Alcohol

Common Name: Alcohol

Clinical Name: Ethanol

Summary

Alcohol

chemical name: Ethanol

overview of interactions:
• substance affecting drug toxicity: Acetaminophen

• substance affected by drug: Acetylsalicylic Acid

• substance toxicity affected by drug: Cimetidine (Tagamet®)

• substance affecting drug performance and toxicity: Corticosteroids, including Prednisone

• substance affecting drug toxicity: Fluoxetine (Prozac®)

• substance affecting drug toxicity: Fluvoxamine

• substance affecting drug toxicity: Haloperidol

• substance affecting drug performance: Heparin

• substance affecting drug activity: Hydralazine

• substance affected by drug: Metronidazole (Flagyl®)

• substance affecting drug toxicity: Nitroglycerin

• substance toxicity affected by drug: Ranitidine (Zantac®)

• substance affecting drug toxicity: SSRI's (Selective Serotonin Reuptake Inhibitors)

• substance affecting drug toxicity: Sulfonylureas

• substance affecting drug toxicity: Tricyclic Antidepressants

• substance affecting drug toxicity: Valproic Acid

• pharmacokinetic interaction with herb: Panax ginseng (Chinese Ginseng)


Interactions

substance affecting drug toxicity: Acetaminophen

• mechanism: Acetaminophen consumption is especially risky for individuals who regularly consume excess amounts of alcohol as they can develop liver toxicity at lower levels of acetaminophen intake.
(Whitcomb DC, Block GD. JAMA 1994 Dec 21;272(23):1845-1850.)

• nutritional caution: Those who take acetaminophen more than occasionally should avoid drinking alcohol because of the increased risk of liver damage.

substance affected by drug: Acetylsalicylic Acid

• mechanism: Alcohol absorption can be enhanced by taking aspirin before drinking.

substance toxicity affected by drug: Cimetidine (Tagamet®)

• mechanism: Cimetidine inhibits gastric alcohol dehydrogenase, thus interfering with alcohol breakdown. As a result, serum alcohol levels increase substantially.

• dietary concern: Individuals taking cimetidine should avoid consumption of large amounts of alcohol, especially in close proximity to taking the drug.

substance affecting drug performance and toxicity: Corticosteroids, including Prednisone

• adverse interaction: Corticosteriods and alcohol are both well known for their tendency to irritate the digestion, particularly the stomach. Using alcohol at the same time one is taking such drugs is likely to increase the frequency and severity of these problems. Furthermore, alcohol can increase the risk of experiencing other serious side effects from cortisone and related substances. Anyone using steroidal anti-inflammatory drugs should avoid alcoholic drinks.
(Holt GA. 1998, 82; Pronsky Z. 1991, 60.)

• research: Research looking at individuals with chronic liver disease, some alcohol related and others not, found a marked deficiency of 11 beta-Hydroxysteroid dehydrogenase. 11 beta HSD, found predominantly in the liver and kidney, is responsible for the shuttling of active cortisol to cortisone. Stewart et al concluded that glucocorticoid excess in patients with chronic alcohol-related liver disease may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism.
(Stewart PM, et al. J Clin Endocrinol Metab 1993 Mar;76(3):748-751.)

substance affecting drug toxicity: Fluoxetine (Prozac®)

• mechanism: Dizziness and drowsiness are side effects commonly associated with fluoxetine, and other SSRI drugs.

• research: Naranjo and Bremner. along with fellow researchers, have published several studies which found that fluoxetine could decrease the desire to consume alcohol and assist in the reduction of alcohol intake in alcoholics .
(Naranjo CA, et al. Int Clin Psychopharmacol 1994 Sep;9(3):163-172; Naranjo CA, Bremner KE. EXS. 1994;71:209-219; Naranjo CA, Bremner KE. Alcohol Alcohol Suppl. 1993;2:221-229; Naranjo CA, et al. Clin Pharmacol Ther. 1990 Apr;47(4):490-498; Cornelius JR, et al Arch Gen Psychiatry 1997 Aug;54(8):700-705; Lejoyeux M. Alcohol Alcohol Suppl. 1996 Mar;1:69-75.)

