The characteristic features of NSAID are:

1. NSAID are weak analgesics than narcotic analgesics.

2. Unlike narcotic (opioid) analgesics, NSAID do not induce central depressant and sedative activity, so they are called non- narcotic (non-opioid) analgesics.

3. Most of NSAID have additional anti- inflammatory and antipyretic effects.

4. NSAID do not produce physical dependence and have no abuse liability.

5. NSAID act primarily on peripheral pain mechanisms; they also raise pain threshold in central nervous system.

6. The major pharmacological actions of NSAID are believed to be due to their ability to inhibit the synthesis of prostaglandins (PGs) by inhibiting cyclogenase (COX) enzyme in arachidonic acid cascade (PGs, PCI2, and TXA2, etc.). Mainly there are two types of cyclooxygenase enzymes, namely COX—1 and COX-2. COX—1 is constitutionally expressed that means it is always present in most of the cells. Traditional non-steroidal anti- inflammatory drugs (NSAIDs) inhibit both COX—1 and COX—2. It appears that their analgesic, antipyretic and platelet aggregation effects are due to their ability to inhibit COX—1 while the anti-inflammatory effect is mainly related to their inhibition of COX—2. The COX—2 is not consecutively expressed. It is induced in inflammatory cells by an inflammatory stimulus such as endotoxins, cytokines, and tumour promoters. It is not predominant at the sites of gastrointestinal tract and platelets.

7. NSAID exhibit anti-inflammatory activity but are not steroids like anti-inflammatory glucocorticoids; so they are popularly known as non-steroidal anti-inflammatory drugs.

8. NSAID are chemically different; however, most of them are organic acids.

Classification of NSAID

I. Non-selective COX inhibitors:

a. Drugs with marked antipyretic but weak anti-inflammatory activity: Paracetamol.

b. Drugs with marked analgesic and anti- inflammatory activity:

  • Salicylic acid derivatives: Aspirin, benorylate, choline magnesium tricyclate, diflunisal, salicylamide, salsalate.
  • Arylacetic acid derivatives: Diclofenac, tolmetin, fenclofence.
  • Indole derivatives: Indomethacin, sulindac.
  • Pyrazolone derivatives: Phenylbutazone, oxyphen-butazone, azapropazone.
  • Oxican’t derivatives: Piroxicam, tenoxicam.
  • Pyrrolo-pyrole derivative: Ketoralac.

c. Drugs with analgesic and mild to moderate anti-inflammatory activity:

  • Fenarnic acid derivatives: Mefenamic acid, enfenamic acid
  • Propionic acid derivatives: Ibuprofen, fenprofen, flurbiprofen, indopr ofen, ketoprofen, naproxen.

II. Selective COX—2 inhibitors:

  • Nimesulide
  • Etodolac
  • Meloxicam
  • Nabumeton
  • Rofecoxib
  • Celecoxib
  • Valdecoxib
  • Etoricoxib

III. Others: Nefopam

Aspirin (Acetylsalicylic Acid)

Aspirin was initially obtained from willowbark. Now it is synthesized. In the body, it is rapidly converted into salicylic acid. So most of the actions of aspirin are due to salicylic acid.

Pharmacological Actions of NSAID

1. Analgesia: Aspirin is less potent analgesic than pethidine. It is effective in relieving non-visceral pain, such as inflammatory, tissue injury related, connective tissue and integumental pain. Its analgesic effect is due to its ability:

  • To inhibit peripheral prostaglandin synthesis
  • To raise the threshold to pain perception at central subcortical level.

2. Antipyretic action: Aspirin does not cause hypothermia in individuals with normal body temperature. It rapidly reduces body temperature of patients having pyrexia by inhibiting prostaglandin synthesis in hypothalamus. Aspirin lowers raised body temperature by promoting heat loss (peripheral vasodilatation and sweating). It does not decrease heat production.

3. Anti-inflammatory action: This occurs at high doses. Aspirin is a potent anti- inflammatory agent. It acts by causing inhibition of PC synthesis. However, there may be other mechanisms such as:

  • stabilization of lysosomal membrane in leukocytes
  • antagonism of certain actions of bradykinin.

