Lecture 19 +20: Immunotherapies Flashcards
Immune mediated or autoimmune: failure of immune regulation- self or non-self antigens inciting a pathologic immune response
Immune mediated disease
How are immune mediated diseases classified
Usually acquired/secondary- caused by another disease process
Multifactorial in etiology
Immune mediated or autoimmune:
Organ specific, start in one place
Antigen/antibody complexes can cause multi-organ dysfunction
Immune mediated
Autoimmune disease is a failure of ____
Self tolerance, known self antigen inciting a pathologic immune response
What is the classification for an autoimmune disease
Primary- acquired through germ line
Secondary
Immune mediated or autoimmune: organ specific, cell type specific effects
Autoimmune
What are some common immune mediated diseases of dogs and cats
Atopic dermatitis, osteoarthritis, chronic bronchitis/asthma/RAO, lymphoplasmacytic rhinitis, IBD, inflammatory/reactive hepatitis, glomerulonephritis, granulomatous meningoencephalitis
What are some common autoimmune diseases of dogs and cats
Immune mediated hemolytic anemia, immune mediated thrombocytopenia, systemic lupus erythematosus, immune mediated poly-arthritis, masticatory mastitis, autoimmune myasthenia Travis, type I DM (dogs)
What is pharmacodynamics
What drugs do to the body, what receptors drug target, how drugs act (antagonist, agonist, competitive vs non-competitive binding), adverse effects (off target or overextension)
What is pharmacokinetics
What the body does to the drug
Absorption
Distribution
Metabolism
Elimination
What is required for a drug to be labeled use
FDA approved
defines a drug (ex: ketoprofen)
given dose/internval and duration (2.2mg/kg q24, 5 days)
Given by a specified route (IV)
For a particular species (horses)
Has been shown by manufacturer to be effective for indicated disease (inflammation and pain with musculoskeletal disorders)
What makes something extra-label use of drug
Allows for us of veterinary FDA approved drug in a non-approved way (ketoprofen use in birds)
Allows for use of human FDA approved drug that lacks veterinary approval (aspirin)
What are some mediators of acute inflammation
Histamine, serotonin, bradykinin, prostaglandins, leukotrienes
Does histamine cause the following: vasodilation, vascular permeability, chemotaxis, and/or pain
Vasodilation: ++
Vascular permeability +++
Chemotaxis: -
Pain: -
Does serotonin cause the following: vasodilation, vascular permeability, chemotaxis, pain
Vasodilation: +/-
Vascular permeability: +
Chemotaxis: -
Pain: -
Does bradykinin cause the following: vasodilation, vascular permeability, chemotaxis, pain
Vasodilation: +++
Vascular permeability: +
Chemotaxis: -
Pain: +++
Do prostaglandins cause the following: vasodilation, vascular permeability, chemotaxis, pain
Vasodilation: +++
Vascular permeability: +
Chemotaxis: +++
Pain: +
Do leukotrienes cause the following: vasodilation, vascular permeability, chemotaxis, pain
Vasodilation: -
Vascular permeability: +++
Chemotaxis: +++
Pain: -
What two things can be used to synthesize arachidonic acid
Phospholipids via PLA2
Diacyglycerols via DG lipase
How is arachidonic acid made into prostaglandins
Via COX-1 and COX-2
COX-1 or COX-2:
Always expressed, generates prostanoids needed for maintenance of normal physiology (ex: gastric cytoprotection and normal renal vasoconstriction)
COX-1
COX-1 or COX-2:Conditionally expressed (inducible), produced in response to cytokines, tumor promoters, growth factors, generates positive feedback loop with cytokines–> cox–> prostaglandins
COX-2
What 3 drugs/classes inhibit COX
Acetaminophen, aspirin, NSAIDS
What are the therapeutic effects of acetaminophen
Analgesia, anti-pyretic
What are the therapeutic effects of aspirin
Analgesia, anti-pyretic anti-inflammatory, anti-thrombotic
What are the therapeutic effects of NSAIDS
Analgesia, anti-pyretic, anti-inflammatory
_____ and ____ are effects from acetaminophen, aspirin, and NSAIDS are due to actions on the nervous system not anti-inflammatory effects
Analgesic and anti-pyretic
What COX inhibitor drug is “added-in” for pain control in dogs but rarely
Acetaminophen
What COX inhibitor drug is highly toxic in cats
Acetaminophen
What COX inhibitor drug is an investigational drug for cats at risk of saddle thrombi
Aspirin
What COX inhibitor drug has minor and variable anti-thrombotic effects
NSAIDS
What are the three classes of NSAIDS in regards to COX inhbition
Non-specific cox inhibitor, COX-2 preferential, and COX-2 exclusive
What are some examples of nonspecific COX inhibitors
Ketoprofen
What are some examples of COX-2 preferential inhibitors
