ANS Physiology and Pharmacology Review

ANS Physiology and Pharmacology
Introduction | Review of the
Autonomic Nervous System
Prepared and presented by:
Marc Imhotep Cray, M.D.
Basic Medical Sciences Teacher
http://www.imhotepvirtualmedsch.com/
From Henry Gray (1821–1865)
Anatomy of the Human Body 1918

2
*Suggested Review Books & Resources
*e-Books & learning tools available to enrolled learners at thePOINT
If you are using a different review book, the chapters may
be organized differently, but the material covered is
approximately the same. Simply find the corresponding
material in your book for each lecture.
Companion Notes:
ANS Summary Notes
Formative Assessment
Clinical Correlate:
e-Medicine Article
Epilepsy and the Autonomic
Nervous System
 Review Test for
Autonomic Nervous
System answers and
explanations
 Review Test for
Autonomic Nervous
System

Overall Goal of Reviews
“ Deconstruction, Reconstruction,
Integration and Relationships”
3
The nineteenth-century physiologist
Claude Bernard put it this way:
“After carrying out an analysis of
phenomena, we must . . . always
reconstruct our physiological
synthesis, so as to see the joint
action of all the parts we have
isolated. . . .”
http://en.wikipedia.org/wiki/Claude_Bernard

Topics Outline
4
 Homeostasis
 Basic Neuroanatomy and Neurophysiology of ANS
 Neurotransmitters
 Receptors
 Receptor-Ligand Interactions & Signal Transduction
 Autonomic and Somatic Pharmacology Terminology

Review Objectives
5
After presentation you should be able to:
 Describe the two divisions of the ANS and the main functions and
effects of each division.
 Explain how sympathetic and parasympathetic nerves interact
with each other to regulate organ function (maintain homeostasis)
 Describe the fight or flight reaction and explain how sympathetic
activation affects the activities of the different organs
 List the main organ effects caused by parasympathetic stimulation
 Describe the different autonomic receptors that are stimulated by
acetylcholine, norepinephrine, and epinephrine
 Describe signaling mechanisms and pharmacology of ANS
receptor subtypes

Autonomic Nervous System (ANS)
6
The autonomic nervous system (ANS) is the
part of the nervous system that is responsible
for homeostasis
Except for skeletal muscle, which gets its
innervation from the somatomotor nervous
system, innervation to all other organs is
supplied by the ANS

Autonomic Nervous System
vs. Endocrine System in Homeostasis
7
Autonomic nervous system (ANS) is the moment-to-
moment regulator of the internal environment, regulating
specific functions that occur without conscious control:
 respiration,
 circulation,
 digestion,
 body temperature,
 metabolism,
 sweating, secretions of certain endocrine glands
Endocrine system, in contrast, provides slower, more
generalized regulation by secreting hormones into the
systemic circulation to act at distant, widespread sites over
periods of minutes to hours to days

ANS and Endocrine System
[common properties]
8
 high-level integration in the brain
 ability to influence processes in distant
regions of body
 extensive use of negative feedback
 maintain homeostasis
 both systems use chemicals for
transmission of information

9
 Referring to animal systems,
pioneering 20th century
physiologist Walter Cannon
coined the word homeostasis
in 1926
 “Coordinated physiological reactions
which maintain most of the steady
states in the body are so complex,
and are so peculiar to the living
organism, that it was suggested
(Cannon, 1929) that a specific
designation for these states be
employed – homeostasis”
Courtesy National Library of Medicine (NLM)
Walter Cannon coined the word homeostasis
Cannon, WB, Organization for Physiological
Homeostasis/PDF
Physiological Rev July 1, 1929 9:399-431
http://en.citizendium.org/wiki/File:William_cannon.jpg
#Licensing
Also see:
Cray MI. Walter Cannon, Homeostasis
and the Physiological Response to
Stress, A Web Interactive PowerPoint
Presentation

10
Homeostasis (1)
 The physiologic process of maintaining
an internal environment (ECF
environment) compatible with normal
health
 Autonomic reflexes maintain set points
and modulate organ system functions
via negative feedback in pursuit of
homeostasis

Homeostasis (2)
11
A dynamic steady state of the constituents in the
internal environment (ECF) that surrounds and
exchanges materials with the cells
Factors homeostatically maintained:
(Controlled Variables)
 Concentration of nutrient molecules
 Concentration of O2 and CO2
 Concentration of waste products
 pH
 Concentration of water, salts, and other electrolytes
 Temperature
 Volume and pressure

