Pharm RA and Gout.

Question 1

Rheumatoid Arthritis

Answer 1

chronic, inflammatory, autoimmune disease - more frequent in women 4-6th decade of life - inflammation of the synovial lining of the joints which causes pain, stiffness, swelling

Question 2

Which cytokines play a central role in rheumatoid arthritis?

Answer 2

TNF-a and IL-1 produced by macrophage

Question 3

What does production of TNF-a and IL-1 lead to?

Answer 3

recruitment of other inflammatory cells to joint and release of metalloporteinases which results in bone and cartilage degradation

Question 4

What leads to the development of the rheumatoid pannus?

Answer 4

hypertrophy and hyperplasia and development of new blood vessels in synovium

Question 5

What does the panes do?

Answer 5

invades and damages cartilage and bone due to cytokine induction of destructive enzymes (esp matrix metalloproteinases)

Question 6

What are the differences between early RA and established RA?

Answer 6

early: synovial membrane beings to invade the cartilage established: synovial membrane becomes transformed into inflammatory tissue (pannus) which invades and destroys adjacent cartilage and bone

Question 7

What is the purpose of aspirin and NSAIDS in RA treatment?

Answer 7

relieve pain and inflammation

Question 8

What is given when aspirin and NSAIDS became ineffective? examples?

Answer 8

DMARD - disease-modifying anti-rheumatic drugs (ex. gold salts and antimalarial drugs)

Question 9

Which NSAIDS are given to treat RA?

Answer 9

indomethacin, naproxen (relieve symptoms) and COX2 inhibitors (like conventional NSAIDS but decrease incidence of gastric and duodenal ulcers)

Question 10

What is the problems with NSAIDS in RA treatment?

Answer 10

eliminate pain and some inflammation - but do not slow progression of the disease “bridge therapy” - provide symptomatic relief until therapeutic effect of DMARD is observed

Question 11

DMARD

Answer 11

drugs that retard or halt the progression of the disease - can take 2 weeks to 6 months to become clinically evident

Question 12

What are DMARDS used for RA treatment?

Answer 12

1. glucocorticoids (no longer) 2. antimalarial drugs 3. sulfasalazine 4. immunosuppressive drugs (methotrexate and leflunomide)

Question 13

Glucocorticoids (example and mechanism)

Answer 13

prednisone: inhibit phospholipase A2 activity which inhibits release of arachidonic acid from cell membranes, blocks formation of prostaglandins - also prevents induction of COX-2

Question 14

Why are glucocorticoids no longer used in treatment of RA?

Answer 14

serious adverse effects (hyperglycemia, osteoporosis, poor wound healing)

Question 15

Antimalarial drugs (examples and mechanism)

Answer 15

chloroquine and hydroxychloroquine - act by inhibiting chemotaxis (t cell activation) - less efficacious than other DMARDS

Question 16

Sulfasalazine (mechanism)

Answer 16

sulfasalazine acts more quickly than antimalarials - retards radiographic progression of RA - inhibits IL-1 and TNF-a release

Question 17

Immunosuppressive drugs (examples and mechanism)

Answer 17

methotrexate and leflunomide (reduce both pain and swelling as well as slow the progression of destruction) - need to be given early in course of disease

Question 18

What is the most commonly used DMARD?

Answer 18

methotrexate and leflunomide (reduce both pain and swelling as well as slow the progression of destruction) - need to be given early in course of disease

Question 19

Methotrexate mechanism

Answer 19

folate analog - inhibits reaction by dihydrofolate reductase which is essential for DNA synthesis (used as anticancer treatment as well) - at low doses in RA - inhibition of AICAR trnsformylase and thymidylate synthetase which have effects on chemotaxis

Question 20

What is the newest member DMARD for RA treatment? What is its mechanism?

Answer 20

leflunomide - active metabolite - inhibits dihydroorotate dehydrogenate which is the rate limiting step for de novo synthesis of pyrimidine so t-lymphocyte response to stimuli is inhibited

Question 21

Biological response modifiers - What do they do and what are the 4 groups?

Answer 21

highly specific therapeutics that target molecules involved in pro-inflammatory roles and surface molecules on different cells involved in pathogenesis of RA Groups: 1. TNF-a antagonists 2. other cytokine antagonists 3. co-stimulation modulators 4. signaling pathway inhibitors

Question 22

What are the TNF-a antagonists?

Answer 22

etanercept, infliximab, adalimumab, golimumab, certolizumab

Question 23

Etanercept

Answer 23

fusion molecule with anti-TNF activity - binds TNF and prevents its binding to receptors - 2x weekly SC injections

Question 24

Infliximab

Answer 24

chimeric monoclonal antibody against TNF-a - antigenic because chimeric

Question 25

Adalimumab

Answer 25

fully human monoclonal anti-TNF-a - 2x monthly SC injection

Question 26

Golimumab

Answer 26

human monoclonal - binds TNF-a, 1x monthly

Question 27

What is side effect of TNFa antagonists?

