Isoprenaline/ Isoproterenol

Isoprenaline belongs to the Alpha/ Beta-Adrenergic Receptor Agonist Pharmacological class.

Isoprenaline is approved for the treatment of Bronchospasm, Heart blocks and as an electrolyte or fluid replacement.

Isoprenaline volume of distribution was found to be 216 ± 57 mL/kg in pediatric populations.

Isoprenaline was found to be 68.8 ± 1.2% protein bound in plasma and mainly to serum albumin. Isoprenaline is found to be predominantly metabolized to glucuronide conjugates. Isoprenaline is found to be 12.2-27.0% recovered in the feces and 59.1-106.8% recovered in the urine after 48 hours.

The common side effects associated with Isoprenaline are anxiety, fast heart rate, coughing up blood, fatigue, low or high blood pressure, weakness, dizziness, fainting, lightheadedness, shortness of breath, worsening symptoms, chest pain, etc.

Isoprenaline is available in the form of Intravenous injections, subcutaneous injections, and intramuscular injections.

Isoprenaline is available in India, the U.K., the U.S., Canada, E.U., China, Japan, and Australia.

Isoprenaline belonging to the pharmacological class of Alpha/ Beta-Adrenergic Receptor Agonist acts as a Sympathomimetic therapeutic agent. Isoprenaline is a non-selective beta-adrenergic receptor agonist which used in a number of indications for heart-related diseases and as bronchospasm in anesthesia. Isoprenaline is known to have a short duration of action as it is rapidly cleared and has a wide therapeutic index. The agonistic action of beta-1 and beta-2 adrenergic receptors causes the alpha subunit of G-protein coupled receptors to exchange GMP. for GTP by activating them and, in turn, allowing the alpha subunit to be dissociated from the beta and gamma subunits. The dissociation of the alpha subunit activates adenylate cyclase, converting ATP to cyclic AMP. The cyclic AMP. activates protein kinase A (PKA), which phosphorylates cardiac L-type calcium channels such as Cav1.2.1.3,1.4. These channels, in turn, depolarize cells by inward active transport of calcium ions.

Isoprenaline has a quick onset of action of 5 minutes, and the duration extends up to 10-15 minutes.

• Intravenous IV: 1-4ucg/min reconstituted with Glucose is given intravenously.
• Subcutaneous: 0.2mg/ml undiluted is administered subcutaneously, followed by subsequent doses.
• Intra Muscular IM: 0.2mg/ml undiluted is administered intramuscularly, followed by subsequent doses.

Isoprenaline can be used in the treatment of:

• Bradycardia
• Heart block
• Fluid or electrolyte replacement

Isoprenaline can help to increase the force of the heartbeat and increase the contractility and strength of heart rate and relieve bronchospasm during anesthesia.

Isoprenaline is approved for use in the following clinical indications:

• Mild or transient episodes of heart block.
• Serious episodes of heart block.
• Adam stocks Attack.
• Cardiac Arrest.
• Adjunct therapy to fluid and electrolyte replacement in septic shock, hypoperfusion, congestive heart failure, hypovolemic shock, and cardiogenic shock.

Off-label indications:

• Hypovolemic shock
• Provocation of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.
• Bradycardia
• Bronchospasm during anesthesia
• Provocation of syncope during tilt table testing
• Torsades de pointes
• Beta-blocker overdose
• Ventricular arrhythmias secondary to AV block
• Short QT syndrome
• Electrical storm in patients with Brugada syndrome
• Bradycardia in a cardiac transplant patient
• Cardiogenic shock

Intravenous

• Bronchospasm during anesthesia

Adult: 0.01-0.02 mg (0.5-1 mL) via bolus inj, may repeat dose if necessary.

Intravenous

• Adjunct in shock condition

Adult: 0.5-5 mcg of Isoprenaline per minute (0.25-2.5 mL of dilution) given via infusion. Adjust the rate of dose according to patient response.

Intravenous

• Cardiac arrest

Adult: Initial dose

of 0.02-0.06 mg of Isoprenaline i.e. 1-3 mL of a 1:50,000 dilution, followed by 0.01-0.2 mg of Isoprenaline (0.5-10 mL) given via bolus in. Alternatively, initially, five mcg per minute of Isoprenaline(1.25 mL of a 1:250,000 dilution) was given via infusion.

