Nonsteroidal anti-inflammatory drugs

I. Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most commonly prescribed and over-the-counter (OTC) medication classes globally. They are used for their analgesic, anti-inflammatory, antipyretic, and in some cases, antiplatelet effects. NSAIDs are widely utilized for the treatment of pain, inflammation, and fever arising from various etiologies such as musculoskeletal disorders, arthritis, injury, dysmenorrhea, and postoperative conditions.

The pharmacological action of NSAIDs is largely based on inhibition of the cyclooxygenase (COX) enzyme, which plays a key role in prostaglandin synthesis, pivotal in the inflammatory response. Despite their efficacy, NSAIDs are associated with well-documented gastrointestinal, cardiovascular, and renal adverse effects, necessitating risk stratification and proper patient selection during therapy.

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II. Classification of NSAIDs

NSAIDs can be classified based on chemical structure, selectivity for COX enzymes, or duration of action.

A. Based on COX Selectivity

1. Non-selective COX inhibitors – inhibit both COX-1 and COX-2:

   • Examples: ibuprofen, naproxen, diclofenac, indomethacin, piroxicam

2. Preferential COX-2 inhibitors – more selective for COX-2 but not fully selective:

   • Examples: meloxicam, etodolac, nabumetone

3. Selective COX-2 inhibitors (Coxibs) – specific inhibition of COX-2:

   • Examples: celecoxib, etoricoxib, parecoxib (injectable form)

4. Irreversible COX inhibitors:

   • Aspirin (acetylsalicylic acid) is the only NSAID with irreversible COX inhibition, particularly of platelet COX-1

B. Based on Chemical Class

1. Salicylates: aspirin, diflunisal

2. Propionic acid derivatives: ibuprofen, naproxen, ketoprofen

3. Acetic acid derivatives: diclofenac, indomethacin, etodolac

4. Enolic acid derivatives (oxicams): piroxicam, meloxicam

5. Fenamates: mefenamic acid, flufenamic acid

6. COX-2 selective inhibitors: celecoxib, etoricoxib, valdecoxib (withdrawn), rofecoxib (withdrawn)

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III. Mechanism of Action

NSAIDs inhibit the cyclooxygenase (COX) enzyme, which exists in two primary isoforms:

1. COX-1: Constitutively expressed in most tissues; involved in:

   • Gastrointestinal mucosal protection

   • Platelet aggregation (via thromboxane A2)

   • Renal blood flow regulation

2. COX-2: Inducible isoform, expressed during inflammation; responsible for:

   • Prostaglandin synthesis at sites of inflammation

   • Pain sensitization

   • Fever regulation in the hypothalamus

By inhibiting COX enzymes, NSAIDs reduce the synthesis of prostaglandins, which are mediators of:

• Pain (hyperalgesia)

• Inflammation (vasodilation, increased permeability)

• Fever (hypothalamic set point elevation)

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IV. Therapeutic Uses of NSAIDs

1. Analgesia (Pain Relief)

   • Mild to moderate pain: headache, dental pain, musculoskeletal pain

   • Inflammatory pain: arthritis, gout, ankylosing spondylitis

   • Postoperative pain

2. Antipyretic (Fever Reduction)

   • Used to control fever of various causes

3. Anti-inflammatory

   • Osteoarthritis and rheumatoid arthritis

   • Bursitis and tendonitis

   • Soft tissue injuries

4. Antiplatelet Effects (Aspirin)

   • Low-dose aspirin for cardiovascular event prevention

   • Inhibits thromboxane A2, reducing platelet aggregation

5. Dysmenorrhea

   • Effective in menstrual pain via prostaglandin inhibition

6. Patent ductus arteriosus (PDA) closure

   • Indomethacin or ibuprofen used in neonates

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V. Pharmacokinetics

• Absorption: Most NSAIDs are well absorbed orally

• Distribution: High plasma protein binding (especially to albumin)

• Metabolism: Primarily hepatic (cytochrome P450 enzymes)

• Excretion: Mainly via kidneys; dosing adjustments may be needed in renal impairment

• Half-life: Varies among agents

  • Short: ibuprofen (~2 hrs)

  • Intermediate: naproxen (~12 hrs)

  • Long: piroxicam (~50 hrs)

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VI. Adverse Effects

NSAIDs are associated with dose- and duration-dependent adverse effects, especially when used chronically.

