Overview

• The autonomic nervous system is made up of sympathetic and parasympathetic pathways that compete to maintain homeostasis in the body.
• The goal of these pathways is to release a neurotransmitter at the end of the final neuron to bind to a receptor at a target cell.
• These pathways start in the brain and end at a target cell.
• Neurons are classified as either preganglionic or postganglionic. The ganglion is the synapse or gap between the two main neuron groups. Acetylcholine is the neurotransmitter released from preganglionic neurons which binds to a receptor on the dendrite of the post ganglionic neuron.
  • For example, let’s say there is a pathway from the brain to the liver. The first neuron starts at the brain and goes down the spinal cord and emerges between two vertebrae around the level of the liver. The neuron then ends and releases acetylcholine from the end of the axon at the terminal of the nerve and binds to a receptor on a second neuron. The second neuron will then be stimulated to continue the signal to the liver. At the liver, this second neuron releases a neurotransmitter (will be different depending on what type of cell it is trying to stimulate) and will bind to a receptor which will cause a response at the liver.
• Sympathetic vs parasympathetic pathways
  • Sympathetic pathways have shorter preganglionic neurons and longer postganglionic neurons. Most of the ganglions for the sympathetic nervous system reside right off the spinal cord and make up the ganglionic chain.
  • The parasympathetic presynaptic nerves start in the brain and go almost all the way to
    the effector organ at which point they synapse to a short postganglionic neuron.
  • Both preganglionic fibers for sympathetic and parasympathetic are myelinated B-fibers and post-ganglionic fibers are unmyelinated C-fibers.
  • Postganglionic neurotransmitters released from the sympathetic nervous system are mostly norepinephrine, but acetylcholine is used in the sympathetic nervous system to bind to muscarinic receptors at sweat glands and piloerector muscles, and some other areas in the body.
  • Sympathetic think “flight or fight ”, parasympathetic think “rest and digest”. Meaning that sympathetic responses correlate with our bodies being scared, energized, or active. For example- sympathetic responses include increased HR, BP, bronchodilation, increase in metabolic rate, and a decrease in digestive tract.  Whereas parasympathetic correlates with the body being relaxed: decrease HR, increased movement through the digestive tract, and increased sexual arousal.
  • Sympathetic pathways typically exit the spinal column in the thoracic or upper lumbar intervertebral spaces. Parasympathetic pathways come from the cranial nerves (ex: vagus) or through the sacral intervertebral spaces.
• Sympathetic Neurotransmitters
  • The main neurotransmitters for the sympathetic nervous system include norepinephrine and epinephrine.
  • Norepinephrine is made in the neurons in the sympathetic pathway. The process starts with tyrosine going through a series of conversions that end up making norepinephrine. The first step in the process requires an enzyme known at tyrosine hydroxylase- this first step is the rate limiting step of this process.
  • Once norepinephrine has been made in these neurons, it is packaged in vesicles at the nerve terminal and stored until it is stimulated to be released. When a signal comes down the axon of the sympathetic postganglionic neuron, it causes calcium to enter the nerve terminal and stimulate the packaged vesicles to release norepinephrine into the synapse.
  • Once norepinephrine has been released into the synapse, it will continue to bind to receptors until the norepinephrine is removed from the synapse which occurs by 3 main mechanisms.
    • 1. The main removal is through the norepinephrine being brought back into the nerve terminal where it can be reused.
    • 2. Diffuses out of the synaptic cleft and enters the circulation.
    • 3. Diffuses out of the synaptic cleft and brought in by other local cells.
  • Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are enzymes that break down norepinephrine.
  • Epinephrine is made in the adrenal medulla. Norepinephrine is converted in the adrenal medulla by the enzyme phenylethanolamine N-methyltransferase. As a result, the adrenal medulla makes 80% epinephrine compared to 20% norepinephrine. A preganglionic neuron comes all the way to the adrenal medulla where it stimulates chromaffin cells to release the epinephrine and norepinephrine into the bloodstream. This is constantly happening which is how our bodies have circulating catecholamines. These catecholamines get broken down by MAO and COMT in the liver.
