Esmolol
Esmolol is a rapid-onset and short-acting selective beta-1 receptor antagonist. These characteristics may make esmolol a useful drug for preventing or treating adverse blood pressure and heart rate increases that occur intraoperatively in response to noxious stimulation, as during intubation of the trachea Menkhaus et al, 1985. Administered as a continuous infusion (200 mg kg -1 min -1 IV) beginning 5 minutes before induction of anesthesia, esmolol prevents increases in heart rate associated with noxious stimulation in patients undergoing coronary artery-bypass graft operations Girard et al. 1986. Alternatively, a bolus of esmolol, 80 mg IV, followed by a continuous infusion (12 mg min -1 IV) lowers heart rate and blood pressure in adult patients undergoing noncardiac surgery Gold et al, 1989. Other reports describe prevention of perioperative tachycardia and hypertension with esmolol, 100 to 200 mg IV, administered over 15 seconds before the induction of anesthesia 1990,Sheppard et al, 1990. Prior administration of esmolol, 500 mg kg -1 min -1 IV, to patients undergoing electroconvulsive therapy with anesthesia induced by methohexital and succinyl-choline results in attenuation of the heart rate increase and a decrease in the length of the electrically induced Seizures Howie et al, 1990. Esmolol has been used during resection of pheochromocytoma and may be useful in the perioperative management of thyrotoxicosis, pregnancy-induced hypertension (toxemia of pregnancy), and epinephrine- or cocaine-induced cardiovascular toxicity Nicholas et al, 1988,Ostman et al, 1988,Pollan and Tadjziechy, 1989,Thorne and Bedford, 1989,Zakowski et al, 1989. The beta-1 selectivity of esmolol may unmask beta-2-stimulated vasodilation by epinephrine-secreting tumors. Administration of esmolol to patients chronically treated with beta-antagonists has not been observed to produce additional negative inotropic effects deBruijn et al, 1987. The presumed reason for this observation is that esmolol, in the dose employed, does not occupy sufficient additional beta-receptors to produce detectable increases in beta-blockade.


Classification:
Autonomic Agents
Sympatholytics
Beta-blockers

Cardiovascular Agents
Antianginals
Beta-blockers

Cardiovascular Agents
Antiarrhythmics
Class II antiarrhythmics

Cardiovascular Agents
Antihypertensive Agents
Beta-blockers

Description: Esmolol is an extremely short-acting beta1-selective beta-blocker. However, unlike other beta1-selective beta-blockers (e.g., metoprolol, atenolol), esmolol is administered via continuous IV infusion. Because of the extremely short duration of action of esmolol, it is useful for acute control of hypertension or certain supraventricular arrhythmias. Esmolol was approved by the FDA in 1986 for the acute, temporary control of ventricular rate in certain supraventricular arrhythmias such as sinus tachycardia and atrial flutter and/or fibrillation in the perioperative, postoperative, or emergency setting. Nonapproved indications include short-term control of perioperative hypertension, management of tachyarrhythmias complicating acute MI, and minimization of acute myocardial ischemia secondary to acute MI or unstable angina.

Mechanism of Action: Beta-adrenergic antagonists counter the effect of sympathomimetic neurotransmitters (e.g., catecholamines) by competing for receptor sites. Similar to metoprolol and atenolol, esmolol, in low doses, selectively blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. Esmolol possesses roughly 100 times more activity on beta1-receptors than on beta2-receptors. Consequently, the pharmacologic effects of esmolol are primarily limited to the myocardium. As with all 'selective' adrenergic agonists, higher doses of esmolol (>300 mcg/kg/min) result in attenuated or lost selectivity for the beta1-receptors. At doses typically used clinically, esmolol does not demonstrate appreciable intrinsic sympathomimetic or membrane-stabilizing activity; however, these effects may be seen at higher doses.

The antiarrhythmic properties of esmolol occur at the nodal level of pacemaker control, increasing sinus cycle length and sinus node recovery time and slowing conduction through the AV node. The pharmacodynamic consequence of this activity is a negative chronotropic effect and, occasionally, conversion to sinus rhythm in the case of atrial fibrillation and/or flutter.

Actions that make esmolol useful in treating hypertension include its negative chronotropic and inotropic activity (which also decreases cardiac output), a reduction in sympathetic outflow from the CNS, and suppression of renin release from the kidneys. The pharmacodynamic consequence of this activity is reduction of both systolic and diastolic blood pressure. Thus, like other beta-blockers, esmolol affects blood pressure via multiple mechanisms. Esmolol is effective in treating angina and post-MI ischemia because the drug decreases the oxygen demand of the heart through its negative chronotropic and inotropic effects as well as its antihypertensive activity.

Pharmacokinetics: Esmolol is administered via IV infusion. Onset of action after IV injection is extremely rapid, with steady-state concentrations achieved within 5 minutes after a loading dose is given. Steady-state esmolol concentrations are proportional to the infusion rate. Following discontinuation, esmolol effects begin to decline in 1—2 minutes, with beta-antagonist activity completely reversed within approximately 20 minutes.

Esmolol is rapidly and widely distributed (apparent volume of distribution is 3.4 L/kg), although the specific body tissues and fluids into which esmolol distributes have not been determined. Esmolol is 55% protein-bound, primarily to albumin and alpha-1-acid glycoprotein.

Esmolol is rapidly hydrolyzed in the blood by plasma esterases to the free acid of the methyl ester of esmolol and methanol. The terminal half-life of esmolol averages 9 minutes, so esmolol-induced beta-blockade is virtually eliminated within 20 minutes after drug discontinuation. This property offers a distinct clinical advantage over IV propranolol, which persists for up to 60 minutes after discontinuation. Within 24—48 hours, the majority of an esmolol dose is excreted renally, primarily as inactive metabolites, with less than 2% as unchanged drug. The remainder of a dose may be excreted via the fecal route.