RESEARCH IN PRACTICE

Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2014-307287 on 20 May 2016. Downloaded from http://ep.bmj.com/ on 3 April 2019 by guest. Protected by copyright.
Paracetamol: pharmacology,
prescribing and controversies
Camilla Moriarty,1 Will Carroll2

1
Chelsea and Westminster INDICATIONS AND MECHANISM OF Importantly, absorption through the
Hospital, London, UK
2 ACTION gastric mucosa is negligible and therefore
Academic Department of
Paediatric, Respiratory Medicine, Paracetamol (internationally known as any process (or disease) that delays
University Hospitals of the North acetaminophen) is the most common gastric emptying will slow down the
Midlands, Stoke-on-Trent, UK medicine encountered in paediatric prac- absorption of an orally administered
Correspondence to
tice. It is used widely by parents and dose. The time to peak blood levels after
Dr Will Carroll, Academic health professionals and it has analgesic oral administration of the drug in chil-
Department of Paediatric, and antipyretic effects. Its short-term dren (aged 6 months to 12 years) ranges
Respiratory Medicine, University safety and efficacy are well established from 0.5 to 1.8 h, broadly similar to
Hospitals of the North Midlands,
Newcastle Road, Stoke-on-Trent and it is readily available for purchase adults. The presence of food delays the
ST4 6QG, UK; over the counter. Its mechanism of action time to peak concentration in the blood-
[email protected] is not fully understood but it is known to stream, but the overall extent of absorp-
inhibit prostaglandin synthesis and is tion is unchanged whether food is
Received 10 October 2015
Revised 25 March 2016 highly selective for cyclooxygenase present or not. It remains unclear as to
Accepted 20 April 2016 enzymes in the central nervous system. It whether the generally slower gastric
Published Online First also has a weak anti-inflammatory action. emptying time in neonates affects
20 May 2016
An understanding of its pharmacology absorption.
can significantly increase the apparent
effectiveness and safety of this useful Biology
medicine. Despite its ubiquitous usage and a wealth
Oral paracetamol is used in children of data on the clinical effects of paraceta-
for mild-to-moderate pain and fever, mol in children and adults, the precise
including postimmunisation fever.1 It biological mechanism of action remains
may also be given by intravenous infusion elusive. It is a weak inhibitor of the syn-
or per rectum when it is most commonly thesis of prostaglandins having clinical
used for the short-term treatment of effects that are similar but not identical
moderate pain, particularly after surgery, to selective cyclooxygenase-2 (COX-2)
and for persistent fever. Unlike opioid inhibitors. However, unlike the selective
analgesia, there is no dependence or tol- COX-2 inhibitors, paracetamol does not
erance seen with paracetamol, but there suppress the inflammation of rheumatoid
is a ceiling effect on analgesia and once arthritis.
this is achieved higher doses do not have Paracetamol is widely distributed in the
an increased effectiveness. Its long-term body throughout the majority of body
use tends to deplete glutathione stores, fluids and has a relatively large volume of
which can enhance toxicity in overdose. distribution, which is largest in the
Overdose may result in irreversible hep- preterm infant and reduces with maturity
atotoxicity, which can be fatal. until it reaches adult levels at about
1 year.3 It rapidly crosses the blood–brain
PHARMACOLOGY OF PARACETAMOL: barrier to the central nervous system; one
AN ABCD APPROACH report found peak cerebrospinal fluid
Absorption levels in children after 57 min when
The pharmacokinetics of paracetamol in administered intravenously. Analgesic
infants and children has been described activity is produced by the fraction that
in detail.2 Oral formulations have high penetrates into the brain, possibly by an
bioavailability and around 80% of a dose action upon serotonergic pathways.4
is absorbed, mainly by passive diffusion. The clinical effects of oral paracetamol
To cite: Moriarty C, Rectal formulations have a reduced bio- suspension in children often appear to be
Carroll W. Arch Dis Child Educ availability compared with other routes very rapid in clinical practice. Fever
Pract Ed 2016;101:331–334. and therefore require higher doses. responds quickly and it typically takes

Moriarty C, Carroll W. Arch Dis Child Educ Pract Ed 2016;101:331–334. doi:10.1136/archdischild-2014-307287 331
 Research in practice

Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2014-307287 on 20 May 2016. Downloaded from http://ep.bmj.com/ on 3 April 2019 by guest. Protected by copyright.
just over 1 h to resolve fever in febrile children
between 6 months and 6 years of age (a mean of
71 min).5 In one study, axillary temperature was
recorded every 30 s. While the study did not include
a placebo arm, axillary temperature began to decline
in the paracetamol group within a few minutes of
administration. However, the decline in temperature
was more rapid in children treated with ibuprofen or
ibuprofen and paracetamol in combination.5

