NSAIDs and Antipyretic Analgesics – Summary Notes

Overview

 Functions: Analgesic (pain relief), Antipyretic (fever reducer), Anti-

inflammatory.
 Comparison with Morphine:

o Do not depress CNS.

o No physical dependence or abuse liability.

o Especially effective in inflammatory pain.

o Called non-narcotic, non-opioid, or aspirin-like analgesics.

Mechanism of Action

 Act primarily on peripheral pain mechanisms.

 Also act in CNS to raise pain threshold.

 Most act via cyclooxygenase (COX) inhibition.

o Selective COX-2 inhibitors: e.g., celecoxib.

Historical Development

 Willow bark (Salix alba): Traditional remedy.

o Salicylic acid: Derived from its bitter glycoside.

o Sodium salicylate used in 1875 for fever and pain.

o Aspirin (acetylsalicylic acid) introduced in 1899.

 Phenacetin and antipyrine: Developed around the same time.

 Phenylbutazone (1949): Anti-inflammatory effect near that of corticosteroids.

 Indomethacin: Introduced in 1963.

 Ibuprofen: Propionic acid derivative; led to more NSAIDs.

Chemical Nature

 Chemically diverse.

 Most are weak organic acids or their active metabolites are organic acids.

Usage

 Commonly used.
 Many are over-the-counter (OTC) or nonprescription drugs.
NSAIDs and Prostaglandin (PG) Synthesis Inhibition – Summary Notes

🔬 Mechanism of Action

 1971: Vane et al. discovered that NSAIDs inhibit prostaglandin (PG)

synthesis.

 PGs, prostacyclin (PGI₂), and thromboxane A₂ (TXA₂) are synthesized

from arachidonic acid via the cyclooxygenase (COX) enzyme.

COX Isoforms

 COX-1: Constitutive; involved in physiological housekeeping (gastric mucosa,

platelet function, renal blood flow).
 COX-2: Inducible by cytokines at inflammation sites; constitutively present in
brain, JG cells, and fetus.

🧪 Types of NSAIDs

 Nonselective NSAIDs: Inhibit both COX-1 and COX-2.

 Selective COX-2 inhibitors: e.g., celecoxib – designed to reduce gastric

toxicity.

💊 Inhibition Characteristics

 Aspirin: Irreversible COX inhibitor via acetylation.

 Other NSAIDs: Reversible, competitive inhibitors.

🌡️ Therapeutic Actions Due to PG Inhibition

1. Analgesic

 PGs cause hyperalgesia by sensitizing nerve endings.

 NSAIDs inhibit pain sensitization mainly via COX-2 inhibition (peripheral and
central).
 Act on spinal dorsal horn neurons and brain to inhibit pain impulse
amplification.

2. Antipyretic

 Fever → Caused by cytokines (ILs, TNFα) → Stimulate PGE₂ in

hypothalamus → Raises set point.
 NSAIDs block cytokine-induced PGE₂ production.

 Do not lower temperature in normothermic individuals.

3. Antiinflammatory

 Primary mechanism: COX-2 inhibition → ↓ PGs at injury site.

 Some contribution from COX-1 inhibition (especially early phase).

 Some NSAIDs (e.g., nimesulide) have antiinflammatory effects via non-COX
pathways.

Additional antiinflammatory mechanisms:

 Inhibition of adhesion molecules (ELAM-1, ICAM-1).

 Reduction of free radicals and cytokines (TNFα, IL-6).

 Stabilization of lysosomes and antagonism of kinins.

4. Dysmenorrhoea

 High PG levels in dysmenorrhoeic women.

 NSAIDs ↓ uterine PGs → Relief in 60–70% of cases + improve associated
symptoms.
5. Antiplatelet Aggregatory

 NSAIDs inhibit TXA₂ (proaggregatory) and PGI₂ (antiaggregatory)

synthesis.
 Aspirin irreversibly inhibits platelet COX → Prolonged antithrombotic
effect.
6. Ductus Arteriosus Closure

 Kept open in fetus by PGE₂ (COX-2).

 Indomethacin or aspirin induces closure postnatally.

 NSAIDs should be avoided in late pregnancy to prevent premature closure

and ↑ postpartum bleeding.

⚠️ Shared Toxicities (Due to PG Inhibition)

1. Gastric Mucosal Damage

 Due to COX-1 inhibition → ↓ PGE₂, PGI₂ → ↓ mucus, HCO₂⁻, ↑ acid.

 Local mucosal injury from back-diffusion of H⁺.

