pharma autonomic

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CHAPTER 16 Review of Neurotransmitters and the Autonomic Nervous System

CHAPTER 17 Cholinergic Agonists

CHAPTER 18 Cholinergic Antagonists

CHAPTER 19 Adrenergic Agonists

CHAPTER 20 Adrenergic Antagonists

Pharmacology of theAutonomic Nervous System

3U N I T

FPO FPO FPO FPO


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Review of Neurotransmitters

and the Autonomic Nervous System

Learning Outcomes

After reading this chapter, the student should be able to:

1. Distinguish between the central and peripheral nervous systems.

2. Compare and contrast the two divisions of the peripheral nervous

system.

3. Compare and contrast the actions of the sympathetic and

parasympathetic divisions of the autonomic nervous system.

4. Explain the process of synaptic transmission.

5. Explain the basic mechanisms by which drugs affect synaptic

transmission.

6. Describe the actions of acetylcholine at cholinergic synapses.

7. Describe the actions of norepinephrine at adrenergic synapses.

8. Assess how the actions of the adrenal medulla compare to those

of other sympathetic effector organs.

9. Explain how higher centers in the brain can influence autonomic

function.

10. Design a method for classifying autonomic drugs based on which

receptors are affected.

Chapter Outline

Basic Structureof the Nervous System

Structure and Functionof the Autonomic Nervous System

Synaptic Transmission

Cholinergic Transmission

Cholinergic Receptorsand Neurotransmitters

Adrenergic Transmission

Adrenergic Receptorsand Neurotransmitters

Adrenal Medulla Hormones

Regulation of Autonomic

Functions

Classifying Autonomic Drugs

Source: Phototake NYC.


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Neuropharmacology represents one of the largest, most com-plicated, and least understood branches of pharmacology.Nervous system drugs are used to treat a large and diverse set

of conditions, including pain, anxiety,depression, schizophre-nia, insomnia, and seizures. Through their action on nerves,

these medications are used to treat disorders affecting otherbody systems such as abnormalities in heart rate and rhythm,

hypertension, glaucoma, asthma, and even a runny nose.Traditionally, the study of neuropharmacology begins with

the autonomic nervous system. This is because autonomicphysiology lays the foundation for understanding nervous,car-diovascular, and respiratory pharmacology. This chapter serves

two purposes. First, it is a comprehensive review of autonomicnervous system physiology, a subject that is sometimes covered

superficially in anatomy and physiology classes. Second, it in-troduces the four fundamental classes of autonomic medica-

tions, which are presented in depth in Chapters 17 through 20.

Basic Structure of the Nervous System16.1 The two major subdivisions of the nervoussystem are the central nervous system and theperipheral nervous system.

The nervous system is considered the master controller of mostactivities occurring within the body. Compared to the other ma-

jor regulator, the endocrine system,cells of the nervous system actinstantaneously to promote homeostasis and make the adjust-ments necessary to maintain vital functions. The brain, spinal

cord,and peripheral nerves act as a smoothly integrated whole toaccomplish minute-to-minute changes in essential functions such

as heart rate,blood pressure, pupil size, and intestinal movement.

The basic functions of the nervous system are to:

Recognize changes in the internal and external environments.

Process and integrate the environmental changes that are

perceived.

Respond to the environmental changes by producing an ac-

tion or response.

Thenervous system hastwo majordivisions: the central ner-

vous system(CNS) andtheperipheral nervoussystem.The CNSis made up of the brain and spinal cord, whereas the peripheral

division consists primarily of nerves that carry messages to andfrom the CNS. Drugs used to treat disorders and conditions of

the CNS are discussed in Chapters 22 through 30. Figure 16.1illustrates the functional divisions of the nervous system.

16.2 The peripheral nervous system is divided intosomatic and autonomic components.

With its immense potential and complexity, the human brainrequires a continuous flow of information to accomplish its

functions. In addition, the brain would be useless without ameans to carry out its commands. The peripheral nervous sys-

tem provides the brain the means to communicate with andreceive sensory messages from the outside world.

Neurons in the peripheral ner-vous system either recognizechanges to the environment (sen-

sory division) or respond to thosechanges by moving muscles or

secreting chemicals (motor divi-sion). The sensory division con-

sists of specialized nerves thatrecognize touch, pain, heat, body

position, light, or specific chemi-cals in body fluids.

The motor division is divided

into two components. Thesomatic nervous system con-

sists of nerves that provide volun-tary control of skeletal muscle.The

nerves of the autonomic nervous

system (ANS) provide involun-tary control of vital functions of

the cardiovascular, digestive,respi-ratory, and genitourinary systems.

The ANS controls vital life activi-ties without people being aware of

its functions. The three main ac-tivities of the ANS include thefollowing:

Contraction of smooth muscle

of the bronchi, blood vessels,gastrointestinal (GI) tract, eye,and genitourinary tract

Contraction of cardiac muscle

Secretion of salivary, sweat, andgastric glands

TheANSis particularly impor-tant to pharmacology because a

large number of medications af-fect autonomic nerves. Some ofthese drug actions produce desir-

able, therapeutic effects, whereasothers produce adverseeffects.Theremainderof this chapter in-

troduces the structure and function of this complex system.

Structure and Functionof the Autonomic Nervous System

16.3 The autonomic nervous system is dividedinto two mostly opposing components:the sympathetic and parasympathetic branches.

