Aspirin/meprobamate Disease Interactions

Anxiolytic, sedative, and hypnotic agents should generally not be given to patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of these agents may be additive with those of alcohol. Severe respiratory depression and death may occur. Therapy with such agents should be administered cautiously in patients who might be prone to acute alcohol intake.

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of most anxiolytics, sedatives and hypnotics. Some of these changes include decreased inhibition, aggressiveness, agitation, and hallucinations. These drugs can cause or exacerbate mental depression and cause suicidal behavior and ideation. Therapy with these drugs should be administered cautiously in patients with a history of depression or other psychiatric disorders. Patients should be monitored for any changes in mood or behavior. It may be prudent to refrain from dispensing large quantities of medication to these patients.

Anxiolytic, sedative, and hypnotic agents have the potential to cause dependence and abuse. Tolerance as well as physical and psychological dependence can develop, particularly after prolonged use of excessive dosages, and abrupt cessation and/or a reduction in dosage may precipitate withdrawal symptoms. In patients who have developed tolerance, overdosage can still produce respiratory depression and death. Therapy with anxiolytic, sedative, and hypnotic agents should be administered cautiously and for as brief a period as possible. Addiction-prone individuals, such as those with a history of alcohol or substance abuse, should be under careful surveillance or medical supervision when treated with these agents. In addition, it may be prudent to refrain from dispensing large quantities of medication to such patients. After prolonged use or if dependency is suspected, withdrawal of medication should be undertaken gradually using a dosage-tapering schedule.

The use of aspirin is contraindicated in patients with significant active bleeding or hemorrhagic disorders such as hemophilia, von Willebrand's disease, or telangiectasia. Aspirin interferes with coagulation by irreversibly inhibiting platelet aggregation and prolonging bleeding time. The non-aceylated salicylates (i.e. salicylate salts such as sodium or magnesium salicylate) do not demonstrate these effects and may be appropriate substitutions in these patients. However, all salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially aspirin, should be administered with extreme caution in patients with hypoprothrombinemia, vitamin K deficiency, thrombocytopenia, thrombotic thrombocytopenic purpura, severe hepatic impairment, or anticoagulant use.

The use of meprobamate is contraindicated in patients with acute intermittent porphyria. Meprobamate has been reported to precipitate acute attacks of porphyria in susceptible patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients. A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps, severe potentially fatal bronchospasm, and/or intolerance to aspirin and other NSAIDs. Since cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, therapy with any NSAID should be avoided in patients with this form of aspirin sensitivity. NSAIDs should be used with caution in patients with preexisting asthma (without known aspirin sensitivity), and these patients should be monitored for changes in the signs and symptoms of asthma.

Salicylates, particularly aspirin, can cause dose-related gastrointestinal bleeding and mucosal damage, which may occur independently of each other. Occult, often asymptomatic GI blood loss is quite common with usual dosages of aspirin and stems from the drug's local effect on the GI mucosa. During chronic therapy, this type of bleeding may occasionally produce iron deficiency anemia. In contrast, major upper GI bleeding rarely occurs except in patients with active peptic ulcers or recent GI bleeding. However, these patients generally do not experience greater occult blood loss than healthy patients following small doses of aspirin. Mucosal damage associated with the use of salicylates may lead to development of peptic ulcers with or without bleeding, reactivation of latent ulcers, and ulcer perforation. Therapy with salicylates and related agents such as salicylamide should be considered and administered cautiously in patients with a history of GI disease or alcoholism, particularly if they are elderly and/or debilitated, since such patients may be more susceptible to the GI toxicity of these drugs and seem to tolerate ulceration and bleeding less well than other individuals. Extreme caution and thorough assessment of risks and benefits are warranted in patients with active or recent GI bleeding or lesions. Whenever possible, especially if prolonged use is anticipated, treatment with non-ulcerogenic agents should be attempted first. If salicylates are used, close monitoring for toxicity is recommended. Some adverse GI effects may be minimized by administration with high dosages of antacids, use of enteric-coated or extended-release formulations, and/or concurrent use of a histamine H2-receptor antagonist or a cytoprotective agent such as misoprostol. Patients with active peptic ulceration or GI bleeding treated with salicylates should generally be administered a concomitant anti-ulcer regimen.

