Caffeine/magnesium salicylate Disease Interactions

Many CNS stimulants are contraindicated in patients with significant cardiovascular impairment such as uncompensated heart failure, severe coronary disease, severe hypertension (including that associated with hyperthyroidism or pheochromocytoma), cardiac structural abnormalities, serious arrhythmias, etc. Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended dosages for attention deficit hyperactivity disorder; use of these agents should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Additionally, stroke, myocardial infarction, chest pain, syncope, arrhythmias, and other symptoms have been reported in adults under treatment. A careful assessment of the cardiovascular status should be done in patients being considered for treatment. This includes family history, physical exam, and further cardiac evaluation (EKG and echocardiogram). Patients who develop symptoms should have a detailed cardiac evaluation and if needed, treatment should be suspended.

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CNS stimulants increase blood pressure and heart rate; the use of some agents may be contraindicated in patients with severe/uncontrolled hypertension. Caution should be used when administering to patients with preexisting high blood pressure (even mild hypertension) and other cardiovascular conditions. All patients under treatment should be regularly monitored for potential tachycardia and hypertension.

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The use of CNS stimulants can cause psychotic symptoms, suicidal ideation, and aggression, and can exacerbate symptoms of behavior disturbance and thought disorder; CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Psychiatric symptoms have been reported in patients with and without history of psychiatric disorders. All patients (particularly those with psychotic or bipolar disorders) should be monitored closely, especially during treatment initiation and at times of dose changes. Extreme caution should be exercised when CNS stimulants are given to patients with a history of psychosis, depression, mania, or bipolar disorder. Prior to initiating therapy, all patients should be screened for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disease, or depression). If any psychiatric symptoms emerge or are exacerbated, treatment suspension should be considered. Some CNS stimulants are contraindicated in patients with marked agitation or anxiety.

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Methylxanthines are known to stimulate peptic acid secretion. Therapy with products containing methylxanthines should be administered with extreme caution in patients with active peptic ulcer disease. Some manufacturers consider their use to be contraindicated under such circumstance.

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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.

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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.

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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.

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Like other methylxanthines, caffeine at high dosages may be associated with positive inotropic and chronotropic effects on the heart. Caffeine may also produce an increase in systemic vascular resistance, resulting in elevation of blood pressure. Therapy with products containing caffeine should be administered cautiously in patients with severe cardiac disease, hypertension, hyperthyroidism, or acute myocardial injury. Some clinicians recommend avoiding caffeine in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an acute myocardial infarction.

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In general, CNS stimulants 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 CNS stimulants should be administered cautiously in patients with moderate to severe liver disease, and the dosage should be adjusted accordingly in certain agents. Additionally, postmarketing reports have shown that atomoxetine can cause severe liver injury; laboratory testing should be done at the first sign/symptom of liver dysfunction (jaundice, dark urine, upper quadrant tenderness) and treatment should be discontinued in patients with evidence of liver injury.

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Overall CNS stimulants should be administered with caution in patients with significantly impaired renal function as the reduction in the rate of elimination may alter the therapeutic response. The dosage should be adjusted accordingly in certain agents.

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Due to general central nervous system stimulation, therapy with CNS stimulant drugs may cause seizures. These drugs may lower the convulsive threshold in patients with history of seizures, with prior electroencephalogram (EEG) abnormalities without seizures, and very rarely, without history of seizures and no prior EEG evidence of seizures. Therapy with CNS stimulants should be used with caution in patients with or predisposed to seizures. If seizures occur, therapy should be discontinued.

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Each gram of anhydrous magnesium salicylate contains approximately 6.7 mEq of magnesium. Therapy with products containing magnesium salicylate should be avoided or administered cautiously in patients with renal impairment because of the risk of hypermagnesemia. The use of products containing magnesium salicylate is contraindicated in patients with chronic advanced renal impairment.

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Methylxanthines increase gastric acidity and may also relax lower esophageal sphincter, which can lead to gastric reflux into the esophagus. Therapy with products containing methylxanthines should be administered cautiously in patients with significant gastroesophageal reflux.

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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.

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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 if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. 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.

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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.

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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.

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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.

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