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NSAIDS & OPIOIDS - Comprehensive Pharmacology Notes

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Q1. NSAIDs - Classification, MOA, Uses, Adverse Effects, Precautions; Selective NSAIDs - Advantages & Disadvantages

Classification of NSAIDs

• Celecoxib, Etoricoxib, Parecoxib, Valdecoxib

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Mechanism of Action (MOA)

• COX-1: Constitutively expressed in stomach (cytoprotection), platelets (TXA2), kidneys
• COX-2: Induced at sites of inflammation, pain, fever; also present in kidney and vasculature

1. Analgesia - PGE2 and PGI2 sensitize nociceptors; blocking them raises pain threshold
2. Anti-inflammatory - Prostaglandins are key mediators of vascular dilation and increased permeability in inflammation
3. Antipyretic - PGE2 raises the hypothalamic set point; NSAIDs lower it by blocking PGE2 synthesis

Note: NSAIDs act peripherally (and some centrally); they do NOT suppress the underlying immunological cause of inflammation - they are symptomatic.

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Important Uses

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Adverse Effects

1. GI toxicity (most common) - Gastric irritation, peptic ulceration, GI bleeding. Due to COX-1 inhibition reducing PGE2-mediated mucus and bicarbonate secretion.
2. Renal toxicity - Acute kidney injury (especially in volume-depleted patients), salt/water retention, hyperkalemia. Prostaglandins normally maintain renal perfusion.
3. Cardiovascular - Na+ retention, edema, hypertension, increased risk of MI and stroke (especially COX-2 selective > non-selective).
4. Platelet dysfunction - Inhibit TXA2-mediated aggregation (reversible with most NSAIDs; irreversible with aspirin).
5. Aspirin-sensitive asthma - NSAIDs shunt arachidonic acid toward lipoxygenase pathway, increasing leukotrienes, triggering bronchospasm in susceptible patients.
6. Hypersensitivity - Rashes, angioedema, anaphylaxis.
7. Hepatotoxicity - Especially diclofenac.
8. Reye's Syndrome - Aspirin in children with viral illness (varicella, influenza) - causes fulminating hepatitis + cerebral edema.
9. Salicylism - Tinnitus, vertigo, hearing loss (chronic high-dose aspirin).
10. Delayed labour - NSAIDs delay closure of ductus arteriosus in fetus; contraindicated in third trimester.

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Precautions

• Avoid in peptic ulcer disease (or co-prescribe PPI/misoprostol)
• Use cautiously in renal or hepatic impairment
• Avoid aspirin in children <19 years with viral infections
• Avoid in third trimester of pregnancy
• Caution in asthma (aspirin-sensitive)
• Avoid in bleeding disorders (especially aspirin)
• Elderly patients are at higher risk of all adverse effects
• Avoid long-term use without gastroprotection

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Selective NSAIDs (COX-2 Inhibitors) - Celecoxib, Etoricoxib

1. Reduced GI toxicity - No COX-1 inhibition means gastric mucosal protection is preserved; fewer ulcers, less GI bleeding
2. No effect on platelets - COX-2 is not expressed in platelets, so platelet aggregation (TXA2) is unaffected
3. No aspirin-sensitive asthma risk (generally)
4. Useful in patients who need long-term anti-inflammatory therapy (e.g., RA, OA) with GI risk factors
5. No antiplatelet effect means safer perioperatively in terms of bleeding

1. Increased cardiovascular risk - By inhibiting endothelial COX-2 (PGI2/prostacyclin production), while platelet TXA2 remains active, the balance shifts toward vasoconstriction and thrombosis. Increased risk of MI and stroke.
2. Rofecoxib (Vioxx) was withdrawn from the market due to significantly increased MI risk.
3. Renal toxicity preserved - COX-2 is expressed in the kidney; thus renal adverse effects remain.
4. More expensive than traditional NSAIDs.
5. Sulfonamide allergy - Celecoxib is a sulfonamide; contraindicated in sulfa allergy.
6. Do not protect against colorectal cancer as effectively as aspirin.

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Q2. Opioids vs NSAIDs - Major Differences

• Opioids suppress pain perception centrally by mimicking endogenous enkephalins/endorphins
• NSAIDs prevent generation of pain signals peripherally by blocking prostaglandin synthesis

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Q3. Diclofenac Sodium - Brief

• Well absorbed orally; significant first-pass metabolism
• Highly protein-bound (>99%)
• Hepatic metabolism; undergoes enterohepatic circulation
• t½ ~ 1-2 hours (but anti-inflammatory effect lasts longer due to concentration in synovial fluid)
• Available as: oral tablets, enteric-coated, SR formulations, topical gel, ophthalmic drops, parenteral (IM/IV)

• Mild-to-moderate pain (dental, post-op, dysmenorrhea)
• Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis
• Acute gout
• Topical: Osteoarthritis of knee/hands (Voltaren gel)
• Ophthalmic: Photophobia after ocular surgery, allergic conjunctivitis
• Parenteral: Renal colic (IM), acute pain

• GI - Gastric irritation, peptic ulcer, GI bleeding (less than indomethacin but significant)
• Hepatotoxicity - Diclofenac has a relatively higher incidence of drug-induced liver injury (DILI) compared to other NSAIDs; elevated transaminases; rare acute hepatocellular hepatitis
• Renal toxicity
• Hypertension, fluid retention
• Local irritation (IM injection can cause muscle necrosis at injection site)
• Rash, dizziness

• Monitor LFTs during prolonged use
• Avoid in severe hepatic/renal disease
• Avoid in pregnancy (especially 3rd trimester)
• Use with PPI in patients with GI risk
• Avoid IM injection at gluteal site (prefer to use IV or oral forms)

