CE Article: A Guide to Autonomic Pharmacology

Objectives

• Review how the autonomic nervous system controls body functions
• Describe the physiology of the autonomic nervous system
• Discuss the physiologic responses that occur with specific neurotransmitters
• Outline the mechanism of action of pharmacological agents

The autonomic nervous system is responsible for the control of a wide variety of body functions. Through a process of chemical signaling and neurotransmitters, it exerts significant control over such crucial physiologic events as cardiovascular response and pulmonary mechanics. Through use of pharmacology, the medical provider can apply their knowledge of these systems to modify human response and interrupt pathological processes. A solid understanding of autonomic physiology and medications is vital to the clinical practice of the prehospital provider. 

Receptor Theory

Although the result of using an autonomic medication can be large and create obvious clinical changes, such as a rapid heart rate or resolution of wheezing, the mechanism of action occurs at the molecular level. The concept of receptors and their activating chemicals is the key to understanding autonomic pharmacology.

Within the body, changes to meet the demands of external or internal stimuli are controlled by a process of chemical signaling molecules, neurotransmitters, and their associated receptors. The neurotransmitters can be released from many organs, including nerves, the brain and the adrenal glands. These chemicals are often small single molecules that freely circulate throughout the body. Various tissues have receptor sites on their surfaces; these sites act as the lock for which the neurotransmitter is the key. When the molecule fits into the receptor, changes within the cells and tissues produce a specific response.¹

Each organ and cell that has a receptor may respond in a different fashion to a given neurotransmitter. In this way a single released chemical, such as epinephrine, may produce a wide variety of responses. The receptors are designed to best fit a single type of neurotransmitter, but there can be overlap with others, allowing for some cross-reactivity between compounds. Additionally some pharmaceuticals can block these receptor sites, stopping and sometimes reversing the body’s physiologic or pathologic response to neurotransmission.¹

Physiology

The autonomic nervous system is often considered to be in control of the unconscious functions of the body. Among the key roles of this system are regulation of heart rate, blood pressure, muscle tone and the gastrointestinal tract. Within the autonomic nervous system, there is a classic separation into the sympathetic and parasympathetic divisions. From the perspective of pharmacology, this is important because the two systems typically utilize different neurotransmitters. Additionally, some of the neurotransmitters used in the parasympathetic system are heavily involved in muscle function (through the somatic nervous system) and within the brain as well.²

The sympathetic nervous system is considered to be responsible for preparing the body for physical activity. This can occur rapidly in response to a perceived threat or desire for intense speed and strength. Often termed the “fight or flight” response, this system utilizes the hormones norepinephrine and epinephrine as neurotransmitters. Epinephrine is also known as adrenaline; the receptors in the sympathetic system are accordingly known as adrenergic.

The parasympathetic nervous system works in opposition to the sympathetic nervous system. It regulates functions of the body that occur during times of rest and recovery. Examples of this include digestion, sexual functions, salivation and control of the bowel and bladder. The parasympathetic system is naturally engaged at times when sympathetic activity is not required. This makes logical sense. For example, if one needed to run or fight for survival, it would not be beneficial to have a mouth full of saliva and feel the overwhelming desire to urinate. The parasympathetic system utilizes acetylcholine as its hormone, an important point given that this transmitter is also used to signal muscle contraction and brain activity.

Autonomic Receptors

A wide variety of physiologic responses can occur with just a few neurotransmitters, thanks to different classes of autonomic receptors. Individual tissues and organs will use different types of receptors to enable the entire body to adjust and prepare for required action or rest. Understanding the normal receptor functions allows for explanation of physiologic responses as well as the use of pharmacologic agents to correct pathology.

Adrenergic Receptors

Adrenergic, or catecholamine, receptors respond to the naturally occurring hormones epinephrine and norepinephrine. Because these hormones are used primarily by the sympathetic nervous system, it stands to reason that the majority of the responses triggered by these receptors help enable vigorous activity. By activating or blocking specific receptors with medications, we can achieve desired clinical effects. Certain classes of adrenergic receptors may cause the opposite effects in a given tissue; the exact clinical outcome is determined by the number of receptors, the strength of their function and the relative ability of the medication/hormone to activate each receptor.

