Gut, 1991,32, 1455-1460 1455 Rebound intragastric hyperacidity after abrupt withdrawal ofhistamine H2 receptor blockade Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from C U Nwokolo, J T L Smith, A M Sawyerr, R E Pounder Abstract an extensive research programme investigating In a series of 24 hour studies, intragastric the phenomenon of tolerance during continued acidity and plasma gastrin concentration were H2 blockade.'2 '4 measured simultaneously in 46 healthy sub- jects before, during, and 24 to 48 hours after abrupt withdrawal of a histamine H2 receptor Methods antagonist regimen. For 34 days subjects were given either cimetidine 800 mg at night (n=8), SUBJECTS AND DRUG REGIMENS ranitidine 150 mg twice daily (n= 10), ranitidine Forty six of48 healthy men completed the study. 300 mg at night (n= 12), nizatidine 300 mg at Their median age was 21 years (range 19 to 24 night (n=8), or famotidine 40 mg at night years), median weight was 74 kg (range 60 to 96 (n=8). All subjects responded to H2 blockade kg), and median height was 1'80 m (range 1.67 to by a decrease in 24 hour intragastric acidity. 1-93 m). Twenty four smoked cigarettes (4-20 Withdrawal ofH2 blockade resulted in a signifi- cigarettes per day). None had been dosed with an cant rise in median nocturnal integrated intra- antisecretory drug for at least eight weeks before gastric acidity in 42 of46 subjects (+36%; 95% entry to this study. CI +19, +55%) compared with prestudy This study was 'open label,' and all the H2 values, but this rise was not associated with a blockers were supplied by the pharmacy of the significant change in the median integrated Royal Free Hospital, London. plasma gastrin concentration (+1%; 95% CI The subjects received no antisecretory drug -12, +13%). A statistically significant rise during the first 24 hour simultaneous study of in nocturnal acidity was observed after all intragastric acidity and plasma gastrin concen- regimens, except after dosing with famotidine. tration. They were then randomly assigned to After stopping, median daytime integrated receive one ofthe following regimens: cimetidine acidity and plasma gastrin concentrations in 800 mg at night (Smith Kline & French Labora- the whole group were raised, but not signifi- tories Ltd, n=8),'2 either ranitidine 300 mg at http://gut.bmj.com/ cantly: values were +15% (95% CI +4, +34%) night (n=12) or ranitidine 150 mg twice daily and +5% (95% CI -2, +12%), respectively. A (n= 10) (Glaxo Laboratories Ltd); nizatidine 300 statistically significant increase in daytime mg at night (n=8) (Eli Lilly and Co Ltd),'2 or acidity was observed only after dosing with famotidine 40 mg at night (n=8) (Thomas ranitidine. In conclusion, intragastric hyper- Morson Pharmaceuticals). 12 The experiments acidity occurs in most subjects after abrupt involving cimetidine, nizatidine, and famotidine withdrawal of a histamine H2 receptor blocker, were extensions of previously published studies on September 29, 2021 by guest. Protected copyright. but this phenomenon is not associated with investigating 'tolerance,' but the ranitidine hypergastrinaemia. experiments were not part of the earlier 'tolerance' experiments. 12 The subjects were dosed with an H2 receptor antagonist for 34 days, When the histamine H2 receptor antagonists and 24 hour profiles of intragastric acidity and were introduced for the management of peptic plasma gastrin concentration were measured for ulceration, there was concern that they would assessment of antisecretory activity on day 29 of induce a surge of gastric acid secretion in the dosing. The final 24 hour study of acidity and days or weeks after their withdrawal.' Experi- plasma gastrin concentration was begun 24 hours ments were performed to explore this possibility, after the last oral dose ofeach H2 blocker. but most reported that no rebound hypersecre- tion could be detected.2"'A It came as a surprise when Fullarton et al" EXPERIMENTAL DESIGN reported rebound nocturnal hypersecretion of The subjects were studied using the Royal Fzee acid occurring after four weeks of treatment with Hospital protocol,'2"' with minor changes as University Department of nizatidine mg at a Medicine, Royal Free 300 night. They found, in specified below. The subjects began fasting at Hospital School of group of eight duodenal ulcer patients, that 1330 hours, and were provided with a standard Medicine, London mean nocturnal acid output was 39.4 mmol/10 light supper at 1815 hours. They had nothing to C U Nwokolo hours before treatment, but rose significantly to eat or drink until 2130 