Pharmacology - Drugs - Rheumatoid Arthritis and Gout

Question 1

What is indomethicin used for?

Answer 1

Like naproxen, NSAID Long-term relief of symptoms in RA and other musculoskeletal disorders

Question 2

Why are COX-2 inhibitors being used more than NSAIDs?

Answer 2

Cox-2 inhibitors decrease the incidence of gastric and duodenal ulcers by 50% as compared with traditional NSAIDs Provide therapeutic relief until a DMARD takes effect.

Question 3

What is sulfasalazine used for?

Answer 3

Oldest DMARD Fast-acting (1 month) Mechanism not understood, may inhibit IL-1 and TNF-alpha release Adverse effects - nausea, rashes, headaches, neutropenia

Question 4

What is one advantage of using antimalarials to treat rheumatic disorders?

Answer 4

Less efficacious than other DMARDs but also less toxic

Question 5

What is the gold-standard DMARD therapy?

Answer 5

Methotrexate

Question 6

Why is cyclosporine A not used more often as a DMARD?

Answer 6

Toxic

Question 7

What is leflunomide?

Answer 7

Similar effects to sulfasalazine and methotrexate DMARD Newest prevents de novo pyrimidine synthesis Side effects are diarrhea, alopecia and hepatotoxicity

Question 8

What is the mechanism of action of prednisone?

Answer 8

Glucocorticoids in general: inhibit phospholipase A2 activity –> inhibits release of arachadonic acid from cell membranes –> inhibits formation of prostaglandins Glucocorticoids also inhibit production of numerous cytokines which prevent induction of COX-2.

Question 9

What are the long term effects of glucocorticoid use?

Answer 9

Hyperglycemia Osteoporosis Poor wound healing Though usually benefits outweigh complications Use glucocorticoids to induce remission while slower-acting DMARD takes effect

Question 10

What are examples of antimalarials in use as DMARDs?

Answer 10

Chloroquine (can cause irreversible retinal damage if used long term) Hydroxychloroquine (better tolerated) for RA, lupus Overall, less efficacious than other DMARDs Act by inhibiting chemotaxis

Question 11

What is the most commonly used DMARD (is also immunosuppressive)?

Answer 11

Methotrexate Folate analog Inhibits reaction catalyzed by dihydrofolate reductase that is essential for DNA synthesis Also used as anticancer agent Major complication is hepatotoxicity At low doses (for rheumatic diseases) –> inhibition of aminoimidazolecarbomide transformylase and thymidylate synthetase with secondary effects on polymorphonuclear chemotaxis –> AMP then accumulates and is converted to adenosine, which inhibits inflammation

Question 12

What are the TNF-alpha antagonists?

Answer 12

Etanercept Infliximab Adalimumab Golimumab Certolizumab

Question 13

How does Etanercept (Enbrel) work?

Answer 13

TNF-alpha antagonist –> less inflammation systemically Binds to TNF and prevents its binding to receptors example of an antagonist that binds a receptor but does not activate it SubQ 2x/wk

Question 14

What is Infliximab (Remicade)?

Answer 14

TNF-alpha antagonist –> less inflammation systemically Monoclonal antibody (chimeric mouse-human) TNF-alpha antagonist Effective within 1 week of injection Antigenic

Question 15

Why is Adalimumab favored over etanercept?

Answer 15

TNF-alpha antagonist –> less inflammation systemically More convenient dosing regimen (2x/monthly) Fully human anti-tnf-alpha mab Not antigenic

Question 16

How does Golimumab work?

Answer 16

TNF-alpha antagonist –> less inflammation systemically Once monthly dosing human mab, binds to both membrane bound and soluble tnf-alpha Opportunistic pathogen infection risk is increased (ie TB) **which is generally true of all TNF-alpha blockers

Question 17

How is Certolizumab different from other TNF-alpha antagonists?

