Pharmacology Lecture Slides on Autonomic Nervous System Introduction by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Introducing The
Autonomic Nervous System

2. Contents
 CNS and PNS
 Somatic Vs Autonomic motor systems
 Pre and Post ganglionic Neurons
 Role of Sympathetic (Fight & Flight)
 Role of Parasympathetic Division (Rest & Digest)
 Interactions of ANS
 Receptors
 Neurotransmitters

3. To-Dorsal Horn of
Spinal Cord
From-Ventral Horn
of Spinal Cord
CNS & PNS

6. ANS possess inherent physiological activity and the nervous activity only augment
or reduce the initial functional level. Interference with ANS does not completely
abolish the vegetative functions.
In contrast skeletal muscles develop paralysis and
atrophy due to loss of innervation.

7. NEUROTRANSMITTERS:
• NEUROTRANSMITTERS are the brain chemicals that
link the action potential of one neuron with a synaptic
potential in another.
• Sympathetic:
ADRENERGIC
EPINEPHRINE
NOR-EPINEPHRINE
• Parasympathetic:
CHOLINERGIC
 ACETYLCHOLINE

8. Autonomic Nervous System
ANS
Can you reduce the intestinal motility?
• Acts on smooth muscles & glands
- Controls & regulates the heart, respiratory system, GI tract,
bladder, eyes & glands
• Involuntary - person has little or no control
– Autonomy-Autonomous-ANS
Somatic Nervous System
Can you move that notebook away from you?
• (Skeletal muscle)
• Voluntary - person has control

10. Summary of parasympathetic
neurons and synapses
Preganglionic neurons
• Long
• Synapse with postganglionic neurons at or near organ
• Release acetylcholine (ACh) to activate nicotinic receptors on
postganglionic neurons
Postganglionic neurons
• Short
• Synapse on the target organ
• Release acetylcholine (ACh) to activate muscarinic receptors on
the target organ

11. Summary of sympathetic neurons and
synapses
Preganglionic neurons
• Short
• Synapse with postganglionic neurons near spinal
cord
• Release acetylcholine (ACh) to activate nicotinic
receptors on postganglionic neurons
Postganglionic neurons
• Long
• Synapse on the target organ
• Release nor-epinephrine to activate adrenergic
receptors on target organs

12. 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 and heart 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 dilated

13. 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

14. Sympathetic
response
Parasympathetic
response
Fight or flight
Rest or Digest

15. Rest or Digest
Fight or flight

16. 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.
• An animal can survive complete elimination of
sympathetic but not of parasympathetic nervous system.

17. Dual Innervation
• Most of viscera receive nerve fibers from both
parasympathetic and sympathetic divisions
• Both divisions do not normally innervate an
organ equally
• They may produce effects that are
– Antagonistic-Heart
• Sympathetic- Increase heart rate, force of contraction
• Parasym- Decrease heart rate , force of contraction
– Agonistic-Genitals
• Sympathetic- Vasodilatation-erection
• Parasym- Ejaculation in males and reflex peristalsis in
females

18. 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
Goose bumps
Vasomotor refers to actions upon a blood vessel which alter its diameter.

19. RECEPTORS
• Sympathetic: ADRENOCEPTORS
 Alpha  α1 , α2
 Beta  1 , 2 , 3
• Parasympathetic: CHOLINOCEPTORS
 Muscarinic
 Nicotinic

20. Adrenergic Receptors
• The two types of adrenergic receptors are
– alpha &
– beta
• Each type has two or three subclasses
(1, 2, 1, 2 , 3)
• Effects of NE binding to:
–  receptors is generally stimulatory
–  receptors is generally inhibitory
• A notable exception – NE binding to  receptors of the heart
is stimulatory

21. RECEPTOR NAME TYPICAL LOCATIONS RESULT OF LIGAND BINDING
Alpha 1 Postsynaptic effector
cells esp. smooth m.
Formation of IP3 and DAG
↑ IC calcium
Alpha 2 Presynaptic adrenergic n.
terminals, platelets,
lipocytes, sm.m.
Inhibition of adenyl
cyclase
↓ cAMP
Beta 1 Postsynaptic effector
cells esp.heart, lipocytes,
brain
Presyn cholinergic &
adrenergic terminals
Stimulation of adenyl
cyclase
↑ cAMP
Beta 2 Posynaptic effector
cells esp. sm. m. &
cardiac m.
Stimulation of adenyl
cyclase
↑ cAMP
Beta 3 Postsynaptic effector
cells esp. lipocytes
Stimulation of adenyl
cyclase
↑ cAMP

