NSAIDs

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-Common properties/use
The ability to decrease inflammation
The 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)
Aspirin
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 is a weak organic acid

Acetyl group that is

transferred to
cyclooxygenase

Aspirin (acetylsalicylic 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 CO2H
O OH O Ser
HO Ser Acetylation +
O
O

Aspirin Enzyme Salicylic acid 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 action
Because 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 action
Peripheral 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 action
Prostaglandin 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 effect
Normally, 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 platelet
Thromboxane 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 vomiting
Prolonged bleeding time
Reversible renal insufficiency: Seen mainly in individuals with
compromised renal function when the compensatory prostaglandin E2-
(PGE2) mediated vasodilatation is inhibited.
Reye's syndrome
Aspirin 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.
Misoprostol
Misoprostol 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.
Dosage
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.
COX-2 Selective Inhibitors
Anti-inflammatory with less adverse effects, especially GI
events.
Increased risk of thrombotic events (Cardiovascular
disorder).
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
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.
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.
How acute overdose (10 gm-20 tablets in single dose) cause
hepatotoxicity:

Paracetamol

One of the metabolite

N-acetyl-p-benzo-quinone imine (toxic)

Conjugate with glutathione

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.