Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 6. Introduction to Autonomic Pharmacology

Introduction to Autonomic Pharmacology: Introduction

The autonomic nervous system (ANS) is the major involuntary, unconscious, automatic portion of the nervous system and contrasts in several ways with the somatic (voluntary) nervous system. The anatomy, neurotransmitter chemistry, receptor characteristics, and functional integration of the ANS are discussed in this chapter. Major autonomic drug groups are discussed in Chapters 7, 8, 9, and 10. Drugs in many other groups have significant autonomic effects, many of which are undesirable.

High-Yield Terms to Learn

Adrenergic A nerve ending that releases norepinephrine as the primary transmitter; also, a synapse in which norepinephrine is the primary transmitter Adrenoceptor, adrenergic receptor A receptor that binds, and is activated by, one of the catecholamine transmitters or hormones (norepinephrine, epinephrine, dopamine) and related drugs Autonomic effector cells or tissues Cells or tissues that have adrenoceptors or cholinoceptors which, when activated, alter the function of those cells or tissues, for example, smooth muscle, cardiac muscle, glands Baroreceptor reflex The neuronal homeostatic mechanism that maintains a constant arterial blood pressure; the sensory limb originates in the baroreceptors of the carotid sinus and aortic arch; efferent pathways run in parasympathetic and sympathetic nerves Cholinergic A nerve ending that releases acetylcholine; also, a synapse in which the primary transmitter is acetylcholine Cholinoceptor, cholinergic receptor A receptor that binds, and is activated by, acetylcholine and related drugs Dopaminergic A nerve ending that releases dopamine as the primary transmitter; also a synapse in which dopamine is the primary transmitter Homeostatic reflex A compensatory mechanism for maintaining a body function at a predetermined level, for example, the baroreceptor reflex for blood pressure Parasympathetic The part of the autonomic nervous system that originates in the cranial nerves and sacral part of the spinal cord; the craniosacral autonomic system Postsynaptic receptor A receptor located on the distal side of a synapse, for example, on a postganglionic neuron or an autonomic effector cell Presynaptic receptor A receptor located on the nerve ending from which the transmitter is released into the synapse; modulates the release of transmitter SympatheticThe part of the autonomic nervous system that originates in the thoracic and lumbar parts of the spinal cord

Anatomic Aspects of the ANS

The motor (efferent) portion of the ANS is the major pathway for information transmission from the central nervous system (CNS) to the involuntary effector tissues (smooth muscle, cardiac muscle, and exocrine glands; Figure 6-1). Its 2 major subdivisions are the parasympathetic ANS (PANS) and the sympathetic ANS (SANS). The enteric nervous system (ENS) is a semiautonomous part of the ANS located in the gastrointestinal tract, with specific functions for the control of this organ system. The ENS consists of the myenteric plexus (plexus of Auerbach) and the submucous plexus (plexus of Meissner); they send sensory input to the parasympathetic and sympathetic nervous systems and receive motor output from them.

FIGURE 6-1

Schematic diagram comparing some features of the parasympathetic and sympathetic divisions of the autonomic nervous system with the somatic motor system. Parasympathetic ganglia are not shown as discrete structures because most of them are diffusely distributed in the walls of the organs innervated. Only 3 of the more than 20 sympathetic ganglia are shown alpha and beta adrenoceptors; ACh, acetylcholine; D, dopamine, D1, dopamine1 receptors; Epi, epinephrine; M, muscarinic; N, nicotinic; NE, norepinephrine.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 6-1.)

There are many sensory (afferent) fibers in autonomic nerves. These are of considerable importance for the physiologic control of the involuntary organs but are directly influenced by only a few drugs.

Central Roots of Origin

The parasympathetic preganglionic motor fibers originate in cranial nerve nuclei III, VII, IX, and X and in sacral segments (usually S2-S4) of the spinal cord. The sympathetic preganglionic fibers originate in the thoracic (T1-T12) and lumbar (L1-L5) segments of the cord.

Location of Ganglia

Most of the sympathetic ganglia are located in 2 paravertebral chains that lie along the spinal column. A few (the prevertebral ganglia) are located on the anterior aspect of the abdominal aorta. Most of the parasympathetic ganglia are located in the organs innervated more distant from the spinal cord. Because of the locations of the ganglia, the preganglionic sympathetic fibers are short and the postganglionic fibers are long. The opposite is true for the parasympathetic system: preganglionic fibers are longer and postganglionic fibers are short.

