Lecture 19+20: Immunotherapies Flashcards
immune-mediated diseases are a failure of immune ______
regulation
- self or non-self antigens inciting a pathologic immune response
auto-immune diseases are a failure of….
self tolerance
- usually a known self antigen inciting a pathogenic immune response
what are some common immune-mediated diseases of dogs & cats
- atopic dermatitis
- osteoarthirits
- chronic bronchitis /asthma / recurrent airway obstruction
- lymphoplasmacytic rhinitis
- IBS
- Glomerulonephritis
common auto-immune diseases in dogs+cats
- immune mediated hemolytic anemia (IMHA)
- immune mediated thrombocytopenia (ITP)
- systemic lupus erythematosus (SLE)
- immune mediated poly-arthiritis (IMPA)
- Type I DI (dogs)
- Autoimmune myasthenia gravis
pharmacodynamics is…
what drugs to do the body
pharmacokinetics is ….
what body does to drugs
what is responsible for the conversion of Arachidonate into prostaglandin H2 (PGH2)
COX 1 + 2
COX metabolizes the first step in….
arachidonic acid metabolism to prostanoids
COX I is constitutive meaning
it is always expressed
COX 2 is inducible meaning
it is conditionally expressed
COX-2 is produced in response to cytokines, tumor promoters, growth factors, etc.
what is COX 2 produced in response to
cytokines, tumor promoters, growth factors, etc
- generates a positive inflammatory feedback loop
what species is acetaminophen highly toxic to
cats
what are the main COX inhibitor drugs that are analgesic and anti-pyretic
- acetaminophen
- aspirin
- NSAIDs
what are the 3 classes of NSAIDs
Nonspecific (COX 1+2)
COX-2 Preferential
COX-2 Exclusive (99% specific for COX2)
what class of NSAID is ketoprofen
Nonspecific (COX 1 and 2)
what class of NSAID is phenybutazone
COX 2 Preferential
what class of NSAID is flunixin meglumine (‘Banamine’)
COX 2 Preferential
what class of NSAID is carprofen
COX 2 Preferential
what class of NSAID is meloxicam
COX 2 Preferential
what class of NSAID is firocoxib
COX 2 Exclusive
what class of NSAID is robenacoxib (‘Onsior’)
COX 2 Exclusive
what class of NSAID is deracoxib
COX 2 Exclusive
NSAIDs target inflammation occurring primarily in the….
synovium (synovitis membrane) and articular cartilage
NSAIDs reduce the production of…
PGE2 by synoviocytes + chondrocytes
PGE2 directly contributes to inducing ________ of chondrocytes
apoptosis
what does PGE2 promote the secretion of
- other cytokines (IL-1, NO, TNF-a) that contribute to the cartilage breakdown leading to synovitis and chondrocyte apoptosis
major NSAID toxicities
- gastric ulcers (pain, bleeding, diarrhea)
- nephrotoxicity (acute renal failure, interstitial nephritis, glomerular nephropathy)
- Hepatotoxicity (enzyme elevation + hepatitis)
also… bronchoconstriction, pancreatitis, agranulocytosis, aplastic anemia
Grapiprant use
pain and inflammation for osteoarthiritis
Grapiprant is a _____ receptor antagonist
EP4
EP4 is one of four ______ receptors that mediate inflammation in osteoarthritis
PGE2
what are the most commonly used and efficacious anti-inflammatory drugs
glucocorticoids
- suppress essentially every component of the inflammatory process, inhibit more mediators of inflammation than any other drug
what is the early effect of glucocorticoids?
inhibition of phospholipase A2
what are the late effects of glucocorticoids?
- increases the synthesis of anti-inflammatory ILs
- decreased synthesis of pro-inflammatory ILs and cytokines
- decreased production of leukocytes
- decreased opsonization
what is the endogenous glucocorticoid?
