CHAPTER 5 Introduction to Autonomic Nervous System Drugs
The autonomic nervous system (ANS) and the endocrine system are the major regulatory systems for controlling homeostatic functions. These two systems collectively regulate and coordinate the cardiovascular, respiratory, gastrointestinal, renal, reproductive, metabolic, and immunologic systems. Drugs that alter the activity of either the ANS or the endocrine system often exhibit multiple actions and side effects. This chapter introduces the pharmacology of the ANS; the endocrine system and drugs are reviewed in Chapters 34 through 37. An understanding of the pharmacology of agents affecting the ANS rests on two basic foundations: a knowledge of the structural and functional organization of the ANS, and an understanding of where certain neurotransmitters are located and how these neurotransmitters affect cellular function.
The ANS, also referred to as the visceral, vegetative, or involuntary nervous system, regulates the function of smooth muscle, the heart, and certain secretory glands. These structures possess intrinsic mechanisms that allow them to function in the absence of neuronal input, but the ANS contributes a regulatory and coordinating function. Most of our knowledge of the ANS is restricted to efferent functions; much less is known about the afferent limb. Sensory afferent fibers carry impulses that are received and organized centrally, often at an unconscious level. A person is unaware of impulses generated at the baroreceptors, although these impulses may trigger a generalized body response, such as a reflex decrease in blood pressure, which the person may sense. It has been estimated that approximately 80% of the vagus nerve consists of primary afferent fibers and that the effects of certain drugs (e.g., opioids) may be mediated in part by altering autonomic sensory inputs.16,30 Nevertheless, most currently available ANS drugs influence efferent activity.
The structural organization of the efferent arm of the ANS differs from that of the somatic nervous system. Somatic efferent fibers originate from cell bodies located in the central nervous system (CNS) and innervate skeletal (striated) muscle without intervening synapses (Figure 5-1). In contrast, the ANS consists of a two-neuron system in which preganglionic nerves emanating from cell bodies in the cerebrospinal axis synapse with postganglionic nerves originating in autonomic ganglia outside the CNS. The ANS is divided into two parts on the basis of the anatomic characteristics of each division. The sympathetic division includes nerve pathways that originate in the thoracolumbar regions of the spinal cord, whereas the parasympathetic division includes nerve pathways from the craniosacral regions of the cerebrospinal axis.
FIGURE 5-1 Functional organization of the somatic nervous system and the autonomic nervous system, with the structures innervated by the different nerves and the chemical mediators responsible for transmission at the various sites. Solid lines indicate somatic motor or preganglionic autonomic nerves; dashed lines indicate postganglionic autonomic nerves. ACh, Acetylcholine; E, epinephrine; NE, norepinephrine.
The organizational anatomy of the two divisions of the ANS is shown in greater detail in Figure 5-2. The sympathetic division originates from neurons with cell bodies located in the intermediolateral columns of the spinal cord, extending from the first thoracic to the third lumbar segments. The myelinated preganglionic fibers emerge with the ventral roots of the spinal nerves and synapse with second neurons in one of three possible types of ganglia: paravertebral (vertebral or lateral), prevertebral, or terminal. The paravertebral ganglia are composed of 22 pairs of ganglia lying on either side of the spinal cord and connected to each other by communicating nerve fibers. The superior cervical ganglia (the topmost pair) innervate structures in the head and neck, including the submandibular glands, whereas the superior, middle, and inferior cervical ganglia all innervate the heart. The prevertebral ganglia are located in the abdomen and pelvis and include the celiac, superior mesenteric, and inferior mesenteric, which innervate the stomach, the small intestine, and the colon. The few terminal ganglia lie near the organs they innervate, principally the urinary bladder and rectum.
FIGURE 5-2 General arrangement of the autonomic nervous system showing one side of the bilateral outflow. On either side of the spinal cord (C1 to S5) are pictured the two chains of the paravertebral sympathetic ganglia. Preganglionic nerves of the sympathetic nervous system are indicated by light solid lines; postganglionic nerves of the sympathetic nervous system are indicated by light dashed lines. Preganglionic nerves of the parasympathetic nervous system, originating from the brain and sacral spinal cord, are shown by bold solid lines; postganglionic nerves of the parasympathetic nervous system are shown by bold dashed lines.