Phenybutazone (bute), flunixin meglumine (banamine), carporfen (rimadyl), meloxicam (metacam)
What are some examples of COX-2 exclusive inhibitors
Firocoxib (previcox)
Robenacoxib (onisor)
Deracoxib (deramaxx)
Why can’t preference/exclusivity of a drug be guaranteed
Because of differences in COX-1 and -2 genes between species that can lead to slightly different binding sites for the drugs
Why are drugs that have increased COX-2 specificity better/safer
Reduce inflammation but also have less effect on prostanoids because COX-1 can still generate normal prostaglandins needed for normal physiological function so fewer adverse effects
What is the most common chronic labeled use of NSAIDS
Osteoarthritis
What do NSAID’s target in treating OA
Inflammation occurring in synovium (synovitis membrane) and degradation of articular cartilage
What is the mechanism of action of NSAID’s in treating OA
NSAID’s reduce the production of PGE2 by synoviocytes and chondrocytes
How does PGE2 negatively impact joints in osteoarthritis
PGE2 directly contributes to inducing apoptosis of chondrocytes and also
PGE2 promotes secretion of other cytokines like IL-1, NO and TNF-alpha that contribute to cartilage breakdown leading to synovitis and chondrocyte apoptosis
What are the three greatest side effects of NSAID toxicities
Gastric ulcers
Nephrotoxicity
Hepatotoxicity
What are some signs of gastric ulcers
Pain and bleeding, diarrhea
Result of decreased secretion of mucous to protect stomach from acid by inhibiting COX-1 and therefore prostaglandins that produce mucous
What are the signs of nephrotoxicity
Acute renal failure, interstitial nephritis, glomerularnephropathy
Prostaglandins blocked by COX-1 inhibitors so can’t control vasoconstriction at kidney by inducing vasodilation
What are some other, less common effects of NSAID toxicities
Bronchoconstriction, pancreatitis, agranulocytosis, aplastic anemia, headache, dizziness, confusion, depression, hypersensitivity reactions
What class of drug is grapiprant (galliprant) and what is the labeled use
Class: NSAID
Labeled only for pain and inflammation associated with OA in dogs
What are the pharmacodynamics of grapiprant (galliprant)
EP4 receptor antagonist, EP4 is one of the four PGE2 receptors that mediate inflammation in OA
Why is grapiprant (galliprant) a safer NSAID
Only blocks one of four PGE2 receptors and doesn’t block production of prostaglandins so at less risk of affecting normal physiology
What are some adverse effects of grapiprant (galliprant)
Vomiting, diarrhea, anorexia, buccal ulcers, IMHA
What is the mechanism of action (rapid onset) for gluocorticoids
Blocks synthesis of arachidonic acid by inhibiting PLA2 which is needed to make arachidonic acid from phospholipids
What is the mechanism of action (delayed onset) for glucocorticoids
Increased transcription of anti-inflammatory genes and decreased transcription of pro-inflammatory genes
What is the most commonly used and efficacious anti-inflammatory drugs that suppresses virtually every component of the inflammatory process and inhibit more mediators of inflammation than any other drug
Glucocorticoids
What is the endogenous glucocorticoid
Hydrocortisone
Some glucocorticoids are inactive precursors, where must they be processed to become active and what is an example
Must be processed by liver
Example: prednisone must be converted to prednisolone by liver 1
Which species can’t absorb nor convert prednisone effectively
Cats, must be given prednisolone
What drug is used to treat hypoadrenocorticism (addion’s disease)
Glucocorticoids
What are three drugs that have labeled use for musculoskeletal/joint injections
Triamcinolone
Isoflupredone
Flumethasone
What species can triamcinolone be used for to be considered labeled use
Dogs, cats, horses
What species can isoflupredone be used in to be considered labeled use
Cattle and swine
What species can flumethasone be used in to be considered labeled use
Dogs and horses
What are some adverse effects of the drugs used for musculoskeletal/joint injections
Causes muscle atrophy due to increased circulating amino acids, inhibits fibrocartilage growth, causes osteoporosis- increased Ca+ excretion and decreased vitamin D activation, inhibits osteoblasts
What animals should just injections not be used in
Growing animals because the drugs inhibit fibrocartilage growth
Glucocorticoids and treating OA
Reduce production of PGE2 by synoviocytes and chondrocytes
Glucocorticoids directly suppress production of IL-1 and TNF-alpha
What drug type is fluticasone (Flovent)
Glucocorticoids
