Pharmacology 101: Beta Agonists, Anticholinergics And How They They Impact The Autonomic Nervous System

How is it that respiratory medicines work? If your a respiratory therapist like me, a quick review is always helpful. If you're a patient, it might be neat to learn how the medicines you have in your medicine cabinet work. So, here is a quick review. Today's focus will be on beta-adrenergic medicine like albuterol and anticholinergic medicine like Spiriva.

For starters, these types of medicines have some impact on the autonomic nervous system.

What is the autonomic nervous (ANS) system? It's the system that contains all the nerves, neurons, and neurotransmitters that control all your inner organs, including your heart, blood vessels, and lungs.
It also controls other organs, but for our purposes, we'll limit our discussion to these three.

The ANS responds to your internal and external environment by releasing certain chemicals (we'll get to these in a moment) that bind to receptor sites (we'll get to these in a moment too) on specific organs to tell them what to do. It contains two parts.

1. Sympathetic Nervous System (SNS). It stimulates your organs to respond to emergency situations. It essentially stimulates what is often referred to as the "flight or fight" response. 
2. Parasympathetic Nervous System (PNS). It inhibits (or shuts off) the SNS response. It returns your body systems back to normal status and controls these organs during normal, ordinary circumstances. 

Here are some of the bodily responses the ANS controls that we need to be concerned with. 

• Blood Pressure. 
• SNS: Narrows blood vessels to speed up the flow of blood to increase blood pressure
• PNS: Dilates blood vessels to slow the flow of blood to decrease blood pressure. 
• Heart Rate.
• SNS: Speeds up the rate and force to pump blood through narrowed vessels.
• PNS: Slows it down as less pressure is needed to pump blood through dilated vessels.
• Airways:
• SNS: Dilates airways to make breathing free and easy.
• PNS: Constricts Airways to return them to normal. 

Now we must delve into how the SNS affects these responses. To begin with, the ANS involves nerve cells that secrete neurotransmitters. There are two types of nerve cells, each of which secretes a neurotransmitter. 

1. Adrenergic. These are nerve cells that secrete the neurotransmitter norepinephrine, which stimulates an SNS response and inhibits a PNS response. 
2. Cholinergic. These are nerve cells that the neurotransmitter norepinephrine, which stimulates a PNS response and inhibits the SNS response. 

Neurotransmitters are transmitted through neurons and are attracted to certain receptors that are attached to certain cells in specific organs. The receptors include...

1. Adrenergic receptors. These are receptors that norepinephrine is attracted to. Another neurotransmitter called epinephrine (adrenaline) is also attracted to them. Neurotransmitters attracted to them are called catecholamines. When a catecholamine binds to an adrenergic receptor, it stimulates some SNS response. 
2. Cholinergic receptors. These are receptors that acetylcholine is attracted to. When acetylcholine binds to a cholinergic receptor, it stimulates some PNS response. 

There are two groups of adrenergic receptors. 

• α (Alpha). 
• α-1-Adrenergic Receptors. They line blood vessels and when stimulated by catecholamines this causes vasoconstriction.  
• β (Beta) Receptors. 
• β-1 Adrenergic Receptors. They line heart muscle tissue and are attracted to catecholamines, which cause an increase in rate and force of the heart to increase cardiac output. This is needed to create the needed pressure to pump blood through narrowed arteries. The purpose of these combined effects is to assure tissues receive adequate oxygenation during a stressful event. 
• β-2 Adrenergic Receptors. They line airway smooth muscles (from the trachea to terminal bronchioles). They are attracted to catecholamines, which cause bronchodilation to open airways. 

Sympathomimetic Medicine. These are medicines that are attracted to adrenergic receptors. They mimic catecholamine and include.

• Short-Acting Beta Agonists (SABA). These are medicines that are attracted to B2 receptors to relax bronchiolar smooth muscles to dilate (open) airways within minutes and only last 4-8 hours. They are non-specific to B1 and B2 receptors, and therefore offer negligible side effects. These include epinephrine (Adrenaline), albuterol (Ventolin, ProAir, Proventil), and levalbuterol (Xopenex). Some SABAs that are no longer used include Isoproterenol (isoprenaline), terbutaline, ephedrine (Ma-huang), and Metaproterenol (Alupent). These are also referred to as rescue medicine because they open airways relatively fast. As a general rule, most experts recommend all asthmatics and COPD patients have it nearby at all times. Epinephrine has the greatest risk for stimulating B1, B2, and A1 receptors and offering side effects. The other ones currently on the market have minimal effect on B1 receptors, although some studies show that they can cause an increased heart rate, increased blood pressure, and EKG changes in some individuals (although this is rare, it should be considered). The recommended dose of albuterol is 2 puffs every 4-6 ours. Studies seem to suggest that the medicine is safe for use in emergencies even at high doses, although the chronic use of high doses (using more than 6 times a day) may cause a decrease in beta 2 adrenergic receptors. This may cause tachyphylaxis, resulting in the need for even higher doses just to obtain minimal results. Excessive use of albuterol is a clear indicator of the need to seek medical attention and for physicians to consider asthma controller medicines or a step-up treatment approach for those already using controller medicines. While initial studies showed levalbuterol to offer fewer side effects to albuterol, more recent studies show it can produce the same side effects, and is therefore not superior to but equal to albuterol in as a bronchodilator, although it costs more due to a current patent. SABA's may also lower potassium. To learn more check out our post, "How Albuterol Lowers Potassium."
• Long-Acting Beta Agonists (LABA). These are beta agonists that last 12-24 hours. These include salmeterol and formoterol. These are rarely given alone for the treatment of asthma, although they remain viable options for asthma and COPD. For asthma, they are usually included in combination with an inhaled corticosteroid in inhalers like Advair, Symbicort, Dulera, and Breo. These are generally used as asthma controller or preventive medicine, and they must be taken every day to truly be effective. For COPD, they are considered a top-line option, although some studies seem to indicate that Spiriva alone offers improved lung function and reduction in the feeling of shortness of breath compared with LABA's alone. Formoterol in Symbicort and Dulera has a rapid onset and can open airways as fast as a SABA. Serevent in Advair opens airways in about 15 minutes. 