Clearance
Paracetamol is primarily metabolised in the liver to
glucuronide and sulfate conjugates that are then
excreted renally. The sulfation pathway predominates
in neonates; the glucuronidation pathway takes time
to develop and is mature at around 2 years of age.
One study analysed the urinary excretion of the two
conjugates (0–36 h) and found that the ratio of para-
cetamol–glucuronide to paracetamol–sulfate for neo-
nates (1–2 days old), children (3–9 years) and older
children (12 years old) was 0.34, 0.75 and 1.61, Figure 2 Paracetamol metabolism.
respectively, with an adult ratio of 1.80 (see figure 1).6
There appears to be no clear clinical consequence of premature neonates, the mean elimination half-life is
this different pattern of metabolism and by adulthood longer still; one study found it was 11 h for 28–
the predominant pathway is one of glucuronidation. A 32 week old neonates (for rectally administered para-
small proportion of the dose (5–10%) is oxidised by cetamol) and 4–5 h in 32–36 week old neonates.7 The
CYP450-dependent pathways in the liver by the recommended dose frequency in preterm neonates
enzyme CYP2E1. This appears to be present at lower reflects this.
levels in neonates than in adults, leading to the forma-
tion of a smaller amount of the toxic intermediate
metabolite N-acetyl-p-benzoquinone imine (NAPQI). Dosing, indications, practical prescribing issues and
NAPQI is normally detoxified by conjugation with controversies in children
glutathione and the bound NAPQI product is elimi- The use of antipyretic medications to achieve a reduc-
nated in the urine or bile. However, if there is not suf- tion of temperature in children with febrile illness is a
ficient glutathione available, either as a result of controversial area. High temperatures in children
malnutrition or if there is a large amount of NAPQI cause parental anxiety and this is a common reason
produced as in overdose, then hepatotoxicity may for seeking medical attention. Undue emphasis on a
result (see figure 2). need for reduction of fever in children has led to pos-
The elimination half-life for paracetamol varies sible overuse of both paracetamol and ibuprofen,
between neonates, infants, children and adolescents. often in combination. There is no evidence that this
In neonates born at term it is between 2.5 and 4 h, reduces morbidity or mortality. The focus of recent
this is about 1 h longer than older children. In National Institute for Health and Care Excellence
(NICE) guidelines8 has therefore shifted away from
reducing fever to ensuring that the child is
comfortable.
There have been concerns that paracetamol will
dampen the immune response when used in standard
therapeutic doses. Two open-label randomised con-
trolled studies examined the effectiveness and safety
of paracetamol suspension following childhood
immunisation. These found a blunting of the func-
tional antibody response in the paracetamol group.
However, the same authors have repeated this study
in children receiving the meningococcal B vaccine in
conjunction with other childhood immunisations
and concluded that there is a reduction in postimmu-
nisation fever that is not accompanied by any signifi-
Figure 1 Ratio of glucuronidation to sulfation in different ages.6 cant attenuation of the immune response. The

332 Moriarty C, Carroll W. Arch Dis Child Educ Pract Ed 2016;101:331–334. doi:10.1136/archdischild-2014-307287
 Research in practice

Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2014-307287 on 20 May 2016. Downloaded from http://ep.bmj.com/ on 3 April 2019 by guest. Protected by copyright.
significance of this possible effect remains unclear.9 6.52 mL. The calibrated spoon was the most accurate
For the time being, reduction of postvaccination fever while the oral syringe had the smallest variance.13
remains a licensed indication. In addition, paracetamol is a component of several
While paracetamol is considered a benign medicine multi-ingredient medicines sold over the counter. It is
without longer term effects, it has effects on cytokine important for all involved to understand that the sim-
production that are only partly understood. Some ultaneous administration of one of these, together
authors have suggested that paracetamol use in preg- with prescribed paracetamol may result in inadvertent
nancy or early infancy may increase the risk of asthma overdose. When prescribing paracetamol, it is import-
in young children. A systematic review and ant to try to avoid vague prescribing instructions such
meta-analysis of studies reporting this association as ‘take when required’; as errors are more commonly
found that there was insufficient evidence to warrant made when instructions are unclear. A minimum time
changing guidelines.10 frame between doses and maximum dosing per 24 h
are essential to minimise the risk of overdose.
PITFALLS IN PRESCRIBING PARACETAMOL There remains debate about whether prescribers
Prescribers should beware of the risk of overdosage should use weight or age to determine the appropriate
and should ensure that the appropriate strength of dose of paracetamol and regular prescribers will be
product is prescribed (there are several available). A aware that the BNF-C has varied this advice over
retrospective study conducted in Australia and New recent years. One study which supported the use of a
Zealand described paracetamol overdose, due to weight-based dose found that children who were
medication errors, being one of the leading causes of underweight or overweight for their age were at risk
acute liver failure in children.11 The common errors of receiving inappropriate doses of paracetamol with
encountered in clinical practice are summarised in the potential of causing harm.14 The UK Medicines
box 1. However, this list is far from complete and a and Healthcare Regulatory body recognised this
recent article has highlighted concerns regarding the
lack of research available about the reasons behind
medication errors made by caregivers of young Test your knowledge
children and of the increasing prevalence of falsified
medicines used.12
Health professionals should ensure that caregivers 1. Which of the following conditions is most likely to
understand what dose to give and the importance of result in oral paracetamol being ineffective?
ensuring that the right strength of product is used. Select ONE answer only:
While measuring a dose seems straightforward to a A. Coeliac disease
health professional, an untrained carer may have more B. Hepatic encephalopathy
difficulty; one study of over 270 caregivers aimed to C. Kawasaki disease
determine the most accurate measuring device by D. Pyloric stenosis
asking carers to measure 5 mL of 120 mg/5 mL para- E. Renal failure
cetamol using either a 5 mL metal teaspoon, a 5 mL 2. You are called to the neonatal unit to review a
calibrated spoon or a 5 mL oral syringe. Results preterm infant of 29 weeks gestation. He is in pain
showed the volumes measured ranged from 0.83 to and you plan to prescribe paracetamol.
Which of the following is most likely to be true?
Select ONE answer only:
Box 1 Errors leading to unintentional paracetamol A. Intravenous administration is safer
overdose by caregivers in children11 B. Most will be metabolised by glucuronidation
C. Paracetamol is unsafe in this child and should be
Common errors that led to overdose were: avoided
▸ Children receiving double doses D. Smaller amounts of the toxic intermediate NAPQI
▸ Co-administration of other paracetamol containing will be formed than in a 1-year-old
preparations E. The elimination half-life is slightly shorter than
▸ Exceeding recommended daily dosages that of a term infant
▸ Increased dose frequency 3. What is the maximum safe daily dose of oral para-
Reported reasons given by caregivers for these errors cetamol in children?
were: A. 60 mg/kg
▸ Failure to understand prescriptions B. 65 mg/kg
▸ The use of incorrect measuring devices C. 70 mg/kg
▸ The use of different concentrations of paracetamol D. 75 mg/kg
▸ Lack of recognition of paracetamol in other common E. 80 mg/kg
‘cold remedies’. Answers are at the end of the references.

