ESMOLOL HCL

Chemistry - A short acting beta1 adrenergic blocker, esmolol occurs as white or off white crystalline powder. It is not as lipophilic as either labetolol or propranolol, but is comparable to acebutolol. 650 mg is soluble in one ml of water and 350 mg is soluble in one ml of alcohol.

Storage, Stability, Compatibility

The concentrate for injection should be stored at room temperature; freezing does not adversely affect the potency of the drug. It is a clear, colorless to light yellow solution. Expiration dates of 3 years are assigned after manufacture.
After diluted to a concentration of 10 mg/ml esmolol HCl is stable (at refrigeration temperatures orroom temperature) for at least 24 hours in commonly used IV solutions. At this concentration it isreportedly compatible with digoxin, dopamine, fentanyl, lidocaine, morphine sulfate, , nitroglycerinand nitroprusside. Compatibility is dependent upon factors such as pH, concentration, temperatureand diluents used. It is suggested to consult specialized references (e.g., Handbook on Injectable
Drugs by Trissel; see bibliography) for more specific information.

Pharmacology - ESMOLOL HCL

Esmolol primarily blocks both beta1 adrenergic receptors in the myocardium. Atclinically used doses, esmolol does not have any intrinsic sympathomimetic activity (ISA) andunlike propranolol, it does not possess membrane-stabilizing effects (quinidine-like) norbronchoconstrictive effects. Cardiovascular effects secondary to esmolol include: negative inotropicand chronotropic activity which can lead to reduced myocardial oxygen demand. Systolic anddiastolic blood pressures are reduced at rest and during exercise. Esmolol's antiarrhythmic effect isthought to be due to its blockade of adrenergic stimulation of cardiac pacemaker potentials. Esmololincreases sinus cycle length, slows AV node conduction and prolongs sinus node recovery time.

Uses, Indications

Esmolol may be used as test drug to indicate whether beta blocker therapy iswarranted as an antiarrhythmic agent or as an infusion in the short term treatment of supraventricular tachyarrhythmias (e.g., atrial fibrillation/flutter, sinus tachycardia).

Pharmacokinetics - ESMOLOL HCL

Esmolol is administered via the IV route. After injection it is rapidly andwidely distributed, but not appreciably to the CNS, spleen or testes. The distribution half life isabout 2 minutes. Steady-state blood levels occur in about 5 minutes if a loading dose was given orabout 30 minutes if no load was given. It is unknown whether the drug crosses the placenta orenters milk. Esmolol is rapidly metabolized in the blood by esterases. Renal or hepatic dysfunctiondo not appreciably alter elimination characteristics. Terminal half life is about 10 minutes andduration of action after discontinuing IV infusion is about 10-20 minutes.

Contraindications, Precautions, Reproductive Safety

Esmolol is contraindicated in patients with overt cardiac failure, 2nd or 3rd degree AV block, sinus bradycardia, or in cardiogenic shock. It should be used with caution (weigh benefit vs. risk ) in patients with CHF, bronchoconstrictive lung disease or with diabetes mellitus.
Studies done in rats and rabbits demonstrated no teratogenic effects at doses up to 3 times themaximum human maintenance dose (MHMD). Higher doses (8 times or more MHMD) demonstrated some maternal death and fetal resorption.

Adverse Effects, Warnings

At usual doses adverse effects are uncommon and generally an extension of the drug's pharmacologic effects. Hypotension (with resultant symptoms) and bradycardia are the most likely adverse effects seen. These are generally mild and transient in nature. Esmolol may mask certain symptoms of developing hypoglycemia (such as increased heart rate or blood pressure).

Overdosage, Acute Toxicity

The IV LD50 in dogs is approximately 32 mg/kg. Dogs receiving 2mg/kg per minute for one hour showed no adverse effects; doses of 3 mg/kg/minute for one hourproduced ataxia and salivation and 4 mg/kg/minute for one hour caused muscular rigidity, tremors, seizures, ptosis, vomiting, hyperpnea, vocalizations and prostration. These effects all resolved within90 minutes of the end of infusion. Because of the short duration of action of the drug, discontinuation or dosage reduction may be all that is required. Otherwise symptomatic andsupportive treatment may be initiated.

Drug Interactions

As esmolol may increase serum digoxin levels up to 20%, it should be usedwith caution in digitalized patients with increased monitoring when necessary. Titrate esmololdosage carefully in patients also receiving morphine. Morphine may increase steady-state esmololserum concentrations up to 50%. Succinylcholine's neuromuscular blockade effects may beprolonged when esmolol is used, but this effect is probably not relevant clinically. If esmolol isused with sympathomimetic amines or xanthines (e.g., theophylline, aminophylline) mutualinhibition of effects may occur. Concurrent use of monoamine oxidase inhibitors (including furazolidone) with esmolol is not recommended due to potentially hypertension occurring.