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Clinical Pharmacology > Immunosuppresion & disease modifying therapy > Flashcards

Immunosuppresion & disease modifying therapy Flashcards

1
Q

What is rheumatoid arthritis?

A

Autoimmune multi-system disease

Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone

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2
Q

How is RA diagnosed?

A

Critical criteria:

  • Morning stiffness >1 hour
  • Arthritis of >3 joints
  • Arthritis of hand and wrist joints
  • smmetrical arthritis
  • Rhematoid nodules

Non clinical criteria:

  • serum rheumatoid factor/Anti CCP antibodies
  • X-ray changes
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3
Q

What are the treatment goals for treating RA?

A
  • Symptomatic relief
  • Prevention of join destruction
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4
Q

What are the treatment goals for SLE and vasculitis?

A
  • Symptomatic relief e.g arhralgia and Raynaud’s phenomenom
  • Reduction in mortality
  • Prevention of organ damage
  • Reduction in long term morbidity caused by disease and by drugs
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5
Q

How do corticosteroids work as a DMARD?

A
  • Prevent interleukin IL-1 and IL-6 production by macrophages
  • Inhibit all stages of T cell activation
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6
Q

What are some of the side effects of corticosteroids?

A
  • weight gain
  • thrush
  • immunosuppresion
  • glaucoma
  • cateracts
  • blood glucose changes
  • accelerates aging
  • mood changes
  • bruising
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7
Q

What is azathioprine used to treat?

A
  • Maintenance therapy in SLE and vasculitis
  • weak evidence of benefit in RA
  • used in inflammatory bowel disease
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8
Q

How can effects of azothioprine differ between individuals?

A
  • 6-MP metabolised by TPMT (thiopurine methyltransferase)
  • TPMT gene highly polymorphic
  • Individuals with low/ absent TPMT levels have risk of myelosuppression
  • TPMT test done before prescribing
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9
Q

What is the mechanism of azathioprine?

A
  • Azathioprine cleaved to 6 mercaptopurine (6-MP)
  • Anti-metabolite decreases DNA and RNA synthesis
  • Immune cells can’t go on to cause inflammatory response
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10
Q

What are some of the adverse effects of azathioprine treatment?

A
  • Bone marrow suppression (monitor FBC)
  • Increased risk of malignancy (true of all immunosuppressants)
  • increased risk of infection
  • hepatitis (monitor LFTs)
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11
Q

When are calcineurine inhibitors used in practice?

A
  • Atopic dermatitis and Psoriasis
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12
Q

Name 2 calcineurin inhibitors

A
  • Ciclosporin
  • Tacrolimus
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13
Q

What is the MoA of ciclosporin and tacrolimus?

A
  • Active against helper T cells - prevents production of IL-2 via calcineurin inhibition
  • Ciclosporin- binds to cyclophilin protein
  • Tacrolimus binds to tacrolimus binding protein
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14
Q

When is mycophenolate mofetil used in practice?

A
  • primarily in transplanation
  • good efficacy as induction and maintenance therapy for SLE and Vasculitis maintenance
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15
Q

What is the mechanism of action of mycophenolate mofetil?

A
  • Pro-drug derived from fungus penicillum stoloniferum
  • Inhibits inosin monophosphate dehydrogenase (required for guanosin synthesis
  • Impairs B and T cell proliferation
  • Spares other rapidly dividing cells
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16
Q

What are some of the adverse effects of mycophenolate mofetil?

A
  • Nausea + Vomiting
  • Diarrhoea
  • Myelosuppression (most serious)
  • Mucocitis- ulceration and sores in mouth
17
Q

How does cyclophosphamide work?

A
  • Cytotoxic agent
  • Alkylating agent- cross links DNA so that it can’t replicate
  • Suppresses T and B cell activity
18
Q

In what conditions is cyclophosphamide indicated?

A
  • Lymphoma
  • Leukaemia
  • Solid cancers
  • Lupus nephritis
  • Wegener’s granulomatosis
19
Q

What are the pharmacodynamics of cyclophosphamide?

A
  • Prodrug needs activating by CYP450 in liver
  • Active metabolite is 4-hydroxycyclophosphamide
  • Exists in equilibrium with its tautomer aldophosphamide
20
Q

How is cyclophosphamide excreted, why can this be problematic?

A
  • Excreted by the kidney
  • Acrolein (a metabolite) is toxic to bladder epithelium → haemorrhagic cystitis
  • Can be prevented by aggressibe hydration and or Mesna
21
Q

What important considerations must you make when prescribing cyclophosphamide?

A

Significant toxicity

  • increased risk of bladder cancer, lymphoma and leukaemia
  • Infertility
  • Monitor FBC
  • Adjust dose in renal impairment
22
Q

What is the gold standard for treatment of rheumatoid arthritis?

A

Methotrexate

23
Q

What conditions other than RA, is methotrexate used to treat?

A
  • Malignancy
  • Psoriasis
  • Crohn’s disease
  • Ectopic pregnancy
24
Q

What is the mechanism of action of methotrexate?

A
  • Competitive, reversible inhibitor of DHFR (dihydrofolate reductase)
  • Affinity x1,000 more than folate for DHFR
  • Inhibits synthesis of DNA, RNA and proteins
  • Cytotoxic during the S-phase of the cycle
  • Greater toxicity in rapidly dividing cells

Mechanism in non-malignant disease is unclear

25
Q

How can you administer methotrexate?

A
  • PO
  • IM
  • SC
26
Q

How is methotrexate dosed?

A

Given weekly not daily

Given with folate supplement

Otherwise: can affect liver and kidney if given daily

27
Q

What is the effect of giving methotrexate and NSAIDs together?

A

Methotrexate is 50% protein bound

NSAIDs can displace methotrexate

28
Q

What are some of the side effects of methotrexate?

A
  • Mucositis
  • Marrow suppression
  • Hepatitis
  • Cirrhosis
  • Pneumonitis
  • Infection risk
  • Highly teratogenic → used as an abortifacient
29
Q

What is sulfasalazine?

A

A conjugate of salicylate designsed to relief pain and stiffness

30
Q

What immunological effects does sulfasalazine have?

A

T cells:

  • inhibits proliferation
  • possible T cell apoptosis
  • inhibits IL-2 production

Neutrophils

  • reduces chemotaxis
  • reduces degranulation
31
Q

Why is sulfasalazine effective in treatment of IBD?

A
  • poorly absorbed
  • Mainly active within the intestine
32
Q

What are some of the side effects of sulfasalazine?

A

Mild

  • nausea
  • adbo pain/ vomiting

Adverse

  • myelosuppression
  • hepatitis
  • rash
33
Q

What are biologicals?

A

Recombinant DNA technoligcal producing substances that are idnetical to the body’s own signalling proteins

34
Q

What are some of the effects of blocking TNF alpha?

A
  • Decrease inflammation
  • Decreased angiogenesis
    • lowers VEGF levels
  • Decreased joint destruction
35
Q

What is one of the main risks of anti-TNF therapy?

A

TB reactivation

TNFalpha is essential for development of maintenance of granulomas - inhibition will break down granuloma

Need screening for latent TB

36
Q

How does rituximab work?

A

Monoclonal antibody- binds to CD20 found of a subset of B cells

B cells; present antigens to T cells, produce cytokines and antibodies → rituximab causes B cell apoptosis

Clinical Pharmacology (25 decks)

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