Isoproterenol


Article Author:
Michael Szymanski


Article Editor:
Davinder Singh


Editors In Chief:
Rhonda Coffman
Lindsay Iverson
Heather Templin


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
5/30/2019 9:19:00 PM

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]


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Isoproterenol - Questions

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Which of the following statements about the hemodynamic effects of medications is false?



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Which sympathomimetic can be used to dilate the pulmonary arteries?



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Which of the following is not a beta-2 selective adrenergic agonist?



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Why is isoproterenol contraindicated for a patient experiencing a myocardial infarction?



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Which drug combination should be avoided due to synergism?



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An 82-year-old male is brought to the emergency department by a basic life support emergency medical services (EMS) crew after a possible syncopal episode lasting 30 seconds, according to witnesses on the scene. Transport to the hospital was unremarkable. The patient has a past medical history consisting of diabetes mellitus type 2, myocardial infarction, coronary artery bypass graft, and asthma. The patient is currently taking metformin, empagliflozin, metoprolol, furosemide, aspirin, and inhaled fluticasone. Vitals are blood pressure 160/102 mmHg, heart rate 38 beats/min, respiratory rate 28, and SaO2 92% on 2L oxygen via nasal cannula initiated by EMS in route. An ECG reveals 3 mm of ST-segment elevation in leads II, III, and aVF and a Mobitz type 2 second degree block. The patient's heart rate abruptly falls to 12 beats/min, and the patient becomes unresponsive for 30 seconds. Afterward, his heart rate increases to 34 beats/min, and he regains consciousness. The emergency medicine resident starts the patient on an isoproterenol infusion while the cath lab is activated. About 5 minutes into the isoproterenol infusion, the patient goes into ventricular fibrillation and is unable to be resuscitated. Which of the following pharmacodynamic or pharmacokinetic properties of isoproterenol most likely contributed to this patient's demise?



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During a medical mission trip to Kenya, a provider encounters a patient presenting with multiple syncopal episodes over the past hour. This problem has never occurred before in the patient. The patient denies any medical issues but is malnourished. Upon obtaining vital signs, the patient's pulse is noted to be at 42 bpm. A rudimentary 3-lead ECG is attached to the patient and reveals a 2nd degree, Mobitz type II heart block. Due to lack of resources, pharmacologic pacing is attempted. The patient's heart rate is now observed to be 78 and regular. Several hours after administration of the drug, the patient is found to have a blood glucose level of 210. Which of the following medications was most likely administered?



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A 76-year-old female is brought to a rural emergency department in East Tennessee due to a syncopal episode. The provider quickly evaluates the patient. Vital signs are as follows: heart rate 46 bpm, blood pressure 100/60 mmHg, respiratory rate 22/min., and SaO2 90% on room air. The patient is sitting upright, non-distressed, and is well nourished. A 12-lead ECG shows ST-segment elevation in leads II, III, and avF with a 2nd-degree heart block. The patient has another syncopal episode that lasts 20 seconds during which time, asystole was observed. The provider decides to pace the patient with isoproterenol pharmacologically. The patient' heart rate improves to 72, but she quickly develops respiratory distress, becomes unconscious, and develops ventricular tachycardia. The emergency department team initiates ACLS protocols. After 20 minutes, the patient is in asystole, and the provider decides to pronounce the patient. Which of the following biochemical or molecular responses to isoproterenol are responsible for this patient's rapid demise?



