AUTONOMIC PHARMACOLOGY

A. Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
AUTONOMIC PHARMACOLOGY

NERVOUS SYSTEM

Sympathetic
(Thoracolumbar)
Somatic Autonomic T1-T12
(voluntary) (involuntary) L1-L5

Parasympathetic
(Craniosacral)
CN 3,7,9,10
S2-S4
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SPINAL ROOTS OF ORIGIN

SYMPATHETIC (SANS)
Preganglionic fibers originate from
Thoracic (T1-T12) segments of the cord
Lumbar (L1-L5) segments of the cord
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SPINAL ROOTS OF ORIGIN

PARASYMPATHETIC (PANS)
Preganglionic motor fibers originate from
Cranial nerve nuclei III, VII, IX and X
Sacral segments (S2-S4)
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LOCATION OF GANGLIA
SYMPATHETIC
Most of the ganglia are located in 2 paravertebral
chains that lie along the spinal cord
Few (prevertebral) on the anterior aspect of the
aorta
Preganglionic fibers are short and the
postganglionic fibers are long
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LOCATION OF GANGLIA
PARASYMPATHETIC
Most of the ganglia are located in the organs
innervated, most distant from the spinal cord
Preganglionic fibers are long and the
postganglionic fibers are short
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NEUROTRANSMITTERS (NTAs)
4 FEATURES
1. Synthesis
2. Storage
3. Release
4. Termination of action
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NEUROTRANSMITTERS
A.CHOLINERGIC TRANSMISSION
Acetylcholine (ACh)
Primary transmitter in all autonomic ganglion
and parasympathetic postganglionic synapses
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NEUROTRANSMITTERS
A. CHOLINERGIC TRANSMISSION
1. Synthesis and storage
ACh is synthesize from acetyl-CoA and choline
by choline acetyltransferase
Inhibited by HEMICHOLINIUM
Actively transported into the vesicle for storage
Inhibited by VESAMICOL
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NEUROTRANSMITTERS
A. CHOLINERGIC TRANSMISSION
2. Release of ACh
Release of transmitter stores from vesicles
in the nerve endings requires the entry of
calcium and interaction between several
proteins in the vesicle
BOTULINUM TOXIN prevents the release
process
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NEUROTRANSMITTERS
A. CHOLINERGIC TRANSMISSION
3. Termination of action of ACh
Metabolized to acetate and choline by
acetylcholinesterase
Not excreted but recycled in the body
Drugs can inhibit acetylcholinesterase
AUTONOMIC PHARMACOLOGY

NEUROTRANSMITTERS
TERMINATION OF ACTION
By metabolism
Monoamine oxidase (MAO)
Cathecol-o-methly transferase (COMT)
Diffuse away from the synaptic cleft and
get metabolized elsewhere
AUTONOMIC PHARMACOLOGY

NEUROTRANSMITTERS
TERMINATION OF ACTION
Taken up to presynaptic cell
UPTAKE 1
Taken up to postsynaptic cell
UPTAKE 2
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DRUG EFFECTS ON THE SYNTHESIS, STORAGE,
RELEASE AND TERMINATION OF ACTION OF ACh

HEMICHOLINIUM
Inhibits synthesis of ACh into the cell
VESAMICOL
Inhibits storage of ACh into the vesicle
BOTULINUM TOXIN
Inhibits the release of ACh

These drugs are not very useful for systemic therapy

because their effects are not sufficiently selective
AUTONOMIC PHARMACOLOGY

NEUROTRANSMITTERS
B. ADRENERGIC TRANSMISSION
Norepinephrine (NE)
Primary transmitter at the sympathetic
postganglionic synapses
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NEUROTRANSMITTERS
B. ADRENERGIC TRANSMISSION
1. Synthesis and storage
tyrosine hydroxylase

Tyrosine –--------------------DOPA
Decarboxylated to dopamine
Hydroxylated to norepinephrine
Tyrosine hydroxylase is inhibited by
METYROSINE
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NEUROTRANSMITTERS
B. ADRENERGIC TRANSMISSION
1. Synthesis and storage
NE and dopamine are transported into
vesicles and stored
MAO inactivates portions of the NTA in
the cytoplasm
MAO INHIBITORS may increase stores
RESERPINE inhibits the transport
AUTONOMIC PHARMACOLOGY

NEUROTRANSMITTERS
B. ADRENERGIC TRANSMISSION
2. Release and termination of action
Release mechanism is the same as ACh
Metabolism is not responsible for termination
of action
Diffusion and reuptake I reduce the
concentration and stop the action
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NEUROTRANSMITTERS
B. ADRENERGIC TRANSMISSION
2. Release and termination of action
Outside the cleft, it can be metabolized by
MAO and COMT and are excreted
GUANETHIDINE inhibits the release
MAO INHIBITORS inhibit the metabolism
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DRUG EFFECTS ON ADRENERGIC TRANSMISSION

