Usually referred to as NSAIDs to distinguish them from

Corticosteroids (which treat inflammation)

The term NSAIDs does not fully describe the pharmacologic

actions of these agents (analgesic, antipyretic, and

anticoagulant)

NSAIDs

The ability to decrease inflammationThe ability to relieve mild to moderate pain (analgesia)The ability to to decrease elevated body temperature associated with fever (antipyresis)The ability to decrease blood clotting by inhibiting platelet aggregation (anticoagulation)

NSAIDs-Common properties/use

Aspirin (acetylsalicylic acid) is part of a group of drugs know as salicylates.

Other salicylates (sodium salicylate, choline salicylate, choline magnesium salicylate) have been used, but aspirin is the most frequently used.

Aspirin

Aspirin (acetylsalicylic acid)

Acetyl group that is transferred to

cyclooxygenase

Aspirin is a weak organic acid

Mechanism of action Aspirin covalently modifies both COX-1 and COX-2, thus resulting in an irreversible inhibition of cyclooxygenase activity.

In the structure of COX-1, aspirin acetylates serine 530, preventing the binding of arachidonic acid to the active site of the enzyme and thus the ability of the enzyme to make prostaglandins.

In COX-2, aspirin acetylates a homologous serine at position 516.

This makes aspirin different from other NSAIDs (such as salicylates, diclofenac and ibuprofen), which are reversible inhibitors.

CO2H

O

O

Aspirin

HO Ser

Enzyme

Acetylation

CO2H

OH

Salicylic acid

+O

O

Ser

Enzyme

Figure: Metabolism of aspirin and acetylation of cyclooxygenase by aspirin

Aspirin (acetylsalicylic acid) acetylates cyclooxygenases thereby irreversibly blocking the conversion of arachidonic acid to prostanoids.

Biotransformation of aspirin yields salicylate, a compound that possesses similar anti-inflammatory, antipyretic, and analgesic effects as aspirin but lacks aspirin's inhibitory effect on the activity of cyclooxygenase.

At present, there is no common agreement about the extent to which salicylate contributes to aspirin's activity, as well as there is still no final conclusion reached about the mechanisms of action of salicylates.

Several reports have also shown interference by salicylates with the expression of cyclooxygenase-2.

Anti-inflammatory actionBecause aspirin inhibits cyclooxygenase activity, it diminishes the formation of prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act as mediators.

It occurs mainly due to aspirin action on peripheral tissue.

Acetaminophen act by inhibiting prostaglandin synthesis in the CNS. This explains their antipyretic and analgesic properties. They have less effect on cyclooxygenase in peripheral tissues, which accounts for their weak anti-inflammatory activity.

Acetaminophen, although a useful analgesic and antipyretic, has weak anti-inflammatory activity and is therefore not useful in the treatment of inflammation such as that seen with rheumatic fever, rheumatoid arthritis and other inflammatory conditions.

Acetaminophen (Paracetamol)

Analgesic actionPeripheral action of aspirin:Prostaglandin E2 (PGE2) is thought to sensitize the nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs suppress the sensation of pain.

Pain-Prostaglandins help mediate painful stimuli, they don’t directly produce pain but increase the sensitivity of pain receptors to effects of other pain-producing substances (like bradykinin)

Central action of aspirin:Inhibits pain stimuli at a subcortical site (probably by inhibiting prostaglandin synthesis).

NSAIDs are superior to opioids in the management of pain in which inflammation is involved; combinations of opioids and NSAIDs are effective in treating pain in malignancy.

Not effective for severe visceral pain.

Antipyretic actionProstaglandin E2 (PGE2) is responsible for elevating hypothalamic set point of temperature. PGE2 synthesis, stimulated when an endogenous fever-producing agent (pyrogen) such as a cytokine is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation.

Aspirin inhibit the synthesis of PGE2 in the hypothalamus and thus temperature set point back to normal.

Aspirin rapidly decreases the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilatation and sweating. Aspirin has no effect on normal body temperature.

Gastrointestinal effectNormally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine.

In the presence of aspirin, these prostanoids are not formed, resulting in increased gastric acid secretion and diminished mucus protection. This may cause epigastric distress, ulceration, and/or hemorrhage.

Buffered and enteric-coated preparations are only marginally helpful in dealing with this problem. The PGE1 derivative, misoprostol, is used in the treatment of gastric damage induced by NSAIDs.

Effect on plateletThromboxane A2 (TXA2) enhances platelet aggregation, (the first step in thrombus formation).

