Isoproterenol

Article Author:
Michael Szymanski
Article Editor:
Davinder Singh
Updated:
5/30/2019 9:19:00 PM
PubMed Link:
Isoproterenol

Indications

Isoproterenol is indicated for the following: 

  • Heart block not requiring pacing 
  • Cardiac arrest from heart block when pacemaker therapy is unavailable[1]

Off-label Uses

  • Bradycardia[2]
  • Bronchospasm during anesthesia 
  • Cardiogenic shock[3]
  • Hypovolemic shock (adjunctive treatment) 
  • Provocation of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy: Used during electrophysiological studies to induce ventricular arrhythmias in patients with a history of arrhythmogenic right ventricular cardiomyopathy[4]
  • Provocation of syncope during tilt table testing[5]
  • Torsades de pointes[6]
  • Beta-blocker overdose 
  • Ventricular arrhythmias secondary to AV block 
  • Short QT syndrome 
  • Electrical storm in patients with Brugada syndrome[7]
  • Bradycardia in a cardiac transplant patient

Mechanism of Action

Isoproterenol is a beta-1 and beta-2 adrenergic receptor agonist resulting in the following: 

  • Increased heart rate 
  • Increased heart contractility 
  • Relaxation of bronchial, gastrointestinal, and uterine smooth muscle 
  • Peripheral vasodilation 

Both beta-1 and beta-2 adrenergic receptors exert their effects through a G-alpha stimulatory second messenger system. G-protein coupled receptors are structurally composed of a seven-transmembrane-spanning protein. The extracellular domain serves as the ligand binding site. In the inactivated state, the intracellular domain is linked to a G-alpha stimulatory protein bound to a GDP molecule. Upon binding of a ligand to the extracellular domain of a beta-1 receptor, the alpha subunit exchanges a GDP molecule for a GTP and becomes activated. The (now active) G-alpha protein dissociates from the intracellular domain and activates adenylate cyclase. Activated adenylate cyclase subsequently converts intracellular ATP to cAMP. The major second messenger in this pathway, cAMP, activates protein kinase A (PKA). Activated PKA phosphorylates L-type calcium channels in cardiac myocytes, resulting in an increase in intracellular calcium. PKA also causes an increase in calcium release from ryanodine receptors on the sarcoplasmic reticulum.

Beta-1 adrenergic receptors are primarily concentrated on the heart. The terminal effects of activation of beta-1 adrenergic receptors are an increase in intracellular calcium. In cardiac pacemaker cells, increased calcium causes an increase in the slope of phase 4 of the cardiac pacemaker action potential. By increasing the slope of phase 4, pacemaker cells reach the threshold at a faster rate, resulting in the characteristic increased heart rate seen in patients on an isoproterenol infusion. In non-pacemaker cardiac myocytes, an increase in intracellular calcium causes the increased contractility characteristic of isoproterenol infusion.[8]

The result of beta-1 agonism on the heart can be summarized as follows:

  • Positive inotropy (contractility)
  • Positive lusitropy (relaxation)
  • Positive chronotropy (heart rate)
  • Positive dromotropy (conduction velocity) 

Beta-2 adrenergic receptors function similarly to beta-1 receptors. Activation of the G-protein coupled receptor results in an increase in intracellular cAMP. The second messenger cAMP then activates protein kinase A (PKA). PKA phosphorylates myosin light chain kinase (MLCK) thus inactivating it. In smooth muscle cells, MLCK is responsible for the phosphorylation of myosin, leading to myosin-actin cross-bridge formation and muscle contraction. As stated, agonism of beta-2 receptors leads to inactivation of MLCK and subsequent relaxation of smooth muscle, bronchial dilation, peripheral vasodilation, and gastrointestinal and uterine smooth muscle relaxation.[9]

Other effects of isoproterenol:

  • Hepatic glycogenolysis (beta-2)
  • Release of glucagon from the pancreas (beta-2)[10]
  • Activation of the renin-angiotensin-aldosterone system in the kidney (beta-1)

Administration

Isoproterenol is administered intravenously via an infusion pump.

Available Forms

Brand and generic: 0.2 mg/mL (1 mL, 5mL) 

Adult Dosage

Bradydysrhythmias, AV nodal block

2 to 10 mcg/minute titrated to desired effect[2] 

Brugada syndrome (off-label)

Bolus 1 to 2 mcg followed by 0.15 to 0.3 mcg/minute for 24 hours[7]

Cardiogenic shock(off-label)

2 to 20mcg/minute continuous infusion[3]

Provocation of syncope during tilt table testing (off-label)

1mcg/minute, initially, then increase based on the desired response; max dose of 5 mcg/minute

Provocation of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (off-label)

45 mcg/minute for 3 minutes, then evaluate rhythm[4]

Refractory torsades de pointes (off-label)

2-10 mcg/minute continuous infusion titrated to patient response[6] 

Pediatric Dosage

Bradycardia, AV nodal block

0.05-0.5 mcg/kg/minute, adjusted to desired effect; max dosage of 2 mcg/kg/minute[2] 

Neonatal Dosage

Bradycardia

0.05 to 1 mcg/kg/minute continuous infusion titrated to effect[11]

Pharmacokinetics

Isoproterenol is immediately active upon infusion. Its half-life is 2.5 to 5 minutes. Conjugation in hepatic and pulmonary tissues is the major method of metabolism. Excretion occurs via urine in the form of sulfate conjugates. 

