CHAPTER 9: Autonomic Nervous System

• The autonomic nervous system plays a central role in maintaining homeostasis and regulates almost every organ system in the body.

• The major functional divisions are the sympathetic and parasympathetic nervous systems. A third division, the enteric nervous system, is an intrinsic neural network that regulates gastrointestinal function.

• In most organs, the sympathetic and parasympathetic nervous systems produce functionally opposite effects and can be viewed in simple terms as physiologic antagonists.

• The sympathetic nervous system is activated in response to changes in the environment and produces a coordinated “fight-or-flight” response to a threat.

• The parasympathetic nervous system is continuously active, and coordinates the function of multiple organs in accord with the physiologic state of the organism, thereby facilitating such functions as digestion and excretion.

• Because of its importance to the physiology of the organism, the autonomic nervous system is a target for many pharmacologic interventions and is also responsible for the untoward effects of many medications and toxins.

• The peripheral autonomic nervous system (both sympathetic and parasympathetic divisions) consists of a preganglionic neuron in the brainstem or spinal cord that innervates postganglionic neurons in peripheral autonomic ganglia. Synaptic transmission in the autonomic ganglia is mediated by acetylcholine interacting with a nicotinic receptor that is pharmacologically distinct from receptors in the brain or at the neuromuscular junction. The postganglionic neurons innervate target organs throughout the body.

• Acetylcholine is the main neurotransmitter used by parasympathetic postganglionic neurons; its target receptors are muscarinic acetylcholine receptors.

• With a few exceptions, postganglionic sympathetic neurons release norepinephrine, which acts on α- and β-adrenergic receptors located on end organs.

The autonomic nervous system (ANS) is a semiautonomous division of the nervous system that innervates virtually every organ in the body. Central control of autonomic function involves integration of afferent information and cortical input by brainstem centers and the hypothalamus. These structures control the overall activity of the ANS (autonomic tone). The peripheral ANS (or visceral system) serves to distribute autonomic efferents throughout the body and can also mediate simple autonomic reflexes independent of central control.

The overall function of the ANS is to maintain homeostasis in the body (ie, optimize conditions for survival) in the face of constantly changing environmental and activity demands. For example, the ANS adjusts blood pressure and heart rate to meet the circulatory needs of the body that can vary tremendously from supine sleep to vigorous exercise. The ANS also maintains a constant body temperature despite changing environmental conditions and metabolic activity. Under ordinary circumstances, the ANS functions independently of consciousness yet can be influenced to some degree by volition and emotion. Without autonomic innervation, most organ systems continue to function but cannot adapt to changing environmental and emotional conditions.

Because of its anatomic accessibility and its robust regulation of peripheral organ functions, the ANS was among the first components of the mammalian nervous system to be studied. Consequently, many of the principles of neuropharmacology were derived from classic studies of autonomic systems. Such studies enabled investigators to establish the chemical basis of neurotransmission, identify acetylcholine (ACh) and norepinephrine as neurotransmitters, explore the pharmacology of cholinergic and adrenergic receptors, and discover the role of inhibitory presynaptic autoreceptors in neurotransmission. Indeed, many of the pharmacologic agents studied during the past century originally were characterized according to their actions on the ANS.

Central autonomic centers are distributed throughout the brain and include limbic cortical areas, amygdala, hypothalamus, and numerous brainstem nuclei 9–1. Cortical autonomic centers and amygdala are involved with initiating autonomic responses to emotion and pain. Brainstem centers receive visceral information and generate patterns of output through the peripheral autonomic nerves. The hypothalamus has multiple roles in autonomic regulation and has direct connections to the pituitary, peripheral autonomic neurons, and central autonomic nuclei. The hypothalamus can be considered the main coordinating center of the ANS. It is involved with control of circadian rhythm, temperature regulation, hunger, and thirst and also serves as a relay center for all sympathetic autonomic information descending to the body 9–2.

Although all parts work together in a coordinated fashion, the ANS can be divided into multiple discrete components. These include the following:

1. Neurohumoral component of the ANS (which is usually considered as part of the endocrine system). This consists of hormones that regulate energy metabolism, blood volume, and other functions (Chapter 10).

2. Intrinsic enteric nervous system. The gut has its own independent nervous system that consists of interconnected neurons in the wall of the bowel from the esophagus to the anus. There are as many neurons in the gut as in the spinal cord. These regulate bowel motility and other functions such that the bowel can operate independent of extrinsic input.

