Pharmacokinetics and pharmacodynamics of cimetidine and metabolites in critically ill children.
Cimetidine and antacids are the mainstays of therapy for the prophylaxis of stress-induced ulceration in critically ill children. Previous cimetidine dosing recommendations have been empiric because of a lack of knowledge about cimetidine disposition kinetics in children. Thirty children, mean age 9 +/- 3.2 years, were admitted to the study with the following primary diagnoses: closed head injury (23 patients), sepsis (four), gunshot wound (two), and bleeding gastric ulceration (one). The mean dose of cimetidine was 26 mg/kg/day, administered intravenously over 15 minutes in four divided doses. Cimetidine disposition was best described by a biphasic elimination curve with t1/2 values for cimetidine, cimetidine sulfoxide, and hydroxymethyl cimetidine of 1.39, 2.6, and 4.7 hours, respectively. Cimetidine plasma concentrations were maintained at greater than or equal to 0.5 microgram/ml for a significantly longer time in patients who received greater than or equal to 20 mg/kg/day. Most patients had a plasma cimetidine concentration below 0.5 to 1.0 microgram/ml 4 hours after infusion. The mean apparent volume of distribution and total body clearance for cimetidine were 1.23 L/kg and 10.4 ml/min/kg, respectively. A significant correlation was found between age and either apparent volume of distribution (r = 0.76, P less than 0.001) or total body clearance (r = 0.75, P less than 0.001). No significant correlation between cimetidine concentrations in either plasma or gastric juice and gastric pH could be determined. However, seven of nine patients who received only cimetidine had a gastric pH of greater than or equal to 4 at 2 hours after infusion when the plasma cimetidine concentration was greater than or equal to 1.0 or the gastric juice concentration was greater than or equal to 2.0 microgram/ml. The mean gastric pH was 2.2 at 6 hours, when plasma and gastric juice concentrations of cimetidine were greater than or equal to 1.0 microgram/ml. On the basis of our data, a cimetidine dosage of 20 to 30 mg/kg/day administered in six divided doses should provide for average steady-state plasma cimetidine concentrations of 1.3 to 2.0 micrograms/ml.
D000293:Adolescent; D001930:Brain Injuries / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D002927:Cimetidine / Q000032:analysis / Q000378:metabolism / Q000627:therapeutic use*; D003422:Critical Care; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D013270:Stomach / Q000032:analysis
D002927:Cimetidine