Alpha-1—The alpha-1 (α1) receptor has the most pronounced clinical effect due to its presence on blood vessels. When it’s activated constriction of both veins and arteries occurs. This can lead to a profound increase in blood flow to the tissues and an increase in blood pressure. Vasoconstriction in some tissues can have other effects as well, such as in the nose and sinuses, where this results in a reduction of congestion.

Alpha-1 is also found in other tissues and produces effects that are important but less relevant to the prehospital provider. The muscles of the iris in the eye will contract due to alpha-1 stimulation, causing a dilated pupil. This same receptor is also responsible for maintaining bladder sphincter tone and preventing urination. Additionally, alpha-1 activates mechanisms in the follicles to cause hair to stand on end.³

Beta-1—Beta-1 (ß1) receptors are crucial to cardiac activity. Found mostly in cardiac tissue, they increase heart rate and the strength of cardiac contraction. This lets the body dramatically increase cardiac output to meet demands. Additionally, the kidney is triggered through a beta-1 pathway to release a hormone called renin, which undergoes several transformations, producing compounds that increase vascular tone and salt retention, leading to increased blood pressure.³

Beta-2—Beta-2 (ß2) receptors are found on various types of muscles where they cause relaxation. Within the lungs beta-2 relaxes smooth muscles around the small airways, opening up the lungs to allow for improved ventilation. This same receptor is also found in the muscle of the arterioles, where it will cause relaxation, dilating the arterial vasculature and causing a decrease in blood pressure. Depending on the state of the remainder of the cardiovascular system, this can improve cardiac output in some circumstances. Beta-2 also relaxes muscles in the uterus and can help regulate and stop contractions during labor.³

Alpha-2—The alpha-2 (α2) receptor is more complicated in its action than the aforementioned adrenergic sites. It primarily lives in the brain. When activated it tells the body to decrease sympathetic nervous system activity. Although this receptor is triggered by the same hormones as the other catecholamine receptors, it acts in an inhibitory function, suppressing further sympathetic output. This allows the body to regulate the degree to which the sympathetic nervous system affects the various tissues and helps prevent overstimulation.

Even more complicated is that, in addition to acting in the brain to decrease sympathetic output, alpha-2 is also found outside the central nervous system, where it has some effects similar to alpha-1. For example, when alpha-2 is triggered on the blood vessels, it causes constriction and increased blood pressure, but when triggered in the brain it decreases sympathetic activity, causing dilation and lowering blood pressure. Certain medications outside the scope of the prehospital environment take advantage of this dual function for controlling hemodynamics and providing sedation.³

Acetylcholine Receptors

Acetylcholine (ACh) is the primary neurotransmitter of the parasympathetic nervous system. It is also the signaling molecule between nerves, traveling long distances within the central nervous system (CNS). Additionally, this chemical is what nerves use to trigger skeletal muscle contractions. The presence in the CNS and muscles is important when using agents that affect parasympathetic physiology. Additionally, this cross-reactivity becomes important in several pathologic conditions relevant to the prehospital provider, such as nerve agent poisoning. There are two main types of ACh receptors, with their location and function dictating their clinical response.

Nicotinic receptor—The nicotinic acetylcholine receptor was so named due to its reactivity to nicotine, a compound well known for its presence in tobacco products. Receptors of this variety are located throughout the nerves in the brain as well as junctions of nerves within the autonomic nervous system. Through their action, acetylcholine is used for a large amount of signaling and nerve transmission.

Nicotinic receptors are also responsible for locomotion and a majority of voluntary movement. Skeletal muscles are triggered to fire through this receptor and the acetylcholine released by nerves.

Muscarinic receptor—The muscarinic acetylcholine receptor is responsible for the majority of the direct effects of the parasympathetic nervous system. It is located on tissues controlled directly by the parasympathetic nerves. Additionally, this receptor exists in between nerves that release hormones of the sympathetic nervous system, which, while not as clinically important, demonstrates interplay between the neurotransmitters. Acetylcholine is needed to activate both branches of autonomic responses.