Uninnervated Receptors

Some receptors that respond to autonomic transmitters and drugs receive no innervation. These include muscarinic receptors on the endothelium of blood vessels, some presynaptic receptors, and, in some species, the adrenoceptors on apocrine sweat glands and 2 and  adrenoceptors in blood vessels.

Neurotransmitter Aspects of the ANS

The synthesis, storage, release, receptor interactions, and termination of action of the neurotransmitters all contribute to the action of autonomic drugs (Figure 6-2).

FIGURE 6-2

Characteristics of transmitter synthesis, storage, release, and termination of action at cholinergic and noradrenergic nerve terminals are shown from the top downward. Circles represent transporters; ACh, acetylcholine; AChE, acetylcholinesterase; ChAT, choline acetyltransferase; DOPA, dihydroxyphenylalanine; NE, norepinephrine; NET, norepinephrine transporter; TCA, tricyclic antidepressant; TH, tyrosine hydroxylase.

Cholinergic Transmission

Acetylcholine (ACh) is the primary transmitter in all autonomic ganglia and at the synapses between parasympathetic postganglionic neurons and their effector cells. It is also the primary transmitter at the somatic (voluntary) skeletal muscle neuromuscular junction (Figure 6-1).

Synthesis and Storage

Acetylcholine is synthesized in the nerve terminal from acetyl-CoA (produced in mitochondria) and choline (transported across the cell membrane) by the enzyme choline acetyltransferase (ChAT). The rate-limiting step is probably the transport of choline into the nerve terminal. This transport can be inhibited by the research drug hemicholinium. Acetylcholine is actively transported into its vesicles for storage by the vesicle-associated transporter, VAT. This process can be inhibited by another research drug, vesamicol.

Release of Acetylcholine

Release of transmitter stores from vesicles in the nerve ending requires the entry of calcium through calcium channels and triggering of an interaction between SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) proteins. SNARE proteins include v-SNARES associated with the vesicles (VAMPs, vesicle-associated membrane proteins: synaptobrevin, synaptotagmin) and t-SNARE proteins associated with the nerve terminal membrane (SNAPs, synaptosome-associated proteins: SNAP25, syntaxin, and others). This interaction results in docking of the vesicle to the terminal membrane and, with influx of calcium, fusion of the membranes of the vesicles with the nerve-ending membranes, the opening of a pore to the extracellular space, and the release of the stored transmitter. The several types of botulinum toxins enzymatically alter synaptobrevin or one of the other docking or fusion proteins to prevent the release process.

Termination of Action of Acetylcholine

The action of acetylcholine in the synapse is normally terminated by metabolism to acetate and choline by the enzyme acetylcholinesterase in the synaptic cleft. The products are not excreted but are recycled in the body. Inhibition of acetylcholinesterase is an important therapeutic (and potentially toxic) effect of several drugs.

Drug Effects on Synthesis, Storage, Release, and Termination of Action of Acetylcholine

Drugs that block the synthesis of acetylcholine (eg, hemicholinium), its storage (eg, vesamicol), or its release (eg, botulinum toxin) are not very useful for systemic therapy because their effects are not sufficiently selective (ie, PANS and SANS ganglia and somatic neuromuscular junctions all may be blocked). However, because botulinum toxin is a very large molecule and diffuses very slowly, it can be used by injection for relatively selective local effects.

Adrenergic Transmission

Norepinephrine (NE) is the primary transmitter at the sympathetic postganglionic neuron-effector cell synapses in most tissues. Important exceptions include sympathetic fibers to thermoregulatory (eccrine) sweat glands and probably vasodilator sympathetic fibers in skeletal muscle, which release acetylcholine. Dopamine may be a vasodilator transmitter in renal blood vessels, but norepinephrine is a vasoconstrictor of these vessels.