Intravenous

• Heart block

Adult: Initial dose of 0.02-0.06 mg of Isoprenaline i.e. 1-3 mL of a 1:50,000 dilution, followed by 0.01-0.2 mg (0.5-10 mL) given via bolus inj. Alternatively initially, five mcg per minute of Isoprenaline (1.25 mL of a 1:250,000 dilution) was given via infusion.

Intravenous

• Stokes-Adams attack

Adult: Initial dose of , 0.02-0.06 mg (1-3 mL of a 1:50,000 dilution), followed by 0.01-0.2 mg (0.5-10 mL) given via bolus inj. Alternatively, initially, 5 mcg per minute of Isoprenaline (1.25 mL of a 1:250,000 dilution) was given via infusion.

Intramuscular

• Stokes-Adams attack

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.02-1 mg (0.1-5 mL).

Intramuscular

• Heart block

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.02-1 mg (0.1-5 mL).

Intramuscular

• Cardiac arrest

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.02-1 mg (0.1-5 mL).

Subcutaneous

• Cardiac arrest

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.15-0.2 mg (0.75-1 mL).

Subcutaneous

• Heart block

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.15-0.2 mg (0.75-1 mL).

Subcutaneous

• Stokes-Adams attack

Adult: Initial dose of 0.2 mg (1 mL), followed by subsequent dose of 0.15-0.2 mg (0.75-1 mL).

Intracardiac

• Stokes-Adams attack

Adult: Initial dose of 0.02 mg (0.1 mL).

Intracardiac

• Cardiac arrest

Adult: Initial dose of , 0.02 mg (0.1 mL).

Intracardiac

• Heart block

Adult: Initial dose of 0.02 mg i.e.(0.1 mL).

Subsequent dosage and method of administration of Isoprenaline depend on the ventricular rate and rapidity with which the pacemaker can take over when the medicine is gradually withdrawn.

Reconstitution:

IV bolus:1 mL of solution labelled as containing 1:5000 solution is diluted with 10mL NaCl inj or dextrose 5% inj to make a 1:50,000 solution.

IV infusion for heart block; Stokes-Adams attacks; cardiac arrest: 10 mL of a solution labeled as containing 1:5000 solution is

diluted with 500 mL dextrose 5% inj to make a 1:250,000 solution. IV infusion for a shock: 5 mL of a solution labeled as containing 1:5000 solution is diluted with 500 mL dextrose 5%.

0.01-0.06mg, 0.2mg, 1mg in 100ml,1 mg in 500ml, 4mg in 250mg, 20mcg/ml

Intravenous, Intramuscular, Subcutaneous.

Maintaining health and smoking cessation is a must.

Avoid or restrict or limit the usage of caffeine as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Diet containing refined and high energy-dense foods, low fiber, food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, low antioxidants, and vitamins needs to be restricted.

The dietary restriction should be individualized as per the patient's requirements.

Isoprenaline may be contraindicated in the following:

• Angina pectoris
• Ventricular arrhythmias
• Tachycardia or heart attack or Tachyarrhythmia
• Digoxin intoxication
• Sulfa allergy: Contains sulfites
• In Cardiovascular disease, Isoproterenol causes an increase in myocardial oxygen demand.
• In Diabetes, Isoproterenol may cause an increase in blood glucose levels
• In Distributive shock, Isoproterenol will further decrease total peripheral resistance
• In Hyperthyroidism, Isoproterenol may induce thyroid storm.

The treating physician must closely monitor the patient while keeping pharmacovigilance as follows:

• Failing heart or injured heart: The treatment uses Isoprenaline, such as increasing myocardial infarction oxygen and decreasing effective coronary perfusion.
• Myocardial Infarction or Cardiogenic Shock: Use of Isoprenaline is discouraged in such conditions.
• Diseases of AV node and its branches: Isoprenaline has been reported to worsen heart attacks.
• In Diabetes, Isoproterenol may cause an increase in blood glucose levels
• In Hyperthyroidism, Isoproterenol may induce thyroid storm

Avoid alcohol usage while on Isoprenaline Medication, as alcohol can worsen the effects of any underlying disease condition.

Isoprenaline or the components of the drug medication has not been found to be excreted in milk. A decision should be made by the treating physician whether to continue or discontinue this medication, and it should only be used if the benefits outweigh the risks.

Pregnancy Category C:

There is no well-established data on pregnant patients. Isoprenaline should be administered and used during pregnancy only if the potential benefit outweighs the risks.

