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17. Clinical Pharmacology and Therapeutics > 10. Immunosuppression > Flashcards

10. Immunosuppression Flashcards

1
Q

What are the diagnostic signs of rheumatoid arthritis?

A

Morning stiffness for over an hour, arthritis of 3+ joints, arthritis of hand joints, symmetrical arthritis, rheumatoid nodules, serum rheumatoid factor, X-ray changes.

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2
Q

What are the goals of rheumatoid arthritis treatment?

A

Symptomatic relief, prevention of joint destruction.

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3
Q

What is the treatment strategy for rheumatoid arthritis?

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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4
Q

What are the treatment goals in systemic lupus erythematosus and vasculitis?

A

Symptomatic relief, reduced mortality, prevent organ damage, reduce long term morbidity from disease and drugs.

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5
Q

What are the main five immunosuppressant drugs?

A

Corticosteroids, azathioprine, ciclosporin, tacrolimus, mycophenolate mofetil.

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6
Q

What is the mechanism of action of corticosteroids?

A

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

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7
Q

What are the disease-modifying anti-rheumatic drugs (DMARDs)?

A

Methotrexate, sulphasalazine, anti-TNF agents, rituximab, cyclophosphamide.

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8
Q

What is azathioprine used for in practice?

A

SLE and vasculitis as maintenance therapy, weak evidence for RA, inflammatory bowel disease, as a steroid sparing drug.

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9
Q

What are the pharmacodynamics of azathioprine?

A

6-MP is metabolised by thiopurine methyltransferase.

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10
Q

Why does azathioprine have different risks of ADRs in different people?

A

6-MP is metabolised by TPMT which is highly polymorphic and levels vary in individuals. Low/absent TPMT - risk of myelosuppression.

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11
Q

What should be tested before prescribing azathioprine and why?

A

TPMT levels, if low/absent, risk of myelosuppression.

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12
Q

What is the mechanism of action of azathioprine?

A

Cleaved to 6-MP - antimetabolite decreases RNA and DNA synthesis.

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13
Q

What are the adverse drug reactions of azathioprine?

A

Bone marrow suppression, increased risk of malignancy, increased risk of infection, hepatitis.

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14
Q

Name two calcineurin inhibitors.

A

Ciclosporin and tacrolimus.

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15
Q

What are the uses of calcineurin inhibitors?

A

Transplantation, atopic dermatitis and psoriasis.

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16
Q

What should be checked regularly with calcineurin inhibitor use?

A

BP and eGFR as risk of hypertension and hyperkalaemia.

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17
Q

What are the DDI with calcineurin?

A

CYP 450 inducers - rifampicin, carbemazepine, phenytoin, omeprazole.
CYP 450 inhibitors - ciprofloxacin, antifungals, fluoxetine, paroxetine, HIV antivirals.

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18
Q

What is the mechanism of action of ciclosporin and tacrolimus (calcineurin inhibitors)?

A

Active against T helper cells, prevents IL-2 production via calcineurin inhibition. Ciclosporin binds cyclophilinprotein, tacrolimus binds tacrolimus-binding protein. The drug/protein complexes bind calcineurin to stop action.

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19
Q

What is the normal action of calcineurin?

A

Phosphatase activity on nuclear factor of activated T cells, factors migrates to nucleus to start IL-2 transciption.

20
Q

When is mycophenolate mofetil used?

A

In transplantation, induction and maintenance therapy for lupus nephritis, transplantation medicine.

21
Q

What are the ADRs of mycophenolate mofetil?

A

Nausea, vomiting, diarrhoea. Seriously - myelosuppression.

22
Q

What is the mechanism of action for mycophenolate mofetil?

A

Inhibits inosine monophosphate dehydrogenase which impairs B and T cell proliferation but spares other rapidly dividing cells.

23
Q

What are the indications for cyclophosphamide use?

A

Lymphoma, leukaemia, solid cancers, lupus nephritis, Wegener’s granulomatosis.

24
Q

What is the overall action of cyclophosphamide?

A

Cytotoxic, immunological effects - suppressed T and B cell activity.

25
Q

What is the mechanism of action of cyclophosphamide?

A

Alkylating agent - cross links DNA so it can’t replicate.

26
Q

Why does cyclophosphamide need conversion in the liver by CP450?

A

It is a prodrug, so needs to be converted to active metabolite for action.

27
Q

Where is cyclophosphamide excreted?

A

By the kidney.

28
Q

How can cyclophosphamide lead to haemorrhagic cystitis?

A

Acrolien, another metabolite, is toxic to the bladder epithelium.

29
Q

How can haemorrhagic cystitis be prevented with cyclophosphamide use?

A

Aggressive hydration and/or mesna (drug).

30
Q

What are the significant toxicity risks of cyclophosphamide?

A

Increased risk of bladder cancer, lymphoma, and leukaemia; infertility.

31
Q

What is a safer alternative for lupus nephritis treatment for cyclophosphamide?

A

Mycophenolate mofetil.

32
Q

What are the indications for use of methotrexate?

A

Acute lymphophatic leukaemia, RA, malignancy, psoriasis, Crohn’s disease.

33
Q

What is the mechanism of action of methotrexate considering treatment for ALL?

A

Competitively and reversibly inhibits dihydrofolate reductase and therefore inhibits synthesis of DNA, RNA and proteins. It is cytotoxic during the S-phase of the cell cycle so kills rapidly dividing cells.

34
Q

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

A

Not clear. Possibly inhibition of enzymes for purine metabolism -> accumulation of adenosine - regulatory autocoid that regulates immune cell function; inhibition of T cell activation; suppression of intercellular adhesion molecule expression by T cells.

35
Q

What is the route of administration of methotrexate?

A

PO, IM, or SC.

36
Q

What is an important about administration of methotrexate?

A

Weekly not daily dosing - THIS IS A NEVER-EVENT.

37
Q

What are the oral and intramuscular bioavailabilities of methotrexate?

A

Oral 33%, intramuscular 76%.

38
Q

What are the ADRs of methotrexate?

A

Mucositis, marrow suppression, hepatitis, cirrhosis, pneumonitis, infection risk. TERATOGENIC and abortifacient.

39
Q

How can mucositis and marrow suppression be prevented with methotrexate use?

A

Folic acid supplementation.

40
Q

What are the goals of treatment with sulfasalazine?

A

Relieve pain and stiffness, and to fight infection.

41
Q

What are the immunological effects of sulfasalazine?

A

T cell - inhibits proliferation, may cause apoptosis, inhibition of IL-2 production.
Neutrophil - reduced chemotaxis and degranulation.

42
Q

What are the ADRs of sulfasalazine?

A

Myelosuppression, hepatitis, rash, nausea, abdominal pain/vomiting.

43
Q

What are the effects of blocking TNF-a?

A

Decreased inflammation, angiogenesis and joint destruction.

44
Q

What is a risk of anti-TNF therapy?

A

TB reactivation.

45
Q

Why can anti-TNF therapy result in TB reactivation?

A

TNFa is needed for development and maintenance of a granulomata so TB trapped in granulomas will stop being a contained infection.

46
Q

What is the mechanism of action of rituximab?

A

Binds to CD20 surface marker on B cells so less presentation of antigens to T cells, fewer cytokines and fewer antibodies and B cell apoptosis.

47
Q

What is rituximab used for?

A

RA.

17. Clinical Pharmacology and Therapeutics (25 decks)

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