Esmolol is a short-acting β1-selective adrenergic blocking agent.1, 2, 17, 18, 113
Esmolol is used in the management of supraventricular tachycardia (SVT) (e.g., atrial flutter and/or fibrillation, sinus tachycardia).1, 2, 53, 54, 55, 56, 57, 58, 59, 68, 87, 88, 100, 113 Esmolol also is used in the management of hypertension63, 64, 71, 72, 73, 74, 75, 109, 113, 125, 542, 1200 and has been used to produce controlled hypotension† during anesthesia.75, 114, 124 In addition, the drug has been used for the management of acute myocardial infarction† (MI)15, 24, 25 and in unstable angina† .15, 24, 58, 82, 113
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.31, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.31, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.156, 157, 158, 159, 162, 164, 165
Esmolol is used IV principally to provide rapid, temporary control of ventricular rate in patients with SVT (e.g., atrial flutter and/or fibrillation, sinus tachycardia).1, 2, 53, 54, 55, 56, 57, 58, 59, 68, 87, 88, 100, 113 The drug may be used in patients with nonpreexcited atrial flutter and/or fibrillation to control rapid heart rate that may be associated with surgical or other manipulative procedures (e.g., cardiac catheterization)1, 2, 37, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or with other emergent situations requiring short-term control of ventricular rate.1, 2, 5, 51, 52, 53, 54, 55, 56, 57, 58, 87, 88, 113 Esmolol also may be useful in patients with noncompensatory sinus tachycardia for short-term control of rapid heart rate requiring intervention.1, 2, 53, 55, 58, 59, 100 Parenteral esmolol is not intended for chronic use when other more appropriate antiarrhythmic agents would be preferred.1, 2
The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of β-blockers in the treatment of various SVTs (e.g., atrial fibrillation or flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia [AVNRT]); in general, an IV β-blocker is recommended for acute treatment, while an oral preparation is recommended for the ongoing management of these arrhythmias.300, 301 Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of patients with SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, an IV β-blocker may be considered in hemodynamically stable patients.300 Although evidence of efficacy is limited, experts state that the overall safety of β-blockers warrants their use in patients with SVT.300 Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.300
IV β-blockers may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia† (i.e., regular SVT arising from a localized atrial site).300 Multifocal atrial tachycardia, characterized by a rapid, irregular rhythm with at least 3 distinct P-wave morphologies, is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drug therapy.300
IV β-blockers are considered one of several drug therapy options for the treatment of junctional tachycardia† (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia.300 Experts state that use of an IV β-blocker is reasonable for the acute treatment of symptomatic junctional tachycardia.300 Although evidence is limited, there is some data indicating that β-blocking agents (specifically propranolol) are modestly effective in terminating and/or reducing the incidence of junctional tachycardia.300
Esmolol may be preferred to longer-acting β-blockers for the short-term control of ventricular rate in patients with SVT because of the drug's rapid onset and short duration of effects, including adverse effects.1, 2, 3, 4, 5, 15, 16, 100, 113, 114, 126 Because adverse effects generally can be reversed rapidly by reducing the rate of or stopping the infusion,1, 2, 3, 4, 5, 51, 53, 54, 55, 58, 100, 109, 113 esmolol may be particularly useful in patients at risk of adverse β-blocking effects (e.g., those with mild congestive heart failure,2, 54, 55, 58 mild chronic obstructive pulmonary disease,2, 54, 55, 58 asthma,55, 113 or diabetes mellitus2, 54, 55, 58 and in geriatric patients).2, 114, 126 The drug has been used safely and effectively to control ventricular rate in patients with acute MI,15, 24, 54, 58 unstable angina,2, 15, 24 angina following MI,24 low left ventricular ejection fraction,25, 34 AV conduction block,2, 58, 113 and other conditions.2, 15, 51, 52, 53, 54, 55, 56, 57, 58, 60, 87
The efficacy of IV esmolol in controlling ventricular rate and in converting the arrhythmia to normal sinus rhythm in patients with SVT appears to be similar to that of other IV β-blockers.2, 53, 54, 58, 113, 120, 121 Approximately 70-90% of patients with SVT respond to IV esmolol with at least a 15-20% reduction in heart rate,51, 52, 53, 54, 55, 56, 57, 58, 87, 88, 113 but the drug converts atrial flutter and/or fibrillation to normal sinus rhythm less frequently (usually in 10-20% of patients, although higher conversion success may occur if the arrhythmia is of recent onset).51, 52, 53, 54, 55, 56, 58, 59, 87, 88, 113, 114 Although the efficacy of IV esmolol in controlling ventricular rate in these patients also appears to be similar to that of IV verapamil,2, 88, 113 there is some evidence that esmolol may be more effective than verapamil for converting atrial flutter and/or fibrillation that is of recent onset to normal sinus rhythm.2, 88, 113 Some clinicians state that IV esmolol may be preferred over IV verapamil for initial acute management of ventricular rate in patients with SVT, since the drugs appear to be comparably effective but dosage and adverse effects (e.g., hypotension) appear to be more readily controllable during esmolol therapy.2, 113 However, verapamil may be preferred in some patients because of its hemodynamic effects.126 Additional study and experience are necessary to more fully elucidate the relative benefits and risks of parenteral esmolol and verapamil therapy in these patients.126 Concurrent cardiac glycoside therapy appears to potentiate the antiarrhythmic efficacy of esmolol in patients with SVT.2, 51, 53, 54, 59, 113, 122
IV β-blockers (e.g., esmolol, propranolol, metoprolol) are recommended as one of several drug therapy options for the acute treatment of hemodynamically stable patients with nonpreexcited atrial fibrillation.301 Choice of a specific β-blocker should be individualized based on the patient's clinical condition.301 While esmolol generally is comparably effective for controlling ventricular rate in patients with atrial flutter or atrial fibrillation,51, 52, 53, 54, 55, 58, 113 atrial flutter may be somewhat more resistant to therapy with the drug.58, 113
Although β-blockers have been used for the treatment of paroxysmal supraventricular tachycardia (PSVT), including AVNRT,300 the value of IV esmolol in the management of this type of arrhythmia has not been fully evaluated to date,51, 54, 55, 58, 87, 126 and the manufacturer suggests that the drug is not effective for converting PSVT to normal sinus rhythm.114
IV esmolol has been used effectively before,37, 60, 61, 62, 63, 64, 66, 67, 101 during,37, 64, 65, 125 or after59, 68, 122 cardiac surgery (e.g., coronary artery bypass, valve replacement) to prevent perioperative SVT37, 60, 61, 62, 63, 64, 65, 66, 67, 113 or to control rapid ventricular rate in patients who develop SVT as a result of increased adrenergic activity associated with surgical events.59, 68, 76, 77, 95, 122, 125 IV esmolol produces a dose-dependent reduction in ventricular rate in patients with postoperative atrial flutter or fibrillation or sinus tachycardia,59, 68, 122 achieving at least a 15% reduction in rate in 60% or more of patients.59, 68, 113, 122 Conversion to normal sinus rhythm occurs less frequently (e.g., in 20-45% of patients).59, 68, 113, 122 Therapeutic response appears to be potentiated by concomitant cardiac glycoside therapy (e.g., administration of a preoperative digitalizing dose).59, 113, 122 Following discontinuance of IV esmolol therapy, sinus tachycardia may return in some patients and prolonged postoperative therapy with an oral β-blocker may be necessary.59 In some patients with atrial fibrillation that is not converted to normal sinus rhythm by esmolol, the addition of a parenteral cardiac glycoside or type I antiarrhythmic agent during or shortly after esmolol therapy may be beneficial.59
Because of its short duration of action, esmolol may be the β-blocker of choice for controlling ventricular rate and blood pressure in surgical patients with underlying cardiovascular disease.2, 5, 15, 60, 70, 73 Rapid modification of β-blocker therapy in response to changing autonomic function may be necessary in these patients.13, 14, 15, 17, 19, 51, 53, 55 Unlike that induced by long-acting IV β-blockers (e.g., propranolol, metoprolol), β-adrenergic blockade induced by IV esmolol dissipates shortly after (approximately 10-30 minutes) discontinuance of the drug.2, 24, 34, 52, 53, 54, 100 Patients with underlying coronary artery disease are at particular risk of developing myocardial ischemia and possibly infarction as a result of increases in adrenergic activity associated with surgical events.81, 113 Esmolol attenuates the effects on heart rate of endotracheal intubation and other surgical manipulation and appears to reduce the risk of myocardial ischemia associated with surgical events.37, 61, 63, 65, 66, 67, 113 In addition, the hypotensive effect of esmolol may be beneficial in some patients undergoing surgery.63, 64, 71, 72, 73, 75, 113 (See Uses: Hypertension.)
