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Orthopaedics > Joint Pain > Flashcards

Joint Pain Flashcards

1
Q

What are the classes of drugs to treat RA?

A

Anti-Inflammatory Agents (NSAIDS & Corticosteroids)
Conventional Synthetic DMARDs - Methotrexate, Sulfasalazine, Leflunomide, Hydroxychloroquine, Ciclosporin
Targeted Synthetic DMARDs - Tofacitinib
Biologic DMARDs - Infliximab, Anakinra, Abatacept, Rituximab, Tocilizumab

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2
Q

What is methotrexate?

A

A folic acid analog

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3
Q

What is so good about methotrexate?

A

Long-term efficacy, acceptable toxicity & low cost, associated with significantly lower mortality

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4
Q

How is methotrexate administered?

A

Oral, Subcutaneous Injection, Intra-muscular

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5
Q

How can efficiacy of methotrexate be increased?

A

Administer with other sDMARDs

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6
Q

What is the major action of methotrexate?

A

Inhibition of AICAR & ATIC, resulting in increased adenosine levels; then via adenosine receptors result in an anti-inflammatory actions
- down regulation of pro-inflammatory cytokines
- inhibition of apoptosis
- inhibition of polymorph chemotaxis

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7
Q

What is the minor action of methotrexate?

A

Inhibits dihydrofolate reductase and thymidylate synthetase, resulting in decreased DNA methylation, pyramidine and purine synthesis

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8
Q

What is the significance of the minor action of methotrexate?

A

Causes adverse effects (hair loss & nausea)

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9
Q

What are the side effects of methotrexate?

A

Nausea & Vomitting, GI Ulcers, Hair thinning
Leukopenia, Hepatic Fibrosis, Pneumonitis

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10
Q

How can the side effects of methotrexate be kept to a minimum?

A

Concomitant folic acid or folinic acid given 12-24h after methotrexate decreases toxicity

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11
Q

Why can’t folate be given to rescue methotrexate toxicity?

A

Folate does not efficiently rescue to toxicity due to depletion of N5, N10-methylene-FH4 as dihydrofolate reductase is inhibited

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12
Q

What is the mechanism of action of sulfasalazine?

A

Poorly absorbed, mediated by effect on gut microflora, leading to:
- Decreased IgA and IgM rheumatoid factors
- suppression of T cells. B cells & macrophages
- decrease in inflammatory cytokines IL-1beta, TNF, IL6

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13
Q

What are the side effects if sulfasalazine?

A

Nausea & Vomitting, Rash, Hemolytic Anemia, Neutropenia, Reversible infertility in men

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14
Q

What is the mechanism of action of leflunomide?

A

Rapidly converted to active metabolite teriflunomide, inhibiting dihydroorotate dehydrogenase
- decrease in pyrimidine synthesis and growth arrest at G1 phase
- inhibits T cell proliferation and B cell autoantibody production
- inhibits NF-kB activation pro-inflammatory

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15
Q

What are the side effects of leflunomide?

A
  1. Diarrhoae
  2. Elevation of liver enzymes
  3. Alopecia
  4. Weight gain
  5. Teratogenic
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16
Q

What are precautions to note with regards to leflunomide?

A
  1. Very long half life (detectable even years after last dosing)
  2. Colestyramine (bile salt binding) wash out (e.g. before pregnancy)
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17
Q

What are chloroquine and hydroxychloroquine also used for?

A

Anti-malarial drugs

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18
Q

What is the mechanism of action for chloroquine and hydroxychloroquine?

A
  1. Reduced MHC class 2 expression and antigen presentation
  2. Reduced TNF-alpha and IL-1 and cartilage resorption
  3. Antioxidant Activity
19
Q

What is the side effects of chloroquine and hydroxychloroquine?

A
  1. Nausea & Vomitting
  2. Stomach Pain
  3. Dizziness
  4. Hair loss
  5. Ocular Toxicity
20
Q

What is the mechanism of action for tofacitinib?

A

Janus kinase (JAK) pathway non-selective inhibitor - blocks cytokine production by blocking JAK-STAT activation of gene transcription

21
Q

What other disease can tofacitinib be used for?