The ANS has two distinct divisions: the sympathetic nervoussystem and the parasympathetic nervous system. Most organsand glands receive nerves from both branches, and the two di-

visions have opposing actions. For example, one branch maycause smooth muscle to contract; the other may cause it to

acetylcholine

(Ach), 190

acetylcholinester

(AchE), 194

adrenergic, 194

autonomic nervou

system (ANS),autonomic tone, 1

catecholamine, 19

catechol-O-

methyltransfer

(COMT), 196

cholinergic, 192

fight-or-flight

response, 188

ganglia, 190

monoamine oxida

(MAO), 196

muscarinic,193

neuroeffector

junction, 190

neurotransmitter,

nicotinic, 193

norepinephrine

(NE), 190

parasympathetic

nervous system

rest-and-digest

response, 188

somatic nervoussystem,187

sympathetic nerv

system, 188

synapse, 190

synaptic cleft, 19

187


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188 UNIT 3 Pharmacology of the Autonomic Nervous System

The Nervous System

Central Nervous System (CNS)

(receives and processes sensory input;

initiates action)

Brain

(receives and processes

sensory information;

initiates responses;

stores memories;

generates thoughts

and emotions)

Spinal Cord

(conducts nerve impulses

to and from the brain;

controls reflex activities)

Somatic Nervous System

(controls voluntary

movements of

skeletal muscles)

Autonomic Nervous System

(controls involuntary responses

of glands, cardiac muscle

and smooth muscle)

Cholinergic (muscarinic) ReceptorsAdrenergic Receptors

Beta

Sympathetic Division

(prepares body for

stressful or energetic

activity; fight or flight)

Motor Division

(carries nerve impulses

from the CNS to

muscles and glands)

Sensory Division

(carries nerve impulses

to the CNS from

sensory organs)

Peripheral Nervous System (PNS)

(carries nerve impulses between the

CNS and the rest of the body)

Alpha

Parasympathetic Division

(dominates during periods of

rest and digest;

directs maintenance activities)

relax.Theultimateactionof thesmooth muscleor glanddepends

on which branch is sending the most signals at a given time. Themajor actions of the two divisions are shown in Figure 16.2. It isessential that the student learn these actions early in the study of

pharmacologybecause knowledgeof autonomiceffects is used topredict the actions and adverse effects of many drugs.

The sympathetic nervous system is activated underemergency conditions or stress and produces a set of actions

called the fight-or-flight response. Activation of this branchprepares the body for heightened activity and for an immedi-ate response to a threat. The brain experiences an increase in

alertness and readiness. Heart rate and blood pressure increaseand blood is shunted to skeletal muscles, thus preparing the

body for sudden, intense physical activity. The liver immedi-ately produces more glucose for energy. The bronchi dilate to

allow maximum airflow into the lungs, and breathing becomesfaster and deeper.The pupils dilate to provide better vision fordealing with the emergency.The body warms and perspiration

increases.At the same time the body is preparing for the threat,

nonemergency maintenance functions such as peristalsis andurine formation are temporarily suspended.

The parasympathetic nervous system is activated under

nonstressful conditions and produces a set of symptomsknown as the rest-and-digest response. These nerves pro-

mote relaxation and body maintenance activities.Digestive se-cretions increase, peristalsis propels substances along the

alimentary canal, and defecation is promoted. Heart rate andblood pressure decline. Because less air is needed, the bronchiconstrict and respiration slows. The student should notice that

the actions of the parasympathetic division are opposite tothose of the sympathetic division.

Under most conditions, the two branches of the ANS co-operate to achieve a balance of readiness and relaxation. Be-

cause they have opposite effects, homeostasis may beachieved by changing one or both branches. For example,heart rate can be increased by either increasing the firing of

Figure 16.1

Functional divisions of the nervous system.


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CHAPTER 16 Review of Neurotransmitters and the Autonomic Nervous System 189

sympathetic nerves or by decreasing the firing of parasympa-thetic nerves. This allows the body a means of fine-tuning itsessential organ systems.

There is always some degree of autonomic activity even in theabsence of stimuli. This background level of activity is known asautonomic tone. For example,sympathetic nerves are constantlyfiring, keeping arterioles in a constant state of constriction. This

sympathetic tone allows for faster changes in blood pressure be-cause the vessels are in a constant state of readiness.On the other

hand,parasympathetic tone on the smooth muscle of the alimen-tary and urinary tracts maintains continuous contractions andkeeps intestinal peristalsis and urine flow steady. With the impor-

tant exception of the vascular system,the predominant tone of au-tonomic tissues is from the parasympathetic nervous system.

The sympathetic and parasympathetic divisions do not al-

ways have opposite effects. For example, the constriction ofarterioles is controlled entirely by the sympathetic branch.Sym-

pathetic stimulation causes constriction of arterioles, whereaslack of stimulation causes vasodilation. Only sympathetic

nerves control the adrenal medulla and the sweat glands. Thesympathetic division is also solely responsible for the release of

renin by the kidneys, an action that increases blood pressure.Metabolic effects such as increases in blood glucose and mobi-lization of lipids for energy are uniquelysympathetic functions.

constrictspupil

stimulatessalivation

slowsheart

constrictsbreathing

stimulatesdigestion

stimulatesgallbladder

contractsbladder

stimulatessex organs

cranialnerves

cervicalnerves

thoracicnerves

lumbarnerves

sacralnerves

SYMPATHETICDIVISION

fight or flight

dilates pupil

inhibitssalivation

acceleratesheart

facilitatesbreathing

inhibitsdigestion

stimulatesrelease ofglucose

secretesepinephrine andnorepinephrine

relaxesbladder

inhibits sexorgans

PARASYMPATHETICDIVISION

rest and digest

Figure 16.2

Effects of the sympathetic and parasympathetic nervous systems.

Source: From Biology: A Guide to the Natural World (4th ed., p. 558), by D. Krogh, 2009, Upper Saddle River, NJ: Prentice Hall. Reprinted

with permission.


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Spinal cordPreganglionic

neuron

Postganglionic

neuron

Autonomic

ganglion

Smooth

muscle

Glands

Cardiac

muscle

Effector organs

Figure 16.3

Basic structure of an autonomic pathway.

In the male reproductive system, the roles are complementary.Erection of the penis is a function of the parasympathetic divi-

sion, and the sympathetic branch controls ejaculation.


16.4 Synaptic transmission allows information

to be communicated between two nerves or fromnerves to muscles or glands.

For information to be transmitted throughout the nervous

system, neurons must communicate with each other and withmuscles and glands.The basic unit of the ANS is a two-neuronchain.The first neuron, called the preganglionic neuron, orig-

inates in the CNS. The preganglionic neuron connects with thesecond nerve outside the CNS in structures called ganglia. A

ganglion (singular ofganglia) contains the neuron cell body ofthe postganglionic neuron, which is waiting to receive the ac-

tion potential.Before the message can be transferred from one nerve to an-

other,however, it must cross the synapse, a physical space be-tween the two neurons. The communication of the messagefrom one cell to another, or synaptic transmission, utilizes spe-

cial chemicals called neurotransmitters. It is important tostudy the details of synaptic transmission because a large num-

ber of drugs affect this process.The basic structure of a synapseis shown in Figure 16.3. The process of synaptic transmissionis illustrated in Pharmacotherapy Illustrated 16.1.

The second (postganglionic) neuron terminates on smoothmuscle, cardiac muscle, or a gland at a specialized synapse

called the neuroeffector junction. As mentioned earlier aneurotransmitter conveys the message from the second neuron

to the muscle or gland. The movement of the nerve impulsefrom the CNS to the ganglia to the neuroeffector junction oc-

curs in several steps.

1. Synthesis of the neurotransmitter. The neurotransmitter,or chem-

ical messenger in the synapse, is synthesized in the cell body ofthe neuron or in the axon terminal where the synapse is located.Over 50 different neurotransmitters have been identified, the

most common of which are shown in Table 16.1. Each neuro-transmitter is associated with particular functions and responses.

The two primary neurotransmitters of the ANS are norepine-

phrine (NE) and acetylcholine (Ach).

2. Storage of the neurotransmitter. Because nerve impulses travelrapidly from neuron to neuron, there must be an ample and

continuous supply of the neurotransmitter.At the terminal endsof each axon lie millions of granules or vesicles loaded with neu-rotransmitters, waiting for an action potential to release them.

3. Release of the neurotransmitter. When the nerve impulse reachesthe end of the axon, it stimulates some of the vesicles to release

their stored neurotransmitter into the synapse. The neurotrans-mitter enters the synaptic cleft, which must be crossed for the

impulse to reach the postganglionic neuron or effector tissue.

4. Binding to the receptor. The neurotransmitter diffuses across

the synaptic cleft to receptors that lie on the surface of the post-synaptic cell. There is a brief delay in impulse conduction of

about 0.2 to 0.5 msec for the neurotransmitter to cross thesynapse. Once the neurotransmitter binds, the message is con-veyed to the postsynaptic cell, which is a muscle cell,glandular

cell, or another neuron. The neurotransmitter induces the tar-get tissue to elicit its characteristic response. Generally, the

more neurotransmitter released into the synapse, the greaterand longer lasting will be the response.


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TABLE 16.1 Selected Neurotransmitters,Their Effects and Clinical Applications

Neurotransmitter Primary Location Clinical Application (Chapter Number)

Acetylcholine Synapses throughout the CNS; preganglionic neurons ending in the ganglia in both thesympathetic and parasympathetic nervous systems (nicotinic); postganglionic neuronsending in neuroeffector target tissues in the parasympathetic nervous system (muscarinic)

Myasthenia gravis (17); Alzheimersdisease (25)

Dopamine Limbic system and hypothalamus; some sympathetic ganglia Attention deficit/hyperactivity disorder (28);Parkinsons disease (25); Psychosis (24)

Gammaaminobutyric acid

(GABA)

Cerebellum, cerebral cortex; interneurons throughout the CNS Anxiety (22); epilepsy (26)

Glutamate Throughout the CNS Seizures (26)

Nitrous oxide CNS, adrenal gland, and nerves to the penis Impotence (72)

Norepinephrine Throughout the CNS; most neuroeffector target junctions in the sympatheticnervous system

Attention deficit/hyperactivity disorder (28);cocaine and amphetamine abuse (8);depression (23)

Serotonin (5-HT) Limbic system and hypothalamus; primary neurotransmitter in the extrapyramidal system;GI tract

Anxiety (22); depression (23); nausea andvomiting (61); psychoses (24)

Substance P Pain pathways in the spinal cord; brain and sensory neurons Analgesia (29)

5. Action potentialcontinues.

4. Neurotransmitter bindsto receptor and opension channel.

Synaptic

vesicle

1. An action potentialis initiated.

2. Action potentialreaches the synapse.

Neurotransmitter

3. Neurotransmitter released

from synaptic vesicles.