3. Sympathetic nervous system.

4. Parasympathetic nervous system.

The latter two components form the traditional peripheral ANS. The sympathetic and parasympathetic systems usually produce opposite functional effects and thus are viewed as physiologic antagonists. Most organs are innervated by both. Because they also are regulated independently, their combined actions result in an especially fine degree of control 9–3; 9–1. The sympathetic nervous system, which is characterized by episodic activity, assists an organism in adjusting to changes in the environment, such as those occurring during periods of danger or stress. It usually discharges as a whole, orchestrating a coordinated, multiorgan response to a threat. Activation of this system is associated with increases in the force and rate of heart contractions, an increase in blood pressure, a shift in blood flow from the skin and viscera to skeletal muscle, an increase in blood glucose, and dilation of the bronchial tree. These responses prepare an organism for fight or flight in response to threatening stimuli. The sympathetic system is also activated in response to emotional stress and anxiety (Chapter 15), exercise, dehydration, and in disease states such as congestive heart failure.

In contrast, the parasympathetic nervous system is characterized by graded activity in anatomically discrete segments that serves to coordinate the functioning of individual organs with the physiologic state of an organism. This system assists in maintaining the organism by facilitating functions such as digestion and excretion. There are many specific functions, including slowing the heart, constricting the pupils, stimulating the gut and salivary glands, stimulating bladder emptying, and sexual function.

It is important to remember that the two branches of the ANS have different neuroanatomy (see 9–3). Both branches of the peripheral ANS have several anatomic similarities with the somatic motor system 9–4. The central (preganglionic) autonomic motor neurons are cholinergic and leave the CNS via cranial nerves and ventral spinal roots 9–5. The preganglionic autonomic fibers synapse with neurons in autonomic ganglia that are spread throughout the body. The ganglionic neurons then send postganglionic axons to innervate multiple targets throughout the body. Autonomic ganglia not only are relay stations but also mediate simple autonomic reflexes and coordinate autonomic function between different organ systems.

Sympathetic Nervous System

Preganglionic sympathetic neurons reside in the intermediolateral cell column of the thoracolumbar (T1 to L2–3) spinal cord 9–3, 9–5. Myelinated preganglionic fibers leave the spinal cord and, in most cases, innervate paravertebral sympathetic ganglia connected in a chain by nerve fibers that extend along either side of the vertebral columns from the base of the skull to the coccyx. The postganglionic axons are nonmyelinated and provide sympathetic innervation to most organ systems.

Among cervical sympathetic ganglia, the superior cervical ganglion is notable because it gives rise to the carotid plexus, a network of postganglionic fibers that follow the ramifications of the carotid arteries and furnish the sympathetic innervation of the entire head. Some fibers end in blood vessels and sweat glands of the head and face; others supply the lacrimal and salivary glands. The eye receives sympathetic fibers that innervate the dilator muscles of the pupil and the smooth muscle fibers that help raise the eyelid. The lower cervical ganglia supply the viscera of the neck.

The heart and lungs receive sympathetic innervation from thoracic sympathetic ganglia. The abdominal and pelvic viscera are supplied by thoracic splanchnic nerves, which synapse with postganglionic autonomic neurons in the celiac, superior mesenteric, and aorticorenal ganglia. Lumbar splanchnic nerves carry preganglionic fibers to inferior mesenteric and hypogastric ganglia, from which postganglionic fibers reach end organs in the lower abdomen and pelvis.

Parasympathetic Nervous System

Preganglionic fibers of the parasympathetic nervous system originate in the brainstem and in the sacral region of the spinal cord. The brainstem fibers travel in cranial nerves, including the vagus nerve (cranial nerve X), which provides parasympathetic input to most of the viscera of the body (from the neck down to the distal one third of the colon). Sacral preganglionic neurons provide innervation to the rectum, bladder, and reproductive organs via pelvic splanchnic nerves. Parasympathetic preganglionic neurons have relatively long myelinated axons that synapse with postganglionic neurons in the many small ganglia located close to or within target organs (see 9–3).

