Principles of Autonomic

Pharmacology
VMED 5223
George M. Strain
 Features of the ANS
• function: to regulate the various body
organ systems during times of
physiological war and peace
• both efferent (motor) and afferent
(sensory) components
• both peripheral and central components
• interacts with endocrine and immune
systems
 Comparison of somatic and
autonomic nervous systems
ANS SOMATIC NS
Innervation: heart sense organs
smooth muscle skeletal muscle
glands - exocrine & bones & joints
endocrine
Control: not consciously mostly conscious
controlled
Effect: modify on-going initiate activity
activity
Composition: synapses outside synapses in CNS
CNS
 Functional Divisions of the ANS
• sympathetic nervous system (SNS, thoraco-
lumbar division) - response to stress (fight-or-
flight)
• parasympathetic nervous system (PSNS,
cranial-sacral division) - homeostatic function
• enteric nervous system (ENS) - regulation of
gastrointestinal function; autonomous
 Classification of neurons by
transmitter released
• Adrenergic
– norepinephrine (NE)
– epinephrine (EPI)
– dopamine (DA)
• Cholinergic (ACh)
• Other (non-adrenergic, non-cholinergic,
NANC)
 Adrenergic
• Release norepinephrine - "N ohne
radikal"
– most post-ganglionic sympathetic nerves
(except sweat glands, which are
sympathetic cholinergic in most species)
– adrenal medulla – NE secondary to EPI,
but species dependent
– CNS
 Adrenergic
• Release epinephrine
– adrenal medulla chromaffin cells
– CNS
• Release dopamine
– intestines, kidney
– CNS
Cholinergic - release acetylcholine

• pre-ganglionic SNS and PSNS

• post-ganglionic PSNS
• post-ganglionic SNS to sweat glands
(except horse, sheep, some human)
• neuromuscular junction (NMJ)
• CNS (99% muscarinic)
 Other (NANC)
• serotonin (5-hydroxytryptamine)
• glycine & GABA - inhibitory
• glutamate & aspartate - excitatory
• peptides: substance P, VIP, CCK, etc
• histamine
• amino acids, purines, indoles, etc
 Comparison of SNS and PSNS

SNS PSNS
pre-ganglionic: cholinergic, short axons cholinergic, long axons

post-ganglionic: adrenergic, long axons cholinergic, short axons

distribution: general, great specific, little

ramification ramification
function: fight-or-flight homeostasis

response duration: relatively long short (AChE)

 Autonomic Nervous System
SNS PSNS NMJ

CNS
ACh ACh ACh PNS

EPI ACh
NE

NANC
NE ACh ACh ACh
Red = SNS Blue = PSNS
 Classification of autonomic
receptors
• Adrenergic receptors - activate a G protein,
then a second messenger (metabotropic)
– alpha (a)
– beta (b)

• Cholinergic receptors
– muscarinic (metabotropic)
– nicotinic (ionotropic)
 Adrenergic Receptor Subtypes

• alpha (a) - excitatory except in the gut

§ a 1 (postsynaptic) - blood vessels, eye,
sphincters, genitals, bladder, gut, liver,
heart [3 further subtypes]
§ a 2 (presynaptic in peripheral NS for
negative feedback; pre- and postsynaptic
in CNS); also on blood vessels,
pancreas, platelets [3 further subtypes]
 Adrenergic Receptor Subtypes
• beta (b) - inhibitory except in the heart
§ b1 - heart, kidney; generally excitatory

§ b2 - lungs, vascular, gastrointestinal,

genitourinary smooth muscle, liver, skeletal
muscle (glycogenolysis, K+ uptake); generally
inhibitory

§ b3 - adipocytes – lipolysis (most species;

horse b2)
 Pre-synaptic adrenergic
receptors
§ presynaptic a 2 receptors are acted on
by released NE to decrease further NE
release

§ presynaptic b receptors are acted on

by circulating EPI from adrenals to
facilitate NE release
 Cholinergic Receptor Types
• Muscarinic – cardiac, smooth muscle,
glands, ganglia
– PSNS postganglionic synapses
– SNS postganglionic synapses on sweat glands
(some species), skeletal muscle blood vessels
– M1 - M5 ; metabotropic, 2nd messengers adenylyl
cyclase or phospholipase C
• Nicotinic - ionotropic
– NN - neuronal (ganglia, CNS)
– NM - skeletal muscle
 Autonomic Nervous System
SNS PSNS NMJ

