This group of drugs include Non Steroidal Anti-Inflammatory Drugs.

The primary effect is inhibition of prostaglandins synthesis, which are potent vasodilators and inflammatory mediators. By, decreasing the production of prostaglandin, NSAIDs depress the inflammatory response.This concentration also raises the threshold for pain conducting nerves thus an analgesic effect is produced.

NSAIDs can be divided into traditional and COX-2 inhibitors. The traditional agents affect both forms of cyclo-oxygenase (COX1 and COX2).

Conventional NSAID's (non-selective COX inhibitors)

Salicylates

Generic Name: Aspirin

Brand Names: Aspirin 350 mg tab, Ecosprin 75,150,325 mg tab, Disprin 350 mg tab, Loprin 75, 162.5 mg tab., Biosprin- Lysine acetyl salicylic acid 900mg + Glycine 100mg/vial for dissolving in water and I.V. injection.

Mechanism of Action

• The antipyretic and anti-inflammatory effects are primarily due to the blockage of prostaglandin synthesis (by inhibiting cyclo-oxygenase enzyme irreversibly) at the thermoregulating centers in the hypothalamus and at peripheral target sites. They also prevent the sensitization of pain receptors to both mechanical and chemical stimuli. It has a uricosuric effect in large doses.
• The blockage in body's production of prostaglandins hormone like substances involved in several functions including making blood platelets sticky. Taking aspirin can prevent platelets from sticking together and forming clots.

Indications

• Analgesic effect: Short term administration for pain relief in myalgia, headache, arthritis, dysmenorrhoe, dental pain, postpartum pain etc.
• Antipyretic effect: Common cold, cough and fever due to any cause.
• Anti-inflammatory effect: For relief of pain and inflammation in high doses ( more than 3mg/day) and for prolonged periods in musculo skeletal disorders like osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, SLE, ankylosing spondylitis etc.
• Antiplatelet effect: Used in low doses for prolonged periods of time.
  • Prevention of recurrent myocardial infarction - reduces mortality by 20% in acute myocardial infarction.
  • For stroke or cerebro vascular disorders – prevention of recurrent episodes.
  • For transient ischemic attacks – prevention of progression to stroke.
  • Prevention of pregnancy induced hypertension and eclampsia.
  • Following arterial bypass to prevent re-stenosis.

Contraindications

• Active Peptic ulcer disease.
• Haemophilia and other haemorrhagic disorders, anticoagulant treatment.
• Apart from low dose aspirin regimes, it should not be used in pregnancy or by lactating mothers.
• Pediatric formulations of aspirin are prohibited in India and UK.
• In treatment of viral haemorrhagic fevers such as dengue.
• Hypersensitive patients, in whom history of bronchial asthma, angioedema or urticaria have been precipitated by aspirin or other NSAIDS.

Precautions

• Alcohol increases the GI adverse effects and hence instruct patients to abstain from alcohol.
• Use with caution in children below 12 years except for the treatment of juvenile rheumatoid arthritis. Aspirin should not be used for any other minor illnesses.
• It is not advisable to take one more NSAID if the patient is already on aspirin – such combinations are more at risk for developing analgesic nephropathy.
• Administration Instructions:
  • Administer along with food to reduce gastro-intestinal side effects.
  • Instruct patients to report if ringing in ears or any bleeding from gums or persistent abdominal pain occurs. Withdraw the drug immediately.
  • Open package immediately before use.
  • Do not administer aspirin exposed to water or air for a long time.

Adverse Effects

Usually occurs at doses of more than 1 gm/day.