METYROSINE
Inhibits the synthesis of NE
RESERPINE
Inhibits the storage of NE

These drugs have been used in several diseases because

they block sympathetic but not parasympathetic functions
AUTONOMIC PHARMACOLOGY

DRUG EFFECTS ON ADRENERGIC TRANSMISSION

GUANETHEDINE
Inhibits release of NE
MAO INHIBITORS
Inhibits metabolism of NE

These drugs have been used in several diseases because

they block sympathetic but not parasympathetic functions
AUTONOMIC PHARMACOLOGY

NEUROTRANSMITTERS
Acetylcholine [ACh (cholinergic)]
Norepinephrine [NE (adrenergic)]
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CHOLINERGIC
A nerve ending that releases acetylcholine as
the primary transmitter
Also a synapse in which acetylcholine is the
primary transmitter
AUTONOMIC PHARMACOLOGY

ADRENERGIC
A nerve ending that releases norepinephrine as
the primary transmitter
Also a synapse in which norepinephrine is the
primary transmitter
AUTONOMIC PHARMACOLOGY
All preganglionic fibers are cholinergic

md ACh heart (parasympathetic)

ACh
heart (sympathetic)

sp
AUTONOMIC PHARMACOLOGY

All postganglionic parasympathetic fibers are

cholinergic
A few postganglionic sympathetic fibers are
cholinergic
Sweating
Sympathetic
ACh
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Most postganglionic sympathetic fibers are

adrenergic
Exception: Postganglionic sympathetic fibers
are cholinergic
Thermoregulatory (eccrine) sweat glands
Vasodilator sympathetic fibers in the skeletal
muscles
AUTONOMIC PHARMACOLOGY

ADRENAL GLAND
Adrenal cortex and medulla
Ductless gland that functions as a ganglion
Postganglionic fibers are cholinergic
AUTONOMIC PHARMACOLOGY

COTRANSMITTERS
Other transmitter molecules in addition to the
primary agents (ACh or NE)
Contained in many autonomic nerves
Localized in the same vesicle as the primary
transmitter or in a separate population of vesicles
AUTONOMIC PHARMACOLOGY

COTRANSMITTERS
ATP, enkephalins, VIP, neuropeptide Y,
substance P, somatostatin
Involved in the modulation of synaptic
transmission
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
Also referred as cholinergic receptors
Respond to ACh and its analogs
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
Subdivided into
1. MUSCARINIC receptors
2. NICOTINIC receptors
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
1. MUSCARINIC receptors
Respond to muscarine (an alkaloid)
Respond to ACh
Mimics the effects of parasympathetic
G-protein coupled
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
1. MUSCARINIC receptors
Located primarily on autonomic effector cells
Heart
Blood vessels
Smooth muscles
Presynaptic nerve terminals
Exocrine glands
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
1. MUSCARINIC receptors
5 subtypes
3 are important in peripheral autonomic
transmission
M1-nerve endings
M2-heart, some nerve endings
M3-effector cells, smooth muscle, exocrine
glands, endothelium
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RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
2. NICOTINIC receptors
Respond to ACh
Respond to nicotine (another ACh mimic)
Do not respond to muscarine
Ligand-gated
 AUTONOMIC PHARMACOLOGY

RECEPTOR CHARACTERISTICS
A. CHOLINOCEPTORS
2. NICOTINIC receptors
2 major subtypes
Nn-neuronal (ANS ganglia)
Nm-neuromuscular endplate (skeletal muscle)
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RECEPTOR CHARACTERISTICS
CHOLINOCEPTORS

MUSCARINIC NICOTINIC
(G-protein coupled) (ion channel)
M 1, M 2, M 3 Nn, Nm
 AUTONOMIC PHARMACOLOGY
CHOLINOCEPTORS
M1 Nerve endings G-coupled Increase IP3

M2 Heart, some nerve endings G-coupled Decrease cAMP,

activates K+ channel

M3 Effector cells, smooth G-coupled Increase IP3

muscle, glands, endothelium

Nn ANS ganglia Ion channel Depolarizes, evokes

action potential

Nm Neuromuscular end plates Ion channel Depolarizes, evokes

action potential
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
Also referred as adrenergic receptors
Respond to NE
G-protein coupled
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
Subdivided into
1. ALPHA receptors
2. BETA receptors
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
1. ALPHA receptors
Located in
Blood vessels
Presynaptic nerve terminals
Blood platelets
Fat cells (lipocytes)
Neurons in the brain
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
1. ALPHA receptors
2 subtypes
ALPHA1-effector tissues, smooth muscles,
glands
ALPHA2-nerve endings, some smooth
muscles
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
2. BETA receptors
Located on
Most types of smooth muscle
Cardiac muscle
Some presynaptic nerve terminal
Lipocytes
Brain
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RECEPTOR CHARACTERISTICS
B. ADRENOCEPTORS
2. BETA receptors
3 major subtypes
BETA1-heart and kidney
BETA2-lungs, uterus, liver, heart
BETA3-fat or adipose tissue
AUTONOMIC PHARMACOLOGY

