INTRODUCTION ABOUT ASPIRIN

Aspirin (USAN), also known as acetylsalicylic acid , is a salicylate drug, often

used as an analgesic to relieve minor aches and pains, as an antipyretic to
reduce fever, and as an anti-inflammatory medication.
Salicylic acid, the main metabolite of aspirin, is an integral part of human and
animal metabolism. While much of it is attributable to diet, a substantial part is
synthesized endogenously.
Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane,
which under normal circumstances binds platelet molecules together to create a
patch over damaged walls of blood vessels. Because the platelet patch can become
too large and also block blood flow, locally and downstream, aspirin is also used
long-term, at low doses, to help prevent heart attacks, strokes, and blood
clot formation in people at high risk of developing blood clots. It has also been
established that low doses of aspirin may be given immediately after a heart attack
to reduce the risk of another heart attack or of the death of cardiac tissue.
The

main undesirable

side

effects of

aspirin

taken

by

mouth

are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher

doses. In children and adolescents, aspirin is no longer indicated to control flu-like
symptoms or the symptoms of chickenpox or other viral illnesses, because of the
risk of Reye's syndrome.

Aspirin is part of a group of medication called nonsteroidal anti-inflammatory

drugs (NSAIDs), but differs from them in the mechanism of action. Though it, and
others in its group called the salicylates, have similar effects (antipyretic, antiinflammatory,

analgesic)

to

other

NSAIDs

and

inhibit

the

same

enzyme cyclooxygenase, they do so in an irreversible manner and unlike others

affect more the COX-1 variant than the COX-2 variant of the enzyme. For
example, NSAIDs' antiplatelet effects normally last in the order of hours, whereas
aspirin's effects last for days (until the body replaces the suppressed platelets).
Hence, when physicians tell patients to stop taking NSAIDs, they usually imply
aspirin as well.
Today, aspirin is one of the most widely used medications in the world, with an
estimated

40,000tonnes of

it

being

consumed

each

year. In

countries

where Aspirin is a registered trademarkowned by Bayer, the generic term

is acetylsalicylic acid (ASA).

ADVANTAGES OF ASPIRIN
Medical uses
Aspirin is used for the treatment of a number of conditions including: fever,
pain, rheumatic

fever,

inflammatory

diseases

such

as rheumatoid

arthritis, pericarditis, and Kawasaki disease. It is used in the prevention of transient

ischemic attacks, strokes, heart attacks, pregnancy loss, and cancer.
Pain
In general, aspirin works well for dull, throbbing pain; it is ineffective for pain
caused by most muscle cramps, bloating, gastric distension, and acute skin
irritation. The most studied example is pain after surgery, such as tooth extraction,
for which the highest allowed dose of aspirin (1 g) is equivalent to 1 g of
paracetamol, 60 mg of codeine, or 5 mg of oxycodone. A combination of aspirin
and caffeine, in general, affords greater pain relief than aspirin alone. Effervescent
aspirin alleviates pain much faster than aspirin in tablets (1530 min vs. 4560
min).
Nevertheless, as a postsurgery painkiller, aspirin is inferior to ibuprofen and has
higher gastrointestinal toxicity. The maximum dose of aspirin (1 g) provides
weaker pain relief than an intermediate dose of ibuprofen (400 mg), and this relief
does not last as long. A combination of aspirin and codeine may have a slightly
higher analgesic effect than aspirin alone; however, this difference is not clinically
meaningful. It appears ibuprofen is at least equally, and possibly more, effective
than this combination. According to a 1998 meta-analysis of clinical trials

for menstrual pain, aspirin demonstrated higher efficacy than placebo, but lower
than ibuprofen or naproxen, although maximum doses of aspirin were never used
in these trials. The authors concluded ibuprofen has the best risk-benefit ratio.
Aspirin did not ease pain during cycling exercise, while caffeine, surprisingly, was
very effective. Similarly, aspirin, codeine or paracetamol were not better than
placebo for muscle soreness after exercise.
Headache
Aspirin is a first-line drug in the treatment of migraine, bringing relief in 5060%
of the cases. When used at a high dose of 1000 mg (as compared to 275325 mg
when used as a pain killer or 81 mg as a antiplatelet therapy), no significant
differences were seen as compared totriptan medication, sumatriptan (Imitrex)] and
other

painkillers

such

as paracetamol(acetaminophen)

or ibuprofen.

