Drug Interactions between chlorpheniramine / guaifenesin / phenylephrine and propranolol

ADJUST DOSING INTERVAL: The bioavailability of propranolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take propranolol at the same time each day, preferably with or immediately following meals.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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.

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

The use of beta-adrenergic receptor blocking agents (aka beta-blockers) in patients with a history of allergic reactions or anaphylaxis may be associated with heightened reactivity to culprit allergens. The frequency and/or severity of attacks may be increased during beta-blocker therapy. In addition, these patients may be refractory to the usual doses of epinephrine used to treat acute hypersensitivity reactions and may require a beta-agonist such as isoproterenol.

Some beta-adrenergic receptor blocking agents (i.e., non-cardioselective beta-blockers) are contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease. In general, beta-adrenergic receptor blocking agents should not be used in patients with bronchospastic diseases. Beta blockade may adversely affect pulmonary function by counteracting the bronchodilation produced by catecholamine stimulation of beta-2 receptors. If beta-blocker therapy is necessary in these patients, an agent with beta-1 selectivity (e.g., atenolol, metoprolol, betaxolol) is considered safer, but should be used with caution nonetheless. Cardioselectivity is not absolute and can be lost with larger doses.

The use of beta-adrenergic receptor blocking agents (aka beta-blockers) is contraindicated in patients with hypotension or cardiogenic shock. Due to their negative inotropic and chronotropic effects on the heart, the use of beta-blockers is likely to further depress cardiac output and blood pressure, which can be detrimental in these patients.

Sympathomimetic agents may cause adverse cardiovascular effects, particularly when used in high dosages and/or in susceptible patients. In cardiac tissues, these agents may produce positive chronotropic and inotropic effects via stimulation of beta- 1 adrenergic receptors. Cardiac output, oxygen consumption, and the work of the heart may be increased. In the peripheral vasculature, vasoconstriction may occur via stimulation of alpha-1 adrenergic receptors. Palpitations, tachycardia, arrhythmia, hypertension, reflex bradycardia, coronary occlusion, cerebral vasculitis, myocardial infarction, cardiac arrest, and death have been reported. Some of these agents, particularly ephedra alkaloids (ephedrine, ma huang, phenylpropanolamine), may also predispose patients to hemorrhagic and ischemic stroke. Therapy with sympathomimetic agents should generally be avoided or administered cautiously in patients with sensitivity to sympathomimetic amines, hyperthyroidism, or underlying cardiovascular or cerebrovascular disorders. These agents should not be used in patients with severe coronary artery disease or severe/uncontrolled hypertension.

Sympathomimetic agents may cause adverse cardiovascular effects, particularly when used in high dosages and/or in susceptible patients. In cardiac tissues, these agents may produce positive chronotropic and inotropic effects via stimulation of beta- 1 adrenergic receptors. Cardiac output, oxygen consumption, and the work of the heart may be increased. In the peripheral vasculature, vasoconstriction may occur via stimulation of alpha-1 adrenergic receptors. Palpitations, tachycardia, arrhythmia, hypertension, reflex bradycardia, coronary occlusion, cerebral vasculitis, myocardial infarction, cardiac arrest, and death have been reported. Some of these agents, particularly ephedra alkaloids (ephedrine, ma huang, phenylpropanolamine), may also predispose patients to hemorrhagic and ischemic stroke. Therapy with sympathomimetic agents should generally be avoided or administered cautiously in patients with sensitivity to sympathomimetic amines, hyperthyroidism, or underlying cardiovascular or cerebrovascular disorders. These agents should not be used in patients with severe coronary artery disease or severe/uncontrolled hypertension.

Some beta-adrenergic receptor blocking agents (i.e., non-cardioselective beta-blockers) are contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease. In general, beta-adrenergic receptor blocking agents should not be used in patients with bronchospastic diseases. Beta blockade may adversely affect pulmonary function by counteracting the bronchodilation produced by catecholamine stimulation of beta-2 receptors. If beta-blocker therapy is necessary in these patients, an agent with beta-1 selectivity (e.g., atenolol, metoprolol, betaxolol) is considered safer, but should be used with caution nonetheless. Cardioselectivity is not absolute and can be lost with larger doses.

