NSAIDS

Pharmacology of NSAIDs

Introduction

  • Overview of the course: Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) as part of the pharmacology curriculum.

  • Reference materials and related topics not covered in testing:

    • Corticosteroids and Inflammation (by McCarter)

    • Eicosanoids and Prostaglandins (by Rajagopalan)

Course Outline

  1. Introduction to NSAIDs

  2. Prostaglandins and their role in NSAIDs

  3. Cyclooxygenase Enzymes: COX-1 and COX-2

  4. Prototypical NSAID: Aspirin

  5. Selective COX-2 Inhibitors

  6. Common Side Effects of NSAIDs

  7. COX-1 Inhibition in the Gastrointestinal System

  8. COX-1 and COX-2 Inhibition in the Renal System

  9. COX-1 and COX-2 Inhibition in the Cardiovascular System

  10. Common Drug-Drug Interactions with NSAIDs

  11. Medicinal Chemistry: Structural Classes of NSAIDs

  12. COX Selectivity

  13. Acetaminophen

Inflammation

  • Definition: Inflammation is the immune response triggered by tissue damage due to foreign or antigenic substances.

  • Characterization:

    • Increases in vascular permeability, temperature, redness, swelling, and pain.

    • Decrease in function.

  • Mediators of Inflammation:

    • Histamine

    • Kinins (e.g., Bradykinin, Angiotensin)

    • Chemokines

    • Neuropeptides

    • Tumor Necrosis Factor-alpha (TNF-alpha)

    • Reactive oxygen species (ROS)

    • Prostaglandins: derived from the oxygenation of polyunsaturated fatty acids, primarily arachidonic acid, acting as local hormones/autacoids.

NSAID Overview

  • Definition: NSAIDs are a diverse class of drugs (over 70 currently in use) that exhibit anti-inflammatory, analgesic, and antipyretic properties.

  • Types of NSAIDs:

    • tNSAIDs: Traditional NSAIDs (non-specific inhibitors of COX-1 and COX-2).

  • Usage Statistics:

    • Global: Approximately 70 million people prescribed NSAIDs daily; 230 million take over-the-counter (OTC) NSAIDs.

    • In the USA: 80 billion aspirin tablets consumed annually; NSAIDs account for 4% of all prescriptions.

  • Primary Effects:

    • Anti-inflammatory properties beneficial in arthritis and cardioprotection.

    • Analgesic properties for pain relief.

    • Antipyretic properties to reduce fever.

  • Indications for Use:

    • Pain and inflammation from conditions like rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, acute gout, headaches, migraines, dysmenorrhea, and postoperative pain.

  • Prophylactic Uses:

    • Prophylaxis of heart disease (e.g., myocardial infarction and stroke with aspirin).

    • Potential prophylaxis of colorectal cancer and treatment of Alzheimer’s disease, both possibly linked to anti-inflammatory properties of NSAIDs.

Prostaglandins and NSAIDs

  • Prostaglandin Overview:

    • Eicosanoids mediate both negative (inflammation, pain, fever) and positive physiological effects (e.g., stomach lining protection).

    • Produced from arachidonic acid via cyclooxygenase (COX) enzymes.

  • Role of NSAIDs:

    • NSAIDs facilitate the inhibition of COX, mitigating inflammation, pain, and fever while diminishing gastroprotective effects.

    • Competitive binding of NSAIDs within the COX enzyme prevents arachidonic acid from being converted to prostaglandins.

    • Prominent COX isoforms include COX-1 (housekeeping functions) and COX-2 (induced during inflammation).

COX Enzymes: COX-1 and COX-2

  • COX-1:

    • Constitutively expressed, performs essential functions including:

    • Mucus production for stomach lining protection.

    • Facilitating clot formation during wound healing.

  • COX-2:

    • Induced expression under inflammatory conditions; also constitutively present in endothelial cells.

Prototypical NSAID: Aspirin

  • History and Development:

    • Salicin (from willow bark) purified in the 1830s.

