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Uses

Propranolol is used for the management of hypertension, angina, supraventricular and ventricular arrhythmias, acute myocardial infarction, and essential tremor. Propranolol also is used for prophylaxis of migraine headache, management of hypertrophic subaortic stenosis, and as an adjunct in the management of pheochromocytoma. The drug also has been used in the management of thyrotoxicosis.

The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.

In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a β₁-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a β₁-selective agent or an agent with intrinsic sympathomimetic activity (ISA) (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy. Nonselective β-blockers are preferred for the management of hypertension or angina pectoris in patients with coexisting essential tremor or vascular (e.g., migraine) headache.

Hypertension

Propranolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Although β-blockers were previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior myocardial infarction, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). (See and in )

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers. Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic. (See and in .)

Propranolol's efficacy in the management of hypertension is similar to that of other β-blockers. Propranolol is not indicated for the treatment of hypertensive emergencies.

In contrast to many other antihypertensive agents, propranolol lowers blood pressure equally well in the upright or supine position. The drug appears to be safe and effective for the treatment of hypertension in patients with renal damage. Although it apparently is more effective in patients with normal or elevated plasma renin concentrations than in those with low plasma renin concentrations, propranolol does lower blood pressure in patients with low-renin hypertension.

For additional information on the role of β-blockers in the management of hypertension, see Uses in and in . For information on overall principles and expert recommendations for treatment of hypertension, see

Angina

Chronic Stable Angina

Propranolol may be useful in some patients for the management of chronic stable angina pectoris. Use of the drug may reduce the frequency of anginal attacks in patients who suffer frequent attacks, allow a decrease in nitrate dosage, and increase the patient's exercise tolerance. Some authorities state that β-blockers are the anti-ischemic drugs of choice in geriatric patients with stable angina.

Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular volume and end-diastolic pressure and wall tension associated with a decrease in heart rate. Combined therapy with a β-blocker and a slow-release or long-acting dihydropyridine-derivative calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker. However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for marked fatigue (with high-dose verapamil or diltiazem), extreme bradycardia, or atrioventricular (AV) block. (See Drug Interactions: Diuretics and Cardiovascular Drugs.)

Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction

A β-blocker is used as part of the standard therapeutic measures for managing unstable angina/non-ST-segment elevation myocardial infarction; these measures also include therapy with aspirin and/or clopidogrel, low-molecular weight or unfractionated heparin, and nitrates (e.g., nitroglycerin) followed by either conservative medical management or early aggressive management, such as angiographic evaluation and revascularization procedures (e.g., percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], coronary artery stent implantation) as required. The American College of Cardiology (ACC) and the American Heart Association (AHA) recommend administration of an IV β-blocker followed by oral β-blocker therapy for patients with unstable angina at high risk of death or nonfatal myocardial infarction (i.e., patients with at least one of the following features: accelerating tempo of ischemic symptoms in preceding 48 hours; prolonged ongoing pain at rest; angina at rest with transient ST-segment changes exceeding 0.5 mV; new or presumed new bundle branch block; sustained ventricular tachycardia; hypotension, bradycardia, or tachycardia; age exceeding 75 years; elevated serum cardiac markers [e.g., troponin T or I concentrations exceeding 0.1 ng/mL]; new or worsening mitral regurgitation murmur; S₃ gallop or new/worsening rales; or pulmonary edema likely resulting from ischemia) who do not have contraindications to these drugs; oral β-blocker therapy is recommended for lower-risk patients. β-Blockers without intrinsic sympathomimetic activity (e.g., metoprolol, atenolol, propranolol, esmolol) are preferable in the management of unstable angina. For additional information on the use of β-blockers and other drug therapy in the management of unstable angina/non-ST-segment elevation myocardial infarction, see

β-Blockers have been shown to be ineffective in the treatment of Prinzmetal's variant angina without fixed obstructive lesions, and may increase the tendency to induce coronary vasospasm. Therefore, many experts recommend that β-blockers not be used for this condition. In addition, calcium-channel blocking agents (e.g., nifedipine) are considered the drugs of choice for this form of angina.

Cardiac Arrhythmias

Supraventricular Arrhythmias

β-Blockers, including propranolol, are used to slow ventricular rate in patients with supraventricular tachycardia (SVT). The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of β-blockers in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia [AVNRT]); in general, an IV β-blocker is recommended for acute treatment, while an oral β-blocker is recommended for ongoing management of these arrhythmias. Vagal maneuvers and/or IV adenosine generally are considered first-line interventions for the acute treatment of SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, an IV β-blocker may be considered in hemodynamically stable patients. Although evidence of efficacy is limited, experts state that the overall safety of β-blockers warrants their use in patients with SVT. Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.

IV β-blockers may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and an oral β-blocker may be used for ongoing management. Multifocal atrial tachycardia, characterized by a rapid, irregular rhythm with at least 3 distinct P-wave morphologies, is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drug therapy.

Propranolol is used to slow ventricular rate in patients with atrial fibrillation or atrial flutter when ventricular rate cannot be controlled with standard measures. For acute treatment of atrial fibrillation or flutter, an IV β-blocker (e.g., esmolol, propranolol, metoprolol) may be used for ventricular rate control in patients without preexcitation; an oral β-blocker may be used for ongoing rate control in such patients. Choice of a specific β-blocker should be individualized based on the patient's clinical condition.

IV β-blockers may be used for the acute treatment of hemodynamically stable patients with paroxysmal supraventricular tachycardia (PSVT), including AVNRT, that is uncontrolled or unconverted by vagal maneuvers and adenosine; an oral β-blocker may be used for the ongoing management of such patients who are not candidates for, or prefer not to undergo, catheter ablation. Propranolol may be useful in the prophylactic management of refractory PSVT, especially when caused by catecholamines or cardiac glycosides or associated with Wolff-Parkinson-White syndrome.

β-Blockers are considered one of several drug therapy options for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia. While evidence is limited, there is some data indicating that β-blockers (specifically propranolol) are modestly effective in terminating and/or reducing the incidence of junctional tachycardia.

Ventricular Arrhythmias

Although propranolol generally is less effective in the management of ventricular arrhythmias than supraventricular arrhythmias and is usually not the first drug of choice for ventricular arrhythmias, it may be considered when cardioversion or other drugs are not effective. Propranolol also may be used in the treatment of persistent premature ventricular complexes that impair the well-being of the patient and do not respond to conventional therapy.

β-Blockers may be useful in the management of certain forms of polymorphic ventricular tachycardia (e.g., associated with acute ischemia).

β-Blockers also have been used in patients with cardiac arrest precipitated by ventricular fibrillation or pulseless ventricular tachycardia. However, AHA states that routine administration of β-blockers after cardiac arrest is potentially harmful (e.g., may worsen hemodynamic instability, exacerbate heart failure, or cause bradyarrhythmias) and is therefore not recommended.

