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Pharmacology > Immunosuppresants > Flashcards

Immunosuppresants Flashcards

1
Q

How do corticosteroids work?

A

Prevent IL-1 and IL-6 production by macrophages and inhibit all stages of T cell activation.

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2
Q

Anti-Rheumatics can be classified into two categories

A

Non-biologics

Biologics

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3
Q

Give an example of each class of disease modifying anti-rheumatic drugs

A

Non-biologics:

  • sulphasalazine
  • hydroxychloroquine

Biologics:

  • anti-TNF
  • rituximab
  • IL-6 inhibitors, JAK inhibitors
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4
Q

Azathioprine is a drug used for what immune disorders?

A 
SLE and vasculitis - maintenance therapy 
RA - weak evidence 
Inflammatory bowel disease 
Bullous skin disease 
Atopic dermatitis
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5
Q

How does azathioprine work ?

A

It is cleaved to 6-mercaptopurine (6-MP); an antimetabolite which decreases DNA and RNA synthesis

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6
Q

Why must individuals be tested for TPMT activity before prescribing azathioprine?

A

6- MP is metabolised by TPMT which is highly polymorphic and therefore people vary in activity. Low/absent levels increase the risk of myelosupression.

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7
Q

What are the possible adverse effects of immunosuppressants and azathioprine ?

A

Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis

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8
Q

Name a calcineurin inhibitor

A

Ciclosporin and tacrolimus

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9
Q

When might calcineurin inhibitors be prescribed?

A

Transplantation
Atopic dermatitis
Psoriasis

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10
Q

Calcineurin inhibitors require which tests to be conducted regularly?

A

Blood pressure

EGFR- renal toxicity

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11
Q

Why are multiple drug interactions possible with calcineurin inhibitors?

A

Use CYP450 and therefore other drugs can alter activity of these enzymes

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12
Q

Give examples of CYP450 inducers

A

Rifampicin
Carbamazepine
Phenytoin
Omeprazole

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13
Q

Give examples of CYP450 inhibitors

A 
Ciprofloxacin
Antifungals 
Fluoxetine 
Paroxetine 
HIV antivirals
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14
Q

How does ciclosporin work?

A

Binds to cyclophilin protein and these complexes then bind calcineurin.
Calcineurin has phosphatase activity of activated T cells, then nuclear factor migration starts IL-2 transcription.
Essentially it prevents IL-2 production

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15
Q

How does tacrolimus work?

A

Tacrolimus binds tracrolimus binding protein and this drug/protein complex binds calcineurin.
This prevents IL-2 production by activated T cells, through inhibiting the phosphatase activity induced by calcineurin.

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16
Q

What is mycophenolate mofetil used for?

A

Transplantation

Induction and maintenance for lupus nephritis and vasculitis

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17
Q

What are the adverse effects of mycophenolate mofetil?

A

Nausea, vomiting and diarrhoea
Myelosupresssion
Mucositis
Skin cancer

18
Q

What is the mechanism of action for mycophenolate mofetil?

A

Prodrug
Inhibit inosine monophosphate dehydrogenase (guanosine synthesis requires it)
Impairs B and T cell proliferation
Spares other rapidly dividing cells as there are guanosine salvage pathways in other cells.

19
Q

What is cyclophosphamide used for?

A

Lymphoma, leukaemia and solid cancers
Lupus nephritis
ANCA vasculitis

20
Q

What is the mechanism of action for cyclophosphamide?

A

Alkylating agent- cross links DNA

Suppresses T and B cell activity

21
Q

What is the pharmacodynamics of cyclophosphamide ?

A

Prodrug
converted in the liver to the main active metabolite 4-hydroxycyclophosphamide.
4-hydroxycyclophosphamide exits in equilibrium with its tautomer aldophosphamide.

Most aldophosphamide is oxidise to carboxyphosphamide, with only a small amount of aldophosphamide being converted to phosphoramide mustard.

22
Q

Why can patients on cyclophosphamide experience haemorrhagic cystitis?

A

Acrolein (another metabolite) is toxic to bladder epithelium.
Can prevent this cystitis by using aggressive hydration and/or Mesna.

23
Q

What are the important considerations regarding cyclophosphamides toxicity?

A

Increased risk of bladder cancer, lymphoma and leukaemia

Infertility

24
Q

Methotrexate is used in which diseases?

A

Rheumatoid arthritis - gold
Malignancy
Psoriasis
Crohn’s disease

25
Q

What is the mechanism of action of methotrexate in malignancy?

A

Competitive and irreversible inhibition of dihydrofolate reductase (DHFR) of 1000 times affinity compared to folate.
Therefore it inhibits purine and thymidine synthesis - inhibiting DNA, RNA and proteins. It is cytotoxic in the S-phase. Greatest effect in rapidly dividing cells.

26
Q

What is the proposed mechanism of action of methotrexate for non-malignant conditions?

A

Inhibition of accumulation of adenosine
Inhibition of T cell activation
Suppression of intercellular adhesion molecule expression by T cells.

27
Q

Why is methotrexate given weekly?

A

Methotrexate itself has a shorter half life, but its metabolites - polyglutamates- have long half lives.

28
Q

What must you be aware of when giving methotrexate ?

A

Use of NSAIDs - NSAIDs displace and 50% is protein bound.

29
Q

Which adverse effects of methotrexate respond to folic acid?

A

It prevents adverse effects of mucositis and marrow suppression.

30
Q

What are the main adverse effects of methotrexate?

A

Hepatitis, cirrhosis
Pneumonitis
Infection risk
Teratogenic and abortifacient

31
Q

Why must sulfasalazine be avoided in those with an aspirin allergy?

A

Similar structure

32
Q

What are the immunological effects of sulfasalazine?

A

Inhibits proliferation, IL-2 production and induces apoptosis of T cells.
Reduces chemotaxis and degranulation of neutrophils.

33
Q

Why is sulfasalazine so effective in the large bowel?

A

It is poorly absorbed and therefore the main activity is within the intestine, effective for IBD.

34
Q

What are the ADRs of sulfasalazine?

A 
Myelosuppression
Hepatitis 
Rash
Nausea 
Abdominal pain 
Vomiting
35
Q

Why is sulfasalazine good in practice?

A

Effective with favourable toxicity
Long term blood monitoring not requires and very few drug interactions
No carcinogenic potential and safe in pregnancy.

36
Q

What are the effects of blocking TNF-alpha?

A

Decreased inflammation - through inhibition of the cytokine cascade
Decreased angiogenesis
Decreased joint destruction by MMP and other destructive enzymes

37
Q

What disease must be screened for before giving anti-TNF therapy and why?

A

Latent TB

It is a risk of reactivating Tb, as TNF-alpha is essential for development and maintenance of a granuloma.

38
Q

Biologic use is linked to cancer by what type of relationship?

A

Unmasking cancer rather than causation

39
Q

What is rituximab and by what mechanism does it work?

A

A monoclonal antibody which binds to CD20, inducing B cell apoptosis.
Very effective in rheumatoid arthritis, with good safety data.

40
Q

What is RA and how is it diagnosed?

A

Autoimmune disease which is initially localised to synovium
Inflammatory change and proliferation of synoviuum leading to dissolution of cartilage and bone

Morning stiffness >1
Arthritis > 3 joints 
HandA/feet/wrist joints 
Symmetrical arthritis 
Rheumatoid nodules 
Serum RF/ anti CCP ab 
X-ray changes

Pharmacology (22 decks)

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