ANS Physiology and Pharmacology

ANS Physiology and Pharmacology
Overview | Review of Autonomic Nervous System
Widmaier, EP. Vander’s human physiology 14th Ed. New York: McGraw-Hill, 2016.
Marc Imhotep Cray, M.D.

Overall Goal
“ Deconstruction, Reconstruction,
Integration and Relationships”
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
2
Topics Outline
 Homeostasis
 Basic Neuroanatomy and Neurophysiology of ANS
 Neurotransmitters
 Receptors
 Receptor-Ligand Interactions & Signal Transduction
 Autonomic and Somatic Pharmacology Terminology
3
Learning Objectives
After this presentation the learner should be able:
To describe the two divisions of the ANS and the main functions and
effects of each division.
To explain how sympathetic and parasympathetic nerves interact with

each other to regulate organ function (maintain homeostasis)
To describe the fight or flight reaction and explain how sympathetic

activation affects the activities of the different organs
To list the main organ effects caused by parasympathetic stimulation
To describe the different autonomic receptors that are stimulated by

acetylcholine, norepinephrine, and epinephrine
To describe signaling mechanisms and pharmacology of ANS receptor

subtypes
4
Autonomic Nervous System (ANS)
 Autonomic nervous system (ANS) is part of

nervous system responsible for homeostasis
 Except for skeletal muscle, which gets its

innervation from somatomotor nervous system,
innervation to all other organs is supplied by
ANS
5
ANS vs. Endocrine System in
Homeostasis
Autonomic nervous system (ANS) is moment-to-moment
regulator of 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
6
ANS and Endocrine System
[common properties]
 high-level integration in the brain
 ability to influence processes in distant

regions of body
 extensive use of negative feedback

 maintaining homeostasis
 both systems use chemicals for

transmission of information
7
Walter Cannon coined word homeostasis
 Referring to animal systems, 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 Courtesy National Library of Medicine
organism, that it was suggested
(Cannon, 1929) that a specific
designation for these states be
employed – homeostasis”
Cannon, WB, Organization for Physiological Homeostasis.pdf
Physiological Rev July 1, 1929 9:399-431
Also see: Cray MI. Walter Cannon, Homeostasis and the Physiological Response
to Stress, A Web Interactive PowerPoint Presentation
8
Homeostasis (1)
 The physiologic process of maintaining an
internal environment (ECF environment)
compatible w normal health
 Autonomic reflexes maintain set points and

modulate organ system functions via
negative feedback in pursuit of homeostasis
9
Homeostasis (2)
A dynamic steady state of constituents in internal
environment (ECF) that surrounds and exchanges
materials with cells
Factors homeostaticly maintained include:

(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
 GFR
 …and others
10
Homeostasis (3)
Nervous versus Endocrine
Wired Wireless
Neurotransmitters Hormones
Hormones
Short
Short Distance
Distance Long
Long Distance
Distance
Closeness Receptor Specificity
Rapid Onset Delayed Onset
Short Duration Prolonged Duration
Rapid Response Regulation

Marc Imhotep Cray, M.D. 11
Components of a negative
feedback control system
Recognizes deviation of
normal set point value Attempt to restore
set point value
Measures control variable
COMPARATOR +
SENSOR
ERROR
stretch receptors, chemo-, SET EFFECTOR
baro-, osmo-, and thermo- SIGNAL
POINT
receptors etc.
-
Negative feedback:
Initiation of responses
CONTROLLED that counter deviations of
controlled variables
VARIABLE
(SEE NEXT SLIDE)
-
NEGATIVE
from their normal range
FEEDBACK
Important variable maintained
within a normal range Effector opposes stimulus
12
Marc Imhotep Cray, M.D. Redrawn after: Kibble JD, Halsey CR, Homeostasis. In: Medical Physiology -The Big Picture; McGraw-Hill , 2009; 2.
Examples of Physiologic
Controlled Variables & Set Points
Controlled Variable Typical Set Point Value
(Arterial Blood Sample)
Arterial O2 partial pressure 100 mm Hg
Arterial CO2 partial pressure 40 mm Hg
Arterial blood pH pH 7.4
Glucose 90 mg/dL (5 mM)
Core body temperature 98.4°F (37°C)
Serum Na+ 140 mEq/L
Serum K+ 4.0 mEq/L
Serum Ca2+ 4.5 mEq/L
Mean arterial blood pressure 90 mm Hg
Glomerular filtration rate 120 mL /min
Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology :The Big Picture.
New York, NY: McGraw-Hill , 2009; 3.
13
Important Negative Feedback
Control Systems
Modified from Carroll RG. Elsevier’s Integrated Physiology. Mosby, Inc. 2007; Table 1-3, Pg. 5.
14
Example: Baroreceptor Reflex
control of blood pressure
COMPARATOR + EFFECTOR
SENSOR cardiac
SET N 95 contractility,
stretch receptors in mm Hg ERROR
Aortic arch and POINT vascular tone,
SIGNAL urinary fluid
Carotid sinus
excretion
CNS|
Medulla Oblongata
Mean Arterial Blood

