Immunosuppressives Flashcards
MOA of oclacitinib
Inhibits Janus-kinase 1 and 3-dependent cytokines
Which cytokines does oclacitinib inhibit?
IL-2/IL-6 (inflammatory cytokines)
IL-4/IL-13 (allergic cytokines)
IL-31 (pruritogenic cytokine)
Side effects of oclacitinib
GI- V/D/anorexia
infections- demodicosis, pneumonia, pyoderma
MOA of lokivetmab
Binds to and neutralizes IL-31
How is lokivetmab metabolized?
Via protein degradation pathways
Side effects of lokivetmab
lethargy vomiting hyperexcitability pain at injection site urinary incontinence
What is lokivetmab?
caninized monoclonal Ab against IL-31
Definition of immunosuppression
to reduce the activation or efficacy of the immune system
Definition of immunomodulation
to modify the immune system
Name 3 categories of cytotoxic drugs
- cycle specific: more toxic to cells actively cycling than in G0 phase
- phase specific: active during specific cycle
- cycle non-specific: toxic to proliferating and intermitotic cells
Which category of cytotoxic drugs are alkylating agents?
“cycle non-specific”; most active during G1 and S phases
MOA for cyclosphosphamide
creates DNA crosslinkages interfering with DNA and RNA replication and function
Which metabolite of cyclophosphamide is responsible for hemorrhagic cystitis?
acrolein
Side effects of cyclophosphamide
myelosuppression loss of vibrissae (cats) hemorrhagic cystitis decreased wound healing alopecia (poodles, OES)
MOA of chlorambucil
creates DNA crosslinkages disrupting DNA synthesis
Side effects of chlorambucil
myelosuppression (thrombocytopenia)
GI- V/D/anorexia
alopecia (poodles, Kerry blue terriers)
MOA of lomustine
not fully understood….inhibit DNA/RNA synthesis
Which type of cutaneous cancer is lomustine commonly used to treat?
cutaneous T cell lymphoma
Name two subclasses of alkylating agents.
- nitrogen mustards (cyclophosphamide & chlorambucil)
2. nitrosoureas (lomustine)
Side effects of lomustine
myelosuppression (neutropenia/thrombocytopenia)
hepatotoxicity
GI effects (V/D/anorexia)
Name 3 subclasses of antimetabolites.
- purine analogs (azathioprine, mycophenolate)
- pyrimidine analogs (5-fluorouracil, leflunomide)
- Antifolates (methotrexate)
Which category of cytotoxic drugs are antimetabolites?
Most are “phase specific”; usually active in S phase
MOA of azathioprine
interferes w/ purine nucleic acid base production–> inhibits DNA/RNA synthesis
What is the prodrug of azathioprine responsible for its effects?
6-mercaptopurine
What is the enzyme mainly responsible for metabolism of 6-mercaptopurine?
Which species or breeds have a decrease or increase in the activity of this enzyme?
thiopurine methyl-transferase (TPMT)
Low TPMT activity: cats, Giant Schnauzers
Elevated TPMT activity: Alaskan malamute
Side effects of azathioprine
Myelosuppression (thrombocytopenia)….NOT for cats
vomiting
hepatotoxicity….monitor enzymes q 2 weeks for first 2 months
pancreatitis
MOA of mycophenolate
inhibits de novo purine synthesis via its prodrug mycophenolic acid
more specifically: reversibly binds to inosine monophosphate dehydrogenase (IMPDH)…rate limiting step in de novo guanine synthesis
Side effects of mycophenolate
myelosuppression
V/D/nausea
increased risk of opportunistic infections
leukocytosis
MOA of 5-fluorouracil
converted to fluoruridine monophosphate (FUMP) and fluoruridine triphosphate (FUTP)…these interfere with DNA and RNA synthesis respectively
Which species should 5-fluorouracil NOT be used in?
CATS!
