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MSK II - Exam 2 > Drugs for RA (Linger DSA) - SRS > Flashcards

Drugs for RA (Linger DSA) - SRS Flashcards

1
Q

In general what do the Disease-modifying antirheumatic drug (DMARD)s do?

A
  • slow or stop the progression of rheumatic diseases;
  • they reduce pain and inflammation
  • reduce or prevent irreversible joint damage,
  • result in longer disease-free remissions and better quality of life
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2
Q

What are the two classes of Disease-Modifying Antirheumatic Drugs (DMARDs)?

A

Nonbiologic

Biologic

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3
Q

What are the commonly used DMARDs? 4

A
  1. Hydroxychloroquine (HCQ)
  2. Leflunomide (LEF)
  3. Methotrexate (MTX)
  4. Sulfasalazine (SSZ)
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4
Q

What are the rarely usedd non-bio DMARDS?

A
  1. Azathioprine
  2. Cyclophosphamide
  3. Cyclosporine
  4. Gold salts
  5. Minocycline
  6. Mycophenolate mofetil
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5
Q

What are the two types of bio-DMARDs?

A
  1. TNF-α Blocking Agents
  2. Other Agents
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6
Q

What are the bio DMARDs that are TNF-α Blocking Agents?

A
  1. Adalimumab (Humera)
  2. Certolizumab
  3. Etanercept (Enbrel)
  4. Golimumab (Simponi)
  5. Infliximab (Remicade)
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7
Q

What are the bio DMARDs that fall under the “other” category?

A
  1. Abatacept (T-cell Fc-fusion)
  2. Rituximab (anti-CD20 mAb)
  3. Tocilizumab (anti-IL-6 mAb)
  4. Tofacitinib (JAK inhibitor, small-molecule TKI)
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8
Q

What are the NSAIDs specifically mentioned as antiinflammatories for RA?

A
  1. Celecoxib (Celebrex)
  2. Ibuprofen
  3. Naproxen
  4. Many others (thanks)
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9
Q

What are the corticosteroid anti inflammatories that were mentioned for RA?

A
  1. Prednisone (oral)
  2. Methylprednisolone (oral, depot IM, IV, intra-articular)
  3. Triamcinolone (intra-articular)
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10
Q

What are the drugs used in the treatment of acute gout?

A
  1. NSAIDs
  2. Colchicine
  3. Corticosteroids
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11
Q

What drugs are used in prevention of recurrent gout?

A
  1. Allopurinol
  2. Febuxostat
  3. Pegloticase
  4. Probenecid
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12
Q

What are the recommended DMARDs for initial treatment of RA?

A

Methotrexate (MTX) or leflunomide (LEF)

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13
Q

What are safer, reasonable alternatives to Methotrexate (MTX) or leflunomide (LEF) for patients with mild disease?

A

Hydroxychloroquine (HCQ) or sulfasalazine

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14
Q

What is the first line bio therapy after an inadequate response to non-bio DMARDs?

A
  1. TNF-α inhibitor as monotherapy or in combination with nonbiologic DMARDs
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15
Q

well-controlled comparative trials have indicated that which TNF inhibitor is best?

A
  1. There is no evidence from well-controlled comparative trials that any one TNF inhibitor is more effective than any other
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16
Q

Despite no TNF inhibitor having a better impact, one drug is commonly a first choice. Which one?

Why?

A
  1. Etanercept is a common first choice because it has a rapid onset of action and short half-life resulting in short duration of toxicity, if it occurs
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17
Q

At high doses (like those used in cancer chemotherapy), MTX is an inhibitor of dihydrofolate reductase that results in impaired DNA synthesis causing cell death. In RA, the dose is low. What is the MOA at this dosage level?

A
  1. At the low doses effective in RA, the primary MOA of MTX is not well characterized, but may involve anti-inflammatory effects mediated by increased extracellular levels of adenosine
  2. MTX also has a direct inhibitory effect on proliferation and stimulates apoptosis in immune-inflammatory cells
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18
Q

What is the typical response time to MTX for RA?

A
  1. Response time: often effective within 4-6 weeks, but sometimes not for several months
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19
Q

MTX doses used in rheumatic diseases are much lower than the doses used to treat cancer, so the incidence and severity of toxicity are much lower as well. Common side effects include nausea, upset stomach, loose stools; stomatitis or soreness of the mouth; alopecia; fever; a macular punctate rash (usually on the extremities); headache, fatigue, or impaired ability to concentrate.

