Beta-adrenergic Receptor Blocking Agent
Action And Clinical Pharmacology: Esmolol is a beta-adrenergic receptor blocking agent with predominant blocking effect on beta-1 receptors. It does not possess significant intrinsic sympathomimetic or membrane stabilizing activity. Esmolol, which is administered only i.v., has a rapid onset and a short duration of action.
Pharmacodynamics: In human electrophysiology studies, esmolol produced effects typical of a beta-blocker: a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.
Studies in normal volunteers have confirmed the beta-blocking activity of esmolol, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol have been shown to correlate with extent of beta-blockade.
Bolus injections of 50 and 100 mg esmolol, given intraoperatively during general anesthesia, decreased heart rate by more than 20% within 2 minutes. Systolic blood pressure fell by 17% within 5 minutes. The effects lasted for up to 10 minutes.
When given 1.5 to 2 minutes before intubation, 100 and 200 mg bolus injections of esmolol attenuated the heart rate and blood pressure response to endotracheal intubation. No effects were detectable 5 minutes after the administration of esmolol.
The hemodynamics were studied during continuous i.v. infusions in patients with elevated heart rate and acute ischemic heart disease (e.g., unstable angina pectoris or acute myocardial infarction). Titrated infusions of esmolol, from 0.05 to 0.3 mg/kg/min, lowered heart rate and blood pressure. There were small increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure, but were not considered to be clinically significant. Cardiac index, however, decreased. Cardiac index returned to pretreatment levels within 30 minutes after discontinuation of the infusion.
The relative cardioselectivity of esmolol was demonstrated in mildly asthmatic patients. Esmolol infusions (0.1, 0.2 and 0.3 mg/kg/min) produced no significant increases in specific airway resistance when compared to placebo. At 0.3 mg/kg/min, esmolol produced slightly enhanced bronchomotor sensitivity to dry-air stimulus but was not considered clinically significant.
Pharmacokinetics: Following bolus injections of esmolol to healthy volunteers, the distribution and elimination half-lives averaged 1.4 and 10.9 minutes respectively. The blood concentrations of esmolol were below quantifiable limits within 10 minutes.
Following a loading infusion of 0.5 mg/kg/min over 1 minute, esmolol infusions of 0.05 to 0.3 mg/kg/min reach steady-state blood levels within 5 minutes with corresponding blood levels from 1.56 Â´ 104to 9.93 Â´ 104mg/mL. Steady state blood levels increase linearly with dose over the dose range of 0.05 to 0.3 mg/kg/min. If a loading dose is not used, approximately 30 minutes are required to reach steady-state blood levels. Fifty-five percent of the amount in blood is bound to plasma proteins while the acid metabolite is only 10% bound. After cessation of the infusion, the blood levels of esmolol decrease rapidly with an elimination half-life of 9 minutes.
The total body clearance of esmolol is about 20 L/hr/kg. Since this is greater than cardiac output, the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver. The central and total volume of distribution were found to be 1.9 L/kg and 3.3 L/kg, respectively.
Esterases in the red blood cell cytosol hydrolyse the ester link of esmolol resulting in the formation of the corresponding free acid and methanol. This acid metabolite, which shows approximately 1/1 500th the beta-blocking activity of esmolol in animal studies, has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with elimination half-life increased to about 10-fold that of patients with normal renal function, and plasma level was considerably elevated.
After several hours of infusion, at rates up to 0.3 mg/kg/min, methanol blood levels approximated endogenous levels (
Less than 2% of esmolol is excreted unchanged in urine. After 24 hours, approximately 73 to 88% of the dose is recovered in the urine as the acid metabolite.
The pharmacokinetics of esmolol and of its major metabolite are unaltered in patients with hepatic cirrhosis. In patients with end-stage renal disease, on hemo- or peritoneal dialysis, the pharmacokinetics of esmolol were unchanged except for an increase in the volume of distribution in patients on peritoneal dialysis. The elimination half-life of the acid metabolite is increased about 10 times in patients with renal disease.
Indications And Clinical Uses: In the perioperative management of tachycardia and hypertension in patients in whom there is a concern for compromised myocardial oxygen balance and who, in the judgment of the physician, are clearly at risk of developing hemodynamically-induced myocardial ischemia.
