Clinical Pharmacology of Paracetamol in Infants and Children

Paracetamol (acetaminophen) has analgesic and antipyretic effects similar to those of aspirin but has only weak anti-inflammatory effects. It is a nonselective cyclooxygenase inhibitor which acts at the peroxidase site of the enzyme and is thus distinct among the nonsteroidal anti-inflammatory drugs. The major metabolites of paracetamol are paracetamol glucuronide and paracetamol sulphate and the minor metabolites are mercapturic acid cysteine conjugates and N-acetyl-p-benzoquinone imine. The last is a highly reactive intermediate and it reacts with sulfhydryl groups in glutathione and is harmless. Paracetamol may be administered orally, rectally, or intravenously. In infants, the oral dosing of paracetamol consist in a loading dose of 20 mg/kg following by subsequent doses of 10 to 15 mg/kg, and in children, the dose varies with the child age and body-weigh. Paracetamol has been found efficacy and safe in infants and children but it may induce adverse-effects. The elimination half-life of paracetamol is 11.0 and 4.38 hours in more immature preterm infants and in less immature preterm infants, respectively, and it is 3.45 hours in children. Propranolol interacts with drugs. The prophylaxis, treatment, and trials with paracetamol have been investigated in infants and children. Paracetamol may induce toxicity and it crosses the human placenta and migrates into the breast milk in significant amounts. The aim of this study in the review of paracetamol dosing, efficacy and safety, adverse-effects, metabolism, pharmacokinetics, drug interaction, prophylaxis, treatment, trials, toxicity in infants and children, and paracetamol transfer across the human placenta and migration into the breast milk.

2 intentionally induced -can cause severe hepatic damage; it leads to nearly 80,000 emergency department visits and 30,000 hospitalizations annually in the U.S. The maximum FDA-recommended dose of acetaminophen is 4 grams daily [1].

Mechanism of action of paracetamol
Paracetamol has analgesic and antipyretic effects similar to those of aspirin but has only weak anti-inflammatory effects.
It is a nonselective cyclooxygenase (COX) inhibitor which acts at the peroxide site of the enzyme and is thus distinct

+Therapeutic use of paracetamol
Paracetamol is suitable for analgesic or antipyretic uses; it is particularly valuable for patients in whom aspirin is contraindicate (e.g., those with aspirin hypersensitivity, children with a febrile illness, patients with bleeding disorders). In adults, the conventional oral dose of paracetamol is 325 to 650 mg 4 times-daily or thrice-daily; total daily dose should not exceed 4 grams (2 grams daily for chronic alcoholics). Single doses for children aged 2 to 11 years depend on age and weight (about 10 to 15 mg/ kg); no more than 5 doses should be administered in 24     Bexsero ® is a British formulation.

Oral post-immunisation pyrexia in infants
Children aged 2 to 3 months. Give: 60 mg for 1 dose, and then 60 mg after 4 to 6 hours if required.
Children aged 4 to 6 months. Give: 60 mg for 1 dose, and then 60 mg after 4 to 6 hours (maximum 4 doses daily).

Efficacy and safety of paracetamol in infants and children
Paracetamol is the treatment of choice for the closure of the patent ductus arteriosus

Rare or very rare general adverse-effects caused by paracetamol in infants and children [4]
Thrombocytopenia

Common or very common specific adverse-effects caused by paracetamol in infants and children [4]
With rectal use: Anorectal erythema.

Rare or very rare specific adverse-effects caused by paracetamol in infants and children [4]
With intravenous use: hypersensitivity, hypotension, leukopenia, malaise, neutropenia. With rectal use: angioedema, liver injury, and skin reactions.

Adverse effects induced by paracetamol in infants and children whose frequency is unknown [4]
With

Pharmacokinetics of paracetamol in infants
van Lingen et al.     This table shows that paracetamol administered as suppositories is rapidly absorbed, the lag time is short, the elimination rate constant is short, the distribution volume is similar to the water volume, the time to reach the peak concentration is short, the total body clearance is limited, the dosing interval is short, the concentration at the steady-state

Interaction of drugs with paracetamol
The paracetamol metabolite N-acetyl-p-benzoquinone imine causes hepatotoxicity and the co-administration of paracetamol with warfarin increases the anticoagulant effects.

Prophylaxis with paracetamol in infants and children
The rate of patent ductus arteriosus is significantly lower in the paracetamol-treated group compared to the control group

Trials with paracetamol in infants and children
Current follow-up results on paracetamol-exposed very preterm infants may not be alarming suggesting that paracetamol administration shortly after birth is not associated with common adverse-consequences [38].
Paracetamol (12.5 mg/kg per dose) and ibuprofen (5 mg/kg per dose) 6 times-daily for 3 days, regardless of the initial loading medication, is more effective than monotherapy in lowering fever in infants and children [39]. Infants who are treated with paracetamol no long-term adverse reactions of early intravenous paracetamol were detected two years later In conclusion, paracetamol (acetaminophen) is used to treat pain and fever. It is a nonselective cyclooxygenase inhibitor which acts at the peroxidase site of the enzyme and is thus distinct among the nonsteroidal anti-inflammatory drugs.
Paracetamol may be administered orally, rectally, or intravenously and the bioavailability is good. In infants, the oral dosing of paracetamol consists in a loading dose followed by subsequent doses and in children the dose varies with the child age and child body-weight. Paracetamol is extensively metabolized; the main metabolites are paracetamol glucuronide and paracetamol sulphate and the minor metabolites are mercapturic acid and cysteine conjugates, and N-acetyl-p-benzoquinone imine. The last is formed by CYP enzymes, it is a reactive metabolite and reacts