Immunosuppression Flashcards

1
Q

What % of the population does RA affect?

A

1%

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2
Q

What is the pathogenesis of RA?

A

Proinflammatory agents outweigh antiinflammatory agents.

IL-1 + IL-6 + TNF alpha > IL-4 + TGF beta

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3
Q

How do we treat RA?

A

Target against proinflammatory agents

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4
Q

What are the aims of treatment of RA?

A

Symptomatic relief and prevention of joint destruction

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5
Q

What are the treatment goals in SLE and vasculitis?

A

Symptomatic relief, reduce mortality, prevent organ damage, and decrease long term morbidity caused by disease and by drugs.

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6
Q

What immunosuppressants can we use?

A
Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil
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7
Q

What DMARDs can we use?

A
Methotrexate
Sulphasalazine
ANti-TNF agents
Rituximab
Cyclophosphomide
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8
Q

How do corticosteroids work? (MoA)

A

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

Inhibits all stages of T cell activation across all systems.

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9
Q

What are the side effects of steroids?

A

H&N - aggravate epilepsy, schizophrenia, exopthalmos, facial erythema, glaucoma, insomnia, corneal thinning, headaches,
Cardioresp - congestive HF, hiccups
GI - abdo distension, acute pancreatitis, dyspepsia
Systemic - bruising, hirsutism, hypercholesterolaemia, hyperhidrosis, hyperlipidaemia, impaired healing, thin skin, bruise easily.
Other - amenorrhoea, candidiasis, cushings syndrome

And others.

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10
Q

What is azothioprine used for?

A

Maintenacnce therapy for SLE and vasculitis, and for difficult to treat IBD.

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11
Q

How is azothioprine metabolised?

A

To 6MP by TPMT

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12
Q

What is important to note about TPMT?

A

TPMT gene is highly polymorphic so everyone has different levels of activity. If those levels are low, high risk of myelosuppression.

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13
Q

What should we test before starting azothioprine?

A

TPMT activity level

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14
Q

What is 6MP?

A

6-mercaptopurine = antimetabolite that decreases DNA and RNA synthesis by inhibiting purine metabolism.

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15
Q

What are the ADRs for azothioprine?

A

Bone marrow suppression
Increased risk of malignancy esp. in transplant pts
Increased risk of infection
Hepatitis

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16
Q

What should be monitored with azothioprine?

A

FBC (myelosuppression)

LFTs (hepatitis)

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17
Q

What class of drug are ciclosporin and tacrolimus?

A

Calcineurin Inhibitors

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18
Q

What is calcineurin and why does it need inhibiting?

A

Enzyme with phosphatase activity which usually produces IL-2 with helper T cells. Drug/protein complexes bind to calcineurin to inactivate it.

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19
Q

What monitoring do pts on ciclosporin/tacrolimus need and why?

A

BP and eGFR - nephrotoxic!

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20
Q

What is mycophenolate mofetil used for?

A

Immunosuppression in transplantation, and in lupus nephritis.

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21
Q

What are the ADRs associated with mycophenolate mofetil?

A

Nausea
V&D
GI ulceration
Myelosuppression

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22
Q

How does mycophenolate mofetil work?

A

Inhibits monophosphate dehydrogenase to prevent guanine synthesis. This impairs B and T cell proliferation.

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23
Q

What is the gold standard treatment for RA?

A

Methotrexate!

24
Q

When else, apart from RA, can methotrexate be used?

A

Malignancy
Severe psoriasis
Crohn’s Disease

25
Q

What is methotrexate similar to in structure?

A

Folic acid

26
Q

What is the MoA of methotrexate?

A

In malignancy, it inhibits dihydrofolate reductase.

Not clear how it works in RA etc but it isn’t via folate inhibition.

27
Q

Tell me about the pharmacokinetics of methotrexate.

A

Administer PO, IM or S/C WEEKLY as its active metabolite has a long half life.
Best bioavailability via IM route = 76%.