Marc Imhotep Cray, M.D. 12
Nervous Endocrine
WirelessWired
Hormones
Short Distance Long Distance
Closeness Receptor Specificity
Rapid Onset Delayed Onset
Short Duration Prolonged Duration
Rapid Response Regulation
versus
Neurotransmitters Hormones
Short Distance Long Distance
Homeostasis (3)

13
ERROR
SIGNAL
COMPARATOR
SET
POINT
+
-
CONTROLLED
VARIABLE
(SEE NEXT SLIDE)
SENSOR
EFFECTOR
-NEGATIVE
FEEDBACK
Components of a negative
feedback control system
Negative feedback:
Initiation of responses
that counter deviations of
controlled variables
from their normal range
Measures control variable
Recognizes deviation of
normal set point value
Redrawn after: Kibble JD, Halsey CR, Homeostasis: In Medical
Physiology -The Big Picture; McGraw-Hill ,2009:2
Attempt to restore
set point value
Important variable maintained
within a normal range Effector opposes stimulus
stretch receptors, chemo-,
baro-, osmo-, and thermo-
receptors etc.

14
Controlled Variable Typical Set Point Value
(Arterial Blood Sample)
Arterial O2 partial pressure
Arterial CO2 partial pressure
Arterial blood pH
Glucose
Core body temperature
Serum Na+
Serum K+
Serum Ca2+
Mean arterial blood pressure
Glomerular filtration rate
100 mm Hg
40 mm Hg
pH 7.4
90 mg/dL (5 mM)
98.4°F (37°C)
140 mEq/L
4.0 mEq/L
4.5 mEq/L
90 mm Hg
120 mL /min
Examples of Physiologic
Controlled Variables
Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -
The Big Picture; McGraw-Hill ,2009:3

Some Important Negative Feedback
Control Systems
15
From Carroll RG. Elsevier’s Integrated Physiology. Mosby, Inc. 2007; TABLE 1-3, Pg. 5

16
ERROR
SIGNAL
COMPARATOR
SET
POINT
+
Mean Arterial Blood
Pressure (MAP)
SENSOR
EFFECTOR
-NEGATIVE
FEEDBACK
Example: Baroreceptor Reflex
control of blood pressure
stretch receptors in
Aortic arch and
Carotid sinus
N 95
mm Hg
CNS|
Medulla Oblongata
cardiac
contractility,
vascular tone,
urinary fluid
excretion
Receptors:
• Aortic arch transmits via vagus nerve to solitary nucleus of medulla (responds
only to BP)
• Carotid sinus transmits via glossopharyngeal nerve to solitary nucleus of
medulla (responds to and in BP)

Baroreceptors(2)
17
Hypotension - arterial pressure stretch afferent baroreceptor firing
efferent sympathetic firing and efferent parasympathetic stimulation
vasoconstriction, HR, contractility, B P
Important in the response to severe hemorrhage
• Carotid massage - pressure on carotid artery stretch afferent
baroreceptor firing H R
Can by tried for Tachycardia (SVT)
• Contributes to Cushing reaction (triad of hypertension, bradycardia,
and respiratory depression) intracranial pressure constricts arterioles
cerebral ischemia and reflex sympathetic increase in perfusion pressure
( hypertension) stretch reflex baroreceptor induced-bradycardia
Also see next 2 Slides

18
From http://www.zuniv.net/physiology/book/chapter6.html

19
Mean Arterial Pressure Control and
Autonomic & Hormonal Feedback Loops
Katzung & Trevor. Pharmacology Examination & Board Review
10th Ed. M-H 2014

Organization of the Nervous System
BRAIN & SPINAL CORD CENTRAL
NERVOUS
SYSTEM (CNS)
PERIPHERAL
NERVOUS
SYSTEM (PNS)
AFFERENT
(Sensory)
NERVES
EFFERENT
(Motor)
NERVES
EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC
EFFECTOR
ORGANS
SKELETAL
MUSCLES
SMOOTH MUSCLE,
CARDIAC MUSCLES
AND GLANDS
VOLUNTARY
Monosynaptic
INVOLUNTARY
Pre & Post Ganglionic Fiber