Tachyarrhythmias Associated with Cardiac Glycoside Intoxication

When AV block is not present, propranolol may be useful in the management of supraventricular or ventricular tachyarrhythmias associated with cardiac glycoside toxicity; however, because of the risk of adverse cardiovascular effects, the drug has a limited role in the management of these arrhythmias and other drugs are usually preferred. Propranolol can compromise conduction through the SA and AV nodes (possibly resulting in sinus bradycardia or asystole) and decrease myocardial automaticity; in addition, β-adrenergic blockade may result in deterioration of hemodynamic status in patients whose myocardial contractility depends on increased sympathetic nervous system activity. Oral propranolol may be useful in some patients for the management of cardiac glycoside-induced tachyarrhythmias that persist following discontinuance of the glycoside and correction of electrolyte abnormalities. IV propranolol should be used only if arrhythmias caused by cardiac glycoside intoxication are life-threatening and other therapy is ineffective. Use of digoxin immune Fab, if available, may be preferable and should be considered for the management of life-threatening cardiac glycoside-induced tachyarrhythmias that are unresponsive to conventional therapy.

Resistant Tachyarrhythmias Associated with Catecholamine Excess During Anesthesia

Propranolol may be used with extreme caution and constant ECG and central venous pressure monitoring in the management of resistant tachyarrhythmias associated with catecholamine excess during anesthesia; however, more effective and less hazardous therapy such as lessening the depth of anesthesia or improving ventilation is preferred. (See Cautions: Precautions and Contraindications.)

Hypertrophic Subaortic Stenosis

Propranolol may be of benefit in the management of exertional or other stress-induced angina, vertigo, syncope, and palpitation in some patients with hypertrophic subaortic stenosis; however, clinical improvement may be only temporary.

Pheochromocytoma

An α-adrenergic blocking agent (e.g., phenoxybenzamine or phentolamine) alone is usually sufficient for management of the signs and symptoms of pheochromocytoma. Propranolol, however, may be used as an adjunct to α-adrenergic blocking agents to control symptoms resulting from excessive β-receptor stimulation in patients with inoperable or metastatic pheochromocytoma, or to control tachycardia prior to or during surgery in patients with pheochromocytoma. To prevent severe hypertension caused by unopposed α-adrenergic stimulation, treatment with an α-adrenergic blocking agent must always be instituted prior to the use of propranolol and continued during propranolol therapy in patients with pheochromocytoma.

Thyrotoxicosis

Propranolol, which will not alter thyroid function tests, may be used orally as short-term (2-4 weeks) adjunctive therapy in the treatment of tachycardia and supraventricular arrhythmias in patients with thyrotoxicosis when these symptoms are distressful or hazardous, or when immediate therapy is necessary. Propranolol has been used IV and orally to treat symptomatic hypercalcemia secondary to thyrotoxicosis, but this use requires further study. Propranolol has also been used for the management of thyrotoxicosis in neonates. Safety of long-term administration of the drug in patients with thyrotoxicosis has not been established. The drug does not affect the underlying disease, which must be treated with an antithyroid agent.

Vascular Headache

Migraine

Propranolol may be used for the prophylaxis of common migraine headache. When used prophylactically, the drug can prevent common migraine or reduce the number of attacks in some patients. The US Headache Consortium states that there is good evidence from multiple well-designed clinical trials that propranolol has medium to high efficacy for the prophylaxis of migraine headache. Propranolol is not recommended for the treatment of a migraine attack that has already started nor for the prevention or treatment of cluster headaches. For further information on management and classification of migraine headache, .

Acute Myocardial Infarction

Propranolol is used to reduce the risk of cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. In these patients, long-term (up to 39 months) administration of propranolol (begun within 5-21 days following myocardial infarction) has reduced overall mortality, cardiovascular mortality, arteriosclerotic heart disease (ASHD) mortality, and sudden death mortality within the ASHD category. The effect of propranolol on reinfarction remains to be fully evaluated.

Because β-blockers can reduce myocardial oxygen demand during the first few hours of an acute myocardial infarction (by reducing heart rate, arterial blood pressure, and/or myocardial contractility) and may favorably influence myocardial blood flow, thus potentially limiting myocardial damage, and because of evidence of efficacy in reducing cardiovascular mortality, early (preferably within the first few hours) IV therapy with the drugs following acute myocardial infarction currently is recommended (unless contraindicated) for patients (including those receiving thrombolytic therapy or primary angioplasty) with reflex tachycardia and/or systolic hypertension (but without signs of heart failure); those with continuing or recurrent ischemic pain, tachyarrhythmias (e.g., atrial fibrillation with a rapid ventricular response), non-ST-segment infarction, and/or cardiac enzyme elevations indicative of recurrent injury; and those with postinfarction angina. Unless contraindicated, early IV therapy with the drugs also can be considered in patients with moderate left ventricular failure (presence of bibasilar rales without evidence of low cardiac output), provided they can be monitored closely, and in other patients who can be treated within the first 12 hours after onset of chest pain. Although the presence of moderate-to-severe left ventricular failure early in the course of acute myocardial infarction should preclude the use of early IV β-blocker therapy, it is a strong indication for the use of oral therapy prior to hospital discharge.

In addition, several large, randomized studies have demonstrated that prolonged oral therapy with a β-blocker can reduce the long-term rates of reinfarction and mortality (e.g., sudden or nonsudden cardiac death) following an acute myocardial infarction. It is estimated that such therapy could result in a relative reduction in mortality of about 25% annually for years 1-3 after infarction, with high-risk patients exhibiting the greatest potential benefit; benefit of continued therapy may persist for at least several years beyond this period, although less substantially. Therefore, propranolol, like other β-blockers, can be used for secondary prevention following acute myocardial infarction to reduce the risk of reinfarction and mortality.

Some experts state that such secondary prevention generally is recommended for all patients considered at moderate to high risk following an acute myocardial infarction, unless contraindicated, and that therapy be initiated within the first few days after infarction (if not already initiated acutely) and continued indefinitely. Secondary prevention also can be considered for low-risk patients who do not have a clear contraindication, for survivors of non-ST-elevation myocardial infarction, and for patients with non-Q-wave myocardial infarction. In addition, although the usefulness and efficacy are less well established by evidence and opinion, secondary prevention with β-blockers also can be considered for patients with moderate-to-severe left ventricular failure or other relative contraindication to β-blocker therapy, provided they can be monitored closely.

IV propranolol has been used in the management of acute tachyarrhythmias complicating acute myocardial infarction even when left ventricular failure caused by the arrhythmia was present. The drug also has been used IV in patients with acute myocardial infarction to produce complete β-adrenergic blockade in order to retard the infarction process.

Essential Tremor

Propranolol is used for the management of essential (familial, hereditary) tremor. The tremor is a postural and action tremor manifested as involuntary, rhythmic, oscillatory movements, principally of the upper limbs and, less frequently, the head; other areas, including the voice, legs, jaw, eyelids, and mouth, also may be involved. Essential tremor occurs during active movement and when the limb is held in a fixed posture or position against gravity; the tremor usually is absent at rest, although, when it is of large amplitude, tremor occasionally may be evident at rest, particularly in geriatric patients.

Propranolol decreases the amplitude but not the frequency of essential tremor; complete suppression of the tremor rarely is achieved with treatment. Response to propranolol therapy is variable, but the drug appears to be most effective in the management of high-amplitude, low-frequency tremor. Clinical benefit often is most evident for tremor affecting the upper extremities, although benefit also has been observed for head and other tremors; voice tremor may be less responsive to therapy with the drug. Propranolol hydrochloride doses of 120-320 mg generally produce tremor amplitude reductions averaging about 4-50%; however, reductions averaging 25-75% have been reported. Therapy with the drug may improve functional ability (e.g., handwriting, eating, drinking, dressing) and provide some subjective improvement (e.g., reduced anxiety and embarrassment), but patients should be advised that complete relief rarely is achieved so that their expectations about potential therapeutic benefit are realistic. Although propranolol often is used for chronic suppressive therapy in essential tremor, single oral doses may be useful in some patients to prevent or minimize tremor that is considered bothersome during specific, planned activity or to manage an exacerbation of tremor during periods of stress (e.g., business meetings, examinations).