Esmolol also has been used to prevent and manage SVT associated with anesthesia in patients with60, 61, 63, 65, 66, 67, 70, 73, 101 or without69, 71, 72 underlying cardiac disease (e.g., coronary artery disease). In patients undergoing surgery in whom long-term oral β-blocker therapy has been withheld temporarily, IV esmolol may be useful for maintaining β-blockade during surgery and thus preventing rebound effects associated with withdrawal of such therapy.2, 93, 94
Because of the drug's short duration of action, the efficacy of IV esmolol in the management of SVT may be transient.51, 52, 53, 54, 55, 58, 113 Heart rate often returns to baseline values within 30 minutes after discontinuance of the drug.1, 2, 5, 51, 52, 58 IV esmolol is not intended for chronic therapy;1, 2, 5, 113 when long-term maintenance therapy is needed, IV esmolol should be replaced with appropriate alternative antiarrhythmic therapy (e.g., a longer-acting β-blocker, a cardiac glycoside, verapamil).1, 2, 113
Esmolol has been used effectively to prevent or treat increases in blood pressure associated with surgical events,63, 64, 71, 72, 73, 74, 75, 109, 113, 125 and, because of its short duration of effects (including adverse effects), may be preferred to longer-acting β-blockers.3, 4, 5, 15, 16, 63, 64, 71, 72, 74, 109, 113 Esmolol has attenuated hemodynamic changes induced by surgical events, including increases in systolic, diastolic, and mean arterial blood pressures and double product (heart rate times systolic blood pressure).59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 109, 113, 125 The drug's hemodynamic effects and effects on heart rate can minimize surgical stimuli-induced increases in myocardial oxygen consumption;60, 61, 63, 65, 113 this action may be particularly useful in patients with underlying coronary artery disease.60, 61, 63, 65, 113 Esmolol also has been useful for the treatment of postoperative hypertension, including that associated with coronary artery bypass graft surgery (CABG).74, 109, 113, 542 Although reductions in systolic blood pressure in patients with hypertension following cardiac surgery are comparable in esmolol- or sodium nitroprusside-treated patients, esmolol therapy appears to provide additional beneficial effects, including a less pronounced reduction in diastolic blood pressure, a reduction in heart rate (sodium nitroprusside may cause reflex tachycardia), and minimal effects on oxygen saturation and partial pressure (which may be decreased with sodium nitroprusside).74, 109, 113
Esmolol also can be used for the management of hypertensive emergencies.542, 1200 Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage.1200 Such emergency situations include hypertensive encephalopathy, acute MI, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, unstable angina pectoris, acute ischemic stroke, and acute renal failure.1200 Patients with hypertensive emergencies require hospitalization and are treated initially with an appropriate parenteral agent.542, 1200 Esmolol may be particularly useful in the management of hypertensive emergencies associated with dissecting aortic aneurysm or acute coronary syndromes.542, 1200 Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.1200 The risks of overly aggressive therapy in any hypertensive crisis must always be considered.542, 1200 Excessive falls in blood pressure should be avoided in any hypertensive emergency since they may precipitate renal, cerebral, or coronary ischemia.542, 1200
IV esmolol hydrochloride also has been used effectively to produce controlled hypotension† during anesthesia in order to reduce bleeding resulting from surgical procedures (e.g., orthopedic surgery, neurosurgery).75, 114, 124 In a limited number of patients undergoing lumbar fusion or cerebrovascular surgery, a comparable reduction in mean arterial blood pressure could be achieved with IV esmolol or sodium nitroprusside; however, esmolol therapy was associated with a reduction in heart rate rather than with reflex tachycardia and was less likely to be associated with rebound hypertension following discontinuance of therapy with the drug.124
Short-term IV esmolol therapy has been used for the management of acute tachyarrhythmias complicating acute MI†, 15, 24, 25 and to minimize myocardial ischemia following acute MI†13, 15, 24, 25, 58, 113 or associated with unstable angina†.15, 24, 58, 82, 113 Esmolol has effectively reduced heart rate, arterial blood pressure, double product, and angina in patients with acute myocardial ischemia, including those with acute MI15, 24, 25, 58, 113 or unstable angina.15, 24, 58, 82, 113 IV β-blockers also have reduced myocardial infarct size in patients with myocardial ischemia; however, early use of β-blockers (particularly when administered IV) during the acute phase of MI has been associated with an increased risk of cardiogenic shock.13, 20, 21, 527, 801, 1100 While current expert guidelines recommend an oral β-blocker in all patients with MI who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy, use of IV β-blockers should be limited to patients with refractory hypertension or ongoing ischemia. 527, 1100 Although cardiac output may decrease during esmolol therapy, this effect generally is readily reversible by reducing the rate of or stopping the esmolol infusion.24, 25, 58, 82, 113 Pulmonary capillary wedge pressure, respiratory rate, and PR interval do not appear to be affected substantially by the drug.24, 113 Because of its short duration, esmolol may be particularly useful in patients at risk of β-blocker-induced or -exacerbated heart failure, bradycardia, AV block, or bronchospasm.13, 20, 24, 58, 113, 114
For additional information on the use of β-blockers in the management of MI, see Uses in Metoprolol 24:24.
Esmolol hydrochloride is administered by IV infusion.1 The drug usually is administered IV via a controlled infusion device to facilitate dosage titration.52, 53, 54, 61, 114, 126
Extravasation of esmolol hydrochloride solutions should be avoided.600 Infusion site reactions, including irritation, inflammation, and severe reactions (e.g., thrombophlebitis, necrosis, blistering), have occurred, particularly following extravasation of the drug.600 If local reactions develop at the site of infusion, an alternate infusion site should be used.1 Use of butterfly needles and very small veins for infusion of the drug should be avoided.1, 114 The drug is infused IV at a rate determined by the response and tolerance of the patient.1, 51, 52, 53, 54, 55, 58, 59, 60, 61, 64, 65, 66, 67, 68
Parenteral solutions of esmolol hydrochloride should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.600 Esmolol hydrochloride injection in vials (10 mg/mL) or premixed injection in plastic containers (10 or 20 mg/mL) needs no dilution.600 Commercially available plastic containers of the premixed injection should be removed from their overwraps according to the manufacturers' directions and checked for minute leaks by firmly squeezing the bags.1 The injection should be discarded if the overwrap has been previously opened or leaks are found; however, some opacity of the plastic container does not affect the quality or safety of the solution.1 Additives should not be introduced into the premixed injection.1 The premixed injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.1 Once the injection container has been opened, unused portions of the solution should be discarded.1 The infusion bag for the premixed injection contains 2 outlet ports; one port may be used once only for withdrawal of the initial loading dose and the other port is attached to the IV administration set.1
Standardized concentrations for esmolol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249, 250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249, 250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249, 250 For additional information on S4S (including updates that may be available), see [Web]249, 250 .
Dosage of esmolol hydrochloride must be adjusted carefully according to individual requirements, response, and tolerance.1, 2, 3, 51, 52, 53, 54, 55, 56, 57, 58 Patients should be monitored closely (e.g., blood pressure, respiratory rate, heart rate, ECG) during esmolol hydrochloride therapy.1, 53, 54, 55 If adverse effects (e.g., hypotension, overt congestive heart failure, bradycardia) occur, the rate of infusion should be reduced or the infusion stopped as necessary.1 (See Cautions: Precautions and Contraindications.)
