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    Non-Selective Beta-Blockers

    BOXED WARNING

    Abrupt discontinuation

    Abrupt discontinuation of any chronically administered beta-adrenergic blocking agent, such as propranolol, can result in the exacerbation of angina and, in some cases, myocardial ischemia or myocardial infarction, ventricular arrhythmias, or severe hypertension, especially in patients with preexisting cardiac disease. If chronic, oral propranolol therapy is to be discontinued, the dosage should be gradually decreased over a minimum of 2 weeks. Downward titration of parenteral therapy may be advisable if the patient will discontinue propranolol treatment. Patients and caregivers should be advised against interruption or cessation of therapy without the advice of a physician. If exacerbation of angina occurs during discontinuation of therapy, it is advised to reinstitute propranolol therapy and take other measures appropriate for the management of unstable angina.

    DEA CLASS

    Rx

    DESCRIPTION

    Competitive, nonselective beta-blocker without intrinsic sympathomimetic activity
    Used for many cardiac indications such as: angina, ventricular rate control, hypertension, PSVT, etc.
    Also used for non-cardiac indications: migraine prophylaxis, tremor, infantile hemangioma

    COMMON BRAND NAMES

    HEMANGEOL, Inderal, Inderal LA, Inderal XL, InnoPran XL

    HOW SUPPLIED

    HEMANGEOL/Propranolol Hydrochloride Oral Sol: 1mL, 4.28mg, 5mL, 20mg, 40mg
    Inderal LA/Inderal XL/InnoPran XL/Propranolol Hydrochloride Oral Cap ER: 60mg, 80mg, 120mg, 160mg
    Inderal/Propranolol Hydrochloride Intravenous Inj Sol: 1mg, 1mL
    Inderal/Propranolol Hydrochloride Oral Tab: 10mg, 20mg, 40mg, 60mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of chronic stable angina.
    Oral dosage (immediate-release formulations)
    Adults

    Initially, 10 to 20 mg PO 2 to 4 times per day, then increase at 3 to 7 day intervals up to 160 to 320 mg/day, given in 2 to 4 divided doses. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Oral dosage (extended-release capsules)
    Adults

    80 mg PO once daily, then increase at 3 to 7 day intervals up to 160 to 320 mg PO once daily. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    For heart rate control in patients with atrial fibrillation and/or atrial flutter.
    Intravenous dosage
    Adults

    The usual dose is 1 to 3 mg IV, given at a rate no faster than 1 mg/minute. If needed, a second dose can be given after 2 minutes with careful monitoring of blood pressure and heart rate. Thereafter, subsequent doses can be given every 4 hours as needed. Reserve IV propranolol for atrial fibrillation or flutter that is unresponsive to standard therapy or when more prolonged control is required. Clinical practice guidelines recommend the use of intravenous beta blockers to slow the ventricular heart rate in the acute setting in patients with atrial fibrillation without pre-excitation; cautious use is needed in patients with cardiac failure with overt congestion, hypotension, or reduced left ventricular ejection fraction. The propranolol IV dose recommended in clinical practice guidelines is 1 mg IV over 1 minute, which may be repeated every 2 minutes to a suggested maximum of 3 doses.

    Children† and Adolescents†

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 3 mg/dose, whichever is less.

    Neonates† and Infants†

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.

    Oral dosage (immediate-release formulations)
    Adults

    Initially, 10 to 30 mg PO 3 or 4 times daily. Clinical practice guidelines recommend the use of beta blockers to control the ventricular rate for patients with paroxysmal, persistent, or permanent atrial fibrillation. The usual maintenance dose recommended by clinical practice guidelines is 10 to 40 mg 3 or 4 times daily.

    Neonates†, Infants†, Children†, and Adolescents†

    Initially, 0.5 to 1 mg/kg/day PO, given in divided doses every 6 to 8 hours. Titrate dosage incrementally by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual maintenance dosage is 2 to 4 mg/kg/day PO. Max: 16 mg/kg/day or 60 mg/day, whichever is less. In older adolescents, 10 to 30 mg/dose PO every 6 to 8 hours may be given.

    For the treatment of paroxysmal supraventricular tachycardia (PSVT) or for paroxysmal supraventricular tachycardia (PSVT) prophylaxis.
    Oral dosage (immediate-release formulations)
    Adults

    Initially, 10 to 30 mg PO 3 or 4 times daily. Dosage may be increased up to 160 to 320 mg/day PO, given in 3 to 4 divided doses. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Neonates†, Infants†, Children†, and Adolescents†

    Initially, 0.5 to 1 mg/kg/day PO, given in divided doses every 6 to 8 hours. Titrate dosage incrementally by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual maintenance dosage is 2 to 4 mg/kg/day PO. Max: 16 mg/kg/day or 60 mg/day, whichever is less. In older adolescents, 10 to 30 mg/dose PO every 6 to 8 hours may be given.

    Intravenous dosage
    Adults

    1 to 3 mg IV at a rate no faster than 1 mg/minute; repeat if necessary in 2 minutes. Separate subsequent doses by at least 4 hours. Clinical practice guidelines recommend 0.5 to 1 mg over 1 minute, repeated up to a total dose of 0.1 mg/kg, if required. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Children† and Adolescents†

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 3 mg/dose, whichever is less.

    Neonates† and Infants†

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.

    For the treatment of an evolving acute myocardial infarction.
    NOTE: For ST-elevation myocardial infarction, oral beta-blocker therapy should be initiated in the first 24 hours for patients who do not have signs of cardiac failure, evidence of low output, increased risk for cardiogenic shock, or other contraindications for beta-blocker therapy.
    Intravenous dosage
    Adults

    0.1 mg/kg IV, administered in 3 equal divided doses at 2 to 3 minute intervals.

    Oral dosage (immediate-release formulations)
    Adults

    180 to 320 mg/day PO, given in 3 to 4 divided doses.

    For reduction of cardiovascular mortality in stable patients who have sustained a myocardial infarction.
    Oral dosage (immediate-release formulations)
    Adults

    180 to 240 mg/day PO, given in 3 to 4 divided doses starting in the first 24 hours post-MI.

    For the treatment of hypertension.
    Oral dosage (immediate-release formulations)
    Adults

    Initially, 40 mg PO twice daily, then increase at 3 to 7 day intervals up to 160 to 480 mg/day, given in 2 to 3 divided doses. Max: 640 mg/day. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Children† and Adolescents†

    Initially, 0.5 to 2 mg/kg/day PO in 2 to 4 divided doses. Titrate gradually every 3 to 7 days as needed for clinical effect; heart rate may be dose-limiting. Usual effective dosage is 1 to 6 mg/kg/day. Max: 8 mg/kg/day or 640 mg/day, whichever is less..

    Neonates† and Infants†

    Initially, 0.25 mg/kg/dose PO every 6 to 8 hours. Titrate gradually as needed for clinical effect; heart rate may be dose-limiting. Max: 3.5 mg/kg/dose; others recommend a max of 5 mg/kg/day.

    Oral dosage (extended-release capsules except InnoPran XL)
    Adults

    Initially, 80 mg PO once daily. Increase dosage at 3 to 7 day intervals up to 120 to 160 mg PO once daily. Max: 640 mg/day. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Oral dosage (InnoPran XL extended-release capsules only)
    Adults

    Initially, 80 mg PO once daily at bedtime (approximately 10 PM). If needed, increase dosage to 120 mg PO once daily at bedtime. Max: 120 mg/day. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    Continuous IV infusion dosage† (for patients unable to tolerate oral therapy)
    Adults

    Limited data suggest a continuous infusion of propranolol may be effective in post-surgical patients who cannot tolerate oral therapy. An infusion rate of 2 to 3 mg/hour achieved therapeutic propranolol serum levels within 3 hours. Continuous infusions were administered for up to 9 days.

    Intermittent intravenous dosage†
    Neonates†

    0.01 mg/kg/dose slow IV push over 10 minutes, repeated every 6 to 8 hours as needed. Titrate gradually as needed for clinical effect; heart rate may be dose-limiting. Max: 0.15 mg/kg/dose.

    For the treatment of idiopathic hypertrophic subaortic stenosis (IHSS).
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    20 to 40 mg PO 3 or 4 times daily. For geriatric patients, begin with low initial doses, followed by careful dosage titration; geriatric patients have unpredictable responses to beta-blockers.

    Oral dosage (extended-release capsules)
    Adults

    80 to 160 mg PO once daily. For geriatric patients, begin with low initial doses, followed by careful dosage titration; geriatric patients have unpredictable responses to beta-blockers.

    For management of pheochromocytoma, including preoperative control of tachycardia before surgery, in conjunction with an alpha-blocker.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    The usual dosage is 60 mg/day PO, given in divided doses for 3 days before surgery, in conjunction with an alpha-blocker. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade. For geriatric patients, begin with low initial doses, followed by careful dosage titration; the elderly have unpredictable responses to beta-blockers.

    For migraine prophylaxis.
    For migraine prophylaxis in pediatric patients†.
    Oral dosage (immediate-release formulations)
    Children and Adolescents

    0.6 to 3 mg/kg/day PO given in 2 to 3 divided doses. In patients weighing 35 kg or less, the recommended maximum daily dose is 60 mg; in patients weighing more than 35 kg, the recommended maximum daily dose is 120 mg. Clinical practice guidelines do not make recommendations regarding migraine prophylaxis with propranolol due to conflicting evidence.

    For migraine prophylaxis in adults.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    Initially, 80 mg/day PO given in divided doses. Dosage may be gradually increased if needed to 160 to 240 mg/day. Doses of 40 to 320 mg/day PO have also been recommended. Discontinue if adequate results not achieved within 4 to 6 weeks. Clinical practice guidelines classify propranolol as effective for migraine prophylaxis.

    Oral dosage (extended-release capsules)
    Adults

    Initially, 80 mg PO once daily. Dosage may be gradually increased if needed to 160 to 240 mg/day. Discontinue if adequate results not achieved within 4 to 6 weeks. Therapy should be withdrawn gradually. Clinical practice guidelines classify propranolol as effective for migraine prophylaxis.

    For the management of tremor.
    For the management of essential tremor.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    40 mg PO twice daily. Increase dose as needed to 120 to 320 mg/day PO given in 2 to 3 divided doses. In geriatric patients, begin with conservative initial doses and titrate carefully; geriatric patients have unpredictable responses to beta-blockers. Clinical practice guidelines consider propranolol effective for the treatment of essential tremor.

