Do Continuous Infusions of Omeprazole and Ranitidine Retain Their Effect With Prolonged Dosing?

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1 GASROENEROLOGY 1994;106:60-64 Do Continuous Infusions of Omeprazole and Ranitidine Retain heir Effect With Prolonged Dosing? HANS S. MERKI and CLIVE H. WILDER-SMIH Gastrointestinal Unit, Department of Medicine, Inselspital, University of Bern, Bern, Switzerland Background/Aims: Prolonged infusions of H2-antag~ nists are commonly used in intensive care units, although little is known about their antisecretory efficacy beyond the initial "24 hours of dosing. he aim of this study was to assess the antisecretory effects of infusions of ranitidine and omeprazole for a period of 72 hours. Methods: welve healthy volunteers received individually titrated 72-hour intravenous infusions of omeprazole, ranitidine, or placebo in a double-blind, crosso~er study. Gastric ph and dosing requirements were compared. Results: he median percentage of time with ph > 4 (interquartile range) was 93% (88%- 95%) on day 1 and 96% (94%-99%) on day 3 with omeprazole and 67% (56%-78%) and 43% (31%-51%), respectively, with ranitidine (both P < vs. omeprazole),. he mean doses (_+SD) required on days 1 and 3 for omeprazole were _+ 44 mg and _+ 37 mg (P < ), and ranitidine doses were _+ 76 mg and _+ 25 mg, respectively (P ~- 0.05). Conclusions: Omeprazole infusions consistently maintained gastric ph above 4 over a period of 72 hours with progressively lower doses. Significant tolerance to the antisecretory effect of ranitidine infusion developed in 72 hours, which was not overcome despite individually titreted doses of more than 500 m g/24 hours. Consequently, application of pharmacodynamic results of single-day H=-blocker and protonpump inhibitor studies to prolonged infusion trials for stress ulcer-related bleeding is inappropriate. he antisecretory effect of intravenous omeprazole has been shown to become more consistent with repeated or continuous dosing. ~-5 Conversely, it is apparent that the antisecretory efficacy of H2-receptor antagonists decreases with repeated oral dosing in healthy volunteers. 6-~ Further evidence suggests that the efficacy of infusions of H2-blockers may also be substantially decreased in the first days of dosing, tz-~3 However, to date no prospective or controlled studies have been performed to investigate the pharmacodynamic efficacy of prolonged intravenous infusions of H2-blockers or omeprazole. It is important to know more about the long-term efficacy of H2-receptor antagonists and the recently developed intravenous infusion formulation of omeprazole became infusions ofantisecretory agents are commonly used in stress ulcer prophylaxis and in the treatment of active gastrointestinal bleeding) 4 In a recent large study, 72- hour infusions of the potent H2-receptor antagonist famotidine followed by oral dosing failed to show any beneficial effect in the treatment of peptic ulcer hemorrhage) 5 he famotidine regimen was chosen on the basis of single-day pharmacodynamic studies. However, there is no information on the ability of this regimen to maintain the accepted ph target of at least 4 with prolonged dosing over several days.*6'17 A progressive loss of effect of infusions of H2-antagonists could explain the ambiguous clinical efficacy of these drugs in the intensive care unit..8,~9 he aim of this study was to assess the efficacy of infusions for a period of 3 days ofranitidine and omeprazole in maintaining the intragastric ph above 4. he randomized crossover study was performed in healthy volunteers. Individual titration of the doses required to maintain ph control was possible with the use of a ph feedback-controlled infusion pump, providing an estimate of the dose-responsiveness during prolonged infusions. ~ 2, Materials and Methods welve healthy volunteers, 5 women and 7 men (mean age, 25.4 years; range, 20-31), participated in a randomized, three-way crossover, double-blind study comparing 72-hour infusions of omeprazole (Antra infusion solution; Astra H~ssle AB, M01ndal, Sweden), ranitidine (Zantic; Glaxo AG, Berne, Switzerland), and placebo (0.9% NaCI). On the first day of each study arm, all subjects had a meal between noon and 1 Vl~ and then fasted until the start of the study. Between 7 and 8 pm, a combined glass ph electrode (Ingold 440 M4, Urdorf, Switzerland) w~ positioned transnasally in the gastric body, and an intravenous catheter was 1994 by the American Gastroenterologlcal'Assoclatlon /94/$3.00

