Download Paracetamol and Ibuprofen for Paediatric Pain and Fever

REVIEW
Paracetamol and Ibuprofen for Paediatric Pain and Fever
Joe Tucci, Emily Bandiera, Rima Darwiche, Zeljko Medos, Robert Nashed, David Trinh
ABSTRACT
Aim: To review the literature on the pharmacology and
pharmacokinetics of paracetamol and ibuprofen pertaining to
their use for paediatric pain and fever.
Data sources: A literature search was conducted using the
PubMed database service on the National Centre for
Biotechnology Information web page.
Study selection: Data from original studies on paediatric
pharmacogenomics, pharmacokinetics and pharmacology of
paracetamol and ibuprofen were included in the analysis.
Results: More published studies are required to
comprehensively define the pharmacology and
phamacokinetics of paracetamol and ibuprofen in paediatrics.
Conclusion: An understanding of drug metabolic processes
during ontogeny may enable predictions about the capacity of
children to cope with medications. Pharmacogenomic screening
may help elucidate the inter-individual variation in drug
metabolism and pharmacokinetics.
J Pharm Pract Res 2009; 39: 223-5.
INTRODUCTION
In Australia, paracetamol and ibuprofen are the most
popular over-the-counter drugs used to manage fever
and pain in children. Paracetamol and ibuprofen are
effective antipyretics and analgesics (ibuprofen is
favoured in inflammatory conditions).1-4 Although these
drugs are considered safe to use in recommended doses,
a recent study has suggested a link between paracetamol
and allergic disorders.5 Although some of the adverse
effects of ibuprofen are well known, its indication and
widespread use in paediatrics creates the potential for
adverse reactions in children previously unexposed to
ibuprofen. These concerns have raised questions about
the empirical use of paracetamol and ibuprofen in
children. In this article we will review the literature on the
pharmacology and pharmacokinetics of paracetamol and
ibuprofen pertaining to their use in paediatric pain and
fever. Further, the inter-individual variation in hepatic
enzymes which metabolise these drugs may account for
some of the toxicity attributable to their use, as well as a
lack of efficacy in some cases.6
STUDY SELECTION
Original articles on paediatric pharmacokinetics,
pharmacology and pharmacogenomics of paracetamol
and ibuprofen were included in the analysis. This is not
an exhaustive review and recent studies (2004 onwards)
were preferentially chosen. Some studies from 1993 were
included if they contained specific data not covered in
later publications. Key reference data from drug reference
resources were also included.
Joe Tucci, BPharm, BSC(Hons), PhD, Senior Lecturer, Emily Bandiera, Rima
Darwiche, Zeljko Medos, Robert Nashed, David Trinh, Fourth Year Students,
School of Pharmacy and Applied Science, La Trobe University, Bendigo, Victoria
Address for correspondence: Dr Joe Tucci, School of Pharmacy and Applied
Science, La Trobe University, Bendigo Vic. 3550, Australia.
E-mail: [email protected]
PARACETAMOL PHARMACOLOGY
Although paracetamol’s exact mechanism of action
remains to be elucidated, it has been postulated that
paracetamol blocks prostaglandin synthesis in the
hypothalamus via inhibition of cyclo-oxygenase-3 (COX3), a splice variant of COX-1 mainly found in the brain
and spinal cord (Figure 1).7-9 This central action produces
antipyretic and analgesic effects. Paracetamol also
reduces hyperalgesia mediated by substance P and
reduces nitric oxide generation in spinal hyperalgesia
induced by substance P or N-nitrosodimethylamine.8
Paracetamol also indirectly activates cannabinoid-1
receptors.10 Regardless of the mechanism, the primary
clinical outcome of paracetamol use is an increase in
pain tolerance via an effect on the central nervous system.
Paracetamol’s analgesic potency is relatively low and its
actions are dose-related (ceiling effect with no further
analgesia or antipyresis despite an increase in dose).8
Paracetamol is not an effective anti-inflammatory as it
does not inhibit prostaglandin synthesis outside the
central nervous system.