(Adapted from Copenhaver WM, editor: Bailey’s textbook of histology, ed 15, Baltimore, 1964, Williams & Wilkins.)
A striking anatomic aspect of the sympathetic nervous system—and one that has great functional significance—is that a single preganglionic nerve may contact 20 or more postganglionic nerves. Impulses arising in one preganglionic neuron of the sympathetic nervous system may ultimately affect many postganglionic neurons, which explains the diffuse and widespread character of sympathetic nervous system responses. Stimulation of the sympathetic nervous system also activates nerves that innervate the adrenal medulla and cause it to release a mixture of the catecholamines epinephrine and norepinephrine. This release provides an additional basis for the widespread effects of the sympathetic nervous system.
The parasympathetic nervous system, or craniosacral division, has its origin in neurons with cell bodies located in the brainstem nuclei of four cranial nerves—the oculomotor (cranial nerve III), the facial (cranial nerve VII), the glossopharyngeal (cranial nerve IX), and the vagus (cranial nerve X)—and in the second, third, and fourth segments of the sacral spinal cord. The preganglionic nerves arising from the brainstem form part of the cranial nerves and travel with them to synapse with postganglionic neurons located in ganglia near or actually within the structures innervated. The midbrain outflow from the nucleus of the oculomotor nerve synapses in the ciliary ganglion located in the orbit. The ganglion gives rise to nerves that supply the ciliary muscle and the sphincter muscle of the eye. Neurons of the facial nerve that synapse in the sublingual and submandibular ganglia form the chorda tympani and provide innervation to the sublingual and submandibular glands. Other neurons of the facial nerve synapse in the sphenopalatine ganglion; postganglionic nerves terminate in the lacrimal gland and in mucus-secreting glands of the nose, palate, and pharynx. Nerves originating in the glossopharyngeal nuclei synapse in the otic ganglion; its postganglionic neurons innervate the parotid gland. A major component of the cranial outflow is the vagus nerve, which originates from vagal nuclei in the medulla oblongata. Preganglionic nerves pass to ganglia located within the heart and the viscera of the thorax and abdomen. Postganglionic nerves, very short in length, arise from these ganglia to terminate in the aforementioned structures. Neurons originating from sacral segments form the pelvic nerves, which synapse in terminal ganglia lying near or within the uterus, bladder, rectum, and sex organs.
In contrast to the arrangement in the sympathetic nervous system, there is little overlap or divergence in the parasympathetic nervous system. With few exceptions (e.g., in Auerbach’s plexus in the gastrointestinal tract, where 1 preganglionic nerve exists for every 8000 postganglionic nerves), there is a one-to-one relationship between preganglionic and postganglionic nerves, which makes possible discrete and limited responses in the parasympathetic nervous system. The parasympathetic nervous system is characterized by long preganglionic and very short postganglionic nerves and, with only a few exceptions, an absence of well-defined, anatomically distinct ganglia.
Most organs are dually innervated by the sympathetic and parasympathetic nervous systems, such as most salivary glands and the heart, lungs (bronchial muscle), and abdominal and pelvic viscera, whereas other organs receive innervation from only one division. The sweat glands, adrenal medulla, piloerector muscles, and most blood vessels receive innervation from only the sympathetic nervous system. The parenchyma of the parotid, lacrimal, and nasopharyngeal glands are supplied only with parasympathetic nerves. Table 5-1 lists the organs to which nerve fibers of the parasympathetic and sympathetic nervous systems are distributed, the effects of stimulation of these nerves, and the autonomic receptors that are activated by neurotransmitters released from autonomic nerves.
To understand or predict the effects of autonomic drugs on a specific organ, it is necessary to know how each division of the ANS affects that organ, whether the organ is singly or dually innervated, and if dually, which of the two systems is dominant in the organ. In most circumstances, one or the other of the two divisions of the ANS will provide the dominant influence, but often neither division is totally dominant in many of the dually innervated organs. The fact that both divisions of the ANS modulate the intrinsic activity of the various tissues cannot be overemphasized.