Pregnancy/Breastfeeding

The use of isoproterenol during pregnancy has not been evaluated. The presence of isoproterenol in breast milk is presently unknown.[12]

Adverse Effects

Common

  • Headache
  • Dizziness
  • Upset stomach
  • Flushing
  • Fatigue
  • Nervousness

Cardiovascular 

  • Angina 
  • Flushing 
  • Hypotension 
  • Hypertension 
  • Palpitations 
  • Ventricular arrhythmia 
  • Premature ventricular contractions 
  • Adams-stokes syndrome 
  • Bradycardia (with tilt table testing) 

Respiratory 

  • Dyspnea 
  • Edema 

Ophthalmic 

  • Blurred vision 

Central Nervous System

  • Headache
  • Dizziness
  • Nervousness
  • Restlessness
  • Seizures 

Gastrointestinal

  • Nausea
  • Vomiting 

Endocrine & Metabolic

  • Hypokalemia
  • Increased serum glucose 

Musculoskeletal 

  • Tremor
  • Weakness 

Contraindications

Absolute Contraindications

  • Angina
  • Tachydysrhythmias
  • Preexisting ventricular arrhythmias
  • Digoxin intoxication
  • Sulfa allergy: Contains sulfites

Use with caution in patients with the following:

  • Cardiovascular disease: Isoproterenol causes an increase in myocardial oxygen demand
  • Diabetes: May cause an increase in blood glucose levels
  • Distributive shock: Beta-2 agonism will further decrease total peripheral resistance
  • Hyperthyroidism: May induce thyroid storm
  • Contains sulfites which may an allergic reaction in patients with a sulfa allergy
  • Elderly

Pregnancy

Isoproterenol is a Pregnancy Risk Factor C. It may interfere with uterine contractions due to its beta-2 agonist properties. Animal reproduction studies have not been conducted at this time. It is currently unknown if isoproterenol is present in breast milk; breastfeeding mothers are advised to exercise caution when taking isoproterenol.[12] 

Drug Interactions

Risk C: Monitor Therapy

  • Atomoxetine: Propensity to increase heart rate
  • Cannabinoid-containing products: Propensity to increase heart rate
  • COMT Inhibitors: Isoproterenol is degraded by catechol O-methyltransferase (COMT) and may rise to dangerous levels in the presence of a COMT inhibitor
  • Doxofylline: Increased risk of doxofylline toxicity
  • Tedizolid: Increased risk of hypertensive episode

Risk D: Consider modifying therapy

  • Topical Cocaine: Heightened risk of hypertension, tachycardia, and increased oxygen demand
  • Linezolid: Increased risk of hypertension due to COMT inhibitor-like action of linezolid
  • Mifepristone: QTc prolongation
  • QTc prolonging agents: Avoid giving isoproterenol in combination with other QTc prolonging agents

Risk X: Avoid

  • Inhaled Anesthetics: Increased risk of arrhythmia

Monitoring

Vitals (i.e., heart rate, respiratory rate, blood pressure) in addition to ECG, arterial blood gas, blood glucose levels, and serum potassium and magnesium levels should be monitored continuously in patients who are administered isoproterenol.

Enhancing Healthcare Team Outcomes

Isoproterenol is used by a multidisciplinary team that consists of ICU nurses, intensivist, cardiologist, cardiac surgeon, and critical care specialists. The drug is only used as an intravenous drip for severe bradycardia and cardiac arrest. It is sometimes used to manage hypovolemic shock and bronchospasm. Isoproterenol can cause tachyarrhythmias and hypertension at high doses. When used in the ICU, the patient must be closely monitored. Because of the availability of pacemakers and other chronotropic drugs, the use of isoproterenol has diminished today.[13]


References

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[5] Benditt DG,Ferguson DW,Grubb BP,Kapoor WN,Kugler J,Lerman BB,Maloney JD,Raviele A,Ross B,Sutton R,Wolk MJ,Wood DL, Tilt table testing for assessing syncope. American College of Cardiology. Journal of the American College of Cardiology. 1996 Jul     [PubMed PMID: 8752825]
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[11] Matsubara S,Morimatsu Y,Shiraishi H,Kuwata T,Ohkuchi A,Izumi A,Takeda S,Suzuki M, Fetus with heart failure due to congenital atrioventricular block treated by maternally administered ritodrine. Archives of gynecology and obstetrics. 2008 Jul     [PubMed PMID: 18066569]
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