NSAIDs

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

Definition

NSAIDs are a diverse class of medications that exert analgesic, anti-inflammatory, and antipyretic effects by inhibiting cyclooxygenase (COX) enzymes involved in prostaglandin synthesis. They are widely used in clinical practice for both acute and chronic pain conditions, including musculoskeletal disorders, headaches, dysmenorrhea, fever, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis

Classification

By Selectivity

Non-selective COX Inhibitors (inhibit both COX-1 and COX-2)

Ibuprofen

Naproxen

Diclofenac

Indometacin

Ketoprofen

Piroxicam

Sulindac

Preferential COX-2 Inhibitors

Meloxicam

Etodolac

Nabumetone

Selective COX-2 Inhibitors (Coxibs)

Celecoxib

Etoricoxib

Parecoxib

Rofecoxib (withdrawn due to cardiovascular risk)

Valdecoxib (withdrawn)

Salicylates

Aspirin (acetylsalicylic acid)

Salsalate

Diflunisal

Other/Unique Mechanisms

Nimesulide

Meclofenamate

Mefenamic acid

Tiaprofenic acid

Mechanism of Action

NSAIDs inhibit cyclooxygenase enzymes responsible for converting arachidonic acid to prostaglandins

COX-1 is constitutive and involved in gastric protection, platelet aggregation, and renal perfusion

COX-2 is inducible and upregulated in response to inflammation and tissue injury

Inhibition of COX reduces prostaglandin synthesis, resulting in decreased inflammation, pain, and fever

Aspirin irreversibly inhibits COX-1 and COX-2, especially in platelets

Non-aspirin NSAIDs reversibly inhibit COX enzymes

COX-2 selective inhibitors aim to minimize GI toxicity associated with COX-1 inhibition

Therapeutic Uses

Pain Management

Acute musculoskeletal pain

Chronic low back pain

Postoperative pain

Headache and migraine

Dental pain

Dysmenorrhea

Inflammatory Conditions

Rheumatoid arthritis

Osteoarthritis

Ankylosing spondylitis

Gouty arthritis (some NSAIDs used in acute flares)

Fever

Ibuprofen and aspirin commonly used in adults

Paracetamol preferred in children, but ibuprofen also used

Antiplatelet Therapy (Aspirin)

Prevention of myocardial infarction, stroke, and thrombosis in high-risk cardiovascular patients

Patent Ductus Arteriosus (PDA) Closure in Neonates

Indomethacin and ibuprofen used to close PDA in preterm infants

Cancer Chemoprevention (Aspirin)

Low-dose aspirin used for colorectal cancer risk reduction in high-risk individuals

Dosage and Administration

Examples of Common NSAIDs

Ibuprofen

Adult: 200–400 mg every 4–6 hours (max 2400 mg/day)

Pediatric: 5–10 mg/kg/dose every 6–8 hours

Naproxen

250–500 mg twice daily (max 1000 mg/day)

Longer half-life allows for twice daily dosing

Diclofenac

50 mg two to three times daily (oral)

Also available as topical gel, suppositories, and injections

Indometacin

25–50 mg two to three times daily

Potent, often reserved for gout or ankylosing spondylitis

Celecoxib (COX-2 Selective)

100–200 mg once or twice daily

Lower GI toxicity, but cardiovascular risks

Etoricoxib

60–120 mg once daily

Approved in many countries outside the US

Topical NSAIDs

Diclofenac gel (1% or 3%) for osteoarthritis, strains

Ketoprofen patch in some countries

Rectal Suppositories

Diclofenac, indometacin available in this form for patients with vomiting or unable to take oral meds

Parenteral Forms

Ketorolac (IV/IM): short-term use for moderate to severe pain

Parecoxib (IV/IM): injectable selective COX-2 inhibitor used perioperatively

Pharmacokinetics

Absorption

Rapidly absorbed orally

Peak plasma levels usually reached within 1–2 hours

Distribution

Highly protein-bound (>90%)

Volume of distribution is low to moderate

Metabolism

Primarily hepatic metabolism via CYP enzymes (e.g., CYP2C9)

Elimination

Renal excretion (unchanged drug or metabolites)

Half-lives vary from 2 hours (ibuprofen) to >50 hours (piroxicam)