  • Pheochromocytoma is a tumor typically on the chromaffin cells at the adrenal gland which means there will be lots of circulating catecholamines being released from this tissue. For more information about management of this disease process, listen to our endocrine episode.
• G-protein Coupled Receptors
  • It is imperative to understand how G-proteins work.
  • G-proteins are receptors embedded in the membrane of target cells that cause a series of events to occur when activated.
  • The process starts when a neurotransmitter (known as the first messenger) released from the neuron binds to a G-protein receptor on the outside surface of the cell membrane. This will activate an alpha subunit on the other side of the G-protein that is on the inside surface of a cell membrane. The alpha subunit will detach from the G protein and will either activate or inhibit another protein called an effector. The effector will activate a second messenger that causes a cascade of events to happen in the cell.
  • There are three main G-proteins we want to talk about: Gs, Gq, and Gi.
  • There are two main effectors we want to talk about: adenylate cyclase and phospholipase C.
  • Common second messengers include: cyclic adenosine monophosphate (cAMP), calcium, inositol triphosphate (IP3), and diacylglycerol (DAG)
  • Let’s talk about the pathway for each of the three G proteins.
  • Activated Gs receptors will stimulate the effector “adenylate cyclase”. Activated adenylate cyclase will cause ATP to make cAMP which results in various cellular functions depending on the type of cell. Keep this in mind as we move forward, cAMP does not cause the same effect on every type of cell- it depends on the cell type in the body.
  • Activated Gi receptors will inhibit adenylate cyclase and will block ATP from making cAMP.
  • Activated Gq receptors will activate the effector “phospholipase C” which causes an increase in calcium, IP3, and DAG. Typically, when these second messengers are present, there will be an increase in contraction.
  • At any point if the first messenger neurotransmitter is removed from the G protein, the pathway is shut off.
  • These G protein pathways are named differently according to what type of cell group they are located on and what function will be performed when they are activated.
• Adrenergic receptors
  • The main adrenergic receptors are beta 1 (B1), beta 2 (B2), alpha 1 (A1), and alpha 2 (A2). Except for alpha 2, think “fight or flight” for these receptors and it will help make sense why they cause certain things to happen in our bodies.
  • Alpha 1 receptors use a Gq pathway. This makes sense because contraction occurs because of this pathway being activated due to the calcium, IP3, and DAG being released. As a result, when A1 receptors in the vascular system are stimulated, we see a rise in blood pressure due to constriction of blood vessels and an increase in systemic vascular resistance (SVR). A1 receptors throughout the body also cause mydriasis, increase in sweat glands, contraction of the uterus and gastrointestinal sphincters, decrease digestive motility, and an increase in serum glucose among other things.
  • A2 receptors are Gi pathways meaning they inhibit adenylate cyclase. As a result, less cAMP will be made. A main first messenger in this pathway is norepinephrine. The effect of stimulating this receptor depends on its location. One location for A2 receptors is on the end nerve terminal of the postganglionic neuron. When norepinephrine is released from the nerve terminal, most of it crosses the synaptic cleft and binds to receptors on the target cell. However, some of the norepinephrine will bind to the A2 receptor on the neuron and cause a negative feedback loop to occur, meaning it decreases the amount of additional norepinephrine being released from the neuron. As a result, we see less sympathetic response and more of a parasympathetic response because less norepinephrine can bind to receptors at the target cell.
    • Additionally, A2 causes sedation which is why precedex and clonidine (A2 agonists) cause sedative effects. A2 also has anti-shivering effects, decreases insulin release, increased platelet aggregation, diuresis, and vasoconstriction.
    • You may ask why vasoconstriction? There are some A2 receptors in the smooth muscles on blood vessels. Norepinephrine can bind to these receptors and because it is a Gi protein pathway, cAMP will be reduced which causes more contraction in this cell type. This is why, if you give a bolus of precedex you may see a transient increase in BP due to the peripheral vasoconstriction but then will see the central A2 effects kick in and overall have a decrease in BP.
  • When it comes to beta receptors think “we have 1 heart and 2 lungs”. B1 receptors are in the heart and B2 are in the lung as well as other places in the body. Both B1 and B2 receptors use a Gs protein pathway which will increase adenylate cyclase and will result in more cAMP.
