Isoproterenol hydrochloride is a synthetic sympathomimetic agent that acts directly on both β1- and β2-adrenergic receptors (nonselective β-agonist).
Cardiac Arrhythmias and Cardiac Arrest
Parenteral isoproterenol hydrochloride is used in the treatment of heart block and Adams-Stokes attacks (except when caused by ventricular tachycardia or fibrillation), generally as a temporary or emergency measure until more definitive therapy (e.g., cardiac pacemaker) can be employed.140, 170 Parenteral isoproterenol also has been used for the treatment of ventricular arrhythmias secondary to atrioventricular (AV) nodal block and carotid sinus hypersensitivity. However, evidence supporting the benefit of isoproterenol in patients with cardiac arrhythmias generally is lacking, and safer and more effective alternatives such as cardiac pacing and other drug therapies are available.170 Isoproterenol must not be administered to patients with tachyarrhythmias, tachycardia or heart block caused by cardiac glycoside intoxication, ventricular arrhythmias that require inotropic therapy, or angina.140
Parenteral isoproterenol also has been used for its positive inotropic and/or chronotropic effects in the treatment of cardiac arrest until defibrillation or emergency pacemaker therapy could be employed. However, most experts currently state that parenteral isoproterenol is not a drug of choice for advanced cardiovascular life support (ACLS) and should only be considered in this setting for treatment of symptomatic bradycardia that is unresponsive to atropine therapy, or as a temporary measure until pacemaker therapy can be instituted;133, 170, 401 these experts state that isoproterenol should not be used for resuscitation in patients with cardiac arrest or hypotension because of potential deleterious effects (e.g., exacerbation of ischemia, arrhythmias, peripheral vasodilation). If used for the treatment of symptomatic bradycardia during ACLS, isoproterenol should only be administered in low doses since higher doses may increase myocardial oxygen consumption and the potential for ventricular arrhythmias.140, 401 Some experts state that isoproterenol must not be administered to patients with acetylcholinesterase-induced bradycardias, however, the drug may be beneficial at high doses in refractory bradycardia caused by β-adrenergic blocking agents.136
Parenteral isoproterenol is used as adjunctive therapy to produce cardiac stimulation and vasodilation in the treatment of shock. By increasing cardiac output, isoproterenol may increase arterial blood pressure in spite of the peripheral vasodilation it produces; however, central venous pressure may be decreased. Individual hemodynamic abnormalities must be identified and monitored so that therapy can be adjusted as necessary.
The value of isoproterenol therapy in shock has been questioned because the drug increases oxygen demand in the myocardium and other tissues to levels that may not be met by increased blood flow. Although isoproterenol may produce beneficial hemodynamic and metabolic effects when used as an adjunct to fluid, electrolytes, and other drugs in patients with various shock states,140 vasopressors such as norepinephrine and epinephrine generally are considered the drugs of choice for effective hemodynamic management of such patients.153 The effectiveness of isoproterenol in reducing mortality in refractory shock has not been convincingly demonstrated. Furthermore, isoproterenol generally is not recommended in the treatment of cardiogenic shock because increases in myocardial oxygen consumption and the work of the heart usually outweigh the beneficial effects of the drug, and risk of arrhythmias is increased when the drug is administered to such patients. Isoproterenol also should not be used in patients with drug-induced distributive shock, a condition associated with normal or high cardiac output and low systemic vascular resistance, since the drug may worsen hypotension by further decreasing systemic vascular resistance.136
Isoproterenol may be useful in bronchospasm occurring during anesthesia but must be administered with extreme caution, if at all, in patients receiving cyclopropane or halogenated hydrocarbon general anesthetics. (See Drug Interactions: General Anesthetics.) Isoproterenol also has been used as a bronchodilator in the symptomatic treatment of bronchial asthma and reversible bronchospasm that may occur in association with chronic bronchitis, pulmonary emphysema, bronchiectasis, and other chronic obstructive pulmonary diseases; however, oral, sublingual, and oral inhalation preparations of the drug no longer are commercially available in the US. For information on the stepped-care approach for drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12.
Isoproterenol has been used by IV infusion to reverse decreases in cardiac output and circulating pulmonary blood volume and to reverse increases in pulmonary arterial pressure and pulmonary vascular resistance occurring during pulmonary embolism†.
