Continuing Education Activity

The autonomic pharmacology program focuses on the sympathetic (SNS) and parasympathetic (PSNS) nervous systems, emphasizing their essential roles in regulating involuntary reactions across multiple organ systems. This activity explores how pathological conditions can disrupt the balance between the SNS and PSNS, leading to overactivity in one branch and inhibition in the other. These imbalances cause a range of clinical issues, from mild symptoms to severe outcomes such as cardiovascular collapse.

This activity highlights the classification of drugs approved by the US Food and Drug Administration (FDA) within autonomic pharmacology, including cholinomimetics or cholinesterase antagonists, anticholinergics, adrenoreceptor agonists or sympathomimetics, and adrenoreceptor antagonists, which participants learn about in detail. This activity covers the indications, mechanisms of action, adverse effects, contraindications, toxicology, and monitoring required to use these drugs effectively. This activity enhances the understanding of interprofessional healthcare providers of the pharmacological effects of drugs impacting the autonomic nervous system by providing a detailed examination of the pharmacology related to autonomic drugs. This activity also prepares the healthcare team to collaborate effectively in administering these medications with greater precision and efficacy, thereby enhancing therapeutic outcomes and ensuring personalized patient care and optimized health outcomes.

Objectives:

• Identify the roles of the sympathetic and parasympathetic nervous systems in regulating involuntary reactions across multiple organ systems.
• Implement appropriate therapeutic interventions using autonomic pharmacology drugs based on clinical indications.
• Select the most effective autonomic drug for specific clinical scenarios.
• Collaborate with interprofessional healthcare teams to optimize the use of autonomic pharmacology in patient care.

Indications

Autonomic pharmacology centers on the physiology of the sympathetic (SNS) and the parasympathetic (PSNS) nervous systems, regulating involuntary reactions to stress across multiple organ systems. When a pathological process disrupts the balance between the SNS and PSNS, one branch may become overactive while the other is excessively inhibited.[1] These disruptions in homeostasis can lead to a spectrum of clinical manifestations, ranging from mild symptoms, such as rhinorrhea, to severe outcomes, such as cardiovascular collapse.[2] The anatomical classification of these systems depends on the location of preganglionic neurons, including the SNS, known as the thoracolumbar division, and the PSNS, referred to as the craniosacral division of the autonomic nervous system (ANS).[3] Drugs in autonomic pharmacology are used across various presentations and severities to restore the homeostasis the ANS strives to maintain.[4]

FDA-Approved Indications

In the field of autonomic pharmacology, drugs are categorized into the following 4 groups based on their effects on the ANS, according to the US Food and Drug Administration (FDA) guidelines:

• Cholinomimetics or cholinesterase antagonists
• Anticholinergics
• Adrenoreceptor agonists or sympathomimetics
• Adrenoreceptor antagonists

These categories encompass various clinical indications, although the following list is not exhaustive due to the extensive scope of this field. The drugs mentioned are exemplary of each category.

Cholinomimetics or cholinesterase antagonists: The drugs belonging to this category are listed below.

• Bethanechol: This drug is used for postoperative and neurogenic ileus and urinary retention.

• Methacholine: This drug is administered during the methacholine challenge test to diagnose bronchial airway hyperactivity in patients without clinically apparent asthma.

• Pilocarpine: This drug is prescribed for glaucoma and alleviating symptoms of Sjögren syndrome.

• Nicotine: This drug is included in smoking cessation regimens.

• Cholinesterase inhibitors: These include neostigmine, edrophonium, pyridostigmine, donepezil, and rivastigmine.

  • Neostigmine is commonly combined with glycopyrrolate to reverse neuromuscular blockade in postoperative anesthesia.
  • Edrophonium is used for diagnosing myasthenia gravis.
  • Pyridostigmine is used for treating myasthenia gravis.
  • Donepezil and rivastigmine are used for the symptomatic treatment of Alzheimer dementia.[5][6][7][8][9]

Anticholinergics: The drugs belonging to this category are listed below.

• Atropine: This drug is utilized in advanced cardiovascular life support (ACLS) guidelines to correct bradyarrhythmias and as a retinal dilator in ophthalmic surgery.

