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Rheumatology > Rheum Pharm 1: Glucocorticoids and RA Meds > Flashcards

Rheum Pharm 1: Glucocorticoids and RA Meds Flashcards

1
Q

Anti-inflammatory effects of Glucocorticoids?

3

A
  1. Bind and block promoter sites of proinflammatory genes IL-1 alpha and IL-2 beta
  2. Decreased production of tumor necrosis factor alpha
  3. Multiple cell specific effects
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2
Q

Actions of glucocorticoids?

6

A
  1. Block IgG production
  2. Block dendritic cell differentiation and antigen presentation
  3. Block cytokine production and activation
  4. Block osteoblast production and differentiation
  5. Block TNF and IL-7
  6. Increase in adipocyte differentiation
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3
Q

Inhibition of proinflammatory mediators such as? 6

A
  1. Phospholipase A2
  2. Cyclooxygenase 2
  3. Nitric oxide synthetase
  4. Prostaglandins
  5. Leukotrienes
  6. Thromboxanes
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4
Q

Glucocorticoids inhibit production of what? 2

What does it interact with to accomplish this? 2

A
  1. interleukins and
  2. tumor necrosis factor alpha

Interacts directly with

  1. specific DNA sequences and
  2. other transcription factors
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5
Q

How are leukocytes affected by glucocorticoid? 3

A
  1. Decreased adherence to vascular endothelium
  2. Can’t exit the circulation as readily
  3. Entry to sites of infection and tissue injury impaired
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6
Q

Suppression of inflammatory response: How are the following affected?

  1. Neutrophils?
  2. Eosinophils?
  3. Monocytes?
  4. Lymphocytes?
A
  1. Neutrophils (↑) results in increased WBC
  2. Eosinophils (↓)
  3. Monocytes (↓)
  4. Lymphocytes (↓)
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7
Q

Why do the following occur with glucocorticoid treatment:
1. Neutrophils (↑) results in increased WBC?

  1. Eosinophils (↓)? 2
  2. Monocytes (↓)? 2
  3. Lymphocytes (↓)? 1
A
    • Impaired transport
    • Increased production from the bone marrow
    • Decreased apoptosis
    • Increased apoptosis,
    • trapped in tissues
    • Decreased tissue accumulation,
    • decreased migration from vasculature
  4. Inhibition of T lymphocytes
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8
Q

GC effects on acquired immunity?

3

A
  1. Decreased antigen presenting cells
    (Macrophages, dendritic cells)
  2. T cells ↓↓
  3. B cells ↓
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9
Q

Chronic glucocorticoid therapy
contraindication for vaccines?
3

A

Contraindication to live virus vaccines

  1. MMR,
  2. Varicella,
  3. small pox
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10
Q

GC have an increased risk of infection such as:
1. In short term high dose therapy? 1

  1. In long term high dose therapy? 3
A
  1. Short term high dose therapy
    - Immediate reduction of phagocytic responses
2. Long term therapy
Main infections
-Herpes zoster
-Staph 
-Candida
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11
Q

Monitoring for GC toxicity: Periodic monitoring of these parameters
5

A
  1. BP
  2. Serum glucose
  3. Lipid profile
  4. Eye exam
  5. Bone density
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12
Q

The best things about steroids
1. No dose adjustment needed when?

  1. They generally give good symptom relief for what?
A
  1. No dose adjustment needed in renal impairment

2. pain secondary to inflammation

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13
Q

Meds for RA?

4

A
  1. NSAIDs
  2. Hydroxychloroquine (Plaquenil)
  3. Sulfasalazine (Azulfidine)
  4. Methotrexate (Rhematrex)
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14
Q

RA: What drugs are used for short term symptom management? 2

When would we withdrawl?

A

NSAIDs or steroids

Withdrawal once the DMARDs have taken effect

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15
Q

NSAIDS may help how?

Do not work on what?

A

May alleviate the symptoms

Do not prevent irreversible joint damage

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16
Q

Glucocorticoids

  1. Good for what?
  2. Effect on decreasing joint destruction?
A
  1. Good for quick symptom relief

2. Do not have a very profound effect on decreasing joint destruction

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17
Q 
Disease-modifying antirheumatic drugs
DMARDs
1. Why is discontinuation rate high?
2. Timeline of treatment?
3. What are the two types?
A
  1. Discontinuation rate is high due to toxicity or lack of efficacy
  2. In general are continued indefinitely unless significant toxicity occurs
  3. Categorized as biological and nonbiological
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18
Q

DMARDS

  1. Nonbiological? 8
  2. Biological? 5
A

Nonbiological:

  1. Methotrexate (Rheumatrex)
  2. Sulfasalazine (Azulfidine)
  3. Hydroxychloroquine (Plaquenil)
  4. Leflunomide (Avara)
  5. D-Penicillamine
  6. Gold salt
  7. Azithroprine (Imuran)
  8. Cyclosporine (Neoral)

Biological:

  1. Etanercept (Enbrel)
  2. Adilimumab (Humira)
  3. Infliximab (Remicade)
  4. Aakinra (Kineret)
  5. Abatacept (Orencia)
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19
Q

When would we change the DMARD or go to combination therapy?

