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NMSK Exam 3 > DMARDS (Disease-Modifying Anti-Rheumatic Drugs) > Flashcards

DMARDS (Disease-Modifying Anti-Rheumatic Drugs) Flashcards

1
Q

Biological DMARDS (Disease Modifying Anti-Rheumatic Drugs)

A
  1. TNA-a blocker
  2. B-cell depleter (CD20 mAb)
  3. T-cell activation inhibitor
  4. IL6-R mAb
  5. JAK-3 inhibitor
  6. Recbominant IL-1 ANT
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2
Q

TNF-a blocker Biologic DMARD

A
  1. Etanercept
  2. Adalimumab
  3. Infliximab
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3
Q

B-cell depleter (CD20 mAb) Biologic DMARD

A
  1. Rituximab
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4
Q

T-cell activator inhibitor: Biologic DMARD

A
  1. Abatacept
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5
Q

IL-6R mAb: Biologic DMARD

A
  1. Tocilizumab
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6
Q

JAK-3 Inhibitor Biologic DMARD

A

Tofacitinib

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7
Q

Recombinant IL-1 ANT: Biologic DMARD

A
  1. Anakinra
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8
Q

Miscellaneous drugs for pain/inflammation in Rhematoid Arthritis

A
  1. Acetominophen
  2. NSAIDS (naproxen, celecoxib)
  3. Glucocorticoids (prednisone)
  4. Opioids (generally NOT used)
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9
Q

Traditional/non-biologic DMARDS (Disease Modifying Anti-Rheumatoid Drugs)

A
  1. Methotrexate
  2. Hydroxychloroquine
  3. Sulfasalaznie
  4. Leflunomide
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10
Q

What are the 3 goals of RA therapy?

A
  1. Stop inflammation (put disease in remission)
  2. Relieve symptoms
  3. Prevent joint and organ damage
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11
Q

Manifestation of RA

A
  1. 40% have involvement of MSK system other than joinits and non-articular organs
  2. Bone loss due to prostaglandins + cytokines + exogenous glucocorticoids
  3. Muscle weakness
  4. Pleurisy and parenchymal lung disease
  5. Anemia
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12
Q

Non-pharmacologic and Preventative therapies for RA

A
  1. Education and counseling
  2. Rest (bc causes fatigue) and exercise (pain and stiffness)
  3. PT/OT
  4. Nutrition and diet therapy
  5. Bone protection
  6. CV risk reduction
  7. Vaccinations
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13
Q

Drugs for 1st choice for RA, due to efficacy and rapid onset of action

A
  1. NSAIDS (either 1st generation; COX1 (ASA) & COX2 inhibitors (Naproxen) OR 2nd generation COX2-I (Celecoxib)) = anti-inflammatory action AND pain relief
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14
Q

When using NSAID analgesis for RA, does it alter the progression of the disease?

A

No

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15
Q

Drug of choie if additional pain relief is required for RA.

A

Acetominophen

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16
Q

Glucocorticoids - Prednisone

  • MOA
A
  1. Goes into cell - binds to glucocorticoid receptor
  2. GR dimer is formed in cytpoplasm => NTRS nucleus
  3. GR complexes with NF-kB and AP-1 TF=>
  4. Activates genes, like lipocortin, PLA2-I => immunosupression
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17
Q

How do glucocorticoids cause immunosupression?

A
  1. Blocks synthesis of eicosanoids (PG, TX,LT, etc)
  2. Reduces activity of immune system via suppressionof IL-1 -6, IL-8 and IFN-γ
  3. Lymphocytes sequestration and apoptosis
  4. Suppresses neutrophil migration
  5. ↓ eosinophil numbers in blood and tissue
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18
Q

Glucocorticoids - Prednisone Use for Rheumatoid Arthritis

How often?

A
  • Treats pain and inflammation that occurs in flares in sicker patients with RA for a SHORT-TIME, while you are waiting for effects of DMARDS
    • ​Use < 1 month => more effective than placebo or NSAID, but use less than 6 months. Do not use chronically without DMARD therapy, however you can take <5mg/day W/O signifant AE, but NO reduction in disease progression.
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19
Q

How is the 1/2 life and potency of prednisolones ↑↑↑?

A
  • Adding F (fluorine)
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20
Q

Name fluorinated prednisolones

A
  1. Betamethasone
  2. Dexamethasone
  3. Triamcinilone
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21
Q

Non-fluorenated prednisolone

A

Methylprednisolone

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22
Q

When DQing exogenous glucocorticoids, what do you have to make sure to do?