28
Q

What % of methotrexate is protein bound?

A

50%

29
Q

What can displace methorexate from protein binding?

A

NSAIDs

30
Q

How is methotrexate excreted?

A

Renally

31
Q

Is methotrexate well tolerated?

A

Yes, over 50% of pts continue the drug for over 5 years.

32
Q

Can methotrexate be used with other drugs?

A

Yes alongside other DMARDs as an anchor drugs

33
Q

What are the ADRs associated with methotrexate?

A

Mucositis (less so at RA doses)
Marrow suppression
Hepatitis, cirrhosis, pneumonitis, increased infection risk.

34
Q

What should we do when methotrexate is prescribed in women of child bearing age?

A

Prescribe contraception as highly teratogenic and abortificient

35
Q

What is sulphasalazine made up of?

A

Salicylate (5 ASA) and sulphapyridine molecules

36
Q

What do the elements of sulphasalazine do?

A

5 ASA - relieve pain and stiffness.

Sulphapyridine - fights infection.

37
Q

What is the MoA of sulphasalazine?

A

Inhibits T cell proliferation, and maybe induces T cell apoptosis. Inhibits IL-2 production.

38
Q

Tell me about the pharmacokiinetics of sulphasalazine.

A

Poor GI absorption so acts mainly in GI tract (effective in IBD).
Few drug interactions, low toxicity, not carcinogenic, safe in pregnancy.

39
Q

What are the ADRs of sulphasalazine?

A

Myelosuppression
Hepatitis
Rash
N&V/abdo pain

Usually only present in the first few weeks.

40
Q

What category do anti-TNF agents come into?

A

Biopharmaceuticals

41
Q

Which biopharmaceuticals bind to TNF alpha?

A

Adalimumab
Infliximab
Golimumab
Etanercept

42
Q

How does rituximab work?

A

Depletes B cells by causing apoptosis so they can’t act as ntigen presenting ells, or produce cytokines or antibodies.

43
Q

What happens when TNF alpha is blocked?

A
  • Reduced inflammation
  • Reduced angiogenesis
  • Reduced joint destruction
44
Q

By what mechanism do TNF alpha blockers reduce inflammation?

A

Cytokine cascade and leukocyte recruitment to joint is reduced.

45
Q

By what mechanism do TNF alpha blockers reduce angiogenesis?

A

Decrease VEGF levels

46
Q

By what mechanism do TNF alpha blockers reduce joint destruction?

A

Decrease bone resorption and erosion, cartilage breakdown and MMPs/enzyme activity.

47
Q

What is the biggest risk with Anti-TNF agents? Why?

A

Reactivation of TB as TNF alpha is essential for the formation and maintenance of granulomas.

48
Q

How effective is cyclophosphamide?

A

Very, and it works much quicker than other agents (10 days rather than 4-6 weeks)

49
Q

How does cyclophosphamide work?

A

As an alkylating agent - cross links DNA so it can’t divide for replication. Suppresses T and B cell activity.

50
Q

What are the indications for cyclophosphamide?

A

Lymphoma, leukaemia, and solid cancers
Lupus nephritis
Wegner’s granulomatosis

51
Q

Tell me abou the pharmacokinetics of cyclophosphamide .

A

Prodrug that is converted to active form in the liver by CYP450. Excreted by kidneys.

52
Q

What is the main active metabolite of cyclophosphamide?

A

4-hydroxycyclophosphamide

53
Q

What ADRs does cyclophosphamide have?

A

Hameorrhagic cystitis
Infertility
Lymphoma and leukaemia risk increases

54
Q

How does cyclophosphamide cause haemorrhagic cystitis?

A

Acrolein = another metabolite of cyclophosphamide is toxic to bladder epithelium.

55
Q

What are JAK inhibitors?

A

Small molecule agents already used in RA and oncology. Inhibit Janus kinases which are enzymes important in cell signalling.