Answer 17

TNF-alpha antagonist –> less inflammation systemically It’s a humanized Fab fragment congugated to polyethylene glycol to delay metabolism and elimination

Question 18

What is Anakinra?

Answer 18

Cytokine antagonist (IL-1) Soluble human IL-1 receptor antagonist Short half life necessitates frequent daily treatment in high doses

Question 19

What IL-6 receptor antagonist has had serious issues with opportunistic infections?

Answer 19

Tocilizumab Approved as “Actemra”

Question 20

What is the MOA of Abatacept?

Answer 20

Inhibits T-cell activation and induces T-cell apoptosis Name brand: Orencia approved for RA refractory to TNF-alpha inhibitors Side effects - headaches, infections

Question 21

What is Rituximab?

Answer 21

Anti-CD20 mAb that reduces circulating B cells considered a “costimulation modulator” approved for RA refractory to TNF-alpha inhibitors

Question 22

What signaling pathway inhibitor is used for RA treatment?

Answer 22

Tofacitinib inhibitor is JAK kinase 1 and 3 inhibits production of inflammatory mediators

Question 23

RA is characterized by chronic inflammation of the synovial membrane and infiltration by blood-derived cells, for example….

Answer 23

CD4+ T-cells, which produce inflammatory cytokines

Question 24

T/F: TNF-alpha and IL-1 play a central role in RA.

Answer 24

True IL-6 also plays a role in pro-inflammatory plathways.

Question 25

What is the rheumatoid pannus?

Answer 25

Synovial membrane –> inflammatory tissue (the pannus) which destroys surrounding cartilage and bone Pannus: type A and B synoviocytes and plasma cells

Question 26

Uric acid, which accumulates and crystallizes in the joints in gout, is the major end product of what metabolic process?

Answer 26

Purine metabolism (catablolism) hypoxanthine –> xanthine –> uric acid (xanthine oxidase used to catalyze both steps)

Question 27

Normal serum uric acid concentration is:

Answer 27

40-50 mg/L Uric acid precipitates at > 100 mg/L

Question 28

Name some causes of hyperuricemia:

Answer 28

Alcohol use (beer) Obesity (high fructose corn syrup) Renal disease (less excretion) Diabetes HTN Drugs is thiazide diuretics, aspirin, diuretics, levodopa, pyrazinimide, cytotoxic drugs, cyclosporine Cancers - diseases associated with rapid production and destruction of cells ie Hodgkins disease

Question 29

What is podagra?

Answer 29

Gouty arthritis attack of metatarsaophalangeal joint of the big toe Tophi (deposits of urate)

Question 30

What is the MOA of colchicine?

Answer 30

Inhibits spindle formation –> neutrophils can’t travel –> lowers inflammatory response **Low therapeutic index means than the diff between therapeutic dose and toxicity is small Side effects: nausea, diarrhea, vomiting…long term can cause peripheral neuropathy, neutropenia

Question 31

What are the commonly used NSAIDs for gout?

Answer 31

Naproxen indomethicin sulindac celecoxib (selective COX-2 inhibitors)

Question 32

Uricosuric agents act by:

Answer 32

Increasing the rate of excretion of uric acid Normally, only 10% of uric acid is excreted Uricosuric acids compete with uric acid in the renal tubule to prevent reabsorption Example: Probenecid (developed as an adjunct to penicillin to increase its effectiveness) –can also have the effect of increasing urate crystal mobilization

Question 33

What is the MOA of Allopurinol?

Answer 33

Inhibits xanthine oxidase competitively AFTER being metabolized to its active form (alloxanthine) by xanthine oxidase itself Used much more often than probenecid Maculopapular rash in 2% of patients

Question 34

What is the other xanthine oxidase antagonist besides allopurinol?

Answer 34

Febuxostate New Non-purine, non-competitive antagonist of xanthine oxidase Cardiovascular safety still under investigation

Question 35

T/F: Developing gout without hyperuricemia is possible.

Answer 35

True