There is no sufficient traceable scientific evidence regarding the use and safety of Isoprenaline in concurrent use with any particular food.

The adverse reactions related to Isoprenaline can be categorized as follows:

Common

• Tremor
• Difficulty sleeping
• Unusual taste in the mouth
• Sweating
• Hoarseness
• Shortness of breath
• Blurred vision, and
• Dry mouth or throat
• Nervousness
• Shakiness
• Headache
• Nausea
• Vomiting
• Diarrhea
• Heartburn,
• Lightheadedness
• Dizziness

Less common

N.A

Rare

N.A

The clinically relevant drug interactions of Isoprenaline are briefly summarized here:

Risk C: Monitoring Therapy

• Atomoxetine has a propensity to increase heart rate
• Cannabinoid-containing products have a propensity to increase heart rate
• Isoproterenol is found to be degraded by catechol O-methyltransferase (C.O.M.T.) and may rise to dangerous levels in the presence of a C.O.M.T. inhibitor.
• Doxofylline might lead to an increased risk of doxofylline toxicity
• Tedizolid might lead to an increased risk of a hypertensive episode

Risk D: Consider a Modifying Therapy

• Topical Cocaine might lead to a heightened risk of hypertension, tachycardia, and increased oxygen demand.
• Linezolid might cause an increased risk of hypertension due to C.O.M.T. inhibitor-like action.
• Mifepristone might lead to QTc prolongation while using Isoprenaline
• Avoid administering Isoproterenol in combination with other QTc prolonging agents.

Risk X: Avoid the Use or Use Alternatives

• Methamphetamine
• Midodrine
• Phendimetrazine
• Procarbazine
• Sotalol
• Inhaled Anesthetics: Increased risk of arrhythmia
• Benzphetamine
• Clomipramine
• Diethylpropion
• Epinephrine

The common side of Isoprenaline includes the following:

• Anxiety
• Fast heart rate
• Coughing up blood or bloody froth
• Fatigue
• High or low blood pressure
• Weakness
• Dizziness
• Fainting
• Lightheadedness
• Shortness of breath
• Worsening symptoms
• Chest pain
• Racing or pounding heartbeats
• Loss of consciousness
• Paleness
• Abnormal movements
• Coldness of the skin

• Pregnancy

Pregnancy Category C

There is no well-established data on pregnant patients. Isoprenaline should be administered and used during pregnancy only if the potential benefit outweighs the risks.

• Labor and Delivery

Use Isoprenaline/Adrenaline with caution during labor and delivery in pregnant women. Although Isoprenaline is found to improve maternal hypotension associated with anaphylaxis, it might result in fetal anoxia, uterine vasoconstriction, and decreased uterine blood flow.

• Nursing Mothers

Isoprenaline or the components of the drug medication has not been found to be excreted in the milk; therefore, a decision should be made by the treating physician whether to continue or discontinue the medication, and it should be only used if the benefits outweigh the risks.

• Pediatric Use

The safety and efficacy of Isoprenaline in pediatric patients have not been established. Intravenous infusions of Isoprenaline in children with refractory asthma at rates of 0.05-2.7 mcg/kg/min of Isoprenaline have caused clinical deterioration, myocardial necrosis, congestive heart failure, and death. The risks of cardiac toxicity have been found to be increased by some factors such as acidosis, hypoxemia, coadministration of corticosteroids, and coadministration of methylxanthines (theophylline, theobromine) or aminophylline. These are especially likely to be present in these patients.

• Geriatric Use

Clinical studies involving Isoprenaline did not include sufficient numbers of elderly patients or subjects aged 65 and over to study and determine whether they respond differently from younger subjects or not. However, there are some data that suggest that elderly healthy or hypertensive patients are less responsive to beta-adrenergic stimulation than younger subjects. In general, a lower dose regimen is recommended for geriatric patients.

The physician should be vigilant about the knowledge pertaining to the identification as well as treatment of over dosage of molecule Isoprenaline.

Excessive doses of Isoprenaline in animals or man has been found to lead to a striking decrease in blood pressure, and repeated large doses in animals might lead to cardiac enlargement and focal myocarditis. While Accidentally, over dosage has been found to cause mainly tachycardia or other arrhythmias, palpitations, angina, hypotension, or hypertension.

Treatment:

Reduce the rate of administration or discontinue isoproterenol hydrochloride injection until the patient's condition stabilizes.