Other Uses

Propranolol has been used in the management of cyanotic spells of Fallot's tetralogy, acute exacerbations of schizophrenic disorder and anxiety states, recurrent GI bleeding in patients with cirrhosis, and many other conditions. In addition to essential tremor (see Uses: Essential Tremor), propranolol also has been used in the management of other action tremors, including those associated with lithium therapy , anxiety, and thyrotoxicosis.

Dosage and Administration

Administration

Propranolol hydrochloride is usually administered orally. When administered orally in divided doses, the drug should be given before meals and at bedtime. When propranolol hydrochloride extended-release capsules are administered, the entire daily dose is given once daily. When propranolol hydrochloride oral concentrate solution is used, the dose should be diluted (e.g., with water, juice, carbonated beverages) or mixed with semisolid foods (e.g., applesauce, puddings) just prior to administration.

For the treatment of cardiac arrhythmias, propranolol has been given IV. Oral therapy should replace IV therapy as soon as possible.

Dosage

Since there is no consistent interpatient correlation between the dosage of propranolol and therapeutic response, especially after oral administration, dosage must be carefully individualized according to the response of the patient. If patients are switched from the conventional tablets to the extended-release capsules, care should be taken to ensure that the desired therapeutic effect is maintained. The extended-release capsules should not be considered a simple substitute for the conventional tablets on a mg-for-mg basis, since the capsules produce lower blood concentrations. If patients are switched to the extended-release capsules, the need for dosage retitration should be considered, especially to maintain effectiveness at the end of the dosing interval.

The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in geriatric patients.

Hypertension

Propranolol Therapy

For the management of hypertension in adults, the initial oral dosage of propranolol hydrochloride, administered either alone or in combination with a diuretic, is 40 mg twice daily as conventional tablets or oral solution or 80 mg once daily as extended-release capsules. The usual effective oral dosage is 120-240 mg daily as conventional tablets or oral solution or 120-160 mg once daily as extended-release capsules; some manufacturers state that some patients may require dosages up to 640 mg daily. However, the manufacturer of Innopran XL states that dosage of the extended-release capsules may be increased, if needed, up to 120 mg once daily, since dosages exceeding 120 mg once daily did not provide additional hypotensive effects. Some experts recommend a dosage of 40-160 mg daily given in 2 divided doses as conventional tablets or oral solution or 60-180 mg once daily as extended-release capsules. The rationale for such reduced dosages is that it usually is preferable to add another antihypertensive agent to the regimen than to continue increasing propranolol hydrochloride dosage since the patient may not tolerate such continued increases. The full hypotensive effect of the drug usually is evident within 2-3 weeks, but the timing is variable. While twice-daily dosing using the conventional tablets or oral solution is usually effective, some patients may require larger doses or 3 divided doses daily to maintain effective blood pressure control throughout the day.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months. In patients who experience intolerable adverse effects with propranolol, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the β-adrenergic blocking agent (β-blocker) and initiate another class of antihypertensive agent.

Propranolol/Hydrochlorothiazide Fixed-combination Therapy

When combination therapy is required, the manufacturers recommend that commercially available preparations containing propranolol hydrochloride in fixed combination with a thiazide diuretic should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. Therapy with propranolol hydrochloride in fixed combination with hydrochlorothiazide is administered twice daily for a total daily dosage of up to 160 mg of propranolol hydrochloride and 50 mg of hydrochlorothiazide; use of this combination formulation is not appropriate for propranolol hydrochloride dosages exceeding 160 mg daily since it would provide an excessive dosage of the thiazide component. When necessary, another antihypertensive agent may be added gradually using half of the usual initial dosage to avoid an excessive decrease in blood pressure.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of propranolol hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

Angina Pectoris

For the management of angina pectoris, the initial oral dosage of propranolol hydrochloride extended-release capsules is 80 mg daily; dosage is gradually increased as needed to control symptoms, usually at 3- to 7-day intervals. Although optimum response usually occurs at a dosage of 160 mg daily, there is a wide variation in individual requirements.

When using conventional tablets or oral solutions, the usual dosage of propranolol hydrochloride is 80-320 mg daily (given in 2-4 divided doses). The value and safety of dosages greater than 320 mg daily have not been established, but some clinicians have stated that dosage may be increased further if there is only a partial response to usual dosage.

During chronic therapy, the patient should be periodically reevaluated to determine the need for dosage alteration or continued therapy. When propranolol hydrochloride is to be discontinued, dosage should be reduced slowly over a period of at least a few weeks (about 2). (See Cautions: Precautions and Contraindications.)

In patients with unstable angina/non-ST-segment elevation myocardial infarction at high-risk for ischemic events, the American College of Cardiology (ACC) and the American Heart Association (AHA) suggest that therapy be initiated with an IV loading dose of a β-blocker (in patients who tolerate IV therapy) followed by conversion to an oral regimen. Propranolol hydrochloride may be given IV in an initial dose of 0.5-1 mg, followed in 1-2 hours by oral therapy with the drug. Oral therapy with conventional tablets or oral solutions should be initiated at a propranolol hydrochloride dosage of 40-80 mg every 6-8 hours; thereafter, patients should be maintained on 20-80 mg twice daily. The target resting heart rate with β-blocker therapy in patients with unstable angina is 50-60 beats per minute in the absence of dose-limiting adverse effects. Patients receiving IV β-blockers should have frequent monitoring of heart rate and blood pressure, continuous ECG monitoring, and auscultation for rales and bronchospasm.

Cardiac Arrhythmias

The usual adult oral dosage of propranolol hydrochloride for the treatment of arrhythmias is 10-30 mg 3 or 4 times daily as conventional tablets or oral solution. For arrhythmias in adults which are life-threatening or occur during anesthesia, the manufacturer states that 1-3 mg may be administered IV under careful monitoring (e.g., ECG, central venous pressure). If necessary, a second IV dose may be administered after 2 minutes. Additional IV doses may be administered at intervals of no less than 4 hours until the desired response is obtained.

For the acute treatment of supraventricular tachycardia (SVT) (e.g., atrial flutter, junctional tachycardia, paroxysmal supraventricular tachycardia [PSVT], atrial tachycardia) in adults, some experts recommend an initial IV propranolol hydrochloride dose of 1 mg administered over 1 minute; additional doses may be given every 2 minutes up to a total of 3 doses. The usual oral maintenance dosage for ongoing treatment of SVT is 40-160 mg daily in divided doses or single doses (with long-acting preparations). To slow ventricular response in adults with acute atrial fibrillation, experts recommend an initial IV propranolol hydrochloride dose of 1 mg administered over 1 minute; additional doses may be given at 2-minute intervals up to a total of 3 doses. The usual oral maintenance dosage for ongoing treatment of atrial fibrillation is 40-160 mg daily in divided doses.

Hypertrophic Subaortic Stenosis

Hypertrophic subaortic stenosis in adults is usually treated with 20-40 mg of propranolol hydrochloride orally 3 or 4 times daily as conventional tablets or oral solution or 80-160 mg once daily as extended-release capsules.

