Immunosuppressives/ treatments for IMHA and IMPT Flashcards
Why can steroids sometimes cause CHF?
Some glucocorticoids, such as prednisolone, also have a mild mineralocorticoid effect; long-term use of high doses is associated with water retention, which can precipitate congestive cardiac failure in patients with pre-existing cardiac disease.
How does Azothiaprine work?
cytotoxic drug that inhibits purine synthesis, which disrupts DNA and RNA synthesis and hence mitosis. The principal effect of this drug is on cell-mediated immunity. Azathioprine has a slow onset of activity and is unlikely to have clinical effects for the first seven to 10 days, although some authorities have suggested a lead-in time of three to six weeks.
What are the s/e of azothiaprine?
myelosuppression, gastrointestinal distress, hepatotoxicity (normally reversible) and pancreatitis. Azathioprine is metabolised by the hepatic enzyme thiopurine methyltransferase (TMTP). The activity of TMTP varies between breeds of dog and is low in cats, which consequently are very susceptible to adverse effects, principally myelosuppression. As a result, azathioprine is difficult to use safely in cats and is not recommended for this species. Azathioprine is a very useful second-line immunosuppressant for dogs, principally in combination with glucocorticoids to allow more rapid tapering or withdrawal of glucocorticoids or as a long-term maintenance agent in cases where the immune-mediated disease relapses on withdrawal of treatment. Azathioprine is cheap and generally well tolerated. The available tablet sizes are inconvenient for small patients, but may be ‘repackaged’ into smaller tablets by compounding pharmacists
Outline the use of chlorambucil
alkylating agent, which causes cross-linkage and breakage of DNA. Although it sometimes causes gastrointestinal signs and, rarely, neurotoxicity in cats, it is much less myelosuppressive than cyclophosphamide (see later) and does not cause haemorrhagic cystitis. It has a slow onset of action. It is a second-choice immunosuppressant for cats already receiving glucocorticoids
How does cyclosporin work?
prevents T cell proliferation by interfering with the enzyme calcineurin, which is involved in calcium-dependent intracellular signalling. Other cells such as eosinophils and mast cells are affected to a lesser extent. Ciclosporin is not myelosuppressive and has a rapid onset of activity.
What are the s/e of cyclosporin?
The most common adverse reactions are gastrointestinal signs (in dogs, these often resolve within the first week of treatment) but several other adverse effects, such as gingival hyperplasia, have been reported. Ciclosporin is metabolised by the hepatic cytochrome P450 system and so numerous drug interactions are possible; these are detailed in the data sheet for Atopica. Ciclosporin may interfere with glycaemic control in diabetic patients. Ketoconazole, which inhibits cytochrome P450, has been used to reduce the dose of ciclosporin required.
What do some people test for in cats before giving cyclosporin?
Generalised toxoplasmosis has been reported in cats receiving ciclosporin treatment and some clinicians will administer ciclosporin only to cats that are seronegative for Toxoplasma.
Outline the use of tacrolimus
Tacrolimus interferes with T cell signalling via the same pathways as those acted on by ciclosporin. Tacrolimus is available as an ointment and has been used successfully to treat canine atopic dermatitis and other immune-mediated skin conditions, and for canine anal furunculosis. Topical ophthalmic tacrolimus may be useful for treating cases of keratoconjunctivitis sicca that are refractory to ciclosporin.
outline the use of mycofenilate
Mycophenolate mofetil (MMF) (CellCept; Roche Products) inhibits purine synthesis. A consequence of this is that proliferation of B and T lymphocytes is inhibited. MMF may also induce apoptosis (programmed cell death) of activated T cells. MMF was originally developed as an alternative to azathioprine with reduced myelotoxicity and hepatotoxicity, although it has been used concurrently with azathioprine in multidrug regimens in dogs. The clinical use of MMF in dogs has emerged from extensive use in experimental models of renal and bone marrow transplantation. The advantages of MMF include a rapid onset of immunosuppression and availability of a parenteral preparation.
Gastrointestinal side effects have been reported and may be reduced by using MMF at lower doses in combination with other agents, such as ciclosporin. Mild allergic responses to the parenteral preparation are possible. A disadvantage of MMF is that it is expensive.
How does leflunomide work?
inhibits pyrimidine synthesis and tyrosine kinases. It inhibits B and T lymphocyte proliferation and has significant anti-inflammatory effects. It may also induce regulatory (formerly known as suppressor) T lymphocytes. Like MMF, leflunomide is another example of a drug that has been used to treat a variety of immune-mediated diseases in dogs, following its successful use in canine transplantation models
Outline the use of leflunomide
Leflunomide has been reported to be effective in canine immune-mediated diseases that are refractory to other immunosuppressants (especially immune-mediated polyarthritis), reactive histiocytosis in dogs, and, in combination with methotrexate, rheumatoid arthritis in cats. The onset of immunosuppression may be slow.
The elimination half-life is long and there is potential for hepatotoxicity and myelotoxicity, although these side effects seem rare. As a result, there are recommendations in the early literature for monitoring the serum trough concentrations of the drug. However, the author has not found a laboratory offering monitoring of blood leflunomide levels in the UK. Leflunomide may be prohibitively expensive except for smaller patients.
Outline the use of vincristine in immune-mediated disease
Low doses of vincristine are not immunosuppressive, but have an adjunctive role in the management of some cases of immune-mediated thrombocytopenia by stimulating megakaryocytes to release platelets and impairing phagocytosis of platelets by macrophages through disruption of microtubule assembly. There is a lack of consensus about whether the platelets released are functional, but the author does use this therapy in cases of severe thrombocytopenia with clinically significant bleeding.
How does human intravenous immunoglobulin work?
Human intravenous immunoglobulin (IVIG) has incompletely understood immune-modulatory and anti-inflammatory effects. Among the most compelling hypotheses for its action is the suggestion that it saturates antibody receptors on canine macrophages and monocytes, thus inhibiting their phagocytosis of antibody-coated particles/cells (such as platelets in immune-mediated thrombocytopenia and erythrocytes in immune-mediated haemolytic anaemia [IMHA]). It has been suggested that IVIG is effective in the management of canine-immune mediated skin disease and immune-mediated haematological disease, but data supporting these practices are limited.
What are the possible complications with intravenous immunoglobulin?
Each unit of IVIG contains a cocktail of foreign proteins derived from large numbers of donors, and so it is not surprising that occasional adverse reactions to infusion of this product have been reported. In dogs, it is advisable to use levels of monitoring comparable with those employed during transfusion of blood or plasma. IVIG has an increasing number of indications in human medicine and is often difficult to source for veterinary usage. It may also be prohibitively expensive.
Outline the use of cytarabine
Cytosine arabinoside (also called cytarabine) competitively inhibits DNA polymerase and hence DNA synthesis. It crosses the blood–brain barrier and is used as an adjunctive therapy (in combination with prednisolone) in patients with inflammatory central nervous system disease (eg, granulomatous meningoencephalitis or breed-specific meningoencephalitis). Cytosine arabinoside can cause myelosuppression.
