Esmolol

Esmolol is a cardio-selective beta-blocking agent belonging to the beta-blocker class.

Esmolol is approved for the treatment of rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short-term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention.

Esmolol is rapidly absorbed. The steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/min) are obtained within five minutes.Esmolol undergoes rapid hydrolysis of the ester linkage, which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinesterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol.

Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals and plasma levels considerably elevated.

The common side effects associated with Esmolol include symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension.

Esmolol is available in the form of dosage forms such as infusion bags and injectable solutions.

Esmolol is available in China, India, Germany, and Russia.

Esmolol, belonging to the beta blocker, acts as a cardio-selective beta-adrenergic blocker.

Esmolol works by blocking the adrenergic activity of epinephrine and norepinephrine, it decreases inotropic contractility, heart rate, and conduction. Esmolol increases atrioventricular refractory time, reduces the oxygen demand of the myocardium, and reduces atrioventricular conduction. Esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to the blockade of adrenergic stimulation of the cardiac pacemaker potentials.

The onset of action of Esmolol occurs within 60 seconds. It maintains a steady state within 5 minutes of initiation of infusion. If a loading dose is administered, a steady-state can be achieved by the 2-minute mark.

The Duration of Action for esmolol is extremely low, about 10 to 30 minutes. The Tmax was found within 20 minutes and Cmax in blood reached 150 ng/ml.

Esmolol is available in the form of infusion bags and injectable solutions.

For Infusion bags: Administer 1 mg/kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg/kg/min if necessary.

Adjust the infusion rate as required to maintain desired heart rate and blood pressure.

For injection solution: a bolus injection of 80 mg is given over 15 to 30 seconds, followed by a 150 micrograms/kg/min infusion.

Esmolol is approved in the treatment of the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short-term control of ventricular rate with a short-acting agent is desirable.

Esmolol is a highly selective β1 receptor blocker with a short half-life, which can be pumped drip. It has the advantages of rapid onset, good tolerance, and easy regulation, which is the most commonly used preparation in critical care medicine.

Esmolol is approved for use in the following clinical indications:

• Supraventricular Tachycardia.

Esmolol is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short-term control of ventricular rate with a short-acting agent is desirable. Esmolol is also indicated in noncompensatory sinus tachycardia where, in the physician's judgment, the rapid heart rate requires specific intervention. Esmolol is not intended for its use in chronic settings where transfer to another agent is anticipated.

• Intraoperative and Postoperative Tachycardia and/or Hypertension

Esmolol is indicated for the treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia, and in the postoperative period, when in the physician's judgment such specific intervention is considered indicated.

Although not approved, there have been certain off-label uses documented for Esmolol. These includes:

• Esmolol has also been reported to be a safe and effective drug for perioperative control of blood pressure, owing to its short half-life.
• It is also indicated in sinus tachycardia, where a rapid rate requires emergent intervention, especially in acute coronary syndrome.
• Esmolol is also recommended for the treatment of tachyarrhythmia in critically ill patients and hypertension induced by intubation.

There have been certain off-labeled uses for esmolol and these include: use in aortic dissection, acute coronary syndrome, non-ST elevation myocardial infarction, hypertensive emergencies, thyrotoxicosis, refractory ventricular tachycardia, refractory to defibrillation ventricular fibrillation.

• It is also used to decrease catecholamine response during electroconvulsive therapy.
• The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Esmolol is available in various dosage strengths:

• For Infusion bags: 2g/100mL, 2.5g/250mL
• For Injection solution: 10mg/mL, 20mg/mL

Esmolol is available in the form of infusion bags and injection solutions.

Esmolol should be used in the treatment of rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short-term control of ventricular rate with a short-acting agent is desirable. Also used in the noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention along with appropriate dietary restrictions:

• Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Supraventricular tachycardia: Alcohol, coffee and its derivative, Chocolates, and Stimulants.

• Migraine: Some commonly triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and 0kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.

• Atrial Fibrillation: Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk They can also lead to other negative health outcomes like weight gain, and diabetes, cognitive decline, and certain cancers.

The dietary restriction should be individualized as per patient requirements.

Esmolol may be contraindicated in the following:

• Esmolol is contraindicated in patients with sinus bradycardia, sick sinus syndrome, atrioventricular heart block, heart failure, cardiogenic shock, pulmonary hypertension, and a history of hypersensitivity reactions to esmolol. In addition, Esmolol and calcium channel blockers should not be given together, as this may exacerbate hypotension and bradycardia.
• Patients with first-degree heart block and nodal dysfunctions are at an increased risk of progressive heart block, bradycardia, and AV dissociation. Patients with preexisting heart failure are at greater risk of decompensated heart failure and cardiogenic shock.
• Patients with airway disease, such as asthma and chronic obstructive pulmonary disease, should be cautious when using any beta-blocker, such as Esmolol. Even though the effects of beta-2 is minimal, some risk may exist.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Hypotension

In clinical trials, 20-50% of patients treated with Esmolol experienced hypotension, generally defined as a systolic pressure less than 90 mmHg and/or diastolic pressure less than 50 mmHg. About 12% of the patients have been symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose but is dose-related, so doses beyond 200 mcg/kg/min (0.2 mg/kg/min) are not recommended. Patients should be closely monitored, especially if pretreatment blood pressure is low. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.