Pheochromocytoma

In adults with pheochromocytoma, 60 mg of oral propranolol hydrochloride may be administered daily in divided doses as conventional tablets or oral solution in conjunction with an α-adrenergic blocking agent for 3 days prior to surgery. As an adjunct to prolonged treatment of inoperable pheochromocytoma, 30 mg of propranolol hydrochloride daily in divided doses with an α-adrenergic blocker is usually sufficient.

Vascular Headaches

Migraine

For prophylaxis of migraine in adults, the initial oral dosage of propranolol hydrochloride is 80 mg daily, given in divided doses as the conventional tablets or oral solution or once daily as the extended-release capsules. Dosage may be increased gradually to achieve optimum migraine prophylaxis. The usual effective dosage is 80-240 mg daily. If an adequate response is not obtained within 4-6 weeks after reaching the maximum dose, propranolol therapy should be discontinued; it may be advisable to withdraw the drug gradually over several weeks.

Acute Myocardial Infarction

If not initiated acutely, long-term β-blocker therapy should be initiated within a few days of an acute myocardial infarction. To reduce mortality in adults who have had a myocardial infarction, propranolol hydrochloride is administered orally in a dosage of 180-240 mg daily in divided doses as conventional tablets or oral solution, beginning 5-21 days after the myocardial infarction. Although the drug was given in 3 or 4 divided doses daily in clinical studies, there are considerable clinical, pharmacologic, and pharmacokinetic data suggesting that a twice-daily dosing regimen would also be adequate. Safety and efficacy of propranolol hydrochloride dosages exceeding 240 mg daily for the prevention of cardiac mortality have not been established; however, higher dosages may be required for the treatment of coexisting conditions such as angina or hypertension. Evidence from long-term studies with β-blockers suggests that optimum benefit may be achieved if oral therapy is continued for at least 1-3 years after infarction when a contraindication to such therapy does not exist; however, some experts recommend that such therapy be continued indefinitely unless contraindicated.

Essential Tremor

The initial oral dosage of propranolol hydrochloride for the management of essential tremor in adults is 40 mg twice daily as conventional tablets. Response to the drug is variable and dosage must be individualized; optimum suppression of tremor usually is achieved with a dosage of 120-320 mg daily (administered in 3 divided doses daily when conventional tablets are used). In adjusting propranolol hydrochloride dosage, it should be remembered that complete suppression of essential tremor rarely is achieved. Some evidence suggests that dosages exceeding 320 mg daily do not provide substantial added benefit but are associated with an increased risk of adverse effects. Although currently not recommended by the manufacturer, usual dosages administered once daily each morning as extended-release capsules appear to be at least as effective as equivalent dosages administered in divided doses daily as conventional tablets. Some patients may benefit from intermittent rather than chronic therapy; single 80- to 120-mg doses as conventional tablets have been administered 1-3 hours before planned activity or anticipated stress associated with tremor.

Pediatric Dosage

Propranolol has not been as extensively or systematically studied in children as in adults, but specific dosing information has been reasonably studied. Weight-adjusted dosage of propranolol hydrochloride in children only serves as an approximation for initial therapy, and dosage must be adjusted according to the therapeutic response of the patient.

The usual pediatric oral dosage of propranolol hydrochloride is 2-4 mg/kg daily, given in 2 equally divided doses as conventional tablets. Dosage should be calculated on a weight basis rather than a body surface area basis since the latter method may result in excessive plasma concentrations of the drug. Dosage must be individualized but should not exceed 16 mg/kg daily.

Hypertension

For the management of hypertension in children, oral propranolol hydrochloride therapy usually is initiated at 1 mg/kg daily, given in 2 equally divided doses as conventional tablets. Dosage should be titrated according to blood pressure response and patient tolerance. The antihypertensive maintenance dosage in children generally ranges from 2-4 mg/kg daily, given orally in 2 equally divided doses, although higher dosages occasionally may be necessary; however, dosages exceeding 16 mg/kg daily should not be used in children. Alternatively, some experts have recommended a usual initial oral dosage of 1-2 mg/kg daily given in 2 or 3 divided doses. Dosage may be increased as necessary to a maximum dosage of 4 mg/kg (up to 640 mg) daily given in 2 or 3 divided doses.

Cardiac Arrhythmias

Although parenteral propranolol hydrochloride currently is not recommended by the manufacturer for use in children, an initial IV dose of 10-20 mcg/kg infused over 10 minutes has been recommended by some clinicians for the treatment of cardiac arrhythmias in children. Some clinicians state that pediatric oral dosages exceeding 4 mg/kg daily may be necessary for the management of supraventricular tachyarrhythmias. Oral propranolol hydrochloride therapy has been initiated at 1.5-2 mg/kg daily and titrated upward as necessary to control the arrhythmia, up to a maximum dosage of 16 mg/kg daily given in 4 divided doses.

Thyrotoxicosis

For the treatment of tachyarrhythmias in neonates with thyrotoxicosis, an oral propranolol hydrochloride dosage of 2 mg/kg daily given in 2-4 divided doses has been used, although higher dosages occasionally may be needed.

Dosage in Hepatic Impairment

The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in patients with hepatic impairment.

Cautions

The most common, serious adverse effects of propranolol are related to its β-adrenergic blocking activity. Adverse reactions are more frequent and may be more severe after IV administration than after oral administration. In one large study of hospitalized patients receiving propranolol, reactions were most common in azotemic patients and in those older than 60 years of age. The incidence of adverse reactions to oral propranolol was unrelated to the dose, and adverse reactions usually occurred soon after the initiation of therapy. The investigators concluded that many severe adverse reactions result from the inability of severely ill patients to withstand a decrease in normal β-adrenergic stimulation.

Cardiovascular Effects

The most common adverse cardiovascular effect of propranolol is bradycardia, especially in patients with digitalis intoxication. Bradycardia is occasionally severe and may be accompanied by hypotension, syncope, shock, or angina pectoris. Severe bradycardia should be treated with IM or IV administration of atropine sulfate. (See Drug Interactions: Sympathomimetic Agents.) In patients with Wolff-Parkinson-White syndrome, propranolol has produced severe bradycardia requiring a demand pacemaker.

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. In patients with inadequate cardiac function, heart failure may be precipitated as a result of removal of β-adrenergic stimulation when propranolol therapy is initiated. A decrease in exercise tolerance may be experienced by patients with left ventricular dysfunction. In patients without a prior history of heart failure, prolonged depression of the myocardium by propranolol has resulted in heart failure in rare instances. (See Cautions: Precautions and Contraindications.) Intensification of AV block, AV dissociation, AV conduction delays, complete heart block, or cardiac arrest may occur, especially in patients with preexisting partial heart block caused by a cardiac glycoside or other factors. Ventricular fibrillation has been reported in a patient with hypertrophic subaortic stenosis.

After sudden cessation of propranolol therapy in some patients treated for angina, increased frequency, duration, and severity of angina episodes have occurred, often within 24 hours. These episodes are unstable and are not relieved by nitroglycerin. Acute and sometimes fatal myocardial infarction and sudden death have also occurred after abrupt withdrawal of propranolol therapy in some patients treated for angina. In hypertensive patients, sudden cessation of propranolol has produced a syndrome similar to florid thyrotoxicosis, characterized by tenseness, anxiety, tachycardia, and excessive perspiration; these symptoms occurred within one week of cessation of the drug and were relieved by reinstituting propranolol therapy.