Aspirin can irreversibly inhibit thromboxane production in platelets. Aspirin irreversibly inhibits platelet cyclooxygenase preventing the formation of prostaglandin H2, and therefore thromboxane A2.

Because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of thromboxane persists for the lifetime of the platelet (3 to 7 days).

As a result of the decrease in TXA2, platelet aggregation is reduced, producing an anticoagulant effect with a prolonged bleeding time.

Aspirin reaction● Not so common● Symptoms ranges to mild skin reactions to anaphylaxis, bronchospasm.● 8-19% asthmatics suffer from aspirin allergy and 30-40% patients with nasal polyps and sinusitis.● Reason behind it is not so clear. May be due to abnormal metabolism of arachidonic acid pathway with increased leukotrienes production.

Other side effects:GI ulceration, dyspepsia, nausea and vomitingProlonged bleeding timeReversible renal insufficiency: Seen mainly in individuals with compromised renal function when the compensatory prostaglandin E2-(PGE2) mediated vasodilatation is inhibited.

Reye's syndromeAspirin given during viral infections has been associated with an increased incidence of Reye's syndrome, an often fatal, fulminating hepatitis with cerebral edema.

This is especially encountered in children, who therefore should be given acetaminophen instead of aspirin when such medication is required.

MisoprostolMisoprostol is a synthetic prostaglandin E1 analog.

Inhibits secretion of HCI & pepsin and enhances mucosal resistance.

Routine prophylactic use of misoprostol may not be justified except in patients taking NSAIDs who are at high risk of NSAID-induced ulcers, such as the elderly or patients with ulcer complications.

Useful in patients with gastric ulcer who chronically take aspirin.

Like other prostaglandins, misoprostol produces uterine contractions and is contraindicated during pregnancy.

Two 325mg aspirin tablets administered 4 times (8 tablets) a day produce analgesia.

12 to 20 tablets (300mg) per day produce both analgesic and anti-inflammatory activity.

Low dosages of aspirin (160 mg every other day) have been shown to reduce the incidence of recurrent myocardial infarction and to reduce mortality in postmyocardial infarction patients.

Aspirin in a dose of 160 to 325 mg/day appears to be beneficial in the prevention of a first myocardial infarction.

Dosage

Anti-inflammatory with less adverse effects, especially GI events.Increased risk of thrombotic events (Cardiovascular disorder).

COX-2 Selective Inhibitors

Two prostanoids regulates cardiovascular

homeostasis namely

Thromboxane A2 (TXA2)

- Platelet aggregator

- Vasoconstrictor

- Synthesis catalyzed exclusively by COX1

Prostacycline I2 (PGI2)

- Produced in endothelium

- Inhibitor of platelet aggregator

- Vasodilator

- Catalyzed by COX-1 and during inflammation by COX-2

- COX-2 inhibitors could suppress PGI2 and thus increase the

amount of TXA2, which promotes thrombus formation.

COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active "housekeeping" COX-1 isoenzyme found in the gastrointestinal tract, kidneys, and platelets.

Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects similar to those of nonselective NSAIDs but with an approximate halving of gastrointestinal adverse effects. These selective agents also have no significant effects on platelets and renal failure.

COX-2 Selective Inhibitors

Selective inhibitors of COX-2 depress PGI2 formation by endothelial cells without concomitant inhibition of platelet thromboxane.

Experiments in mice suggest that PGI2 inhibition restrains the cardiovascular effects of TXA2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis.

Placebo-controlled trials have now revealed an increased incidence of myocardial infarction and stroke in patients treated with rofecoxib, valdecoxib, and celecoxib.

Meloxicam and Nimesulide are the first generation drugs of this type. It is 3 times more specific for Cox-2 than Cox-1.

The currently approved Cox-2 inhibitors Celecoxib and Rofecoxib are highly selective for Cox-2 in comparison with traditional NSAIDs (375-fold and 1000-fold respectively).

On September 30, 2004, Merck voluntarily withdrew rofecoxib (Vioxx) from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.

Paracetamol

N-acetyl-p-benzo-quinone imine

One of the metabolite

Conjugate with glutathione

(toxic)

Toxic metabolites are inactivated and excreted

But in acute overdose, glutathione depleted, toxic metabolite accumulated and react with nucleophilic constituents in cell and thus produce hepatotoxicity.

How acute overdose (10 gm-20 tablets in single dose) cause hepatotoxicity: