ANS Pharmacology
Introduction to the
Autonomic Nervous System
Prepared and Presented by:
Marc Imhotep Cray, M.D.
Pharmacology and Basic Medical Sciences Teacher
See: Autonomic Nervous System Summary
http://www.imhotepvirtualmedsch.com/
Marc Imhotep Cray, M.D. 2
*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
Marc Imhotep Cray, M.D.
Topics Outline
3
Homeostasis Basic Neuroanatomy and Neurophysiology
Hypothalamus
Neurotransmitters
Receptors
Autonomic and Somatic Pharmacology Terminology
Marc Imhotep Cray, M.D.
GOAL OF REVIEW
“ Deconstruction, Reconstruction, Integration and Relationships”
4
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
Marc Imhotep Cray, M.D.
Learning Objectives
5
After studying this presentation you should be able to: Describe the two divisions of the ANS and the main functions 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
Marc Imhotep Cray, M.D.
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 somatomotor nervous system, innervation to all other organs is supplied by the ANS
Marc Imhotep Cray, M.D. 7
Homeostasis
The physiologic process of maintaining an internal environment compatible with normal health
Autonomic reflexes maintain set points and modulate organ system functions in pursuit of homeostasis
See: Human homeostasis http://en.wikipedia.org/wiki/Human_homeostasis
hypothalamus orchestrates many homeostatic functions via autonomic and endocrine systems
Marc Imhotep Cray, M.D.
Components of a negative feedback control system
8
A set point value Sensors Comparator Effectors Controlled Variable
From: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture, , Fig. 1-1, Pg. 2; McGraw-Hill ,2009
Negative feedback initiations responses that counter deviations of controlled variables from their normal range NF is the major control process used to maintain a stable internal environment
Marc Imhotep Cray, M.D. 9
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 Redrawn from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture, , Tab. 1-2, Pg. 3 The McGraw-Hill ,2009
40 mm Hg 100 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
Marc Imhotep Cray, M.D. 10
Overview of Hypothalamus Fnx
Orchestrates many homeostatic functions via autonomic and endocrine systems
Afferents of hypothalamus include fibers from amygdala, septal area & to brainstem
Some hypothalamic neurons directly sense changes in hormone concentrations, osmotic pressure, and temperature of the blood
Hypothalamic efferent fibers go to the brainstem and spinal cord, for control of autonomic and other involuntary functions
Some hypothalamic neurons secrete hormones, including those of the posterior lobe of the pituitary gland (neurosecretory output)
Releasing factors enter the hypophysal portal vessels and control the
secretion of secretion of anterior pituitary hormones
Marc Imhotep Cray, M.D.
Anatomy of hypothalamic nuclei & homeostatic
functions hypothalamus (2)
11
Marc Imhotep Cray, M.D. 12
Hypothalamus (3)
Click for full size view
Diagram from Kiernan JA, Basic functional neuroanatomy pdf
Marc Imhotep Cray, M.D. 13
From: Kiernan JA, Basic functional neuroanatomy pdf
Hypothalamus (4)
Marc Imhotep Cray, M.D. 14
Organization of the Nervous System
Structures of the nervous system are intimately interconnected, but for convenience we divide them into two parts: (1) the central nervous system
(CNS), composed of the brain and spinal cord, and
(2) the peripheral nervous System (PNS), consisting of the nerves that connect the brain or spinal cord with the body’s muscles, glands, and sense organs
Marc Imhotep Cray, M.D. 15
Overview of structural and functional organization of the nervous system
From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig. 6-37 Pg. 173, McGraw-Hill 2008
Marc Imhotep Cray, M.D. 16
Autonomic (Visceral) Reflex
Afferent fibers from periphery to CNS
CNS integration Cortex
Thalamus
Hypothalamus
Medulla
Spinal cord
Efferent fibers from CNS to periphery
Marc Imhotep Cray, M.D. 17
Efferent Autonomic Nerves
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
Marc Imhotep Cray, M.D. 18
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-L2/3
Preganglionic axons originate in the thoracolumbar 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) http://www.vivo.colostate.edu/hbooks/pathphys/digestion/basics/gi_nervous.html
Has been described as a "second brain" for several reasons. ENS can operate autonomously. It normally communicates with CNS through the parasympathetic (e.g., via the vagus nerve) and sympathetic (e.g., via the prevertebral ganglia) nervous systems.
Vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.
