I&I week 9 Inflammatory mediators and pharmacologic treatment

What are the two types of chemical mediators of inflammation?

Cellular derived

Plasma derived

What is cellular derived chemical mediators?

Pre-made mediators released from cells

What are plasma derived chemical mediators?

Soluble cascade system with activated subunits that have wide ranging inflammatory affects

What are the 4 types of cell-derived chemical mediators?

Lipid Mediators

Cytokines and chemokine

Vasoactive amine

lysosomal components within inflammatory cells

Lipid mediators lead to what type of pathway?

Arachidonic acid pathway

What is produced when the phospholipid bilayer is broken down by phospholipase A2?

Arachidonic Acid

What enzymes are used to breakdown Archidonic acid to produce Thromboxane and Protaglandins?

Cyclooxygenase 1 and 2

What are the products of Archidonic acid being broken down by Cyclooxygenase 1 and 2?

Thromboxane and prostaglandins

What enzyme is used to breakdown arachidonic acid into Leukotrienes?

Lipoxygenase

What is the product of arachidonic acid being broken down by Lipoxygenase?

Leukotrienes

What does does Thromboxanes express?

COX-1

What is COX-1?

Is expressed in healthy animals

Cytoprotection of mucosal cells and renal function but is increased during inflammation

What does Prostaglandins express?

COX-1

COX-2

What is COX-2?

Expressed during inflammation

Thromboxanes expressed during inflammation cause what?

Vasoconstriction

Platelet aggregation

Prostaglandins expressed during inflammation cause what?

Fever

Pain

Loss of function

Vascular response

Cellular Response

What does leukotrienes cause?

Smooth muscle contractions

vascular response

cellular response

mucous secretion

Leukotrines are seen in what two major immune responses?

Allergies and hypersensitivities

What are the therapeutic goals of lipid mediators?

Reduce inflammation

What are the therapeutic targets for lipid mediators?

Receptors

Iron channels

Pumps

Enzymes

What are the 4 types of enzyme inhibitors?

Phospholipase A2-inhibitors

COX-inhibitors

LOX inhibitors

Prostaglandine Receptor blockers

What drugs are used as a Phospholipase A2-inhibitor?

Glucocortiosteroid

What drugs are used as a COX-inhibitors?

Non-steroidal anti-inflammatory drugs

What are the three types of non-steroidal anti-inflammatory drugs?

COX-1 selective

COX-2 selective

COX-1/2 preferential

what is an example of a preferential or selective COX-1 inhibitor?

Acetyl salicylic acid

What are examples of non-specific cox inhibitors?

Carprfen

Flunixin meglumine

Phenylbutazone

Tolfenamic acid

What does it mean to be preferential to cox-2?

the drug prefers cox to at a 60/40 split meaning it will still bind to both but not at equal rates.

What type of binding does acetyl salicylic acid have?

irreversible binding

What are examples of preferential or moderately selective COX2 inhibitors?

Meloxican

Deracoxib

Etodolac

What are examples of highly selective COX-2 inhibitors?

Fibrocoxib

Robenacoxib

What is an example of Cox3 inhibitor?

Acetaminophen

What are the NSAID pharnacokinetics?

Weak acids

Reasonable Vd

Hepatic metabolism

Enterohepatic recirculation

What are the adverse effects of NSAIDS?

Stomach ulcerations

Kidney Damage

Hepatotoxixity

Slow bone healing

Buddy is a 9 year old, neutered lab retriever. His owners report that he has been slowing down on walks, has difficulty getting up from a lying position, and seems to being pain at times. What body system is likely involved?

Skeletal/muscle system

Buddy is a 9 year old, neutered lab retriever. His owners report that he has been slowing down on walks, has difficulty getting up from a lying position, and seems to being pain at times. What diagnostics do you want to run to figure out a diagnosis?

PE

X-rays

NSAID panel

Buddy’s owners are looking for ways to help manage his condition and improve his QOL. What is the therapeutic goal when treating buddy?

