(note "typical" UK dose of metronidazole is 400mg 3x daily)
(and the label with y instructions WILL tell you to avoid alcohol if it wasn't handwritten by a GP)
A man who had been in a drunken stupor for 3 days was given two "metronidazole" tablets (a total of 500 mg) one hour apart by his wife in the belief that they might sober him up. Twenty minutes after the first tablet he was awake and complaining that he had been given disulfiram (which he had taken some months before). Immediately after the second tablet, he took another drink and developed a classic disulfiram-like reaction with flushing of the face and neck, nausea and epigastric discomfort. 1 Other individual cases have been reported, 2 including a reaction with a "metronidazole" vaginal insert. 3
In a test of the value of "metronidazole" 250 mg twice daily as a possible drink-deterrent, all 10 alcoholic patients studied experienced some disulfiram-like reactions of varying intensity (facial flushing, headaches, sensation of heat, fall in blood pressure, vomiting) when given alcohol. 4 In another study in 60 alcoholic patients, given "metronidazole" 250 to 750 mg daily, most developed mild to moderate disulfiram-like reactions during an alcohol tolerance test. 5 A lower incidence of this reaction, between 2 and 24%, has also been reported. 6-8
Pharmaceutical preparations containing alcohol have also been implicated. A 2-year-old child became flushed and dyspnoeic when "metronidazole" was given with both Stopayne syrup (an analgesic/sedative combination) and a phenobarbital syrup, both of which contained alcohol. 9 Another reaction has been seen in a patient receiving intravenous "metronidazole" and a co-trimoxazole preparation containing alcohol 10%. 10 A further patient who had just finished a 7-day course of "metronidazole" developed severe, prolonged nausea and vomiting postpartum: she had received a single 800-mg dose of prophylactic clindamycin intravenously before the birth and it was thought that the benzyl alcohol present in the clindamycin preparation could have caused the reaction. However, other factors such as intrathecal anaesthesia may have also contributed to the adverse effects. 11 For mention of other preparations containing alcohol, see ‘Alcohol + Disulfiram’.
An interaction has also been reported in association with metabolic acidosis in an intoxicated man 4 hours after he was given intravenous "metronidazole" as prophylaxis following injury. 12 A fatality occurred in a frail 31-year old woman, which was attributed to cardiac arrhythmias caused by acetaldehyde toxicity resulting from the interaction between alcohol and "metronidazole", linked to autonomic distress caused by a physical assault. 13 Alcohol is also said to taste unpleasant 1,4 or to be less pleasurable 8 while taking "metronidazole". Some drug abusers apparently exploit the reaction for ‘kicks’. 14
In contrast, a study in 207 patients with inflammatory bowel disease, assessed using a phone survey, the presence of adverse reactions to alcohol in patients taking chronic "metronidazole" and/or mercaptopurine or neither drug; all of the patients consumed less than 4 alcoholic beverages per day. There was a trend towards more adverse effects in both the "metronidazole" and mercaptopurine study groups, but no statistically significant interaction between alcohol and "metronidazole" was found. 15 There are other reports, including two well-controlled studies, showing that "metronidazole" has no disulfiram-like effects. 16-18
Mechanism
Not understood. In the disulfiram reaction, the accumulation of acetaldehyde appears to be responsible for most of the symptoms, see Mechanism, under ‘Alcohol + Disulfiram’. Some workers have reported an increase in acetaldehyde levels due to the interaction between "metronidazole" and alcohol, 13 but others have reported no effect 18 or a reduction in plasma acetaldehyde levels. 19 Furthermore, some studies with "metronidazole" indicate a lack of a disulfiram-like reaction, 16,17 and it has been suggested that if such a reaction does occur it may be by a mechanism other than the inhibition of hepatic acetaldehyde dehydrogenase. 18 It appears that "metronidazole", like disulfiram, can inhibit other enzymes related to alcohol metabolism including xanthine oxidase and alcohol dehydrogenase. 20,21 Inhibition of xanthine oxidase may cause noradrenaline excess, and inhibition of alcohol dehydrogenase can lead to activation of microsomal enzyme oxidative pathways that generate ketones and lactate, which could produce acidosis. 12
(a) Alcoholic patients
A study into the effects of alcohol on "doxycycline" and tetracycline pharmacokinetics found that the half-life of "doxycycline" was 10.5 hours in 6 alcoholics (with normal liver function) compared with 14.7 hours in 6 healthy subjects. The serum "doxycycline" levels of 3 of the alcoholic patients fell below the generally accepted minimum inhibitory concentration at 24 hours. The half-life of tetracycline was the same in both groups. All of the subjects were given "doxycycline" 100 mg daily after a 200-mg loading dose, and tetracycline 500 mg twice daily after an initial 750-mg loading dose. 1
(b) Non-alcoholic patients
Single 500-mg doses of tetracycline were given to 9 healthy subjects with water or alcohol 2.7 g/kg. The alcohol caused a 33% rise in the maximum serum levels of tetracycline from 9.3 to 12.4 micrograms/mL, and a 50% rise in the AUC of tetracycline. 2 The clinical relevance of this rise is unknown.
Another study in healthy subjects found that cheap red wine, but not whisky (both 1 g/kg) delayed the absorption of "doxycycline", probably because of the presence of acetic acid, which slows gastric emptying. However, the total absorption was not affected. The authors concluded that acute intake of alcoholic beverages has no clinically relevant effects on the pharmacokinetics of "doxycycline". 3
Mechanism
Heavy drinkers can metabolise some drugs much more quickly than non-drinkers due to the enzyme-inducing effects of alcohol. 4 The interaction with "doxycycline" would seem to be due to this effect, possibly allied with some reduction in absorption from the gut.
Importance and management
Information is limited, but the interaction between "doxycycline" and alcohol appears to be established and of clinical significance in alcoholics but not in non-alcoholic individuals. One possible solution to the problem of enzyme induction is to give alcoholic subjects double the dose of "doxycycline", 5 or in some cases tetracycline may be a suitable non-interacting alternative. There is nothing to suggest that moderate or even occasional heavy drinking has a clinically relevant effect on any of the "tetracyclines" in non-alcoholic subjects.