Marc Imhotep Cray, M.D. 19
From: Barrett KE, Boitano S, Barman SM, Brook HL, Ganong’s Review of Medical Physiology 24e , Fig 13-2, Pg.258, McGraw-Hill 2012
Cholinergic nerves red Noradrenergic nerves blue Preganglionic nerves solid lines Postganglionic nerves dashed
lines
Organization of Sympathetic and Parasympathetic Nervous Systems
Marc Imhotep Cray, M.D. 20
Schematized Anatomic Comparison
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Pre Ganglion Effector
organ
Post Cranial or sacral cord
Parasympathetic
Sympathetic
Marc Imhotep Cray, M.D. 21
Somatic Nervous System
Efferent innervation of skeletal muscle
No peripheral ganglia
Rapid transmission, discrete control of motor units
Any spinal
segment Motor neuron
Striated muscle
(Included for comparison)
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Neurochemical Transmission in the Peripheral Nervous System
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
Marc Imhotep Cray, M.D. 23
Cholinergic Neurotransmission
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Pre
Ganglion Effector
organ
Post Cranial or sacral cord
Parasympathetic
Sympathetic Denotes ACh
Denotes ACh
Marc Imhotep Cray, M.D. 24
Neurochemical Transmission in the PNS
Adrenergic nerves
Norepinephrine is the neurotransmitter
Locations
Postganglionic, sympathetic axons
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Sympathetic Denotes Norepinephrine
Denotes ACh
Marc Imhotep Cray, M.D. 25
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% of Epinephrine and ~20% of 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
Marc Imhotep Cray, M.D. 26
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
Marc Imhotep Cray, M.D. 27
Organizational Summary of the ANS
From: Costanzo L., Neurophysiology: In BRS Physiology , Fig. 2-1 pg. 32, LLW 5thEd , 2011
Marc Imhotep Cray, M.D. 28
Generic Neuron Anatomy
From: http://en.wikipedia.org/wiki/Neuron
structural unit of nervous system >>> neuron
Marc Imhotep Cray, M.D. 29
From: Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Figs.6-18 & 6-19 Pg. 152-53, McGraw-Hill 2008
RMP & AP electrochemical conductance
Marc Imhotep Cray, M.D. 30
1 Steady resting membrane potential is near
EK, PK > PNa, due to leak K+ channels
2 Local membrane is brought to threshold
voltage by a depolarizing stimulus.
3 Current through opening voltage-gated Na+
channels rapidly depolarizes the membrane,
causing more Na+ channels to open.
4 Inactivation of Na+ channels and delayed
opening of voltage-gated K+ channels halts
membrane depolarization.
5 Outward current through open voltage gated
K+ channels repolarizes the membrane
back to a negative potential.
6 Persistent current through slowly closing
voltage-gated K+ channels hyperpolarizes
membrane toward EK; Na+ channels return
from inactivated state to closed state (without
opening).
7 Closure of voltage-gated K+ channels returns the membrane potential to its resting value.
RMP & AP electrochemical conductance (2)
From: Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig.6-18 Pg. 152, McGraw-Hill 2008
Marc Imhotep Cray, M.D. 31
Action Potential Propagation
From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig. 6-22 & 623 Pg. 156-157 McGraw-Hill 2008
Marc Imhotep Cray, M.D. 32
Axonal transport along microtubules by dynein & kinesin
Kinesin transport occurs from cell body toward the axon terminals (anterograde)
important in moving nutrient molecules, enzymes, mitochondria, neurotransmitter-filled vesicles, and other organelles
• Dynein movement (retrograde), carrying recycled
membrane vesicles, growth factors, and other chemical
signals that can affect the neuron’s morphology,
biochemistry, and connectivity
• Retrograde transport=route by which some harmful
agents CNS, Ex. Tetanus toxin and the herpes simplex,
rabies, and polio viruses.
From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig. 6-3. Pg. 140, McGraw-Hill 2008
Marc Imhotep Cray, M.D. 33
Organization of the ANS (2)
structural unit of nervous system >>> neuron
& functional unit of nervous
system >>> reflex arc
From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig. 6-3. Pg. 140, McGraw-Hill 2008
Marc Imhotep Cray, M.D. 34
Schematic of the PANS Showing the Origin and Distribution
of Parasympathetic Nerves
Source: Hitner and Nagle, Introduction to the Autonomic Nervous System, Pg. 64 In PHARMACOLOGY: AN INTRODUCTION; McGraw-Hill 2012
Marc Imhotep Cray, M.D. 35
Schematic of the SANS Showing the Origin and Distribution
of Sympathetic Nerves
Source: Hitner and Nagle, Introduction to the Autonomic Nervous System, Pg. 63 In PHARMACOLOGY: AN INTRODUCTION; McGraw-Hill 2012
Marc Imhotep Cray, M.D. 36
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 )
Source: http://www.alexmed.edu.eg/forums/showthread.php?2116-Today-s-lecture-gt-gt-gt-BY-M..S
Functional Unit of ANS >>> Reflex Arc
Afferent fibers from periphery to CNS CNS integration
Cortex Thalamus Hypothalamus Medulla Spinal cord
Efferent fibers from CNS to periphery
Marc Imhotep Cray, M.D. 37
Source of illustrations: VANDER’S HUMAN PHYSIOLOGY: THE MECHANISMS OF BODY FUNCTION, 11th ed. , Pg. 177-79, McGraw-Hill 2008
Spinal Nerve (1)
Marc Imhotep Cray, M.D. 38
Source: Anatomy 530a at UWO (Functional Neuroanatomy) http://instruct.uwo.ca/anatomy/530/530notes.htm
Spinal Nerve (2)
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Projection of sympathetic preganglionic & postganglionic fibers
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Neurotransmitters (Ligands)
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: http://en.wikipedia.org/wiki/Neurotransmitter
Transmission at synaptic junctions between preganglionic and postganglionic neurons and between postganglionic neurons and autonomic effectors are chemically mediated by Neurotransmitters
Marc Imhotep Cray, M.D. 41
Neurotransmitter storage and release
Neurotransmitter storage
and release at the
synapse and binding to
the postsynaptic
receptor.
