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DEPARTMENT OF PHARMACOLOGYFACULTY OF MEDICINE AND SURGERY
UNIVERSITY OF SANTO TOMAS
The NS and UTONOMIC DRUGS
Prof. Maria Minerva P. Calimag, MD, DPBA, FPSECP, MSc
Objectives of the lecture
The lecture consists of a general overview of the anatomy, physiology and neurochem-
istry of the sympathetic and parasympathetic subdivisions of the autonomic nervous sys-
tem. An overview of the steps in autonomic neurotransmission that can be affected by vari-ous pharmacological agents, with specific examples, is also provided.
At the end of the Course, with 75% accuracy, the student should be able to: 1) discuss
the synthesis, fate and action of the neurotransmitters as the possible target of action of
autonomic drugs, and 2) name, classify and differentiate the autonomic drugs according to
their mechanism of action and spectrum of pharmacologic effects.
Suggested Reading
v Chapter 6, Neurotransmission The autonomic and somatic motor nervous systems.
In: Goodman & Gilmans The Pharmacological Basis of Therapeutics
SUBDIVISIONS OF THE PERIPHERAL NERVOUS SYSTEM
Somatic nervous system
Motor and sensory divisions
Autonomic nervous system
Sympathetic and parasympathetic divisions
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SOMATIC NERVOUS SYSTEM
The somatic nervous system consists of the motor and the sensory divisions, i.e.,
Anatomical considerations
Somatic innervations consist of a single neuron (final common motor neuron
arising in spinal cord and extending via the ventral root to the skeletal muscles.
Releases acetylcholine (Ach) at neuromuscular junctions
Functional considerations
Innervation of skeletal muscles (movement) with CNS control via the corticospinal
or pyramid tracts comprise the motor division
Innervation of organs that send afferent impulses centrally, comprise the sensory di-
vision
Functions in these systems occur under conscious, voluntary control
AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system consists of the sympathetic and parasympathetic di-visions
Anatomical considerations
v in contrast to somatic efferents, autonomic innervations consist of 2 sequen-
tial neurons
v these sequential neurons are the preganglionic and postganglionic neurons
which synapse at autonomic ganglia
Functional considerations:
mediates control of vegetative or involuntary functions
innervation of cardiac muscle, vascular and non-vascular smooth muscle and exo-
crine glands
v functions in these systems often occur without conscious control
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Sympathetic nervous system
Preganglionic neuronsexit the spinal cord at the thoraco-lumbarlevel to synapse
with postganglionic nerves at para vertebral ganglia (22 pairs on each side
of spinal cord) or prevertebral ganglia (celiac, mesenteric) in the abdomen.
The adrenal medulla is considered to be a modified sympathetic ganglion; the
medulla is embryonically and anatomically homologous to the sympathetic
ganglia
Sympathetic innervations usually consist of one short preganglionic fiber synaps-
ing with several (one or more) long postganglionic fibers in the sympatheric
ganglia
There is a greater ramification of sympathetic fibers compared to the parasympa-
thetic system (the ratio of pre to postganglionic fibers = 1:20)
Diffuse action; fight or flight responses (i.e., stress)
Not essential for life
This system is normally active with the degree of activity varying from moment
to moment and organ to organ
This system constantly adjusts to a changing environment, especially during rage
or fright
Typical sympathetic responses include:
Increase in heart rate
Shift of blood flow in muscles
Increase in blood glucose levels
Dilation of the pupils
Parasympathetic Nervous System
Preganglonic neuronsoriginate in the cranial nervesof the brain stem and the
sacral portion of the spinal cord
These neurons synapse with post-ganglionic neurons in ganglia very close or in
the organs innervated
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Parasympathetic innervations typically consist of one long preganglionic fiber
synapsing with one short post-ganglionic fiber in the parasympathetic gan-
glia.
This system is more circumscribed than the sympathetic system, although a 1:1
ratio of pre to postganglonic fibers is not always the case
Discrete action; conservation and restoration of energy, localized control of dis-
crete functions
Essential for life
Typical parasympathetic responses include:
Slowing the heart rate
Lowering blood pressureProtecting the retina from light
Emptying the bladder
Physiological antagonism
The sympathetic and parasympathetic systems usually do not function independ-
ently; i.e., they are physiological antagonists.
