Comprehensive Overview of NSAIDs: Mechanisms, Uses, and Safety

Comprehensive Overview of NSAIDs: Mechanisms, Uses, and Safety

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  NSAIDs: Non -Steroidal Anti-Inflammatory Drugs Dr. Rumana Afroz Associate Professor Department of Pharmacology Dhaka Medical College, Bangladesh
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  Introduction to NSAIDs WhatAre NSAIDs? A chemically heterogeneous group of drugs sharing analgesic, antipyretic, and anti-inflammatory properties Primary Mechanism Inhibit cyclooxygenase (COX) enzymes → reduce prostaglandin synthesis at sites of injury and inflammation Clinical Significance One of the most widely used drug classes globally — available both OTC and on prescription worldwide Prototype Drug Aspirin (acetylsalicylic acid), first synthesized by Felix Hoffmann in 1897 — the cornerstone of NSAID pharmacology
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  Arachidonic Acid Cascade Phospholipas eA₂ Releases arachidonic acid LOX Pathway Leukotrienes produced (not blocked) Cell Membrane Phospholipids reservoir COX Pathway Prostaglandins, TXA₂, prostacyclin (blocked) NSAIDs selectively block the COX pathway — prostaglandins mediate pain sensitization, fever, inflammation, platelet aggregation, and gastric mucosal protection. The LOX pathway (leukotrienes) remains unaffected, which explains the incomplete anti-inflammatory effect of NSAIDs.
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  Classification of NSAIDs— Overview Non -Selective COX Inhibitors • Aspirin, Ibuprofen, Naproxen • Diclofenac, Indomethacin • Piroxicam, Ketorolac, Mefenamic acid Preferential COX -2 Inhibitors • Nimesulide • Meloxicam • Nabumetone Selective COX -2 Inhibitors (Coxibs) • Celecoxib • Etoricoxib • Parecoxib Analgesic -Antipyretic (Weak Anti - inflammatory) • Paracetamol (Acetaminophen) • Metamizole (Dipyrone)
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  Classification by ChemicalClass Salicylates Aspirin, Sodium salicylate, Diflunisal Propionic Acid Derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Acetic Acid Derivatives Indomethacin, Diclofenac, Ketorolac, Sulindac, Etodolac Oxicams Piroxicam, Tenoxicam, Meloxicam Fenamates Mefenamic acid, Meclofenamic acid Pyrazolone Derivatives Phenylbutazone, Metamizole (Dipyrone)
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  COX -1 vsCOX -2 — Key Differences The therapeutic goal of selective COX-2 inhibitors (Coxibs) is to inhibit COX-2 (anti-inflammatory) while sparing COX-1 (gastric protection) — reducing GI adverse effects. Understanding this distinction is fundamental to rationalizing NSAID therapy and selecting the right drug for the right patient.
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  Mechanism of Actionof NSAIDs COX Inhibition NSAIDs competitively and reversibly inhibit COX-1 and/or COX-2 (except Aspirin — irreversible) ↓ Prostaglandins ↓ PGE₂ and PGI₂ → ↓ sensitization of nociceptors → Analgesia; ↓ PGE₂ in hypothalamus → Antipyresis ↓ Inflammation ↓ vasodilation, ↓ vascular permeability, ↓ leukocyte migration → Anti-inflammatory effect
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  Aspirin — UniqueMechanism Irreversible COX Inhibition Aspirin irreversibly acetylates the serine residue at the active site of both COX-1 and COX-2 — unlike all other NSAIDs which bind reversibly. Why Platelets Are Special Platelets lack a nucleus → cannot synthesize new COX enzyme → antiplatelet effect lasts the entire platelet lifespan of 7–10 days Dose -Dependent Effects • Low dose (75–150 mg): Selective COX-1 inhibition → antiplatelet • High dose (>300 mg): COX-2 inhibition → anti-inflammatory
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  Pharmacological Actions —Analgesia Types of Pain Relieved Effective for mild to moderate pain: headache, myalgia, arthralgia, dysmenorrhea, dental pain, postoperative pain Peripheral Action ↓ PG synthesis at site of injury → ↓ sensitization of nociceptors → raises pain threshold locally Central Action ↓ PG synthesis in spinal cord and brain → ↑ central pain threshold Advantage Over Opioids Do NOT cause euphoria, dependence, or respiratory depression — safer for long-term pain management
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  Pharmacological Actions —Antipyresis ↓ PGE₂ NSAIDs Fever ↑ PGE₂ Pyrogens Key Points • NSAIDs reduce elevated body temperature only — do NOT lower normal temperature • Act by resetting the hypothalamic thermostat, not by cooling • Increased heat dissipation: sweating, vasodilation Aspirin is contraindicated in children with viral fever — risk of Reye's syndrome. Use Paracetamol instead.