Principal Neurotransmitters

The ANS functions predominantly through the actions of ACh and norepinephrine 9–4. As discussed in Chapter 6, ACh is the neurotransmitter released at the neuromuscular junction. In the ANS, all preganglionic neurons in both the sympathetic and parasympathetic nervous systems are cholinergic. These autonomic neurons are analogous to the anterior horn cells of the somatic motor system. Thus, all of the efferent fibers that leave the CNS are cholinergic. In both sympathetic and parasympathetic ganglia, the synaptic connection between the cholinergic preganglionic neuron and the postganglionic neuron is mediated by nicotinic ACh receptors. These neuronal ACh receptors are structurally similar but pharmacologically different from those at the neuromuscular junction, based on differences in their constituent subunits (Chapter 6). ACh is also the main neurotransmitter used by postganglionic neurons in the parasympathetic nervous system 9–4. The cholinergic signal from postganglionic parasympathetic fibers is transmitted to target organs primarily through muscarinic ACh receptors.

In contrast, norepinephrine is used by most of the postganglionic neurons of the sympathetic nervous system. The norepinephrine signal acts on several α- and β-adrenergic receptors located on target organs. Not all postganglionic sympathetic neurons are adrenergic. Sympathetic neurons that innervate sweat glands and certain blood vessels are cholinergic and act by means of muscarinic ACh receptors. Moreover, chromaffin cells of the adrenal medulla receive innervation from preganglionic sympathetic cholinergic fibers that act through neuronal nicotinic ACh receptors. In response to stimulation, chromaffin cells release epinephrine, which, like norepinephrine, acts on α- and β-adrenergic receptors located on end organs. In this way, adrenal chromaffin cells are functionally analogous to sympathetic postganglionic neurons.

Neuropeptides

Most sympathetic and parasympathetic neurons express, in addition to their principal neurotransmitters, a variety of neuropeptides. Neuropeptide Y (NPY) is most often coexpressed with norepinephrine in postganglionic sympathetic neurons, and vasoactive intestinal peptide (VIP) is typically coexpressed with ACh in postganglionic parasympathetic neurons. Other peptides expressed more sparingly in the ANS include galanin, enkephalin, somatostatin, and substance P. Most evidence suggests that, at least in the ANS, peptide transmitters act synergistically with small-molecule transmitters; for example, VIP promotes salivary gland secretion by itself, and the effect is intensified when VIP is coupled with ACh. Similarly, NPY increases vascular smooth muscle contraction by itself and produces synergistic increases in vascular tone when coupled with norepinephrine. These synergistic actions are significant because, outside of the ANS, peptide cotransmitters sometimes antagonize the actions of small-molecule transmitters (Chapter 7).

As previously mentioned, pharmacologic studies of the ANS in many ways defined the field of neuropharmacology during the past 100 years. Indeed, the number and variety of pharmacologic agents that influence autonomic function are vast and well beyond the scope of this book. The sections that follow provide a concise summary of the classes of drugs that affect the ANS and an overview of their physiologic actions. Examples of drugs that act on the ANS and their clinical uses are summarized in 9–2.

Ganglionic Stimulating and Blocking Agents

Because cholinergic transmission through sympathetic and parasympathetic ganglia is mediated by nicotinic cholinergic receptors, nicotinic cholinergic agonists and antagonists have profound effects on autonomic function. The best characterized ganglionic stimulating drugs are nicotine and lobeline 9–6. Nicotine, also discussed in Chapters 6 and 16, is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists at nicotinic cholinergic receptors, although their actions are complicated by the fact that they can rapidly desensitize these receptors. The initial effects of nicotine and lobeline are consistent with the activation of autonomic ganglionic transmission. Such effects include increased heart rate and blood pressure (due to activation of sympathetic neurons and adrenal medulla), increased salivation (due to activation of the sympathetic and parasympathetic systems), and increased contractile activity of the gut that may lead to nausea, vomiting, and diarrhea (due to activation of enteric and parasympathetic neurons regulating bowel motility). Prolonged exposure to nicotine leads to desensitization of nicotinic receptors, resulting in sustained inhibition of autonomic activity.

A small number of synthetic nicotinic cholinergic agonists, such as tetramethylammonium, have been identified 9–7. However, the clinical usefulness of such agents is limited. Most efforts in nicotinic cholinergic pharmacology have focused on the use of agonists that selectively activate nicotinic receptors in the brain and spinal cord for cognitive enhancement or analgesia, respectively (Chapters 6, 11, and 14). Other efforts have been directed toward the treatment of nicotine addiction (Chapter 16).