Synapticcleft

Postsynapticneuron

Preganglionic

neuron

Ionchannel

PHARMACOTHERAPY ILLUSTRATED 16.1



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5. Termination of neurotransmitter action. Once the message istransmitted, the two cells must return to baseline conditions

and ready themselves for future messages. This is accom-plished by removal of the neurotransmitter. The neurotrans-

mitter is either degraded in the synaptic cleft by enzymes, or itdiffuses back into the preganglionic neuron, thus stopping theaction of the muscle or gland.

Conduction of action potentials in the ANS is much slowerthan in the somatic nervous system. Because somatic nerves

are myelinated and have no ganglia, impulses more quicklyreach their target tissues. Autonomic messages must cross the

synaptic cleft, and postganglionic nerves are unmyelinated,which slows the action potential.

16.5 Autonomic drugs exert their effects by actingat synapses.

The student is likely wondering why it is necessary to learnANS anatomy and physiology to such depth. The reason is

that a large number of drugs affect autonomic function by al-

tering neurotransmitter activity. Some medications are iden-tical to endogenous neurotransmitters, or have a very similarchemical structure, and are able to directly activate a gland or

muscle. Other drugs are used to stimulate or block theactionsof natural neurotransmitters. A firm grasp of autonomic

physiology is essential to understanding the actions of hun-dreds of drugs.

The two-neuron anatomic structure of the ANS allows

multiple locations at which drugs can act. Drugs can affect theoutflow of impulses traveling along the preganglionic neuron

at their sourcethe CNS. A second site is in the ganglia, whichis at the synapse where the preganglionic and postganglionic

neurons meet. Yet a third site is at the end of the chain, at the

target tissues of the postganglionic neuron.Despite the complexity of the ANS, actions of drugs affect-

ing this system can be grouped into just a few categories. Thefollowing are the five general mechanisms by which drugs af-

fect synaptic transmission.

Medications may affect the synthesis of the neurotransmit-

ter in the preganglionic nerve. Drugs that decrease neuro-transmitter synthesis inhibit autonomic responses. Those

that increase neurotransmitter synthesis have the oppositeeffect.

Medications can prevent the storage of the neurotransmit-ter in vesicles within the preganglionic nerve.Prevention of

neurotransmitter storage inhibits autonomic actions.

Medications can influence the release of the neurotransmit-

ter from the preganglionic nerve. Promoting neurotrans-mitter release stimulates autonomic responses, whereaspreventing neurotransmitter release has the opposite effect.

Medications can bind to the neurotransmitter receptor siteon the postganglionic cell. Drugs that bind to postgan-

glionic receptors and stimulate the cell will increase auto-nomic responses. Those that attach to the postganglionic

cell and prevent the natural neurotransmitter from reach-ing its receptors will inhibit autonomic actions.

Medications can prevent the normal destruction or reup-take of the neurotransmitter. These drugs cause the neuro-

transmitter to remain in the synapse for a longer time andwill stimulate autonomic actions.

It is important to understand that autonomic drugs arerarely given to correct physiological defects in the ANS itself.

Compared to other body systems, the ANS has remarkably lit-

tle disease. Rather,medications are used to stimulate or inhibittarget organs or glands of the ANS, such as the heart, lungs,ordigestive tract.With few exceptions, the disorder lies in the tar-get organ,not the ANS.Thus when an autonomic drugis ad-

ministered, the goal is not to treat an autonomic disease; itcorrects disorders of target organs through its effects on auto-

nomic nerves.

Cholinergic Transmission

16.6 Acetylcholine is the neurotransmitter releasedat cholinergic receptors,which may be nicotinic or

muscarinic.Ach was the first neurotransmitter to be identified.Neurons re-

leasing Ach are called cholinergic nerves. Located on postgan-glionic or neuroeffector cell membranes, cholinergic receptors

bind Ach and either continue the impulse (at the ganglia) orcause an autonomic action (at the neuroeffector tissue). When

reading the following sections, the student should refer to thesites of Ach and NE action shown in Figure 16.4.

Sir Henry Dale identified acetylcholine as a neurotrans-

mitter in 1914, and Otto Loewi demonstrated its physi-

ology. The pair was awarded the Nobel Prize inPhysiology or Medicine in 1936 for their work. Dale also

is responsible for creating the terminology ergic when

naming synapses, such as cholinergic or adrenergic.

Source: Nobelprize.org, 2008.

Ach is synthesized in the preganglionic nerve terminal andstored in synaptic vesicles. A preganglionicneuron maycontain300,000 vesicles, each housing as many as 50,000 Ach mole-

cules. When an action potential reaches the nerve terminal, abrief burst of Ach is released into thesynaptic cleft, where it dif-

fuses across to attach to its receptors on the postganglionic cell.

Cholinergic Receptorsand NeurotransmittersThere are two types of cholinergic receptors that bind Ach.

They are named after certain chemicals that bind to them.

Nicotinic receptors. Located at preganglionic neurons ending inthe ganglia in both the sympathetic and parasympathetic

nervous systems

Muscarinic receptors. Located at postganglionic neurons ending

in neuroeffector target tissues in the parasympathetic ner-vous system


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Early research on laboratory animals found that the actionsof Ach at the ganglia resemble those of nicotine, the active chem-

ical in tobacco products. Because of this similarity, receptors forAch in the ganglia are called nicotinic receptors. Nicotinic re-ceptors are also found in skeletal muscle, which is controlled by

the somatic nervous system,and in the adrenal medulla.Becausenicotinic receptors are present in so many locations, drugs af-

fecting these receptors produce profound effects on both theANS and somatic nervous system. Activation of Ach nicotinic

receptors causes tachycardia, hypertension, and increased toneand motility in the digestive tract. Although nicotinic receptorblockers were some of the first drugs used to treat hypertension,

they are rarely used for this purpose today due to the discoveryof safer drugs. The primary current therapeutic application of

these agents is to produce skeletal muscle relaxation (a somaticeffect) during surgical procedures. A complete discussion of

nicotinic blockers can be found in Chapter 18.

16.1

Nicotine is presented in Chapter 8 as an addictive

drug. Describe the effects that nicotine has on the

body. See Answer to Connection Checkpoint 16.1 in Appendix A.

Activation ofAch receptors at postganglionic nerve endings inthe parasympathetic nervous system results in the classic symp-

toms of parasympathetic stimulation shown in Figure 16.2.Earlyresearch determined that these actions closely resemble those

produced after eating the poisonous mushroom Amanita mus-

caria. The active substance in this mushroom is the chemicalmuscarine; thus, these Ach receptors were namedmuscarinic re-

ceptors.Muscarinic receptors are also found in most sweat glandsand in blood vessels serving skeletal muscles. The locations of

nicotinic and muscarinic receptors are illustrated in Figure 16.5.When Ach binds to nicotinic receptors, the action is always

stimulatory. Examples include increased sweat production, in-

creased release of adrenal medullary hormones, and enhancednerve conduction in the ganglia. Ach action at muscarinic re-ceptors, however, may be stimulatory or inhibitory,dependingon the target tissue.Examples include decreased heart rate and

increased peristalsis. Muscarinic receptors are affected by alarger number of drugs that have more pharmacologic appli-

cations than the nicotinic agents. Drugs that block muscarinicreceptors are used during ophthalmic procedures, as preanes-

thetic agents, and in the pharmacotherapy of asthma andbradycardia (see Chapter 20).

Although Ach itself can stimulate both muscarinic and

nicotinic receptors, some drugs are selective to only one type.

Spinalcord

Cholinergic

preganglionicneuron

Ach

Ganglia

Cholinergicreceptors(nicotinic)

Adrenergicpostganglionic

neuron

NE

Targettissue

Spinalcord

Cholinergicpreganglionicneuron

Ach

Ganglia

Cholinergicreceptors(nicotinic)

Cholinergic

postganglionicneuron

Ach

Ach = Acetylcholine

NE = Norepinephrine

(a) Sympathetic pathway

(b) Parasympathetic pathway

Targettissue

Adrenergicreceptor(a or b)

Cholinergicreceptor

(muscarinic)

Figure 16.4

Receptors in the autonomic nervous system: (a) Sympathetic pathway: Ach is released at the ganglia(nicotinic receptor) and NE at the effector organ (adrenergic receptor); (b) Parasympathetic pathway:Ach is released at both the ganglia (nicotinic receptor) and effector organ (cholinergic receptor).


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Table 16.2 summarizes the types of responses produced by

activation of the two types of Ach receptors.

Termination of Acetylcholine ActionThe goal of nerve transmission is to produce an immediate,though transient, response. To accomplish this, Ach must berapidly removed from the synaptic cleft after its effect is pro-

duced. The enzyme that resides in the synaptic cleft and cat-alyzes the destruction of Ach is called acetylcholinesterase(AchE). (Note: The suffix erase can be thought of as wipingout the Ach.) AchE is quite efficient at performing its task. Itis estimated that over half the Ach molecules released from the

vesicles are destroyed before they have a chance to reach theirreceptors. Following the breakdown of Ach, choline is re-

formed and is taken up by the preganglionic neuron, where itis used to synthesize more Ach.The life cycle of Ach in the neu-

ron is shown in Pharmacotherapy Illustrated 16.1.Pseudocholinesterase,also known as plasma cholinesterase,

is another enzyme that destroys Ach. Found primarily in the

liver, pseudocholinesterase rapidly inactivates Ach and drugswith a chemical structure similar toAch as they circulate in the

plasma. Some people are born with a genetic deficiency of thisenzyme and are unable to inactivate plasma Ach or succinyl-

choline, a surgical drug structurally similar to Ach. These pa-tients are particularly sensitive to the effects of succinylcholine

because theyare unable to inactivate thedrug (see Chapter 30).

Adrenergic Transmission16.7 Norepinephrine is the primaryneurotransmitter released at adrenergic receptors,which may be alpha or beta.

In the sympathetic nervous system, NE is the neurotransmitterreleased at almost all postganglionic nerves. NE belongs to aclass of endogenous hormones called catecholamines, all of

which are involved in neurotransmission. Other catecholaminesinclude epinephrine (adrenaline) and dopamine. The receptors

at the ends of postganglionic sympathetic neurons are calledadrenergic, which is derived from the word adrenaline.