In patients with supraventricular tachycardia (SVT), the rate and duration of esmolol hydrochloride infusion should be adjusted carefully according to the patient's tolerance and response as indicated by ventricular rate and blood pressure.1, 51, 52, 53, 54, 55, 58 During titration, each dosage adjustment of esmolol hydrochloride usually consists of a loading dose followed by a maintenance dose.1, 51, 52, 53, 54, 55, 58
For initiation of esmolol hydrochloride therapy in adults with SVT, an IV loading dose of 500 mcg/kg per minute is administered for 1 minute,1, 51, 52, 53, 54, 55, 58, 300, 301 followed by a maintenance infusion at a rate of 50 mcg/kg per minute for 4 minutes.1, 2, 3, 51, 52, 53, 54 The response to this initial dosage should give a rough estimate of the responsiveness of ventricular rate.1 If optimum response is not attained within 5 minutes, the maintenance dosage may be continued at a rate of 50 mcg/kg per minute or increased in 50-mcg/kg per minute increments (i.e., to 100 mcg/kg per minute, then to 150 mcg/kg per minute) up to a maximum of 200 mcg/kg per minute, with each new incremental infusion rate being maintained for 4 or more minutes.1 If a more rapid slowing of ventricular response is required, a second loading dose of 500 mcg/kg per minute is administered for 1 minute followed by a maintenance infusion at a rate of 100 mcg/kg per minute for 4 minutes.1, 2, 3, 51, 52, 53, 54 If necessary, a final loading dose of 500 mcg/kg per minute for 1 minute is administered, followed by a maintenance infusion of 150 mcg/kg per minute for 4 minutes; this maintenance infusion may be increased to a maximum of 200 mcg/kg per minute if needed.1, 52, 55, 57, 58 Once the desired ventricular rate1 or a patient tolerance end-point (e.g., reduction in blood pressure)52, 53, 54 has been nearly achieved,1, 114 loading doses should be omitted and maintenance infusion rates titrated upward (to 300 mcg/kg per minute) or downward as appropriate; in addition, the interval between dosage titrations may be increased if desired.1
Optimum response usually (in more than 95% of patients) is achieved with esmolol hydrochloride maintenance dosages averaging 100 mcg/kg per minute (range: 50-200 mcg/kg per minute),1, 2, 3, 51, 52, 53, 54, 55, 58 but some patients may achieve adequate heart rate control with dosages as low as 25 mcg/kg per minute.1, 55 Maintenance dosages up to 300 mcg/kg per minute have been used occasionally,1, 2, 3, 51, 52, 53, 54, 55, 58, 300, 301 but such doses are not recommended by the manufacturer for the management of SVT since maintenance doses exceeding 200 mcg/kg per minute are associated with an increased frequency of adverse effects and provide little additional clinical benefit.1, 2, 51, 53, 58, 114 The safety of maintenance doses exceeding 300 mcg/kg per minute has not been established.1, 3
Esmolol hydrochloride infusions have been administered for 24 hours or less in most patients,1, 2, 55 but limited data indicate that infusions of the drug may be well tolerated for up to 48 hours.1 Once adequate control of heart rate has been achieved with esmolol therapy and the patient's clinical condition is stabilized, attempts to transfer the patient to alternative antiarrhythmic therapy (e.g., a longer-acting β-adrenergic blocker, digoxin, verapamil) should be made.1 When transferring a patient to alternative therapy, the infusion rate of esmolol may be decreased by 50% 30 minutes after administration of the first dose of the alternative drug;1 if an adequate response is achieved and maintained for at least 1 hour after administration of the second dose of the alternative drug, the esmolol infusion can be discontinued.1 In determining the appropriateness of this guideline for transferring therapy, the characteristics and dosing guidelines for the alternative drug must be considered.1
Intraoperative and Postoperative Tachycardia and/or Hypertension
When esmolol hydrochloride is used in intraoperative and postoperative settings for the treatment of tachycardia and/or hypertension, it may be difficult or inadvisable to slowly titrate dosage of the drug.1 Therefore, when immediate intraoperative or postoperative control is required, the manufacturer states that a loading dose of 1 mg/kg of the drug may be given by direct IV injection over 30 seconds and, if necessary, this may be followed by an infusion at the rate of 150 mcg/kg per minute.600 The infusion rate should be adjusted as required up to a maximum of 200 mcg/kg per minute to maintain the desired heart rate or up to 250-300 mcg/kg per minute to maintain the desired blood pressure.600 In the management of tachycardia, dosages exceeding 200 mcg/kg per minute provide little additional benefit in lowering heart rate but are associated with an increased incidence of adverse effects.600 The manufacturer states that the safety of dosages exceeding 300 mcg/kg per minute in the management of hypertension has not been established.600 For gradual control of postoperative tachycardia and hypertension, the dosing schedule recommended for the treatment of SVT should be used.1 (See Dosage: Supraventricular Arrhythmias.)
The optimum hypotensive dosage of esmolol hydrochloride has not been established, and dosage of the drug should be adjusted according to the patient's blood pressure response and tolerance.74, 75, 124 To produce controlled hypotension during anesthesia† in adults, esmolol dosage has been titrated upward to a level necessary to maintain the required reduction in blood pressure (e.g., a 15% reduction in mean arterial pressure) or until a maximum rate of 300 mcg/kg per minute was achieved.75, 124, 126 For the management of postoperative hypertension in adults undergoing cardiac surgery, a loading dose of 500 mcg/kg per minute has been administered for 30 seconds (250 mcg/kg total) followed by a maintenance infusion dose of 25 mcg/kg per minute for 4 minutes; the maintenance infusion dose was increased by increments of 50 mcg/kg per minute for 4 minutes up to a maximum rate of 300 mcg/kg per minute, each preceded by a loading dose of 500 mcg/kg per minute for 1 minute.74
When esmolol hydrochloride is used in the management of a hypertensive emergency in adults, an initial IV loading dose of 500-1000 mcg/kg may be administered over 1 minute, followed by an IV infusion of 50 mcg/kg per minute.1200 If necessary, the IV loading dose may be repeated and the IV infusion rate may be increased in increments of 50 mcg/kg per minute as needed to a maximum of 200 mcg/kg per minute.1200 The initial goal of such therapy in adults without a compelling indication is to reduce systolic blood pressure by no more than 25% within the first hour, followed by further blood pressure reduction if stable to 160/110 or 160/100 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.542, 1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal blood pressure can be implemented in the next 24-48 hours.1200 Adults who have hypertensive crisis with a compelling indication (e.g., aortic dissection, severe preeclampsia or eclampsia, pheochromocytoma crisis) should have their systolic blood pressure reduced to less than 140 mm Hg during the first hour, and, in patients with aortic dissection, to less than 120 mm Hg within the first 20 minutes.1200
For rapid reduction in blood pressure in pediatric patients with acute severe hypertension† and life-threatening symptoms, some experts recommend an IV esmolol hydrochloride infusion of 100-500 mcg/kg per minute.1150 These experts suggest that blood pressure should be reduced by no more than 25% of the planned reduction over the first 8 hours.1150 Because esmolol hydrochloride is a short-acting drug, continuous infusion is preferred.1150
Esmolol hydrochloride shares the toxic potentials of β-adrenergic blocking agents (β-blockers);1, 2, 3, 4, 5 however, because of esmolol's short duration of action, adverse effects generally resolve more rapidly than with other β-blockers.1, 2, 3, 4, 5, 113 In therapeutic doses, esmolol usually is well tolerated and has a low incidence of adverse effects.1, 2, 52, 54, 55, 57, 58, 71 Most adverse effects are mild and transient,1, 2 and do not require discontinuance of the drug;1, 2, 52, 54, 55, 57, 58, 71 however, adverse effects may be severe enough to require discontinuance of esmolol in about 5-25% of patients.1, 2, 51, 53, 55, 59, 109 The most common adverse effects of the drug are cardiovascular and nervous system effects,1, 2, 3, 4, 5, 113 and the most common adverse reactions requiring discontinuance of esmolol are cardiovascular effects.1, 2, 3, 4, 5, 51, 53, 55, 59 Several fatalities have been reported in patients with complex clinical states who were receiving esmolol, presumably for the management of ventricular rate.1
