Immunomodulatory Drugs. Viviano Vet clinics + Nelson/Couto

Question 1

Where in the body do glucocorticoids work?

Answer 1

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

Question 2

What is the mechanism of action of glucocorticoids at anti-inflammatory dosages?

Answer 2

• Phospholipase A2 inhibition
• inhibition of inflammatory cytokine release
• granulocyte cell membrane stabilization

Question 3

What is the function of phospholipase A2?

Answer 3

converts cell membrane phospholipids to arachidonic acid

Question 4

What are the two main target cells of the immunosuppresive mechanism of action of glucocorticoids

Answer 4

Macrophages
T cells

inhibits B cell antibody production in some animals with chronic use

Question 5

How do immunosuppressive doses of glucocorticoids affect macrophages?

Answer 5

• downregulates Fc receptor expression
• decreases responsiveness of antibody sensitized cells
• decreases antigen processing

Question 6

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)?

Answer 6

4-5 times higher AUC

Question 7

Why could dexamethasone be a better option for animals with underlying heart disease?

Answer 7

dexamethasone lacks mineralocorticoid activity > minimizes Na and water retention

Question 8

How does the potency of dexamethasone compare to prednisone?

Answer 8

4-10 times higher potency of dexamethasone

Question 9

Where within the intestines does budesonide have its most acitivity?

Answer 9

distal small intestines

Question 10

List adverse effects of glucocorticoids

Answer 10

• 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

Question 11

How do glucocorticoids induce an elevation in serum ALKP?

Answer 11

ALKP is elevated secondary to the induction of the steroid-induced isoenzyme (corticosteroid-induced alkaline phosphatase isoenzyme)

Question 12

What is the main target cell of cyclosporine?

Answer 12

T cells/ T lymphocytes

Question 13

Explain how T cells are activated

Calcineurin

Answer 13

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)

Question 14

Explain how cyclosporin inhibits T cell activation

Answer 14

Cyclosporine binds to cytoplasmic cyclophilin -> this complex binds to calcineurin and inhibits its dephosphorylation of NFAT

Question 15

What other cells does cyclosporine secondarily affect and how

Answer 15

granulocytes, macrophages, NK cells, mast cells, eosinophils
via decrease in production of IL-2,-3,-4, TNF-alpha, INF-gamma

Question 16

can cyclosporine be given with food?

Answer 16

bioavailability is improved if given without food, current recommendation: give 2 hours before or after meal

Question 16

What are the adverse effects of cyclosporine?

Answer 16

• GI upset
• gingival hyperplasia
• opportunistic infections
• hepatotoxicity
• anaphylaxis
• thromboembolic complications
• lymphoproliferative disorders

Question 17

Explain the pathway of the mechanism of action of azathioprine

6-MP, purines

Answer 17

azathioprine -> 6-MP -> 6-TGNs -> 6-TGNs compete with purines for RNA/DNA incorporation -> disrupts mitosis of cells

Question 18

What cells does azathioprine mostly affect. Why is azathioprine selective for these cells?

Answer 18

lymphocytes
they lack salvage pathways for purine biosynthesis

main target: T lymphocytes

Question 19

What is TPMT and what does it have to do with the toxicity of azathioprine

Answer 19

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

Question 20

What are the adverse effects of azathioprine?

Answer 20

• GI upset
• hepatotoxicity/ hepatic necrosis
• myelosuppression
• pancreatitis

Question 21

explain the mechanism of action of chlorambucil

Answer 21

• metabolized in liver to active metabolite: phenylacetic acid
• cell-cycle nonspecific, cytotoxic, alkylating agent capable of cross-linking DNA.
• main target: B cells

Question 22

What are the adverse effects of chlorambucil?

Answer 22

• myelosuppression
• neurotoxicity (with overdose)
• kidney disease (fanconi syndrome reported)

Question 23

Explain the mechanism of action of myocphenolate

Answer 23

mycophenolate -> metabolized to mycophenolic acid (MPA) -> inhibitor of IMPDH (type II isoform)
IMPDH as rate-limiting step of the de novo biosynthesis of purines

Question 24

what are the target cells of myocphenolate. how does it target these cells?

Answer 24

lymphocytes
IMPDH type II isoform more common than type I isoform in these cells
no salvage purine synthesis in lymphocytes

Question 25

what are the adverse effects of mycophenolate?

Answer 25

• GI upset
• opportunistic infections
• allergic reactions

Question 26

How are glucocorticoids carried in the circulation?

Answer 26

glucocorticoid-binding globulin
aka transcortin

Question 27

Summarize all effects of glucocorticoids that cause immunosuppresion

Answer 27

• 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)

Question 28

Order Cortisone, hydrocortisone, prednisone and dexamethasone from most to least mineralocorticoid effects

Answer 28

Hydrocortisone
Cortisone
Prednisone
Dexamethasone

Question 29

How long does Azathioprine take from initiation of treatment to full clinical effect?

Answer 29

4-8 weeks