Immunotherapies

Failure of immune regulation - ie over-reaction of the immune system to self/nonself

Define immune mediated dz?

Failure to self tolerate - immune cells target self antigens

Define autoimmune dz?

It is a acquired as a secondary issue and can have multi factory etiology

Immune mediated dz typically presents when?

Primary - aquired through gremline/ (inherited/mutation)

can be secondary

autoimmune dz typically presents when?

Autoimmune

What immune dz will be organ or cell type specific?

Immune-mediated.

Wat immune dz will start in one place and result in antigen/ antibody complex that cause multi-organ dysfunction?

Atopic dermitits

osteothritis

chronic bronchitis

IBD

Any non-infectious -itis

Name a few immune mediated dz of dogs and cats?

Immune mediated hemolytic anemia

Immune mediated trombocypeinia

Systemic lupus erythematosus

Autoimmune myasthenia gravis

Masticatory myositis

Type 1 DM

Name a few autoimmune dz of cats and dogs?

What drugs will do to the body, and what receptor they act on.

Pharmodynamics refers to what?

What the body does to the drugs and the paths the drug takes.

Pharmacokinetics refers to what?

Act as an agonist(activate)/ antagonist (inhibit)

A drug can do what two possible things to a receptor?

False it can be competitive/ reversible as well depending on the drug.

True or false, all binding of drugs to receptors is non-competitive or irreversible?

When a drug over reaches/ affects cells that you don't want to target.

What is an adverse effect?

Absorption

Distribution

Metabolism

Elimination

What are the four factors of Pharmokenetics?

Where the drug goes,

ex Into the cells, interstitial space, circulation, trapped in fat.

What can the distribution of a drug be?

True, it is already in circulation

True or false a drug is not absorbed if it is given IV?

They are given in the inactive form orally and metabolisms of the drug will make it active and allow it to act

Why do some drugs need to be metabolized?

Liver - pumps into GI

Kidney - urine

What organs will eliminate a drug? how?

1/2 life.

What is the term for how long a drug takes to leave the body?

Drug that is given at a specific dose and interval for a defined duration and route for a specific species and is known to be effective for dz. Approved by FDA- for vet use.

Explain label usage of drugs?

A non-FDA approved use of the drug that is still legal and allows vets to use human FDA approved medications/ or medications in other species/ for other disorders that seem to work

Explain extra label uses of drugs?

Prostaglandins.

What acute mediator of inflammation will contribute to vasodilation, vascular permeability chemotaxis and pain>?

Phospholipids will be cleaved by PLA2 to remove the Arachidonate molecule which will be acted upon by COX 1 & 2 to produce prostaglandin H2

Explain the methods of prostaglandin production using Phospholipids?

A lipid of the bilayer in which the phosphorus head (Diacylglycerols) was cleaved previously will interact with DG lipidase and remove the Arachidonate portion and it will be acted upon by COX 1 & 2 to produce prostaglandin H2

Explain the methods of prostaglandin production using Diacylglycerols?

Cox-1

Responsible for tone of Afferent arteriole and the production of mucus in the GI to protect from acid

What cox gene will be constitutive? What is it responsible for?

COX-2

Responsible for cytokines, tumor promotors, growth factors creating inflammation

What COX gene will be inducible? What will this lead to?

Positive,

Increased prostaglandin production produces more inflammation and those cytokines will stim more prostaglandin production

A COX-2 gown will result in what kind of feedback loop?

Acetaminophen

Aspirin

NSAIDS

What are the three classes of COX inhibitors?

NSAIDs; Acetaminophen

Of the three classes of COX inhibitors what will be most used in animals, what will almost never be used?

Aspirin, due to the anti-thrombotic properties

What drug would we use for a cat w/ saddle thrombi? Why?

Actions of the NS and not anti-inflammatory effects

What is going to allow of the analgesic and anti-pyretic effects of COX inhibitors?

Ketoprofen,

Will target COX -1 & 2

Name a nonspecific NSAID? What does this mean?

Phenybutazone

Flunixin meglumine

Carprofen

Meloxicam

Name COX-2 Preferential NSAIDS?

Will try to mostly target COX-2 but still has effect on COX-1, Will see less adverse effect

What does it mean to be COX-2 preferential?

Fibrocoxib

Robenacoxib

Deracoxib

Name COX-2 Exclusive drugs?

False, if used for long enough will start effect COX-1

True or false, COX-2 exclusive drugs only act on COX-2?

The destruction of the articular cartilage and synovial capsule due to prostaglandin production.

Osteoarthritis is caused by what?

Reduction of inflammation primarily in synovium and a bit in the articular cartilage

What will an NSAID result in OA?

PGE2 which will in turn also reducing cytokines like IL-1, TNF-a and NO

What molecule is going to be reduced dramatically by NSAID uses in OA?

Directly contribute to apoptosis of chondrocytes

What is PGE2 going to do in OA?

Gastric ulcer,

nephrotoxicity

hepatotoxicity

What are some major adverse effects NSAID toxicities?

It can cause bronchoconstriction

Why shouldn't we uses an NSAID in an animal w/ asthma?

For asteothritis in dogs that act as a EP4 receptor antagonist

What are the pharmacodynamics of Galiprant?