21
Peripheral Nervous System (PNS)
Peripheral nerves contain both motor and sensory
neurons
Motor neurons:
somatic innervate skeletal muscles
autonomic innervate smooth muscle, cardiac muscle,
and glands (autonomic motor neurons)
Sensory neurons are not subdivided into somatic and
autonomic b/c there is overlap in function (input can be
from either somatic or ANS)
e.g., pain receptors can stimulate both somatic
(withdrawal reflex) and autonomic reflexes (increased
heart rate)

22
Generic Neuron Anatomy
From: http://en.wikipedia.org/wiki/Neuron
Basic structural unit of nervous system >>> neuron

23
Autonomic (Visceral) Reflex
“Functional unit of the ANS”
 Afferent fibers from periphery to CNS
 CNS integration
 Cortex
 Thalamus
 Hypothalamus
 Medulla
 Spinal cord
 Efferent fibers from CNS to periphery
See Baroreflex pdf

Sympathetic Nervous System Wiring
24
Gray ramus
Sympathetic trunk
White ramus
Intermediolateral cell column
(IML)
Dorsal root
ganglion
See: ANS Summary Notes

25
organ receptors ( in the viscus ) >>>> sensory (afferent ) neuron >>>>CNS
lateral horn cell of spinal cord >>>> motor (efferent) neuron ( two neurons: pre
& post ganglionic ) >>>> effector organ ( smooth, cardiac muscle or gland )
From: http://www.alexmed.edu.eg/forums/showthread.php?2116-Today-s-lecture-gt-gt-gt-BY-M..S
Functional Unit of ANS >>> Reflex Arc
Illustration
Afferent fibers from
periphery to CNS
CNS integration
Spinal cord
Medulla
Hypothalamus
Thalamus
Cortex
Efferent fibers from
CNS to periphery
Effector response

26
Neurotransmitters
 Chemicals synthesized and stored in
neurons
 Liberated from axon terminus in response
to action potentials
 Interact with specialized receptors
 Evoke responses in the innervated tissues
See: IVMS Neurotransmitters Notes

ANS Neurotransmitters
27
Class
Small molecule
Transmitters
Catecholamines
Chemical
Acetylcholine
Dopamine
Norepinephrine
Synthesis
Choline + acetyl
CoA, via the
enzyme choline
Acetyltransferase
From the amino
acid tyrosine via
the enzyme
Tyrosine
hydroxylase
in the
catecholamine
pathway
From dopamine
in the
catecholamine
pathway
Postsynaptic
Receptors
Nicotinic
(cation channel)
Muscarinic
(G-protein–
coupled)
D1 (stimulatory
G- protein–
coupled)
D2 (inhibitory
G-protein–
coupled)
α & β Adrenergic
receptors
Signal
Termination
Extracellular
hydrolysis by
Acetylcholinestrase
Reuptake
Reuptake or
breakdown via the
enzymes
monoamine oxidase
and catechol–O-
methyltransferase
Functions
ANS
Movement
control
Cognition
ANS
Movement
control
General
affect
ANS
Alertness
General
affect
N.B Epinephrine is a catecholamine released upon stimulation of SANS, produced in
the adrenal medulla. It is a neurohormone, not an ANS neurotransmitter

28
Efferent Autonomic Nerves
general arrangement
 Innervation of smooth muscle, cardiac
muscle, and glands
 Preganglionic neuron
 Peripheral ganglion - axodendritic synapse
 Postganglionic neuron(s)
 Effector organ(s)
Pre
Ganglion
Post
Effector
organ

29
Anatomic Divisions of the ANS
 Parasympathetic (PANS) (CN3,7,9,10) & (S2-S4)
 Preganglionic axons originate in brain, and sacral spinal cord
 Peripheral ganglia are near, often within* the effector organs
 Ratio of postganglionic-to-preganglionic axons is small,
resulting in discrete responses
 Sympathetic (SANS) T1-L2/L3
 Preganglionic axons originate in the thoracic and lumbar cord
 Peripheral ganglia are distant from the effector organs
 Ratio of post-to-preganglionic axons is large, resulting in
widely distributed responses
 Enteric Nervous System (ENS) (Discussed in GI)
Has been described as a "second brain" for several reasons:
 operate autonomous of SANS & PANS
 Vertebrate studies show when the vagus nerve is severed,
ENS continues to function
* Exceptions are the four paired parasympathetic ganglia of the head and neck

