Pharmacolunetics and ~harmacodvnarnics of ranitidine after burn injury J
l .
The pharmacokinetics and pharmacodynarnics of ranitidine were studied in 10 hypermetabolic burned patients with normal creatinine clearance and compared with healthy volunteers. Ranitidine was administered as a single 50 mg intravenous bolus and multiple blood samples were obtained up to 10 hours after the dose for determination of plasma ranitidine concentrations. Gastric pH in burned patients was monitored by way of a nasogastric tube. Burned patients exhibited significanlty higher (p < 0.01) rani1.71 ml/min/kg) and steady-state distributidine clearance (mean + SD; 10.80 i. 2.38 versus 7.53 tion volume (1.63 + 0.13 versus 1.16 + 0.33 Lkg). Within an hour of administration of drug the gastric pH was 24.0 in all but one patient. This pH was maintained for at least 6 hours. In five patients the pH was 24.0 throughout the 10-hour study. Thus, despite increased ranitidine clearance, the recommended dose of ranitidine maintained gastric pH 24.0 throughout the normal dosing interval in the majority of patients. Dosage adjustment reported for many other drugs after burn injury may not be necessary for ranitidine. (CLINPHARMACOL THER1992;51:408-14.)
*
J. A. J. Martyn, MD, A. L. Bishop, PhD, and M. P. Oliveri, RN Boston, Mass.,and Research Triangle Park, N.C.
Acute stress ulceration of the stomach and duodenum is the most common gastrointestinal complication of bum injury.' In postmortem studies more than 100 years ago curling2 described its appearance in burned patients. More recently Czaja et al., 3 by endoscopic evaluation, documented that acute stress ulceration develops within 72 hours of bum injury in patients with greater than 40% body surface area (BSA) burn.3 Although hyperacidity does not appear to be a causative factor, the use of acid neutralizing agents decreases the incidence of this ~ o m ~ l i c a t i o The n . ~ therapeutic maneuvers used to neutralize acidity include early enteral feeding and the administration of oral antacids or H2-receptor antagonists.5 The presence of bum- or sepsis-induced intestinal ileus precludes the enteral adFrom the Clinical Pharmacology Laboratory, Department of Anesthesiology, Harvard Medical School, and Anesthesia Services, Massachusetts General Hospital and Shriners Bums Institute, Boston, and Clinical Development, Glaxo Inc., Research Triangle Park. Supported by grants from National Institutes of Health, Bethesda, Md. (GM31569); Shriners Bums Institute Boston, Mass.; and Glaxo Inc., Research Triangle Park, N.C. Received for publication March 6, 1991; accepted h . 30, 1991. Reprint requests: J. Martyn, MD, Clinical Pharmacology Laboratory, Department of Anesthesia, Massachusetts General Hospital, Boston, MA 021 14. 1311134686
ministration of food and oral antacids because of the danger of pulmonary aspiration of gastric contents. In these instances, parenterally administered H,-receptor antagonists are useful. Previous studies have documented decreased efficacy of cimetidine in burned patients.6-8 This decreased efficacy was related to increased cimetidine clearance (CL) attributable to the hypermetabolic state that accompanies thermal i n j ~ r y Altered .~ pharmacodynamics also plays a role.7 Alternative drugs for control of gastric pH in burned patients have not been evaluated. This study was carried out to examine the pharmacokinetics and pharmacodynamics of ranitidine in burned patients relative to healthy volunteers.
METHODS Study population. Patients with bum sizes that exceed 35% of BSA and healthy volunteers of comparable age, weight, and sex were enrolled in the study. The healthy patients were paid volunteers from the Boston area. The demographics of the study population are indicated in Table I. The burned patients were studied in the hypermetabolic phase, which begins approximately 48 hours after injury9 and persists until wound coverage is complete.' Clinical signs of the hypermetabolic state included tachypnea, tachycardia, and pyrexia. All subjects in this study demonstrated normal renal function assessed by measurement of
VOLUME 51 NUMBER 4
BUN (
l .
