INTRODUCTION TO AUTONOMIC PHARMACOLOGY

V. John Massari, Ph.D. (C)

Introductory comments
A. "A clear understanding of the anatomy and physiology of the autonomic
nervous system is essential to a study of the pharmacology of the autonomic
drugs. The actions of an autonomic agent on various organs of the body can
often be predicted if the response to nerve impulses that reach the organs
are known."(G & G, 1997, p105).
1. We will begin therefore with a brief review of autonomic anatomy and
physiology, then progress to subsequent lectures on cholinergic and
adrenergic pharmacology.
II Anatomy of the Autonomic Nervous System
A. The classical definition of the ANS is that of Langley, who proposed that
the ANS "...consists of the nerve cells and nerve fibers, by means of
which efferent impulses pass to tissues other than... skeletal muscle . In
effect, therefore, the ANS has been traditionally viewed as a MOTOR system
which controls those visceral functions vital for the maintenance of
HOMEOSTASIS. In a more modern view, however, scientists have recognized
the importance of SENSORY nerves in the ANS. These sensory components
help to establish feedback loops essential for the smooth control of
autonomic functions. For example, the baro- and chemoreceptors of the
carotid sinus and carotid body are vital to the control of cardiac rate,
rhythm, and respiration through a feedback loop that enters the CNS.
The ANS is responsible for the regulation of all glandular secretions, smooth
muscles, and the extrinsic regulation of cardiac muscle, as well as various
metabolic processes (due to its control over the release of epinephrine,
insulin and glucagon).
B. There are two major divisions of the ANS ie sympathetic and
parasympathetic.
1. The anatomical distinction depends on the site in the CNS in which the
cell body of the preganglionic neuron is found, ie parasympathetic
preganglionic perikarya are found in the brain (Nn III, VII, IX, X, XI) and
sacral spinal cord, while sympathetic preganglionic perikarya are found in
the intermediolateral cell column of the thoracic and upper lumbar spinal
cord. (Cranio-sacral vs thoraco-lumbar).
2. All autonomic preganglionic neurons make synapses with clusters of
neurons outside the CNS which are contained
in ganglia. These postganglionic neurons then send an axon to
autonomically innervated organs.
3. Sympathetic ganglia are found close to the spinal column (paravertebral
ganglia) or further distally (prevertebral ganglia), ie usually (but not always,
ie terminal sympathetic ganglia in the urinary bladder and rectum) not close
to the organs innervated.
4. Parasympathetic ganglia are found close to the organ innervated and
often are contained within the innervated organ.
5. Activation of a sympathetic preganglionic neuron results in the activation
of many sympathetic postganglionic neurons because the sympathetic
preganglionic traverses multiple ganglia giving off multiple synapses.
6. Parasympathetic preganglionics usually activate only a few postganglionic
neurons in a single or very few ganglia.
C. Although the ANS was defined by Langley as being composed exclusively
of efferent neurons, most authors today also view visceral afferent neurons
as being a component of the ANS.
1. The perikarya of visceral afferents are found in the dorsal root ganglia, or
in the sensory ganglia of certain cranial nerves. Of particular importance for
example are the visceral afferent terminals of neurons originating in the
petrosal ganglion (IX) which innervate special chemoreceptors and
baroreceptors of the carotid body and carotid sinus respectively. These
visceral afferents monitor blood pressure and oxygen levels and participate
in important cardiorespiratory reflexes.

III Highlights from the history of neurohumoral transmission in the

autonomic nervous system

A. Lewandowsky (1898) and Langley (1901) independently noted the

similarity between the effects of injection of extracts of the adrenal gland
and stimulation of sympathetic nerves.
B. T.R. Elliott (1905) postulated that the sympathetic nerves release minute
amounts of an epinephrine-like substance.
C. Cannon and collaborators (1921) showed actual release of a epinephrine
like compound upon stimulation of a sympathetic nerve.
D. von Euler (1946) showed that the substance released was actually nor-
epinephrine.
E. Langley (1905) suggested that effector cells have excitatory and
inhibitory "receptive substances", and that the response to epinephrine
depended upon which type of substance was present.
F. Dixon (1907) was so impressed by the similarity between the effects of
muscarine and the effects of stimulating the vagus nerve that he proposed
that the vagus released a muscarine-like substance.
G. Otto Loewi (1921) provided the first proof of the chemical mediation of
synaptic transmission with his studies on the frog heart and its vagal
innervation in vitro. In 1926 Loewi and Navratil provided evidence that
"vagusstuff" was actually acetylcholine.
H. Neurotransmitters of the ANS
1. Amost All sympathetic postganglionic neurons release NE.
a. The sympathetic postganglionic innervation of the sweat glands is an
exception to this rule, since it releases ACh.
2. All other sympathetic and parasympathetic efferent neurons release ACh
3. The vast majority of neurons which have been examined in both the ANS
and CNS appear to contain more than one neurotransmitter. Almost
all sympathetic postganglionic neurons innervating the vasculature of the
gut and hindlimbs for example contain NE and neuropeptide Y. On the
other hand, the sympathetic postganglionic neurons innervating the sweat
glands release ACh (not the expected NE), and also contain atleast two
other peptides, ie Calcitonin Gene Related Polypeptide (CGRP), and
Vasoactive Intestinal Polypeptide (VIP). Many postganglionic
parasympathetic neurons contain ACh and VIP. The amount of release of
these peptides which are co-localized with classical neurotransmitters
appears to be dependent upon the rate of firing of the neuron. In
sympathetic nerve terminals innervating vascular smooth muscle, for
example, cerebral, coronary, renal, skeletal muscles) mild degrees of
stimulation or reflex activation cause the release of NE alone. This results in
a brief period of vasoconstriction. On the other hand, intense stimulation of
these nerves or a profound stress (intense reflex) causes the release of both
NE and NPY, and leads to aprolonged period of vasoconstriction. In the
presence of alpha 1 antagonists, the brief vasoconstrictor effects of NE are
blocked, but intense stimulation still causes prolonged vasoconstriction
which is NPY-induced. This latter effect can be blocked by the addition of
an NPY receptor antagonist. The development of NPY receptor antagonists
has recently undergone a considerable breakthrough, (Because NPY
profoundly stimulates feeding) and you will doubtless be seeing such drugs
in the future.
4. Visceral Afferents associated with the sympathetic nervous system are
located in the dorsal root ganglia. Tlhese ganglia are arranged segmentally,
and project to both sympathetic ganglia and peripheral targets such as the
heart. Many visceral afferents probably release substance P or glutamate,
however numerous neuropeptides including angiotensin, bombesin, CGRP,
VIP, enkephalin, oxytocin, and somatostatin have been identified in the
perikarya of dorsal root ganglion afferents.
Visceral afferents associated with the parasympathetic nervous system are
found most commonly in the nodose ganglia and travel widely through the
body via branches of the vagus nerve. They have also been found in
the sacral dorsal root ganglia. They also have been shown to contain a wide
varierty of neuropeptides.
5. Terminology.....
a. Adrenergic, cholinergic
b. Adrenoceptive, cholinoceptive
c. Sympathomimetic, parasympathomimetic, cholinomimetic
d. Sympatholytic, parasympatholytic
I. Receptors of the ANS
1. All autonomic preganglionic neurons primarily activate nicotinic receptors
(Nn).
a. A somewhat different nicotinic receptor is also found at the skeletal
neuromuscular junction (Nm).
b. Molecular cloning studies have indicated the presence of atleast a dozen
subtypes of Nicotinic receptor, especially in the CNS. More in the future...
2. Postganglionic parasympathetic neurons activate muscarinic receptors.
M1 receptors are found in autonomic ganglia (even though the major effect
of ACh in ganglia is through Nicotinic (Nn) receptors), and some secretory
glands. M2 Receptors are found in the heart. M3 receptors are found on
many smooth muscles and glands. All are found in the CNS.
a. Molecular cloning studies have indicated the presence of atleast 5
subtypes of Muscarinic receptor. More in the future...
3. Postganglionic sympathetic neurons activate adrenergic receptors. There
are atleast 6 subtypes of alpha receptor, and three beta receptors. Their
widespread location and functions are described in detail in the texts
suggested for the course.
4. Presynaptic Receptors
a. The best characterized presynaptic receptor, the alpha 2 receptor, is
found on adrenergic nerve terminals. Activation of this receptor results in
the inhibition of the release of NE. It also inhibits the release of NPY. Beta 2
receptors are also found on noradrenergic nerve terminals, and the
activation of these Beta 2 receptors facilitates the release of NE and NPY.
5. Lots more about subtypes and characteristics of receptors later... in the
meantime be aware that you will be expected to know which receptors are
found on any given organ in the body, and understand the physiological
effect of its activation or inhibition. ie G & G (1997, pp. 110-111, Table 6-
1). Pay particular attention to the receptors of the eye, heart, blood
vessels, lung, intestines, bladder, sex organs, adrenal medulla, liver,
pancreas, fat cells, salivary glands, & lacrimal glands. "A clear
understanding of the response of the various effector organs to autonomic
nerve impulses makes it possible to anticipate the actions of drugs that
mimic or inhibit the actions of these drugs"(G & G, 1990, p88).
6. As an example of autonomic innervation, describe the innervation of
the heart, including pertinent afferents (dorsal root ganglia for pain, and
petrosal ganglia for the baroreceptor reflex); as well as the appropriate
parasympathetic efferents via the vagus nerve and the SA, AV, and CV
ganglia; and the sympathetic efferents via the nodose ganglion
(paraverterbral ganglion) also projecting to various regions of the heart.
Include a discussion of the transmitters, and receptors found in these
neurons.

IV Autonomic Physiology

A. In general the ANS regulates the activities of structures that are not
under voluntary control and function below the level of consciousness. ie
respiration, circulation, digestion, body temperature, metabolism,
sweating, and secretions of certain endocrine glands. As Claude Bernard
(1878) and Cannon (1929) have emphasized, the ANS serves to maintain the
constancy of the internal environment, that is homeostasis.
1. The involuntary nature of the ANS should not be overemphasized, ie
voluntary control of bladder and bowel by all, while some can also
voluntarily regulate heart rate and blood pressure.
B. In most instances the SNS and PNS act as physiological antagonists. If one
system inhibits a particular function, the other will augment it. Most viscera
are innervated by both divisions of the ANS, and the level of activity of any
organ reflects a summation of the influences of both the SNS and PNS.
1. In the heart and intestine SNS and PNS effects are antagonistic through an
action on the same cells.
2. Conversely, in the eye, SNS activation opens pupil by contracting radial
muscles, while PNS activation closes pupil by contracting the circular
muscles. In effect physiological antagonism via an effect on different cells.
3. Sometimes, PNS and SNS effects are integrated and not antagonistic; ie
PNS activation gives copious watery salivary secretion, while SNS activation
gives thick viscous secretion. PNS activation gives erection in male, while
SNS activation leads to ejaculation.
4. Autonomic innervation of most blood vessels is almost completely through
the SNS. ie no antagonism present here (exceptions include cerebral and
coronary arteries).
C. Physiological characteristics of the SNS
1. It is normally active continuously. Its activity varies from moment to
moment and from organ to organ.
2. The sympathoadrenal system can fire as a unit in order to facilitate "fight
or flight".
a. This results in increased heart rate, increased blood pressure, blood flow
shifts from the skin to the skeletal muscles, blood glucose rises, the
bronchioles and pupil dilate etc.
3. In the absence of stress, and in a controlled environment, the SNS is not
necessary for life.
D. Physiological characteristics of the PNS.
1. It is organized mainly for discrete and localized, not global discharge as a
unit.
2. Its main functions are conservation of energy and maintenance of organ
function during periods of minimal activity.
a. This results in decreased heart rate, decreased blood pressure, increased
gastrointestinal tract motility and secretions, protection of the retina from
excessive light, and emptying of the bladder and rectum.