There are two groups of cholinergic receptors. 

• Muscarinic Receptors. Acetylcholine is attracted to them. When acetylcholine binds to them, this causes airways to narrow and mucus secretion to increase. 
• Nicotine. I won't even go here. This is a discussion for another day. 

Anticholinergic/ Muscarinic Medicine. These are medicines that are attracted to Muscarinic Receptors and thereby bind to them to prevent acetylcholine from binding to them. They are called anticholinergics because they block their effects by preventing them from binding to muscarinic receptors. Cholinergic stimulation has a primary effect on COPD, so anticholinergics are a top-line treatment for COPD. Studies seem to show that anticholinergics are equal in their bronchodilation effect for a patient with COPD compared to b2 agonists, and may even have a superior bronchodilation effect. Cholinergic stimulation has a secondary effect on asthma, so anticholinergics are a second-line treatment for asthma, although they remain an option worth trying for some with severe asthma.  Anticholinergic medicine cause bronchodilation, although do not decrease mucus secretion.

• Short-Acting Anticholinergics. They last 4-6 hours and are taken 4 times per day. Studies show they are helpful for treating acute asthma and COPD flare-ups. These include ipratropium bromide (Atrovent) and oxitropium bromide (not available in the U.S.). 
• Long-Acting Anticholinergics. These last 24 hours. They include tiotropium bromide (Spiriva), glycopyrrolate, (Seebri), umeclidinium (Incruse), and aclidinium bromide (Ttudorza). Older medicines include belladonna, stramonium, and atropine. Anticholinergic medicine remains second-line options for asthma and top-line options for COPD. Studies show that tiotropium bromide is slightly more effective at improving lung function, improving the quality of life, and reducing COPD flare-ups, compared with short-acting anticholinergics. Studies also show it is better at opening airways than LABA's for COPD. Side effects are negligible, with the most common being dry mouth. Incruse and Tudorza are the newer LABA's and I will look into studies regarding them in the future. 

There is a reason I listed the current medicines used and older medicines that are no longer used. This is because, over time, the molecules were adjusted to eliminate side effects and to increase the desired effect. Epinephrine, for instance, has a strong effect on α-1 leading to increased blood pressure, β-1 leading to increased heart rate and palpitations, and β-2 receptors leading to bronchodilation. So, while it opened airways, it also caused cardiac side effects along with tremors and nervousness. Ventolin, on the other hand, has a strong β-2 effect with a minimal effect on α-1 and β-1 receptors, meaning it has an equal bronchodilator effect to epinephrine with negligible side effects. Tremors and nervousness continue to be side effects, although these are acceptable tradeoffs to most asthmatics. 

Another good example is atropine. It was isolated in 1833 as the active ingredient of stramonium and belladonna. By the late 19th century it was routinely recommended for the treatment of asthma. Giving atropine alone was an improvement over stramonium and belladonna, which also had a strong effect on the mind, similar to marijuana. Atrovent was a mild bronchodilator, although enhance the salivatory response in the mouth, causing oral dehydration. It may also cause tachycardia. It also dilated pupils if you ever splashed it into your eyes. Atropine was a top-line asthma medicine in the 1980's, only to be replaced by Atrovent in the early 1990's. Atrovent was formulated in a way that side effects are negligible, although it can cause a dry mouth by oral absorption (which is a good reason to rinse after each use). The nebulizer solution of Atrovent, if splashed, can cause pupil dilation. The formula was modulated again to create the long-acting anticholinergics Spiriva, Incruse and Tudorza. 

So, there you have the basics of how the ANS affects the lungs and how it relates to the respiratory medicines. Any further questions, comments, or suggestion let me know in the comments below. 

References:

1. Low, Philip, "Overview of the Autonomic Nervous System," Merck Manual, https://www.merckmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/autonomic-nervous-system-disorders/overview-of-the-autonomic-nervous-system, accessed 7/717
2. Golan, David E., et al., editors, "Principles of Pharmacology," 3rd Ed., 2012, Lippincott, pates 113, 827
3. Albert, Richard K., Stephen G. Spiro, James R. Jett, editors, "Clinical Respiratory Medicine," 3rd ed., 2008, MosbyElsevier, pages 524-526