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CPT > Immunosuppression and disease modifying therapy > Flashcards

Immunosuppression and disease modifying therapy Flashcards

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1
Q

What is rheumatoid arthritis?

A
  • An autoimmune multi-system disease
  • Initially localised to synovium
  • Inflammatory change and proliferation of synovium (pannus) causes dissolution of cartilage and bone
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2
Q

What is the pathogenesis of rheumatoid arthritis?

A
  • Imbalance between pro-inflammatory mediators (IL-1, IL-6, TNF a) and anti-inflammatory mediators
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3
Q

What is the strategy for rheumatoid arthritis treatment?

A
  • Early use of disease-modifying drugs
  • Aim to achieve good disease control
  • Use of adequate doses
  • Use of combinations of drugs
  • Avoidance of long-term corticosteroids
  • Aim to achieve remission assisted by drugs
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4
Q

What are the treatment goals in SLE and vasculitis?

A
  • Symptomatic relief
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and drugs
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5
Q

Give some examples of immunosuppressants

A
  • Corticosteroids
  • Azathioprine
  • Mycophenolate mofetil
  • Ciclosporin
  • Tacrolimus
  • Cyclophosphamide
  • Methotrexate
  • Sulfasalazine
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6
Q

What is the mechanism of action of corticosteroids?

A
  • Prevent IL-1 and IL-6 production by macrophages
  • Inhibit all stages of T cell activation
  • Not very targeted in its approach
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7
Q

Which rheumatoid arthritis drugs are non-biologics?

A
  • Sulfasalazine
  • Methotrexate
  • Azathioprine
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8
Q

Which rheumatoid arthritis drugs are biologics?

A
  • Anti-TNF agents
  • Rituximab
  • IL-6 inhibitors, JAK inhibitors
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9
Q

What are the uses of azathioprine?

A
  • Maintenance therapy in SLE and vasculitis
  • Not especially useful in RA
  • IBD
  • Steroid sparing drug
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10
Q

What is the mechanism of action of azathioprine?

A
  • Cleaved to 6-mercaptopurine (6-MP)
  • Acts as an anti-metabolite
  • Decreases DNA and RNA synthesis (purine synthesis)
  • Inflammatory cells are inhibited
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11
Q

What are the adverse effects of azathioprine?

A
  • Bone marrow suppression
  • Monitor FBC
  • Increased risk of malignancy
  • Increased risk of infection e.g. Hepatitis
  • Monitor LFTs
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12
Q

Give some examples of calcineurin inhibitors?

A
  • Ciclosporin
  • Tacrolimus
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13
Q

What are calcineurin inhibitors used to treat?

A
  • Used in transplantation
  • Atopic dermatitis
  • Psoriasis
  • Not often used in rheumatology - renal toxicity
  • Check BP and eGFR regularly
  • Multiple drug interactions are possible (CYP450)
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14
Q

What is the mechanism of action of calcineurin inhibitors?

A
  • Active against helper T-cells
  • Prevents production of IL-2 via calcineurin inhibition
  • Ciclosporin binds to cyclophilin protein
  • Tacrolimus binds to tacrolimus-binding protein
  • Drug/protein complexes bind calcineurin
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15
Q

What are the uses of mycophenolate mofetil in practice?

A
  • Primarily in transplantation
  • Good efficacy as induction and maintenance therapy for lupus nephritis
  • Vasculitis maintenance
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16
Q

What is the mechanism of action of mycophenolate mofetil?

A
  • Inhibits inosine monophosphate dehydrogenase
  • Required for guanosine synthesis
  • Impairs B and T cell proliferation
  • Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)
17
Q

What are the adverse effects of mycophenolate mofetil?

A
  • Most common include nausea, vomiting, diarrhoea
  • Most serious is myelosuppression
18
Q

What is the mechanism of action of cyclophosphamide?

A
  • Alkylating agent - cross-links DNA so that it cannot replicate
  • Many immunological effects - suppresses T cell activity and B cell activity
19
Q

What are the indications of cyclophosphamide?

A
  • Lymphoma, leukaemia, solid cancers
  • Lupus nephritis
  • Wegener’s granulomatosis
20
Q

What are the pharmacodynamics of cyclophosphamide?

A
  • prodrug
  • Converted in the liver (cytochrome P450) to active forms
21
Q

What are the pharmacokinetics of cyclophosphamide?

A
  • Excreted by the kidney
  • Can result in haemorrhagic cystitis
  • Can be prevented through the use of aggressive hydration and/or Mesna
22
Q

What are the important considerations of cyclophosphamide?

A
  • Significant toxicity
  • Increased risk of bladder cancer, lymphoma, and leukaemia
  • Infertility (especially between ages 25-30)
  • Monitor FBC
  • Adjust dose in renal impairment
23
Q

What are the indications for methotrexate?

A
  • Gold standard for rheumatoid arthritis
  • Malignancy
  • Psoriasis
  • Crohn’s disease
  • Vasculitis
24
Q

What is the mechanism of action of methotrexate?

A
  • Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
  • DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate
  • Tetrahydrofolate is key for purine and thymidine synthesis
  • Methotrexate therefore inhibits synthesis of DNA, RNA and proteins
  • Greater toxic effect on rapidly dividing cells which replicate their DNA more often
25
Q

What is the mechanism of action of methotrexate in non-malignant disease?

A
  • Mechanism of action is not clear
  • Not via anti-folate action
26
Q

How is methotrexate administered?

A
  • Administered PO, IM, or SC
  • Weekly not daily dosing
  • Metabolised to polyglutamates with long half lives
27
Q

What are the adverse effects of methotrexate?

A
  • Mucositis and marrow suppression (both respond to folic acid supplementation)
  • Hepatitis
  • Cirrhosis
  • Pneumonitis
  • Infection risk
  • Highly teratogenic
28
Q

What are the benefits of methotrexate?

A
  • Well-tolerated
  • Improved QOL
  • Retardation of joint damage
  • Good adherence
29
Q

What is the mechanism of action of sulfasalazine?

A
  • T cell - inhibits proliferation and causes apoptosis
  • Inhibits IL-2 production
  • Reduced chemotaxis and degranulation of neutrophils
30
Q

What are the adverse effects of sulfasalazine?

A
  • Mainly due to sulfapyridine moiety - myelosuppression, hepatitis, rash
  • Milder side effects include nausea and abdo pain/vomiting
31
Q

What are the benefits of using sulfasalazine?

A
  • Effective
  • Favourable toxicity
  • Long term blood monitoring not always needed
  • Very few drug interactions
  • No carcinogenic potential
  • Safe in pregnancy
32
Q

Give 3 examples of monoclonal antibodies used to treat RA?

A
  • Adalimumab (Humira) - binds TNFa
  • Infliximab (Remicade) - binds TNFa
  • Rituximab (Mabthera) - depletes B cells
33
Q

What are the effects of blocking TNFa?

A
  • Decreases inflammation
  • Decreased angiogenesis
  • Decreased joint destruction
34
Q

What are the risks of Anti-TNF therapy?

A
  • TB reactivation
  • TNFa is essential for development and maintenance of granulomata
  • Screen for latent TB before anti-TNF treatment

CPT (22 decks)

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