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.
9–2Examples of Drugs That Act on the Autonomic Nervous System ||Download (.pdf) 9–2 Examples of Drugs That Act on the Autonomic Nervous System
|Drug Class ||Examples ||Examples of Clinical Uses|
β agonist (ns1)
β antagonist (ns1)
Phenylephrine, methoxamine, midodrine
Atenolol, labetalol, metoprolol
Terbutaline, salbutamol, salmeterol
Nasal congestion; orthostatic hypotension
Hypertension; benign prostatic hypertrophy
Hypertension; opiate withdrawal; ADD; Tourette syndrome
Severe cardiac failure
Heart ischemia; hypertension; social phobia
Heart ischemia; hypertension
Chronic obstructive pulmonary disease
| || || |
Xerostomia, Sjögren syndrome
Extrapyramidal side effects; motion sickness
Chronic obstructive pulmonary disease
| || |
| || || |
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.
Chemical structures of nicotine and lobeline.
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).
Chemical structures of representative nicotinic cholinergic agonists and antagonists.
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.
9–3Predominance of Sympathetic or Parasympathetic Tone at Various End Organs and Effects of Autonomic Ganglionic Blockade ||Download (.pdf) 9–3 Predominance of Sympathetic or Parasympathetic Tone at Various End Organs and Effects of Autonomic Ganglionic Blockade
|Site ||Predominant Tone ||Effect of Ganglionic Blockage|
|Arterioles ||Sympathetic ||Vasodilation; increased peripheral blood flow; hypotension |
|Veins ||Sympathetic ||Dilation; peripheral pooling of blood; decreased venous return; decreased cardiac output |
|Heart ||Parasympathetic ||Tachycardia |
|Iris ||Parasympathetic ||Mydriasis |
|Ciliary muscle ||Parasympathetic ||Cycloplegia—loss of accommodation |
|Gastrointestinal tract ||Parasympathetic ||Reduced tone and motility; constipation; decreased gastric and pancreatic secretions |
|Urinary bladder ||Parasympathetic ||Urinary retention |
|Salivary glands ||Parasympathetic ||Xerostomia |
|Sweat glands ||Sympathetic1 ||Anhidrosis |
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 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.
Chemical structures of representative β-adrenergic agonists and antagonists.
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 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 α1A-adrenergic receptor, which is enriched in the prostate gland, are used to treat benign prostatic hypertrophy.
Chemical structures of representative α-adrenergic agonists and antagonists.
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.
Chemical structures of representative muscarinic cholinergic agonists and antagonists.
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).
Chemical structures of prototypical acetylcholinesterase inhibitors. See Chapter 18 for structures of acetylcholinesterase inhibitors that are used in the treatment of Alzheimer disease.
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.