Hydrocortisone (Cortisol)
can cats utilize prednisone
no b/c they cannot absorb nor convert prednisone effectively
glucocorticoid replacement is used to treat ?
hypoadrenocorticism (addison’s)
glucocorticoids used for musculoskeletal / joint infections
triamcinolone: dogs, cats, horses
isoflupredone: cattle and pigs
flumethasone: dogs and horses
adverse effects of glucocorticoids used for musculoskeletal / joint infections
- muscle atrophy
- inhibits fibrocartilage growth
* DON’T USE IN GROWING ANIMALS - causes osteoperosis
use of Fluticasone
- upper tracheobronchial disease in dogs
- asthma in cats
- RAO in horses ($$$)
effect of Fluticosane
local pulmonary immunosuppression to reduce inflammation and epithelial damage
adverse effects of Fluticosane
- pharyngitis and upper resp. infections
- may decrease the production of endogenous corticosteroids = systemic effect
- risk of lethargy, bradycardia, anemia, hypovolemic shock
- not for use in acute asthmatic attacks
what are the 5 most common glucocorticoids used for skin, eyes, ears (Don’t Honk I’ll Tinkle Pee)
- dexamethasone
- hydrocortisone
- isoflupredone
- triamcinolone
- prednisolone
main reasons to NOT use glucocorticoids
- cutaneous food allergies (rare in herbivores)
- infectious or parasitic (bacterial or fungal skin infections….flea allergy dermatitis)
what is the common length of txt time w/ glucocorticoids
> 2 weeks
main adverse effects of glucocorticoid use
- gastric ulcers and colonic perforation
- infections
—> increases susceptibility to infections b/c of immune suppression & inhibition of inflammation masks signs of disease - polyuria, polydipsia, polyphagia
- muscle atrophy
- laminitis in horses
adverse effects caused by the systemic
use of glucocorticoids
- chronically high exogenous glucocorticoids suppress the HPA axis
- adrenals reduce glucocorticoid and mineralocorticoid production
- adrenals may atrophy
- slowly reduce exogenous glucocorticoid dose over time to allows HPA axis to recover
what are the itch cytokines
IL- 2
IL-4
IL-6
IL-13
IL-31
what does Cyclosporin A (‘Atopica’) do
- binds cyclophilin to calcineurin
- inhibits all T-cell response by blocking the transcription of IL-2 and INF-y
what is Cyclosporin A used for
- atopic dermatitis
- keratoconjunctivitis sicca and autoimmune disorders (extra-label)
adverse effects of Cyclosporin A
- V+/D+, anorexia
- hypersensitivity
- gingival hyperplasia
- DM (dogs)
- hepatic lipidosis (cats)
when should Cyclosporin A NOT be used
- history of malignant neoplasia
- use of live Vx
- FIV or FeLV positive
- latent Toxoplasma gondii infection
what is the use of Oclacitinib (‘Apoquel’)
txt of atopic dermatitis in dogs >1yr
what are the adverse effects of Oclacitinib?
- D+/V+
- polydipsia
- lethargy
- immunosuppression, neoplasia, skin disorders
what is the MOA of Oclacitinib?
competitive inhibitor of Janus kinases (JAK1 primarily)
what is Lokivetmab (‘Cytopoint’), how does it work
- “caninized” (only works in dogs) monoclonal antibody
- Neutralizes IL-31 (a pro-pruritic cytokine acting through JAK1/2 pathway)
Adverse effects of Lokivetmab
- lethargy
- V+
- hyperexcitability
- injection site pain
- urinary incontinence
how are monoclonal antibodies traditionally produced?
using an in vitro cell culture known as hybridoma that uses mouse cells
immune-mediated diseases are usually acquired or secondary, this means that…
they are caused by another disease process
- multifactoral etiology
autoimmune diseases are primary mostly, this mean…
diseases are acquired through the germ line
what does it mean for effects to be off-target
they can end up binding something else somewhere else in the body
what does it mean for drug effects to be overextended
the drug causes more of an effect than expected
what do labeled use drugs (FDA-approved for veterinary use) require
- defines a drug
- defines dose/interval and duration of the drug
- is given by a specified route
- given for a particular species
- has been shown (by manufacturer) to be effective for the indicated disease
what is extra-label use of a drug?
