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1. Two Divisions of the ANS and their alternate names

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1. Two Divisions of the ANS and their alternate names

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-The Sympathetic Nervous System and the Parasympathetic Nervous System are the two divisions of the Autonomic Nervous System.
-An alternate name for the Sympathetic Nervous System is the Thoracolumbar division
https://www.britannica.com/science/sympathetic-nervous-system
-An alternate name for the Parasympathetic Nervous System is the Craniosacral division.
https://www.sciencedirect.com/topics/neuroscience/parasympathetic-nervous-system

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Heart Rate

Sympathetic and parasympathetic nervous system influences underlie the cardiovascular system's first response to exercise-an increase in heart rate. Sympathetic outflow to the heart and systemic blood vessels increases while vagal outflow decreases. Vagal withdrawal is responsible for the initial change of 10 to 30 beats per minute, and the remainder is thought to be largely sympathetically mediated. Of the two major components of cardiac output, heart rate and stroke volume, heart rate is responsible for most of the increase in cardiac output during exercise, particularly at higher levels. Heart rate increases linearly with workload and oxygen uptake. Increases in heart rate occur primarily at the expense of diastolic, not systolic, time. Thus, at very high heart rates, diastolic time may be so short as to preclude adequate ventricular filling.

The heart rate response to exercise is influenced by several factors, including age, type of activity, body position, fitness, the presence of heart disease, medications, blood volume, and environment. Of these, the most important factor is age; a decline in maximal heart rate occurs with increasing age. This decline appears to be due to intrinsic cardiac changes rather than to neural influences. It should be noted that there is a great deal of variability around the regression line between maximal heart rate and age; thus age-related maximal heart rate is a relatively poor index of maximal effort (see Chapter 5). Maximal heart rate is unchanged or may be slightly reduced after a program of training. Resting heart rate is frequently reduced after training as a result of enhanced parasympathetic tone.

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Parasympathetic Nervous System

Preganglionic fibers in the PNS arise from the midbrain, medulla oblongata, and sacral segments of the spinal cord. Cranial nerves III, VII, IX, and X carry preganglionic parasympathetic fibers directly to ganglia located near or directly in innervated organs. The sacral segments S2-S4 provide innervation to the rectum and genitourinary tissues (see Fig. 13.1).

The vagus nerve (X) is the major carrier of parasympathetic neuronal traffic. These preganglionic fibers affect the heart, lungs, and abdominal organs with the exception of the distal portion of the colon. A combination of the distal location of the ganglion and the smaller two- to threefold amplification factor between preganglionic and postganglionic fibers causes parasympathetic effects to be specific to each organ.

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Preganglionic Neurons Use Acetylcholine as a Transmitter

Most preganglionic neurons of both the SNS and PSNS have a cholinergic transmitter phenotype. Only relatively small subpopulations of preganglionic neurons express other (e.g., dopaminergic or adrenergic) phenotypes. In the peripheral ganglia of these two divisions of the ANS, most postganglionic neurons, which receive inputs from the preganglionics, express a predominance of a nicotinic form of the cholinergic receptor on their somata. As discovered by the early autonomic pharmacologists, nicotine can serve as a general "ganglionic blocker" to thwart transmission at these synapses. Additional specificity and response selectivity, or coding, at the ganglionic level normally are maintained by the segregation of sympathetic and parasympathetic postganglionic neurons in separate ganglia, by point-to-point axonal projections, by distinguishing neuropeptides colocalized with the transmitter, and by the spatial separation of synapses within ganglia.

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Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780323393072000059 Read full chapter URL: https://www.sciencedirect.com/science/article/pii/B9780323481106000296 Sympathetic and parasympathetic nervous system influences underlie the cardiovascular system's first response to exercise-an increase in heart rate. Sympathetic outflow to the heart and systemic blood vessels increases while vagal outflow decreases.

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For the Sympathetic Nervous System:
-Acetylcholine (ACH) - Cholinergic
-Norepinephrine (NE) - Adrenergic
-Epinephrine (EPI) - Adrenergic
-Dopamine (DA)

For the Parasympathetic Nervous System:
-Acetylcholine (ACH)

Sources: U2 ANS Part 1 and U2 ANS Part 2 PowerPoints (Tammie Petersen)

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3. Locations where each NT is released in each division:

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3. Locations where each NT is released in each division:

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Sympathetic
Acetylcholine- NT released at ganglia
Norepinephrine- NT released at postganglionic nerve endings
Epinephrine- NT produced by adrenal medulla
Dopamine- Precursor to NE
Parasympathetic
-Acetylcholine- NT at ganglia and postganglionic nerve endings
Sources: U2 ANS Part 1 and U2 ANS Part 2 PowerPoints (Tammie Petersen)