The most frequent adverse cardiovascular effect of esmolol is hypotension (systolic blood pressure less than 90 mm Hg),1, 2, 24, 50, 51, 53, 54, 55, 56, 57, 58, 59, 63, 100, 113, 114, 122 which occurs in about 20-50% of patients receiving the drug for the management of supraventricular tachycardia (SVT).1, 2, 51, 53, 54, 55, 56, 57, 58, 59, 100, 113 Symptomatic hypotension, manifested as dizziness,1, 2, 51, 54, 55, 58, 113, 122 diaphoresis,1, 2, 50, 51, 54, 55, 58, 113, 122 and/or headache,51, 55, 58, 59 occurs in about 12% of patients,1, 2 and asymptomatic hypotension occurs in about 25% of patients receiving the drug.1, 2, 113 Diaphoresis occurs in about 10% of patients who develop hypotension.1, 2 Hypotension has required discontinuance of esmolol therapy in about 6-20% of patients;1, 2, 51, 53, 55, 59, 113 50% of hypotension requiring discontinuance of the drug was symptomatic.1, 2 Hypotension has resolved in approximately 63% of patients despite continued esmolol therapy, and in 80% of patients within 30 minutes after stopping the IV infusion.1, 2, 51, 52, 53, 54, 55, 58, 113
The risk of developing hypotension appears to be greatest within the first 30 minutes of esmolol infusion.5 Esmolol-induced hypotension may be dose related,1, 2, 51, 53, 58, 113 and maintenance doses exceeding 200 mcg/kg per minute are not recommended by the manufacturer for the management of SVT.1, 2, 114 (See Dosage and Administration: Dosage.) Patients should be monitored closely during esmolol infusion, especially if pretreatment blood pressure is low.1, 2 The risk of developing esmolol-induced hypotension appears to be related inversely to baseline blood pressure55, 58, 113 and related directly to baseline heart rate.58, 113 The risk of hypotension does not appear to be affected by gender, age, or type of supraventricular arrhythmia.5
Peripheral ischemia occurs in about 1% of patients receiving esmolol.1, 2, 63, 113 Pallor,1, 2, 113 flushing,1, 2, 113 bradycardia (heart rate less than 50 beats per minute),1, 2, 51, 113 chest pain,1, 2 pulmonary edema,1, 2 heart block,1 and syncope1 occur in less than 1% of patients receiving the drug.1 Pulmonary congestion has been reported rarely.56 Sinus bradycardia, pause, and arrest, which resolved following discontinuance of esmolol, have occurred in several patients without underlying supraventricular tachycardia, but these patients had serious preexisting coronary artery disease (e.g., recent inferior myocardial infarction, unstable angina).1, 2 Other adverse cardiovascular effects include increased pulmonary artery pressure,51, 109 increased and coupled ventricular premature complexes,51, 54, 59 junctional rhythm,51 hypertension,63 and transient ST changes on ECG.63
Despite relatively minimal distribution of esmolol into the CNS,2, 28 adverse CNS effects may occur in patients receiving the drug.1, 2, 50, 51, 53, 54, 55, 56, 58, 113 The most common adverse nervous system effects of the drug are dizziness1, 2, 50, 51, 54, 55, 58, 113 and somnolence,1, 2, 50, 55, 58, 113 which occur in about 3% of patients.1, 2, 50, 51, 54, 55, 58 Confusion,1, 2, 55, 58, 113 headache,1, 2, 51, 55, 58, 59, 113 and agitation1, 2, 55, 58, 63, 113 occur in about 2% of patients,1, 2, 50, 51, 54, 55, 58, 59, 63 and asthenia occurs in about 1% of patients receiving esmolol.1, 56
Anxiety,1, 2 paresthesia,1, 2, 51 depression,1, 2 speech disorder,1, 2 tonic-clonic (grand mal) seizures,1, 2 and abnormal thinking1, 2 occur in less than 1% of patients receiving esmolol.1, 2 Irritability also has occurred.1
The most frequent adverse GI effect associated with esmolol therapy is nausea, occurring in about 7% of patients.1, 2, 51, 55, 56, 58, 59, 113 Vomiting occurs in about 1% of patients,1, 2 and constipation, dyspepsia, abdominal pain, xerostomia, and anorexia occur in less than 1% of patients receiving the drug.1, 2 Dysgeusia also has occurred.1, 2
Despite the relative β1-selective blocking activity of esmolol, β2-adrenergic blockade leading to bronchoconstriction and wheezing may occur with the drug.1, 2, 55, 63, 74 Bronchospasm,1, 2, 55, 63, 74, 113 wheezing,1, 2, 55, 63, 74, 109 dyspnea,1, 2, 51, 55, 58 nasal congestion,1, 2 rhonchi,1, 2 and rales1, 2, 54 occur in less than 1% of patients receiving esmolol.1, 2
Dermatologic and Local Effects
IV infusion of esmolol has produced inflammation1, 2, 54, 55, 58 and induration at the injection site1, 2, 55, 58, 59 in about 8% of patients.1, 2 Edema,1, 2 erythema,1, 2, 51, 54 skin discoloration,1, 2 and burning1, 2, 54 occurred at the IV infusion site in less than 1% of patients.1, 2 Thrombophlebitis1, 3, 56 and local skin necrosis from extravasation1 were reported in less than 1% of patients. Infiltration of the IV injection site58 and venous irritation1 have occurred rarely. Infiltration and extravasation of esmolol hydrochloride IV infusions have been associated with sloughing of the skin and necrosis.1 The risk of adverse local effects at the IV site appears to be directly related to the duration3, 51, 55 and concentration1, 3 of esmolol hydrochloride infusion. IV infusion concentrations exceeding 10 mg/mL should be avoided.1, 2, 3 Adverse local effects can be minimized by rotating the site of IV infusion.3, 5 The drug has been well tolerated when administered via a central vein.1, 114
Rash, which was diffuse, nonpruritic, erythematous, and maculopapular, also has been reported during esmolol therapy.59
Urinary retention,1, 2 visual disturbances,1, 2, 56 midscapular pain,1, 2 chills,1, 2 and fever1, 2 have occurred in less than 1% of patients receiving esmolol.1, 2 Serum concentrations of LDH and hemoglobin occasionally have increased and decreased, respectively.55
The possibility that other adverse effects associated with other β-blockers may occur during esmolol therapy should be considered.1
Precautions and Contraindications
Esmolol shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed.1
In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function.1 Esmolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when esmolol therapy is administered.1, 2 In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure.104 Although β-blockers should be avoided in patients with overt heart failure, esmolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., that controlled with cardiac glycosides and/or diuretics).1 At the first sign or symptom of impending cardiac failure, esmolol should be discontinued;1, 2 if necessary, specific therapy (e.g., a cardiac glycoside and/or diuretic) for the failure should be initiated.1, 2 If continued esmolol therapy is necessary, infusion of the drug can be restarted at a slower rate once manifestations of cardiac failure have subsided.114
Esmolol should be used with caution for the control of ventricular response in patients with supraventricular arrhythmias who are compromised hemodynamically or are taking other drugs that reduce peripheral resistance, myocardial filling, myocardial contractility, and/or electrical impulse propagation in the myocardium.1 (See Drug Interactions: Cardiovascular Drugs.) IV β-blockers, including esmolol, should be used with caution in patients with acute atrial fibrillation who have overt congestion, hypotension, or heart failure with reduced ejection fraction.301 The fact that several deaths have been reported in patients with complex clinical states who were receiving esmolol (presumably to control ventricular rate) should be considered.1
