Immunosuppressives Flashcards
What is the mechanism of action of cyclophosphamide?
Cell-cycle nonspecific nitrogen mustard derivative alkylating agent
Prodrug metabolized by cytochrome p450 in the liver to form active metabolites
Ultimately forms phosphoramide mustard and acrolein in cell cytoplasm
Phosphoramide mustard replaces hydrogen with alkyl group on guanine base
Forms crosslinks both within and between nucleotide strands
What is the mechanism of action of chlorambucil?
Cell-cycle nonspecific nitrogen mustard derivative alkylating agent
What is the mechanism of action of azathioprine?
Purine sysnthesis inhibitor
Prodrug for the active metabolite 6-mercaptopurine
Blocks amidophosphoribosyltranserase enzyme
Inhibits synthesis of purines adenine and guanine with resultant production of nonfunctional nucleic acid strands
Disruption of purine synthesis inhibits DNA and RNA synthesis, inhibiting proliferation of fast-growing cells such as lymphocytes
What is the mechanism of action of danazol?
Impeded androgen
What is the mechanism of action of vincristine?
Disrupts microtubules
Disappears immediately in blood stream because it binds to tubulin that is an ultrastuctural protein
Tubulin give platelets their normal shape
Vincristine binds to the inside of platelets typically meaning the drug is useless
In immune thrombocytopenia, these cycle around and macrophages attack them in 1 to 2 hours instead of circulating for a week
A phagosome form and a lysosome eats it.. Phagolysosome forms
Macrophage stops after eating one platelet
Very rapidly increases the survival time of circulating platelets
What is the mechanism of action of cyclosporine?
Primary immunosuppressive mechanism of action is inhibition of T lymphocyte function
Suppresses T cell production of several important cytokines, including IL-2, IL-4, TNF-α, INF-γ
Calcineurin inhibitor
What is the mechanism of action of leflunomide?
Prodrug for its primary active malononitrolamide metabolite, teriflunomide
Inhibits dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis
Resultant inhibition of the pyrimidine ribonucleotide UMP, with decreased DNA and RNA synthesis and GI cell cycle arrest
Pyrimidine synthesis inhibitor
What is the mechanism of action of mycophenolate?
Prodrug form of mycophenolic acid
Inhibits inosine monophosphate dehydrogenase, enzyme that control guanine monophosphate (and purine) synthesis
Purine synthesis inhibitor
What are the indications for using cyclophosphamide?
Rarely used as an immunosuppressive agent anymore
Commonly used as an anticancer agent
What are the indications for using chlorambucil?
Immune skin disease (cats)
IBD (dogs)
Commonly used as anticancer agent
What are the indications for using azathioprine?
We do not give this to cats because they lack the TPMT enzyme
Commonly used immunosuppressive agent in dogs
What are the indications for using danazol?
Rarely used as an immunosuppressive agent
What are the indications for using vincristine?
Immune-mediated thrombocytopenia
Commonly used as an anticancer agent
What are the indications for using cyclosporine?
Wide range of immune-mediated diseases
What are the indications for using leflunomide?
Wide range of immune-mediated diseases
What are the indications for using mycophenolate?
Wide range of immune-mediated diseases
What are the side effects of cyclophosphamide?
Myelosuppression
GI disease
Alopecia
Refractory cystitis (sterile) or bladder neoplasia
What are the side effects of chlorambucil?
Myelosuppression GI disease Alopecia Neurologic signs in cats (rare) Fanconi syndrome in cats (rare) NO sterile cystitis
What are the side effects of azathioprine?
Mild anemia
Myelosuppression
Hepatotoxicity (occurs in 15% of dogs)
Pancreatitis
What are the side effects of danazol?
Hepatotoxicity
Masculinization of female dogs
What are the side effects of vincristine?
Use with caution in breeds with potential MDR1 (ABCB1) deficiency( Don’t use in Australian Sheppards, collies, sheltie, wire haired whippets)
Myelosuppression
Neuropathy
Extravasation
What are the side effects of cyclosporine?
GI disturbances Gingival hyperplasia Hepato/nephrotoxicity These are uncommon if the dose is adjusted based on blood levels Does not suppress marrow
What are the side effects of leflunomide?
Few have been identified as it is a new drug
What are the side effects of mycophenolate?
Diarrhea
What are the pharmacokinetics of cyclosporine?
This is important in drugs that are unpredictably absorbed
If you give this drug and don’t monitor anything, you shouldn’t give the drug
If you want to make sure it works, you need to achieve certain blood levels
Pharmacokinetics measures how much is absorbed
What are the pharmacodynamics of cyclosporine?
Alternative way to do TDM
Monitors what the drug does to the body
Pharmacodynamics was developed with and for cyclosporine
Individual variability:
Cytochrome p450
Efflux pumps
Utilize pharmacodynamic monitoring in addition to standard pharmacokinetic assays by looking at the T cell expression of IL-2 and IFN-γ
What are the secondary infections that cause a patient to be at risk for with immunosuppresive drugs?
You can see susceptibility to bacterial infections:
Cystitis
Pyoderma
Pneumonia
You can see overwhelming, unusual infections:
Fungal (Aspergillus)
Protozoal (Toxoplasma)
Parasitic (Demodex)
How can you prevent secondary infections?
Prophylactic antibiotics are usually not indicated
They can help treat the bacterial infections but not the unusual infections