Among ganglionic blocking agents, tetraethylammonium was the first to be identified; other examples include trimethaphan, hexamethonium, and mecamylamine 9–7. The net effect of these agents on end-organ function depends on whether sympathetic or parasympathetic regulation of the organ predominates and on the physiologic state of the organism 9–3. These principles can be illustrated by a consideration of blood pressure, which is regulated by sympathetic tone. Under normal conditions, when an individual is reclining, the maintenance of blood pressure does not require an appreciable level of sympathetic activity. In contrast, when an individual is sitting or standing, the maintenance of blood pressure depends on increased sympathetic tone. Accordingly, ganglionic blocking agents have little effect on supine blood pressure but can cause a precipitous decline in blood pressure when administered to someone sitting or standing.

Ganglionic blocking agents were used clinically to treat hypertension several decades ago but for the most part have been replaced by medications with fewer side effects. Other nicotinic cholinergic antagonists, such as tubocurarine 9–7 or the snake venom α-bungarotoxin, act on nicotinic receptors at both autonomic ganglia and the neuromuscular junction, although actions at the latter site, such as muscular paralysis, predominate. So-called depolarizing agents, such as succinylcholine, exert effects primarily on the nicotinic ACh receptors in skeletal muscle. Initially, they activate nicotinic receptors, resulting in muscle contractions, but quickly cause paralysis through sustained depolarization of postsynaptic specializations on muscle cells and subsequent depolarization blockade (Chapter 2). Nondepolarizing agents such as vecuronium and rocuronium (see 9–7) are also commonly used in clinical practice as paralytics, for example, during endotracheal intubation. Advantages of nondepolarizing agents include the potential for reversal of their effects and their shorter duration of action. Reversal can be achieved by use of drugs such as sugammadex, a modified γ-cyclodextrin, which binds to the charged quaternary nitrogen found on the paralytic agents.

Adrenergic Receptor Agonists and Antagonists

Agonists and antagonists at various adrenergic receptors exert profound effects on the functioning of many organs by mimicking or antagonizing, respectively, sympathetic innervation. Agonists often are termed sympathomimetics, and antagonists are referred to as sympatholytics. Further information on adrenergic agonists and antagonists is provided in Chapter 6.

Much of our early knowledge of adrenergic function was obtained from studies of natural plant alkaloids that potently affect sympathetic nervous system activity. A prominent example of such an alkaloid is reserpine, which is synthesized from Rauwolfia serpentina, a shrub found on the Indian subcontinent 9–8. Reserpine is a potent sympatholytic agent, which acts by depleting body stores of norepinephrine and other monoamines, including dopamine and serotonin. As discussed in Chapter 6, this effect is mediated through the inhibition of the vesicular monoamine transporter (VMAT), which is responsible for concentrating monoamines into synaptic vesicles. Although reserpine was one of the first antihypertensive and antipsychotic agents used clinically, its use has been supplanted by that of more specific, and hence safer, medications.

Early information about adrenergic function also was drawn from studies of ergot alkaloids, which are produced by Claviceps purpurea, a fungus that grows on rye and other grains (see 9–8). Ergot-containing preparations have been used medicinally for more than two millennia for indications as varied as uterine bleeding and headache. During the 20th century, a large number of ergot derivatives were prepared; these exerted a variety of effects on the adrenergic system, including receptor agonist and antagonist activity. Such compounds served as invaluable tools in the pharmacologic characterization of different subtypes of adrenergic receptors and in the delineation of their physiologic functions. Some ergot derivatives, such as lysergic acid diethylamide (LSD), affect the serotonin system (Chapters 6 and 17). Others affect the dopamine system; an example is bromocriptine, an agonist at D₂ dopamine receptors that is used in the treatment of prolactin-secreting pituitary tumors and less commonly nowadays in the treatment of Parkinson disease (Chapter 18).

β-Adrenergic ligands

β-Adrenergic agonists have profound effects on many peripheral organs; clinically, their most important targets are the cardiovascular and pulmonary systems. The activation of β-adrenergic receptors increases the force and rate of heart contractions, and also can lead to the relaxation of vascular smooth muscle. The net effect is a large increase in cardiac output and a relatively modest increase in blood pressure. β-Adrenergic receptor activation causes relaxation of bronchial smooth muscle in the lungs, which increases pulmonary function and facilitates respiration. β-Adrenergic antagonists exert opposite effects. Chemical structures of representative β-adrenergic agonists and antagonists are shown in 9–9.