Muscarinic receptors play one of their most important roles in the regulation of the heart. Present at both the SA and AV nodes, this system allows for fine-tune control of the heart rate. Stimulation at the SA node by the parasympathetic system (by way of the vagus nerve) results in bradycardia. At the AV node, muscarinic activation slows the electrical conduction of the heart. In this manner high amounts of parasympathetic activity can result in bradycardia and heart blocks.

Within the lung acetylcholine acts through muscarinic sites to contract bronchial muscles. This normally regulates air flow through the lungs but can lead to bronchospasm and wheezing when in pathologic states.

The muscarinic receptor is also primarily responsible for urination. By relaxing the urinary sphincter and contracting the muscles of the bladder, the parasympathetic nervous system coordinates this activity.

Other Receptors

In addition to the adrenergic receptors, the body produces two other receptors: dopamine and beta-3 receptors.

Dopamine—Dopamine receptors of varying types exist throughout many systems in the body. As it applies to autonomic physiology, dopamine works as an indirect catecholamine. This neurotransmitter encourages the release of such compounds as epinephrine and norepinephrine, leading to sympathetic effects. Dopamine’s receptors can cause some vasodilation within various tissues, such as the kidney, gastrointestinal tract, brain and heart, but these effects are generally not clinically useful to the EMS provider. Dopamine receptors play a large role in neuropharmacology and may be best discussed in the setting of psychiatric medications.

Beta-3—Beta-3 (ß3) receptors have been discovered primarily in adipose (fat) tissue. Here they serve to increase breakdown of fat and increase heat generation in the body. There is growing interest in study of this topic as it relates to exercise physiology, obesity and cardiovascular disease.⁴

EMS Autonomic Medications

Armed with an understanding of the various autonomic receptors, one can begin to understand the mechanism of action of many pharmaceutical agents. Several commonly used prehospital medications directly stimulate or block the sympathetic nervous system. Less common but still important is pharmacologic control of parasympathetic response.

Epinephrine

The first thing to understand about epinephrine is its mechanism of action. Epinephrine acts as a direct stimulator of the adrenergic receptors throughout the body. At high enough doses, it is a strong activator of all types of alpha and beta receptors. Even at lower doses it is more active at the beta-2 receptor than several other autonomic medications.⁵ Because of epinephrine’s ability to trigger multiple classes of receptors, it is considered nonselective, and one must anticipate all the pharmacologic responses of administration.

Cardiac arrest is a condition in which epinephrine is frequently administered. Because this medication can produce stimulation of the beta-1 receptor, the thought is that it can drive a heart into beating more effectively, increasing heart rate and contractility. Additionally, the poor vascular tone found in cardiac arrest would be improved with alpha activity.

Recent discussion has raised controversy over the use of epinephrine in cardiac arrest. Advanced Cardiac Life Support (ACLS) guideline revisions over the years have trended toward a reduction in interventions and a focus on high-quality CPR.⁶ With the removal of routine atropine and pacing from the pulseless electrical activity (PEA)/asystole algorithm, few medications and procedures remain in the guidelines.6 Epinephrine remains one of the only medications to be given during cardiac arrest, every 3–5 minutes regardless of nonperfusing rhythm.

The question remains of the efficacy of epinephrine in cardiac arrest. Many providers are reluctant to consider abandoning this medication because it remains one of the few interventions in the arsenal. It has been well demonstrated that epinephrine can lead to return of spontaneous circulation (ROSC) in cardiac arrest patients.⁷ However, convincing evidence doesn’t yet exist to support the theory that epinephrine can lead to improved survival to hospital discharge. People may be revived in the field or hospital only to die several days later. Furthermore, survival with good neurological outcome is even less supported.⁸ Discussion continues regarding the ethics of reviving a patient who remains 100% dependent on medical support to remain alive in a long-term care facility.⁹

With regard to decision-making on epinephrine in cardiac arrest, critics will cite the lack of available evidence of good outcomes. Recent reviews suggest some conflicting data and poor methodology in finding a benefit for epinephrine use for meaningful results.¹⁰ Supporters can point to improvement of ROSC. This, combined with such new technology as extracorporeal membrane oxygenation, may lead to a paradigm shift and more research in coming years. If technology not available in the prehospital environment can lead to improved survival to discharge, it may become more desirable to use epinephrine in the field because the higher rate of ROSC could then translate into better neurologically intact survival rates.

