ISOPROTERENOL HCL (Generic for ISUPREL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is pinkish or darker than slightly yellow or contains a precipitate.
Intravenous Administration
Continuous IV Infusion
-Dilute isoproterenol in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to yield a final concentration of 2 to 64 mcg/mL.
-Infuse at the lowest recommended dose and titrate gradually, if necessary, based on the patient's systemic blood pressure, heart rate, central venous pressure, urine flow, and blood gases.

Nervousness, headache, dizziness, nausea, and blurred vision have been reported with isoproterenol use.

Isoproterenol is a direct cardiac stimulant and may cause arrhythmia or arrhythmia exacerbation. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation) and tend to increase cardiac work and oxygen requirements. Sinus tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, and tachyarrhythmias have been reported with isoproterenol use. In a few patients, presumably with organic disease of the AV node and its branches, isoproterenol has been reported to paradoxically worsen heart block or precipitate Adams-Stokes attacks during normal sinus rhythm or transient heart block. Clinical deterioration, myocardial necrosis, congestive heart failure, and death have occurred in refractory asthmatic children receiving isoproterenol. The risks of cardiac toxicity appear to be increased by some factors (e.g., respiratory acidosis, metabolic acidosis, hypoxemia, coadministration of methylxanthines or corticosteroid therapy) likely to be present in such patients. If intravenous isoproterenol is used in children with refractory asthma, monitor vital signs continually, electrocardiography frequently, and cardiac enzymes, including CPK-MB, daily.

Dyspnea has been reported with isoproterenol use.

Flushing, diaphoresis, mild tremor, weakness, and pallor have been reported with isoproterenol use.

Isoproterenol relaxes almost all varieties of smooth muscle when the tone is high, but this action is most pronounced on bronchial and gastrointestinal smooth muscle. It prevents or relieves bronchoconstriction, but tolerance to this effect develops with overuse of the drug.

Isoproterenol can cause glycogenolysis and insulin resistance, which may complicate the management of diabetes mellitus. Isoproterenol causes less hyperglycemia than does epinephrine.

Isoproterenol is contraindicated in patients with tachyarrhythmias (e.g., atrial fibrillation, atrial flutter, sinus tachycardia, ventricular tachycardia, ventricular fibrillation), including ventricular tachyarrhythmias requiring inotropic therapy, and digitalis toxicity-induced AV block or tachycardia. Isoproterenol is a direct cardiac stimulant and may induce or worsen arrhythmias. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias. In a few patients, presumably with organic disease of the AV node and its branches, isoproterenol has been reported to paradoxically worsen heart block or precipitate Adams-Stokes attacks during normal sinus rhythm or transient heart block.

Isoproterenol is contraindicated in patients with angina pectoris. By increasing myocardial oxygen requirements while decreasing coronary perfusion, isoproterenol may have a deleterious effect on the injured or failing heart. Doses sufficient to increase the heart rate to more than 130 beats per minute tend to increase cardiac work and oxygen requirements, adversely affecting patients with heart failure or a heart with a significant degree of arteriosclerosis. Most experts discourage its use as the initial agent in treating cardiogenic shock after myocardial infarction; however, isoproterenol may produce beneficial hemodynamic and metabolic effects when a low arterial pressure has been elevated by other means.

Use isoproterenol with caution in patients with diabetes mellitus. Isoproterenol can cause glycogenolysis and insulin resistance, which may complicate the management of diabetes mellitus.

Use isoproterenol with caution in patients with hyperthyroidism, as it may induce thyroid storm.

If intravenous isoproterenol is used in children with refractory asthma, monitor vital signs continually, electrocardiography frequently, and cardiac enzymes, including CPK-MB, daily. Clinical deterioration, myocardial necrosis, congestive heart failure, and death have occurred in refractory asthmatic children receiving isoproterenol. The risks of cardiac toxicity appear to be increased by some factors (e.g., respiratory acidosis, metabolic acidosis, hypoxemia, coadministration of methylxanthines or corticosteroid therapy) likely to be present in such patients.

Isoproterenol may contain sodium metabisulfite, which may cause mild to severe allergic reactions, including anaphylaxis or asthmatic episodes, particularly in persons with a history of allergies. The presence of metabisulfite in isoproterenol does not preclude use for treatment in emergency situations, even if persons are sulfite-sensitive or have a sulfite hypersensitivity. Alternatives to isoproterenol in a life-threatening situation may not be effective.

Description: Isoproterenol is a parenteral nonselective beta-adrenergic agonist with a very low affinity for alpha-receptors. It is a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors. In pediatric patients, it is mainly used for the treatment of bradyarrhythmias and conditions associated with AV block. As an inotrope for the treatment of shock, isoproterenol has largely been replaced by dobutamine, a beta1-specific agonist. Although not FDA-approved, isoproterenol is used in pediatric patients as young as neonates.