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  Pharmacological Actions —Anti - Inflammation ↓ Vasodilation & Permeability ↓ PGE₂ → ↓ vasodilation and vascular permeability → ↓ redness (rubor) and swelling (tumor) ↓ Pain Sensitization ↓ PGE₂ and PGI₂ at inflamed site → ↓ sensitization of pain receptors → ↓ dolor (pain) Limitation: LOX Pathway Intact NSAIDs do NOT inhibit leukotriene synthesis → incomplete anti-inflammatory effect; may even shunt to LOX pathway Symptomatic Only Do NOT suppress the underlying disease process — unlike DMARDs or corticosteroids in rheumatoid arthritis
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  Pharmacological Actions —Other Effects Antiplatelet ↓ TXA₂ via COX-1 → ↓ platelet aggregation. Aspirin most potent (irreversible) Renal Effects ↓ PGs → ↓ renal blood flow, ↓ GFR, Na⁺ and water retention, edema Uricosuric High-dose Aspirin → ↑ uric acid excretion; Low-dose Aspirin → ↑ uric acid retention Ductus Arteriosus Closure Indomethacin used in neonates with patent ductus arteriosus (PDA) to promote closure
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  Indications of NSAIDs Pain Management Headache,dental pain, postoperative pain, dysmenorrhea, musculoskeletal pain Fever Antipyresis in adults (Paracetamol preferred in children) Inflammatory Conditions Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout Cardiovascular Low-dose Aspirin for MI prophylaxis, stroke prevention, ACS Other Uses PDA closure (Indomethacin), Bartter's syndrome, pericarditis, colon cancer prevention
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  Adverse Effects —Gastrointestinal Common GI Symptoms Epigastric distress, nausea, vomiting, diarrhea — most common adverse drug reactions with NSAIDs Gastric Ulceration & Bleeding Due to ↓ PGE₂ → ↓ mucus secretion, ↓ bicarbonate, ↓ mucosal blood flow → mucosal breakdown Risk Factors Older age, H. pylori infection, high doses, prolonged use, concurrent corticosteroids or anticoagulants Prevention Strategies Take with food; enteric-coated tablets; co-prescribe PPI (omeprazole) or misoprostol
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  Adverse Effects —Renal High -Risk Patients Renal adverse effects are most likely in: • Elderly patients • Congestive heart failure (CHF) • Liver cirrhosis with ascites • Pre-existing renal disease • Volume-depleted states (dehydration, diuretic use) In these patients, prostaglandins maintain renal perfusion — blocking them precipitates acute renal failure.