 Paracetamol and COX-2 inhibitors are safer.

 Misoprostol (PG analog) helps protect mucosa.

2. Renal Effects
  In compromised patients (CHF, renal disease):

o ↓ renal blood flow (COX-1).

o Na⁺ and water retention (COX-2).

o Risk of papillary necrosis.

 NSAIDs blunt diuretic and antihypertensive action.

3. Parturition

 PG synthesis ↑ before labor → NSAIDs may delay labor.

4. Analgesic Nephropathy

 Seen in chronic heavy NSAID users.

 Lesions: Papillary necrosis, tubular atrophy, renal fibrosis.

 Risk ↑ with NSAID combinations + UTI.

5. Anaphylactoid Reactions
 Aspirin and NSAIDs may cause asthma, urticaria, rhinitis.

 Likely due to diversion of AA to leukotrienes (not immune-mediated).

Aspirin (Acetylsalicylic Acid) – Salicylates

General

 Rapidly converted to salicylic acid, responsible for most effects.

 Also acts by acetylation (e.g., COX inhibition).

 One of the oldest analgesic-antiinflammatory drugs.

Pharmacological Actions

1. Analgesic, Antipyretic, Antiinflammatory

 Weaker analgesic than opioids (Aspirin 600 mg ≈ Codeine 60 mg).

 Effective for inflammatory, tissue injury, connective tissue pain.

 Ineffective for visceral and ischemic pain.

 Mechanism:
o Inhibits PG-mediated sensitization of pain receptors (peripheral).
o Raises pain threshold (central).

o No sedation, tolerance, dependence.

  Antipyretic: Resets hypothalamic thermostat, promotes heat loss.

 Antiinflammatory: Requires high doses (3–6 g/day or 100 mg/kg/day).

o Inhibits COX, reduces inflammation signs.

o Free radical quenching may also help.

o Does not stop disease progression in RA, OA, etc.

2. GIT Effects

 Irritates gastric mucosa → epigastric distress, N/V.

 High doses stimulate CTZ → vomiting.

 Ion trapping (pKa 3.5): Aspirin ionizes in mucosal cells → enhanced gastric
toxicity.

 Causes:
o Focal necrosis, erosive gastritis, microscopic hemorrhages.

o Occult blood loss (~5 mL/day at therapeutic dose).

 Buffered formulations reduce irritation but not ulcer risk significantly.

3. Blood Effects

 Irreversibly inhibits TXA2 in platelets → inhibits aggregation.

 Prolongs bleeding time (effect lasts ~1 week).

 Large doses reduce liver clotting factor synthesis → bleeding risk.

o Preventable with vitamin K prophylaxis.

4. Metabolic & Toxic Effects (High doses: 3–5 g/day)

a. Metabolism

 ↑ Cellular metabolism, especially in muscles (uncouples oxidative

phosphorylation).
 ↑ Glucose use → hypoglycemia, liver glycogen depletion.
 Toxic doses may increase blood sugar via sympathetic stimulation.

b. Respiration
 Stimulates respiratory center → hyperventilation.
  Causes respiratory alkalosis (compensated by HCO₂⁻ excretion).

 Toxic dose → respiratory depression + continued CO₂ production →

respiratory acidosis.

 Combined with metabolic acidosis (↑ lactic, pyruvic acids, etc.).

c. Dehydration

 From urine loss, sweating, hyperventilation.

 More severe in children (common in salicylate poisoning).

d. Cardiovascular

 No direct cardiac effect.

 ↑ Metabolism → ↑ cardiac output.

 Toxic doses: ↓ BP due to vasomotor center depression.

 May precipitate CHF if cardiac reserve is low.

e. Uric Acid

 Interferes with urate excretion.

 Antagonizes probenecid effect.

 High doses (≥5 g/day) may be uricosuric but unreliable.

Aspirin (Salicylates) – Pharmacokinetics, Adverse Effects & Precautions

Pharmacokinetics

 Absorption: From stomach & small intestine. Poor water solubility limits
absorption.
o Improved by microfining particles and alkaline medium (↑ solubility
but also ↑ ionization → ↓ diffusibility).
 Metabolism:

o Rapidly deacetylated to salicylic acid (active form) in gut wall, liver,

plasma, tissues.

o ~80% plasma protein bound.

o Volume of distribution: ~0.17 L/kg.

o Slow brain entry, but crosses placenta easily.

o Metabolized in liver via:

  Glycine conjugation → salicyluric acid (major)

 Glucuronic acid conjugation

 Excretion: Primarily via glomerular filtration and tubular secretion.

o Only 10% excreted as free salicylic acid.