V. Steps involved in neurohumoral transmission

A. Initiation of an action potential and axonal conduction

1. At rest, the interior of a typical axon is 70 mV negative with respect to
the interior. There is a high concentration of K intracellularly, and low Na
and Cl. The opposite is found extracellularly. These ionic gradients are
maintained by an energy dependent active transport pump. In response to
depolarization to threshold levels, there is a rapid increase in the
permeability of the neuronal membrane to Na
and the whole membrane is rapidly depolarized. Subsequently there is a
delayed opening of K channels which results in the outward movement of K
and repolarization of the membrane. During this process ion currents are
produced which depolarize adjacent regions of neuronal membrane, and
hence the action potential is propagated.
2. The puffer fish poison, tetrodotoxin, and the shellfish poison, saxitoxin
selectively block axonal conduction by preventing the increase in
permeability to Na associated with the rising phase of the action potential.
3. Batrachotoxin, a steroidal alkaloid secreted by a South American frog,
causes a lasting increase in Na permeability, and hence a depolarization
blockade.
B. Arrival of an action potential at the nerve terminal results in the release
of the neurotransmitter.
1. Classical neurotransmitters are synthesized in the nerve terminal and
stored within synaptic vesicles. Arrival of an action potential in the nerve
terminal results in the influx of Ca which promotes the fusion of synaptic
vesicles with adjacent axoplasmic membrane. The contents of the vesicle
are then discharged into the synaptic cleft. Adjacent sections of membrane
are pinched off to form new vesicles. Neuropeptides are synthesized in the
perikaryon of the neuron, and must be transported to the nerve terminal
before they can be released.
C. Released neurotransmitters diffuse across the synaptic cleft, interact
with postjunctional receptors, and produce a postjunctional potential
(either an EPSP, or an IPSP).
D. Termination of the effect of the released neurotransmitter.
1. At cholinoceptive sites, this occurs by metabolic inactivation by an
exceedingly efficient enzyme, acetylcholinesterase.
2. At adrenoceptive sites, the major mechanism is inactivation by reuptake
of the neurotransmitter into the presynaptic nerve terminal, although some
metabolic inactivation also occurs.
3. Diffusion also occurs to some extent in both cholinergic and adrenergic
receptor sites.
4. Peptides are hydrolyzed by peptidases and dissipated by diffusion.
Reuptake has as yet not been demonstrated.

VI Mechanisms of action of drugs that influence the ANS

A. Interference with synthesis of the transmitter

1. Cholinergic
a. Hemicholinium causes blockade of choline uptake with consequent
depletion of ACh.
2. Adrenergic
a. alpha methyl tyrosine inhibits TH, therefore decreases NE.
B. Metabolic transformation by the same pathway as the precursor of the
neurotransmitter.
1. Cholinergic-NO EXAMPLE
2. Adrenergic
a. Methyldopa results in the formation of the false transmitter alphamethyl
norepinephrine.
C. Blockade of reuptake of released transmitter into the cytoplasm of the
presynaptic nerve terminal.
1. Cholinergic-NO EXAMPLE
2. Adrenergic
a. Cocaine, tricyclic antidepressants cause an accumulation of NE in the
synaptic cleft.
D. Blockade of reuptake from the cytoplasm into the synaptic vesicles and of
storage capacity of the synaptic vesicles.
1. Cholinergic-NO EXAMPLE
2. Adrenergic
a. Reserpine causes destruction of NE which is released from vesicles by
intracytoplasmic MAO
E. Release of transmitter from the axon terminal
1. Cholinergic
a. Black widow spider venom
2. Adrenergic
a. Amphetamine, tyramine
F. Prevention of transmitter release
1. Cholinergic
a. Botulinus toxin
2. Adrenergic
a. Bretylium, guanethidine
G. Mimickry of the endogenous transmitter postsynaptically
1. Cholinergic
a. Muscarinic- methacholine
b. Nicotinic- nicotine
2. Adrenergic
a. Alpha 1- phenylephrine
b. Alpha 2- clonidine
c. Beta - isoproterenol
d. Beta 1- Dobutamine
e. Beta 2- Terbutaline
H. Blockade of the endogenous transmitter postsynaptically
1. Cholinergic
a. Muscarinic- Atropine
b. Nicotinic, Nm- Tubocurarine (neuromuscular blockade)
c. Nicotinic, Nn- Trimethaphan (Ganglionic blockade)
2. Adrenergic
a. Alpha- phenoxybenzamine
b. Beta- propranolol
c. Beta 1- metoprolol
I. Inhibition of enzymatic degradation
1. Cholinergic
a. Anticholinesterases,ie physostigmine, neostigmine, DFP
2. Adrenergic
a. MAO inhibitors, ie pargyline