• Ipratropium and tiotropium: These drugs are used to treat acute exacerbations of bronchospasm (asthma/chronic obstructive pulmonary disease [COPD]) and as prevention for these conditions.

• Scopolamine: This drug prevents motion sickness and postoperative nausea or vomiting.

• Oxybutynin: This drug addresses urge incontinence and postoperative bladder spasms.

• Dicyclomine and glycopyrrolate: These drugs are used for abdominal pain associated with irritable bowel syndrome. Glycopyrrolate also aids in cholinesterase reversal of neuromuscular blockades in postoperative anesthesia to prevent bronchospasm and is being investigated as an adjunct treatment in COPD.[10][11][12][13][14][15][16]

Adrenoreceptor agonists or sympathomimetics: The drugs belonging to this category are listed below.

• Clonidine: This drug is an antihypertensive agent.

• Dobutamine, phenylephrine, and epinephrine: These drugs are used to correct severe hypotension in cardiogenic shock and acute heart failure. Epinephrine is also used in ACLS guidelines for non-shockable heart rhythms in cardiac arrest and for rapid reversal of fatal anaphylactic reactions.

• Albuterol: This is a fast-acting bronchodilator used in acute asthma exacerbations.

• Fenoldopam: This drug addresses hypertension.

• Bromocriptine: This is used in managing Parkinson disease and conditions involving prolactinomas.[17][18][19][20][21][22][23]

Adrenoreceptor antagonists: The drugs in this category are listed below.

• Phenoxybenzamine and phentolamine: These drugs are used to address high catecholamine states.

• Prazosin, doxazosin, terazosin, and tamsulosin: These drugs are indicated to treat urinary retention in benign prostatic hyperplasia.

• β-Blockers, including propranolol, metoprolol, and labetalol: These drugs are indicated for various cardiovascular conditions as class II antiarrhythmics, as well as for managing tachyarrhythmias, hypertension, angina, heart failure, and migraine prophylaxis.[24][25][26]

Mechanism of Action

As with the homeostasis facilitated by the SNS and PSNS, drugs from each of the 4 categories listed above also have inverse effects on each other. The primary mechanism of action for most of these agents involves acting as either agonists or antagonists of specific receptors within these systems.[2] Below is a list of these receptors, along with their locations and physiological actions.

For adrenoreceptors stimulated by norepinephrine (synapses) and epinephrine (endocrine) involved in SNS processes:[27][28]

• Alpha-1 (α1): This is primarily located in postsynaptic effector cells found in smooth muscle. Effects mediated by the IP3/DAG pathway include mydriasis through contraction of radial muscles, constriction of arteries and veins, urinary retention via contraction of internal or external urethral sphincters, and a decrease in renin release from renal juxtaglomerular cells.

• Alpha-2 (α2): This is found in presynaptic adrenergic terminals in lipocytes and smooth muscle. Effects mediated by decreased cAMP include a reduction in norepinephrine release, stimulation of platelet aggregation, and reduced insulin secretion.

• Beta-1 (β1): This is located in postsynaptic effector cells in the SA node of the heart, lipocytes, brain, juxtaglomerular apparatus of renal tubules, and the ciliary body epithelium. Effects mediated by increased cAMP include an increased heart rate and conduction velocity through the cardiac nodes and an increase in renin release from renal juxtaglomerular cells.

• Beta-2 (β2): This is found in postsynaptic effector cells in smooth muscle and cardiac myocytes. Effects mediated by increased cAMP include vasodilation, bronchiole dilation, increased insulin secretion, and uterine relaxation.

• Beta-3 (β3): This is located in postsynaptic effector cells in lipocytes and myocardium and exhibits effects similar to β1 receptors, mediated by increased cAMP.

For cholinoreceptors stimulated by acetylcholine, most involved in PSNS processes:[29]

• Muscarinic-1 (M1): This is uniquely involved in an SNS process and located in the skin's sweat glands. Effects mediated by the IP3/DAG pathway include glandular contraction and increased secretion.

• Muscarinic-2 (M2): This is found in the SA and AV nodes and myocardium. Effects mediated by decreased cAMP include a reduction in heart rate and myocardial conduction velocity.