 Half-life:

o Aspirin: 15–20 min

o Salicylic acid: 3–5 hours

o High doses: 8–12 hours

o In poisoning: up to 30 hours (dose-dependent elimination)

Adverse Effects

a) At Analgesic Doses (0.5–2.0 g/day)

 Nausea, vomiting, epigastric distress

 Occult blood loss in stools

 Most serious: Gastric mucosal damage, peptic ulcer

b) Hypersensitivity/Idiosyncratic Reactions

 Can be serious but infrequent.

 Symptoms:
o Rashes, urticaria, rhinorrhea

o Angioedema, asthma, anaphylactoid reactions

 Rare: Profuse gastric bleeding

c) At Antiinflammatory Doses (3–5 g/day)

 Salicylism Syndrome:
o Dizziness, tinnitus, vertigo

o Reversible hearing & vision impairment

o Excitement, hyperventilation, electrolyte imbalance

 Children with RA: ↑ serum transaminases → liver damage

 Risk of Reye’s syndrome (hepatic encephalopathy in children with viral

infections)
  In adults: Long-term use may cause hepatic injury

 Salt and water retention (dose-related)

d) Acute Salicylate Poisoning

 More common in children

 Fatal dose in adults: 15–30 g

 Symptoms:
o Vomiting, dehydration, acidotic breathing

o Electrolyte imbalance, hyper/hypoglycemia

o Petechial hemorrhages, delirium, hallucinations

o Hyperpyrexia, convulsions, coma

o Death from respiratory failure + cardiovascular collapse

 Treatment:

o Symptomatic & supportive

o External cooling, IV fluids (Na⁺, K⁺, HCO₂⁻, glucose)

o Vit K and blood transfusion if bleeding occurs

Precautions & Contraindications

 Contraindicated in:

o Aspirin hypersensitivity

o Peptic ulcer or bleeding disorders

o Children with chickenpox/influenza (→ Reye’s syndrome risk)

 Avoid in:

o Chronic liver disease (→ hepatic necrosis)

o Diabetics

o Low cardiac reserve/CHF

o Juvenile rheumatoid arthritis

 Pregnancy:
o Avoid near term: risk of low birth weight, prolonged labour,
postpartum bleeding, ductus arteriosus closure
  Surgery: Stop 1 week prior

 Breastfeeding: Avoid use

 G-6PD deficiency: High doses → haemolysis

Aspirin – Interactions & Uses

Important Drug Interactions

1. Displacement from Plasma Proteins:

o Displaces: Warfarin, Sulfonylureas, Phenytoin, Methotrexate

o Result: ↑ Free drug levels → ↑ Toxicity/overdose symptoms

o ↑ Bleeding risk with oral anticoagulants due to antiplatelet effect

2. Inhibition of Tubular Secretion:

o ↓ Uric acid excretion → Antagonizes uricosuric action of probenecid

o ↓ Excretion of methotrexate → ↑ toxicity

3. Blunting Diuretic Effect:

o ↓ Furosemide and thiazides diuretic action

o ↓ K⁺ conserving action of spironolactone

o Competes with canrenone (spironolactone’s active metabolite) for

transport in proximal tubules

Therapeutic Uses of Aspirin

1. Analgesic (Pain relief):

o Indications: Headache, backache, muscle/joint pain, toothache,

dysmenorrhoea, neuralgias

o Dose: 0.3–0.6 g every 6–8 hrs; max effect at ~1000 mg single dose

2. Antipyretic (Fever reducer):

o Effective for fevers of any origin

o Dose same as for analgesia

o Paracetamol preferred due to better safety

3. Acute Rheumatic Fever:

o First-line drug
 o Dose: 4–5 g/day or 75–100 mg/kg/day in divided doses

o Relief in 1–3 days

o Maintenance: 50 mg/kg/day for 2–3 weeks

o Taper gradually over 2 weeks

o Does not alter cardiac damage, chorea, or disease duration

4. Rheumatoid Arthritis:

o Dose: 3–5 g/day

o Relieves: Pain, swelling, morning stiffness

o Does not halt disease progression

o Rarely used now due to side effects and better alternatives (NSAIDs)
5. Osteoarthritis:

o Provides symptomatic relief

o Rarely used; paracetamol preferred

6. Cardiovascular Protection:

o Post-MI / Post-stroke: ↓ reinfarction risk by inhibiting platelet TXA₂

synthesis

o Effective dose: 75–150 mg/day

o Low dose avoids inhibition of PGI₂ (vasodilator, antiaggregatory)