The

combination of aspirin, paracetamol (acetaminophen) and caffeine (as found in the

OTC brand Excedrin) is even more potent. For the treatment of migraine headache,
this formulation works better than any of its three components taken separately,
[21]

better than ibuprofen and better than sumatriptan. Similarly to all other

medications for migraine, it is recommended to take aspirin at the first signs of the
headache, and it is the way these medications were used in the comparative clinical
trials.
Aspirin alleviates pain in 6075% of patients with episodic tension headaches. It is
equivalent to paracetamol (acetaminophen) in that respect, except for the higher
frequency

of

gastrointestinal

side

effects. Comparative

clinical

trials

indicated metamizole and ibuprofen may relieve pain faster than aspirin, although
the difference becomes insignificant after about two hours. The addition of caffeine
in a dose of 60130 mg to aspirin increases the analgesic effect in headache. The
combination of aspirin, paracetamol (acetaminophen) and caffeine is still more
effective, but at the cost of more stomach discomfort, nervousness and dizziness.
There is some evidence low-dose asprin has benefit for reducing the occurrence of
migraines in susceptible individuals.
Prevention of heart attacks and strokes
There are two distinct uses of aspirin for prophylaxis of cardiovascular events:
primary prevention and secondary prevention. Primary prevention is about
decreasing strokes and heart attacks in the general population of those who have no
diagnosed heart or vascular problems. Secondary prevention concerns patients with
known cardiovascular disease.
Low doses of aspirin are recommended for the secondary prevention of strokes
and heart attacks. For both males and females diagnosed with cardiovascular
disease, aspirin reduces the chance of a heart attack and ischaemic stroke by about
a fifth. This translates to an absolute rate reduction from 8.2% to 6.7% of such
events per year for people already with cardiovascular disease. Although aspirin
also raises the risk of hemorrhagic stroke and other major bleeds by about twofold,
these events are rare, and the balance of aspirin's effects is positive. Thus, in
secondary prevention trials, aspirin reduced the overall mortality by about a tenth.

For persons without cardiovascular problems, the benefits of aspirin are unclear. In
the primary prevention trials, aspirin decreased the overall incidence of heart
attacks and ischaemic strokes by about a tenth. However, since these events were
rare, the absolute reduction of their rate was low: from 0.57% to 0.51% per year. In
addition, the risks of hemorrhagic strokes and gastrointestinal bleeding almost
completely offset the benefits of aspirin. Thus, in the primary prevention trials,
aspirin did not change the overall mortality rate. Further trials are in progress.[33]
The expert bodies diverge in their opinions regarding the use of aspirin for primary
prevention, such as can be accomplished by including aspirin in a polypill for the
general population. The US Government Preventive Services Task Force
recommended making individual, case by case choices based on the estimated
future risk and patients' preferences. On the other hand, Antithrombotic Trialists
Collaboration argued such recommendations are unjustified, since the relative
reduction of risk in the primary prevention trials of aspirin was same for persons in
high- and low-risk groups and did not depend on the blood pressure. The
Collaboration suggested statins as the alternative and more effective preventive
medication.
Coronary and carotid arteries, bypasses and stents
The coronary arteries supply blood to the heart. Aspirin is recommended for one to
six months after placement of stents in the coronary arteries and for years after
a coronary artery bypass graft.

The carotid arteries supply blood to the brain. Patients with mild carotid artery
stenosis benefit from aspirin; it is recommended after a carotid endarterectomy or
carotid artery stent.
After vascular surgery of the lower legs using artificial grafts that are sutured to the
arteries to improve blood supply, aspirin is used to keep the grafts open.
Other uses
Although aspirin has been used to combat fever and pains associated with common
cold for more than 100 years, its efficacy in this role was only recently confirmed
in controlled clinical trials on adults. One gram of aspirin, on average, reduced the
oral body temperature from 39.0 C(102.2 F) to 37.6 C (99.7 F) after three
hours. The relief began after 30 minutes, and after six hours, the temperature still
remained below37.8 C (100.0 F). Aspirin also helped with "achiness", discomfort
and headache, and with sore throat pain, for those who had it. The effects of aspirin
were indistinguishable from those obtained using paracetamol in any respect,
except for, possibly, a slightly higher incidence of sweating and gastrointestinal
side effects.
Fever and joint pain of acute rheumatic fever respond extremely well, often within
three days, to high doses of aspirin. The therapy usually lasts for one to two weeks;
and only in about 5% of the cases it has to continue for longer than six months.
After fever and pain have subsided, the aspirin treatment is unnecessary, as it does
not decrease the incidence of heart complications and residual rheumatic heart
disease. In addition, the high doses of aspirin used caused liver toxicity in about