Adrenaline was isolated and identified by John Jacob

Abel in 1897, who founded the very first Department of

Pharmacology at the University of Michigan. The

name was changed to epinephrine in the United

States because Parke, Davis, and Co. owned the

trademark rights to the wordadrenalin (without a final

e). It is still known as adrenaline in the rest of the

world. Source: Aronson, 2000.

NE is synthesized in the nerve terminal and stored in vesi-cles until an action potential triggers its release into the synap-

tic cleft. NE then diffuses across the cleft to bind to its receptorson the effector cell.

Adrenergic receptors are of two basic types: alpha () andbeta (). These receptors are further divided into the subtypesbeta1, beta2, alpha1, and alpha2. Activation of each type of sub-

receptor results in a characteristic set of physiological re-sponses, which are summarized in Table 16.2.

Alpha-Adrenergic ReceptorsWhen alpha receptors are stimulated, enzymes on the inside ofthe plasma membrane are activated and a cascade of changes

occurs within the cell. These changes occur due to the produc-tion of a second messenger, the G-protein, which initiates the

cascade. In alpha1 receptors intracellular calcium stores are re-leased, causing excitatory effects such as smooth muscle con-traction or sphincter closure. Drugs affecting alpha1 receptors

are primarily used for their effects on vascular smooth musclein the treatment of hypertension (see Chapter 20).

Stimulation of alpha2 receptors causes different effects due tothe activation of a separate cascade of events.By increasing cyclic

adenosine monophosphate (cAMP) within the cell, activation ofalpha2 receptors causes mostly inhibitory actions. Activation ofthe alpha2 receptor will inhibit NE release from sympathetic

nerve endings. In addition, activation of alpha2 receptors in theCNS can suppress the outflow of sympathetic activity from the

brain. Indeed,as discussed in Chapter 19,drugs that affect alpha2receptors are usually used for their ability to decrease blood pres-

sure due to their effects on the CNS, not the ANS.

TABLE 16.2 Types of Autonomic Receptors

Neurotransmitter Receptor Primary Locations Selected Responses

Acetylcholine(cholinergic)

Muscarinic Parasympathetic target: organs other than the heart Stimulation of smooth muscle and gland secretions; decreasedheart rate and force of contraction

Nicotinic Postganglionic neurons and neuromuscular junctionsof skeletal muscle

Stimulation of smooth muscle and gland secretions

Norepinephrine(adrenergic)

Alpha1 All sympathetic target organs except the heart Constriction of blood vessels; dilation of pupils

Alpha2 Presynaptic adrenergic nerve terminals Inhibition of norepinephrine release

Beta1 Heart and kidneys Increased heart rate and force of contraction; release of renin

Beta2 All sympathetic target organs except the heart Inhibition of smooth muscle contraction


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Beta-Adrenergic ReceptorsThree subtypes of beta-adrenergic receptors have been identi-

fied,although only beta1 and beta2 have pharmacologic impor-tance. Beta receptors act by increasing the second messenger

cAMP in target cells. The specific response caused by activa-tion of the beta receptor depends on its location.

The primary tissues served by beta1 receptors are the heartand coronary vessels. Activation of these receptors increases

the heart rate and strength of contraction and dilates the coro-nary arteries, thus preparing the heart for fight or flight. Beta1receptors in the kidney respond by releasing renin, which helps

to maintain blood pressure.Beta2 receptors are more widely distributed than beta1

receptors, with locations in the smooth muscle in blood

vessels, the GI tract, and the lung. Activation of these recep-tors will inhibit vasoconstriction (thus causing vasodila-

tion), dilate bronchioles, slow peristalsis, and decrease urineproduction.

The significance of adrenergic receptor subtypes to phar-

macology cannot be overstated. Some drugs are selective andactivate only one type of adrenergic receptor, whereas others

affect all of them. Furthermore, a drug may activate one typeof receptor at low doses and begin to affect other receptor sub-types as the dose is increased. Committing the receptor types

and their responses to memory is an essential step in learningautonomic pharmacology.

Other types of adrenergic receptors exist.Although the func-tional role of dopamine was once thought to be only a chemical

Acetylcholine

Acetylcholinesterase

Choline Acetate

Presynapticneuron

Synapticcleft

Muscle

1

2

3

4

A

A

A

A

A

A

AA

A

A

A

A

A

A

Ch

Ch

Ch

Ch

ChCh

Ch

Ch

Ch

Ch

Ch

ACh

Ch

Ch

Ch

h

Postsynapticneuron

Achreceptor

Figure 16.5

Life cycle of acetylcholine (Ach): (1) Ach is released into the synaptic cleft; (2) Ach binds to receptors on the postsynapticmembrane; (3) Ach binds to the acetycholinesterase enzyme; (4) Ach is broken down into acetate and choline.


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precursor to NE, research has determined that this agent servesa larger role as neurotransmitter. Five dopaminergic receptors

(D1 through D5) have been discovered in the CNS. Dopamin-ergic receptors are important to the action of certain antipsy-

chotic medicines (see Chapter 24) and in the treatment ofParkinsons disease (see Chapter 25).Dopamine receptors in the

peripheral nervous system are located in the arterioles of thekidney and other viscera. Although these receptors likely have a

role in autonomic function, their therapeutic importance hasyet to be discovered.

Termination of Norepinephrine ActionThe termination of NE action occurs through mechanisms dif-

ferent from those of Ach. From 50% to 80% of the NE is takenback into the preganglionic nerve, a process known as reuptake.