Beta-adrenergic receptor blocking agents (aka beta-blockers) in general should not be used in patients with overt congestive heart failure (CHF). Sympathetic stimulation may be important in maintaining the hemodynamic function in these patients, thus beta-blockade can worsen the heart failure. However, therapy with beta-blockers may be beneficial and can be administered cautiously in some CHF patients provided they are well compensated and receiving digitalis, diuretics, an ACE inhibitor, and/or nitrates. Carvedilol, specifically, is indicated for use with these agents in the treatment of mild to severe heart failure of ischemic or cardiomyopathic origin. There is also increasing evidence that the addition of a beta-blocker to standard therapy can improve morbidity and mortality in patients with advanced heart failure, although it is uncertain whether effectiveness varies significantly with the different agents. Data from one meta-analysis study suggest a greater reduction of mortality risk for nonselective beta-blockers than for beta-1 selective agents.

Beta-adrenergic receptor blocking agents (aka beta-blockers) may mask symptoms of hypoglycemia such as tremors, tachycardia and blood pressure changes. In addition, the nonselective beta-blockers (e.g., propranolol, pindolol, timolol) may inhibit catecholamine-mediated glycogenolysis, thereby potentiating insulin-induced hypoglycemia and delaying the recovery of normal blood glucose levels. Since cardioselectivity is not absolute, larger doses of beta-1 selective agents may demonstrate these effects as well. Therapy with beta-blockers should be administered cautiously in patients with diabetes or predisposed to spontaneous hypoglycemia.

The use of beta-adrenergic receptor blocking agents (aka beta-blockers) is contraindicated in patients with sinus bradyarrhythmia or heart block greater than the first degree (unless a functioning pacemaker is present). Due to their negative inotropic and chronotropic effects on the heart, the use of beta-blockers is likely to exacerbate these conditions.

Sympathomimetic agents may cause adverse cardiovascular effects, particularly when used in high dosages and/or in susceptible patients. In cardiac tissues, these agents may produce positive chronotropic and inotropic effects via stimulation of beta- 1 adrenergic receptors. Cardiac output, oxygen consumption, and the work of the heart may be increased. In the peripheral vasculature, vasoconstriction may occur via stimulation of alpha-1 adrenergic receptors. Palpitations, tachycardia, arrhythmia, hypertension, reflex bradycardia, coronary occlusion, cerebral vasculitis, myocardial infarction, cardiac arrest, and death have been reported. Some of these agents, particularly ephedra alkaloids (ephedrine, ma huang, phenylpropanolamine), may also predispose patients to hemorrhagic and ischemic stroke. Therapy with sympathomimetic agents should generally be avoided or administered cautiously in patients with sensitivity to sympathomimetic amines, hyperthyroidism, or underlying cardiovascular or cerebrovascular disorders. These agents should not be used in patients with severe coronary artery disease or severe/uncontrolled hypertension.

The use of beta-adrenergic receptor blocking agents (aka beta-blockers) is contraindicated in patients with hypotension or cardiogenic shock. Due to their negative inotropic and chronotropic effects on the heart, the use of beta-blockers is likely to further depress cardiac output and blood pressure, which can be detrimental in these patients.

Heightened sensitivity to catecholamines may occur after prolonged use of beta-adrenergic receptor blocking agents (aka beta-blockers). Exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following abrupt withdrawal of therapy. Cessation of beta-blocker therapy, whenever necessary, should occur gradually with incrementally reduced dosages over a period of 1 to 2 weeks in patients with coronary insufficiency. Patients should be advised not to discontinue treatment without first consulting with the physician. In patients who experience an exacerbation of angina following discontinuation of beta-blocker therapy, the medication should generally be reinstituted, at least temporarily, along with other clinically appropriate measures.

Propranolol is primarily metabolized by the liver. Patients with liver disease may be at greater risk for adverse effects from propranolol due to decreased drug clearance. Therapy with propranolol should be administered cautiously in patients with liver disease. Dosage adjustments may be necessary.

Due to their negative inotropic and chronotropic effects on the heart, beta-adrenergic receptor blocking agents (aka beta-blockers) reduce cardiac output and may precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. In addition, the nonselective beta-blockers (e.g., propranolol, pindolol, timolol) may attenuate catecholamine-mediated vasodilation during exercise by blocking beta-2 receptors in peripheral vessels. Therapy with beta-blockers should be administered cautiously in patients with peripheral vascular disease. Close monitoring for progression of arterial obstruction is advised.

