salicylates and Liver-Diseases

The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use both prescription and over-the-counter-makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Diclofenac; Humans; Liver Diseases; Risk Factors; Salicylates; Sulindac

Aspirin can be more closely controlled than other nonsteroidal anti-inflammatory drugs because serum salicylate levels can be measured. Dosages of 80 to 100 mg/kg per day usually lead to the desired serum salicylate levels of 20 to 25 mg/dl. Gastric irritation, the most frequent cause for cessation of aspirin therapy, is significantly reduced by the use of enteric-coated aspirin. At the onset of aspirin therapy in children, there is frequently moderate elevation of SGOT and SGPT liver enzyme levels. With continued treatment these levels usually fall into the range of mild elevations. Although these children with arthritis often take high doses of aspirin for years, Reye's syndrome is virtually never seen.

Topics: Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Humans; Liver Diseases; Protein Binding; Salicylates; Serum Albumin

The potential for hepatic injury associated with the therapeutic use of salicylates and acetaminophen has recently attracted considerable attention. About 300 cases have been reported in which elevated transaminase levels or other evidence of hepatic injury developed following treatment with salicylates. Review of the spectrum of abnormalities reveals a group of patients (4 percent) with symptomatic liver damage in whom progressive or chronic liver disease is a possibility with continued use of the drug. In a few patients in this group, jaundice developed; several had abnormal prothrombin times; 11 (70 percent) had transaminase values in excess of 500 units; and five patients (30 percent) had encephalopathy and/or Reye's syndrome. In several reports liver damage has also been associated with the use of acetaminophen in therapeutic or near-therapeutic dosages. Of 18 patients, nine appeared to have ingested acetaminophen in amounts approaching overdose. Of the remaining nine patients, six were alcoholics. In the entire group, only five patients did not have a history of alcohol abuse; in three, glutathione depletion was suggested as a possible explanation for hepatotoxicity. The association with alcoholism or glutathione depletion suggests that host susceptibility may play a critical role. In two patients, long-term use of acetaminophen resulted in liver injury suggestive of chronic active hepatitis, possibly on the basis of an idiosyncratic reaction. In a study of chronic liver disease, acetaminophen half-life was prolonged (168 percent) without accumulation at 4 g a day over five days. In a double-blind, two-week, cross-over study, no clinical or laboratory evidence of adverse effects was found. There is, therefore, no evidence that chronic liver disease increases the risk of hepatotoxicity following the administration of acetaminophen in therapeutic doses. Thus, acetaminophen is the preferred antipyretic analgesic in patients with liver disease. Salicylates should be avoided since many of the adverse effects associated with these drugs are similar to the complications of chronic liver disease.

Topics: Acetaminophen; Alcohol Drinking; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Chronic Disease; Humans; Liver Diseases; Salicylates

This article attempts to help in the understanding of the mechanisms responsible for a modified drug pharmacokinetic profile in disease states. The main factors influencing the fate of the drug as it moves from the site of administration to the sites of elimination are depicted. Changes in absorption kinetics can be due to altered gastrointestinal peristalsis and secretions as well as modifications of splanchnic blood flow. Pathological states may affect the binding of drugs to plasma proteins, mainly human serum albumin and alpha 1 acid glycoprotein. The resulting modifications in the free fraction of the drug can cause a change in the volume of distribution. The distribution can also be influenced by circulatory disorders modifying local blood flows and thus impeding drug entry into the tissues. Many diseases can alter hepatic and/or renal clearance. This is not surprising since the elimination mechanisms are dependent upon many factors such the enzymatic status of the liver, plasma protein binding, and blood flow to both the liver and the kidney. Some examples such as the modification of furosemide pharmacokinetics in acute renal failure, the impaired metabolism of opiate analgesics in hepatic insufficiency, the alterations of the usual disposition process in salicylic acid intoxication, and the influence of cardiac failure upon some drugs pharmacokinetics, have been chosen to illustrate some of the aspects discussed. Some simple rules for making a rational selection of drugs in pathological states are also outlined.

