Immunosuppressants (NAVDF Tham) Flashcards
What controls HPA axis and CRH release (3)
*Circadian cycle
*Inflammation
*Stress
Which part of the pituitary gland secretes CRH
Anterior
Steroid biosynthesis pathway
(fun fact: trilostane inhibits 3-β-hydroxysteroid dehydrogenase)
Glucocorticoid MOA, genomic mechanisms
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
Glucocorticoid MOA (how it enters cell)
Diffuses through plasma membrane
In cytosol: binds glucocorticoid receptor, which RELEASES GR from chaperone protein
GR+GC go into nucleus –> induce genomic effects
Glucocorticoid MOA, NONgenomic mechanisms
*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
Functions of genes upregulated by NFkB
*Proinflammatory cytokines, chemokines
*Anti-apoptosis proteins (BCL-2)
*Lymphocyte survival, activation
*Adhesion molecules (ICAM1, VCAM1)
Which cells have glucocorticoid receptors?
All nucleated cells
Wide distribution of GRs, many AEs
Does antiinflammatory prednisolone (1-2 mg/kg/d) for 14d affect in hemodynamic and ECG changes in healthy cats?
No
Generic modified cyclosporine achieved ______ blood concentrations at 1 hr post-administration than Atopica
HIGHER (but only for the 1st hour!!)
After 1.5 hours, no significant difference!!!
We need bioequivalent pharmacokinetic studies based on AUC + Cmax
NFAT function
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
Mechanism of cyclosporine
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
Is bioavailability of CsA decreased when frozen?
No per Bachtel 2015 study
Most common AEs with cyclosporin
*Vomiting
*Diarrhea
*Gingival hyperplasia
Pathogenesis of CsA induced gingival hyperplasia
*Inhibition of MMPs
*Inhibition of gingival cell apoptosis
*Increased proliferation of HGF
*Overexpression of ECM proteins
*Upregulation of IL-1a, IL-6, IL-8
Cyclosporine AEs
*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)
2 causes of psoriasiform lichenoid dermatosis
1) Cyclosporine-induced
2) Spontaneous (Springer spaniel, Staph infx)
T or F: CsA will reactivate Toxoplasma gondii oocyst shedding and subclinical disease
False
What is the riskiest timeframe to develop Toxoplasma with regards to cyclosporine administration
*Toxoplasma exposure in naive cats while on CsA
Recommendation for outdoor cats on CsA?
Avoid hunting/raw food to avoid Toxoplasmosis (esp if naive cat)
Azathioprine is the prodrug of ________
6-mercaptopurine (6-MP)
Interferes with nucleotide synthesis
What is the toxic metabolite of azathioprine
6-thioguanine monophosphate (6-TGN)
Via HRPT enzyme
What are the 2 nontoxic metabolites of azathioprine
6-MMP
6-thiouric acid
AEs of AZA
*Myelosuppression
*Hepatotoxicosis
T or F: lower TPMT levels are correlated with higher risk of myelosuppression in dogs
FALSE
But it IS in cats!
Which enzyme is lower in cats, leading to their higher risk of myelosuppression with AZA?
TPMT
Adjusting azathioprine dosing to ______ with decrease risk of hepatotoxicosis
EOD
Median time for hepatotoxicity to occur 2’ azathioprine
14 days
What type of bonds does Chlorambucil induce (reactive electrophile, alkylating agent)
Covalent bonds
What are the cytotoxic effects of chlorambucil
Alkylate the nucleophilic portion of DNA through formation of covalent bonds
Which type of DNA cross linking is MOST devastating: intrastrand or interstrand
Interstrand is worse!
Which DNA nucleotide does chlorambucil act on?
Guanine
MOA chlorambucil
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
Which diseases is chlorambucil useful for in dogs?
*Vaccine-induced ischemic dermatopathy
*Canine eosinophilic granuloma
Chlorambucil AEs
1) Myelosuppression in 7-14 days
2) Reversible myoclonus
3) Fanconi syndrome
Which immunosuppressive medication can cause Fanconi syndrome
Chlorambucil
Active metabolite of mycophenolate mofetil
Mycophenolic acid
MOA of mycophenolate mofetil
Interferes with guanine synthesis via inhibition of inosine monophophate dehydrogenase (IMPDH) enzyme
Which leukocytes rely on guanine synthesis via the de novo synthesis pathway
T cells
B cells
Which disease was successfully treated with mycophenolate monotherapy
ECLE
Mycophenolate AEs
*Diarrhea most common (20%)
Mechanism of Oclacitinib
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
Higher doses of Apoquel can cause immunosuppression via reduction in _________
*IL-2
*IL-15
*IL-18
*IFNg
*Induces apoptosis of CD4+, CD8+ T cells
Apoquel can be used to treat ____:
*cAD
*AISBD
*Ischemic dermatopathy
*Hyperkeratotic EM
*Canine ear tip ulcerative dermatitis
*Feline PF
*Canine PV
*ECLE, MCLE, FDLE
AEs of Apoquel
*Cutaneous papilloma
*Demodicosis
*Bacterial pneumonia in 6-month and 12-month old dogs
Safety of BID Apoquel in dogs
AEs: Pyoderma, GI upset, OE, mild neutropenia, eosinopenia, leukopenia
*Hypercholesterolemia in 3 dogs
What infectious disease can cause death in cats receiving oclacitinib
Fatal disseminated toxoplasmosis (FIV+)
Which cells are NOT affected by Bruton’s tyrosine kinase
T cells
BCR not present in T cells!
Function of Bruton’s tyrosine kinase
Links B-cell receptor, TLR, CD19, chemokine receptor with B cell proliferation and survival
Other cells with BTK
Mast cells
Monocytes
Macrophages
Neutrophils
Platelets
Where on BTK molecule do BTK inhibitors bind
Catalytic domain
BTK inhibitors in dogs (PRN 473, PRN 1008)
Good response with PF
AEs with BTK inhibitor
*Pyometra??
*IMPA
*Peripheral lymphadenopathy
*Diarrhea, inappetance
*Mast cell tumor??