• Muscarinic-3 (M3): This is located in the smooth muscle of various organ systems. Effects mediated by the IP3/DAG pathway include contraction of the ciliary muscle causing miosis, contraction of bronchioles, increased bronchiole secretions, enhanced gastrointestinal motility, detrusor muscle contraction, and relaxation of internal or external urethral sphincters.

• Muscarinic-4 (M4) and muscarinic-5 (M5): This is primarily located in the central nervous system (CNS), specifically the forebrain and substantia nigra, respectively.

• Nicotinic-N (NN): This is located in the postsynaptic dendrites of both sympathetic and parasympathetic postganglionic neurons. Effects mediated by Na⁺/K⁺ depolarization include increased neurotransmission.

• Nicotinic-M (NM): This is found in neuromuscular endplates of skeletal muscles. Effects mediated by Na⁺/K⁺ depolarization include skeletal muscle contraction.

For dopamine receptors, which are involved in both SNS and PSNS processes:[30]

• Dopamine 1 to 5 (D1-5): This is primarily located in the CNS, except for dopamine-1 receptors, which are also found in renal vasculature. Effects mediated by the cAMP pathway include renal artery vasodilation, increased renal blood flow, and modulation of neuroendocrine signaling.

In the context of the 4 mentioned categories, each acts as an agonist and/or antagonist of the listed receptors. Cholinomimetics exhibit agonist activity at muscarinic receptors, enhancing PSNS activity to produce effects such as increased gastrointestinal motility and decreased intraocular pressure.[5][6] In contrast, cholinesterase antagonists achieve similar effects by inhibiting acetylcholinesterase enzymes within the synaptic cleft, thereby increasing acetylcholine concentration and enhancing PSNS neurotransmission and skeletal muscle contraction.[8] Conversely, anticholinergic agents inhibit PSNS activity, primarily through antagonism of muscarinic receptors, which increases heart rate and conduction velocity and stimulates bronchodilation.[10][11]

Within the SNS system, adrenoreceptor agonists or sympathomimetics target α- and β-receptors to enhance SNS activity, leading to increased cardiac output and rapid bronchodilation.[18][20] Conversely, adrenoreceptor antagonists target the same receptors to decrease SNS neurotransmission, which helps reduce heart rate, temper high catecholamine states, and promote urinary smooth muscle relaxation.[24][25][26]

Administration

Most agents are available as intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) formulations.[31][32][33] Some agents can also be administered topically as eye drops, specific to ophthalmologic surgery requiring extended pupillary dilation and the medical treatment of open-angle and closed-angle glaucoma.[34][35]

Adverse Effects

Due to the various effects of the ANS on cardiovascular, pulmonary, gastrointestinal, and genitourinary systems, reactions to these medications involve these organ systems. The various adverse reactions to each of the categories of agents are listed below.[18][20][26][24][25]

• Cholinomimetics or cholinesterase inhibitors: Nausea, vomiting, diarrhea, urinary urgency, excessive salivation, sweating, cutaneous vasodilation, and bronchial constriction.

• Anticholinergics: Tachycardia, urinary retention, xerostomia (dry mouth), constipation, and increased intraocular pressure.

• Adrenoreceptor agonists or sympathomimetics: Tremor, tachycardia, hypertension, urinary retention, and piloerection.

• Adrenoreceptor antagonists: Bradycardia, bronchospasm, and hypotension.

Contraindications

Based on the adverse reaction profiles of each category, several significant contraindications have been documented:[33][36][37]

• Cholinomimetics or cholinesterase inhibitors: Relative contraindications in asthma/COPD, bradycardia, volume-depleted/hypotension, cardiogenic shock, sepsis, and reduced ejection fraction heart failure.

• Anticholinergics: Relative contraindications in glaucoma, especially angle-closure, older men with benign prostatic hyperplasia, and peptic ulcer disease. Atropine is specifically not recommended for children, especially infants who are sensitive to its hyperthermic effects.

• Adrenoreceptor agonists or sympathomimetics: Relative contraindications in patients with a previous or current history of tachycardia or hypokalemia, hypertension, urinary retention, and gastroparesis. Clonidine is particularly contraindicated in older adults who are more prone to fall from orthostatic hypotension, and epinephrine is contraindicated in those with angle-closure glaucoma.

