Drug Interactions between acetaminophen / aluminum hydroxide / aspirin / caffeine / magnesium hydroxide and Metoprolol Succinate ER

MONITOR: Chronic administration of antacids may reduce serum salicylate concentrations in patients receiving large doses of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to urinary alkalinization by antacids, resulting in increased renal salicylate clearance. In three children treated with large doses of aspirin for rheumatic fever, serum salicylate levels declined 30% to 70% during coadministration with a magnesium and aluminum hydroxide antacid. Other studies have found similar, albeit less dramatic results. Antacids reportedly have no effect on the oral bioavailability of aspirin in healthy adults. However, administration of antacids containing either aluminum and magnesium hydroxide or calcium carbonate two hours before aspirin dosing led to reduced absorption of aspirin in uremic patients.

MANAGEMENT: Patients treated chronically with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

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MONITOR: Chronic administration of antacids may reduce serum salicylate concentrations in patients receiving large doses of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to urinary alkalinization by antacids, resulting in increased renal salicylate clearance. In three children treated with large doses of aspirin for rheumatic fever, serum salicylate levels declined 30% to 70% during coadministration with a magnesium and aluminum hydroxide antacid. Other studies have found similar, albeit less dramatic results. Antacids reportedly have no effect on the oral bioavailability of aspirin in healthy adults. However, administration of antacids containing either aluminum and magnesium hydroxide or calcium carbonate two hours before aspirin dosing led to reduced absorption of aspirin in uremic patients.

MANAGEMENT: Patients treated chronically with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

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High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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Concurrent administration with aluminum and magnesium antacids has been shown to decrease the oral bioavailability of certain beta-blockers, although data are conflicting. The exact mechanism of interaction is unknown but may involve cation binding of beta-blockers or a reduction in the dissolution rate due to increased gastric pH. In six healthy volunteers, concomitant administration of a single dose of antacid (magnesium hydroxide-aluminum oxide 1200 mg-1800 mg) reduced the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and 24-hour urinary excretion of sotalol (160 mg) by 27%, 21% and 9%, respectively, while administration of the antacid 2 hours after the sotalol dose produced no change. Pharmacodynamic data suggest that the negative chronotropic effect of sotalol was also reduced up to 4 hours after administration of the combination, although the lack of a placebo control might have confounded the results. In another study, concomitant administration of an aluminum hydroxide antacid in six healthy volunteers decreased atenolol (100 mg) Cmax and AUC by 37% and 33%, respectively. However, the Cmax and AUC of metoprolol (100 mg) in the same group was increased 25% and 11%, respectively, by administration of the antacid. Two other studies with aluminum hydroxide failed to find a significant effect on pharmacokinetics or pharmacodynamics of atenolol and propranolol. Based on available data, the clinical significance of this potential interaction is difficult to determine. As a precaution, patients may want to consider separating the administration times of beta-blockers and antacids or other aluminum- or magnesium-containing products by at least 2 hours.

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Concurrent administration with aluminum and magnesium antacids has been shown to decrease the oral bioavailability of certain beta-blockers, although data are conflicting. The exact mechanism of interaction is unknown but may involve cation binding of beta-blockers or a reduction in the dissolution rate due to increased gastric pH. In six healthy volunteers, concomitant administration of a single dose of antacid (magnesium hydroxide-aluminum oxide 1200 mg-1800 mg) reduced the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and 24-hour urinary excretion of sotalol (160 mg) by 27%, 21% and 9%, respectively, while administration of the antacid 2 hours after the sotalol dose produced no change. Pharmacodynamic data suggest that the negative chronotropic effect of sotalol was also reduced up to 4 hours after administration of the combination, although the lack of a placebo control might have confounded the results. In another study, concomitant administration of an aluminum hydroxide antacid in six healthy volunteers decreased atenolol (100 mg) Cmax and AUC by 37% and 33%, respectively. However, the Cmax and AUC of metoprolol (100 mg) in the same group was increased 25% and 11%, respectively, by administration of the antacid. Two other studies with aluminum hydroxide failed to find a significant effect on pharmacokinetics or pharmacodynamics of atenolol and propranolol. Based on available data, the clinical significance of this potential interaction is difficult to determine. As a precaution, patients may want to consider separating the administration times of beta-blockers and antacids or other aluminum- or magnesium-containing products by at least 2 hours.

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