General dosing information:
-The pediatric advanced cardiac life support guidelines do not recommend isoproterenol in pediatric patients during cardiac arrest.
-Isoproterenol is no longer recommended as an inotropic agent during the treatment of pediatric or neonatal shock.
-The National Asthma Education and Prevention Program Expert Panel recommends against the use of IV isoproterenol in the treatment of asthma, including status asthmaticus, due its potential for myocardial toxicity.

For the treatment of severe bradycardia* or AV block*:
Intravenous dosage:
Neonates: 0.03 to 0.1 mcg/kg/minute continuous IV infusion initially. Titrate every 5 minutes until goal heart rate is attained. Max: 2 mcg/kg/minute.

Infants, Children, and Adolescents: 0.03 to 0.1 mcg/kg/minute continuous IV infusion initially. Titrate every 5 minutes until goal heart rate is attained. Max: 2 mcg/kg/minute.

For use during head-up tilt testing for neurocardiogenic syncope diagnosis*:
Intravenous dosage:
Children and Adolescents: 0.02 to 0.08 mcg/kg/dose IV in escalating doses every 2 minutes for 20 minutes or less until target heart rate of 150 beats per minute is attained.
Continuous Intravenous Infusion dosage:
Children and Adolescents: 1 to 3 mcg/minute continuous IV infusion for 20 minutes.

Maximum Dosage Limits:
-Neonates
2 mcg/kg/minute continuous IV infusion.
-Infants
2 mcg/kg/minute continuous IV infusion.
-Children
2 mcg/kg/minute continuous IV infusion.
-Adolescents
2 mcg/kg/minute continuous IV infusion.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Isoproterenol is a potent agonist of both beta1- and beta2-adrenergic receptors, with minimal to no effects on alpha-adrenergic receptors at therapeutic doses. Isoproterenol stimulates beta-receptors throughout the body except for the sweat glands and facial arteries. Intracellularly, the actions of isoproterenol are mediated by cyclic adenosine monophosphate (cAMP), the production of which is augmented by beta stimulation. Consequently, isoproterenol stimulates myocardial performance primarily via stimulation of beta1-receptors on the myocardium and conducting system of the heart. The stimulation of these receptors results in increased inotropic and chronotropic effects. Systolic blood pressure is usually elevated due to increased inotropy, although diastolic blood pressure is decreased secondary to isoproterenol-induced vasodilation. As a result, pulse pressure is increased. Isoproterenol indirectly causes coronary artery vasodilation. Despite the increase in myocardial oxygen supply that can occur secondary to coronary vasodilation, the positive inotropic and chronotropic effects on the heart result in increased oxygen consumption, particularly relative to cardiac work, increased myocardial excitability, and automaticity. These latter cardiac effects of isoproterenol markedly increase the potential for developing dysrhythmias.

The major therapeutic effects of systemic isoproterenol include bronchial smooth muscle relaxation, cardiac stimulation, vasodilation in skeletal or GI muscle, and stimulation of glycogenolysis in the liver and other calorigenic mechanisms such as the release of free fatty acids. Isoproterenol also induces the release of insulin, which offsets the hyperglycemia that follows glycogenolysis. This activity is somewhat unique among other adrenergic compounds, particularly epinephrine. Isoproterenol's effects on smooth muscle are varied and determined by relative receptor density and hormonal effects. Isoproterenol exerts its relaxant effect on bronchial smooth muscle primarily via stimulation of beta2-receptors. Beta2 stimulation also prevents mast cell secretion of histamine and other autocoids, thus antagonizing its effect on end organs and reversing bronchoconstriction and edema.

Pharmacokinetics: Isoproterenol is administered intravenously. Isoproterenol is rapidly metabolized in the liver and other tissues by catechol-O-methyltransferase (COMT) to the 3-O-methyl isoproterenol metabolite, which is subsequently conjugated with sulfate. It is a relatively poor substrate for monoamine oxidase (MAO). Excretion occurs via the urine. Half-life is 2.5 to 5 minutes.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
The onset of action of isoproterenol is immediate.


-Special Populations
Pediatrics
Infants and Children
The pharmacokinetics of isoproterenol were described in a study of infants and children (n = 19) with reactive airway disease or postoperative cardiac dysrhythmias who received the drug intravenously. Vd was 216 +/- 57 mg/kg. The steady-state plasma concentration (normalized to a rate of 0.05 mcg/kg/minute) was 1.9 +/- 0.3 ng/mL. The average plasma half-life was 4.2 +/- 1.5 minutes. The average clearance rate was 42.5 +/- 5 mg/kg/minute; postoperative cardiac patients had a lower clearance rate compared to airway disease patients (33.2 +/- 4.9 mg/kg/minute vs. 48.4 +/- 7.3 mg/kg/minute). This lower clearance rate may be due to diminished cardiac function and perfusion to the liver and kidneys or nonlinear pharmacokinetics.