Topics: Acute Kidney Injury; Blood Proteins; Disease; Furosemide; Glomerular Filtration Rate; Heart Failure; Humans; Intestinal Absorption; Kidney; Kinetics; Liver Diseases; Narcotics; Pharmaceutical Preparations; Protein Binding; Salicylates; Tissue Distribution

Topics: Anti-Inflammatory Agents; Arthritis, Juvenile; Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Cryoglobulinemia; Felty Syndrome; Giant Cell Arteritis; Humans; Liver Diseases; Lupus Erythematosus, Systemic; Polymyalgia Rheumatica; Rheumatic Diseases; Rheumatic Fever; Salicylates; Scleroderma, Systemic; Sjogren's Syndrome; Vasculitis

The roles of changes in cellular redox, interorgan lactate flux and balance, and quantitative aspects of lactate metabolism in the pathogenesis of lactic acidosis are discussed. Altered metabolism of pyruvate is central to the development of lactic acidosis and hyperlactatemia. Lactic acidosis occurs as a result of a relative or absolute imbalance in lactate production and utilization. Lactate utilization for oxidative purposes and for the resynthesis of glucose is essential for the maintenance of acid-base balance. Because of its role in lactate homeostasis the liver may play a central role in acid-base balance. Impairment of hepatic utilization of lactate may produce lactic acidosis.

Topics: Acidosis; Animals; Diabetic Ketoacidosis; Dichloroacetic Acid; Ethanol; Homeostasis; Humans; Hypoglycemia; Kidney; Lactates; Liver; Liver Diseases; Neoplasms; Phenformin; Renal Dialysis; Salicylates; Seizures; Vasodilator Agents

Topics: Animals; Anticoagulants; Barbiturates; Blood Coagulation; Blood Coagulation Factors; Cholestyramine Resin; Clofibrate; Disulfiram; Diuretics; Dogs; Drug Interactions; Heparin; Humans; In Vitro Techniques; Intestinal Absorption; Kinetics; Liver Diseases; Phenylbutazone; Protein Binding; Prothrombin Time; Rats; Receptors, Drug; Salicylates; Serum Albumin; Time Factors; Vitamin K; Vitamin K Deficiency

Topics: Administration, Oral; Adrenal Cortex Hormones; Animals; Anti-Bacterial Agents; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Clofibrate; Coumarins; Diuresis; Dogs; Heparin; Humans; Hypnotics and Sedatives; Liver Diseases; Metabolic Diseases; Phenylbutazone; Rats; Salicylates; Sulfonamides; Thrombosis; Uremia; Vitamin K

Aspirin can be more closely controlled than other nonsteroidal anti-inflammatory drugs because serum salicylate levels can be measured. Dosages of 80 to 100 mg/kg per day usually lead to the desired serum salicylate levels of 20 to 25 mg/dl. Gastric irritation, the most frequent cause for cessation of aspirin therapy, is significantly reduced by the use of enteric-coated aspirin. At the onset of aspirin therapy in children, there is frequently moderate elevation of SGOT and SGPT liver enzyme levels. With continued treatment these levels usually fall into the range of mild elevations. Although these children with arthritis often take high doses of aspirin for years, Reye's syndrome is virtually never seen.

Topics: Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Humans; Liver Diseases; Protein Binding; Salicylates; Serum Albumin

The interactions of selezen (imidazole salicylate) with human blood components were studied by equilibrium dialysis. These interactions were limited to the binding of salicylate to human serum albumin (HSA). The binding was saturable and involved several classes of binding sites with different association constants. A competition study indicated that salicylic acid at high concentration was able to displace warfarin and digitoxin but not glibenclamide from their HSA sites. On the other hand, selezen serum binding was decreased in renal impaired patients and this result was probably linked to the decreases in HSA concentration. So the use of small dosage regimens of selezen to these patients can be proposed. The same recommendation may be done for cirrhotic patients, where the decrease of selezen binding percentage was observed and due to both hypoalbuminemia and hyperbilirubinemia.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Chronic Disease; Dialysis; Erythrocytes; Humans; Imidazoles; Kidney Failure, Chronic; Liver Diseases; Salicylates; Salicylic Acid

