Autonomic Pharmacology

The basis of autonomic pharmacology reflects the physiology of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) to regulate involuntary reactions to stresses on multiorgan systems within the body. When a pathologic process is present that affects the homeostasis achieved between the SNS and PSNS in this process, either of these branches can become overactive while the other is excessively inhibited.[1] This break in homeostasis results in various clinical manifestations that can range in severity from simply presenting rhinorrhea symptomology to fatal presentations like cardiovascular collapse.[2] For a wide range of presentations and severity of pathologies, the agents classified in autonomic pharmacology are indicated to re-establish the homeostasis that the human body attempts to produce via the autonomic nervous system (ANS).[3]

Within autonomic pharmacology, there are four specific categories of drugs based on how they affect the ANS:

1. Cholinomimetics/cholinesterase antagonists
2. Anticholinergics
3. Adrenoreceptor agonists/sympathomimetics
4. Adrenoreceptor antagonists

The clinical indications of medications from each of the four categories are listed below. Important to note is that this is not a complete list due to the vastness of this topic; the drugs included are representative of each category.

 FDA-labeled indications:

Cholinomimetics/Cholinesterase antagonists[4][5][6][7]:

• Bethanechol - postoperative and neurogenic ileus and urinary retention
• Pilocarpine - glaucoma and alleviating the symptoms of Sjogren’s syndrome
• Nicotine - found in smoking cessation regimens
• Cholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine, physostigmine) - the diagnosis and treatment of myasthenia gravis, maintenance treatment of Alzheimer disease, and specifically neostigmine used commonly with glycopyrrolate to reverse neuromuscular blockade in postoperative anesthesia practice

Anticholinergics[8][9][10][11][12][13][14]:

• Atropine - used in ACLS guidelines to correct bradyarrhythmias and in ophthalmic surgery as a retinal dilator
• Ipratropium and tiotropium - correct acute exacerbations of bronchospasm (asthma, COPD), as well as exacerbation prophylaxis for those conditions
• Scopolamine - prevents motion sickness and postoperative nausea/vomiting
• Oxybutynin - urge incontinence and postoperative bladder spasm
• Dicyclomine, glycopyrrolate - can be used for reducing diarrhea output in irritable bowel syndrome; glycopyrrolate can also be added to cholinesterase reversal of neuromuscular blockades in postoperative anesthesia care to prevent bronchospasm and is currently undergoing investigation as an adjunct treatment in COPD

Adrenoreceptor agonists/Sympathomimetics[15][16][17][18][19][20][21]:

• Clonidine - used as an antihypertensive
• Dobutamine, phenylephrine, epinephrine - used to correct severe hypotension in cardiogenic shock and acute heart failure exacerbation; epinephrine specifically also used in ACLS guidelines for non-shockable heart rhythms in cardiac arrest and rapid reversal of fatal anaphylactic reactions
• Albuterol - fast-acting bronchodilator used in acute asthma exacerbations
• Fenoldopam - corrects hypertension
• Bromocriptine - involved in the maintenance of Parkinson disease and conditions involving prolactinoma

Adrenoreceptor antagonists[22][23][24]:

• Phenoxybenzamine, phentolamine - used to correct high catecholamine states
• Prazosin, doxazosin, terazosin, tamsulosin - indicated to correct urinary retention in benign prostatic hyperplasia
• Beta-blockers (propranolol, metoprolol, labetalol, etc.) - indicated for many cardiovascular conditions since they are in the classification of class II antiarrhythmics; these agents are used to manage tachyarrhythmias, hypertension, angina, heart failure, and migraine prophylaxis            

As with the homeostasis established via processes performed by the SNS and PSNS, drugs from each of the four categories listed above also work inversely to each other. The primary mechanism of action for most of these agents are to serve as either agonists or antagonists of specific receptors within these systems.[2] The receptors with their locations and physiologic actions are listed below.  

For adrenoreceptors stimulated by norepinephrine (synapses) and epinephrine (endocrine), involved in SNS processes[25][26]:

• Alpha-1 (A1) – located mostly in postsynaptic effector cells found in smooth muscle; effects mediated by IP3/DAG path, include mydriasis due to contraction of radial muscles, constriction of arteries and veins, urinary retention due to internal/external urethral sphincter contraction, and a decrease in renin release from renal juxtaglomerular cells   
• Alpha-2 (A2) – located in presynaptic adrenergic terminals found in lipocytes and smooth muscle; effects mediated by decreasing cAMP, including a decrease in norepinephrine release, stimulates platelet aggregation and decreases insulin secretion 
• Beta-1 (B1) – 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 increasing cAMP, including increased heart rate and the conduction velocity through the cardiac nodes, also increases renin release from renal juxtaglomerular cells
• Beta-2 (B2) – located in postsynaptic effector cells in smooth muscle and cardiac myocytes; effects mediated by increasing cAMP, include vasodilation, bronchiole dilation, increased insulin secretion, and uterine relaxation
• Beta-3 (B3) – located in postsynaptic effector cells in lipocytes and myocardium; similar effects to beta-1 receptors mediated by increasing cAMP

