Immunosuppressants and DMARDs Flashcards Preview

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Flashcards in Immunosuppressants and DMARDs Deck (40)
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1
Q

Pathogenesis of RA

A

Proliferation of synovium into a PANNUS. This then leads to gross deformation of bone and cartilage. RA is effectively an imbalance between pro inflammatory factors (such as IL1, IL6 and TNF-alpha) and inflammatory factors (such as IL4 and TGF-Beta).

2
Q

RA Diagnostic Criteria

A

Clinical: Morning stiffness lasting for >1hr? Signs in >3 joints? Small joints preferentially attacked? Rheumatoid nodules? Symmetry (same joint affected on both sides of body)? Raised RF or Anti-CCP? X-Ray changes should never be seen in 21st Century!

3
Q

Goals of RA Treatment

A
  • Relieving symptoms.

- Preventing progression to joint destruction, deformity and the resulting disability.

4
Q

Why should DMARDs be used in RA?

A

Early use is the best way to prevent progression.

They have steroid sparing properties, meaning we can avoid systemic steroids and all of their adverse effects.

5
Q

Why should DMARDs be used in Lupus/Vasculitis?

A

Reducing mortality by preventing organ damage. Relieving symptoms.

6
Q

MOA of Steroids

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

- Prevent T-cell activation at all stages.

7
Q

Adverse effects of steroids…

A

We an think of them as accelerated processes of ageing.

  • Hyperglycaemia
  • Trunkal obesity
  • Glaucoma
  • Hypertension
  • Irregular menstrual cycle
  • Impaired healing.
  • Growth limitation in children.
8
Q

Indications for Azathioprine?

A

Maintenance in SLE and Vasculitis.

Inflammatory Bowel Disease.

9
Q

How is Azathioprine metabolised?

A

1) It is cleaved to 6-MP.
2) This goes on to become one of three molecules, one of these TIMP itself has metabolites that decrease DNA and RNA synthesis. This inhibits the rapid multiplication in immune cells that is seen in cases of autoimmunity.

10
Q

In Azathioprine therapy, polymorphisms in what gene must be checked for and how does hypofunction here put a patient at risk?

A

6-MP is metabolised by TPMT (Thiopurine Methyltransferase). Low levels of this enzyme mean that active 6-MP can build up causing MYELOSUPRESSION.

11
Q

How can we detect myelosuppression?

A

FBC to monitor white cells. Investigate signs of infections thoroughly as pts on immunosuppressants are at a greater risk than the general population.

12
Q

Give two other adverse effects of Azathioprine…

A
  • Hepatitis - monitor LFT’s for this.

- Increased risk of malignancy.

13
Q

Name the two common Calcineurin Inhibitors

A
  • Ciclosporin

- Tacrolimus

14
Q

Some common uses of Calcineurin inhibitors…

A
  • Atopic Dermatitis.
  • Psoriasis
  • Solid organ transplant recipients.
15
Q

What are some adverse effects of the Calcineurin inhibitors?

A
  • They are nephrotoxic so we need to assess kidney function regularly.
  • They are CYP inhibitors so they have effects on other drug levels. Inhibit CYP 3A4.
16
Q

What part of the immune system do calcineurin inhibitors act on?

A

Inhibit the calcineurin pathway in T-helper cells preventing IL-2 production. This acts to suppress T cell reactions. These cell mediated reactions are central to transplant rejection.

17
Q

Name some uses of Mycophenolate Mofetil

A
  • Preventing organ rejection in transplant.
  • Induction and maintenance therapy in Lupus Nephritis.
  • Maintenance therapy in Vasculitis.
18
Q

In transplantation medicine, which parameter (relating to Mycophenolate) may be monitored.

A

Mycophenolic Acid - Mycophenolate Mofetil is the pro-drug to this.

19
Q

How does Mycophenolate work?

A

It inhibits an enzyme required for guanosine synthesis, impairing B and T cell proliferation. The effect of this is more controlled than steroids as other (non pathological) rapidly dividing cells have guanosine salvage mechanisms.

20
Q

Adverse effects of Mycophenolate…

A

N, V and D. Myelosuppression and mouth ulcers.