o Also used for unstable angina: 100–150 mg/day for 12 weeks

o ↓ TIA and stroke risk in high-risk patients

o Does not reduce stroke risk in post-MI patients

7. Prevention of Preeclampsia:

o Cause: Imbalance of TXA₂ and PGI₂

o Dose: 80–100 mg/day from 12th week of gestation till delivery

o Used in: Pregnant women with diabetes, CKD, or other risks

Other Uses

 Familial Colonic Polyposis:

o ↓ Polyp formation and provides symptom relief

  Prevention of Colon Cancer:

o ↓ Risk in regular aspirin users

o Colonic tumors express high COX-2

o However, COX-2 inhibitors like rofecoxib, celecoxib were

withdrawn/stopped due to ↑ cardiovascular events

 Prevention of Nicotinic Acid-induced Flushing:

o Flushing caused by PGD₂ release in skin

Common Brands and Formulations

 Tablets:

o ASPIRIN: 350 mg
o COLSPRIN: 100, 325 mg

o ECOSPRIN: 75, 150, 325 mg

o DISPRIN: 350 mg (with Ca carbonate + citric acid)

o LOPRIN: 75, 162.5 mg

 Injectable:

o BIOSPIRIN: Lysine acetylsalicylate 900 mg + glycine 100 mg/vial (for

IV use)
PROPIONIC ACID DERIVATIVES (NSAIDs)

Examples

 Ibuprofen (first introduced in 1969)

 Naproxen (most potent in this group)

 Others: Ketoprofen, Flurbiprofen, Oxaprozin, etc.

Mechanism of Action

 Inhibit prostaglandin (PG) synthesis via COX inhibition

 Naproxen is the most potent in PG synthesis inhibition

 Antiplatelet effect:
o Short-lasting with ibuprofen
 o Longer-lasting with naproxen

Adverse Effects

 Better tolerated than aspirin

 Common side effects:

o Gastric discomfort, nausea, vomiting (less than aspirin)

o Rare: Gastric erosion, occult GI blood loss

 CNS effects:

o Headache, dizziness, tinnitus, blurred vision

 Hypersensitivity:

o Rashes, itching (infrequent)

o May precipitate aspirin-induced asthma

 Fluid retention: Less compared to other NSAIDs

 Contraindications:

o Pregnancy

o Peptic ulcer

Pharmacokinetics

 Well absorbed orally

 Highly protein bound (90–99%)

o Displacement interactions not clinically significant

o No need to adjust doses of oral anticoagulants or hypoglycaemics

 Distributed to:

o Brain

o Synovial fluid
o Crosses placenta

 Metabolism:

o In liver (hydroxylation and glucuronide conjugation)

 Excretion:
 o Via urine and bile

Drug Interactions

 Avoid with anticoagulants: Risk of bleeding due to inhibition of platelet

function
 May reduce efficacy of:

o Diuretics (e.g., furosemide, thiazides)

o β-blockers (antihypertensive effect)

✅ Propionic Acid Derivatives (NSAIDs)

🔹 Uses

1. Ibuprofen:

o Analgesic & antipyretic (like low-dose aspirin)

o Effective in dysmenorrhoea (via PG synthesis inhibition)

o Used in RA, OA, musculoskeletal pain (pain > inflammation)

o Helpful in soft tissue injuries, fractures, dental/post-op pain

o OTC availability; safer traditional NSAID (UK ADR data)

o Not suitable for acute gout (weak anti-inflammatory)

2. Interaction with Aspirin:

o Ibuprofen interferes with low-dose aspirin's antiplatelet action

o Prevents irreversible COX-1 inhibition → reduces cardioprotection

3. Naproxen:

o Stronger anti-inflammatory

o Potent inhibitor of leukocyte migration → useful in acute gout (750

mg stat → 250 mg 8 hourly)
o Indicated in RA & ankylosing spondylitis
o Longer half-life → twice-daily dosing

o More gastric bleeding vs ibuprofen

o Lower thrombotic risk than diclofenac, etoricoxib

o Reduce dose in elderly

 o Available as active S(–) enantiomer

4. Ketoprofen:

o Stabilizes lysosomes & inhibits lipoxygenase (LOX)

o Similar efficacy to ibuprofen but more side effects

5. Flurbiprofen:

o Additional mechanisms of action

o More effective than ibuprofen, but more gastric side effects

o Used in ophthalmology:

 Eye drops: OCUFLUR, FLURBIN 0.03%, 1 drop 6 hourly

🔹 Choice

 Naproxen is likely better tolerated and more effective in anti-inflammatory

doses
 Individual response varies → clinical preference matters

✅ FENAMATE – Mephenamic Acid

🔹 Mechanism of Action

 Inhibits PG synthesis and antagonizes PG actions

🔹 Adverse Effects

 Dose-related diarrhoea (most important)

 Epigastric distress (gut bleeding rare)

 Skin rashes, dizziness, CNS effects

 Rare: Haemolytic anaemia

🔹 Pharmacokinetics

 Oral absorption: Slow but complete

 Highly protein-bound
 Metabolized & excreted via urine and bile

 Plasma t½: 2–4 hrs

🔹 Uses
  Analgesic for:

o Muscle, joint & soft tissue pain (where inflammation is mild)

o Dysmenorrhoea

o Can be used in RA/OA (no clear advantage)

 Dose: 250–500 mg TDS

🔹 Preparations

 MEDOL 250, 500 mg cap

 MEFTAL 250, 500 mg tab

 PONSTAN 125, 250, 500 mg tab; 50 mg/ml syrup

✅ ENOLIC ACID DERIVATIVES (Oxicams)

🔹 Piroxicam

 Action: Potent, long-acting NSAID; reversible nonselective COX inhibitor

 Mechanism:

o ↓ PGs in synovial fluid

o Inhibits platelet aggregation → ↑ bleeding time

o ↓ Free radicals & IgM rheumatoid factor

o Inhibits leukocyte chemotaxis

 Pharmacokinetics:

o 99% protein-bound, enterohepatic circulation

o t½ ≈ 2 days → Once daily dosing

 Adverse Effects:

o More GI toxicity than ibuprofen

o Less ulcerogenic than indomethacin (in low doses)

o Rash, pruritus (~1%), edema, reversible azotemia

 Uses:

o Long-term treatment in RA, OA, ankylosing spondylitis

o Acute gout, musculoskeletal pain, dental pain

o Not first-line due to toxicity
  Dose: 20 mg BD × 2 days → 20 mg OD
(e.g., DOLONEX, PIROX, PIRICAM)

🔹 Tenoxicam

 Congener of piroxicam
 Similar use and action

 Dose: 20 mg OD (TOBITIL)

✅ ACETIC ACID DERIVATIVES

🔹 Ketorolac

 Potent analgesic, mild anti-inflammatory

 Comparable to morphine in post-op pain, no opioid side effects

 Peripheral mechanism (PG synthesis inhibition)

 Pharmacokinetics:

o Oral/i.m. absorption is rapid

o t½ = 5–7 hrs; 60% excreted unchanged

 Adverse Effects:

o Nausea, dyspepsia, ulcers, drowsiness, dizziness

o ↑ Serum transaminases, fluid retention

o Avoid in patients on anticoagulants

 Uses:

o Post-op, dental, musculoskeletal pain

o Renal colic, migraine, bone metastasis pain

o Not for RA/OA or >5 days use

o Topical: for noninfective ocular inflammation

 Dose:

o 15–30 mg i.m./i.v. every 4–6 hrs (max 90 mg/day)

o 10–20 mg PO q6h (short term)

 o Eye drops: 0.5%, 1–2 drops 2–4x/day
(e.g., KETOROL, KETANOV, ACULAR)

🔹 Indomethacin

 Highly potent anti-inflammatory & antipyretic

 Mechanism:

o Strong PG synthesis inhibitor

o Suppresses neutrophil motility

o In toxic doses, uncouples oxidative phosphorylation

 Pharmacokinetics:

o 90% protein-bound, t½ = 2–5 hrs

 Adverse Effects (high incidence ~50%):

o GI: Irritation, bleeding, nausea, diarrhoea

o CNS: Headache, confusion, hallucination, psychosis

o Leukopenia, rash, hypersensitivity

o ↓ Platelet function → ↑ bleeding risk

 Contraindications:

o Machinery operators, epilepsy, psychosis, renal disease, pregnancy,

children
 Uses:

o Reserve drug for severe RA, gout, psoriatic arthritis, ankylosing

spondylitis

o Closure of PDA: 0.1–0.2 mg/kg i.v. 12 hrly × 3 doses

o Refractory fever in malignancy, Bartter’s syndrome

 Dose: 25–50 mg BD to QID

(e.g., IDICIN, INDOCAP, RECTICIN suppository)
NSAIDs - Important Drugs & Their Features

1. Nabumetone (Enolic Acid Derivative)

 Prodrug: Converted to active metabolite 6-MNA.
  Mechanism: Inhibits COX-1 & COX-2.

