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
Marc Imhotep Cray, M.D.
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Topics Outline Homeostasis Basic Neuroanatomy and Neurophysiology of ANS Neurotransmitters Receptors Receptor-Ligand Interactions & Signal Transduction Autonomic and Somatic Pharmacology Terminology Marc Imhotep Cray, M.D.
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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 Marc Imhotep Cray, M.D.
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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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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 Marc Imhotep Cray, M.D.
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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 Marc Imhotep Cray, M.D.
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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 organism, that it was suggested (Cannon, 1929) that a specific designation for these states be employed – homeostasis”
Courtesy National Library of Medicine
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 Marc Imhotep Cray, M.D.
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Homeostasis (1) ď Ž
ď Ž
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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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 Marc Imhotep Cray, M.D.
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Homeostasis (3) Nervous
versus
Endocrine
Wired
Wireless
Neurotransmitters
Hormones Hormones
Short Distance Distance Short
Long Distance Distance Long
Closeness
Receptor Specificity
Rapid Onset
Delayed Onset
Short Duration
Prolonged Duration
Rapid Response
Regulation
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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 stretch receptors, chemo-, baro-, osmo-, and thermoreceptors etc.
SET POINT
ERROR SIGNAL
EFFECTOR
CONTROLLED VARIABLE (SEE NEXT SLIDE)
Important variable maintained within a normal range Marc Imhotep Cray, M.D.
+
-
Negative feedback: Initiation of responses that counter deviations of controlled variables from their normal range
NEGATIVE FEEDBACK Effector opposes stimulus
Redrawn after: Kibble JD, Halsey CR, Homeostasis. In: Medical Physiology -The Big Picture; McGraw-Hill , 2009; 2.
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Examples of Physiologic Controlled Variables & Set Points Controlled Variable (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
Typical Set Point Value 100 mm Hg 40 mm Hg pH 7.4 90 mg/dL (5 mM) 98.4°F (37°C) 140 mEq/L 4.0 mEq/L 4.5 mEq/L 90 mm Hg 120 mL /min
Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology :The Big Picture. New York, NY: McGraw-Hill , 2009; 3. Marc Imhotep Cray, M.D.
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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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Example: Baroreceptor Reflex control of blood pressure COMPARATOR SENSOR stretch receptors in Aortic arch and Carotid sinus
SET POINT
N 95 mm Hg
+
EFFECTOR
ERROR SIGNAL
cardiac contractility, vascular tone, urinary fluid 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) Marc Imhotep Cray, M.D.
See Baroreflex pdf
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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 Marc Imhotep Cray, M.D.
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Baroreceptors & Chemoreceptors Mechanism Illustrated
Marc Imhotep Cray, M.D.
Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
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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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Organization of Nervous System CENTRAL NERVOUS SYSTEM (CNS)
BRAIN & SPINAL CORD
AFFERENT
EFFERENT
(Sensory)
(Motor)
NERVES
NERVES
EXTEROCEPTORS
INTEROCEPTORS
EFFECTOR ORGANS
SKELETAL MUSCLES
VOLUNTARY Monosynaptic Marc Imhotep Cray, M.D.
PERIPHERAL NERVOUS SYSTEM (PNS)
SOMATIC
AUTONOMIC
SMOOTH MUSCLE, CARDIAC MUSCLES AND GLANDS INVOLUNTARY 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)
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Generic Neuron Anatomy Basic structural unit of nervous system >>> neuron
http://en.wikipedia.org/wiki/Neuron
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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
Marc Imhotep Cray, M.D.
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Sympathetic Nervous System Wiring Dorsal root ganglion
Intermediolateral cell column (IML)
Sympathetic trunk Gray ramus White ramus
See: ANS Summary Notes Marc Imhotep Cray, M.D.
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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)
Marc Imhotep Cray, M.D.