Diagnosis of Coronary Artery Disease
Isoproterenol has been used as an aid in the diagnosis of coronary artery disease†. Following IV infusion in patients with substantial coronary artery obstruction, the drug produces a greater increase in cardiac output than in mean coronary blood flow and decreases total peripheral resistance more than coronary artery resistance (when calculated as % change from control values). In patients without significant coronary artery obstruction, the increase in mean coronary artery blood flow exceeds the increase in cardiac output, and coronary artery resistance is decreased more than total peripheral resistance. Isoproterenol also may aid in the diagnosis of coronary artery disease by increasing myocardial oxygen consumption and intensifying symptoms of ischemia. In one study, the drug was administered by IV infusion while the electrocardiogram was monitored until ST segment depression occurred, the patient developed chest pain, or heart rate reached 130 beats per minute. Evidence of ischemia obtained with isoproterenol was compared with that obtained in the same patients by the treadmill test; confirmation of coronary artery disease was achieved by coronary arteriography. The presence or absence of coronary artery disease was correctly predicted in 71% of the patients with isoproterenol and in 68% by the treadmill test.
Isoproterenol hydrochloride usually is administered by direct (“bolus”) IV injection or IV infusion.140 In extreme emergencies, the drug may be administered by intracardiac injection in adults.140 In less urgent situations in adults, initial administration by IM or subcutaneous injection is preferred.140
For IM, subcutaneous, or intracardiac injection, commercially available isoproterenol hydrochloride injection is administered undiluted.140
Isoproterenol hydrochloride injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.140 The injection should be discarded if the solution is pinkish or darker than slightly yellow or contains a precipitate.140
Isoproterenol hydrochloride injection should be diluted prior to IV administration.140 For direct IV injection in the treatment of heart block, Adams-Stokes attacks, or cardiac arrest, the manufacturer recommends that IV solutions be prepared by diluting 1 mL of the commercially available injection containing isoproterenol hydrochloride 0.2 mg/mL with 9 mL of 0.9% sodium chloride injection or 5% dextrose injection.140 If administered as an IV infusion for heart block, Adams-Stokes attacks, or cardiac arrest, solutions may be prepared by diluting 10 mL of the injection containing isoproterenol hydrochloride 0.2 mg/mL with 500 mL of 5% dextrose injection.140 For the treatment of shock, the manufacturer recommends that the IV solution for infusion be prepared by diluting 5 mL of the commercially available injection containing isoproterenol hydrochloride 0.2 mg/mL with 500 mL of 5% dextrose injection.140 When the drug is administered by IV infusion, especially as an adjunct in the treatment of shock, the rate of infusion should be adjusted on the basis of the patient's heart rate, central venous pressure, systemic blood pressure, and urine flow. If the heart rate exceeds 110 beats/minute or if premature heart beats or changes in ECG develop, consideration should be given to slowing the rate of infusion or temporarily discontinuing the infusion.
Standardized concentrations for isoproterenol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249, 250Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249, 250 For additional information on S4S (including updates that may be available), see[Web].249, 250
Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
Adults | 4 mcg/mL | mcg/min or mcg/kg/mina |
Pediatric patients (<50 kg) | 20 mcg/mL | mcg/kg/min |
64 mcg/mL |
aThe S4S panel recommends trying to standardize dosing units but understands that some protocols may use “flat” dosing while others may require weight-based dosing.
Isoproterenol should be initiated at the lowest recommended dose and increased gradually, if necessary, while carefully monitoring the patient.140
Cardiac Arrhythmias and Cardiac Arrest
Dosage and method of administration of isoproterenol hydrochloride should be selected and adjusted according to patient response and the specific clinical situation.140 For emergency treatment, isoproterenol usually is administered by direct IV injection or IV infusion. The commercially available injection should be diluted prior to IV administration.140 (See Dosage and Administration: Administration.) If the drug is administered by direct IV injection for the treatment of heart block, Adams-Stokes attacks, or cardiac arrest in adults, the manufacturer states that the usual initial dose is 0.02-0.06 mg (1-3 mL of the diluted solution), with subsequent doses ranging from 0.01-0.2 mg (0.5-10 mL of the diluted solution).140 If the drug is administered by IV infusion, the initial rate of administration is 5 mcg/minute (1.25 mL of the diluted solution per minute) in adults;140 subsequent dosage is adjusted according to patient response and generally ranges from 2-20 mcg/minute. In less urgent situations, adults may receive an initial IM or subcutaneous dose of 0.2 mg (1 mL of the commercially available 0.2-mg/mL injection without dilution), with subsequent IM doses ranging from 0.02-1 mg (0.1-5 mL of the commercially available 0.2-mg/mL injection without dilution) and subsequent subcutaneous doses ranging from 0.15-0.2 mg (0.75-1 mL of the commercially available 0.2-mg/mL injection without dilution).140 Although the manufacturer makes dosage recommendations for the treatment of cardiac arrest,140 most experts state that isoproterenol should not be used for cardiopulmonary resuscitation. (See Uses: Cardiac Arrhythmias and Cardiac Arrest.)