What are three potentially life threatening ADRs sometimes seen with RA even at this level though?

A
  1. Potentially life-threatening hepatotoxicity,
  2. pulmonary damage,
  3. myelosuppression
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20
Q

In what patients is MTX CI?

A

Pregnant ones

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21
Q

Leflunomide MOA?

A
  1. : Prodrug is converted to active metabolite, A77-1726, in the intestine and the plasma
    1. A77-1726 inhibits dihydroorotate dehydrogenase, leading to reduced ribonucleotide synthesis and G1 arrest
    2. Ultimately, T-cell proliferation and B-cell production of autoantibodies are inhibited
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22
Q

Response rates are better with combination MTX and leflunomide than with either drug alone, but?

A
  • hepatotoxicity may be additive
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23
Q

What are the ADRs associated with Leflunomide?

7

A
  1. Diarrhea
  2. Elevated LFT
  3. Alopecia
  4. Weight gain
  5. HTN
  6. leukopenia
  7. thrombocytopenia
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24
Q

In what scenarios is leflunomide CI?

A

Pregnancy

25
Q

How long after the discontinuation of leflunomide does it take before a woman can become pregnant without risk of teratogenicity?

What can be done to shorten this time?

A

2 years

cholestyramine can be used to detox

26
Q

What is the MOA of Hydroxychloroquine (HCQ) and chloroquine?

A

MOA: anti-inflammatory mechanisms of action are poorly understood; proposed possible mechanisms include…

  1. suppression of T-cell responses to mitogens,
  2. decreased leukocyte chemotaxis,
  3. stabilization of lysosomal enzymes,
  4. inhibition of DNA and RNA synthesis,
  5. trapping of free radicals
27
Q

Apart from RA, what are some other uses for Hydroxychloroquine (HCQ) and chloroquine?

A
  1. Malaria
  2. Lupus
28
Q

What ADRs are associated with Hydroxychloroquine (HCQ) and chloroquine?

A
  1. Ocular/retinal toxicity
  2. dyspepsia
  3. N/V
  4. Abdominal Pain
  5. Rashes
  6. Nightmares
29
Q

What is the MOA of sulfasalazine?

A

MOA: anti-inflammatory mechanisms of action are poorly understood; proposed possible mechanisms include

  1. decreased IgA and IgM rheumatoid factor production,
  2. suppression of T-cell responses and B-cell proliferation,
  3. inhibition of inflammatory cytokine release
30
Q

What are the clinical uses for sulfasalazine?

A
  1. Reduces radiologic disease progression in RA
  2. Also used for treatment of ulcerative colitis and juvenile idiopathic arthritis
  3. Off-label uses include ankylosing spondylitis, Crohn’s disease, psoriasis, and psoriatic arthritis
31
Q

What ADRs are associated with sulfasalazine?

A
  1. N/V
  2. headache
  3. anorexia
  4. rash
  5. infertility (reversible) in males
32
Q

What are the agents that are rarely used for RA?

A
  1. Azathioprine
  2. Cyclophosphamide
  3. Cyclosporine
  4. Gold salts
  5. Minocycline
  6. Mycophenolate mofetil
33
Q

MOA of Azathioprine?

Used in?

A

Immunosuppression, purine analog

Reserved for refractory RA or systemic involvement (limited d/t toxicity)

34
Q

Azathioprine is CI in pregnancy, and can cause what ADRs? 4

A
  1. Gi intolerance
  2. hepatitis
  3. bone marrow suppression
  4. lymphoma risk increase
35
Q

MOA cyclophosphamide?

A

Suppresses T and B cell funtion by cross linking DNA

36
Q

MOA cyclosporine?

A

peptide antibiotic that inhibits T cell activation

37
Q

Gold salts can induce complete remission; injectable is more effective than oral. Numerous side effect arise, including what three serious ones?

A

enterocolitis

anaplastic anemia

interstitial pneumonitis

38
Q

Gold therapy is reserved for what patients?

A
  1. patients with progressive disease who do not obtain satisfactory relief from therapy with NSAIDs and who cannot tolerate the more commonly used immunosuppressants or cytokine receptor antagonists
39
Q

Minocycline MOA?

A

30S inhibition

40
Q

MOA mycophenolate mofetil?

