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. Adrenergic drugs must be classified based on the specific receptors they bind. This activity examines the pharmacology, various therapeutic effects, and adverse events that class members can exert, which covers a wide variety of clinical manifestations.

Objectives:

• 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.

Indications

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.[1] Examples of indirect drugs are amphetamines and cocaine.[2] 

The major effects of agonist binding depend on their adrenergic receptors.[3][4][5] The broad categories are:

• 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 and 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 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 adrenergic receptors when administered at higher doses, i.e., they can lose selectivity.

The following are key clinical indications of various adrenergic drugs: 

Selective 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.[6] Olson C. et al. reported on a patient who developed ischemic priapism from high doses of hydroxyzine hydrochloride (200 to 600 mg) for insomnia treatment. The patient received treatment with aspiration and 560 micrograms of intracavernosal phenylephrine, which led to detumescence.[7]
• Oxymetazoline: FDA-approved as a decongestant and to treat rosacea. A patient with ptosis of the right eye caused by myasthenia gravis was treated with one eye drop of oxymetazoline (0.1%).[8] The ptosis was eliminated after 2 hours, and the effect lasted seven hours. This is a potential clinical use of oxymetazoline.

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.[9]
• Dexmedetomidine: This drug is indicated for sedation in the intensive care unit and does not cause respiratory depression. It causes an arousable state of sedation which is helpful during brain tumor surgery and implantation of deep brain stimulators because the patient is able to respond to neurological tests.[10]

Beta-1 Receptor Agonists

• Dobutamine: Indicated for the treatment of cardiogenic shock and heart failure.[11] Patients in shock require hemodynamic support. Vasopressors (e.g., norepinephrine), inotropes (e.g., dobutamine), and IV fluid support are used for treatment. In most patients with shock (e.g., cardiogenic or septic), norepinephrine is commonly used to achieve appropriate arterial pressure. If the patient continues to have low tissue and organ perfusion, dobutamine can be added to increase cardiac output.[12]

Beta-2 Receptor Agonists

• Bronchodilators: Indicated for treating obstructive lung disease, such as asthma.[13]

Beta-3 receptor Agonists

• Mirabegron: This agent is indicated for treating overactive bladder, e.g., urinary incontinence and frequency. It is also indicated to treat pediatric (greater or equal to 3 years old) neurogenic detrusor overactivity.[14] 

Non-Selective Drugs

• 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. [15]

Mechanism of Action

Adrenergic receptors, otherwise known as adreno-receptors, are classified as either alpha or beta receptors. Those two classes are further subdivided 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 the formation of inositol triphosphate (IP3) and diacylglycerol (DAG). As a result, intracellular calcium rises. 

Alpha-2 Receptor

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

Beta-1 Receptor

Adenylate cyclase is activated, and intracellular cAMP increases.

Beta-2 Receptor

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.[16][17]

Investigators screened several cardiovascular drugs (e.g., methyldopa, amiodarone, doxazosin) and found that these affected in vitro Schistosoma mansoni viability.[18] This suggests that methyldopa might have antiparasitic properties.

Administration

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. [19]

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. [20]

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 reflex bradycardia.[21]

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.[20]

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.[22] Pediatric status asthmaticus is treated with continuous albuterol, which can cause hypokalemia.[23]

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.[15]

Contraindications

Alpha-1 receptor agonists are relatively contraindicated in those with the following medical conditions: hypertension, bradycardia, prostatic hyperplasia, and anyone using medications that 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.[22][24]

Monitoring

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.[19] 

While prescribing alpha-2 agonists, patients should be monitored for bradycardia, hypotension, and potential substance abuse.[20]

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.[25]

There are case reports of patients abusing clonidine alone or with benzodiazepines and opioid analgesics. Clonidine may extend the opioid-induced euphoria and decrease the opioid dose needed for euphoria.[26]

Toxicity

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 liver aminotransferase concentrations.[25]

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.[19][20]

Enhancing Healthcare Team Outcomes

There are many types of adrenergic agents, and clinicians, including physicians, nurse practitioners, and physician assistants who prescribe these agents, should be aware of their side effects and contraindications. Management requires an interprofessional team approach to drug therapy with these drugs since they cover such a broad spectrum of indications and effects, both therapeutic and adverse. 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.

All interprofessional team embers must document any changes in patient status in the patient's medical record and communicate their findings to other team members so therapeutic adjustments can be made. An interprofessional team approach is vital to coordinate the care of patients taking these medications safely and effectively. [Level 5]