Drugs and the Immune System II Flashcards
How do disease modifying drugs function?
Alter underlying disease rather than treating symptoms
Name 2 types of DMDs
- Conventional DMDs (slow acting)
2. Biological therapies (fast acting)
Name 3 conventional DMDs
- Cyclosporine
- Thiopurines
- Methotrexate
Name 2 examples of biological therapies
- Anti-TNF drugs
2. Drugs which target cytokines
Describe how biological therapies are usually used
- 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
Describe cyclosporine A as a chemical
Cyclic undeca-peptide isolated from T. inflatum (fungus found in soil)
Name 2 major uses for cyclosporine A
- Organ transplant
2. Autoimmune diseases
Name 4 autoimmune diseases
- Rheumatoid arthritis
- Posterior uveitis
- Myasthenia gravis
- Crohn’s disease
Describe the chain of events which causes release of IL-2 from activated T cells
- 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
How do cyclosporine drugs influence the chain of events which causes the release of IL-2?
- Cyclosporine acts as a CaN inhibitor
- Reduction of IL-2 produced
- Reduced proliferation of T lymphocytes so suppression of the immune response
Describe 2 types of actions by cyclosporine
- Antibody mediated suppression
2. Cell mediated suppression
What is the major side effect of cyclosporine?
Nephrotoxicity
Name 3 types of nephrotoxicity which can be caused by cyclosporine
- Acute toxicity
- Chronic toxicity
- Glomerular filtration affected
What 2 components of a renal biopsy would suggest progressive nephrotoxicity in cyclosporine use?
- Arteriolar changes
2. Strips of fibrosis
Name 4 minor side effects of cyclosporine
- Mild hepatotoxicity
- Lethargy
- Hypertrophy
- Diarrhoea
How do thiopurines function?
Purine metabolite antagonists
Name 2 uses of thiopurines
- Anti-cancer agents
2. Immunosuppressive agents
Name a type of thiopurine drug
Azathioprine
How are thiopurines metabolised?
(S)-methyltransferase
Describe how purines are synthesised
- Adenine / Guanine in DNA and RNA synthesis
- Adenosine found in cAMP and principle energy source in ATP and ADP
Describe how purines have a major role in inflammation
- 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
Name 2 adenosine receptor type which have anti-inflammatory roles
- A2A
2. A2B
Describe the mechanism of action for azathioprine
- 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
What does TPMT stand for?
Thiopurine S methyltransferase
What does HPRT stand for?
Hypoxanthine-guanine phosphoribosyltransferase
Name 2 side effects of thiopurines
- Therapy-related cancer (mainly skin)
2. Methylated DNA 6-TG is cytotoxic
How does methotrexate function?
Anti-metabolite of folic acid by competitive inhibition
What is the DHFR enzyme?
Dihydrofolic acid reductase
Describe the importance of the DHFR enzyme
- Catalyses dihydrofolate to tetrahydrofolate (active form)
- Necessary for de novo synthesis of nucleoside thymidine (DNA synthesis)
- Necessary for purine base synthesis (adenine and guanine)
Describe how methotrexate is a useful treatment in cancer
- 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
Describe the possible anti-inflammatory action of methotrexate
- 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
Describe how methotrexate stimulates adenosine release
- 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
Describe 4 most common side effects when using methotrexate
- Low WBC count
- Highly teratogenic
- Effects on CNS e.g. myelopathies
- Nausea
Name a rare side effect of methotrexate
Pulmonary fibrosis
Name 2 drug interactions of methotrexate
- Penicillin (decrease elimination of MTX)
2. Carbamazepine (increase neurotoxicity of MTX)
What form of cytokine is used as a novel immunoregulator?
Recombinant forms
Name 3 cytokine products licensed in the UK
- Aldesleukin (recombinant IL-2)
- Adalimumab / Infliximab (TNF-α antagonist)
- Ankinra (IL-1R antagonist)
Describe the mechanism of action of aldesleukin
Stimulation of cytotoxic CD8 and NK cells in response to antigen
What is aldesleukin licenced for?
Metastatic renal cell carcinoma
What 3 factors may exclude patients with metastatic renal cell carcinoma from receiving aldesleukin as treatment?
- Performance status of Eastern Co-Operative Oncology Group over 1
- More than one organ with metastatic disease sites
- Period of 23 months between initial diagnosis and date of evaluation of treatment
How is aldesleukin usually administered?
Subcutaneous injection
Why is aldesleukin not administered IV?
Increased risk of capillary leak syndrome, which can cause pulmonary oedema and hypotension
Name 4 uses of TNF-α antagonists
- Rheumatic disease
- Inflammatory bowel disease
- Plaque psoriasis
- Psoriatic arthritis
Name the major side effect of TNF-α antagonist drugs
Associated with infections, sometimes severe, including tuberculosis and septicaemia
Name 4 minor side effects of TNF-α antagonist drugs
- Nausea
- Abdominal pain
- Fever / headache
- Hypersensitivity reactions
What is anakinra licenced for?
Treatment of rheumatoid arthritis which has not responded to methotrexate alone
What is a common side effect of anakinra?
Neutropenia
Describe the mechanism of action of anakinra
Recombinant form of IL-1 receptor antagonist inhibiting IL-1 activity by competitive inhibition
