Pharmacology of NSAIDs

Pharmacology of NSAIDs - Detailed Study Notes

Course and Instructor Information

• Pharmacology of NSAIDs - Parts I and II

• Course Code: PHARD 0584-0594-0994

• Instructor: Dr. Prasanth Puthanveetil, PhD

• Dates: October 17th and 22nd, 2025

Learning Objectives

• Understanding Inflammation

  • Steps involved in inflammation

  • Pathophysiology and consequences of inflammation

• COX Enzymes

  • Differences between COX-1 and COX-2

  • Mechanism of action of Aspirin, NSAIDs, and COX-2 inhibitors

• Adverse Effects and Interactions

  • Mechanisms of major adverse effects of aspirin, NSAIDs, COX-2 inhibitors, and acetaminophen

  • Drug-drug interactions between NSAIDs and other medications

Abbreviations Used

• AA: Arachidonic acid

• AC: Adenylate cyclase

• AngII: Angiotensin II

• COX: Cyclooxygenase

• cAMP: Cyclic adenosine monophosphate

• EET: Epoxyeicosatetraenoic acids

• 15 R-HETE: 15-Hydroxyicosatetraenoic acid

• EP: PGE2 receptor

• IP: PGI2 receptor

• 5 LO: 5-Lipoxygenase

• NSAIDs: Nonsteroidal anti-inflammatory drugs

• PLA2: Phospholipase A2

• PLC: Phospholipase C

• RA: Rheumatoid arthritis

• TxA2: Thromboxane A2

• TP: Thromboxane A2 receptor

Definition of Inflammation

• Inflammation:

  • Definition: The response of the body to any injury.

Classification of Inflammation

• Types of Inflammation:

  • Sterile: Due to injury, such as mechanical or metabolic stress.

  • Pathogenic: Due to infections.

Adaptive Skill and Inflammation

• Organisms Capable of Inflammation:

  • Animals with a vascular system show the capability of inflammation (Wu M & Sato TN, Plos One 3: e4045, 2008).

Signs and Symptoms of Inflammation

• Cardinal Signs (Local Reactions):

  • Heat (Calor)

  • Redness (Rubor)

  • Swelling (Tumor)

  • Pain (Dolor)

  • Loss of Function (Functio laesa)

Leukocyte Migration

• Consequences of Injury:

  • Importance of leukocyte migration in the inflammatory response.

Mediators of Inflammation

• Eicosanoids:

  • Components: Prostaglandins, thromboxanes, leukotrienes (pro-inflammatory), and lipoxins (anti-inflammatory).

  • Major mediators of the inflammatory and immune response

  • Produced from cell membrane phospholipids following injury, primarily through arachidonic acid (AA) metabolites.

Arachidonic Acid Pathways

• Metabolic Pathways:

  • Phospholipids → Phospholipase A2 → Arachidonic acid (AA)

  • Generates isoprostanes, lipoxins, leukotrienes through lipoxygenase pathways.

  • Generates prostaglandins, prostacyclin, and thromboxane via cyclooxygenase pathways.

COX Enzymes Overview

• COX-1 and COX-2:

  • Share 60% homology and common enzymatic path.

  • Steps in COX Pathway:

  1. Oxygen-dependent cyclization of AA to PGG2 (first step).

  2. Conversion of PGG2 to PGH2 via peroxidase reaction (second step).

• Tissue-specific Functions:

  • COX-1: Ubiquitous expression maintaining physiologic functions.

  • COX-2: Inducible in inflamed peripheral tissues for pro-inflammatory effects.

Properties of COX Enzymes

Mechanisms of Non-Steroidal Anti-inflammatory Agents

• Actions of NSAIDs:

  • Possess anti-inflammatory, antipyretic, and analgesic effects.

  • Inhibit COX-mediated effects on PGE2 → decrease vasodilation and edema, thus reducing inflammation.

  • Anti-pyretic actions are mediated via PGE2 inhibition in the hypothalamus.

  • Pain reduction through inhibition of bradykinins and histamine mediated increase in PGE2 → decreases pain receptor sensitization.