Blood pressure, pulse, respiration, and ECG should be monitored.

Pharmacodynamics

Isoprenaline is a non-selective beta-adrenergic receptor agonist which used in a number of indications for heart-related diseases, as well as bronchospasm in anesthesia. Isoprenaline is known to have a short duration of action as it is rapidly cleared and has a wide therapeutic index.

Pharmacokinetics

• Absorption

The Data regarding absorption kinetics of Isoprenaline are not available.

• Volume of distribution

In pediatrics, the volume of distribution was found to be 216 ± 57 mL/kg.7

• Protein binding

Isoprenaline was found to be 68.8 ± 1.2% protein bound in plasma, mainly to serum albumin.

• Metabolism

Isoprenaline has been found to be predominantly metabolized to glucuronide conjugates. Also, it can be O-methylated by catechol O-methyltransferase to the metabolite 3-O-methylisoprenaline, which can also be further glucuronidated.

• Route of elimination

Isoprenaline is found to be 12.2-27.0% recovered in the feces and 59.1-106.8% recovered in the urine after 48 hours of administration. The majority of the recovered dose in the urine sample is found to be conjugated Isoprenaline, with 6.5-16.2% free Isoprenaline and 2.6-11.4% 3-O-methylisoprenaline and conjugates.

There are some clinical studies of the drug Isoprenaline mentioned below:

1. Almquist A, Milstein S, Goldenberg IF, et al., "Provocation of Bradycardia and Hypotension by Isoproterenol and Upright Posture in Patients With Unexplained Syncope," N Engl J Med, 1989, 320(6):346-51.

2. Benditt DG, Ferguson DW, et al., "Tilt Table Testing for Assessing Syncope. American College of Cardiology," J Am Coll Cardiol, 1996, 28(1):263-75.
3. Castilla M, Jerez M, Llácer M, Martinez S. Anaesthetic management in a neonate with congenital complete heart block. Paediatr Anaesth. 2004;14(2):172-175.
4. Denis A, Sacher F, et al. Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol. 2014;7(4):590-597.
5. Eichenwald EC, Hansen AR, Martin CR, eds. Cloherty and Stark's Manual of Neonatal Care. 8th ed. Lippincott William and Wilkins; 2017.

6. Isoproterenol Hydrochloride [prescribing information]. East Brunswick, NJ: Avet Pharmaceuticals Inc; December 2021.
7. Isuprel (isoproterenol). Bridgewater, NJ: Valeant Pharmaceuticals North America L.L.C.; August 2016.
8. Keren A, Tzivoni D, et al., "Etiology, Warning Signs and Therapy of Torsade de Pointes. A Study of 10 Patients," Circulation, 1981, 64(6):1167-74.
9. Mahon WA, Day R.A.R.A., et al. "The in vivo Effects of Beta-Adrenergic Stimulation and Blockade on the Human Uterus at Term," J Pharmacol Exp Ther, 1967, 156(1):178-85.
10. Matsubara S, Morimatsu Y, et al. Fetus with heart failure due to congenital atrioventricular block treated by maternally administered ritodrine. Arch Gynecol Obstet. 2008;278(1):85-88.
11. Morillo CA1, Klein GJ, Zandri S, et al. Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J. 1995;129(5):901-906.

12. Sinclair-Pingel J, Grisso AG, Hargrove FR, et al. Implementation of standardized concentrations for continuous infusions using a Computerized Provider Order Entry System Hosp Pharm. 2006;41(11):1102-1106.
13. Van Diepen S, Katz JN, et al.; American Heart Association Council on Clinical Cardiology; Council of Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; Mission: Lifeline. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation. 2017;136(16):e232-e268.

1. https://www.drugs.com/sfx/isoproterenol-side-effects.html
2. https://www.webmd.com/drugs/2/drug-13986/isoproterenol-injection/details
3. https://www.medindia.net/doctors/drug_information/isoprenaline.htm#Sideeffects
4. https://www.rxlist.com/isuprel-drug.htm#description
5. https://www.just.edu.jo/DIC/AZLibrary/Isoprenaline.pdf
6. https://reference.medscape.com/drug/isuprel-isoproterenol-342438#0
7. go.drugbank.com/drugs/DB01064
8. www.accessdata.fda.gov/drugsatfda_docs/label/2013/010515s031lbl.pdf
9. https://pubchem.ncbi.nlm.nih.gov/compound/Isoproterenol#section=2D-Structure