30
Schematized Anatomic Comparison of
PANS & SANS (1) (click to expand)

31
Schematized Anatomic Comparison of
PANS & SANS (2)
Pre
Ganglion Effector
organ
PostThoracic or lumbar
cord
Pre
Ganglion Effector
organ
Post
Cranial or sacral cord
Parasympathetic
Sympathetic
Effectors: cardiac muscle, smooth mm, vascular endothelium,
exocrine glands, and presynaptic nerve terminals
ANS functions:
 circulation
 digestion
 respiration
 temperature
 sweating
 metabolism
 some endocrine
gland secretions

32
Cranial Nerve Parasympathetic
Innervations

33
Somatic Nervous System
(included for comparison)
 Efferent innervation of skeletal muscle
 No peripheral ganglia
 Rapid transmission, discrete control of
motor units
 Voluntary
Any spinal
segment
Motor neuron
Striated muscle
Myelinated with a high
conduction velocity
In contrast
Postganglionic neurons of
ANS are unmyelinated with a low
conduction velocity

34
Neurochemical Transmission in
Peripheral Nervous System (PNS)
 Cholinergic nerves
 Acetylcholine is the neurotransmitter
 Locations
 Preganglionic neurons to all ganglia
 Postganglionic, parasympathetic neurons
 “Preganglionic” fibers to adrenal medulla
 Postganglionic, sympathetic neurons to sweat
glands in most species
 Somatic motor neurons

35
Cholinergic
Neurotransmission
Pre
Ganglion
Effector
organs
cord
Pre
Ganglion Effector
organ
Post
Parasympathetic
Sympathetic Denotes ACh
Denotes ACh

36
Adrenergic
Neurotransmission
 Adrenergic nerves
 Norepinephrine is the neurotransmitter
 Locations
 Postganglionic, sympathetic axons
Pre
Ganglion
Effector
organs
cord
Sympathetic Denotes Norepinephrine
Denotes ACh

37
Adrenal Medulla
 Presynaptic nerves are cholinergic
 Medullary cells (*Chromaffin cells) synthesize
and release two, related catecholamines into
the systemic circulation
 Epinephrine (adrenaline)
 Norepinephrine
 Epi and NE stimulate adrenergic sites
*They release catecholamines: ~80% Epinephrine and ~20%
Norepinephrine into systemic circulation for systemic effects on multiple
organs (similarly to secretory neurons of the hypothalamus), can also send
paracrine signals, hence they are called neuroendocrine cells

38
Adrenal Medulla(2)
Cholinergic neuron
Adrenal medulla
Epi and NE released
into systemic circulation
Denotes ACh
 Chromaffin cells are neuroendocrine cells found in the
medulla of the adrenal glands
 They are in close proximity to pre-synaptic
sympathetic ganglia of the sympathetic nervous
system, with which they communicate
 structurally they are similar to post-synaptic
sympathetic neurons

39
Summary of Actions of SANS and PANS (1)
SYMATHETIC
Fright-Fight-or-Flight
widely distributed responses
PARASYMPATHETIC
Rest-Relax-Restoration
discrete responses
 increase in heart rate  decrease in heart rate
 decrease in gastric motility  increase in gastric motility
 decrease secretion of salivary
and digestive glands
 increase in secretion of salivary
and digestive glands
 dilation of pupils  constriction of pupils
 ejaculation  penile erection
 vasoconstriction
 contraction of smooth muscle in
walls of bladder
 dilation of bronchioles
 increased secretion of sweat
glands
Of note: Cannon’s emergency reaction:
An immediate sympathetic response to life-
threatening situations with both SANS and
PANS overactivity. The PANS phenomenon
includes vagal cardiac arrest with involuntary
defecation and urination

40
Summary of Actions of SANS and PANS (2)
Illustration from: Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, Autonomic
Sympathetic Nervous System, In Case Files: Pharmacology;
McGraw-Hill 2 ed. 2008:16
(click to expand)
Sympathetic
Responses
 heart rate increases
 blood pressure
increases
 blood is shunted
from skin & viscera
to skeletal muscles
 blood glucose
increase
 bronchioles dilate
 pupils dilate
Parasympathetic
Responses
 slows heart rate
 protects retina from
excessive light (near
 lowers blood pressure
 empties the bowel
and bladder
 increases
gastrointestinal
motility
 promotes absorption
of nutrients

