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Week 11- Musculoskeletal > Immunosuppressants > Flashcards

Immunosuppressants Flashcards

1
Q

What are the side effects of steroids?

A
  • Weight gain and fluid retention
  • Glaucoma
  • Osteoporosis
  • Infection
  • Hypertension and hypokalaemia
  • Peptic ulceration and GI bleed
  • Psychological/psychiatric symptoms
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2
Q

Describe the mechanism of action of corticosteroids

A
  • Glucocorticoid enters the cell and encounters the steroid receptor
  • Once joined moves in to the nucleus and becomes associated with the DNA, altering transcription (up regulates anti-inflammatory protein gene and inflammatory protein gene)
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3
Q

Name two classes of non steroid immunosuppressant drugs

A
  • Inhibitors of DNA synthesis

* Lymphocyte signalling inhibitor

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4
Q

Name the inhibitors of DNA synthesis

A
  • Methotrexate

* Azathioprine

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5
Q

Name the lymphocyte signalling inhibitors

A

•Cyclosporin

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6
Q

What is methotrexate?

A
  • Inhibits DNA synthesis
  • At high dose: kills rapidly dividing cells, causing neutropenia, cytotoxic chemo agent
  • Low dose: immunosuppressant
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7
Q

What is the mechanism of action of methotrexate?

A
  • Inhibits a variety of enzymes involved in metabolism which is linked to nucleotide synthesis and leads to a reduction in DNA synthesis
  • Inhibits DHFR (dihydrofolate reductase), TYMS (Thymidylate synthetase) and ATIC
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8
Q

What stage of the cell cycle do cells get stuck in with methotrexate?

A

S phase arrest

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9
Q

What are the actions of methotrexate

A
  • Folate antagonism
  • Adenosine signalling (anti-inflammatory)
  • Methyl donors
  • Eicosanoids and MMPs
  • Cytokines
  • Adhesion molecules
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10
Q

What are the adverse effects of methotrexate?

A 
•Gastrointestinal: 
 - nausea and vomiting 
 - hepatitis 
 - stomatitis 
•Haematological: 
 - leukopenia 
•Other: 
 - frequent infection 
 - pulmonary fibrosis (methotrexate lung)
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11
Q

What can be given to reduce methotrexate toxicity?

A

•folic acid - 5mg given 4 days after methotrexate

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12
Q

How often is methotrexate given?

A

Once a week

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13
Q

What is azathioprine?

A
  • Inhibitor of DNA synthesis

* Prodrug of 6-mercaptopurine which is an adjunct of hypoxanthine (a precursor of adenosine monophosphate)

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14
Q

What is the mechanism of action of azathioprine?

A
  • Converted within cells into a nucleoside analogue (6-mercaptopurine)
  • Incorporated into DNA and RNA chains leading to the termination of nucleic acid strands
  • Cell growth and metabolism halts
  • Preferential action of lymphocytes as other cells have purine salvage pathway
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15
Q

What are the adverse effects of azathioprine?

A

•Gastrointestinal

  • nausea, vomiting, diarrhoea
  • hepatitis, cholestasis

•Haematological

  • leukopenia
  • thrombocytopenia

•Other

  • frequent infection
  • hair loss
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16
Q

Explain the metabolism of azathioprine

A
  • TPMT enzyme
  • 0.2-0.6% of individuals lack this enzyme so you need to check TPMT activity prior to treatment
  • Without it there is an accumulation of the most active metabolites of azathioprine within cells and development of severe toxicity
17
Q

What are the clinical indications for azathioprine?

A

•Most commonly used for inflammatory bowel disease

  • ulcerative colitis
  • Chrons

•Other severe autoimmune diseases:

  • myasthenia gravis
  • eczema
18
Q

Describe the clinical use of azathioprine

A
  • Orally on a daily basis
  • Effects take several weeks to become evident
  • need to monitor bloods on a monthly basis
19
Q

What is cyclosporin?

A
  • Lymphocyte signalling inhibitor

* Small molecule inhibitor of calcineurin

20
Q

What is the mechanism of action of cyclosporin?

A
  • Small molecule inhibitor of calcineurin
  • Effect of inhibiting signal transduction from the activated TCR complex
  • Profound inhibition of T cell activation
21
Q

What are the adverse effects of cyclosporin?

A
  • Nephrotoxicity
  • Hypertension
  • Hepatotoxicity
  • Anorexia and lethargy
  • Hirsutism
  • Paraesthesia
22
Q

What is tacrolimus?

A
  • Different classes drug to cyclosporin but similar mechanism of action
  • More potent activity
  • Similar use to cyclosporin but may be a little better tolerated
23
Q

What are the indications of cyclosporin?

A
  • organ transplantation
  • Sometimes used for inflammatory conditions
  • can be used topically
24
Q

Describe the clinical use of cyclosporin

A
  • Given orally on a daily basis
  • Dose established using therapeutic drug monitoring
  • Main drug interactions through cytochrome P450 enzymes
  • Need to monitor blood tests regularly
25
Q

What are the disadvantages of immunosuppressants?

A

Effectiveness:
•Often insufficient to control inflammatory disease with subsequent progression
•Usually have a slow rate of onset limiting usefulness in acute severe disease

Toxicity
•Even at low doses have significant toxicities
•Class effects include:
- bone marrow suppression (not cyclosporin)
- frequent infections

26
Q

What are infliximab?

A

Monoclonal antibody

27
Q

What is infliximab’s target?

A

Soluble cytokine - TNF inhibitor

28
Q

What is etanercept?

A

Soluble receptor

29
Q

What is the target of etanercept?

A

Soluble cytokine -TNF inhibitor

30
Q

what is rituximab?

A

monoclonal antibody

31
Q

What is the target of rituximab?

A

Surface marker - CD20

32
Q

How are biologic therapies delivered?

A

Parenteral route

33
Q

What are the side effects of the biologics?

A
  • Hypersensitivity reactions
  • Infusion reactions
  • Mild GI toxicity
34
Q

What are the increased infection risks with anti TNF therapy?

A
  • Increased risk of TB, particularly disseminated TB
  • Need to screen for latent TB before prescribing
  • Increased risk of salmonella and listeria
35
Q

What are the increased infection risk with Rituximab?

A
  • Generalised increased risk of serious infection

* high risk of hep B reactivation, need to screen and prophlax if necessary

36
Q

Which biologics have a high risk of TB?

A

Anti-TNF therapy

37
Q

How can you screen for latent TB?

A

Interferon gamma release assay

Week 11- Musculoskeletal (11 decks)

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