Because of the risk of esmolol-induced hypotension, blood pressure should be monitored closely during therapy with the drug, especially in patients with low pretreatment blood pressure (e.g., systolic blood pressure less than 105 mm Hg).1, 2, 55, 58, 114 The development of diaphoresis or dizziness may be a sign of hypotension induced by the drug;1, 2, 50, 51, 54, 55, 58 however, hypotension usually is asymptomatic.1, 2, 3, 5, 53, 54, 55, 58, 59 Hypotension can occur at any dose level with esmolol but usually is dose related,1, 2, 51, 53, 58 and doses exceeding 200 mcg/kg per minute are not recommended by the manufacturer for the management of SVT.1, 2, 114 (See Dosage and Administration: Dosage.) Reversal of hypotension usually occurs within 30 minutes of discontinuing the drug or reducing the rate of IV infusion.1 Esmolol should not be used for the treatment of hypertension in patients in whom increased blood pressure is principally the result of vasoconstriction associated with hypothermia.1
Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease;1, 2, 105, 106, 107, 116, 117 however, because of its relative β1-selective adrenergic blocking activity and short duration of action, esmolol may be used with caution in such patients.1, 2 Since β1-selectivity is not absolute, the lowest possible effective dose of esmolol should be used.1, 2 If bronchospasm occurs, esmolol infusion should be discontinued immediately.1 If necessary, a bronchodilator (e.g., a β2-adrenergic agonist) may be administered, but with extreme caution since the patient may have a preexisting rapid ventricular rate.1, 2
Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenge with such allergens while receiving a β-blocker.1 These patients may be less responsive than other patients to usual dosages of epinephrine or may develop a paradoxical response to epinephrine when that drug is used to treat anaphylactic reactions.1
Esmolol may mask signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, blood pressure changes, tremor, feelings of anxiety, but not sweating or dizziness) and may potentiate insulin-induced hypoglycemia;1, 2, 108 therefore, the drug should be used with caution in patients with diabetes mellitus or hypoglycemia.1, 2
Because the de-esterified metabolite (ASL 8123) of esmolol is eliminated mainly by the kidneys,1, 47 the manufacturer states that the drug should be used with caution in patients with renal impairment, especially severe impairment.1, 2
Although abrupt cessation of esmolol therapy has not produced withdrawal effects (e.g., exacerbation of angina symptoms, precipitation of myocardial infarction) associated with such cessation of chronic therapy with other β-blockers to date, the possibility that such effects could occur with esmolol in patients with coronary artery disease should be considered.1 Therefore, caution should be exercised when esmolol infusions are stopped abruptly in such patients.1 Extravasation should be avoided because skin necrosis may occur.1
The manufacturer states that esmolol is contraindicated in patients with second- or third-degree AV block,1 sinus bradycardia,1 cardiogenic shock,1 or overt cardiac failure.1
Although safety and efficacy of esmolol remain to be established in children younger than 18 years of age,1, 114 some experts have recommended pediatric dosages, preferably administered as a short-acting continuous infusion, for severe hypertension based on clinical experience.1150 Esmolol may cause profound bradycardia when used for rapid reduction of blood pressure in pediatric patients with acute severe hypertension† .1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Mutagenicity and Carcinogenicity
Esmolol did not exhibit mutagenic activity in vitro in several mammalian cell (e.g., Chinese hamster ovary, human lymphocytes) and microbial (Ames test) systems.114, 130 Because the drug is intended for short-term use, studies to determine the carcinogenic potential of esmolol have not been performed.1, 114
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using esmolol hydrochloride doses up to 3 (10 times the maximum recommended human maintenance dose) and 1 mg/kg per minute, respectively, for 30 minutes daily, have not revealed evidence of maternotoxicity, embryotoxicity, or teratogenicity.1 However, esmolol hydrochloride doses of 10 mg/kg per minute produced maternal toxicity and death in rats, and doses of 2.5 mg/kg per minute produced minimal maternal toxicity and increased fetal resorptions in rabbits.1 There are no adequate and controlled studies to date using esmolol in pregnant women.1 Use of esmolol in the last trimester of pregnancy or during labor and delivery has been reported to cause fetal bradycardia, which continued after infusion of the drug was discontinued.1 Esmolol should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1
Because the drug is intended for short-term use, reproduction studies to determine esmolol's potential for affecting fertility have not been performed.1
Since it is not known whether esmolol hydrochloride is distributed into milk, the drug should be used with caution in nursing women.1
Concomitant administration of esmolol and digoxin in healthy adults has resulted in a 10-20% increase in serum digoxin concentrations.1, 2, 49, 113 Digoxin did not affect the pharmacokinetics of esmolol.1, 2, 49, 113 Digoxin has been used safely and effectively in combination with esmolol in patients with supraventricular tachyarrhythmias undergoing cardiac surgery, and combined therapy appeared to be somewhat more effective than esmolol alone in lowering heart rate.59, 113
Concomitant therapy with an IV β-adrenergic blocking agent (β-blocker) and IV verapamil has resulted rarely in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.1, 141 Fatal cardiac arrest has occurred in patients with depressed myocardial function receiving IV esmolol and verapamil concomitantly.1
Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-blocker therapy.139, 140
Esmolol should not be used to control supraventricular tachycardia in patients receiving drugs that are vasoconstrictive or inotropic (e.g., dopamine, epinephrine, norepinephrine) because of the potential for blocked cardiac contractility when systemic vascular resistance is high.1
When esmolol and a catecholamine-depleting drug (e.g., reserpine) are administered concomitantly, the effects of the drugs may be additive.1 Patients receiving both drugs concurrently should be observed closely for evidence of marked bradycardia or hypotension, which may be manifested as vertigo, syncope, or orthostatic changes in blood pressure.1
Concomitant administration of esmolol and morphine in healthy adults resulted in about a 50% increase in steady-state blood esmolol concentrations, although the pharmacokinetics of morphine were not affected.1, 2, 49, 113 If the drugs are used concomitantly, esmolol dosage should be titrated carefully.1, 2, 49
Esmolol may prolong the effects of succinylcholine, although the onset of neuromuscular blockade is not affected.1, 2, 113 Succinylcholine-induced neuromuscular blockade has been prolonged by about 60% during concomitant esmolol administration in some patients;1, 2, 86 however, such prolongation does not appear to be clinically important.1, 2, 86, 114 In addition, the duration of neuromuscular blockade was not prolonged in other patients during concomitant therapy.2, 84
Blood esmolol concentrations may be increased slightly during concomitant warfarin therapy,1, 2, 49, 113 but such increases do not appear to be clinically important.1 Plasma warfarin concentrations are not affected by concomitant esmolol therapy.1, 2, 49, 113 If the drugs are used concomitantly, esmolol dosage should be titrated carefully.1
Limited information is available on the acute toxicity of esmolol hydrochloride.1, 2
The acute lethal dose of esmolol hydrochloride in humans is not known.1, 2, 4, 114, 126 The IV LD50 of the drug is approximately 93, 71, 40, and 32 mg/kg in mice, rats, rabbits, and dogs, respectively.2 The IV LD50 of the de-esterified metabolite (ASL 8123) of esmolol is 452 mg/kg in mice.2