22. Cholinergic Receptors
• The two types of receptors that bind ACh are nicotinic and
muscarinic
• These are named after drugs that bind to them and mimic
ACh effects

23. MUSCARINIC RECEPTORS
Receptor
Type
Location Post-receptor
Mechanism
M1
Nerves IP3, DAG cascade
M2
Heart, nerves, smooth
muscles
Inhibition of cAMP
prod’n, activation of
K+
channels
M3
Glands, smooth
muscle, endothelium
IP3, DAG cascade
NM
Skeletal muscle NMJ
(M=Muscle)
Na+
, K+
depolarizing
ion channel
NN
Postganglionic cell
body, dendrites
(N=Neurons)
Na+
, K+
depolarizing
ion channel

24. NEUROTRANSMITTERS:
• NEUROTRANSMITTERS are the brain chemicals
that link the action potential of one neuron
with a synaptic potential in another.
• Sympathetic: ADRENERGIC
 Central: EPINEPHRINE
 Peripheral: NOR-EPINEPHRINE
Parasympathetic: CHOLINERGIC
 Acetylcholine

25. SUMMARY OF NEUROHUMORAL
TRANSMISSION PROCESS:
I. Impulse conduction
II. Release of Neurotransmitter
III. Transmitter action on post-junctional
membrane
IV. Post-junctional activity
V. Termination of transmitter action

26. NEURO-
TRANSMITTER
SYNTHESIS

27. Adrenergic Transmission
• Transmitter synthesis involves the
following.
– L-tyrosine is converted to
dihydroxyphenylalanine (DOPA) by
tyrosine hydroxylase (rate-limiting
step). Tyrosine hydroxylase occurs
only in catecholaminergic neurons.
– DOPA is converted to dopamine by
DOPA decarboxylase.
– Dopamine is converted to
noradrenaline by dopamine β-
hydroxylase (DBH), located in
synaptic vesicles.
– In the adrenal medulla,
noradrenaline is converted to
adrenaline by phenylethanolamine
N-methyl transferase.

28. Adrenergic Transmission
• Depolarisation of the nerve terminal membrane opens calcium
channels in the nerve terminal membrane, and the resulting
entry of Ca2+
promotes the fusion and discharge of synaptic
vesicles.
• A single neuron possesses many thousand varicosities, so one
impulse leads to the discharge of a few hundred vesicles,
scattered over a wide area. This contrasts sharply with the
neuromuscular junction, where the release probability at a
single terminal is high, and release of acetylcholine is sharply
localized.
• NE IS RELEASED BY INDIRECT SYMPATHOMIMETICS
(AMPHETAMINE, EPHEDRINE, GUANETHIDINE, TYRAMINE...)

29. Adrenergic Transmission
• ACUTELY REPLACED VESICULAR NE IS PARTLY
METABOLIZED AND PARTLY RELEASED INTO THE SYNAPSE,
PROBABLY VIA REVERSAL OF UPTAKE 1
• INHIBITION OF MAO POTENTIATES THE EFFECT OF
INDIRECT SYMPATHOMIMETICS
• THE POOL OF NE AVAILABLE FOR RELEASE IS ONLY 10-20%
OF TOTAL NEURONAL NE
• THIS LIMIT EXPLAINS THE PHENOMENON OF
TACHYPHYLAXIS, I.E. DECREASING RESPONSES TO
REPEATED EXPOSURES TO INDIRECT SYMPATHOMIMETICS

30. Adrenergic Transmission
• Circulating adrenaline and noradrenaline are degraded
enzymically, but much more slowly than acetylcholine, where
synaptically located acetylcholinesterase inactivates the
transmitter in milliseconds.
• The action of released noradrenaline is terminated mainly by
reuptake of the transmitter into noradrenergic nerve terminals.
• Some is also sequestered by other cells in the vicinity.
• The two main catecholamine-metabolising enzymes
monoamine oxidase (MAO) and catechol-O-methyl transferase
(COMT) which are located intracellularly, so uptake into cells
necessarily precedes metabolic degradation.

33. Fate of Acetylcholine
• ACh is synthesised within nerve terminal from choline,
which is taken up into nerve terminal by a specific carrier.
• The rate-limiting process in ACh synthesis appears to be
choline transport, the activity of which is regulated
according to the rate at which ACh is being released.
• Cholinesterase is present in the pre-synaptic nerve
terminals, and ACh is continually being hydrolysed and
resynthesised.
• Most of the ACh synthesised, however, is packaged into
synaptic vesicles, in which its concentration is very high
(about 100 mmol/1), and from which release occurs by
exocytosis triggered by Ca2+
entry into the nerve
terminal.