After reuptake, NE in the nerve terminal is repackaged in vesi-cles for future use or destroyed enzymatically bymonoamineoxidase (MAO). NE entering the circulation, such as that se-creted by the adrenal glands or given as medication, is destroyed

by the enzyme catechol-O-methyltransferase (COMT) inkidney and liver cells. Many drugs affect autonomic function by

influencing the synthesis, storage, release, reuptake, or destruc-tion of NE. The life cycle of NE is shown in Figure 16.6.

The effects produced by sympathetic activation last longerthan those of parasympathetic activation.This is because NE actsindirectly through a second messenger mechanism. Its effects are

produced more slowly than Ach, which acts directly at choliner-gic sites.Furthermore, the primary means of inactivation of NE

is through reuptake,which is a slower process than the direct en-zymatic destruction of Ach.

Enzymes thatterminatethe action ofnorepinephrine

MOA = Monoamine oxidaseCOMT = Catecholamine

O-methyl transferase

1

2

3

5 4

6

Tyrosine

Dopa

Dopamine

Norepinephrine

Norepinephrine

Postsynaptic

neuron

NEreceptor

COMT

MAO

Inactiveproducts

Synapticcleft

Presynapticneuron

Figure 16.6

Life cycle of norephinephrine (NE): (1) NE is synthesized from the amino acid tyrosine; (2) NE is released into the synaptic cleft;(3) NE binds to receptors on the postsynaptic membrane; (4) NE is taken back into the presynaptic neuron; (5) NE is degraded byMAO; (6) Small amounts of NE enter the postsynaptic cell and are degraded by COMT.


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16.8 The adrenal medulla is a specialized typeof sympathetic nervous system tissue that secretesepinephrine and norepinephrine.

The adrenal medulla is closely associated with the sympatheticnervous system but has a different anatomic and physiologicalarrangement than the rest of the sympathetic branch. Early in

embryonic life, the adrenal medulla is part of the neural tissue

that is destined to become the sympathetic nervous system.The primitive tissue splits, however, and the adrenal medullabecomes its own functional division. Preganglionic neurons

from the spinal cord terminate in the adrenal medulla and re-lease the neurotransmitters epinephrine and NE directly intothe blood. Approximately 80% of the secretion is epinephrine,

with the other 20% being NE. Once released, these agents arewidely distributed to target organs,where they elicit the classic

fight-or-flight symptoms.When released into the systemic circulation, the effects of

epinephrine and NE are more diffuse and longer lasting thanthose produced by activation of postganglionic sympatheticneurons in the ANS. In addition, when released into the

bloodstream, these agents are distributed to most body cells,not just those innervated by the ANS. Significant concentra-

tions of epinephrine and NE may persist for as long as 30 sec-onds, and their effects on the tissues may continue for several

minutes until the liver deactivates the hormones. It is esti-mated that 25% to 50% of all sympathetic nervous system re-

sponses at any given time are due to circulating hormonesfrom the adrenal medulla.

Regulation of Autonomic Functions

16.9 The autonomic nervous system is influencedby higher levels of control in the cerebral cortexand hypothalamus.

Although it is often stated that control of the ANS is involuntary,this is an oversimplification. For example, strong emotions such

as rage are seated in the brain, but they trigger the heart to race,the blood pressure to rise, and the respiration rate to increase.

Mental depression can have the opposite effects.The smell of steakor chicken cooking on the grill can increase peristalsis,resulting in

grumblingof the stomach and increased salivation. Clearly, au-tonomic actions can be modified by higher brain centers.

The roles of higher centers in regulating the ANS are

shown in Figure 16.7. The hypothalamus is thought to be themain integration center of the ANS. This tissue receives sig-

nals from the cerebrum and sensory input,such as emotions,from the limbic system of the brain. The hypothalamus

Cerebral Cortex

Thoughts

Limbic System

Emotions

Hypothalamus

ANS integration

Pons and Medulla

Cardiac, respiratory,

blood pressure, swallowingcenters

Spinal Cord

Reflexes for defecation,

urination, erection, and

ejaculation

Figure 16.7

Higher centers influencing autonomic function.


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interprets the information and responds by sending mes-sages to the various portions of the ANS, such as increasing

peristalsis and salivation when the sights, sounds, and smellsof the grilled steak are experienced. Messages from the hypo-

thalamus travel along the medulla oblongata, the brainstem,and the spinal cord.

Drugs can affect the ANS by influencing these higher centers.For example, drugs that decrease anxiety or diminish the inci-

dence of panic attacks can slow the heart rate and lower bloodpressure through their ability to affect conscious thought. It isimportant to understand that these drugs do not necessarily act

on autonomic receptors. Nor does the patient consciously lowertheir blood pressure or heart rate. The autonomic effect is indi-

rect, caused by a reduction of stress, and it is at a subconsciouslevel. Controlling autonomicactivity through conscious thoughtis the principle underlying biofeedback therapy.

Classifying Autonomic Drugs

16.10 Autonomic drugs are classified

by which receptors they stimulate or block.At this point of the chapter, it is normal for students to feeloverwhelmed by the complexity of the various autonomic re-

ceptors and their actions. It is the existence of these differentreceptors, however, that allows drugs to cause very specific

therapeutic actions. For example, it is desirable to have drugsthat affect blood pressure without increasing heart rate, ordrugs that dilate bronchi without causing hypertension. At

this stage in the study of pharmacology, it is enough that thestudent memorizes the receptor types and actions, because

applications in the coming chapters will provide clarity tothis subject.