Following IV infusion of esmolol hydrochloride doses up to 2 mg/kg per minute for 1 hour in dogs, no adverse effects were observed.2 However, doses of 3 mg/kg per minute for 1 hour produced ataxia and salivation, and doses of 4 mg/kg per minute for 1 hour produced muscular rigidity, head tremors, seizures, ptosis, emesis, vocalization, hyperpnea, and prostration.2 All these adverse effects resolved within 90 minutes after completion of the infusion, and additional toxic manifestations were not apparent during 2 weeks of observation; however, autopsy revealed hemorrhagic foci on the lungs of one male dog.2 Following continuous IV infusion of esmolol hydrochloride doses up to 400 mcg/kg per minute for 2 weeks in dogs, no adverse effects were observed, but decreased activity, emesis, periods of prostration, unresponsiveness, ataxia, decreased muscle tone, salivation, constipation, and decreased food consumption occurred following continuous IV infusion of 800 mcg/kg per minute for 2 weeks.2
Following IV administration of esmolol hydrochloride dosages of 5 mg/kg daily for 2 weeks in rats, no adverse effects were observed, but reduced motor activity, ataxia, and respiratory distress occurred with dosages of 20 mg/kg daily for 2 weeks; death occurred in some animals at 40 mg/kg daily for 2 weeks.2
In general, overdosage of esmolol may be expected to produce effects that are mainly extensions of pharmacologic effects, particularly those involving the cardiovascular system.114, 126 Overdosage of esmolol has resulted in cardiac arrest.1, 136, 137 As with other β-adrenergic blocking agents (β-blockers), hypotension, symptomatic bradycardia, advanced AV block, intraventricular conduction defects, impaired conduction, decreased cardiac contractility, acute cardiac failure, shock, seizures, and, in susceptible individuals, bronchospasm, hypoglycemia, electromechanical dissociation, and loss of consciousness might occur with esmolol overdosage.1, 110, 111, 112 Cases of massive accidental overdosage of esmolol have occurred because of errors in dilution.1, 136, 137 While some cases of overdosage have been fatal, other cases have resulted in permanent disability.1 Fatal overdosage has been associated with administration of a wide range of esmolol hydrochloride doses (0.625-2.5 g [12.5-50 mg/kg]).1 However, some patients have recovered completely from esmolol hydrochloride doses of up to 1.75 g given over 1 minute and from doses of 7.5 g given over 60 minutes during cardiovascular surgery.1 Generally, survival has occurred in those patients whose circulation could be supported while the effects of esmolol resolved.1
Treatment of esmolol overdosage generally involves symptomatic and supportive care.1, 126, 127, 128, 129 In acute esmolol overdose, the drug should be discontinued immediately.1 Because of esmolol's short duration of effect, this measure may provide adequate relief of toxicity,114, 126 but other specific therapy for toxic effects of the drug should be considered for severe toxicity.1, 126, 127, 128, 129 For symptomatic bradycardia, an IV anticholinergic agent (e.g., atropine sulfate) may be considered.1 The manufacturer states that IV administration of a cardiac glycoside and/or a diuretic may be considered for the management of heart failure and administration of fluids or pressor agents may be considered for the management of symptomatic hypotension.1 IV glucagon has been used for the management of myocardial depression and hypotension associated with β-blocker toxicity.126, 127, 128, 129 A vasopressor and/or a positive inotropic agent (e.g., dobutamine, dopamine, isoproterenol) may be considered for the management of shock resulting from inadequate cardiac contractility.1, 126 IV administration of a β2-adrenergic agonist and/or a theophylline derivative may be considered for bronchospasm.1 In addition, high-dose insulin and IV calcium salts also have been used for the treatment of refractory hemodynamic instability due to overdosage of β-blockers.196
Esmolol is a short-acting β1-selective adrenergic blocking agent and has pharmacologic actions similar to those of other β-adrenergic blocking agents (β-blockers).1, 2, 3, 4, 5, 13, 14, 15, 16, 17, 18, 19, 20, 113 Esmolol selectively inhibits response to adrenergic stimuli by competitively blocking cardiac β1-adrenergic receptors,1, 2, 3, 4, 5, 17, 113 while having little effect on the β2-adrenergic receptors of bronchial and vascular smooth muscle.1, 2, 3, 4, 5, 17, 35, 113 At high doses (e.g., greater than 300 mcg/kg per minute), this selectivity of esmolol for β1-adrenergic receptors usually diminishes, and the drug will competitively inhibit β1- and β2-adrenergic receptors.1, 2, 5, 29, 35, 114 In vitro studies indicate that the β1-adrenergic blocking activity of esmolol on a molar basis is approximately 1.5-2.5% that of propranolol, 7% that of labetalol, or 10-20% that of metoprolol.3, 13, 17, 113 In vivo studies in animals13 and humans22, 23 indicate that the relative β1-adrenergic blocking activity of esmolol, on a weight basis, is approximately 3-10% that of propranolol,2, 5, 13, 22, 23, 27, 113 as determined by inhibition of exercise- or isoproterenol-induced tachycardia in patients with stable angina22, 23 or healthy individuals.27
At usual clinical doses, esmolol does not exhibit appreciable intrinsic sympathomimetic2, 5, 9, 17, 18, 113 or membrane-stabilizing activity,2, 5, 17, 113 nor does the drug exhibit α-adrenergic blocking activity.2, 17, 113 However, the drug may exhibit sympathomimetic and membrane-stabilizing activity at doses substantially exceeding those used clinically.3, 5, 18, 29, 113
By inhibiting myocardial β1-adrenergic receptors, esmolol produces negative chronotropic and inotropic activity.2, 17, 18, 19, 20, 22, 23, 24, 26, 36, 113, 123 Through its myocardial β1-adrenergic blocking action, esmolol decreases resting1, 2, 17, 18, 19, 20, 22, 23, 24, 26, 27, 36, 113, 123 and exercise-induced heart rate,1, 2, 22, 23, 27, 113 reflex orthostatic tachycardia,1, 2, 17, 18, 19 myocardial contractility,2, 18 rate of left ventricular pressure rise (dp/dt),2, 18, 20, 36 right ventricular contractility,9, 18 and cardiac index.1, 2, 22, 23, 36
Following IV administration of esmolol hydrochloride doses of 200 mcg/kg per minute in patients with stable angina pectoris undergoing angiography, heart rate, systolic blood pressure, double product (heart rate times systolic blood pressure), right ventricular ejection fraction (RVEF), and cardiac index were reduced at rest or during exercise;1, 2, 22, 23 left ventricular ejection fraction (LVEF) was reduced only at rest.2, 22, 23 Following IV administration of 300 mcg/kg per minute in patients undergoing cardiac catheterization, hemodynamic effects were similar to those in patients undergoing angiography; however, increases in left ventricular end-diastolic pressure (LVEDP) and pulmonary capillary wedge pressure also were observed.1 In patients with preexisting low ejection fractions, LVEF was further decreased following administration of the drug.2, 25 Following IV administration of esmolol in patients with ischemic heart disease who were about to undergo myocardial revascularization, endotracheal intubation- or laryngoscopy-induced increases in heart rate, systolic blood pressure, and double product were attenuated by esmolol;37, 60, 61, 62, 63, 64, 65, 66, 67, 101 in some patients, pulmonary capillary wedge pressure increased.61, 66
Following IV administration of esmolol in a limited number of patients with elevated ventricular rate (greater than 75 beats per minute) and ischemic heart disease, including those with myocardial infarction, postmyocardial infarction angina, or acute unstable angina, heart rate, systolic blood pressure, cardiac output, cardiac index, and double product were decreased; stroke volume index was increased or decreased; and total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, left ventricular filling pressure, respiratory rate, and PR interval were not affected substantially.24
The decrease in myocardial contractility, arterial pressure, and heart rate produced by esmolol can lead to a reduction in myocardial oxygen consumption, which may account for the effectiveness of the drug in myocardial ischemia.18, 24, 114
Esmolol decreases systolic1, 2, 20, 22, 23, 24, 26, 27, 109 and diastolic26, 27, 109 blood pressure at rest1, 2, 20, 22, 23, 24, 26, 27 and during exercise.1, 2, 22, 23 The precise mechanism of esmolol's hypotensive action has not been determined.18, 19, 24, 27 It has been postulated that β-blockers reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.30, 31, 32 It has been suggested that esmolol may have a direct vasodilating effect independent of its β-adrenergic blocking activity;19, 27 however, the mechanism of this possible direct effect is not known,19, 27 and some clinicians question whether the drug itself has such an effect.126 In some patients, systemic vascular resistance has been unchanged or slightly increased.3, 36