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  Adverse Effects —Cardiovascular Coxibs & Prothrombotic State Selective COX-2 inhibitors → ↓ PGI₂ (vasodilator, antiaggregatory) without ↓ TXA₂ → unopposed platelet aggregation → prothrombotic state ↑ MI and Stroke Risk Elevated risk of MI, stroke, and venous thrombosis with Coxibs AND high-dose non-selective NSAIDs Rofecoxib Withdrawal Rofecoxib (Vioxx) voluntarily withdrawn in 2004 after clinical trials showed significantly increased cardiovascular events Safest CV Profile Naproxen has the most favorable cardiovascular profile among non-selective NSAIDs — preferred in high CV- risk patients needing NSAID therapy
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  Adverse Effects —Respiratory & Hypersensitivity Samter's Triad (Aspirin -Sensitive Asthma) • Asthma • Nasal polyps • Aspirin/NSAID hypersensitivity Mechanism ↓ COX → ↑ arachidonic acid → shunted to LOX pathway → ↑ leukotrienes (LTC₄, LTD₄) → bronchoconstriction Other Hypersensitivity Reactions • Urticaria, angioedema • Anaphylaxis — especially with Aspirin • Cross-sensitivity among NSAIDs is common in aspirin-sensitive patients
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  Adverse Effects —Hematological & Hepatic Antiplatelet & Bleeding Prolonged bleeding time — avoid NSAIDs before surgery. Aspirin causes dose-dependent irreversible inhibition of platelet aggregation lasting 7–10 days Hepatotoxicity Diclofenac, Sulindac, Nimesulide — elevated liver enzymes; rare but serious hepatic failure reported Nimesulide & Children Nimesulide banned in children <12 years in India due to unacceptable hepatotoxicity risk; also banned in several European countries
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  Adverse Effects —CNS & Others Salicylism (Aspirin Toxicity) Tinnitus, vertigo, headache, confusion — occur at high therapeutic doses; reversible on dose reduction Reye's Syndrome Aspirin in children with viral illness (influenza, varicella) → hepatic encephalopathy — rare but potentially fatal; Aspirin is absolutely contraindicated in children Indomethacin CNS Toxicity Severe headache, dizziness, psychosis, depression — most CNS-toxic NSAID; limits its use despite potency Obstetric Effects ↓ Prostaglandins involved in parturition → prolonged gestation, delayed labor; premature closure of ductus arteriosus in fetus (3rd trimester)
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  Contraindications of NSAIDs Activepeptic ulcer disease or GI bleeding Severe renal or hepatic impairment Aspirin -sensitive asthma or NSAID hypersensitivity Pregnancy (3rd trimester) Risk of premature closure of ductus arteriosus and delayed labor Children with viral fever —Aspirin contraindicated (Reye's syndrome) Bleeding disorders or anticoagulant therapy
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  Drug Interactions ofNSAIDs Interacting Drug Mechanism Clinical Effect Warfarin Protein binding displacement + antiplatelet effect ↑ Bleeding risk Antihypertensives Na⁺ retention, ↓ PG-mediated vasodilation Blunted antihypertensive effect Methotrexate ↓ Renal excretion of MTX ↑ Methotrexate toxicity Lithium ↓ Renal clearance of lithium ↑ Lithium levels → toxicity Corticosteroids Additive GI mucosal damage ↑↑ GI ulceration risk
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  CHAPTER 2 Individual DrugProfiles A systematic review of key NSAIDs — mechanisms, doses, clinical uses, and adverse effects
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  Aspirin (Acetylsalicylic Acid) Mechanism IrreversibleCOX-1 and COX-2 inhibition via acetylation of serine residue Doses • Analgesic/Antipyretic: 325–650 mg • Anti-inflammatory: 3–6 g/day • Antiplatelet: 75–150 mg/day Uses Fever, pain, RA, MI prophylaxis, ACS, stroke prevention, Kawasaki disease ADRs GI irritation, salicylism, Reye's syndrome, bleeding, hypersensitivity reactions
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  Aspirin — Pharmacokinetics 01 Absorption Wellabsorbed orally; hydrolyzed to salicylate in gut wall and liver immediately after absorption 02 Distribution Plasma protein binding: 80–90%; Volume of distribution: 0.1–0.2 L/kg 03 Metabolism & Elimination Hepatic conjugation; Renal elimination (pH-dependent); Half-life: 15–20 min (Aspirin), 2–3 hrs (low-dose salicylate), 15–30 hrs (high dose — zero-order kinetics) 04 Toxicity Management Alkalinization of urine (NaHCO₃) → ↑ ionization of salicylate → ↑ renal excretion — used in overdose management
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  Ibuprofen Class Propionic acid derivative; reversible non-selectiveCOX inhibitor Dose 400–800 mg TDS; OTC dose: 200–400 mg Uses Mild-moderate pain, fever, RA, OA, dysmenorrhea, juvenile arthritis ADRs GI upset, edema, rash — least GI toxicity among NSAIDs Ibuprofen has the best GI tolerability among NSAIDs — considered the safest NSAID for OTC use
