Immunosuppressants Flashcards
How do cytotoxic drugs, lymphocyte drugs, and glucocorticoids work as immunosuppressants?
CYTOTOXIC = cause cell necrosis and apoptosis, or impair proliferation
LYMPHOCYTE = suppress the immune system by inhibiting function of lymphocytes and production of cytokines
GLUCOCORTICOIDS = affect innate and adaptive immunity
What are the main 3 classifications of immunosuppressants? What other 2 immunomodulators can be used?
- ANTIMETABOLITES - purine synthesis inhibitors (Azathioprine, Mycophenolic acid), pyrimidine synthesis inhibitors (Leflunomide)
- MATRIx METALLOPROTINASE INHIBITORS - tetracycline
- CYTOKINE INHIBITORS - IL-2 (cyclosporine, tacrolimus), TNFα (pentoxifylline)
- gold therapy: auranofin, gold sodium thiomalate
- niacinamide
What is Azathioprine (Imuran)? What is its 2 mechanisms of action?
purine synthesis inhibitor that inhibits the cellular synthesis of nucleic acids required for RNA and DNA synthesis resulting in cellular proliferation and function arrest
- inhibits DNA synthesis in B- and T-lymphocytes
- blocks CD28 signaling on T-cells, resulting in impaired RNA synthesis
How is Azathioprine (Imuran) most commonly used?
in conjunction with steroids to treat immune-mediated diseases, like:
- immune-mediated hemolytic anemia and thrombocytopenia
- colitis and skin disease
- myasthenia gravis
- IBD
- immune-mediated inflammatory conditions and perianal fistulas in dogs
- autoimmune skin diseases in horses
What is important to note about Azathioprine pharmacokinetics? Is it given to cats?
its a prodrug that is well absorbed in the gut
NO - causes toxicity
What are 4 possible adverse effects associated with Azathiprine (Imuran)?
- bone marrow suppression, leadint to an increased risk for infection
- fatal leukopenia and thrombocytopenia
- hepatotoxicity and acute pancreatitis
- mutagenic, teratogenic, carcinogen
What is Leflunomide? What is its mechanisms of action?
pyrimidine synthesis inhibitor
inhibits mitochondrial enzyme necessary for de novo pyrimidine synthesis, particularly affecting B- and T-lymphocyte synthesis
What is Leflunomide most commonly used to treat? What are 3 other possible uses?
immune-mediated polymyositis
- immune-mediated hemolytic anemia and thrombocytopenia
- multifocal nonsuppurative encephalitis/meningomyelitis
- Evan’s syndrome
Are adverse effects common in dogs with use of Leflunomide?
no, but can cause Gi disturbances and anemia
What is polymyositis? What are the 3 main causes?
relatively common inflammatory disease in dogs that causes muscle weakness and fatigue
- infectious agents: bacteria, viruses, protozoa, parasites
- immune-mediated: autoimmune
- paraneoplastic: tumor invading muscles
What are the 5 signs of polymyositis in dogs?
- generalized weakness that worsens with exercise
- muscle swelling and pain
- anorexia
- exercise intolerance
- muscle wasting
What are the 4 most common treatments of polymyositis?
- Azathioprine
- Leflunomide
- Cyclosporine
- Prednisone
What is cyclosporine? How does it work?
IL-2 inhibitor
binds to CsA, which blocks calcineurin, making it unable to dephosphorylate NF-ATc to block IL-2 production
What are the main pharmacological effects cyclosporine has on T-lymphocytes and mast cells?
T-CELLS: decreases the production of IL-2, 3, 4, G-CSF, and TNFα, and decreases the proliferation of CD4+ and CD8+ lymphocytes, increases TGFβ (inhibits IL-2)
MAST CELLS: decreases histamine release in canine mast cells
What are the 3 main uses of cyclosporine?
- keratoconjunctivitis sicca
- perianal fistulas
- IMHA in conjunction with glucocorticoids
What are 4 possible adverse effects of cyclosporine?
- GI disturbances
- gingival hyperplasia
- papillomatosis in dogs
- viral infections in cats
What is tacrolimus (FK-506)? How does it work?
IL-2 inhibitor
binds to FKBP12 and blocks calcineurin, making it unable to dephosphorylate NF-ATc to block IL-2 production
What are the main 2 therapeutic uses of tacrolimus? What is the most common adverse effect?
- keratoconjunctivitis sicca
- localized topical treatment of immune-mediated dermatological diseases
local irritation due to topical application
What is pentoxifylline (PTX)? How does it work?
TNFα inhibitor
downregulates the release of production of profibrotic TNF, suppresses the production of platelet-activating factor, and inhibits action on neutrophils
What are the most common uses of pentoxifylline (PTX) in dogs and horses?
canine skin diseases, like vasculitis, dermatomyositis, contact allergy, atopic dermatitis, and vaccine-induced ischemic dermatitis
systemic inflammatory response syndrome, caudal heal syndrome
How are tetracyclines used as immunosuppressors? What are the 2 types?
inhibits matrix metalloproteinase, which is responsible for cell proliferation, differentiation, and migration, angiogenesis, and host defense
- SHORT-ACTING: tetracycline, oxytetracycline
- LONG-ACTING: doxycycline, minocycline
What 2 drugs are used in gold therapy (chrysotherapy)? What is thought to be their mechanism of action?
- Auranofin*
- gold sodium thiomalate
inhibits phagocytes (macrophages) and T-cells
What are the main uses of gold therapy in dogs, cats, and horses?
DOGS: idiopathic polyarthritis, rheumatoid arthrisi, pemphigus foliaceous
CATS: pemphigus foliaceous, chronic gingivitis/stomatitis
HORSES: pemphigus foliaceous
What is niacinamide? How is it thought to work as an immunosuppressant?
vitamin B2, common nutritional supplement with other medications
blocks mast cell degranulation and inhibits protease release for leukocytes
What are the main 4 uses of niacinamide as an immunosuppressant?
- discoid lupus erythematosus
- pemphigus erythematosus
- pemphigus foliaceous
- autoimmune disease
What causes autoimmune disorders? What 3 things happen? What are the 2 major causes?
disorders where the immune system attacks healthy cells in the body by mistake
- body has lost its ability to differentiate between antigens and its own cells
- antibodies attack self-antigens
- inflammation leading to tissue damage
genetic, environmental