During surgery, some patients who have been receiving propranolol may experience severe, protracted hypotension and, occasionally, difficulty in restarting and maintaining heart beat. These adverse cardiovascular effects of propranolol may be reversed during surgery by IV administration of β-adrenergic agonists such as isoproterenol or norepinephrine.

Severe hypertension has been reported in a few patients with schizophrenic disorder who received only propranolol orally in rapidly increasing doses; the hypertension responded to treatment with IV phentolamine followed by oral phenoxybenzamine.

Fluid retention, pulmonary edema, and peripheral arterial insufficiency, usually of the Raynaud's type, may occur in patients receiving propranolol. When the drug is used alone, dietary sodium restriction may be necessary. Intermittent claudication has occurred in patients with previously asymptomatic peripheral arterial disease who received propranolol, although one study which used the drug for the treatment of intermittent claudication did not note any deterioration of occlusive peripheral arterial disease.

Nervous System Effects

A number of adverse CNS effects which are usually reversible after withdrawal of the drug have been reported. Adverse CNS effects usually occur after long-term treatment with high doses of propranolol and range from lightheadedness, giddiness, ataxia, dizziness, irritability, sleepiness, hearing loss, and visual disturbances to vivid dreams, hallucinations, and confusion. Insomnia, lassitude, weakness, fatigue, and mental depression progressing to catatonia have been reported. Dosages exceeding 160 mg daily, when administered in divided doses exceeding 80 mg each, may be associated with an increased incidence of fatigue, lethargy, and vivid dreams. Organic brain syndrome, characterized by disorientation to time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometric tests, has been reported rarely. Paresthesia of the hands, peripheral neuropathy, and precipitation of myotonia have been reported. Impotence has been reported rarely. Ptosis has been reported in 2 patients. Two patients receiving propranolol for hypertrophic obstructive cardiomyopathy developed migraine; in one patient this was associated with sensory disturbances and teichopsia.

GI Effects

Adverse GI effects such as nausea, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, and flatulence may occur in patients receiving propranolol and occasionally necessitate reduction of dosage or withdrawal of the drug. Mesenteric arterial thrombosis and ischemic colitis have also occurred.

Dermatologic and Sensitivity Reactions

Rarely, rashes have been reported during propranolol usage. Rashes are most commonly erythematous (maculopapular or acneiform), dry, scaly, pruritic, psoriasiform lesions which occur on the trunk, extremities, and scalp. Hyperkeratosis of the scalp, palms, and soles of the feet have been reported during treatment with propranolol; nail changes such as thickening, pitting, and discoloration have occurred. At least one case of exfoliative dermatitis has been reported. Dermatologic reactions disappear after the drug is withdrawn. Other allergic manifestations reported during propranolol therapy include fever accompanied by aching and sore throat, rhinitis, dry mouth, laryngospasm, respiratory distress, and pharyngitis. A lupus-like syndrome characterized by fever, pruritus, severe myalgia, and positive lupus erythematosus cell tests has been reported in at least one patient receiving propranolol. Reversible alopecia, which recurred following readministration of the drug, has been reported.

Hematologic Effects

Adverse hematologic effects of propranolol include transient eosinophilia (a pharmacologic effect of β-adrenergic blockade) and idiosyncratic reactions including thrombocytopenic and nonthrombocytopenic purpura and, rarely, agranulocytosis.

Endocrine Effects

Results of a large prospective cohort study of adults 45-64 years of age indicate that use of β-adrenergic blocking agents (β-blockers) in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy. In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blocker or no drug therapy, respectively. The association between the risk of developing diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate. It is not known if the risk of developing diabetes is affected by β-receptor selectivity. Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance. Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing diabetes mellitus.

Hypoglycemia, which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-blockers. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.

β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia. Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients receiving propranolol. Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blockers (e.g., atenolol). In addition, selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.

Other Adverse Effects

Propranolol may cause elevated BUN in patients with severe heart disease, elevated serum creatinine, aminotransferase, alkaline phosphatase, or lactic dehydrogenase concentrations. In hypertensive patients, propranolol may cause small increases in serum potassium concentration. Peyronie's disease and dry eyes have been reported rarely. Generalized hyperemia of the conjunctivae with decreased tear production and a prickling sensation of the eyes has been reported in a patient receiving the drug. Eye dryness and pain occurred in one patient receiving propranolol. Discoloration of the tongue and bad taste were reported in two patients receiving the drug.

Precautions and Contraindications

Propranolol shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed. When propranolol is used as a fixed-combination preparation that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with propranolol.

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. Propranolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when propranolol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure. Although β-blockers should be avoided in patients with overt heart failure, propranolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving propranolol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, propranolol should be discontinued, gradually if possible.

Abrupt withdrawal of propranolol may exacerbate angina symptoms or precipitate myocardial infarction in patients with coronary artery disease. Abrupt withdrawal of the drug in patients treated for hypertension has also been associated with adverse effects. (See Cautions: Cardiovascular Effects.) Therefore, patients receiving propranolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician. When discontinuance of propranolol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of at least a few weeks (about 2). When propranolol therapy is discontinued, patients should be carefully monitored and their activity restricted. If exacerbation of angina occurs after propranolol therapy is interrupted, treatment with the drug should generally be reinstituted and appropriate measures taken for the management of unstable angina pectoris. Because coronary artery disease is common and may be unrecognized, the manufacturers caution that it may be prudent not to discontinue propranolol therapy abruptly, even in patients receiving the drug for conditions other than angina.

The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers. As with other β-blockers, the effects of propranolol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol). If propranolol therapy is discontinued prior to major surgery, oral therapy with the drug may be restarted as soon after surgery as possible; patients who are unable to take oral drugs after surgery may be treated with IV propranolol if necessary.

Caution should be used when administering propranolol to patients with sinus node dysfunction, since the drug can cause marked depression of SA node automaticity. Propranolol should be used with extreme caution for the management of arrhythmias occurring during anesthesia with myocardial depressant anesthetics (e.g., methoxyflurane [no longer commercially available in the US], trichloroethylene), since excessive myocardial depression, bradycardia, and hypotension may occur.

Signs of hyperthyroidism may be masked by propranolol, and patients with thyrotoxicosis who receive the drug should be monitored closely. In addition, the drug may alter thyroid function test results, increasing thyroxine (T₄) and reverse triiodothyronine (rT₃) and decreasing triiodothyronine (T₃) determinations.

It is recommended that propranolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes or those prone to hypoglycemia) since the drug also may block the signs and symptoms of hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating). However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers. In addition, the drug occasionally causes hypoglycemia, even in nondiabetic patients, presumably by interfering with catecholamine-induced glycogenolysis. Propranolol may also inhibit the insulin-releasing mechanism of the pancreas and has been implicated in hyperglycemic reactions. Propranolol-induced alterations in glucose tolerance appear to occur only rarely. (See Cautions: Endocrine Effects.) Some sources state that hypertensive patients who are prone to hypoglycemia should not receive propranolol because the drug may cause a sharp rise in blood pressure.

Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease. Propranolol should be used with caution in patients with a history of nonallergic bronchospasm (e.g., chronic bronchitis, emphysema). β-adrenergic blockade may lead to an increase in airway resistance and bronchospasm, particularly in patients with a history of asthma. Bronchospasm may be treated with IV administration of aminophylline; isoproterenol may also be administered. (See Drug Interactions: Sympathomimetic Agents.) IV administration of atropine has been suggested if the patient fails to respond to the above or if bradycardia is present.

