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Abbey MSII Unit 1 pt 2 > Pharm RA and Gout. > Flashcards

Pharm RA and Gout. Flashcards

1
Q

Rheumatoid Arthritis

A

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

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2
Q

Which cytokines play a central role in rheumatoid arthritis?

A

TNF-a and IL-1 produced by macrophage

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3
Q

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

A

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

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4
Q

What leads to the development of the rheumatoid pannus?

A

hypertrophy and hyperplasia and development of new blood vessels in synovium

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5
Q

What does the panes do?

A

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

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6
Q

What are the differences between early RA and established RA?

A

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

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7
Q

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

A

relieve pain and inflammation

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8
Q

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

A

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

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9
Q

Which NSAIDS are given to treat RA?

A

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

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10
Q

What is the problems with NSAIDS in RA treatment?

A

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

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11
Q

DMARD

A

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

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12
Q

What are DMARDS used for RA treatment?

A
  1. glucocorticoids (no longer) 2. antimalarial drugs 3. sulfasalazine 4. immunosuppressive drugs (methotrexate and leflunomide)
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13
Q

Glucocorticoids (example and mechanism)

A

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

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14
Q

Why are glucocorticoids no longer used in treatment of RA?

A

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

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15
Q

Antimalarial drugs (examples and mechanism)

A

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

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16
Q

Sulfasalazine (mechanism)

A

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

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17
Q

Immunosuppressive drugs (examples and mechanism)

A

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

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18
Q

What is the most commonly used DMARD?

A

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

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19
Q

Methotrexate mechanism

A

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

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20
Q

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

A

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

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21
Q

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

A

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

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22
Q

What are the TNF-a antagonists?

A

etanercept, infliximab, adalimumab, golimumab, certolizumab

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23
Q

Etanercept

A

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

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24
Q

Infliximab

A

chimeric monoclonal antibody against TNF-a - antigenic because chimeric

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25
Q

Adalimumab

A

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

26
Q

Golimumab

A

human monoclonal - binds TNF-a, 1x monthly

27
Q

What is side effect of TNFa antagonists?

A

blocking TNF so become susceptible to opportunistic pathogens

28
Q

Certolizumab

A

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

29
Q

What are the other cytokine antagonists?

A

anakinra and tocilizumab

30
Q

Anakinra

A

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

31
Q

Tocilizumab

A

IL-6 receptor antagonist - opportunistic infections occur

32
Q

What are co-stimulation modulators?

A

abatacept and rituximab

33
Q

Abatacept

A

inhibits T-cell activation and induces T cell apoptosis

34
Q

Rituximab

A

anti-CD20 mAb that reduces B cells

35
Q

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

A

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

36
Q

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

A

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

37
Q

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

A

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

38
Q

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

A

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

39
Q

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

A

Anti-TNF therapy with or without methotrexate

40
Q

Gout

A

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

41
Q

What is gout associated with?

A

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

42
Q

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

A

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

43
Q

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

A

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

44
Q

What is the general mechanism of drugs that treat gout?

A

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

45
Q

What are the causes of hyperuricemia?

A

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

46
Q

What drugs are capable of inhibiting urate secretion?

A

thiazide diuretics

47
Q

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

A

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

48
Q

Which drugs are used to treat acute gout?

A

colchicine, NSAIDs, corticosteroids

49
Q

Colchicine mechanism

A

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

50
Q

What is an adverse side effect of colchicine?

A

low therapeutic index

51
Q

NSAIDs in gout

A

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

52
Q

Corticosteroids in gout

A

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

53
Q

What types of drugs are used in chronic gout?

A

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

54
Q

Probenecid

A

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

55
Q

What is a side effect of probenecid?

A

secretion of weak acids, esp penicillin, is reduced

56
Q

Allopurinol

A

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

57
Q

febuxostat

A

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

58
Q

Pharmacologic intervention for acute gout

A

NSAIDs, colchicine, glucocorticoids

59
Q

Pharmacologic intervention for asymptomatic hyperuricemia

A

none

60
Q

Pharmacologic intervention for chronic gout?

A

allopurinal, probenecid, febuxostat

Abbey MSII Unit 1 pt 2 (21 decks)

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