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  Naproxen Class & Dosing Propionicacid derivative; long-acting. Dose: 250–500 mg BD — twice-daily dosing improves patient compliance Clinical Uses Arthritis, acute gout, dysmenorrhea, musculoskeletal pain, migraine prophylaxis Key Advantage Most favorable cardiovascular safety profile among all NSAIDs — preferred when CV risk is a concern ADRs GI effects, photosensitivity, peripheral edema — similar to other propionic acid derivatives
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  Diclofenac Class Phenylacetic acid derivative;preferential COX-2 inhibitor Dose 50 mg TDS or 75 mg SR BD; topical gel also available for local musculoskeletal conditions Uses RA, OA, ankylosing spondylitis, postoperative pain, dysmenorrhea, renal colic Unique Feature Also inhibits phospholipase A₂ and lipoxygenase → broader anti-inflammatory action beyond COX inhibition alone ADRs Hepatotoxicity (monitor LFTs), GI effects, cardiovascular risk at higher doses
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  Indomethacin Class & Potency Indoleacetic acid derivative; most potent non-selective COX inhibitor. Dose: 25–50 mg TDS; SR 75 mg BD Clinical Uses Acute gout (DOC), ankylosing spondylitis, PDA closure in neonates, Bartter's syndrome, pericarditis Toxicity Profile Most toxic NSAID: severe headache, dizziness, GI ulcers, psychosis, depression, bone marrow suppression Despite its toxicity, Indomethacin remains the drug of choice for acute gout and the only NSAID used for PDA closure in neonates.
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  Ketorolac Class Pyrrolizine carboxylic acidderivative; potent parenteral analgesic Dose & Route 10–30 mg IM/IV; 10 mg oral; maximum 5 days use only — strictly short-term Uses Short-term management of moderate-to-severe postoperative pain, renal colic, opioid-sparing analgesia Key Advantage Analgesic potency comparable to Morphine 10 mg IM — without opioid side effects (no respiratory depression, no dependence) ADRs GI bleeding, renal impairment — NOT for chronic use; strict 5-day limit
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  Piroxicam Class Oxicam derivative; long-acting non-selectiveCOX inhibitor Dose & Half -life 20 mg once daily; very long t½: 45–50 hours — among the longest of all NSAIDs Clinical Uses RA, OA, ankylosing spondylitis, acute gout, dysmenorrhea Advantage Once-daily dosing → excellent patient compliance ADRs Highest GI toxicity among oxicams, photosensitivity, peripheral edema — long half-life means effects (including toxicity) persist longer
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  Mefenamic Acid Class Fenamate (anthranilicacid derivative) Dose 500 mg loading, then 250 mg QID; max 7 days Uses Dysmenorrhea (DOC), menorrhagia, mild- moderate pain ADRs Diarrhea (characteristic), hemolytic anemia, GI irritation; avoid in renal disease Dual mechanism: Inhibits COX and directly antagonizes prostaglandin receptors — explaining its superior efficacy in dysmenorrhea
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  Nimesulide Class Sulfonanilide; preferential COX-2inhibitor — popular in India Dose & Use 100 mg BD (adults only); used for pain, fever, OA, dysmenorrhea Advantages Better GI tolerability; also inhibits PAF (platelet activating factor) and free radicals — additional anti-inflammatory mechanisms Hepatotoxicity Warning Banned in children <12 years in India and several European countries due to serious hepatotoxicity risk
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  Meloxicam Class Oxicam derivative; preferentialCOX-2 inhibitor Dose 7.5–15 mg once daily Uses OA, RA, ankylosing spondylitis — first-line in arthritis management Advantages vs Piroxicam • Better GI tolerability than piroxicam • Once-daily dosing (good compliance) • Lower cardiovascular risk than true coxibs ADRs GI effects (less than piroxicam), peripheral edema, renal effects at higher doses
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  Celecoxib Class & Dose Diarylsubstituted pyrazole; selective COX-2 inhibitor (Coxib). Dose: 100–200 mg BD Clinical Uses OA, RA, ankylosing spondylitis, familial adenomatous polyposis (FAP), acute pain Key Advantages No GI ulceration (spares COX-1); no antiplatelet effect → safer in patients on anticoagulants; safe in aspirin-sensitive patients ADRs & Cautions ↑ Cardiovascular risk (MI, stroke), edema, hypertension; sulfonamide allergy cross-reactivity — check allergy history before prescribing
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  Etoricoxib Why Etoricoxib StandsOut Etoricoxib is the most selective COX-2 inhibitor currently available — providing maximum GI protection among coxibs. However, this high selectivity also confers the highest cardiovascular risk among coxibs — it is contraindicated in established cardiovascular disease. Never prescribe Etoricoxib to patients with established CVD, uncontrolled hypertension, or heart failure.