What are the labeled uses of fluticasone (Flovent)
Dogs: upper tracheobronchial disease
Cats: asthma
Horses: RAO (expensive so prednisolone, dexamethasone, and isoflupredone are alternatives
What are the pharmacodynamics of Fluticasone (flovent)
Local, pulmonary immunosuppression reducing inflammation and epithelial damage
What are some adverse effects of fluticasone (Flovent)
Pharyngitis and URI’s
May decrease production of endogenous corticosteroids (systemic effect), lethargy, bradycardia, anemia, hypovolemic shock(latrogenic addisonian crisis)
What drug should not be used in acute asthma attacks that can even cause bronchospasms
Fluticasone (Flovent)
What are the five major glucocorticoids
Dexamethasone, hydrocortisone, isoflupredone, prednisolone, triamcinolone
What are some major reasons not to use glucocorticoids
Cutaneous food allergies (adjust diet first)
Infectious or parasitic infections (don’t want to suppress immune system when trying to fight infection)
What are the most important adverse effects of systemic use of glucocorticoids that are most common with treatment > 2 weeks
Gastric ulcers and colonic perforation (messing with AA not Prostgladins to produce mucous)
Infections- immune suppression so increased susceptibility to infection and masks signs of disease
Systemic use of glucocorticoids and HPA axis
Chronically high exogenous glucocorticoids suppress HPA axis so adrenals will reduce glucocorticoid and mineralcorticoid production, adrenals can atrophy so must slowly reduce exogenous glucocorticoid dose over time via a taper to allow HPA axis to recover
What are some therapeutic options for atopic dermatitis
Cyclosporine A, lokivetmab, oclacitinib, glucocorticoids
What are the itch cytokines
IL-2, IL-4, IL-6, IL-13, IL-31
What are the pharmacodynamics of cyclosporine A (atopica)
Binds cyclophilin to calcineurin, inhibits all T cell responses by blocking transcription of IL-2 and INF-gamma
What is the labeled use for cyclosporin A (atopica)
Atopic dermatitis in dogs and cats
What are some extra lable uses of cyclosporin A (atopica)
Keratoconjunctivitis sicca and autoimmune disorders
What are the adverse effects of cyclosporin A (atopica)
Vomiting, diarrhea, anorexia, hypersensitivity, gingival hyperplasia, hypertrichosis, DM (dogs), hepatic lipidosis (cats)
What are some contraindications for cyclosporin A (atopica)
History of malignant neoplasia, use of live vaccines, FIV or FeLV +, latent toxoplasma gondii infection
What is the labeled use of olacitinib (Apoquel)
Treatment of atopic dermatitis in dogs > 1yr
What are the pharmacodynamics of olcacitinib (Apoquel)
Competitive inhibitor of JAK1, competes with histamine and cytokines released from mast cells and basophils
Why is specificity of olcacitnib (Apoquel) for JAK1 important
JAK2 is needed for erythropoietin—> RBC
What are some adverse effects of olcacitnib (Apoquel)
Diarrhea, vomiting, anorexia, polydipsia, and lethargy, immunosuppression, neoplasia, skin disorders, anemia
What are the pharmacodynamics of lokivetmab (cytopoint)
Canonized monoclonal antibody for dogs
Neutralizes IL-31 which is a pro-itch cytokine working through JAK1/2 pathways
What are some adverse effects of lokivetmab (apoquel)
Lethargy, vomiting, hyper excitability, injection site pain, urinary incontinence
What is the process of caninization
Genetically engineering the therapeutic antibody from mouse to be structurally closer to endogenous antibodies of target species to decrease immunogenecity (decrease opsonization)
A small number of dogs have a declining response to lokivetmab over time, why?
caninization is not 100%, overtime many develop immune response to antibodies so lose efficacy, develop response to mouse parts
What are the pharmacodynamics of mycophenylate mofetil (cellcept)
Reduces DNA synthesis by inhibiting production of guanine nucleotides
What are the pharmacodynamics of Azathioprine (imuran)
Reduces DNA synthesis by two mechanisms:
1. Introduces this-guanine bases into elongating DNA Strands
2. Inhibits adenine and guanine (purine) production
Promotes T cell apoptosis by inhibiting RAC stimulation from CD28
What are some adverse effects of mycophenylate mofetil (cellcept)
Dogs:
Vomiting, diarrhea, anorexia, lymphopenia associated with increased occurrence of skin infection
Cats???
What are some adverse side effects of azathioprine in dogs
Vomiting, diarrhea, anorexia, leukopenia and thrombocytopenia, pancreatitis, hepatopathy
What are some adverse side effects of azathioprine in cats
More marked bone marrow suppression, because of lower capacity to metabolize drug (thiopurine methyltranferase)