If used for the treatment of symptomatic bradycardia during advanced cardiovascular life support (ACLS) in adults, the recommended dosage of isoproterenol hydrochloride is 2-10 mcg/minute; the infusion rate should be adjusted according to heart rate and rhythm response.401 Higher dosages may be associated with increased myocardial oxygen consumption, increased infarct size, and malignant ventricular arrhythmias.133
No well-controlled studies have been conducted in pediatric patients to inform dosing; however, the American Heart Association (AHA) recommends an initial IV infusion rate of 0.1 mcg/kg per minute in children†, with usual dosage generally ranging from 0.1-1 mcg/kg per minute.140
For the management of complete heart block following closure of ventricular septal defects, isoproterenol has been administered to infants in IV doses of 0.01-0.03 mg and to adults in IV doses of 0.04-0.06 mg. With such doses, acceleration of heart rate often persists for 15-20 minutes. Sinus rhythm sometimes occurs and persists for a variable time but often relapses again into complete block. In other patients, such doses merely maintain a heart rate greater than 90-100 beats/minute.
As adjunctive therapy in the treatment of shock, isoproterenol hydrochloride may be administered by IV infusion or direct IV injection.140 The commercially available injection should be diluted prior to IV administration.140 (See Dosage and Administration: Administration.) IV infusion rates of 0.5-5 mcg (0.25-2.5 mL of the diluted solution) per minute are recommended by the manufacturer; the rate of infusion should be adjusted according to patient response (i.e., heart rate, central venous pressure, systemic blood pressure, and urine output).140 In advanced stages of shock, rates exceeding 30 mcg/minute have been used.140 If isoproterenol hydrochloride is administered by direct IV injection for the treatment of shock, an initial dose of 0.01-0.02 mg (0.5-1 mL of the diluted solution) is recommended by the manufacturer; the dose may be repeated if necessary.140
For control of bronchospasm occurring during anesthesia, 0.01-0.02 mg of isoproterenol hydrochloride has been administered IV to adults and repeated when necessary.
Isoproterenol hydrochloride has been administered by IV infusion at a rate of 4 mcg/minute as an aid in diagnosing the etiology of mitral regurgitation† or at a rate of 1-3 mcg/minute in the diagnosis of coronary artery disease or lesions†.
Serious adverse reactions to isoproterenol occur infrequently. Most adverse effects subside rapidly when isoproterenol is discontinued or may abate while the drug is still in use.
Isoproterenol may cause nervousness, restlessness, insomnia, anxiety, tension, blurring of vision, fear, or excitement. Rarely, sweating, weakness, pallor, dizziness, mild tremor, headache, flushing of the face or skin, nausea, vomiting, tinnitus, lightheadedness, or asthenia may occur. Swelling of the parotid glands has been reported with prolonged use; if this occurs the drug should be discontinued. The drug has produced pulmonary edema in a patient intolerant to other sympathomimetic drugs; dyspnea also has been reported.
Disturbances of cardiac rhythm and rate produced by isoproterenol may result in palpitation and ventricular tachycardia. Isoproterenol can cause potentially fatal ventricular arrhythmias in doses sufficient to increase heart rate above 130 beats/minute. Arrhythmias are most likely to occur in patients with cardiogenic shock; in those receiving other drugs that sensitize the heart to arrhythmias including cardiac glycosides, cyclopropane, or halogenated hydrocarbon general anesthetics; or in those with acidosis, hypoxia, hypercapnia, hypokalemia, or hyperkalemia. Risk factors for cardiotoxicity (e.g., ventricular tachyarrhythmias frequently culminating in ventricular fibrillation, sudden death, and myocardial necrosis) with isoproterenol infusions for the treatment of severe asthma include the presence of hypercapnia (PCO 2 greater than 50 mm Hg), acidosis (pH below 7.3) and/or concomitant use of other agents such as theophylline derivatives (e.g., aminophylline in particular) or corticosteroids that may potentiate the cardiotoxic effects of isoproterenol.132 (See Drug Interactions: Xanthine Derivatives.) Paradoxically, isoproterenol has been reported to precipitate Adams-Stokes seizures in some patients with normal sinus rhythm or transient AV block. It was suggested that these patients may have had organic disease of the AV node or its branches.