• dietary concerns: Given the tendency of both fluoxetine and alcohol to cause disorientation and diminished motor control the combined use of these two substances represents serious risk to the user and those around them. Individuals taking fluoxetine should avoid consumption of alcohol during the course of treatment.

substance affecting drug toxicity: Fluvoxamine

• interaction: Fluvoxamine, along with other SSRI drugs, is known to cause dizziness or drowsiness and thereby increase the risk of accidental injury. The combination of alcohol and fluvoxamine may result in intensified drowsiness and greater risk of such injury.

• research: Individuals taking fluvoxamine should avoid consumption of alcohol while using the drug.

substance affecting drug toxicity: Haloperidol

• mechanism: Drowsiness and decreased coordination are common side effects of haloperidol. The consumption of alcohol by individuals taking haloperidol increases the risk of accidents and should be avoided. Furthermore, research with rat hearts indicates that ethanol potentiates haloperidol-induced electromechanical cardiac depression. It is interesting to note that haloperidol (and lorazepam) are commonly used to sedate ethanol-intoxicated patients in emergency rooms.
(Risinger FO, et al. Psychopharmacology (Berl). 1992;107(2-3):453-456; Broadbent J, et al. Psychopharmacology (Berl) 1995 Aug;120(4):475-482; Medlin RP Jr, et al. J Cardiovasc Pharmacol 1996 Dec;28(6):792-798.)

• dietary concerns: Individuals taking haloperidol should avoid consuming alcohol, alcohol-containing products, in order to minimize risk of adverse effects or accidents.

substance affecting drug performance: Heparin

• research: The consumption of alcohol by individuals undergoing heparin therapy has been associated with increased risk of excessive bleeding.
(Holt GA. 1998, 127.)

• dietary concerns: Individuals taking heparin should avoid the consumption of alcohol, or alcohol-containing substances.

substance affecting drug activity: Hydralazine

• mechanism: Hydralazine intentionally lowers blood pressure; alcohol also lowers blood pressure by dilating blood vessels. The use of alcohol while taking hydralazine could result in unintentionally lowering blood pressure to unsafe levels, thereby increasing the possibility of lightheadedness, dizziness and/or fainting and subsequent injury. Case reports also indicate the possibility of cardiac irregularities associated with this interaction, as well as aggravations of gastric lesions due to alcohol consumption.
(Smith BA, et al. Ann Emerg Med. 1992 Mar;21(3):326-330; Bhandare PN, et al. Indian J Physiol Pharmacol. 1992 Apr;36(2):130-132; Rataboli PV, et al. Indian J Physiol Pharmacol. 1993 Jan;37(1):88-90.)

• dietary concerns: Individuals taking hydralazine should avoid the consumption of alcohol, or alcohol-containing substances.

substance affected by drug: Metronidazole (Flagyl®)

• research: Metronidazole can produce a reaction similar to that of disulfiram (Antabuse) when administered to patients drinking ethanol. This drug/chemical interaction results in accumulation of acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and arrythmogenic. Typical symptoms include light-headedness, headache, facial flushing, nausea, stomach pains, and shortness of breath. Cases have been reported of fatal outcomes resulting from this interaction.
(Cina SJ, et al. Am J Forensic Med Pathol 1996 Dec;17(4):343-346; Tunguy-Desmarais GP. S Afr Med J. 1983 May 28;63(22):836; Plosker GL. Clin Pharm. 1987 Mar;6(3):189, 192-193; Harries DP, et al. Scott Med J. 1990 Dec;35(6):179-180.)