Synthesis and Storage

The synthesis of dopamine and norepinephrine requires several steps (Figure 6-2). After transport across the cell membrane, tyrosine is hydroxylated by tyrosine hydroxylase (the rate-limiting step) to DOPA (dihydroxyphenyl-alanine), decarboxylated to dopamine, and (inside the vesicle) hydroxylated to norepinephrine. Tyrosine hydroxylase can be inhibited by metyrosine. Norepinephrine and dopamine are transported into vesicles and stored there. Monoamine oxidase (MAO) is present on mitochondria in the adrenergic nerve ending and inactivates a portion of the dopamine and norepinephrine in the cytoplasm. Therefore, MAO inhibitors may increase the stores of these transmitters and other amines in the nerve endings (Chapter 30). The vesicular transporter can be inhibited by reserpine , resulting in depletion of transmitter stores.

Release and Termination of Action

Dopamine and norepinephrine are released from their nerve endings by the same calcium-dependent mechanism responsible for acetylcholine release (see prior discussion). Termination of action, however, is quite different. Metabolism is not responsible for termination of action of the catecholamine transmitters, norepinephrine and dopamine. Rather, diffusion and reuptake (especially uptake-1, Figure 6-2, by the norepinephrine transporter, NET, or the dopamine transporter, DAT) reduce their concentration in the synaptic cleft and stop their action. Outside the cleft, these transmitters can be metabolized—by MAOand catechol-O-methyltransferase (COMT)—and the products of these enzymatic reactions are excreted. Determination of the 24-h excretion of metanephrine, normetanephrine, 3-methoxy-4-hydroxymandelic acid (VMA), and other metabolites provides a measure of the total body production of catecholamines, a determination useful in diagnosing conditions such as pheochromocytoma. Inhibition of MAO increases stores of catecholamines and has both therapeutic and toxic potential.

Drug Effects on Adrenergic Transmission

Drugs that block norepinephrine synthesis (eg, metyrosine) or catecholamine storage (eg, reserpine) or release (eg, guanethidine) have been used in treatment of several diseases (eg, pheochromocytoma, hypertension) because they block sympathetic but not parasympathetic functions. Other drugs promote catecholamine release (eg, the amphetamine-like agents) and predictably cause sympathomimetic effects.

Cotransmitters

Many (probably all) autonomic nerves have transmitter vesicles that contain other transmitter molecules in addition to the primary agents (acetylcholine or norepinephrine) previously described. These cotransmitters may be localized in the same vesicles as the primary transmitter or in a separate population of vesicles. Substances recognized to date as cotransmitters include ATP (adenosine triphosphate), enkephalins, vasoactive intestinal peptide, neuropeptide Y, substance P, neurotensin, somatostatin, and others. Their main role in autonomic function appears to involve modulation of synaptic transmission. The same substances function as primary transmitters in other synapses.

Skill Keeper: Drug Permeation

(See Chapter 1)

Botulinum toxin is a very large protein molecule and does not diffuse readily when injected into tissue. In spite of this property, it is able to enter cholinergic nerve endings from the extracellular space and block the release of acetylcholine. How might it cross the lipid membrane barrier? The Skill Keeper Answer appears at the end of the chapter.

Receptor Characteristics

The major receptor systems in the ANS include cholinoceptors, adrenoceptors, and dopamine receptors, which have been studied in some detail. The numerous receptors for cotransmitter substances have not been as fully defined.

Cholinoceptors

Also referred to as cholinergic receptors, these molecules respond to acetylcholine and its analogs. Cholinoceptors are subdivided as follows (Table 6-1):

Muscarinic Receptors

As their name suggests, these receptors respond to muscarine (an alkaloid) as well as to acetylcholine. The effects of activation of these receptors resemble those of postganglionic parasympathetic nerve stimulation. Muscarinic receptors are located primarily on autonomic effector cells (including heart, vascular endothelium, smooth muscle, presynaptic nerve terminals, and exocrine glands). Evidence (including their genes) has been found for 5 subtypes, of which 3 appear to be important in peripheral autonomic transmission. All 5 are G-protein-coupled receptors (see Chapter 2).

Nicotinic Receptors

These receptors are located on ion channels and respond to acetylcholine and nicotine, another acetylcholine mimic (but not to muscarine) by opening the channel. The 2 major nicotinic subtypes are located in ganglia and in skeletal muscle end plates. The nicotinic receptors are the primary receptors for transmission at these sites.

TABLE 6-1 Characteristics of the most important cholinoceptors in the peripheral nervous system.