If the heart rate increases sharply, precordial ache or angina and/or ECG evidence of coronary insufficiency may result from increased myocardial oxygen demand. This may be most likely to occur in patients with cardiogenic shock or ischemic heart disease including acute myocardial infarction, coronary arteriosclerosis, or preexisting angina pectoris. Evidence of transient myocardial ischemia (i.e., ECG changes and serum elevation of the cardiac isoenzyme MB of serum creatine kinase [CK, creatine phosphokinase, CPK]) or myocardial dysfunction (i.e., abnormal ECG findings) has been reported with the use of isoproterenol IV infusion for the treatment of severe asthma exacerbation in children.132 Occasionally, the drug has caused a shock-like state in patients with angina pectoris. In patients with acute myocardial infarction, the drug may increase the extent of ischemic injury to the myocardium. After IV infusion, isoproterenol also may cause focal necrosis of myocardial cells. In experimental animals, the drug has caused cardiac enlargement.
Excessive doses of isoproterenol may produce a slight increase in blood pressure followed by a substantial decrease. Profound hypotension is especially likely to occur if the inotropic effect of the drug is decreased as a result of severe depression of the myocardium. In some patients, shock-like symptoms may develop. Therapy consists of general supportive measures.
Precautions and Contraindications
Administration of isoproterenol to patients who are in shock is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Blood volume depletion must be corrected as fully as possible before isoproterenol is administered. Additional volume replacement also may be required during administration of the drug; fluid administration must be adequate to compensate for isoproterenol-induced vasodilation or shock may be worsened. Monitoring of central venous pressure or left ventricular filling pressure is required for detecting and treating hypovolemia. In addition, monitoring of central venous pressure or pulmonary arterial diastolic pressure is necessary to avoid overloading the cardiovascular system and precipitating congestive heart failure. Hypoxia, acidosis, hypokalemia, hyperkalemia, or hypercapnia may reduce the effectiveness and/or increase the incidence of adverse effects of isoproterenol and must be identified and corrected prior to or during administration of the drug. Appropriate measures should be taken to ensure adequate ventilation. Patients who are in shock must be monitored carefully during administration of isoproterenol. The ECG should be monitored closely, and arterial blood pressure, heart rate, urine flow, central venous pressure, blood pH, and blood PCO 2 or bicarbonate concentrations should be determined frequently. Measuring cardiac output and circulation time also may be helpful in determining the patient's condition and response to therapy. The possibility that isoproterenol may not produce improved capillary perfusion and oxygen delivery while increasing oxygen demand in the myocardium and other tissues must be kept in mind.
Commercially available formulations of isoproterenol hydrochloride may contain sulfites that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. The possibility of adverse reactions to sulfite(s) contained in the preparation should be considered in asthmatic patients who show paradoxical worsening of respiratory function following use of the drug or whose symptoms worsen or in whom bronchodilatory response decreases with increasing use of the drug.
Administration of isoproterenol to patients with severe disturbances of ventilation distribution or status asthmaticus and abnormal blood gas tensions may not produce improvement in vital capacity. Arterial oxygen tension may not be increased and may be further reduced even though bronchodilation occurs. In patients with asthma receiving isoproterenol infusion, care should be taken to ensure that oxygen is co-administered.132 Heart rate, blood pressure, and arterial blood gases should be monitored and arterial oxygen pressure (PaO 2) should be maintained above 60 mm Hg in patients with asthma receiving isoproterenol infusions.132 The ECG should be monitored, and ECG changes suggestive of myocardial ischemia should be confirmed by determining cardiac-specific serum isoenzyme MB concentrations of serum CK (CPK).132
Isoproterenol should be administered with caution to geriatric patients, diabetics, patients with renal or cardiovascular disease (including hypertension, coronary artery disease, coronary insufficiency, angina pectoris, or degenerative heart disease), hyperthyroidism, and/or those with a history of sensitivity to sympathomimetic amines. Isoproterenol therapy should be discontinued if precordial distress, angina, or ventricular arrhythmias occur. Use of the injection is contraindicated in patients with angina pectoris.