20% of the treated children, who are the majority of rheumatic fever patients, and
increased the risk of their developing Reye's syndrome. Naproxen was shown to
be as effective as aspirin and less toxic; due to the limited clinical experience,
however, naproxen is recommended only as a second-line treatment.
Along with rheumatic fever, Kawasaki disease remains one of the few indications
for aspirin use in children, although even this use has been questioned by some
authors. In the United Kingdom, the only indications for aspirin use in children and
adolescents under 16 are Kawasaki disease and prevention of blood clot formation.
Aspirin is also used in the treatment of pericarditis, coronary artery disease, and
acute myocardial infarction.
Taking aspirin before air travel in cramped conditions has been suggested to
decrease the risk of deep-vein thrombosis (DVT). The reason for taking aspirin is
the long period of sitting without exercise, not air travel itself. A large, randomized,
controlled trial in 2000 of aspirin against placebo in 13,000 patients with hip
fractures found "a 29% relative risk reduction in DVT with 160 mg of aspirin taken
daily for five weeks. Although there are obvious problems with extrapolating the
data to long-distance travelers, this is the best evidence we could find to justify
aspirin use".

DISADVANTAGES OF ASPIRIN

Resistance
For some people, aspirin does not have as strong an effect on platelets as for
others, an effect known as aspirin resistance or insensitivity. One study has
suggested women are more likely to be resistant than men, and a different,
aggregate study of 2,930 patients found 28% to be resistant. A study in 100 Italian
patients found that of the apparent 31% aspirin-resistant subjects, only 5% were
truly resistant, and the others were noncompliant.

Contraindications
Aspirin

should

not

to ibuprofen or naproxen, or

be

taken
who

by

people

have salicylate

who

are

intolerance or

allergic
a

more

generalized drug intolerance to NSAIDs, and caution should be exercised in those

with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the
stomach

lining,

manufacturers

recommend

people

with peptic

ulcers,

mild diabetes, or gastritis seek medical advice before using aspirin. Even if none of
these conditions is present, there is still an increased risk of stomach
bleeding when aspirin is taken withalcohol or warfarin. Patients with hemophilia or
other bleeding tendencies should not take aspirin or other salicylates. Aspirin is
known to cause hemolytic anemia in people who have the genetic disease glucose6-phosphate dehydrogenase deficiency (G6PD), particularly in large doses and

depending on the severity of the disease. Use of aspirin during dengue fever is not
recommended owing to increased bleeding tendency. People with kidney
disease, hyperuricemia, or gout should not take aspirin because it inhibits the
kidneys' ability to excrete uric acid, and thus may exacerbate these conditions.
Aspirin should not be given to children or adolescents to control cold or influenza
symptoms, as this has been linked with Reye's syndrome.
Gastrointestinal
Aspirin

use

has

been

shown

to

increase

the

risk

of gastrointestinal

bleeding. Although some enteric coated formulations of aspirin are advertised as

being "gentle to the stomach", in one study enteric coating did not seem to reduce
this risk. Combining aspirin with other NSAIDs has also been shown to further
increase this risk. Using aspirin in combination with clopidogrel or warfarin also
increases the risk of upper gastrointestinal bleeding.
In addition to enteric coating, "buffering" is the other main method companies
have used to try to mitigate the problem of gastrointestinal bleeding. Buffering
agents are intended to work by preventing the aspirin from concentrating in the
walls of the stomach, although the benefits of buffered aspirin are disputed. Almost
any buffering agent used in antacids can be used; Bufferin, for example, uses MgO.
Other preparations use CaCO3.
Taking it with vitamin C is a more recently investigated method of protecting the
stomach lining. According to research done at a German university, taking equal

doses of vitamin C and aspirin decreases the amount of stomach damage that
occurs compared to taking aspirin alone.
Deglycyrrhizinated licorice (DGL), an extract of the popular herb licorice,
reportedly helps relieve the symptoms of gastritis. In a 1979 research study, a dose
of 350 milligrams of DGL was shown to decrease the amount of gastrointestinal
bleeding induced by three adult-strength aspirin tablets (750 milligrams).
A dose of 500 milligrams of S-adenosyl-methionine (SAMe, an amino acid
naturally formed in the body) given together with a large dose of aspirin (1300
milligrams) in a research study reduced the amount of stomach damage by 90
percent.
A study found that, in contrast to oral aspirin, intravenous injection of aspirin did
not produce detectable histological damage or significantly alter gastric mucosal
potential difference, and concluded that high blood levels of circulating salicylate
did not acutely damage gastric mucosa, so that gastric mucosal damage produced
acutely after single oral doses of aspirin are due to its topical, rather than systemic,
action.