The pharmacokinetics and pharmacodynarnics of ranitidine were studied in 10 hypermetabolic burned patients with normal creatinine clearance and compared with healthy volunteers. Ranitidine was administered as a single 50 mg intravenous bolus and multiple blood samples were obtained up to 10 hours after the dose for determination of plasma ranitidine concentrations. Gastric pH in burned patients was monitored by way of a nasogastric tube. Burned patients exhibited significanlty higher (p < 0.01) rani1.71 ml/min/kg) and steady-state distributidine clearance (mean + SD; 10.80 i. 2.38 versus 7.53 tion volume (1.63 + 0.13 versus 1.16 + 0.33 Lkg). Within an hour of administration of drug the gastric pH was 24.0 in all but one patient. This pH was maintained for at least 6 hours. In five patients the pH was 24.0 throughout the 10-hour study. Thus, despite increased ranitidine clearance, the recommended dose of ranitidine maintained gastric pH 24.0 throughout the normal dosing interval in the majority of patients. Dosage adjustment reported for many other drugs after burn injury may not be necessary for ranitidine. (CLINPHARMACOL THER1992;51:408-14.)
*
J. A. J. Martyn, MD, A. L. Bishop, PhD, and M. P. Oliveri, RN Boston, Mass.,and Research Triangle Park, N.C.
Acute stress ulceration of the stomach and duodenum is the most common gastrointestinal complication of bum injury.' In postmortem studies more than 100 years ago curling2 described its appearance in burned patients. More recently Czaja et al., 3 by endoscopic evaluation, documented that acute stress ulceration develops within 72 hours of bum injury in patients with greater than 40% body surface area (BSA) burn.3 Although hyperacidity does not appear to be a causative factor, the use of acid neutralizing agents decreases the incidence of this ~ o m ~ l i c a t i o The n . ~ therapeutic maneuvers used to neutralize acidity include early enteral feeding and the administration of oral antacids or H2-receptor antagonists.5 The presence of bum- or sepsis-induced intestinal ileus precludes the enteral adFrom the Clinical Pharmacology Laboratory, Department of Anesthesiology, Harvard Medical School, and Anesthesia Services, Massachusetts General Hospital and Shriners Bums Institute, Boston, and Clinical Development, Glaxo Inc., Research Triangle Park. Supported by grants from National Institutes of Health, Bethesda, Md. (GM31569); Shriners Bums Institute Boston, Mass.; and Glaxo Inc., Research Triangle Park, N.C. Received for publication March 6, 1991; accepted h . 30, 1991. Reprint requests: J. Martyn, MD, Clinical Pharmacology Laboratory, Department of Anesthesia, Massachusetts General Hospital, Boston, MA 021 14. 1311134686
ministration of food and oral antacids because of the danger of pulmonary aspiration of gastric contents. In these instances, parenterally administered H,-receptor antagonists are useful. Previous studies have documented decreased efficacy of cimetidine in burned patients.6-8 This decreased efficacy was related to increased cimetidine clearance (CL) attributable to the hypermetabolic state that accompanies thermal i n j ~ r y Altered .~ pharmacodynamics also plays a role.7 Alternative drugs for control of gastric pH in burned patients have not been evaluated. This study was carried out to examine the pharmacokinetics and pharmacodynamics of ranitidine in burned patients relative to healthy volunteers.
METHODS Study population. Patients with bum sizes that exceed 35% of BSA and healthy volunteers of comparable age, weight, and sex were enrolled in the study. The healthy patients were paid volunteers from the Boston area. The demographics of the study population are indicated in Table I. The burned patients were studied in the hypermetabolic phase, which begins approximately 48 hours after injury9 and persists until wound coverage is complete.' Clinical signs of the hypermetabolic state included tachypnea, tachycardia, and pyrexia. All subjects in this study demonstrated normal renal function assessed by measurement of
VOLUME 51 NUMBER 4
BUN (