34. Cholinergic transmission
Acetylcholine (ACh) synthesis:
– requires choline, which enters the neuron via carrier-mediated
transport
– requires acetylation of choline, utilising acetyl coenzyme A as
source of acetyl groups, and involves choline acetyl transferase, a
cytosolic enzyme found only in cholinergic neurons.
• ACh is actively transported and packaged into synaptic vesicles at
high concentration by carrier-mediated transport.
• ACh release occurs by Ca2+
-mediated exocytosis, which triggers
interaction between
– vesicle proteins (synaptobrevin, synaptotagmin)
– nerve ending membranes (syntaxin)
causing the fusion of membranes and release of Ach.
• At the neuromuscular junction, one presynaptic nerve impulse
releases 100-500 vesicles.

35. Cholinergic transmission
• At the neuromuscular junction, ACh acts on nicotinic receptors to open
cation channels, producing a rapid depolarisation (endplate potential),
which normally initiates an action potential in the muscle fibre.
Transmission at other 'fast' cholinergic synapses (e.g. ganglionic) is similar.
• Termination of ACh action occurs by metabolism to acetate and choline by
the enzyme cholineesterases-
– Acetyl cholinesterases
– Butyryl cholinesterases (Pseudocholineesterases)
Following the hydrolysis of Ach more than 50% of this choline is normally
recaptured by the nerve terminals.

36. Cholinergic transmission
• At 'fast' cholinergic synapses, ACh is hydrolysed within about 1 ms
by acetylcholinesterase, so a presynaptic action potential
produces only one postsynaptic action potential.
• Transmission mediated by muscarinic receptors is much slower in
its time course.
• Main mechanisms of pharmacological block:
– Inhibition of choline uptake- Hemicholinium
– Inhibition of ACh storage-- Vesamicol
– Inhibition of ACh release—Botulinum toxin
– Block of postsynaptic receptors or ion channels,
– Persistent postsynaptic depolarisation.

37. Cholinergic transmission
• ACh IS ACUTELY AND MASSIVELY RELEASED BY
A BLACK WIDOW SPIDER VENOM
COMPONENT (ALPHA-LATROTOXIN) AND THE
RELEASE IS BLOCKED BY CLOSTRIDIUM
BOTULINUM TOXIN
• CLOSTRIDIUM BOTULINUM TOXIN (BOTOX) IS
USED IN NYSTAGMUS AND WRINKLE
REMOVAL.

38. How do drugs influence the ANS?
• Mimic or block the effects of the two primary neurotransmitters,
Acetylcholine and Nor-epinephrine /Epinephrine
Agnoists
• Drugs that mimic neurotransmitters are referred to as “receptor
agonists”
 These drugs activate receptors
Antagonists
• Drugs that block neurotransmitters are referred to as “receptor
antagonists”
 These drugs block the endogenous neurotransmitters from
activating receptors

39. Classification of drugs affecting ANS
• Parasympathetic nervous system
Rest or Digest
Mimic acetylcholine = cholinergic = muscarinic agonists = parasympathomimetic
Block acetylcholine = anticholinergic = muscarinic antagonist = parasympatholytic
• Sympathetic nervous system-
Fight or flight
Mimic norepinephrine = adrenergic = adrenergic agonist = sympathomimetic
Block norepinephrine = antiadrenergic = adrenergic antagonist = sympatholytic

40. Adrenaline rush
• An adrenaline rush is the fight or flight response of
the adrenal gland, in which it releases adrenaline.
When releasing adrenaline, one's body
releases dopamine which can act as a natural pain
killer.
Adrenaline junkie
• An adrenaline junkie is a person addicted to the thrill
of the adrenaline rush: the exciting, pleasurable effect
produced when the adrenal glands dump a large dose
of adrenaline into the bloodstream.

41. Disorders of the ANS
• Raynaud’s disease – characterized by constriction of blood
vessels
- Provoked by exposure to cold or by emotional stress
• Hypertension – high blood pressure
- Can result from overactive sympathetic vasoconstriction
• Mass reflex reaction – uncontrolled activation of autonomic
and somatic motor neurons
- Affects quadriplegics and paraplegics
• Achalasia of the cardia – defect in the autonomic innervation
of the esophagus

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