Download Introduction to Autonomic Pharmacology

Introduction to Autonomic
Pharmacology
Gloanne C. Adolor, RPh, MD, MS, MBA, FPCP
Outline
• Review of ANS (favorite YL5 subjects)
• Drugs Acting on the ANS
– Cholinoceptor-Activating and
Cholinesterase-Inhibiting Drugs
– Cholinoceptor-Blocking Agents
Main Reference: Basic and Clinical
Pharmacology by Katzung (11th ed).
Autonomic Nervous System
(ANS)
• The ANS consists of motor neurons
that:
– Innervate smooth and cardiac muscle and
glands
– Make adjustments to ensure optimal
support for body activities
– Operate via subconscious control
– Have viscera as most of their effectors
Functions and origins of the ANS
ANS branches
• cholinergic fibers - acetylcholine
• adrenergic fibers noradrenaline (norepinepherine
NE)
ANS Versus Somatic Nervous
System (SNS)
• The ANS differs from the SNS in the
following three areas
– Effectors
– Efferent pathways
– Target organ responses
Comparison of Somatic and
Autonomic Systems
Efferent Pathways
• Heavily myelinated axons of the somatic
motor neurons extend from the CNS to
the effector
• Axons of the ANS are a two-neuron
chain
– The preganglionic (first) neuron has a
lightly myelinated axon
– The ganglionic (second) neuron extends to
an effector organ
Effectors
• The effectors of the SNS are skeletal
muscles
• The effectors of the ANS are cardiac
muscle, smooth muscle, and glands
Efferent (motor) nerves
• Two systems
– Autonomic nerves (unconscious)
• Eg cardiac output, respiration, etc
– Somatic nerves (voluntary)
Interactions of the Autonomic
Divisions
• Most visceral organs are innervated by both
sympathetic and parasympathetic fibers
• This results in dynamic antagonisms that
precisely control visceral activity
• Sympathetic fibers increase heart and
respiratory rates, and inhibit digestion and
elimination
• Parasympathetic fibers decrease heart and
respiratory rates, and allow for digestion and
the discarding of wastes
Role of the Parasympathetic
Division
• Concerned with keeping body energy use low
• Involves the D activities – digestion, defecation, and
diuresis
• Its activity is illustrated in a person who relaxes after
a meal
– Blood pressure, heart rate, and respiratory rates are low
– Gastrointestinal tract activity is high
– The skin is warm and the pupils are constricted
Role of the Sympathetic
Division
• The sympathetic division is the “fight-or-flight” system
• Involves E activities – exercise, excitement, emergency,
and embarrassment
• Promotes adjustments during exercise – blood flow to
organs is reduced, flow to muscles is increased
• Its activity is illustrated by a person who is threatened
– Heart rate increases, and breathing is rapid and deep
– The skin is cold and sweaty, and the pupils dilate
Visceral Reflexes
Figure 14.7
Action of ANS drugs
• Drugs to block ANS chemical
transmission
• Drugs to mimic ANS action
• ANS drugs can modify a variety of
effector tissues
– Cardiac muscle
– Blood pressure
– Exocrine glands
Cholinergic transmission
• Acetylcholine is at motor neuron and CNS nerve
terminals
• Synthesized from
– Acetyl coA (mitochondria)
– Choline (dietary)
– Catalyzed by choline acetyl transferase (ChAT)
• Release is dependent on Calcium (Ca2+)
• Causes muscle contraction
Acetylcholine
•
•
•
•
•
Identified 1921
Present at all NMJ and also CNS
Synthesized in the axon terminal
Diffuses across synaptic cleft
Two receptor subtypes
– Nicotinic ACh receptors
– Muscarinic ACh receptors
Neuromuscular Junction
Synaptic End Plate
1999 Sinauer Associates Inc
T.Caceri Veterinary Histology 2003
Acetylcholine and NMJ
Characteristics of a
neurotransmitter
• Synthesized in (or transported to)
presynaptic terminal
• Stored in vesicles
• Regulated release
• Receptor located on postsynaptic
membrane
• Termination of action
Neurotransmitter Effects
• All somatic motor neurons release Acetylcholine
(ACh), which has an excitatory effect
• In the ANS:
– Preganglionic fibers release ACh
– Postganglionic fibers release norepinephrine or ACh and the
effect is either stimulatory or inhibitory
– ANS effect on the target organ is dependent upon the
neurotransmitter released and the receptor type of the
effector
Synaptic vesicles at the NMJ (EM)
Heuser and Heuser
Presynaptic events
• Calcium influx releases synaptic
vesicles from microtubules
• Movement of synaptic vesicles to
sites of action
• Interaction of specific proteins
• Vesicle docking
• Membrane fusion
• Calcium dependent exocytosis
Synthesis and release of
neurotransmitters
Synaptic Transmission in: Basic Neurochemistry 6th Edition
Fusion proteins regulate
neurotransmitter release
• Vesicle proteins
– Synaptobrevin
• Presynaptic membrane proteins
– Syntaxins
– SNAP-25
The SNARE hypothesis
SNARE (Soluble
N’ethylmalemide
sensitive fusion
Attachment
protein
REceptor)
A. Pestronk www.neuro.wustl.edu/neuromuscular 2003
Many presynaptic proteins
regulate neurotransmitter release
Synaptic Transmission in: Basic Neurochemistry 6 th Edition
Vesicular transport of NT – drug
implications
• Toxins targeting neurotransmitter
release
– Spider venom (excess ACh release)
– Botulinum (blocks ACh release)
• Tetanus
Postsynaptic events
•
•
•
•
Boutons have multiple nerve terminals
Simultaneous release
Stimulation of contraction via AP
Acetylcholine degraded after action
– ACETYLCHOLINESTERASE (AChE)
RECEPTORS
Cholinergic receptors
• Two classes for acetylcholine
• Nicotinic and muscarinic
– Nicotinic are ion channels
Ionotrophic
– Muscarinic are G-protein coupled
Metabotrophic
Nicotinic Receptors
• Nicotinic receptors are found on:
– Motor end plates (somatic targets)
– All ganglionic neurons of both sympathetic
and parasympathetic divisions
– The hormone-producing cells of the
adrenal medulla
• The effect of ACh binding to nicotinic
receptors is always stimulatory
Muscarinic Receptors
• Muscarinic receptors occur on all
effector cells stimulated by
postganglionic cholinergic fibers
• The effect of ACh binding:
– Can be either inhibitory or excitatory
– Depends on the receptor type of the target
organ
Ionotropic AChR
• Consist of five polypeptide
subunits
• Receptors vary in:
– subunit structure
– agonist sensitivity
– distribution
• Mediate fast synaptic
transmission
Nicotinic AChR are sodium
channels
1999 Sinauer Associates Inc
Metabotropic AChR
• Five muscarinic AChR subtypes
• G protein coupled
• Slower synaptic transmission
via intracellular signaling
cascade
Muscarinic AChR activate Gproteins
1999 Sinauer Associates Inc
Many G proteins for many uses
G alpha class
Initiating signal
Downstream
signal
G alpha s
b-Adrenergic amines, Stimulates
glucagon, parathyroid adenylate cyclase
hormone, many others
G alpha i
Acetylcholine, aadrenergic amines,
many neurotransmitters
Inhibits adenylate
cyclase
G alpha t
Photons
Stimulates cGMP
phosphodiesterase
G alpha q
Acetylcholine, aadrenergic amines,
many neurotransmitters
Increases IP3 and
intracellular calcium
G alpha 13
Thrombin, other
agonists
Stimulates Na+
and H+ exchange
G proteins activate enzymes,
most commonly the following:
• Adenylyl cyclase - converts ATP into
cyclic AMP (cAMP)
• Phospholipase C - cleaves a lipid
(inositol phospholipid) into inositol-1,4,5trisphosphate (IP3, a hydrophilic sugar)
and diacylglycerol (DAG, a lipid in the
membrane)
Phospholipase C activates 2 signaling
pathways
Martini,
Fundamentals of
Anatomy and Physiology, 5th Edition,
Prentice Hall 2001
The Organization of the
Sympathetic Nervous System
The
Organization
of the
Sympathetic
Nervous
System
Thoracic
Lumbar
Martinit,
Fundamentals of
Anatomy and Physiology,
5th Edition,
Prentice Hall 2001
Sympathetic Synapses
Note location of
synapse
The Organization of the Sympathetic
Nervous System: The Adrenal Medulla
The Adrenergic
Synapse
The
Adrenergic
Synapse
From: Basic and
Clinical Pharmacology
8th edition, B.G.
