17 - Immunosuppressants Flashcards

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1
Q

What is the pathogenesis of rheumatoid arthritis and how do we treat it?

A
  • Autoimmune disease causing inflammation to joints destroying cartilage and bone
  • Associated with morning stiffness, rheumatoid nodules, symmetrical, arthritis of more than three joints (mainly hands)
  • Can look at x-ray changes and serum rheumatoid factor
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2
Q

What is the treatment goals with RA?

A
  • Symptomatic relief
  • Prevent joint destruction
  • Avoid long term corticosteroids
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3
Q

What are some of the symptoms of systemic lupus erythematosus? (SLE)

A
  • Autoimmune disease where body attacks own health tissue over a number of systems
  • Joint pain, rash, mouth ulcers, swollen lymph nodes
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4
Q

What is vasculitis?

A
  • Autoimmune condition causing inflammation of blood vessels (can occur as a result of SLE)
  • Leads to things like temporal arteritis (need corticosteroids like prednisolone) that causes headache, tiredness, stiff jaw and pain wose on touch
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5
Q

What are some examples of immunosupressants?

A
  • Glucocorticoids
  • Calcineurin inhibitors
  • Antiproliferative
  • Biologics
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6
Q

What is the mechanism of action of systemic corticosteroids, what are some examples of this drug and what are the side effects?

A
  • Prevent IL-1 and IL6 production by macrophages stopping T cell activation and inflammation

- Prednisolone, Hydrocortisone, Dexamethasone, Betamethasone

  • Can cause osteoporosis, diabetes, hypertension, weight gain, glaucoma, cataracts (accelerated old age)
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7
Q

What are the side effects of corticosteroids?

A
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8
Q

What is the mechanism of action of Azathioprine and what is it used to treat?

A
  • Treatment of SLE and Vasculitis (not good for RA) and sometimes atopic dermatitis, IBS and organ transplants
  • TPMT is an enzyme that breaks down this drug and activates it to 6-mercaptopurine so individual needs high TPMT activty (highly polymorphic)

- 6-MP metabolite blocks purine synthesis and therefore DNA synthesiswhich helps as lupus activates temporal and humoral cell division so stops them dividing

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9
Q

What are some adverse drug reactions associated with azathioprine use?

A

- Bone marrow suppression

- Cancer risk (especially skin)

  • Hepatitis (deranged LFTs)
  • Infections
  • Thrombocytopenia

Need to monitor FBCs and LFTs as the longer you use the drug the more the risk

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10
Q

What are some examples of antiproliferative immunosupressants?

A
  • Azathioprine
  • Cyclophosphamide
  • Mycophenolate mofetil
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11
Q

What are some of the side effects of calcineurin inhibitors?

A
  • Ciclosporin and Tacrolimus
  • Used for organ transplant rejection, atopic dermatitis, psoriasis, RA, Crohn’s

- Renal toxicity so check BP and eGFR frequently

- Gingival hyperplasia can occur

  • Lots of drug interactions as uses CYP450
  • Eye discomfort
  • Hepatitis
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12
Q

What is the mechanism of action of calcineurin inhibitors as immunosuppressants?

A

- Prevent IL-2 production by helper T cells (more targeted than corticosteroids)

  • Ciclosporin bids to cyclophilin protein and tacrolimus binds to tacrolimus-binding proteins and the drug complexes bind to calcineurin inhibiting it
  • Calcineurin usually exerts force on activated helper T cells by starting IL2 transcription
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13
Q

What are some CYP450 inhibitors and inducers?

A
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14
Q

What is mycophenolate mofetil used for and what is it its mechanism of action?

A
  • Used in lupus nephritis to induce remission (which azathioprine can’t do) and transplantation
  • Prodrug from fungus and inhibits inosine monophosphate dehydrogenase which is needed for guanosine synthesis so impairs B and T cell proliferation
  • Spares other rapidly dividing cells by guanosine salvage pathways
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15
Q

What are some adverse effects of mycophenolate mofetil?

A
  • Mucositis
  • Long term cancer risk (especially skin)
  • Bone marrow suppression
  • N+V and diarrhoea

Safer option for women if they want children.

Impairs B and T cell proliferation

(less immunosuppression than azithioprine)

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16
Q

What is cyclophosphamide used for and what is its mechanism of action?

