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2.1
ACETAMINOPHEN

Acetaminophen
or in its synthesis name known as 4′-hydroxyacetanilide is described as pure
white crystal and has a molecular weight of 151.06 g/mol. It is commonly used
both as an antipyretic and analgesic. Acetaminophen, also known as
N-acetyl-p-aminophenol or paracetamol, is widely used in both adult and
paediatric practice. It is the most frequently prescribed drug in treating
mild-to-moderate pain and fever. It can be administered by different routes;
through oral, rectal or intravenous. Despite its analgesic and antipyretic
activity, it has only very modest peripheral anti-inflammatory properties. (Pacifici & Allegaert, 2015). Although the
mechanism of action of acetaminophen is still unclear, it has been used
clinically for over a century and remains one of the most widely used drugs.

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Antipyretics
agents promotes the return of thermostatic set-point of hypothalamus to normal
by inhibiting conversion of arachidonic acid to prostaglandin-E2.
Meanwhile, physical antipyresis is mainly based on external cooling methods,
where it accelerates heat loss through the skin by conduction, convection, or
evaporation. External cooling should be used only after antipyretic drugs have
started to lower the elevated thermostatic set-point because physical
antipyresis can results in increased heat production, metabolic rate and oxygen
consumption. For this reason, antipyretic drug administration has been
recommended as the first-line treatment, with addition of external cooling in
cases of refractory fever or when rapid temperature decrease is considered
necessary. However, neither conventional external cooling techniques, nor the
combined use of pharmaceutical and physical antipyresis compared to antipyretic
drugs alone, have been confirmed to be more effective in lowering temperature (Kiekkas et al., 2013).

Paracetamol
is often included with non-steroidal anti-inflammatory drugs (NSAIDs) in
classifications of analgesics, despite having differences in both action and
side-effect profile. Even though the mechanism of action of acetaminophen is
still investigated, it has been proposed that paracetamol exerted its analgesic
action by inhibition of centrally situated isoforms of the cyclo-oxygenase
enzyme (COX). For oral route of administration, acetaminophen is well absorbed
from the gastrointestinal tract in human, with oral bio-availability estimated
at 63-89% compared with the intravenous form. The formulation of the dose (i.e.
soluble or plain) has little effect on speed of absorption, which suggests that
acetaminophen is absorbed beyond the stomach, and that gastric emptying occurs
before significant absorption takes place. Addition to that, ingestion of food
along with paracetamol does not seem to affect its absorption.

 

 

Meanwhile,
the rectal route of administration of paracetamol is erratic and unpredictable
compared with the oral, where the values of rectal bio-availability range from
24-98%. Several properties of suppositories such as the variation of physical
makeup between manufacturers, and the ‘lag time’ between the insertion of
suppository and its absorption, complicate the predictability of the rectal
dosing. Besides that, the use of more than one suppository can also lead to unpredictable
absorption.

For
intravenous route, acetaminophen is not particularly soluble and cannot be
given intravenously. A prodrug is available called ‘propacetamol’, which is
N-acetylparaminophenol diethyl aminoacetic ester of paracetamol but it is not
currently available outside continental Europe.

Acetaminophen
has a plasma half-life of around two hours. The metabolism of the drug is
primarily in the liver, via conjugation with glucuronic (60%) and sulphuric
(35%) acids, or cysteine (3%). After 24 hours, 90-100% of the drug is
recoverable in the urine as conjugates (Ward & I, 1999).

Unintentional
overdose of acetaminophen can lead to hepatoxicity and acute liver failure.
During the first 24 hours; nausea, vomiting, anorexia, diarrhoea, and abdominal
pain can occur. Clinical evidence of hepatic damage may take 2-6 days to
appear. It is likely that the liver damage can be prevented only in the first
24 hours even though most patients appear well in the first 3 days of
ingestions. The hepatotoxic single dose of acetaminophen in healthy adults is
between 23 to 30 regular-strength (325 mg) doses; while for children, it is 150
mg/kg (Aminoshariae & Khan, 2015).

A
study has reported that acetaminophen have some potential in body temperature
in patients admitted with acute stroke. It is found in the first 24 hours,
acetaminophen had substantially favourable influence on body temperature
reduction in patients with acute stroke (Fang et al., 2017). Recent studies
had also suggested that acetaminophen has an underappreciate antioxidant
properties and at low doses, it can protect the brain from
oxidative-stress-induced toxicity C8H9NO2 and
neurodegeneration, while higher doses does have toxic effects in the brain (Temoçin et al., 2017). 

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