Katzung; Lange 2001
Adrenergic receptors
• Four receptor subtypes
 a1, a2, b1, b2
• G protein linked
– Bind either norepinephrine or epinephrine
Adrenergic Receptors
• The two types of adrenergic receptors are
alpha and beta
• Each type has two or three subclasses
(a1, a2, b1, b2 , b3)
• Effects of NE binding to:
– a receptors is generally stimulatory
– b receptors is generally inhibitory
• A notable exception – NE binding to b
receptors of the heart is stimulatory
Adrenergic Receptors
It will be important to understand how alpha and beta receptors
From: Basic and
and the subtypes are distinguished:
Clinical Pharmacology
•Originally by relative potency
8th edition, B.G.
Katzung; Lange 2001
•Now by cloning
Pharmacologic Demonstration of
Adrenoreceptor Types
• The existence of
alpha and beta
receptors was
originally proposed
by Ahlquist in 1948
• Latter Lands et al
1967, suggested
the beta1 beta2
distinction
Adrenergic Receptors
Adrenergic transmission
•
•
•
•
Catecholamines are the neurotransmitters
Complex synthesis
Secretion at nerve terminals and adrenal glands
Adrenal glands
– Two adrenal glands
– Consist of cortex (outer) medulla (inner)
medulla secretes:
– Epinephrine (adrenaline)
– Norepinephrine
NE and E are
released at nerve
terminals and
secreted by the
adrenal medulla
Norepinephrine and epinephrine
•
•
•
•
Catecholamines
Synthesized from dopamine
Present in CNS and sympathetic nerves
Widely distributed, general behavioral
arousal eg raise blood pressure etc
• Stress increases release of norepinephrine
Epinephrine targets a G-protein coupled
receptor
Beta-adrenergic receptor
pathway 1
• On binding of ligand, the
receptor activates a G
protein.
Dual Innervation
• Most of viscera receive nerve fibers from both
parasympathetic and sympathetic divisions
• Both divisions do not normally innervate an
organ equally
Dual Innervation
• Antagonistic effects
– oppose each other
– exerted through dual innervation of same effector
• heart rate decreases (parasympathetic)
• heart rate increases (sympathetic)
– exerted because each division innervates different
cells
• pupillary dilator muscle (sympathetic) dilates pupil
• constrictor pupillae (parasympathetic) constricts pupil
Dual Innervation
• Cooperative effects seen when 2 divisions act on different
effectors to produce a unified effect
– parasympathetics increase salivary serous cell secretion
– sympathetics increase salivary mucous cell secretion
• ANS cooperation is best seen in control of the external
genitalia
– Parasympathetic fibers cause vasodilation and are responsible for
erection of the penis and clitoris
– Sympathetic fibers cause ejaculation of semen in males and reflex
peristalsis in females
Dual Innervation of the Iris
Without Dual Innervation
• Some effectors receive only sympathetic
– adrenal medulla, arrector pili muscles, sweat
glands and many blood vessels
• Sympathetic tone
– a baseline firing frequency
– vasomotor tone provides partial constriction
• increase in firing frequency = vasoconstriction
• decrease in firing frequency = vasodilation
• can shift blood flow from one organ to another as
needed
– sympathetic stimulation increases blood to skeletal and cardiac
muscles -- reduced blood to skin
Sympathetic and Vasomotor Tone
Sympathetic division
prioritizes blood vessels
to skeletal muscles and
heart in times of
emergency.
Blood vessels to skin
vasoconstrict to
minimize bleeding if
injury occurs during
stress or exercise.
Regulation of ANS
• Autonomic reflexes control most of activity of
visceral organs, glands, and blood vessels.
• Autonomic reflex activity influenced by
hypothalamus and higher brain centers, but it is
the hypothalamus that has overall control of the
ANS.
• Sympathetic and parasympathetic divisions
influence activities of enteric (gut) nervous system
through autonomic reflexes.
Levels of ANS Control
• The hypothalamus is the main
integration center of ANS activity
• Subconscious cerebral input via limbic
lobe connections influences
hypothalamic function
• Other controls come from the cerebral
cortex, the reticular formation, and the
spinal cord
Hypothalamic Control
• Centers of the hypothalamus control:
– Heart activity and blood pressure
– Body temperature, water balance, and
endocrine activity
– Emotional stages (rage, pleasure) and
biological drives (hunger, thirst, sex)
– Reactions to fear and the “fight-or-flight”
system
Levels of ANS Control
Figure 14.9