In cardiovascular medicine, β-adrenergic agonists such as dobutamine are used only under extraordinary circumstances; for instance, they may be used to stimulate a failing heart in an intensive care setting. The prototypical β-adrenergic agonist is isoproterenol; it is the agonist most often used in preclinical studies, although it is rarely used clinically. However, β-adrenergic antagonists such as metoprolol continue to be mainstays in the treatment of ischemic heart disease and hypertension. In the lungs, β-adrenergic stimulation increases pulmonary function, as previously mentioned. Accordingly, β-adrenergic agonists are one of the primary agents used to treat asthma and other chronic obstructive pulmonary diseases. The expression of different subtypes of β-adrenergic receptors in the heart (β₁) and lung (β₂) has enabled the development of relatively selective adrenergic agents. Selective β₁-adrenergic antagonists such as metoprolol and atenolol can be used to treat ischemic heart disease and hypertension without causing excessive bronchoconstriction; likewise, selective β₂-adrenergic agonists such as salmeterol can be used to treat obstructive pulmonary disease without causing excessive tachycardia. β-Adrenergic antagonists, like propranolol, are also used clinically to reduce sympathetic activity in individuals with stage fright, a type of social anxiety disorder (Chapter 15). Interestingly, the attenuation of peripheral symptoms of social anxiety—including increased heart rate, palpitations, sweating, and flushing of skin—that occurs in response to the administration of a β-adrenergic antagonist is often sufficient to improve an individual’s performance dramatically.

α-Adrenergic ligands

α-Adrenergic agonists and antagonists also are potent modulators of sympathetic nervous system activity. The predominant effect of α₁-adrenergic agonists is the constriction of arterial smooth muscle, which in turn causes an increase in blood pressure. α₁-Adrenergic agonists such as phenylephrine 9–10 are occasionally used in clinical practice to increase blood pressure during severe hypotensive episodes, while other α₁-adrenergic agonists, such as methoxamine, have been discontinued. The newer α₁-adrenergic agonist, midodrine 9–10, is approved to treat severe orthostatic hypotension due to autonomic failure. Although this drug increases standing blood pressure, its limiting side effect is supine hypertension, related to the above-noted fact that under normal circumstances sympathetic tone is low when an individual is in a supine or reclined position. Phenylephrine and related α₁-adrenergic agonists are widely used as nasal decongestants; their decongestive action may be mediated by the constriction of blood flow to nasal mucosa or by a reduction in airway secretions. α₁-Adrenergic antagonists (eg, prazosin 9–10) are used as antihypertensive drugs; antagonists (eg, tamsulosin) selective for the α_1A-adrenergic receptor, which is enriched in the prostate gland, are used to treat benign prostatic hypertrophy.

α₂-Adrenergic receptors function as inhibitory autoreceptors on noradrenergic neurons (Chapter 6); thus, it is not surprising that α₂-adrenergic agonists such as clonidine and guanfacine reduce sympathetic nervous system activity (see 9–10). Yet it is believed that such agents produce this effect by acting not on nerve terminals of postganglionic sympathetic neurons, but on neurons of the CNS: α₂-adrenergic agonists inhibit the firing of noradrenergic neurons in the CNS, such as those in the locus ceruleus, which in turn leads to reduced sympathetic activity. Such agonists are commonly used in the treatment of hypertension and of several neuropsychiatric disorders, such as opiate withdrawal, attention deficit hyperactivity disorder, and Tourette syndrome (Chapters 14 and 16). α₂-Adrenergic antagonists such as yohimbine (see 9–10) exert opposite effects: they stimulate sympathetic activity by activating noradrenergic neurons of the CNS.

Muscarinic Cholinergic Receptor Agonists and Antagonists

Muscarinic cholinergic agonists and antagonists exert profound effects on the ANS and on many regions of the brain. The last decade has provided new insight into the role of the five different subtypes of muscarinic receptors, termed M₁ to M₅, in these various actions (Chapter 6). Because all receptor subtypes share very similar structures at their ligand-binding sites, the development of subtype-selective agonists and antagonists has been challenging, although progress has been made in recent years (see 6–6 in Chapter 6). The development of allosteric modulators, which act outside the ligand-binding domains of the receptors, may have more promise for future drug development, for example, the use of selective positive or negative allosteric modulators (PAMs or NAMs, respectively) of specific muscarinic receptors to treat memory disorders (Chapter 14).