Isoproterenol is contraindicated in patients with preexisting cardiac arrhythmias (particularly ventricular arrhythmias requiring inotropic therapy and tachyarrhythmias).140 The drug also is contraindicated in patients with angina pectoris and in those with tachycardia or heart block caused by cardiac glycoside intoxication.140
The safety and efficacy of isoproterenol hydrochloride in pediatric patients have not been established.140 However, the drug has been used in children† for certain conditions such as refractory asthma and cardiac arrhythmias (e.g., bradycardia).132, 136, 137, 140
IV infusions of isoproterenol hydrochloride (0.05-2.7 mcg/kg per minute) in pediatric patients with refractory asthma have caused clinical deterioration, myocardial necrosis, congestive heart failure (CHF), and death.140 The risk of developing such cardiac toxicity may be increased by acidosis, hypoxia, and/or concomitant use of other agents such as xanthine derivatives or corticosteroids, drugs that are likely to be used in these children.140 (See Drug Interactions: Xanthine Derivatives.) If IV isoproterenol is used in pediatric patients with refractory asthma, vital signs should be monitored continuously, ECG monitored frequently, and cardiac-specific serum isoenzyme MB concentrations of serum CK (CPK) should be determined daily.140
Clinical studies of isoproterenol hydrochloride did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.140 Some data suggest that geriatric healthy individuals or hypertensive patients are less responsive to β-adrenergic stimulation than younger adults.140 In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.140 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.140
Mutagenicity and Carcinogenicity
Studies to determine the mutagenic and carcinogenic potentials of isoproterenol have not been performed to date.
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using orally inhaled isoproterenol doses up to 6400 times the usual human dose have not revealed evidence of teratogenic effects. There are no adequate and well-controlled studies using isoproterenol in pregnant women, and the drug should be used during pregnancy only when clearly needed.
It is not known if isoproterenol can affect reproduction capacity.
Since it is not known whether isoproterenol is distributed into milk, the drug should be used with caution in nursing women.
Isoproterenol should not be administered concomitantly with epinephrine or most other sympathomimetic bronchodilators because of the possibility of additive effects and increased cardiotoxicity. The drugs may be given alternately provided that enough time has elapsed (at least 4 hours) for the effects of one drug to subside before the alternate drug is given.
There is some evidence from animal studies that concomitant administration of a sympathomimetic agent (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce increased cardiotoxic effects.100, 101, 102, 103 Use of isoproterenol hydrochloride infusion in conjunction with IV xanthine derivatives (e.g., aminophylline) and IV corticosteroids may have additive cardiotoxic effects; hypertension, tachycardia, arrhythmias, seizures, myocardial ischemia, and fatal myocardial necrosis have been reported with the concurrent use of these agents.100, 101, 132
Administration of isoproterenol in patients who are receiving cyclopropane or halogenated hydrocarbon general anesthetics may result in arrhythmias, and the drug should be used with caution, if at all, in patients receiving these anesthetics.
The cardiac, bronchodilating, and vasodilating effects of isoproterenol are antagonized by β-adrenergic blocking drugs such as propranolol. Propranolol may be used to treat tachycardia occurring during administration of isoproterenol but should not be given to asthmatic patients because it can increase bronchospasm. Ergot alkaloids increase blood pressure in patients receiving isoproterenol, apparently by enhancing isoproterenol-induced increases in cardiac output while producing peripheral vasoconstriction.
Isoproterenol may be used in patients who are fully digitalized, but the fact that arrhythmias may occur more readily in patients receiving the drug concomitantly with digitalis glycosides must be kept in mind. Isoproterenol is contraindicated in patients with tachycardia caused by digitalis intoxication. Arrhythmias also may occur more readily in patients receiving potassium-depleting diuretics or other drugs that affect cardiac rhythm.
Isoproterenol acts directly on β-adrenergic receptors. In therapeutic doses, the drug has little or no effect on α-adrenergic receptors. It is believed that β-adrenergic effects result from stimulation of the production of cyclic adenosine-3',5'-monophosphate (AMP) by activation of the enzyme adenyl cyclase. The main effects of therapeutic doses of isoproterenol are relaxation of smooth muscle of the bronchial tree, cardiac stimulation, and peripheral vasodilation. Tolerance to the bronchodilating and cardiac effects of the drug may develop with prolonged or too frequent use.
