NSAIDs-1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

  • Presenter: Dr. André Escobar, DVM, Ms, PhD, DACVAA

  • Associate Professor of Anesthesiology

  • Content adapted and delivered by Dr. Miguel Martinez, Dip ECVAA

Objectives

  • Understand the mechanism of action of NSAIDs

  • Learn about the classification of NSAIDs

  • Discuss indications and clinical effects

  • Identify adverse effects and contraindications

  • Review commonly used NSAIDs

Historical Perspective

  • Willow Bark: Traditional NSAID; its use dates back thousands of years

  • Ancient Civilizations: Used by Egyptians and Sumerians (3.5k years ago)

  • Hippocrates: Known as the "father of medicine" (2.5k years ago)

  • Salicylic Acid: Isolated in Germany, 1878

  • Acetylsalicylic Acid (Aspirin): Developed by Bayer in 1899

  • Post WWI: Bayer lost trademark rights due to war reparations

  • COX Inhibition Theory: Proposed 40 years ago

Mechanism of Action

  • Competitive Inhibition: NSAIDs inhibit cyclo-oxygenase (COX) pathways

  • COX Isoforms:

    • COX-1: Constitutive enzyme, present in most tissues (e.g., platelets, liver, kidney, gastric mucosa); involved in normal physiological functions

    • COX-2: Inducible enzyme, produced by inflammatory cells and activated by cytokines

    • COX-3: Variant of COX-1, primarily in brain and heart

Arachidonic Acid Pathway

  • Source: Predominant fatty acid in cell membranes

  • Biotransformation: Arachidonic acid is transformed into eicosanoids, influencing inflammation and physiology

  • Products:

    • Prostaglandins (PGE2, PGF2, PGD2)

    • Prostacyclin (PGI2)

    • Thromboxane (TXA2)

Role of Prostaglandins

  • Sensitization: Prostaglandins sensitize nociceptors to inflammatory mediators

  • Biological Functions:

    • GI: Increase mucosal blood flow, bicarbonate and mucus secretion, decrease acid production

    • Kidneys: Induce renal vasodilation and diuresis

    • Uterus: Increase blood flow and contractions

    • Brain: Induce fever

    • Blood Vessels: Cause vasodilation

    • Platelets: Inhibit (PGI2) or promote (TXA2) aggregation

COX Isoforms and Their Effects

  • COX-1: Generally considered "good"; inhibition leads to side effects but plays roles in homeostasis

  • COX-2: Considered "bad"; inhibition helps alleviate pain and fever, primarily acts in inflammatory process

NSAIDs Classification

  • COX-1: COX-2 Inhibitory Ratio (IC50):

    • Determines the selectivity of NSAIDs towards COX enzymes

    • Higher ratios indicate greater action on COX-2

Common NSAIDs and Their Ratios

  • Aspirin: 0.3 – 0.4

  • Ketoprofen: 0.1 – 0.6

  • Meloxicam: 2.7 – 10.0

  • Carprofen: 1.8 - 65

  • Firocoxib: 384 - 427

  • Deracoxib: 12 - 1275

Clinical Effects

  • Analgesic: Provides pain relief both centrally and peripherally

  • Anti-inflammatory: Inhibits mediators of inflammation, acts as a free radical scavenger, stabilizes membranes, and reduces leukocyte accumulation

  • Anti-pyretic: Reduces fever associated with endotoxemia

Indications for Use

  • Used for chronic pain, osteoarthritis, neoplasia, and otitis

  • Commonly prescribed post-operatively for acute surgical pain

  • Ideal candidates: Well-hydrated, normotensive, young to middle-aged animals with normal renal function

  • Compared to opioids: NSAIDs are usually longer acting, more effective for inflammatory conditions, easier for at-home use, and cost-effective

Contraindications

  • Avoid use in cases of:

    • GI disorders

    • Dehydration

    • Hypotension

    • Shock or unstable cases

    • Azotemia

    • Thrombocytopenia

    • Hepatic insufficiency

    • Concurrent corticosteroid therapy

Routes of Administration

  • Common Routes:

    • Oral, Subcutaneous (SC)

  • Less Common (In hospital use):

    • Intravenous (IV)

  • Oral Medications: Well absorbed (>90% protein binding, weak acids with high lipophilicity)

  • Topical Formulations: Creams

Adverse Effects

  • Gastrointestinal: Potential for vomiting, diarrhea, inappetence; gastric ulceration/perforation is a major concern

    • Risk Management: Use of gastric protectors (sucralfate, omeprazole, famotidine)

  • Renal Function: NSAIDs are not inherently nephrotoxic but can cause damage under certain risk factors

    • Associated with dehydration, pre-existing renal disease, concurrent corticosteroid usage

  • Coagulation: Impaired by TXA2 inhibition; increases the risk of perioperative bleeding

    • Example: Aspirin causes irreversible COX-1 inhibition

  • Cardiovascular Risks: Potential for creating a prothrombotic state leading to thrombosis

    • Historical Context: Rofecoxib and valdecoxib withdrawn from market due to safety concerns

  • Hepatic Injury: NSAIDs metabolized in the liver can have predictable reactions or idiosyncratic reactions

    • Cats show higher susceptibility due to metabolic pathways

Special Considerations

  • Pregnant Animals: Caution due to COX-2's role in reproduction and nephrogenesis

  • Pediatric Patients: Avoid NSAIDs before 4 weeks of age due to nephrogenesis completion

  • Fracture Healing: COX-2 importance in bone healing; NSAIDs to be used sparingly

  • Felines: Slow metabolic clearance; under dosing is crucial due to toxicity risks associated with overdose from common analgesics

Precautionary Measures

  • Ensure access to food and water

  • Monitor blood pressure and maintain normal blood volume

  • Regular monitoring of BUN and creatinine levels

  • Washout period of 4-10 days is necessary for most NSAIDs

Specific NSAIDs

Robenacoxib (Onsior, Novartis)

  • Routes: SC and oral

  • Approved for use in cats and dogs for up to 3 days

  • COX-2 selective inhibitor with minimal adverse effects

Other Coxibs

  • Deracoxib (Deramaxx): Approved for dogs

  • Firocoxib (Previcox): Special caution is required for use according to veterinarian's guidance

Carprofen

  • Available as injectable (SC and IV) and oral formulation

  • Generally approved for dogs; limited use in cats (only single use)

  • Considered a COX-2 preferential inhibitor with few side effects

Meloxicam

  • Available as injectable and oral (liquid) formulation

  • Approved for various species including cats, dogs, cattle, and pigs

Phenylbutazone

  • Administered both orally and via injection

  • Used for musculoskeletal inflammation and pain but poses higher risks for GI and renal toxicity

Ketoprofen

  • Non-selective COX inhibitor used in various species; carries risk of adverse effects

Flunixin Meglumine

  • Utilized in dogs, cats, horses, and cattle; only FDA approved for inflammation and fever in food animals

Acetylsalicylic Acid (Aspirin)

  • Non-specific COX inhibitor not approved for veterinary use; serious risks of GI bleeding

Acetaminophen (Tylenol)

  • Not approved for veterinary use; highly toxic to cats

  • Death in cats can occur from overdose or accidental ingestion

  • Common signs of toxicity include vomiting and cyanosis

Grapiprant (Galliprant)

  • Latest development approved for dogs

  • Works as an antagonist of EP4 receptors to relieve osteoarthritis pain without liver or GI effects

Questions?

  • Open floor for questions on content.