NSAIDS + DMARDS

Question 1

NSAIDS

Answer 1

Pharmacologic Action:
- Anti-inflammatory activity mediated thru inhibition of PG biosynthesis primarily due to COX-2 inhibition
-Analgesic activity mediated through central and local PG inhibition
- Antipyretic activity by prevention of PGE2 synthesis
- Prolonged Bleeding time due to inhibition of COX-1 in platelets, resulting in decreased TXA2 production (except acetominophen)
Side Effects: Primarily due to Cox-1 inhibition
- Gastric and intestinal ulcers
- Prolong gestation due to decreased PGE2 and PGF2a which contract uterine muscles
- Intereference w/ renal function- concern w/ renal insufficiency
- Closure of ductus arteriosus- used to treat PDA in newborns
- Aspirin intolerance syndrome- shunting of arachidonic acid to 5-LOX pathway
- Disturbance of platelet function- low dose aspirin to prevent CVD, must stop before surgery

Question 2

Methotrexate

Answer 2

• DHFR (anti-folate)
• Uses: RA + psoriasis, psoriatic arthritis, polymyositis, SLE
• Supplement w/ folic acid
• Effective orally but can give IV/SUBQ if GI problems
• Contraindicated in pregnancy

Question 3

Hydroxychloroquine

Answer 3

• Target unclear but tx for RA
• Requires 3-6 mo. for benefit
  Side effects: Peripheral neuropathies, retinal damage (rare, premanent)

Question 4

Sulfasalazine

Answer 4

• Sulfapyridine thought to be active in RA; RA tx

- IgA and IgM RF decreases, benefit in 2-3 mo.

Question 5

Leflunomide

Answer 5

• Metabolite inhibits pyrimidine synth, induces cell cycle arrest of activated lymphocytes
• RA tx
• Parent drug and metabolite have T1/2 of 19 days
• Teratogenic, must stop 2 yrs before preg.

Question 6

Glucocorticoids

Answer 6

• Local injections useful for RA and other flares

- Inhibits PLA2 and prevents COX-2 synth

Question 7

Etancercept

Answer 7

• Recombinant fusion protein consisting of 2 soluble p75 TNF receptors linked to Fc portion of human IgG1
• Binds TNF-alpha w/ high affinity and neutralizes its activity
  Tx: RA, Juvenile arthritis, psoriatic arthritis, ankylosing spondylitis
• SubQ admin weekly, t1/2 115 hrs
• Equally effected as MTX, combo of MTX and etanercept is more effective

Question 8

Anti- TNF- alpha Drugs

Answer 8

• mABs that bind TNF and blocks its ability to bind to its receptor
• Infliximab, adalimumab, golimumab, certolizumab pegol

Question 9

Rituximab

Answer 9

• Anti-CD20 mAB
• Selectively depletes CD20+ B-cells which play a role in AI response and in chronic synovitis associated w/ RA
• Commonly given w/ MTX for pt. who had inadequate response to MTX or TNF agents
• IV admin given 2 weeks apart, then repeated after 6 mo.
  Side effects: - Anaphylaxis w/in 2 hrs of infusion, fatalities reported
• Reactivation of Hep B
• PML

Question 10

Abatacept

Answer 10

• Fusion protein of CTLA-5 linked to IgG1
• Prevents T-Cell activation and lowers serum concentrations of inflammatory markers, cytokines and RF
• Tx for moderate-severe RA in pt. who haven’t responded to one or more DMARD
• Should not be given w/ other biologics

Question 11

Toclizumab

Answer 11

• IL-6 Receptor inhibitor, mAB

- Second majro advance in cytokine blockade in RA!