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CPT > Session 10 Immunosupressants > Flashcards

Session 10 Immunosupressants Flashcards

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1
Q

What is rheumatoid arthritis?

A

An autoimmune multi-system disease

It is initially localised to synovium followed by inflammatory change and proliferation (of the synovium) leading to dissolution of cartilage and bone

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2
Q

When diagnosing rheumatoid arthritis - what are the clinical criteria?

A 
Morning stiffness >1 hour 
Arthritis of 3 or more joints 
Arthritis of hand joints
Symmetrical arthritis 
Rheumatoid nodules
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3
Q

When diagnosing rheumatoid arthritis, what are the non-clinical criteria?

A

Serum rheumatoid factor / anti CCP antibodies

X ray changes

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4
Q

What are the goals of treatment for rheumatoid arthritis?

A

Symptomatic relief

Prevention of joint destruction

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5
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 combination of drugs

Avoidance of long term corticosteroids

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6
Q

What are the goals of treatment in SLE and vasculitis?

A

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

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7
Q

What is the general MoA for corticosteroids?

A

Prevent interleukin IL-1 and IL-6 production by macrophages

Inhibit all stages of T-cell activation

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8
Q

What are two examples of disease-modifying anti-rheumatic drugs (DMARDs) that are NON-biologics?

A

Sulphasalazine

Hydroxychloroquine

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9
Q

hat are two examples of disease-modifying anti-rheumatic drugs (DMARDs) that are biologics?

A

Anti-TNF agents

Rituximab

IL-6 inhibitors, JAK inhibitors

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10
Q

What can azathioprine be used for?

A

SLE and vasculitis

RA (weak evidence)

IBD

= ‘steroid sparing’ drug

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11
Q

Pharmacodynamics of Azathioprine?

Metabolised by?

A

6-MP is metabolised by thiopurine methyltransferase (TPMT)

TPMT gene is highly polymorphic THEREFORE Individuals vary markedly in TPMT activity

If you have low TPMT levels - risk of myelosupression
SO need to test TPMT activity before prescribing

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12
Q

Aziothioprine MoA?

A

Cleaved to 6-mercaptopurine (6-MP) then to 6-MeMP (inactive) / TIMP (active) or 6-TU (inactive)

TIMP > 6-MeMPN = inhibition of de novo purine synthesis
TIMP > 6-TGN = incorporation into DNA

Anti-metabolite decrease DNA and RNA synthesis

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13
Q

ADR of azathioprine?

A

Bone marrow suppression (need to monitor FBC)

Increased risk of malignancy

Increased risk of infection

Hepatitis (need to monitor LFTs)

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14
Q

What are Ciclosporin and tacrolimus examples of?

A

Calcineurin inhibitors

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15
Q

What are ciclosporin and tacrolimus widely used for?

A

In transplantation

But also for atopic dermatitis and psoriasis

Lots of drug interactions!!

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16
Q

Ciclosporin and tacrolimus MoA?

A

Active against helper T cells, preventing production of IL-2 via calcineurin inhibition

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

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17
Q

When would you use mycophenolate mofetil in practice?

A

Transplantation

Good efficacy as induction and maintenance therapy for lupus nephritis / vasculitis maintenance

18
Q

Mycophenolate mofetil MoA?

A

Prodrug

Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)

Impairs B and T cell proliferation

Spaces other rapidly dividing cells

19
Q

How does mycophenolate mofetil spare other rapidly dividing cells? I.e. only impairs B- and T- cell proliferation?

A

Due to guanosine salvage pathways in other cells

20
Q

What are the adverse effects associated with mycophenolate mofetil?

A

Nausea, vomiting, diarrhoea = most common

Myelosuppression = most serious

21
Q

How does cyclophosphamide work?

A

It is an alkylation agent that cross links DNA so that it cannot replicate

It suppresses T and B cell activity

22
Q

When would you use cyclophosphamide?

