ANS Pharmacology Introduction to the to the... · ANS Pharmacology Introduction to the ... -The Big...

transcript

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

Topics Outline

Homeostasis Basic Neuroanatomy and Neurophysiology

Hypothalamus

Neurotransmitters

Receptors

Autonomic and Somatic Pharmacology Terminology

GOAL OF REVIEW

“ 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

Learning Objectives

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

Autonomic Nervous System (ANS)

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

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

Components of a negative feedback control system

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

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

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

Anatomy of hypothalamic nuclei & homeostatic

functions hypothalamus (2)

Hypothalamus (3)

Click for full size view

Diagram from Kiernan JA, Basic functional neuroanatomy pdf

From: Kiernan JA, Basic functional neuroanatomy pdf

Hypothalamus (4)

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

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

Autonomic (Visceral) Reflex

Afferent fibers from periphery to CNS

CNS integration Cortex

Thalamus

Hypothalamus

Medulla

Spinal cord

Efferent fibers from CNS to periphery

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

Effector

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.

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

Organization of Sympathetic and Parasympathetic Nervous Systems

Schematized Anatomic Comparison

Ganglion Effector

organs

Post Thoracic or lumbar

Pre Ganglion Effector

Post Cranial or sacral cord

Parasympathetic

Sympathetic

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)

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

Cholinergic Neurotransmission

Ganglion Effector

organs

Ganglion Effector

Parasympathetic

Sympathetic Denotes ACh

Denotes ACh

Neurochemical Transmission in the PNS

Adrenergic nerves

Norepinephrine is the neurotransmitter

Locations

Postganglionic, sympathetic axons

Ganglion Effector

organs

Sympathetic Denotes Norepinephrine

Denotes ACh

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

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

Organizational Summary of the ANS

From: Costanzo L., Neurophysiology: In BRS Physiology , Fig. 2-1 pg. 32, LLW 5thEd , 2011

Generic Neuron Anatomy

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

structural unit of nervous system >>> neuron

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

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

Action Potential Propagation

From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. , Fig. 6-22 & 623 Pg. 156-157 McGraw-Hill 2008

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

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

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

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

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

Source of illustrations: VANDER’S HUMAN PHYSIOLOGY: THE MECHANISMS OF BODY FUNCTION, 11th ed. , Pg. 177-79, McGraw-Hill 2008

Spinal Nerve (1)

Source: Anatomy 530a at UWO (Functional Neuroanatomy) http://instruct.uwo.ca/anatomy/530/530notes.htm

Spinal Nerve (2)

Projection of sympathetic preganglionic & postganglionic fibers

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

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

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)

ACh Synthesis, Release, and Fate (2)

Source: http://www.neurophysiology.ws/autonomicns.htm

Synthesis and fate of synaptically released acetylcholine at cholinergic synapse.

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)

NE Synthesis, Release, and Fate

NE Synthesis, Release, and Fate (2)

Source: E. Klabunde, http://www.cvpharmacology.com/norepinephrine.htm

Synthesis and fate of synaptically released norepinephrine at adrenergic synapse.

NE Synthesis, Release, and Fate (3)

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.)

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.

Cholinergic Receptors

Activated by ACh and cholinergic drugs

Anatomic distribution

Postganglionic, parasympathetic neuroeffector junctions

All autonomic ganglia, whethe parasympathetic or sympathetic

Somatic neuromuscular junctions

Cholinergic Receptor Locations

Ganglion Effector

organs

Ganglion Effector

Parasympathetic

Sympathetic Denotes ACh receptors

Denotes ACh receptors

Cholinergic Receptor Subtypes

Cholinergic Receptor Subtype Locations

Ganglion Effector

organs

Ganglion Effector

Parasympathetic

Sympathetic

Adrenergic Receptors

Activated by NE, Epi, and adrenergic drugs

Anatomic distribution

Postganglionic, sympathetic, neuroeffector junctions

Subtypes

Alpha-1, 2; Beta-1, 2, 3

Adrenergic Receptor Locations

Sympathetic

Ganglion Effector

organs

Alpha or Beta

adrenergic receptors

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

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

G-protein-linked 2nd messengers (2)

From: Modified from First Aid for the USMLE Step 1 2012 , Pg. 263

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

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

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

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

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)

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

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

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

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

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

Effect of ANS on Organ Systems

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

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.

Cholinergic-Receptor

Physiologic Agonist Signaling Mechanism

Pharmacologic Agonist

Pharmacologic Antagonist

N1=NM Acetylcholine Ionotropic receptor

Nicotine D-Tubocurarine

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.

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

ANS Pharmacology Introduction to the to the... · ANS Pharmacology Introduction to the ... -The Big...

Documents