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A 56-year-old male is brought to the emergency department by ambulance for the acute onset of substernal chest pain that radiates to the left shoulder. During the transfer of care, a paramedic states that the patient's ECG shows 4 mm of ST elevation in leads V3-5. Current vital signs are a blood pressure of 99/58 mmHg, pulse 50 bpm, SaO2 88% and, a respiratory rate of 28/min. The patient is in visible distress. The patient is administered aspirin, morphine, nitroglycerin, oxygen via nasal cannula at 4 LPM, unfractionated heparin, and atorvastatin. The patient is prepped for transport to a percutaneous coronary intervention 40 minutes. While waiting for a critical care transport unit, the patient's pulse drops to 40. The provider administers atropine 0.5 mg without a change in heart rate. The physician then decides to administer isoproterenol. The patient's heart rate increases to 68. Twenty minutes after infusion, the patient develops ventricular fibrillation and subsequently passes away after 30 minutes of ACLS. Which of the following is the most likely cause of this patient's demise?



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A patient presents for an electrophysiology study following the incidental finding of nonsustained ventricular tachycardia in an ambulatory surgery center. The electrophysiologist decides to administer a nonselective beta agonist during the exam. Which of the following would be most appropriately categorized as a relative contraindication to the use of this medication?



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A patient presents for an electrophysiology study following the incidental finding of nonsustained ventricular tachycardia in an ambulatory surgery center. The electrophysiologist decides to administer a nonselective beta agonist during the exam. Which of the following is best described as a relative contraindication to the use of this medication?



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Isoproterenol - References

References

Neumar RW,Otto CW,Link MS,Kronick SL,Shuster M,Callaway CW,Kudenchuk PJ,Ornato JP,McNally B,Silvers SM,Passman RS,White RD,Hess EP,Tang W,Davis D,Sinz E,Morrison LJ, Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2     [PubMed]
Watanabe A,Fukushima Kusano K,Morita H,Miura D,Sumida W,Hiramatsu S,Banba K,Nishii N,Nagase S,Nakamura K,Sakuragi S,Ohe T, Low-dose isoproterenol for repetitive ventricular arrhythmia in patients with Brugada syndrome. European heart journal. 2006 Jul     [PubMed]
van Diepen S,Katz JN,Albert NM,Henry TD,Jacobs AK,Kapur NK,Kilic A,Menon V,Ohman EM,Sweitzer NK,Thiele H,Washam JB,Cohen MG, Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation. 2017 Oct 17     [PubMed]
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]
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Al-Khatib SM,Stevenson WG,Ackerman MJ,Bryant WJ,Callans DJ,Curtis AB,Deal BJ,Dickfeld T,Field ME,Fonarow GC,Gillis AM,Hlatky MA,Granger CB,Hammill SC,Joglar JA,Kay GN,Matlock DD,Myerburg RJ,Page RL, 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2017 Oct 30     [PubMed]
Field JM,Hazinski MF,Sayre MR,Chameides L,Schexnayder SM,Hemphill R,Samson RA,Kattwinkel J,Berg RA,Bhanji F,Cave DM,Jauch EC,Kudenchuk PJ,Neumar RW,Peberdy MA,Perlman JM,Sinz E,Travers AH,Berg MD,Billi JE,Eigel B,Hickey RW,Kleinman ME,Link MS,Morrison LJ,O'Connor RE,Shuster M,Callaway CW,Cucchiara B,Ferguson JD,Rea TD,Vanden Hoek TL, Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2     [PubMed]
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Matera MG,Page C,Rinaldi B, β2-Adrenoceptor signalling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases. Current opinion in pharmacology. 2018 Jun     [PubMed]
Biazi GR,Frasson IG,Miksza DR,de Morais H,de Fatima Silva F,Bertolini GL,de Souza HM, Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats. Journal of cellular biochemistry. 2018 May 15     [PubMed]
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]
Mahon WA,Reid DW,Day RA, The in vivo effects of beta adrenergic stimulation and blockade on the human uterus at term. The Journal of pharmacology and experimental therapeutics. 1967 Apr     [PubMed]
Kislitsina ON,Rich JD,Wilcox JE,Pham DT,Churyla A,Vorovich EB,Ghafourian K,Yancy CW, Shock - Classification and Pathophysiological Principles of Therapeutics. Current cardiology reviews. 2018 Dec 12;     [PubMed]

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