4. Respiration: In therapeutic doses, aspirin stimulates the respiratory center due to increased CO2 production by its metabolic effects. Larger doses (anti-inflammatory doses) stimulate respiration by peripheral (increased CO2 production) and central (increased sensitivity of respiratory center to C02) actions and increase the rate and depth of respiration. Respiratory alkalosis may develop which is compensated by renal loss of bicarbonates along with sodium, potassium and water. So over- dosage of aspirin can lead to hypokalaemia, dehydration and respiratory depression; death is due to respiratory failure.

5. Metabolic effects:

a. Due to uncoupling of oxidative phosphorylation in skeletal muscles, aspirin causes increased 0, consumption and CO2 production.

b. In severe poisoning, metabolic acidosis will occur due to:

i. Accumulation of lactic and pyruvic acids, caused by interference with enzymes of Kreb’s cycle; and

ii. Accumulation of acetoacetic acid, caused by increase in lipid metabolism.

c. Aspirin decreases blood sugar (especially in diabetics) due to increased utilization of glucose and causes depletion of liver glycogen. However, there occurs hyperglycaemia at toxic doses of aspirin due to central sympathetic stimulation and release of adrenaline and corticoids.

d. Chronic use of large doses of aspirin causes:

i. Negative N2 balance by increased conversion of proteins to carbohydrates;

ii. Reduction in plasma free fatty acids and cholesterol.

6. Gastrointestinal tract: Aspirin inhibits mucoprotective PC of gastrointestinal tract. So it can cause gastric and intestinal erosions and hemorrhage. It also stimulates chemoreceptor trigger zone; so vomiting, caused by aspirin, has also a central component at higher doses.

7. Cardiovascular system: In therapeutic doses, aspirin has no direct effect on cardiovascular system. At larger doses, cardiac output is increased to meet with increased peripheral oxygen demand. It also causes direct vasodilatation. Toxic doses cause fall in blood pressure by depressing vasomotor centre and it may precipitate congestive heart failure in patients with low cardiac reserve due to increased cardiac work and sodium + water retention.

8. Effect on coagulation: At therapeutic doses, aspirin does not significantly modify coagulation because it inhibits the generation of both eicosanoids (thromboxane A2 induces platelet aggregation; and PCI2 inhibits platelet aggregation). However, low doses of aspirin specifically inhibit thromboxane A2 (TXA2) synthesis arid do not affect levels of PCk. So it may reduce intravascular clotting and prevent thrombogenesis. Hypoprothrombinaemia occurs at large doses of aspirin. It can be reversed by vitamin K.

9. Uric acid excretion: The effects of aspirin are dose dependent.

i. Therapeutic doses of aspirin (less than 2 g/day) may cause hyperuricaemia by inhibiting tubular secretion of uric acid.

ii. Larger doses (8—10 g/day) inhibit uric acid reabsorption in renal tubules and produce a uricosuric effect.

Pharmacokinetics of NSAID: On oral administration, aspirin is absorbed from stomach and small intestine. Its absorption can be enhanced by microfining drug particles and inclusion of an alkali. Alkalinization of urine would also lead to increased elimination of aspirin.

Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. Half-life of aspirin is only 15 minutes but half-life of salicylic acid is 3 hours. Both aspirin and salicylic acid are metabolized in liver (glycine and glucuronide conjugation) and are excreted in urine.

Therapeutic Uses of NSAID

1. As an analgesic in mild to moderate pain of non-visceral aetiology. NSAID is, therefore, used for headache, backache, myalgia, joint pain, toothache, neuralgias and dysmenorrhoea (primary dysmenorrhoea may be due to increased uterine PC activity).

2. As an antipyretic for symptomatic relief of fever of any origin.

3. As an anti-inflammatory agent in rheumatic fever, rheumatoid arthritis, oteoarthritis, Dressler’s syndrome.

4. Cardioprotective: In low doses, aspirin has been employed for primary or secondary prevention of myocardial infarction.

5. Aspirin has also been used in the treatment of cerebral ischaemia and for prevention of cerebral stroke.

6. Miscellaneous uses:

  • In radiation induced diarrhoea: Prostaglandins are probably involved.
  • Patent ductus arteriosus: Aspirin may bring about closure and avoid surgery.
  • Pregnancy associated hypertension and pre-eclampsia: They are believed to be due to imbalance between TX1% and PCI2. Aspirin 100 mg/day may benefit by selectively suppressing TXA2 production.