Acute anaphylactic shock is another life-threatening and time-sensitive condition in which epinephrine may prove useful. Its prompt recognition and treatment may be crucial to patient survival. Many EMS systems have protocols in place to allow for all levels of provider to administer epinephrine to these patients. Additionally some jurisdictions allow prescribing to lay individuals and first aid providers, letting them have epinephrine auto-injectors on hand in the event of an emergency (summer camps being the classic example).

Epinephrine treats anaphylaxis through multiple mechanisms. As a strong adrenergic agent, it activates alpha-1 receptors, improving blood pressure and the vasodilation of shock. Beta-1 effects improve cardiac output and further treat shock. Beta-2 stimulation helps with the bronchospasm and wheezing elements. Additionally, through the beta receptors, epinephrine works inside the cells of the immune system that trigger anaphylaxis to stop their release of further detrimental chemicals.

In shock: Similar to its use in cardiac arrest, epinephrine can function to reverse multiple other shock states. It is considered a second- (or first-) line agent in multiple etiologies of hypoperfusion. By increasing vascular tone using its alpha agonism, it can counteract pathology in distributive shock states, such as sepsis, anaphylaxis and neurogenic shock from spinal injury. In cases of low cardiac output, epinephrine increases heart rate and contractility with beta-1 stimulation. However, epinephrine is a relatively potent medication and is nonselective for adrenergic receptors, so take care to monitor for adverse events resulting from overaggressive vasoconstriction or heart rate increase. Tachyarrhythmias and poor perfusion of end organs (including the heart) are potential complications.

In asthma: Prior to the advent of inhaled beta-agonists, epinephrine and similar injectable medications were used in the treatment of asthma. In stimulating beta-2 receptors, this intervention can reduce bronchospasm and improve ventilation. It can be efficacious in treatment of severe acute asthma attacks, but the ubiquity of inhaled therapies means they have largely replaced epinephrine. Still, there may be a small subset of patients best suited for a trial of epinephrine—usually asthmatics on the verge of respiratory arrest for whom this medication can be given to prevent intubation or while the airway equipment is being prepared. Patients with such profound bronchospasm may not ventilate well enough to distribute the inhaled medications, so parenteral ß2 agonists, such as epinephrine, may facilitate further treatment.¹¹

Norepinephrine

One of the body’s naturally occurring adrenergic hormones, norepinephrine, has a role as a pharmaceutical intervention. This medication is often given as an intravenous infusion and thus is often limited to EMS units operating with supplemental or critical care protocols. Norepinephrine is considered to be a vasopressor and has strong activity at the alpha-1 receptors. It can be used in shock states to improve blood pressure and end organ perfusion. This medication also has beta-1 activity and is known to augment heart rate, contractility and cardiac output, although the vasoconstriction effects are more pronounced than those on heart rate. It has less beta-2 agonism than epinephrine so is not typically used for such conditions as asthma. Norepinephrine is considered the first-line vasopressor for adult septic shock refractory to fluid administration.12 Because all strong α1 agonists cause constriction of small blood vessels, it is important to have adequate intravascular volume prior to administration. This is to avoid causing ischemia.¹²

Dopamine

Dopamine is a medication carried by many ALS-level providers for treatment of shock. Through an indirect mechanism of stimulating release of other catecholamines, dopamine can augment blood pressure and cardiac output. Dopamine is known to induce tachycardia, which can be a detrimental side effect, especially in patients with underlying arrhythmias such as atrial fibrillation.¹³ The corollary is that dopamine is often considered a pharmacologic intervention for bradycardia because of its direct stimulation of heart rate. There is some incorrect classical teaching that dopamine is safer than norepinephrine when administered through a peripheral (rather than central) intravenous site; case reports of dopamine extravasation reveal potential for severe skin and tissue damage. Careful titration and patient monitoring must occur during administration, with awareness of the possibility of adverse events.¹⁴

Albuterol

A well-known medication to EMS providers, inhaled albuterol is a mainstay of treatment for asthma and chronic obstructive pulmonary disease. Albuterol is considered to be a ß2-selective agonist and works mainly to cause bronchodilation. This relieves airway obstruction, allowing improvement of exhalation and expulsion of carbon dioxide. Clinically one may appreciate improved lung sounds and reduction of wheezing with administration.