Pressure (MAP)
-
NEGATIVE
FEEDBACK
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)
See Baroreflex pdf 15
Baroreceptors & Chemoreceptors
Baroreceptors:
• Hypotension- arterial pressure stretch afferent baroreceptor firing
efferent sympathetic firing and efferent parasympathetic stimulation
vasoconstriction, HR, contractility BP important in response to severe
hemorrhage
• Carotid massage - pressure on carotid artery stretch afferent

baroreceptor firing HR 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
Chemoreceptors:
• Peripheral—carotid and aortic bodies are stimulated by PO2 (< 60 mm Hg),
PCO2, and pH of blood
• Central—are stimulated by changes in pH and PCO2 of brain interstitial fluid, which
in turn are influenced by arterial CO2 Do not directly respond to PO2
16
Baroreceptors &
Chemoreceptors
Mechanism Illustrated
Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017. 17
Mean Arterial Pressure Control and
Autonomic & Hormonal Feedback Loops
Katzung & Trevor. Pharmacology Examination & Board

Review 10th Ed. New York: ; McGraw-Hill , 2014.
18
Organization of Nervous System
BRAIN & SPINAL CORD CENTRAL
NERVOUS
SYSTEM (CNS)
AFFERENT EFFERENT
PERIPHERAL
(Sensory) (Motor) NERVOUS
NERVES NERVES SYSTEM (PNS)
EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC
SMOOTH MUSCLE,
EFFECTOR SKELETAL
CARDIAC MUSCLES
ORGANS MUSCLES
AND GLANDS
VOLUNTARY
INVOLUNTARY
Monosynaptic
Pre & Post Ganglionic Fiber
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)
20
Generic Neuron Anatomy
Basic structural unit of nervous system >>> neuron
http://en.wikipedia.org/wiki/Neuron
21
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
22
Sympathetic Nervous System Wiring
Dorsal root Intermediolateral cell column
ganglion (IML)
Sympathetic trunk
Gray ramus
White ramus
See: ANS Summary Notes

23
Functional Unit of ANS >> Visceral Reflex Arc
Afferent fibers from periphery to CNS

CNS integration
Spinal cord
Medulla
Hypothalamus
Thalamus
Cortex
Efferent fibers from CNS to periphery
Effector response
Organ receptors ( in 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)
24
Neurotransmitters
 Chemicals synthesized and stored in neurons
 Liberated from axon terminus in response to
action potentials
 Interact with specialized receptors
 Evoke responses in innervated tissues
See: IVMS Neurotransmitters Notes
25
ANS Neurotransmitters
Class Chemical Synthesis Postsynaptic Signal Functions
Receptors Termination
Small molecule
Transmitters ANS
Acetylcholine Choline + acetyl Nicotinic Extracellular Movement
CoA, via enzyme (cation channel) hydrolysis by control
Choline Muscarinic Acetylcholinestrase Cognition
Acetyltransferase (G-protein–
Catecholamines Dopamine From the amino coupled) Reuptake ANS
acid tyrosine via D1 (stimulatory Movement
the enzyme G- protein– control
Tyrosine coupled) General
hydroxylase D2 (inhibitory affect
in the G-protein–
catecholamine coupled)
pathway
Norepinephrine From dopamine α & β Adrenergic Reuptake or ANS
in the receptors breakdown via the Alertness
catecholamine enzymes General
pathway monoamine oxidase affect
and catechol–O-
methyltransferase
NB: Epinephrine is a catecholamine released upon stimulation of SANS, produced in

adrenal medulla. It is a neurohormone, not an ANS neurotransmitter
26
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)
Effector
Pre Post organ
Ganglion
27
Anatomic Divisions of 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 head and neck
28
Schematized Anatomic Comparison of
PANS & SANS (1) (click to expand)
29
Schematized Anatomic Comparison
of PANS & SANS (2)
Effectors: cardiac muscle, smooth mm, vascular endothelium,
exocrine glands, and presynaptic nerve terminals
Cranial or sacral cord

Parasympathetic
ANS functions:
 circulation Post
Pre
 digestion
 respiration Ganglion Effector
 temperature
 sweating
organ
 metabolism Sympathetic
 some endocrine
gland secretions
Thoracic or lumbar Pre