Doses (Oral)

AnalgesialAntipyretic: 300—900mg 4—6 hourly

Rheumatic fever: 900—1200 mg 4—6 hourly

Rheumatoid arthritis: 600—900mg 4—6 hourly

Cardioprotective: 50—75 mg per day.

Adverse Effects

1. Side effects of NSAID: Commonest adverse effects are nausea, vomiting, epigastric distress, heartburn, abdominal pain and increased occult blood loss in stools. Aspirin causes gastric mucosal damage and peptic ulceration by:

  • Back diffusion of W ions in the gastric mucosa
  • Decreased secretion of mucus and bicarbonates
  • Decreased synthesis of cytoprotective prostaglandins
  • Occurrence of local mucosal ischaemia

2. Salicylism (a syndrome) occurs at high doses or with chronic use of aspirin. It is characterized by tinitus, hearing defects, blurring of vision, dizziness, mental confusion and headache. It is reversible.

3. Hypersensitivity and idiosyncrasy (infrequent): Aspirin may cause rashes, fixed drug eruptions, severe rhinitis, bronchospasm, urticaria, angioneurotic oedema and anaphylactic shock.

4. Rarely aspirin can cause irreversible renal damage (analgesic nephropathy) due to inhibition of local vasodilator PGs, resulting in focal ischaemia. The condition is characterized by chronic interestitial nephritis, papillary necrosis and acute renal failure.

5. Reye’s syndrome (liver damage and encephalopathy) may be precipitated in infants and children by aspirin who are recovering from febrile viral infection. Hence paracetamol is preferred in pyrexia of uncertain origin in children under the age of 12 years.

6. During pregnancy, aspirin may prolong gestation and delay labour due to inhibition of PC synthesis in uterus.

7. Aspirin may aggravate acute gout due to retention of uric acid in therapeutic doses.

8. Acute salicylate poisoning: It is more common in children. Manifestations are vomiting, dehydration, restlessness, hyperpyrexia, electrolyte imbalance, delirium, hallucinations, acidotic breathing, convulsions and coma. Death occurs due to respiratory failure and cardiovascular collapse.


  • Gastric lavage
  • External cooling
  • Intravenous infusion of sodium bicarbonate (1.26%) with dextrose (5%). Potassium chloride may be added to infusion (20 mM/h)
  • Vitamin K 10 mg i.v.
  • Peritoneal dialysis or haemodialysis


  • Gout
  • Ulcerative colitis
  • Peptic ulcer
  • Renal failure
  • Hypersensitive patients.

Drug interactions: Important drug interactions are given

Other Clinically used Salicylates

1. Salicylic acid: It is a keratolytic agent. It is used to remove corn. It is used locally in epidermophytosis in combination with benzoic acid (Whitfield ointment).

2. Methylsalicylate: It acts as a counterirritant. It is used topically in the form of liniments and ointments in muscle and joint pain. Systemic absorption can lead to toxicity.

3. Salicylamide: It is not recommended now because its anti-inflammatory effects are rather unreliable.

4. Benorylate: It is an ester of aspirin and paracetamol; well absorbed from GIT; broken within the body into its constituents; causes less gastric irritation and bleeding. So it is a better tolerated alternative to aspirin (Dose: 4 g/day).

5. Diflunisal: It is fluorine containing, long acting salicylate. It is not marketed in India.


A large number of NSAID are now available.

Qualitatively NSAID possess similar pharmacological actions, clinical uses and adverse effects as that of aspirin. So salient features of these clinically important NSAID will be described in brief.