For cholinoreceptors stimulated by acetylcholine, most involved in PSNS processes[27]:

• Muscarinic-1 (M1) – important to note is the only cholinoreceptor involved in an SNS process, located in sweat glands of the skin; effects mediated by IP3/DAG path, include glandular contraction and increased secretion  
• Muscarinic-2 (M2) – located in SA and AV nodes and myocardium; effects mediated by decreasing cAMP, include decreasing heart rate and myocardial conduction velocity 
• Muscarinic-3 (M3) – located in the smooth muscle of various organ systems; effects mediated by IP3/DAG path, include contraction of the ciliary muscle causing miosis, contraction of bronchioles, increased bronchiole secretions, increased GI motility, detrusor muscle contraction, and internal/external urethral sphincter relaxation
• Muscarinic-4 (M4) and Muscarinic (M5) - located primarily in the CNS, e.g., forebrain and substania nigra, respectively
• Nicotinic-N (NN) – located in postsynaptic dendrites of both sympathetic and parasympathetic postganglionic neurons; effects mediated by Na+/K+ depolarization, include increased neurotransmission   
• Nicotinic-M (NM) – located in neuromuscular endplates of skeletal muscle; effects mediated by Na+/K+ depolarization, include skeletal muscle contraction

For dopamine receptors, most involved in both SNS and PSNS processes[28]:

• Dopamine 1-5 (D1-5) – located in the CNS, except for Dopamine-1 receptors, which also appear in renal vasculature; effects mediated by cAMP path, include renal artery vasodilation, increased renal blood flow, and modulation of neuroendocrine signaling

In terms of the four categories mentioned, each is an agonist and/or antagonist of the receptors listed. Cholinomimetics have agonist activity at muscarinic receptors augmenting PSNS activity to achieve the desired effects of increasing GI motility and decreasing intraocular pressure.[4][5] Whereas the other agents mentioned work directly on receptors as agonists/antagonists, the subcategory of drugs that also achieve similar effects to cholinomimetics is the cholinesterase antagonists. These agents inhibit acetylcholinesterase enzymes within the synaptic cleft to increase the concentration of acetylcholine, resulting in increased PSNS neurotransmission and facilitating skeletal muscle contraction.[7] Inversely, the anticholinergic agents work to inhibit PSNS activity, the main mechanism of action involving antagonism of muscarinic receptors resulting in increased heart rate and conduction velocity and stimulate bronchodilation.[8][9]

Within the SNS system, adrenoreceptor agonists/sympathomimetics work at alpha and beta receptors to potentiate SNS activity to achieve higher cardiac output and fast bronchodilation.[16][18] Inversely, adrenoreceptor antagonists are also active at alpha and beta receptors in decreasing SNS neurotransmission to reduce heart rate, dampen high catecholamine states, and increase urinary smooth muscle relaxation.[24][22][23]

Most agents are available as IV, IM, SC, PO formulations.[29][30][31] Some agents can also be given topically as eye drops, specific to ophthalmologic surgery requiring extended pupillary dilation and the medical treatment of open-angle and closed-angle glaucoma.[32][33]

Due to the various effects of the ANS on cardiovascular, pulmonary, gastrointestinal, and genitourinary systems, the general theme of reactions to these medications involves effects on these organ systems. The various reactions to each of the categories of agents include[16][18][24][22][23]:

• Cholinomimetics/cholinesterase inhibitors – nausea, vomiting, diarrhea, urinary urgency, excessive salivation, sweating, cutaneous vasodilation, bronchial constriction
• Anticholinergics – tachycardia, urinary retention, xerostomia (dry mouth), constipation, increased intraocular pressure
• Adrenoreceptor agonists/sympathomimetics – tremor, tachycardia, hypertension, urinary retention, piloerection
• Adrenoreceptor antagonists – bradycardia, bronchospasm, hypotension 

Based on the adverse reaction profiles of each category, several significant contraindications can be elucidated[34][35][31]:

• Cholinomimetics/Cholinesterase inhibitors – relative contraindications in asthma/COPD, bradycardia, volume-depleted/hypotension, cardiogenic shock, sepsis, reduced ejection fraction heart failure
• Anticholinergics – relative contraindications in glaucoma especially angle-closure, older men with benign prostatic hyperplasia, and peptic ulcer disease; atropine specifically not recommended for children, especially infants who are sensitive to its hyperthermic effects
• Adrenoreceptor agonists/Sympathomimetics – relative contraindications in patients with a previous/current history of tachycardia or hypokalemia, hypertension, urinary retention, gastroparesis; for clonidine specifically in elderly who are more prone to fall from orthostatic hypotension, and epinephrine in those with angle-closure glaucoma
• Adrenoreceptor antagonists – relative contraindications for alpha-blockers in orthostatic hypotension, tachycardia, myocardial ischemia; for beta-blockers asthma/COPD for the nonselective agents, bradycardia, hypotension