Isoproterenol relaxes bronchial, GI, and uterine smooth muscle by stimulation of β2-adrenergic receptors. In addition, isoproterenol inhibits antigen-induced release of histamine and the slow reacting substance of anaphylaxis. In patients with bronchial constriction, usual doses of the drug may relieve bronchospasm, increase vital capacity, decrease residual volume in the lungs, and facilitate passage of pulmonary secretions when administered parenterally or by oral inhalation (an oral aerosol preparation no longer is commercially available in the US). However, arterial oxygen tension may be further reduced. Rebound bronchospasm may occur when the effects of isoproterenol end.
Isoproterenol acts on β1-adrenergic receptors in the heart, producing a positive chronotropic effect through the sinoatrial (SA) node and a positive inotropic effect on the myocardium. Cardiac output usually is increased. Increased cardiac output is accompanied by an increase in stroke volume in some patients, but significant increases in stroke volume do not occur consistently. Isoproterenol also increases myocardial oxygen consumption and the work of the heart and decreases cardiac efficiency. Although the drug may increase coronary artery blood flow by both direct and indirect dilation of coronary arteries, the increased coronary blood flow may not provide sufficient oxygen to overcome the greatly increased myocardial oxygen requirement; coronary insufficiency and myocardial hypoxia may result. It has been suggested that coronary artery vasodilation in patients with coronary disease may divert blood from ischemic areas of the heart to areas with dilatable coronary vessels. In patients with acute myocardial infarction, isoproterenol may therefore increase the extent of ischemia.
In patients with atrioventricular (AV) block, isoproterenol shortens conduction time and the refractory period of the AV node and increases the rate and strength of ventricular contraction. Bradycardia and syncopal episodes may be abolished and recurrent attacks prevented. In some patients, isoproterenol may temporarily suppress ventricular fibrillation or tachycardia by producing sinus tachycardia, which shortens diastole and suppresses ventricular pacemakers.
Arrhythmias, including premature ventricular contractions, ventricular tachycardia, ectopic ventricular beats, or fibrillation may occur in patients receiving isoproterenol, especially if the drug is given in large doses to patients with cardiogenic shock, acidosis, hypoxia, hypokalemia, or hyperkalemia, or to those whose hearts have been sensitized to this action by other drugs including digitalis or certain general anesthetics. (See Drug Interactions: General Anesthetics.)
Isoproterenol dilates arteries and arterioles in skeletal muscle and to a lesser extent in the mesenteric, intestinal, pulmonary, and femoral vascular beds by its effect on β2-adrenergic receptors. The effect of the drug on cerebral blood vessels in humans has not been reported. Peripheral vascular resistance is reduced and venous return to the heart is increased in patients receiving isoproterenol. Blood flow to vital organs and tissue perfusion may be improved in some patients who are in shock. However, isoproterenol increases arteriovenous shunting so that improved capillary perfusion and oxygen delivery may not always result from increases in total blood flow. Renal blood flow usually is decreased in normotensive patients, but is substantially increased in patients with shock.140
Isoproterenol has been reported to cause venoconstriction following injection into limb veins, apparently resulting from reflex activity involving sympathetic venoconstrictor fibers.
After systemic administration, isoproterenol increases systolic blood pressure by increasing cardiac output; after oral inhalation (an oral aerosol preparation no longer is commercially available in the US), systolic blood pressure may be increased slightly or unchanged. The drug usually decreases diastolic blood pressure by producing vasodilation when administered by any route. Mean blood pressure usually is decreased slightly but it may remain unchanged or may be increased slightly if the vasculature is already maximally dilated. Large doses of isoproterenol cause a substantial fall in mean blood pressure. Increases in systolic and/or mean blood pressure are especially likely to occur following IV administration of the drug to patients who are in shock because of distributive or cardiac defects; however, central venous pressure may be decreased in these patients. Isoproterenol does not alter pulmonary arterial pressure in most patients but may reverse increases in pulmonary arterial pressure occurring in patients with pulmonary embolism.
Isoproterenol can cause CNS stimulation, which is rarely clinically important with usual doses. However, nervousness, excitability, insomnia, or tremor may occur in some patients.