Post
cord Ganglion Effector
organ
30
Cranial Nerve Parasympathetic
Innervations
31
Somatic Nervous System
(included for comparison)
 Efferent innervation of skeletal muscle

 No peripheral ganglia
 Rapid transmission, discrete control of motor
units
Striated muscle
 Voluntary
Any spinal Motor neuron
segment Myelinated with a high
conduction velocity
In contrast
Postganglionic neurons of
ANS are unmyelinated w a low
conduction velocity
32
Neurochemical Transmission in
Peripheral Nervous System (PNS)
 Cholinergic nerves
 Acetylcholine is neurotransmitter
 Locations of Ach
 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

33
Cholinergic
Neurotransmission
Denotes ACh
Parasympathetic
Pre Post
Ganglion Effector
organ
Sympathetic Denotes ACh

Post
cord Ganglion
Effector
organs 34
Adrenergic
Neurotransmission
 Adrenergic nerves
 Norepinephrine is the neurotransmitter
 Locations
 Postganglionic, sympathetic axons
Sympathetic Denotes Norepinephrine

Post
cord Ganglion
Effector
Denotes ACh organs
35
Adrenal Medulla
 Presynaptic nerves are cholinergic
 Medullary cells (*Chromaffin cells) synthesize
and release two, related catecholamines into
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
36
Adrenal Medulla (2)
Adrenal medulla
Cholinergic neuron 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 sympathetic nervous system, with which they
communicate
 structurally similar to post-synaptic sympathetic neurons
37
Summary of Actions of SANS & PANS (1)
SYMATHETIC PARASYMPATHETIC
Fright-Fight-or-Flight Rest-Relax-Restoration
widely distributed responses discrete responses
 increase in heart rate  decrease in heart rate
 decrease in gastric motility  increase in gastric motility
 decrease secretion of salivary  increase in secretion of salivary
and digestive glands and digestive glands
 dilation of pupils  constriction of pupils
 ejaculation  penile erection
 contraction of smooth muscle in
 vasoconstriction
walls of bladder
 dilation of bronchioles Of note: Cannon’s emergency reaction:
An immediate sympathetic response to life-
 increased secretion of sweat threatening situations with both SANS and
glands PANS overactivity. The PANS phenomenon
includes vagal cardiac arrest with involuntary
defecation and urination 38
Summary of Actions of SANS and PANS (2)
(click to expand)
Sympathetic
Parasympathetic
Responses
Responses
"fight, fright, flight" or
"rest and digest" or
fight or flight" system
"feed and breed" system
 heart rate increases  slows heart rate
 blood pressure  protects retina from
increases excessive light (near
 blood is shunted  lowers blood pressure
from skin & viscera  empties the bowel
to skeletal muscles and bladder
 blood glucose  increases
increase gastrointestinal
 bronchioles dilate motility
 pupils dilate  promotes absorption
of nutrients
Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, Autonomic Sympathetic

Nervous System, In Case Files: Pharmacology 2 ed. McGraw-Hill 2008; 16.
39
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)
40
ACh Synthesis, Release, and Fate (2)
 CHT - Choline transporter

 ChAT - Choline acetyl transferase
 VAT - Vesicle-associated
transporter
 VAMPs - Vesicle-associated
membrance proteins
 SNAP’s - Synaptosome-
associated proteins
41
Cholinergic Neuron Pharmacology
From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017. 42
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)
43
NE Synthesis, Release, and Fate (2)
VMAT-Vesicular Monoamine
transporter
44
Adrenergic Neuron Pharmacology
45
Marc Imhotep Cray, M.D. From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017.
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, 7th ed. Churchill Livingstone; 2011.
*“not to be confuse with other drug targets such as enzymes etc.”

46
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
47
Steps in Signal Transduction Process
See: G-protein Signal Transduction (video animations)
 There are four general classes of signal transducing receptors:
 G-proteins are one and are referred to as serpentine receptors
Binding of 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
See: Raffa RB. Netter's Illustrated Pharmacology,Updated

Ed. Philadelphia, PA: Elsevier, 2014; Pgs. 15-17. (offline)
48
GPCR structure & function (simplified)
G-Protein Coupled Receptor
Binding of NT, 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
Mechanism of cAMP dependent signaling (offline video)
Neurohormone epinephrine and its receptor (pink) is used in tis example:

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
49
G Protein Messenger Pathways
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
* Remember there are four major classes of ligand–receptor interactions (more in Pharm.)
50
G-protein-linked 2nd messenger
mechanisms (1)
Sympathetic (Adrenergic-Noradrenergic-R)
Receptor G-Protein Class Major Function
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
 Via Stim. AC-cAMP
51
G-protein-linked 2nd messenger
mechanisms (2)
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
Offline video
52
G-protein-linked 2nd
messenger mechanisms (3)
 Dopamine:
D1 Receptor - s - Relax Renal Vascular Smooth Muscle
D2 Receptor - i - Modulate Neurotransmitter release (espec. 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)
53
Cholinergic Receptors
 Activated by ACh and cholinergic drugs
 Anatomic distribution
 Postganglionic, parasympathetic neuroeffector
junctions
 All autonomic ganglia, whether
parasympathetic or sympathetic
 Somatic neuromuscular junctions
54
Schematic of Cholinergic Receptor
Locations
Denotes ACh receptors

Parasympathetic

Pre Post
Ganglion Effector
organ
Sympathetic Denotes ACh receptors

Post
cord Ganglion
Effector
55
Marc Imhotep Cray, M.D. organs
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
56
Schematic representation of
Cholinergic Receptor Subtype Locations
Parasympathetic
Cranial or sacral cord N1 M

Pre Post
Ganglion Effector
organ
Sympathetic
N1
Post
cord Ganglion Effector
organ
57
Adrenergic Receptors
 Activated by NE, Epi, and adrenergic drugs
 Anatomic distribution
 Postganglionic, sympathetic, neuroeffector
junctions
 Subtypes
 Alpha-1, 2; Beta-1, 2, 3
58
Schematic representation of Adrenergic
Receptor Locations
Alpha or Beta
adrenergic receptors
Sympathetic

Post
cord Ganglion
paravertebral ,
Effector
prevertebral or lateral organs
59
Functional Significance of ANS (1)
“Organ system integration & Dual innervation”
Organ system integration

 Parasympathetic
 Discrete innervation
 Energy conservation
 Sympathetic
 Highly distributed innervation, global responses
 Energy expenditure
 Fight or flight responses
60
Functional Significance of ANS (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
61
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)
62
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
63
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
64
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
65
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
66
Effect of ANS on Organ Systems (1)
Sympathetic (NE)
Receptor Function Distribution
α1 Constriction of smooth Blood vessels and piloerectors in skin

muscles (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 Presynaptic ganglionic neurons
autonomic ganglia GI tract (less important pharmacologically)
(decreases SANS)
67
Sympathetic (NE)
Receptor Function Distribution|Organ
β1 Increase cardiac performance Heart-most important (increased

and liberation of energy chronotropy, inotropy, dromotropy)
Fat cells (release fat for energy via lipolysis)
Kidney (release renin to conserve water)
β2 Relaxation of smooth muscles Lungs (bronchodilation)

and liberation of energy Blood vessels in muscles (vasodilation)
Uterus (uterine relaxation)
GI (intestinal relaxation)
Bladder (bladder relaxation)
Liver (to liberate glucose via
glycogenolysis)
68
Parasympathetic (Ach)
Receptor Function Distribution|Organ
N (Nicotinic) "Nerve to nerve" & SANS & PANS ganglia

"nerve to muscle" Neuromuscular junction (NMJ)
communication
M (Muscarinic) To oppose most Lung (bronchoconstriction)
sympathetic actions Heart (slower rate, decreased conduction, decreased
at the level of the contractility)
organs
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)
Acetylcholine receptors
Nicotinic ACh receptors are ligand-gated Na+/K+ channels
Two subtypes: NN (found in autonomic ganglia, adrenal
medulla) and NM (found in NMJ of skeletal muscle)
Muscarinic ACh receptors are G-protein–coupled receptors

that usually act through 2nd messengers
Five subtypes: M1–5 found in heart, smooth muscle, brain,
exocrine glands, and on sweat glands (cholinergic sympathetic)
70
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
Important note:
There is no parasympathetic fiber innervation of blood vessels,

but bld vessels do have muscarinic receptors
For example, in coronary arteries stimulation M3 receptors cause
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

71
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
72
Signaling Mechanisms and Pharmacology of
ANS Receptor Subtypes- SANS
Adrenergic- Physiologic Signaling Pharmacologic Pharmacologic

Receptor Type Agonist Mechanism Agonist Antagonist
α1 Norepi ≥ Epi IP3/DAG/Ca2+ Phenylephrine Prazosin
α2 Norepi ≥ Epi ↓ [cAMP] Clonidine, Yohimbine

methyldopa
β1 Epi > Norepi ↑ [cAMP] Dobutamine (β1 Metoprolol

> β2),
isoproterenol (β1
= β2)
β2 Epi > Norepi ↑ [cAMP] Albuterol, Propranolol

isoproterenol (nonselective β1
(β1 = β2) and β2)
73
Signaling Mechanisms and Pharmacology of
ANS Receptor Subtypes- PANS
Cholinergic- Physiologic Signaling Pharmacologic Pharmacologic

