Drugs Affecting the Autonomic Nervous System PDF

UNIT II Drugs Affecting the Autonomic Nervous System 3 The Autonomic Nervous System I. OVERVIEW The autonomic nervous system (ANS), along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the l...

UNIT II Drugs Affecting the Autonomic Nervous System 3 The Autonomic Nervous System I. OVERVIEW The autonomic nervous system (ANS), along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the levels of bloodborne hormones. In contrast, the nervous system exerts its influence by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances. Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the autonomic nervous system are called autonomic drugs and are discussed in the following four chapters. These autonomic agents act either by stimulating portions of the autonomic nervous system or by blocking the action of the autonomic nerves. This chapter outlines the fundamental physiology of the ANS and describes the role of neurotransmitters in the communication between extracellular events and chemical changes within the cell. II. INTRODUCTION TO THE NERVOUS SYSTEM The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of the brain and spinal cord, and the peripheral nervous system, which includes neurons located outside the brain and spinal cord—that is, any nerves that enter or leave the CNS (Figure 3.1). The peripheral nervous system is subdivided into the efferent division, the neurons of which carry signals away from the brain and spinal cord to the peripheral tissues, and the afferent division, the neurons of which bring information from the periphery to the CNS. Afferent neurons provide sensory input to modulate the function of the efferent division through reflex arcs, or neural pathways that mediate a reflex action. A. Functional divisions within the nervous system The efferent portion of the peripheral nervous system is further divided into two major functional subdivisions, the somatic and the autonomic systems (see Figure 3.1). The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion. The autonomic system, conversely, regulates the everyday requirements of vital bodily functions without the conscious participation of the mind. Because of the involuntary nature of the autonomic nervous system as well as its functions, it is also known as the visceral, vegetative, or involuntary Nervous System Peripheral Nervous System Central Nervous System Efferent Division Afferent Division Autonomic System Somatic System Enteric Parasympathetic Sympathetic Figure 3.1 Organization of the nervous system. 38 3. The Autonomic Nervous System Brainstem or spinal cord Cell body nervous system. It is composed of efferent neurons that innervate smooth muscle of the viscera, cardiac muscle, vasculature, and the exocrine glands, thereby controlling digestion, cardiac output, blood flow, and glandular secretions. B. Anatomy of the ANS 1 Preganglionic neuron Ganglionic transmitter 2 Postganglionic neuron Neuroeffector transmitter Effector organ Figure 3.2 Efferent neurons of the autonomic nervous system. 1. Efferent neurons: The ANS carries nerve impulses from the CNS to the effector organs by way of two types of efferent neurons (Figure 3.2). The first nerve cell is called a preganglionic neuron, and its cell body is located within the CNS. Preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous system). These ganglia function as relay stations between a preganglionic neuron and a second nerve cell, the postganglionic neuron. The latter neuron has a cell body originating in the ganglion. It is generally nonmyelinated and terminates on effector organs, such as smooth muscles of the viscera, cardiac muscle, and the exocrine glands. 2. Afferent neurons: The afferent neurons (fibers) of the ANS are important in the reflex regulation of this system (for example, by sensing pressure in the carotid sinus and aortic arch) and in signaling the CNS to influence the efferent branch of the system to respond. 3. Sympathetic neurons: The efferent ANS is divided into the sympathetic and the parasympathetic nervous systems as well as the enteric nervous system (see Figure 3.1). Anatomically, the sympathetic and the parasympathetic neurons originate in the CNS and emerge from two different spinal cord regions. The preganglionic neurons of the sympathetic system come from thoracic and lumbar regions (T1 to L2) of the spinal cord, and they synapse in two cordlike chains of ganglia that run close to and in parallel on each side of the spinal cord. The preganglionic neurons are short in comparison to the postganglionic ones. Axons of the postganglionic neuron extend from these ganglia to the tissues that they innervate and regulate (see Chapter 6). The sympathetic nervous system is also called the thoracolumbar division because of its origins. In most cases, the preganglionic nerve endings of the sympathetic nervous system are highly branched, enabling one preganglionic neuron to interact with many postganglionic neurons. This arrangement enables this division to activate numerous effector organs at the same time. [Note: The adrenal medulla, like the sympathetic ganglia, receives preganglionic fibers from the sympathetic system. Lacking axons, the adrenal medulla, in response to stimulation by the ganglionic neurotransmitter acetylcholine, influences other organs by secreting the hormone epinephrine, also known as adrenaline, and lesser amounts of norepinephrine, into the blood.] 