Chapter 4. Introduction to Autonomic Pharmacology

The motor (efferent) portion of the nervous system can be divided into two major subdivisions: autonomic and somatic. The autonomic nervous system (ANS) is largely autonomous (independent) in that its activities are not under direct conscious control. The ANS is concerned primarily with visceral functions that are necessary for life. The somatic system is largely concerned with consciously controlled functions such as movement and posture. Both systems have important afferent (sensory) inputs that provide sensation and modify motor output through reflex arcs of varying size and complexity.

The nervous system has several properties in common with the endocrine system, which is the other major system for control of bodily functions. These properties include high-level integration in the brain, the ability to influence processes in distant regions of the body, and extensive use of negative feedback. Both systems use chemicals for the transmission of information. In the nervous system, chemical transmission occurs between nerve cells and between nerve cells and their effector cells. Chemical transmission takes place through the release of small amounts of transmitter substances from the nerve terminals into the synaptic space. The transmitter crosses the space by diffusion and activates or inhibits the postsynaptic cells by binding to a specialized receptor molecule.

Drugs that mimic or block the actions of chemical transmitters can selectively modify many autonomic functions. These functions involve a variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals. Drugs affecting the autonomic nervous system are useful in many clinical conditions. Conversely, a very large number of drugs used for other purposes have unwanted effects on autonomic function.

The autonomic nervous system lends itself to division on anatomic grounds into two major portions: the sympathetic (thoracolumbar) division and the parasympathetic (craniosacral) division (Figure 4–1). Both divisions originate in nuclei within the central nervous system and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia. The sympathetic preganglionic fibers leave the central nervous system through the thoracic and lumbar spinal nerves. The parasympathetic preganglionic fibers leave the central nervous system through several of the cranial nerves and the third and fourth sacral spinal roots.

Sympathetic preganglionic fibers terminate in ganglia located in the paravertebral chains that lie on either side of the spinal column, or terminate in prevertebral ganglia, which lie in front of the aorta. From these ganglia, postganglionic sympathetic fibers traverse to the innervated tissues. The majority of parasympathetic preganglionic fibers terminate on ganglion cells in the walls of the organs innervated, others terminate in parasympathetic ganglia located outside the innervated organs.

In addition to these clearly defined peripheral motor portions of the autonomic nervous system, there are large numbers of afferent fibers that run from the periphery to integrating centers, including the enteric plexuses in the gut (Chapter 36), the autonomic ganglia, and the central nervous system. Many of the sensory neurons that end in the central nervous system terminate in the integrating centers of the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described above.

An important traditional classification of autonomic nerves is based on the primary transmitter—acetylcholine or norepinephrine—that is released from the presynaptic terminal. A large number of peripheral autonomic nervous system fibers synthesize and release acetylcholine (Figure 4–1). These are cholinergic fibers, and they include all preganglionic efferent autonomic fibers. The somatic motor fibers to skeletal muscles are also cholinergic. Thus, almost all efferent fibers leaving the central nervous system are cholinergic. In addition, most parasympathetic postganglionic and a few sympathetic postganglionic fibers are cholinergic (Figure 4–1). A number of parasympathetic postganglionic neurons also utilize nitric oxide or peptides for transmission (Table 4–1).

Most sympathetic postganglionic fibers release norepinephrine (Figure 4–1). These are noradrenergic, and are often referred to as adrenergic fibers. A few sympathetic postganglionic fibers release acetylcholine. Dopamine is a very important transmitter in the central nervous system, and there is evidence that it is released by some peripheral sympathetic fibers in the cardiac, gastrointestinal, and renal systems. Adrenal medullary cells, which are embryologically analogous to postganglionic sympathetic neurons, release a mixture of epinephrine and norepinephrine.

Five key features of neurotransmitter function represent potential targets for pharmacologic therapy: synthesis, storage, release, activation of receptors, and termination of transmitter action.