    • Acetylsalicylic acid synthesized in the 1850s; analgesic, antipyretic, anti-inflammatory properties.

    • Aspirin discovered as an irreversible inhibitor of COX.

  • Mechanism of Action:

    • Irreversible inhibition of COX-1 and COX-2 via acetylation of serine residues (Ser 530 in COX-1 and Ser 516 in COX-2).

    • Results in inhibition of thromboxane A2 (TXA2) synthesis, crucial for platelet function.

  • Cardiovascular Protection:

    • Single doses can double bleeding time for 4-7 days due to irreversible inhibition of platelet COX-1.

  • Gastrointestinal Side Effects:

    • Strong COX-1 inhibition leads to gastric lining damage, increasing ulcer risk and GI bleeding.

Selective COX-2 Inhibitors

  • Development Purpose:

    • Developed to reduce GI adverse effects associated with COX-1 inhibition.

  • Notable COX-2 Selective Drugs:

    • Celecoxib (Celebrex)

    • Rofecoxib (Vioxx)

    • Valdecoxib (Bextra)

    • Newer options: Parecoxib, Lumiracoxib, Etoricoxib.

  • Health Implications:

    • Notably associated with cardiovascular risks (myocardial infarction, stroke) while offering reduced GI toxicity.

Common NSAID Side Effects

  • GI Effects:

    • Abdominal pain, peptic ulcers, GI hemorrhage.

  • Renal Effects:

    • Sodium and water retention, edema, hyperkalemia.

  • CNS Effects:

    • Dizziness, confusion, potential lowering of seizure threshold.

  • Uterine Effects:

    • Prolongation of gestation, increased postpartum hemorrhage risk.

  • Hypersensitivity Reactions:

    • Including vasomotor rhinitis, urticaria, bronchial asthma.

    • Special caution with aspirin in children under 20 years (risk of Reye’s Syndrome).

Inhibition of COX-1 in the Gastrointestinal System

  • COX-1’s role and companion prostaglandins are crucial for maintaining gastric protection.

  • Inhibition leads to decreased mucus secretion and bicarbonate production, elevating ulceration risk and GI bleeding.

Inhibition of COX-1 and COX-2 in the Renal System

  • Prostaglandins are vital for normal renal function; lower prostaglandin levels lead to hypertension and acute kidney injury.

Inhibition of COX-1 and COX-2 in the Cardiovascular System

  • COX-1 and COX-2 derivatives balance hemostasis and vascular tone; inhibiting these can result in thrombosis and blood pressure regulation issues.

Common NSAID Drug-Drug Interactions

  • Notable interactions include:

    • NSAIDs with aspirin: Increases GI adverse effects.

    • NSAIDs with ACE inhibitors: May block effectiveness of ACE inhibitors.

    • NSAIDs with Warfarin: Increased risk of bleeding; co-administration should be avoided.

NSAID Medicinal Chemistry & Structural Classes

  • Diverse structural classes contribute to the varied properties and selectivity of NSAIDs. Examples include:

    • Carboxylic acids (e.g., Aspirin, Diclofenac)

    • Propionic acids (e.g., Ibuprofen, Naproxen)

    • Selective COX-2 inhibitors (e.g., Celecoxib).

NSAID COX Selectivity

  • The degree of selectivity for COX-1 versus COX-2 determines their therapeutic applications and risk profiles.

Acetaminophen (Paracetamol)

  • History:

    • Initially an active metabolite of phenacetin; first used as an analgesic in 1893.

    • Offers analgesic and antipyretic effects but weak anti-inflammatory properties compared to NSAIDs.

  • Mechanism of Action:

    • Not fully understood but thought to involve central inhibition of prostaglandin synthesis.

  • Safety and Overdose Risks:

    • Generally well-tolerated.

    • Overdose can lead to hepatic necrosis due to toxic metabolite: N-acetyl-p-benzoquinoneimine (NAPQI).