    For the management of lithium-induced tremor†.
    Oral dosage
    Adults

    Limited data suggest 30 to 80 mg/day PO may be effective; the daily dose is divided into 3 or 4 doses for administration. A common starting dose is 10 mg PO 3 times daily. In a single-blind crossover comparison of propranolol and placebo in 10 patients with lithium-induced tremor, propranolol (30 to 80 mg/day PO) and placebo were administered during two 2-week periods, 1 week on propranolol and 1 on placebo in random order. In period 1, 8 patients reported a preference for propranolol over placebo and 5 patients in period 2 reported a preference for propranolol. Treatment with propranolol resulted in a reduction in the intensity of tremor from very troublesome or somewhat troublesome to noticeable but not troublesome or not present. No adverse reactions were reported with propranolol treatment. In a case report of 5 patients with lithium-induced tremor, treatment with propranolol 30 to 40 mg/day PO, in 3 or 4 divided doses, resulted in control of the tremor. Recurrence of the tremor was reported in 3 of the cases when propranolol therapy was discontinued. In geriatric patients, begin with conservative initial doses and titrate carefully; geriatric patients have unpredictable responses to beta-blockers.

    For the management of essential tremor in pediatric patients.
    Oral dosage (immediate-release formulations)
    Adolescents†

    Limited experience; dosage often not reported in the literature; efficacy rate of 50%, along with side effect profile may lead to pursuit of other treatment options. 0.5 to 1 mg/kg/day PO, given in 3 divided doses has been recommended by some experts as an initial dose. Titrate dosage gradually once weekly. Alternatively, 30 mg PO once daily, then increased to 30 mg PO twice daily has been effective in improving hand tremor. Many patients respond to a total daily dosage of 60 to 80 mg/day PO. Max: 4 mg/kg/day PO. Dosage may also be taken as needed 30 minutes prior to activities disrupted by essential tremor. Pharmacotherapy should be reserved for patients whose tremor is functionally or socially limiting. Once an optimal dosage is determined, patients may transition to an extended-release formulation of propranolol, to be given once daily. Many patients require larger doses after 1 year of therapy, due to drug tolerance and disease progression.

    Children†

    Limited experience; dosage often not reported in the literature; efficacy rate of 50%, along with side effect profile may lead to pursuit of other treatment options. 0.5 to 1 mg/kg/day PO, given in 3 divided doses has been recommended by some experts as an initial dose using immediate release dose forms. Titrate dosage gradually once weekly as necessary; many patients respond to a total daily dosage of 60 to 80 mg/day PO. Max: 4 mg/kg/day PO. Dosage may also be taken as needed 30 minutes prior to activities disrupted by essential tremor. Pharmacotherapy should be reserved for patients whose tremor is functionally or socially limiting; most do not require therapy until adolescence. Once an optimal dosage is determined, patients may transition to an extended-release formulation of propranolol, to be given once daily. Many patients require larger doses after 1 year of therapy, due to drug tolerance and disease progression.

    For the treatment of a proliferating infantile hemangioma requiring systemic therapy.
    To reduce the risk of hypoglycemia, administer propranolol immediately after or concurrently with a feeding. Avoid fasting; if inevitable, hold medication or support with a product such as Pedialyte or glucose-containing IV fluids. Vital signs and cardiorespiratory exam or ECG should be obtained at baseline. Obtain blood pressure and heart rate measurements at 1 and 2 hours after the initial dose and any significant dose increase (e.g., more than 0.5 mg/kg/day). Experts have recommended propranolol therapy continue until full involution of the lesion has occurred or the patient is at least 1 year of age; recurrences have been reported with early discontinuation. At the end of therapy, gradually taper propranolol over 2 to 4 weeks. If hemangiomas recur, treatment may reinitiated.
    Oral dosage (FDA-approved dosage)
    Infants 5 weeks to 5 months at initiation

    0.6 mg/kg/dose PO twice daily, given at least 9 hours apart. After 1 week of treatment, increase dosage to 1.1 mg/kg/dose PO twice daily. After 2 weeks of treatment, increase dosage to 1.7 mg/kg/dose PO twice daily and maintain this dosage for 6 months. Readjust dosage periodically based on weight increases.

    Oral dosage (alternative dosage recommended in clinical practice guidelines)†
    Neonates and Infants

    Consensus guidelines recommend treatment in the presence of ulceration, vital function impairment (e.g., ocular compromise, airway obstruction), or risk of permanent disfigurement. Initiation protocols are based on corrected gestational age, social support status, and patient comorbidities affecting the cardiovascular or respiratory systems, and/or blood glucose maintenance. The guidelines recommend a target dose of 1 to 3 mg/kg/day PO; 2 mg/kg/day is the median target reported in the literature. Infantile hemangiomas often respond rapidly even to low doses of propranolol; dose escalation and optimal target dose should be based on individual patient response. Inpatient initiation (neonates and infants younger than 8 weeks, inadequate social support, or comorbidities): 0.33 mg/kg/dose PO every 8 hours. If tolerated, increase dose to 0.66 mg/kg/dose PO every 8 hours and prepare for discharge. If the dose is not tolerated at any point in time, reduce the dosage and gradually increase to the target dose; it is recommended patients be discharged on a tolerated dose of at least 1 mg/kg/day. Outpatient initiation (infants older than 8 weeks and adequate social support): 0.33 mg/kg/dose PO, given 3 times daily at least 6 hours apart. If tolerated for 3 to 7 days, increase dose to 0.5 mg/kg/dose PO, given 3 times daily. If once again tolerated for 3 to 7 days, increase dose to 0.66 mg/kg/dose PO, given 3 times daily. If the dose is not tolerated at any point in time, reduce the dosage and gradually increase to the target dose; consider a target dose of 1 mg/kg/day.

    For the treatment of unstable angina†.
    Intravenous dosage
    Adults

    0.5 to 1 mg IV, followed in 1 to 2 hours by a switch to oral therapy. Per clinical practice guidelines, the intravenous dose can be reserved for high-risk patients and eliminated from the regimen in intermediate- and low-risk patients. In geriatric patients, use conservative dose; the elderly have unpredictable responses to beta-blockers.

    Oral dosage (immediate-release formulations)
    Adults

    40 to 80 mg PO every 6 to 8 hours; begin 1 to 2 hours after initial IV therapy. Per clinical practice guidelines, the intravenous dose can be reserved for high-risk patients and eliminated from the regimen in intermediate- and low-risk patients. In geriatric patients, begin with conservative initial doses and titrate carefully; the elderly have unpredictable responses to beta-blockers.

    For the treatment of anxiety† or panic attacks†.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    10 to 80 mg PO, given 1 hour prior to the anxiety-producing event. For geriatric patients, begin with low initial doses, followed by careful dosage titration; geriatric patients have unpredictable responses to beta-blockers.

    For the short-term symptomatic management of thyrotoxicosis† and thyroid storm†.
    For the short-term symptomatic management of thyrotoxicosis† and thyroid storm† in pediatric patients.
    Oral dosage (immediate-release tablets or oral solution)
    Neonates and Infants

    For thyrotoxicosis, 1 to 2 mg/kg/day PO, given in divided doses every 6 to 12 hours. Higher doses may be needed. Monitor heart rate and blood glucose closely.

    Children and Adolescents

    For thyroid storm, 20 to 40 mg PO every 8 hours has been used. The American Thyroid Association and American Association of Clinical Endocrinologists recommend beta-blocker therapy for the symptomatic treatment (e.g., tachycardia, muscle weakness, tremor, etc.) of Graves hyperthyroidism (e.g., thyrotoxicosis) in children, however dosing is not specified; consider propranolol doses of 1 to 2 mg/kg/day, given in divided doses every 6 to 12 hours and titrated to response (not to exceed adult dose). For thyrotoxicosis, the recommended adult dose is 10 to 40 mg PO every 6 to 8 hours. For thyroid storm, the recommended adult dose is 60 to 80 mg every 4 hours.

    Intravenous dosage
    Children and Adolescents

    For thyroid storm, 1 to 3 mg slow IV push over 10 minutes as a single dose.

    For the short term management of thyrotoxicosis† or thyroid storm in adults†.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    The American Thyroid Association and American Association of Clinical Endocrinologists recommend beta-blocker therapy for the symptomatic treatment (e.g., tachycardia, muscle weakness, tremor, etc.) of Graves hyperthyroidism (e.g., thyrotoxicosis). Propranolol has been used adjunctively in adults for decades. The recommended adult dose for thyrotoxicosis is 10 to 40 mg PO every 6 to 8 hours. For thyroid storm, the recommended adult dose is 60 to 80 mg PO every 4 hours. In geriatric patients, use conservative initial dosing and titrate to response and tolerance.

    For the treatment of hypertension and the subsequent decline in renal function associated with scleroderma renal crisis (SRC)†.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    Initially, 40 mg PO twice daily, then increase at 3 to 7 day intervals up to 160 to 480 mg/day PO to attain desired blood pressure response. For geriatric patients, begin with low initial doses, followed by careful dosage titration; geriatric patients have unpredictable responses to beta-blockers.

    For the treatment of portal hypertension† and/or variceal bleeding prophylaxis† in patients with esophageal varices†.
    For the prevention of first variceal bleed (primary variceal bleeding prophylaxis).
    Oral dosage (immediate-release formulations)
    Adults

    40 mg PO twice daily or 20 mg PO 3 times daily, which is then titrated to heart rate reduction of 25% from baseline or to 55 bpm or to the maximum tolerated dose. Of 77 patients, 29% had variceal bleeding with propranolol 40 mg PO twice daily titrated to a resting heart rate reduction of 20 to 25% or to 55 bpm, or to the maximum tolerated dose. Nonselective beta-blockers adjusted to the maximal tolerated dose are recommended for patients with medium or large varices regardless of Child-Pugh class or presence of red wale marks and are preferred for patients with class A and no red signs. For small varices, nonselective beta-blockers are recommended for patients regardless of Child-Pugh class in the presence of red wale marks and for patients with Child-Pugh class B or C without red wale marks. Nonselective beta-blockers may be used for patients with Child-Pugh class A and small varices without red wale marks, but their long-term benefit has not been established.

    For prevention of recurrence of variceal bleed (secondary variceal bleeding prophylaxis).
    Oral dosage (immediate-release formulations)
    Adults

    40 mg PO twice daily or 20 mg PO 3 times daily, which is then titrated to heart rate reduction of 25% from baseline or to 55 bpm. Propranolol 20 mg PO 3 times a day titrated to a resting heart rate reduction of 25% from baseline or to 55 bpm led to re-bleeding in 28 of 49 patients as compared with 18 of 46 patients who also received isosorbide mononitrate (ISMN, 10 mg PO nightly titrated over 7 days to a maximum of 20 mg PO twice daily, if tolerated). Nonselective beta-blockers adjusted to the maximal tolerated dose plus a nitrate and endoscopic variceal ligation are recommended for patients without shunt surgery/TIPS and no evidence of hemorrhage for 24 hours or more.