41
ACh Synthesis, Release, and Fate (1)
 Synthesized from choline and acetyl-CoA
 Released in response to neuronal depolarization
(action potential)
 Calcium enters the nerve cell
 Transmitter vesicles fuse with cell membrane
 ACh released by exocytosis
 Inactivated by acetylcholinesterase (AChE)

ACh Synthesis, Release, and Fate (2)
42
 CHT - Choline transporter
 ChAT - Choline acetyl transferase
 VAT - Vesicle-associated
transporter
 VAMPs - Vesicle-associated
membrance proteins
 SNAP’s - Synaptosome-
associated proteins

Cholinergic Neuron Pharmacology
43
From Le T., Bhushan V.
First Aid 2015. M-H 2015; Pg. 249

44
NE Synthesis, Release, and Fate (1)
 Catecholamine - synthesized in a multistep
pathway starting with tyrosine as the rate limiting
step
 Released by exocytosis in response to axonal
depolarization
 Duration of activity primarily limited by neuronal
reuptake
 Minor metabolism by synaptic monoamine oxidase
(MAO) and catechol-O-methyl transferase (COMT)

NE Synthesis, Release, and Fate (2)
45
VMAT-Vesicular Monoamine
transporter

Adrenergic Neuron Pharmacology
46
From Le T., Bhushan V.
First Aid 2015. M-H 2015; Pg. 249

47
Receptors*
 Specialized proteins that are binding sites for
neurotransmitters and hormones
 Postsynaptic cell membranes
(neurotransmitters)
 Cell nucleus (steroid hormones)
 Linked to one of many signal transduction
mechanisms
“Receptor” (According to Rang & Dale Pharmacology):
A target or binding protein for a small molecule (ligand),
which acts as an agonist or antagonist.
Rang HP, Maureen M. Dale MM, Ritter JM , Flower J Henderson G . Rang & Dale's
Pharmacology, Churchill Livingstone; 7th edition 2011
*“not to be confuse with other drug targets such as enzymes etc.”

48
Ligand-Receptor Interactions
 Complementary conformations in 3 dimensions
 Similar to enzyme-substrate interactions
 Physiologic interactions are weak attractions
 H-bonding, van der Waal’s forces
 Drug mechanisms
 Agonists - bind and activate receptors
 Antagonists - bind but DO NOT activate receptors
"Receptor" according to IUPHAR:
(International Union of Basic and Clinical Pharmacology)
A cellular macromolecule, or an assembly of macromolecules, that is
concerned directly and specifically in chemical signaling between and within
cells. Combination of a hormone, neurotransmitter, drug, or intracellular
messenger with its receptor(s) initiates a change in cell function.
See: Basic Receptor Pharmacology/ PDF

Steps in Signal Transduction Process
See: G-protein Signal Transduction (video animations)
49
 There are three general classes of signal transducing receptors:
 G-proteins are one and are referred to as serpentine receptors
Also see:
http://themedicalbiochemistrypage.org/s
ignal-transduction.html
Binding of the neurotransmitter,
hormone or drug to receptor>
signaling of G-protein> enzyme
activation> production of a
second-messenger> protein
kinase activation >
phosphorylation of specific
proteins (effect)> termination

50
The neurohormone epinephrine and its receptor (pink) is used in tis example:
The activated receptor releases the Gs alpha protein (tan) from the beta and gamma
subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha
protein in turn activates adenylyl cyclase (purple) that converts ATP into the second
messenger cAMP From: http://en.wikipedia.org/wiki/Signal_transduction
Mechanism of cAMP dependent signaling
GPCR structure & function (simplified)
G-Protein Coupled Receptor
Binding of the
neurotransmitter, hormone
or drug to receptor>
signaling of G-protein>
enzyme activation>
production of a second-
messenger> protein kinase
activation
>phosphorylation of
specific proteins
(effect)>termination

51
3 major G-Protein class subtypes: Compose the largest class of *receptors:
1) Gq Messenger Pathway: (used by H1, Alpha 1, V1, M1, M3 Receptors)
(HAVM1&3)
Receptor → Gq → Phospholipase C that turns Lipid into PIP2 that is split into IP3
(Increases IC Calcium) and DAG (Activates Protein Kinase C - PKC)
2) Gαs Messenger Pathway: (used by Beta 1, Beta 2, D1, H2, V2 Receptors)
(1D2BHV)
Receptor → Gαs → Adenylyl Cyclase (AC) that turns ATP into cAMP that activates
Protein Kinase A - PKA
3) Gαi Messenger Pathway: (used by M2, Alpha 2, and D2 Receptors)
(2MAD)
Receptor → Gαi that inhibits Adenylyl Cyclase that in turn decreases cAMP , thus
making less active Protein Kinase A
G Protein Messenger Pathways
* Remember there are four major classes of ligand–receptor interactions
(more on this in Pharm.)

