Lecture 19 - Anti-Inflammatory Agents

Which T cells are pro-inflammatory? Which are anti-inflammatory?

Th1 and Th17 are pro-inflammatory

Th2 is anti-inflammatory

What biologic processes are druggable regarding inflammation?

Enzymes: COX-1/COX-2

Intracellular signaling: IL-2 signaling

Drug classes that can be effective against inflammation

Anti-inflammatory: NSAIDs, corticosteroids (low dose)

Immunosuppressive agents: corticosteroids (high dose), small molecule inhibitors

Immunomodulatory agents: subcutaneous exposure to allergens

Arachidonic acid can produce what inflammatory compounds?

Thromboxanes

Leukotrienes

Prostaglandins

Corticosteroids block...

Phospholipase A2, which is needed to produce arachidonic acid

What do NSAIDs inhibit?

COX synthesis

Characteristics of COX-1

Physiologic/constitutive, always turned on

Produces prostaglandins and thromboxanes that are needed in the stomach, intestine, kidney, and platelets

Function of COX-1

Mucosal protection

Renal blood flow

Haemostasis

Characteristics of COX-2

Inducible

Produce prostaglandins that are needed in inflammatory sites, macrophages, and synovocytes

Function of COX-2

Inflammation, pain, fever

Why is it undesirable to block COX-1?

It produces PGE2, which protects the stomach through increased mucus secretion, bicarb production, and mucosal blood flow

Results in peptic ulcers and GI bleeding

Compromise to kidney function

How does COX-1 and COX-2 inhibition impact the kidney?

Produce PGE2 and OGI2, which are responsible for afferent arteriolar vasodilation to increase GFR and increasing Na and water excretion

Results in Na/water retention, hypertension, and hemodynamic acute kidney injury

How does COX-1 and COX-2 inhibition impact the cardiovascular system?

COX-2 produces PGI2, responsible for vasodilation and inhibiting platelet aggregation

COX-1 produces TXA2, responsible for vasoconstriction and platelet aggregation

> COX-2 inhibition can cause stroke/myocardial infarction because it promotes platelet clumping/vasoconstriction

What is the primary function of preferential COX-2 inhibitors?

To inhibit COX-2, an enzyme involved in the inflammation pathway, while sparing COX-1

What advantage do COX-2 selective inhibitors have over traditional NSAIDs?

They reduce gastrointestinal toxicity by sparing COX-1

Types of COX-2 selective inhibitors

Carprofen (Rimadyl)

Deracoxib (Deramaxx)

Meloxicam

What is Galliprant's mechanism of action?

Blocks EP4 receptor, which blocks signaling of prostaglandins

Theorized to be safer because prostaglandins are still formed for kidney/gut health

Corticosteroid mechanism of action

More than inhibition of

inflammatory eicosanoid production

Block phospholipase A2, no arachidonic acid to form COX enzymes

Have broad effects on multiple cell types and regulate gene expression networks through binding of nuclear receptors

Net effect of corticosteroids

Neutrophilia and monocytosis

Lymphopenia and eosinopenia

Examples of calcineurin inhibitors

Cyclosporin and tacrolimus

How do calcineurin inhibitors function?

Block the signaling cascade required for IL-2 production/prevent T-cell proliferation by inhibiting calcineurin

Apoquel (oclacitinib) mechanism of action

Preferential JAK1 inhibitor

JAK1-dependent cytokines involved in allergy & inflammation (IL-2, IL-4, IL-6, & IL-13) & pruritus (IL-31)

Immunosuppression targets...

T-cells

What drugs allow us to target T-cells?

• High dose corticosteroids

• Calcineurin inhibitors (cyclosporine)

• Apoquel

• Immunomodulation (hypo-sensitization strategies)

What is another name for allergen immunotherapy?

Desensitization or hypo-sensitization therapy

What is the purpose of allergen immunotherapy?

To reestablish immune tolerance to allergens by challenging with progressively greater concentrations of allergens

What are the two methods of allergen administration in immunotherapy?

SQ or sublingual

How does allergen immunotherapy affect the immune response?

It shifts the immune response away from Th2 (humoral immunity with IgE production) to Th1 (cell-mediated immunity with IgG production) and regulatory T cells that secrete IL-10 and TGFβ

Why is atopy so important?

• Skin is largest organ of the body

• 21 square feet

• 15% of total body weight

What drug can we use to prevent degranulation of mast cells?

Hydrocortisone

Mechanism of hydrocortisone

Reduces histamine levels by blocking conversion of histidine to histamine and stimulates mast-cell production of cAMP.

Anti-inflammatory

How can we attenuate the effects of degranulation?

Antihistamines

Mechanism of antihistamines

• Block H1 and H2 receptors on target cells (endothelium)

• Minimize local and systemic effects of histamine