• Cardiac Failure

Sympathetic stimulation is necessary for supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Continued depression of the myocardium with the beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, Esmolol should be withdrawn. Although the withdrawal may be sufficient because of the short elimination half-life of Esmolol, specific treatment may also be considered. The use of Esmolol for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. Despite the rapid onset and offset of the effects of Esmolol, several cases of death have been reported in complex clinical states where Esmolol was presumably being used to control ventricular rate.

• Intraoperative and Postoperative Tachycardia and/or Hypertension

Esmolol should not be used as the treatment for hypertension in patients in whom the increased blood pressure is primarily due to the vasoconstriction associated with hypothermia.

• Bronchospastic Diseases:

Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta1 selectivity and titratability, Esmolol may be used with caution in patients with bronchospastic diseases. However, since beta1 selectivity is not absolute, Esmolol should be carefully titrated to obtain the lowest possible effective dose. In event of bronchospasm, the infusion should be terminated immediately; a beta2 stimulating agent may be administered if the conditions warrant but should be used with particular caution as patients already have rapid ventricular rates.

• Diabetes Mellitus and Hypoglycemia

Esmolol should be used with caution in diabetic patients requiring a beta-blocking agent. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

• PRECAUTIONS

General

Because the acid metabolite of Esmolol is primarily excreted unchanged by the kidney, Esmolol should be administered with caution to patients having impaired renal function. The elimination half-life of acid metabolite was prolonged ten-fold, and the plasma level was considerably elevated in patients with end-stage renal disease.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers blood pressure.

Esmolol use in breastfeeding patients is not recommended.

Teratogenicity studies in rats at intravenous dosages of Esmolol up to 3000 mcg/kg/min (3 mg/kg/min) (ten times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity, or teratogenicity, while a dosage of 10,000 mcg/kg/min (10 mg/kg/min) produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min (1 mg/kg/min) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity, or teratogenicity, while 2500 mcg/kg/min (2.5 mg/kg/min) produced minimal maternal toxicity and increased fetal resorptions. Although there are no adequate and well-controlled studies on pregnant women, the use of esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Esmolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are some specific food warnings mentioned below for esmolol:

• Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium, when taken along with esmolol, can be led to an increase in blood potassium levels.

• Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to Esmolol can be categorized as follows:

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, infusion site reaction such as blistering /necrosis/ thrombophlebitis.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

• Post Marketing Experience:

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

The clinically relevant drug interactions of Esmolol are briefly summarized here:

• Catecholamine-depleting drugs, e.g., reserpine, may have an additive effect when given with beta-blocking agents. Patients treated concurrently with esmolol (Esmolol Hydrochloride) and a catecholamine depletion should therefore be closely observed for evidence of hypotension or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.
  

• A study of the 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.
  

• When digoxin esmolol was concomitantly administered intravenously to normal volunteers, there was a 10-20% increase in digoxin blood levels at some time points. Digoxin did not affect esmolol pharmacokinetics. When intravenous morphine and esmolol were concomitantly administered in normal subjects, no effect on morphine blood levels was seen, but esmolol steady-state blood levels were increased by 46% in the presence of morphine. 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 also unaffected by esmolol, but the duration of neuromuscular blockade was prolonged from 5 to 8 minutes.
  

• Although the interactions observed in these studies do not appear to be of major clinical importance esmolol should be titrated with caution in patients being treated concurrently with digoxin, morphine, succinylcholine, or warfarin.
  

• While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

• Caution should be exercised when considering the use of esmolol and verapamil in patients with depressed myocardial function. Fatal cardiac arrests have occurred in 11 patients receiving both drugs. Additionally, Esmolol should not be used to control supraventricular tachycardia in the presence of agents which are vasoconstrictive and inotropic such as dopamine, epinephrine, and norepinephrine because of the danger of blocking cardiac contractility when systemic vascular resistance is high.
  

• Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use:

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

An overdose of esmolol can result in a myriad of symptoms and effects. Cardiac signs of toxicity include but are not limited to bradycardia, AV block of any degree, complete AV dissociation, decrease contractility, cardiogenic shock, asystole, and pulseless electrical activity. Neurologic signs of toxicity include but are not limited to respiratory irregularities, seizures, coma, and psychiatric symptomatology. Other symptoms of toxicity may include bronchospasms, gastrointestinal mesenteric ischemia, and peripheral cyanosis.

Since esmolol has a very short half-life (9 minutes), toxicity should be treated by discontinuing the esmolol infusion. Acute toxicity is often self-limited and is treated supportively. Toxicity that results in bradycardia should be treated by atropine, pacing, and other anticholinergic agents. Cardiogenic shock can be treated with inotropic agents like dobutamine, dopamine, and isoproterenol. Bronchospasms, even though rare, should be treated with a beta-2 agonist, such as albuterol

Pharmacodynamics:

Clinical pharmacology studies in normal volunteers have confirmed the beta-blocking activity of esmolol hydrochloride showing a reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride have been shown to correlate with the extent of betablockade. After termination of the infusion, substantial recovery from beta-blockade is observed within 10 to 20 minutes. The acid metabolite of the esmolol exhibits negligible pharmacological activity.

In human electrophysiology studies, esmolol hydrochloride produced effects typical of a beta-blocker; a decrease in heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the Atrial His Bundle interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.

Pharmacokinetics:

• Absorption:

Esmolol is rapidly absorbed, the onset of action is within 60 seconds, and it maintains a steady state within 5 minutes of initiation of infusion. If a loading dose is administered, a steady-state can be achieved by the 2-minute mark. The drug has a 9-minute half-life and rapid renal clearance.

• Metabolism:

Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinesterase or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol.

• Elimination:

Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite 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 the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated.

The rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours.

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