    For the treatment of chronic agitation† or aggressive behavior.
    Oral dosage (immediate-release tablets or oral solution)
    Adults

    Most of the literature describing positive outcomes in the treatment of chronic aggression with propranolol involved patients with co-existing organic brain disease or schizophrenia recalcitrant to other aggression modalities. For patients without preexisting cardiovascular disorders, some authors have suggested a beginning dose of 20 mg PO 3 times per day, increasing the total dose by 40 to 60 mg/day every 3 days. Mean dosages range from 160 to 320 mg/day. For geriatric patients, begin with low initial doses, followed by careful dosage titration; geriatric patients have unpredictable responses to beta-blockers.

    For the prevention and management of hypercyanotic episodes associated with tetralogy of Fallot (i.e., tetralogy spells†).
    Oral dosage (immediate-release formulations)
    Infants and Children

    Initially, 1 mg/kg/day PO given in divided doses every 6 hours has been recommended for palliation. After 1 week, may titrate dosage by 1 mg/kg/day every 24 hours as necessary (Max: 5 mg/kg/day). Average dose: 2.3 mg/kg/day (range: 0.8 to 5 mg/kg/day). If the patient becomes refractory after initial control, may increase dosage gradually to a maximum of 10 to 15 mg/kg/day; monitor heart size, heart rate, and cardiac contractility closely. Alternatively, 4 mg/kg/day PO, given in divided doses every 6 hours has been used as an initial dose.

    Intravenous dosage
    Infants and Children

    0.15 to 0.25 mg/kg/dose IV administered over 10 minutes. Max initial dose: 1 mg. May repeat once. Alternatively, lower initial doses of 0.01 to 0.02 mg/kg/dose IV have been used, reserving higher doses for refractory spells.

    For the attenuation of hypermetabolism in patients with severe burns†.
    For the attenuation of hypermetabolism in adult patients with severe burns.
    Oral dosage (immediate-release formulations)
    Adults

    1 mg/kg/day PO, given in divided doses every 4 hours. Adjust dose as needed to achieve a target 20% reduction in heart rate from baseline to a maximum dose of 1.98 mg/kg/day. Median dose: 80 mg/day.

    For the attenuation of hypermetabolism in pediatric patients with severe burns.
    Oral dosage (immediate-release formulations)
    Infants, Children, and Adolescents

    1 to 4 mg/kg/day PO, given in divided doses every 6 hours. Adjust dose as needed to decrease heart rate by 10% to 20% of the admission value or mean age-based population value. 4 mg/kg/day PO was the mean effective dose in an interim analysis of children (n = 90; mean age 7 +/- 5 years) with more than 30% total body surface area burns. Propranolol therapy began 96 hours postburn and continued for 1 year with few adverse effects. Propranolol therapy significantly reduced heart rate and resting energy expenditure, decreased truncal fat accumulation, prevented bone loss, and improved lean body mass accretion. Maximum dose not clearly defined; severely burned adult patients standardly receive 20 mg PO every 6 hours, with dosage titrated as needed.

    For the treatment of heart failure† (ischemic origin or cardiomyopathy†) usually in conjunction with digoxin, diuretics, or ACE inhibitor therapy in children and infants.
    Oral dosage (immediate-release formulations)
    Infants and Children

    Initially, 0.5 to 1 mg/kg/day PO, given in divided doses every 6 to 8 hours has been recommended for sympathetic inhibition. Titrate dosage gradually every 3 to 14 days to a target dose of 2 mg/kg/day PO (range: 1.5 to 3 mg/kg/day). Monitor heart rate and blood pressure.

    For the maintenance of sinus rhythm in patients with supraventricular arrhythmias†, including Wolff-Parkinson-White (WPW) syndrome† and junctional ectopic tachycardia† (JET).
    Oral dosage (immediate-release formulations)
    Neonates, Infants, Children, and Adolescents

    Initially, 0.5 to 1 mg/kg/day PO, given in divided doses every 6 to 8 hours. Titrate dosage incrementally by 1 mg/kg/day every 3 to 5 days as needed for clinical effect. Usual maintenance dosage is 2 to 4 mg/kg/day PO. Max: 16 mg/kg/day or 60 mg/day, whichever is less. In older adolescents, 10 to 30 mg/dose PO every 6 to 8 hours may be given.

    Intravenous dosage
    Children and Adolescents

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 3 mg/dose, whichever is less.

    Neonates and Infants

    0.01 mg/kg/dose slow IV push over 10 minutes, repeat every 6 to 8 hours as needed. May titrate dosage gradually as needed for clinical effect. Max: 0.15 mg/kg/dose or 1 mg/dose, whichever is less.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    160 mg/day PO for idiopathic hypertrophic subaortic stenosis (IHSS); 240 mg/day PO for migraine prophylaxis, myocardial infarction prophylaxis, or post-myocardial infarction; 320 mg/day PO for angina, paroxysmal supraventricular tachycardia (PSVT), or tremor; 640 mg/day PO for hypertension. NOTE: Assumes equivalent maximum daily dosage for immediate-release and extended-release products.

    Geriatric

    160 mg/day PO for idiopathic hypertrophic subaortic stenosis (IHSS); 240 mg/day PO for migraine prophylaxis, myocardial infarction prophylaxis, or post-myocardial infarction; 320 mg/day PO for angina, paroxysmal supraventricular tachycardia (PSVT), or tremor; 640 mg/day PO for hypertension. NOTE: Assumes equivalent maximum daily dosage for immediate-release and extended-release products.

    Adolescents

    Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO (or 120 mg/day PO in older adolescents) or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 120 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used.

    Children

    Children weighing more than 35 kg: Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 120 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).
    Children weighing 35 kg or less: Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 60 mg/day PO or 0.25 mg/kg/dose IV (Max: 3 mg/dose) have been used. For hypertension, doses up to 8 mg/kg/day PO (Max: 640 mg/day) have been used. For migraine prophylaxis, doses up to 60 mg/day PO have been used. For essential tremor, doses up to 4 mg/kg/day PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).

    Infants

    3.4 mg/kg/day PO for infantile hemangiomas. Safety and efficacy for other indications have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 16 mg/kg/day PO (Max: 60 mg/day) or 0.15 mg/kg/dose IV (Max: 1 mg/dose) have been used. For hypertension, doses up to 3.5 mg/kg/dose PO have been used. For tetralogy spells, doses up to 15 mg/kg/day PO have been used (doses more than 5 mg/kg/day PO require close monitoring).

    Neonates

    Safety and efficacy have not been established; the dose required is dependent on route of administration, indication, and often clinical response. For tachyarrhythmias, doses up to 16 mg/kg/day PO (Max: 60 mg/day) or 0.15 mg/kg/dose IV (Max: 1 mg/dose) have been used. For hypertension, doses up to 3.5 mg/kg/dose PO or 0.15 mg/kg/dose IV have been used.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Since propranolol is primarily metabolized by the liver, initiate therapy at a reduced dosage for the specified indication; carefully titrate the dosage to attain the desired clinical goals.

    Renal Impairment

    No dosage adjustment needed.
     
    Intermittent hemodialysis
    No dosage adjustments are needed; propranolol is not significantly dialyzable.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Regular-release tablets: When given in divided doses, administer propranolol before meals and at bedtime.
    Extended-release formulations: Extended-release products should not be crushed or chewed. Swallow whole. InnoPran XL is an extended-release 24-hour chronological formulation of propranolol that is designed for bedtime-dosing (approximately 10 PM).

    Oral Liquid Formulations

    Generic Oral Solution (4 mg/ml or 8 mg/ml):
    Administer with food.
     
    Hemangeol Oral Solution (4.28 mg/ml; for infantile hemangioma):
    Record the date on the box when the bottle is first opened.
    Do not shake the bottle before use.
    Administer during or right after a feeding. Do not administer the dose if the patient is not eating or vomiting.
    Using an oral syringe, administer the medicine directly into the child's mouth, against the inside of the cheek. If this is not feasible, the solution may be diluted in a small quantity of milk or fruit juice and given immediately.
    Keep the child in an upright position for a few minutes after giving the dose.
    Monitor blood pressure and heart rate for 2 hours after the initial dose and after any significant dose increase.
    Storage: Store the bottle in the box at room temperature and discard 2 months after opening.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    IV bolus injection:
    No dilution necessary.
    Monitor ECG and central venous pressure during IV administration.
    Adults: Inject IV at a rate not to exceed 1 mg/minute.
    Children: Infuse slowly IV over 10 minutes.
     
    Continuous IV infusion:
    Dilute 15 mg in 500 ml D5W; may be concentrated to 15 mg propranolol in 250 ml D5W for fluid-restricted patients.
    For adult patients, infuse at a rate of 2—3 mg/hr.

    STORAGE

    Generic:
    - Store at room temperature (between 59 to 86 degrees F)
    HEMANGEOL:
    - Dispense in original container or USP equivalent tight container
    - Do not freeze
    - Product should be used within 2 months after opening
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Inderal:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Inderal LA:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Inderal XL:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    InnoPran XL:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Abrupt discontinuation

    Abrupt discontinuation of any chronically administered beta-adrenergic blocking agent, such as propranolol, can result in the exacerbation of angina and, in some cases, myocardial ischemia or myocardial infarction, ventricular arrhythmias, or severe hypertension, especially in patients with preexisting cardiac disease. If chronic, oral propranolol therapy is to be discontinued, the dosage should be gradually decreased over a minimum of 2 weeks. Downward titration of parenteral therapy may be advisable if the patient will discontinue propranolol treatment. Patients and caregivers should be advised against interruption or cessation of therapy without the advice of a physician. If exacerbation of angina occurs during discontinuation of therapy, it is advised to reinstitute propranolol therapy and take other measures appropriate for the management of unstable angina.

    Hyperthyroidism, thyroid disease, thyrotoxicosis

    Beta-blockers, like propranolol, should be used with caution in patients with hyperthyroidism or thyrotoxicosis because beta-blockade can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. Note that beta-blockers (particularly atenolol, propranolol and esmolol) are generally useful for the acute symptomatic treatment of the thyrotoxic patient. Beta-blockers can reduce tachycardia, tremor, and anxiety in the hyperthyroid patient.

