Immunosuppressants Flashcards
(4 cards)
Azathioprine
Oral immunosuppressive agent used in dogs for a variety of immune-mediated diseases
Azathioprine is a prodrug of 6-mercaptopurine (6-MP), the active metabolite of azathioprine. 6-MP competes with endogenous purines, thereby causing breaks in DNA and RNA secondary to incorporation into nucleic acids and termination of the replication process. Azathioprine specifically targets lymphocytes due their lack of a salvage pathway for purine biosynthesis. Cellular metabolism may become disrupted by the drug’s ability to inhibit coenzyme formation. Evidence suggests azathioprine interferes with CD28 costimulation of T lymphocytes to trigger apoptosis.
Azathioprine has greater activity on delayed hypersensitivity and cellular immunity than on antibody responses. Clinical response to azathioprine is gradual and may not be fully observable for up to 5 weeks.
Azathioprine did not influence platelet function or coagulation in healthy dogs.
Not recommended in cats, as they are highly sensitive to myelosuppression
May take several weeks for immunosuppression to occur; doses are given daily the first 2 weeks
Often used in combination with corticosteroids to reduce doses and frequency of each drug
Use with caution in patients with hepatic disease.
Myelosuppression is the principal adverse effect; GI effects include GI distress, anorexia, pancreatitis, hepatotoxicity.
Known mutagen and teratogen
Purine antagonist; 6MP prodrug; targets lymphocytes
Not recc in cats due to severity of myelosuppression
Cyclosporine
FDA approved for atopic dermatitis, extra label for immune mediated disorders
Cyclosporine, a calcineurin inhibitor, is an immunosuppressive agent that focuses on cell-mediated immune responses, with some humoral immunosuppressive action. Cyclosporine binds to T-cell cyclophilin and blocks calcineurin-mediated T-cell activation. T-helper lymphocytes are the primary target, but T-suppressor cells are also affected. Cyclosporine can also inhibit cytokine production and release (including interleukin [IL]-2 and interferon-gamma in dogs and IL-3, IL-4, and tissue necrosis factor-alpha in humans), thereby affecting the function of eosinophils, mast cells, granulocytes, and macrophages. It may also inhibit antigen-presenting functions of the dermal immune system. It is not considered myelosuppressive. One study suggests that cyclosporine therapy does not affect circulating lymphocyte CD4/CD8 ratio. Cyclosporine appears to increase thromboxane production in dogs and low-dose aspirin inhibits this effect.
GI adverse effects (eg, anorexia, vomiting, soft stools) are common at the start of treatment but typically resolve within a few weeks. Gingival hyperplasia, altered glucose metabolism, hypertrichosis, papillomatosis, hepatotoxicity, thromboembolic events.
Only use modified cyclosporine formulations. Sandimmune is a human-labeled product that is not bioequivalent to, and MUST NOT be interchanged with, modified formulations.
For indications other than atopic dermatitis, consider therapeutic drug monitoring to assess efficacy and minimize adverse effect potential.
Many potential drug interactions
binds T-cell cyclophilin; blocks calcineurin-med. T-cell activation
Inhib release of IL2, IFg, IL3, IL4, and TNFa; affects eos, mast cells, granulocytes, macrophages; increases thromboxane; Gingival hyperplasia
Leflunomide
Immunomodulating drug used in small animal medicine as an immunosuppressant, particularly in patients refractory to treatment with conventional medications or when glucocorticoids are contraindicated
Leflunomide is a pyrimidine synthesis inhibitor that inhibits autoimmune T-cell proliferation and autoantibody production by B cells. Leflunomide acts almost exclusively via its primary active metabolite, teriflunomide (A77 1726), which reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase. The disruption of this enzyme prevents formation of ribonucleotide uridine monophosphate (rUMP), resulting in decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. These cytostatic effects occur primarily in lymphocytes, sparing GI, hematopoietic, and other rapidly dividing cells. Leflunomide also has antiviral and tyrosine kinase inhibiting properties, the importance of which is unclear. An antiplatelet effect also has been demonstrated.
Appears to be well-tolerated by dogs and cats, but numbers treated are low; appear to be dose related; GI, increased LE, unexplained hemorrhage, leukocytopenia, lymphopenia, thrombocytopenia, hypercholesterolemia, anemia
Teratogenic and carcinogenic
Pyrimidine inhib. revers inhib dihydroorotate dehydrog; prev rUMP
Hypercholesterolemia, unexplained hemorrhage
Mycophenolate
Oral or IV administration may be useful for treating dogs with immune-mediated hemolytic anemia (IMHA), immune-mediated thrombocytopenia (ITP), glomerulonephritis, myasthenia gravis, idiopathic chronic hepatitis, or meningoencephalomyelitis of unknown etiology in dogs
prodrug that must be hydrolyzed in vivo to mycophenolic acid (MPA) to be pharmacologically active. MPA noncompetitively, but reversibly, inhibits inosine monophosphate dehydrogenase (IMPDH). Two distinct forms of IMPDH exist in the body, including type 1 found in most cells and type 2 existing in activated lymphocytes. MPA has a 5-fold greater affinity for the type 2 IMPDH isoform. IMPDH is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. As T cells and B cells are dependent on de novo synthesis of purines (eg, guanosine) and, unlike other cells, cannot use salvage pathways, proliferative responses of T cells and B cells are inhibited and suppression of B-cell antibody formation occurs, thus inhibiting both cell-mediated and humoral immune responses. These effects enable MPA to inhibit leukocyte recruitment to inflammatory sites and allotransplant tissues.
did not inhibit proliferating CD5+ T lymphocytes at any time point. MPA demonstrated in vitro antiproliferative activity in feline lymphocytes; however, in healthy cats, oral administration of MMF resulted in little change in peripheral blood mononuclear cell counts or CD4+/CD8+ T-cell ratios
Pharmacokinetic data in cats suggest the usefulness for this species is limited
Avoid modified live vaccines during use.
Adverse effects include GI signs (eg, diarrhea, vomiting, anorexia), which may be dose-limiting and can be severe. Lymphopenia, papillomatosis, increased dermal infections, ulcerative colitis
Can be administered PO or IV. Compounding into appropriate oral dosage forms may be needed.
inhibits IMPDH which is enzyme for synthesis of guanosine nucleotides
Inhibits proliferative responses of T and B cells; inhib leukocyte recruitment