 Action: Analgesic, antipyretic, antiinflammatory.

 Uses: Rheumatoid arthritis, osteoarthritis, soft tissue injury.

 Adverse Effects: Lower gastric erosion/ulcers; may cause abdominal

cramps, diarrhea, rashes, photosensitivity.
 T½: 24 hrs.

 Dose: 500 mg OD.

Brand: NABUFLAM

2. Pyrazolones

Mostly withdrawn due to toxicity (agranulocytosis, bone marrow depression).

 Phenylbutazone & Oxyphenbutazone: Potent, slow-onset antiinflammatory,
toxic, no longer used.
 Propyphenazone:

o Still available in India (not elsewhere).

o Uses: OTC analgesic for headache, fever, body ache.

o FDC: SARIDON (propyphenazone + paracetamol + caffeine)

3. Nimesulide (Preferential COX-2 Inhibitor)

 Mechanism: Weak PG synthesis inhibitor; reduces superoxide, PAF, TNFα;

antioxidant; COX-2 selective.
 Uses: Painful inflammation (sports injury, ENT disorders, dental pain,
dysmenorrhoea, osteoarthritis).
 Absorption: Almost complete; 99% protein bound.

 T½: 2–5 hrs.

 Adverse Effects: GI (epigastralgia, nausea), skin rash, dizziness, liver toxicity

(→ withdrawn in several countries).
 Special Note: Useful in aspirin-sensitive asthma patients.

 Dose: 100 mg BD.

Brands: NIMULID, NIMEGESIC
4. Diclofenac Sodium (Preferential COX-2 Inhibitor)

 Mechanism: Inhibits PG synthesis, neutrophil chemotaxis; mildly COX-2

selective.
 Advantages: Good tissue penetration, prolonged synovial fluid concentration.

 Uses: RA, OA, ankylosing spondylitis, dysmenorrhoea, trauma, toothache,

renal colic.
 T½: ~2 hrs.

 Adverse Effects: GI irritation, dizziness, hepatotoxicity, cardiovascular risk.

 Dose: 50–75 mg TDS or BD; 75 mg i.m.

Brands: VOVERAN, DICLONAC, DYNAPAR AQ, ULTRA-K (K+ salt),
VOVERAN OPHTHA (eye drops), VOVERAN GEL (topical).

5. Aceclofenac

 Related to: Diclofenac.

 Mechanism: Moderately COX-2 selective; may enhance glycosaminoglycan

synthesis (chondroprotective).
 Dose: 100 mg BD.
Brands: Aceclo, Dolokind

6. Meloxicam (Preferential COX-2 Inhibitor)

 Mechanism: COX-2/COX-1 selectivity ~10.

 Uses: RA and OA.

 T½: 15–20 hrs (OD dose).

 Adverse Effects: Milder GI symptoms; ulcer complications possible on long-
term use.
 Dose: 7.5–15 mg OD.
Brands: MELFLAM, M-CAM, MEL-OD

7. Etodolac

 Class: Indole-acetic acid derivative.

 Mechanism: Moderately COX-2 selective; better GI tolerance at low doses.

 Uses: RA, OA, acute musculoskeletal pain.
 T½: 7 hrs; analgesia lasts 6–8 hrs.

 Adverse Effects: Abdominal pain, rash, dizziness.

 Dose: 200–400 mg BD–TDS.

Brands: ETOVA, ETOGESIC
Injection: 400 mg/2 ml approved for postop orthopedic pain.

Selective COX-2 Inhibitors (Coxibs) – Notes

Overview:

 Selectively inhibit COX-2 (induced at inflammation sites).

 Spare COX-1 (responsible for gastric protection, platelet function).

 Advantages:

o Less gastric mucosal damage.

o Lower incidence of peptic ulcers and bleeds.

 Disadvantages:
o Do not inhibit TXA₂ (thromboxane A2, COX-1 dependent) → no
antiplatelet effect.

o Reduce PGI₂ (prostacyclin) → loss of vasoprotective effect → ↑

cardiovascular risk.

o Lack cardioprotective property of aspirin.

Cautions:

 Use only in patients at high risk of GI complications.

 Use at the lowest effective dose for shortest duration.