The receptor PGE2 will bind to cause pain.

What is EP4?

We have less risk of kidney damage because we aren't reducing natural prostaglandins.

Why might we use Galiprant instead of NSAIDS?

Endocrine functions

glucocorticoid steroids are going to effect what system?

The production of prostaglandins by inhibiting Phospholipidase A2

What will a glucocorticoid target?

NSAIDS, They both block prostaglandin production and using both would increase adverse affects.

Steroids and what should never be used together? Why?

Increased transcription of anti-inflammatory genes and a decrease of pro-inflammatory genes.

Delayed onset of of Glucocorticoids will cause what?

Nearly all components, inhibits more mediators than any other drug

glucocorticoid will suppress______ of the inflamitory component?

Apoptosis,

Except T-reg

glucocorticoid will stimulate what in most immune cells except?

Hydrocortisone

What is the glucocorticoid that is endogenous?

Dogs can convert inactive prednisone to prednisolone in the liver

Cats don't do this effectively and need the active portion

Why do we give dogs prdnisone and cats Prednisolone?

No must be proccessed/ metabolized

Glucocorticoid prodrugs can be affective in local administration?

Replacement - tx hypoadrenocortism

Inflammatory dz from autoimmunity

Cancers and more.

What are some major uses of glucocorticoids?

Triamcinolone: Dogs, Cats, Horses

Isoflupredone: Cattle, swine

Flumethasone: Dogs, Horses

Label which musculoskeletal joint inj are for what animals?

Triamcinolone:

Isoflupredone:

Flumethasone:

Can make musculoskeletal issue worse, don't use in growing animals

A musculoskeletal joint inj can cause what kind of adverse effects?

Suppress production of PGE2, IL-1, TNF-a

Glucocorticoids are going to have what direct effects on osteoarthritis?

Asmthma in cats,

tracheobronchial dz - dogs

RAO in horses

What is Fluticasone used for?

Reduce inflammation

epithelial damage

pulmonary immunosuppresion

What will fluticasone do?

Pharyngitis

Upper resp infections

Decresed endogenous corticosteroids.

Iatrogenic Addisons crisis

What are adverse effects of Fluticasone?

abruptly stopping use of steroids after long term usage resulting in the body becoming dependent on exogenous steroids and won't produce endogenous steroids.

Why might the hypothalamic pituitary adrenal axis cause a problem if we abruptly stop a steroid after long term use instead of tapering?

Lethargy bradycardia, anemia, hypovolemic shock

What are signs of a iatrogenic Addisons crisis?

Dexamethasone

Hydrocortisone

Isoflupredone

prednisolone

Triamcinolone

What are the five glucocorticoids used for skin eyes and ears?

Food allergies,

infectious/ parasitic causes

Why might we not uses steroids for skin issues?

GI ulcers and colonic perforations

Infections due to immune suppressants

Suppression of the hypothalamic pituitary adrenal axis

What are major adverse effects of steroids that are systemic?

Cyclosporine A - T cells (represses)

Lokicetmab - cytokine suppression

Oclacitinib - cytokines suppression

What are som alternative therapeutic options for atopic dermatitis?

Cyclophilin binds to calcineurin to inhibit Tcell transcription factors to block IL-2 and INF-y

How will cyclosporin A prevent puritis?

kcs

What is the off label for cyclosporin A?

DM - dogs

Hepatic lipidosis - cats

What are two concerning adverse effects of cyclosporin?

-Hx malignant neoplasia (stops immune system from suppressing cancer)

-Live vax

-FIV/FeLV pos

-Toxoplasma gondii latent infection

What are contraindications of Cyclosporin?

Apoquel, will be a competitor inhibitor for JAK1 to reduce IL-2 from binding to cells.

What is Oclacitinib? What is it going to do?

JAK-1 can sometimes get confused w/ Erythropoietine receptor JAK2

Why can Apoquel cause Anemia?

Cytopoint a caninized monoclonal antibody

- neutralizes IL-31 so it can't bind to JAK 1/2

What is Lokivetmab? What does it act on?

IL-2,

IL-4

IL-6

IL-13

IL-31

What cytokines that stimulate itch?

It doesn't affect neoplasia

Why might we prefer Lokivetmab over other therapies?

Mouse antibodies are used and are genetically engenered so that they are closer to endogenous antibodies

How are caninized antibodies produced?

Canine anti-mouse antibodies

What is CAMA?

variable regions are kept as mouse.

What portion of caninized antibiodies are not typically changed to mouse antibodies?

Mycophenylate mofetil, and azathioprine

What are two drugs that affect DNA synthesis?

It is going to inhibit the production of Guanine

How does Mycophenylate mofetil work?

Thio-guanine bases are going to occur and the body cannot function with that and it inhibits division

Inhibition of purines and G proteins

How does azathioprine going to work?

Inhibits RAC stimulation from CD28.

How does Azathioprine going to promote T-cell apoptosis?

LYMPOPENIA AND INCREASED SKIN INFECTIONS.

What is an adverse effect of Mycophenylate mofetil?

Leukopenia

thrombocytopenia,

pancreatitis

hepatophathy

bone marrow suppression in cats

What is an adverse affect of Azathioprine?