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Q4. Aspirin vs COX-2 Inhibitors - Compare & Contrast

• Aspirin = cardioprotective (low dose) but GI-toxic
• Coxibs = GI-safe but cardiotoxic
• This cardiovascular-GI trade-off is the central clinical dilemma

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Q5. Aspirin - MOA, Uses, Adverse Effects, Contraindications, Precautions

MOA of Aspirin

• PGE2, PGI2 (prostacyclin) - pain sensitization, vasodilation, fever, gastric protection
• TXA2 (thromboxane A2) - platelet aggregation, vasoconstriction

• Platelets (anucleate) cannot synthesize new COX → antiplatelet effect lasts 8-10 days (platelet lifespan)
• Nucleated cells (vascular endothelium) can regenerate COX within hours

• Low dose (75-325 mg): Antiplatelet only (inhibits COX-1 in platelets)
• Analgesic/antipyretic dose: 325-650 mg every 4-6 hours
• Anti-inflammatory dose: >3-4 g/day (rarely used now)

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Uses of Aspirin

• Secondary prevention of MI, TIA, ischemic stroke (75-100 mg/day)
• Acute MI (300 mg stat, then 75 mg maintenance)
• Unstable angina
• Prevention of thrombosis post-coronary bypass, stent placement
• Kawasaki disease (anti-inflammatory + antiplatelet)
• Prevention of preterm preeclampsia (100 mg/day in high-risk women)

• Headache, dental pain, musculoskeletal pain, dysmenorrhea
• Combined with other analgesics

• Fever (but AVOID in children with viral illness - Reye's risk)

• Rheumatoid arthritis (now largely replaced by other NSAIDs/DMARDs)
• Pericarditis
• Rheumatic fever (high dose - 4-6 g/day)

• Regular aspirin use associated with reduced risk of colorectal cancer, possibly other cancers (emerging evidence)

• Indomethacin preferred, but aspirin has historical use

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Adverse Effects of Aspirin

1. GI Effects (most common):
   • Gastric irritation, nausea, vomiting
   • Peptic ulceration (COX-1 inhibition → ↓ PGE2 → ↓ mucus, ↓ bicarbonate, ↓ blood flow)
   • GI bleeding, hematemesis, melena
   • Occult blood loss leading to iron-deficiency anemia
2. Salicylism (chronic toxicity):
   • Tinnitus, hearing loss, vertigo, headache, mental confusion
   • Occurs at doses >4 g/day
3. Acute Salicylate Poisoning (overdose):
   • Stimulation of respiratory center → hyperventilation → respiratory alkalosis
   • Then metabolic acidosis (accumulation of salicylate, lactic acid)
   • Hyperthermia, hypoglycemia, electrolyte disturbances, convulsions
   • Treatment: Alkalinize urine (NaHCO3 IV) to trap ionic form, hemodialysis in severe cases
4. Reye's Syndrome:
   • Children with viral illness (influenza, varicella) + aspirin → fulminating hepatitis + cerebral edema
   • Mechanism: Mitochondrial dysfunction
5. Bleeding:
   • Prolonged bleeding time
   • Surgical bleeding risk
   • Contraindicated in hemophilia
6. Aspirin-sensitive Asthma:
   • In ~10% of asthmatics
   • COX inhibition → arachidonic acid → lipoxygenase pathway → ↑ leukotrienes (LTC4, LTD4) → bronchospasm
   • Cross-reacts with other NSAIDs
7. Hypersensitivity:
   • Urticaria, angioedema, anaphylaxis (rare but severe)
8. Renal:
   • Decreased GFR, Na+ and water retention, hyperkalemia
   • Risk of acute renal failure in volume-depleted patients
9. Hepatotoxicity:
   • Mild reversible transaminase elevation; rare severe hepatitis
10. Uterine/Neonatal:
    • Prolongs labor
    • Premature closure of ductus arteriosus in fetus
    • Neonatal bleeding
11. Drug Interactions:
    • Displaces warfarin from albumin → ↑ bleeding risk
    • Antagonizes probenecid's uricosuric effect
    • Displaces methotrexate → toxicity
    • NSAIDs reduce antihypertensive efficacy

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Contraindications of Aspirin

1. Children <19 years with viral infections (Reye's syndrome)
2. Active peptic ulcer or GI bleeding
3. Aspirin-sensitive asthma / hypersensitivity to NSAIDs
4. Hemophilia and other bleeding disorders
5. Gout (low doses retain uric acid)
6. Pregnancy (especially 3rd trimester)
7. Severe hepatic failure
8. Severe renal failure
9. Dengue fever (increased hemorrhagic risk)
10. Concurrent use of anticoagulants (warfarin) - relative contraindication

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Precautions

• Always take with food or antacids to reduce GI irritation
• Use with a PPI (e.g., omeprazole) for prolonged use
• Monitor for signs of GI bleeding (melena, hematemesis)
• Stop 7-10 days before elective surgery
• Monitor renal function in elderly and those with hypertension
• Avoid in patients with urate stones or hyperuricemia
• Use the lowest effective dose for shortest duration
• Monitor for signs of salicylism (tinnitus) at higher doses

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Quick Reference: Key Mnemonics

• GI bleeding/ulceration
• Inhibit platelet function
• Renal toxicity
• Asthma exacerbation
• Cardiovascular risk
• Kidney - fluid retention

• Irreversible platelet inhibition
• Reye's syndrome
• Salicylism
• Uricosuric (high dose) / uric acid retention (low dose)
• Respiratory centre stimulation in overdose

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