REVIEW PAPER

TITLE: ACITOAMINOPHEN (PANADOL)

By
SUMMAN KHAN
BS-Environmental Sciences-V

ENV 310 – Environmental Toxicology

DEPARTMENT OF EARTH & ENVIRONMENTAL SCIENCES
Fall’ 2020

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 TABLE OF CONTENTS
ABSTRACT 01
INTRODUCTION 1-2
ETIOLOGY
EPIDEMIOLOGY
ACETAMINOPHEN TOXICITY SYMPTOMS 3-4
PETHOPHYSIOLOGY:
a. PARACITAMOL TOXICITY
b. SYNONYMS:
c. PHYSICAL APPEARANCE

TOXICOKINETIC: 5

1. OVERDOSE:

MECHANISM OF PARACETAMOL TOXICITY 6-7

2. GASTROINTESTINAL (GI) EFFECTS:

CHRONIC TOXIC 7-8

3. Toxic dose:

DIAGNOSES

HEPATOTOXICITY RISK FACTOR

Acute Management 8-9

PREVENTION 9
CONCLUSION 10-11
REFERANCE 11

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Abstract
Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record
of use in acute and chronic pain. In recent years, the benefit of paracetamol use in chronic
conditions has been questioned, notably in the areas of osteoarthritis and lower back pain.
Over the same period, concerns over the long‐term adverse effects of paracetamol use have
increased, initially in the field of hypertension, but more recently in other areas as well. The
evidence base for the adverse effects of chronic paracetamol use consists of many cohort and
observational studies, with few randomized controlled trials, many of which contradict each
other, so these studies must be interpreted with caution. Nevertheless, there are some areas
where the evidence for harm is more robust, and if a clinician is starting paracetamol with the
expectation of chronic use it might be advisable to discuss these side effects with patients
beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg)
increase in systolic blood pressure are adverse effects for which the evidence is particularly
strong, and which show a degree of dose dependence. As our estimation of the benefits
decreases, an accurate assessment of the harms is ever more important. The present review
summarizes the current evidence on the harms associated with chronic paracetamol use,
focusing on cardiovascular disease, asthma and renal injury, and the effects of in exposure.

Keywords: Acetaminophen, adverse effect, acetaminophen toxicity; poisoning; chronic;

hepatotoxicity, kidney disease.

INTRODUCTION
The use of analgesics had been increased recently and many of us take it for minimum
symptoms. One of these analgesics is Panadol which have been like water for many people
without knowing its ingredients, action and side effects. Panadol is a brand name including
within other commercial terms around the whole world. And its follow the pharmaceuticals
group which called analgesics and antipyretics. The chemical formula for Panadol is C8H9NO2
and its made of white crystals, its melting point between 167-172 and it dissolves easily in
water , ethanol and acetone but difficult to dissolve in chloroform and ether . The scientific
term for Panadol is paracetamol which use as antipyretic and analgesic. Paracetamol classified
as a chemical drug works to relieve pain through its effect on chemicals material known as
prostaglandin which is a chemicals that released in response to pain, and paracetamol work to
prevent its secretion and reduce body temperature. Unfortunately the Panadol is sold without
prescription which led to its Random use. (Reddy 2013; Michaud et al. 2014).
Paracetamol (acetaminophen) was first synthesized in 1878 from its precursor phenacetin. Its
use was not widespread initially, due to early reports of a link to methaemoglobinaemia. After
this association was discredited, it was marketed in the 1950s as a safer alternative to
phenacetin, which by then had been found to be nephrotoxic and potentially carcinogenic. In
the early 1980s, paracetamol overtook aspirin as the most widely used over‐the‐counter (OTC)
analgesic in the UK. It is now the most commonly used analgesic in the world, and the first step

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of the World Health Organization (WHO) analgesic ladder for the treatment of cancer pain.
Paracetamol is currently marketed as an analgesic and antipyretic, to be used for no more than
3 days without consulting a doctor. However, due in part to its inclusion in the WHO analgesic
ladder, as well as decades of clinical experience, it is also prescribed in chronic conditions such
as osteoarthritis and lower back pain. Recently, meta‐analyses of the randomized controlled
trials (RCTs) covering these conditions have shown the effect sizes to be modest, although still
statistically significant, compared with placebo (averaging a 4–5% reduction in pain). (Schilling et
al. 2010)