Central effects
Large doses of salicylate, a metabolite of aspirin, have been proposed to
cause tinnitus (ringing in the ears) based on experiments in rats, via the action
on arachidonic acid and NMDA receptors cascade.[91]

Hives and swelling

For a small number of people, taking aspirin can result in symptoms that resemble
an allergic reaction, including hives, swelling and headache. The reaction is caused
by salicylate intolerance and is not a true allergy, but rather an inability to
metabolize even small amounts of aspirin, resulting in an overdose.
Other effects
Aspirin can induce angioedema (swelling of skin tissues) in some people. In one
study, angioedema appeared one to six hours after ingesting aspirin in some of the
patients participating in the study. However, when the aspirin was taken alone, it
did not cause angioedema in these patients; the aspirin had been taken in
combination with another NSAID-induced drug when angioedema appeared.[94]
Aspirin causes an increased risk of cerebral microbleeds having the appearance
on MRI scans of 510 mm or smaller hypointense (dark holes) patches. [95][96] Such
cerebral microbleeds are important since they often occur prior to ischemic
stroke or intracerebral hemorrhage,Binswanger disease and Alzheimer's disease.
Aspirin and other NSAIDs can cause hyperkalemia by inducing a hyporenin
hypoaldosteronic state via inhibition of prostaglandin synthesis; however, these
agents do not typically cause hyperkalemia by themselves in the setting of normal
renal function and euvolemic state.
Aspirin can cause prolonged bleeding after operations for up to 10 days. In one
study, 30 of 6499 elective surgical patients required reoperations to control
bleeding. Twenty had diffuse bleeding and 10 had bleeding from a site. Diffuse,

but not discrete, bleeding was associated with the preoperative use of aspirin alone
or in combination with other NSAIDS in 19 of the 20 diffuse bleeding patients.
Overdose
Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is
taken; in chronic poisoning, higher than normal doses are taken over a period of
time. Acute overdose has a mortality rate of 2%. Chronic overdose is more
commonly lethal, with a mortality rate of 25%; chronic overdose may be especially
severe in children. Toxicity is managed with a number of potential treatments,
including activated charcoal, intravenous dextrose and normal saline, sodium
bicarbonate,

and

dialysis. The

diagnosis

of

poisoning

usually

involves

measurement of plasma salicylate, the active metabolite of aspirin, by automated

spectrophotometric methods. Plasma salicylate levels generally range from 30
100 mg/L after usual therapeutic doses, 50300 mg/L in patients taking high doses
and 7001400 mg/L following acute overdose. Salicylate is also produced as a
result of exposure to bismuth subsalicylate, methyl salicylate andsodium salicylate.
Interactions
Aspirin

is

known

to interact with

other

drugs.

For

example, acetazolamide and ammonium chloride have been known to enhance the
intoxicating effect of salicyclates, and alcohol also increases the gastrointestinal
bleeding associated with these types of drugs. Aspirin is known to displace a
number of drugs from protein binding sites in the blood, including the antidiabetic
drugs tolbutamide andchlorpropamide,

the immunosuppressant methotrexate, phenytoin, probenecid, valproic

acid (as

well as interfering with beta oxidation, an important part of valproate metabolism)

and any nonsteroidal anti-inflammatory drug. Corticosteroids may also reduce the
concentration of aspirin. Ibuprofen can negate the antiplatelet effect of aspirin used
for cardioprotection and stroke prevention. The pharmacological activity
of spironolactone may be reduced by taking aspirin, and aspirin is known to
compete with Penicillin G for renal tubular secretion. Aspirin may also inhibit the
absorption of vitamin C.

SYNTHESIS
The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is
treated with acetic anhydride, an acid derivative, causing achemical reaction that
turns salicylic acid's hydroxyl group into an ester group (R-OH R-OCOCH3).
This process yields aspirin and acetic acid, which is considered a byproduct of this
reaction. Small amounts of sulfuric acid (and occasionally phosphoric acid) are
almost always used as a catalyst. This method is commonly employed in
undergraduate teaching labs.

Reaction Mechanism

Formulations containing high concentrations of aspirin often smell

like vinegar because aspirin can decompose through hydrolysis in moist
conditions, yielding salicylic acid and acetic acid. The acid dissociation
constant (pKa) for acetylsalicylic acid is 3.5 at 25 C (77 F).