hours, when a 10 FG J T L Smith A M Sawyerr 74-1 mmol/10 hours when measured two days Salem Sump nasogastric tube (Argyle Medical, R E Pounder after stopping. They observed no significant Crawley, West Sussex) was positioned in the Correspondence to: change in daytime intragastric acidity. stomach; its position was checked by a water Dr R E Pounder, University Department of Medicine, The object of this series of experiments was to recovery test. Aliquots (5-10 ml) of intragastric Royal Free Hospital School of measure 24 hour intragastric acidity and plasma contents were aspirated hourly throughout the Medicine, Pond Street, London NW3 2QG. gastrin concentration before, during, and after study, and the pH of each aliquot was measured Accepted for publication five different H2 antagonist regimens. These immediately to the nearest 0.01 pH unit by 18 March 1991 experiments were performed in conjunction with means of a glass electrode and digital pH meter 1456 Nwokolo, Smith, Sawyerr, Pounder LU r , Day 0 Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from 1001 N N Day 29 Day 36 801F Day 36 0 E E 60 V ci Figure 1: 24 hour median 401F hourly intragastric acidity before dosing (), on day 29 ofdosing (-4--), and 24 20 hours after stopping cimetidine 800 mg at night (0 ), in eight healthy 5 a a a a 9 a a a a A a a a a a a a a a subjects. N=nightcap, B= 0 breakfast, C=coffee, L= 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 lunch, T=tea, D=dinner. Time (hours) 120 Day 0 0 100 Day 29 Day 36 80 ....... 0E E 60 40 Figure 2: 24 hour median 20 hourly acidity before dosing (-0-), on day 29 ofdosing (-4-), and 24 hours after 0 stopping ranitidine 150 mg http://gut.bmj.com/ twice daily( a , in 10 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 healthy subjects. Time (hours) 120 Day 0 Day 29 on September 29, 2021 by guest. Protected copyright. Day 36 .......* .... 0 E E E C.) Figure 3: 24 hour median hourly intragastric acidity before dosing (-0-), on day 29 ofdosing (-4), and 24 hours after stopping - ranitidine 300 mg at night (* a), in 12 healthy 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 subjects. Time (hours) (Radiometer, Copenhagen). The electrode was Newbury). The tubes were centrifuged immedi- calibrated with standard buffers (pH 7-00, 4.01, ately, and the plasma transferred to plastic tubes and 1.09; Radiometer, Copenhagen) before and and frozen to -20°C. All the plasma samples after every six samples in each hourly batch of from each subject were analysed for gastrin in aspirates. one batch, by radioimmunoassay using the anti- Every hour from 2300 hours to 2300 hours the body GAS 179 in Professor Bloom's laboratory next day (apart from 0100, 0300, 0500, and 0700 at the Royal Postgraduate Medical School hours) blood was taken via a venous cannula for London. 16 assay of the plasma gastrin concentration. The The subjects were fully ambulant around the blood was collected in lithium heparin tubes ward during the study. The food and environ- which contained 0-2 ml aprotinin (Bayer UK Ltd, mental conditions for all studies were identical to Rebound intragastric hyperacidity after abrupt withdrawal ofhistamine H2 receptor blockade 1457 120 Day 0 Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from 100 N A B Day 29 I Day 36 <80 l 60 < 40 Figure 4: 24 hour median 20 hourly intragastnc acidity before dosing (-4-), on day 29 ofdosing (-4), and 24 hours after stopping 0 * nizatidine 300mg at night 23 24 1 2 3 4 5 6 7 8 9 10 (- ),ineight healthy subjects. Time (hours) 120 _ Day 0 0 100oo N B C L T D N Day 29 Day 36 80 .......* .. 0 E E 60 : a U 40 V Figure 5: 24 hour median hourly intragastric acidity 20 h before dosing (-4-), on day 29 ofdosing (@--), and 24 http://gut.bmj.com/ hours after stopping 0 famotidine 40 mg at night (* a), in eight healthy 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 subjects. Time (hours) those used in earlier experiments at the Royal ing dose of ranitidine 150 mg was taken by one Free Hospital.'5 The standard meals (bedtime group at 0830 hours. snack, breakfast, coffee, lunch, tea and dinner) on September 29, 2021 by guest. Protected copyright. were eaten at 2245, 0815, 1045, 1315, 1545, and 1815 hours, respectively. The bedtime doses of STATISTICAL ANALYSES medication were taken at 2305 hours; the morn- Profiles ofintragastric acidity and plasma gastrin concentration and were obtained for each sub- TABLE I Median integrated nocturnal (2400-0800 hours) intragastric acidity (mmol.hll) in 46 healthy subjects before, during, and after dosing with an H2 antagonist regimen ject.