    Acute heart failure, AV block, bradycardia, cardiogenic shock, hypotension, pheochromocytoma, pulmonary edema, sick sinus syndrome, vasospastic angina, ventricular dysfunction

    Because beta-blockers, including propranolol, depress conduction through the AV node, they are contraindicated in patients with severe bradycardia or advanced AV block, unless a functioning pacemaker is present. Propranolol is also contraindicated in patients with sick sinus syndrome unless a functioning pacemaker is present. In addition, beta-blockers should be used with caution in combination with other drugs that depress conduction through the AV node. Reduction in heart rate and cardiac output may cause or worsen bradycardia and hypotension. Propranolol oral solution for infantile hemangioma (Hemangeol) is specifically contraindicated in babies with significant bradycardia (< 80 beats per minute) or hypotension (blood pressure < 50/30 mmHg). In general, beta-blockers should not be used in patients with acute pulmonary edema and are contraindicated in patients with cardiogenic shock or decompensated acute heart failure, particularly in those with severely compromised left ventricular dysfunction, because the negative inotropic effect of these drugs can further depress cardiac output. In stable patients with heart failure, however, beta-blockers (e.g., bisoprolol, carvedilol, metoprolol) given in low doses have been documented to be beneficial. Many beta-blockers are used in the treatment of hypertrophic cardiomyopathy. Propranolol oral solution for infantile hemangioma (Hemangeol) is strictly contraindicated in patients with pheochromocytoma. In general, beta-blocker monotherapy should be used with caution in patients with a pheochromocytoma or vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed alpha-receptor stimulation. In patients with pheochromocytoma, an alpha-blocking agent should be used prior to the initiation of any beta-blocker. In the treatment of myocardial infarction, beta-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg).

    Wolff-Parkinson-White syndrome

    Beta-blockade in patients with Wolff-Parkinson-White syndrome and tachycardia can result in severe bradycardia requiring treatment with a pacemaker. In one case, this occurred after an initial propranolol dose of 5 mg.

    Cerebrovascular disease, PHACE syndrome, stroke

    Because of potential effects of beta-blockade on blood pressure and pulse, beta-blockers, like propranolol, should be used with caution in patients with cerebrovascular insufficiency (cerebrovascular disease) or stroke. If signs or symptoms suggesting reduced cerebral blood flow develop after initiation of beta-blocker, alternative therapy should be considered. In young patients being treated for an infantile hemangioma, propranolol therapy may increase the risk of stroke in PHACE syndrome (Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/aortic coarctation, and abnormalities of the Eye) patients with severe cerebrovascular anomalies. Prior to initiation of propranolol therapy, investigate patients with large facial hemangiomas for potential arteriopathy associated with PHACE syndrome.

    Diabetes mellitus, hypoglycemia

    Beta-blockers, such as propranolol, have been shown to increase the risk of developing diabetes mellitus in hypertensive patients; however this risk should be evaluated relative to the proven benefits of beta-blockers in reducing cardiovascular events. Propranolol should be used with caution in patients with poorly controlled diabetes mellitus, particularly brittle diabetes. Beta-blockers can prolong or enhance hypoglycemia by interfering with glycogenolysis; this effect may be less pronounced with beta-1-selective beta-blockers than with nonselective agents. Beta-blockers can also mask signs of hypoglycemia, especially tachycardia, palpitations, diaphoresis, and tremors; in contrast, the hypertensive response to hypoglycemia is not suppressed with beta-blockade. Beta-blockers can occasionally cause hyperglycemia. This is thought to be due to blockade of beta-2-receptors on pancreatic islet cells, which would inhibit insulin secretion. Thus, blood glucose levels should be monitored closely if a beta-blocker is used in a patient with diabetes mellitus. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion. Patients with renal insufficiency may be more likely to have hypoglycemic reactions to propranolol. Babies receiving propranolol for the treatment of hemangioma are also at increased risk for hypoglycemia (see pediatric precautions content).

    Hepatic disease

    Use propranolol with caution in patients with hepatic disease, because of possible decreased clearance of the drug; reduced doses may be indicated (see Dosage). Propranolol is extensively metabolized by the liver.

    Acute bronchospasm, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease

    Propranolol is contraindicated in patients with bronchial asthma or a history of bronchospasm. Propranolol should generally not be used in patients with pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD), emphysema, bronchitis), or during acute bronchospasm because bronchodilation can be inhibited. When used for the treatment of hemangioma, the FDA-approved product label recommends interrupting propranolol therapy in the event of a lower respiratory tract infection associated with dyspnea and wheezing.

    Beta-blocker hypersensitivity

    Propranolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol. Do not use propranolol in patients with known beta-blocker hypersensitivity. Cross-sensitivity between beta-blockers may occur. In addition, patients receiving beta-blockers who have a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated allergen challenge and unresponsive to usual doses of epinephrine used to treat anaphylaxis.

    Raynaud's phenomenon

    Avoid propranolol in patients with Raynaud's phenomenon or peripheral vascular disease because reduced cardiac output and the relative increase in alpha stimulation can exacerbate symptoms.

    Myasthenia gravis, myopathy

    Beta-blockers, like propranolol, may potentiate muscle weakness in patients with myasthenia gravis. Use propranolol with caution in patients with other underlying skeletal muscle disease. Isolated cases of exacerbation of myopathy and myotonia have been reported.

    Depression

    The use of propranolol has been associated with depression. Beta-blockers with high lipophilicity, such as propranolol, are more likely to cause CNS adverse effects, including depression. Propranolol should be avoided in patients with major depression; alternative hydrophilic beta-blocking agents (e.g., acebutolol, atenolol, nadolol) may be considered as alternative therapy.

    Driving or operating machinery

    Beta-blockers, like propranolol, may be associated with dizziness or drowsiness in some patients. Patients should be cautioned to avoid driving or operating machinery until the drug response is known.

    Renal failure, renal impairment

    Use propranolol with caution in patients with renal impairment because decreased plasma clearance may occur. In patients with renal failure, down-regulation of hepatic microsomal enzymes may result in decreased drug metabolism.

    Psoriasis

    Beta-blockers, like propranolol, may exacerbate conditions such as psoriasis.

    Surgery

    The necessity or desirability of withdrawing beta-blockers, such as propranolol, prior to major surgery is controversial; the risks versus benefits should be evaluated in individual patients. Patients receiving beta-blockers before or during surgery involving the use of general anesthetics with negative inotropic effects (e.g., ether, cyclopropane, or trichloroethylene) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in patients receiving beta-blockers. It should also be noted that because beta-blocker therapy reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli, the risks of general anesthesia and surgical procedures may be augmented. Although, gradual withdrawal of beta-blockers is sometimes recommended prior to general anesthesia to limit the potential for hypotension and heart failure, the manufacturer does not recommend withdrawal of chronically-administered propranolol prior to major surgery. The risk of precipitating adverse cardiac events (e.g., myocardial infarction, tachycardia) following preoperative withdrawal of beta-blockers may outweigh the risks of ongoing beta-blocker therapy, particularly in patients with co-existing cardiovascular disease. Consideration should be given to the type of surgery (e.g., cardiac vs. noncardiac), anesthetic strategy, and co-existing health conditions. The anesthetic technique may be modified to reduce the risk of concurrent beta-blocker therapy. If needed, the negative inotropic effects of beta-blockers may be cautiously reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Vagal dominance, if it occurs, may be corrected with atropine (1—2 mg IV).

    Children, infants, neonates, premature neonates

    Propranolol oral solution for infantile hemangiomas (Hemangeol) is contraindicated in premature neonates, neonates, and infants with a corrected age less than 5 weeks as well as any infant weighing less than 2 kg. Although other propranolol products are not FDA-approved for pediatric use, they are used clinically in patients as young as neonates. Bronchospasm and congestive heart failure have been reported coincident with propranolol use in children. Additionally, propranolol can cause hypoglycemia particularly in infants and children, especially during fasting (e.g., irregular feeding schedules, preoperative intake abstinence, vomiting). Neonates and infants less than 3 months of age are at higher risk for drug-induced hypoglycemia. Hypoglycemic symptoms are often difficult to detect in infants and young children. Careful monitoring (vital signs, blood glucose concentrations) during initiation and slow dose escalation are recommended. Clinicians should advise caregivers of appropriate measures to decrease the risk of hypoglycemia, focusing on the importance of frequent feedings (every 3 to 4 hours, with nutrition given shortly before or after administration). In addition, caregivers should be provided with special instructions for dosage adjustment or discontinuation during intercurrent illness (if clinical condition allows) and alternative dietary recommendations. Inform caregivers to discontinue propranolol and seek immediate medical attention if signs of hypoglycemia are present.

    Obstetric delivery, pregnancy

    There are no adequate and well-controlled studies in pregnant women; propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates born to mothers who received propranolol at parturition (obstetric delivery) have exhibited bradycardia, hypoglycemia, and respiratory depression. Adequate facilities for monitoring such infants at birth should be available. In a series of reproductive and developmental toxicology studies, propranolol was given to rats throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the maximum recommended human dose (MRHD) on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol was also administered to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the MRHD orally); no evidence of embryo or neonatal toxicity was noted. Animal studies are not always predictive of human response.

    Breast-feeding

    According to the manufacturer, propranolol should be used with caution in breast feeding mothers because the drug is distributed into breast milk. The selection of a beta-blocker during lactation should take into account the indication for use and clinical goals for the mother. Propranolol has generally been considered compatible with breast-feeding in clinical use. Other beta-blockers that the AAP regards as usually compatible with breast feeding include labetalol, metoprolol, nadolol, sotolol, and timolol; these agents may represent preferable alternatives for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Clinical studies of propranolol (various dose forms) have generally not included sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Most clinical experience has not determined differences between geriatric and younger adult patients given propranolol. Geriatric subjects have decreased clearance and a longer mean elimination half-life of propranolol. These findings suggest that dose adjustment of propranolol may be required for older adult patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Adjust doses to tolerance and desired clinical response. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Additionally, beta-blockers are associated with depression, bronchospasm, cardiac decompensation that may require dose adjustments in those with acute heart failure, and they may mask some symptoms of hypoglycemia (e.g., tachycardia). Beta-blockers metabolized in the liver may have an increased effect or accumulate in those with hepatic impairment. There are many drug interactions that can potentiate the effects of antihypertensives. Beta-blockers may cause or exacerbate bradycardia, particularly in patients receiving other medications that affect cardiac conduction. When discontinuing, a gradual taper may be required to avoid adverse consequences caused by abrupt discontinuation. The OBRA guidelines also caution that antiarrhythmic agents can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.

    Tobacco smoking

    Tobacco smoking can increase the clearance rate of propranolol, due to induction of hepatic microsomal enzymes by the hydrocarbons in tobacco. At this time, no specific dosage recommendations are recommended for smokers. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of propranolol (and potentially other beta-blockers), despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.