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  Paracetamol (Acetaminophen) Class &Mechanism Para-aminophenol derivative. Inhibits COX-3 (central); acts on endocannabinoid system. Does NOT significantly inhibit peripheral COX → no anti-inflammatory action peripherally Dose 500 mg–1 g TDS/QID; max 4 g/day (adults); 2 g/day in liver disease Uses Drug of choice for fever in children; mild-moderate pain, OA, headache; safest NSAID-equivalent in pregnancy Advantages No GI irritation, no antiplatelet effect, no renal effects at therapeutic doses — best-tolerated analgesic-antipyretic
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  Paracetamol — Toxicity& Antidote Hepatocellula r Necrosis Glutathione Depleted NAPQI Accumulates CYP2E1 Metabolism Overdose Risk Factors for Toxicity • Chronic alcoholism (induces CYP2E1) • Fasting (↓ glutathione stores) • Enzyme-inducing drugs: rifampicin, phenytoin Antidote: N -Acetylcysteine (NAC) Replenishes glutathione stores; most effective when given within 8–10 hours of overdose • Also used: Methionine (oral), Activated charcoal (early) • Severe overdose → renal tubular necrosis also occurs Paracetamol overdose is the leading cause of acute liver failure in developed countries — never exceed 4 g/day
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  Phenylbutazone Class Pyrazolone derivative; potentnon-selective COX inhibitor Historical Uses Ankylosing spondylitis (limited), acute gout — now largely obsolete due to severe toxicity Why It Was Abandoned • Agranulocytosis & aplastic anemia — life-threatening • Peptic ulceration • Sodium and water retention • Hepatotoxicity Current Status Banned for human use in many countries; still used in veterinary medicine (horse racing injuries)
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  NSAIDs in SpecialSituations Pregnancy Avoid in 3rd trimester — premature closure of DA, oligohydramnios, delayed labor. Paracetamol is safest throughout pregnancy Children Ibuprofen or Paracetamol preferred; Aspirin absolutely contraindicated (Reye's syndrome); Nimesulide banned <12 years Elderly Use lowest effective dose; prefer short-acting agents; always add PPI; monitor renal function and blood pressure regularly Peptic Ulcer Patients Use Coxibs + PPI combination; avoid non-selective NSAIDs; test and treat H. pylori before starting NSAID therapy
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  NSAIDs in RheumatoidArthritis Role of NSAIDs in RA NSAIDs provide symptomatic relief (pain, morning stiffness, swelling) but do NOT modify disease progression — they address symptoms, not the underlying autoimmune process. Adjuncts to DMARDs Used alongside Disease-Modifying Anti-Rheumatic Drugs: • Methotrexate (first-line DMARD) • Hydroxychloroquine • Sulfasalazine Preferred NSAIDs in RA • Indomethacin, Diclofenac, Naproxen — commonly used • Coxibs preferred in patients with GI risk factors
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  NSAIDs in Gout AcuteGout — Treatment Indomethacin (DOC), Naproxen, Etoricoxib — reduce PG-mediated inflammation at the joint and inhibit leukocyte migration to the crystal deposit Aspirin — Avoid in Gout Low-dose Aspirin → ↑ uric acid retention (blocks tubular secretion); High-dose uricosuric but impractical — Aspirin should be avoided in gout Alternatives When NSAIDs Contraindicated Colchicine (inhibits leukocyte migration) and corticosteroids (intra-articular or systemic) — use when NSAIDs are contraindicated (renal failure, GI bleeding)
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  NSAIDs in Dysmenorrhea ↓PGF₂α → Pain Relief NSAIDs Inhibit COX Uterine Contractions PGF₂ α Rise Drugs of Choice Mefenamic Acid Dual action (COX inhibition + receptor antagonism) Ibuprofen Effective, well-tolerated, widely available OTC Naproxen Long-acting; fewer daily doses needed Start NSAIDs 1–2 days before expected menstruation for maximum benefit — inhibit PG synthesis before they peak