• dietary concerns: Individuals taking metronidazole should refrain from drinking alcohol and avoid consuming alcohol-containing products while taking the drug and for three days afterwards. It is also advisable to read all product labels carefully for alcohol content.

substance affecting drug toxicity: Nitroglycerin

• alcohol-related concerns: Consumption of alcohol while using nitroglycerin therapy has, in extreme cases, been found to cause low blood pressure and contribute to circulatory collapse. Alcohol should be avoided by anyone taking nitroglycerin.
(Threlkeld DS, ed. Apr 1992.)

substance toxicity affected by drug: Ranitidine (Zantac®)

• research: Ranitidine reduces alcohol breakdown causing serum alcohol levels to increase substantially. Studies with rats have indicate that ranitidine, and to some degree other H2-receptor antagonists, impair alcohol dehydrogenase (ADH) activity when taken at therapeutic doses. Ranitidine also demonstrated either mixed or competitive inhibition of rat hepatic ADH. Thus, in alcoholics and in social drinkers who require treatment with H2-receptor antagonists, the prescribing physicians might choose to prescribe famotidine, instead of ranitidine or cimitidine, as a less problematic H2 blocker. Of course, stopping alcohol consumption represents a more direct route to eliminating this risk and would most likely also provide significant benefits in reducing the symptoms for which the ranitidine was originally prescribed. Even so, the levels of alcohol intake necessary to induce this interactions may be significantly higher than commonly consumed by most social drinkers on any consistent basis.
(Caballeria J, et al. Dig Dis Sci 1991 Dec;36(12):1673-1679.)

substance affecting drug toxicity: SSRI's (Selective Serotonin Reuptake Inhibitors)

• mechanism: Dizziness and drowsiness are side effects commonly associated with SSRI drugs.

• research: Naranjo and Bremner. along with fellow researchers, have published several studies which found that fluoxetine could decrease the desire to consume alcohol and assist in the reduction of alcohol intake in alcoholics .
(Naranjo CA, et al. Int Clin Psychopharmacol 1994 Sep;9(3):163-172; Naranjo CA, Bremner KE. EXS. 1994;71:209-219; Naranjo CA, Bremner KE. Alcohol Alcohol Suppl. 1993;2:221-229; Naranjo CA, et al. Clin Pharmacol Ther. 1990 Apr;47(4):490-498; Cornelius JR, et al Arch Gen Psychiatry 1997 Aug;54(8):700-705; Lejoyeux M. Alcohol Alcohol Suppl. 1996 Mar;1:69-75.)

• dietary concerns: Given the tendency of both SSRI agents and alcohol to cause disorientation and diminished motor control the combined use of these two substances represents serious risk to the user and those around them. Individuals taking SSRI drugs should avoid consumption of alcohol during the course of treatment.

substance affecting drug toxicity: Sulfonylureas

• mechanism: Individuals taking sulfonylureas have been known to develop an intolerance to alcohol which can manifest as a disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea and occasionally tachycardia. Among the sulfonylureas, chlorpropamide has the most propensity to induce this type of reaction. Alcohol ingestion, by individuals taking sulfonylureas, has also been associated with unpredictable fluctuations in serum glucose levels, especially hypoglycemia.

• dietary concerns: Individuals taking sulfonylurea class drugs should avoid consuming alcohol while taking the prescription.

substance affecting drug toxicity: Tricyclic Antidepressants

• research: Alcohol and tricyclic antidepressants interact synergistically to reduce mental clarity and coordination and increase drowsiness and dizziness. An increased risk of accidental injury can result from combining alcohol and amitriptyline and other tricyclic antidepressants.
(Kerr JS, et al. Br J Clin Pharmacol 1996 Aug;42(2):239-241; Threlkeld DS, ed. Apr 1990.)

• dietary concerns: Individuals using tricyclic antidepressants should avoid consuming alcohol while taking drugs of this class.

substance affecting drug toxicity: Valproic Acid

• research: Alcohol and valproic acid interact synergistically to reduce mental clarity and coordination and increase drowsiness and dizziness. An increased risk of accidental injury can result from consuming alcohol while taking valproic acid. Elmazar and Nau have also published findings showing that the combination of ethanol and valproic acid can induce neural tube defects in mice due to toxicokinetic interactions.
(Threlkeld DS, ed. May 1997; Elmazar MM, Nau H. Reprod Toxicol 1995 Sep-Oct;9(5):427-433.)