• GIT - stomach pain, heart burn, nausea, vomiting, epigastric discomfort. The most important side effect of aspirin is gastric mucosal damage and ulcerations.
• Hypersensitivity – angioedema, skin eruptions, paroxysmal bronchospasm and anaphylactoid reaction.
• Salicylism - anti-inflammatory doses more than 3-6g/day results in this syndrome. Features include: headache, dizziness, tinnitus, vertigo, mental confusion, hyperventilation and electrolyte imbalance.
• Acute Salicylate poisoning - It is more common in children. Fatal dose in adults is estimated to be 15- 30g, but lower in children. Symptoms – headache, dizziness, tinnitus, vertigo, mental confusion, restlessness, marked alteration in acid base balance, acidosis, sweating, dehydration, hyperpyrexia, nausea, vomiting, hyperventilation, coma followed by cardiovascular collapse and respiratory arrest due to its CNS depressant activity.

Pyrazolone, Indole and Aryl-acetic acid derivatives

Generic Name: Phyenylbutazone

Brand Name: Phenabid 100 mg tab.

Mechanism of Action

It inhibits COX and is a potent anti-inflammatory drug.

Indication

• Because of fatal agranulocytosis and other serious reactions, phenylbutazone is mostly not used world wide. These drugs are used only when other NSAID's fail to act.
• During acute exacerbation of rheumatoid arthritis and ankylosing spondylitis.
• Acute gout.

Adverse effects

• It is more toxic than aspirin.
• Nausea, vomiting, epigastric distress and peptic ulcerations.
• Hypersensitivity: Rashes, serum sickness, hepatitis, stomatitis.
• Bone marrow depression, agranulocytosis and other serious reactions.

Other Similar Drugs

Generic Name: Oxyphenbutazone

Brand Name: Butaflogin, Butazone, Tandalgesic, Flogistin.

Generic Name: Metamizol

Brand Name: Analgin 0.5mg tab, Novalgin, Baralgan 0.5mg tab, 0.5 mg/ml inj in 2ml and 5ml ampoule.

Indole Derivatives

Generic Name: Indomethacin

Brand Name: Indicin, Indocap 25mg cap, 75 mg SR cap,Articid 25,50mg cap, Indoflam 25,75 caps, 1% eye drop.

Mechanism of Action

It is a highly potent inhibitor of prostaglandin synthesis in peripheral tissues. Apart from its anti-inflammatory action.

Indication

• Rheumatoid arthritis not controlled by aspirin.
• Anti-inflammatory agent in musculoskeletal disorders like rheumatoid arthritis, ankylosing spondylitis and osteoarthritis and acute exacerbations of destructive arthropathies.
• Malignancy associated fever refractory to other antipyretics may respond to indomethacin.
• Acute gout.
• Used in medicinal closure of Patent Ductus Arteriosus.
• Route of administration: Oral, I.M., I.V., S.C.

Contraindications

• Patients hypersensitive to other NSAID's and asthmatics, in whom bronchospasm may be precipitated.
• Patients with acid peptic disease – either active disease or with previous history.
• Third trimester of pregnancy – may cause premature closure of PDA.
• Impaired renal function.
• Bleeding disorders and patients on anticoagulants.

Precautions / Practice points

• Avoid in children – risk of side effects such as hepatotoxicity are higher; if used, liver function tests must be monitored frequently.
• May cause fluid retention, hence, use with caution in congestive cardiac failure.
• Use with caution in elderly – a reduction of dose is advised.

Adverse Effects

• Common effects
  • Gastro intestinal disturbance – initially dyspepsia, nausea, etc. may progress to marked gastric irritation, bleeding and diarrhoea, ulcers, perforation of ulcers may occur.
• Rare effects
  • Headache, dizziness, vertigo, somnolence, depression, psychiatric disturbances.
  • Hypersensitivity reactions – bronchospasm, urticaria, skin eruptions, Steven Johnson’s syndrome.
  • Fluid retention and edema.
  • Ocular – retinal, macular and corneal deposits, with blurring of vision.
  • Thrombocytopenia.

Aryl-Acetic acid Derivatives

Generic Name: Diclofenac Sodium

Brand Name: Diclonac, Voveran, Movonac

Mechanism of action: It is a cyclo-oxygenase inhibitor. Its anti- inflammatory property is due to decreased prostaglandin synthesis in the tissues.