  • Variability in the duration of action:

  • Short-acting (<6h): Ibuprofen, diclofenac.

  • Long-acting (>10h): Naproxen, celecoxib, piroxicam.

Types of COX Inhibitors

• Types of COX Inhibitors/Modifiers:

  1. Salicylates (e.g., Aspirin)

  2. Non-specific and COX-2 specific inhibitors (Propionic acid derivatives, Oxicam derivatives, Fenamate derivatives, Ketone derivatives, and Sulfonic acid derivatives)

  3. Non-NSAID COX inhibitor (e.g., Acetaminophen)

Salicylates

• Aspirin:

  • Known for analgesic, antipyretic, anti-inflammatory, and anti-platelet properties.

  • Used for mild to moderate pain, headache, myalgia, and arthralgia.

  • Mechanism of Action:

  • Irreversible acetylation of serine residues in COX-1 and COX-2 proteins.

  • Anti-thrombogenic effect due to irreversible inhibition of COX-1 in platelets, lasting almost the life span of platelets (10 days) and gastric epithelial cells (4 days).

  • Prodrug:

  • Transformed into salicylate in the liver by CYPs (CYP2C19/CYP3A) and intestinal lining.

  • Aspirin-Triggered Lipoxins (ATLs):

  • Acetylation of COX results in conversion of AA to 15 R-HETE, which is then acted upon by lipoxygenase to form 15-Epi lipoxins, leading to anti-inflammatory action.

Protective Effects of Aspirin

• Effects on platelets, vasculature and arachidonic acid metabolism.

Aspirin Mechanism of Action Summary

Adverse Effects of Salicylates

• Common adverse effects include:

  1. Gastropathy

  2. Nephropathy

1. Gastrointestinal ulceration and hemorrhage; risk increases with high doses (1,800 - 3,200 mg daily & salicylate levels >25 mg/dL).

   4. Aspirin-induced airway hyperactivity, especially in asthmatic patients.

• Aspirin Exacerbated Respiratory Disease (AERD):

  • Characterized by asthma, nasal congestion, and recurrent nasal polyps.

  • Contraindicated in patients with asthma.

Contraindications and Drug-Drug Interactions

• Contraindications for Children:

  1. Risk of Reye’s Syndrome associated with hepatic encephalopathy and mitochondrial toxicity if administered during febrile viral infections.

• Drug Interactions:

  1. Drugs like amiodarone, valproate worsen Reye’s syndrome and should not be co-administered.

  2. Other NSAIDs (Ibuprofen, Indomethacin, Naproxen) taken within 2 hours of low-dose aspirin may compromise its antiplatelet action due to steric interference on platelet COX-1 site.

Alternate Salicylates

1. Diflunisal (Dolobid):

   • 4 times more potent as analgesic than Aspirin, but reduced anti-pyretic effect and long-acting (12h).

2. Salsalate (Disalcid):

   • Lacks acetylating property, possesses anti-inflammatory property similar to ASA but lesser analgesic effect; preferred in patients with compromised renal function.

Non-Specific COX Inhibitors

• Mechanism:

  • Bind to hydrophobic channels in COX enzyme, blocking AA conversion to prostaglandins.

Propionic Acid Derivatives

• Include: Ibuprofen, Naproxen, Ketoprofen, and Fenoprofen.

• Characteristics:

  1. Highly potent and long-acting, preferred for chronic diseases (RA, Osteoarthritis, gout).

  2. Longer half-life.

  3. Less gastrointestinal adverse effects than aspirin.

Oxicam Derivatives

• Include: Piroxicam, Meloxicam.

• Characteristics:

  • Non-specific COX inhibition that regulates neutrophil function by inhibiting chemokines; causes gastrointestinal ulceration and prolongs bleeding due to antiplatelet effect.

Acetic and Phenyl Acetic Acid Derivatives

• Include: Indomethacin, Sulindac, Etodale, Diclofenac, and Ketorolac.

• Mechanism:

  • Incorporate unesterified AA into triglycerides, decreasing AA interaction with COX and LOX.

  • Also associated with gastrointestinal bleeding.