In animals, esmolol has reduced myocardial infarct size2, 5, 13, 20, 21 and has enhanced functional recovery of reperfused ischemic myocardium.2, 5, 21, 102
Antiarrhythmic and Electrophysiologic Effects
Esmolol exhibits antiarrhythmic activity1, 2, 5, 29, 34, 51, 52, 53, 54, 55, 56, 57, 58, 87, 88 and, like other β-blockers, is considered a class II antiarrhythmic agent.33 The antiarrhythmic and electrophysiologic effects of esmolol appear to be mediated principally via the drug's β-blocking activity.2, 5, 34 Esmolol increases sinus cycle length, prolongs sinus node recovery time, and slows conduction in the atrioventricular (AV) node;1, 2, 3, 5, 29, 34 ECG abnormalities manifested as Wenckebach period and prolongation of the AH interval during normal sinus rhythm and atrial pacing may result.1, 2, 3, 5, 29, 34 Esmolol does not appear to substantially affect sinoatrial conduction time, corrected sinus node recovery time, AV node refractoriness, retrograde AV nodal conduction time, or atrial, His-Purkinje, or ventricular conduction.2, 5, 29
Because of its β1-receptor selectivity, usual doses of esmolol generally have little effect on bronchial airway resistance.1, 2, 3, 5, 35 Following IV administration of esmolol hydrochloride doses of 100-300 mcg/kg per minute in a limited number of patients with asthma and/or chronic obstructive pulmonary disease (COPD), the drug did not substantially increase airway resistance.1, 2, 5, 35 However, IV esmolol hydrochloride doses of 300 mcg/kg per minute have increased bronchomotor sensitivity to dry air provocation.1, 2, 5, 35
Following IV administration of usual doses of esmolol, no adverse pulmonary effects were observed in patients with COPD who were treated for arrhythmias51, 52 or were undergoing surgery.1, 2 Esmolol's effect on airway resistance appears to be less than that of nonselective β-blockers (e.g., propranolol).1, 2, 35 Usual doses of esmolol hydrochloride are unlikely to inhibit β-adrenergic agonist-induced bronchodilation appreciably;35, 114, 126 however, in certain patients with asthma, some bronchodilation may be inhibited by the drug.2, 5, 35
Steady-state blood esmolol concentrations are achieved within 10-30 minutes when the drug is infused IV at rates ranging from 50-400 mcg/kg per minute in healthy adults.1, 39, 40, 114 Steady-state blood concentrations can be achieved more rapidly when a loading dose of the drug is injected initially.1, 2, 51, 52, 53, 54, 55, 58, 59, 60, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 Following IV injection of a 500-mcg/kg loading dose and then infusion of maintenance doses ranging from 50-300 mcg/kg per minute, steady-state blood concentrations of the drug are achieved within 5 minutes.1, 2, 27 Steady-state blood esmolol concentrations reportedly increase proportionally with IV infusion rates ranging from 50-400 mcg/kg per minute.1, 2, 39, 40, 113 IV infusion of the drug at 50, 150, or 400 mcg/kg per minute results in steady-state blood concentrations of 0.164, 0.563, or 1.59 mcg/mL, respectively.39, 40 Results from animal studies indicate that blood esmolol concentrations may depend on the site from which the blood specimen is withdrawn, being substantially higher when measured in arterial rather than peripheral venous blood.99
Because esmolol is hydrolyzed rapidly in blood (see Pharmacokinetics: Elimination), 1, 2, 39, 40, 45, 46, 113 blood concentrations decline rapidly following discontinuance of IV infusions of the drug, with only negligible concentrations being present in blood 30 minutes after discontinuance.1, 2, 3, 5, 39, 40, 49 Peak blood concentrations of the de-esterified metabolite (ASL 8123) occur approximately 30 minutes after completion of the infusion and average about 80 mcg/mL following IV infusion of esmolol hydrochloride at 400 mcg/kg per minute.5, 40 Steady-state blood concentrations of ASL 8123 generally are reached within about 15 hours after initiation of esmolol infusion.39, 113
Following rapid IV injection of 180 mg of esmolol hydrochloride in healthy exercising adults, a 13-18% decrease in heart rate, an 11-18% decrease in systolic blood pressure, and a 13-22% prolongation of the PR interval were evident within 1, 2, and 4 minutes, respectively.41 The time required to recover 50, 75, and 90% of the decrement in heart rate was 8, 10, and 13 minutes, respectively.41 Following IV infusion of maintenance esmolol hydrochloride doses of 25-300 mcg/kg per minute in patients with postoperative supraventricular tachyarrhythmias, a 15-20% decrease in heart rate was apparent within 5-22 minutes after initiation of the infusion.59, 68
A correlation between blood esmolol concentrations and pharmacologic effects (e.g., reduction in heart rate) appears to exist.39, 40, 113 In healthy adults, blood esmolol concentrations of 0.3 and 1 mcg/mL were associated with a 50 and 80% reduction in isoproterenol-induced tachycardia, respectively, and a 30 and 50% reduction in isoproterenol-induced increase in blood pressure, respectively.39, 40 Pharmacologic effects also appear to be dose related5, 39, 50, 51, 52, 53, 54, 55, 58, 59, 113, 125 up to doses of at least 200 mcg/kg per minute.1, 2, 39, 50, 51, 52, 53, 54, 55, 58, 59, 113 Following IV infusion of 50, 100, 150, or 200 mcg/kg per minute for about 30 minutes in patients with chronic atrial fibrillation, average decreases in heart rate were approximately 8, 11, 14, or 15%, respectively;5, 50 however, doses exceeding 200 mcg/kg per minute were not associated with additional decreases in heart rate.59 In addition, at doses substantially higher (e.g., 500-750 mcg/kg per minute) than usual, suppression of exercise-induced tachycardia may be reversed, possibly secondary to reflex cardiac stimulation resulting from substantial esmolol-induced hypotension.27 After discontinuance of esmolol infusion, dissipation of β-blockade is apparent within about 1-2 minutes, substantial recovery occurs within approximately 10-20 minutes, and complete reversal of β-blockade occurs within about 20-30 minutes.1, 2, 5, 27, 34, 39, 113 The presence of cardiac pathology, congestive heart failure, or both does not appear to prolong the drug's duration of action.52
Distribution of esmolol hydrochloride into body tissues and fluids has not been fully characterized.1, 2, 28 Following IV administration in rats, esmolol is distributed into liver and kidneys, but only minimally into CSF, spleen, or testes.2, 28
Following IV administration, esmolol is rapidly and widely distributed.2, 39, 99, 113 The apparent volumes of distribution (Vβ) of esmolol and its de-esterified metabolite (ASL 8123) in healthy adults are approximately 3.4 and 0.41 L/kg, respectively, following IV administration.2, 39, 40 In healthy adults, the volumes of distribution of esmolol in the central compartment (Vc) and at steady state (Vss) are approximately 0.87 and 1.2 L/kg, respectively, following IV administration.39 The apparent volume of distribution appears to be decreased in patients undergoing coronary artery bypass surgery99 and increased in patients with renal impairment undergoing peritoneal dialysis2, 43 and in patients with liver cirrhosis.44
In vitro, esmolol is approximately 55% bound to plasma proteins,1, 2, 28, 113 mainly albumin and α1-acid glycoprotein (α1-AGP).28 Protein binding of esmolol to α1-AGP does not appear to be concentration dependent at esmolol concentrations of 3-110 mcg/mL.28 In vitro, ASL 8123 is approximately 10% bound to plasma proteins.1, 2, 113
It is not known whether esmolol and/or ASL 8123 cross the placenta in humans,114, 126 but the drug has been shown to cross the placenta in animals.114, 115 In animals, fetal artery esmolol concentrations were about 10% of maternal concentrations at the completion of infusion.114 It also is not known whether esmolol and/or ASL 8123 are distributed into milk.1