1. Gastrointestinal (GI) Toxicity

• Gastritis, dyspepsia, gastric ulcer, GI bleeding, perforation

• Due to COX-1 inhibition and prostaglandin deficiency

• Risk increases with age, corticosteroids, anticoagulants, high doses

2. Renal Toxicity

• Reduced renal perfusion, sodium and water retention

• Acute kidney injury (especially in hypovolemia, CKD, or CHF)

• Papillary necrosis (rare with chronic use)

3. Cardiovascular Risks

• Increased risk of myocardial infarction, stroke, hypertension

• Especially with COX-2 inhibitors and high-dose diclofenac

• NSAIDs may reduce efficacy of antihypertensive drugs

4. Hematologic Effects

• Platelet dysfunction (mainly with aspirin)

• Increased bleeding risk

5. Hypersensitivity Reactions

• Urticaria, bronchospasm (aspirin-sensitive asthma)

• Anaphylaxis (rare)

6. Hepatotoxicity

• Rare; elevated liver enzymes, hepatitis

7. CNS Effects

• Headache, dizziness, confusion (especially in the elderly)

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VII. Contraindications and Cautions

1. Absolute Contraindications

   • Active peptic ulcer

   • NSAID allergy

   • Severe renal impairment

   • Advanced liver disease

   • Recent coronary artery bypass graft (CABG) surgery (for COX-2 inhibitors)

2. Relative Contraindications

   • Hypertension

   • Congestive heart failure

   • Elderly patients

   • Anticoagulant therapy

   • Pregnancy (especially third trimester due to risk of premature ductus arteriosus closure)

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VIII. Drug Interactions

1. With Antihypertensives:

   • NSAIDs may reduce effectiveness of ACE inhibitors, ARBs, and diuretics

2. With Anticoagulants and Antiplatelets:

   • Increased bleeding risk (e.g., warfarin + NSAIDs, aspirin + ibuprofen)

3. With Methotrexate:

   • Decreased clearance of methotrexate; increased toxicity

4. With Lithium:

   • NSAIDs reduce renal lithium clearance, raising serum levels

5. With Corticosteroids:

   • Synergistic risk of GI bleeding

6. With SSRIs:

   • Additive bleeding risk due to platelet dysfunction

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IX. Special Populations

1. Pregnancy

• Avoid NSAIDs in the third trimester (ductus arteriosus closure, oligohydramnios)

• Use paracetamol as the analgesic of choice

2. Pediatrics

• Ibuprofen widely used; avoid aspirin due to risk of Reye’s syndrome

3. Elderly

• Higher risk of GI, renal, and cardiovascular complications

• Use lowest effective dose for shortest duration

4. Renal and Hepatic Impairment

• Use with caution or avoid altogether; consider alternatives

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X. NSAIDs vs Acetaminophen (Paracetamol)

Parameter	NSAIDs	Acetaminophen (Paracetamol)
Anti-inflammatory	Yes	No
Analgesic	Yes	Yes
Antipyretic	Yes	Yes
GI risk	Moderate to High	Low
Renal impact	Moderate	Low (except in overdose)
Platelet effect	Yes (aspirin)	No
Preferred in CVD	No (except aspirin)	Yes

XI. COX-2 Selective Inhibitors (Coxibs)

1. Celecoxib

   • Selective COX-2 inhibitor

   • Lower GI risk but higher cardiovascular risk

   • Approved for osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea

2. Etoricoxib

   • Used in many countries but not approved by the FDA

   • Effective in musculoskeletal pain and gout

3. Withdrawn COX-2 Inhibitors

   • Rofecoxib (Vioxx) and valdecoxib (Bextra) withdrawn due to increased cardiovascular events

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XII. Strategies to Minimize NSAID Toxicity

1. Use the lowest effective dose for the shortest possible time

2. Combine with gastroprotective agents (e.g., PPIs or misoprostol in high-risk GI patients)

3. Avoid in patients with uncontrolled hypertension or CKD

4. Consider COX-2 inhibitors for patients with GI risk but without high CV risk

5. Routine monitoring of renal function and blood pressure during long-term use

6. HB testing before initiating chronic NSAID therapy in at-risk patients

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XIII. Common NSAID Agents

Generic Name	Brand Names	Notes
Ibuprofen	Advil, Nurofen	OTC, short half-life, well-tolerated
Naproxen	Aleve, Naprosyn	Longer half-life, CV safer profile
Diclofenac	Voltaren, Cataflam	Effective, high CV risk
Indomethacin	Indocin	Potent, higher CNS side effects
Piroxicam	Feldene	Long half-life, high GI risk
Celecoxib	Celebrex	COX-2 selective, lower GI risk
Etoricoxib	Arcoxia	Not FDA approved, used globally
Aspirin	Ecotrin, Bayer	Antiplatelet at low doses
Mefenamic acid	Ponstan	Used for dysmenorrhea
Meloxicam	Mobic	Preferential COX-2 activity

XIV. Formulations and Routes of Administration

1. Oral tablets and capsules – most common

2. Injectable (IV/IM) – for acute pain (e.g., ketorolac)

3. Topical gels and creams – diclofenac gel, ibuprofen creams

4. Rectal suppositories – useful in nausea/vomiting

5. Patches – localized musculoskeletal pain

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XV. Future Directions and Research

1. Development of NO-NSAIDs – release nitric oxide to counter GI toxicity

2. Dual inhibitors – target COX and 5-LOX pathways

3. Nanoformulations – enhance drug delivery and reduce systemic toxicity

4. Biomarker-guided NSAID therapy – personalized risk stratification

5. Combination therapies – combining NSAIDs with PPIs, antacids, or gastroprotective agents