Receptor Location Mechanism Major Functions M1

Nerve endings Gq-coupled

 IP 3, DAG cascade

M2

Heart, some nerve endings Gi-coupled

 cAMP, activates K+ channels

M3

Effector cells: smooth muscle, glands, endothelium Gq-coupled

 IP3, DAG cascade

NN

ANS ganglia Ion channel Depolarizes, evokes action potential NM

Neuromuscular end plate Ion channel Depolarizes, evokes action potential

Adrenoceptors

Also referred to as adrenergic receptors, adrenoceptors are divided into several subtypes (Table 6-2).

TABLE 6-2 Characteristics of some important adrenoceptors in the ANS.

Receptor Location G Protein Second Messenger Major Functions Alpha1 (1)

Effector tissues: smooth muscle, glands Gq

 IP 3, DAG

 Ca2+, causes contraction, secretion

Alpha2 (2)

Nerve endings, some smooth muscle Gi

 cAMP  Transmitter release, causes contraction Beta1 (1)

Cardiac muscle, juxtaglomerular apparatus Gs

 cAMP  Heart rate,  force;  renin release Beta2 (2)

Smooth muscle, liver, heart Gs

 cAMP Relax smooth muscle;  glycogenolysis;  heart rate, force Beta3 (3)

Adipose cells Gs

 cAMP  Lipolysis Dopamine 1 (D1)

Smooth muscle Gs

 cAMP Relax renal vascular smooth muscle

ANS, autonomic nervous system.

Alpha Receptors

These are located on vascular smooth muscle, presynaptic nerve terminals, blood platelets, fat cells (lipocytes), and neurons in the brain. Alpha receptors are further divided into 2 major types, 1 and 2. These 2 subtypes constitute different families and use different G-coupling proteins.

Beta Receptors

These receptors are located on most types of smooth muscle, cardiac muscle, some presynaptic nerve terminals, and lipocytes as well as in the brain. Beta receptors are divided into 3 major subtypes, 1, 2, and 3. These subtypes are rather similar and use the same G-coupling protein.

Dopamine Receptors

Dopamine (D, DA) receptors are a subclass of adrenoceptors but with rather different distribution and function. Dopamine receptors are especially important in the renal and splanchnic vessels and in the brain. Although at least 5 subtypes exist, the D1 subtype appears to be the most important dopamine receptor on peripheral effector-cells. D2 receptors are found on presynaptic nerve terminals. D1, D2, and other types of dopamine receptors also occur in the CNS.

Effects of Activating Autonomic Nerves

Each division of the ANS has specific effects on organ systems. These effects, summarized in Table 6-3, should be memorized.

TABLE 6-3 Direct effects of autonomic nerve activity on some organ systems.

Effect of Sympathetic Parasympathetic Organ Actiona

Receptorb

Actiona

Receptorb

Eye Iris Radial muscle Contracts 1

. . . . . . Circular muscle . . . . . . Contracts M3

Ciliary muscle [Relaxes]  Contracts M3

Heart Sinoatrial node Accelerates 1, 2

Decelerates M2

Ectopic pacemakers Accelerates 1, 2

. . . . . . Contractility Increases 1, 2

Decreases (atria) [M2]

Blood vessels Skin, splanchnic vessels Contracts  . . . . . . Skeletal muscle vessels Relaxes 2

. . . . . . Contracts  . . . . . . [Relaxes] [Mc]

. . . . . . Bronchiolar smooth muscle Relaxes 2

Contracts M3

Gastrointestinal tract Smooth muscle Walls Relaxes 2,d 2

Contracts M3

Sphincters Contracts 1

Relaxes M3

Secretion Inhibits 2

Increases M3

Myenteric plexus . . . . . . Activates M1

Genitourinary smooth muscle Bladder wall Relaxes 2

Contracts M3

Sphincter Contracts 1

Relaxes M3

Uterus, pregnant Relaxes 2

. . . . . . Contracts  Contracts M3

Penis, seminal vesicles Ejaculation  Erection M Skin Pilomotor smooth muscle Contracts  . . . . . . Sweat glands . . . . . . Thermoregulatory Increases M . . . . . . Apocrine (stress) Increases  . . . . . . Metabolic functions Liver Gluconeogenesis 2, 

. . . . . . Liver Glycogenolysis 2, 

. . . . . . Fat cells Lipolysis 3

. . . . . . Kidney Renin release 1

. . . . . . Autonomic nerve endings Sympathetic . . . . . . Decreases NE release Me

Parasympathetic Decreases ACh release  . . . . . .

aLess important actions are shown in brackets.

bSpecific receptor type: , alpha; , beta; M, muscarinic.

cVascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers.

dProbably through presynaptic inhibition of parasympathetic activity.

eProbably M1, but M2 may participate in some locations.

