anti inflammatory

Anti-Inflammatory Drugs: NSAIDs & Acetaminophen - Chapter 75

Objectives

  • Discuss the role of inflammation in pain.
  • Understand the role of anti-inflammatory, anti-rheumatoid, and other related medications in pain reduction.
  • Differentiate the classifications and understand their mechanisms of action, significant interactions, indications, adverse effects, and contraindications.
  • Identify maximum recommended doses for the prototype medications.
  • Identify signs of toxicity.

The Inflammatory Response

Signs of Inflammation
  • Mechanisms of Inflammation:
    • The inflammatory response is characterized by various signs which include redness, heat, swelling, pain, and loss of function. These symptoms arise as a result of complex biological processes triggered by tissue injury.
Release of Mediators During Inflammation
  • Mediators Released by Tissue Injury:
    • Conditions such as muscle damage or chemical irritation provoke the release of several key substances, including:
    • Prostaglandins
    • Bradykinin
    • Histamine
    • Leukotrienes
    • Serotonin
Characteristics of Autacoids
  • Functions of Local Mediators:
    • These mediators cause:
    • Vasodilation
    • Increased vascular permeability
    • Chemotaxis (the movement of cells towards sites of injury)
    • Induction of pain
Pathway of Arachidonic Acid Production
  1. Stimulus: Initiates the activation of Phospholipase A₂.
  2. Release of Phospholipids from the cell membrane.
  3. Formation of Arachidonic Acid.
  4. Cyclooxygenase Enzyme Action:
    • COX-1 and COX-2: These enzymes convert arachidonic acid into prostanoids (prostaglandins and related compounds).
    • The main pathway leads to the formation of PGH₂, which subsequently forms various active prostaglandins (PGD₂, PGE₂, PGF₂α, and TXA₂).

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Mechanism of Action of NSAIDs
  • NSAIDs exert their effects primarily by blocking either or both cyclooxygenase (COX) enzymes (COX-1 & COX-2), the enzymes responsible for converting arachidonic acid into prostanoids. This inhibition limits the undesirable inflammatory effects of prostaglandins and related substances.
Properties of NSAIDs
  • Characteristics:
    • Analgesic: Effective in alleviating pain.
    • Anti-inflammatory: Reduces inflammation.
    • Antipyretic: Lowers fever.
Indications for NSAIDs
  • Pain Relief: Mild to moderate pain.
  • Conditions Treated:
    • Osteoarthritis
    • Rheumatoid arthritis
    • Juvenile rheumatoid arthritis
    • Acute gout
    • Various bone, joint, and muscle pain
    • Dysmenorrhea
    • Fever
    • Other pain-related conditions.
Non-Selective NSAIDs
  • Examples:
    • Acetylsalicylic acid (Aspirin)
    • Ketorolac (Toradol)
    • Sodium salicylate
    • Ibuprofen (Motrin, Advil)
    • Naproxen (Aleve)
    • Diclofenac sodium (Voltaren)
Adverse Effects of NSAIDs
  • **Gastrointestinal issues:
    • Risk of gastric ulceration (erosions), dyspepsia, heartburn, and nausea; potential for GI bleeding.**
  • Renal implications:
    • NSAIDs may lead to decreased renal function, acute tubular necrosis, and renal failure.
Acetylsalicylic Acid (ASA/Aspirin)
  • Overview:
  • Standard NSAID used for comparisons.
  • Derived from salicylic acid initially extracted from willow bark.
  • Mechanism:
    • ASA irreversibly inhibits COX, while other NSAIDs do so reversibly.
  • Dosage:
    • 80-160 mg daily for prophylaxis against myocardial infarction (MI) and stroke.
  • Contraindications:
    • Pregnancy, bleeding disorders, renal dysfunction, and cessation 1 week before surgery to prevent excessive bleeding.
Adverse Effects of ASA
  • Concerns:
    • Gastrointestinal issues including gastric ulceration and Reye's syndrome in children associated with influenza or chickenpox, which can lead to severe neurological complications.
  • Signs of salicylate toxicity:
    • Adults: tinnitus and hearing loss.
    • Children: hyperventilation due to CNS stimulation.
Non-ASA NSAIDs
  • Characteristics:
    • Similar at alleviating pain with fewer GI, renal, and hemorrhagic adverse effects compared to ASA. They do not protect against MI and stroke.
Selective COX-2 Inhibitors
  • Examples:
    • Celecoxib (Celebrex), Rofecoxib (Vioxx) - withdrawn from the market in 2004 due to safety concerns. These are effective against inflammation with potentially lower gastrointestinal side effects but can still pose cardiovascular risks.

Acetaminophen

  • Classification:
    • Non-opioid analgesics such as Tylenol.
    • Characteristics: Analgesic and antipyretic properties but little to no anti-inflammatory effect.
  • Mechanism of Action:
    • Acts on the COX enzyme in the CNS, providing analgesic effects without peripheral action.
  • Dosage Guidelines:
    • Maximum daily allowance: 4000 mg/day for adults; 2400 mg for children aged 11-12 years. Extreme caution is advised with alcohol consumption due to hepatoxicity risks.
Toxicity and Overdose
  • Signs of Toxicity:
    • Can lead to hepatic necrosis, particularly in overdose situations, whether intentional or due to unintentional misuse.
  • Antidote for Overdose:
    • Acetylcysteine (Mucomyst) protects the liver from acetaminophen-induced damage, most effective when given within 8-10 hours of ingestion.
Contraindications
  • Severe hepatic and renal disease, chronic alcoholism, known drug allergies.
Warnings and Safety Information
  • Over 700 acetaminophen products exist with half of their use in combination therapies, leading to significant hospitalization rates for overdose and liver injuries and emphasizing the need for clearer labeling and consumer education concerning proper dosing and potential interactions with alcohol.