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EV ACVD Study > Immunosuppressants (NAVDF Tham) > Flashcards

Immunosuppressants (NAVDF Tham) Flashcards

1
Q

What controls HPA axis and CRH release (3)

A

*Circadian cycle
*Inflammation
*Stress

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2
Q

Which part of the pituitary gland secretes CRH

A

Anterior

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3
Q

Steroid biosynthesis pathway

A

(fun fact: trilostane inhibits 3-β-hydroxysteroid dehydrogenase)

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4
Q

Glucocorticoid MOA, genomic mechanisms

A

1) Direct binding to GC Receptor Element (GRE)
-Induces:
*Annexin-1
*GC-induced leucine zipper (GLIZ) –> inhibits NFkB, MAPk
*Mitogen-activated protein kinase phosphatase 1 (MPK1)

-Inhibits:
*CRH
*B-endorphins
*MSH

2) Tethering:
*GC/GR binds to transcription factor (not to DNA GRE)
*Induces or inhibits certain transcription of genes
-Inhibits transcription of:
*NFkB
*AP-1
*STAT
*NFAT

3) Composite GRE binding
*GC/GR binds to both GRE DNA AND transcription factor

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5
Q

Glucocorticoid MOA (how it enters cell)

A

Diffuses through plasma membrane

In cytosol: binds glucocorticoid receptor, which RELEASES GR from chaperone protein

GR+GC go into nucleus –> induce genomic effects

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6
Q

Glucocorticoid MOA, NONgenomic mechanisms

A

*Glucocorticoid binds to mGR (in cell membrane) or cGR (in cytoplasm)
*GC can also bind to nonspecific part of cell membrane

Leads to changes in cell that affects:
*Transmembrane currents
*Phosphorylation events
*Calcium levels

RAPID ONSET

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7
Q

Functions of genes upregulated by NFkB

A

*Proinflammatory cytokines, chemokines
*Anti-apoptosis proteins (BCL-2)
*Lymphocyte survival, activation
*Adhesion molecules (ICAM1, VCAM1)

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8
Q

Which cells have glucocorticoid receptors?

A

All nucleated cells

Wide distribution of GRs, many AEs

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9
Q

Does antiinflammatory prednisolone (1-2 mg/kg/d) for 14d affect in hemodynamic and ECG changes in healthy cats?

A

No

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10
Q

Generic modified cyclosporine achieved ______ blood concentrations at 1 hr post-administration than Atopica

A

HIGHER (but only for the 1st hour!!)

After 1.5 hours, no significant difference!!!

We need bioequivalent pharmacokinetic studies based on AUC + Cmax

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11
Q

NFAT function

A

1) Autoantigen binds TCR
2) Increase intracellular calcium
3) High Ca2+ causes calmodulin to bind calcineurin enzymes
4) Calmodulin/calcineurin complex dephosphorylates NFAT
5) NFAT translocates to nucleus
6) Upregulation of IL-2
7) Stimulates CD4+ lymphocytes
*Activate CD8 cells (which attack host cells in CLE!)
*C cells –> plasma cells

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12
Q

Mechanism of cyclosporine

A

1) CsA binds cyclophillin
2) Cyclophillin binds to calcineurin, which inhibits calcineurin function (does not dephosphorylate NFAT)
3) NFAT cannot translocate to nucleus
4) No increase in IL-2

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13
Q

Is bioavailability of CsA decreased when frozen?

A

No per Bachtel 2015 study

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14
Q

Most common AEs with cyclosporin

A

*Vomiting
*Diarrhea

*Gingival hyperplasia

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15
Q

Pathogenesis of CsA induced gingival hyperplasia

A

*Inhibition of MMPs

*Inhibition of gingival cell apoptosis
*Increased proliferation of HGF
*Overexpression of ECM proteins
*Upregulation of IL-1a, IL-6, IL-8

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16
Q

Cyclosporine AEs

A

*Vomiting, diarrhea
*Gingival hyperplasia
*Cutaneous papillomatosis
*Hypertrichosis
*Psoriasiform lichenoid dermatitis
*Opportunistic infections (esp when given with oral GC)
-Bacterial (Nocardia, Burkholderia cepacian)
-Fungal (Alternaria, Curvularia, Aspergillus)

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17
Q

2 causes of psoriasiform lichenoid dermatosis

A

1) Cyclosporine-induced
2) Spontaneous (Springer spaniel, Staph infx)

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18
Q

T or F: CsA will reactivate Toxoplasma gondii oocyst shedding and subclinical disease

A

False

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19
Q

What is the riskiest timeframe to develop Toxoplasma with regards to cyclosporine administration

A

*Toxoplasma exposure in naive cats while on CsA

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20
Q

Recommendation for outdoor cats on CsA?