Cholinergic Transmission

The terminals of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the synaptic portion of the cell membrane (Figure 4–2) as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane. The latter vesicles contain cotransmitters with or without acetylcholine (Table 4–1). Vesicles are initially synthesized in the neuron’s soma and transported to the terminal. They may also be recycled several times within the terminal. Acetylcholine is synthesized in the cytoplasm from acetyl coenzyme A (CoA) and choline (Figure 4–2). The acetyl CoA is synthesized in the mitochondria and the choline is transported into the cell. Once synthesized, acetylcholine is transported from the cytoplasm into the vesicles. Acetylcholine synthesis is a rapid process capable of supporting a very high rate of transmitter release. Storage of acetylcholine is accomplished by the packaging of acetylcholine molecules, usually 1,000 to 50,000 molecules in each vesicle. Release of the transmitter is dependent on extracellular calcium, and occurs when an action potential reaches the terminal and triggers a sufficient influx of calcium ions. The increased intracellular Ca2+ concentration allows fusion of the vesicular membranes with the presynaptic terminal membrane. Fusion of the membranes results in release of the contents of the vesicle into the synaptic space. After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor. Eventually all of the acetylcholine released will diffuse within range of an acetylcholinesterase (AChE) molecule, which splits acetylcholine into choline and acetate, terminating its action (Figure 4–2). Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine in the synapse is therefore very short.

Adrenergic Transmission

Adrenergic neurons also transport a precursor molecule, tyrosine, into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles (Figure 4–3). Several catecholamine transmitters and cotransmitters are listed in Table 4–1. As indicated in Figure 4–4, the synthesis of the catecholamine transmitters is more complex than that of acetylcholine. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine. Conversely, synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system. Several important processes in these nerve terminals are potential sites of drug action.

Release of transmitters from noradrenergic nerve endings is similar to the calcium-dependent process described above for cholinergic terminals. Various chemicals in the diet, such as tyramine or drugs (amphetamines), are capable of releasing stored transmitter from noradrenergic nerve endings. These compounds are taken up into presynaptic noradrenergic nerve endings, and may displace norepinephrine from storage vesicles, inhibit the enzyme responsible for metabolism and inactivation of the neurotransmitter, or have other effects that result in increased norepinephrine activity in the synapse. Termination of noradrenergic transmission results from simple diffusion of the neurotransmitter away from the receptor site with eventual metabolism in the plasma or liver, or reuptake into presynaptic or postsynaptic locations (Figure 4–3). Metabolism of norepinephrine and epinephrine may occur by several enzymes such as monoamine oxidase (MAO) in the presynaptic terminal or catechol-O-methyltransferase (COMT) at other tissue locations (Figure 4–4).

Historically, careful comparisons of the potency of a series of autonomic agonists and antagonists led to the definition of different autonomic receptor subtypes, including muscarinic and nicotinic receptors, and alpha (α), beta (β), and dopamine (D) receptors (Table 4–2). The primary cholinergic receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine. Both muscarinic and nicotinic receptors are stimulated by acetylcholine. The adrenergic receptors are subdivided into α, β, and D subtypes on the basis of both agonist and antagonist selectivity. The α and β receptor subtypes respond mainly to norepinephrine. The D receptors respond to dopamine. Development of more selective blocking drugs has led to the naming of subclasses within these major subtypes. Within α receptors, both α1 and α2 receptors have been characterized, and within β receptors, β1, β2, and β3 receptors have been defined. The tissue locations and physiological actions of these receptors are presented in Table 4–3.

A basic understanding of the interactions of autonomic nerves with each other and with their effector organs is essential for an appreciation of the actions of drugs affecting the autonomic nervous system, especially because of the significant reflex, i.e., compensatory, effects that may be evoked by these agents. Autonomic reflexes are particularly important in understanding cardiovascular responses to these drugs. As indicated in Figure 4–5, the primary controlled variable in cardiovascular function is mean arterial pressure. Changes in any variable contributing to mean arterial pressure will evoke powerful secondary homeostatic responses that tend to compensate for the directly evoked change.

