Drugs and the Immune System II

Question 1

How do disease modifying drugs function?

Answer 1

Alter underlying disease rather than treating symptoms

Question 2

Name 2 types of DMDs

Answer 2

1. Conventional DMDs (slow acting)

2. Biological therapies (fast acting)

Question 3

Name 3 conventional DMDs

Answer 3

1. Cyclosporine
2. Thiopurines
3. Methotrexate

Question 4

Name 2 examples of biological therapies

Answer 4

1. Anti-TNF drugs

2. Drugs which target cytokines

Question 5

Describe how biological therapies are usually used

Answer 5

• In combination with a conventional DMD
• Given to people who do not respond to conventional DMDs
• Given to people who have side-effects with conventional DMDs

Question 6

Describe cyclosporine A as a chemical

Answer 6

Cyclic undeca-peptide isolated from T. inflatum (fungus found in soil)

Question 7

Name 2 major uses for cyclosporine A

Answer 7

1. Organ transplant

2. Autoimmune diseases

Question 8

Name 4 autoimmune diseases

Answer 8

1. Rheumatoid arthritis
2. Posterior uveitis
3. Myasthenia gravis
4. Crohn’s disease

Question 9

Describe the chain of events which causes release of IL-2 from activated T cells

Answer 9

• APC activates T cells by variety of receptors including T Cell Receptors (TCR)
• Activation produces calcineurin (CaN) which catalyses the dephosphorylation of NFAT
• NFAT allows for transcription factors, including IL-2, to be produced
• Transcription factors cause proliferation of T lymphocytes

Question 10

How do cyclosporine drugs influence the chain of events which causes the release of IL-2?

Answer 10

• Cyclosporine acts as a CaN inhibitor
• Reduction of IL-2 produced
• Reduced proliferation of T lymphocytes so suppression of the immune response

Question 11

Describe 2 types of actions by cyclosporine

Answer 11

1. Antibody mediated suppression

2. Cell mediated suppression

Question 12

What is the major side effect of cyclosporine?

Answer 12

Nephrotoxicity

Question 13

Name 3 types of nephrotoxicity which can be caused by cyclosporine

Answer 13

1. Acute toxicity
2. Chronic toxicity
3. Glomerular filtration affected

Question 14

What 2 components of a renal biopsy would suggest progressive nephrotoxicity in cyclosporine use?

Answer 14

1. Arteriolar changes

2. Strips of fibrosis

Question 15

Name 4 minor side effects of cyclosporine

Answer 15

1. Mild hepatotoxicity
2. Lethargy
3. Hypertrophy
4. Diarrhoea

Question 16

How do thiopurines function?

Answer 16

Purine metabolite antagonists

Question 17

Name 2 uses of thiopurines

Answer 17

1. Anti-cancer agents

2. Immunosuppressive agents

Question 18

Name a type of thiopurine drug

Answer 18

Azathioprine

Question 19

How are thiopurines metabolised?

Answer 19

(S)-methyltransferase

Question 20

Describe how purines are synthesised

Answer 20

• Adenine / Guanine in DNA and RNA synthesis

- Adenosine found in cAMP and principle energy source in ATP and ADP

Question 21

Describe how purines have a major role in inflammation

Answer 21

• Extracellular signalling pathways
• Extracellular levels increase during inflammation and act on specific purinergic receptors
• Activation of adenosine receptors mediates cytoprotection in response to inflammation
• Activation of ATP-sensitive P2X₇ receptor triggers pro-inflammatory signalling

Question 22

Name 2 adenosine receptor type which have anti-inflammatory roles

Answer 22

1. A2A

2. A2B

Question 23

Describe the mechanism of action for azathioprine

Answer 23

• Metabolised to 6-MP to become active via HPRT catalysed reaction
• 6-MP converted to TIMP and then meTIMP via TPMT catalysed reaction which is an inhibitor of de novo purine biosynthesis
• Any TIMP which escapes catabolism is converted to TGMP and then meTGMP via TPMT catalysed reaction
• Any TGMP which escapes catabolism is converted to thio-dGTP which is cytotoxic

Question 24

What does TPMT stand for?

Answer 24

Thiopurine S methyltransferase

Question 25

What does HPRT stand for?

