What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), their classification, mechanism of action, pharmacokinetics, clinical uses, adverse effects, contraindications, and drug interactions?

NSAIDs: Clinical Approach and Therapeutic Considerations

NSAIDs are effective anti-inflammatory, analgesic, and antipyretic medications that work primarily through inhibition of cyclooxygenase enzymes, but must be prescribed with careful consideration of their significant gastrointestinal, cardiovascular, and renal adverse effects. 1

Definition and Classification

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are a diverse group of medications that inhibit prostaglandin synthesis through cyclooxygenase (COX) enzyme inhibition. They can be classified into:

1. Non-selective COX inhibitors (nsNSAIDs):

   • Salicylic acid derivatives: Aspirin (ASA), salsalate
   • Propionic acids: Ibuprofen, naproxen, ketoprofen
   • Acetic acids: Indomethacin, diclofenac
   • Enolic acids: Piroxicam, meloxicam

2. Preferential COX-2 inhibitors:

   • Meloxicam, etodolac, nabumetone

3. Selective COX-2 inhibitors (Coxibs):

   • Celecoxib (only coxib currently available in the US) 1

Mechanism of Action

NSAIDs work by inhibiting cyclooxygenase enzymes (COX-1 and COX-2), which convert arachidonic acid to prostaglandins:

• COX-1 (constitutive): Present in most tissues, maintains normal physiological functions including gastric mucosal protection, platelet aggregation, and renal blood flow
• COX-2 (inducible): Primarily expressed at sites of inflammation, mediates pain and inflammatory responses

Key differences in inhibition patterns:

• nsNSAIDs: Reversibly inhibit both COX-1 and COX-2
• Aspirin: Irreversibly blocks both COX enzymes
• Coxibs: Selectively inhibit COX-2 with minimal effect on COX-1 1

Pharmacokinetics

Most NSAIDs share similar pharmacokinetic properties:

• Absorption: Rapid oral absorption
• Metabolism: Primarily hepatic via CYP450 enzymes
• Protein binding: High (>90% for most)
• Half-life: Variable (short for ibuprofen [2-4h]; longer for naproxen [12-17h])
• Excretion: Primarily renal

Clinical Uses

1. Pain management:

   • Acute pain (headache, dysmenorrhea, post-operative)
   • Chronic pain (arthritis, musculoskeletal disorders)

2. Anti-inflammatory conditions:

   • Rheumatoid arthritis
   • Osteoarthritis
   • Ankylosing spondylitis
   • Gout (especially indomethacin)

3. Antipyretic use:

   • Fever reduction

4. Specialized uses:

   • Aspirin: Cardiovascular prophylaxis (antiplatelet effect)
   • Indomethacin: PDA closure in neonates

Adverse Effects

1. Gastrointestinal Effects

• Upper GI: Dyspepsia, gastritis, peptic ulcers, bleeding, perforation
• Lower GI: Enteropathy, bleeding, protein loss
• Risk factors: Advanced age, history of peptic ulcer disease, concomitant anticoagulants/corticosteroids, high-dose or multiple NSAIDs 1, 2

2. Cardiovascular Effects

• Increased risk of myocardial infarction, stroke, and heart failure
• Blood pressure elevation
• Risk varies by agent (coxibs and diclofenac have higher CV risk; naproxen may have better CV safety profile) 1, 3

3. Renal Effects

• Acute kidney injury
• Sodium and water retention
• Hyperkalemia
• Interstitial nephritis 4

4. Other Effects

• Hematologic: Platelet dysfunction and bleeding (especially with aspirin)
• Hypersensitivity: Bronchospasm, urticaria, anaphylaxis
• Hepatic: Transaminitis, rarely liver failure
• Skin: Rash, photosensitivity, Stevens-Johnson syndrome (rare)

Contraindications

Absolute contraindications:

• Active peptic ulcer disease
• History of NSAID-induced asthma/anaphylaxis
• Severe heart failure
• Third trimester pregnancy (risk of premature closure of ductus arteriosus)
• Perioperative pain in CABG surgery 3

Relative contraindications:

• History of GI bleeding
• Cardiovascular disease
• Renal impairment
• Concurrent use of anticoagulants
• Advanced age (>65 years)
• Liver disease

Drug Interactions

• Anticoagulants (warfarin, DOACs): Increased bleeding risk
• Antiplatelets (clopidogrel): Increased bleeding risk
• Antihypertensives (ACE inhibitors, ARBs, diuretics): Reduced efficacy, worsened renal function
• Corticosteroids: Increased GI bleeding risk
• SSRIs/SNRIs: Increased bleeding risk
• Lithium: Increased lithium levels
• Methotrexate: Reduced methotrexate clearance

Risk Reduction Strategies

1. GI risk reduction:

   • Use lowest effective dose for shortest duration
   • Add PPI for high-risk patients (superior to H2-blockers)
   • Consider COX-2 selective agents for high GI risk patients without CV risk
   • Test and treat H. pylori if present 1, 2

2. CV risk reduction:

   • Avoid NSAIDs in high CV risk patients when possible
   • Consider naproxen if NSAID needed in patients with CV risk
   • Avoid coxibs in patients with established CV disease 1, 5

3. Renal risk reduction:

   • Monitor renal function
   • Avoid in severe renal impairment
   • Use caution with diuretics

Monitoring Recommendations

For patients on chronic NSAID therapy:

• Regular assessment of GI symptoms
• Blood pressure monitoring
• Periodic laboratory testing (CBC, renal function, liver enzymes)
• Fecal occult blood testing for high-risk patients
• Annual comprehensive assessment for patients on therapy >1 year 2

Common Pitfalls

1. Failure to assess baseline risk: Not evaluating GI and CV risk before prescribing
2. Inappropriate dosing: Using higher doses than necessary
3. Prolonged use: Continuing NSAIDs longer than needed
4. Inadequate monitoring: Not following patients for adverse effects
5. Multiple NSAID use: Combining different NSAIDs (including OTC)
6. Failure to provide gastroprotection: Not prescribing PPIs for high-risk patients
7. Aspirin in children: Risk of Reye's syndrome

Remember that NSAIDs should be used at the lowest effective dose for the shortest duration possible to minimize adverse effects while achieving therapeutic goals 3, 6.