Moriarty C, Carroll W. Arch Dis Child Educ Pract Ed 2016;101:331–334. doi:10.1136/archdischild-2014-307287 333
 Research in practice

Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2014-307287 on 20 May 2016. Downloaded from http://ep.bmj.com/ on 3 April 2019 by guest. Protected by copyright.
concern and developed new guidance with narrower guideline). Clinical guidance 160 National Centre for Health
age ranges for certain doses.15 Following concerns and Care Excellence. 2013. https://www.nice.org.uk/guidance/
about hepatotoxicity at therapeutic doses, there has cg160 (accessed 7 Aug 2015).
9 Prymula R, Siegrist CA, Chlibek R, et al. Effect of
also been a move to reduce the maximum total daily
prophylactic paracetamol administration at time of vaccination
dose to 75 mg/kg/day from 90 mg/kg/day. Prescribers
on febrile reactions and antibody responses in children: two
should always seek help and advice if they are at all open-label, randomised controlled trials. Lancet 2009;374:
unsure of what dose to use and even experienced pre- 1339–50.
scribers are advised to check the latest version of the 10 Cheelo M, Lodge CJ, Dharmage SC, et al. Paracetamol
BNF-C from time to time to keep up to date with exposure in pregnancy and early childhood and development
changes. of childhood asthma: a systematic review and meta-analysis.
Arch Dis Child 2015;100:81–9.
SUMMARY 11 Rajanayagam J, Bishop JR, Lewindon PJ, et al.
Paracetamol is a useful medicine. Its benefits as an Paracetamol-associated acute liver failure in Australian and
analgesic and antipyretic are widely known but it New Zealand children: high rate of medication errors. Arch
should be used with caution and an appreciation of its Dis Child 2015;100:77–80.
mechanism of action. It works optimally when the 12 Star K, Choonara I. How safe is paracetamol? Arch Dis Child
right dose is given by the right route. As with all med- 2014;100:73–4.
icines, adverse effects can (and do) occur as a result of 13 Beckett VL, Tyson LD, Carroll D, et al. Accurately
poor prescribing and following accidental or purpose- administering oral medication to children isn’t child’s play.
ful ingestion. There may be longer term effects on Arch Dis Child 2012;97:838–41.
14 Eyers S, Fingleton J, Eastwood A, et al. British National
general health that should not be overlooked—and it
Formulary for Children: the risk of inappropriate
certainly should not be simply ‘prescribed routinely’
paracetamol prescribing. Arch Dis Child 2012;97:
to all children admitted to hospital or given indiscrim- 279–82.
inately to all children who are febrile. 15 Lenney W. Editorial: Paracetamol prescription by age or by
weight? Arch Dis Child 2012;97:277–8.
Contributors CM and WC jointly prepared the review and
contributed equally to the final version.
Competing interests None declared.
Answers to the quiz questions
Provenance and peer review Commissioned; externally peer
reviewed.
1. Answer—D. Pyloric stenosis
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334 Moriarty C, Carroll W. Arch Dis Child Educ Pract Ed 2016;101:331–334. doi:10.1136/archdischild-2014-307287