Since treatment with β-blockers (e.g., propranolol) may reduce intraocular pressure, patients should be advised that such therapy may interfere with glaucoma screening tests. Withdrawal of propranolol may lead to an increase in intraocular pressure.

Propranolol should be used with caution in patients with renal or hepatic impairment. Laboratory parameters should be monitored in patients receiving prolonged therapy with the drug.

Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenge with such allergens while receiving a β-blocker. These patients may be unresponsive to usual doses of epinephrine or may develop a paradoxical response to epinephrine when it is used to treat anaphylactic reactions.

Propranolol is contraindicated in patients with Raynaud's syndrome, bronchial asthma, sinus bradycardia and heart block greater than first degree, and overt and decompensated heart failure (unless the failure is secondary to a tachyarrhythmia treatable with propranolol). The drug is not indicated in the management of hypertensive emergencies. Although the manufacturers state that propranolol is contraindicated in patients with cardiogenic shock, results of some studies indicate that the drug may have a beneficial effect in patients with myocardial infarction with or without cardiogenic shock. (See Uses: Acute Myocardial Infarction.) Because propranolol has produced a myasthenic condition characterized by ptosis, weakness of limbs, and double vision in 2 patients, the drug may be contraindicated in patients with myasthenia gravis. In addition, since propranolol appears to impair metabolism of thioridazine which may result in increased plasma concentrations of thioridazine that may be associated with prolongation of the QT interval, the manufacturer of thioridazine states that concomitant use of thioridazine and propranolol is contraindicated.(See Drug Interactions: Phenothiazines and Other Psychotherapeutic Agents.)

Pediatric Precautions

Although safety and efficacy of propranolol have not been as extensively or systematically studied in children as in adults, current information from the medical literature allows fair estimates, and specific dosing information has been reasonably studied. Cardiovascular diseases that are common to adults and children generally are as responsive to propranolol therapy in children as in adults, and adverse reactions also are similar. One manufacturer states that the possibility that oral bioavailability of propranolol hydrochloride may be increased in children with Down's syndrome should be considered. Safety and efficacy of propranolol hydrochloride extended-release capsules, oral solution, and injection have not been established in children.

Geriatric Precautions

Clinical studies of propranolol tablets, injections, and extended-release capsules did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. If propranolol is used in geriatric patients, dosage of the drug should be selected with caution, usually initiating therapy at the low end of the dosage range since decreased hepatic, renal, or cardiac function and concomitant disease or other drug therapy are more common in this age group than in younger patients.

Decreased propranolol clearance and a prolonged elimination half-life have been reported in geriatric patients receiving propranolol hydrochloride injection, and the manufacturers recommend that dosage reduction be considered in these patients.

Carcinogenicity

In long-term studies in animals, no evidence of propranolol-related tumorigenic effects was observed.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies to date using propranolol in pregnant women. Safe use of propranolol during pregnancy has not been established. Low birthweight infants with respiratory distress and hypoglycemia have been born to women who received propranolol throughout pregnancy. Bradycardia, hypoglycemia, and respiratory depression also have been reported in neonates whose mothers received propranolol at parturition; adequate facilities for monitoring such infants at birth should be available. The manufacturers state that the drug should be used during pregnancy only when the possible benefits outweigh the potential risks to the fetus.

Embryotoxicity (reduced litter size, increased resorption rates) and neonatal toxicity (deaths) have been reported in reproductive studies in rats receiving propranolol hydrochloride 150 mg/kg daily by gavage or in the diet throughout pregnancy and lactation; however, such effects were not observed in rats receiving 80 mg/kg daily (equivalent to the maximum recommended human dosage on a mg/m basis). No evidence of embryotoxicity or neonatal toxicity was observed in rabbits receiving oral doses of propranolol hydrochloride of up to 150 mg/kg daily (about 5 times the maximum recommended oral human daily dose) throughout pregnancy and lactation.

Fertility

Reproduction studies in animals using propranolol have not revealed evidence of impaired fertility.

Lactation

Since propranolol is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Because metabolism of propranolol is mediated by cytochrome P-450 (CYP) isoenzymes 2D6, 1A2, and 2C19, drugs that induce or inhibit these isoenzymes may alter the metabolism of propranolol, which may result in clinically important drug interactions. Inhibitors or substrates of the isoenzymes 2D6 (e.g., amiodarone, cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, ritonavir), 1A2 (e.g., cimetidine, ciprofloxacin, fluvoxamine, imipramine, isoniazid, ritonavir, rizatriptan, theophylline, zileuton, zolmitriptan), or 2C19 (e.g., cimetidine, fluconazole, fluoxetine, fluvoxamine, teniposide, tolbutamide) could decrease the metabolism and increase plasma concentrations of propranolol. Drugs that induce cytochrome P-450 activity (e.g., alcohol, rifampin) may increase the metabolism of propranolol and decrease its plasma concentrations; in current smokers, plasma propranolol concentrations also may be decreased because cigarette smoking may induce hepatic metabolism of the drug, increasing propranolol clearance up to 100%.

Phenothiazines and Other Psychotherapeutic Agents

Phenothiazines and propranolol may have additive hypotensive activity, especially when phenothiazines are administered in large doses. Chlorpromazine has been shown to reduce the clearance of propranolol and increase plasma propranolol concentrations. Increased plasma concentrations of chlorpromazine also have been reported in patients receiving the drug concomitantly with propranolol. Hypotension and cardiac arrest have occurred during concomitant therapy with propranolol and haloperidol.

In addition, since propranolol may inhibit metabolism of thioridazine, concomitant use of propranolol (100-800 mg daily) and thioridazine, reportedly resulted in increased plasma concentrations of thioridazine and its metabolites by about 50-400 and 80-300%, respectively. Because such increased concentrations of thioridazine may enhance thioridazine-induced prolongation of the QT_c interval, and increase the risk of serious, potentially fatal cardiac arrhythmias (e.g., torsades de pointes), the manufacturer of thioridazine states that concomitant use of thioridazine and propranolol is contraindicated.

Complete heart block has been reported in a patient receiving fluoxetine concomitantly with propranolol. The mechanism of this interaction is not known; however, it has been postulated that fluoxetine may inhibit metabolism of lipophilic β-adrenergic blocking agents (β-blockers) (e.g., propranolol, metoprolol), increase their bioavailability, and increase their β-adrenergic blocking effects. Therefore, some clinicians recommend that fluoxetine be administered with caution in patients receiving β-blockers and in those with impaired cardiac conduction.

The hypotensive effects of monoamine oxidase (MAO) inhibitors or tricyclic antidepressants may be exacerbated in patients receiving β-blockers.

Decreased metabolism and increased plasma concentrations of diazepam and its metabolites have been reported in patients receiving the drug concomitantly with propranolol; propranolol does not appear to alter pharmacokinetics of other benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, triazolam). Diazepam does not alter pharmacokinetics of propranolol.

Sympathomimetic Agents

The β-adrenergic stimulating effects of sympathomimetic agents are antagonized by propranolol. This interaction is especially pronounced with isoproterenol, and very large doses of isoproterenol may be needed to overcome the β-adrenergic blocking effects of propranolol. The effects of propranolol also can be reversed by administration of dobutamine. In addition, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Patients receiving long-term propranolol therapy may experience uncontrolled hypertension upon administration of epinephrine as a result of unopposed α-receptor stimulation. In patients receiving propranolol, epinephrine should be administered with caution since a decrease in pulse rate with first- and second-degree heart block may occur.