52
Sympathetic (Adrenergic-Noradrenergic-R)
Alpha 1 Receptor - q - Vasoconstriction and Pupillary Dilator Muscle
contraction (Mydriasis), and increased Intestinal Sphincters and
Bladder Sphincter contraction
 Via PLC-IP3-DAG
Alpha 2 Receptor - i - Decreased Sympathetic Outflow, and
decreased Insulin release
 Via Inhib. AC-cAMP
Beta 1 Receptor - s - Increase Heart Rate, Increase Contractility,
Increase Renin release, and increase Lipolysis
 Via Stim. AC-cAMP
Beta 2 Receptor - s - Vasodilation, Bronchodilation, Increase Heart
Rate, Increase Contractility, Increase Lipolysis, Increase Insulin
release, Decrease Uterine Muscle tone
Receptor G-Protein Class Major Function
G-protein-linked
2nd messenger mechanisms (1)

53
G-protein-linked
Parasympathetic (Ach-Cholinergic-R)
M1 Receptor - q - found in CNS and Enteric Nervous System
M2 Receptor - i - Decrease Heart Rate and Contractility of Atria
M3 Receptor - q - Increase Exocrine Gland secretions (Sweat
Gland, Parietal Cells), Increase Gut Peristalsis, Increase Bladder
Contraction, Bronchoconstriction, Increase Pupillary Sphincter
Muscle Contraction (Miosis), Ciliary Muscle Contraction
(Accommodation)
N.B. Nicotinic ACh receptors are ligand-gated Na+/K+ channels

54
G-protein-linked
 Dopamine:
D1 Receptor - s - Relax Renal Vascular Smooth Muscle
D2 Receptor - i - Modulate Neurotransmitter release (especially in
Brain)
(For sake of completeness)
 Histamine:
H1 Receptor - q - Increase Mucus production in Nose and Bronchi,
Bronchiole Constriction, Pruritis, Pain
H2 Receptor - s - Increase Gastric Acid secretion (Parietal Cells)
 Vasopressin:
V1 Receptor - q - Increase Vasoconstriction
V2 Receptor - s - Increase Water Permeability and Water
Reabsorption in Collecting Tubule (V2 in 2 Kidneys)

55
Cholinergic Receptors
 Activated by ACh and cholinergic drugs
 Anatomic distribution
 Postganglionic, parasympathetic neuroeffector
junctions
 All autonomic ganglia, whether
parasympathetic or sympathetic
 Somatic neuromuscular junctions

56
Schematic of Cholinergic Receptor Locations
Pre
Ganglion
Effector
organs
cord
Pre
Ganglion Effector
organ
Post
Parasympathetic
Sympathetic Denotes ACh receptors
Denotes ACh receptors

57
Cholinergic Receptor Subtypes
 Muscarinic
 Postganglionic, parasympathetic, neuroeffector
junctions (M1-M5)
 Nicotinic
 Distinction of two different subtypes
 Ganglia - type II or type NG
 Neuromuscular junctions - type I or type NM
 N.B.-Nicotinic ACh receptors are ligand-gated
Na+/K+ channels

58
Schematic representation of
Cholinergic Receptor Subtype Locations
Pre
Ganglion Effector
organ
cord
Pre
Ganglion Effector
organ
Post
Parasympathetic
Sympathetic
N1
M
N1

59
Adrenergic Receptors
 Activated by NE, Epi, and adrenergic drugs
 Anatomic distribution
 Postganglionic, sympathetic, neuroeffector
junctions
 Subtypes
 Alpha-1, 2; Beta-1, 2, 3

60
Schematic representation of
Adrenergic Receptor Locations
Sympathetic
Pre
Ganglion
paravertebral ,
prevertebral or lateral
Effector
organs
cord
Alpha or Beta
adrenergic receptors