Esmolol is also indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in acute situations when the use of a short-acting agent is desirable.
Esmolol is not indicated for use in chronic settings.
Contra-Indications: In patients who require inotropic agents and/or vasopressors to maintain systemic blood pressure and cardiac output.
Esmolol is also contraindicated in patients with hypotension, sinus bradycardia, second and third degree AV block, right ventricular failure secondary to pulmonary hypertension, overt cardiac failure or cardiogenic shock (see Warnings).
Manufacturers’ Warnings In Clinical States: During the administration of esmolol patients should be carefully monitored, with particular attention to heart rate and blood pressure.
Hypotension: The administration of esmolol has been associated with excessive hypotension. The hypotensive effect of esmolol is dose related and may increase in the presence of both narcotic analgesics and inhalational anesthetics. In patients with low pretreatment blood pressure or with a propensity to develop hypotension (e.g., hypovolemic patients) esmolol should be used with special caution and only when in the physician’s judgment, the potential benefits outweigh the risk. In the event of hypotension, the dosage of esmolol should be reduced or the drug should be discontinued.
Sinus Bradycardia: Severe bradycardia and cardiac arrest may occur with the use of esmolol. Therefore, in patients with low pretreatment heart rates esmolol should be used with special caution and only when in the physician’s judgment, the potential benefits outweigh the risk. In the event of bradycardia, the dosage of esmolol should be reduced or the drug should be discontinued.
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in patients with congestive heart failure. Inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility. Therefore, special caution should be exercised when administering esmolol to patients with a history of heart failure. Beta-blockers act selectively without abolishing the inotropic action of digitalis on the heart muscle. The effects of beta-blockers and digitalis are additive in depressing AV nodal conduction. Even in patients with no history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, the dosage of esmolol should be reduced or the drug should be withdrawn. Because of the short elimination half-life of esmolol, these measures may be sufficient but specific treatment may also be considered.
Abrupt Cessation of Therapy: Abrupt cessation of esmolol in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta-blockers following chronic use in coronary artery disease patients. However, caution should be used in discontinuing esmolol infusions abruptly in these patients.
Concurrent use of Esmolol with Verapamil: The use of i.v. verapamil with a beta-blocker may cause severe depression of ventricular function. Accordingly, patients with atrial fibrillation or atrial flutter who have received verapamil should only be administered esmolol if the benefits outweigh the risk.
Bronchospastic Diseases: Patients with bronchospastic diseases should not, in general, receive beta-blockers. Because of its relative beta-1 selectivity and titratability, esmolol may be used with caution in patients with bronchospastic diseases. Since beta-1 selectivity is not absolute, esmolol should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately and a beta-2 stimulating agent may be administered if conditions warrant.
Precautions: Renal Impairment: The pharmacokinetics of esmolol are unchanged in kidney-impaired patients except that the volume of distribution is increased. However the acid metabolite of esmolol is primarily excreted unchanged by the kidney, thus esmolol should be administered with caution to patients with impaired renal function. The elimination half-life of the acid metabolite was prolonged tenfold and the plasma level was considerably elevated in patients with end-stage renal disease.
Diabetes Mellitus/Hypoglycemia: Esmolol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia.
Venous Irritation: Prolonged infusion concentrations of 20 mg/mL have been associated with significant venous irritation in humans and thrombophlebitis in animals. Therefore, concentrations greater than 10 mg/mL should be avoided.
Pregnancy: There are no studies in pregnant women. Esmolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether esmolol is excreted in human milk. Caution, however, should be exercised when esmolol is administered to a nursing mother.
Children: The safety and effectiveness of esmolol in children have not been established.
Drug Interactions: Catecholamine-depleting drugs, (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated concurrently with esmolol and a catecholamine depletor should, therefore, be closely observed for evidence of hypotension or marked bradycardia.
When digoxin and esmolol were concomitantly administered i.v. to normal volunteers, a 10 to 20% increase in digoxin blood level was observed at some time points. Digoxin did not affect esmolol pharmacokinetics.
When the interaction of i.v. morphine and esmolol was studied in normal subjects, no effect on morphine blood level was seen. However the steady-state blood levels of esmolol were increased by 46% in the presence of morphine, but no other pharmacokinetic parameters were changed.
