Immunomodulatory drugs Flashcards
What are the most commonly used immunomodulatory drugs
The most commonly used immunomodulatoory drugs are the glucocorticoids, particularly prednisolone
What is the mechanism of action of corticosteroids
Corticosteroids act by binding to intra-cytoplasmic receptors
These steroid-receptor complexes then move to the nucleus where they alter gene transcription
- these effects are widespread, and many genes in many different cell types are affected
At low doses, anti-inflammatory effects are mediated via:
- the suppression of the arachidonic acid cascade
- the inhibition of inflammatory cytokines
- membrane stabilisation
What are the immunosuppresive effects of corticosteroids
At higher doses, immunosuppressive effects of corticosteroids include:
- decreased movement of leukocytes out of the blood stream (particularly neutrophils)
- inhibition of phagocytosis, antigen presentation and interleukin-1 produced by macrophages - decreased T-cell cytokine production - inhibition of complement pathways - decreased passage of immune complexes through basement membranes
What important monitoring should be observed in obese cats or Burmese when using corticosteroids
Cats that may be predisposed to Type 2 diabetes mellitus should be monitored for signs of insulin resistance
Why care is needed when using corticosteroids in cats with previously diagnosed heart disease
There is some evidence that the mineralocorticoid effects may precipitate volume overload and congestive heart failure
In this case, the lowest effective dose should be implemented and the use of drugs with low mineralocorticoid activity should be considered
- dexamethasone injections seem to carry the highest risk
What is the most commonly used alkylating agents in cats? and why?
Chlorambucil is the most commonly used alkylating agent in cats and is employed as an adjunct to corticosteroid therapy
Dose:
- 2 mg per cat, PO, q48h in cats > 4kg
- 2 mg per cat, PO, q72h in cats < 4kg
- then taper after 3-4 weeks
What is the mechanism of actionn of chlorambucil
Chlorambucil causes breaks or cross-linkages in the DNA, which affects cell division and also RNA production
What is the main side effect of chlorambucil
The main side effect of chlorambucil is myelosuppression (hallmarked primarily by neutropenia), which tends to occur 7-14 days after commencement of therapy
This drug seems to be generally well tolerated and dose reduction are not commonly needed
What would be a monitoring plan for chlorambucil use
Occasionally, cats can develop bone marrow depression with chronic therapy, so it is appropriate to check the hemogram of cats on long-term chlorambucil therapy every 1-2 months
What are other potential side effects with chlorambucil use
Other rarely reported side effects are:
- seizures and muscle twitching (myoclonus)
- acquired Fanconi syndrome (development of glucosuria despite normoglycemia and aminoaciduria)
It is then sensible to perform regular (e.g. every 2-3 months) urinalysis
What is cyclosporin
Cyclosporin is a polypeptide produced by the fungus Tolypocladium inflatum
It functions as an immunosuppressant by binding to the intra-cytoplasmic protein cyclophilin in activated lymphocytes (especially T-cells)
What is the mechanism of action of cyclosporin
The binding of cyclosporin to cyclophilin inhibits the enzyme calcineurin that is responsible for the transcription of interleukin-2 (which is important for T-cell clonal expansion) and interleukin-4 (that induces the differentiation of naïve T-cells into T-helper cells, amongst other effects)
Cyclosporin also inhibits:
- the recruitment of eosinophils
- the lymphocyte-activating functions of antigen presenting cells
- cytokine secretion by keratinocytes
- IgE and mast cell-dependent cellular infiltration
What are the side effects of cyclosporin
Generally, cyclosporin produces minimal side effects if blood levels are kept within the recommended therapeutic range (200-500 ng/ml)
- starting dose: 5 mg/kg, PO, q24h
Reported side effects includee gingival hypertrophy and GIT signs
Nephrotooxicity and fatal toxoplasmosis have also been rarely reported
What is the mechanism of action of leflunomide
Leflunomide is metabolized by the intestinal mucosa into a compound that suppresses T-cell proliferation via antagonism of a lymphocyte growth factor receptor and inhibition of mitochondrial enzymes
It also decreases B-cell proliferation and antibody production
Explain why leflunomide doses need to be adjusted in cats with renal failure
The active compound resulting from leflunomide metabolisation is further metabolised by the liver and the resulting metabolites are excreted via the urine
What is the indication of leflunomide
Leflunomide has been administered concurrently with methotrexate to control erosive arthritis in cats
- dose: 2-4 mg/kg, q24h
- once remission is achieved this dose can then be administered once to twice weekly
What is mycophenolate mofetil
Mycophenolate mofetil is the prodrug of mycophenolic acid
It is a selective, reversible, non-competitive inhibitor of inosine-5’-monophosphate dehydrogenase
What are the indication for mycophenolate mofetil
Mycophenolate mofetil has been used for:
- IMHA
- immune mediated polyarthritis
What are the potential side effects of mycophenolate mofetil
Diarrhea and hyporexia (dose-dependent incidence)
Concurrent hepatopathy and pancreatitis
