Immunosurpressive Therapy Flashcards
Name the classes of drug which can be used to treat rheumatoid arthritis
Disease Modifying Anti Rheumatoid Drugs (inc. immunosuppressants)
Corticosteroids
Analgesics - paracetamol, NSAIDs
Name the principle of DMARD therapy in rheumatoid arthritis
DMARD therapy is designed to modify the conditions course as opposed to simply managing the symptoms. They can include drugs which suppress the chronic inflammation associated with RA.
Describe the typical standard pharmacotherapy of rheumatoid arthritis.
Conventional DMARDs can take a number of weeks to start to have an effect, hence a bridging therapy of corticosteroids is required in addition to DMARD therapy. This can later be removed.
Analgesics in the form of Paracetamol can be used to minimise the long term use of NSAIDs, which can have significant ADRs.
Corticosteroids are also prescribed for flare ups.
Ideally treatment should begin with three months of the onset of symptoms.
List some DMARDs which can be prescribed to RA patients.
Methotrexate Cyclosporine Mycophenolate mofetil Cyclophosphamide Sulfasalazine
Describe the application of corticosteroids in Rheumatoid arthritis
Corticosteroids are used as a bridging therapy at the start of RA treatment, while the slower acting DMARDs take effect. They are also used for flare-ups, however long term steroid use is avoided where possible.
What is the mechanism of action of corticosteroids as an immunosuppressant?
Corticosteroids work by altering gene expression, losing transactivation (of anti-inflammatory cytokines) and transrepression (of pro-inflammatory cytokines such as IL-1 and IL-6).
They also induce apoptosis is inflammatory cells.
What are the ADRs of long term corticosteroid treatment? What factors increase or decrease the likelihood of ADRs?
Long term glucocorticoid therapy can result in Cushing’s syndrome. This can involve central obesity, thinning skin, purple striae, proximal muscle wasting, hypertension, hypernatraemia, hypokalaemia, steroid diabetes. Also Addisonian crisis if the patient is stopped suddenly.
Factors which increase ADR with steroid treatment include treatment for more than three weeks, oral dosing (rather than inhaled or injected) and a higher dose.
Inhaled doses are more likely to cause thrush and sore throat.
What is the mechanism of action of mycophenolate mofetil in RA?
Mycophenolate mofetil is a DMARD which is a prodrug, being activated to mycophenolic acid (MPA). MPA is an inhibitor of a key enzyme in the de novo pathway of guanosine nucleoside synthesis. Guanosine is used for DNA and RNA synthesis, as well as the synthesis of energy molecules for intracellular processes.
B- and T- lymphocytes are dependant on the de novo pathway of nucleoside synthesis and so MPA can be selective for such cells, since others can use the salvage pathway for synthesis.
What are the ADRs of the use of mycophenolate mofetil?
They can cause bone marrow suppression resulting in leukopenia and neutropenia, increasing the risk of infection.
Outline the pathophysiology of Rheumatoid arthritis
RA is a chronic, autoimmune inflammatory condition which affects mainly the joints of the fingers and the wrists, however can become a systemic issue involving the lung, eye, GI tract and skin.
RA involves the presentation of the autoantigen to T-cells by macrophages, resulting in the activation and proliferation of Th cells, which recruit a range of cells to the site and mediate inflammation initially against the synovium, then the cartilage and eventually the underlying bone.
Such cells recruited include macrophages, neutrophils, fibroblasts and osteoclasts. Fibroblasts produce MMPs which break down connective tissue. Release of cytokines can also mediate the acute phase response and a fever/cachexia.
Describe the indications and mechanism of action of cyclophosphamide.
Cyclophosphamide is an immunosuppressant drug which is used in transplantation medicine, in chemotherapy and in rheumatoid arthritis.
This drug is a prodrug, activated by the CYP450 system to an activate metabolite which acts as an alkylating agent, forming a covalent bond to a guanine residue and damaging eh DNA. This is most effective against cells with a high turnover.
What are the indications for the prescription of mycophenolate mofetil?
mycophenolate mofetil is mainly used in transplantation medicine, however can also be used in RA as a DMARD.
What side effects have been associated with the use of cyclophosphamide?
Cyclophosphamide targets cells which have a high mitotic rate, hence ADRs are often related to this property. Therefore it can cause mouth ulcers, stomach pain, diarrhoea, hair loss and infertility.
The drug acts by damaging DNA, hence its effects on non-target cells can result in the development of cancers such as leukaemia and lymphoma. Also a risk of infection.
What is the mechanism of action of azathioprine? What is important about its PKs?
Azathioprine is a DMARD used in the therapy of RA, generally only in severe cases in which patients have not responded to other DMARDS. It is a prodrug which is activated to 6-MP (mercaptopurine). 6-MP acts as an antimetabolite to purine synthesis, hence interfering with DNA and RNA synthesis. It is selective to cells without a salvage pathway for purine synthesis - i.e. T- and B- lymphocytes.
6-MP is metabolised and removed by TPMT, which is highly polymorphic hence drug monitoring is required
What are the main adverse drug reactions associated with azathioprine?
Azathioprine is an immunosuppressant and can suppress bone marrow activity to cause pancytopenia, leaving the individual susceptible to anaemia, infection and bleeding.