Often when one system inhibits a process, the other system will augment the
level of activity so that the total response depends on the influence of both
systems, although this is not always the case.
The integration of these system regulates functions below the level of conscious-
ness
Potential ways to affect autonomic neurotransmission
Synthesis
availability of precursors for the NT
availability of synthesis enzymesStorage vesicles)
Protects the NT from degradation
Release of the neurotransmitter
Release (Ca2+ dependent exocytosis)
Agents could interfere with or enhance the release of the NT
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Reuptake of neurotransmitter
Binding to and activation of receptor
Agonist high affinity and high intrinsic activity
Antagonist high affinity but NO intrinsic activity
Breakdown of neurotransmitter with termination of effect
Acetylcholine metabolism in synaptic cleft via acetylcholine esterase
Norepinephrine reuptake into presynaptic neuron
Neurochemical classification of Peripheral Nervous System
Acetylcholine (Ach or Cholinergic) synapses include:
All preganglionic fibers outside CNS (sympathetic & parasympathetic)
All parasympathetic postganglionic nerve endings (ACh is the transmitter)
Exception: sympathetic postganglionic nerve endings of sweat glands
Somatic motor neurons innervating skeletal muscle
Noradrenergic (NE) synapses
All postganglionic sympathetic fibers (except those to sweat glands)
Adrenal medulla (norepinephrine & epinephrine)
Acetylcholine
Chemistry
Acetylcholine is synthesized from acetyl co-enzyme A and choline using the enzyme cho-
line acetyl transferase
The major means of inactivation of acetylcholine is degradation in the synapse using the
enzyme acetylcholine esterase
Acetylcholine cholinergic) Receptors
Muscarinic receptors
Postganglionic parasympathetic fibers innervating heart, smooth muscle and exo-
crine glands
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Exception: postganglionic sympathetic fibers innervating sweat glands
Blocked by antimuscarinic agents (e.g., atropine)
Nicotinic receptors
Classically a biphasic response is observed with stimulation at low doses and
inhibition at high doses
Sympathetic and parasympathetic autonomic ganglia, the adrenal medulla and
the neuromuscular junction of skeletal muscle
Effects blocked with ganglionic blockers (e.g., trimethapahan, hexamethonium)
and neuromuscular blockers (e.g., curare)
Norepinephrine
Chemistry
Norepineprine is ultimately synthesized from tyrosine using the enzyme tyrosine hy-
droxylase which converts tyrosine to DOPA
Aromatic L-amino acid decarboxylase converts DOPA to dopamine
Dopamine b-hydroxylase converts dopamine to norepinephrine
Phenylethanolamine N-methyl-transferase converts norepinephrine to epinephrine
The major means of inactivation of norepinephrine is reuptake back into the presynaptic
neuron from which it was released
Norepineprine noradrenergic) receptors
1 alpha 1)
vascular smooth muscle, genitourinary smooth muscle, liver (contraction)
intestinal smooth muscle (hyperpolarization and relaxation)
heart (increased contractile force, arrhythmias)
2 alpha 2)
pancreatic islets (b cells, decreased insulin secretion)
platelets (aggregation)
vascular smooth muscle (contratin)
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1 beta 1)
heart (increased force and rate of contraction, AV nodal conduction velocity)
juxtraglomerular cells (increased renin secretion)
2 beta 2)
smooth muscle (vascular, bronchial, gastrointestinal, genitourinary) {relaxation}
skeletal muscle (glycogenolysis; uptake of K+)
liver (glycogenolysis; gluconeogenesis)
Cellular Mechanisms of Drug Action
Receptors
Receptorsare large proteins that bind specific molecules (ligands) stereoselectively
Plasma membrane receptors
Intracellular receptors
Ligandsmay be either agonists, antagonists or inverse agonists
Ion Channels
Membrane-spanning proteins with a central porethrough which ions traverse the cell
membrane. Very fast response times (milliseconds)
Two types
Voltage-gated channelsopen and close in response to changes in the membrane
potential
Ligand-gated channelsopen in response to binding of specific ligand. Often
have several ligand-binding sites
Receptors and ion channels
G protein-coupled receptors
The binding of ligands to many receptors leads to an increase in the concentra-
tion of intracellular molecules called second messenger, which trigger changes in the
activity of other intracellular enzymes or proteins thereby producing the final cellular
response. The process is known as intracellular signaling.