A
  • Used in lupus (nephritis), vasculitis and lymphomas/leukaemias

- Supresses B and T cell activity as it is an alkylating agent so cross links DNA so it cannot replicate

- Prodrug converted in the liver by CYP450 and excreted by kidney. Active metabolite **4hydroxy CP

17
Q

What are the side effects of cyclophosphamide?

A

- Acrolein is a toxic metabolite which can cause haemorraghic cystitis and bladder cancer (rehydrate!!)

  • Risk of lymphomas, leukaemia and bladder cancer
  • Renal impairment
  • Infertility (measure FBC)
18
Q

What is the safest antiproliferative immunosuppressant to use in lupus nephritis?

A
  • Mycophenolate mofetil as less renal impairment and no hair loss at low doses
19
Q

What is methotrexate used for and what is it’s dosing schedule?

A

- Gold standard for RA

  • Chemotherapy
  • Psoriasis arthritis
  • Crohn’s disease
  • Abortion

Given weekly due to long half life (30 hours) of its polyglutamate metabolites

20
Q

What is the mechanism of action of methotrexate in cancer treatment and as a DMARD?

A
  • Competitive and reversible Dihydrofolate reductase inhibitor (in cancer treatment)
  • Uses up all the folate which is needed for thymidine and puring synthesis so cannot do DNA, RNA and protein synthesis
  • Greater effect on rapidly dividing cells in S phase
  • In RA it works by reducing pyrimidines
21
Q

What are some adverse drug reactions with methotrexate?

A
  • Highly protein bound but NSAIDs can displace
  • Low oral bioavailability
  • If nausea swap to SC
  • Can cause pneumonitis, hepatitis and stomatitis
22
Q

What is the mechanism of action of sulphasalazine and what is it used for?

A
  • Used for RA as a DMARD and IBD as main activity in the gut
  • Inhibits T cell and neurotrophils by reducing chemotaxis by being a 5-aminosalicyclic acid donor
  • Antiinflammatory and fights infection
23
Q

What are some adverse effects of sulfasalazine?

A
  • Hepatitis
  • N+V
  • Abdo pain
  • Rash
  • Myelosuppression/Leucopenia
  • Dizziness
  • Arthralgia

Mainly due to sulfapyridine moiety

24
Q

What are some TNF-a inhibitors (biologics), what are they used for and what is their mechanism of action?

A

Infliximab and Adalimumab

  • Used for RA, psoriasis, crohn’s

- Monoclonal antibody that binds TNFa which is nomally proinflammatory so stops inflammation, angiogenesis and joint destruction

25
Q

What is the mechanism of action of rituximab and what is it used for??

A

- B-lymphocyte lytic monoclonal antibody

  • Binds to CD20 on specific subset of B cells and causes B cell apoptosis
  • Effective in RA
26
Q

What are the side effects of anti-TNF agents?

A
  • Risk of TB activation as TNFa is needed for stabilisation of granulomas
  • Need to test for latent TB before giving these drugs
27
Q

Why do we need to wean people off of steroids?

A

When given steroids, adrenal glands decrease their cortisol production so an immediate withdrawal is dangerous as adrenal glands do not have time to adjust so may have Addison’s crisis

28
Q

What is the treatment goal in SLE and vasculitis?

A
29
Q

What are ‘biologicals’ used in the treatment of RA?

A
  • Extracted from living systems e.g stem cell therapy
  • Very few side effects because they are ‘sniper like’
30
Q

What clinical monitoring do we need to do when prescribing the following drugs:

  • Cyclophosphamide
  • Methotrexate
  • Sulfasalazine
A

- C: quite safe, can stop monitoring after 2 years

- M: FBC, renal and LFTs every few months. CXR at baseline and monitor for symptoms of pneumonitis

- S: FBCs, LFTS, renal

31
Q

What is a steroid sparing drug?

A

Immunosuppresive medications given in addition or instead of steroids to limit side effects when low doses of steroids (prednisolone) cannot be used

32
Q

How can we prevent haemorraghic cystitis with the use of cyclophosphamide?

A

Aggressive hydration and MESNA to stop acrolein damaging the bladder epithelium

33
Q

What is the mechanism of action of hydroxychloroquinine and what is it used to treat?

A

RA, Lupus and Malaria

Increase pH inside macrophage lysosomes which stops antigen processing and MHC II presentation, therefore decreasing T-Cell activation

34
Q

Should DMARDs be used in combination?

A

Evidence suggests methotraxate used in conjunction with hydroxychloroquine, ciclosporin or sulfasalazine have greater benefits