    ADVERSE REACTIONS

    Severe

    AV block / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypoglycemia / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    paresthesias / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    insomnia / Early / Incidence not known
    drowsiness / Early / Incidence not known
    agitation / Early / Incidence not known
    weakness / Early / Incidence not known
    emotional lability / Early / Incidence not known
    irritability / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    nightmares / Early / Incidence not known
    fatigue / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    cough / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    pharyngitis / Delayed / Incidence not known
    fever / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    headache / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Acetaminophen; Propoxyphene: (Minor) Propranolol is significantly metabolized by CYP2D6 isoenzymes and CYP2D6 inhibitors, such as propoxyphene, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Adenosine: (Moderate) Because the pharmacologic effects of beta-blockers include depression of AV nodal conduction and myocardial function, additive effects are possible when used in combination with adenosine. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients.
    Albiglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Aldesleukin, IL-2: (Moderate) Beta blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: (Moderate) Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving beta-blockers.
    Alfuzosin: (Moderate) The manufacturer warns that the combination of alfuzosin with antihypertensive agents has the potential to cause hypotension in some patients. Alfuzosin (2.5 mg, immediate-release) potentiated the hypotensive effects of atenolol (100 mg) in eight healthy young male volunteers. The Cmax and AUC of alfuzosin was increased by 28% and 21%, respectively. Alfuzosin increased the Cmax and AUC of atenolol by 26% and 14%, respectively. Significant reductions in mean blood pressure and in mean heart rate were reported with the combination.
    Aliskiren; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Alogliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alogliptin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alogliptin; Pioglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Alpha-blockers: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Alpha-glucosidase Inhibitors: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. the can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as beta-clockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving beta-blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.
    Amiodarone: (Major) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers including propanolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of beta-blockers metabolized by CYP2D6 (metoprolol and propranolol) is possible. Caution is advised as metoprolol in combination with amiodarone has resulted in severe sinus bradycardia. While the combination should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
    Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Benazepril: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Telmisartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Amobarbital: (Moderate) Although concurrent use of amobarbital with antihypertensive agents may lead to hypotension, barbiturates, as a class, can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include betaxolol, labetalol, metoprolol, pindolol, propranolol, and timolol. Clinicians should closely monitor patients blood pressure during times of coadministration.
    Amyl Nitrite: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Antacids: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Antithyroid agents: (Minor) Hyperthyroidism may cause increased clearance of beta blockers that possess a high extraction ratio. A dose reduction of some beta-blockers may be needed when a hyperthyroid patient treated with methimazole becomes euthyroid.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents.
    Apraclonidine: (Minor) Theoretically, additive blood pressure reductions could occur when apraclonidine is combined with antihypertensive agents.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.
    Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as propranolol during coadministration with armodafinil.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and propranolol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propranolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Articaine; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects.
    Ascorbic Acid, Vitamin C: (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of propranolol. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known; the propranolol dosage may need to be adjusted.
    Aspirin, ASA: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection. (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Atazanavir: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.
    Atazanavir; Cobicistat: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block. (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Azelastine; Fluticasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Beclomethasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Beta-agonists: (Moderate) Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patients lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites, and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used. Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present.
    Betamethasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Bismuth Subsalicylate: (Moderate) Concurrent use of beta-blockers with bismuth subsalicylate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent use of beta-blockers with bismuth subsalicylate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with beta-blockers.
    Bretylium: (Major) Because the pharmacologic effects of propranolol include AV nodal conduction depression, additive effects are possible when used with other antiarrhythmics, that exert significant effects on AV nodal conduction including bretylium.
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Bromocriptine: (Minor) Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy.
    Budesonide: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Budesonide; Formoterol: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Bupivacaine Liposomal: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine. Local anesthetics may also cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bupivacaine: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine. Local anesthetics may also cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bupivacaine; Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers. (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine. Local anesthetics may also cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of bupivacaine and antihypertensive agents or rapid-onset vasodilators, such as nitrates. Peripheral vasodilation may occur after use of bupivacaine. Thus, patients receiving antihypertensive agents may experience additive hypotensive effects. Blood concentrations of local anesthetics achieved after therapeutic doses are associated with minimal change in peripheral vascular resistance. Higher blood concentrations of local anesthetics may occur due to inadvertent intravascular administration or repeated doses.
    Bupropion: (Minor) Monitor for an increased incidence of propranolol-related adverse effects if bupropion and propranolol are used concomitantly. Coadministration of bupropion and propranolol may result in increased plasma concentrations of propranolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Propranolol is a CYP2D6 substrate.
    Bupropion; Naltrexone: (Minor) Monitor for an increased incidence of propranolol-related adverse effects if bupropion and propranolol are used concomitantly. Coadministration of bupropion and propranolol may result in increased plasma concentrations of propranolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Propranolol is a CYP2D6 substrate.
    Cabergoline: (Major) Because of its potential to cause coronary vasospasm, ergot alkaloids could theoretically antagonize the therapeutic effects of beta-blockers.
    Caffeine; Ergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Calcium Carbonate: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Calcium Carbonate; Risedronate: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Calcium; Vitamin D: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Canagliflozin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Canagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Carbidopa; Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Ceritinib: (Major) Avoid coadministration of ceritinib with propranolol due to the risk of additive bradycardia. If unavoidable, monitor heart rate and blood pressure regularly. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary.
    Cevimeline: (Moderate) Cevimeline may alter cardiac conduction and/or heart rate. Conduction disturbances are possible with concurrent use of beta-blockers and cevimeline.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpromazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. Chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Chlorthalidone; Clonidine: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Cholestyramine: (Moderate) Absorption of propranolol may be reduced by concurrent administration with colestipol or cholestyramine. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Chondroitin; Glucosamine: (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Ciclesonide: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Cimetidine: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if cimetidine and propranolol are used concomitantly. Reduced clearance and increased serum concentrations of propranolol have been reported during concurrent use of cimetidine. Cimetidine is a CYP2D6 inhibitor. Propranolol is a CYP2D6 substrate.
    Cinacalcet: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including propranolol.
    Citalopram: (Minor) Citalopram mildly inhibits the hepatic CYP2D6 isoenzyme at therapeutic doses. This can result in increased concentrations of drugs metabolized via the same pathway, including propranolol. Increased serum levels of the beta-blockers could result in alterations in cardioselectivity or other clinical effects.
    Clevidipine: (Moderate) Calcium-channel blockers, like clevidipine, and beta-blockers frequently are used together with no adverse reactions. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension if these drugs are given together.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as propranolol, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If propranolol is used in combination, it is advisable to monitor the patient for adverse reactions related to beta-blockers.
    Clonidine: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Colestipol: (Moderate) Colestipol can bind with and possibly decrease the oral absorption of propranolol. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol.
    Collagenase: (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Conivaptan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Corticosteroids: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Corticotropin, ACTH: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Cortisone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Cranberry, Vaccinium macrocarpon Ait.: (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Crizotinib: (Major) Bradycardia has been reported in patients treated with crizotinib, which may be exacerbated when crizotinib is administered concomitantly with agents known to cause bradycardia, such as beta-blockers. This combination should be avoided if possible. In addition, concomitant use of crizotinib and carvedilol may result in altered concentrations of either drug. Crizotinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while carvedilol is a CYP3A4 inhibitor and P-gp inhibitor and substrate.
    Dapagliflozin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Dapagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Dapagliflozin; Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Darunavir; Cobicistat: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
    Deflazacort: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Delavirdine: (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes and CYP2D6 inhibitors, such as delavirdine, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Desflurane: (Moderate) Concurrent use of beta-blockers with desflurane may result in exaggerated cardiovascular effects (e.g., hypotension and negative inotropic effects). Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects. Withdrawal of a beta-blocker perioperatively may be detrimental to the patient's clinical status and is not recommended. Caution is advised if these drugs are administered together.
    Desiccated Thyroid: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Desvenlafaxine: (Major) Dosage adjustments of some beta-blockers may be necessary during concurrent use of desvenlafaxine. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as propranolol, metoprolol, or nebivolol, be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
    Dexamethasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Dexmedetomidine: (Major) In general, the concomitant administration of dexmedetomidine with antihypertensive agents could lead to additive hypotensive effects. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that lower the heart rate such as beta-blockers.
    Dextromethorphan; Quinidine: (Major) Patients receiving combined therapy with quinidine and propranolol should be monitored for potential hypotension, orthostasis, bradycardia and/or AV block and heart failure, Reduce the beta-blocker dosage if necessary. Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with beta-blockers, such as propranolol. Quinidine is a known inhibitor of CYP2D6, and may additionally impair the hepatic clearance of propanolol (CYP2D6 substrate); patients should be monitored for excess beta-blockade.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agent. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving beta-blockers.
    Digoxin: (Moderate) Use with caution due to additive pharmacodynamic effects on cardiac conduction, especially in patients with pre-existing left ventricular dysfunction. The risk of additive inhibition of AV conduction is symptomatic bradycardia with hypotension or advanced AV block; whereas additive negative inotropic effects could precipitate overt heart failure in some patients. Despite potential for interactions, digoxin sometimes is intentionally used in combination with a beta-blocker to further reduce conduction through the AV node. Dosages may need adjustment in some patients.
    Dihydroergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Diltiazem: (Moderate) The combination of diltiazem and a beta-blocker, like propranolol, is usually well tolerated; the combination is often used for their combined therapeutic benefits to reduce angina and improve exercise tolerance. However, because beta-blockers and diltiazem are negative inotropes and chronotropes, the combination of beta-blockers and diltiazem may cause heart failure, excessive bradycardia, hypotension, cardiac conduction abnormalities, or heart block. In addition, diltiazem has been shown to inhibit the metabolism of propranolol and increase bioavailability by 50%.
    Dipyridamole: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Disopyramide: (Major) Because the pharmacologic effects of propranolol include AV nodal conduction depression and negative inotropy, additive effects are possible when used in combination with disopyramide. Propranolol has occasionally been used with disopyramide; however, the manufacturer states that the concomitant use of disopyramide with propranolol should be reserved for patients with refractory life-threatening arrhythmias. Such use may produce serious negative inotropic effects, or may excessively prolong conduction. In healthy subjects, no significant drug interaction has been observed when propranolol is coadministered with disopyramide.
    Donepezil: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Donepezil; Memantine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Doxazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Dronedarone: (Major) In dronedarone clinical trials, bradycardia was seen more frequently in patients also receiving beta blockers. If coadministration of dronedarone and a beta blocker is unavoidable, administer a low dose of the beta blocker initially and increase the dosage only after ECG verification of tolerability. Concomitant administration may decreased AV and sinus node conduction. Furthermore, dronedarone is an inhibitor of CYP2D6, and some beta blockers are substrates for CYP2D6 (e.g., metoprolol, propranolol, nebivolol, carvedilol). Coadministration of dronedarone with a single dose of propranolol and multiple doses of metoprolol increased propranolol and metoprolol exposure by 1.3- and 1.6-fold, respectively.
    Dulaglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of propranolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Eletriptan: (Minor) Periodically monitor blood pressure in patients who regularly use eletriptan and are taking propranolol. Monitor for the rare patient who might experience an increase in dose-related side effects of eletriptan, such as nausea, dizziness, and drowsiness. No dosage adjustment appears to be needed for eletriptan. The Cmax and AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. The interaction should not be significant for most patients.
    Eliglustat: (Moderate) Coadministration of propranolol and eliglustat may result in increased plasma concentrations of propranolol. Consider reducing the propranolol dosage and titrating to clinical effect. Propranolol is a CYP2D6 and P-glycoprotein (P-gp) substrate; eliglustat is a CYP2D6 and P-gp inhibitor.
    Empagliflozin: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Empagliflozin; Linagliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Empagliflozin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Encainide: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with encainide. When used together, AV block can occur. In addition, encainide was found to increase propranolol concentrations in patients receiving concomitant therapy. The significance of elevated propranolol concentrations is not known as beta-blockers have a wide therapeutic range. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Enflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Epoprostenol: (Moderate) Epoprostenol can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Ergonovine: (Major) Whenever possible, concomitant use of beta-blockers and ergot alkaloids should be avoided, since propranolol has been reported to potentiate the vasoconstrictive action of ergotamine. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergot alkaloids are coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Ergotamine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Escitalopram: (Minor) Escitalopram modestly inhibits the hepatic CYP2D6 isoenzyme. This can result in increased concentrations of drugs metabolized via the same pathway, including propranolol. Increased serum levels of the beta-blockers could result in reductions in cardioselectivity.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