IBUPROFEN PHARMACOLOGY
Non-selective non-steroidal anti-inflammatory drugs,
such as ibuprofen, inhibit COX-1 and COX-2 and limit
the production of prostaglandins involved in the
inflammatory response (Figure 1). The non-steroidal antiinflammatory drugs have a direct spinal action in blocking
excessive sensitivity to pain induced by the activation
of glutamate and substance P receptors. The analgesic,
antipyretic and anti-inflammatory activities are achieved
principally through COX-2 inhibition (peripheral or
central), whereas COX-1 inhibition is responsible for the
unwanted effects on the kidneys, gastrointestinal
mucosa and on platelet aggregation (reversible).
PAEDIATRIC PHARMACOKINETICS
In general, caution should be exercised with paediatric
dosing, as their is potential for dramatic variability in
drug levels depending on the neonate’s age. At six months
of age, the neonate’s renal clearance is almost twice that
of adults, while in premature infants clearance can be
impaired by 50% when compared to term infants. These
mechanisms are being elucidated with studies describing
the precise changes occurring in glomerular filtration
rates in the perinatal period, as well as the ontogeny of
cytochrome P450 (CYP) enzymes, glucuronidation and
other phase II reactions. 11,12 Drafting drug dosage
guidelines based on the changing pharmacokinetic
parameters and physiology during the postnatal period
is an important and ongoing contribution to paediatric
pharmacopoeias.13 The capacity of participants in clinical
trials to respond to and deal with the drugs tested is an
issue that has so far been overlooked by those
undertaking such screens. Results from trials comparing
paracetamol and ibuprofen could be influenced by interindividual variation in pharmacokinetics and
pharmacodynamics, to the extent that children in clinical
Journal of Pharmacy Practice and Research Volume 39, No. 3, 2009.
223
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Figure 1. Cyclo-oxygenase pathways and pharmacological action of paracetamol and non-steroidal anti-inflammatory
drugs (COX = cyclo-oxygenase. NSAIDs = non-steroidal anti-inflammatory drugs. PGE 2 = prostaglandin E2).
trials may respond differently to a particular analgesic
depending on how long they are exposed to it, which is a
direct consequence of how quickly they clear the drug.6
Pharmacogenomic screening of participants in trials would
be an important contribution to the data as it could
highlight individuals who are either not able to metabolise
the drugs tested, or metabolise them at a higher rate.
Paracetamol
Oral paracetamol is rapidly absorbed from the small bowel
and has an onset of action of approximately 30 minutes
and duration of action of four hours.14 Paracetamol readily
crosses into the cerebrospinal fluid and into the brain,
where it exhibits its main analgesic effect. Paracetamol
undergoes extensive first-pass hepatic metabolism
(substrate of CYP 1A2, 2E1, 3A4) and is renally excreted.
Therefore, paracetamol should be administered with
caution in patients with renal or hepatic dysfunction as
metabolite production (reactive oxidative species) in
overdose may lead to severe hepatic toxicity. Absorption
via the rectal route is highly variable and unpredictable –
reported bioavailability ranging from 24 to 98% – with
absorption from the rectum of neonates being at the higher
end of this scale.4,8 Intravenous paracetamol is only used
when the oral and rectal routes are not available.4 The
recommended paediatric doses of paracetamol in
medically supervised and unsupervised settings are listed
in Table 1.4
Ibuprofen
Oral ibuprofen is rapidly absorbed and has an onset of
action of approximately 30 to 90 minutes with a duration
of action of six to eight hours (Table 2). Ibuprofen is
extensively bound to plasma proteins and is mainly
metabolised in the liver by CYP2C9. While mutations (e.g.