2 January 1994 OMEPRAZOLE AND RANIIDINE INRJSIONS 61 A %ph>4 90 n=12 B C %ph>4 n= 12 % PH >r-4 ez 80 7o- I I : D I ' I, o - ~ I I 0 J Day 3 A/172 h I Day I I Day 2 I Day 3 n=12 Figure 1. Box-Whisker plots of the percentage of time with gastric ph > 4 during intravenous feedback-regulated infusions of (A) placebo, (B) ranitidine, and (C) omeprazole. he~ntire 72-hour period and the individual days 1-3 are shown. See Appendix for explanation of Box- Whisker plots. placed in a forearm vein for infusion of the study drug. ph measurements, priming doses, and infusions began simultaneously at 8 PM. Priming doses of 80 mg omeprazole, 50 mg ranitidine, or placebo (0.9% NaCl) were infused for 30 minutes in 100 ml 0.9% NaCI. he 72-hour infusions of omeprazole, ranitidine, or placebo began simultaneously in the respective groups. All infusions were given using the previously validated ph feedback-controlled infusion system (Gastrojet; Medical Instruments Corp., Solothum, Switzerland), which was programmed to maintain the gastric ph above a target of 5.12'*~'2 '2~ he ph feedback device consists ofa ph datalogger registering the median ph every 5 seconds and a microprocessor-controlled pump. he pump has 11 freely programmable infusion rates, between which the processor chooses to maintain the desired ph target. Minimum and maximum infusion rates in this study were 2 and 12 mg/h for omeprazole (maximum 24-hour dose, 288 mg) and 4 and 24 mg/h for ranitidine (maximum 24-hour dose, 576 mg), respectively. All infusions were changed every 12 hours to ensure stability of the infusions. In the placebo group, any of the above infusion rate programs were used. Intravenous hydration was maintained with 1000 ml 0.9% NaCl/12 h. hroughout the following 72-hour study period, standardized meals were given at 8 AM, 12 noon, 4 PM, 6 PM, and 10 PM. he ph of the meals was between 5 and 6. No further food or drink, except for small sips of tap water, was allowed. Smoking or chewing gum were prohibited, add subjects remained in the research ward for the entire study duration. here was a washout period of 10 days between study arms. Confirmative statistical analysis of the percentage time of ph ~ 4 (Wilcoxon signed-rank test) and the drug doses (Student's t test for paired samples, two-tailed) used in the complete 72 hours and the individual 24-hour periods was prede- fined. he median ph in these time periods was analyzed descriptively. All volunteers gave their written informed consent, and University Ethics Committee approval was obtained for the study. Results he data from all 12 volunteers were evaluated. Because of equipment failure, data on individual days was excluded from analysis for one volunteer in the placebo arm, one with ranitidine dosing on day 2, and another with ranitidine on days 2 and 3. Intragastric Acidity Box-Whisker plots of the percentage of time of ph > 4 are shown for the entire 72-hour period and for individual days 1, 2, and 3 in Figure 1. he median ph with omeprazole infusion was 5.5 (interquartile range, ) in the entire 72-hour period; it was 5.5 ( ) on day 1, 5.4 ( ) on day 2, and 5.5 ( ) on day 3. Corresponding values with ranitidine were 4.0 ( ), 4.6 ( ), 4.0 ( ), and 3.5 ( ) (all P < vs. omeprazole on respective days). In the placebo group, the median ph in the 72- hour period and on days 1, 2, and 3 was 1.7 ( ), 1.6 ( ), 1.7 ( ), and 1.6 ( ), respectively. he 72-hour ph-time profiles are illustrated ' in Figure 2. Drug Doses he doses of omeprazole and ranitidine required on days 1, 2, and 3, including the initial boll on day 1,

3 62 MERKI AND WILDER-SMIH GASROENEROLOGY Vol. 106, No. 1 A 3,0 A ph I I I 8. ' ; s ' E 150, o "~ 1 O0 :4 o,,, O doy 600 -Pt ' ' I ~. 500 I~ t $ dock ~me.fc,,ee 400 II) m e-.o m r- ~ I I I doy O I ~ csock ~e Figure 2. Median ( ) and individual ( ) 72-hour gastric ph time profiles during intravenous feedback-regulated infusions of (A) placebo, (B) ranitidine, and (C) omeprazole. Mealtimes are denoted with arrows. Rgure 3. Doses of (A) omeprazole and (B) ranitidine given by ph feedback-controlled infusion pump to maintain ph above 4 on days 1, 2, and 3. Symbols denote individual doses; lines connect the group mean doses. Maximum daily doses allowed were 288 mg of omeprazole (plus 80-mg bolus on day 1) and 576 mg of ranitidine (plus 50-mg bolus on day 1). are shown in Figure 3. he mean doses of omeprazole required were lower on days 2 and 3 than on day 1 (P <0.0001) and lower on day 3 than on day 2 (P < 0.05). he mean doses of ranitidine were progressively higher on days 2 and 3 than on day 1 (day 1 vs. day 2, P = 0.06; day 1 vs. day 3, P = 0.05; day 2 vs. day 3, not significant). Discussion With continuous and individually titrated infusions of omeprazole, gastric ph was maintained above 4 for over 95% of the 72-hour study period. his effect was achieved from the first infusion day onwards, but the doses of omeprazole required decreased by 43% from the first day to the third. An opposite effect was observed with ranitidine infusions, in which increasing doses approaching the ceiling doses allowed were progressively less able to maintain gastric ph > 4. It is apparent that the tolerance developing to ranitidine within the first 72 hours cannot be overcome, even with doses of >500 mg/ 24 h. By the third day of dosing, the ph was <4 for more than 12 hours in 9 of 12 volunteers. hese data