Female Wistar rats received an oral dose of 700 mg salicylic acid/kg body wt., given as sodium salicylate. Some of the salicylate-treated rats received two subcutaneous injections of 100 mumol kg-1 ZnCl2 (24 h before and simultaneously with the salicylate administration). Other animals were given one subcutaneous injection of 100 mumol kg-1 ZnCl2 simultaneously with the salicylate treatment. Control rats were similarly injected with ZnCl2. Twenty four hours after salicylate treatment, serum and livers were taken for histochemical and biochemical analysis. The most remarkable effects of the treatment were enrichment of lipid droplets and iron and a reduction of glycogen, particularly in the periportal hepatocytes. The effects of salicylate were partially prevented by two ZnCl2 injections. The protective effects of ZnCl2 may be due to lower iron uptake into hepatocytes and by the induction of zinc metallothionein, which can serve as a scavenger for oxygen radicals.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Cations; Chemical and Drug Induced Liver Injury; Female; Histocytochemistry; Iron; Lipids; Liver Diseases; Liver Glycogen; Metallothionein; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Zinc

The protein binding of tolfenamic acid in plasma from patients with renal and hepatic disorders was studied by equilibrium dialysis. Drug binding to the cellular components of whole blood and blood cell suspensions was also measured. Salicylic acid was used as the reference drug in all experiments. Renal and hepatic diseases increased the unbound fraction of tolfenamic acid. Free drug fractions were significantly correlated with changes in creatinine, urea, and total bilirubin, but not with those in albumin or total protein in plasma. Comparison of the theoretical binding parameters in control plasma and similar changes in protein binding in all the plasma samples studied revealed that tolfenamic acid and salicylic acid probably share a common primary binding site. The significance of the correlation permits use of salicylic acid as a model drug for predicting changes in the protein binding of tolfenamic acid. The measurements of binding properties in whole blood and blood cell--buffer suspension showed that tolfenamic acid interacts with the lipid membrane structures of blood cells, while salicylic acid is distributed into the aqueous cell space.

Topics: Adult; Aged; Erythrocytes; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; ortho-Aminobenzoates; Protein Binding; Salicylates; Salicylic Acid

Factor analysis of admission data from 209 Reye's syndrome patients yielded three factors. Factor 1 was associated with encephalopathy, blood ammonia, creatinine kinase (CK), uric acid and, to a lesser extent, bilirubin. This factor was linked to the encephalopathy and hypermetabolic changes in muscle, possibly prostaglandin-mediated proteolysis. Factor 2 was associated with serum alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT), and was identified as a hepatic lesion component. These factors correspond to two etiologic components of Reye's syndrome. Salicylate was only weakly associated with neuropathic and hypercatabolic indicators and not at all associated with the hepatic damage indicators.

Topics: Brain Diseases; Child; Child, Preschool; Coma; Humans; Liver Diseases; Respiratory Tract Infections; Reye Syndrome; Salicylates; Statistics as Topic

The practical importance of BSR and blood cell changes for the early recognition should not be overestimated. But every symptomless person with raised BSR should be examined very carefully, especially for occult hepatic diseases (active hepatitis, liver cirrhosis), for anaemias, leukaemias, malignant lymphomas and other malignant diseases. The practical use of the diagnosis of blood cell changes is the possible recognition of anaemias, leukaemias and malignant lymphomas.