CYP2C9*3/*3) can result in up to 50% reduction in
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Table 1. Paracetamol and ibuprofen paediatric doses
Paracetamol
Ibuprofen
Community Setting
15 mg/ kg every 4 to 6 hours;
Maximum 4 doses (60 mg/kg)
per day for up to 48 hours
5 to 10 mg/kg 3 or 4 times a day
Hospital Setting
For juvenile rheumatoid arthritis:
Up to 90 mg/kg per day under
medical supervision with review 10 mg/kg 3 or 4 times a day
after 48 hours; single doses of
30 mg/kg for night-time dosing
ibuprofen clearance, the clinical consequences remain to
be elucidated.15 Elevation of liver transaminases following
exposure to ibuprofen have been reported, with levels
returning to normal following discontinuation. 16
Ibuprofen’s capacity to bind plasma proteins raises
several issues, such as whether changes in hepatic
protein production during neonatal development would
result in fluctuations to free and bound levels. There is
also the question of how easily ibuprofen displaces
bilirubin from albumin binding sites, although research
suggests that even though displacement may occur at
high ibuprofen concentrations, the free bilirubin levels
are not appreciably increased. 17 The recommended
paediatric doses of ibuprofen in medically supervised
and unsupervised settings are listed in Table 1.4
With reference to alternating regimens using
ibuprofen and paracetamol, a risk factor could be the
accumulation of reactive metabolites of paracetamol in
the renal medulla, if they are not adequately dealt with in
the liver (Table 2). This could lead to tubular necrosis
and renal toxicity, as ibuprofen blocks the production of
renal prostaglandins (inhibiting renal perfusion) and may
also potentially inhibit the production of glutathione,
which detoxifies the toxic metabolites of paracetamol.18
Journal of Pharmacy Practice and Research Volume 39, No. 3, 2009.
Table 2. Comparison of paracetamol and ibuprofen pharmacokinetics
Parameters
Paracetamol
Ibuprofen
Onset of action
< 1 hour
Analgesic: 30 to 60 minutes
Anti-inflammatory: < 7 days
Duration of action
4 to 6 hours
6 to 8 hours
Absorption
Incomplete, depends on dosage form
Oral: rapid (85%)
Protein binding
8 to 43% at toxic doses
90 to 99%
Metabolism
At therapeutic doses: hepatic metabolism to sulfate and
glucuronide metabolites, and a small amount is metabolised
by CYP to a highly reactive intermediate (acetylimidoquinone), which is conjugated with glutathione and
inactivated.
At toxic doses (single doses of 10 to 15 g): glutathione
conjugation becomes insufficient to meet the metabolic
demand causing an increase in acetyl-imidoquinone
concentration, which may cause hepatic cell necrosis.
Hepatic metabolism via oxidation
Half-life elimination Neonates: 2 to 5 hours
Adults: 1 to 3 hours (may be increased in the elderly)
Premature infants day 3: 35 to 51 hours; day 5: 20
to 33 hours.
Children 3 months to 10 years: 1.6 ± 0.7 hours.
Adults: 2 to 4 hours; unchanged in end-stage renal
disease
Time to peak, serum Oral: 10 to 60 minutes; may be delayed in acute overdoses
1 to 2 hours
Excretion
Urine (1% as free drug); some faeces
Urine (2 to 5% unchanged; 55% glucuronide metabolites;
30% sulfate metabolites)
CONCLUSION
Although the pharmacology of the paracetamol and
ibuprofen has not been totally elucidated, they have been
used for many years, with clearly defined clinical effects.
With respect to the ontogeny of hepatic enzymes during
neonatal development, more research is required before
a complete picture emerges of the changes to metabolic
capacity during this period. This is crucial if we are to
confidently predict how certain medications will be dealt
with by children. Pharmacogenomic screening of patients
may assist in clarifying results from clinical trials.
15. Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450
2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16.
16. Riley TR, Smith JP. Ibuprofen induced hepatotoxicity in patients with chronic
hepatitis C: a case series. Am J Gastroenterol 1998; 93: 1563-5.
17. Ambat MT, Ostrea EM Jr, Aranda JV. Effect of ibuprofen L-lysinate on bilirubin
binding to albumin as measured by saturation index and horseradish peroxidase
assays. J Perinatol 2008; 28: 287-90.
18. McIntire S, Rubenstein R, Gartner JJ, Gilboa N, Ellis D. Acute flank pain and
reversible renal dysfunction associated with nonsteroidal anti-inflammatory
drug use. Pediatrics 1993; 92: 459-60.
Received: 17 April 2009
Revisions requested after external review: 4 August 2009
Revised version received: 7 August 2009
Accepted: 31 August 2009
Competing interests: None declared
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