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Examples of G protein-coupled receptors are: 1) acetylcholine muscarinic recep-
tors; 2) adrenergic receptors; 3) dopamine receptors; 4) Adenosine receptors; 5) 5-
HT (serotonin) receptors; 6) GABAB receptors.
Acetylcholine receptors
Acetylcholine (ACh) is an example of an endogenous neurotransmitter that
binds to more than one receptor type: the nicotinic (nAChR) which
preferentially binds nicotine and the muscarinic receptor, which binds
muscarine. The latter is a G protein-coupled receptor whereas nAChR is
an excitatory ligand-gated ion channel which transports Na+ ions.
Nicotinic receptors are found in the autonomic ganglia and the neuro-
muscular junction of skeletal muscles.
Adrenergic receptors
The adrenoceptors are G protein-coupled receptors but second messenger
and G protein linkage differ between the subtypes
The alpha1 and beta adrenoceptors are located in postsynaptic junction of
sympathetic nerve terminals innervating smooth muscles and endocrine
glands or cardiac cells (beta1)
Most vasoconstrictor responses to sympathetic stimulation are mediated by
alpha1
In general alpha2 and beta2 are prejunctional adrenergic neuronal mem-
branes and inhibit and facilitate, respectively the release of norepineph-
rine
Prejunctional alpha2 adrenoceptors also exist on cholinergic neurons and
inhibit the release of acetylcholine
The beta1 receptor is present mainly in the heart
The beta2 adrenoceptors is found in skeletal muscle, the uterus and in the
bronchial smooth muscle, where beta2 agonists act as bronchodilators
The main location of the beta3 is the adipose tissue where it seems to regu-
late norepinephrine-induced changes in energy metabolism and ther-
mogenesis
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Dopamine receptors
Dopamine is a major neurotransmitter which acts on multiple receptors. It
can activate both alpha and beta receptors in addition to acting on spe-
cific dopamine receptors
Six CNS and 2 peripheral dopamine receptors have been identified
The antiemetic metoclopramide is a dopamine antagonist whose central ef-
fects are mediated via D2 receptors in the CTZ in the area postrema
The effect of low concentrations of dopamine in enhancing urine output is
due to its action on DA1 receptors in the renal vasculature
Dopexamine is a DA1 agonist with beta2 adrenoceptor agonist activity
Ligand-gated ion channels
Acetylcholine nicotinic receptors
GABAA receptors
NMDA receptors
5-HT3 receptors
Receptors with intrinsic enzyme activity
Protein kinases
Guanylyl cyclase
Receptors: Affinity and Efficacy
Agonists
-binding to receptors triggers a pharmacologic response 9 with affinity and
intrinsic efficacy)
Full agonist produces maximum response(intrinsic activity = 1)
Partial agonist cannot produce maximum response (intrinsic activity
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Inverse agonist ligand binding produces opposite effects to those of an agonist. They
are no the same as antagonistis, which block the effects of both Agonists and inverse
agonists
The Sympathetic receptors and subtypes
Alpha receptorsare found in smooth muscles and glands
v Alpha1 are postsynaptic receptors which are excitatory
v Alpha2 are presynaptic receptors that cause feedback inhibition on the re-
lease of NE
Beta receptors
v Beta1 are excitatory to the heart and fat cells
v Beta2 are inhibitory to smooth muscles and glands
The Parasympathetic receptors and subtypes
Nicotinic receptors are ligand-gated ion channels
v Nicotinic muscle-subtypefound in the NM junction
v Nicotinic neuronal-subtypein the autonomic ganglia
Muscarinic receptorsare part of the transmembrane G protein coupled receptors
(5 subtypes)
v M1 - found in the autonomic ganglia and CNS
v M2 - supraventricular parts of the heart
v M3 smooth muscles and glands, and on endothelial cells in the vascula-
ture.
v M1 and M3 receptors generally mediate excitatory responses in effector
cells.
v M1 receptorspromote depolarization of postganglionic autonomic
nerves, and
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v M3 receptorsmediate contraction of all smooth muscles and increased
secretion in glands, except for the effect of ACh on blood vessels. Ach
causes vasodilation and decreased blood pressure. This is mediated by an
effect of ACh on the endothelial cells of the vasculature.
