List some classes of drug used to treat RA and give an example of each
- Antiproliferative immunosuppressants, e.g. Azathioprine
- Calcineurin inhibitors - e.g. ciclosporin
- DMARDs - Methotrexate
- Biopharmaceuticals - e.g. Infliximab
Apart from RA, give some other uses for Azathioprine
Outline the mechanism of action of Azathioprine
- Prodrug - cleaved to 6-MP and then to thioinosinic acid
- Inhibits purine metabolism - i.e. an antimetabolite
What is important about Azathioprine metabolism?
Metabolised by a gene which is highly polymorphic - TMPT (thiopurine methyltransferase)
Therefore test TMPT levels before starting treatment
List 4 important ADRs of Azathioprine
Increased risk of malignancy
Increased risk of infection
Hepatitis - monitor LFTs
Give some uses of cyclophosphamide apart from RA
What is the broad mechanism of action of cyclophosphamide?
Cytotoxic alkylating agent
Give 4 ADRs associated with cyclophosphamide
- Bladder cancer
What is the primary use for mycophenolate mofetil?
What is the mechanism of action of Mycophenolate mofetil?
Inhibits enzyme inosine monophosphate dehydrogenase required for de novo synthesis of the purine guanosine
Give 4 ADRs of mycophenolate mofetil
- Infection risk
Name two calcineurin inhibitors and give some of their uses
- Ciclosporin, Tacrolimus
- Used post-transplant and in psoriasis
What is the mechanism of action of the calcineurin inhibitors?
- Binds to intracellular immunophilin
- Drug/protein complex binds to calcineurin, inhibiting it
- Thus prevents phosphotase activity which would result in IL-2 transcription
Give 4 ADRs of calcineurin inhibitors
Which drug is the gold-standard treatment for RA?
What else is it used for?
Also used in malignancy, psoriasis, IBD
What is its mechanism of action in non-malignant disease?
We’re not entirely sure - possibly increases adenosine, possibly inhibits T cell activation
Give some important features of methotrexate administration
- Poor bioavailability - can be given IM instead of orally
- Highly plasma bound. Displaced by NSAIDs
- Weekly dosing NOT daily
Give 4 ADRs of methotrexate
- Thinning hair
Which two compounds comprise Sulfasalazine?
- 5-aminosalicylate (5-ASA)
Give some possible immunological effects of sulfasalazine
- Inhibition of T cell proliferation
- Possible T cell apoptosis
- Inhibition of IL-2 production
Which part of Sulfasalazine treats IBD?
What about the other bit?
- 5-ASA stays in gut - IBD
- Sulfapyridine absorbed - systemic
Give 3 ADRs of sulfasalazine
Which moeity produces these?
Produced by sulfapyridine as systemically absorbed
Give 2 examples of anti-TNF drugs
Give some ADRs of anti-TNF agents
- Risk of serious infections
- TB reactivation
- Risk of malignancy if had prior malignancy
What is the mechanism of action of Rituximab?
Binds specifically to CD20 on surface of some B cells - causes B cell depletion