drug itself is FDA approved but the way it used isn’t - however using it is still allowed legally
also allows for use of Human FDA approved drugs that lack veterinary approval
using ketoprofen in birds is an example of what type of drug use (labeled vs extra labeled)
Extra label use
what does COX-1 produce
prostanoids needed for the maintenance of normal physiology
ex: gastric cytoprotection and normal renal vasoconstriction
the analgesic and anti-pyretic properties of COX inhibitors are due to actions of the ________, not anti-inflammatory effects
Nervous system
COX inhibitor that is an investigational drug for cats at risk of saddle thrombi
Aspirin
what are the most common chronic, labeled indications for NSAIDs usage?
musculoskeletal pain and inflammation and osteoarthritis
what is one of the major differences b/w indications for glucocorticoid use
different doses
can you give Cylosporin A to a cat who is positive for FIV or FeLV ?
naur
what can result from using murine (human) antibodies to treat other species?
can cause an immune response against the therapeutic antibody
patients endogenous immune system opsonizes the therapeutic antibody = HAMA respnse = Human Anti-Mouse Antibody
what is a HAMA response
Human Anti-Mouse Antibody
occurs when a murine antibody is used to treat other species and the patients endogenous immune system ends up opsonizes the therapeutic antibody
what is the effect of Mycophenylate mofetil
reduces DNA synthesis by inhibiting production of guanine nucleotides
what is the effect of Azathioprine
reduces DNA synthesis by…
- introducing thio-guanine bases into elongating DNA strands
- inhibiting adenosine and guanine (purine) production
how does Azathioprine promote T-cell apoptosis
by inhibiting Rac stimulation from CD28
what drug can be used in combination w/ corticosteroids to reduce corticosteroid dose
Azathioprine
adverse effects caused by Mycophenylate mofetil
V+/D+, anorexia
lymphopenia w/ increased skin infections
adverse effects caused by Azathioprine
in dogs…
-V+/D+, anorexia
-leukopenia and thrombocytopenia
-pancreatitis
-hepatopathy
in cats…
bone marrow suppression b/c they have lower capacity to metabolize the drug
if a drug ends in “-coxib”, it is a COX-2 _________ NSDAID
COX 2 exclusive
if a drug ends in ‘-one’ it is probably a glucocorticoid… but there are 2 exceptions what are they
Phenylbutazone (COX 2 Preferential NSAID)
Budenoside is a glucocorticoid
cyclosporine, oclacitinib and lokivetmab all act on ________ function
Cytokine function
what is Triamcinolone, what is its use, and in what species?
glucocorticoid used in musculoskeletal/joint infections
dogs, cats, horses
what is Isoflupredone, what is its use, and in what species?
glucocorticoid used in musculoskeletal/joint infections
cattle, pigs
what is Flumethasone, what is its use, and in what species?
glucocorticoid used in musculoskeletal/joint infections
dogs, horses
what drug is a treatment for atopic dermatitis and works by inhibiting all T-cell response by blocking the transcription of IL-2 and INF-y
Cyclosporin A
what drug is a treatment for atopic dermatitis and can cause hepatic lipidosis in cats
Cyclosporin A
what drug promotes T-cell apoptosis by inhibiting Rac stimulation from CD28
Azathioprine
symptoms of gastric ulcers (an NSAID toxicity)
pain, bleeding, diarrhea
symptoms of hepatotoxicity (NSAID toxicity)
enzyme elevation + hepatitis
symptoms of nephrotoxicity (NSAID toxicity)
acute renal failure, interstitial nephritis, glomerular nephropathy