Answer 25

Hypoxanthine-guanine phosphoribosyltransferase

Question 26

Name 2 side effects of thiopurines

Answer 26

1. Therapy-related cancer (mainly skin) | 2. Methylated DNA 6-TG is cytotoxic

Question 27

How does methotrexate function?

Answer 27

Anti-metabolite of folic acid by competitive inhibition

Question 28

What is the DHFR enzyme?

Answer 28

Dihydrofolic acid reductase

Question 29

Describe the importance of the DHFR enzyme

Answer 29

- Catalyses dihydrofolate to tetrahydrofolate (active form) - Necessary for de novo synthesis of nucleoside thymidine (DNA synthesis) - Necessary for purine base synthesis (adenine and guanine)

Question 30

Describe how methotrexate is a useful treatment in cancer

Answer 30

- Inhibits all purine synthesis - Acts specifically during DNA and RNA synthesis - Cytotoxic during the S-phase of the cell cycle - Greater toxic effect on rapidly dividing cells than normal cells

Question 31

Describe the possible anti-inflammatory action of methotrexate

Answer 31

- Inhibition of enzymes involved in purine metabolism - Inhibits trans-methylation reactions required for inflammation (no clinical evidence) - Induction of adenosine release (inflammation inhibitor) - Suppression of T cell activation

Question 32

Describe how methotrexate stimulates adenosine release

Answer 32

- MTX is polyglutamated in the cell - MTXglu inhibits AICART - Increased levels of AICAR which inhibits adenosine deaminase - Enhanced levels of adenosine released - Binds to adenosine receptor A2 to reduce inflammation

Question 33

Describe 4 most common side effects when using methotrexate

Answer 33

1. Low WBC count 2. Highly teratogenic 3. Effects on CNS e.g. myelopathies 4. Nausea

Question 34

Name a rare side effect of methotrexate

Answer 34

Pulmonary fibrosis

Question 35

Name 2 drug interactions of methotrexate

Answer 35

1. Penicillin (decrease elimination of MTX) | 2. Carbamazepine (increase neurotoxicity of MTX)

Question 36

What form of cytokine is used as a novel immunoregulator?

Answer 36

Recombinant forms

Question 37

Name 3 cytokine products licensed in the UK

Answer 37

1. Aldesleukin (recombinant IL-2) 2. Adalimumab / Infliximab (TNF-α antagonist) 3. Ankinra (IL-1R antagonist)

Question 38

Describe the mechanism of action of aldesleukin

Answer 38

Stimulation of cytotoxic CD8 and NK cells in response to antigen

Question 39

What is aldesleukin licenced for?

Answer 39

Metastatic renal cell carcinoma

Question 40

What 3 factors may exclude patients with metastatic renal cell carcinoma from receiving aldesleukin as treatment?

Answer 40

1. Performance status of Eastern Co-Operative Oncology Group over 1 2. More than one organ with metastatic disease sites 3. Period of 23 months between initial diagnosis and date of evaluation of treatment

Question 41

How is aldesleukin usually administered?

Answer 41

Subcutaneous injection

Question 42

Why is aldesleukin not administered IV?

Answer 42

Increased risk of capillary leak syndrome, which can cause pulmonary oedema and hypotension

Question 43

Name 4 uses of TNF-α antagonists

Answer 43

1. Rheumatic disease 2. Inflammatory bowel disease 3. Plaque psoriasis 4. Psoriatic arthritis

Question 44

Name the major side effect of TNF-α antagonist drugs

Answer 44

Associated with infections, sometimes severe, including tuberculosis and septicaemia

Question 45

Name 4 minor side effects of TNF-α antagonist drugs

Answer 45

1. Nausea 2. Abdominal pain 3. Fever / headache 4. Hypersensitivity reactions

Question 46

What is anakinra licenced for?

Answer 46

Treatment of rheumatoid arthritis which has not responded to methotrexate alone

Question 47

What is a common side effect of anakinra?

Answer 47

Neutropenia

Question 48

Describe the mechanism of action of anakinra

Answer 48

Recombinant form of IL-1 receptor antagonist inhibiting IL-1 activity by competitive inhibition