• Adrenoreceptor antagonists: Relative contraindications for α-blockers include orthostatic hypotension, tachycardia, and myocardial ischemia, whereas for β-blockers, they include asthma/COPD. For the nonselective agents, contraindications include bradycardia and hypotension.

Monitoring

Vital signs, including blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature, should be closely monitored when attempting to reestablish autonomic homeostasis with ANS agents.[2] Several common conditions which require autonomic pharmacological correction need specific monitoring:[38][39][40][41]

• Glaucoma: Ocular telemetry sensors can help monitor intraocular pressure continuously.

• Shock: This requires several monitoring functions, as listed below.

  • A MAP of 65 mm Hg or higher should be maintained.
  • MAP measurements via an arterial line.
  • Pulse pressure variation to guide fluid therapy.
  • Bedside echocardiography to assess heart chambers, determine cardiogenic shock versus obstructive shock (massive pulmonary embolism), and calculate cardiac output/ejection fraction.
  • A pulse index continuous cardiac output (PiCCO) device can monitor continuous cardiac output and assess fluid response continuously.

• Asthma/COPD: Pulmonary function testing is the standard method for diagnosing and monitoring the severity of pulmonary obstruction. This method can also evaluate the effectiveness of inhaled autonomic agents in reversing obstructive processes.

• Arrhythmias: For acute monitoring, the 4-lead and 12-lead electrocardiograms (ECGs) are standard for monitoring tachycardias or bradycardias. If extended monitoring is required, extended continuous ambulatory rhythm monitors (ECAMs) are the preferred monitoring modality.

Toxicity

Toxic profiles of the 4 categories described are primarily involved in overdose, exhibiting the same effects that are augmented so that the benefits no longer outweigh the risks. The primary reversal strategy for these situations is discontinuing the offending agent and treating the resultant symptoms.[1]

Several agents of each category have toxic effects that require more specific reversal methods, as listed.[8][42][43][44]

• Cholinesterase inhibitors, including neostigmine, pyridostigmine, and physostigmine: Historically, high doses of these agents were used in chemical warfare and would present as miosis, bronchial constriction, vomiting, and diarrhea, progressing to convulsions, coma, and finally death. This toxicity profile remains the same and can be reversed with pralidoxime with adjunctive parenteral atropine and benzodiazepines for possible seizure activity.

• Atropine: In excess, atropine can cause vision disturbances, resulting in prolonged mydriasis and cycloplegia. This drug can also exacerbate closed-angle glaucoma by increasing intraocular pressure. Reversal generally involves discontinuation; however, physostigmine can be used in extreme cases, such as severe elevation of body temperature and rapid supraventricular tachycardia.

• Clonidine: Excessive clonidine use can lead to xerostomia and sedation. Currently, there is no approved reversal agent. However, studies are underway investigating the use of naloxone as a potential reversal agent.

• β-Blockers: In addition to severe hypotension and bradycardia, tremors and bronchospasm are worrisome in cases of overdose. Glucagon serves as the reversal agent in such situations.

Enhancing Healthcare Team Outcomes

Healthcare professionals prescribing medications affecting the autonomic system must fully understand the adverse effects of these agents. Physicians, nurses, and pharmacists should collaborate when utilizing medications that interact with the ANS to ensure safe and effective pharmacotherapy for each patient. ANS agents are used to treat conditions such as asthma, myasthenia gravis, nicotine replacement therapies, motion sickness, abdominal pain associated with irritable bowel syndrome, hypertension, hypotension, and Alzheimer disease. Clinicians are advised to conduct drug interaction checks when prescribing medications that influence the ANS for medical conditions. Nurses should verify dosage and ensure proper administration techniques are used for medications. Pharmacists are responsible for checking dosage, strength, and clinical appropriateness to minimize medication errors and educate patients about the drug’s adverse reactions.

Medical toxicologists are essential for managing severe poisoning or overdose of ANS agents. In cases of deliberate overdose, psychiatric consultation is necessary. Clinicians, specialists, pharmacists, nurses, and other healthcare providers are critical in caring for patients undergoing therapy with ANS agents. Effective collaboration among all healthcare professionals within an interprofessional team enhances efficacy, reduces adverse reactions, and ultimately improves patient outcomes.

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Disclosure: Derek Clar declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.