Indication

• Acute or short term analgesia
  • Post-operative analgesia.
  • Dental extraction.
  • Dysmenorrhoea, abdominal and renal colic.
• In localized soft-tissue inflammatory lesions following trauma to tendons, ligaments, muscles and joints, acute attacks of gout.
• Long term use in musculo skeletal disorders like rheumatoid arthritis, juvenile rheumatoid arthritis, osteo arthritis, ankylosing spondylitis.
• Route of Administration: Oral.

Precautions / Practice points

• Warn chronic users about symptoms of liver toxicity like nausea, fatigue, lethargy, pruritis, right hypochondrial pain, flu like symptoms.
• Use with caution in patients with compromised renal, hepatic or cardiac failure; renal failure can be precipitated due to reduction of renal blood flow.
• Monitor blood counts, hepatic and renal parameters periodically in patients on long term therapy.
• Administration Instructions: Take with food to reduce GI effects.

Adverse Effects

• Common effects
  • Epigastric pain, bleeding from ulcers and perforation. Old debilitated patients, smokers, alcoholic patients are especially at risk for GI side effects.
• Rare effects
  • Hepatic enzymes like SGOT, SGPT may be elevated, especially in chronic users, rarely acute fulminant hepatitis can occur. Therefore, periodic monitoring of liver function tests to be done in chronic users.
  • Fluid retention and edema.
  • Precipitation of asthmatic attacks in susceptible individuals.
  • Rashes, pruritis, bullous dermatitis and erythema multiforme.

Propionic acid and Anthranilic acid derivates

Propionic acid derivatives

Generic Name: Ibuprofen

Brand Name: Brufen, Emflam, Ibusynth 200,400,600 mg tab; Ibugesic also 100 mg/5ml.

Mode of Action: It is a reversible inhibitor of the cyclo-oxygenase enzyme. Thus, it inhibits the synthesis of prostaglandins and not that of leukotrienes.

Ibuprofen inhibits both COX-1 and COX-2. It appears that its analgesic, antipyretis and anti-inflammatory activity are achieved principally through COX-2 inhibition; whereas COX-1 inhibition is responsible for its unwanted effects on platelet aggregation and the GI mucosa.

Indication

• Short term analgesia in minor aches and pain due to colds, flu, sore throat, headache, dental pain, dysmenorrhoea etc.
• For relief of pain and inflammation, osteo arthritis and other chronic inflammatory disorders.
• Routes of Administration: Oral, Parenteral (I.M.). Never I.V.

Contraindication

• Contraindicated in pregnancy and children less than 6 months.
• Do not administer in case of active gastro-duodenal ulcer disease or liver failure.
• Individuals in whom angioedenia and bronchospasm have been precipitated by NSAIDS like aspirin.

Adverse effects

• Ibuprofen and all its congeners are well tolerated.
• Side effects are normal and milder.
• Gastric discomfort, nausea and vomiting, though less than aspirin but are still the common side effect.
• CNS side effects include headache, dizziness, blurring of vision and depression.
• Rashes, itching other type hypersensitivity phenomenon are infrequent.
• As with other NSAIDs, ibuprofen has been reported to be a photosensitizing agent.

Other Similar Drugs

Generic Name: Naproxen

Brand Name: Naprosyn, Naxid, Artagen, Xenobid 250 mg tab., Naprosyn 500mg tab.

Generic Name: Ketoprofen

Brand Name: Ketofen 50, 100 mg tab; Ostofen 50 mg cap. Rhofenid 100mg tab, 200 mg SR tab, 100mg/2ml amp.

Anthranilic Acid derivatives

Generic Name: Mefenemic Acid

Brand Name: Medol 250,500mg; Meftal, 250, 500 mg tab, 50mg/ml syp.

Mechanism of action

Mefenemic acid exerts peripheral as well as central analgesic action. It inhibits COX as well as antagonises certain action of PG's.

