Dr.R.Murali and Dr.

Sweta Krishnan:
Paracetamol : Health
I have always entertained mixed feelings about over-the-counter drugs. Even about
the simpler ones like Paracetamol or Acetaminophen- more commonly known by
brand names, like Calpol, Fepanil or Crocin. On the positive side, I have always
imagined that a patient would be thankful to these over-the-counter drugs and be
happy to skip hours of waiting in a crowded hall to see a physician for an ailment
like a viral fever, for which he already knows the drug. On the flip side, I have
wondered what happens if he or she goes wrong about the dosage.
I have noticed from the queries that come pouring in from the neighbours, friends
and acquaintances that though the very interesting pharmacodynamics of this
much used drug remains a mystery to them, they have figured out its uses in fever
and body pain. And especially the absence of an upper quadrant pain that might
follow the ingestion of a pain killer like Aspirin. What people do not know is that
aspirin and paracetamol though not very different in their modes of action (both
causing inhibition of prostaglandin synthesis), act at different sites and probably
through the inhibition of different pathways of prostaglandin secretion.
But before I go into the details, there is probably a necessity at this juncture to
explain this very interesting chemical that the body produces called prostaglandin.
First isolated from the seminal fluids, it derives its name from the prostate gland in
the body. But now it is known that every nucleated cell in the body, with the
exception of lymphocytes can synthesise these chemicals. They can be classified
into many types depending on their chemical structure and action, but are all
basically derivatives of the fatty acid, Arachidonic acid.
They act as local chemical messengers in the body, having a role in the process of
inflammation and therefore being responsible for the production of fever and pain.
But apart from this it is also known that prostaglandins play a role in the process of
blood coagulation, the induction of labour and the very essential process of
regulating the levels of acid in the secretions of the stomach. Experiments show
that prostaglandins increase the secretion of the protective mucus coating in the
stomach, keeping it safe from the hydrochloric acid that is produced in it to aid
digestion.
So one can imagine what side effects a prostaglandin inhibitor can cause. But here
again, I must introduce an enzyme to the reader cyclooxygenase (COX), which
plays a vital role in the conversion of Arachidonic acid into Prostaglandins. But there
are two isoforms of this enzyme COX 1 and COX 2. COX1 it had been discovered is
responsible for maintaining the basic levels of prostaglandins in the body or in
other words, the amount necessary to carry out the normal physiological function
dependent on prostaglandins. But COX 2 on the other hand is stimulated in
inflammatory processes and is chiefly responsible for producing pain and fever.

Aspirin and the family of Non steroidal anti inflammatory drugs (NSAIDS) act as
active inhibitors of COX. Though the more recent drugs in the family are selective
COX 2 inhibitors, the earlier drugs like aspirin and ibuprofen (Brufen) act on both
COX 1 and COX 2, resulting in side effects like dyspepsia, heartburn and stomach
pain. Paracetamol on the other hand causes none of these side effects. Though the
exact mechanism of action of paracetamol is still under research, it is thought to act
by inhibiting central production of prostaglandins (in the brain). Because of this
unique property paracetamol retains its functions as an antipyretic and analgesic,
without being corrosive on the gastric mucosa or interfering with the blood clotting
mechanism of the body.
This renders the drug safer than most other analgesics and antipyretics, but a study
of drug misuse and overdose in the UK and the USA show that paracetamol
ingestion is among the leading causes of drug induced poisoning. A study by the
BMJ (British Medical Journal) shows that not only is acetaminophen poisoning the
cause for up to 70000 of the reported cases, and the commonest drug employed in
intentional self harm, but also its overdose is the leading cause of acute liver failure.
The study also shows that this is due to its availability over the counter and in
combination with other drugs in order to increase its effect.
This brings me to a case that I saw as an intern. One night while on call in the
orthopaedics ward, we received a strange phone call from the nurse on duty in the
special wards. One of the patients, who had been admitted with a fracture of the
Radius, had ingested a whole strip of paracetamol. On our arrival at the scene, we
immediately gave her activated charcoal via a naso-gastric tube and had her shifted
to the poison care centre. The patient survived since we had intervened before any
symptoms set in. But when questioned about this irrational use of the drug, she said
that she had not known that the fever tablet could do any harm. She had fought
with her daughter, who was staying with her at the hospital and to threaten her, she
had ingested a whole strip.
Ever since I have been thinking about the number of accidental poisonings that
must be occurring in any country, due to the patients ignorance of the
pharmacokinetics of the drug or in other words, what the body does to the drug.
Paracetamol is absorbed from the stomach and small intestine and reaches its peak
concentration in the blood about an hour after ingestion. It is inactivated in the liver
through two pathways. The first pathway leads to the inactivation of the active
metabolites of the drug by its conjugation in the liver to form two harmless
products. When this pathway is saturated, an alternate pathway swings into use and
paracetamol is metabolised to a toxic product called N-acetyl-p-benzoquinoneimine. Under normal circumstances this is immediately inactivated by glutathione in
the liver. The end products are excreted in the urine.
What the patient must also know here is that the maximum levels of paracetamol
tolerance are 150mg/kg body weight and a normal adult can withstand only up to a

maximum of 2.5 to 4 grams of paracetamol in a day. In alcoholics the levels are still
lower (75 mg/kg body weight). Also one concept that patients must understand is
the frequency with which the drug can be taken. This is dependent on the half-life of
a drug the period of time when it is active (between ingestion and deactivation in
the liver). Paracetamol is usually given three to four times a day depending on its
effect on the fever.
In cases of drug overdose, the metabolism in the liver is challenged by the
inundation of the pathways by the excess amounts of acetaminophen. The first
pathway -the preferred one-gets saturated first and most of the drug is channelled
to the second pathway. This pathway one must recall is responsible for the
production of a toxic metabolite which is dependent on liver glutathione for
deactivation. When the liver runs out of glutathione, symptoms of paracetamol
poisoning set in.
A patient with otherwise normal liver functions can remain asymptomatic for up to
24 hours. After this signs of hepatic cell necrosis begins to set in as the excess toxic
metabolite begins to damage the liver cells. Untreated, this leads to hypoglycaemia,
encephalopathy (compromised brain activity), oliguria (reduced output of urine) and
slowly to renal failure as well. Luckily, all this can be reversed by treating the
patient with N-acetyl cystine within 8 hours of ingestion of toxic doses of
paracetamol. This drug acts as a precursor for glutathione and so effectively
deactivates the toxic metabolite causing the damage in the liver.
Still it has been noticed that 150-200 deaths and about 15-20 liver transplants
every year in the UK are due to cases of paracetamol overdose. While, the incidence
in India is still very low, I was actually tempted to write this article after reading one
possible reason for the high incidence of poisoning in the UK and the USA. Most
patients who are admitted for overdose claim to know what the drug could do. They
only did not know how much can be taken and how frequently it can be
administered.
Since India is fast becoming aware of the simple uses of this over-the-counter drug,
I think it is necessary for the patient to be aware of the ways in which this drug acts
on the body as an analgesic and antipyretic and also understand what overdose
can do, before self medicating oneself. In doses less than 150mg/kg body weight
this is a safe and effective drug and perhaps the safest too among the over-the
counter medications, but one must remember that accidental poisoning can be very
dangerous. Hope this awareness will lead to more judicious usage of this drug.