ACh, acetylcholine; NE, norepinephrine.

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Dually innervated organs such as the iris of the eye and the sinoatrial node of the heart receive both sympathetic and parasympathetic innervation. The pupil has a natural, intrinsic diameter to which it returns when the influence of both divisions of the ANS is removed. Pharmacologic ganglionic blockade, therefore, causes it to move to its intrinsic size. Similarly, the cardiac sinus node pacemaker rate has an intrinsic value (about 100-110/min) in the absence of both ANS inputs. How will these variables change (increase or decrease) if the ganglia are blocked? The answer is predictable if one knows which system is dominant. For example, both the pupil and, at rest, the sinoatrial node are dominated by the parasympathetic system. The resting pupil diameter and sinus rate are therefore under considerable PANS influence. Thus, blockade of both systems, with removal of the dominant PANS and nondominant SANS effects, result in mydriasis and tachycardia.

Nonadrenergic, Noncholinergic (NANC) Transmission

Some nerve fibers in autonomic effector tissues do not show the histochemical characteristics of either cholinergic or adrenergic fibers. Some of these are motor fibers that cause the release of ATP and other purines related to it. Purine-evoked responses have been identified in the bronchi, gastrointestinal tract, and urinary tract. Other motor fibers are peptidergic, that is, they release peptides as the primary transmitters (see list in earlier Cotransmitters section).

Other nonadrenergic, noncholinergic fibers have the anatomic characteristics of sensory fibers and contain peptides, such as substance P, that are stored in and released from the fiber terminals. These fibers have been termed "sensory-efferent" or "sensory-local effector" fibers because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself, from local axon branches, and from collaterals that terminate in the autonomic ganglia. In addition to their neurotransmitter roles, these peptides are potent agonists in many autonomic effector tissues, especially smooth muscle (see Chapter 17).

Sites of Autonomic Drug Action

Because of the number of steps in the transmission of autonomic commands from the CNS to the effector cells, there are many sites at which autonomic drugs may act. These sites include the CNS centers; the ganglia; the postganglionic nerve terminals; the effector cell receptors; and the mechanisms responsible for transmitter synthesis, storage, release, and termination of action. The most selective effect is achieved by drugs acting at receptors that mediate very selective actions (Table 6-4). Many natural and synthetic toxins have significant effects on autonomic and somatic nerve function.

TABLE 6-4 Steps in autonomic transmission: effects of drugs.

Process Drug Example Site Action Action potential propagation Local anesthetics, tetrodotoxin,a saxitoxinb

Nerve axons Block sodium channels; block conduction Transmitter synthesis Hemicholinium Cholinergic nerve terminals: membrane Blocks uptake of choline and slows synthesis Alpha-Methyltyrosine (metyrosine) Adrenergic nerve terminals and adrenal medulla: cytoplasm Blocks synthesis Transmitter storage Vesamicol Cholinergic terminals: vesicles Prevents storage, depletes Reserpine Adrenergic terminals: vesicles Prevents storage, depletes Transmitter release Manyc

Nerve terminal membrane receptors Modulate release -Conotoxin GVIAd

Nerve terminal calcium channels Reduces transmitter release Botulinum toxin Cholinergic vesicles Prevents release Alpha-latrotoxine

Cholinergic and adrenergic vesicles Causes explosive release Tyramine, amphetamine Adrenergic nerve terminals Promote transmitter release Transmitter uptake after release Cocaine, tricyclic antidepressants Adrenergic nerve terminals Inhibit uptake; increase transmitter effect on post-synaptic receptors 6-Hydroxydopamine Adrenergic nerve terminals Destroys the terminals Receptor activation or blockade Norepinephrine Receptors at adrenergic junctions Binds  receptors; causes activation Phentolamine Receptors at adrenergic junctions Binds  receptors; prevents activation Isoproterenol Receptors at adrenergic junctions Binds  receptors; activates adenylyl cyclase Propranolol Receptors at adrenergic junctions Binds  receptors; prevents activation Nicotine Receptors at nicotinic cholinergic junctions (autonomic ganglia, neuromuscular end plates) Binds nicotinic receptors; opens ion channel in post-synaptic membrane Tubocurarine Neuromuscular end plates Prevents activation Bethanechol Receptors, parasympathetic effector cells (smooth muscle, glands) Binds and activates muscarinic receptors Atropine Receptors, parasympathetic effector cells Binds muscarinic receptors; prevents activation Enzymatic inactivation of transmitter Neostigmine Cholinergic synapses (acetylcholinesterase) Inhibits enzyme; prolongs and intensifies transmitter action Tranylcypromine Adrenergic nerve terminals (monoamine oxidase) Inhibits enzyme; increases stored transmitter pool