ETIOLOGY:

Even though acetaminophen has a good safety profile at therapeutic levels, it can cause severe
liver toxicity if taken in large amounts. The recommended dose of acetaminophen for adults is
650 mg to 1000 mg every 4 to 6 hours, not to exceed 4 grams/day. In children, the dose is 15
mg/kg every 6 hours, up to 60 mg/kg/day. Toxicity develops at 7.5 g/day to 10 g/day or 140
mg/kg. (Blieden et al. 2014)

EPIDEMIOLOGY:
Acetaminophen toxicity is the second most common cause of liver transplantation worldwide
and the most common in the US. It is responsible for 56,000 emergency department visits, 2600
hospitalizations, and 500 deaths per year in the United States. Fifty percent of these are
unintentional overdoses. Although acetaminophen poisoning is more common in children,
adults often present with more serious and fatal presentation. (Blieden et al. 2014)

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 a. ACETAMINOPHEN TOXICITY SYMPTOMS

Initial symptoms of acetaminophen toxicity can take up to 12 hours to appear. Symptoms and
side effects include: Abdominal pain , Irritability, Generalized weakness, Loss of appetite,
Jaundice (yellow appearance of skin and eyes), Diarrhea, Nausea, Vomiting, Convulsions, and
Coma.

b. PETHOPHYSIOLOGY:
Acetaminophen is rapidly absorbed from the gastrointestinal (GI) tract and reaches therapeutic
levels in 30 minutes to 2 hours. Overdose levels peak at 4 hours unless other factors could delay
gastric emptying, such as a co-ingestion of an agent that slows gastric motility, or if the
acetaminophen is in an extended-release form. (Jaeschke et al. 2012)
Acetaminophen has an elimination half-life of 2 hours, but can be as long as 17 hours in
patients with hepatic dysfunction. It is metabolized by the liver, where it is conjugated to
nontoxic, water-soluble metabolites that are excreted in the urine.
c. PARACITAMOL TOXICITY:
Covalent binding to protein oxidation stress calcium and signal transduction mitochondrial
damage ATP depletion nucleic degradation.
It is a nonseroidal anti-inflammatory drug with potent antipyretic and analgesic with weak anti-
inflammatory action. (Jaeschke et al. 2012)
SYNONYMS: Acetaminophen, N-acetyl-p-aminophenol, Hydroxyactanilide.
PHYSICAL APPEARANCE: Paracetamol exists as white, odorless, bitter tasting crystals.

TOXICOKINETIC:

Paracetamol gets rapidly absorbed in GIT completely. Plasma half-life is about 2hrs .Well
absorbed from the small intestine. Peak concentration 1-2 hours post ingestion (30mins for
liquid).Small volume of distribution 0.9 L/kg. Hepatic metabolism and renal excretion . (Blieden
et al. 2014).

1. OVERDOSE: Peak plasma isn’t achieved in 4hr and absorption may delay due to drugs
and high carbohydrate food. Protein binding for paracetamol is 5 to 2%.Volume of
distribution is 0.8 to 1/kg (adult). The half-life of paracetamol may exceed 12 hr in acute
overdose. (Blieden et al. 2014).

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MECHANISM OF PARACETAMOL TOXICITY:
1. Most paracetamol is metabolized by glucouronidation and sulfation.
2. Some (~5%) is metabolized.
3. In the course of this, superoxide and NAPQI are generated
4. In the presence of ample glutathione, NAPQI is rapidly detoxified by conjugation.
5. In the presence of massive overdose, glutathione is rapidly depleted
6. As NAPQI levels increase, it binds covalently to numerous proteins, causing toxicity.
7. Of particular interest is the uncoupling of oxidative phosphorylation, which results in a
failure of ATP synthesis, lactic acidosis, and the release of ionized calcium from
mitochondrial stores.
8. The consequence of this is hepatocellular apoptosis and necrosis. ( Michaud et al. 2014).

GASTROINTESTINAL (GI) EFFECTS:

The acute effects on the liver of paracetamol in overdose have been well documented.
However, the effect of chronic therapeutic‐dose paracetamol use on the liver and GI system in
general is less clear. Concerns are generally focused around GI blood loss and chronic
hepatotoxicity. (Michaud et al. 2014).