4. Parasympathetic neurons: The parasympathetic preganglionic fibers arise from cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus) as well as from the sacral region (S2 to S4) of the spinal cord and synapse in ganglia near or on the effector organs. [The vagus nerve accounts for 90% of preganglionic parasympathetic fibers in the body. Postganglionic neurons from this nerve innervate most of the organs in the thoracic and abdominal cavity.] Due to the origin of the parasympathetic nervous system, it II. Introduction To The Nervous System 39 is also called the craniosacral division. Thus, in contrast to the sympathetic system, the preganglionic fibers are long, and the postganglionic ones are short, with the ganglia close to or within the organ innervated. In most instances there is a one-to-one connection between the preganglionic and postganglionic neurons, enabling the discrete response of this division. 5. Enteric neurons: The enteric nervous system is the third division of the ANS. It is a collection of nerve fibers that innervate the gastrointestinal (GI) tract, pancreas, and gallbladder, and it constitutes the “brain of the gut.” This system functions independently of the CNS and controls the motility, exocrine and endocrine secretions, and microcirculation of the GI tract. It is modulated by both the sympathetic and parasympathetic nervous systems. C. Functions of the sympathetic nervous system Although continually active to some degree (for example, in maintaining the tone of vascular beds), the sympathetic division has the property of adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, and exercise (Figure 3.3). Red = sympathetic actions Blue = parasympathetic actions LACRIMAL GLANDS Stimulation of tears EYE Contraction of iris radial muscle (pupil dilates) Contraction of iris sphincter muscle (pupil contracts) Contraction of ciliary muscle (lens accommodates for near vision) SALIVARY GLANDS Thick, viscous secretion Copious, watery secretion TRACHEA AND BRONCHIOLES Dilation Constriction, increased secretions ADRENAL MEDULLA HEART Increased rate; increased contractility Decreased rate; decreased contractility Secretion of epinephrine and norepinephrine KIDNEY Secretion of renin (β1 increases; α1 decreases) URETERS AND BLADDER GASTROINTESTINAL SYSTEM Decreased muscle motility and tone; contraction of sphincters Increased muscle motility and tone GENITALIA (female) Relaxation of detrusor; contraction of trigone and sphincter Relaxation of uterus Contraction of detrusor; relaxation of trigone and sphincter (skeletal muscle) Dilation BLOOD VESSELS GENITALIA (male) Stimulation of ejaculation Stimulation of erection Figure 3.3 Actions of sympathetic and parasympathetic nervous systems on effector organs. BLOOD VESSELS (skin, mucous membranes, and splanchnic area) Constriction 40 3. The Autonomic Nervous System "Fight or flight" stimulus Sympathetic output (diffuse because postganglionic neurons may innervate more than one organ) "Rest and digest" stimulus 1. Effects of stimulation of the sympathetic division: The effect of sympathetic output is to increase heart rate and blood pressure, to mobilize energy stores of the body, and to increase blood flow to skeletal muscles and the heart while diverting flow from the skin and internal organs. Sympathetic stimulation results in dilation of the pupils and the bronchioles (see Figure 3.3). It also affects GI motility and the function of the bladder and sexual organs. 2. Fight or flight response: The changes experienced by the body during emergencies have been referred to as the “fight or flight” response (Figure 3.4). These reactions are triggered both by direct sympathetic activation of the effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine. Hormones released by the adrenal medulla directly enter the bloodstream and promote responses in effector organs that contain adrenergic receptors (see Figure 6.6). The sympathetic nervous system tends to function as a unit and often discharges as a complete system, for example, during severe exercise or in reactions to fear (see Figure 3.4). This system, with its diffuse distribution of postganglionic fibers, is involved in a wide array of physiologic activities. Although it is not essential for survival, it is nevertheless an important system that prepares the body to handle uncertain situations and unexpected stimuli. D. Functions of the parasympathetic nervous system Parasympathetic output (discrete because postganglionic neurons are not branched, but are directed to a specific organ) Sympathetic and parasympathetic actions often oppose each other Figure 3.4 Sympathetic and parasympathetic actions