    Etomidate: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Exenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Ezetimibe; Simvastatin: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as propranolol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of propranolol during coadministration with fenofibric acid.
    Fentanyl: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Fingolimod: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flecainide: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with flecainide. When used together, AV block can occur. During flecainide clinical trials, increased adverse events have not been reported in patients receiving combination therapy with beta-blockers and flecainide. However, propranolol and flecainide each appear to inhibit the clearance of the other and additive negative inotropic activity has been noted during combination therapy. Patients should be monitored closely and the dose should be adjusted according to clinical response.
    Fludrocortisone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Flunisolide: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fluorescein: (Moderate) Patients on beta-blockers are at an increased risk of adverse reaction when administered fluorescein injection. It is thought that beta-blockers may worsen anaphylaxis severity by exacerbating bronchospasm or by increasing the release of anaphylaxis mediators; alternately, beta-blocker therapy may make the patient more pharmacodynamically resistance to epinephrine rescue treatment.
    Fluoxetine: (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could impair propranolol metabolism. Bradycardia has occurred in a patient receiving propranolol after fluoxetine was added. Monitor for decreased blood pressure, reduced heart rate, or for other propranolol-induced side effects if these drugs are coadministered.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could impair propranolol metabolism. Bradycardia has occurred in a patient receiving propranolol after fluoxetine was added. Monitor for decreased blood pressure, reduced heart rate, or for other propranolol-induced side effects if these drugs are coadministered.
    Fluphenazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Fluticasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fluticasone; Salmeterol: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fluticasone; Vilanterol: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fluvoxamine: (Moderate) Fluvoxamine can also inhibit hepatic cytochrome P-450 isoenzymes and has been shown to interfere with propranolol clearance however clinical symptoms of excessive beta-blocker effects were not seen.
    Food: (Major) Avoid administering marijuana and beta-blockers together as concurrent use may result in decreased beta-blocker efficacy. Marijuana is known to produce significant increases in heart rate and cardiac output lasting for 2-3 hours. Further, rare case reports of myocardial infarction and cardiac arrhythmias have been associated with marijuana use. These marijuana-induced cardiovascular effects may be detrimental to patients requiring treatment with beta-blockers; thus, coadministration of beta-blockers and marijuana should be avoided.
    Formoterol; Mometasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Fosphenytoin: (Minor) Phenytoin has been shown to accelerate the hepatic metabolism of propranolol. Because fosphenytoin is metabolized to phenytoin, fosphenytoin will most likely also accelerate the hepatic metabolism of propranolol.
    Fospropofol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Gabapentin: (Minor) The combination of propranolol and gabapentin may induce dystonia via a pharmacodynamic interaction.
    Galantamine: (Moderate) The increase in vagal tone induced by cholinesterase inhibitors, such as galantamine, may produce bradycardia or syncope. The vagotonic effect of galantamine may theoretically be increased when given with beta-blockers.
    Gefitinib: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if gefitinib and propranolol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is primarily responsible for the metabolism of propranolol. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as propranolol.
    General anesthetics: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of inotropes; however, no clinical data are available.
    Glipizide; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Glucagon: (Minor) Because beta-blockers blunt sympathomimetic-mediated hepatic gluconeogenesis, beta-blockers can inhibit the hyperglycemic actions of glucagon. In addition, intravenous administration of glucagon has been shown to have positive inotropic and chronotropic effects. A transient increase in both blood pressure and pulse rate may occur following the administration of glucagon, especially in patients taking beta-blockers. Clinicians should be aware of these opposing pharmacologic actions of glucagon and beta-blockers.
    Glyburide; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Guanabenz: (Moderate) Guanabenz can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Guanfacine: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Haloperidol: (Moderate) Haloperidol should be used cautiously with propranolol due to the possibility of additive hypotension and increased concentrations of propranolol. Propranolol is significantly metabolized by CYP2D6 isoenzymes. A case report of 3 severe hypotension episodes (2 requiring cardiopulmonary resuscitation) has been reported in one 48 year old woman when propranolol and haloperidol have been coadministered. Additive hypotensive effects and haloperidol-mediated CYP2D6 inhibition may have contributed to this interaction.
    Halothane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the beta-blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Hydrocortisone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Hydroxychloroquine: (Minor) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as hydroxychloroquine, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Icosapent ethyl: (Moderate) Beta-blockers may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Additive reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Imatinib: (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as imatinib, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Incretin Mimetics: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Indocyanine Green: (Minor) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, propranolol decreased clearance by 21%.
    Insulin Degludec; Liraglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Insulin Glargine; Lixisenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Insulins: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Isoniazid, INH; Rifampin: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Isosorbide Mononitrate: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Isradipine: (Moderate) Although concomitant therapy with beta-blockers and isradipine is generally well tolerated and can even be beneficial in some cases, coadministration of these agents can induce excessive bradycardia or hypotension. Isradipine when used in combination with beta-blockers, especially in heart failure patients, can result in additive negative inotropic effects. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly when isradipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of isradipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with other non-dihydropyridine calcium channel blockers than with isradipine.
    Ivabradine: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Ketamine: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as beta-blockers, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
    Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., beta-adrenergic blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the beta-blocker dose if necessary.
    Levobupivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Levodopa: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Levothyroxine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Lidocaine: (Major) Drugs such as beta-blockers that decrease cardiac output reduce hepatic blood flow and thereby decrease lidocaine hepatic clearance. Also, opposing effects on conduction exist between lidocaine and beta-blockers while their effects to decrease automaticity may be additive. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction. This interaction is possible with other beta-blocking agents since most decrease hepatic blood flow. Monitoring of lidocaine concentrations is recommended during concomitant therapy with beta-blockers.
    Linagliptin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Linagliptin; Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Linezolid: (Moderate) Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor. Bradycardia may be worsened when MAO-inhibitors are co-administered to patients receiving beta-blockers. Use linezolid cautiously in patients receiving beta-blockers.
    Liothyronine: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Liotrix: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Liraglutide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lithium: (Moderate) Beta-blockers have been used to treat lithium-induced tremor. Because tremor may be a sign of lithium toxicity and may be masked by the coadministration of beta-blockers, patients should be monitored for other clinical signs of lithium toxicity if these medications are taken concurrently. Other clinical signs of toxicity include: anorexia; visual impairment; drowsiness; muscular weakness; fasciculations or myoclonia; ataxia; dysarthria or slurred speech; stupor or coma; confusion or impaired cognition; seizures; and arrhythmias. Limited data suggest that using propranolol, even in low doses, with lithium can lead to bradycardia and syncope. In addition, lithium renal clearance has been shown to be lower when propranolol was coadministered. It is not clear if these effects are unique for propranolol or hold true for all beta-blockers. Until more data are known, clinicians should use beta-blockers with caution in patients receiving lithium.
    Lixisenatide: (Moderate) Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of propranolol and lumacaftor; ivacaftor may decrease the systemic exposure of propranolol; caution and monitoring of blood pressure and other therapeutic effects are advised if these drugs are used together. Propranolol is partially metabolized by CYP2C19; in vitro data suggest that lumacaftor may induce CYP2C19.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Salicylate: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Mefloquine: (Major) Concurrent use of mefloquine and beta blockers can result in ECG abnormalities or cardiac arrest.
    Mephobarbital: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include propranolol. Clinicians should monitor patients for loss of beta-blockade.
    Mepivacaine: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine.
    Mepivacaine; Levonordefrin: (Major) Propranolol has been shown to significantly decrease the clearance of the amide local anesthetics (e.g., lidocaine, bupivacaine, and mepivacaine). Lidocaine and bupivacaine toxicity have been reported after coadministration with propranolol. The mechanism of the interaction between propranolol and lidocaine is thought to be due to propranolol-induced decreased hepatic blood flow causing decreased elimination of lidocaine.
    Mesoridazine: (Severe) The manufacturer of thioridazine, the parent drug for mesoridazine, considers propranolol to be contraindicated for use with mesoridazine. Propranolol appears to inhibit the hepatic metabolism of certain phenothiazine neuroleptics (e.g., chlorpromazine, thioridazine), and some phenothiazines may decrease the hepatic metabolism of pindolol and propranolol. Increased serum concentrations and pharmacologic effects (e.g., cardiac, CNS, hypotension) of either drug may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Pioglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Repaglinide: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Metformin; Rosiglitazone: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metformin; Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Methohexital: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension.
    Methylergonovine: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Methylprednisolone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Methysergide: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Mexiletine: (Moderate) Mexiletine has been found to increase propranolol concentrations in patients receiving concomitant therapy. The significance of the elevated propranolol concentration is not known as beta-blockers have a wide therapeutic range. It may be prudent to monitor patients for adverse effects when mexiletine are combined with propranolol.
    Milnacipran: (Moderate) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as propranolol may be increased when co-administered with mirabegron. Propranolol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Modafinil: (Moderate) In vitro data indicate that modafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as propranolol during coadministration with modafinil.
    Mometasone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Nateglinide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Nicardipine: (Moderate) Although concomitant therapy with nicardipine and propranolol generally is well tolerated and can even be beneficial in some cases (by inhibiting reflex tachycardia induced by nicardipine), propranolol can induce excessive bradycardia or hypotension. This combination also can cause additive negative inotropic effects. Nicardipine has been reported to increase plasma concentrations and oral bioavailability of certain beta-blockers (e.g., propranolol). Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nicardipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nicardipine therapy can minimize or eliminate this potential interaction. Patients should be monitored carefully, however, for excessive bradycardia, cardiac conduction abnormalities, or hypotension when these drugs are given together. In general, these reactions are more likely to occur with verapamil or diltiazem than with nicardipine.
    Nifedipine: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nilotinib: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of propranolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as propranolol.
    Nimodipine: (Moderate) Nimodipine, a selective calcium-channel blocker, can enhance the antihypertensive effects of beta-blockers. Although often used together, concurrent use of calcium-channel blockers and beta-blockers may result in additive hypotensive, negative inotropic, and/or bradycardic effects in some patients.
    Nisoldipine: (Moderate) Concurrent use of nisoldipine with propranolol can be beneficial (i.e., inhibition of vasodilation-induced reflex tachycardia by beta-blockade); however, the additive negative inotropic and/or chronotropic effects can cause adverse effects, especially in patients with compromised ventricular function or conduction defects (e.g., sinus bradycardia or AV block). Pharmacokinetic interactions between nisoldipine and propranolol are variable and not significant. Propranolol attenuated the heart rate increase following the administration of immediate release nisoldipine.
    Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with any beta-blockers.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Non-Ionic Contrast Media: (Moderate) Some clinicians consider patients taking beta-blockers to be at increased risk for anaphylactoid reactions and administer prophylactic corticosteroids/antihistamines prior to the administration of radiopaque contrast agents.
    Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
    Omeprazole; Sodium Bicarbonate: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Oritavancin: (Moderate) Propranolol is metabolized by CYP2C19 and CYP2D6; oritavancin is a weak inhibitor of CYP2C19 and a weak CYP2D6 inducer. Coadministration may result in altered propranolol plasma concentrations. If these drugs are administered concurrently, blood pressure should be monitored closely.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by beta-blockers. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses of paliperidone may be necessary in patients receiving antihypertensive agents concomitantly. In addition, altered concentrations of paliperidone and/or carvedilol may occur during coadministration. Carvedilol and paliperidone are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Paroxetine: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including propranolol. Clinicians should use paroxetine cautiously with propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
    Pasireotide: (Major) Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as beta-blockers. Dose adjustments of beta-blockers may be necessary.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to propranolol if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while propranolol is a CYP2D6 substrate.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perindopril; Amlodipine: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
    Perphenazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Perphenazine; Amitriptyline: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenoxybenzamine: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Phentolamine: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Phenytoin: (Minor) Phenytoin is an inducer of hepatic enzymes, and has been shown to accelerate the hepatic metabolism of propranolol.
    Pilocarpine: (Moderate) Systemically administered pilocarpine (e.g., when used for the treatment of xerostomia or xerophthalmia) should be administered with caution in patients taking beta-blockers because of the possibility of cardiac conduction disturbances. The risk of conduction disturbances with beta-blockers and ophthalmically administered pilocarpine is low.
    Pramlintide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Prazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Prednisolone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Prednisone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Prilocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Prilocaine; Epinephrine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Primidone: (Moderate) Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver, such as propranolol. Clinicians should monitor patients for loss of beta-blockade.
    Procainamide: (Major) High or toxic concentrations of procainamide may prolong AV nodal conduction time or induce AV block; these effects could be additive with the pharmacologic actions of beta-blockers, like propranolol. In general, patients receiving combined therapy with procainamide and beta-blockers should be monitored for potential bradycardia, AV block, and/or hypotension. Procainamide's elimination half-life was not significantly changed when administered concomitantly with propranolol.