Contraindications

Active peptic ulcer disease

Severe heart failure

Hypersensitivity to NSAIDs

History of NSAID-induced asthma or anaphylaxis

Severe renal or hepatic impairment

Third trimester of pregnancy (risk of premature ductus arteriosus closure)

Perioperative use in coronary artery bypass graft (CABG) surgery (especially for COX-2 inhibitors)

Warnings and Precautions

Gastrointestinal Toxicity

Risk of GI bleeding, ulcers, and perforation

Highest with non-selective NSAIDs, especially in elderly and those with history of ulcers

Concomitant use of corticosteroids, anticoagulants, SSRIs increases risk

Co-prescription with PPIs or misoprostol advised for high-risk patients

Cardiovascular Risk

Increased risk of myocardial infarction and stroke, especially with long-term use

COX-2 inhibitors (e.g., celecoxib, etoricoxib) carry higher CV risk

Lowest effective dose for shortest duration recommended

Naproxen considered the NSAID with lowest CV risk

Renal Toxicity

NSAIDs reduce renal blood flow by inhibiting prostaglandins

Risk of acute kidney injury, sodium retention, hypertension

Monitor renal function, especially in elderly, those with CKD, heart failure, or on diuretics/ACE inhibitors

Hepatic Injury

Rare hepatotoxicity reported

Monitor LFTs in long-term therapy

CNS Effects

Headache, dizziness, confusion reported

Indometacin associated with depression, psychosis in high doses

Hypersensitivity Reactions

Urticaria, bronchospasm, anaphylaxis possible

Aspirin-exacerbated respiratory disease (AERD) in susceptible individuals

Hematologic Effects

Platelet dysfunction with aspirin and non-selective NSAIDs

Monitor bleeding risk when used with anticoagulants or antiplatelets

Pregnancy and Lactation

Pregnancy

Avoid NSAIDs in third trimester due to risk of premature closure of ductus arteriosus

May impair labor or fetal renal function

Aspirin in low doses used for preeclampsia prevention

Lactation

Ibuprofen and naproxen considered safe

Avoid long-term or high-dose NSAID use during breastfeeding

Adverse Effects

Common

Dyspepsia

Nausea

Gastric irritation

Headache

Dizziness

Fluid retention

Mild elevations in liver enzymes

Serious

GI bleeding

Peptic ulcer perforation

Myocardial infarction

Stroke

Acute kidney injury

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Aplastic anemia (rare)

Overdose

Symptoms

Nausea, vomiting

Drowsiness, dizziness

Seizures (in high doses)

Metabolic acidosis

Renal failure

Management

Supportive care

Activated charcoal if early ingestion

IV fluids, correction of acid-base disturbances

No specific antidote

Dialysis not effective due to high protein binding

Drug Interactions

ACE inhibitors, ARBs, diuretics (triple whammy)

Increased risk of renal impairment

Monitor creatinine and electrolytes

Anticoagulants and antiplatelets

Increased bleeding risk

Avoid combining NSAIDs with warfarin, apixaban, or clopidogrel without clear indication

SSRIs and SNRIs

Additive risk of GI bleeding

Consider PPI co-prescription

Methotrexate

NSAIDs may reduce methotrexate clearance

Monitor for toxicity, especially in high-dose methotrexate therapy

Lithium

NSAIDs reduce lithium clearance

Monitor serum lithium levels

Cyclosporine

Increased nephrotoxicity risk

Avoid or monitor renal function closely

Use in Special Populations

Elderly

Higher risk of GI bleeding, renal impairment, CV events

Use gastroprotection and monitor closely

Renal Impairment

Avoid or use with extreme caution

Monitor renal function regularly

Hepatic Impairment

Use cautiously, especially with drugs like diclofenac known for hepatic metabolism

Asthma

NSAIDs may trigger bronchospasm in aspirin-sensitive asthma

Pediatrics

Ibuprofen commonly used

Aspirin contraindicated due to risk of Reye’s syndrome

Monitoring Parameters

Renal function (creatinine, BUN)

Blood pressure

Signs of GI bleeding (black stools, anemia)

Liver function tests (ALT, AST) in long-term use

CV risk assessment

Therapeutic response (pain, swelling, fever)

Regulatory and Legal Status

Most NSAIDs are available over-the-counter (OTC) in low doses

Higher doses and certain formulations require prescription

All carry warnings for cardiovascular and GI risks per FDA labeling