Topics: Adrenal Cortex Hormones; Anemia; Blood Cell Count; Blood Sedimentation; Eosinophilia; Humans; Hyperlipidemias; Leukemia; Liver Diseases; Lymphoma; Multiple Myeloma; Parasitic Diseases; Salicylates

Topics: Adult; Alkaline Phosphatase; Arthritis, Juvenile; Aspirin; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Diseases; Salicylates; Transaminases

Glucocorticoids are used in physiological and pharmacological amounts in the management of a variety of clinical conditions. Concomitant utilisation of other drugs or the presence of some diseases may affect the physiological action of the steroid in the tissues. Phenytoin, phenobarbitone, ephedrine and rifampicin accelerate the metabolism of glucocorticoids thereby decreasing their biological activity. A similar phenomenon occurs in patients with hyperthyroidism. In contrast, glucocorticoid action is enhanced in hypothyroid patients and in those with hepatic damage as the result of a defect in the clearance of the hormone from blood. In turn, glucocorticoids antagonise the effects of cholinesterase inhibitors and ganglion blocking agents. The above mentioned effects should be kept in mind whenever glucocorticoids are utilised in the diagnosis and management of endocrine or non-endocrine conditions.

Topics: Anticonvulsants; Cholinesterase Inhibitors; Contraceptives, Oral; Cushing Syndrome; Dexamethasone; Diuretics; Drug Interactions; Ephedrine; Ganglionic Blockers; Glucocorticoids; Humans; Hypnotics and Sedatives; Insulin; Kinetics; Liver Diseases; Pancuronium; Rifampin; Salicylates; Thyroid Diseases

Topics: Arthritis, Juvenile; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Liver Diseases; Salicylates

(1) Plasma protein binding of salicylate was studied in 14 patients with cutaneous hepatic porphyria (CHP) and 11 normal subjects using ultrafiltration with centrifugation (membrane cones) and continuous ultrafiltrations. (2) Albumin and haemoglobin levels were significantly reduced in patients with CHP, and salicylate binding by ultrafiltration/centrifugation was 65% compared with 84% in normal subjects. (3) Plasma porphyrin levels were raised, but did not correlate with salicylate binding, and protoporphyrin or uroporphyrin added to plasma did not alter the amount of drug bound. (4) Palmitate added to plasma reduced salicylate binding by 9 to 20% but a crossover of patient and normal plasma proteins and ultrafiltrates confirmed that no other ultrafiltrable metabolites present in patient plasma appeared to cause decreased binding. (5) Scatchard plots obtained by continuous ultrafiltration for normal and patient plasma showed a reduction in the number of primary and secondary binding sites and an increase in the intrinsic association constants for both these sites. (6) It was concluded that the decreased salicylate binding in CHP was due to a reduced albumin concentration and altered salicylate albumin interaction.

Topics: Blood Proteins; Hemopexin; Humans; Liver Diseases; Porphyrias; Porphyrins; Protein Binding; Salicylates; Ultrafiltration

The plasma protein binding of a representative acidic drug, salicylate, and a representative basic drug, quinidine, has been studied in patients with several diseases that are sometimes associated with uraemia or a change in serum albumin level. Decreased plasma protein binding of salicylate was observed in plasma from patients with uraemia and liver disease. Low albumin levels in these patients could only account inpart for the decreased binding. On the other hand, salicylate binding to plasma proteins appeared to be increased in patients with hypoxia. Decreased plasma protein binding of quinidine was observed in some patients with uraemia and in the majority of patients with liver disease.

Topics: Adult; Aged; Blood Proteins; Chronic Disease; Humans; Kidney Failure, Chronic; Liver Diseases; Middle Aged; Protein Binding; Quinidine; Respiratory Insufficiency; Salicylates

The binding of 3 drugs to serum proteins of patients with chronic hepatic disease has been studied by an ultrafilitration technique, and compared to that of normal subjects. The binding of phenylbutazone was reduced in all patients, salicylate in patients with inactive liver disease and sulphadiazine in patients whose disease was active. Analysis of binding data showed a real reduction in the capacity of albumin to bind the drugs in the majority of patients. Addition of bilirubin to normal plasma caused a reduction in sulphadiazine binding, but had no effect on the binding of salicylate or phenylbutazone. The possible causes of this reduction in binding are discussed.