Indication

• For relief of mild to moderate pain in patients ≥14 years of age, when therapy will not exceed one week.
• For treatment of primary dysmenorrhea. The drug can also help reduce blood loss caused by meno/metrorrhagias and it can reduce pain caused by premenstrual syndrome.
• Its use for acute pain is well known. Pain after dental interventions or after traumas are significantly reduced with mefenamic acid.

Contraindication

• Inflammatory intestinal diseases.
• Active peptic ulcers.
• Hypersensitivity to aspirin (acetylsalicylic acid) or other non- steroidal anti-inflammatory agents.
• Renal failure.
• Since hepatic metabolism plays a significant role in mefenamic acid elimination, patients with known liver deficiency may be prescribed lower doses.

Adverse Effects

• Dependent on the dose and the duration of treatment, mefenamic acid frequently causes diarrhea.
• Long-term treatment can lead to enteritis or colitis (sometimes with steatorrhea). The drug can also cause nausea, vomiting and upper abdominal pain. Like other anti- inflammatory agents, it occasionally is the cause of peptic ulcers or even of bleeding or perforations.
• Mefenamic acid seems to cause hematologic problems. Heamolytic anaemia is a rare but serious complication.

Oxicam and Pyrrolo-pyrrole derivatives

Oxicam Derivatives

Generic Name: Pirioxicam

Brand Name: Dolonex, Pirox 10,20 mg cap, 20 mg dispersible tab, 20 m/ml inj in 1 and 2 ml amp, Piricam 10, 20 mg tab.

Mechanism of Action

• It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and inhibits platelet aggregation.
• It decreases the production of IgM, rheumatoid factor.

Indication

It is used as short term analgesia and a long term anti-inflammatory-- rheumatoid and osteo arthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, etc.

Adverse Effects

• Common side effects
  • Heart burn, anorexia and nausea.
• Rare side effects
  • Rashes and pruritis.

Pyrrolo-Pyrrole Derivative

Generic Name: Ketorolac

Brand Name: Ketorol, Zorovon, Ketanov, Torolac 10 mg tab, 30mg in 1ml amp.

Indication

• Ketorolac is indicated for short-term management of moderate to severe postoperative pain. Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use.
• Acute musculoskeletal pain.
• May also be used in treatment of renal colic, migraine and pain due to metastasis.

Contraindication

Ketorolac is contraindicated in patients with a previously demonstrated hypersensitivity to ketorolac and in patients with the complete or partial syndrome of nasal polyls, angioedema, bronchospastic reactivity or other allergic manifestations to aspirin.

Adverse Effects

Nausea, abdominal pain, dyspepsia, ulcerations, loose stools, headache, dizziness, nervousness, pruritis, pain at injection site. Rise in transaminase and fluid retention.

Preferential COX-2 inhibitors

• Nimesulide
• Meloxicam
• Nabumentone

Generic Name: Nimesulide

Brand Name: Nimulid, Nimgesic, Nimodol, Nise, Nimutab 100 mg tab, 50mg/5ml susp.

Mechanism of Action

Nimesulide, alongwith its preferential activity on COX-2 and a short half-life that correlates with a rapid onset of its analgesic action, acts also through a variety of COX independent pathways that contribute to its potent anti- inflammatory and analgesic activity.

Dosage: The recommended oral dose of Nimesulide for adults and adolescents above 12 years is 100 mg twice daily.

Indication

• Nimesulide is indicated for the treatment of acute pain, the symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea.
• Short lasting painful inflammatory conditions like sports injuries, sinusitis, ENT disorders, post dental surgeries and for fever.

Contraindication

• The drug is contraindicated in children below 12 years.

Adverse effects

• Gastrointestinal- Epigastralgia, heart burn, nausea, loose motion.
• Dermatological- Rashes, pruritis.
• Central- Somnolence, dizziness.
• Nimesulide, a widely used nonsteroidal anti-inflammatory drug containing a nitroaromatic moiety, has been associated with rare but serious hepatic adverse effects. The mechanisms underlying this idiosyncratic hepatotoxicity are unknown; however, both mitochondrial injury and oxidative stress have been implicated in contributing to liver.

