The Autonomic Nervous System (ANS) plays a significant role in unconscious and automatic processes in the human body. As prescribers of medications, what you prescribe can have profound impacts on the ANS, and it is important to be aware of how and why medications affect the ANS.
The nervous system can be broken down into:
The Autonomic Nervous System (ANS) operates independently of the CNS (e.g. - you do not need to consciously tell your heart to beat faster when you run). However, the ANS can be influenced by the brain (e.g. - salivating at the smell of food).
The Autonomic Nervous System (ANS) has 2 parts:
The Sympathetic and Parasympathetic Nervous Systems exit the brain and spinal cord and enter “relay stations” known as a ganglion. The parasympathetic ganglia are located close to the organs they innervate. Sympathetic ganglia, on the other hand, are in the sympathetic chain (which runs along the spinal column) and are far away from the organs (see figure 1). Messages from the brain pass from the preganglionic neuron, through the ganglion, to the postganglionic neuron, and finally to the target organ.
Acetylcholine (Ach) is the “preganglionic nerve to ganglion to postganglionic nerve” neurotransmitter for both the sympathetic and parasympathetic systems. Acetylcholine is also the “postganglionic nerve to organ” neurotransmitter for the parasympathetic system (PNS)
Norepinephrine (NE) is the “postganglionic nerve to organ” neurotransmitter for the sympathetic system (SNS)
So which neurotransmitter binds onto which receptor on the autonomic pathway?
Neurotransmitter | Acetylcholine (ACh) | Norepinephrine (NE), Epinephrine (E) |
---|---|---|
Preganglionic neuron (SNS/PNS) | - | |
Ganglion (SNS/PNS) | - | |
Postganglionic neuron (SNS/PNS) | - | |
Postganglionic nerve to organ (PNS) | - | |
Postganglionic nerve to organ (SNS) | - | |
Receptor | Muscarinic (M) and nicotinic (N) receptors | Alpha (α) and beta (β) receptors |
Receptor Subtype Examples | M1, M2, M3 | α1, α2, β1, β2 |
The following table details the function and location of sympathetic receptors, as well as example agonists and antagonists.
Receptor | Neurotransmitter | Receptor Type | Function | Location | Agonist | Antagonist |
---|---|---|---|---|---|---|
Alpha-1 (α1) | Norepinephrine | G-protein | Constriction of smooth muscles | • Blood vessels and skin piloerectors (vasoconstriction and goosebumps) • Sphincters (bladder, GI) • Uterus (contraction) • Eye (constriction of radial muscle, leading to pupillary dilation (mydriasis) | • Epinephrine • Phenylephrine • Midodrine | • Prazosin (antihypertensive) • Tamsulosin • Terazosin • Trazodone (blockade can cause priapism) • Antipsychotics (α1-blockade can cause orthostatic hypotension) |
Alpha-2 (α2) | Norepinephrine | G-protein | Inhibition of the sympathetic ganglia (i.e. - decreasing SNS activity) | • Presynaptic ganglionic neurons • GI tract | • Clonidine, guanfacine (antihypertensive, helps with ADHD, tics) | • Mirtazapine, trazodone (antidepressant effect) |
Agonist | Non selective blocker | Selective blocker (-osin ending) | |
---|---|---|---|
α1 | • Epinephrine • Phenylephrine • Midodrine | • Phenoxybenzamine • Phentolamine | • Prazosin • Terazosin • Doxazosin • Tamsulosin |
α2 | • Clonidine • Guanfacine | • Phenoxybenzamine • Phentolamine | • Mirtazapine |
Receptor | Function | Location | Agonist | Antagonist |
---|---|---|---|---|
Beta-1 (β1) | Increases cardiac performance, liberation of energy, and conservation of water | • Heart • Fat cells (lipolysis) • Kidneys (releases renin to conserve water) | • Dobutamine (used as a positive inotrope for heart failure and cardiogenic shock) | • Atenolol • Bisporolol (selective β1 receptor antagonist) • Metoporolol (selective β1 receptor antagonist) • Propranolol (β1- and β2-adrenergic receptor antagonist) |
Beta-2 (β2) | Relaxation of smooth muscles (e.g. in the lungs), and liberation of energy | • Lungs (bronchodilation) • Blood vessels in muscles (vasodilation) • uterus (uterine relaxation) • GI (intestinal relaxation) • Bladder (relaxation) • Liver (liberate glucose via glycogenolysis) | • Salbutamol [AKA Albuterol] (Short-acting β2 agonist, SABA) • Formoterol (Long-acting β2 agonist (LABA) | • Propranolol (β1- and β2-adrenergic receptor antagonist) |
β1-selective antagonists (β1 > β2)
Nonselective antagonists (β1 = β2)
Most of the time, the SNS and PNS are opposing each other. Therefore, to change this balance, one system can be strengthened, or the other weakened.