Sympathomimetic agents may cause adverse cardiovascular effects, particularly when used in high dosages and/or in susceptible patients. In cardiac tissues, these agents may produce positive chronotropic and inotropic effects via stimulation of beta- 1 adrenergic receptors. Cardiac output, oxygen consumption, and the work of the heart may be increased. In the peripheral vasculature, vasoconstriction may occur via stimulation of alpha-1 adrenergic receptors. Palpitations, tachycardia, arrhythmia, hypertension, reflex bradycardia, coronary occlusion, cerebral vasculitis, myocardial infarction, cardiac arrest, and death have been reported. Some of these agents, particularly ephedra alkaloids (ephedrine, ma huang, phenylpropanolamine), may also predispose patients to hemorrhagic and ischemic stroke. Therapy with sympathomimetic agents should generally be avoided or administered cautiously in patients with sensitivity to sympathomimetic amines, hyperthyroidism, or underlying cardiovascular or cerebrovascular disorders. These agents should not be used in patients with severe coronary artery disease or severe/uncontrolled hypertension.

The use of beta-adrenergic receptor blocking agents (aka beta-blockers) is contraindicated in patients with sinus bradyarrhythmia or heart block greater than the first degree (unless a functioning pacemaker is present). Due to their negative inotropic and chronotropic effects on the heart, the use of beta-blockers is likely to exacerbate these conditions.

It has been suggested that the anticholinergic effect of antihistamines may reduce the volume and cause thickening of bronchial secretions, resulting in obstruction of respiratory tract. Some manufacturers and clinicians recommend that therapy with antihistamines be administered cautiously in patients with asthma or chronic obstructive pulmonary disease.

Sympathomimetic agents may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate.

Antihistamines may infrequently cause cardiovascular adverse effects related to their anticholinergic and local anesthetic (quinidine-like) activities. Tachycardia, palpitation, ECG changes, arrhythmias, hypotension, and hypertension have been reported. Although these effects are uncommon and usually limited to overdosage situations, the manufacturers and some clinicians recommend that therapy with antihistamines be administered cautiously in patients with cardiovascular disease, hypertension, and/or hyperthyroidism.

Beta-adrenergic blocking agents (beta-blockers), should be used with caution in patients with cerebrovascular insufficiency because of their potential effects relative to blood pressure and pulse. If signs or symptoms suggesting reduced cerebral blood flow are observed, consideration should be given to discontinuing these agents.

It has been suggested that the anticholinergic effect of antihistamines may reduce the volume and cause thickening of bronchial secretions, resulting in obstruction of respiratory tract. Some manufacturers and clinicians recommend that therapy with antihistamines be administered cautiously in patients with asthma or chronic obstructive pulmonary disease.

Sympathomimetic agents may cause increases in blood glucose concentrations. These effects are usually transient and slight but may be significant with dosages higher than those normally recommended. Therapy with sympathomimetic agents should be administered cautiously in patients with diabetes mellitus. Closer monitoring of blood glucose concentrations may be appropriate.

Antihistamines often have anticholinergic activity, to which elderly patients are particularly sensitive. Therapy with antihistamines should be administered cautiously, if at all, in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders. Conventional, first-generation antihistamines such as the ethanolamines (bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine) tend to exhibit substantial anticholinergic effects. In contrast, the newer, relatively nonsedating antihistamines (e.g., cetirizine, fexofenadine, loratadine) reportedly have low to minimal anticholinergic activity at normally recommended dosages and may be appropriate alternatives.

Systemic beta-adrenergic receptor blocking agents (aka beta-blockers) may lower intraocular pressure. Therefore, patients with glaucoma or intraocular hypertension may require adjustments in their ophthalmic regimen following a dosing change or discontinuation of beta-blocker therapy.

Sympathomimetic agents can induce transient mydriasis via stimulation of alpha-1 adrenergic receptors. In patients with anatomically narrow angles or narrow-angle glaucoma, pupillary dilation can provoke an acute attack. In patients with other forms of glaucoma, mydriasis may occasionally increase intraocular pressure. Therapy with sympathomimetic agents should be administered cautiously in patients with or predisposed to glaucoma, particularly narrow-angle glaucoma.

Antihistamines often have anticholinergic activity, to which elderly patients are particularly sensitive. Therapy with antihistamines should be administered cautiously, if at all, in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders. Conventional, first-generation antihistamines such as the ethanolamines (bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine) tend to exhibit substantial anticholinergic effects. In contrast, the newer, relatively nonsedating antihistamines (e.g., cetirizine, fexofenadine, loratadine) reportedly have low to minimal anticholinergic activity at normally recommended dosages and may be appropriate alternatives.

Beta-adrenergic receptor blocking agents (aka beta-blockers) may alter serum lipid profiles. Increases in serum VLDL and LDL cholesterol and triglycerides, as well as decreases in HDL cholesterol, have been reported with some beta-blockers. Patients with preexisting hyperlipidemia may require closer monitoring during beta-blocker therapy, and adjustments made accordingly in their lipid-lowering regimen.