RECEPTOR CHARACTERISTICS
ADRENOCEPTORS

ALPHA BETA
(G-protein coupled) (G-protein coupled)
ALPHA1 BETA1
ALPHA2 BETA2
BETA3
 AUTONOMIC PHARMACOLOGY
ADRENOCEPTORS
Alpha1 Effector tissues, G- Increase Increase Ca2+ ,causes
smooth muscle, IP3 contraction, secretion
glands
Alpha2 Nerve endings, some G- Decrease Decrease transmitter
smooth muscle cAMP release, causes
contraction
Beta1 Cardiac muscle, G- Increase Increase heart rate, force,
kidney cAMP increase renin release

Beta2 Lungs, uterus, heart G- Increase Relax smooth muscle,

cAMP increase glycogenolysis,
increase HR, force
Beta3 Adipose cells G- Increase Increase lipolysis
cAMP
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CENTRAL INTEGRATION
Predominant state in any situation
SYMPATHETIC
Ergotrophic (energy expenditure)
”Fight or flight” response
AUTONOMIC PHARMACOLOGY

CENTRAL INTEGRATION
PARASYMPATHETIC
Tropotrophic (energy saving)
Leading to growth
”Rest and digest”
 RESPONSES OF MAJOR ORGANS TO
AUTONOMIC NERVE IMPULSES
Parasympathetic
Sympathetic Stimulation
Organ Stimulation

Increased heart rate beta1 (& beta2) Decreased heart rate

Increased force of contraction beta1 (& beta2) Decreased force of contraction

Heart

Increased conduction velocity Decreased conduction velocity

Constriction (alpha1)
Arteries Dilation
Dilation (beta2)

Constriction (alpha1)
Veins
Dilation (beta2)

Bronchial muscle contraction

Lungs Bronchial muscle relaxation (beta2)
Increased bronchial gland
secretions

Decreased motility (beta2) Increased motility

Gastro-
intestinal tract
Contraction of sphincters (alpha) Relaxation of sphincters
 RESPONSES OF MAJOR ORGANS TO
AUTONOMIC NERVE IMPULSES
Parasympathetic
Sympathetic Stimulation
Organ Stimulation
Glycogenolysis (beta2 & alpha)

Liver Gluconeogenesis (beta2 & alpha) Glycogen synthesis

Lipolysis (beta2 & alpha)

Kidney Renin secretion (beta2)

Detrussor relaxation (beta2) Detrussor contraction

Bladder
Contraction of sphincter (alpha) Relaxation of sphincter

Contraction of pregnant uterus (alpha)

Uterus
Relaxation of pregnant and non-pregnant
uterus (beta2)

Constricts pupil
Eye Dilates pupil (alpha)
Increased lacrimal gland
secretions

Submandibular & parotid

Viscous salivary secretions (alpha) Watery salivary secretions
glands
AUTONOMIC PHARMACOLOGY

PRESYNAPTIC REGULATION
Principle of negative feedback control
Eg, alpha receptors located on noradrenergic
terminals which are activated by NE and other
similar molecules
Activation diminishes further the release of NE
from these nerve endings
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PRESYNAPTIC REGULATION
AUTORECEPTORS
Presynaptic receptors that respond to
transmitter substances released by the
nerve endings
AUTONOMIC PHARMACOLOGY

POSTSYNAPTIC REGULATION
Up- and down-regulation are known to
occur in response to decreased or
increased activation of the receptors
Up regulation (agonist)
Down regulation (antagonist)
AUTONOMIC PHARMACOLOGY

PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION
Transmission involves different mechanisms
in different segments of the ANS
Some drugs produce highly specific effects
Others drugs are much less selective in their
actions
AUTONOMIC PHARMACOLOGY

PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION
LOCAL ANESTHETICS
Drug that block action potential
Very nonselective
Act on the process that is common to all
neurons
AUTONOMIC PHARMACOLOGY

PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION
Drugs that act on the biochemical processes
involved in transmitter synthesis and storage
are more selective
AUTONOMIC PHARMACOLOGY

PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION
Biochemistry of adrenergic transmission is
very different from cholinergic transmission
(Table 6-5 Katzung)
AUTONOMIC PHARMACOLOGY
PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

TYRAMINE AND AMPHETAMINE

Promote the release of NE
Effect is sympathetic
HEMICHOLINIUM
Blocks uptake of ACh
Slows synthesis of ACh
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PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

VESAMICOL
Prevents storage of ACh
BOTULINUM TOXIN
Prevents release ACh
AUTONOMIC PHARMACOLOGY

PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

NOREPHINEPHRINE
Binds alpha receptors
Causes activation (agonist)
PHENTOLAMINE
Binds alpha receptors
Prevents activation (antagonist)
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PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

ISOPROTERENOL
Binds beta receptors
Activates adenyl cyclase (agonist)
PROPRANOLOL
Binds to beta receptors
Prevents activation (antagonist)
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PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

NICOTINE
Causes skeletal muscle contraction
(agonist)
TUBOCURARINE
Prevents skeletal muscle contraction
(antagonist)
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PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

BETANECHOL
Binds muscarinic receptors
Activates (agonist)
ATROPINE
Binds muscarinic receptors
Prevents activation
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PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION

NEOSTIGMINE
Inhibits enzyme acetylcholinesterase
Prolongs and intensifies transmitter action
TRANYLCYPROMINE
Inhibits MAO
Increases stored transmitter pool