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

aToxin of puffer fish, California newt.

bToxin of Gonyaulax (red tide organism).

cNorepinephrine, dopamine, acetylcholine, angiotensin II, various prostaglandins, etc.

dToxin of marine snails of the genus Conus.

eBlack widow spider venom.

Integration of Autonomic Function

Functional integration in the ANS is provided mainly through the mechanism of negative feedback and is extremely important in determining the overall response to endogenous and exogenous ANS transmitters and their analogs. This process uses modulatory pre- and postsynaptic receptors at the local level and homeostatic reflexes at the systemic level.

Local Integration

Local feedback control has been found at the level of the nerve endings in all systems investigated. The best documented of these is the negative feedback of norepinephrine upon its own release from adrenergic nerve terminals. This effect is mediated by 2 receptors located on the presynaptic nerve membrane (Figure 6-3).

FIGURE 6-3

Local control of autonomic nervous system function via modulation of transmitter release. In the example shown, release of norepinephrine (NE) from a sympathetic nerve ending is modulated by norepinephrine itself, acting on presynaptic 2 autoreceptors, and by acetylcholine and angiotensin II. Many other modulators (see text) influence the release process. AT1, angiotensin II receptor; M, muscarinic receptor; NET, norepinephrine transporter.

Presynaptic receptors that bind the primary transmitter substance and thereby regulate its release are called autoreceptors. Transmitter release is also modulated by other presynaptic receptors (heteroreceptors); in the case of adrenergic nerve terminals, receptors for acetylcholine, histamine, serotonin, prostaglandins, peptides, and other substances have been found. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers.

Postsynaptic modulatory receptors, including 2 types of muscarinic receptors and at least 1 type of peptidergic receptor, have been found in ganglionic synapses, where nicotinic transmission is primary. These receptors may facilitate or inhibit transmission by evoking slow excitatory or inhibitory postsynaptic potentials (EPSPs or IPSPs).

Systemic Reflexes

Systemic reflexes include mechanisms that regulate blood pressure, gastrointestinal motility, bladder tone, airway smooth muscle, and other processes. The control of blood pressure—by the baroreceptor neural reflex and the renin-angiotensin-aldosterone hormonal response—is especially important (Figure 6-4). These homeostatic mechanisms have evolved to maintain mean arterial blood pressure at a level determined by the vasomotor center and renal sensors. Any deviation from this blood pressure "set point" causes a change in ANS activity and renin-angiotensin-aldosterone levels. These changes are very important in determining the response to conditions or drugs that alter blood pressure. For example, a decrease in blood pressure caused by hemorrhage causes increased SANS discharge and renin release. As a result, peripheral vascular resistance, venous tone, heart rate, and cardiac force are increased by norepinephrine released from sympathetic nerves. Blood volume is replenished by retention of salt and water in the kidney under the influence of increased levels of aldosterone. These compensatory responses may be large enough to overcome some of the actions of drugs. For example, the treatment of hypertension with a vasodilator such as hydralazine will be unsuccessful when the compensatory tachycardia (via the baroreceptor reflex) and the salt and water retention (via the renin system response) are not prevented through the use of additional drugs. It is therefore essential that the clinician understand this homeostatic system.