    Procaine: (Minor) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Prochlorperazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Propafenone: (Major) Pharmacologically, beta-blockers, like propranolol, cause AV nodal conduction depression and additive effects are possible when used in combination with propafenone. When used together, AV block can occur. Additionally, propafenone, a CYP2D6 inhibitor, appears to inhibit the metabolism of propranolol. Coadministration of propafenone with propranolol increases the plasma concentrations and prolongs the elimination half-life of propranolol; these affects were associated with a 15% decrease in diastolic blood pressure. Patients should be monitored closely and a reduction in the dosage of propranolol may be indicated.
    Propofol: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Propoxyphene: (Minor) Propranolol is significantly metabolized by CYP2D6 isoenzymes and CYP2D6 inhibitors, such as propoxyphene, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Quinidine: (Major) Patients receiving combined therapy with quinidine and propranolol should be monitored for potential hypotension, orthostasis, bradycardia and/or AV block and heart failure, Reduce the beta-blocker dosage if necessary. Quinidine may have additive effects (e.g., reduced heart rate, hypotension) on cardiovascular parameters when used together with beta-blockers, such as propranolol. Quinidine is a known inhibitor of CYP2D6, and may additionally impair the hepatic clearance of propanolol (CYP2D6 substrate); patients should be monitored for excess beta-blockade.
    Quinine: (Minor) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as quinine, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Ranolazine: (Moderate) Propranolol is metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ranolazine, could theoretically impair propranolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Remifentanil: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Repaglinide: (Moderate) Beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. They can prolong hypoglycemia by interfering with the mobilization of glycogen stores or can promote hyperglycemia. Also, beta-blockers can blunt some of the physiologic symptoms of hypoglycemia, such as tremors and tachycardia. Diabetic patients on beta-blockers should closely monitor their blood glucose.
    Reserpine: (Moderate) Reserpine may have additive orthostatic hypotensive effects when used with beta-blockers due to catecholamine depletion. Beta-blockers may also interfere with reflex tachycardia, worsening the orthostasis. Patients treated concurrently with a beta-blocker and reserpine should be monitored closely for evidence of hypotension or marked bradycardia and associated symptoms (e.g., vertigo, syncope, postural hypotension).
    Rifabutin: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Rifampin: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Rifamycins: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Rifapentine: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of propranolol. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving propranolol concomitantly.
    Ritonavir: (Moderate) Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
    Rivastigmine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may theoretically be increased when given with other medications known to cause bradycardia such as beta-blockers.
    Rizatriptan: (Major) Concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg resulted in a 70% increase in the mean rizatriptan AUC. The AUC of the active N-monodesmethyl metabolite was not affected by propranolol. This interaction is most likely due to first-pass metabolic interaction between rizatriptan and propranolol. Based on in vitro data, no pharmacokinetic interaction is expected with timolol or atenolol. This interaction requires a dose adjustment of rizatriptan when it is given concurrently with propranolol. The recommended dose of rizatriptan 5 mg up to a maximum of 15 mg in 24 hours when given with propranolol. Patients receiving concomitant administration of other antimigraine agents (e.g., beta-blockers including propranolol) with rizatriptan had similar adverse reaction rates as compared to those who did not receive these medications concomitantly.
    Rolapitant: (Major) Use caution if propranolol and rolapitant are used concurrently, and monitor for propranolol-related adverse effects, including bradycardia. Propranolol is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Ropivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Salsalate: (Moderate) Concurrent use of beta-blockers with salsalate and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
    Saxagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with beta-blockers. Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Sevoflurane: (Major) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Beta-blockers may be continued during general anesthesia as long as the patient is monitored for cardiac depressant and hypotensive effects.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. In addition, increased concentrations of silodosin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and silodosin is a P-gp substrate.
    Simvastatin: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Simvastatin; Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Sitagliptin: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Sodium Bicarbonate: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Succinylcholine: (Moderate) Beta-blockers can enhance the neuromuscular blocking activity of succinylcholine.
    Sufentanil: (Moderate) The incidence and degree of bradycardia and hypotension during induction with sufentanil may be increased in patients receiving beta-blockers.
    Sulfonylureas: (Moderate) Beta-blockers can prolong hypoglycemia or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Pharmacokinetic interactions are also possible between individual drugs. Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Carvedilol is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Sympathomimetics: (Major) Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Tacrine: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope in some patients. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Tamsulosin: (Minor) Tamsulosin did not potentiate the hypotensive effects of atenolol. However, since the symptoms of orthostasis are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents
    Tasimelteon: (Major) The efficacy of tasimelteon in treating circadian rhythm disruptions may be reduced in patients receiving beta-blockers. Because the circadian rhythm of melatonin is regulated by the sympathetic nervous system, administration of beta-blockers may result in a clinically relevant blockade of melatonin secretion.
    Terazosin: (Moderate) Orthostatic hypotension may be more likely if beta-blockers are coadministered with alpha-blockers.
    Terbinafine: (Minor) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as terbinafine, could theoretically impair propranolol metabolism.
    Testosterone: (Moderate) Testosterone cypionate has been shown to increase the clearance of propranolol in one study. Monitor patients taking testosterone and proprantolol together for decreased therapeutic efficacy of propranolol.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use caution with the concomitant use of tetracaine and antihypertensive agents.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as beta-blockers should be used cautiously due to the potential for additive bradycardia.
    Theophylline, Aminophylline: (Major) Propranolol may significantly decrease aminophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If aminophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose required to achieve a therapeutic serum theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of aminophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits aminophylline clearance will result in decreased serum theophylline concentrations, unless the aminophylline dose is appropriately increased. (Major) Propranolol may significantly decrease theophylline clearance by inhibiting CYP1A2. In some patients, theophylline levels can increase up to 100%. On average, co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. If theophylline is being initiated in a patient who is already taking a drug that inhibits its clearance, the dose of theophylline required to achieve a therapeutic theophylline concentration will be smaller. Patients should be closely monitored for toxicity. Serum theophylline concentrations should be monitored. Because propranolol is non-selective, the beta-2 blocking activity may reduce the effectiveness of theophylline and other treatments for asthma or COPD. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased theophylline concentrations, unless the theophylline dose is appropriately increased.
    Thiazolidinediones: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response.
    Thiethylperazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Thiopental: (Moderate) General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Patients receiving beta-blockers before or during surgery involving thiopental should be monitored closely for signs of heart failure.
    Thioridazine: (Severe) The manufacturer of thioridazine considers propranolol to be contraindicated for use with thioridazine. Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and phenothiazines appear to decrease the hepatic metabolism of these two beta-blockers. Increased serum concentrations and pharmacologic effects (e.g., cardiac, CNS, hypotension) of either drug may occur. It is not known if other hepatically-metabolized beta-blockers (e.g., carvedilol, metoprolol, timolol) interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Thyroid hormones: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tobacco: (Major) Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic CYP450 microsomal enzymes and may increase the systemic clearance of propranolol. At this time, no specific propranolol dosage adjustments are recommended for tobacco smokers. Monitor patients carefully for the desired clinical effects when changes in tobacco smoking status occur.
    Tocainide: (Major) Tocainide increases propranolol concentrations in patients receiving concomitant therapy. It may be prudent to monitor patients for adverse effects when tocainide is combined with propranolol.
    Trandolapril; Verapamil: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., propranolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated. In addition, limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Triamcinolone: (Moderate) Patients receiving corticosteroids during propranolol therapy may be at increased risk of hypoglycemia due to the loss of counter-regulatory cortisol response. This effect may be more pronounced in infants and young children. If concurrent use is necessary, carefully monitor vital signs and blood glucose concentrations as clinically indicated.
    Trifluoperazine: (Major) Propranolol appears to inhibit the hepatic metabolism of phenothiazine neuroleptics, and the phenothiazines appear to decrease the hepatic metabolism of propranolol. For example, chlorpromazine concentrations increase by up to 5-fold in the presence of propranolol. Increased serum concentrations and pharmacologic effects (e.g., CNS, hypotension) may occur. It is not known if other hepatically-metabolized beta-blockers interact with the phenothiazines in this manner. Beta-blockers with greater renal elimination (e.g., atenolol, nadolol) are less likely to have an interaction with phenothiazines.
    Vemurafenib: (Moderate) Propranolol is significantly metabolized by CYP2D6 and secondarily by the CYP1A2 isoenzymes. CYP2D6 and CYP1A2 inhibitors, such as vemurafenib, could theoretically impair propranolol metabolism. The clinical significance of such interactions is unknown.
    Verapamil: (Moderate) Verapamil can inhibit the metabolism of some beta-blockers (e.g., propranolol), and can cause additive effects on slowing of AV conduction and depression of blood pressure. Oral calcium-channel blockers and beta-blockers are used together for their therapeutic benefits to reduce angina and improve exercise tolerance. However, concomitant administration of beta-adrenergic blocking agents and verapamil can lead to significant AV nodal blockade. This can manifest as heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Congestive heart failure or severe hypotension also can occur. The combination of beta-blockers and verapamil should be avoided in patients with poor ventricular function due to increased negative inotropic effects.
    Voriconazole: (Moderate) Voriconazole is metabolized by CYP3A4 and, theoretically, inhibitors of CYP3A4, such as propranolol, could lead to increased serum levels of voriconazole.
    Warfarin: (Moderate) Propranolol has been shown to increase warfarin AUC, and concurrent increases in INR values have been reported. Patients should be monitored for changes in anticoagulation parameters during concurrent therapy with propranolol and warfarin.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled blood pressure.
    Zileuton: (Moderate) Concomitant administration of zileuton and propranolol results in a significant increase in propranolol serum concentrations, AUC, and elimination half-life. Bradycardia is also potentiated by the drug combination. Clinicians should monitor vital signs carefully if zileuton is added to a regimen containing propranolol and adjust dosages as needed.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Zolmitriptan: (Minor) Periodically monitor blood pressure and for zolmitriptan-related side effects in patients who regularly use zolmitriptan and are taking propranolol. Rarely, a patient might experience an increase in dose-related common side effects of zolmitriptan, such as dizziness, nausea or drowsiness. No dosage adjustment of zolmitriptan appears to be needed. During pharmacokinetic studies, the Cmax and AUC of zolmitriptan increased 1.5-fold after 1 week of dosing with propranolol. Cmax and AUC of the active N-desmethyl metabolite of zolmitriptan were reduced by 30% and 15%, respectively. However, in clinical trials, the efficacy of zolmitriptan was not affected by the concurrent use of common migraine prophylactic drugs (e.g., propranolol). There were no interactive effects on blood pressure or pulse rate. The interaction should not be significant for most patients.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, propranolol should be used with caution in breast feeding mothers because the drug is distributed into breast milk. The selection of a beta-blocker during lactation should take into account the indication for use and clinical goals for the mother. Propranolol has generally been considered compatible with breast-feeding in clinical use. Other beta-blockers that the AAP regards as usually compatible with breast feeding include labetalol, metoprolol, nadolol, sotolol, and timolol; these agents may represent preferable alternatives for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Like other beta-adrenergic antagonists, propranolol competes with adrenergic neurotransmitters (e.g., catecholamines) for binding at sympathetic receptor sites. Similar to atenolol and metoprolol, propranolol blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. Pharmacodynamic consequences of beta1-receptor blockade include a decrease in both resting and exercise heart rate and cardiac output, and a decrease in both systolic and diastolic blood pressure. Propranolol may reduce reflex orthostatic hypotension. The fall in cardiac output induced by beta1 effects is often countered by a moderate reflex increase in peripheral vascular resistance that can be magnified by beta2 blockade (unmasked alpha stimulation). As a result, nonselective beta-blocking agents can produce a more modest decrease in (diastolic) blood pressure compared with selective beta1-antagonists. In addition, propranolol also can competitively block beta2-adrenergic responses in the bronchial muscles, potentially inducing bronchospasm.Actions that make propranolol useful in treating hypertension include a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect that decreases cardiac output; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys. Thus, propranolol, like other beta-blockers, affects blood pressure via multiple mechanisms. In general, beta-blockers without intrinsic sympathomimetic activity (ISA) exert detrimental effects on LVH and the lipid profile, and cause sexual dysfunction.Actions that make propranolol useful in treating hypertension also apply to managing chronic stable angina. The reduction in myocardial oxygen demand induced by propranolol results in decreases in the frequency of anginal attacks and requirements of nitrate, and increases exercise tolerance. Other postulated anti-anginal actions include an increase in oxygen delivery to tissues, due to propranolol-induced lowering of hemoglobin's affinity for oxygen, and a reduction of platelet aggregation, postulated to be related to interference with calcium ion flux.Propranolol has been used to treat portal hypertension and to prevent bleeding of esophageal varices. Nonselective beta-blockers decrease portal venous pressure, decrease blood flow in the superior portosystemic collateral circulation, and decrease blood flow in the splanchnic region. Beta-blockade decreases cardiac output reducing hepatic arterial and portal venous perfusion. Activation of unopposed alpha-receptors lead to splanchnic vasoconstriction, thus decreasing portal perfusion.Propranolol is used to treat hypertension and the subsequent decline of renal function in patients with scleroderma renal crisis (SRC). SRC is associated with elevated peripheral renin concentrations. Propranolol blocks beta-receptors located on the surface of the juxtaglomerular cells which decreases the release of renin. In turn, this affects the renin-angiotensin-aldosterone system reducing blood pressure.Numerous mechanisms may contribute to the efficacy of propranolol in preventing migraine headaches. Beta-blockade can prevent arterial dilation, inhibit renin secretion, and can interfere with catecholamine-induced lipolysis. A decrease in lipolysis decreases arachidonic acid synthesis and, subsequent, prostaglandin production. Inhibition of platelet aggregation is due to this decrease in prostaglandins and blockade of catecholamine-induced platelet adhesion. Other actions include increased oxygen delivery to tissues and prevention of coagulation during epinephrine release.Propranolol has two roles in the treatment of thyrotoxicosis; these actions are determined by the different isomers of propranolol. L-propranolol causes beta-blockade and can ameliorate the symptoms associated with thytotoxicosis such as tremor, palpitations, anxiety, and heat intolerance. D-propranolol blocks the conversion of T4 to T3, but the therapeutic effect of this action is minimal.Propranolol has been used in the management of hereditary or familial essential tremor. Beta-blockade controls the involuntary, rhythmic and oscillatory movements of essential tremor. Tremor amplitude is reduced, but not the frequency of tremor. The mechanism of action is unclear, but the antitremor effect may be mediated by blockade of peripheral beta2 receptor mechanisms.Propranolol can dampen the peripheral physiologic symptoms of anxiety. Beta-blockade can attenuate somatic symptoms of anxiety such as palpitations and tremor, but it is less effective in controlling psychologic components, such as intense fear. These effects are thought to be due to improvement in somatic symptoms secondary to beta-blockade, although the mechanism of action is unclear.