Receptor Agonist Mechanism Agonist Antagonist
Type
N1=NM Acetylcholine Ionotropic Nicotine D-Tubocurarine
receptor
N2=NG Acetylcholine Ionotropic Nicotine Hexamethonium,

receptor mecamylamine
M1–5 Acetylcholine Various Bethanechol, Atropine,

methacholine, benztropine,
pilocarpine ipratropium
74
PNS summary schematic
Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
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 ANS, you will need understand how
two divisions of 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
Summary: Take Home Points (2)
 By using drugs that mimic or block 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 ubiquitous nature of ANS,
autonomic drugs are frequently non-selective and thus can be assoc. w
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
77
THE END
See next slide for further study tools.

78
Further study:
Companion notes
ANS Summary Notes
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. Walter Cannon, Homeostasis and the Physiological Response to Stress.
A Web Interactive PowerPoint Presentation , 2014
79

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ANS Physiology and Pharmacology

Overview | Review of Autonomic Nervous System

Marc Imhotep Cray, M.D.

 Basic Neuroanatomy and Neurophysiology of ANS

 Receptor-Ligand Interactions & Signal Transduction

 Autonomic and Somatic Pharmacology Terminology

To explain how sympathetic and parasympathetic nerves interact with

To describe the fight or flight reaction and explain how sympathetic

To list the main organ effects caused by parasympathetic stimulation

To describe the different autonomic receptors that are stimulated by

To describe signaling mechanisms and pharmacology of ANS receptor

 Autonomic nervous system (ANS) is part of

 Except for skeletal muscle, which gets its

Endocrine system, in contrast, provides slower, more

 ability to influence processes in distant

 extensive use of negative feedback

 both systems use chemicals for

 Autonomic reflexes maintain set points and

Factors homeostaticly maintained include:

Closeness Receptor Specificity

Rapid Onset Delayed Onset

Short Duration Prolonged Duration

Rapid Response Regulation

Mean Arterial Blood

• Carotid massage - pressure on carotid artery stretch afferent

• Contributes to Cushing reaction (triad of hypertension, bradycardia,

Katzung & Trevor. Pharmacology Examination & Board

EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC

Sensory neurons are not subdivided into somatic and

See: ANS Summary Notes

Afferent fibers from periphery to CNS

Organ receptors ( in viscus ) >>>> sensory (afferent ) neuron >>>>CNS

See: IVMS Neurotransmitters Notes

NB: Epinephrine is a catecholamine released upon stimulation of SANS, produced in

Cranial or sacral cord

Thoracic or lumbar Pre

 Efferent innervation of skeletal muscle

 Postganglionic, parasympathetic neurons

 “Preganglionic” fibers to adrenal medulla

 Postganglionic, sympathetic neurons to sweat glands in

 Somatic motor neurons

Thoracic or lumbar Pre

Sympathetic Denotes Norepinephrine

Thoracic or lumbar Pre

Cholinergic neuron Epi and NE released

 Chromaffin cells are neuroendocrine cells found in the

 They are in close proximity to pre-synaptic sympathetic

Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, Autonomic Sympathetic

 Transmitter vesicles fuse with cell membrane

 ACh released by exocytosis

 Inactivated by acetylcholinesterase (AChE)

 CHT - Choline transporter

 Catecholamine - synthesized in a multistep

 Linked to one of many signal transduction

*“not to be confuse with other drug targets such as enzymes etc.”

Binding of neurotransmitter, hormone

See: Raffa RB. Netter's Illustrated Pharmacology,Updated

Binding of NT, hormone or drug

Mechanism of cAMP dependent signaling (offline video)

Neurohormone epinephrine and its receptor (pink) is used in tis example:

1) Gq Messenger Pathway: (used by H1, Alpha 1, V1, M1, M3 Receptors)

2) Gαs Messenger Pathway: (used by Beta 1, Beta 2, D1, H2, V2 Receptors)

3) Gαi Messenger Pathway: (used by M2, Alpha 2, and D2 Receptors)

Alpha 1 Receptor - q - Vasoconstriction and Pupillary Dilator Muscle

M2 Receptor - i - Decrease Heart Rate and Contractility of Atria

M3 Receptor - q - Increase Exocrine Gland secretions (Sweat

"For sake of completeness"