1.       Paracetamol (acetaminophen): It is a good analgesic and antipyretic drug but has negligible anti-inflammatory action. A new third form of COX—3 mRNA is expressed most abundantly in cerebral cortex and heart of humans. It is involved in pain perception and fever but not in inflammation. Paracetamol is reported to be selective COX—3 inhibitor. Another reason for lack of anti-inflammatory effect of paracetamol is its poor ability to inhibit COX—1 in the presence of peroxides, generated at inflammatory sites by leukocytes. Plasma half-life of paracetamol is 2—4 hours. It is a safe drug with mild gastric toxicity. However, in paracetamol overdosage or on prolonged use, N-acetylp-benzoquinone (minor, toxic metabolite) tends to accumulate and can induce hepatic and acute tubular necrosis. There is delay in the appearance of clinical signs of acute toxicity such as jaundice, liver tenderness, (1—2 days) and hepatic failure(3—7 days). So it is vital to provide effective and energetic anticipatory treatment as given in the box.

a. Acetylcystein: It is administered i,v. in a phased manner:

  • 150 mg/kg in 200 nil 5% dextrose – administered over 15 mm,
  • 50 mg/kg in 500 ml 5% dextrose – administered over 4 hours
  • 100 mg/kg in 100 ml 5% dextrose – administered over 16 hrs.

b. Methionine: It may be administered orally in doses of 10gm in divided doses in patients who are unlikely to have severe hepatic damage. Limiting factor is vomiting. Hepatic microsomal enzyme inducers (phenobarbitone, phenytoin, rifampicin and griseofulvin) may enhance paracetamol toxicity.

2. Diclofenac: It is a potent analgesic, antipyretic and anti-inflammatory drug; similar in efficacy to ibuprofen. Adverse effects are common. It is also available as gel for topical use. It may also inhibit lipoxygenase. Its plasma half-life is 2—3 hours.

3. Tolmetin: It is a potent analgesic, antipyretic and anti-inflammatory drug. Side effects are frequent. Plasma half-life is 3—5 hours.

4. Indomethacin: Clinically very effective pptent anti-inflammatory and antipyretic drug. As an analgesic, it mainly relieves inflammatory or tissue injury related pain. It has high incidence of adverse effects. It may aggravate pre-existing renal disease and induce mental confusion and hallucinations. Its plasma half-life is 2—3 hours. It reduces efficacy of diuretics and antihypertensive action of propranolol by causing inhibition of renal prostaglandins.

5. Sulindac: It is a prodrug. In the body, it is converted into active metabolite (a sulphide) by gut flora and hepatic

enzymes. It is less potent and less toxic than indomethacin. It is safe in presence of renal disease because it does not inhibit renal POs. It is a long acting drug.

6. Phenylbutazone: It is a potent anti- inflammatory agent but poor analgesic and antipyretic drug. It is uricosuric by virtue of a metabolite which inhibits renal tubular reabsorption of uric acid. Its clinical use is limited because of bone marrow depression and other severe adverse effects. Plasma half-life is 50—100 hours.

7. Oxyphenbutazone: It is a biotransformation product of phenylbutazone and has similar actions as that of parent drug but not a uricosuric agent. Its clinical use is limited because it causes bone marrow depression. Plasma half-life is 10—14 hours.

8. Piroxicam: It is a long acting potent anti- inflammatory, analgesic and antipyretic drug. It has enterohepatic circulation. It can be used safely in renal disease. Adverse effects are common. Plasma half- life is 45 hours.

9. Tenoxicam: It is a congener of piroxicam with similar properties and uses.

10. Ketorolac: It is a potent analgesic and modest anti-inflammatory agent. In postoperative pain, its efficacy is equal to morphine but it does not interact with opioid receptors and free from morphine like adverse effects. It is used for short- term management of moderate pain. Continuous use for more than 5 days is not at present recommended.

11. Ibuprofen: It is better tolerated than aspirin as analgesic, antipyretic and anti- inflammatory drug. It is a drug of choice in the treatment of rheumatoid arthritis because of lesser adverse effects. Plasma half-life is 2—3 hours.

12. Naproxen: It is better tolerated than aspirin as analgesic, antipyretic and anti- inflammatory agent. It is long acting and its half-life is 12—14 hours. It is second choice after ibuprofen in the treatment of rheumatoid arthritis.

13. Fenprofen: Prodrug; activated in liver, hence less gastric toxicity; plasma half-life is 8—12 hours.

14. Flubiprofen: No special advantage over ibuprofen.

15. Ketoprofen: It inhibits both cyclooxygenase and lipooxygenase.

16. Mephenamic acid: It has not gained popularity because of lower efficacy as analgesic, antipyretic and anti-inflammatory agent.

