Drug Interactions between Chardonna-2 and Inderide LA

MONITOR: Anticholinergic agents frequently cause drowsiness and other central nervous system-depressant effects that may be additive with those induced by beta blockers. In addition, these agents may increase heart rate and theoretically may counteract the bradycardic effects of beta blockers. Pharmacokinetically, anticholinergic agents may delay the gastrointestinal absorption of beta blockers and other drugs that are administered orally. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In healthy volunteers, pretreatment with propantheline has been shown to prolong the time to reach peak plasma concentration (Tmax) for both atenolol and metoprolol. Propantheline also decreased metoprolol peak plasma concentration (Cmax) but had no effect on its systemic exposure (AUC). In contrast, propantheline increased atenolol AUC but had no effect on its Cmax. The clinical relevance of these changes is probably minimal.

MANAGEMENT: Clinicians should be aware of the potential for diminished effects of beta blockers during coadministration with anticholinergic agents. Patients should also be monitored for potentially excessive CNS adverse effects (e.g., drowsiness, dizziness, lightheadedness, confusion, blurred vision) if these agents are used in combination. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Coadministration with barbiturates may decrease the plasma concentrations and pharmacologic effects of certain beta-blockers when administered orally. The proposed mechanism is barbiturate induction of hepatic microsomal and first-pass metabolism. The interaction has been studied with alprenolol, metoprolol and timolol, but probably can occur with any beta-blocker that is primarily metabolized in the liver such as propranolol. In six healthy volunteers, pretreatment with pentobarbital (100 mg daily for 10 days) reduced the plasma levels of alprenolol (200 mg single oral dose) and its metabolite 4-hydroxyalprenolol by approximately 40% without altering their plasma half-lives. The inhibition of exercise-induced tachycardia during a 7-hour period following alprenolol administration was reduced from 14% to 10.7% by pentobarbital, and the reduction was proportional to the decreased drug levels. In another study, pentobarbital reduced alprenolol levels by 59% and 4-hydroxyalprenolol levels by 24% in 6 hypertensive patients treated with alprenolol 400 mg twice daily. The effect of pentobarbital was significant after 3 doses and declined over 4 to 5 days after discontinuation. The decreases were associated with a 6% increase in pulse rate and 8% increase in systolic and 9% increase in diastolic blood pressure, as well as an 18% reduction in inhibition of exercise tachycardia by alprenolol. In eight healthy subjects, administration of metoprolol (100 mg single oral dose) with pentobarbital (100 mg daily for 10 days) resulted in a mean 32% reduction in metoprolol systemic exposure (AUC) compared to administration alone. The same dose of pentobarbital given for 7 days reduced AUC of timolol (10 mg) by just 24% in 12 healthy volunteers.

MANAGEMENT: Barbiturates may variously reduce the effects of certain beta-blockers when given for more than a few days. Pharmacologic response to beta-blockers should be monitored more closely whenever a barbiturate is added to or withdrawn from therapy, and the beta-blocker dosage adjusted as necessary. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Anticholinergic agents frequently cause drowsiness and other central nervous system-depressant effects that may be additive with those induced by beta blockers. In addition, these agents may increase heart rate and theoretically may counteract the bradycardic effects of beta blockers. Pharmacokinetically, anticholinergic agents may delay the gastrointestinal absorption of beta blockers and other drugs that are administered orally. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In healthy volunteers, pretreatment with propantheline has been shown to prolong the time to reach peak plasma concentration (Tmax) for both atenolol and metoprolol. Propantheline also decreased metoprolol peak plasma concentration (Cmax) but had no effect on its systemic exposure (AUC). In contrast, propantheline increased atenolol AUC but had no effect on its Cmax. The clinical relevance of these changes is probably minimal.

MANAGEMENT: Clinicians should be aware of the potential for diminished effects of beta blockers during coadministration with anticholinergic agents. Patients should also be monitored for potentially excessive CNS adverse effects (e.g., drowsiness, dizziness, lightheadedness, confusion, blurred vision) if these agents are used in combination. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.

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MONITOR: Anticholinergic agents frequently cause drowsiness and other central nervous system-depressant effects that may be additive with those induced by beta blockers. In addition, these agents may increase heart rate and theoretically may counteract the bradycardic effects of beta blockers. Pharmacokinetically, anticholinergic agents may delay the gastrointestinal absorption of beta blockers and other drugs that are administered orally. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In healthy volunteers, pretreatment with propantheline has been shown to prolong the time to reach peak plasma concentration (Tmax) for both atenolol and metoprolol. Propantheline also decreased metoprolol peak plasma concentration (Cmax) but had no effect on its systemic exposure (AUC). In contrast, propantheline increased atenolol AUC but had no effect on its Cmax. The clinical relevance of these changes is probably minimal.

MANAGEMENT: Clinicians should be aware of the potential for diminished effects of beta blockers during coadministration with anticholinergic agents. Patients should also be monitored for potentially excessive CNS adverse effects (e.g., drowsiness, dizziness, lightheadedness, confusion, blurred vision) if these agents are used in combination. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.

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Anticholinergic agents may increase the absorption and oral bioavailability of thiazide diuretics. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In six healthy volunteers, pretreatment with propantheline prolonged the time to reach peak plasma concentration (Tmax) for hydrochlorothiazide from 2.4 to 4.8 hours and increased its total 48-hour urinary recovery by 36%. Similar results were reported for chlorothiazide in another study. The clinical significance of these changes is unknown.

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Anticholinergic agents may increase the absorption and oral bioavailability of thiazide diuretics. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In six healthy volunteers, pretreatment with propantheline prolonged the time to reach peak plasma concentration (Tmax) for hydrochlorothiazide from 2.4 to 4.8 hours and increased its total 48-hour urinary recovery by 36%. Similar results were reported for chlorothiazide in another study. The clinical significance of these changes is unknown.

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Anticholinergic agents may increase the absorption and oral bioavailability of thiazide diuretics. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In six healthy volunteers, pretreatment with propantheline prolonged the time to reach peak plasma concentration (Tmax) for hydrochlorothiazide from 2.4 to 4.8 hours and increased its total 48-hour urinary recovery by 36%. Similar results were reported for chlorothiazide in another study. The clinical significance of these changes is unknown.

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