Given the opposite actions of the sympathetic and parasym-pathetic nervous systems, autonomic drugs are classified basedon one of four possible actions.

1. Stimulation of the sympathetic nervous system. These

drugs are called sympathomimetics or adrenergic agonistsand they produce the classic symptoms of the fight-or-

flight response.

2. Stimulation of the parasympathetic nervous system.

These drugs are called parasympathomimetics or mus-carinic agonists and they produce the characteristic symp-toms of the rest-and-digest response.

3. Inhibition of the sympathetic nervous system. These drugs

are called adrenergic antagonists or adrenergic blockersand they produce actions opposite to those of the sympa-thomimetics.


TABLE 16.3 Indications for Autonomic Agents

Autonomic Class Chapter Indication

Beta-a drene rgi c blockers 37 Angi na pe ctoris

Beta-adrenergic agonists

Anticholinergics

73 Asthma and COPD

Alpha-adrenergic blockers 72 Benign prostatic

hyperplasia

Beta-adrenergic blockers 39 Dysrhythmias

Anticholinergics 77 Eye examinations

Alpha-adrenergic blockers

Beta-adrenergic blockers

Cholinergic agonists

77 Glaucoma

Beta-adrenergic blockers 38 Heart failure

Alpha1-adrenergic blockers

Alpha2-adrenergic agonists

Beta-adrenergic blockers

36 Hypertension

Beta-a drene rgi c blockers 37 Myoc ardial infarc tion

Anticholinergics 25 Parkinsons disease

Anticholinergics 60 Peptic ulcer disease

Beta-adrenergic agonists 38 Shock

4. Inhibition of the parasympathetic nervous system. Thesedrugs are called anticholinergics, parasympatholytics, or

muscarinic blockers and they produce actions opposite tothose of the parasympathomimetics.

There is a method for simplifying the learning of auto-

nomic pharmacology. On examining the preceding four drugclasses, it is evident that only one group need be learned be-

cause the others are logical extensions of the first. If the fight-or-flight symptoms of the sympathomimetics are learned, the

other three groups are either the same or opposite. For exam-ple, both the sympathomimetics and the anticholinergics in-

crease heart rate and dilate the pupils. The other two groups,the parasympathomimetics and the adrenergic antagonists,have the opposite effects of slowing heart rate and constricting

the pupils. Although this is an oversimplification and excep-tions exist, it is a timesaving means of learning the basic ac-

tions and adverse effects of dozens of drugs affecting the ANS.It should be emphasized again that mastering the actions and

terminology of autonomic drugs early in the study of pharma-cology will reap rewards later in the course when these drugs

are applied to various systems. Table 16.3 shows the many ap-plications of autonomic drugs in medicine.


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References

Aronson, J.K. (2000). Where name and image

meetthe argument for adrenaline.

British Medical Journal, 320, 506509.

Bear, M. F., Connors, B. W., & Paradiso, M. A.

(2007). Neuroscience, exploring the brain

(3rd ed.). Philadelphia: Lippincott Williams

& Wilkins.

Krogh, D. (2009). Biology: A guide to the nat-

ural world(4th ed.). Upper Saddle River,

NJ: Benjamin Cummings.

Martini, F. H. (2009). Fundamentals of human

anatomy and physiology(8th ed.). San Fran-

cisco: Benjamin Cummings.

McCorry, L. K. (2007). Physiology of the au-

tonomic nervous system. American Jour-

nal of Pharmacy Education, 71(4), 78.

Nobelprize.org. (2008). The Nobel prize inphysiology or medicine 1936. Retrieved

May 9, 2008, from http://nobelprize.org/

nobel_prizes/medicine/laureates/1936/

Silverthorn, D. U. (2009). Human physiology:

An integrated approach (4th ed.). Upper

Saddle River, NJ: Pearson Education/

Benjamin Cummings.

Westfall, T. C., & Westfall, D. P. (2006). Neuro-

transmission: The autonomic and somatic

motor nervous systems. In L. L. Brunton,

J. S. Lazo, & K. L. Parker (Eds.), Goodman

and Gilmans: The pharmacological basis

of therapeutics (11th ed.). New York:

McGraw Hill.

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16.1 The two major subdivisions of the nervous system arethe central nervous system and the peripheral nervous

system.

16.2 The peripheral nervous system is divided into somaticand autonomic components.

16.3 The autonomic nervous system is divided into two

mostly opposing components: the sympathetic andparasympathetic branches.

16.4 Synaptic transmission allows information to be

communicated between two nerves or from nerves tomuscles or glands.

16.5 Autonomic drugs exert their effects by acting atsynapses.

16.6 Acetylcholine is the neurotransmitter released atcholinergic receptors, which may be nicotinic or

muscarinic.

16.7 Norepinephrine is the primary neurotransmitter releasedat adrenergic receptors,which may be alpha or beta.

16.8 The adrenal medulla is a specialized type of

sympathetic nervous system tissue that secretesepinephrine and norepinephrine.

16.9 The autonomic nervous system is influenced by higher

levels of control in the cerebral cortex and hypothalamus.

16.10 Autonomic drugs are classified by which receptors

they stimulate or block.

Key Concepts Summary

pharma autonomic

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