However, multiple studies report that children do metabolize it more quickly, and therefore, the duration of action tends to be on the lower end of the range (around four hours).
Interestingly, this faster metabolism in children increases the rate of a side effect we don't typically associate with Benadryl.
Children have a far higher rate of what is known as 'paradoxical excitation'. While we typically expect Benadryl to cause sedation since it is a sedating first-generation antihistamine, this doesn't always occur in children. The prescribing information for Benadryl products warn of this:
As in adults, antihistamines may diminish mental alertness in pediatric patients. In the young pediatric patient, particularly, they may produce excitation.
In terms of giving Benadryl with Zyrtec, using both can increase the risk of certain side effects (like sedation and dizziness). Nevertheless, giving Zyrtec 4 hours after giving Benadryl to a child won't likely cause too much trouble as most of the Benadryl dose is likely to be already metabolized.
Children Metabolize Benadryl Faster
As mentioned above, studies consistently show that Benadryl is metabolized more quickly in children than in adults.
Not only is it cleared from the body more quickly in children, the half-life of the drug (which is the time it takes to metabolize 50% of a drug) is also shorter.
One study reported the following numbers in regard to Benadryl clearance (the rate at which a drug is removed from the plasma) and half-life:
- Elderly: 13.5 hours
- Adults: 9.5 hours
- Children: 5.4 hours
- Elderly: 11.7 mL/min/kg
- Adults: 23.3 mL/min/kg
- Children: 49.2 mL/min/kg
Since children metabolize Benadryl faster than adults, it makes sense that its duration of action would be shorter.
Additionally, since Benadryl is cleared more slowly in the elderly, that would account for the fact that it is known to cause more sedation and dizziness in that age group:
Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients.
Excitation In Children
An interesting characteristic of Benadryl is that it is known to cause 'paradoxical excitation' in children (as opposed to sedation).
While the exact mechanism as to why this occurs isn't well understood, it appears to be that the faster metabolism of Benadryl in children increases the concentrations of an 'excitatory' metabolite.
One study reported that individuals classified as 'ultrarapid metabolizers' of Benadryl (due to an increased concentration of the CYP2D6 metabolizing enzyme) had an increased risk of the excitatory side effects.
Therefore, since we know that children also metabolize Benadryl more quickly than other patient populations, an increased concentration of the excitatory metabolite could be the reason excitation occurs in some. 
The published duration of action for Benadryl is essentially the same for both children and adults (around four to six hours) but we do know that children clear it from their system more quickly.
In your situation, giving Zyrtec just a few hours after Benadryl, it may increase the risk of sedation or other side effects, but aside from that, it shouldn't cause many issues.
Only cases of extreme antihistamine overdose have resulted in severe side effects (such as hallucinations and shallow breathing).
SummaryBenadryl lasts around 4 to 6 hours per dose in children, which is similar to the duration of action in adults. However, multiple studies show that children metabolize Benadryl faster than adults.
- ^ Elsevier ClinicalKey: Benadryl Monograph. ClinicalKey
- AccessFDA Diphenhydramine Prescribing Information.
- PubMed Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children.
- PubMed Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports.
- PubMed Dose-dependent toxicity of diphenhydramine overdose.