  • B1 causes an increase in heart rate and contractility of the heart myocardium. Think of B1 as the driving receptor for our heart pump. As B1 is stimulated, there will be more forward push from the pump.
  • B2 is most thought of as being the primary receptor in the lungs that causes bronchodilation. B2 is a Gs receptor which stimulates adenylate cyclase to make more cAMP. Think of B2 as a dilating receptor whereas A1 as a contraction receptor. B2 receptors cause relaxation/dilation of bronchioles, vasodilation, detrusor muscle, gallbladder, and uterus. B2 also stimulates an increase in glucose levels and insulin release. B2 stimulation causes a decrease in potassium due to more potassium leaving the circulation and moving into the cells.
• Parasympathetic Neurotransmitter
  • Acetylcholine is the main neurotransmitter for the parasympathetic nervous system.
  • Cholinergic neurons produce acetylcholine made from combining choline circulating in the vascular system to acetyl CoA that is made in the mitochondria of the cholinergic neuron. Acetylcholine is packaged into vesicles similarly to the sympathetic neurotransmitters. When the signal comes down the neuron, calcium floods into the nerve terminal through voltage gated channels and causes the acetylcholine to be released into the synapse.
  • Acetylcholine is released from the preganglionic neuron in the sympathetic nervous system pathway as well as from neurons synapsing at the neuromuscular junction. But for the most part, we want to discuss acetylcholine being released in the muscarinic/parasympathetic system. These nerves release acetylcholine to bind to muscarinic receptors- M1-M5 which we will discuss in a moment.
  • In order to get rid of the acetylcholine once it is released into the synapse, it is mainly metabolized by an enzyme in the synaptic cleft called acetylcholinesterase. The byproducts are acetate and choline. The choline can be reused by the neuron to make more neurotransmitters and the acetate goes into the circulation.
  • Muscarinic receptors 1,3, and 5 use a Gq pathway and stimulate the release of IP3, DAG, and calcium. It should make since that M3 receptors in the lung cause bronchoconstriction when stimulated.
  • M2 and M4 use a Gi protein pathway which inhibits cAMP. An example of M2 is in the right atrium of the heart where the vagus nerve releases acetylcholine and will lower the HR when it binds to M2 receptors.
• Reflexes
  • The autonomic nervous system has reflexes that try to maintain homeostasis in our bodies.
  • Baroreceptor reflex: The baroreceptor reflex is the idea that as blood pressure rises, the ANS will lower HR, contractility, and SVR to lower the blood pressure to a normal level. The opposite is true as well.
    • In order to do this, there are pressure sensors in the carotid sinus and the transverse aortic arch that are constantly reading the BP and sending a signal to the medulla. The carotid sinus sends signals via the glossopharyngeal nerve while the transverse aortic arch sends a signal via the vagus nerve.
    • If the sensors are reading the BP too high, then the medulla will send out signals through the parasympathetic pathway via the vagus nerve to the M2 receptors in the heart to slow the HR. The medulla will also block sympathetic signals which will limit alpha and beta receptor stimulation which cause vasodilation and decreased inotropy.
    • This is why if we give a bolus of phenylephrine, the BP will increase due to increasing the SVR, so the baroreflex causes the HR to decrease.
    • In theory, the HR and BP should be constantly adjusting with the baroreceptor reflex to maintain a normal HR and BP. However, our anesthesia drugs can impair this reflex such as propofol, volatile anesthetics, and any beta blockers we give the patient.
  • Cushing reflex occurs when there is intracranial hypertension. It results in hypertension, bradycardia and irregular respiration due to an increased pressure on the brain stem. Listen to our neuro talk for more information on this.
  • Bainbridge reflex- the idea that when preload into the heart is high, the HR will increase to keep a forward flow through the heart. There are sensors in the SA node and right ventricle that send a signal to the medulla which will inhibit the vagus nerve to the heart if the preload is high. This results in an increase in HR because the vagus nerve will not be stimulating the M2 receptor.