61
Organ system integration
 Parasympathetic
 Discrete innervation
 Energy conservation
 Sympathetic
 Highly distributed innervation, global responses
 Energy expenditure
 Fight or flight responses
Functional Significance of the
Autonomic Nervous System (1)
“Organ system integration & Dual innervation”

62
Functional Significance of the
Autonomic Nervous System (2)
Dual innervation
 Organ responses moderated by both
parasympathetic and sympathetic influences
 Parasympathetic dominant at rest
 Predominate tone
 Balance of opposing neurologic influences
determines physiologic responses

63
Alpha-1 Adrenergic Receptor
 Vascular smooth muscle contraction
 Arterioles, veins
 Increased arterial resistance
 Decreased venous capacitance
 Agonists support systemic blood pressure
 Increased resistance
 Redistribution of blood toward heart,
increased cardiac output
 Antagonists decrease blood pressure
 Iris
 Pupillary dilation (mydriasis)

64
Alpha-2 Adrenergic Receptor
 postsynaptic α2-adrenoceptors (located in bld
vessels) cause constriction
 Modulation of NE release
 Presynaptic receptors on axon terminus
 Spinal alpha-2 receptors mediate analgesia
 Agonists used clinically as epidural and spinal
analgesics
 Sedation

65
Beta-1 Adrenergic Receptor
 To myocardium (renal-renin and fat cell also)
 Agonists
 Increase HR, contractility, and impulse
conduction speed
 May be arrhythmogenic
 Antagonists
 Decrease HR, contractility, and impulse
conduction speed
 Used clinically as antiarrhythmics

66
Beta-2 Adrenergic Receptor
 Vascular smooth muscle in skeletal
muscle
 Agonists evoke active vasodilation,
increased blood flow
 Bronchial smooth muscle
 Agonists evoke bronchodilation, decreased
airway resistance

67
Muscarinic Cholinergic Receptor
(mAChR)
 Myocardium
 Agonists decrease HR, contractility and AV conduction
velocity
 Antagonists used clinically to increase HR & facilitate AV
conduction such as in heart block
 Iris sphincter muscle
 Agonists evoke pupillary constriction (miosis)
 Antagonists evoke mydriasis
 Gastrointestinal tract
 Agonists increase peristalsis and relax sphincter
 Urinary bladder
 Agonists evoke urination
 Detrusor muscle (bladder) contraction
 Trigone (sphincter) relaxation

68
Receptor Function Distribution
α1 Constriction of smooth
muscles
Blood vessels and
piloerectors in skin
(vasoconstriction and goose
bumps)
Sphincters (bladder,
gastrointestinal [GI])
Uterus and prostate
(contraction)
Eye (contraction of the radial
muscle = pupillary
dilation/mydriasis)
α2 Inhibition of sympathetic
autonomic ganglia
(decreases SANS)
Presynaptic ganglionic
neurons
GI tract (less important
pharmacologically)
Effect of ANS on Organ Systems (1)
Sympathetic (NE)

69
Sympathetic (NE)
Receptor Function Distribution|Organ
β1 Increase cardiac
performance and liberation
of energy
Heart-most important
(increased chronotropy,
inotropy, dromotropy)
Fat cells (release fat for
energy via lipolysis)
Kidney (release renin to
conserve water)
β2 Relaxation of smooth
muscles and liberation of
energy
Lungs (bronchodilation)
Blood vessels in muscles
(vasodilation)
Uterus (uterine relaxation)
GI (intestinal relaxation)
Bladder (bladder relaxation)
Liver (to liberate glucose via
glycogenolysis)

Parasympathetic (Ach)
Receptor Function Distribution|Organ
N (Nicotinic) "Nerve to nerve" & "nerve to
muscle" communication
SANS & PANS ganglia
Neuromuscular junction (NMJ)
M (Muscarinic) To oppose most sympathetic
actions at the level of the organs
Lung (bronchoconstriction)
Heart (slower rate, decreased
conduction, decreased
contractility)
Sphincters of GI and bladder
(relax)
Bladder (constriction)
GI (intestinal contraction)
Eye (contraction of the
circular muscle = pupillary
constriction or miosis)
Eye (contraction of the ciliary
muscle = focus for near vision)

