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semester 4 - CPT & Prescribing > 15. Immunosuppressants > Flashcards

15. Immunosuppressants Flashcards

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1
Q

What diseases do rheumatologists manage?

A
  • Inflammatory arthritis e.g. rheumatoid arthritis (RA)
  • Systemic lupus erythematosus (SLE)
  • Systemic vasculitis
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2
Q

What is rheumatoid arthritis?

A
  • autoimmune multi-system disease
  • Initially localized to synovium
  • Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
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3
Q

What are the clinical criteria for diagnosis of RA? (5)

A
  • Morning stiffness ≥ 1 hour
  • Arthritis of ≥ 3 joints
  • Arthritis of hand joints
  • Symmetrical arthritis
  • Rheumatoid nodules
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4
Q

What are the non-clinical criteria for diagnosis of RA?

A
  • Serum rheumatoid factor/Anti-CCP antibodies

* X-ray changes

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5
Q

which pro-inflammatory cytokines are over expressed in RA?

A

TNF a
IL-1
IL-6

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6
Q

What x-ray changes are seen in RA?

A
  • reduced joints space
  • periarticular osteopenia
  • juxta-articular bony erosion
  • subluxation and gross deformity
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7
Q

What is the treatment strategy for RA?

A
  • Early use of disease-modifying drugs
  • Aim to achieve good disease control
  • Use of adequate dosages
  • Use of combinations of drugs
  • Avoidance of long-term corticosteroids
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8
Q

RA treatment goals?

A

symptomatic relief

prevention of joint destruction

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9
Q

What is SLE?

A

Multisystem autoimmune disorder related to antibody-mediated cellular attack and deposition of antigen-antibody complexes

  • arthralgia and rashes most common clinical features
  • cerebral and renal disease the most serous problems
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10
Q

What are the treatment goals for SLE and vasculitis?

A
  • Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and by drugs
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11
Q

Give examples of immunosuppressant (7)(some are DMARDs)

A
  • Corticosteroids
  • Methotrexate
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
  • Leflunomide
  • Cyclophosphamide
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12
Q

Give examples of disease modifying anti-rheumatic drugs (DMARDs) non-biologics used in rheumatology.

A
  • Hydroxychloroquine

* Sulphasalazine

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13
Q

Give examples of DMARDs biologics used in rheumatology.

A
  • Anti-TNF agents
  • Rituximab
  • IL-6 inhibitors, JAK inhibitors
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14
Q

What is the mechanism of action of corticosteroids?

A
  • bind to cytoplasmic receptor
  • activated steroid-receptor complexes form dimers
  • move into the nucleus
  • bind to steroid response elements in the DNA
  • either repress or induce particular genes
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15
Q

How are corticosteroids immunosuppresants?

A
  • Prevent interleukin IL-1 and IL-6 production by macrophages
  • Inhibit all stages of T-cell activation
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16
Q

What are some short term side effects of corticosteroid use?

A
  • an increase in appetite,
  • weight gain,
  • insomnia,
  • fluid retention, and
  • mood changes, such as feeling irritable, or anxious
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17
Q

WHat are some long term side effects of corticosteroid use?

A
  • osteoporosis (fragile bones),
  • hypertension (high blood pressure),
  • diabetes,
  • weight gain,
  • increased vulnerability to infection,
  • cataracts and glaucoma (eye disorders),
  • thinning of the skin,
  • bruising easily, and
  • muscle weakness
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18
Q

What is azathioprine used in?

A
  • maintenance therapy in SLE and vasculitis (cannot induce remission)
  • IBD
  • severe atopic dermatitis
  • bullous skin disease
  • (steroid sparing drugs)
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19
Q

How does azathioprine work?

A

Inhibits purine synthesis and therefore DNA/RNA synthesis

- antimetabolite

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20
Q

What is the mechanism of action of azathioprine?

A

It is converted into 6-mercaptopurine (6-MP) (the main active metabolite) which is conjugated with ribose and incorporated into DNA halting DNA replication (also other things)

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21
Q

Which enzyme is important in the metabolism of 6-MP?

A

Thiopurine methyltransferase (TPMT)

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22
Q

What is important to check for in patients before giving azathioprine?

A

Levels of TPMT

- lower levels can result in myelosuppression

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23
Q

What are the adverse effects of azathioprine?

