Week 2 Drugs for rheumatoid arthritis

Question 1

What is the mechanism of glucocorticoids (anti inflammatory action) and their effects on leukocytes?

Answer 1

-reduces activity of phospholipase A2 via increasing synthesis of lipocortins, which then inhibit Phospholipase A2
-also suppress expression of Cox-2
On LEUKOCYTES
-decreases circulating leukocytes by redistributing into lymphoid tissue, inhibit return to circulation
-increase PMNs circulating by increasing influx from bone marrow
-decreases production of Il-1
-change WBC receptors for chemotactic factors and arachidonic acid cascade

Question 2

Discuss general properties of glucocorticoids.

Answer 2

• natural cortisol and cortisone have sodium retaining properties, but synthetics prednisone and prednisolone have less sodium retention
• fluorinated synthetics (dexamethasone, betamethasone, triamcinolone) have no sodium retention

Question 3

What are long term side effects of glucocorticoids?

Answer 3

-hypothalamic-pituitary-adrenal suppression, growth retardation, peptic ulceration, susceptibility to infections, osteoporosis, myopathy, cataracts, hyperglycemia, psychosis

Question 4

What is the mechanism of methotrexate as an anti inflammatory agent?

Answer 4

• upregulates cAMP to stop cell signaling
• methotrexate polyglutamate stops AICAR–> FAICAR. AICAR blocks AMP deaminase and adenosine deaminase
• causes buildup of adenosine, which increases cAMP via adenosine receptor, and decreases inflammatory cytokines
• high Caffeine correlates to poor response to methotrexate

Question 5

What are the side effects and contraindications for methotrexate?

Answer 5

Side Effects
-generally well tolerated, can cause GI disturbances, mild alopecia, myelosuppression.
-effects can be reduced by folate or leucovorin supplements
-pneumonitis
-liver cirrhosis: rare
Contraindications
-liver, lung, kidney disease
-pregnancy
-moderate to high alcohol use
-can’t uses with aspirin, which displaces it from albumin

Question 6

What is the mechanism of leflunomide?

Answer 6

• active metabolite M1
• inhibits dihydroorotate dehydrogenase, the rate limiting enzyme for de novo pyrimidine nucleotide synthesis. Inhibits lymphocyte clonal expansion
• in RA/autoimmune diseases, lymphocytes require 8x increase in pyrimidine nucleotide pool
• doesn’t increase opportunistic infections bc still has salvage pathway for nucleotide pool

Question 7

What are the side effects of leflunomide?

Answer 7

1. diarrhea
2. elevated ALT and AST, not as hepatotoxic as methotrexate
3. teratogenic. Cat X contraindicated during pregnancy. Cholestyramine can be taken for 11 days to eliminate M1 metabolite (half life 15 days) to eliminate before considering pregnancy
   Cholestyramine can be given in case of overdose

Question 8

Describe clinical uses of hydroxychloroquine

Answer 8

1. RA, longer onset of action 3-6 mos., used in combo therapy with methotrexate
2. relatively safe in pregnancy
3. also used for SLE and Sjogren’s
   Mechanism is unclear: trap free radicals, inhibit DNA and RNA synthesis, prevent release of hydrolytic enzymes.

Question 9

List the commonly used DMARDs.

Answer 9

hydroxychloroquine, metrotrexate, sulfasalazine, leflunomide, TNF-a inhibitors

Question 10

Describe the mechanism of Sulfasalazine.

Answer 10

1. prodrug, broken down in colon bacteria to sulfapyridine (antibacterial) and 5-aminosalicylic acid
2. 5 aminosalicylate acid has anti-inflammatory activity (Used in IBS). Inhibits Cox and 5-lipoyxgenase.
3. treatment for RA-Mechanism unclear
   Also used in AS, Juvenile chronic arthritis ulcerative colitis, limited use in Crohns disease

Question 11

What are the side effects of sulfasalazine?

Answer 11

1. nausea, vomiting, headache, diarrhea. Based on N acetyltransferase genetic polymorphism
2. Sulfa allergic reactions
3. safe in early pregnancy but decreases folate absorption. Not used in Near term, causes kernicterus by displacing bilirubin

Question 12

What is the mechanism of TNF a inhibitors?

Answer 12

• Binds to TNF and prevents it from binding to cell surface receptors, blocking inflammatory cascade and preventing tissue destruction
• Mainly Etanercept (fusion of TNF receptor and Fc region of human IgG) and Infliximab (TNF binding site from mouse with human Fc of IgG)
• Etanercept: nonneutralizing antibodies bind and doesn’t interfere with ability of drug to bind TNF
• Infliximab: neutralizing antibody

Question 13

What are the side effects of TNF-a inhibitors?

Answer 13

1. serious infections: TB, sepsis, demyelinating disorders
2. contraindicated in TB infections
3. Drug induced lupus-rare