Week 2 Lesson 14: Therapeutic Drug targets of the musculoskeletal system

What is the primary mechanism of action for NSAIDs?

Inhibition of the cyclooxygenase (COX) enzyme.

Which enzyme is considered "constitutive" and responsible for "housekeeping" functions?

COX-1.

Which enzyme is "inducible" and upregulated at sites of tissue damage?

COX-2.

What is the role of PGE2 in the stomach?

Provides gastric protection by increasing mucosal blood flow and mucus secretion.

Which molecule regulated by COX-1 promotes blood clotting via platelet aggregation?

TxA2 (Thromboxane).

Which molecule produced by the vascular endothelium prevents blood clotting?

PGI2 (Prostacyclin).

Why is COX-1 vital during general anesthesia?

It maintains renal blood flow during periods of "shock" or low systemic blood pressure.

Where is COX-2 upregulated besides peripheral tissue damage sites?

In the Central Nervous System (CNS).

What role does COX-2 play in the CNS?

Mediation of pain and the febrile response.

In which tissues is COX-2 found constitutively under basal conditions?

Brain, kidney, ovary, uterus, ciliary body, and bone.

Which acid is the precursor that COX enzymes act upon?

Arachidonic acid.

What are the two major effects of PGD2 and PGE2 at inflammatory sites?

Inflammation and pain.

COX-2 is upregulated in which type of cancerous growths?

Colorectal polyps and adenocarcinomas.

What are "Non-selective NSAIDs"?

Drugs that inhibit both COX-1 and COX-2.

What are "COX-2 selective NSAIDs"?

Drugs designed to primarily inhibit COX-2 to reduce GI side effects.

NSAID Drugs and Specific Indications

Name a common COX-1 inhibitor used in veterinary medicine.

Acetylsalicylic acid (Aspirin).

What is a common non-specific COX inhibitor used as an anti-inflammatory in horses and dogs?

Phenylbutazone (Bute).

What is the active metabolite of Phenylbutazone?

Oxyphenbutazone.

Which NSAID is preferred for its anti-endotoxic effects in septic shock?

Flunixin meglumine.

What is the brand name for Flunixin meglumine?

Banamine.

What is the duration of action for Flunixin meglumine in horses?

24-36 hours.

Which NSAID provides more specific inhibition of COX-2 and is safer for osteoarthritis?

Carprofen.

What is the brand name for Carprofen?

Rimadyl.

Which NSAID is FDA-approved specifically for myositis and soft-tissue inflammation in horses?

Naproxen.

Which drug inhibits both COX and lipo-oxygenase enzymes?

Ketoprofen.

Ketoprofen acts as an inhibitor of which pain-mediating peptide?

Bradykinin.

What is the name of the 1% diclofenac sodium topical cream for horses?

Surpass.

Which COX-2 preferential drug is approved for postoperative pain in cats (SC injection)?

Meloxicam.

What is a brand name for Meloxicam?

OroCAM.

Which COX-2 inhibitor is available as chewable tablets for dogs with better bioavailability when given with food?

Deracoxib (Deramaxx).

What is the brand name for Firocoxib used in dogs?

Previcox.

What is the brand name for Firocoxib used in horses?

Equioxx.

How long is the recommended treatment period for Firocoxib in horses?

14 days.

What is the brand name for Robenacoxib?

Onsior.

What is the maximum recommended treatment duration for Robenacoxib in cats?

3 days.

Novel NSAIDs: Grapiprant

How does Grapiprant differ from traditional NSAIDs?

It is a non-cyclooxygenase-inhibiting NSAID.

What is the specific target of Grapiprant?

The prostaglandin EP4 receptor.

Which receptor is the main intermediary of PGE2-driven inflammation?

The EP4 receptor.

How many prostaglandin receptor subgroups exist for PGE2?

Four (EP1, EP2, EP3, and EP4).

For which condition is Grapiprant primarily indicated?

Canine osteoarthritis.

NSAID Pharmacokinetics and Toxicity

What is the typical pKa range for NSAIDs?

3.5 to 6 (weak acids).

Why do NSAIDs have decreased permeability into healthy tissues?

They are ionized in plasma due to their acidic nature.

How do NSAIDs reach the site of inflammation?

They are released from plasma proteins during the exudation of interstitial fluid.

Where are NSAIDs primarily metabolized?

In the liver via oxidation or conjugation.

Why is NSAID excretion rapid in herbivorous animals?

Because they have alkaline urine.

Why is reabsorption of NSAIDs higher in carnivores?

Because they have acidic urine.

What are the three primary gastrointestinal side effects of NSAIDs?

Irritation, ulceration, and vomiting.

What is the term for kidney damage caused by NSAIDs?

Nephrotoxicity.

