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Flashcards in Drugs for rheumatoid arthritis Deck (18):
1

Glucocorticoid (GCC) mechanism of action

-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

GCCs effects on leukocytes

-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

Types of GCCs

-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

Side effects and use of GCCs

-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

Disease-modifying anti rheumatic drugs (DMARDs) selection

-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

Combinations of DMARDs

-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

Mechanism of action of MTX for RA 1

-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

Mechanism of action of MTX for RA 2

-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

Side effects and interactions of MTX

-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

Contraindications of MTX

-Pregnancy
-Liver, lung, or kidney disease
-Moderate-high etoh consumption (other liver complications)

11

Leflunomide (LFU)

-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

LFU mechanism for RA Rx

-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

Side effects of LFU

-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

Hydroxychloroquine (HCQ) in RA Rx

-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

Sulfasalazine (SZN) in RA Rx

-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

16

SZN side effects and contraindications

-Most common: nausea, vomiting, headache, and diarrhea
-These are related to N-acetyltransferase genetic polymorphisms, which may require dosage reduction
-Contraindicated in those w/ sulfa allergies
-Not teratogenic: safe during early pregnancy, but since its a sulfa drug it causes kernicterus and thus is not recommended for pregnant women near term
-Decreases folate absorption, thus pregnant women must have folate supplementation

17

TNFa inhibitors (biologics)

-TNFa is pro-inflammatory cytokine made by macrophages that is responsible for the joint destruction in RA
-TNFa-inh bind to TNF preventing it from binding to its receptor and blocking the inflammatory cascade leading to joint destruction
-The body can begin to make antibodies against these drugs which reduces their effectiveness
-Etanercept: portions of the human TNF receptor + human IgG Fc, binds both TNFa/b, subQ, MTX added recommended, anti-antiTNF Abs are non-neutralizing and MTX reduces these
-Infliximab: mouse Ag binding domain + human IgG Fc, binds only TNFa, IV infusion, MTX added required, anti-antiTNF Abs are neutralizing and MTX reduces these

18

Side effects of TNFa inhibitors

-Serious infections: sepsis, TB, demyelinating diseases
-Contraindicated for pts w/ active infections or latent TB
-Drug induced lupus is rare but possible