 Avoid in patients with:

o Ischaemic heart disease

o Hypertension

o Cardiac failure

o Cerebrovascular disease
 Do not combine with low-dose aspirin (↑ GI toxicity, no CV benefit).

Currently Available Coxibs in India:

1. Celecoxib
 2. Etoricoxib

3. Parecoxib

Withdrawn:

 Rofecoxib, Valdecoxib – ↑ CV risk

 Lumiracoxib – hepatotoxicity (withdrawn in Europe)

Celecoxib – Details:

 Selectivity: ~10 times COX-2 > COX-1

 Actions: Anti-inflammatory, analgesic, antipyretic

 GI Tolerability: Better than traditional NSAIDs

 Does not affect:

o Platelet aggregation

o Serum TXB₂ (Thromboxane B2)

 Side effects:

o Abdominal pain, dyspepsia, mild diarrhoea

o Rash, edema, slight ↑ BP

Pharmacokinetics:

 Absorbed slowly

 97% plasma protein bound

 Metabolized by CYP2C9

 t½ ~10 hours
Uses:

 Osteoarthritis
 Rheumatoid arthritis

Dose:

 100–200 mg BD

Brand Names:

 Celact, Revibra, Colcibra 100, 200 mg caps

COX-2 Inhibitors & Other Analgesics – Notes
 🧪 Etoricoxib

 Selectivity: Highest COX-2 selectivity.

 Indications:

o Osteoarthritis

o Rheumatoid arthritis

o Acute gouty arthritis

o Ankylosing spondylitis

o Dysmenorrhoea

o Acute dental pain

 Benefits:

o Once-daily dosing

o No platelet function suppression

o Minimal gastric mucosal damage

 Half-life: ~24 hours

 CV Risk: Similar to diclofenac (thrombotic events)

 Side Effects:

o Dyspepsia, abdominal pain

o Pedal edema

o ↑ BP, dry mouth

o Aphthous ulcers, taste disturbances

o Paresthesias
 Dose: 60–120 mg OD

 Brands: ETOSHINE, Torocoxia, Etoxib, Nucoxia (60, 90, 120 mg tabs)

🧪 Parecoxib

 Prodrug of: Valdecoxib

 Route: Injectable (oral/i.m./i.v.)

 Use: Short-term postoperative pain (efficacy like ketorolac)
 Risk: Severe cutaneous reactions → Stop at first sign of rash

 Dose: 40 mg (oral/i.m./i.v.), repeated after 6–12 hrs

 Brands: Revaldo, Valto-P 40 mg inj., Paroxib 40 mg tab

🧪 Para-Amino Phenol Derivatives

🧪 Paracetamol (Acetaminophen)

 Active Metabolite of: Phenacetin

 Mechanism:

o Central COX inhibition (↑ pain threshold)

o Weak peripheral anti-inflammatory

o Strong antipyretic effect

o Inhibits COX-3 in brain (hypothetical)

 Does NOT:

o Affect respiration, acid-base balance, or CVS

o Cause gastric irritation (safe in ulcers)

o Affect platelet function or clotting

 Pharmacokinetics:

o Well absorbed, low protein binding

o Metabolized by glucuronidation/sulfation

o t½: 2–3 hrs; Effects last 3–5 hrs

 Dose:

o Adults: 325–650 mg 3–4×/day (Max: 2600 mg/day per US-FDA)

o Children: 10–15 mg/kg

 Brands:

o CROCIN, METACIN, PARACIN, CALPOL, NEOMOL, PYRIGESIC

o KABIPARA, AEKNIL (injections)

o JUNIMOL-RDS, PARACETAMOL RECTAL SUPPOSITORY

(suppositories)
o CROCIN PAIN RELIEF: 650 mg + Caffeine 50 mg
 ⚠️ Paracetamol Toxicity

 Toxic dose:

o Adults: >10 g

o Children: >150 mg/kg (fatal >250 mg/kg)

 Toxic metabolite: NAPQI (detoxified by glutathione)

 Mechanism:

o Overdose → glutathione depletion → NAPQI binds liver cells →

hepatic necrosis
 High Risk: Children, alcoholics (↑ CYP2E1)

 Symptoms:

o Early: Nausea, vomiting, abdominal pain

o 12–18 hrs: Hepatic necrosis, renal failure, hypoglycemia, coma

o After 2 days: Jaundice

 Treatment:

o Activated charcoal

o N-acetylcysteine (antidote):