    PHARMACOKINETICS

    Propranolol is administered orally or intravenously. Propranolol is highly lipophilic and is widely distributed throughout the body. It readily crosses the blood-brain barrier and the placenta, and is distributed into breast milk. Propranolol is about 90% bound to plasma proteins, the R(+)-enantiomer primarily binds albumin while the S(-)-enantiomer is primarily bound to alpha-1 acid glycoprotein. The volume of distribution is about 4 L/kg. In normal subjects receiving oral doses of racemic propranolol, S(-)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism.
     
    Propranolol is extensively metabolized upon first pass through the liver, and the extent of metabolism is dependent on liver blood flow. The drug also binds to and saturates nonspecific hepatic binding sites before the drug reaches the systemic circulation. An equipotent, pharmacologically active metabolite, 4-hydroxypropranolol, is produced with the initiation of oral therapy, but it is eliminated faster than the parent drug. With chronic or IV therapy, this metabolite is produced to a lesser degree. Overall, at least eight metabolites of propranolol have been identified. Important differences may exist among ethnic groups in the ability to metabolize propranolol, which can affect the overall efficacy of the drug in some instances. Excretion of propranolol occurs renally, primarily as metabolites, with only 1—4% of a dose excreted fecally as unchanged drug. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+)-propranolol after intravenous and oral doses. The elimination half-life of propranolol ranges from 2—6 hours, with chronic administration yielding longer half-lives, possibly due to saturation of liver binding sites and/or systemic clearance.
     
    Affected cytochrome P450 enzymes:
    Cytochrome P450 enzymes involved in the metabolism of propranolol include 2D6, 1A2, and 2C19. Propranolol is also a substrate for the efflux transporter PGP.  The aromatic hydroxylation of propranolol to form the active metabolite, 4-hydroxypropranolol, is mediated by CYP2D6. 4-hydroxypropranolol is a substrate and weak inhibitor of CYP2D6. In healthy subjects, no difference in clearance or half-life of propranolol was observed between extensive and poor CYP2D6 metabolizers. In extensive metabolizers, a significant increase in 4-hydroxypropranolol clearance and a significant decrease in the clearance of naphthyloxyactic acid, an inactive metabolite, was noted.

    Oral Route

    After oral administration of immediate-release propranolol, the dose is almost completely absorbed, however, due to high first pass metabolism, bioavailability is only about 25%. Peak concentrations of immediate release tablets and long acting capsules are achieved in 1-4 hours and about 6 hours, respectively. Food can increase the bioavailability of the immediate release formulation by approximately 50% but does not affect the time to peak concentration. The effect of food on the bioavailability of the sustained-release formulation has not been investigated.

    Intravenous Route

    The distribution half-life of intervenously administered propranolol is 5 to 10 minutes. Pharmacodynamic effects are seen immediately and maintained for 2—4 hours.