21
Q

MOA of Cyclophosphamide…

A

It is an alkylating agent so it forms cross links both within and between DNA strands so they cannot replicate, suppressing T and B call activity.

22
Q

Uses of Cyclophosphamide…

A

A classical induction therapy. Used to treat lupus nephritis, and ANCA Vasculitis. Remember, this is a chemotherapy agent so has its uses in haem-onc.

23
Q

Metabolism of cyclophosphamide…

A

Prodrug, metabolised in the liver into active 4-hydroxycyclophosphamide. It goes through several metabolites before forming its main active metabolite, PHOSPHORAMIDE MUSTARD.

24
Q

Main risk of Cyclophosphamide.

A

It is excreted by the kidney. One of its metabolites (Acrolein) is toxic to bladder epithelium –> haemorrhagic cystitis. This can be prevented by combining agressive hydration and MESNA which mops up the acrolein.

25
Q

Long term risks of Cyclophosphamide…

A

Increases the risk of bladder cancer, leukaemia and lymphoma.
Can cause infertility with increasing cumulative dose and patient age.
Can, of course, myelosuppress.

26
Q

Mycophenolate vs Cyclophosphamide in Lupus Nephritis

A

Mycophenolate safer, no less effective.

27
Q

Methotrexate

A

Developed as an anti-cancer agent. Now the treatment of choice in RA. Some use in Crohn’s and psoriasis.

28
Q

MOA of Methotrexate

A

Commonly known as a dihydrofolate reductase inhibitor which is how it exerts its anti-cancer effects but its DMARD effects are via a different pathway, the AICAR pathway, PREVENTING THE ACCUMULATION OF ADENOSINE.

29
Q

Dosing of Methotrexate.

A

Given weekly not daily. Oral bioavaliability of c. 1/3. It is higher if given s/c or i/m. Convert to s/c injection if patient experiencing nausea or has only limited response to oral drug.

30
Q

DDI’s with Methotrexate

A

It is 50% protein bound so NSAID’s displace it. It is excreted by the kidneys.

31
Q

Bridging treatment in RA while Methotrexate starts to work…

A

Steroids. These can be tapered when methotrexate starts to work, can be used in primary care to manage an acute flare up.

32
Q

Adverse effects of Methotrexate

A

Mucositis and myelosuppression can be both managed by giving folinic acid.
Can also cause hepatitis, cirrhosis and pneumonitis.
Highly teratogenic and ABORTIFACIENT; this explains how it can be used to medically manage ectopic pregnancy.

33
Q

Sulfasalazine / 5-Aminosalicylic acid effects on B and T cells.

A

T cells: inhibits proliferation and IL2 production as well as (possibly) stimulating T cell apoptosis.
Neutrophils: it reduces chemotaxis and degranulation.

34
Q

Absorption characteristics of Sulfasalazine and how this influences its uses.

A

Poorly absorbed but is primarily active in the intestines, making it useful in managing inflammatory bowel diseases.

35
Q

Sulfasalazine adverse effects

A
  • Myelosupression
  • Hepatitis
  • Rash

Milder side effects include abdominal pain, N+V.

36
Q

Advantages of Sulfasalazine

A

Few interactions
Long term blood monitoring often not needed.
Safe in pregnancy
No carcinogenic potential.

37
Q

Biologics of choice in RA

A

TNF - alpha blockers. ADALIMUMAB AND INFLIXIMAB.

38
Q

How does TNF-alpha blockade help in RA?

A

Decreases inflammation and thus the recruitment of leukocytes to a joint.
Angiogenesis and VEGF levels are decreased.
Lower levels of matrix metalloproteases and other destructive enzymes.

39
Q

Main infective risk of TNF-alpha blockade?

A

Reactivation of Latent TB infection as TNF plays a large role in walling TB mycobacteria off in granulomas. IGRA testing is needed before starting a patient on adalimumab or infliximab.

40
Q

Rituximab

A

An Anti-CD2- mAb used a lot in B cell lymphomas. Also has a use in RA as B cells produce cytokines, antibodies and present antigens to T cells.