Central Integration

Central integration occurs at the highest level in the midbrain and medulla. The two divisions of the autonomic nervous system and the endocrine system are integrated with each other, with sensory input, and with information from higher central nervous system centers. Within the various organ systems of the body, the interactions between the sympathetic and parasympathetic divisions are often in opposition to each other (Table 4–4). Thus, the parasympathetic system is often referred to as a trophotropic system, leading to growth, and the sympathetic system is referred to as an ergotropic system, leading to energy expenditure. For example, slowing of the heart and stimulation of digestive activity are typical energy-conserving (“rest and digest”) actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving an attack (“fight or flight”). At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers have a major influence on sympathetic outflow from the vasomotor center. Similarly, parasympathetic sensory fibers in the wall of the urinary bladder significantly influence sympathetic inhibitory outflow to that organ.

Peripheral Integration

In the peripheral tissues, integration may be regulated at either presynaptic or postsynaptic locations. Presynaptic regulation uses the concept of negative or positive feedback control to regulate neurotransmitter release. Important presynaptic inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves α2 receptors located on noradrenergic nerve terminals. Norepinephrine and similar molecules activate these receptors; activation diminishes further release of norepinephrine from the nerve endings. Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine. Presynaptic receptors that respond to the primary transmitter substances released by the nerve ending are called autoreceptors (Figures 4–2 and 4–3). Autoreceptors are usually inhibitory, but many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors. Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors (Figures 4–2 and 4–3) may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the compounds that influence these receptors may diffuse to the receptors from the blood or from nearby tissues. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers.

Postsynaptic regulation can be considered from two perspectives. The first is modulation by the prior history of activity at the primary receptor, that is, receptor up-regulation or down-regulation, or receptor desensitization. Up-regulation occurs in response to decreased activation of the receptors. In contrast, down-regulation and desensitization occurs in response to increased activation of the receptors. For additional information, see Chapter 2. Alternatively, receptor modulation may occur by other temporally associated conditions such as electrolyte levels inside or outside of the effector cell, or circulating hormones.

Because transmission involves different mechanisms in different segments of the autonomic nervous system, some drugs produce highly specific effects, whereas others are much less selective in their actions. A summary of the steps in transmission of impulses is presented in Figure 4–6. Modifying any step in this process may increase or decrease the amount of neuro-transmitter reacting with appropriate receptors.

Drugs that block action potential propagation are very nonselective in their action, since these drugs act on a process that is common to all neurons. On the other hand, drugs that act on the biochemical processes involved in transmitter release and turnover are more selective. Modulation at this level may either increase or decrease the concentration of transmitters interacting with their receptors. Inhibition of transmitter synthesis, storage, or release may decrease the amount of transmitter interacting with the receptors. These agents are classified as indirect-acting antagonists. This is in contrast to agents that have affinity, but no efficacy, and block the postsynaptic receptors. These agents are classified as direct-acting antagonists. Within the adrenergic drug group, these indirect and direct antagonists are called sympatholytics; that is, agents that antagonize the sympathetic system. In contrast, agents that decrease reuptake of the transmitter, or inhibit the enzyme(s) responsible for breakdown of the transmitter, increase the interaction of the transmitter with the receptors. These agents are classified as indirect-acting agonists. Agents that have both affinity and efficacy for the postsynaptic receptors are called direct-acting agonists. Within the adrenergic drug group, these indirect and direct agonists are called sympathomimetics; that is, agents that mimic the sympathetic system. Similar direct-acting and indirect-acting classifications exist for agonists and antagonists that interact with the parasympathetic system.

Finally, the biochemistry of adrenergic transmission is very different from that of cholinergic transmission. Owing to these differences, activation or blockade of either adrenergic or cholinergic receptors on effector cells offers maximum flexibility and selectivity of effect. Furthermore, individual subgroups within nicotinic cholinergic receptors or α- and β-adrenergic receptors can often be selectively activated or blocked. The subsequent chapters in this section (Chapters 5, 6, 7, 8, 9, and 10) provide examples of selective receptor activation or blockade in the clinical use of these drugs.