 150 mg/kg IV over 15 min → same dose over 20 hrs

 Orally: 75 mg/kg every 4–6 hrs for 2–3 days

o Must be started within 16 hours

🧪 Uses of Paracetamol

 Common analgesic for:

o Headache, mild migraine

o Musculoskeletal pain, dysmenorrhoea

 Preferred in:

o Osteoarthritis (first choice)

o Children (no Reye’s syndrome risk)
o Ulcer patients, pregnancy, aspirin contraindications
 Safe across all ages, no major drug interactions

🧪 Benzoxazocine Derivative

🧪 Nefopam

 Non-opioid analgesic

 No PG synthesis inhibition
 Uses:

o Traumatic pain

o Postoperative pain

o Musculoskeletal pain
 Side Effects:

o Anticholinergic: Dry mouth, urinary retention, blurred vision

o Sympathomimetic: Tachycardia, nervousness

o Nausea (dose-limiting)

 Contraindication: Epileptics

 Dose:

o Oral: 30–60 mg TDS

o I.M.: 20 mg every 6 hrs

 Brand: NEFOMAX 30 mg tab, 20 mg/ml amp.

Topical NSAIDs – Summary Notes

Uses

 Indications: Osteoarthritis, sprains, sports injuries, tenosynovitis, backache,

spondylitis, soft tissue rheumatism.
 Often used in mild-to-moderate pain or adjunctively with oral NSAIDs.

Mechanism & Pharmacokinetics

 Designed for local action: high local concentration, low systemic levels.

 Systemic absorption is slow, takes ~10x longer to reach peak level than oral
NSAIDs.
 Blood levels <15% compared to oral dosing.
 Effective drug penetration: up to 4–6 mm (dermis); at 25 mm (muscle), drug
levels similar to blood (low).
Efficacy

 High variability in response based on:

o Formulation

o Depth and site of application

o Individual differences
 More effective in short-lasting musculoskeletal pain.

 Shown to be superior to placebo in knee osteoarthritis trials (especially

diclofenac and ketoprofen).

Safety
 Very safe due to low systemic absorption.

 Doubts exist about efficacy beyond placebo effects, massage, and presence
of counterirritants (e.g., menthol, methyl salicylate).

Common Topical NSAID Preparations

Drug Strength Brand Examples

Diclofenac 1% gel Volini, Relaxyl, Diclonac

Ibuprofen 10% gel Ribufen

Naproxen 10% gel Naprosyn

Ketoprofen 2.5% gel Rhofenid

Flurbiprofen 5% gel Froben

Nimesulide 1% gel Nimulid Trans, Zolandin, Nimegesic-T

Piroxicam 0.5% gel Dolonex, Movon, Pirox, Minicam

Choice of NSAID – Summary

General Principles

 No single NSAID is best for all.

 Selection depends on:

o Type and severity of pain

o Inflammation level
 o Age, allergies, comorbidities, drug history

o Past patient response

o Risk of adverse effects (GI, renal, cardiac)

Clinical Guidelines

1. Mild pain: Paracetamol or low-dose ibuprofen.

2. Acute short pain: Injectable ketorolac, oral diclofenac, nimesulide.

3. Severe acute pain (e.g., colic, trauma): Parenteral ketorolac, diclofenac,

parecoxib.
4. Inflammatory conditions (e.g., RA, spondylitis): Naproxen, piroxicam,
indomethacin.
5. GI intolerance: Use COX-2 inhibitors or paracetamol + PPI.
6. NSAID allergy/asthma: Nimesulide or COX-2 inhibitors.

7. Heart risk patients: Avoid COX-2 inhibitors; prefer low-dose aspirin/propionic

acid NSAIDs.
8. Children: Use paracetamol, ibuprofen, naproxen. Avoid aspirin (Reye’s
syndrome).
9. Elderly: Use lower doses.

10. Fever/headache: Fast-acting NSAIDs.

11. Chronic pain: Long-acting or sustained-release NSAIDs.

12. Pregnancy: Paracetamol is safest; low-dose aspirin may be used.

13. Long-term medication users: Monitor for interactions with NSAIDs.

Analgesic Combinations

Types

 Paracetamol + NSAID (e.g., ibuprofen/diclofenac):

o Additive effect (not superior)

o Ceiling dose = ~1000 mg

o Use short-term only

 Paracetamol/Aspirin + Codeine:
o Provides additional analgesia beyond ceiling
 o Opioid side effects: nausea, constipation, drowsiness, dependence
Precautions

 Fixed-dose combinations with sedatives/hypnotics/anxiolytics banned in

India to prevent misuse/dependence.