Although considered selective for beta-2, there are still some beta-1 effects that cross over, and patients may become tachycardic or feel anxious with treatment. In the majority of patients, the benefit of improved ventilation outweighs the side effects of albuterol, and the medication is considered safe and effective.

Atropine

Compared to previously discussed medications that function by stimulating the various receptors of the sympathetic nervous system, atropine has a different mechanism of action. This pharmacologic agent acts by blocking the acetylcholine receptors of the parasympathetic system. In doing so, atropine blocks many parasympathetic functions, which can be useful clinically.

The primary EMS use of atropine is for treatment of bradycardia. Parasympathetic signaling through the vagus nerve is used to slow heart rate at both the SA and AV nodes. By counteracting this control with atropine, certain bradycardic rhythms can be treated with varying degrees of efficacy. Atropine also has a role in certain toxicological conditions.

Ipratropium Bromide

Ipratropium is an inhaled anticholinergic medication. By blocking the muscarinic acetylcholine receptors in the lungs, it causes relaxation of smooth muscles and leads to bronchodilation. Anticholinergic medications such as this can also help reduce secretions, further improving pulmonary function. It is typically used in the treatment of COPD and asthma. This medication is sometimes given in combination with albuterol, which reduces bronchospasm through a different cellular mechanism and provides a synergistic response. It is considered a safe medication with limited adverse side effects.

Metoprolol

Metoprolol is a medication sometimes used by EMS agencies for treatment of cardiac pathology. This drug functions by blocking the beta-1 receptors in the heart. Doing so causes a decrease in heart rate and cardiac contractility. This medication may be used for treating certain tachyarrhythmias due to this property. As beta-1 blockade decreases cardiac output, blood pressure may drop; however, the body may compensate in the peripheral vasculature through an alpha-1 mechanism, which is not altered by this medication. The prehospital provider should be aware that patients’ home medications may include metoprolol or a similar beta-blocking agent, and they consequently may not demonstrate tachycardia as a warning sign for pathology.

Labetalol

Labetalol, with a similar suffix to the previous medication, is also a beta-blocking agent. However, unlike metoprolol, labetalol is considered to be nonselective. This medication causes a blockade of beta-1, beta-2 and alpha-1 receptors. Through beta-1 antagonism, heart rate and contractility are decreased, lowering cardiac output and pulse. The addition of alpha-1 blocking produces a decrease in blood pressure in normal patients. The most frequent use of labetalol in the acute setting is rapid control of blood pressure during hypertensive emergencies. Because this medication also blocks beta-2 receptors, it can cause bronchospasm, so care must be given in the setting of asthma or COPD.¹⁵

Rocuronium

Advanced airway management by appropriately trained and credentialed EMS providers may sometimes include rapid sequence induction. Along with multiple elements of preparation and ensuring patient safety, this requires a key series of medications. After the use of a sedative to induce unconsciousness, a medication like rocuronium is given to cause muscular relaxation and paralysis, allowing for improved intubation conditions.
Rocuronium achieves a neuromuscular blockade by acting on the nicotinic acetylcholine receptors at the nerve-muscle junction. With nerve signaling interrupted, the skeletal muscles become unable to contract, and both voluntary and reflex movement is halted. This medication is one of a large class of drugs with similar effects, with succinylcholine and vecuronium as other examples used in the prehospital setting due to their desirable onset time and duration of action.¹⁶

Autonomic Pathology

In addition to the varying medical conditions that can be treated by autonomic agents, many pathologic conditions are related specifically to the autonomic nervous system. Understanding these processes, mechanisms and treatments helps to illustrate the pharmacologic properties of interventions.