Isoproterenol increases glycogenolysis in the liver; unlike epinephrine, however, isoproterenol stimulates insulin secretion and is less likely to cause hyperglycemia. Isoproterenol increases plasma concentrations of free fatty acids. The drug has calorigenic activity and increases the oxygen demand in most tissues to levels that may not be met by increased blood flow. Arterial lactic acid concentrations may be elevated due to increased anaerobic metabolism.
Isoproterenol is rapidly absorbed following oral inhalation; absorption following sublingual or rectal administration (using sublingual tablets) is variable and often unreliable, and the drug is rapidly metabolized in the GI tract after oral ingestion. However, preparations for oral, sublingual, rectal, or oral inhalation administration no longer are commercially available in the US.
Bronchodilation occurs promptly after oral inhalation and persists for up to 1 hour. Effects of the drug reportedly persist for a few minutes after IV administration and up to 2 hours after subcutaneous or sublingual administration, and 2-4 hours after rectal administration of a sublingual tablet.
It is not known if isoproterenol is distributed into milk in humans.
The pharmacologic actions of isoproterenol appear to be terminated principally by tissue uptake. The drug is metabolized by conjugation in the GI tract and by the enzyme catechol- O -methyltransferase in the liver, lungs, and other tissue. The major metabolite after IV administration is 3- O -methylisoproterenol (which has been reported to have weak β-adrenergic blocking activity) and its conjugates. After oral administration or oral inhalation (preparations for oral or oral inhalation administration no longer are commercially available in the US), the major metabolite is the sulfate conjugate of isoproterenol. It has been suggested that most of an inhaled dose actually is swallowed and that in some patients, toxic effects after oral inhalation of isoproterenol may result from failure of the conjugation mechanism. Results of one study in severely ill, brain-damaged children indicate that isoproterenol may be more rapidly and extensively metabolized in children than in adults.
In adult asthmatics, approximately 75% of an IV dose of isoproterenol is excreted in urine within 15 hours after a bolus dose and within 22 hours when the dose is infused over 30 minutes. About 40-50% of the dose is excreted unchanged and the remainder as 3- O -methylisoproterenol. After IV administration to seriously ill pediatric patients, about 75-90% of the dose was excreted in urine within 24 hours as conjugates of isoproterenol and 3- O -methylisoproterenol and less than 15% of the dose was excreted unchanged. After oral administration or oral inhalation in adults (preparations for oral administration or oral inhalation no longer are commercially available in the US), 50-80% of the dose is excreted in urine as the sulfate conjugate of isoproterenol, about 5-15% unchanged, and less than 15% as free or conjugated 3- O -methylisoproterenol within 48 hours. Small quantities of unidentified metabolites also were excreted in feces after IV administration to children.
Isoproterenol is a synthetic sympathomimetic drug that is structurally related to epinephrine, but that differs pharmacologically. Isoproterenol is commercially available as the hydrochloride salt. Isoproterenol occurs as a racemic mixture.132 Isoproterenol hydrochloride occurs as a white to practically white, crystalline powder that is freely soluble in water and sparingly soluble in alcohol. Commercially available 0.02% (1:5000) isoproterenol hydrochloride injection is nonpyrogenic and has a pH of 2.5-4.5, which may have been adjusted with hydrochloric acid.135
Isoproterenol hydrochloride preparations gradually darken on exposure to air, light, and heat and must be stored in tight, light-resistant containers. Some commercially available isoproterenol preparations contain sulfites or sulfur dioxide as an antioxidant. In some commercially available injections, the air has been replaced by inert gas to avoid oxidation. Solutions of isoproterenol salts become pink to brownish-pink on exposure to air, alkalies, or metals, and they must not be used if discoloration or a precipitate is evident.
Isoproterenol hydrochloride injection should be stored at 20-25°C.140
Isoproterenol hydrochloride injection appears to be compatible with all IV fluids; however, stability of the drug is dependent on pH. Isoproterenol hydrochloride solutions containing 5 mcg/mL in 5% dextrose injection have been reported to lose 5% of their potency in 6 hours at pH 7.6, in 8 hours at pH 6.5, and in more than 24 hours at pH 3.7-5.7. It has been recommended that caution be used if isoproterenol injection is mixed with other drugs which will result in pH greater than 6, and these solutions should be used immediately after preparation.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 0.2 mg/mL* | Isoproterenol Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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