Immunomodulatory Drugs. Viviano Vet clinics + Nelson/Couto Flashcards
Where in the body do glucocorticoids work?
virtually on any cell of the body
glucocorticoids bind to cytoplasmic glucocorticoid receptors
the glucocorticoid-receptor complex then moves into the nucleus –> binds to glucocorticoid response elements –> and affects DNA transcription
What is the mechanism of action of glucocorticoids at anti-inflammatory dosages?
- Phospholipase A2 inhibition
- inhibition of inflammatory cytokine release
- granulocyte cell membrane stabilization
What is the function of phospholipase A2?
converts cell membrane phospholipids to arachidonic acid
What are the two main target cells of the immunosuppresive mechanism of action of glucocorticoids
Macrophages
T cells
inhibits B cell antibody production in some animals with chronic use
How do immunosuppressive doses of glucocorticoids affect macrophages?
- downregulates Fc receptor expression
- decreases responsiveness of antibody sensitized cells
- decreases antigen processing
prednisone is metabolized to its active form prednisolone. Comparing prednisolone to prednisone administration in cats, how much higher is the prednisolone plasma cc when prednisolone is administered (as opposed to prednisone)?
4-5 times higher AUC
Why could dexamethasone be a better option for animals with underlying heart disease?
dexamethasone lacks mineralocorticoid activity > minimizes Na and water retention
How does the potency of dexamethasone compare to prednisone?
4-10 times higher potency of dexamethasone
Where within the intestines does budesonide have its most acitivity?
distal small intestines
List adverse effects of glucocorticoids
- iatrogenic hyperadrenocorticism (PU/PD, polyphagia, weight gain, panting)
- adrenal gland suppression
- GI ulceration
- insulin resistance and secondary diabetes mellitus (more so in cats)
- muscle catabolism
- delayed wound healing
- opportunistic infections
- behavioral changes
How do glucocorticoids induce an elevation in serum ALKP?
ALKP is elevated secondary to the induction of the steroid-induced isoenzyme (corticosteroid-induced alkaline phosphatase isoenzyme)
What is the main target cell of cyclosporine?
T cells/ T lymphocytes
Explain how T cells are activated
Calcineurin
T cell receptor activation -> increased IC Ca -> calcineurin activation -> caclineurin dephosphorylates NFAT (nuclear factor of activated T cells) -> NFAT translocates into nucleus -> binds to AP-1 -> transcription of genes for T cell activation (production of interleukine-2 and other cytokines)
Explain how cyclosporin inhibits T cell activation
Cyclosporine binds to cytoplasmic cyclophilin -> this complex binds to calcineurin and inhibits its dephosphorylation of NFAT
What other cells does cyclosporine secondarily affect and how
granulocytes, macrophages, NK cells, mast cells, eosinophils
via decrease in production of IL-2,-3,-4, TNF-alpha, INF-gamma
can cyclosporine be given with food?
bioavailability is improved if given without food, current recommendation: give 2 hours before or after meal
What are the adverse effects of cyclosporine?
- GI upset
- gingival hyperplasia
- opportunistic infections
- hepatotoxicity
- anaphylaxis
- thromboembolic complications
- lymphoproliferative disorders
Explain the pathway of the mechanism of action of azathioprine
6-MP, purines
azathioprine -> 6-MP -> 6-TGNs -> 6-TGNs compete with purines for RNA/DNA incorporation -> disrupts mitosis of cells
What cells does azathioprine mostly affect. Why is azathioprine selective for these cells?
lymphocytes
they lack salvage pathways for purine biosynthesis
main target: T lymphocytes
What is TPMT and what does it have to do with the toxicity of azathioprine
TPMT is an alternative pathway for 6-MP (first metabolite of azathioprine) which produces the inactive 6-MMP
cats have less TPMT and are at increased risk of toxicity from the active azathioprine metabolites
patients with high activity may have inadequate response to treatment
myelosuppression associated with decreased TPMT activity
What are the adverse effects of azathioprine?
- GI upset
- hepatotoxicity/ hepatic necrosis
- myelosuppression
- pancreatitis
explain the mechanism of action of chlorambucil
- metabolized in liver to active metabolite: phenylacetic acid
- cell-cycle nonspecific, cytotoxic, alkylating agent capable of cross-linking DNA.
- main target: B cells
What are the adverse effects of chlorambucil?
- myelosuppression
- neurotoxicity (with overdose)
- kidney disease (fanconi syndrome reported)
Explain the mechanism of action of myocphenolate
mycophenolate -> metabolized to mycophenolic acid (MPA) -> inhibitor of IMPDH (type II isoform)
IMPDH as rate-limiting step of the de novo biosynthesis of purines
what are the target cells of myocphenolate. how does it target these cells?
lymphocytes
IMPDH type II isoform more common than type I isoform in these cells
no salvage purine synthesis in lymphocytes
what are the adverse effects of mycophenolate?
- GI upset
- opportunistic infections
- allergic reactions
How are glucocorticoids carried in the circulation?
glucocorticoid-binding globulin
aka transcortin
Summarize all effects of glucocorticoids that cause immunosuppresion
- inhibits NFkappaB –> therefore reduces inflammatory cytokine production
- Inhibits phospholipase A2 and COX (arachidonic acid pathway inhibition)
- suppress T cell function and cause apoptosis of T cells
- inhibit B cell antibody production
- inhibits granulocytes by stabilizing their membranes
- inhibits macrophages (downregulates Fc receptor expression)
Order Cortisone, hydrocortisone, prednisone and dexamethasone from most to least mineralocorticoid effects
Hydrocortisone
Cortisone
Prednisone
Dexamethasone
How long does Azathioprine take from initiation of treatment to full clinical effect?
4-8 weeks