FIGURE 6-4

Autonomic and hormonal control of cardiovascular function. Note that 2 feedback loops are present: the autonomic nervous system loop and the hormonal loop. Each major loop has several components. In the neuronal loop, sensory input to the vasomotor center is via afferent fibers in the ninth and tenth cranial (PANS) nerves. On the efferent side, the sympathetic nervous system directly influences 4 major variables: peripheral vascular resistance, heart rate, contractile force, and venous tone. The parasympathetic nervous system directly influences heart rate. In addition, angiotensin II directly increases peripheral vascular resistance (not shown), and the sympathetic nervous system directly increases renin secretion (not shown). Because these control mechanisms have evolved to maintain normal blood pressure, the net feedback effect of each loop is negative; feedback tends to compensate for the change in arterial blood pressure that evoked the response. Thus, decreased blood pressure due to blood loss would be compensated by increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow and renin release and increased parasympathetic (vagal) outflow.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 6-7.)

Complex Organ Control: The Eye

The eye contains multiple tissues with various functions, several of them under autonomic control (Figure 6-5). The pupil, discussed previously, is under reciprocal control by the SANS (via  receptors on the pupillary dilator muscle) and the PANS (via muscarinic receptors on the pupillary constrictor). The ciliary muscle, which controls accommodation, is under primary control of muscarinic receptors innervated by the PANS, with insignificant contributions from the SANS. The ciliary epithelium, on the other hand, has important  receptors that have a permissive effect on aqueous humor secretion. Each of these receptors is an important target of drugs that are discussed in the following chapters.

FIGURE 6-5

Some pharmacologic targets in the eye. The diagram illustrates clinically important structures and their receptors. The heavy arrow (blue) illustrates the flow of aqueous humor from its secretion by the ciliary epithelium to its drainage through the canal of Schlemm. M, muscarinic receptor; , alpha receptor; , beta receptor.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 6-9.)

Skill Keeper Answer: Drug Permeation

(See Chapter 1)

Botulinum toxin is too large to cross membranes by means of lipid or aqueous diffusion. It must bind to membrane receptors and enter by endocytosis. Botulinum-binding receptors for endocytosis are present on cholinergic neurons but not adrenergic neurons.

Checklist

When you complete this chapter, you should be able to:

 Describe the steps in the synthesis, storage, release, and termination of action of the major autonomic transmitters.

 Name 2 cotransmitter substances.

 Name the major types of autonomic receptors and the tissues in which they are found.

 Describe the organ system effects of stimulation of the parasympathetic and sympathetic systems.

Name examples of inhibitors of acetylcholine and norepinephrine synthesis, storage, and release. Predict the effects of these inhibitors on the function of the major organ systems.

List the determinants of blood pressure and describe the baroreceptor reflex response for the following perturbations: (1) blood loss, (2) administration of a vasodilator, (3) a vasoconstrictor, (4) a cardiac stimulant, (5) a cardiac depressant.

Describe the effects of loss of sympathetic output to the face (Horner syndrome) and list the transmitters involved if the lesion is preganglionic.

 Describe the results of transplantation of the heart with interruption of its autonomic nerves on cardiac function.

 Describe the actions of several toxins that affect nerve function: tetrodotoxin, saxitoxin, botulinum toxins, and latrotoxin.

Summary Table: Introductory Autonomic Drugs

Drug Comment Acetylcholine Primary transmitter at cholinergic nerve endings (preganglionic ANS, postganglionic parasympathetic, postganglionic sympathetic to thermoregulatory sweat glands, and somatic neuromuscular end plates) Amphetamine Sympathomimetic drug that facilitates the release of catecholamines from adrenergic nerve endings Botulinum toxin Bacterial toxin that enzymatically disables release of acetylcholine from cholinergic nerve endings Cocaine Drug that impairs reuptake of catecholamine transmitters (norepinephrine, dopamine) by adrenergic nerve endings Dopamine Important central nervous system (CNS) transmitter with some peripheral effects (renal vasodilation, cardiac stimulation) Epinephrine Hormone released from adrenal medulla, neurotransmitter in CNS Hemicholiniums Drugs that inhibit transport of choline into cholinergic nerve endings Metanephrine Product of epinephrine and norepinephrine metabolism Metyrosine Inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in norepinephrine synthesis Norepinephrine Primary transmitter at most sympathetic postganglionic nerve endings; important CNS transmitter Reserpine Drug that inhibits uptake of dopamine and norepinephrine into transmitter vesicles of adrenergic nerves Tetrodotoxin, saxitoxin Toxins that block sodium channels and thereby limit transmission in all nerve fibers Vesamicol Drug that inhibits uptake of acetylcholine into its transmitter vesicles



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