Anthranilic Acid Derivatives

• Include: Mefanamic acid, Flufenamic acid, Meclofenamic acid

• Mechanism:

  • Inhibit COX-1 and COX-2; show down-regulation of IL-1 beta (cytokine in inflammation) in animal models.

Ketone Class Derivative

• Nabumetone:

  • Pro-drug rapidly converted to active acetic acid derivative.

  • More selective for COX-2, providing relatively lower gastrointestinal side effects.

Major Adverse Events Associated with Non-Specific COX Inhibitors

1. Gastrointestinal hemorrhage

2. Gastric ulceration and perforation

3. Tinnitus

4. Nephrotoxicity

5. Steven-Johnson Syndrome

6. Pseudo porphyria (specific to naproxen)

Role of COX-1 in Gastric Epithelium

• Functions:

  1. In parietal cells, inhibits H+ secretion (EP3 receptors).

  2. Promotes secretion of mucus and HCO3- ions, maintaining intact gastric lining.

  • Intact mucosa requires COX-1; COX-2 has a remodeling role in wound healing.

Rationale for Developing COX-2 Inhibitors

• To avoid gastrointestinal side effects associated with COX-1 inhibition while targeting inflammatory responses linked to COX-2, due to significant structural differences between COX-1 and COX-2.

Specific COX-2 Inhibitors

• Types:

  1. Sulfonic acid derivatives: Celecoxib, Rofecoxib, Valdecoxib.

  2. 100 times more selective for COX-2 than COX-1.

  3. Celecoxib is the only FDA-approved COX-2 inhibitor; others withdrawn due to cardiovascular effects.

Adverse Effects of COX-2 Inhibitors

1. Increased risk of myocardial infarction due to decreased antiplatelet effects.

2. Renal papillary necrosis.

3. Peripheral edema.

4. Gastrointestinal bleeding is not as severe as non-specific COX inhibitors.

Cardiovascular Complications Associated with COX-2 Inhibition

• COX-2 inhibitors prevent synthesis of prostacyclin in vascular endothelium, leading to vasoconstriction and platelet aggregation.

Steven-Johnson Syndrome and NSAIDs

• Linked to NSAIDs and COX-2 specific inhibitors.

• Characteristics include:

  • Epidermal necrolysis, skin inflammation, and mucous membrane inflammation.

• Can be life-threatening; treatment options include cyclosporine and TNF-alpha blocking agents.

Acetaminophen Overview

• Classified alongside NSAIDs due to antipyretic and analgesic actions.

• Regulates COX-3 along with COX-1/2 isoforms responsible for antipyretic action.

• Notably lacks significant anti-inflammatory properties as it does not inhibit peripheral COX effectively.

Acetaminophen Metabolism

• Metabolized via hepatic CYP450 to NAPQI, a toxic byproduct.

• Detoxified by glutathione conjugation; overuse leads to depletion of glutathione and potential hepatic damage.

Adverse Effects of Acetaminophen

1. Hepatotoxicity

2. Nephrotoxicity

3. Hypothermia

Drug Interactions with Acetaminophen

• Medications like phenytoin and phenobarbital can inhibit glucuronidation of acetaminophen.

• Ethanol and isoniazid can induce CYP2E1, increasing toxicity potential.

Selecting Appropriate NSAIDs

1. Selection logic based on indication: antipyretic, analgesic, or anti-inflammatory needs.

2. Minimize gastrointestinal adverse effects via H2 receptor antagonists or proton pump inhibitors (e.g., Omeprazole).

3. Consideration of cardiovascular health risks during selection.

NSAID Selection Criteria Chart

Bibliography

1. Goodman & Gilman, The Pharmacological Basis of Therapeutics, 14th Ed.

2. Katzung BG, Basic and Clinical Pharmacology, 15th Ed.

3. Golan DE, Principles of Pharmacology, 3rd Ed., Chapter 42.

4. Nan Chiang et al. Arterioscler Thromb Vasc Biol. 2006;26:e14-e17.

5. Ricciotti et al.; Arterioscler Thromb Vasc Biol. 2011 May; 31(5): 986–1000.

Contact Information

• Questions can be directed towards: pputha@midwestern.edu