• dietary concerns: Individuals taking any form of valproic acid should avoid consuming alcohol.

pharmacokinetic interaction with herb: Panax ginseng (Chinese Ginseng)

• mechanism: Ginseng increases metabolic activity of alcohol dehydrogenase and aldehyde dehydrogenase in rodents. A human study showed a 30-50% increase in alcohol clearance in healthy volunteers compared to controls after a single dose of Panax ginseng.
(Lee FC, et al. Clin Exp Pharmacol Physiol. 1987;14:543-546.)

• herbal concerns: Individuals taking Panax ginseng may experience changes in their response to alcohol.


Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Bachmann KA, Sullivan TJ, Jauregui L, Reese J, Miller K, Levine L. Drug interactions of H2-receptor antagonists. Scand J Gastroenterol Suppl 1994;206:14-19.
Abstract: Three drug interactions of nizatidine and of other antisecretory agents were studied comparatively. First, the effects of nizatidine, cimetidine and ranitidine on the dispositional kinetics of theophylline were evaluated in chronic obstructive pulmonary disease (COPD) patients. Second, the effect of magnesium/aluminium hydroxide on the relative bioavailability of nizatidine, famotidine, cimetidine and ranitidine was evaluated in healthy volunteers. Finally, the effects of nizatidine and omeprazole on the dispositional kinetics of phenytoin were evaluated in healthy volunteers. Only cimetidine altered the steady-state kinetics of oral theophylline, slowing theophylline clearance by 25%. Each of the H2-receptor antagonists exhibited a modest decline in relative bioavailability when ingested with antacid. Antacid ingestion decreased the bioavailability of famotidine, ranitidine and cimetidine by 20-25%, and the bioavailability of nizatidine by 12%. Each of these effects was statistically significant. Finally, it was found that neither omeprazole nor nizatidine affected the single dose kinetics of phenytoin.

Bhandare PN, Rataboli PV, Diniz D'Souza RS, Dhume VG. Aggravating action of hydralazine on ethanol-induced gastric lesions. Indian J Physiol Pharmacol. 1992 Apr;36(2):130-132.

Broadbent J, Grahame NJ, Cunningham C. Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization. Psychopharmacology (Berl) 1995 Aug;120(4):475-482.

Caballeria J, Baraona E, Deulofeu R, Hernandez-Munoz R, Rodes J, Lieber CS. Effects of H2-receptor antagonists on gastric alcohol dehydrogenase activity. Dig Dis Sci 1991 Dec;36(12):1673-1679.
Abstract: Inhibition of gastric alcohol dehydrogenase (ADH) activity by cimetidine results in elevated blood levels of ethanol after moderate consumption. To search for alternative H2-blockers lacking such an effect, we compared cimetidine, ranitidine, nizatidine, and famotidine. They inhibited rat gastric ADH noncompetitively, with a Ki for ethanol oxidation of 0.68 mM for cimetidine, 0.5 mM for ranitidine, 1 mM for nizatidine, and 4.5 mM for famotidine. These concentrations are higher than therapeutic plasma levels, but intracellular concentrations in the gastric mucosa (assessed with [3H]cimetidine and [14C]famotidine) were at least 10- and 2-fold greater than in the blood, respectively. These results suggests that, given at therapeutic doses in vivo, the degree of inhibition by cimetidine and ranitidine should be significant and comparable, that by nizatidine should be smaller, and that by famotidine should be negligible. These drugs also exerted either mixed or competitive inhibition of rat hepatic ADH, but the effects of cimetidine and famotidine were observed at concentrations unlikely to occur in vivo. Thus, in alcoholics and in social drinkers who require treatment with H2-receptor antagonists, famotidine might be preferable to the other H2 blockers tested.

Cina SJ, Russell RA, Conradi SE. Sudden death due to metronidazole/ethanol interaction. Am J Forensic Med Pathol 1996 Dec;17(4):343-346.

Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Perel JM, Thase ME, Black A. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997 Aug;54(8):700-705.
Abstract: BACKGROUND: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. METHODS: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n = 25) or placebo (n = 26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. RESULTS: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. CONCLUSIONS: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.

