ISOPROTERENOL HCL
  • ISOPROTERENOL HCL

  • (Generic for ISUPREL)
  • QTY 1 • 0.2 MG/ML • AMPUL • Near 77381

ISOPROTERENOL HCL Pediatric Monographs
  • 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 a solution that is pinkish to brownish in color or contains a precipitate.
    Intravenous Administration
    Continuous IV infusion
    -Dilute isoproterenol in normal saline or D5W, considering the patient's fluid requirements or fluid limitations.
    -Final concentration range 10-20 mcg/ml.
    -Administer diluted infusion initially at the lowest recommended rate. Adjust rate based on patient's heart rate, systemic blood pressure, central venous pressure, and urine flow.

    Nervousness, diaphoresis, pallor, flushing, weakness, dizziness, mild tremor, blurred vision, and headache can occur during therapy with intravenous isoproterenol. Insomnia, headache, tremor, vertigo, and central excitation have been reported with other isoproterenol dosage forms.

    As an extension of its beta-adrenergic agonist effects (including sinus tachycardia, positive inotropic effects, hypotension, palpitations), isoproterenol can cause cardiac arrhythmias (or arrhythmia exacerbation). Increased cardiac workload can exacerbate angina. Ventricular arrhythmias (i.e., ventricular tachycardia, ventricular fibrillation) can occur. Proarrhythmias are most likely to occur in patients with predisposing factors such as electrolyte imbalances (e.g., hypomagnesemia, hypokalemia, or hyperkalemia) or taking other drugs sensitizing the heart to arrhythmias (e.g., other antiarrhythmic agents, sympathomimetics). Hypertension as well as pulmonary edema have been observed. Adam-Stokes attacks have rarely been reported during normal sinus rhythm or transient heart block; it is presumed that these reactions occur in patients with organic disease of the AV node and its branches. Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05-2.7 mcg/kg/min have caused clinical deterioration, myocardial infarction (necrosis), congestive heart failure, and death. The risks of cardiac toxicity appear to be increased by some factors (acidosis, hypoxemia, coadministration of corticosteroids, coadministration of methylxanthines such as theophylline, theobromine, or aminophylline) that are especially likely to be present in these patients. If intravenous isoproterenol is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB. In addition to the cardiac effects seen with the intravenous use of isoproterenol, cardiac arrest also has been reported with the inhaled use of isoproterenol.

    Dyspnea has been reported with intravenous isoproterenol. Rebound bronchospasm can occur with the use of isoproterenol. If this occurs, immediately discontinue therapy and initiate alternative therapy.

    Nausea has been reported with the inhaled and intravenous use of isoproterenol.

    Prolonged use of beta-agonists can lead to tolerance to their effects. If this occurs with isoproterenol, the dosage should not be increased in an effort to regain effectiveness. Alternative therapy should be instituted.

    Exercise caution with isoproterenol use in patients with known sympathomimetic hypersensitivity because they are at risk of developing subsequent allergic reactions including anaphylaxis.

    Isoproterenol is contraindicated in cardiac arrhythmias associated with tachycardia (atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation) because the drug has cardiac-stimulant effects and can exacerbate tachyarrhythmias. Isoproterenol is also contraindicated in patients with tachycardia or digitalis toxicity-induced AV block because of the drug's cardiac-stimulant effects, which pose an increased risk of exacerbating the digitalis-induced arrhythmia.

    Isoproterenol stimulates insulin production, increases glycogenolysis in the liver, and can complicate the management of diabetes mellitus.

    Isoproterenol should be administered with extreme caution to patients with severe and/or uncontrolled hypertension. Dose-related increases in hypertension may occur from sympathomimetic activity.

    Because thyroid disease patients with hyperthyroidism can be more sensitive to sympathomimetics, caution must be used when administering isoproterenol to this patient population to avoid thyrotoxic effects.

    Isoproterenol is contraindicated in patients with angina and should be used with care in patients with severe coronary artery disease (cardiac disease) so as to maintain the appropriate balance of myocardial oxygen supply and demand.

    Patients with pheochromocytoma should receive isoproterenol or any adrenergic agent with extreme caution, if at all, given the risk for hypertensive crisis or emergency associated with their condition.

    Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05-2.7 ug/kg/min have caused clinical deterioration, myocardial necrosis, congestive heart failure and death. The risks of cardiac toxicity appear to be increased by some factors including acidosis (respiratory acidosis or metabolic acidosis), hypoxemia, concomitant corticosteroid therapy, or the coadministration of methylxanthines (e.g., aminophylline or theophylline) that are especially likely to be present in these patients. If intravenous isoproterenol is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB.

    Description: Isoproterenol is a potent bronchodilator and parenteral inotrope. It is a synthetic sympathomimetic amine structurally similar to epinephrine, with potent beta-agonist properties. In pediatric patients, the drug is mainly used for the treatment of bradyarrhythmias and conditions associated with AV block, as well as during head-up tilt testing for syncope diagnosis. As an inotrope for the treatment of shock, isoproterenol has largely been replaced by dobutamine, a beta1-specific agonist. Isoproterenol is also used infrequently as a bronchodilator due to the FDA approval of longer-acting and beta2-specific agents such as albuterol and salmeterol. Although not FDA approved, isoproterenol is used off-label for bradyarrhythmias and AV block 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 hemodynamically-significant bradycardia*, conditions associated with AV block*, or for the treatment of Adams-Stokes syndrome*:
    Intravenous dosage:
    Neonates, Infants, Children, and Adolescents: 0.05 to 2 mcg/kg/minute continuous IV infusion. Initiate at the minimum dose and increase every 5 to 10 minutes by 0.1 mcg/kg/minute to desired effect. Maximum dose is 2 mcg/kg/minute. Tachycardia is the major limit to infusion rate. An initial dose of 0.03 mcg/kg/minute then titrated to heart rate was used as initial management of AV block in patients after closure of perimembranous ventricular septal defects; both patients in this small case report also received steroids and required a pacemaker.

    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, targeting a heart rate of 150 bpm; 1 to 3 mcg/minute IV infusion for 20 minutes has also been used. In both protocols, patients were supine for several minutes and then tilted to a head-up position at 85 degrees or 70 degrees for 20 minutes. If patients did not experience symptoms, they continued in the tilted position for another 20 minutes and received isoproterenol. The test was considered positive if patients experienced syncope, presyncope, a drop in systolic blood pressure (more than 40 mm Hg in 1 study and more than 25 mm Hg in another ), or a change in heart rate (more than 30 beats/minute decrease in 1 study or decrease to less than 50 bpm in another) during isoproterenol therapy. Isoproterenol was found to be more sensitive for diagnosis than nitroglycerin with less vasovagal symptoms.

    Maximum Dosage Limits:
    -Neonates
    2 mcg/kg/min continuous IV infusion.
    -Infants
    2 mcg/kg/min continuous IV infusion.
    -Children
    2 mcg/kg/min continuous IV infusion.
    -Adolescents
    2 mcg/kg/min 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. The latter two 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 distributed throughout the body. The pharmacologic activity of isoproterenol is rapidly terminated by uptake and metabolism in the synaptic cleft. Circulating drug is metabolized by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase in the liver and other tissues. These inactive metabolites are then conjugated to either sulfates or glucuronides and are renally excreted. Minimal amounts of the drug are excreted unchanged in the urine.

    Affected cytochrome P450 isoenzymes: none


    -Route-Specific Pharmacokinetics
    Intravenous Route
    The onset of action after IV administration of isoproterenol is immediate. The average plasma half-life is 4 minutes with IV administration.


    -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. Dosing rates ranged from 0.01-5.5 mcg/kg/min. Blood samples were drawn at steady state after the start of a dosing rate and at various times following discontinuation to a maximum of 20 minutes. The normalized steady state concentration (to a rate of 0.05 mcg/kg/min) for all patients was 1.9 +/- 0.3 ng/ml, and volume of distribution was 216 +/- 57 mg/kg. The average plasma half-life was 4.2 +/- 1.5 minutes. The average clearance rate was 42.5 +/- 5 mg/kg/min; postoperative cardiac patients had a lower clearance rate compared to airway disease patients (33.2 +/- 4.9 mg/kg/min vs. 48.4 +/- 7.3 mg/kg/min). The lower clearance rate may be due to diminished cardiac function and perfusion to the liver and kidneys, or nonlinear pharmacokinetics.

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