NSAIDS

pain management

Joint supplements

Buddy is diagnosed with osteoarthritis. What pathway within the arachidonic acid breakdown is primarilu associated with the clinical sign (pain, loss of function) seen in buddy?

Prostaglandins

The owners are looking for ways to help manage buddyes condition and improve his QOL. What is the most appropriate initial treatment recommendation for Buddy’s osteoarthritis?

Prescribe a non-steroidal anti-inflammatory drugs (NSAID)

Before beginning Buddy on a regimen of NAIDS it is recommended that a plasma biochem and urinalysis be preformed. What organ should be examined and why?

Liver- drugs metabolized in the lover and can cause hepatotoxicity

Kidneys- drugs can cause renal toxicity and damage to kidney due to lack of blood flow

What are alternatives can be used in the treatment of buddy?

Exercise

Weight loss

Use of prostaglandine receptor blockers

What is the mechanism of prostaglandine receptor blockers?

EP4 receptor is blocked

Why is EP4 receptor important when using prostaglandine blockers?

EP4 is the primary mediator for PG sensitization and sensory neurons and PG elicited inflammation

What is the routes of administration for Glucocorticouds?

IV

IM

Inhalation

Topical

Local

What are the Glucocorticoid Pharmacokinetics?

Large Vd

Liver metabolism

Inactive metabolites are eliminated via the kidneys

What drug needs to be converted to be given to cats and horses?

Prednisone

What are the three types of formulations of Glucocorticoid?

Succinate/phosphate

Acetate/Phenylpropionate/isonicotinate

Acetonide

What is an example of a succinate glucocorticoid?

Prednisolone sodium succinate

What is an example of an acetate glucocorticoid?

Prednisolone Acetate

What is an example of an phenylproprionate?

Dexmethasone phenylproprionate

What is an example of an acetonide?

Triamcinolone acetonide

What are the adverse effects of glucocorticoids?

Vomiting diarrhea

bodyweight gain or loss

polyuria and polydipsia

delayed wound healing

immunosuppression and predisposition to infection

Zorro, a 12-year-old Warmblood gelding, presents for an evaluation of chronic cough and exercise intolerance. The horse has a history of respiratory issues during the hay feeding months over the past few years. Physical examination reveals bilateral expiratory wheeze and flared nostrils at rest. What body system is likely involved?

Respiratory system

Zorro, a 12-year-old Warmblood gelding, presents for an evaluation of chronic cough and exercise intolerance. The horse has a history of respiratory issues during the hay feeding months over the past few years. Physical examination reveals bilateral expiratory wheeze and flared nostrils at rest. What diagnostics do you want to run to figure out a diagnosis?

PE, scope down nose, x-rays

Zorro, a 12-year-old Warmblood gelding, presents for an evaluation of chronic cough and exercise intolerance. The horse has a history of respiratory issues during the hay feeding months over the past few years. Physical examination reveals bilateral expiratory wheeze and flared nostrils at rest. It seems like the diagnosis is asthma. What type of hypersensitivity is associated with equine asthma?

Type 1

What pathways within the Archidonic acid breakdown is primarily associated with the clinical signs seen in zorro?

Prostaglandins and Leukotrienes

What is the therapeutic goal for zorro?

Block phospholipase A2 which will block both pathways so prostaglandins and leukotrienes cannot be produced.

What is the most appropriate treatment for Zorro?

Systemic glucocoticoids

Are adverse effects from glucocorticoids every seen in Horses?

Very rarely seen in horses with athsma

Which cytokine does fever, neutrophilia, and activation of phospholipase A2, stimulate acute phase proteins?

IL-1

What cytokine does shock, activation of neutrophils and endothelial cells, stimulate the production of other cytokines?

TNF-Alpha

What cytokine fosters a shift from acute to chronic inflammation, and activates macrophages and lymphocytes?

INF-gamma

What do IL-1, TNF-Alpha, and INF-gamma have in common?

Stimulate the immune system

What cytokine does immune system suppression?