A
  • bone marrow suppression
  • increased risk of infection
  • increased risk of malignancy
  • hepatitis
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24
Q

What are 2 examples of calcineurin inhibitors?

A

Ciclosporin & tacrolimus

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25
Q

What are calcineurin inhibitors used for?

A
  • widely used in transplantation
  • atopic dermatitis and psoriasis
  • (not often used in rheumatology)
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26
Q

What is important to regularly monitor when using calcineurin inhibitors?

A

Check BP and eGFR regularly

- can cause it to dip

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27
Q

What DDI are important with calcineurin inhibitors?

A

Multiple drug interactions are possible (Cytochrome P-450) - CYP450 inducers and inhibitors

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28
Q

which drugs are CYP450 inducers?

A

rifampicin
carbemazepine
phenytoin
omeprazole

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29
Q

which drugs are CYP450 inhibitors?

A 
ciprofloxacin
many antifungals
fluoxetine
paroxetine
HIV antivirals e.g indinavir
30
Q

What is the MOA of ciclosporin and tacrolismus?

A
  • Active against helper T-cells, preventing production of IL-2 via calcineurin inhibition - reduce helper T cell activity
  • Ciclosporin binds to cyclophilin protein
  • Tacrolimus binds to tacrolimus-binding protein
  • Drug/protein complexes bind calcineurin
  • Calcineurin exerts phosphatase activity of activated T- cells then nuclear factor migration starts IL-2 transcription
31
Q

ADRs of ciclosporin and tacrolismus?

A

renal toxicity

32
Q

What is mycophenolate mofetil used for?

A
  • Primarily in transplantation
  • Good efficacy as induction and maintenance therapy for lupus nephritis/Vasculitis maintenance
  • In transplantation medicine: Mycophenolic acid may be monitored
33
Q

How does Mycophenolate Mofetil work?

A

Inhibits purine synthesis

- guanosine specifically

34
Q

What is the MOA of mycophenolate mofetil?

A
  • Inhibits inosine monophosphate (IMP) dehydrogenase (required for guanosine synthesis)
  • impairs B- and T-cell proliferation (selectively??)
  • spares other rapidly dividing cells
35
Q

What are the adverse effects of mycophenolate mofetil?

A
  • Most common include nausea, vomiting, diarrhea
  • GI disease
  • Most serious is myelosuppression
36
Q

What is cyclophosphamide used for?

A
  • Lymphoma, leukaemia, solid cancers
  • Lupus nephritis
  • Wegener’s granulomatosis (ANCA-vasculitis)
37
Q

What is the MOA of cyclophosphamide?

A 
Cytotoxic Agent :
Alkylating agent -cross links DNA so that it cannot replicate
Many immunological effects:
– suppresses T cell activity
– suppresses B cell activity
38
Q

Describe the metabolism of cyclophosphamide.

A
  • is a pro-drug
  • metabolised by CYPs in liver to 4-hydroxycyclophosphamide (4HCP)
  • 4HCP exists in equilibrium with its tautomer, aldophosphamide
  • Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
39
Q

what is the effect on cyclophosphamide on kidneys?

A
  • Cyclophosphamide is excreted by the kidney

* Acrolein, another metabolite is toxic to the bladder epithelium and can lead to hemorrhagic cystitis

40
Q

How is haemorrhagic cystitis prevented in use of cyclophosphamide?

A

through the use of aggressive hydration and/or Mesna

41
Q

What ADRs are associated with cyclophosphamide?

A
  • increased risk of bladder cancer, lymphoma and leukaemia
  • Infertility: Risk relates to cumulative dose and patient age
  • toxic metabolite to bladder epithelium
42
Q

what is a contraindication of cyclophosphamide?

A

Adjust dose in renal impairment

43
Q

What is usually considered instead of cyclophosphamide?

A

Mycophenolate mofetil

- safer and as effective in lupus nephritis

44
Q

action of cyclophosphamide and Mycophenolate mofetil ?

A

antiproliferative - B and T cells

45
Q

DDIs of cyclophosphamide?

A

caution with many vaccines

46
Q

What is the gold standard treatment for RA?

A

Methotrexate

47
Q

What are the indications for use of methotrexate?