  • Bezold-Jarisch reflex- idea that when preload drops significantly (a.k.a. severe hypotension), the HR slows down to allow more time for the blood to fill in the heart prior to each contraction. The heart constantly sends signals to the medulla and the medulla will send a parasympathetic signal through the vagus nerve to decrease the HR if the filling pressure is too low. The patient typically presents with bradycardia in the presence of hypotension as well as coronary artery dilation. This is often seen in patients receiving anesthesia in the sitting position undergoing a shoulder procedure with an interscalene block.
  • Celiac reflex- occurs during laparoscopic surgery when filling up the peritoneum with gas. As the contents of the abdominal cavity are stretched, the vagus nerve is stimulated to cause bradycardia and hypotension. Often transient when the belly is first being distended. Often just have the surgeon lower the pressure of gas going into the belly or you can give Robinul/atropine.
• Catecholamines
• Epinephrine
  • Epinephrine binds to beta 1 and 2 as well as alpha 1 and 2.
  • As a result, there will be bronchodilation due to B2, increased HR due to B1, increased SVR and BP due to A1, A2 does slightly inhibit the amount of vasoconstriction, B2 also causes vasodilation.
  • At low doses, epinephrine favors beta receptors, and as the dose increases it switches to favor alpha receptors.
  • So, by stimulating all of these receptors, some of the effects will contradict each other. Therefore, it is important to give medications that can isolate specific target receptors.
• Norepinephrine
  • Will stimulate B1 as well as A1 and A2.
  • At low dose, more B1 will be stimulated which will increase HR and contractility. As the dose increases, more A1 and A2 effects so there will be more vasoconstriction which will hinder the amount of total increase in HR due to the baroreceptor reflex.
  • This is the most common pressor we gave in the ICU which is used for most shock states except for cardiogenic shock because you don’t want to increase afterload from A1 stimulation.
  • Be careful about infusing this through a peripheral IV because if the IV infiltrates it can cause necrosis to the local tissue.
  • Blood flow decreases to the pulmonary, renal, and mesenteric organs with long use of this
    medication.
• Dopamine
  • Known for “renal protection” because at lower doses it causes renal vasodilation and increased blood flow to the kidneys.
  • We have dopamine receptors in our body, but we won’t go into them for the sake of time.
  • As the dose of dopamine increases, B1 receptors become more stimulated, and with higher doses A1 is stimulated.
• Synthetic Catecholamines
• Isoproterenol
  • Stimulates B1 and B2 receptors and causes increased HR, contractility, and bronchodilation.
    Vasodilation from B2 effects.
  • This is often used in heart transplant patients because their hearts are denervated and will be unresponsive to manipulation of the SA node via atropine. Heart transplant patients also have depleted/absent catecholamines.
  • Isoproterenol acts as a chemical pacemaker for the heart.
• Phenylephrine
  • Specific for A1. Causes increase BP due to increased SVR, can cause baroreceptor reflex to lower HR.
  • Give this when you want to increase afterload and lower HR.
• Ephedrine
  • Acts by both a direct and indirect stimulation of both alpha and beta receptors. It stimulates more of the natural catecholamines to bind to these receptors.
  • This increases both HR and SVR so it is useful when the patient is bradycardic and hypotensive.
  • Because it stimulates the release of natural catecholamines, it doesn’t work well in septic patients or heart transplant patients.
• Vasopressin
  • Naturally made in the hypothalamus and stored in the posterior pituitary gland.
  • Causes vasoconstriction due to vasopressin 1 (V1) receptors. Vasopressin 2 (V2) receptors cause water to be reabsorbed in the collecting ducts of the kidney.
  • Give vasopressin if other pressors are not working, or first line if the patient is on ACE inhibitors or ARBs.
• Dobutamine
  • Beta agonist that causes increased HR and contractility. Great for cardiogenic shock due to helping the heart pump blood forward.
• Selective Beta 2 Agonists
  • Can give medications such as albuterol that stimulate B2 receptors which help with bronchodilation.
  • These meds are given to help with the bronchodilation effects with limited effect on the HR.
  • Usually given to treat asthma or other causes of bronchoconstriction.
  • Can also result in decreased potassium, vasodilation, and increased glucose/insulin.
  • Can be given to delay premature labor because they relax the uterus.