17. Enphenamic acid: It has modest analgesic, antipyretic and weak anti-inflammatory action. It is claimed not to cause sodium and water retention like other nonsteroidal anti-inflammatory drugs.

18. Selective COX—2 inhibitor non-steroidal anti-inflammatory drugs:

General features of NSAID are:

  • NSAID selectively block COX—2 activity more than COX—1 activity.
  • NSAID interfere less with the protective action of COX—1 in the stomach, blood vessels, and kidneys.
  • On oral administration, they are completely absorbed.
  • NSAID are as effective as the established analgesic-anti-inflammatory nonsteroidal anti-inflammatory drugs.
  • NSAID cause fewer gastric ulcers.
  • They do not inhibit platelet aggregation.
  • On long-term use, coxibs can reduce whole body PCI2 production without affecting T)(A2 content of platelets. Due to this, they disturb the cardioprotective PCI2: TXA2 ratio. Hence increased TXA2 concentration may exert prothrombotic influence. So they are responsible for higher incidence of cardiovascular side effects during their long-term use.
  • Common side effects are nausea, vomiting, dyspepsia, diarrhea, abdominal pain and oedema of the lower extremities. Since celecoxib and valdecoxib are sulfonamide derivatives, they may cause rashes and hypersensitivity reactions.
  • Like NSAID COX inhibitors, they may cause renal toxicity because COX—2 is consecutively present in kidney.
  • NSAID may interfere with wound (ulcer) healing, bone-remodeling, ovulation and prenatal renal development.
  • NSAID should not be used in children, lactating mothers and women of child bearing age.

The characteristic features of each drug of NSAID are as under:

i. Nimesulide: It is a weak PC synthesis inhibitor with 5 to 10-fold more COX—2 selective inhibition than COX—1 inhibition. So other important actions are involved for its anti- inflammatory action such as:

  • Reduction of superoxide generation.
  • Free radical scavenging action.
  • Inhibition of platelet activation factor synthesis.
  • Inhibition of metalloproteinase activity in cartilage.

The advantages are:

  • Causes no bronchospasm.
  • Shows no cross-resistance to aspirin.

Following are preferential COX—2 inhibitors with 70 to 20-fold more COX—2 inhibition than COX—1 inhibition:

ii. Etodolac is more potent than aspirin but has less gastrointestinal toxicity.

iii. Meloxicam is longer acting. It is less toxic than piroxicam and other NSAID.

iv. Nabumetone is a prodrug which is convertated to active acetic acid derivative (6-methoxy-2-naphthyl acetate acid). It is long acting. It is more potent antipyretic than aspirin with less marked side effects.

v. Coxibs (celecoxib, roficoxib, valdecoxib, and etoricoxib) are selective COX—2 inhibitors (>50-fold COX—2 selective). These drugs selectively inhibit COX—2 isoenzyme that is induced at the site of inflammation. They do not affect the action of COX— 1 present in gastrointestinal tract and platelets. Coxibs have analgesic, antipyretic and anti-inflammatory actions similar to that of NSAID. These are mainly used to treat osteoarthritis, rheumatoid arthritis, gouty arthritis, acute musculoskeletal pain, dysmenorrhoea and familial colonic polyposis.

Oral doses (mg):

  • Nimesulide: 200—300 daily in divided doses
  • Etodolac: 200—400 three times or four times a day
  • Nabumeton: 500—1000 once daily
  • Meloxican: 7.5—15 once daily
  • Celecoxib: 200—400 once daily or twice a day
  • Rofecoxib: 12.5—50 once daily
  • Valdicoxib: 10—20 once daily
  • Etoricoxib: 60 once daily

19. Nefopam: It is a NSAID. It does not inhibit prostaglandin synthesis. It has been found useful to relieve traumatic and musculoskeletal pain. Important side effects are blurred vision, urinary retention, tachycardia, nervousness. It should not be used in epileptic patients. Its oral dose is 30—60 mg three times a day.

About Dr. Muna

Dr. Muna Taqi is a Dental surgeon from India who has more than 10 years of experience in the field of Oral & Maxillofacial surgery, Endodontics, & Pedodontics. She has worked in multinational medical corporates in Middle East and is also a consultant dental surgeon for many. She has authored many articles for medical journals & websites and is a consultant dental expert for Healthdrip.

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