A

Lymphoma, leukaemia, solid cancers

Lupus nephritis

Wegener’s granulomatosis (ANCA-vasculitis)

23
Q

Describe the pharmacodynamic of cyclophosphamide

A

Prodrug

Converted in the liver (cytochrome P450) to active forms

Main active metabolite = 4-hydroxycyclophosphamide
(This exists in equilibrium with its tautomer - aldophosphamide)

Most of the aldophosphamide is oxidised to make carboxyphosphamide

A small portion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)

24
Q

Describe the pharmacokinetics of cyclophosphamide

A

Excreted by the kidney

Acrolein (another metabolite) is toxic to the bladder epithelium and can lead to haemorrhagic cystitis

This can be prevented through the use of aggressive hydration

25
Q

How can we prevent acrolein from causing Haemorrhagic cystitis (as is toxic to bladder epithelium) ?

A

Aggressive hydration and/or mesna

26
Q

When prescribing cyclophosphamide - what are some important considerations?

A

It is significantly toxic

  • increased risk of bladder cancer, lymphoma and leukaemia
  • infertility
  • monitor FBC
  • adjust dose in renal impairment
27
Q

What is safer and just as effective in treating lupus nephritis?

(When compared to cyclophosphamide)

A

Mycophenolate mofetil

28
Q

Describe the pathogenesis of RA

A

there is an imbalance of autoinflammatory cytokines

i.e. more pro-inflammatories than anti-inflammatories

29
Q

what are some examples of pro-inflammatories?

A

IL1
IL6
TNF-a

30
Q

what are some examples of anti-inflammatories?

A

IL4

TGF-b

31
Q

What is the gold standard treatment for RA?

A

methotrexate

other indications

  • malignancy
  • psoriasis
  • crohn’s disease
  • ectopic pregnancy
32
Q

methotrexate MoA?

A

it competitively and reversibly inhibits dihydrofolate reductase

normally: dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate

tetrahydrofolate = key carrier of C units in purine and thymidine synthesis

therefore, methotrexate inhibits synthesis of DNA, RNA and proteins

33
Q

Which stage of the cell cycle is methotrexate cytotoxic to?

A

S-phase

acts during DNA and RNA synthesis

greater toxic effect on rapidly dividing cells which replicate their DNA more frequently

34
Q

Oral bioavailability of methotrexate =
IM bioavailability =

how should it be taken and why?

excreted by?

A 
oral = 33%
IM = 76%

weekly dosing NOT daily

  • has a long half life
  • taken with folic acid

renal excretion

35
Q

adverse effects of methotrexate?

A 
mucositis 
marrow suppression 
hepatitis, cirrhosis
pneumocitis 
infection risk

HIGHLY teratogenic

36
Q

effects of sulfasalazine?

A

T cell

  • inhibition of proliferation
  • apoptosis
  • inhibition of IL-2 production

neutrophil
* reduce chemotaxis and degranulation

37
Q

adverse effects of sulfasalazine?

A

these are mainly due to the sulfapyridine moiety

  • myelosuppression
  • hepatitis
  • rash
  • nausea
  • abdo pain and vomiting
38
Q

what are the benefits associated with sulfasalazine use in practice?

A 
effective 
favorable toxicity 
long term blood monitoring not needed
few drug interactions
no carcinogenic potential 
safe in pregnancy!!
39
Q

what are the effects of blocking TNF-a (through using anti TNF)?

A

decreased inflammation

decreased angiogenesis

decreased joint destruction

40
Q

what is a major risk when using anti TNF therapy?

A

TB reactivation!

TNFa is released by macrophages in response to TB infection and is essential for development and maintenance of granulomata

need to screen for latent TB before prescribing anti-TNF treatment

41
Q

what does rituximab cause?

A

B cell apoptosis

NB: v effective in RA

42
Q

how does rituximab work?

A

binds to CD20 (a unique cell surface marker)

CD20 is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell so is v specific! - good safety data

CPT (23 decks)

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