Voltage-gated calcium
channels in the terminal
open in response to an
action potential,
triggering release of
neurotransmitter. Source of illustrations: VANDER’S HUMAN PHYSIOLOGY: THE MECHANISMS OF BODY FUNCTION, 11th ed. , Pg. 161, McGraw-Hill 2008
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ACh Synthesis, Release, and Fate
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)
Marc Imhotep Cray, M.D.
ACh Synthesis, Release, and Fate (2)
43
Source: http://www.neurophysiology.ws/autonomicns.htm
Synthesis and fate of synaptically released acetylcholine at cholinergic synapse.
Marc Imhotep Cray, M.D. 44
NE Synthesis, Release, and Fate
Catecholamine - synthesized in a multistep pathway starting with tyrosine
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)
Marc Imhotep Cray, M.D. 45
NE Synthesis, Release, and Fate
Marc Imhotep Cray, M.D.
NE Synthesis, Release, and Fate (2)
46
Source: E. Klabunde, http://www.cvpharmacology.com/norepinephrine.htm
Synthesis and fate of synaptically released norepinephrine at adrenergic synapse.
Marc Imhotep Cray, M.D. 47
NE Synthesis, Release, and Fate (3)
Marc Imhotep Cray, M.D. 48
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
See: Basic Receptor Pharmacology/ PDF
"Receptor“ (according to Rang & Dale): Target- or binding protein for a small molecule (ligand), which acts as an agonist or antagonist. (not to be confuse with other drug targets as enzymes etc.)
Marc Imhotep Cray, M.D. 49
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): 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.
Marc Imhotep Cray, M.D. 50
Cholinergic Receptors
Activated by ACh and cholinergic drugs
Anatomic distribution
Postganglionic, parasympathetic neuroeffector junctions
All autonomic ganglia, whethe parasympathetic or sympathetic
Somatic neuromuscular junctions
Marc Imhotep Cray, M.D. 51
Cholinergic Receptor Locations
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Pre
Ganglion Effector
organ
Post Cranial or sacral cord
Parasympathetic
Sympathetic Denotes ACh receptors
Denotes ACh receptors
Marc Imhotep Cray, M.D. 52
Cholinergic Receptor Subtypes
Marc Imhotep Cray, M.D.