To increase (↑) sympathetic activity | To decrease (↓) sympathetic activity |
---|---|
You want to increase stimulation of the α and β receptors:
| You want to decrease stimulation of the α and β receptors:
|
The following table details the function and location of parasympathetic receptors, as well as example agonists and antagonists.
Receptor | Function | Location | Agonist | Antagonist |
---|---|---|---|---|
Nicotinic (N) | “Nerve to nerve” and “nerve to muscle” communication | • Sympathetic and parasympathetic ganglia • Neuromuscular junction (NMJ) | • Nicotine • Varenicline • Succinylcholine (indirect anticholinergic)* | • Pancuronium • Vecuronium |
Muscarinic (M) | Opposes most sympathetic actions at the level of the organs | • Lungs (bronchoconstriction) • Heart (bradycardia, decreased conduction, decreased contractility) • Sphincters of GI and bladder (relaxes) • Bladder wall (constriction) • GI (intestinal contraction) • Eye (contraction of the circular muscle = pupilary constriction/miosis) • Eye (contraction of the ciliary muscle = focus for near vision) • Glands: lacrimal, salivary, bronchial (secretions) | • Pilocarpine (stimulates secretion of large amounts of saliva and sweat, and increases aqueous humour turnover in open angle glaucoma) • Methacholine | • Atropine (non-selective antagonism), causes tachycardia • Benztropine (selective M1 muscarinic receptor antagonist) • Ipratropium (non-selective antagonism), bronchodilation • Tiotropium (non-selective antagonism), bronchodilation • Scopolamine • Hydroxyzine • Diphenhydramine “Benadryl” (non-selective antagonism) • Dimenhydrinate “Gravol” • Oxybutynin • Procyclidine (non-selective antagonism), for idiopathic or drug-induced Parkinson's |
Muscarinic Receptor Subtype | Location | Description |
---|---|---|
M1 | Central nervous system | Involved in perception, attention, and cognition. Delirium is also associated with the antagonism of post-synaptic M1 receptors. |
M2 | Brain, heart | Decreases heart rate below baseline normal sinus rhythm by slowing the speed of depolarization. |
M3 | Smooth muscles, salivary glands | Causes contraction of smooth muscle, including bronchoconstriction and bladder voiding. |
M4 | Brain, lungs, salivary glands | There is a possible role for M4 receptors in regulating salivary protein secretion. Agonism of M4 is thought to be involved in clozapine-induced sialorrhea. |
Most of the time, the SNS and PNS are opposing each other. Therefore, to change this balance, one system can be strengthened, or the other weakened.
To increase (↑) parasympathetic activity | To decrease (↓) parasympathetic activity |
---|---|
You want to increase stimulation of the M (and N) receptors: • Give a muscarinic (M) agonist (AKA cholinergic - also called a vagotonic, since the vagus nerve is the primary PNS nerve) • Inhibit the breakdown or removal of endogenous acetylcholine (e.g. - acetylcholinesterase inhibitor such as physostigmine) | You want to decrease stimulation of the M (and N) receptors: • Give a muscarinic (M) antagonist (AKA anticholinergic or parasympatholytic) (e.g. - atropine to increase heart rate) |