Effect of Acetylcholine on Blood Vessels
Activation of M3 receptors on the surface of the endothelial cells in-
creases intracellular Ca++ and causes activation of the enzyme nitric oxide
synthetase (NOS)increases synthesis of the highly diffusable free radical,
nitric oxide (NO) NO diffuses from endothelialcells into the adja-
cent smooth muscle cells of the vasculature NO activates the cytoplas-
mic enzyme, guanylate cyclase causing an increase in intracellular cyclic
GMP or cGMP, which promotes relaxation of the vascular smooth mus-cle cells.
Note:The relaxation of vascular smooth muscle by ACh is an indirect effect
that is utterly dependent on the presence of intact endothelial cells. If the
endothelium is removed, ACh exerts a stimulatory effect on vascular smooth
muscle cells, as it does on other smooth muscle cells. The interaction be-
tween endothelial and vascular smooth muscle cells was demonstrated by
Robert Furchgott who was recently awarded the Nobel Prize.
v M2 muscarinic receptors, in contrast to M1 and M3 receptors, tend to me-
diate inhibition of cellular activity
v They do so through G proteins that inhibit adenylyl cyclase (opposite of
the activation of adenylyl by beta adrenergic receptors) and by activation
of K channels in the plasma membrane
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The NS Drugs
The Sympathetic Drugs
Adrenergic Agonists Sympathomimetic)
v Direct acting
v Mixed alpha and beta (NE, EPI)
v Alpha2 selective (clonidine)
v Beta2 selective (terbutaline, isoproterenol)
v Indirect acting (amphetamine, cocaine)
v Dual-acting (ephedrine)
Adrenergic Antagonists Sympatholytic)
v Alpha blockers
v Nonselective (phenoxybenzamine, phentolamine)
v Selective alpha1 (prazosin)
v Beta blockers
v Nonselective (propanolol)
v Selective beta1 (metoprolol)
Structure-Activity Relationships of Sympathetic Drugs
Substitution of the benzene ring
v Substitution of hydroxyl groups at the 3- and 4-positions of the benzene
ringconverts benzene to catechol, and thus the dihydroxylated phenylethyl-
amine compounds are known as catecholamines with maximal and ef-
fects.
v Absence of one or the other substituent particularly at the 3-position causes
marked diminution in potency. effect is decreased a 100-fold and effect
is negligible.
v Substitution of hydroxyl groups at the 3- and 5-positions of the benzene
ringimparts2 selectivity
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Unsubstituted benzene ring
v The catecholamines are primarily metabolized by COMT. Loss either of thetwo hydroxyl groups enhances oral effectiveness and duration of action be-
cause the drug is no longer metabolized by COMT. It also causes increased
CNS effects.
v Noncatecholamines are primarily metabolized by MAO.
Substitution at the carbon
v Noncatecholamines that have a substituted -carbon have a longer duration
of action because they are not metabolized by either COMT or MAO.
Substitution at the carbon
v Typical of direct acting agonists, important for storage of sympathomimetic
amines in neural vesicles
Substitution at the amine side chain
v Substitution of bulky structuresto the catecholamine amino group increases2-selectivity, decreases affinity for-receptors, and protects against me-
tabolism by COMT. Examples are 1) epinephrine with 1 methyl substitu-
ent; 2) Isoproterenol with 2 methyl substituents and 3) Terbutaline with 3
methyl substituents
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Adrenergic Agonists Sympathomimetic Drugs)
Drug
Mechanism of Ac-
tion
Indications
Epinephrine Act directly on bothalpha and beta receptors
Used in asthma and other allergicdiseases it relaxes airways and re-duces swelling
Pseudo
ephedrine
Causes release ofnoradrenaline
Used as treatment for rhinitis andcolds as a decongestant
Phenylephrine Acts directly on alphareceptors. Selective al-pha 1 agonist
Used as decongestant in rhinitisand colds
Amphetamines Causes accumulation ofnoradrenaline at the syn-apses
No longer used clinically exceptfor treatment of narcolepsy andattention deficiency hyperkinesis
Ephedrine Acts indirectly on bothalpha and beta receptors.Causes release of en-
dogenous catechola-mines
Used as vasopressor
Terbutaline Selective beta 2 agonist Used as a bronchodilator inasthma and as a tocolytic agent inpremature labor.