Elmazar MM, Nau H. Ethanol potentiates valproic acid-induced neural tube defects (NTDs) in mice due to toxicokinetic interactions. Reprod Toxicol 1995 Sep-Oct;9(5):427-433.
Abstract: Both the antiepileptic drug valproic acid (VPA) and ethanol interfere with fetal folate metabolism, which may contribute to their mechanism of teratogenesis. Therefore, the possible interaction between VPA and ethanol was investigated in mice. Ethanol (2 x 2.5 g/kg) was given orally 4 and 1 h prior to VPA (300 and 400 mg/kg, SC) in day 8.25 pregnant NMRI mice. Fetuses were examined for exencephaly, embryolethality, and fetal weight retardation on day 18 of gestation. Higher doses of ethanol (2 x 5 g/kg, orally) at day 7.5 and 8 of gestation resulted in 22% embryolethality and 1.7% exencephaly with no effect on fetal weight. Ethanol, however, increased VPA (400 mg/kg, SC)-induced exencephaly, embryolethality, and fetal weight retardation. It also increased VPA (300 mg/kg, SC)-induced exencephaly without affecting embryotoxicity. A minimum of two oral doses of 2.5 g/kg ethanol, 1 and 4 h, or 1 and 6 h prior to VPA administration were needed to produce maximum potentiation of the effects observed. These ethanol doses increased plasma VPA levels of day 8.25 pregnant mice given 400 mg/kg VPA to values comparable to the levels of mice given only VPA at a higher dose level (500 mg/kg). The incidence of exencephaly was increased from 35% for VPA (400 mg/kg) to 59% when VPA was given with ethanol. This incidence was similar to that of 60% for the high dose of VPA (500 mg/kg) administered without ethanol. Maternal plasma ethanol concentration peaked at 193, 196, and 183 mg/dL 15, 30, and 60 min, respectively, after oral ethanol administration (2.5 g/kg), and fell to 110 mg/dL by 2 h.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Harries DP, Teale KF, Sunderland G. Metronidazole and alcohol: potential problems. Scott Med J. 1990 Dec;35(6):179-180.

Kerr JS, Powell J, Hindmarch I. The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance. Br J Clin Pharmacol 1996 Aug;42(2):239-241.

Lee FC, et al. Effects of Panax ginseng on blood alcohol clearance in man. Clin Exp Pharmacol Physiol. 1987 14:543-546.
Abstract:1. Fourteen healthy male volunteers were studied to assess the effects of Panax ginseng on blood alcohol clearance, utilizing each subject as his own control. 2. At 40 min after the last drink, the blood alcohol level in the test group receiving ginseng extract (3 g/65 kg body weight) along with alcohol (72 g/65 kg body weight) was about 35% lower than their control values. 3. When the blood alcohol level was compared on individual bases, alcohol concentrations in 10 out of 14 test subjects ranged from 32 to 51% lower than their control values. 4. These results demonstrate that P. ginseng extract enhances blood alcohol clearance in man.

Lejoyeux M. Use of serotonin (5-hydroxytryptamine) reuptake inhibitors in the treatment of alcoholism. Alcohol Alcohol Suppl. 1996 Mar;1:69-75. (Review)
Abstract: Animal studies have shown that alcohol consumption is reduced when serotonin (5-hydroxytryptamine, 5-HT) levels are increased in the central nervous system. Similarly, studies of alcohol-dependent human subjects have shown that treatment with 5-HT reuptake inhibitors (i.e. zimeldine, citalopram, fluoxetine, and fluvoxamine) decreases the desire to drink alcohol and improves symptoms of alcohol-related anxiety and depression in patients who have undergone detoxification. However, not all studies have shown them to be an effective treatment to help maintain recovery in alcohol dependence. The exact mechanisms of action of the 5-HT reuptake inhibitors are not yet fully understood and additional studies are needed. However, at this time, the 5-HT reuptake inhibitors may be effective pharmacotherapies for alcohol-related depression.

Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997 Mar 15;57(6):1098-1102.
Abstract: Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C-->T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake. We used a nested case-control design within the Physicians' Health Study. Participants were ages 40-84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancer-free controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels. Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3.42) among those whose plasma folate levels indicated deficiency (<3 ng/ml) compared with men with adequate folate levels. Among men with adequate folate levels, we observed a 3-fold decrease in risk (OR, 0.32; 95% CI, 0.15-0.68) among men with the homozygous mutation compared with those with the homozygous normal or heterozygous genotypes. However, the protection due to the mutation was absent in men with folate deficiency. In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who drank little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03-0.57), and for moderate drinkers, a 2-fold decrease in risk (OR, 0.42; 95% CI, 0.15-1.20); no decrease in risk was seen in those drinking 1 or more drinks/day. Our findings provide support for an important role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677C-->IT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.

Medlin RP Jr, Ransom MM, Watts JA, Kline JA. Effect of ethanol, haloperidol, and lorazepam on cardiac conduction and contraction. J Cardiovasc Pharmacol 1996 Dec;28(6):792-798.
Abstract: Haloperidol and lorazepam are commonly used to sedate ethanol (E)-intoxicated patients in emergency departments. This study was conducted to explore the role of ethanol in altering the potency of haloperidol and lorazepam with respect to cardiac conduction and contraction. For mechanical studies, isolated rat hearts were studied under isovolumetric conditions by using standard Langendorff technique. Hearts were perfused with Krebs-Heinseleit-Bicarbonate buffer containing haloperidol or lorazepam in concentrations ranging from 100 to 750 ng/ml (one heart per drug concentration). For both haloperidol and lorazepam individually, significant reductions in Left ventricular-generated pressure (LVGP) were observed at a concentration of 750 ng/ml (haloperidol = 2,250 nM and lorazepam = 2,000 nM). The addition of 20 and 65 mM ethanol shifted the concentration-response effect of haloperidol such that LVGP was significantly reduced at haloperidol = 500 and 300 ng/ml, respectively (p < 0.05 vs. basal control; paired t test). Ethanol produced no observable shift on the lorazepam concentration-response for LVGP. For electrophysiologic studies, hearts were perfused with haloperidol and lorazepam (300 ng/ml) +/- 65 mM ethanol. Compared with basal control, E + H significantly decreased heart rate (-74 +/- 12 beats/min) and increased His-ventricular conduction time (+7.6 +/- 1.5 ms vs. +1.7 +/- 0.6 ms for control hearts). Both haloperidol and EH significantly increased atrioventricular (AV) effective refractory period and the atrioventricular-His (AH) conduction interval. No significant changes in any electrophysiologic parameter were observed with ethanol or lorazepam perfused individually or with the combination of ethanol and lorazepam. Ethanol potentiates haloperidol-induced electromechanical depression of isolated rat hearts. Ethanol had no such effect on lorazepam.

