4/19 NSAIDs and DMARDs - Walworth

Question 1

overview

Answer 1

Question 2

NSAID

difference between NSAID and glucocorticoid?

Answer 2

non steroidal antiinflammatory drug

• antiinfl (lke corticosteroids) but NOT steroids!

what’s the diff b/w NSAIDs and corticosteroids?

• mechanism of action
  
  • corticosteroids inhibit phospholipase A (PLA2)
    
    • cant convert phospholipids → arachidonic acid
      
      • AA would be substrate for 5LOX → leukotrienes
      • AA would be substrate for COX → prostaglandins, thromboxane, prostacyclin
  • NSAIDs inhibit COX (COX1 or COX2 or both)
• adverse effects
  
  • glucocorticoids usually not curative, can be dangerous
    
    • Cushingoid effects due to muscle wasting, fat dep, hyperglycemia
  • NSAID side effects primarily related to GI disturbances, bleeding, renal fx interference

Question 3

NSAID basics

Answer 3

Question 4

why is aspirin unique?

Answer 4

inhibits COX irreversibly

why important?

• in platelets : aspirin acetylates COX1 for lifetime of platelet
• in other tissues, aspirin effect only lasts as long as COX turnover

Question 5

COX1 and COX2

Answer 5

COX1: platelets

• inhibition leads to thromboxane blockade → excess prostacyclin in endothelium → REDUCES THROMBOSIS

COX2: endothelial cells

• inhibition leads to prostacyclin reduction → excess thromboxane in platelets → EXCESS THROMBOSIS

for this reason, COX2-selective inhibitors withdrawn from market

Question 6

pharmaco action of NSAIDs

Answer 6

1. anti-inflammatory activity
   
   • ​​inhibition of PG synth (mostly COX2 inhibition)
2. analgesic activity
   
   • ​​​​​​inhibition of PG synth, centrally/locally
3. antipyretic activity
   
   • ​​prevention of PGE2 synthesis
4. prolongation of bleeding time
   
   • ​​COX1 inhibition in platelets → reduced TXA2 production

other effects: table

• closure of ductus arteriosus

Question 7

toxicity of acetominophen

Answer 7

considered an NSAID even though not big anti-infl

metabolized by liver vis CYP450 2E1 → NAPQI

• NAPQI is reactive, toxic, can react w/ proteins and lead to cell death

glutathione is the key to reduce and get rid of NAPQI

• compromised liver fx can therefore lead to liver failure!!!

Question 8

NSAIDs summary

Answer 8

Question 9

macrophage-lymphocyte interactions in chronic infl

Answer 9

interactions between macrophages and lymphocytes → production of infl mediators!

Question 10

infl in rheumatoid joint

2 mechs to slow disease?

Answer 10

• antigen drives lymphocyte proliferation
  
  • production of Rf autoantibody
• complement fixation → amplifies destructive cascade
  
  • attracts infl cells → production of cytokines and enzymes

mechanisms to slow disease progression

1. limit proliferation of lymphocytes
2. limit signaling by pro-infl cytokines

Question 11

DMARDs

biologic vs nonbiologic

Answer 11

non-biologic (sm molecules) → limit lymphocyte proliferation

• leflunomide
• MTX

biologics (proteins) → interfere with infl signaling

• etanercept
• adalimumab
• infliximab
• anakinra

how different? (slide)

Question 12

nonbiologic summary

Answer 12

leflunomide: metabolite inhibits pyrimidine synthesis → cell cycle arrest of activated lymphocytes!

• teratogenic!

Question 13

agents targeting…

• TNFalpha x5
• IL6r
• IL1
• CD20
• CD80, CD86

Answer 13

Question 14

TNFalpha targeting drugs

Answer 14

etanercept: recombo fusion protein

monoclonal abs to TNF

• infliximab
• adalimumab
• golimumab
• certolizumab pegol

Question 15

drugs targeting stuff other than TNFalpha

Answer 15

Question 16

tocilizumab

Answer 16

anti-IL6 monoclonal antibody

Question 17

rituximab

Answer 17

anti-CD20 monoclonal ab

Question 18

abatacept

Answer 18

fusion protein of cytotoxic T lymphocyte assoc antigen 4 (CTLA4)

inhibits binding of CD80 and 86 to CD28 → prevents T cell activation (via no costimulation!)

Question 19

DMARD limitations

Answer 19

Question 20

DMARD contraindications

Answer 20

Question 21

DMARD summary tables

Answer 21

Question 22

psoriasis and tx

Answer 22