71
Exception
Sympathetic innervation of adrenal medulla is direct from
spinal cord and uses ACh as neurotransmitter
Adrenal gland functions as a special form of ganglion that secretes
Epi & NE in a 4 to 1 ratio directly into the bloodstream
Sympathetic postganglionic neurons that innervate renal
vascular smooth muscle release dopamine rather than
norepinephrine
N.B. Note
There is no parasympathetic fiber innervation of blood vessels, but
bld vessels do have muscarinic receptors
For example, in the coronary arteries stimulation M3 receptors
cause the release of NO which result in vasodilation
Sweat glands are innervated by sympathetic nerves, but paradoxically
use mAChR
Sexual arousal is parasympathetic, but orgasm is sympathetic

72
Autonomic and Somatic NS
Pharmacology Terminology
 Many drugs evoke effects by interacting with receptors
 Affinity
 Efficacy or (synonym) Intrinsic activity
 Agonists
 Mimic physiologic activation
 Have both high affinity and efficacy
 Antagonists
 Block actions of neurotransmitters or agonists
 Have high affinity, but no efficacy
 Often used as pharmacologic reversal agents

73
Adrenergic-
Receptor Type
Physiologic
Agonist
Signaling
Mechanism
Pharmacologic
Agonist
Pharmacologic
Antagonist
α1 Norepi ≥ Epi IP3/DAG/Ca2+ Phenylephrine Prazosin
α2 Norepi ≥ Epi ↓ [cAMP] Clonidine,
methyldopa
Yohimbine
β1 Epi > Norepi ↑ [cAMP] Dobutamine (β1
> β2),
isoproterenol (β1
= β2)
Metoprolol
β2 Epi > Norepi ↑ [cAMP] Albuterol,
isoproterenol
(β1 = β2)
Propranolol
(nonselective β1
and β2)
Signaling Mechanisms and Pharmacology of
ANS Receptor Subtypes- SANS

74
Cholinergic-
Receptor
Type
Physiologic
Agonist
Signaling
Mechanism
Pharmacologic
Agonist
Pharmacologic
Antagonist
N1=NM Acetylcholine Ionotropic
receptor
Nicotine D-Tubocurarine
N2=NG Acetylcholine Ionotropic
receptor
Nicotine Hexamethonium,
mecamylamine
M1–5 Acetylcholine Various Bethanechol,
methacholine,
pilocarpine
Atropine,
benztropine,
ipratropium
Signaling Mechanisms and Pharmacology of
ANS Receptor Subtypes- PANS

75
Summary: Take Home Points (1)
ANS functions involve a variety of effector tissues,
including: cardiac muscle, smooth mm, vascular
endothelium, exocrine glands, and presynaptic
nerve terminals
To understand ANS function , and by extension how to
pharmacologically manipulate the ANS, you will need
understand how the two divisions of the ANS coexist and
function, how each subdivision exerts its effects, and
finally what physiologic and pharmacologic mechanisms
exist to increase or decrease each subdivision’s activity

76
By using drugs that mimic or block the actions of chemical
transmitters and / or their receptor mechanisms, we can
selectively modify autonomic functions
Autonomic drugs are useful in many clinical conditions, however
a large number of drugs used for other clinical purposes have
unwanted effects on autonomic function; and because of the
ubiquitous nature of the ANS, autonomic drugs are frequently
non-selective and thus can be associated with side effects
Bottom line| memorization of receptors, their distribution,
signal transduction mechanisms and their effects is mandatory
and will enable you to accurately predict effects, side effects,
potential toxicities and interactions of ANS drugs
Summary: Take Home Points (2)

77
Articles
Laurie Kelly McCorry. Physiology of the Autonomic Nervous System
Am J Pharm Educ. 2007 August 15; 71(4): 78.
Goldstein DS, Robertson D, Straus SE, et al. Dysautonomias: clinical disorders of the
autonomic nervous system. Ann Intern Med 2002;137(9):753–63.
Cannon, WB, Organization for Physiological Homeostasis. PDF Physiological Rev July 1,
1929 9:399-431
PowerPoint Presentation:
Cray MI. (2014) Walter Cannon, Homeostasis and the Physiological Response to Stress,
A Web Interactive PowerPoint Presentation
Review Books
 Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture; McGraw-Hill
,2009
 Costanzo L., Neurophysiology: In BRS Physiology , LLW 5thEd , 2011
 Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, In Case Files: Pharmacology; McGraw-
Hill 2 ed. 2008
 Rosenfeld GC, Loose DS. BRS Pharmacology (Board Review Series); LLW 6thEd, 2013
References and further study:
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