Esmolol hydrochloride is a beta1-selective (cardioselective) adrenergic receptor blocking agent with a very short duration of action (elimination half-life is approximately 9 minutes). The chemical name for esmolol hydrochloride is (±)-Methyl p-[2-hydroxy-3-(isopropylamino)propoxy]hydrocinnamate hydrochloride and it has the following structure:
structure
Esmolol hydrochloride has the molecular formula
C16H26NO4CI and a molecular weight of 331.8. It has one asymmetric
center and exists as an enantiomeric pair.Esmolol Hydrochloride is a
white to off-white crystalline powder. It is a relatively hydrophilic
compound which is very soluble in water and freely soluble in alcohol.
Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to
17.0 for propranolol.Esmolol HCl Injection is a clear, colorless to
light yellow, sterile, nonpyrogenic solution.Esmolol powder
100 mg, 10 mL Single Dose Vial - Each mL contains 10 mg Esmolol Hydrochloride and Water for Injection; buffered with 2.8 mg Sodium Acetate Trihydrate and 0.546 mg Glacial Acetic Acid. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary, to adjust pH to 4.5 to 5.5.
3CLINICAL PHARMACOLOGY
Esmolol hydrochloride is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. Esmolol inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.
3.1Pharmacokinetics and Metabolism
Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylchoIinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes.
Using an appropriate loading dose, steady-state blood levels of esmolol for dosages from 50 to 300 mcg/kg/min (0.05 to 0.3 mg/kg/min) are obtained within five minutes. (Steady-state is reached in about 30 minutes without the loading dose.) Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.
Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, approximately 73% to 88% of the dosage has been accounted for in the urine as the acid metabolite of esmolol.
Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have about 1/1500th the activity of esmolol and in normal volunteers its blood levels do not correspond to the level of beta blockade. 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.
Methanol blood levels, monitored in subjects receiving esmolol for up to 6 hours at 300 mcg/kg/min (0.3 mg/kg/min) and 24 hours at 150 mcg/kg/min (0.15 mg/kg/min), approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.Esmolol has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.