A

Failure to achieve remission in 3 months

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20
Q

Takes several months for maximal results
1. When should we assess efficacy?

  1. If undesirable results? 2
A
  1. Assess efficacy at 3-6 months

2. If undesirable results add on therapy or switch to another agent

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21
Q

Drug choice is dependent on? 3

A
  1. Disease severity
  2. Prognostic factors
  3. Patient preference
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22
Q

What is the initial tx of RA with DMARDs?

A

Methotrexate(Rheumatrex)

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23
Q

Methotrexate(Rheumatrex)

  1. Benefits seen in what time?
  2. Tolerated how?
  3. Starting dose?
A
  1. Benefits seen in 2-6 weeks
  2. Generally well tolerated
  3. Starting dose 7.5mg once weekly

Most commonly used drug for RA

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24
Q

Methotrexate (Rheumatrex)
MOA
6

A
  1. Stimulates adenosine release from fibroblasts and endothelial cells
  2. Reduces neutrophil adhesion
  3. Suppression of cell mediated immunity
  4. Antiproliferative effect on synovial fibroblasts and endothelial cells
  5. Inhibition of IL-1, IL-6 and IL-8
  6. Inhibits synovial collegenase gene suppression
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25
Q

Methotrexate
1. Structural analog of what?

  1. Inhibits binding of dihydrofolic acid to dihydrofolate reductase inhibiting what?
  2. All patients need supplemental of what?
    • __________ drug interactions,
    • _____ excretion,
    • ___% protein bound
A
  1. folic acid
  2. purine synthesis
  3. folic acid of 1mg daily
    • Minimal
    • renal
    • 50%
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26
Q

Methotrexate

  1. Modes of administration? 3
  2. Contraindications? 4
  3. Dosing should be patterned how?
A
  1. PO, IM, SQ
  2. Contraindications
    - Women who are contemplating pregnancy
    - Pregnancy
    - Liver disease or excessive ETOH intake
    - GFR
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27
Q

Methotrexate side effects

14

A
  1. Hepatotoxicity
  2. Pulmonary toxicity
  3. Myelosuppression
  4. Nephrotoxicity
  5. Fatigue
  6. Decreased ability to concentrate
  7. Alopecia
  8. Nausea
  9. Stomach upset
  10. Loose stools
  11. Soreness of the mouth
  12. Rash on the extremities
  13. Headache
  14. Fever

At about 2-5 years up to 35% of patients have discontinued the drug due to side effects.

28
Q

Toxicities associated with Methotrexate? 3

Monitoring every 1-2 months with what?
5

A
  1. Myelosuppression- Worse if concomitant use of NSAIDs
  2. Hepatotoxicity including cirrhosis
  3. Pulmonary toxicity

Monitoring every 1-2 months

  1. CBC
  2. Liver function tests (LFTs)
  3. Albumin
  4. Creatinine
  5. (Pre treatment CXR)
29
Q

What will make myelosuppression with methotrexate worse?

A

NSAIDs

30
Q

Second line drug for RA?

A

Sulfasalazine (Azulfidine)

31
Q

Sulfasalazine (Azulfidine) MOA?

4

A
  1. Inhibition of PMN cell migration
  2. Reduced lymphocyte responses
  3. Inhibits angiogenesis
  4. Decreases inflammatory cytokines and IgM rheumatoid factor production
32
Q

Sulfasalazine

  1. Describe its absorption and excretion?
  2. What do you need to break down this drug?
  3. What does it break down into? 2
A
  1. 30% absorbed in the small bowel then excreted into the feces in the bile = about 90% of the drug remains in the feces by the time it reaches the large bowel
  2. Need coliform bacteria to break it down into
    • sulfapyridine and
    • 5-aminosalicylic acid
33
Q

Sulfasalazine contraindications

8

A
  1. Sulfa allergy
  2. Pregnancy category D (at full term)
  3. GI or GU tract obstruction
  4. Porphyria
  5. Platelet count less than 50K
  6. LFTs > 2X ULN
  7. Hepatitis
  8. Men wanting to conceive
34
Q

Sulfasalazine side effects – dose dependent

9

A
  1. Nausea and diarrhea
  2. Intestinal or urinary obstruction
  3. Oral ulcers
  4. Orange-yellow pigmentation of the skin
  5. Headache
  6. Depression
  7. Neutropenia
  8. Thrombocytopenia
  9. Agranulocytosis
35
Q