2. Chronic toxic

There is no specific reason that neither paracetamol nor N-acetylcysterine is teratogenic.

Severe maternal toxicity might be one of the reasons. It is majorly seen in children rather than
adults, because of dose miscalculation.It occurs in rare case where the patient has taken larger
doses of paracetamol for certain to get rid of chronic pain due to toxic hepatitis. Chronic
poisoning. (Blieden et al. 2014).

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Toxic dose: Acute overdose is usually considered be signal ingestion generally; 7.5 gm in an
adult or 150 mg/kg in a child are the lowest threshold capable of toxicity.

DIAGNOSES
Based on serum paracetamol level. Based on myocardial damage, Based on renal damage.
Based on hepatocellular injury, Elevated aspirate aminotransferase (AST), alanine
aminotransferase (ALT), blirubin and prothrombin time. AST and ALT rise with in 24hrs after
ingestion, peak-48-72hrs. Hypophosphatemia. Decreased serum interlukin-6 or C-reactive
protein blirubin level greater then 4mg/100ml. Based on hypoglycemia, metabolic acidosis.
Diagnosis. (Blieden et al. 2014).

HEPATOTOXICITY RISK FACTOR:

The interplay between paracetamol and alcohol is an interesting one, because these compounds are
competitive substrates for CYP2E1, which reduces the production of the reactive NAPQI species
generated in paracetamol metabolism; as a result, acute alcohol ingestion may in fact act as a protective
mechanism against paracetamol hepatotoxicity. On the other hand, paracetamol hepatotoxicity is
augmented with chronic alcohol consumption through the up-regulation and increased synthesis and
activity of CYP2E1 as well as the decreased production of glutathione; these activities result in enhanced

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liver necrosis and an exacerbated prognosis While the risk of liver failure may be increased in the case of
chronic alcoholism in combination with paracetamol overdose, alcoholism does not necessarily increase
the risk of paracetamol hepatotoxicity when in combination with therapeutic doses. Beyond alcohol,
there are various prescribed and over-the-counter medications that can predispose a patient to
paracetamol hepatotoxicity, including opioids, anti-tuberculosis drugs and anti-epileptic drugs as well as
herbs and dietary supplements, such as St. John’s worth, garlic and germander, through their effects on
CYP450 metabolism.

HISTORY AND PHYSICAL:

The clinical course of acetaminophen toxicity is divided into four stages.
 During the first stage (30 min to 24 hours), the patient may be asymptomatic or may have
emesis.
 In the second stage (18 hours to 72 hours), there may be emesis plus right upper quadrant pain
and hypotension.
 In the third stage (72 hours to 96 hours), liver dysfunction is significant with renal failure,
coagulopathies, metabolic acidosis, and encephalopathy. Gastrointestinal (GI) symptoms
reappear, and death is most common at this stage.
 The fourth stage (4 days to 3 weeks) is marked by recovery.

Acute Management
 Serum paracetamol concentration at (or as soon as possible after) 4 hours post ingestion
determines the need for N-acetyl cytosine (NAC) administration.  (see monogram)
 There is no benefit in measuring paracetamol concentration earlier than 4 hours post ingestion.
 It is safe to wait for the paracetamol concentration to decide on the need for NAC in all cases
that present within 8 hours of ingestion AND where a paracetamol concentration result will be
available for interpretation within 8 hours of ingestion.
 Children who present >8 hours after a toxic ingestion (>200 mg/kg) or after an ingestion in
association with symptoms of toxicity (RUQ pain or tenderness, nausea, vomiting) should be
commenced on NAC immediately.  The decision to continue or cease NAC is then based on the
paracetamol concentration. 
 Delaying NAC administration beyond 8 hours post ingestion is associated with a progressive
increased risk of liver injury.
 There is little evidence to guide management in repeated supratherapeutic doses.  Potential
toxicity should be assessed and a toxicologist consulted when:

 >200 mg/kg (or 10g) ingested over a 24 hour period

 >150 mg/kg/day (or 6 g) ingested over a 48 hour period
 >100 mg/kg/day ingested over a 72 hour period
Consult Toxicologist in very large or massive dose ingestion (>30g) or if initial paracetamol
concentration very high (i.e. ≥ double the monogram value).
For IV paracetamol medication errors consult a toxicologist.