Antihistamines may infrequently cause cardiovascular adverse effects related to their anticholinergic and local anesthetic (quinidine-like) activities. Tachycardia, palpitation, ECG changes, arrhythmias, hypotension, and hypertension have been reported. Although these effects are uncommon and usually limited to overdosage situations, the manufacturers and some clinicians recommend that therapy with antihistamines be administered cautiously in patients with cardiovascular disease, hypertension, and/or hyperthyroidism.

When beta-adrenergic receptor blocking agents (aka beta-blockers) are used to alleviate symptoms of hyperthyroidism such as tachycardia, anxiety, tremor and heat intolerance, abrupt withdrawal can exacerbate thyrotoxicosis or precipitate a thyroid storm. To minimize this risk, cessation of beta-blocker therapy, when necessary, should occur gradually with incrementally reduced dosages over a period of 1 to 2 weeks. Patients should be advised not to discontinue treatment without first consulting with the physician. Close monitoring is recommended during and after therapy withdrawal.

During chronic administration, the clearance of beta-blockers that are primarily metabolized by the liver (e.g., labetalol, metoprolol, penbutolol, propranolol) may be increased in patients with hyperthyroidism due to increased liver blood flow and enhanced activity of drug-metabolizing enzymes. Pharmacokinetic studies have demonstrated an approximately 50% increase in systemic clearance of propranolol during long-term therapy. In general, the dosage required to achieve therapeutic blood concentrations in such patients may be higher than that required in euthyroid patients and should be individualized.

Antihistamines may infrequently cause cardiovascular adverse effects related to their anticholinergic and local anesthetic (quinidine-like) activities. Tachycardia, palpitation, ECG changes, arrhythmias, hypotension, and hypertension have been reported. Although these effects are uncommon and usually limited to overdosage situations, the manufacturers and some clinicians recommend that therapy with antihistamines be administered cautiously in patients with cardiovascular disease, hypertension, and/or hyperthyroidism.

Limited pharmacokinetic data are available for the older, first-generation antihistamines. Many appear to be primarily metabolized by the liver, and both parent drugs and metabolites are excreted in the urine. Patients with renal and/or liver disease may be at greater risk for adverse effects from antihistamines due to drug and metabolite accumulation. Therapy with antihistamines should be administered cautiously in such patients. Lower initial dosages may be appropriate.

Beta-adrenergic receptor blocking agents (aka beta-blockers) may potentiate muscle weakness consistent with certain myasthenic symptoms such as diplopia, ptosis, and generalized weakness. Several beta-blockers have been associated rarely with aggravation of muscle weakness in patients with preexisting myasthenia gravis or myasthenic symptoms. Use cautiously in patients with myasthenia gravis.

Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta receptor-mediated vasodilatation in skeletal muscle. In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Caution should be taken in the administration of these agents to patients suspected of having pheochromocytoma.

Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. the use of non-selective beta blockers is not recommended in these patients. Caution should be taken in the administration of these agents to patients suspected of having Prinzmetal's variant angina.

Sympathomimetic agents may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate.

The use of beta-blockers in psoriatic patients should be carefully weighed since the use of these agents may cause an aggravation in psoriasis.

Propranolol plasma clearance was reduced in patients with chronic renal failure. Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity resulting in a lower "first-pass" clearance; therefore, therapy with propranolol should be administered cautiously in patients with impaired renal function. Propranolol is not significantly dialyzable.

Limited pharmacokinetic data are available for the older, first-generation antihistamines. Many appear to be primarily metabolized by the liver, and both parent drugs and metabolites are excreted in the urine. Patients with renal and/or liver disease may be at greater risk for adverse effects from antihistamines due to drug and metabolite accumulation. Therapy with antihistamines should be administered cautiously in such patients. Lower initial dosages may be appropriate.

Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. The use of beta-adrenergic receptor blocking agents (aka beta-blockers) should be administered cautiously in these patients.

Antihistamines often have anticholinergic activity, to which elderly patients are particularly sensitive. Therapy with antihistamines should be administered cautiously, if at all, in patients with preexisting conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders. Conventional, first-generation antihistamines such as the ethanolamines (bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine) tend to exhibit substantial anticholinergic effects. In contrast, the newer, relatively nonsedating antihistamines (e.g., cetirizine, fexofenadine, loratadine) reportedly have low to minimal anticholinergic activity at normally recommended dosages and may be appropriate alternatives.