Answer 27

blocking TNF so become susceptible to opportunistic pathogens

Question 28

Certolizumab

Answer 28

humanized antibody Fab fragment conjugated to polythylene glycol to delay its metabolism and elimination

Question 29

What are the other cytokine antagonists?

Answer 29

anakinra and tocilizumab

Question 30

Anakinra

Answer 30

IL-1 receptor antagonist, short half life (daily injection) - not really used anymore

Question 31

Tocilizumab

Answer 31

IL-6 receptor antagonist - opportunistic infections occur

Question 32

What are co-stimulation modulators?

Answer 32

abatacept and rituximab

Question 33

Abatacept

Answer 33

inhibits T-cell activation and induces T cell apoptosis

Question 34

Rituximab

Answer 34

anti-CD20 mAb that reduces B cells

Question 35

What is the signaling pathway inhibitor? What is its mechanism?

Answer 35

tofacitinib - inhibitor of JAK1 and 3 tyrosine kinases - inhibits production of inflammatory mediators - WORKS INSIDE CELL (different from other biological response modifiers)

Question 36

What is the current approach to therapy for patients with early RA and low disease activity?

Answer 36

treated with non biologic DMARD mono therapy (hydroxychloroquine, minocycline, lefunomide, methotrexate, sulfasalazine)

Question 37

What is the current approach to therapy for patients with moderate or high RA but without poor prognostic features?

Answer 37

initial treatment with DMARD mono therapy or the combination of methotrexate and hydroxychloroquine

Question 38

What is the current approach to therapy for patients with moderate or high disease activity and evidence of poor prognostic features?

Answer 38

combination therapy with mehtotrexate/hydroxychloroquine, methotrexate/sulfasalazine, or methotrexate/sulfasalazine/hydroxychloroquine

Question 39

What is the current approach to therapy for patients with high disease activity and features of poor prognosis?

Answer 39

Anti-TNF therapy with or without methotrexate

Question 40

Gout

Answer 40

acute arthritis mediated by crystallization of uric acid within the joints - associated with hyperuricemia

Question 41

What is gout associated with?

Answer 41

high serum levels of uric acid - poorly soluble and major end product of purine metabolism

Question 42

What is normal serum uric acid concentration? When does it begin forming crystals?

Answer 42

normal: 40-50 mg/L crystals: >100 mg/L

Question 43

Where is uric acid reabsorbed and secreted? What amount is excreted?

Answer 43

middle segment of the proximal tubule. 10% excreted of filtered

Question 44

What is the general mechanism of drugs that treat gout?

Answer 44

compete with urate for the transporters in proximal tubule, inhibiting reabsorption of uric acid and increase its secretion

Question 45

What are the causes of hyperuricemia?

Answer 45

high rate of urate production (disease states, metabolism, drug induced, diet) and low rate of urate excretion (renal problems, suboptimal urine volumes, drugs)

Question 46

What drugs are capable of inhibiting urate secretion?

Answer 46

thiazide diuretics

Question 47

What is the recommended therapy for patients with acute gouty arthritis?

Answer 47

lifestyle changes (weight loss, diet control, reduced alcohol intake) or altering drug intake will be sufficient to control BOTH forms of gout

Question 48

Which drugs are used to treat acute gout?

Answer 48

colchicine, NSAIDs, corticosteroids

Question 49

Colchicine mechanism

Answer 49

an alkaloid isolated from plant autumn crocus - alleviates inflammation by binding to cytoskeletal protein tubule, preventing its polymerization and leads to inhibition of leukocyte activity

Question 50

What is an adverse side effect of colchicine?

Answer 50

low therapeutic index

Question 51

NSAIDs in gout

Answer 51

inhibit eicosanoid-mediated pain and inflammation - doses at higher end of therapeutic range often needed

Question 52

Corticosteroids in gout

Answer 52

intraarticular injection - pain relief - used when colchicine and NSAIDS ineffective

Question 53

What types of drugs are used in chronic gout?

Answer 53

uricosuric agents (probenecid - increase rate of excretion of uric acid) and allopurinol and febuxostat which reduce synthesis of uric acid

Question 54

Probenecid

Answer 54

compete with urate at the anionic transport sites of the renal tubule - inhibit reabsorption

Question 55

What is a side effect of probenecid?

Answer 55

secretion of weak acids, esp penicillin, is reduced

Question 56

Allopurinol

Answer 56

reduces synthesis of uric acid - competitive inhibitor of xanthine oxidase - metabolized by xanthine oxidase to alloxantlhine which is a non-competitive inhibitor of xanthine oxidase

Question 57

febuxostat

Answer 57

non-purine, non-competitive antagonist of xanthine oxidase - newer, still be studied

Question 58

Pharmacologic intervention for acute gout

Answer 58

NSAIDs, colchicine, glucocorticoids

Question 59

Pharmacologic intervention for asymptomatic hyperuricemia

Answer 59

none

Question 60

Pharmacologic intervention for chronic gout?

Answer 60

allopurinal, probenecid, febuxostat