Immunosuppressives

Question 1

What is the mechanism of action of cyclophosphamide?

Answer 1

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

Question 2

What is the mechanism of action of chlorambucil?

Answer 2

Cell-cycle nonspecific nitrogen mustard derivative alkylating agent

Question 3

What is the mechanism of action of azathioprine?

Answer 3

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

Question 4

What is the mechanism of action of danazol?

Answer 4

Impeded androgen

Question 5

What is the mechanism of action of vincristine?

Answer 5

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

Question 6

What is the mechanism of action of cyclosporine?

Answer 6

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

Question 7

What is the mechanism of action of leflunomide?

Answer 7

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

Question 8

What is the mechanism of action of mycophenolate?

Answer 8

Prodrug form of mycophenolic acid
Inhibits inosine monophosphate dehydrogenase, enzyme that control guanine monophosphate (and purine) synthesis
Purine synthesis inhibitor

Question 9

What are the indications for using cyclophosphamide?

Answer 9

Rarely used as an immunosuppressive agent anymore

Commonly used as an anticancer agent

Question 10

What are the indications for using chlorambucil?

Answer 10

Immune skin disease (cats)
IBD (dogs)
Commonly used as anticancer agent

Question 11

What are the indications for using azathioprine?

Answer 11

We do not give this to cats because they lack the TPMT enzyme
Commonly used immunosuppressive agent in dogs

Question 12

What are the indications for using danazol?

Answer 12

Rarely used as an immunosuppressive agent

Question 13

What are the indications for using vincristine?

Answer 13

Immune-mediated thrombocytopenia

Commonly used as an anticancer agent

Question 14

What are the indications for using cyclosporine?

Answer 14

Wide range of immune-mediated diseases

Question 15

What are the indications for using leflunomide?

Answer 15

Wide range of immune-mediated diseases

Question 16

What are the indications for using mycophenolate?

Answer 16

Wide range of immune-mediated diseases

Question 17

What are the side effects of cyclophosphamide?

Answer 17

Myelosuppression
GI disease
Alopecia
Refractory cystitis (sterile) or bladder neoplasia

Question 18

What are the side effects of chlorambucil?

Answer 18

Myelosuppression
GI disease
Alopecia
Neurologic signs in cats (rare)
Fanconi syndrome in cats (rare)
NO sterile cystitis

Question 19

What are the side effects of azathioprine?

Answer 19

Mild anemia
Myelosuppression
Hepatotoxicity (occurs in 15% of dogs)
Pancreatitis

Question 20

What are the side effects of danazol?

Answer 20

Hepatotoxicity

Masculinization of female dogs

Question 21

What are the side effects of vincristine?

Answer 21

Use with caution in breeds with potential MDR1 (ABCB1) deficiency( Don’t use in Australian Sheppards, collies, sheltie, wire haired whippets)
Myelosuppression
Neuropathy
Extravasation

Question 22

What are the side effects of cyclosporine?

Answer 22

GI disturbances
Gingival hyperplasia
Hepato/nephrotoxicity
These are uncommon if the dose is adjusted based on blood levels
Does not suppress marrow

Question 23

What are the side effects of leflunomide?

Answer 23

Few have been identified as it is a new drug

Question 24

What are the side effects of mycophenolate?

Answer 24

Diarrhea

Question 25

What are the pharmacokinetics of cyclosporine?

Answer 25

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

Question 26

What are the pharmacodynamics of cyclosporine?

Answer 26

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

Question 27

What are the secondary infections that cause a patient to be at risk for with immunosuppresive drugs?

Answer 27

You can see susceptibility to bacterial infections:
Cystitis
Pyoderma
Pneumonia

You can see overwhelming, unusual infections:
Fungal (Aspergillus)
Protozoal (Toxoplasma)
Parasitic (Demodex)

Question 28

How can you prevent secondary infections?

Answer 28

Prophylactic antibiotics are usually not indicated

They can help treat the bacterial infections but not the unusual infections