Cholinergic Receptor Subtype Locations
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Pre
Ganglion Effector
organ
Post Cranial or sacral cord
Parasympathetic
Sympathetic
N1 M
N1
Marc Imhotep Cray, M.D. 54
Adrenergic Receptors
Activated by NE, Epi, and adrenergic drugs
Anatomic distribution
Postganglionic, sympathetic, neuroeffector junctions
Subtypes
Alpha-1, 2; Beta-1, 2, 3
Marc Imhotep Cray, M.D. 55
Adrenergic Receptor Locations
Sympathetic
Pre
Ganglion Effector
organs
Post Thoracic or lumbar
cord
Alpha or Beta
adrenergic receptors
Marc Imhotep Cray, M.D. 56
In this figure, the neurotransmitter epinephrine and its receptor (pink) is used as an 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 Source: http://en.wikipedia.org/wiki/Signal_transduction
Mechanism of cAMP dependent signaling
GPCR structure & function G-Protein Coupled Receptor
Marc Imhotep Cray, M.D. 57
G-protein-linked 2nd messengers
Receptor G-Protein Class Major Function
Source: Modified from First Aid for the USMLE Step 1 2012: A Student-to-Student Guide, Pg. 263
Marc Imhotep Cray, M.D. 58
G-protein-linked 2nd messengers (2)
From: Modified from First Aid for the USMLE Step 1 2012 , Pg. 263
Marc Imhotep Cray, M.D. 59
Marc Imhotep Cray, M.D. 60
Functional Significance of the Autonomic Nervous System
Organ system integration
Parasympathetic Discrete innervation
Energy conservation
Sympathetic Highly distributed innervation, global responses
Energy expenditure
Fight or flight responses
Marc Imhotep Cray, M.D. 61
Functional Significance of the Autonomic Nervous System (2)
Dual innervation
Organ responses moderated by both parasympathetic and sympathetic influences
Parasympathetic dominant at rest
Balance of opposing neurologic influences determines physiologic responses
Marc Imhotep Cray, M.D. 62
The medulla, located in brainstem, receives sensory input from different systemic and central receptors (e.g., baroreceptors and chemoreceptors) as well as signals from other brain regions (e.g., cerebral cortex and hypothalamus) Autonomic outflow from brainstem is divided into sympathetic and parasympathetic (vagal) branches
Autonomic Innervation of the Heart and Vasculature (1)
Source of graphic: Cardiovascular Pharmacology Concepts, RE Klabunde, http://www.cvpharmacology.com/norepinephrine.htm
Marc Imhotep Cray, M.D. 63
Efferent fibers of these ANS nerves travel to the heart and blood vessels where they modulate activity of these target organs S-A node is innervated by vagal (parasympathetic) and sympathetic fibers Sympathetic efferent nerves are present throughout the atria (especially in the S-A node) and ventricles, and in the conduction system of the heart Sympathetic nerves also travel to most arteries & veins Parasympathetic fibers innervate blood vessels in certain organs such as salivary glands, gastrointestinal glands, and in genital erectile tissue
Autonomic Innervation of the Heart and Vasculature (2)
Source of graphic: Cardiovascular Pharmacology Concepts, RE Klabunde, http://www.cvpharmacology.com/norepinephrine.htm
Marc Imhotep Cray, M.D. 64
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)
Marc Imhotep Cray, M.D. 65
Alpha-2 Adrenergic Receptor
Vasoconstriction
Modulation of NE release Presynaptic receptors on axon terminous
Spinal alpha-2 receptors mediate analgesia Agonists used clinically as epidural and
spinal analgesics
Sedation
Marc Imhotep Cray, M.D. 66
Beta-1 Adrenergic Receptor
Exclusive to myocardium
Agonists
Increase HR, contractility, and impulse conduction speed
May be arrhythmogenic
Antagonists
Decrease HR, contractility, and impulse conduction speed
Used clinically as anti-arrhythmics
Marc Imhotep Cray, M.D. 67
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
Marc Imhotep Cray, M.D. 68
Muscarinic Cholinergic Receptor
Myocardium Agonists decrease HR and AV conduction velocity Antagonists used clinically to increase HR and facilitate
AV conduction in heart block Iris sphincter muscle
Agoinists evoke pupillary constriction (miosis) Antagoinists evoke mydriasis
Gastrointestinal tract Agonists increase peristalsis and relax sphincters
Urinary bladder Agonists evoke urination
Detrusor muscle (bladder) contraction Trigone (sphincter) relaxation
Marc Imhotep Cray, M.D. 69
Source: Barrett KE, Boitano S, Barman SM, Brook HL, Ganong’s Review of Medical Physiology 24e , Fig 13-2, Pg.258, McGraw-Hill 2012
Cholinergic nerves red noradrenergic nerves
blue Preganglionic nerves are
solid lines Postganglionic nerves are
dashed lines
Organization of Sympathetic and Parasympathetic Nervous Systems
Marc Imhotep Cray, M.D. 70
Effect of ANS on Organ Systems
Marc Imhotep Cray, M.D. 71
Autonomic and Somatic 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
Marc Imhotep Cray, M.D. 72
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)
β3 Epi > Norepi ↑ [cAMP] Isoproterenol
Signaling Mechanisms and Pharm. of ANS Receptor Subtypes- SANS
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol 1,4,5-triphosphate;
M1-5, muscarinic receptors (five subtypes);
N1, nicotinic receptor at the neuromuscular junction; N2, nicotinic receptor at autonomic ganglia; Norepi,
norepinephrine.
Marc Imhotep Cray, M.D. 73
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 Pharm. of ANS Receptor Subtypes- PANS
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol 1,4,5-triphosphate;
M1-5, muscarinic receptors (five subtypes);
N1, nicotinic receptor at the neuromuscular junction; N2, nicotinic receptor at autonomic ganglia; Norepi,
norepinephrine.
Marc Imhotep Cray, M.D. 74
THE END, THANK YOU FOR YOUR ATTENTION
Additional learning tools for this presentation Companion Notes: ANS Summary 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
Next Lecture: ANS Pharmacology-Cholinergic Agents