A
  • RA
  • malignancy
  • psoriasis
  • Crohn’s disease
48
Q

What is the MOA of methotrexate (neoplasms)?

A

Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
- 1000x more affinity than folate

49
Q

What does inhibition of dihydrofolate reductase result in?

A
  • normally converts dihydrofolate to tetrahydrofolate
  • key carrier of one-carbon units in purine and thymidine synthesis
  • methotrexate therefore inhibits the synthesis of DNA/RNA
50
Q

Why does methotrexate affect rapidly dividing cells more?

A

Acts during DNA and RNA synthesis hence cytotoxic during S-phase of the cell cycle. Greater toxic effect on rapidly dividing cells which replicate their DNA more frequently

51
Q

What are the possible MOA in non-malignant disease?

A

mechanism unclear but not via anti-folate action
possible:
– Inhibition of accumulation of adenosine
- the inhibition of T cell activation activation
- suppression of intercellular adhesion molecule expression by T cells

52
Q

How is methotrexate administered, what is its bioavailability?

A
  • Mean oral bioavailability is 33% (13-76%)
  • Mean intramuscular bioavailability is 76%
  • Administered PO, IM or S/C
53
Q

What is the dosing of methotrexate?

A
  • WEEKLY NOT DAILY DOSING,

- metabolized to polyglutamates with long half lives

54
Q

What percent of methotrexate is protein bound?

A

50%

- NSAIDs displace

55
Q

how is methotrexate excreted?

A

renally

56
Q

What ADRs are associated with methotrexate?

A 
• mucositis
• marrow suppression (both respond to folic acid supplementation)
• hepatitis, cirrhosis
• pneumonitis
• infection risk
- reduced fertility (reversible)
57
Q

Should methotrexate be given during pregnancy?

A

No

  • highly teratogenic, abortifacient
  • need to take contraceptives whilst taking drug
58
Q

What are the indications for sulfasalazine?

A
  • IBD

- RA

59
Q

What is sulfasalazine a conjugate of and what breaks it into these component parts?

A
  • salicylate (5aminosalicylic acid, 5ASA)
  • sulfapyridine (antibiotic)

Broken into these by gut bacteria

60
Q

action of sulfasalazine?

A

• Designed to relieve pain & stiffness
(5-ASA = anti-inflammatory)
• And to fight infection
(sulfapyridine = sulfonamide)

61
Q

What are the immunological effects of sulfasalazine?

A 
T-cell 
- inhibition of proliferation 
- possible T-cell apoptosis 
- inhibition of IL-2 production 
Neutrophil 
- reduced chemotaxis 
- reduced degranulation
62
Q

Why is sulfasalazine effective in IBD?

A

Poorly absorbed -main activity is within intestine

63
Q

What ADRs are associated with sulfasalazine?

A 
• Mainly due to sulfapyridine moiety 
- myelosuppression 
- hepatitis 
- Rash 
• Milder side effects 
- nausea 
- abdo pain/vomiting
64
Q

DDIs of sulfasalazine?

A

very few

some caution with PPIs

65
Q

Is Sulfasalazine safe in pregnancy?

A

Yes

66
Q

Give examples of biologics used in treatment of RA.

A

rituximab, infliximab

67
Q

How does rituximab work?

A

Binds specifically to a unique cellsurface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type. Causes B cell apoptosis.

causes B cell apoptosis

68
Q

Effects of blocking TNF-alpha?

A 
• reduced  Inflammation
Cytokine cascade
Recruitment of leukocytes to joint 
- elaboration of adhesion molecules 
- production of chemokines
•  reduced Angiogenesis 
VEGF levels 
•  reduced Joint destruction
MMPs and other destructive enzymes 
Bone resorption and erosion 
Cartilage breakdown
69
Q

What does anti-TNF therapy increase risk of, what should be screened before therapy?

A

TB reactivation

  • TNFα is released by macrophages in response to M TB infection
  • TNFα is essential for development + maintenance of granulomata

Screen for latent TB before treatment

70
Q

DDIs of methotrexate?

A

NSAIDs and other drugs that reduce renal excretion or displace bound drug

71
Q

DDIs of corticosteroids?

A

CYP inducers, bleeding risk increased with NSAIDs

semester 4 - CPT & Prescribing (25 decks)

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