Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children

Summary

We have studied the mechanisms of the increased dosage requirements of the H₂-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study.

Cimetidine (10–15 mg·kg⁻¹) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis.

The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml⁻¹.

The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg⁻¹ and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg⁻¹ and 2.21 h respectively.

Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min⁻¹. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r ²=0.85).

The plasma concentration of cimetidine needed to increase gastric pH to ≥4.0 was ≥1.0 µg·ml⁻¹, which contrasts with the value of >0.5 µg·ml⁻¹ required for adult burned patients.

These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.