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Aspirin
Aspirin
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
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
HO
Ser
Acetylation
CO2H
OH
O
Aspirin
Ser
O
Enzyme
Salicylic acid
Enzyme
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 antiinflammatory activity.
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 dont
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).
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 PGF2 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.
Two
prostanoids
homeostasis namely
regulates
cardiovascular
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.
(toxic)