• Alpha 2 Agonists
  • Precedex and Clonidine are the two most common A2 agonists.
  • They will lower BP by inhibiting norepinephrine release from neurons and results in vasodilation. Will also cause sedative effects. Often a symptom seen is bradycardia.
  • Limited effect on respiratory drive which makes these nice sedative drugs.
• Alpha Antagonists
  • Can either do A1 blockade, A2 blockade, or both.
  • Common A1 selective blockers end in the suffix -osin such as prazosin. Selective A1 blockers cause vasodilation due to decreasing SVR. Usually we see patients with benign prostatic hypertrophy on these meds.
  • Yohimbine is an A2 selective antagonist. If you remember, A2 receptors will inhibit the release of norepinephrine when they are stimulated. By blocking A2, there will be more release of norepinephrine so it will raise BP and HR.
  • Phenoxybenzamine is a noncompetitive antagonist of both A1 and A2 receptors. By blocking A1, it results in vasodilation. However, because A2 is also blocked, there is more norepinephrine being released. Since A1 receptors are blocked, we don’t see a compensatory vasoconstriction, but the norepinephrine causes an increase in HR from binding to B1 receptors.
  • Phentolamine is a competitive antagonist of both A1 and A2. Similar to phenoxybenzamine, it causes vasodilation and tachycardia.
• Beta Blockers
  • Beta blockers are used to decrease the strain on the heart by decreasing HR and/or contractility which will lower the oxygen demand of the heart tissue. As a result, beta blockers are typically used in patients with coronary artery disease, congestive heart failure, hypertension, etc.
  • Block B1 and B2 receptors. Can be either selective for B1 or nonselective meaning they block both B1 and B2.
  • Typically end with the suffix -olol. If it starts with a letter from the 1st half of the alphabet then its B1 selective, the 2nd half of the alphabet is nonselective. Exceptions are metoprolol and carvedilol- metoprolol is B1 selective and carvedilol is nonselective.
  • B1 selective drugs will decrease HR and contractility.
  • Nonselective beta blockers also have bronchoconstriction and some vasoconstriction effects due to inhibiting B2 as well as B1 receptors.
  • Labetalol and carvedilol have both alpha and beta blocking effects.
  • Esmolol is very fast on/off because it’s metabolized by plasma esterases.
  • Consequences of overdosing on beta blockers results in severe hypotension, bradycardia, and or bronchoconstriction depending on the type of beta blocker. Treatment for overdose of beta blockers include cardiac pacing, isoproterenol, glucagon, calcium, phosphodiesterase III inhibitors, and epinephrine. Phosphodiesterase is the enzyme that breaks down cAMP. If we give a phosphodiesterase III inhibitor such as milrinone, this means more cAMP would remain in the cells to cause increased HR and contractility.

Bibliography:

Flood, P., & Shafer, S. (2015). Neurophysiology. In P. Flood, J. P. Rathmell, & S. Shafer (Eds.), Stoelting’s pharmacology & physiology in anesthetic practice (5th ed., pp. 77-89). Wolters Kluwer.

Lo, S. S., & Shanewise, J. S. (2015). Sympathomimetic drugs. In P. Flood, J. P. Rathmell, & S. Shafer (Eds.), Stoelting’s pharmacology & physiology in anesthetic practice (5th ed., pp. 449-470). Wolters Kluwer.

Miller, S. (2015). Sympatholytics. In P. Flood, J. P. Rathmell, & S. Shafer (Eds.), Stoelting’s pharmacology & physiology in anesthetic practice (5th ed., pp. 474-489). Wolters Kluwer.

Nagelhout, J. J. (2018). Autonomic and cardiac pharmacology. In J. J. Nagelhout & S. Elisha (Eds.), Nurse anesthesia (6th ed., pp. 165-189). Elsevier, Inc.

Paagel, P. S., & Grecu, L. (2017). Cardiovascular pharmacology. In P. G. Barash, B. F. Cullen, R. K. Stoelting, M. K. Cahalan, M. C. Stock, R. Ortega, S. R. Sharar, & N. F. Holt (Eds.), Clinical anesthesia (8th edition., pp. 301-329). Wolters Kluwer.