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.