are elicited by different stimuli. The parasympathetic division is involved with maintaining homeostasis within the body. To accomplish this, it maintains essential bodily functions, such as digestive processes and elimination of wastes. The parasympathetic division is required for life. It usually acts to oppose or balance the actions of the sympathetic division and is generally dominant over the sympathetic system in “rest and digest” situations. The parasympathetic system is not a functional entity as such and it never discharges as a complete system. If it did, it would produce massive, undesirable, and unpleasant symptoms, such as involuntary urination and defecation. Instead, discrete parasympathetic fibers are activated separately and the system functions to affect specific organs, such as the stomach or eye. E. Role of the CNS in the control of autonomic functions Although the ANS is a motor system, it does require sensory input from peripheral structures to provide information on the state of affairs in the body. This feedback is provided by streams of afferent impulses, originating in the viscera and other autonomically innervated structures that travel to integrating centers in the CNS, such as the hypothalamus, medulla oblongata, and spinal cord. These centers respond to the stimuli by sending out efferent reflex impulses via the ANS (Figure 3.5). 1. Reflex arcs: Most of the afferent impulses are translated into reflex responses without involving consciousness. For example, a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers in the brain. This prompts a reflex response of increased sympathetic output to the heart and vasculature and decreased parasympathetic output to the heart, which results in a compensatory rise in blood pressure and tachycardia (see Figure 3.5). [Note: In each case, the reflex arcs of the ANS comprise a sensory (or afferent) arm, and a motor (or efferent, or effector) arm.] II. Introduction To The Nervous System 41 2. Emotions and the ANS: Stimuli that evoke strong feelings, such as rage, fear, and pleasure, can modify the activities of the ANS. 1 AFFERENT INFORMATION Sensory input from the viscera: F. Innervation by the ANS 1. Dual innervation: Most organs in the body are innervated by both divisions of the ANS. Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation increases the heart rate. Despite this dual innervation, one system usually predominates in controlling the activity of a given organ. For example, in the heart, the vagus nerve is the predominant factor for controlling rate. This type of antagonism is considered to be dynamic and is fine-tuned at any given time to control homeostatic organ functions. The activity of a system represents integration of influence of both divisions. • Drop in blood pressure • Reduced stretch of baroreceptors in aortic arch • Reduced frequency of afferent impulses to medulla (brainstem) 2. Organs receiving only sympathetic innervation: Although most tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic system. The control of blood pressure is also mainly a sympathetic activity, with essentially no participation by the parasympathetic system. G. Somatic nervous system The efferent somatic nervous system differs from the autonomic system in that a single myelinated motor neuron, originating in the CNS, travels directly to skeletal muscle without the mediation of ganglia. As noted earlier, the somatic nervous system is under voluntary control, whereas the autonomic system is involuntary. Responses in the somatic division are generally faster than those in the ANS. H. Summary of differences between sympathetic, parasympathetic, and motor nerves Major differences in the anatomical arrangement of neurons lead to variations of the functions in each division (Figure 3.6). The sympathetic nervous system is widely distributed, innervating practically all effector systems in the body. In contrast, the parasympathetic division’s distribution is more limited. The sympathetic preganglionic fibers have a much broader influence than the parasympathetic fibers and synapse with a larger number of postganglionic fibers. This type of organization SYMPATHETIC 2 REFLEX RESPONSE Efferent reflex impulses via the autonomic nervous system cause: • Inhibition of parasympathetic and activation of sympathetic divisions • Increased peripheral resistance and cardiac output • Increased blood pressure Figure 3.5 Baroreceptor reflex arc responds to a decrease in blood pressure. PARASYMPATHETIC Sites of origin Thoracic and lumbar region of the spinal cord (thoracolumbar) Length of fibers Short preganglionic Long postganglionic Location of ganglia Close to spinal cord Within or near effector organs Preganglionic fiber branching Extensive Minimal Distribution Wide Limited Type of response Diffuse Discrete Figure 3.6 Characteristics of the sympathetic and parasympathetic nervous systems. Brain and sacral area of spinal cord (craniosacral) Long preganglionic Short postganglionic 42 3. The Autonomic Nervous System permits a diffuse discharge of the