Clonide Selective alpha2 agonist Used for the treatment of hyper-tension.
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Adrenergic Antagonists Sympatholytic Drugs)
Drug Mechanism of Action Indications
Reserpine Blocks the synthesis andstorage of noradrenaline
Used in the management of sometypes of hypertension. Sedation is aside effect.
Phenoxy-
benzamine
Noncompetitively blocksalpha receptors
Used in the management of malignanthypertension secondary to pheochro-mocytoma.
Phento-
lamine
Competitively blocks alphareceptors
Used for the management of malig-nant hypertension during operations
for pheochromocytoma .
Prazosin Selectively blocks alpha 1receptors
Used in the management of sometypes of hypertension. No reflextachycardia and postural hypotension.
Propanolol Nonselectively blocks betareceptors
Used in hypertension, angina, mi-graine headaches and mitral valveprolapse.
Metoprolol Selectively blocks beta 1receptors.
Predominant effects are cardiac
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The Parasympathetic Drugs
Cholinergic Agonists parasympathomimetic)
v Direct-acting muscarinic
v Naturally occurring alkaloids (muscarine, arecoline, pilocarpine)
v Synthetic alkaloids (carbachol betanechol)
v Indirect-acting muscarinic AchE inhibitors)
v Short Acting (edrophonium)
v Medium Acting (neostigmine, physostigmine)
v Long Acting (organophosphates)
v Direct-acting nicotinic depolarizing NMB
Cholinergic Antagonists parasympatholytic)
v Antimuscarinic belladona alkaloids
v Antinicotinic nondepolarizing NMB and ganglionic blockers
Cholinergic Agonists Parasympathomimetic Dugs)
At Muscarinic Sites
Drug
Mechanism of
Action
Indications
Acetylcholine Acts directly on mus-carinic receptors
Used a eye drops in Ophthalmologyto constrict the Iris of the eye.
Pilocarpine Acts directly on mus-carinic receptors
Used as eye drops in ophthalmology
to constrict the iris of the eye. Usedin the treatment of acute angle clo-sure glaucoma
Betanechol Acts directly on mus-carinic receptors
Used for the treatment of GI andbladder atony.
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At Nicotinic Sites
Cholinergic Antagonists Parasympatholytic Drugs)
At Muscarinic Sites
Drug
Mechanism of
Action
Indications
Succinylcholine Acts directly onnicotinic NMJ receptors Depolarizing NMJ blocker. Causesnoncompetitive inhibition on nicon-tinic NMJ receptors. Faciculationsfollowed by paralysis is a hallmark.
Acetylcholi-
nesterase Inhibi-
tors
Acts indirectly on nico-tinic receptors
Quaternary am-
monium com-
pounds
edrophonium)
Short-acting reversible Used as a diagnostic aid in the diag-nosis of myasthenia gravis.
Carbamates
neostigmine,
physostigmine
Moderately reversible Used to reverse nondepolarizingNMJ blockers.
Organophos-
phates
Irreversible Used as insecticides. Poisoning withorganophosphates is treated withanticholinergic drugs.
Drug
Mechanism of
Action
Indications
Atropine Acts directly on mus-carinic receptors
Used as anticholinergic agent to reducesalivation, increase heart rate, decreasegastric motility, cause mild bronchodila-
tation, and in the treatment of organo-phosphate poisoning.
Scopolamine Acts directly on mus-carinic receptors
Same as atropine, but with more centraleffect, may cause mild sedation.
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At Nicotinc Sites
Drug
Mechanism of
Action
Indications
Nondepolarizig
NMJ blockers
gallamine, pan-
curonium, atra-
curium,
vecuronium, ro-
curonium)
Competitively inhib-its acetylcholine atnicotinic NMJ sites
Causes nondepolarizing block of theNMJ. Block can b reversed by increasingthe amount of acetylcholine at the NMJ