salicylates and Alcoholism

Most reports of interactions involving analgesics deal with their effects on the actions of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must be the most common and most important interaction affecting analgesic toxicity. Combined overdosage of aspirin with central nervous system depressants may be particularly hazardous because suppression of the salicylate-induced respiratory stimulation further shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen (paracetamol) depends primarily on the balance between the rate of formation of the hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals, prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged by the urinary excretion of its cysteine and mercapturic acid conjugates, is not increased in heavy drinkers or in patients induced by long-term treatment with anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important species differences and different agents may selectively induce different variants of the multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent decrease in cysteine and mercapturic acid conjugate production. Thus ingestion of ethanol should reduce the risk of liver damage following acetaminophen overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent of the animals. However, contrary to expectations, cimetidine does not inhibit the oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for sulphate conjugation but is unlikely to potentiate toxicity following overdosage since sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the hepatotoxicity of acetaminophen after overdosage may be increased by othe

Topics: Acetaminophen; Alcoholic Intoxication; Alcoholism; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethanol; Humans; Salicylates

We assessed the relative roles of alcohol and infection with Helicobacter pylori in the pathogenesis of chronic gastritis in alcoholic patients. Helicobacter pylori was found in 14 of 18 alcoholics with dyspepsia and was associated with chronic antral gastritis. Gastric biopsy specimens were normal in four H pylori-negative alcoholics. Studies were repeated 3 to 4 weeks after controlled abstinence. There was no change in histologic findings during this period, indicating that alcohol itself was not the major causative agent. We then eliminated H pylori in 10 subjects by giving triple therapy (bismuth subsalicylate, amoxicillin, and metronidazole). Treatment for H pylori was associated with almost complete normalization of histologic findings. Four control subjects who received antacids alone showed no improvement. Dyspeptic symptoms in H pylori-positive patients significantly improved after elimination of this organism, whereas there was no change with antacid treatment.

Topics: Adult; Alcoholism; Aluminum Hydroxide; Amoxicillin; Bismuth; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Metronidazole; Organometallic Compounds; Salicylates; Temperance

Hydroxylation of salicylate into 2,3 and 2,5-dihydroxybenzoic acids (2,3-DHBA and 2,5-DHBA) by human liver microsomal preparations was investigated. Kinetic studies demonstrated that salicylate was 5-hydroxylated with two apparent Km: one high-affinity Km of 606 microM and one low-affinity Km greater than 2 mM. Liver microsomes prepared from 15 human samples catalyzed the formation of 2,5-DHBA at metabolic rate of 21.7 +/- 8.5 pmol/mg/min. The formation of 2, 3-DHBA was not P-450 dependent. Formation of 2,5-DHBA was inhibited by 36 +/- 14% following preincubation of microsomes with diethyldithiocarbamate, a mechanism-based selective inhibitor of P-450 2E1. Furthermore, the efficiency of inhibition was significantly correlated with four catalytic activities specific to P-450 2E1, whereas the residual activity was correlated with three P-450 3A4 catalytic activities. Troleandomycin, a mechanism-based inhibitor selective to P-450 3A4, inhibited by 30 +/- 12% the 5-hydroxylation of salicylate, and this inhibition was significantly correlated with nifedipine oxidation, specific to P-450 3A4. The capability of seven recombinant human P-450s to hydroxylate salicylate demonstrated that P-450 2E1 and 3A4 contributed to 2, 5-DHBA formation in approximately equal proportions. The Km values of recombinant P-450 2E1 and 3A4, 280 and 513 microM, respectively, are in the same range as the high-affinity Km measured with human liver microsomes. The plasmatic metabolic ratio 2,5-DHBA/salicylate, measured 2 h after ingestion of 1 g acetylsalicylate, was increased 3-fold in 12 alcoholic patients at the beginning of their withdrawal period versus 15 control subjects. These results confirm that P-450 2E1, inducible by ethanol, is involved in the 5-hydroxylation of salicylate in humans. Furthermore, this ratio was still increased by 2-fold 1 week after ethanol withdrawal. This finding suggests that P-450 3A4, known to be also inducible by alcoholic beverages, plays an important role in this increase, because P-450 2E1 returned to normal levels in less than 3 days after ethanol withdrawal. Finally, in vivo and in vitro data demonstrated that P-450 2E1 and P-450 3A4, both inducible by alcohols, catalyzed the 5-hydroxylation of salicylate.