4 January 1994 OMEPRAZOLE AND RANIIDINE INFUSIONS 63 compare well with earlier studies in which tolerance developed during oral dosing of ranitidine could not be overcome with individually ph feedback-titrated infusion doses of more than 500 mg/24 h.3 or more than 700 mg/24 h 12 of ranitidine. he tolerance during infusions of ranitidine developed within 48 hours and progressed further in the third day of dosing. It remains uncertain whether a further loss of effect would occur with continued dosing. However, it is clear that previous studies examining the efficacy of H2-blocker infusions in preventing or treating stress ulcer-related hemorrhage were fallacious in assuming that the antisecretory effect is maintained unchanged with prolonged dosing. he dosage regimens used in these studies have been based on 24-hour pharmacodynamic studiesj 5 he results become even more difficult to inter- Appendix he followirig is an Whisker plots in Figure 1. ~2 ~ ,4- explanation of the Box- 2 values further than 2 times the IQD Value within 1.5 to 2 times the IQD from the 3rd quarljle Value within 1 to 1.5 times the IQD Greatest value within one IQD 3rd quarble.a~erage / Smallest value within one IQD from the 1st quartile Value within 1 to 15 times the IQD from the 1st quarli]e 2 values within 1,5 to 2 times the IQD from the 1st quarse Interquartile distance (IOI3) One value further than 2 lbnes the IQD from the 1st quarl]]e pret ifmultiday infusions are followed by oral H2-blocker dosing, '5 in which tolerance is an established phenomenon in a population without duodenal ulcer disease. 6-t It can be speculated that the ambiguous efficacy of infusions (and possibly also of boli) of H2-blockers may in part be attributed to the failure to rfiaintain the postulated critical ph target of at least 4 because of tolerance. 15,, he progressive development of tolerance to intravenous ranitidine was clearly shown in an earlier, uncontrolled study in infants, but received little further attention.' Infusions of omeprazole can consistently fulfill the current guidelines for elevation of gastric phfcr stress ulcer prophylaxis and the treatment of established upper gastrointestinal bleeding. he marked tolerance seen during prolonged infusions of ranitidine implies that ph control with H2-antagonists in these indications is insufficient. In light of this, previous studies on clinical efficacy must be interpreted with caution. References 1. Baak LC, Jansen JBMJ, Lamers CBHW. Effect of intravenous omeprazole on intragastric ph during intravenous infusion of amino acids. Dig Dis Sci 1990;35: Baak LC, Biemond I, Jansen JBMJ, Lamers CBHW. Repeated intravenous bolus injections of omeprazole: effects on 24 h intragastric ph, serum gastrin, and serum pepsinogen A and C. Scand J Gastroenterol 1991;26: Jansen JBMJ, Lundberg P, Baak LC. Effect of single and repeated doses of omeprazole on pentagastrin-stimulated gastric acid secretion and pharmacokinetics in man. Gut 1988;29: Wilder-Smith CH, Gwerder C, Hurlimann S, Merki HS. Dosing requirements during omeprazole infusions diminish with time: individually titrated and constant infusions of omeprazole over 48 h (abstr). Gastroenterology 1993;104:A Cederberg C, hompson ABR, Kirdeikis P, Kristersson C. Effect of continuous intravenous infusion of omeprazole on 24-hour intragastric ph in fasting DU-patients: comparison to repeated bolus doses of omeprazole or raniudine (abstr). Gastroenterology 1992; 102:A Wilder-Smith CH, Ernst, Genonni M, Zeyen B, Halter F, Merki HS. olerance to oral H2-raceptor antagonists. Dig Dis Sci 1990;8: Wilder-Smith CH, Halter F, Ernst, Genonni M, Zeyen B, Varga L, Roehmel J J, Merki HS. Loss of acid suppression during dosing with H2-receptor antagonists. Aliment Pharmacol her 1990;4(Suppl 1): Smith JL, Gavey C, Nwokolo CU, Pounder RE. olerance during 8 days of high-dose H2-blockade. Aliment Pharmacol her 1990;4(Suppl 1): Rogers M J, Holmfield JHM, Primrose JN, Johnston D. he effect of 15 days dosing with placebo, sufotidine 600 mg nocte or sufotidine 600 mg twice dally upon 24-hour Intragastric acidity ' and 24-hour plasma gastrin. Aliment Pharmacol her 1990; 4(Suppl 1): Nwokolo CU, Smith JL, Gavey C, Sawyerr AM, Pounder RE. olerance during 29 days of conventional dosing with clmetidlne, nizato idine, famotidlne or ranitidine. Aliment Pharmacol her 1990;4(Suppl 1):29-45.

