Adrenergic Drugs


Article Author:
Khashayar Farzam


Article Editor:
Anand Lakhkar


Editors In Chief:
Stephen Leslie
Karim Hamawy


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Carrie Smith
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Khalid Alsayouri
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James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/29/2019 2:21:04 PM

Indications

Adrenergic drugs are a broad class of medications which bind to adrenergic receptors throughout the body. These receptors include: alpha-1, alpha-2, beta-1, beta-2, beta-3. Adrenergic drugs will bind directly to one or more of these receptors to induce various physiologic effects. There are also drugs which indirectly act at these receptors to induce certain effects.

Adrenergic drugs must be classified based on the specific receptors they bind. Direct acting drugs, which are the primary focus of this article, include vasopressors, bronchodilators and other drugs.[1] Examples of indirect drugs are amphetamines and cocaine.[2] 

Major effects of agonist binding at adrenergic receptors:

  • Alpha-1 receptor: Smooth muscle contraction, mydriasis[3]
  • Alpha-2 receptor: Mixed smooth muscle effects[4]
  • Beta-1 receptor: Increased cardiac chronotropic and inotropic effects[5]
  • Beta-2 receptor: Bronchodilation
  • Beta-3 receptor: Increased lipolysis

Examples of adrenergic drugs which only bind on alpha-1 receptors are phenylephrine, oxymetazoline. Selective alpha-2 receptor drugs include methyl-dopa and clonidine. The key beta-1 selective drug is dobutamine. Lastly, beta-2 selective drugs are bronchodilators, such as albuterol and salmeterol. 

Adrenergic drugs can also be non-selective and hence bind to a combination of adrenergic receptors. Norepinephrine binds to the alpha-1, alpha-2, and beta-1 receptors. Dopamine binds to the alpha-1, alpha 2, beta-1 receptors, and also the two dopamine receptors. Epinephrine binds to all of the adrenergic receptors. These drugs bind to more of the adrenergic receptors when administered at higher doses.

The following are key non-comprehensive indications of various adrenergic drugs: 

Selective Drugs

Alpha-1 Receptor Agonists

Phenylephrine: FDA-approved as a decongestant and vasopressor. It is used in cases of hypotension due to shock, such as septic shock.[6]

Dexmedetomidine: Indicated for sedation in the intensive care unit and does not cause respiratory depression.

Oxymetazoline: FDA-approved as a decongestant and to treat rosacea. 

Alpha-2 Receptor Agonists

Methyldopa: FDA-approved for hypertension and gestational hypertension.

Clonidine: FDA-approved for treating hypertension and attention deficit hyperactivity disorder (ADHD). Non-FDA approved indications include sleep disorders, post-traumatic stress disorder (PTSD), anxiety, restless leg syndrome, hot flashes associated with menopause and other illnesses.[7]

Beta-1 Receptor Agonists

Dobutamine: Indicated for the treatment of cardiogenic shock and heart failure.[8]

Beta-2 Receptor Agonists

Bronchodilators: Indicated for the treatment of obstructive lung disease, such as asthma.[9]

Beta-3 receptors carry no clinical significance.

Non-Selective Drugs

Norepinephrine: Indicated for the treatment of shock and hypotension.

Adrenaline: Indicated for the treatment of cardiac arrest, anaphylaxis, and croup.

Dopamine: Treats hypotension, bradycardia, and cardiac arrest.

Isoprenaline: Indicated for treating bradycardia and heart block.

Many of these medications, especially the non-selective ones, are used in the critical care and emergency setting. They are referred to as vasopressors. Side effects depend on the specific agent. However, changes in heart rate and blood pressure are the most common side effects. 

Indirect acting adrenergic drugs increase norepinephrine and epinephrine through various mechanisms. Hence, their side effect profiles are similar to those seen with vasopressors.

Mechanism of Action

Adrenergic receptors, otherwise known as adreno-receptors, are classified based into alpha and beta receptors. Those two classes are further divided into alpha-1, alpha-2, beta-1, beta-2, and beta-3. Alpha-1 and alpha-2 receptors both have three subtypes. These receptors are all G-protein-coupled receptors. 

Alpha-1 receptors are Gq coupled-receptors; whereas alpha-2 receptors are Gi coupled-receptors. Beta-2 and beta-3 are also Gi coupled-receptors. All beta receptors are also Gs coupled-receptors. 

Agonist binding to the adrenergic receptors induces the following cellular mechanisms:

Alpha-1 Receptor

Phospholipase C is activated which leads to induction of inositol triphosphate (IP3) and diacylglycerol (DAG). As a result, calcium rises. 

Alpha-2 Receptor

Adenylate cyclase is inactivated which leads to a decrease in cyclic adenosine monophosphate (cAMP).

Beta-1 Receptor

Adenylate cyclase is activated, and cAMP increases.

Beta-2 Receptor

Adenylate cycle is activated through the Gs-protein-coupled receptors, and there is an increase in cAMP. Gi protein-coupled receptors are also activated, and this will decrease cAMP.[10][11]

Administration

Given adrenergic drugs are a broad class of medications; they are collectively available in almost every form. Common methods of administration are oral, intravenous, intranasal, and topical.

Adverse Effects

The adverse effects seen with adrenergic drugs are broad. The most common side effects are changes in heart rate and blood pressure. 