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4. Receptors of each division and their main locations

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4. Receptors of each division and their main locations

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Sympathetic
1. alpha 1
-found on glands, eyes, arteries, veins and smooth muscles
2. beta 1
-located on the heart
3. beta 2
-located on smooth muscle, coronary arteries, skeletal muscle arteries, uterus, and lungs
Parasympathetic
1. muscarinic
-found on cardiac, smooth muscle, and glands
2. nicotinic 1
-found at ganglia of parasympathetic nerves and also sympathetic nerves
3. nicotinic 2
-neuromuscular junction of skeletal muscle

Sources: U2 Part 1 and U2 Part 2 PowerPoints (Tammie Petersen)

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Adrenergic Receptors
-Beta 1 stimulates the heart.
Therefore there's greater increase in heart rate, force of contraction, and atrioventricular conduction
-Alpha 1 stimulates the arteries and veins, and the eye
Therefore there's vasoconstriction and contraction of the pupils
-Alpha 2 stimulates the adrenergic nerve endings
Therefore there's a decrease in norepinephrine
-Beta 2 stimulates the smooth muscles on the lungs, uterus, and skeletal blood vessels
Therefore there's bronchodilation, relaxation, and vasodilation.

Sources: U2 Part 1 and U2 Part 2 PowerPoints (Tammie Petersen)

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6. Drug Classifications for Each Division

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6. Drug Classifications for Each Division

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Parasympathetic NS
Cholinergics
-ACH is released
-decreased HR, miosis, bronchoconstriction, increased digestion, urinary bladder contraction, more urination and defecation
Anticholinergics
-bind to a cholinergic receptor
-they act as a blocking drug

Sympathetic NS
Adrenergic Agonists
-stimulates alpha and beta receptors, cardiac stimulant, and bronchodilator
Adrenergic Blockers
-binds to alpha 1 receptors and blocks them

Sources: U2 Part 1 and U2 Part 2 PowerPoints (Tammie Petersen) and https://www.ncbi.nlm.nih.gov/books/NBK538180/

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Continuing Education Activity

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. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of the broad array of physiological possibilities when using autonomic pharmacology.

Objectives:

Identify the four major classes of pharmacological agents in autonomic pharmacology.

Summarize the mechanism of action of each of the four main categories of autonomic pharmacological agents.

Review the side effects of each of the four classes of autonomic pharmacological agents.

Outline interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with these classes of medications, leading to optimal patient outcomes.

Access free multiple choice questions on this topic.
Indications

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. Adrenoreceptor agonists/sympathomimetics

3. 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]:

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

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

Mechanism of Action

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

Administration

Adverse Effects

Contraindications

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

Enhancing Healthcare Team Outcomes

Glaucoma - ocular telemetry sensors can help to continuously monitor intraocular pressure.

Shock - requires several monitoring functions as listed:

Maintaining a MAP of 65 and above

MAP measurements via an arterial line

Pulse pressure variation to guide fluid therapy

Bedside echocardiography to assess chambers of the heart and looking for cardiogenic shock vs. obstructive shock (massive PE) and calculate cardiac output/ejection fraction

Pulse index continuous cardiac output (PiCCO) device which can serve to continuously monitor continuous cardiac output and assess fluid response

Asthma/COPD - pulmonary function testing is the standard to diagnose and monitor the severity of pulmonary obstruction; can also evaluate the effectiveness of inhaled autonomic agents in reversing obstructive processes

Arrhythmias - for acute monitoring 4-lead ECG and 12-lead EKG are standard for monitoring tachycardias or bradycardias; if extended monitoring is required extended continuous ambulatory rhythm monitors (ECAM) is the monitoring modality of choice

Physicians, nurses, and pharmacists need to work collaboratively when using medications that interact with the autonomic nervous system to make sure that the pharmacotherapy is safe and effective for each patient. [Level V]

References

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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.

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7. Specific Drug Examples under each Drug Classification

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7. Specific Drug Examples under each Drug Classification

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Adrenergic Agonist
- ephedrine
- phenylephrine (Neo-Synephrine®)
- epinephrine (Adrenalin®)
- prazosin (Minipress®)
- terazosin (Hytrin®)
- doxazosin (Cardura®)
-dobutamine
-formoterol (Foradil®)
-albuterol (Proventil®/Ventolin®)
-terbutaline (Brethine®)
Cholinergic Agonist
-acetylecholine
-pilocarpine (Pilocar®)
-bethanechol (Urecholine®)
-neostigmine (Prostigmin®)
Anticholinergic
-atropine
-dicyclomine (Bentyl®)
-ipratropium bromide (Atrovent®)
Sources: Master Drug List Unit 2 Document (Tammie Petersen)