A
  1. MOA: Prodrug converted to mycophenolic acid, which inhibits inosine monophosphate dehydrogenase; ultimately results in suppression of T-cells and B-cells
41
Q

What is the general MOA of the Biologic DMARDs?

A

prevent binding of TNF-α (and sometimes TNF-β, now called lymphotoxin-α) to TNF receptors, resulting in down-regulation of macrophages and T-cells

42
Q

Clinical response time for Bio DMARDs?

Response time for non-bios?

A

Bios: 1-2 weeks

Non-Bios: 1-6 months

43
Q

What biological DMARDs should be combined with each other for maximal efficacy?

A

None, this increases infections and has no appreciable benefit

44
Q

Biological DMARD injection site reactions are common with the agents administered SubQ; infusion reactions can occur with infliximab and may include fever, urticaria, dyspnea, and hypotension.

Cytopenias can occur with any TNF inhubutor, and CBC should be regularly monitored. What are the main ADR’s beyond this?

A
  1. Bacterial Sepsis
  2. TB (typically reactivation and dissemination)
  3. Disseminated Viral and fungal Infections
  4. Lymphomas (and other malignancies)
  5. autoantibody production
  6. Heart failure
45
Q

Abatacept is what kind of molecule?

A

Fusion protein

46
Q

What is the MOA of Abatacept?

A

; abatacept binds to CD80 and CD86, inhibiting binding to CD28 and preventing T-cell activation

47
Q

MOA of Rituximab?

A

chimeric monoclonal antibody that depletes CD20-expressing B lymphocytes through cell-mediated and complement-dependent cytotoxicity and stimulation of apoptosis

48
Q

MOA of tocilizumab?

A
  1. humanized monoclonal antibody that binds to and inhibits signaling of IL-6 receptors
49
Q

Tocilizumab can cause Infusion reactions, hypertension, neutropenia, elevated transaminases, and dyslipidemia can occur and may necessitate dosage adjustment.

What are the serious complications?

A

Gi perforation

Infections

Anaphylaxis

50
Q

MOA of tofacitinib?

A
  1. MOA: oral inhibitor of Janus Kinase (the JAKs in the JAK-STAT receptor pathway); technically not a biologic therapy since it is small molecule tyrosine kinase inhibitor (TKI)
51
Q

MOA of colchicine?

A
  1. binds to tubulin and prevents its polymerization into microtubules, leading to inhibition of leukocyte migration and phagocytosis; antimitotic effects, arresting cell division in G1 by interfering with microtubule and spindle formation; may alter neutrophil motility; renders cell membranes more rigid and decreases the secretion of chemotactic factors by activated neutrophils
52
Q

Acute overdose of colchicine is characterized by burning throat pain, bloody diarrhea, shock, hematuria, and oliguria and what fatal toxicity?

A

fatal ascending CNS depression has been reported

53
Q

MOA of allopurinol?

A
  1. MOA: purine analog that competitively and irreversible inhibits xanthine oxidase
54
Q

ADRs of allopurinol?

A
  1. Can precipitate acute gouty arthritis; NSAID or colchicine should be used for prophylaxis during the first few months of therapy
55
Q

MOA febuxostat?

A

XO inhibitor, NON-PURINE

56
Q

MOA Pegloticase?

A
  1. recombinant mammalian uricase covalently attached to methoxy polyethylene glycol to prolong circulating half-life and reduce immunogenicity; uricase converts uric acid to allantoin and is absent in humans due to mutational inactivation; IV dosing every 2 weeks reduces urate levels
57
Q

Pegloticase ADRs:

  1. Can precipitate acute gouty arthritis; NSAID or colchicine should be used for prophylaxis while initiating therapy
  2. Infusion reactions are common and anaphylaxis has been reported

What is another ADR worth mention?

A
  1. Most patients exhibit an immune response; antibody formation is associated with reduced half-life, decreased response, and higher incidence of infusion reactions; rising plasma uric acid levels indicate antibody production and allows for monitoring of safety and efficacy
58
Q

In what patients is Pegloticase CI?

A
  1. Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency due to concern for hemolytic anemia
59
Q

Probenacid MOA?

A
  1. MOA: an organic acid that acts at the anionic transport sites of the renal tubules to reduce reabsorption of uric acid; tophaceous deposits of urate are reabsorbed

MSK II - Exam 2 (7 decks)

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