Salicylate and its metabolites are eliminated almost entirely by the kidney. Therapy with salicylate drugs should be administered cautiously in patients with renal impairment, especially if it is severe. Reduced dosages may be necessary to avoid drug accumulation. Clinical monitoring of renal function is recommended during prolonged therapy, since the use of salicylate drugs has rarely been associated with renal toxicities, including elevations in serum creatinine, renal papillary necrosis, and acute tubular necrosis with renal failure. Most of the data have been derived from experience with aspirin but may apply to other salicylates as well. In patients with impaired renal function, aspirin has caused reversible and sometimes marked decreases in renal blood flow and glomerular filtration rate. Adverse renal effects have usually reversed rapidly following withdrawal of aspirin therapy.

The use of salicylates, primarily aspirin, in children with varicella infections or influenza-like illnesses has been associated with an increased risk of Reye's syndrome. Although a causal relationship has not been established, the majority of evidence to date seems to support the association. Most authorities, including the American Academy of Pediatrics Committee on Infectious Diseases, recommend avoiding the use of salicylates in children and teenagers with known or suspected varicella or influenza and during presumed outbreaks of influenza. If antipyretic or analgesic therapy is indicated under these circumstances, acetaminophen may be an appropriate alternative. The same precautions should also be observed with related agents such as salicylamide or diflunisal because of their structural and pharmacological similarities to salicylate.

Some hypnotic drugs can have an anticholinergic effect and should be used with caution in patients with glaucoma, and trouble urinating due to retention or enlarged prostate.

In general, anxiolytics, sedatives and hypnotics are extensively metabolized by the liver. Their plasma clearance may be decreased and their half-life prolonged in patients with impaired hepatic function. Therapy with these drugs should be administered cautiously in patients with liver disease (some are not recommended in severe liver impairment), and the dosage should be adjusted accordingly. Laboratory testing is recommended prior and during treatment.

Some anxiolytics, sedatives and hypnotics are extensively metabolized by the liver, and excreted in the urine. Patients with impaired renal and/or hepatic function may be at greater risk for adverse effects, including central nervous system and respiratory depression, due to drug and metabolite accumulation. Therapy with these drugs should be administered cautiously in such patients, with careful dose selection usually starting at the low end of the dosing range.

Oral anxiolytic, sedative, and hypnotic agents may cause respiratory depression and apnea when given in high dosages or following acute overdose. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with anxiolytic, sedative, and hypnotic agents should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are recommended.

Physical dependence, psychological dependence, and abuse have occurred with the use of meprobamate. Chronic intoxication from prolonged use usually involves ingestion of greater than recommended doses, and it is manifested by ataxia, slurred speech, and vertigo. Careful supervision of dose and amounts prescribed is advised, as well as avoidance of prolonged administration, especially in alcoholics and other patients with known propensity for taking excessive quantities of drugs.

Meprobamate may occasionally precipitate seizures in epileptic patients. Therapy with meprobamate should be administered cautiously in patients with a history of epilepsy.

Occult, often asymptomatic GI blood loss occurs quite frequently with the use of normal dosages of aspirin and stems from the drug's local effect on the GI mucosa. During chronic therapy, this type of bleeding may occasionally produce iron deficiency anemia. Other salicylates reportedly cause little or no GI blood loss at usual dosages, but may do so at high dosages. Prolonged therapy with salicylates, particularly aspirin, should be administered cautiously in patients with or predisposed to anemia. Periodic monitoring of hematocrit is recommended. The same precautions should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

Salicylate and its metabolites are readily removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis.

Salicylates, particularly aspirin, may cause or aggravate hemolysis in patients with pyruvate kinase or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. However, this effect has not been clearly established. Until more data are available, therapy with salicylates should be administered cautiously in patients with G-6-PD deficiency. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

The use of salicylates has occasionally been associated with acute, reversible hepatotoxicity, primarily manifested as elevations of serum transaminases, alkaline phosphatase and/or, rarely, bilirubin. Hepatic injury consistent with chronic active hepatitis has also been reported in a few patients, which resulted rarely in encephalopathy or death. Salicylate-induced hepatotoxicity appears to be dependent on serum salicylate concentration (> 25 mg/dL) and has occurred most frequently in patients with juvenile arthritis, active systemic lupus erythematosus, rheumatic fever, or preexisting hepatic impairment. Therapy with salicylates, particularly when given in high dosages, should be administered cautiously in these patients, and periodic monitoring of liver function is recommended. The same precautions should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate. A dosage reduction may be necessary if liver function abnormalities develop and serum salicylate concentration exceeds 25 mg/dL, although serum transaminase elevations may sometimes be transient and return to pretreatment values despite continued therapy without dosage adjustment.