Which serious SE occur in up to 25% of pts taking sulfasalazine? 2

A
  1. Neutropenia

2. Thrombocytopenia

36
Q
  1. Sulfasalaxine monitoring for toxicity? 1

2. Monitor with what? 2

A
  1. Toxicity
    - Myelosuppression
  2. Monitoring*
    - CBC monthly X 3
    - Then CBC every 3 months
37
Q

Leflunomide (Avara)
1. What is it? 2

  1. Beneficial affects on RA? 2
A
    • Antiinflammatory
    • Antiproliferative
    • Decreases progression of joint erosions and
    • joint space narrowing
38
Q

Leflunomide (Avara) MOA
2

How is it different from Methotrexate

A
  1. Competitive inhibitor of dihydrofolate reductase
  2. This decreases the production of pyrimidines
    - Decreased B and T cell proliferation

Similar to methotrexate but inhibits pyrimidine synthesis instead of purine.

39
Q

Leflunomide (Avara)

  1. Half-life of active metabolite is 15-18 days
    - Washout period for women who want to conceive is how long?
  2. What can be used to reduce the half life to 1 day? 2
  3. Time to response is how long?
A
  1. 2 years
    • Activated charcoal and
    • cholestyramine
  3. 1-3 months
40
Q

Leflunomide (Avara) Contraindications? 3

A
  1. Pregnancy
  2. Preexisting liver disease
  3. Alcoholism
41
Q

Leflunomide (Avara) side effects
Most common? 4

Others? 3

A
  1. Most common
    - Diarrhea,
    - rash,
    - reversible alopecia,
    - hepatoxicity
  2. Others:
    - Weight loss
    - Hypertension
    - Bone marrow suppression
42
Q

Leflunomide (Avara)
1. Toxicities? 2

  1. Monitoring what and how often? 3
A
  1. Toxicity
    - Hepatotoxicity
    - Bone marrow suppression
2. Monitoring
Monthly X6, then every 2 months
-CBC
-Liver enzymes
-Creatinine
43
Q

Leflunomide (Avara)interactions

4

A
  1. Weak inhibitor of CYP2C9
  2. May increase warfarin levels
  3. Rifampin may increase levels of leflunomide
  4. Bile acid sequesterants decrease effectiveness of leflunomide
44
Q

Hydroxychloroquine (Plaquenil)

  1. What class of drug?
  2. What does it not do?
  3. Time to response?
A
  1. Antimalarial
  2. Does not limit the progression of RA
  3. Time to response -2-6 months
45
Q

Hydroxychloroquine (Plaquenil)
In what situations will we use this drug as a single agent?
3

Otherwise we use it as an addon to what?

A

Used as a single agent only with

  1. mild RA and
  2. no evidence of joint destruction on xray and
  3. no inflammatory markers or autoimmune markers on labs

Otherwise usually is used as an add-on to methotrexate

46
Q

Hydroxychloroquine (Plaqueni)
MOA?
3

A
  1. Interferes with normal antigen processing
  2. Inhibits lysosomal enzymes and IL-1 release
  3. Inhibition of PMNs and lymphocyte responses
47
Q

Hydroxychloroquine (Plaqueni)
1. Toxicity?

  1. What sign will we see with this?
  2. Monitoring?
A
  1. Toxicity
    Macular damage
  2. Bulls eye maculopathy of hydroxychloroquine
  3. Monitoring
    Fundoscopic and visual field exams every 6-12 months
48
Q

Hydroxychloroquine (Plaquenil)
SE? 7

Drug interactions? 3

A

Side effects

  1. Nausea
  2. Diarrhea
  3. Abdominal discomfort
  4. Photosensitivity
  5. Skin pigmentation changes
  6. Rash
  7. Macular damage

Drug interactions

  1. Decreased metabolism of beta blockers (except for atenolol and nadolol)
  2. May increase cyclosporine
  3. digoxin levels
49
Q

Treatment of severe RA
Options?
4

A
  1. Use combination of DMARD therapy
  2. Switch to another TNF inhibitor with a different mechanism of action
  3. May need ongoing glucocorticoid therapy
  4. May need ongoing NSAIDs
50
Q

Role of narcotics in RA?

A

No role for narcotic analgesics unless end stage disease

51
Q

What are our TNF inhibitors?

3

A
  1. Etanercept (Enbrel)
    SQ injection 1-2 times weekly
    Self-administered
  2. Infliximab (Remicade)
    IV infusion every 6 weeks
  3. Adalimumab (Humira)
    SQ injection every 2 weeks
52
Q

TNF inhibitors MOA?