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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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ANS Neurotransmitters Class
Chemical
Synthesis
Small molecule Transmitters Acetylcholine
Catecholamines
Dopamine
Norepinephrine
Choline + acetyl CoA, via enzyme Choline Acetyltransferase From the amino acid tyrosine via the enzyme Tyrosine hydroxylase in the catecholamine pathway From dopamine in the catecholamine pathway
Postsynaptic Receptors
Signal Termination
Functions ANS
Nicotinic (cation channel) Muscarinic (G-protein– coupled) D1 (stimulatory G- protein– coupled) D2 (inhibitory G-protein– coupled)
Extracellular hydrolysis by Acetylcholinestrase
Movement control Cognition
Reuptake
ANS Movement control General affect
α & β Adrenergic receptors
Reuptake or breakdown via the enzymes monoamine oxidase and catechol–Omethyltransferase
ANS Alertness General affect
NB: Epinephrine is a catecholamine released upon stimulation of SANS, produced in adrenal medulla. It is a neurohormone, not an ANS neurotransmitter Marc Imhotep Cray, M.D.
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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)
Post
Pre
Effector organ
Ganglion Marc Imhotep Cray, M.D.
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Anatomic Divisions of ANS
Parasympathetic (PANS) (CN3,7,9,10) & (S2-S4)
Sympathetic (SANS) T1-L2/L3
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 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 Marc Imhotep Cray, M.D.
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Schematized Anatomic Comparison of PANS & SANS (1) (click to expand)
Marc Imhotep Cray, M.D.
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Schematized Anatomic Comparison of PANS & SANS (2) Effectors: cardiac muscle, smooth mm, vascular endothelium, exocrine glands, and presynaptic nerve terminals Cranial or sacral cord ANS functions: circulation digestion respiration temperature sweating metabolism some endocrine gland secretions
Thoracic or lumbar cord Marc Imhotep Cray, M.D.
Parasympathetic Post
Pre Ganglion
Effector organ
Sympathetic Pre Ganglion
Post
Effector organ
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Cranial Nerve Parasympathetic Innervations
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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 segment
Motor neuron
Myelinated with a high conduction velocity
In contrast
Postganglionic neurons of ANS are unmyelinated w a low conduction velocity
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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
Marc Imhotep Cray, M.D.
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Cholinergic Neurotransmission Denotes ACh
Parasympathetic Cranial or sacral cord
Post
Pre Ganglion
Sympathetic Thoracic or lumbar cord Marc Imhotep Cray, M.D.
Pre Ganglion
Effector organ
Denotes ACh
Post
Effector organs
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Adrenergic Neurotransmission
Adrenergic nerves
Norepinephrine is the neurotransmitter Locations
Postganglionic, sympathetic axons
Sympathetic Thoracic or lumbar cord
Pre Ganglion Denotes ACh
Marc Imhotep Cray, M.D.
Denotes Norepinephrine
Post
Effector 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 Marc Imhotep Cray, M.D.
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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 Marc Imhotep Cray, M.D.
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Summary of Actions of SANS & PANS (1) SYMATHETIC
PARASYMPATHETIC
widely distributed responses
discrete responses
Fright-Fight-or-Flight
Rest-Relax-Restoration
increase in heart rate
decrease in heart rate
decrease in gastric motility
increase in gastric motility
decrease secretion of salivary and digestive glands
increase in secretion of salivary and digestive glands
dilation of pupils
constriction of pupils
ejaculation
penile erection
vasoconstriction
contraction of smooth muscle in walls of bladder
dilation of bronchioles increased secretion of sweat glands Marc Imhotep Cray, M.D.
Of note: Cannon’s emergency reaction: An immediate sympathetic response to lifethreatening situations with both SANS and PANS overactivity. The PANS phenomenon includes vagal cardiac arrest with involuntary defecation and urination
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Summary of Actions of SANS and PANS (2) (click to expand)
Sympathetic Responses
Parasympathetic Responses
"fight, fright, flight" or fight or flight" system
heart rate increases blood pressure increases blood is shunted from skin & viscera to skeletal muscles blood glucose increase bronchioles dilate pupils dilate
"rest and digest" or "feed and breed" system
slows heart rate protects retina from excessive light (near lowers blood pressure empties the bowel and bladder increases gastrointestinal motility 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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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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ACh Synthesis, Release, and Fate (2) CHT - Choline transporter ChAT - Choline acetyl transferase VAT - Vesicle-associated transporter VAMPs - Vesicle-associated membrance proteins SNAP’s - Synaptosomeassociated proteins
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Cholinergic Neuron Pharmacology
Marc Imhotep Cray, M.D.