Naranjo CA, Pouos CX, Bremner KE, Lanctot KL. Fluoxetine attenuates alcohol intake and desire to drink. Int Clin Psychopharmacol 1994 Sep;9(3):163-172.
Abstract: Several serotonin uptake inhibitors, including the long-acting fluoxetine, have been found to decrease alcohol intake in moderately dependent alcoholics. While the mechanism of their effect is not fully elucidated, a previous study with citalopram indicated that decreased desire to drink may be an important factor. Therefore, we tested fluoxetine effects on alcohol intake and desire to drink in a placebo-controlled study. Subjects, recruited by advertisement, were mildly/moderately dependent alcoholics (12 male, four female, aged 19-59 years, healthy, non-depressed) who did not believe they had a drinking problem and were not requesting treatment. After a 1 week baseline they received, single-blind, 2 weeks placebo followed by 2 weeks fluoxetine 60 mg/day. As out-patients, subjects recorded daily standard drinks (13.6 g ethanol) and rated interest, desire, craving and liking for alcohol biweekly. Each out-patient period was immediately followed by a double-blind experimental drinking session. Out-patient daily drinks slightly decreased during fluoxetine to 6.6 +/- 0.9 (mean +/- S.E.M.) compared with during placebo (7.16 +/- 0.95, p = 0.07, N.S.) and baseline (7.18 +/- 1.0, p > 0.1, N.S.). Desire, interest and craving for alcohol decreased during fluoxetine vs placebo baseline (p < 0.05), but not vs placebo. Appetite loss and decrease in food intake (p < 0.01, fluoxetine vs placebo) correlated with each other (r = 0.91, p < 0.01) but neither correlated with decrease in alcohol intake (appetite: r = 0.26, N.S.; food intake: r = 0.22, N.S.). Weight loss occurred during fluoxetine (p < 0.05 vs placebo) but did not correlate with decrease in alcohol intake (r = 0.1, N.S.). In the experimental drinking sessions after placebo and fluoxetine treatments subjects rated their desire for each of 18 mini-drinks (each one-third of a standard drink) offered at 5 min intervals. Fluoxetine decreased desire to drink throughout the sessions; both mean and maximum desire ratings were lower after fluoxetine than after placebo (ANOVA, p < 0.05). Therefore, fluoxetine seems to have a robust effect on decreasing desire for alcohol. We propose that in the absence of intention by subjects to reduce drinking, their habitual drinking patterns mitigated against reduced consumption in the out-patient phase. However, fluoxetine could be a useful adjunct for patients in a treatment context who are motivated to reduce their drinking.

Naranjo CA, Bremner KE. Serotonin-altering medications and desire, consumption and effects of alcohol-treatment implications. EXS. 1994;71:209-219. (Review)
Abstract: The relationship between serotonin neurotransmission and alcohol consumption (AC) was first determined in preclinical studies. AC generally increases following treatments which decrease serotonin activity, and levels of 5-HT and metabolites are low in some brain regions of alcohol-preferring rats. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled trials, SUI consistently decreased short-term (2-4 weeks) AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Some subjects decreased AC by up to 60%. The effects of SUI on AC were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI decreased desire to drink and liking for alcohol, suggesting a mechanism of action, to be considered in the development of treatments to reduce AC and prevent relapse. However, while an adjunctive brief psychosocial intervention enhanced the short-term effect of a SUI, the long-term (12-week) effects of SUI and placebo were similar. Other drugs acting on the 5-HT system have been tested in humans, but results are inconclusive. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). Ritanserin, a 5-HT2 antagonist, reduced desire to drink and prevented relapse in a small (n = 5) study, and there was some indication that it reduced desire to drink and enhanced alcohol effects without reducing AC, in another study. The therapeutic potential of these medications is being studied. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for AC.

Naranjo CA, Bremner KE. Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption. Alcohol Alcohol Suppl. 1993;2:221-229. (Review)

Naranjo CA, Kadlec KE, Sanhueza P, Woodley-Remus D, Sellers EM.  Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther. 1990 Apr;47(4):490-498.

Plosker GL. Possible interaction between ethanol and vaginally administered metronidazole. Clin Pharm. 1987 Mar;6(3):189, 192-193.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Rataboli PV, et al. Effect of antihypertensive drugs on ethanol induced gastric lesions: is there a correlation with mucosal blood flow? Indian J Physiol Pharmacol. 1993 Jan;37(1):88-90.

Risinger FO, Dickinson SD, Cunningham CL.  Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference. Psychopharmacology (Berl). 1992;107(2-3):453-456.
Abstract: This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP)+ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Smith KA, Fairburn CG, Cowen PJ. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Arch Gen Psychiatry 1999 Feb;56(2):171-176.

