6.2 Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen

NSAIDs and acetaminophen are key players in pain management. They work differently: NSAIDs block COX enzymes, reducing inflammation, while acetaminophen mainly affects the central nervous system, offering pain relief without much anti-inflammatory action.

These drugs have unique properties and uses. NSAIDs are great for inflammatory conditions, but they come with risks like stomach issues and heart problems. Acetaminophen is safer for some but can harm the liver in high doses. Choosing between them depends on the patient's specific needs and health status.

NSAID vs Acetaminophen Mechanisms

COX Inhibition and Prostaglandin Synthesis

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• NSAIDs inhibit cyclooxygenase (COX) enzymes reducing prostaglandin synthesis
  • Provides analgesic, anti-inflammatory, and antipyretic effects
  • Affects both peripheral and central nervous systems
• Acetaminophen primarily acts centrally inhibiting prostaglandin synthesis in the central nervous system
  • Provides analgesic and antipyretic effects without significant anti-inflammatory action
  • Limited effect on peripheral tissues

NSAID Classification and Action Sites

• NSAIDs classified as non-selective COX inhibitors (inhibiting both COX-1 and COX-2) or selective COX-2 inhibitors
  • Influences efficacy and side effect profiles
  • Non-selective NSAIDs (ibuprofen, naproxen)
  • Selective COX-2 inhibitors (celecoxib)
• NSAIDs peripheral action contributes to anti-inflammatory effects
  • Reduces inflammation at injury sites
  • Modulates both nociceptive and inflammatory pain pathways
• Acetaminophen central action limits anti-inflammatory properties
  • Primarily modulates nociceptive pain
  • Minimal effect on peripheral inflammation

Pharmacokinetic Differences

• NSAIDs duration of action varies due to different pharmacokinetic properties
  • Short-acting (ibuprofen, 4-6 hours)
  • Long-acting (naproxen, 8-12 hours)
• Acetaminophen typically has shorter duration of action
  • 4-6 hours for regular formulations
  • Extended-release formulations available for longer effect

Pharmacological Properties of NSAIDs and Acetaminophen

Therapeutic Uses and Indications

• NSAIDs manage acute and chronic pain, inflammation, and fever
  • Specific indications osteoarthritis, rheumatoid arthritis, and dysmenorrhea
  • Useful for post-operative pain and sports injuries
• Acetaminophen primarily used for pain relief and fever reduction
  • Particularly useful when anti-inflammatory effects not necessary or desired
  • Common for headaches, menstrual cramps, and minor aches

Common NSAIDs and Dosing Regimens

• Ibuprofen 200-400 mg every 4-6 hours (maximum 1200 mg/day for OTC use)
• Naproxen 220-550 mg every 12 hours (maximum 1375 mg/day)
• Diclofenac 50 mg every 8 hours or 75 mg every 12 hours
• Celecoxib 200 mg daily or 100 mg twice daily for osteoarthritis

Acetaminophen Dosing Considerations

• Weight-based dosing in pediatric patients
  • 10-15 mg/kg every 4-6 hours
• Maximum daily dose in adults 4000 mg to prevent hepatotoxicity
  • Some guidelines recommend 3000 mg/day for long-term use
• Available in oral, rectal, and intravenous formulations
  • Oral dosing 325-1000 mg every 4-6 hours
  • IV dosing 1000 mg every 6 hours or 650 mg every 4 hours

NSAID Administration and Dosing Strategies

• NSAIDs administered orally, topically, or parenterally
  • Oral most common for chronic conditions
  • Topical useful for localized pain (diclofenac gel)
  • Parenteral for acute severe pain or when oral route not available
• Use lowest effective dose for shortest duration possible to minimize adverse effects
  • Particularly important in high-risk patients (elderly, history of GI bleeding)
• Consider time-dependent vs. dose-dependent efficacy when selecting and dosing NSAIDs
  • Time-dependent (ibuprofen) may require more frequent dosing
  • Dose-dependent (naproxen) may allow for less frequent dosing

Adverse Effects of NSAIDs and Acetaminophen

Gastrointestinal and Cardiovascular Risks

• NSAIDs can cause gastrointestinal toxicity including ulceration and bleeding
  • Risk factors advanced age, history of peptic ulcer disease, and concomitant corticosteroid use
  • Strategies to reduce risk include using COX-2 selective NSAIDs or adding proton pump inhibitors
• Cardiovascular risks associated with NSAIDs include increased risk of myocardial infarction, stroke, and heart failure
  • Particularly with long-term use and in patients with pre-existing cardiovascular disease
  • Naproxen may have lower cardiovascular risk compared to other NSAIDs

Renal and Hepatic Effects

• Renal adverse effects of NSAIDs include acute kidney injury, fluid retention, and hypertension
  • Necessitates caution in patients with renal impairment or heart failure
  • Monitor renal function in long-term NSAID users
• Acetaminophen can cause severe hepatotoxicity when taken in excessive doses
  • Risk increased in patients with liver disease or chronic alcohol use
  • N-acetylcysteine used as antidote in acetaminophen overdose

Contraindications and Drug Interactions

• NSAIDs contraindicated in patients with active gastrointestinal bleeding, severe renal impairment, and during third trimester of pregnancy
  • Increased risk of premature closure of the ductus arteriosus in fetus
• Drug interactions with NSAIDs include increased bleeding risk with anticoagulants
  • Reduced efficacy of certain antihypertensive medications (ACE inhibitors, beta-blockers)
  • Increased risk of nephrotoxicity when combined with diuretics or ACE inhibitors
• Acetaminophen has fewer drug interactions compared to NSAIDs
  • Can interact with warfarin increasing INR
  • May interact with certain anti-epileptic drugs (carbamazepine) altering their metabolism

Selecting NSAID or Acetaminophen Therapy

Patient-Specific Considerations

• Patient age, comorbidities, and concomitant medications guide selection between NSAIDs and acetaminophen
  • Elderly patients may be at higher risk for NSAID-related adverse effects
  • Patients with multiple comorbidities require careful consideration of drug interactions
• For inflammatory conditions, NSAIDs generally preferred over acetaminophen
  • Rheumatoid arthritis, osteoarthritis with inflammatory component
• In patients with history of gastrointestinal complications, COX-2 selective NSAIDs or acetaminophen may be preferred
  • Consider adding gastroprotective agents (proton pump inhibitors) with NSAID therapy

Cardiovascular and Renal Considerations

• For patients with cardiovascular risk factors, naproxen may be NSAID of choice
  • Potentially lower cardiovascular risk profile compared to other NSAIDs
  • Still use with caution and for shortest duration necessary
• In patients with renal impairment, acetaminophen often preferred over NSAIDs
  • Use with caution and dose adjustment based on degree of renal dysfunction
  • Monitor renal function if long-term use necessary

Special Populations and Long-Term Management

• In pregnancy, acetaminophen generally considered safer than NSAIDs
  • Especially during first and third trimesters
  • NSAIDs may be used cautiously in second trimester if necessary
• For long-term pain management, multimodal approach may be more effective and safer
  • Combining different analgesics (NSAIDs, acetaminophen, topical agents)
  • Incorporating non-pharmacological interventions (physical therapy, acupuncture)
• Regular reassessment of pain management strategy essential
  • Evaluate efficacy and monitor for adverse effects
  • Adjust therapy based on patient response and changing risk factors