Prototypical muscarinic agonists, which activate all receptor subtypes, include synthetic agents such as carbachol and bethanechol, and natural plant products such as arecoline, pilocarpine, and muscarine 9–11. These agents affect the peripheral nervous system by slowing the heart and reducing blood pressure, actions mediated primarily via the M₂ receptor. In the CNS, they exert a characteristic cortical activation, mainly via M₁ receptors (Chapters 6 and 14). Because muscarinic agonists stimulate emptying of the bladder, an action mediated predominantly via M₃ receptors, a major clinical use of such drugs is in the treatment of urinary retention. These drugs are also sometimes used to stimulate motility of the gastrointestinal tract and to stimulate salivary gland secretion. Cevimeline, which preferentially activates M₃ receptors, is used to treat xerostomia (ie, dry mouth) in Sjögren syndrome. In addition, muscarinic agonists have nonmedicinal uses in several Eastern cultures; for example, arecoline is used recreationally on the Indian subcontinent.

The effects of muscarinic cholinergic antagonists can be predicted based on their blockade of postganglionic parasympathetic transmission. Prototypical antagonists, which antagonize all receptor subtypes, include atropine and scopolamine 9–11. Such drugs have variable effects on the rate and force of cardiac contractions, depending on the dose administered, cause hot and dry skin, pupillary dilation and reduced accommodation (resulting in blurred vision), and decreased gastrointestinal motility. Nonselective muscarinic antagonists (eg, tolterodine and fesoterodine) are used to treat overactive bladder, and the recent development of M₃-selective antagonists (eg, solifenacin and darifenacin) has improved the treatment of this condition (see 9–11). Combined M₁–M₃ antagonists, such as tiotropium and ipratropium, are used in the treatment of chronic obstructive pulmonary disease as the drugs reverse airway constriction and reduce bronchial secretions. Muscarinic antagonists were once widely used in the treatment of gastrointestinal symptoms (nausea, motion sickness, and diarrhea), but for the most part have been supplanted by newer agents with fewer side effects. Regular clinical use of muscarinic antagonists occurs in ophthalmology; for example, these drugs are used in routine eye examinations to produce mydriasis. These agents also are used as adjuncts in anesthesia to reduce pharyngeal and bronchial secretions and in patients with sialorrhea (hypersalivation). In emergency situations, intravenous administration of muscarinic antagonists, such as atropine, is used to treat severe bradycardia. Independent of their effects on the ANS, nonselective muscarinic antagonists powerfully affect the CNS and result in pervasive delirium, including confusion, disorientation, and hallucinations (Chapter 14). Muscarinic cholinergic antagonists are used in the treatment of Parkinson disease and in the management of parkinsonian side effects associated with D₂ antagonist antipsychotic drugs; however, movement disorders specialists generally avoid this practice (Chapter 18). The use of many psychotropic medications, including tricyclic antidepressants and phenothiazine antipsychotic agents, is limited by side effects such as blurred vision, dry mouth, constipation, and delirium that are caused by muscarinic cholinergic antagonism.

Acetylcholinesterase Inhibitors

Cholinergic transmission can be enhanced not only by cholinergic receptor agonists but also by acetylcholinesterase inhibitors. As mentioned in Chapter 6, acetylcholinesterase is the enzyme responsible for the degradation of ACh. Inhibitors of this process in current clinical use include pyridostigmine, physostigmine, neostigmine, and edrophonium 9–12. These agents are used for a variety of ophthalmic and gastrointestinal indications as well as for the treatment of atonic bladder and myasthenia gravis. In patients with orthostatic hypotension due to autonomic insufficiency, pyridostigmine may improve standing blood pressure without causing supine hypertension, presumably by enhancing transmission at sympathetic ganglia. Other acetylcholinesterase inhibitors, including donepezil, galantamine, rivastigmine, and tacrine, are used to diminish cognitive symptoms of Alzheimer disease, although their effectiveness is limited (Chapter 18).

Most of the toxins used in nerve gas weapons (including sarin, soman, and Vx) are potent irreversible acetylcholinesterase inhibitors. They exert their lethal effects on cholinergic synapses in the CNS, ANS, and somatic motor system.