Blood esmolol concentrations appear to decline in a biphasic manner following IV administration of the drug.1, 2, 39, 99, 113 Following IV infusion in adults, the half-life of esmolol averages about 2 minutes in the initial distribution phase (t½α)1, 2, 39, 99 and about 9 minutes (range: 5-23 minutes) in the terminal elimination phase (t½β),1, 2, 39, 40, 99, 114 although considerable interindividual variation in blood elimination half-life exists.5, 39, 99 Because elimination of esmolol (but not its metabolites) occurs principally by nonrenal and nonhepatic means,1, 2, 47, 99, 113 it is not altered appreciably in patients with renal impairment, including those undergoing hemodialysis or peritoneal dialysis,2, 43 nor in patients with hepatic impairment.2, 44
Esmolol is rapidly and extensively metabolized via esterases (probably arylesterase), principally in the cytosol of erythrocytes.1, 2, 39, 40, 45, 46, 99, 113 Metabolism of the drug also may occur in highly perfused tissues that contain esterases (e.g., liver, kidneys).39, 99 Hydrolysis of the methyl ester moiety results in formation of the de-esterified (free acid) metabolite, 4-[2-hydroxy-3-[(1-methylethyl)amino]- propoxy]benzenepropanoic acid (ASL 8123), and methanol.1, 2, 39, 40, 45, 46, 113 Esmolol does not appear to be susceptible to hydrolysis via serum cholinesterase (pseudocholinesterase),1, 2, 28, 45, 113 acetylcholinesterase,1, 2, 28, 45, 113 or carbonic anhydrase.45 It is estimated that about 83% of an esmolol dose is metabolized to ASL 8123.39 ASL 8123 has a low affinity for β-adrenergic receptors,113 exhibiting only minimal (about 1000- to 1500-fold less potent than esmolol) β-blocking activity in animals1, 2, 28, 47, 113 and no appreciable blockade in humans.1, 2, 40 Unlike esmolol, ASL 8123 is eliminated principally by the kidneys, and the elimination half-life of the metabolite may be increased up to tenfold in patients with renal impairment; however, such accumulation is not thought to be clinically important since ASL 8123 has only minimal β-blocking activity.2, 43 The amount of methanol formed during hydrolysis of the drug does not appear to be clinically important.1, 2, 113 Following IV infusion of esmolol hydrochloride doses of 300 mcg/kg per minute for up to 6 hours or 150 mcg/kg per minute for 24 hours, blood methanol concentrations ranged from 2.8-5.9 or 2.9-13.2 mcg/mL, respectively, being less than 2% of those usually associated with methanol toxicity.1, 2, 114
Following IV administration of esmolol hydrochloride, the drug is excreted principally in urine, mainly as ASL 8123.1, 2, 5, 47 Following IV infusion of the drug in healthy adults, about 75-90% of a dose is excreted in urine within 24-48 hours, about 73-88% as ASL 8123 and less than 2% as unchanged drug.1, 2, 5, 39, 47, 113 There is some evidence from animal studies that small amounts of the drug (less than 5% of a dose) may be eliminated in feces following IV administration.28, 114
Following IV administration, total blood clearances of esmolol and ASL 8123 are reported to be approximately 285-333 and 1.28 mL/minute per kg, respectively, in healthy adults with normal renal function;1, 2, 39, 40 renal clearance of the drug is about 1% of total blood clearance.47 Total blood clearance of esmolol was only about 120 mL/minute per kg in patients undergoing coronary artery bypass surgery;99 the reason for reduced blood clearance of the drug in these patients is not known, although hemodynamic changes induced by anesthesia and/or by long-term β-blocker therapy that preceded surgery may have contributed.99 Total blood clearance of esmolol does not appear to be affected by changes in renal or hepatic function, but total blood clearance of ASL 8123 is reduced in patients with renal impairment.114 The apparent renal clearance of ASL 8123 is approximately equivalent to glomerular filtration rate (GFR),1 and the amount of the metabolite excreted in urine decreases with decreasing renal function.1 The fraction of esmolol excreted in urine as unchanged drug and ASL 8123 may be affected by urinary pH and flow rate;47 however, because of the rapid metabolism of esmolol, such alterations are not clinically important.114, 126
Approximately 24 and 21% of an esmolol dose is removed as ASL 8123 by hemodialysis and by peritoneal dialysis, respectively, after a 4-hour infusion of the drug at 150 mcg/kg per minute;114 however, the amount of drug removed during dialysis depends on several factors (e.g., dialysis flow-rate, dwell time).131, 132, 133, 134 Because esmolol is metabolized rapidly in blood, unchanged drug does not appear in the dialysate.114
Esmolol is a short-acting β1-selective adrenergic blocking agent.1, 2, 17, 18, 113 Esmolol is related structurally to atenolol and metoprolol in that the drugs contain substituents in the para position of the benzene ring.10, 113 The presence of large substituents in the para position is believed to account in part for the selective β1-adrenergic blocking effect of these drugs.10, 11, 113 Esmolol differs structurally from metoprolol by the presence of a terminal methyl ester rather than a methoxy group in one of these substituents.2, 3, 10, 11 Because of the presence and position of this ester group, esmolol is rapidly hydrolyzed by blood esterases, resulting in a short duration of action.1, 2, 3, 6, 7, 8, 9, 39, 45, 113
Esmolol hydrochloride occurs as a white or off-white, crystalline powder1, 2, 3 and has solubilities of more than 650 mg/mL in water and of 350 mg/mL in alcohol at room temperature.114 The lipophilicity of esmolol is substantially less than that of labetalol or propranolol but comparable to that of some other currently available β-adrenergic blocking agents (β-blockers) (e.g., acebutolol).2, 3, 12 The apparent pKa of the drug in water is 9.5.2, 3
Esmolol hydrochloride is commercially available as premixed solutions in ready to use bags for IV infusion and as a solution for direct IV injection.600 The premixed injections containing 10 or 20 mg of esmolol hydrochloride per mL are sterile iso-osmotic solutions of the drug in sodium chloride injection and have a pH of 4.5-5.5 and an osmolarity of 312 mOsm/L.1 Esmolol hydrochloride injection containing 10 mg/mL is a sterile iso-osmotic solution of the drug in water for injection; the solution also may contain hydrochloric acid and/or sodium hydroxide to adjust the pH.600 Esmolol hydrochloride injection and premixed injection also contain sodium acetate and glacial acetic acid as a buffer.1
Esmolol hydrochloride injection should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C; the injection should be protected from excessive heart or freezing. 1 The commercially available premixed injections of the drug in sodium chloride injection are provided in plastic containers fabricated from specially formulated multilayer plastic (PL 2408).1 Solutions in contact with the plastic can leach out some of its chemical components in very small amounts; however, safety of the plastic has been confirmed in biologic tests.1
At a concentration of 10 mg/mL, esmolol hydrochloride is chemically and physically stable for at least 24 hours at 15-30°C or when refrigerated in the following IV solutions: 5% dextrose; 5% dextrose and Ringer's or lactated Ringer's; 5% dextrose and 0.45 or 0.9% sodium chloride; lactated Ringer's; or 0.45 or 0.9% sodium chloride; or 5% dextrose and potassium chloride 40 mEq/L.1, 2 Esmolol hydrochloride is physically and chemically compatible with digoxin, dopamine hydrochloride, fentanyl citrate, lidocaine hydrochloride, morphine sulfate, nitroglycerin, or sodium nitroprusside,2 but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).98 Specialized references should be consulted for specific compatibility information.
Esmolol hydrochloride is physically and/or chemically incompatible with diazepam,2 furosemide,2, 119 sodium bicarbonate,1, 2, 3 or thiopental sodium (no longer commercially available in the US),2 and should not be admixed with any of these drugs.1, 2
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use | 10 mg/mL (100 mg)* | ||
Esmolol Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use | 10 mg/mL (2.5 g) in 0.59% Sodium Chloride Injection | Brevibloc® Premixed | Baxter |
20 mg/mL (2 g) in 0.41% Sodium Chloride Injection | Brevibloc® Double Strength Premixed | Baxter |
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