The anatomic and functional characteristics of the two divisions of the ANS show that there are striking differences between the sympathetic and parasympathetic nervous systems. Cannon11 was the first to recognize that the sympathetic nervous system is capable of producing the kind of widespread and massive response that would enable an organism confronted with a stressor (e.g., pain, asphyxia, or strong emotions) to mount an appropriate response (“fright, fight, or flight”). Controlled clinical trials in dental patients indicate that oral surgical procedures constitute physiologically significant stressors for stimulating the sympathetic nervous system, with noticeable increases in circulating norepinephrine concentrations observed in patients during surgery and with the development of postsurgical pain (Figure 5-3). The stress of oral surgery is mediated by the CNS because drugs that reduce anxiety (e.g., diazepam) also reduce the sympathetic response to surgical stress and postoperative pain.15,19 The parasympathetic division is primarily concerned with the protection, conservation, and restoration of bodily resources. These differences in function are subserved by some of the anatomic characteristics that have already been mentioned, including the involvement of the adrenal medulla and the high ratio of postganglionic to preganglionic nerves in the sympathetic, but not the parasympathetic, nervous system.
FIGURE 5-3 Response of the sympathetic nervous system to the stress of oral surgery, as indicated by the circulating concentration of norepinephrine. Plasma norepinephrine was measured 1 week before surgery (baseline) and on the day of surgery at the indicated time points. Patients were randomly injected intravenously with either placebo or diazepam (0.3 mg/kg), followed by intraoral injections of 2% lidocaine with 1 : 100,000 epinephrine before surgical removal of impacted third molars. Placebo-treated patients showed significant increases (asterisks) in norepinephrine at the intraoperative and 3-hour postoperative periods, whereas diazepam-treated patients did not.
(Adapted from Hargreaves KM, Dionne RA, Mueller GP, et al: Naloxone, fentanyl, and diazepam modify plasma β-endorphin levels during surgery, Clin Pharmacol Ther 40:165-171, 1986.)
The concept that chemical mediators were responsible for transmission of information in the ANS emerged at the end of the nineteenth and the beginning of the twentieth century. Acetylcholine was identified as the primary neurotransmitter released from preganglionic nerves and from postganglionic nerves in the parasympathetic nervous system. Norepinephrine was found to be the neurotransmitter released from most postganglionic sympathetic nerves, whereas norepinephrine and epinephrine are released after sympathetic stimulation of the adrenal medulla. More recently, dopamine has also been found to be an important neurotransmitter at some sites in the ANS. Although acetylcholine, norepinephrine, epinephrine, and possibly dopamine have come to be recognized as the principal mediators of ANS activity, evidence exists that other molecules may also serve as chemical transmitters for specific neuronal circuits. Among these are histamine; 5-hydroxytryptamine (5-HT, serotonin); γ-aminobutyric acid (GABA); prostanoids; aspartate; adenosine triphosphate (ATP); glutamate; glycine; and various peptides, including neuropeptide Y, cholecystokinin, enkephalins, substance P, calcitonin gene–related peptide, and vasoactive intestinal peptide.
Figure 5-1 shows the sites at which the neurotransmitters acetylcholine and norepinephrine and the hormone epinephrine act as chemical mediators. With the exception of effectors (smooth muscle, the heart, and secretory glands) that are innervated by postganglionic sympathetic nerves where the neurotransmitter is norepinephrine, all other sites are innervated by cholinergic nerves, including the ganglia of the ANS, the adrenal medulla, a few effectors of the sympathetic nervous system, and all the effectors of the parasympathetic nervous system. At cholinergic junctions, cholinergic nerves release acetylcholine, which acts on cholinergic receptors to produce an effect. These ubiquitous cholinergic receptors are composed of two structurally unrelated types, called muscarinic and nicotinic, which are located at specific sites in the ANS. Muscarinic receptors are located on effectors innervated by cholinergic nerves; this includes effectors at postganglionic parasympathetic junctions and a few postganglionic sympathetic junctions (most sweat glands and some blood vessels). Nicotinic receptors are found at different anatomic sites, including postganglionic nerve cell bodies at all autonomic ganglia, the adrenal medulla, and skeletal muscle. There are also different types of structurally related adrenergic receptors (α1, α2, β1, β2, β3)10,37 that are found at postganglionic sympathetic junctions where norepinephrine is released from postganglionic sympathetic nerves. These adrenergic receptors do not have a precise anatomic distribution, however; some effector organs have only a single adrenergic receptor, whereas other organs have two or more adrenergic receptor types. The fact that there are significant differences in autonomic receptor types is supported by the discovery of agonists that stimulate one receptor type but not others and of antagonists that block one receptor but not others. Research has revealed the existence of additional subtypes for adrenergic and cholinergic receptors, and it is anticipated that drugs highly selective for these additional receptor subtypes will be developed for future clinical use.