Autonomic dysfunction, or dysautonomia, occurs in a large number of diseases that affect either the central or peripheral nervous systems. 9–4 provides a classification of autonomic disorders. Autonomic dysfunction may involve the sympathetic or parasympathetic nervous system, or both. A disorder that is primarily sympathetic may render the body incapable of dealing appropriately with strenuous physical or emotional stimulation. In contrast, parasympathetic dysfunction may result in more circumscribed symptoms such as bowel or sexual dysfunction. A comprehensive description of autonomic failure is beyond the scope of this text; however, a small number of illustrative examples are included in the following sections of this chapter. Autonomic dysfunction also appears to be important in certain pain syndromes, such as causalgia and reflex sympathetic dystrophy, which are discussed in Chapter 11. Some of the methods used to diagnose and characterize autonomic disorders are listed in 9–5.

Dopamine β-Hydroxylase Deficiency

Congenital absence of the enzyme dopamine β-hydroxylase (DBH), which converts dopamine into norepinephrine (Chapter 6), results in sympathetic adrenergic failure, with preserved sympathetic cholinergic and parasympathetic function. The clinical syndrome consists of childhood onset of orthostatic hypotension, hypothermia, and hypoglycemia, which progresses in adulthood to marked hypotension, bilateral ptosis, decreased sweating, retrograde ejaculation, reduced vaginal secretions, and hyporeflexia.

Individuals with DBH deficiency have abnormally elevated levels of dopamine but a virtual absence of circulating norepinephrine and epinephrine. Results of parasympathetic tests of heart rate control and sympathetic cholinergic sweat tests are normal. Skin biopsies can be used to demonstrate the absence of the enzyme. Commercial genetic testing is also available for diagnostic purposes. L-Dihydroxyphenylserine (L-DOPS, also known as droxidopa) can dramatically improve the symptoms of this enzyme deficiency; converted by aromatic amino acid decarboxylase directly into norepinephrine, it bypasses the DBH step and thus restores adrenergic function 9–13. This drug can also be useful in patients with sympathetic failure due to degenerative neurologic disease.

Experimental sympathectomy can be achieved with 6-hydroxydopamine, guanethidine, or antibodies to nerve growth factor (NGF) or acetylcholinesterase. These agents, administered peripherally, selectively damage sympathetic neurons and exert little or no effect on the parasympathetic nervous system or on enteric or peripheral nerves. Affected animals exhibit a shortened life span, decreased weight gain, low blood pressure, ptosis, and diarrhea.

Familial dysautonomia

Familial dysautonomia, also known as Riley–Day syndrome or type III hereditary sensory and autonomic neuropathy, is an autosomal recessive disease that occurs primarily in children of Jewish descent. The disease is associated with degenerative changes in the CNS and peripheral autonomic system that commence in infancy. The main clinical features are decreased or absent lacrimation, transient skin blotching, hyperhidrosis or erratic sweating, episodes of hypertension and labile blood pressure, episodes of hyperpyrexia and vomiting, impaired taste discrimination, and relative insensitivity to pain. Areflexia, corneal insensitivity and abrasions, loss of fungiform tongue papillae, poor motor coordination, and emotional instasbility also occur. Poor feeding and recurring aspiration-induced pulmonary infections and dehydration are the usual causes of death during infancy and childhood. During adolescence most autonomic symptoms decrease, with the exception of postural hypotension. Early diagnosis and better management of complications have increased the life expectancy of patients with this disease.

The pathogenesis of familial dysautonomia is believed to involve the abnormal development of neural crest cells. Preganglionic neurons in the intermediolateral columns are reduced in number, as are small myelinated fibers in the ventral roots. Because reduced amounts of NGF have been detected in cultured human fibroblasts and in the serum of patients with familial dysautonomia, investigations have attempted to determine whether the disease is linked to NGF-related defects. Moreover, levels of vanillylmandelic acid (VMA), a urinary norepinephrine and epinephrine metabolite, are decreased in patients with familial dysautonomia, while levels of homovanillic acid (HVA), a dopamine metabolite, are normal; thus, an abnormal VMA to HVA ratio may be a sign of this disease.

Diabetes

Diabetes mellitus is the most common cause of autonomic neuropathy. The prevalence of autonomic dysfunction in diabetics varies tremendously, 1% to 90%, depending on the population studied and the means of assessment. The likelihood of autonomic failure increases with the severity of hyperglycemia, the duration of the diabetes, and the age of the patient. Autonomic dysfunction is seen in animal models of diabetes mellitus, involving genetically diabetic animals or animals treated with pancreatic islet β-cell toxins such as streptozotocin and alloxan.