Antimuscarinic Agents and Drugs with Anticholinergic Effects

Antimuscarinic agents, such as atropine, may counteract the bradycardia caused by propranolol by reestablishing the balance between sympathetic and parasympathetic actions on the heart. Tricyclic antidepressants (e.g., amitriptyline) also have anticholinergic activity and may similarly antagonize the cardiac β-adrenergic blocking effects of propranolol, although not as intensely as do the antimuscarinics.

Catecholamine-depleting Drugs

When propranolol and a catecholamine-depleting drug (e.g., reserpine) are administered concomitantly, the effects of the drugs may be additive. Excessive reduction of resting sympathetic nervous system activity, which may lead to hypotension, severe bradycardia, vertigo, syncope, or orthostatic hypotension, has been reported in patients receiving both drugs concurrently. Concomitant use of reserpine and propranolol also may potentiate depression.

Selective Serotonin Agonists

Increased concentrations of zolmitriptan and rizatriptan have been reported in patients receiving concomitant propranolol therapy.

Diuretics and Cardiovascular Drugs

When propranolol is administered with diuretics or other antihypertensive drugs, the hypotensive effect of propranolol may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. In addition to its potentially additive hypotensive effect, reserpine theoretically may add to the β-adrenergic blocking activity of propranolol through its catecholamine-depleting activity. (See Drug Interactions: Catecholamine-depleting Drugs.)

Clonidine

The antihypertensive effects of clonidine may be antagonized by β-blockers, including propranolol. Because β-blockers (e.g., propranolol) may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, β-blockers should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued in patients receiving a β-blocker and clonidine concurrently.

Angiotensin-converting Enzyme Inhibitors

Concomitant therapy with angiotensin-converting enzyme (ACE) inhibitors and β-blockers (e.g., propranolol) may result in hypotension, particularly in patients with acute myocardial infarction. Increased bronchial hyperreactivity has been reported in patients receiving ACE inhibitors concomitantly with propranolol.

α-Adrenergic Blocking Agents

Prolonged hypotension associated with administration of a first prazosin dose has been reported in patients receiving β-blockers. In addition, postural hypotension has been reported in patients receiving β-blockers concomitantly with terazosin or doxazosin.

Other Cardiovascular Agents

When propranolol is administered with antiarrhythmic drugs such as lidocaine, phenytoin, procainamide, quinidine, or verapamil , cardiac effects may be additive or antagonistic and toxic effects may be additive.

Concomitant use of β-blockers (e.g., propranolol) and certain other cardiovascular drugs (e.g., cardiac glycosides, lidocaine, nondihydropyridine calcium-channel blocking agents) can have additive negative effects on SA or AV nodal conduction. Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy. Concomitant therapy with an IV β-blocker and IV verapamil has resulted rarely in serious adverse reactions, especially in patients with severe cardiomyopathy, heart failure, or recent myocardial infarction. Severe bradycardia, heart failure, and cardiovascular collapse have been reported in patients receiving verapamil concomitantly with β-blockers.

Caution should be used in patients receiving propranolol concomitantly with a calcium-channel blocking agent with negative inotropic and/or chronotropic effects, since both drugs may depress myocardial contractility and AV conduction. Severe bradycardia, asystole, heart failure, and cardiovascular collapse have been reported in patients receiving propranolol concomitantly with disopyramide or verapamil. In addition, bradycardia, hypotension, high-degree heart block, and heart failure have been reported in patients with cardiac disease receiving concomitant therapy with propranolol and diltiazem. Concomitant use of propranolol with amiodarone also may result in additive negative chronotropic effects, while additive negative inotropic and β-adrenergic blocking effects may occur when propafenone and propranolol are used concomitantly. In patients currently receiving a cardiac glycoside, concomitant propranolol therapy may reduce the positive inotropic effect of the glycoside. (See Cautions: Precautions and Contraindications.)

Increased propafenone exposure has been reported in patients receiving the drug concomitantly with propranolol. Verapamil does not appear to affect pharmacokinetics of propranolol and propranolol does not affect pharmacokinetics of verapamil or norverapamil. Increased propranolol concentrations have been reported in patients receiving concomitant therapy with nisoldipine or nicardipine with propranolol; increased concentrations of nifedipine may occur in patients receiving the drug concomitantly with propranolol.

Administration of quinidine has been reported to cause decreased propranolol metabolism, resulting in increased propranolol plasma concentrations and increased β-blocking effects (and possible postural hypotension). Reduced lidocaine metabolism and clearance resulting in lidocaine toxicity have been reported in patients receiving the drug concomitantly with propranolol.

Antilipemic Agents

Decreased propranolol plasma concentrations have been reported in patients receiving the drug concomitantly with cholestyramine or colestipol. Decreased plasma concentrations of lovastatin and pravastatin have been reported in patients receiving the drugs concomitantly with propranolol; however, the pharmacodynamics of the antilipemics were not altered.

Warfarin

Increases in warfarin bioavailability and prothrombin time have been reported in patients receiving warfarin concomitantly with propranolol. Prothrombin time should be monitored in patients receiving warfarin concomitantly with propranolol.

Neuromuscular Blocking Agents

High doses of propranolol may potentiate the effects of neuromuscular blocking agents such as tubocurarine chloride, possibly because of propranolol's interference with ionic permeability of the postjunctional membrane. Propranolol should be administered with caution to patients who are receiving neuromuscular blocking agents or who are recovering from their effects.

Antidiabetic Agents

β-Blockers may impair glucose tolerance; increase the frequency or severity of hypoglycemia; block hypoglycemia-induced tachycardia but not hypoglycemic sweating, which may actually be increased; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. Nonselective β-blockers (e.g., propranolol, nadolol) without intrinsic sympathomimetic activity are more likely to affect glucose metabolism than more selective β-blockers (e.g., metoprolol, atenolol) or those with intrinsic sympathomimetic activity (e.g., acebutolol, pindolol). Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of anxiety) mediated by catecholamines may be masked by either nonselective or selective β-blockers. When an oral antidiabetic agent or insulin and a β-blocker are used concomitantly, the patient should be advised about and monitored closely for altered antidiabetic response.

Ergot Alkaloids

One case of severe peripheral vasoconstriction with pain and cyanosis has been reported in a patient who received propranolol orally and high doses of ergotamine in a rectal suppository concurrently for the treatment of migraine; however, several patients have received these drugs concomitantly without adverse effects. Caution should be used during simultaneous administration of propranolol and high doses of ergot alkaloids because of the possibility of additive peripheral vasoconstriction.

Cimetidine

Cimetidine can substantially reduce the clearance of propranolol (apparently by inhibiting the hepatic metabolism of propranolol), which results in increased propranolol concentrations. If propranolol and cimetidine are administered concomitantly, the patient should be monitored for signs and symptoms of increased β-adrenergic blocking activity.

Antacids

Concomitant oral administration of an aluminum hydroxide antacid with propranolol may reduce the GI absorption of propranolol. In a study in healthy adults, oral administration of 30 mL of an aluminum hydroxide (1.2 g) suspension with a single, 80-mg dose of propranolol hydrochloride reduced the peak plasma propranolol concentration and bioavailability of the drug by about 60%. The mechanism of this potential interaction has not been elucidated, but propranolol adsorption to or complexation with aluminum hydroxide does not appear to be involved. In another study in healthy adults, however, concomitant oral administration of 30 mL of an aluminum hydroxide suspension with a single, 40-mg dose of propranolol hydrochloride did not substantially affect bioavailability of propranolol. The need to avoid concomitant use or stagger dosing of an aluminum hydroxide antacid and propranolol has not been fully elucidated, but increasing propranolol dosage may be considered if an interaction is suspected.