sympathetic nervous system. The parasympathetic division is more circumscribed, with mostly one-toone interactions, and the ganglia are also close to, or within, organs they innervate. This limits the amount of branching that can be done by this division. [A notable exception to this arrangement is found in the myenteric plexus, where one preganglionic neuron has been shown to interact with 8000 or more postganglionic fibers.] The anatomical arrangement of the parasympathetic system results in the distinct functions of this division. The somatic nervous system innervates skeletal muscles. One somatic motor neuron axon is highly branched, and each branch innervates a single muscle fiber. Thus, one somatic motor neuron may innervate 100 muscle fibers. This arrangement leads to the formation of a motor unit. The lack of ganglia and the myelination of the motor nerves enable a fast response by this (somatic nervous) system. Endocrine signaling III. CHEMICAL SIGNALING BETWEEN CELLS Hormone Target cell Blood vessel Direct contact Gap junction Signaling cell Target cells A. Hormones Specialized endocrine cells secrete hormones into the bloodstream where they travel throughout the body, exerting effects on broadly distributed target cells in the body. (Hormones are described in Chapters 23 through 26.) B. Local mediators Synaptic signaling Target cell Nerve cell Neurotransmission in the ANS is an example of the more general process of chemical signaling between cells. In addition to neurotransmission, other types of chemical signaling include the secretion of hormones and the release of local mediators (Figure 3.7). Neurotransmitter Figure 3.7 Some commonly used mechanisms for transmission of regulatory signals between cells. Most cells in the body secrete chemicals that act locally, that is, on cells in their immediate environment. Because these chemical signals are rapidly destroyed or removed, they do not enter the blood and are not distributed throughout the body. Histamine (see p. 550) and the prostaglandins (see p. 549) are examples of local mediators. C. Neurotransmitters All neurons are distinct anatomic units, and no structural continuity exists between them. Communication between nerve cells, and between nerve cells and effector organs, occurs through the release of specific chemical signals, called neurotransmitters, from the nerve terminals. This release is triggered by the arrival of the action potential at the nerve ending, leading to depolarization. An increase in intracellular Ca2+ initiates fusion of the synaptic vesicles with the presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse across the synaptic cleft, or space (synapse), between neurons and combine with specific receptors on the postsynaptic (target) cell (Figure 3.8 and see Chapter 2). 1. Membrane receptors: All neurotransmitters, and most hormones and local mediators, are too hydrophilic to penetrate the lipid bilayers of target-cell plasma membranes. Instead, their signal is mediated by binding to specific receptors on the cell surface of target organs. [Note: A receptor is defined as a recognition site for a substance. It has a binding specificity and is coupled to processes that eventually evoke a response. Most receptors are proteins. III. Chemical Signaling Between Cells 43 AUTONOMIC SOMATIC Sympathetic innervation of adrenal medulla Sympathetic Parasympathetic Acetylcholine Acetylcholine Acetylcholine Preganglionic neuron Ganglionic transmitter Nicotinic receptor Nicotinic receptor Adrenal medulla Neuroeffector transmitter No ganglia Nicotinic receptor Postganglionic neurons Epinephrine and norepinephrine releasedinto the blood* Norepinephrine Acetylcholine Acetylcholine Adrenergic receptor Adrenergic receptor Muscarinic receptor Nicotinic receptor Effector organs Skeletal muscle Figure 3.8 Summary of the neurotransmitters released and the types of receptors found within the autonomic and somatic nervous systems. [Note: This schematic diagram does not show that the parasympathetic ganglia are close to or on the surface of the effector organs and that the postganglionic fibers are usually shorter than the preganglionic fibers. By contrast, the ganglia of the sympathetic nervous system are close to the spinal cord. The postganglionic fibers are long, allowing extensive branching to innervate more than one organ system. This allows the sympathetic nervous system to discharge as a unit.] *Epinephrine 80% and norepinephrine 20% released from adrenal medulla. 2. Types of neurotransmitters: Although over fifty signal molecules in the nervous system have tentatively been identified, six signal compounds, including norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin, histamine, and γ-aminobutyric acid (GABA), are most commonly involved in the actions of therapeutically useful drugs. Each of these chemical signals binds to a specific family of receptors. Acetylcholine and norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of neurotransmitters function in the CNS. Not only are these neurotransmitters released on nerve stimulation, but also cotransmitters, such as adenosine, often accompany them and modulate the transmission process. 