The precise pathophysiologic mechanisms that underlie changes in the ANS associated with diabetes are unknown. Manifestations of diabetic peripheral neuropathy are heterogeneous, but most commonly include distal sensory and sensorimotor involvement as well as impaired sweating (anhidrosis), pupillary abnormalities, diminished heart rate variability, esophageal and gastrointestinal motor abnormalities, atonic bladder, and male impotence.

In patients with diabetes, clinical autonomic neuropathy has been associated with poor long-term prognoses and survival rates. It also is associated with an increased incidence of cardiac arrest and sudden death. A large controlled clinical trial has indicated that long-term diabetic complications, including autonomic dysfunction, are delayed and slowed in response to tight glucose control. In addition, a number of trials have shown that aldose reductase inhibitors offer a slight benefit in halting or slowing the progression of neuropathy.

Toxin- or drug-induced neuropathies

Autonomic dysfunction occurs in some individuals exposed to environmental and pharmacologic toxins. Such dysfunction is best documented after exposure to organic solvents such as carbon disulfide and heavy metals. Workers exposed to various hydrocarbons, alcohols, ketones, esters, or ethers typically exhibit altered autonomic function. Industrial exposure to acrylamide has caused peripheral sensory polyneuropathy, which often is preceded by blue skin color and excessive sweating of the extremities. Arsenic also produces abnormal extremity sweating. Mercury poisoning leads to acrodynia, which is characterized by hypertension, tachycardia, and pain and redness of the fingers, toes, and ears. Acrodynia is effectively treated with ganglionic blocking agents. Ingestion of vacor (N-3-pyridylmethyl-N9-p-nitrophenylurea), a rat poison that antagonizes nicotinamide metabolism, results in acute hyperglycemic ketoacidosis and a combined somatic and autonomic neuropathy.

Some commonly used chemotherapeutic agents also cause a dose-dependent and cumulative effect on autonomic function. Vincristine, a natural product of vinca alkaloids used to treat several cancers, has limited applications because of its neurotoxic effects revealed by prominent autonomic symptoms. Cisplatin, a nonspecific cytotoxic agent that inhibits the cell cycle, causes ototoxicity, retrobulbar neuritis, and a sensory polyneuropathy or a dorsal root ganglionopathy.

The ANS can be a target of immunologic attack in several disorders. A rare but dramatic example is autoimmune autonomic neuropathy (AAN, described in 9–1).

Guillain–Barré Syndrome

This acute-onset neuropathy commonly involves autonomic hypoactivity or hyperactivity. Approximately 65% of patients with Guillain–Barré syndrome have some dysautonomia, which is attributed to demyelination of preganglionic fibers of the sympathetic nervous system. Afferent baroreflex abnormalities in individuals with this syndrome can cause intermittent episodes of orthostatic hypotension, and abrupt fluctuations in blood pressure may precede fatal arrhythmias. Many cases of Guillain–Barré syndrome occur in the context of a viral infection and are thought to be mediated by an autoimmune mechanism. While Guillain–Barré syndrome has been associated with recent exposure to immunizations, this topic remains controversial. Regardless of the association, all studies are in agreement that, even if there is a small increase in risk of Guillain–Barré syndrome with vaccinations, this risk is heavily outweighed by the higher risk of developing Guillain–Barré syndrome after an illness that could be prevented by vaccination. In many patients, the syndrome is self-limited and resolves spontaneously over time.

Paraneoplastic Neurologic Syndromes

Patients with cancer may develop an autoimmune syndrome, where immune responses against the cancer cells cross-react with and damage normal tissues. The paraneoplastic disorders can affect any part of the nervous system including the ANS. The symptoms of autonomic dysfunction usually reflect impairment of both limbs of the ANS. Paraneoplastic gastroparesis is an especially characteristic manifestation, most common in patients with occult small cell lung cancer, and results from inflammation and destruction of myenteric ganglia that control gut motility.

The Lambert–Eaton myasthenic syndrome is another disorder that may present in patients with small cell carcinomas. Most patients have antibodies against neuronal voltage-gated calcium channels. These antibodies reduce presynaptic quantal release of ACh at the neuromuscular junction and at other peripheral cholinergic synapses, including the autonomic ganglia (Chapter 12). In addition to weakness, patients have characteristic autonomic symptoms: dry mouth, constipation, impotence, and reduced sweating.