Levodopa

Propranolol may antagonize the hypotensive and positive inotropic effects of levodopa. This interaction is not well documented; however, the possibility of its occurrence should be kept in mind.

Nonsteroidal Anti-inflammatory Agents

The possibility that nonsteroidal anti-inflammatory agents (NSAIAs; e.g., indomethacin) may reduce the hypotensive effect of β-blockers such as propranolol should be considered.

Theophylline

Propranolol decreases the clearance of theophylline in a dose-dependent manner by inhibiting hepatic microsomal metabolism (principally demethylation). In addition, propranolol can antagonize theophylline-induced bronchodilation.

Pharmacokinetics

Absorption

Propranolol is almost completely absorbed from the GI tract; however, plasma concentrations attained are quite variable among individuals. There is no difference in the rate of absorption of the 2 isomers of propranolol. Propranolol appears in the plasma within 30 minutes, and peak plasma concentrations are reached about 60-90 minutes after oral administration of the conventional tablets. The time when peak plasma concentrations are reached may be delayed, but concentrations are not necessarily lowered, when the drug is administered with food. One manufacturer states that oral bioavailability of the drug may be increased in children with Down's syndrome; higher than expected plasma propranolol concentrations have been observed in such children. Bioavailability of a single 40-mg oral dose of propranolol hydrochloride as a conventional tablet or oral solution reportedly is equivalent in adults. Propranolol hydrochloride is slowly absorbed following administration of the drug as extended-release capsules, and peak blood concentrations are reached about 6 hours after administration. When measured at steady-state over a 24-hour period, the area under the plasma concentration-time curve (AUC) for the extended-release capsules is about 60-65% of the AUC for a comparable divided daily dose of the conventional tablets. The lower AUC is probably caused by the slower rate of absorption of the drug from the extended-release capsules with resultant greater hepatic metabolism. After administration of a single dose of propranolol as the extended-release capsules, blood concentrations are fairly constant for about 12 hours and then decline exponentially during the following 12 hours.

Plasma propranolol concentrations attained after IV administration of the drug are relatively consistent among individuals. After administration of a 0.5-mg IV bolus of propranolol, peak plasma concentrations of 40 ng/mL are produced in 1 minute and the drug is undetectable in the plasma in 5 minutes. Following IV administration of propranolol, the onset of action is almost immediate. Animal studies indicate that propranolol is rapidly absorbed after IM administration.

After absorption from the GI tract, propranolol is bound by the liver through nonspecific tissue binding. There are large individual differences in hepatic extraction, probably because of differences in hepatic blood flow. Following oral administration, the drug does not reach the general circulation until hepatic binding sites are saturated. Once saturation occurs, hepatic binding no longer affects the passage of the drug into the blood. The amount of drug that reaches the circulation after oral administration also depends on the amount of drug metabolized on the first pass through the liver. Propranolol decreases its own rate of metabolism by decreasing hepatic blood flow. Studies indicate that hepatic extraction and possibly metabolism of propranolol are reduced following oral administration of the drug in patients with chronic renal disease, resulting in higher peak plasma concentrations of the drug after the first dose than are attained in patients with normal renal function.

There is considerable interpatient variation in the relationship of plasma propranolol concentrations and therapeutic effect, but therapeutic plasma concentrations of propranolol are usually 50-100 ng/mL. Concentrations of 100 ng/mL generally represent a high degree of β-adrenergic blockade. There are several possible metabolic explanations for the discrepancies between plasma concentrations and therapeutic effect. (See Pharmacokinetics: Elimination.) Individual differences in sympathetic tone may also contribute to interpatient differences in response.

Distribution

Propranolol is widely distributed into body tissues including lungs, liver, kidneys, and heart. Propranolol readily crosses the blood-brain barrier and the placenta. The drug is distributed into milk.

The apparent volume of distribution of propranolol at steady-state varies widely in proportion to the fraction of unbound drug in whole blood. Propranolol is more than 90% bound to plasma proteins over a wide range of blood concentrations. Both free and protein-bound propranolol are metabolized. Increased plasma protein binding of the drug increases its metabolism and decreases its volume of distribution, resulting in a shorter terminal half-life.

Elimination

Elimination of propranolol appears to follow first-order kinetics and seems to be independent of plasma concentration or the dose administered, at least with oral doses of 160-320 mg/day. The reported elimination half-life varies considerably among different studies. After IV administration of 10 mg of propranolol hydrochloride at a rate of 1.03 mg/minute in one study, plasma concentrations declined in a biphasic manner; the half-life during the initial phase (t_½α) was 10 minutes and that during the terminal phase (t_½β) was 2.3 hours. Results from one study indicate that the half-life of the l-isomer is about 50% longer than that of the d-isomer. When usual therapeutic doses of propranolol are administered chronically, the half-life ranges from 3.4-6 hours. Single-dose studies generally have shown a shorter half-life of 2-3 hours. This difference in half-life between chronic and single-dose studies may be the result of initial removal of the drug into a large extravascular space (especially hepatic binding sites) and also a saturation of systemic clearance (including drug metabolizing enzymes and excretion). The half-life of propranolol may decrease with decreasing renal function; however, there is insufficient evidence to indicate that any alteration in maintenance dosage is necessary in patients with impaired renal function.

During initial oral therapy (but not during IV or chronic oral therapy), an active metabolite, 4-hydroxypropranolol, is formed. 4-Hydroxypropranolol has about the same β-adrenergic blocking potency as does propranolol and may be present in plasma in amounts about equal to propranolol. This metabolite is eliminated more rapidly than propranolol and is virtually absent from the plasma 6 hours after oral administration of the drug. Results of one study indicate that after IV administration or chronic oral administration of propranolol, 4-hydroxypropranolol is not formed to a substantial extent, and β-adrenergic blocking activity is more closely reflected by propranolol concentrations. Individual variations in ability to hydroxylate propranolol to the active metabolite may also exist. In addition, some other metabolites of propranolol may possess antiarrhythmic activity without β-adrenergic blocking activity.

Propranolol is almost completely metabolized in the liver and at least 8 metabolites have been identified in urine. Only 1-4% of an oral or IV dose of the drug appears in feces as unchanged drug and metabolites. In patients with severely impaired renal function, a compensatory increase in fecal excretion of propranolol occurs. Reduced propranolol plasma clearance and increased peak plasma concentrations have been reported in patients with chronic renal failure compared with healthy individuals and patients receiving dialysis. Chronic renal failure may be associated with reduced drug metabolism secondary to downregulation of hepatic cytochrome P-450 (CYP) enzyme system activity. Propranolol is apparently not substantially removed by hemodialysis.

Decreased propranolol clearance and prolonged elimination half-life have been reported in geriatric patients compared with younger patients. In addition, reduced clearance, increased volume of distribution, decreased protein binding, and considerable variation in elimination half-life of propranolol have been reported in patients with chronic liver disease compared with individuals with normal liver function. Increased propranolol exposure and decreased clearance also have been reported in obese individuals compared with nonobese individuals.