Smith BA, Ferguson DB. Smith BA, et al. Acute hydralazine overdose: marked ECG abnormalities in a young adult. Ann Emerg Med. 1992 Mar;21(3):326-330.
Abstract: Although hydralazine is a commonly prescribed antihypertensive agent, reports of acute human poisoning are uncommon. Most of the literature focuses on chronic toxicity, most notably, the drug-induced systemic lupus erythematosus syndrome. A case of acute hydralazine overdose associated with marked ECG ST segment depression in a young adult is presented. Although the patient also had mild hypotension, acidemia, and ethanol intoxication, the ECG abnormality was alarming and suggestive of myocardial ischemia. The patient was managed conservatively in an ICU setting, and the metabolic and ECG abnormalities resolved. No reports of such marked ECG changes associated with acute hydralazine poisoning in a young adult could be found. Clinical and experimental data on acute hydralazine exposure suggest that the possibility of direct drug effects, including positive inotropic and chronotropic effects and myocardial cell injury, should be considered.

Sohn M, Sikora R. Ginkgo biloba extract in the therapy of erectile dysfunction. J Sex Educ Ther 1991;17:53-61.

Stewart PM, Burra P, Shackleton CH, Sheppard MC, Elias E. 11 beta-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease. J Clin Endocrinol Metab 1993 Mar;76(3):748-751.
Abstract: 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD), found predominantly in liver and kidney, is responsible for the shuttling of active cortisol to cortisone. A defect in this shuttle mechanism, e.g. after liquorice ingestion, results in an increase in the ratio of urinary cortisol [tetrahydrocortisol (THF)] to cortisone [tetrahydrocortisone (THE)] metabolites. The plasma cortisol half-life is prolonged, but concentrations remain normal because of a concomitant fall in cortisol production. Alcohol-induced pseudo-Cushing's syndrome is an ill defined cause of Cushing's syndrome. Because many of the documented cases have abnormal liver function tests, we have investigated whether abnormal hepatic 11 beta HSD activity may play a role in the pathogenesis of the condition. Fourteen patients with alcoholic (ALD) and 14 patients with non-alcoholic (CLD) chronic liver disease had marked deficiency of 11 beta HSD [5 alpha-THF + THF/THE: ALD, 1.94 +/- 0.38 (+/- SEM); CLD, 1.82 +/- 0.20] compared to controls (0.94 +/- 0.04; P < 0.01 and 0.001, respectively). In the CLD group, the daily cortisol production rate (as assessed by summation of principal cortisol metabolites) was reduced appropriately [median, 3,510; range, 1,101-8,940 micrograms/24 h; controls, 5,492 (range, 3,818-14,996) micrograms/24 h; P < 0.001], and normal 0900 h plasma cortisol and urinary free cortisol levels were maintained. However, in the ALD group, there was no concomitant fall in the cortisol production rate (sum of cortisol metabolites, 5,043 micrograms/24 h; range, 520-27,344). As a consequence, 0900 h plasma cortisol in the ALD group was significantly elevated (633 +/- 52 nmol/L) compared to values in the CLD group (487 +/- 48 nmol/L; P < 0.05) and controls (432 +/- 27 nmol/L; P < 0.001). Our findings of glucocorticoid excess in patients with chronic ALD may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism. The latter is mediated by defective hepatic 11 beta HSD activity; the former by either abnormal glucocorticoid feedback or stimulation of cortisol secretion at the level of the hypothalamus/pituitary.

Threlkeld DS, ed. Blood Modifiers, Anticoagulants, Heparin. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jun 1997.

Threlkeld DS, ed. Central Nervous System Drugs, Acetaminophen. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Mar 1997.

Threlkeld DS, ed. Central Nervous System Drugs, Antidepressants, Selective Serotonin Reuptake Inhibitors. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparison, Apr 1997.

Threlkeld DS, ed. Central Nervous System Drugs, Anticonvulsants, Valproic Acid and Derivatives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, May 1997.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Antianginal Agents, Nitrates. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Apr 1992.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Antihypertensives, Vasodilators, Hydralazine. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Dec 1993.

Threlkeld DS, ed. Systemic Anti-Infectives, Metronidazole. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Nov 1992.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

Tunguy-Desmarais GP. Interaction between alcohol and metronidazole. S Afr Med J. 1983 May 28;63(22):836.

Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994 Nov 1;121(9):676-683. (Review)
Abstract: PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance. DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin. DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted kappa statistic. RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted kappa statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado. CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994 Dec 21;272(23):1845-1850.