Neuro and hepatotoxic
Side effects of 5-fluorouracil
myelosuppression
GI toxicity
neurotoxicity (seizures)
MOA of leflunomide
inhibits dihydroorotate dehydrogenase enzyme, thus preventing formation of ribonucleotide uridine monophosphate (rUMP)–> decreased DNA/RNA synthesis
Side effects of leflunomide
hepatotoxicity
vomiting
myelosuppression (lymphopenia, anemia)
TEN/SJS in people
MOA of methotrexate
binds and inhibits dihydrofolate reductase needed for purine and pyrimidine synthesis
S-phase specific
Side effects of methotrexate
GI (V/D/inappetence) myelosuppression hepatopathy renal tubular necrosis Alopecia and depigmentation
MOA of cyclosporine
calcineurin inhibitor
binds to cyclophilin–> CsA/cyclophilin bind to calcineurin–> inhibits signal transmission–> inhibits T cell activation and production of IL-2, -3, -4
Name 10 drugs which increase CsA levels
cytochrome P450 INHIBITORS--> increase CsA acetazolamide allopurinol amlodipine azithromycin azoles bromocriptine diltiazem carvedilol cimetidine chloramphenicol cipro/enrofloxacin cisapride clarithromycin clopidogrel colchicine corticosteroids- NOT methylprednisolone danazol digoxin estrogens fluvoxamine glipizide grapefruit juice (flavonoids) imipenem losartan medroxyprogesterone metronidazole omeprazole sertraline tinidazole
Name 10 drugs which decrease CsA levels
Cytochrome P450 INDUCERS--> decrease CsA levels azathioprine carbamazepine clindamycin cyclophosphamide famotidine griseofulvin octreotide rifampin phenobarbital phenytoin St. John's wart sulfadiazine sulfasalazine terbinafine trimethoprim warfarin
Side effects of cyclosporine
GI- V/D/anorexia benign gingival hyperplasia papillomatosis/histiocytomas hirsutism fatal systemic toxoplasmosis in cats
MOA of tetracycline and niacinamide
Exact MOA unknown
tetracycline: anti-inflammatory, affects complement and Ab production, inhibits leukocyte chemotaxis, PG synthesis
niacinamide: blocks Ag specific IgE induced histamine release, inhibits mast cell degranulation
Side effects of tetracycline/niacinamide
V/D/anorexia
elevated liver enzymes (niacinamide)
enamel hypoplasia and esophageal erosions/ulcerations (tetracycline)
MOA of pentoxifylline
methylxanthine derivative
increases microcirculation via increased RBC flexibility
decreases platelet aggregation
decreases leukocyte response to IL-1/TNF-alpha
decreased production of IL-1, -4, -12, TNF-alpha
Side effects of pentoxifylline
V/D
dizziness in people
EM- 2 cases reported
MOA of dapsone
interferes w/ myeloperoxidase activity
decreases complement activity, mast cell degranulation, Ab production
Side effects of dapsone
myelosuppression (anemia, neutropenia, thrombocytopenia)
hepatotoxicity
GI
CADR
MOA of human IVIG
interferes w/ Fas-Fas ligand apoptosis
inhibits T cell proliferation
eliminates circulating immune complexes
Side effects of IVIG
anaphylaxis during infusion
acute renal failure
MOA of gold salts (chrysotherapy)
inhibit lysosomal enzymes, complement, chemotaxis, DNA/RNA synthesis, Ig synthesis
suppresses inflammatory mediator release, suppressor T cells
Side effects of gold salts
myelosuppression
oral ulceration
glomerulonephropathy
fatal TEN
MOA of colchicine
suppresses neutrophil chemotaxis
inhibits lysosomal degranulation, Ig secretion, IL-1 production, histamine release, cell division
Side effects of colchicine
GI
myelosuppression (when given w/ NSAIDs)
Which drugs should colchicine NOT be used with?
azathioprine and chlorambucil
Which diseases is colchicine commonly used for?
Shar Pei fever, amyloidosis, EBA, JEB
MOA of imiquimod
activation of TLR7–> IFN-alpha, IL-12, TNF-alpha secretion–> Th1 response and cell-mediated immunity
Side effects of imiquimod
local irritation- burning, erythema, pain, erosion, oozing
depigmentation/hair loss after use