CNS
ACh N ACh N ACh N PNS

EPI ACh N
NE
a, b

NE a, b ACh M ACh M ACh N

 Autonomic responses
• generally make sense within the
concepts of "fight-or-flight" vs
homeostasis

• cholinergic effects are generally

antagonistic to adrenergic effects,
but….
Exceptions to antagonistic effects
• chorda tympani
– PSNS - thin, copious saliva (muscarinic)
– SNS - thick saliva (alpha)
• piloerector muscles - SNS only
• uterus - may be only SNS, response
depends on state
– pregnant - contract (alpha)
– non-pregnant - relax (beta)
Exceptions to antagonistic effects

• sweat glands - SNS only, but the post-

ganglionic neurons vary as to the
released transmitter
– ACh in most species, including most
human sweat glands
– NE in horse, sheep, some human glands
Exceptions to antagonistic effects
• blood vessels
– PSNS is negligible - where it does occur it
causes dilation: penis, submaxillary gland,
tongue
– SNS
• coronary, pulmonary - dilation
• skin, mucosa, viscera - constriction
• skeletal m.
– constriction (NE – a 1) or
– dilation (low EPI - b)
Acetylcholine Metabolism

acetylcholine
ACh choline + acetate
esterase (AChE)

• metabolism is in the synaptic cleft; choline is

recaptured in the presynaptic terminal
• other esterases present in body also
Possible drug sites/mechanisms:
• block ACh synthesis - hemicholinium, blocks
choline entrance to cell
• block ACh release - botulinum toxin, lead
• inhibition of AChE - organophosphates,
carbamates
• block of ACh receptors - atropine, curare
• direct receptor stimulation - bethanechol,
nicotine
Catechol: 3,4-
dihydroxyphenyl-
(3,4-dihydroxyphenylalanine)
 Catecholamine Metabolism
• monoamine oxidase (MAO) - mitochondria

• catechol-O-methyl transferase (COMT) -

synaptic cleft

• both enzymes act sequentially: MAO then

COMT, or COMT then MAO; no clinically
useful COMT-related drugs
Possible drug sites/mechanisms:
• interference with synthesis - a-methyl-p-tyrosine,
false transmitters (a-methyl dopa)
• block of NE active uptake by pre-synaptic
membrane - cocaine
• block of NE active transport into vesicles -
reserpine
• triggered release of NE from pre-synaptic
terminal into cleft - amphetamine
• triggered release of NE from vesicles -
guanethedine
Possible drug sites/mechanisms:
• block of NE release from action potential -
bretylium
• direct stimulation of receptors - isoproterenol,
phenylephrine
• block of receptors – propranolol (b),
phenoxybenzamine (a)
• MAO inhibition - tranylcypromine, pargyline
• COMT inhibition - none yet
 Ganglionic Transmission
• nicotinic - major effect and first effect
(fast EPSP)
• alpha adrenergic/DA from chromaffin
cell - IPSP ends the fast EPSP
• muscarinic - ends the IPSP with an
EPSP, preparing the post-synaptic cell
to be acted on again
• peptidergic – very slow EPSP
Sympathetic Ganglia action
potential B
transmembrane
potential

fast EPSP IPSP slow EPSP late, slow EPSP

-70 m V

NN M2 + CA M1 peptide

A electrode

preganglionic neuron M1
NN

P postganglionic neuron
CA

acetylcholine
catecholamine
peptide
M2

interneuron
Division Dominance by Organ
• sympathetic • parasympathetic
– peripheral – heart
vasculature – eye
– sweat glands – gut
– bladder
 Required:
• Table 5.1 - Typical Responses of Effector
Tissues To Sympathetic and
Parasympathetic Nerve Impulses

In Adams: Veterinary Pharmacology and

Therapeutics, 8th edition, pp 73-74

• YOU MUST KNOW THE CONTENTS OF

THIS TABLE!