Further Evidence for an Interaction between Alcohol and Certain H₂‐Receptor Antagonists

Abstract

EVERAL FACTORS control the rate and amount of S alcohol absorbed during acute oral intake including the rate of gastric emptying and the degree of first-pass metabolism. The putative interaction between some H2-receptor antagonists (H2RA) and alcohol is through inhibition of gastric alcohol dehydrogenase (ADH).4 This increases blood alcohol concentrations (BAC) and the absolute bioavailability of alcohol although the results have produced ~ontention.~-~ On the one hand it has been argued that the frequency of ingestion of alcohol and H2RA makes this a potential major concern' whereas on the other it has been suggested that the interaction is observed only under unusual experimental conditions.5** H2RA are among the most commonly taken drugs worldwide, and alcohol is the most commonly imbibed drug. Since alcohol is one of the commonest determinants of dyspepsia in the population," this issue is a potential public health concern.The objective of the present study was to examine for an interaction between different antisecretory drugs and alcohol at a potentially intoxicating dose. METHODSSix healthy male physicians (mean age 34 years, age range 29 to 42) were given alcohol on six separate occasions following pretreatment in random order with cimetidine 800 mg once daily, ranitidine 300 mg once daily, nizatidine 300 mg once daily, famotidine 40 mg once daily, or omeprazole 20 mg once daily for 6 days prior to each study. Subjects received an additional dose of the study medication on the day of alcohol administration. There was a 6-to 7day washout period between courses of medication.The absorption of alcohol was studied on each occasion after a 6-hr fast and I hr after eating a standard meal (one egg omelet, two slices of toast, and 200 ml of orange juice). Each subject then drank 400 ml of orange juice containing grain alcohol (0.75 g/kg of absolute ethanol equivalent). Blood alcohol levels were measured at 0, 15, 30, 45, 60, 90, and 120 min by gas chromatography. Data were compared using the paired two-tailed Student's t test. Area under the alcohol concentration/ time curve (AUC) was calculated using the linear trapezoidal rule.

Effect of histamine-2 receptor antagonists on blood alcohol levels

“…This analysis does not include one study, 25 because the fed or fasted status was not described. Regardless of food intake, cimetidine and ranitidine resulted in modestly higher serum 28 C,R 10 Fasted 0.5 DiPadova et al 2 C,R,F 6 Fed 0.3 Dobrilla et al 24 C 6 C,R,F 12 Fed 0.3 Fraser et al 4 C,R,F 23 Fed 0.8 Fraser et al 18 R 20 Fed 0.3 Guram et al 3 C,R,F,N 6 Fed 0.75 Hernandez-Munoz et al 14 C,F 5 Fed 0.15 Jonsson et al 27 C,R 12 Fasted 0.8 Kendall et al 20 C,R,F 24 Fed 0.5-0.8 Mallat et al 15 C,R,F 12 Fed 0.3 Palmer et al 17 C 23 Fed 0.15 Palmer et al 17 C,R,N 23 Fed 0.15 Papke et al 26 C 10 Fasted 0.8 Raufman et al 5 C,R,F,N 23 Fed 0.3 Seitz et al 13 C,R 8 Fed 0.8 Sharma et al 16 C 11 Fed 0.3 Tanaka & Nakamura 22 C,R,F 6 Fasted 0.8 Toon et al 29 R 18 Fed/Fasted 0.5 Webster et al 25 C,R 7 Not 0.7 * C indicates cimetidine; R, ranitidine; F, famotidine; N, nizatidine. alcohol levels, while famotidine had no effect.…”

“…The average change variance was derived from 17 comparisons reported in 11 studies. 2,3,[12][13][14][15][16][17][18][19][20] Two other choices of weights described by Follmann et al 11 gave similar results, so only the results using sample size weights are presented.…”

“…Early studies suggested that cimetidine, ranitidine, and nizatidine, but not famotidine, increased blood ethanol levels in volunteers when administered concurrently with alcohol. [1][2][3][4] Subsequent studies have reached conflicting results. 5 Many of these reports have been criticized regarding issues of study design including small sample sizes, heterogeneity of study populations, amount and timing of alcohol ingestion, and the fed or fasted status of participants.…”

Bioavailability of Alcohol: Role of Gastric Metabolism and Its Interaction with Other Drugs

“…nor is apparent in the entire series of studies, in which the blood levels before H?-blocker administration were not consistently lower in the responders. Moreover, in the same or in a similar population which showed significant effects of either cimetidine or ran itidine, famotidine had none [33,83,107]. The trend toward a 23% increase in AUC pro duced by famotidine after a small alcohol dose in an unselected population [33] with substantial preexisting FPM was selected [108], although this is a small effect compared to the 77% increase produced by cimetidine under the same conditions in nonselected populations [33,76].…”

“…Some studies aimed at reaching levels associ ated with gross intoxication have been carried out with single doses as large as 1.5 g/kg [113], at which the contribution of the FPM to the blood levels is minimal [2,3] and the lack of effect of cimetidine can be anticipated. Nev ertheless, in some of the studies with alcohol doses of 0.75-0.8 g/kg [86,107,114] the blood alcohol levels after treatment with Hireceptor antagonists exceeded the legal limits for driving of many countries, including some states in the USA [115], and one documented a significant rise in intoxication scores associ ated with the cimetidine-induced increase in BAC [114], The legal limits have been pro gressively decreasing as the evidence for clini cally significant impairment is obtained at much lower blood alcohol levels. Impaired performance of complex psychomotor tasks has been reported at BAC as low as 15 mg/dl or 3.3 mM [116,117] and impaired judgemenl has been documented at 25 mg/dl or 5.4 m M [118], Thus, if we consider the data by DiPadova et al [83], on the average, an individual taking ranitidine will reach BACs above those at which impaired judgement was detected and impairment to perform complex tasks will persist for a longer time than when the same dose of alcohol (0.3 g/kg) is imbibed in the absence of ranitidine administration ( fig.…”