The current understanding of exocytotic neurotransmitter release has arisen from the work of many different investigators. Although several mechanisms for neurotransmitter release may exist, as summarized in reviews on the subject,26,36 one main model has been developed for the secretion of classic neurotransmitters, such as acetylcholine (Figure 5-4) and norepinephrine (Figure 5-5). It has been proposed that when an action potential reaches the axon terminal it depolarizes the membrane, leading to the opening of voltage-gated Ca++ channels.31 This activation of Ca++ channels causes high, but transient, increases in intracellular Ca++ concentrations near the neurotransmitter storage vesicles. Intracellular Ca++ activates calmodulin, a small Ca++-binding protein found in nearly all cells.14 Calmodulin activates an enzyme called Ca++/calmodulin-dependent protein kinase. This enzyme, found in extremely high concentrations in neurons (approximately 1% of total protein), catalyzes the phosphorylation of several proteins associated with the storage vesicle, including synapsin I. Synapsin I binds to actin present on the cytoskeleton and is thought to interact with other proteins (e.g., synaptobrevin, synaptophysin, and synaptoporin) to initiate docking and fusion of the storage vesicle with the cell membrane, followed by exocytotic neurotransmitter release. The neurotransmitter crosses the synaptic or junctional cleft and binds to its receptor on the nerve or effector cell membrane, which could be located on a ganglionic neuron, a skeletal muscle fiber, an autonomic effector, or a cell in the CNS.
FIGURE 5-4 Cholinergic nerve terminal and its effector, in which are shown the intraneuronal synthesis of acetylcholine (ACh), the vesicles containing ACh, the release of ACh into the junctional cleft, its removal by the action of acetylcholinesterase (AChE) and diffusion, and the subsequent reuptake of choline back into the nerve terminal. CoA, Coenzyme A; ChAc, choline acetyltransferase; M, muscarinic receptor.
(Adapted from Hubbard JI: Mechanism of transmitter release from nerve terminals, Ann N Y Acad Sci 183:131-146, 1971.)
FIGURE 5-5 Adrenergic nerve terminal and its effector cell. Shown are the precursors of norepinephrine (NE), the sites of synthesis and storage of dopamine and NE, and the location of prejunctional and postjunctional adrenergic receptors (α2, α, β). It also shows the enzymatic (catechol-O-methyltransferase [COMT], monoamine oxidase [MAO]) and uptake-1 (U1) and uptake-2 (U2) mechanisms by which the action of NE is terminated. Dopa, Dihydroxyphenylalanine; Tyr, tyrosine.
The catecholamines norepinephrine and epinephrine are the primary neurotransmitters and hormones released after stimulation of the sympathetic nervous system. The synthesis and storage of the catecholamines can be modified by a number of clinically useful drugs. The synthetic process, shown in Figure 5-6, involves numerous enzymes that are synthesized in the nerve cell body and carried by axoplasmic transport to the nerve endings. The enzyme tyrosine hydroxylase, which catalyzes the conversion of tyrosine to dihydroxyphenylalanine, is the rate-limiting enzyme in this process; any drug that inhibits the function of tyrosine hydroxylase reduces the rate at which norepinephrine is produced in the nerve terminal. The concentration of norepinephrine in the cytoplasm is one of the factors that regulates its own formation, principally by feedback inhibition on tyrosine hydroxylase activity.27 The enzyme phenylethanolamine-N-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine, occurs almost exclusively in the chromaffin cells of the adrenal medulla and is missing in peripheral nerve terminals.3 Norepinephrine is the final product in most adrenergic nerves, whereas mainly epinephrine (80%), with some norepinephrine (20%), is produced in adrenal chromaffin cells in human beings.