The effect of esmolol on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery. The onset of neuromuscular blockade by succinylcholine was unaffected by esmolol, but the duration of neuromuscular blockade was prolonged from 5 to 8 minutes.
A study of interaction between esmolol and warfarin showed that concomitant administration of esmolol and warfarin does not alter warfarin plasma levels. Esmolol concentrations were equivocally higher when given with warfarin, but this is not likely to be clinically important.
For interaction with verapamil see Warnings.
Adverse Reactions: During Management of Perioperative Tachycardia and Associated Hypertension: In clinical trials 763 patients were treated with esmolol in operative settings.
Esmolol as a bolus of 100 mg and 200 mg was given in a total of 367 patients during clinical studies. Hypotension was reported in 16% among esmolol treated patients compared to 8% in the placebo group (187 patients). Bradycardia occurred in 4% of patients, in both the esmolol and placebo groups.
Other adverse effects with a frequency of less than 1% occurred as frequently in the esmolol as it did with the placebo group. They were: bronchospasm, pain at injection and wheezing.
When esmolol was infused in 396 patients, hypotension was the most commonly observed side effect in 5% of patients. The other reported adverse effect was bradycardia (heart rate less than 50 beats/minute), observed in 1% of patients. Other adverse effects occurring with a less than 1% incidence were the following: ST segment depression, ECG changes, myocardial ischemia, junctional rhythm, hypertension, atrial fibrillation, bronchospasm, agitation, nausea, vomiting, urticaria and itching.
None of these side effects were judged to be severe, and all resolved after the discontinuation of esmolol.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with esmolol can produce bradycardia, congestive heart failure, hypotension, bronchospasm, electromechanical dissociation, drowsiness, loss of consciousness, hypoglycemia and cardiac arrest.
Cases of massive accidental overdoses of esmolol have occurred due to dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 to 3 500 mg (12.5 to 70 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1 750 mg given over 1 minute or doses of 7 500 mg given over 1 hour for cardiovascular surgery. The patients who survived appear to be those whose cardiovascular circulation could be supported until the effects of esmolol were resolved.
The first step in the management of toxicity should be to discontinue the esmolol infusion. Then, because of its approximately 9-minute elimination half-life and based on the observed clinical effects, the following measures should also be considered.
1. General: Esmolol is a competitive antagonist of isoproterenol and hence larger doses of isoproterenol may be needed to reverse many of the effects of excessive dosage of esmolol. However, the complications of excessive isoproterenol should not be overlooked.
2. Bradycardia: atropine or another anticholinergic drug.
3. Heart Block (second or third degree): isoproterenol or transvenous cardiac pacemaker.
4. Congestive Heart Failure: conventional therapy such as diuretic and/or digitalis glycoside. In shock due to inadequate cardiac contractility: dopamine, dobutamine, isoproterenol.
5. Hypotension (depending on associated factors): Epinephrine, rather than isoproterenol, or norepinephrine may be useful in addition to atropine and digitalis.
6. Bronchospasm: aminophylline or isoproterenol or other beta-2 agonists.
7. Hypoglycemia: i.v. glucose.
Dosage And Administration: Esmolol 2 500 mg/10 mL ampuls are not for direct i.v. injection. These are concentrated solutions of a potent drug which must be diluted prior to its infusion. Esmolol should not be admixed with sodium bicarbonate. Esmolol should not be mixed with other drugs prior to dilution (see Reconstituted Solutions).
Infusions should be used within 24 hours of preparation due to the possibility of microbial contamination.
Management of Perioperative Tachycardia and Hypertension: Intubation: 10 mg/mL (100 mg/10 mL vial) should be administered by a bolus injection (over 30 seconds). For the management of postintubation tachycardia and hypertension, give 1.5 mg/kg (up to a maximum of 100 mg) as a bolus injection (over 30 seconds) 1 to 2 minutes before intubation.
For Intra- and Postoperative Tachycardia and Hypertension: For intraoperative and postoperative treatment of tachycardia and/or hypertension give 1.5 mg/kg as a bolus injection (over 30 seconds) followed by 0.15 mg/kg/min infusion. Adjust infusion rate as required up to 0.3 mg/kg/min to maintain desired heart rate and/or blood pressure.
