reduce the activity of phospholipase A2, thus reducing the amount of arachidonic acid generation and reducing the synthesis of prostaglandins/leukotrienes
- They do this by influencing the transcription of proteins
- They increase the expression of lipocortins (lipomodulin), which inhibits the action of PL A2
- GCCs also suppress the expression of COX2 directly
- However they have no direct inhibitory effect on COX or LOX, which makes them different from NSAIDs
2
Q
GCCs effects on leukocytes
A
- They decrease the number of circulating lymphocytes, redistributing them to lymphoid tissue and preventing their return to circulation
- They increase the number of circulating neutrophils, by increasing their influx from BM and preventing migration from blood vessels
- This results in a reduction in the number of PMNs at site of inflammation
- GCCs also cause a decrease in the production of IL1 from leukocytes, and change WBC receptors for chemokines
3
Q
Types of GCCs
A
- Naturally occurring (cortisol/cortisone) cause sodium retention
- Synthetic GCCs (prednisone): greater anti-inflammatory effects and less Na retention
- Fluorinated synthetic GCCs (dexamethasone, betamethasone, triamcinolone): no Na retention and greatly enhanced anti-inflammatory effects
4
Q
Side effects and use of GCCs
A
- Long term use causes hypothalamic-pituitary associated adrenal suppression (adrenal atrophy), growth retardation, peptic ulceration, infection susceptibility, osteoporosis, myopathy, cataracts, hyperglycemia
- Large doses of prednisone can cause fluid and electrolyte imbalance
- Indicated for occasional intraarticular injection for local relief of synovitis
5
Q
Disease-modifying anti rheumatic drugs (DMARDs) selection
A
- First start w/ NSAIDs (aspirin or ibuprofen unless contraindicated)
- For gastric protection: use ibuprofen (enteric coating) or COX2 inh+ misoprostol (gastric protection) or omeprazole (decrease acid secretion)
- For coagulation problems: COX2 inh
- For mild RA: hydroxychloroquine (HCQ) or salfasalazine (SZN)
- Moderate-severe RA: methotrexate alone (MTX)
- Inadequate response to MTX: another DMARD is added to MTX
- Still not responding: TNFa inhibitor added to MTX
6
Q
Combinations of DMARDs
A
- Used for severe RA
- MTX + HCQ/SZN: no additive toxicity
- MTX + leflunomide (LFU): synergistic interaction in that MTX inhibits de novo purine synthesis and LFU inhibits de novo pyrimidine synthesis
- MTX + TNFa-inh: MTX decreases production of autoAbs to the TNFa-inh thus prolonging their actions
7
Q
Mechanism of action of MTX for RA 1
A
- MTX in RA is used only in low doses, to prevent it from inhibiting dihydrofolate reductase (which it does at high concentrations)
- MTX at low doses is anti-inflammatory and does not increase opportunistic infections
- W/in the cell it is polyglutamated, and MTX-polyglu inhibits conversion of AICAR->FAICAR by transflormylase (involved in purine synthesis)
8
Q
Mechanism of action of MTX for RA 2
A
- Accumulated AICAR inhibits adenosine deaminase and AMP deaminase, resulting in intra and extracellular increase in adenosine and AMP
- A cell surface nz (ecto-5-nucelotidase) converts AMP to adenosine
- Extracellular adenosine binds to its receptor and increases cAMP, which decreases the production of inflammatory cytokines (TNFa, INFg) by T cells and macs, O2 radicals by PMNs, and IL1-induced prostaglandins and proteases by synoviocytes (fibroblasts)
9
Q
Side effects and interactions of MTX
A
- High intake of caffeine (adenosine antagonist) correlates w/ poor clinical response to MTX
- Frequent side effects: GI disturbances, alopecia, myelosuppression (may be reduced w/ folate intake)
- Pneumonitis can occur (need baseline CXr)
- Liver cirrhosis: rare but must monitor AST/ALT. Etoh consumption, DM, hep C or B exacerbates
- Side effects can be reduced by taking leucovorin (folate)
- Taking aspirin and MTX: decrease MTX dose b/c aspirin displaces it from albumin (more bioavailable) and decreases renal excretion of MTX
10
Q
Contraindications of MTX
A
- Pregnancy
- Liver, lung, or kidney disease
- Moderate-high etoh consumption (other liver complications)
11
Q
Leflunomide (LFU)
A
- Orally administered prodrug that is converted to active metabolite (M1) in the intestinal wall and liver
- M1 has long half-life due to enterohepatic recirculation
- Incase of OD, cholestyramine is given to remove M1 from the gut
12
Q
LFU mechanism for RA Rx
A
- Activated lymphocytes require an 8-fold increase in pyrimidine nucleotide pool to progress from G1->S
- M1 inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting nz for de novo pyrimidine synthesis
- This results in cell cycle arrest (G1 phase) and inhibition of lymphocyte clonal expansion
- Is selective to activated lymphocytes: resting lymphocytes and other tissues w/ high turnover rate (BM, GI) require only a limited pyrimidine nucleotide pool to divide
- Thus LFU does not increase opportunistic infections
13
Q
Side effects of LFU
A
- Diarrhea (30%)
- Elevated liver nzs (AST/ALT) but not as hepatotoxic as MTX
- Teratogenic (cat X): women considering pregnancy need cholestyramine Rx for 11 days before getting pregnant
14
Q
Hydroxychloroquine (HCQ) in RA Rx
A
- Mechanism is not clear, is a weak base so interferes w/ functioning of lysosomes and release of hydrolytic nzs
- Interacts w/ nucleoproteins and inhibits DNA and RNA synthesis
- Traps free radicals
- Onset of action is longer (3-6 mo) than other DMARDs, side effects are relatively mild
- Thus it is used in combination Rx w/ MTX
- Relatively safe during pregnancy
15
Q
Sulfasalazine (SZN) in RA Rx
A
- Sulfasalazine is a prodrug, little of it (10-20%) is absorbed and most of it (70%) is broken down in the colon to sulfapyridine and 5-aminosalicylic acid (which is not absorbed and has anti-inflammatory effects thus is used in IBD)
- Sulfapyridine is absorbed and its mechanism is not known, but it has the ability to increase adenosine levels and inhibits IL1 and TNFa release
- Is more effective than HCQ