3

A
  1. TNF blockers bind to tumor necrosis factor-alpha making it inactive
  2. interferes with inflammatory activity
  3. Bind to surface TNF-alpha, cell lysis occurs
53
Q

TNF inhibitors MOA:

  1. Decreased production of what? 2
  2. Ultimately decreasing what?
  3. Time to effect?
A
  1. IL-6 and CRP
  2. joint damage
  3. Time to effect
    2-3 doses
54
Q

SE of TNF inhibitors?

4

A
  1. Injection site infections
  2. Infusion reaction infliximab (Remicade)
  3. Serious infections leading to sepsis *
  4. Do not administer live vaccines while on these meds
    Response to other vaccines may be diminished
    *stop medication until infections clear
55
Q

Contraindications of TNF inhibitors?

A
  1. Latent TB infection
    Black box warning!!!
  2. High risk for opportunistic infections
56
Q

BBW for TNF inhibitors??

A

Latent TB infection

57
Q

Infliximab (Remicade)
Used in conjunction with what? What does this help to do?

Not to be used in conjunction with what due to increased risk of infection?
2

Disadvanateg of (Etanercept) Enbrel?

A
  1. methotrexate
    - Decreases the development of infliximab antibodies
    • abatacept (Orencia)
    • anakinra (Kineret)
  3. Usual dose is 25mg SQ twice weekly or 50mg SQ once weekly
    $758 per week
    $39,416 per year
58
Q

TNF inhibitors
1. Toxicity? 2

  1. Monitor? 2
A
  1. Toxicity
    - Injection site reaction
    - Increased risk of local or systemic infection
  2. Monitoring
    - PPD prior to therapy
    - Periodic CBC
59
Q

Immune modulator: Anakinra (Kineret)

  1. What class is it?
  2. administered how?
  3. MOA?
  4. Dose response?
  5. Decrease dose when?
  6. Dont give in combination with what? and why?
A
  1. Recombinant IL-1 receptor antagonist
  2. Daily SQ injection
  3. MOA
    Blocks IL-1 receptor to decrease degree of joint destruction and inflammation
  4. Dose response
    Within 12 weeks
  5. Decrease dose in with GFR less than 30 ml/min
  6. Don’t give in combination with TNF inhibitors due to increased risk of infection
60
Q

Anakinra contraindications

3

A
  1. Sensitivity to E coli-derived proteins
  2. Preexisting infection or high risk for infection
  3. Not to be used in combo with TNF inhibitors
61
Q

Anakinra (Kineret)
SE? 3

Monitor what? And on what timeline?

A
  1. Skin irritation at the injection site (50% of patients)
  2. Possibility of angioedema and anaphylaxis
  3. Decrease in WBCs

Monitoring
CBC monthly X3 then Q4 months X 1 year

62
Q

Nonpreferred DMARDs
?
4

A
  1. D-penicillamine (Depen, Cuprimine)
  2. Azithroprine (Imuran)
  3. Cyclosporine A (Sandimmune, Neoral)
  4. Gold compounds
63
Q

D-Penicillamine (Depen, Cuprimine)

  1. What is it and what is it used for? 5
  2. MOA?
  3. Preg cat?
A
  1. Chelating agent used for treatment of
    - Wilson’s disease,
    - arsenic poisoning,
    - copper,
    - lead and
    - mercury poisoning
  2. Unknown MOA in RA other than depresses T cell activity
  3. Pregnancy category D
64
Q

Azithroprine (Imuran)

  1. Class?
  2. Inhibits what?
  3. Decreases what production?
  4. Adjust dose for who?
  5. Preg cat?
  6. Major toxicity?
  7. Carcinogenic how? 2
A
  1. Prodrug for mercaptopurine
  2. Inhibits enzymatic activity required for DNA synthesis
  3. Decrease production of T and B cells
  4. Adjust dose for decreased renal clearance
  5. Pregnancy category D
  6. Major toxicity is bone marrow suppression
  7. Carcinogenic
    - Lymphoma in post transplant patients
    - Hepatosplenic T cell lymphoma in IBD patients
65
Q

Cyclosporine A (Sandimmune, Neoral)

  1. MOA?
  2. Follow what levels?
  3. Major toxicity?
  4. BBW?
A
  1. Blocks activation of T cells and IL-2
  2. Follow blood levels
  3. Major toxicity is renal failure
  4. Black box warning “Only physicians experienced in immunosuppressive therapy…”
66
Q

Gold compounds

  1. Why dont we use it very often?
  2. MOA?
  3. Mostly used as what?
A
  1. Parenteral gold (injection) has similar efficacy but greater toxicity compared with other traditional (DMARDs) used in RA (Oral gold has less efficacy than most other agents)
  2. MOA: unknown, decreases prostaglandin production
  3. Mostly used as an add on

Starting dose for oral therapy $1345/month!

Rheumatology (11 decks)

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