Organophosphate Poisoning

Organophosphates are chemical compounds found in nature and also used by farming and manufacturing industries. They are used in agriculture as pesticides, and this offers a potential for human exposure. Additionally, organophosphates are the compound behind the chemical weapons commonly known as “nerve agents,” such as sarin and VX. Accidental poisoning in rural areas can occur, but they also carry the potential for mass casualties from terrorism, as was seen in the 1995 attack on the Tokyo subway system.¹⁷

Physiologically organophosphates deactivate a molecule in the body known as acetylcholinesterase. This enzyme is responsible for regulating the amount of acetylcholine present and freely available to cause effects. With the enzyme disabled, an overabundance of acetylcholine leads to overstimulation of the nicotinic and muscarinic receptors.¹⁷

The muscarinic acetylcholine receptors are responsible for the majority of the direct functions of the parasympathetic nervous system. As a result the poisoned patient will have an exaggerated and inappropriate amount of activity from this autonomic system. They will have nausea, vomiting, diarrhea and spasm of the gastrointestinal tract. The increase in heart activity can cause bradycardia. The most lethal portion of this toxidrome is the increase in respiratory secretions and salivation; the patient can aspirate and drown in their own bodily fluids.

As the nicotinic receptors are involved in muscular signaling, overstimulation can cause muscle spasm and convulsions. As muscles become fatigued, weakness can develop. Effects of too much acetylcholine in the brain can lead to seizures and mental status changes.

Treatment of acetylcholinesterase or organophosphate poisoning involves the use of atropine. In addition to aggressive supportive care and treatment of seizures, atropine helps block acetylcholine and reverse the underlying cause of pathology. Although bradycardia may be reversed early with this medication, goals of treatment are to improve the respiratory status by drying out the profuse secretions and allowing for oxygenation. An additional medication, pralidoxime, is also sometimes given to prevent the poison from permanently deactivating the vital enzyme. If this were to occur, it would prolong the duration of poisoning.¹⁷

Cocaine Abuse

Cocaine functions through a complex mechanism that increases the amount of neurotransmitters present in the body. The mental status effects as well as its addictive properties are a direct result of the chemical alteration in the brain. Additionally, the abundance of adrenergic hormones causes a surge in the sympathetic nervous system. The patient may be altered, agitated or combative but also be profoundly hypertensive and tachycardic.

As these vital sign abnormalities may lead to end-organ damage such as stroke or heart attack, it is tempting to use medications as an intervention. Beta-blocking agents are considered contraindicated in cocaine use. When given, the vasodilation of beta-2 receptors is removed, and the patient is left with all the sympathetic stimulation focused on the α1 sites, resulting in potential for a further surge in blood pressure and increased potential for negative outcomes. Labetalol, although considered to have α1 blocking activity, is much more potent of a beta-blocker. Studies have shown labetalol to be unsafe in cocaine toxicity.¹⁸ If a medication is given in response to vital sign abnormalities alone, care must be taken to reduce alpha-adrenergic activity. Benzodiazepines are often considered the mainstay of initial treatment due to their effects on the central nervous system; calming the patient may additionally cause an improvement in cardiovascular status.

Conclusion

Autonomic pharmacology represents a complex system of control over the working of many physiologic mechanisms. By understanding neurotransmitters and their receptors, prehospital providers can somewhat reliably choose the correct medication for a given disease state. The division of sympathetic and parasympathetic systems allows the provider to approach several acute issues with different modalities of treatment, such as the use of combined albuterol and ipratropium for obstructive lung disease. As new medications are deployed with EMS providers, this fundamental understanding of autonomic workings can allow for easier adoption of best practices.

References

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18. McCord J, Jneid H, Hollander JE, et al.; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation, 2008 Apr 8; 117(14): 1,897–907.

Bryan B. Kitch, MD, is an EMS fellowship-trained emergency physician practicing in Greenville, NC. He is a full-time faculty member at East Carolina University. In addition to medical direction for local EMS, he provides oversight to the regional disaster team and hospital disaster management. He previously served as a firefighter/EMT in central Pennsylvania.