Selective agonist binding to the alpha-1 receptor can lead to hypertension. Certain drugs that bind to the alpha-1 receptor, such as phenylephrine, may cause bradycardia.[12]

Drugs that selectively bind to alpha-2 receptors may cause hypotension, dry mouth, and sedation. At higher doses, respiratory depression and somnolence may occur. These effects are most pronounced with clonidine and similar acting drugs.[13]

Selective binding to beta-1 receptors commonly causes tachycardia, palpitations, and hypertension. Tachyarrhythmias and anxiety can also be common. High doses may induce dangerous arrhythmias. An example of a selective beta-1 receptor agonist is dobutamine.

Beta-2 receptor agonists can cause tremor, tachycardia, palpitations, and anxiety. Common examples are the various bronchodilator drugs such as albuterol and salmeterol.[14]

Non-selective binding to the adrenergic receptors can cause different side effects that vary based on the specific agent as well as the dosage. The common non-selective agonists are norepinephrine, epinephrine, and isoprenaline. Common side effects are tachycardia, hypertension, arrhythmias, palpitations, and anxiety. Norepinephrine is less likely to cause arrhythmias than some of the other pressor medications.

Contraindications

  • Alpha-1 receptor agonists are relatively contraindicated in those who suffer from hypertension, bradycardia, prostatic hyperplasia and anyone using medications which may also increase blood pressure.[15]
  • Alpha-2 receptor agonists should be used cautiously in anyone who has low blood pressure. Geriatric patients may be at greater risk of falls due to the sedating and hypotensive effects. 
  • Beta-1 receptor agonists are to be used with caution in patients who have arrhythmias. 
  • Beta-2 receptor agonists are relatively contraindicated in patients who have hypokalemia.[14] 
  • Norepinephrine is relatively contraindicated when certain anesthetics are used. When halothane or cyclopropane are used, the risk of dangerous arrhythmias is increased.
  • Epinephrine is contraindicated in patients who have angle-closure glaucoma.

Monitoring

There is a broad variation in the therapeutic index of adrenergic drugs given the large number of medications.

Toxicity

Adrenergic receptors all have antagonists. Alpha-blockers are not generally indicated for the treatment of alpha agonist overdoses. Beta-blockers may be used to treat adverse effects arising from adrenergic receptor agonists acutely. The tachycardia and hypertension that may arise from vasopressors are treated with beta-blockers.

Enhancing Healthcare Team Outcomes

There are many types of adrenergic agents and healthcare workers including the nurse practitioner, physicians assistants, and physicians who prescribe these agents and each should be aware of their side effects and contraindications. It is important to consult with a pharmacist if there is any question about the use of an adrenergic agent. An interprofessional team approach is important to coordinate the care of patients taking these medications in a safe and effective manner. [Level V]


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Adrenergic Drugs - Questions

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Which of the following is the correct classification of adrenergic drugs?



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A 65-year-old male is started on clonidine. Which of the following side effects is he at risk for if the clonidine is used at very high doses?



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A 33-year-old male with a history of severe alcohol used disorder presents with delirium tremens. He is started on dexmedetomidine. Which of the following receptors does this drug bind to?



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Which class of adrenergic receptor agonists is useful in the treatment of asthma?



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A 57-year-old male patient is diagnosed with benign prostatic hyperplasia. He reports taking an over-the-counter decongestant to help with his hay fever. Which of the following medication classes is contraindicated in this patient given his new diagnosis, and would include his decongestant?



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Adrenergic Drugs - References

References

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Ciccarone D, Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy. Primary care. 2011 Mar     [PubMed]
Piascik MT,Perez DM, Alpha1-adrenergic receptors: new insights and directions. The Journal of pharmacology and experimental therapeutics. 2001 Aug     [PubMed]
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Hatton RC,Winterstein AG,McKelvey RP,Shuster J,Hendeles L, Efficacy and safety of oral phenylephrine: systematic review and meta-analysis. The Annals of pharmacotherapy. 2007 Mar     [PubMed]
Ming X,Mulvey M,Mohanty S,Patel V, Safety and efficacy of clonidine and clonidine extended-release in the treatment of children and adolescents with attention deficit and hyperactivity disorders. Adolescent health, medicine and therapeutics. 2011     [PubMed]
Dubin A,Lattanzio B,Gatti L, The spectrum of cardiovascular effects of dobutamine - from healthy subjects to septic shock patients. Revista Brasileira de terapia intensiva. 2017 Oct-Dec     [PubMed]
Matera MG,Rinaldi B,Page C,Rogliani P,Cazzola M, Pharmacokinetic considerations concerning the use of bronchodilators in the treatment of chronic obstructive pulmonary disease. Expert opinion on drug metabolism     [PubMed]
Seiler R,Rickenbacher A,Shaw S,Balsiger BM, alpha- and beta-adrenergic receptor mechanisms in spontaneous contractile activity of rat ileal longitudinal smooth muscle. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2005 Feb     [PubMed]
Ruiz-Medina BE,Cadena-Medina DA,Esparza E,Arrieta AJ,Kirken RA, Isoproterenol-induced beta-2 adrenergic receptor activation negatively regulates interleukin-2 signaling. The Biochemical journal. 2018 Sep 18     [PubMed]
Atkinson HC,Potts AL,Anderson BJ, Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review. European journal of clinical pharmacology. 2015 Aug     [PubMed]
Yasaei R,Saadabadi A, Clonidine null. 2018 Jan     [PubMed]
Almadhoun K,Sharma S, Bronchodilators null. 2018 Jan     [PubMed]
Roehrborn CG,Schwinn DA, Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. The Journal of urology. 2004 Mar     [PubMed]

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