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 See management algorithm and NAC infusion guide. (Reddy 2013; Michaud et al. 2014).

Detection in body fluids

Paracetamol may be quantified in blood, plasma, or urine as a diagnostic tool in clinical
poisoning situations or to aid in the medico legal investigation of suspicious deaths. The
concentration in serum after a typical dose of paracetamol usually peaks below 30 mg/l, which
equals 200 µmol/L. Levels of 30–300 mg/L (200–2000 µmol/L) are often observed in overdose
patients. Postmortem blood levels have ranged from 50–400 mg/L in persons dying due to
acute over dosage. Automated colorimetric techniques gas chromatography and liquid
chromatography are currently in use for the laboratory analysis of the drug in physiological
specimens.

PREVENTION
Limitation of availability
Limiting the availability of paracetamol tablets has been attempted in some countries. In the
UK, sales of over-the-counter paracetamol are restricted to packs of 32 x 500 mg tablets in
pharmacies, and 16 x 500 mg tablets in non-pharmacy outlets. Pharmacists may provide up to
100 tablets for those with chronic conditions at the pharmacist's discretion. In Ireland, the
limits are 24 and 12 tablets, respectively. Subsequent study suggests that the reduced

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availability in large numbers had a significant effect in reducing poisoning deaths from
paracetamol overdose.
Combination with other agents
One strategy for reducing harm done by acetaminophen overdoses is selling paracetamol pre-
combined in tablets either with or an antidote. Paradoxes was a tablet sold in the UK which
combined 500 mg paracetamol with 100 mg methionine, an amino acid formerly used in the
treatment of paracetamol overdose.

TREATMENT
Timing is a vital factor in the treatment of acetaminophen toxicity, and
therefore doctors attempt to begin treatment of acetaminophen overdose within eight hours of
ingestion in order to achieve the best possible outcome for the patient. The majority of patients
survive acetaminophen toxicity with supportive care such as intravenous fluids and anti-nausea
medication, activated charcoal, if used within one hour after ingestion, and antidotal therapy,
including N-acetylcysteine. (Reddy 2013)

For patients who fail the above therapies and develop liver failure, liver transplantation may be
the only treatment option. Doctors will determine if transplantation is necessary if the above
tests are significantly abnormal and the patient has developed hepatic encephalopathy, a
disorder of the brain caused by a dysfunctional liver. (Reddy 2013)

Panadol use in covid-19: Paracetamol is approved to treat fever and mild to moderate pain in
various conditions. Patients should always use the lowest effective dose to relieve symptoms
and taking the lowest effective dose for the shortest period of time.

Patients presenting symptoms of corona virus infection should seek appropriate medical advice
and follow local guidance on management of symptoms.

Paracetamol is currently recommended by public health authorities, including the World Health
Organization (WHO), as part of symptomatic treatment to relieve mild to moderate pain and
reduce fever in COVID-19. When starting treatment for fever or pain in COVID-19, patients and
healthcare professionals should consider all available treatment options including paracetamol 

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CONCLUSION
This is an important public health concern given the ready access to OTC paracetamol products
for children. To address these knowledge gaps, it is important to consider multiple strategies,
which could include improving pharmacist–consumer communication and general knowledge
about paracetamol and potential adverse events associated with overdose. Standard treatment
of paracetamol overdose is acetylcysteine, which, based on animal studies and clinical
Experience, is widely believed to reduce liver damage and mortality, although few studies have
been done.
Adverse effects from acetylcysteine include rash, urticaria, vomiting, and anaphylactic
reactions, which can (although, rarely) be fatal. These may be reduced by using novel regimens
for acetylcysteine treatment. At the time of publication of this overview, the standard regimen
in the UK for most patients is 21-hour intravenous acetylcysteine.
We don't know what the optimal dose, route, and duration of acetylcysteine treatment should
be. However, liver damage is unlikely to occur if treatment is started within 8 to 10 hours of
ingestion. We found no direct information from RCTs comparing acetylcysteine with
methionine in the treatment of people with paracetamol poisoning

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