A

Avoid hunting/raw food to avoid Toxoplasmosis (esp if naive cat)

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21
Q

Azathioprine is the prodrug of ________

A

6-mercaptopurine (6-MP)

Interferes with nucleotide synthesis

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22
Q

What is the toxic metabolite of azathioprine

A

6-thioguanine monophosphate (6-TGN)

Via HRPT enzyme

23
Q

What are the 2 nontoxic metabolites of azathioprine

A

6-MMP
6-thiouric acid

24
Q

AEs of AZA

A

*Myelosuppression
*Hepatotoxicosis

25
Q

T or F: lower TPMT levels are correlated with higher risk of myelosuppression in dogs

A

FALSE

But it IS in cats!

26
Q

Which enzyme is lower in cats, leading to their higher risk of myelosuppression with AZA?

A

TPMT

27
Q

Adjusting azathioprine dosing to ______ with decrease risk of hepatotoxicosis

A

EOD

28
Q

Median time for hepatotoxicity to occur 2’ azathioprine

A

14 days

29
Q

What type of bonds does Chlorambucil induce (reactive electrophile, alkylating agent)

A

Covalent bonds

30
Q

What are the cytotoxic effects of chlorambucil

A

Alkylate the nucleophilic portion of DNA through formation of covalent bonds

31
Q

Which type of DNA cross linking is MOST devastating: intrastrand or interstrand

A

Interstrand is worse!

32
Q

Which DNA nucleotide does chlorambucil act on?

A

Guanine

33
Q

MOA chlorambucil

A

Guanine binds to chlorambucil instead of DNA cytosine

Same chlorambucil molecule binds MULTIPLE guanines on MULTIPLE strands

–> results in UNWANTED DNA crosslinking!

INTERSTRAND linkage is the worst! But BOTH lead to cytotoxic effects, cel death

34
Q

Which diseases is chlorambucil useful for in dogs?

A

*Vaccine-induced ischemic dermatopathy
*Canine eosinophilic granuloma

35
Q

Chlorambucil AEs

A

1) Myelosuppression in 7-14 days
2) Reversible myoclonus
3) Fanconi syndrome

36
Q

Which immunosuppressive medication can cause Fanconi syndrome

A

Chlorambucil

37
Q

Active metabolite of mycophenolate mofetil

A

Mycophenolic acid

38
Q

MOA of mycophenolate mofetil

A

Interferes with guanine synthesis via inhibition of inosine monophophate dehydrogenase (IMPDH) enzyme

39
Q

Which leukocytes rely on guanine synthesis via the de novo synthesis pathway

A

T cells
B cells

40
Q

Which disease was successfully treated with mycophenolate monotherapy

A

ECLE

41
Q

Mycophenolate AEs

A

*Diarrhea most common (20%)

42
Q

Mechanism of Oclacitinib

A

JAK inhibitor

*Apoquel binds JAK
*STATs can dimerize, but do not become phosphorylated
*Because STAT is not phophorylated, it cannot enter nucleus to act as a TF

-Selective for JAK 1

43
Q

Higher doses of Apoquel can cause immunosuppression via reduction in _________

A

*IL-2
*IL-15
*IL-18
*IFNg

*Induces apoptosis of CD4+, CD8+ T cells

44
Q

Apoquel can be used to treat ____:

A

*cAD
*AISBD
*Ischemic dermatopathy
*Hyperkeratotic EM
*Canine ear tip ulcerative dermatitis
*Feline PF
*Canine PV
*ECLE, MCLE, FDLE

45
Q

AEs of Apoquel

A

*Cutaneous papilloma
*Demodicosis
*Bacterial pneumonia in 6-month and 12-month old dogs

46
Q

Safety of BID Apoquel in dogs

A

AEs: Pyoderma, GI upset, OE, mild neutropenia, eosinopenia, leukopenia
*Hypercholesterolemia in 3 dogs

47
Q

What infectious disease can cause death in cats receiving oclacitinib

A

Fatal disseminated toxoplasmosis (FIV+)

48
Q

Which cells are NOT affected by Bruton’s tyrosine kinase

A

T cells

BCR not present in T cells!

49
Q

Function of Bruton’s tyrosine kinase

A

Links B-cell receptor, TLR, CD19, chemokine receptor with B cell proliferation and survival

50
Q

Other cells with BTK

A

Mast cells
Monocytes
Macrophages
Neutrophils
Platelets

51
Q

Where on BTK molecule do BTK inhibitors bind

A

Catalytic domain

52
Q

BTK inhibitors in dogs (PRN 473, PRN 1008)

A

Good response with PF

53
Q

AEs with BTK inhibitor

A

*Pyometra??
*IMPA
*Peripheral lymphadenopathy
*Diarrhea, inappetance
*Mast cell tumor??

EV ACVD Study (52 decks)

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