IL-10

What chemokine attracts neutrophils?

IL-8

What chemokine attracts Eosinophils?

Eotaxin

What chemokine attracts Lymphocytes

CCL1

CCL2

CCL17

CCL22

What chemokine attracts monocytes?

MCP-1

CCL2

What is believed to increase the efficiency of leukocytes and iron sequestration, impair replication of microorganisms, and stimulate acute-phase inflammatory responses including resting?

Fever

What is a sign of inflammation but not necessarily infection?

Fever

High fevers occur during what kind of infections?

Acute

Low grade fevers occur during what kind of infection?

Chronic

What are the 3 types of vasoactive amines?

Histamine

Serotonin

Nitric oxide

Where is vasoactive amines produced?

WBC

Endothelial cells

Platelets

What does vasocative amines cause?

Vasodilation locally or systemically

Why are lysosomal components within inflammatory cells important?

Intracellular digestion and extracellular digestion of pathogens, dead cells, and debris

What are the types of inflammatory cells?

Neutrophils and Macrophages

What inflammatory cells phagocytosis?

Neutrophils and Macrophages

What inflammatory cells cause degranulation?

Neutrophils, Eosinophils, Mast cells, and Basophils

What groups of lysosomal components are most likely to contribute to liquefactive necrosis?

Enzymes

Reactive oxygen species

What enzymes have lysosomal components?

Proteases

Esterases

Nucleases

Collagenases

Histamineases

What are enzymes with a lysosomal components function?

Non-specific break down of cellular structures

What are antimicrobial peptides that have lysosomal components?

Defensin (neutrophils)

Major basic protein (eosinophils)

What are characteristics of antimicrobial peptides that have lysosomal components?

Specifically target pathogens

Many mechanisms of killing still not known

What are ROS cells that have lysosomal components?

Free-radicals

What cells produce free-radicals?

Inflammatory cells

Endothelial cells

What is a characteristic of ROS?

High concentration they are damaging to pathogens and host cells

Dr. Fonseca’s experimenting in the lab with a new workout powder. He wants to increase blood flow to his pecs. Which mediator would be least useful to drop in his orange juice?

Thromboxane

The complement system is comprised of activated proteins that do what?

Attack pathogens directly

Enhance vascular and cellular inflammatory responses

What complement proteins are anaphylatoxins?

C3a and C5a

What do anaphylatoxins cause?

Vascular and cellular response

What complement proteins are opsonization?

C3b

What is the function of opsonization?

Enhanced phagocytosis by neutrophils and macrophages

A 5 year old gelding presents with a recurring fever, lethargy and back pain. Cerebrospinal tap is pictured. Pure culture of streptococcus is isolated from the fluid. Laboratory studies show C3 levels are at 25% normal with normal levels of C2.C5.C7. What would this patient be at increased risk for developing bacterial meningitis?

Reduced activity of the alternative and common pathway.

decreased MAC attack

Decreased anaphylatoxins

decreased opsonins

A 5 year old gelding presents with a recurring fever, lethargy and back pain. Cerebrospinal tap is pictured. Pure culture of streptococcus is isolated from the fluid. Laboratory studies show C3 levels are at 25% normal with normal levels of C2.C5.C7. What if the defect was in C1 levels?

Loss of classical pathway

What is the Fibrinolytic system?

Activated at the same time as the clotting cascade to degrade fibrin and blood clots

Plasmin also cleaves C3 of the complement system

What body system are you worries about in this dog?

Cardiovascular

Interpret this CBC

Low red blood cell (anemia)

Low platelets (thrombocytopenia)

High White blood cells (Leukocytosis-eosinophilia)

What are characteristics of Babesia canis?

Protozoa spread by brown dog tick

infects and completes life cycle in RBC

Can cause hemolytic anemia

What does this pathway explain?

How an infection can cause a clotting disorder

What is disseminated intravascular coagulation?

Causes widespread consumption of clotting factors, only so many factors in storage.

Cause massive bleeding that cannot be stopped without major intervention