How do NSAIDs affect the hematological system?

They inhibit platelet aggregation, leading to prolonged bleeding time.

Which specific healing processes can be impaired by NSAIDs?

Bone, tendon, ligament, and soft tissue healing.

List two contraindications for NSAID use.

Renal insufficiency and gastrointestinal ulcers.

Why are NSAIDs contraindicated in patients with reduced cardiac output?

Risk of decreased renal blood flow during dehydration or hypovolemia.

Which class of drugs should never be given concurrently with NSAIDs?

Corticosteroids.

Phenylbutazone is known to potentially cause which specific organ toxicity?

Hepatic toxicity.

Phenylbutazone is more toxic in which specific equine age group?

Foals.

Glucocorticoids: Mechanisms and Effects

To which receptors do glucocorticoids bind in the cytoplasm?

GRC (Glucocorticoid receptors).

What is the name of the DNA sequence glucocorticoids bind to?

Glucocorticoid-responsive element (GRE).

Which protein do glucocorticoids induce to inhibit phospholipase A2?

Lipocortin.

What is the ultimate result of inhibiting phospholipase A2?

Inhibition of chemical mediators of inflammation.

Which nuclear factor's translocation is inhibited by glucocorticoids?

Nuclear factor kappa B (NF-κB).

What effect do glucocorticoids have on glucose levels?

They increase glucose through gluconeogenesis.

What is the effect of glucocorticoids on proteins?

Protein catabolism.

How do glucocorticoids affect the CNS?

They can cause euphoria.

How do glucocorticoids affect the cardiorespiratory system?

They increase catecholamine sensitivity and have positive inotropic effects.

What are the "Immune and hematologic" effects of glucocorticoids regarding cell counts?

Lymphopenia and eosinopenia.

How do glucocorticoids affect cell-mediated immunity?

They suppress it.

What effect do glucocorticoids have on fibroblast proliferation?

They suppress it, leading to poor wound healing.

Glucocorticoid Classification and Drugs

Name a short-acting glucocorticoid (<24 hours).

Hydrocortisone (or Cortisone, Prednisone, Methylprednisolone).

Name an intermediate-acting glucocorticoid (24-48 hours).

Triamcinolone.

Name a long-acting glucocorticoid (>48 hours).

Dexamethasone (or Flumethasone, Betamethasone).

Which glucocorticoid has the highest relative potency (30x compared to hydrocortisone)?

Dexamethasone or Betamethasone.

Which glucocorticoid has significant mineralocorticoid (sodium retention) potency?

Hydrocortisone or Cortisone.

What is the brand name for Methylprednisolone Acetate?

Depo-Medrol.

Which glucocorticoid is specifically indicated for acute arthritis and allergic disorders in dogs, cats, and horses?

Triamcinolone acetonide.

Which drug is FDA-approved for treating ketosis in bovines?

Flumethasone.

What is the brand name for the Dexamethasone sodium phosphate injection for horses?

Dexium-SP.

Glucocorticoid Toxicity and Contraindications

What iatrogenic endocrine disease can be caused by long-term glucocorticoid use?

Cushing’s disease.

How do glucocorticoids affect Vitamin D and Calcium levels?

They reduce Vitamin D and increase urinary calcium excretion.

What dermatologic effect is characterized by skin mineralization?

Calcinosis cutis.

Glucocorticoids are contraindicated in patients with which type of eye lesion?

Corneal ulcers.

Why are glucocorticoids contraindicated in pregnancy?

They can cause abortion or teratogenic effects.

List two systemic infections where glucocorticoids are contraindicated.

Systemic fungal infections and viral infections.

What is "pseudo-rheumatism"?

Lameness and stiffness caused by abrupt glucocorticoid withdrawal.

How should glucocorticoid treatment be ended?

Withdrawal should be gradual.

Which metabolic condition is a contraindication for glucocorticoid use?

Diabetes.

Joint-Modifying Agents and Orthobiologics

What is the primary function of Hyaluronic acid in the joint?

It acts as a shock absorber and aids in lubrication.

Which component of cartilage aids in maintaining elasticity?

Chondroitin sulphate.

How does Chondroitin sulphate protect cartilage?

By inhibiting proteolytic enzymes that damage the cartilage matrix.

What is Glucosamine a precursor for?

The synthesis of glycosylated proteins and lipids.

Which joint-modifying agent is a semisynthetic polysaccharide that preserves cartilage integrity?

Pentosan polysulphate.

What is the FDA-approved brand of Pentosan polysulphate for horses?

Zycosan.

What is a potential side effect of intra-articular Pentosan polysulphate in horses?

Intra-articular bleeding.

What does the acronym IRAP stand for?

Autologous conditioned serum (Interleukin-1 Receptor Antagonist Protein).