Isoproterenol

Overview

Isoproterenol (Isuprel®) is a nonselective beta-adrenergic agonist that is infrequently used in veterinary medicine. In dogs and cats, it is primarily used for the treatment of acute bronchial constriction, complete atrioventricular (AV) block, and occasionally as adjunctive therapy in shock or heart failure, although its use is limited because of its marked chronotropic effects and arrhythmogenic potential.

Isoproterenol has a very short duration of action. Following IV administration, its effects occur immediately but persist for only a few minutes after discontinuation. The drug is rapidly inactivated after oral administration and undergoes metabolism by catechol-O-methyltransferase (COMT) in the liver and other tissues.

Mechanism of Action (MOA): Isoproterenol is a synthetic beta-1 and beta-2 adrenergic agonist with no appreciable alpha-adrenergic activity at therapeutic doses. It stimulates cyclic AMP production, producing positive inotropic and chronotropic effects, relaxation of bronchial smooth muscle, and peripheral vasodilation. Hemodynamic effects include decreased total peripheral resistance, increased cardiac output, increased venous return, and increased cardiac pacemaker activity. It may also increase myocardial oxygen demand while decreasing coronary perfusion.

Indications

Isoproterenol is an infrequently used beta-adrenergic agonist in dogs and cats. It is primarily reserved for selected cardiovascular emergencies and acute bronchospastic conditions requiring rapid beta-adrenergic stimulation.

• Acute bronchial constriction: Used for the treatment of acute bronchospasm requiring rapid bronchodilation.
• Complete atrioventricular (AV) block: Used to increase heart rate and improve cardiac output in patients with complete AV block.
• Shock or heart failure (adjunctive use): Occasionally used as adjunctive therapy, although its use is limited by increased heart rate and ventricular arrhythmogenicity.
• Bradyarrhythmias: Short-term treatment of bradyarrhythmias such as symptomatic persistent sinus bradycardia until pacing can be accomplished, symptomatic sinus arrest or sinoatrial block, acute, life-threatening second-degree AV block (Mobitz type II), and an idioventricular rhythm when atropine or glycopyrrolate is ineffective.
• Drug overdose: An alternative to atropine for bradycardia or AV block in calcium channel blocker overdose; for bradycardia in beta-blocker overdose (for atenolol and metoprolol, given cautiously if atropine fails) and in amiodarone overdose.

Dosage (Reference)

Dog

In dogs, isoproterenol is administered as a carefully titrated IV infusion for selected cardiac emergencies. Treatment should be performed only with continuous cardiovascular monitoring.

Cat

The same dosage recommendations apply to cats. Isoproterenol should be administered as a carefully titrated IV infusion with continuous cardiovascular monitoring.

Warnings & Precautions

Isoproterenol should be used only in appropriately selected patients with close cardiovascular monitoring because of its potent chronotropic and inotropic effects. It is not a substitute for appropriate fluid therapy in shock.

• Tachyarrhythmias: Contraindicated in patients with tachyarrhythmias or ventricular arrhythmias that do not require increased inotropic activity.
• Cardiac glycoside intoxication: Contraindicated in patients with tachycardia or AV block caused by cardiac glycoside intoxication.
• Coronary insufficiency: Use cautiously because increased myocardial oxygen demand and reduced coronary perfusion may worsen cardiac ischemia.
• Hyperthyroidism: Use with caution in hyperthyroid patients.
• Renal disease: Use cautiously in patients with renal disease.
• Hypertension: Use with caution in hypertensive patients.
• Diabetes mellitus: Use cautiously in diabetic patients.
• Shock: Isoproterenol should not be used as a substitute for adequate fluid replacement in patients with shock.
• Repeated treatment: Recommended for short-term use only, because repeated treatment causes cardiac injury.
• Pregnancy and lactation: Safe use during pregnancy has not been established, so it should only be used when the maternal benefits outweigh the potential risks to offspring; beta-adrenergic agonists have a tocolytic effect and may interfere with uterine contractions at parturition, and it is rapidly deactivated in the gut and unlikely to pose much risk to nursing offspring.