44 3. The Autonomic Nervous System a. Acetylcholine: The autonomic nerve fibers can be divided into two groups based on the chemical nature of the neurotransmitter released. If transmission is mediated by acetylcholine, the neuron is termed cholinergic (Figure 3.9 and Chapters 4 and 5). Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. It is the neurotransmitter at the adrenal medulla. Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system, and a few sympathetic system organs, also involves the release of acetylcholine. In the somatic nervous system, transmission at the neuromuscular junction (that is, between nerve fibers and voluntary muscles) is also cholinergic (see Figure 3.9). b. Norepinephrine and epinephrine: When norepinephrine or epinephrine is the transmitter, the fiber is termed adrenergic (adrenaline being another name for epinephrine). In the sympathetic system, norepinephrine mediates the transmission of AUTONOMIC Sympathetic innervation of adrenal medulla Sympathetic SOMATIC Parasympathetic Preganglionic neuron Ganglionic transmitter Acetylcholine Nicotinic receptor Acetylcholine Nicotinic receptor Epinephrine released into the blood Adrenergic receptor No ganglia Nicotinic receptor Postganglionic neurons Adrenal medulla Neuroeffector transmitter Acetylcholine Norepinephrine Adrenergic receptor Effector organs Acetylcholine Muscarinic receptor Acetylcholine Nicotinic receptor Skeletal muscle Figure 3.9 Cholinergic (red) and adrenergeric (blue) neurons found within the autonomic and somatic nervous systems. IV. Second–messenger Systems In Intracellular Response nerve impulses from autonomic postganglionic nerves to effector organs. Norepinephrine and adrenergic receptors are discussed in Chapters 6 and 7. A summary of the neuromediators released, and the type of receptors within the peripheral nervous system, is shown in Figure 3.9. [Note: A few sympathetic fibers, such as those involved in sweating, are cholinergic, and, for simplicity, they are not shown in the figure. Also postganglionic renal smooth muscle is innervated by dopamine] 45 A Receptors coupled to ion channels Neurotransmitter Extracellular space Cl– Cell membrane Cell membrane IV. SECOND–MESSENGER SYSTEMS IN INTRACELLULAR RESPONSE The binding of chemical signals to receptors activates enzymatic processes within the cell membrane that ultimately results in a cellular response, such as the phosphorylation of intracellular proteins or changes in the conductivity of ion channels. A neurotransmitter can be thought of as a signal, and a receptor as a signal detector and transducer. Second-messenger molecules produced in response to a neurotransmitter binding to a receptor translate the extracellular signal into a response that may be further propagated or amplified within the cell. Each component serves as a link in the communication between extracellular events and chemical changes within the cell (see Chapter 2). Cl– Cytosol Changes in membrane potential or ionic concentration within cell B Receptors coupled to adenylyl cyclase Hormone or neurotransmitter β γ α A. Membrane receptors affecting ion permeability Neurotransmitter receptors are membrane proteins that provide a binding site that recognizes and responds to neurotransmitter molecules. Some receptors, such as the postsynaptic receptors of nerve or muscle, are directly linked to membrane ion channels. Therefore, binding of the neurotransmitter occurs rapidly (within fractions of a millisecond) and directly affects ion permeability (Figure 3.10A). [Note: The effect of acetylcholine on these chemically gated ion channels is discussed on p. 27.] ATP GTP Active adenylyl cyclase cAMP + PPi Protein phosphorylation C Receptors coupled to diacylglycerol and inositol trisphosphate B. Regulation involving second-messenger molecules Many receptors are not directly coupled to ion channels. Rather, the receptor signals its recognition of a bound neurotransmitter by initiating a series of reactions that ultimately result in a specific intracellular response. Second-messenger molecules, so named because they intervene between the original message (the neurotransmitter or hormone) and the ultimate effect on the cell, are part of the cascade of events that translates neurotransmitter binding into a cellular response, usually through the intervention of a G protein. The two most widely recognized second messengers are the adenylyl cyclase system and the calcium/phosphatidylinositol system (Figure 3.10B and C). [Note: Gs is one protein involved in the activation of adenylyl cyclase, and Gq is one subunit that activates phospholipase C to release diacylglycerol and inositol trisphosphate (see p. 27).] Hormone or neurotransmitter Receptor γ β α Gq protein Diacylglycerol Phospholipase C Inositol trisphosphate Protein phosphorylation and increased intracellular Ca2+ Figure 3.10 Three mechanisms whereby binding of a neurotransmitter leads to a cellular effect.