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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

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Marc Imhotep Cray, M.D.
Topics Outline
 Homeostasis

 Basic Neuroanatomy and Neurophysiology of ANS

 Neurotransmitters

 Receptors

 Receptor-Ligand Interactions & Signal Transduction

 Autonomic and Somatic Pharmacology Terminology

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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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.
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Marc Imhotep Cray, M.D.
Important Negative Feedback
Control Systems

Modified from Carroll RG. Elsevier’s Integrated Physiology. Mosby, Inc. 2007; Table 1-3, Pg. 5.

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Marc Imhotep Cray, M.D.
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
Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
Baroreceptors &
Chemoreceptors
Mechanism Illustrated

Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017. 17
Marc Imhotep Cray, M.D.
Mean Arterial Pressure Control and
Autonomic & Hormonal Feedback Loops

Katzung & Trevor. Pharmacology Examination & Board
Review 10th Ed. New York: ; McGraw-Hill , 2014.

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Marc Imhotep Cray, M.D.
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
Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
Generic Neuron Anatomy
Basic structural unit of nervous system >>> neuron

http://en.wikipedia.org/wiki/Neuron

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
Sympathetic Nervous System Wiring
Dorsal root Intermediolateral cell column
ganglion (IML)

Sympathetic trunk

Gray ramus

White ramus

See: ANS Summary Notes
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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
Schematized Anatomic Comparison of
PANS & SANS (1) (click to expand)

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
Cranial Nerve Parasympathetic
Innervations

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
Cholinergic
Neurotransmission

Denotes ACh
Parasympathetic
Cranial or sacral cord
Pre Post
Ganglion Effector
organ
Sympathetic Denotes ACh

Thoracic or lumbar Pre
Post
cord Ganglion
Effector
organs 34
Marc Imhotep Cray, M.D.
Adrenergic
Neurotransmission
 Adrenergic nerves
 Norepinephrine is the neurotransmitter
 Locations
 Postganglionic, sympathetic axons

Sympathetic Denotes Norepinephrine

Thoracic or lumbar Pre
Post
cord Ganglion
Effector
Denotes ACh organs
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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
Marc Imhotep Cray, M.D.
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.

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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
Cholinergic Neuron Pharmacology

From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017. 42
Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
NE Synthesis, Release, and Fate (2)

VMAT-Vesicular Monoamine
transporter

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Marc Imhotep Cray, M.D.
Adrenergic Neuron Pharmacology

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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.”
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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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.)

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Marc Imhotep Cray, M.D.
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
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G-protein-linked 2nd messenger
mechanisms (2)
Parasympathetic (Ach-Cholinergic-R)
Receptor G-Protein Class Major Function
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

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Marc Imhotep Cray, M.D.
G-protein-linked 2nd
messenger mechanisms (3)
Receptor G-Protein Class Major Function
 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)
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Marc Imhotep Cray, M.D.
Cholinergic Receptors
 Activated by ACh and cholinergic drugs
 Anatomic distribution
 Postganglionic, parasympathetic neuroeffector
junctions
 All autonomic ganglia, whether
parasympathetic or sympathetic
 Somatic neuromuscular junctions

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Marc Imhotep Cray, M.D.
Schematic of Cholinergic Receptor
Locations

Denotes ACh receptors
Parasympathetic

Cranial or sacral cord
Pre Post
Ganglion Effector
organ
Sympathetic Denotes ACh receptors

Thoracic or lumbar Pre
Post
cord Ganglion
Effector
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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

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Marc Imhotep Cray, M.D.
Schematic representation of
Cholinergic Receptor Subtype Locations

Parasympathetic

Cranial or sacral cord N1 M
Pre Post
Ganglion Effector
organ
Sympathetic

N1
Thoracic or lumbar Pre
Post
cord Ganglion Effector
organ
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Marc Imhotep Cray, M.D.
Adrenergic Receptors
 Activated by NE, Epi, and adrenergic drugs
 Anatomic distribution
 Postganglionic, sympathetic, neuroeffector
junctions
 Subtypes
 Alpha-1, 2; Beta-1, 2, 3

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Marc Imhotep Cray, M.D.
Schematic representation of Adrenergic
Receptor Locations

Alpha or Beta
adrenergic receptors
Sympathetic

Thoracic or lumbar Pre
Post
cord Ganglion
paravertebral ,
Effector
prevertebral or lateral organs

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
Effect of ANS on Organ Systems (2)
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)

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Marc Imhotep Cray, M.D.
Effect of ANS on Organ Systems (3)
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)
Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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
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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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)

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
PNS summary schematic

Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.
THE END

See next slide for further study tools.
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Marc Imhotep Cray, M.D.
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

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Marc Imhotep Cray, M.D.