Topics: Alcoholism; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Gentisates; Humans; Hydroxybenzoates; Hydroxylation; Kinetics; Microsomes, Liver; Mixed Function Oxygenases; Salicylates

A six-month survey of the urinary concentrations of drugs and alcohol of 176 patients within one hour of their admission to the acute psychiatric wards of the Macquarie Hospital, Sydney, is reported. Non-prescribed drugs were detected in the urine specimens of 29.5% of patients and alcohol in the urine specimens of 13.6% of patients. The survey demonstrated inconsistencies between patients' reports of their recent drug or alcohol intake and the laboratory findings, and inadequacies in the information recorded and relayed to the laboratory at the time of patients' admission to the hospital.

Topics: Adolescent; Adult; Aged; Alcoholism; Australia; Cannabis; Central Nervous System Agents; Drug Utilization; Ethanol; Female; Hospitals, Psychiatric; Humans; Male; Marijuana Abuse; Middle Aged; Patient Admission; Phenothiazines; Salicylates

The anticoagulant property of aspirin has long been appreciated. Recently, the physiologic mechanism has been identified and documented extensively. Despite the long-lasting inhibition of platelet function and clinically significant postoperative hemorrhage following aspirin use, few serious complications or fatalities are reported in the current literature. We report a case in which fatal hemorrhage resulted from minor trauma following massive salicylate ingestion. A review of the cyclo-oxygenase mechanism is presented.

Topics: Alcoholism; Aspirin; Death, Sudden; Hemorrhage; Humans; Lung Diseases; Male; Mediastinal Diseases; Middle Aged; Purpura; Salicylates; Thrombocytopenia; Wounds, Nonpenetrating

The mechanism for aspirin-caused liver injury is not clear. Aspirin produces hepatotoxic reactions as a cumulative phenomenon, requiring days or weeks to develop. Patients with active rheumatic or collagen disease, as well as children, are especially susceptible. Blood levels of salicylate higher than 25 mg/dL are particularly likely to lead to hepatic injury. Levels lower than 15 mg/dL rarely do. The mechanism for acetaminophen liver damage is quite clear. It produces hepatic injury as a result of a large single overdose, usually suicidal in intent. Patients with acetaminophen blood levels higher than 300 mg/dL at four hours after intake are most likely to develop hepatic damage; when N-acetylcysteine is used within the first ten hours after ingestion of an overdose, the recovery rate is reported to be virtually 100%. The conditions of patients receiving long-term full doses of either aspirin or acetaminophen should be intermittently monitored for hepatic injury.

Topics: Acetaminophen; Adolescent; Adult; Alcoholism; Arthritis, Juvenile; Aspirin; Child; Female; Humans; Liver; Lupus Erythematosus, Systemic; Male; Salicylates

Persons admitted to hospital emergency rooms for treatment of drug misuse with concomitant alcohol use were generally found to be heavy drinkers.

Topics: Adolescent; Adult; Alcoholism; Barbiturates; Benzodiazepines; Emergency Service, Hospital; Ethanol; Female; Humans; Male; Middle Aged; Salicylates; Substance-Related Disorders; Time Factors

Topics: Adolescent; Adult; Aged; Alcohol Drinking; Alcoholism; Caffeine; Colorado; Ethanol; Female; Hallucinogens; Hospitalization; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Middle Aged; MMPI; Narcotics; Salicylates; Substance-Related Disorders; Tranquilizing Agents

Topics: Adult; Alcoholism; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Salicylates; Uric Acid

Topics: Acidosis; Acute Kidney Injury; Alcoholism; Anuria; Child; Diabetes Mellitus; Dialysis; Humans; Hypertension; Hypertension, Malignant; Hyponatremia; Malaria; Peritoneal Dialysis; Poisoning; Renal Dialysis; Renal Insufficiency; Salicylates; Uremia