5 64 MERKI AND WILDER-SMIH GASROENEROLOGY Vol. 106, No. 1 idine, famotidine or ranitidine. Aliment Pharmacol her 1990;4(Suppl 1): Hyman PE, Garvey Q, Abrams CE. olerance to intravenous ranitidine. J Pediatr 1987; 110: Wilder-Smith CH, Halter F, HScki W, Merki HS. ph-feedback controlled infusions of ranitidine are no more effective than fixeddose infusions in reducing gastric acidity and variability in antisecretory responses. Br J Clin Pharmacol 1992;33: Merki HS, Wilder-Smith CH, Walt RP, Hunt R, Renner EL, Halter F. Differential circadian effects and development of tolerance to an H2-receptor antagonist (abstr). Gastroenterology 1990; 98:A Ballesteros MA, Hogen DL, Koss MA, Isenberg JI. Bolus or intravenous infusion of ranitidine: effects on gastric ph and acid secration. Ann Intern Meal 1990;112: Walt RP, Cottrell J, Mann SG, Freemantle NP, Langman MJS. Continuous intravenous famotidine for haemorrhage from peptic ulcer. Lancet 1992; 340: Fullarton GI~I, MacDonald AM, Mann SG, McColl KEL. Controlled study of the effects of intravenous famotidine on intragastric ph in bleeding ulcers. Aliment Pharmacol ]-her 1991; 5: Merki HS, Witzel L, Kaufmann D, Kempf M, Neumann J, R6hmel J, Walt RP. Continuous intravenous infusions of famotidine maintain high intragastric ph in duodenal ulcer. Gut 1988;29: Wilder-Smith CH, Merki HS. Antisecretory agents in stress ulcer prophylaxis: a critical reappraisal. Eur J Gastroenterol Hepatol 1992;4: Lacroix J, Infante-Rivard C, Jenicek M, Gauthier M. Prophylaxis of upper gastrointestinal tract bleeding in intensive care units: a meta analysis. Crit Care Med 1989; 17: Hannah A, Chesner IM, Merki HS, Walt RP. Use of automatic computerised pump to maintain constant tntragastric ph. Gut 1990; 31: Merki HS, Hunt RH, Walt RP, Wilder-Smith CH, Gennoni MA, Ernst, Zeyen B, Roehmel J, Halter F. A new programmable infusion pump for individual control of intragastric ph: validation and effect of ranitidine. Eur J Gastroenterol Hepatol 1991;3: Reid SR, Bayliff CD. he comparative efficacy of cimetidine and ranitidine in controlling gastric ph in critically ill patients. Can Anaesth Soc J 1986;33: Rigaud D, Chastre J, Accary JP, Bonfils S, Gibert C, Hance AJ. Intragastric ph profile during acute respiratory failure in patients with chronic obstructive pulmonary disease. Chest 1986; 90: Albin M, Friedlos J, Hillman K. Continuous intragastric ph measurement in the critically ill and treatment with parenteral ranitidine. Intensive Care Med 1985;11: Van den Berg B, Van Blankenstein M. Prevention of stress-induced upper gastrointestinal bleeding by cimetidine in patients on assisted ventilation. Digestion 1985; 31: Kingsley AH. Prophylaxis for acute stress ulcers: antacids or cimetidine. Am J Surg 1985;51: Received June 29, Accepted August 24, Address requests for reprints to: Hans S. Merkl, M.D., Bubenbergplatz 11, CH-3011, Berne, Switzerland. Supported by Astra H~ssle AB, M61ndal, Sweden.