Topics: Adult; Aged; Bilirubin; Blood Proteins; Chronic Disease; Female; Humans; Liver Diseases; Male; Middle Aged; Pharmaceutical Preparations; Phenylbutazone; Protein Binding; Salicylates; Serum Albumin; Sulfadiazine

Siblings, aged 9 and 7 years, had simultaneous onset of vomiting, disorientation, ataxia, and coma. Both children had prodromal symptoms of upper respiratory tract infections, and had been treated with large doses of aspirin. Laboratory data showed evidence of hepatocellular dysfunction, with an elevated serum ammonia level in one patient; salicylate levels were 50 and 44 mg/100 ml. The child who died had autopsy evidence of cerebral edema and fatty liver. The difficulty in clinically differentiating Reye syndrome from salicylate intoxication is discussed.

Topics: Aspirin; Brain; Brain Diseases; Child; Diagnosis, Differential; Female; Humans; Liver; Liver Diseases; Male; Pharyngitis; Reye Syndrome; Salicylates

Topics: Anemia; Animals; Cattle; Dihydroxyphenylalanine; Dogs; Down Syndrome; Fever; Glycine; Humans; Hypertension; Liver Diseases; Methyldopa; Mitochondria, Liver; Pheochromocytoma; Rats; Salicylates; Swine; Uremia; Wounds and Injuries

Topics: Adrenal Insufficiency; Carbohydrate Metabolism, Inborn Errors; Ethanol; Glycogen Storage Disease; Hormones, Ectopic; Humans; Hypoglycemia; Hypopituitarism; Insulin; Islets of Langerhans; Liver Diseases; Nutrition Disorders; Pancreatic Neoplasms; Salicylates; Sulfonylurea Compounds

Topics: Animals; Chemical and Drug Induced Liver Injury; Dogs; Gastric Acidity Determination; Gastric Juice; Histamine; Liver Diseases; Meat; Pepsin A; Salicylates; Time Factors

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

Topics: Animals; Female; Fetal Death; Fetal Diseases; Fetus; Gestational Age; Hemorrhage; Liver Diseases; Mice; Necrosis; Pregnancy; Salicylates; Sodium; Species Specificity

Topics: Acetates; Animals; Autoanalysis; Bile Acids and Salts; Bilirubin; Cattle; Cellulose; Chemical Phenomena; Chemistry; Cholestasis; Coloring Agents; Electrophoresis; Erythroblastosis, Fetal; Fatty Acids, Nonesterified; Female; Humans; Infant, Newborn; Liver Diseases; Methods; Oleic Acids; Penicillin G; Pregnancy; Salicylates; Serum Albumin; Serum Albumin, Bovine; Spectrophotometry; Sulfisoxazole

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Blood Protein Disorders; Humans; Kidney Failure, Chronic; Leukemia; Liver Diseases; Salicylates; Thrombocythemia, Essential; Uremia

Topics: Child; Child, Preschool; Hematemesis; Humans; Hypertension, Portal; Infant; Liver Diseases; Liver Function Tests; Portacaval Shunt, Surgical; Radiography; Salicylates; Splenectomy; Splenomegaly; Thrombophlebitis

Topics: Bile Acids and Salts; Bilirubin; Blood Protein Electrophoresis; Blood Proteins; Dialysis; Humans; Liver Diseases; Protein Binding; Salicylates; Serum Albumin; Spectrophotometry

Topics: Humans; Liver Diseases; Rheumatic Diseases; Rheumatic Fever; Salicylates; Toxicology

Topics: Amino Acids; Antifibrinolytic Agents; Child; Coxiella; Humans; Infant; Infections; Liver Diseases; Nitrogen; Salicylates

Topics: Administration, Oral; Adrenal Cortex Hormones; Antipyrine; Hepatic Insufficiency; Humans; Liver Diseases; Salicylates

Topics: Benzenesulfonates; Humans; Liver Diseases; Liver Function Tests; Salicylates

Topics: Benzenesulfonates; Hepatitis A; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Salicylates