A

Psoriatic Arthritis

22
Q

How may tofacitinib be prescribed?

A
  1. Combined with methotrexate for moderate to severe RA
  2. Monotherapy in cases of intolerance to methotrexate or methotrexate and multiple bDMARD0refractory active RA
23
Q

What are side effects of tofacitinib?

A
  1. Cytopenia including neutrophils, lymphocytes, platelets and natural killer cells
  2. Immunosuppression resulting in opportunistic infections [increased risk of herpes zoster infection esp in asian population]
  3. Anemia (affects JAK2 activation by EPO)
  4. Hyperlipidemia: Increases in total, LDL, and HDL cholesterol and triglycerides
24
Q

What is a precaution in taking tofacitinib?

A

Do not combine it with biological DMARDs: risk of too great immunosuppression resulting in increased risk of opportunistic infections

25
Q

What are the biological DMARDs that target TNF?

A
  1. Infliximab
  2. Adalimumab
  3. Golimumab
  4. Etanercept
26
Q

What construct are the biological DMARDs that target TNF?

A
  1. Infliximab – Chimeric
  2. Adalimumab – Human mAb
  3. Golimumab – Human mAb
  4. Etanarcept – Recombinant Fusion Protein (Decoy Soluble TNF-IgG1 Receptor that intercepts TNF)
27
Q

What are the half lives of anti-TNF biologics?

A
  1. Infliximab – 8-9 days
  2. Adalimumab – 14 days
  3. Golimumab – 12 days
  4. Etanercept – 70h
28
Q

When are anti-TNF biologics prescribed?

A

For RA patients that do not respond well to sDMARD therapies

29
Q

What is the method of administration for anti-TNF biologics?

A
  1. Infliximab – IV
  2. Adalimumab – Subcutaneous
  3. Etanercept – Subcutaenous
30
Q

What are the side effects of anti-TNF biologics?

A

Respiratory and Skin infection
Increased risk of lymphoma
3. optic neuritis
4. exacerbation of multiple sclerosis
5. leukopenia
6. aplastic anemia

31
Q

What are the contraindications for prescribing anti-TNF biologics?

A

Live vaccination, hep b

32
Q

What must be monitored for when prescribing Anti-TNF biologics?

A

Latent or active TB

33
Q

What is an IL1 antagonist?

A

Anakira

34
Q

What is the mechanism of action of anakira?

A

Binds to IL-1 receptor and blocks signalling

35
Q

What are side effects of anakira?

A
  1. Infections
  2. Injection site reactions
36
Q

What is the disadvantage of anakira?

A

Less effective than anti-TNF bDMARDs

37
Q

What is an IL6 receptor antagonist?

A

Tocilizumab

38
Q

What is the mechanism of action of tocilizumab?

A

Humanized mAb directed at IL-6R chain; prevents binding of IL-6 to IL6-Ralpha and prevents homodimerisation of IL-6Rbeta signalling

39
Q

What are the side effects of tocilizumab?

A

Infections, Skin eruptions, stomatitis, fever. neutropenia, increase in ALT/AST, hyperlipidemia, interacts with CYP450 enzymes 34A, 1A2, 2C9 (metabolised by proteolytic enzymes, but IL6 normally decreases expression fo CYP450 enzymes, so as tocilizumab decreases IL6 these CYP450 enzymes increase)

40
Q

What is the mechanism of action of abatacept?

A

Recombinant fusion protein with CTLA-4-FcIgG1
Binds to CD80 & CD86 and prevents CD28 activation
T-cell therapy

41
Q

What are the side effects of abatacept?

A

Respiratory infection in COPD
Increased lymphoma incidence

42
Q

What is the mechanism of action of Rituximab?

A

Chimeric mAb IgG1 directed at CD20 on pre- and mature B cells
Depletes CD20+ B cells
B cell therapy
Blocks antigen presentation, autoantibody and cytokines

43
Q

What are side effects of rituximab?

A

Rash in first dose
Respiratory infection in COPD

Orthopaedics (6 decks)

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