Adrenergic Drugs

Article Author:
Khashayar Farzam
Article Editor:
Anand Lakhkar
Updated:
11/11/2018 3:04:16 PM
PubMed Link:
Adrenergic Drugs

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.