Management of Atrial Fibrillation and Atrial Flutter: Responses to esmolol usually (over 95%) occur within the range of 0.05 to 0.2 mg/kg/min. The average effective dosage is approximately 0.1 mg/kg/min (7 mg/70 kg/min) although dosages as low as 0.025 mg/kg/min have been sufficient in some patients. Dosages as high as 0.3 mg/kg/min have been used but provided little added effect with an increased rate of adverse effects, and are not recommended. Dosage must be individualized by titration in which each step consists of a loading dose followed by a maintenance infusion.
To initiate treatment, administer a loading dose infusion of 0.5 mg/kg/min of esmolol for 1 minute followed by a 4-minute maintenance infusion of 0.05 mg/kg/min. If the therapeutic response is inadequate at this point, repeat the same loading dose and increase the maintenance infusion to 0.1 mg/kg/min.
Continue the titration procedure as above, repeating the loading dose (0.5 mg/kg/min for 1 minute), and increasing the maintenance infusion by increments of 0.05 mg/kg/min (for 4 minutes). As the desired heart rate or a safety end point (e.g., lowered blood pressure) is approached, omit the loading dose and reduce the incremental dose of the maintenance infusion from 0.05 mg/kg/min to 0.025 mg/kg/min or lower. Also if desired, increase the interval between titration steps from 5 to 10 minutes.
Maintenance dosages above 0.2 mg/kg/min have not been shown to have significantly increased benefits. The effectiveness of dosages above 0.3 mg/kg/min has not been studied.
If a safety end point is exceeded, discontinue the infusion of esmolol and re-start at a lower dose. In the event of an adverse reaction, the dosage infusion of esmolol should be discontinued. If a reaction occurs at the site of the local infusion, an alternate infusion site should be used. Avoid the use of butterfly needles. The use of esmolol infusions up to 24 hours has been well documented.
Stability and Storage: Infusions should be used within 24 hours of preparation due to the possibility of microbial contamination.
Direct I.V. Injection: Esmolol 10 mg/mL (100 mg/10 mL vial) does not require dilution.
Reconstituted Solutions: Esmolol 250 mg/mL (2 500 mg/10 mL ampul) is not for direct i.v. injection. This is a concentrated solution of a potent drug which must be diluted prior to its infusion.
Continuous I.V. Infusion: Esmolol should be infused at concentrations of no greater than 10 mg/mL (see Precautions). To prepare solutions of 10 mg/mL, reconstitute each esmolol ampul (10 mL) in 240 mL of a suitable i.v. fluid.
Esmolol was tested for compatibility with 9 commonly used i.v. fluids at a final concentration of 10 mg/mL esmolol. It was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature (15 to 25°C) or under refrigeration: Dextrose (5%) Injection, USP; Dextrose (5%) in Ringer’s Injection; Dextrose (5%) in lactated Ringer’s Injection; Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP; Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP; Lactated Ringer’s Injection, USP; Sodium Chloride (0.45%) Injection, USP; Sodium Chloride (0.9%) Injection, USP; Potassium Chloride (40 mEq/L) in Dextrose (5%), USP.
Esmolol injection is not compatible with sodium bicarbonate (5%).
Availability And Storage: Ampuls: Each mL of solution for continuous i.v. infusion contains: esmolol HCl 250 mg. Nonmedicinal ingredients: alcohol, glacial acetic acid, hydrochloric acid or sodium hydroxide for pH adjustment, propylene glycol, sodium acetate and water for injection. Glass ampuls of 10 mL. Boxes of 10. This solution is not for direct i.v. injection. It is a concentrated solution of a potent drug which must be diluted prior to its infusion.
Vials: Each mL of solution for direct i.v. injection contains: esmolol HCl 10 mg. Nonmedicinal ingredients: glacial acetic acid, hydrochloric acid or sodium hydroxide for pH adjustment, sodium acetate and water for injection. Amber glass vials of 10 mL. Boxes of 20.
Store at controlled room temperature (15 to 25°C).
BREVIBLOC® Zeneca Esmolol HCl Beta-adrenergic Receptor Blocking Agent