Selective COX-2 Inhibitors

Generic name: Celecoxib

Brand Name: Celact, Colcibra 100, 200mg caps.

Mechanism of action

These are highly selective COX-2 inhibitors without affecting COX-1 function. Inhibition of COX-2 inhibits only prostaglandin synthesis without affecting thromboxane and thus has no effect on platelet aggregation or blood clotting.

Dosage: 100-200 mg BD.

Indication

• Its primary indication is in patients who need regular and long term pain relief. There is probably no advantage to using celecoxib for short term or acute pain relief over conventional NSAIDs.
• Celecoxib is licensed for osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms.
• To reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis.

Adverse effects

Allergy

• Celecoxib contains a sulfonamide moiety and may cause reactions in those allergic to other sulfonamide- containing drugs. This is in addition to the contraindication in patients with severe allergies to other NSAID's.

Gastrointestinal ADRs

• In theory the COX-2 selectivity should result in a significantly lower incidence of gastrointestinal ulceration than traditional NSAIDs.

Other Similar Drugs

Generic Name: Rofecoxib

Brand Name: Rofegesic, Rofibax, Roflam 12.5, 25 mg tabs.; Doloroff 12.5, 25, 50 mg tabs.

Indication

• Osteoarthritis, rheumatoid arthritis as well as dysmenorrhoea.
• Dental post operative and acute musculoskeletal pain.

Side effects

• Mild complaints of headache and dizziness may occur.
• Pedal edema and rise in BP may occur rarely.
• It should be avoided in the presence of hepatic/renal disease and in those receiving rifampicin, warfarin and methotrexate.

Generic Name: Valdecoxib

Brand Name: Vorth, Valus 10 mg tab

It is similar to rofecoxib.

Analgesics and Antipyretics with poor anti-inflammatory action

Paraaminophenol derivative

Generic Name: Paracetamol

Brand Name: Crocin 500mg, 1g; Metacin; Paracin 500mg tab, 125 mg/5 ml syrup, 150mg/ml pead. drops; Calpol 500mg tab; Neomol; Febrinil 300mg/2ml inj.

Mechanism of Action

It acts by inhibiting prostaglandin synthesis in the CNS (hence acting as antipyretic and analgesic). It has weak anti-inflammatory activity in the peripheral tissues and does not inhibit platelet aggregation.

Indication

• Pain relief
  • Minor aches and pains, associated with colds and other infections.
  • Postpartum pain.
  • Headache.
  • Dental pain.
  • Myalgia.
  • Dysmenorrhoea.
• Pyrexia
  • For reducing fever of any cause – infective or any other. 

Contraindication

• Patients who are hypersensitive to paracetamol.

Adverse Effects

• Use with great caution in patients with hepatic dysfunction and in alcoholics. It is preferable to aspirin in the following patient groups:
• Patients with acid peptic disease.
• Patients with bleeding disorders and haemophiliacs.
• Children with viral infections.
• Patients in whom bronchospasm is precipitated by aspirin.
• Infants less than 6 months of age.
• Safe in pregnancy and lactation.
• Administration instructions:
  • Administration with food.
  • Do not give intravenously.
  • Instruct patients not to drink alcohol.

Acute Paracetamol Poisoning

If a large dose is taken >10g in an adult, toxicity occurs.

Early manifestation are nausea, vomiting, abdominal pain and liver tenderness with no impairment of consciousness.

After 12 - 18 hrs centrilobular hepatic necrosis occurs.

Jaundice starts after 2 days. Fulminating hepatic failure and death can occur.

Treatment: Involves gastric lavage, activated charcoal should be given orally to prevent further absorption.

Antidote:N-acetylcysteine should be infused via I.V. or given orally. Initial bolus dose of 150 mg/kg in 5% dextrose given over 15-60 min. Maintenance dose is 50 mg/kg every 4 hours. It replenishes the glutathione stores of liver and prevents binding of toxic metabolite to other cellular constituents.