Pharmacology: Pharmacodynamics: Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of Esmolol HCl, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of Esmolol HCl have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes.
In human electrophysilogy studies, Esmolol HCl 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.
In patients undergoing radionuclide angiography, Esmolol HCl, at dosages of 200 micrograms/kg/min (0.2 milligrams/kg/min), produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 milligrams). During exercise, Esmolol HCl produced reductions in heart rate, rate pressure product and cardiac index which were also similar to the produced by propranolol but produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catherterization, the maximum therapeutic dose of 300 micrograms/kg/min (0.3 milligrams/kg/min) of Esmolol HCl produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At thirty minutes after the discontinuation of Esmolol HCl infusion, all of the hemodynamic parameters had returned to pretreatment levels.
The relative cardioselectivity of Esmolol HCl was demonstrated in 10 mildly asthmatic patients. Infusions of Esmolol HCl [100, 200 and 300 micrograms/kg/min (0.1, 0.2 and 0.3 milligrams/kg/min)] produced no significant increases in specific airway resistance compared to placebo. At 300 micrograms/kg/min (0.3 milligrams/kg/min), Esmolol HCl produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and Esmolol HCl was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 milligrams, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of Esmolol HCl for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).
Supraventricular Tachycardia: In two multicenter, randomized, double-blind, controlled comparisons of Esmolol HCl with placebo and propranolol, maintenance doses of 50 to 300 micrograms/kg/min (0.05 to 0.3 milligrams/kg/min) of Esmolol HCl were found to be more effective than placebo and about as effective as propranolol, 3-6 milligrams given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with Esmolol HCl had a desired therapeutic effect (either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely conversion to NSR) and about 95% of those who responded did so at a dosage of 200 micrograms/kg/min (0.2 milligrams/kg/min) or less. The average effective dosage of Esmolol was approximately 100-115 micrograms/kg/min (0.1-0.115 milligrams/kg/min) in the two studies. Other multicenter baseline-controlled studies gave essentially similar results. In the comparison with propranolol, about 50% of patients in both the Esmolol HCl and propranolol groups were on concomitant digoxin. Response rates were slightly higher with beta blockers in the digoxin-treated patients.
In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressures less than 50 mmHg. The hypotension was symptomatic (mainly diaphoresis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. In comparison to propranolol, hypotension was about three times as frequent with Esmolol HCl, 53% vs 17%. The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with Esmolol HCl. For both Esmolol HCl and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.
Pharmacokinetics: Esmolol HCl 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 acetylcholinesterases. 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 HCl 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 HCl 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 HCl 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 HCl for dosages from 50-300 micrograms/kg/min (0.05-0.3 milligrams/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 HCl 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 HCl 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 HCl, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, approximately 73-88% of the dosage has been accounted for in the urine as the acid metabolite of Esmolol HCl.
Metabolism of Esmolol HCl 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 HCl for up to 6 hours at 300 micrograms/kg/min (0.3 milligrams/kg/min) and 24 hours at 150 micrograms/kg/min (0.15 milligrams/kg/min), approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.
Esmolol HCl has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.