Drug Interactions

Clinically significant interactions with isoproterenol are primarily related to additive cardiovascular stimulation, increased arrhythmogenic potential, or antagonism of its beta-adrenergic effects. Careful monitoring is recommended when these drugs are used concurrently.

• Inhalant anesthetics (e.g., isoflurane, sevoflurane): May increase the risk of cardiac arrhythmias, particularly in patients receiving cyclopropane or halogenated hydrocarbon anesthetics. Propranolol may be used if arrhythmias develop.
• Beta-blockers (e.g., atenolol, propranolol): Antagonize the cardiac, bronchodilating, and vasodilating effects of isoproterenol. Although beta-blockers may be used to treat isoproterenol-induced tachycardia, they should be used cautiously in patients with bronchospastic disease.
• Digoxin: Concurrent administration may increase the risk of cardiac arrhythmias.
• Linezolid: May enhance the hypertensive effects of isoproterenol.
• Oxytocin: May increase the risk of hypertension.
• Selegiline: May enhance the hypertensive effects of isoproterenol.
• Other sympathomimetic agents (e.g., phenylpropanolamine): Concurrent use may increase toxicity and should be avoided.
• Theophylline, aminophylline: Isoproterenol may reduce theophylline concentrations, and toxic synergism (CNS stimulation, arrhythmias) may possibly occur with concurrent use.

Side Effects & Overdose

Side Effects

Adverse effects of isoproterenol are primarily related to excessive beta-adrenergic stimulation. Because of its short duration of action, most adverse effects are transient and usually improve after reducing the dose or infusion rate.

• Tachycardia: The most common adverse effect resulting from beta-1 adrenergic stimulation.
• Hypotension: May occur secondary to peripheral vasodilation.
• Cardiac arrhythmias: Isoproterenol is more arrhythmogenic than dopamine or dobutamine and is therefore rarely used in the treatment of heart failure.
• CNS effects: Anxiety, tremors, excitability, headache, and weakness may occur.
• Vomiting: May occur during treatment.
• Dose adjustment: Most adverse effects are transient and may only require reducing the dose or infusion rate rather than discontinuing therapy.
• Potassium imbalance: Adrenergic agonists can produce potassium imbalance; monitor serum potassium with repeated use.

Overdose

Overdose results in exaggerated beta-adrenergic stimulation, leading to severe cardiovascular effects. Management consists primarily of discontinuing or reducing the infusion and providing supportive care.

• Hypertension followed by hypotension: High doses may initially cause hypertension, followed by hypotension.
• Tachycardia and arrhythmias: Severe tachycardia and other cardiac arrhythmias may develop.
• Cardiac necrosis: Associated with high doses of isoproterenol.
• Supportive care: Reduce or discontinue the infusion and provide appropriate supportive treatment.
• Persistent tachycardia: A beta-blocker (e.g., propranolol) may be considered if tachycardia persists, provided the patient does not have bronchospastic disease.
• Experimental lethal dose: IV doses of 10–50 µg/kg were lethal in hypoxic dogs under experimental conditions.

Key Notes

Practical clinical points that help optimize the appropriate use of isoproterenol in dogs and cats:

• Limited clinical use: Isoproterenol is used infrequently in veterinary medicine because safer or more selective alternatives are available for many indications.
• Immediate onset: IV administration produces an almost immediate clinical response, making it useful when rapid beta-adrenergic stimulation is required.
• Brief duration: Clinical effects persist for only a few minutes after discontinuation of the infusion, allowing rapid dose adjustment.
• Bronchospasm management: Injectable isoproterenol has largely been replaced by selective β2-adrenergic agonists (e.g., terbutaline) for the treatment of bronchospasm.
• Administration setting: Isoproterenol should be administered only by trained personnel in facilities where continuous patient monitoring is available.
• Dilution: For an IV infusion, dilute 1–10 mL of the 0.2 mg/mL injection in 500 mL of 5% dextrose, 0.9% sodium chloride or LRS to give 0.4–4 µg/mL (5 mL, or 1 mg, in 500 mL gives 2 µg/mL).
• Storage: Protect from light. Exposure to air, light or heat darkens the solution; do not use a solution that is pink or darker, or that contains a precipitate.