From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017.
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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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NE Synthesis, Release, and Fate (2) VMAT-Vesicular Monoamine transporter
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Adrenergic Neuron Pharmacology
Marc Imhotep Cray, M.D.
From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017.
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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.” Marc Imhotep Cray, M.D.
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Ligand-Receptor Interactions
Complementary conformations in 3 dimensions
Physiologic interactions are weak attractions
Similar to enzyme-substrate interactions 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 Marc Imhotep Cray, M.D.
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Steps in Signal Transduction Process See: G-protein Signal Transduction (video animations)
ď&#x201A;§ There are four general classes of signal transducing receptors: ď&#x201A;§ G-proteins are one and are referred to as serpentine receptors
Binding of neurotransmitter, hormone or drug to receptor> signaling of Gprotein> 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) Marc Imhotep Cray, M.D.
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GPCR structure & function (simplified) G-Protein Coupled Receptor Binding of NT, hormone or drug to receptor> signaling of Gprotein> enzyme activation> production of a secondmessenger> 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 Marc Imhotep Cray, M.D.
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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.)
Marc Imhotep Cray, M.D.
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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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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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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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Schematic of Cholinergic Receptor Locations Denotes ACh receptors
Parasympathetic Cranial or sacral cord
Post
Pre Ganglion
Sympathetic
Thoracic or lumbar cord Marc Imhotep Cray, M.D.
Pre Ganglion
Effector organ
Denotes ACh receptors
Post
Effector organs
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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
Marc Imhotep Cray, M.D.
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Schematic representation of Cholinergic Receptor Subtype Locations Parasympathetic M
N1
Cranial or sacral cord
Post
Pre Ganglion
Effector organ
Sympathetic Thoracic or lumbar cord Marc Imhotep Cray, M.D.
Pre
N1
Ganglion
Post
Effector organ
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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.
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Schematic representation of Adrenergic Receptor Locations
Alpha or Beta adrenergic receptors
Sympathetic Thoracic or lumbar cord
Pre Ganglion paravertebral , prevertebral or lateral
Marc Imhotep Cray, M.D.
Post
Effector organs
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Functional Significance of ANS (1) “Organ system integration & Dual innervation”
Organ system integration Parasympathetic
Discrete innervation Energy conservation
Sympathetic
Marc Imhotep Cray, M.D.
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
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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.
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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
Marc Imhotep Cray, M.D.
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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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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.
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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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Effect of ANS on Organ Systems (1) Sympathetic (NE) Receptor Îą1
Function Constriction of smooth muscles
Distribution Blood vessels and piloerectors in skin (vasoconstriction and goose bumps) Sphincters (bladder, gastrointestinal [GI])
Îą2
Inhibition of sympathetic autonomic ganglia (decreases SANS)
Marc Imhotep Cray, M.D.
Uterus and prostate (contraction) Eye (contraction of the radial muscle = pupillary dilation/mydriasis) Presynaptic ganglionic neurons GI tract (less important pharmacologically)
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Effect of ANS on Organ Systems (2) Sympathetic (NE) Receptor β1
Function
Distribution|Organ
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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Effect of ANS on Organ Systems (3) Parasympathetic (Ach) Receptor
Function
N (Nicotinic)
"Nerve to nerve" & SANS & PANS ganglia "nerve to muscle" Neuromuscular junction (NMJ) communication 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)
M (Muscarinic)
Distribution|Organ
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-proteinâ&#x20AC;&#x201C;coupled receptors that usually act through 2nd messengers Five subtypes: M1â&#x20AC;&#x201C;5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands (cholinergic sympathetic)
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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 Marc Imhotep Cray, M.D.
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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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Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- SANS AdrenergicReceptor 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)
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Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- PANS CholinergicReceptor 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
M1â&#x20AC;&#x201C;5
Acetylcholine
Various
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Atropine, benztropine, ipratropium
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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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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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Summary: Take Home Points (2) ď&#x192;&#x2DC; By using drugs that mimic or block actions of chemical transmitters and / or their receptor mechanisms, we can selectively modify autonomic functions ď&#x192;&#x2DC; 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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THE END
See next slide for further study tools. Marc Imhotep Cray, M.D.
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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):753â&#x20AC;&#x201C;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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