A

DQ slowly: abruptly DQ them can be deadly

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23
Q

Patients with pain due to RA are often administered _____ or ____ despite their lack of effect on disease progression while waiting for a drug from DMARD class to begin exertings its effects

A

NSAIDS

Glucocorticoids

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24
Q

Glucocorticoid, prednisolone prodrug, short-term use is useful in therapy for RA until DMARD effects are seen

A

Prednisone

25
Q

Describe Mild RA

A
  1. < 5 inflamed joints and pain
  2. NL to slighly ↑ ESR and C-reactive protein levels
  3. No extra-articular disease, erosions or cartilage loss on XR of the hands, wrists, and feet
  4. Low levels of measures of disease activity such as the DAS28, CDAI, SDAI, or RAPID
  5. Most patients lack poor prognostic features: rheumatoid factor or Ab to cyclic citrullinated peptides
26
Q

Describe Moderate RA

A
  1. ≥ 5 inflamed joints
  2. ↑↑↑ (ESR) and/or (CRP) concentration
  3. Rheumatoid factor and/or anticyclic citrullinated peptide(CCP) antibodies present in most patients
  4. Evidence of inflammation on XR of the hands, wrists, or feet, such as osteopenia and/or periarticular swelling….
  5. Minimal joint space narrowing and small peripheral erosions
27
Q

Mild RA treatment

A
28
Q

Moderate RA treatment

A
29
Q

Methotrexate: Traditional/ non-biologic DMARD

  • MOA for RA and cancer
A

Blocks thymidine and purine synthesis: purinergic GPCR mediates anti-inflammatory effects

For RA

  1. Undergoes polyglutamation => MTX-(glu)n, which accumulates in cells over multiple weeks
  2. Also blocks thymidylate synthase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase
  3. => AICAR accumulation => adenosine efflux, which binds to purinergic GPCRs on cell surface => anti-inflammatory effects
  4. => fastest DMARD, with effects in 3 - 6 weeks and works in 80% of pts

For cancer

  1. Inhibits dihydrofolatereductase with loss of TH4 causing a thymineless death when used as antiproliferative to treat cancer
30
Q

How efficacious is MTX (methotrexate)?

A

Fastest DMARD, with effects in 3-6 weeks and works in up to 80% of patients.

31
Q

Uses of MTX (Methotrexate)

A
  1. Drug of 1st choice for RA, due to efficacy, safety, low cost and extensive use
  2. Use in combo wit other traditional DMARDS
  3. Continued when pt is switched to biologic DMARD
32
Q

Pharmokinetics of MTX

A

1x/ per week, either: orally(but variable absorption) or injection

33
Q

Methotrexate toxicities

A
  1. Low doses used for immunosuppression = well-tolerated, but patient should take weekly folate supplements
  2. Higher doses => life threatening major AE: bone marrow suppression, hepatic fibrosis, GI ulceration and pneumonitis
  3. Fetal death and congenital abnormalities
34
Q

Hydroxychloroquine

  1. MOA
  2. Uses
A

MOA: Lipophilic weak base that accumulates in lysosomes is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media => ↑↑↑ the pH of the lysosome from 4 -> 6 => higher pH of these lysomal vesicles in APC limits the association of peptides (including autoantigens) with class II MHC molecules => Slow disease progression, but has a delayed onset (3-6 months

Use:

  1. Malaria
  2. Mild RA in PREGNANT WOMEN w/o poor prognostic features
  3. Combined with methotrexate ±sulfasalazine if more severe RA
  4. Lupus erythematosus
35
Q

Which traditional/non-biologic DMARD is safe to use when PG?

A

Hydroxychloroquine

36
Q

Hydroxychloroquine

  • Pharmacokinetics
  • Toxicities
A
  • Pharmacokinetics:
    • 1/2 life = 23 days and eliminated by kidneys
    • Use loading doses to speed up onset
  • Toxicities
    • Retinal damage, but low doses have little risks
37
Q

Agent used as a traditional DMARD alone or in combo w/ other Traditional DMARDS and also to tx IBD, GI side effects are a common reason for discontinuing

A

Sulfasalazine

38
Q

Refers to the use of methotrexate, hydroxychloroquine, and sulfasalazine together to treat RA

A

Triple therapy

39
Q

2nd-choice traditional DMARD that disrupts pyrimidine synthesis and causes more common serious adverse effects

A

Leflunomide

40
Q

Methotrexate is the most effective and fastest acting of the traditional DMARDs, we most ofren monitor for ___________ but generally well tolerated at low doses, often added to _________

A
  • Myelosupression (fever, symptoms of infection, bleeding)
  • Biologic DMARDS
41
Q

As a general rule, what can/can’t biologic DMARDs be combined with?

