Continuing Education Activity
Adrenergic drugs are a broad class of medications that 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. This activity examines the pharmacology, various therapeutic effects, and adverse events that class members can exert, which covers a wide variety of clinical manifestations.
- Identify the various actions of adrenergic medications based on the receptor to which they bind.
- Describe the various adverse effects of adrenergic drugs based on the binding site.
- Review the contraindications to various adrenergic drugs based on their preferred binding sites.
- Outline the importance of collaboration and coordination among the interprofessional team leading to improved patient care when using adrenergic agents.
Adrenergic drugs are a broad class of medications that 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. Some drugs 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. Examples of indirect drugs are amphetamines and cocaine.
Major effects of agonist binding at adrenergic receptors:
- Alpha-1 receptor: Smooth muscle contraction, mydriasis
- Alpha-2 receptor: Mixed smooth muscle effects
- Beta-1 receptor: Increased cardiac chronotropic and inotropic effects
- Beta-2 receptor: Bronchodilation
- Beta-3 receptor: Increased lipolysis
Examples of adrenergic drugs which selectively bind to alpha-1 receptors are phenylephrine, oxymetazoline. Selective alpha-2 receptor drugs include methyldopa 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 dopamine receptors. Epinephrine binds to all of the adrenergic receptors. These drugs bind to more of the adrenergic receptors when administered at higher doses, i.e., can lose selectivity.
The following are key clinical indications of various adrenergic drugs:
Alpha-1 Receptor Agonists
- Phenylephrine: FDA-approved as a decongestant and vasopressor. It has utility in cases of hypotension due to shock, such as septic shock.
- 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.
- Dexmedetomidine: Indicated for sedation in the intensive care unit and does not cause respiratory depression.
Beta-1 Receptor Agonists
- Dobutamine: Indicated for the treatment of cardiogenic shock and heart failure.
Beta-2 Receptor Agonists
- Bronchodilators: Indicated for the treatment of obstructive lung disease, such as asthma.
Beta-3 receptor Agonists
- Mirabegron: Indicated for the treatment of overactive bladder, e.g., urinary incontinence, urinary frequency
- Norepinephrine: Indicated for the treatment of shock and hypotension
- Epinephrine (Adrenaline): Indicated for the treatment of cardiac arrest, anaphylaxis, and croup
- Dopamine: Indicated for the treatment of 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 critical care and emergency settings. 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 endogenous concentrations of 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 as either alpha or beta receptors. Those two classes further subdivide 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:
Phospholipase C is activated, which leads to the formation of inositol triphosphate (IP3) and diacylglycerol (DAG). As a result, intracellular calcium rises.
Adenylate cyclase is inactivated, which leads to a decrease in intracellular cyclic adenosine monophosphate (cAMP).
Adenylate cyclase is activated, and intracellular cAMP increases.
The adenylate cycle becomes activated through the Gs-protein-coupled receptors, and there is an increase in intracellular cAMP. Gi protein-coupled receptors are also activated, and this will decrease intracellular cAMP.
Given adrenergic drugs are a broad class of medications, they are collectively available in almost every drug dosage form. Common methods of administration are oral, intravenous, intranasal, and topical. Dosages for Beta-1 agonists such as dobutamine can begin with 0.5 to 1 mcg/kg/min and go up to 40 mcg/kg/min on the maximum end. The doses at the lower end can also be prescribed at 2.5 mcg/kg/min to 5 mcg/kg/min. While doses at the higher end can be prescribed at 5 mcg/kg/min to 20 mcg/kg/min. 
While other medications such as clonidine (alpha-2 agonists) may be prescribed as transdermal patches with dosages of 0.1 mg/day to 0.3 mg/day while changing the patch every week. Clonidine can also be prescribed via an immediate-release tablet at 0.1 mg/day to 0.3 mg/day and an extended-release tablet with a dosage of 0.1 mg/day. Caution should be used when prescribing the medication to patients with renal failure as and it is recommended to begin with a low dose and increase as needed. 
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 reflex bradycardia.
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 similarly acting drugs.
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 tremors, tachycardia, palpitations, and anxiety. Common examples are the various bronchodilator drugs such as albuterol and salmeterol.
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 isoproterenol (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, probably because it is more alpha-1 receptor-selective as compared with the beta-1 receptor. 
- Alpha-1 receptor agonists are relatively contraindicated in those who have the following medical conditions: hypertension, bradycardia, prostatic hyperplasia, and anyone using medications, which may also increase blood pressure.
- Alpha-2 receptor agonists should be used cautiously in anyone who has low blood pressure. Geriatric patients may be at increased risk of falls due to the sedating and hypotensive effects.
- Beta-1 receptor agonists require caution in patients who have arrhythmias.
- Beta-2 receptor agonists are relatively contraindicated in patients who have hypokalemia.
- Norepinephrine is relatively contraindicated when using certain anesthetics. When dosing halothane or cyclopropane, there is an increased risk of dangerous arrhythmias.
- Epinephrine is contraindicated in patients who have angle-closure glaucoma.
There is a broad variation in the therapeutic index of adrenergic drugs given a large number of medications. When prescribing beta-1 agonists, care should be taken to monitor hypertension as well as potential arrhythmias. 
While prescribing alpha-2 agonists, patients should be monitored for bradycardia, hypotension, and potential substance abuse. 
Recent research has also counseled caution when administering beta-2 agonists as patients should be monitored for paradoxical bronchospasm, blood pressure, heart rate, and central nervous system effects. 
Adrenergic receptors all have drug 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. Beta-blockers can treat tachycardia and hypertension that may occur from vasopressors. Toxicity should be monitored in the pediatric population when using beta-2 agonists as they can increase concentrations of liver aminotransferase. 
In addition, when prescribing alpha-2 agonists, there are instances where angioedema, atrioventricular (AV) block, and hypersensitivity may occur. Potential toxicities of beta-1 agonists may include tremors, headaches, and vomiting. 
Enhancing Healthcare Team Outcomes
There are many types of adrenergic agents, and healthcare professionals, including the nurse practitioner, physician assistants, and physicians who prescribe these agents, should be aware of their side effects and contraindications. It is essential to consult with a pharmacist if there is any question about the use of an adrenergic agent; this can include drug-drug interactions, appropriate dosing based on the condition treated, and adverse event profile. Nurses can also access this resource as they will often administer the drugs inpatient and will need to know what signs to watch for in the event of an adverse reaction of any sort. An interprofessional team approach is vital to coordinate the care of patients taking these medications safely and effectively. [Level 5]