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  Low-Dose Aspirin — CardiovascularUses Dose & Mechanism 75–150 mg/day — irreversibly inhibits platelet COX-1 → ↓ TXA₂ → ↓ platelet aggregation → antithrombotic Secondary Prevention (Established CVD) Post-MI, ACS, post-CABG, post-stent, TIA, stroke, peripheral arterial disease — well-established indication Dual Antiplatelet & Primary Prevention Aspirin + Clopidogrel in ACS and post-coronary stenting. Primary prevention benefit-risk debated — recommended only in high-risk patients currently
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  Comparison: Non -Selectivevs COX -2 Selective NSAIDs Parameter Non-Selective NSAIDs Preferential COX-2 Selective Coxibs GI Safety Lowest Intermediate Best CV Risk Low (Naproxen safest) Intermediate Highest Antiplatelet Effect Yes (Aspirin irreversible) Minimal None Renal Effects Present Present Present (similar) Cost Cheapest Moderate Most expensive
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  GI Protection Strategieswith NSAIDs Proton Pump Inhibitors (PPIs) — First Choice Omeprazole, Pantoprazole — most effective gastroprotection; co- prescribed with NSAIDs in all high-risk patients (elderly, prior PUD, concurrent steroids) Misoprostol — Prostaglandin Analogue PGE₁ analogue that replaces depleted mucosal prostaglandins; effective but commonly causes diarrhea and cramping H₂ Blockers Ranitidine — less effective than PPIs; useful for prevention of duodenal ulcers but inadequate for gastric ulcer protection Formulation Strategies Enteric-coated/SR formulations — reduce local GI irritation but do NOT prevent systemic GI effects (which are mechanism-based)
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  Aspirin Toxicity —Salicylism & Overdose 1 Severe Toxicity Hyperthermia, convulsions, coma, cardiovascular collapse 2 Moderate Toxicity Respiratory alkalosis (stimulates respiratory center) → progresses to metabolic acidosis 3 Mild Toxicity — Salicylism Tinnitus, vertigo, headache, nausea, vomiting, hyperventilation Treatment Gastric lavage → IV fluids → NaHCO₃ (alkalinize urine → ↑ ionization → ↑ renal excretion of salicylate) → hemodialysis in severe cases
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  Newer Developments inNSAID Research NO -Releasing NSAIDs Naproxcinod — releases nitric oxide → vasodilation, gastric protection → reduced GI and cardiovascular toxicity H₂S -Releasing NSAIDs Hydrogen sulfide-releasing NSAIDs — gastroprotective via H₂S-mediated mucosal protection mechanisms Dual COX/LOX Inhibitors Licofelone — inhibits both COX and 5-LOX → broader anti-inflammatory effect + reduced GI toxicity by avoiding LOX shunting Topical NSAIDs Diclofenac gel — local musculoskeletal effect with minimal systemic absorption → reduced systemic ADRs
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  Summary — KeyPoints to Remember 1 Core Mechanism NSAIDs inhibit COX enzymes → ↓ prostaglandin synthesis → analgesia, antipyresis, anti-inflammation 2 Aspirin — Unique Drug Irreversible COX inhibitor; low dose = antiplatelet (7–10 days); high dose = anti- inflammatory 3 Coxib Trade -Off COX-2 selective agents: ↓ GI toxicity BUT ↑ cardiovascular risk — select carefully based on patient profile 4 Paracetamol — Safest Antipyretic Drug of choice for fever in children; overdose → hepatotoxicity; antidote = N-Acetylcysteine (NAC) 5 Always Protect the GI Tract Co-prescribe PPI (omeprazole) in all high-risk patients on long- term NSAID therapy Master the big four: Aspirin (irreversible, antiplatelet), Indomethacin (most potent, PDA closure, gout DOC), Paracetamol (children's antipyretic, NAC antidote), and Celecoxib (COX-2 selective, GI safe, CV risk).
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  Thank You