A

CAN be combined with non-biologic DMARDS,

NEVER combined with other biologic DMARDS

42
Q

What are the pros/cons between Biologic DMARDS and Nonbiologic DMARDS?

A
  • PRO: Faster onset of action and HIGH rate of response.
  • CONS: More expensive and ↑↑↑ risk of AE.
43
Q

What does each mean?

  • “-cept” = ______________
  • “-mab” = _________
  • “-ximab” = ___________
  • “-zumab” = ___________
  • “-umab” = _____________
A
  1. “-cept” = fusion of a receptor to the Fc part of human IgG1
  2. “-mab” = monoclonal antibody (mAb)
  3. “-ximab” = chimeric mAb
  4. “-zumab” = humanized mAb
  5. “-umab” = human mAb origin
44
Q

Blocking the effects of ______ inflammatory mediator is a common target in tx of RA and various other autoimmune diseases

A

TNF via TNF-ANT.

45
Q

TNF-ANT are indicated for what?

What are the AE?

A
  • Moderate => severe RA, generally after traditional DMARDs have proven to be ineffective
  • Toxicities
      1. All drugs => risk of serious infection, like TB
    • 2. Severe allergic reactions
46
Q

Chimeric (human and mouse) monoclonal Ab directed against TNF that can be administered IV every 6 weeks as a biologic DMARD

A

Inflixumab

47
Q

Anti-TNF biologic DMARD; this recombinant fully humanized monoclonal Ab is administered SQ every 2 weeks; also used for _psoriatic arthriti_s, ankylosing spondylitis, and Crohns disease

A

Adalimumab = BEST SELLING DRUG IN THE WORLD

48
Q

What is the best selling drug in the world?

A

Adalimumab

49
Q

Fusion protein made from Fc portion of IgG and two TNF receptors, a biologic DMARD administered 1-2x/week by SQ injection; also used for psoriasis

A

Etanercept

50
Q

Ab that targets CD20 antigen on B cells, begining in the pre-B cell stage to cause a B cell “do-over”, used to treat NHL (non-hodgekins) and CLL (chronic lymphocytic leukemia) and can be effective in some antibody-dependent autoimmune diseases

A

Rituximab

51
Q

What is Rituximab MOA?

A
  1. Targets CD20 on surface of B-cells but SPARES plasma cells: bc CD20 is present begining at the pre-B cell stage UNTIL they differentiate into plasma cell
  2. Bc plasma cells are NOT affected => Ig levels stay NL despite B-cell lymphopenia that persists for months after cause.
  3. AutoAB that can cause disease are affected by B-cell depletion
52
Q

Rituximab

  • Use
  • Who responds the highest
A
  • Use with [methotrexate] for patients with RA who do not respond to TNF-ANT
  • If _(+) for rheumatoid facto_r or anti-CCP AB => responds higher.
53
Q

Biologic DMARD, fusion protein blocks T cell CD80/86 co-stimulatory signal needed for activation

A

Abatacept

54
Q

Biologic DMARD that is a humanized antihuman IL-6-R AB => competes for membrane-bound and soluble forms of IL-6R, among its effects is to

↓ ↓↓ acute-phase response of liver and (+) T/B-cells, MO and osteoblasts

A

Tocilizumab

55
Q

Tocilizumab

  1. Use
  2. Toxicities
A
  1. Uses
    1. Moderate - severe RA, if other DMARDS and TNF-a ANT do not work
    2. Use w or w/o methotrexate
  2. MC toxicities
    1. URT infection
    2. Life threatening infectiosn
56
Q

JAK3 enzyme ANT used as a biologic DMARD, UNIQUE in that it is administered ORALLY

A

Tofacitinib

57
Q

Biologic DMARD that is least efficacious (last choice DMARD), recombinant, non-glycolsylated version of endogenous human IL-1-R ANT

A

Anakinra

58
Q

MOA of MTX

A
  1. Polyglutamine of MTX => AICAR to accumulate in the cell and adenosine to acculinate outide the cell;
    1. Polyglutamination is assx with its low-dose ability to tx RA and the persistence of effects AFTER DQd
  2. Adenosine then binds to purigenic GCPR on surface of cell => anti-inflammatory response

NMSK Exam 3 (17 decks)

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