ANS

Pharmacology
 Many systems of the body are controlled
automatically by ANS (and the endocrine system)
Digestion
Circulation
Control involves negative feedback

A fall in BP
Baroreceptors
Sympathetic outflow
Anatomy of the autonomic nervous system
Sympathetic neurones
leave the thoracolumbar region of the spinal cord
(T1-L3).
Synapse in two cord-like chains of ganglia that run
in parallel on each side of the spinal cord
The preganglionic neurons are short in comparison
to the postganglionic ones
Postganglionic non-myelinated nerve fibers arising
from the ganglia innervate most organs of the body
adrenal medulla influences other organs by
secreting the hormone epinephrine
Parasympathetic neurons:
Preganglionic fibers arise from
the cranium (cranial nerves III, VII, IX, and X) and
from
the sacral region of the spinal cord and
Synapse in ganglia near or on the effector
organs
Preganglionic fibers are long, and the
postganglionic ones are short
 Dual innervation
Many organs are innervated by
both systems, which in general
have opposing actions.
E.g heart
Despite dual innervation, one
system predominates

Adrenal medulla, kidney,

pilomotor muscles, sweat
glands????
BP controlled mainly by SNS
 Functions of the sympathetic nervous system

Adjustment in response to stressful situations,

such as trauma, fear, hypoglycemia, cold, or exercise.
The effect of sympathetic output is:
to increase heart rate and BP,
to mobilize energy stores of the body,
to increase blood flow to skeletal muscles while
diverting flow from the skin and internal organs.
dilation of the pupils and the bronchioles
It also affects gastrointestinal motility and the
function of the bladder and sexual organs.
Fig. 45.34(TE Art)
Hypothalamus activates
sympathetic division of
nervous system
Heart rate, blood pressure,
and respiration increase
Adrenal medulla
secretes
epinephrine and
norepinephrine

Blood flow to Stomach

skeletal muscles contractions
increases are inhibited
Fight or flight response
Triggered both by direct sympathetic
activation of the effector organs and
by stimulation of the adrenal medulla to
release E and lesser amounts of NE
 Functions of the parasympathetic NS
Maintains essential bodily functions, such as
digestive processes and
elimination of wastes,
and is required for life
Generally dominant over the sympathetic
system in rest and digest situations
Neurotransmitter release sites
Ach mediates the transmission of nerve impulses across
autonomic ganglia in both SNS and PSNS.
SNS fibers terminating in adrenal medulla.
postganglionic nerves to the effector organs in PSNS
A few sympathetic fibers, such as those involved in
sweating, are cholinergic
In the somatic nervous system, transmission at the
NMJ is also cholinergic

NE mediates the transmission of nerve impulses from

postganglionic nerves to effector organs in the SNS
Neurotransmitters released and the types of receptors found
within the autonomic and somatic nervous systems.
 Neurotransmitters
The autonomic nerve fibers can be divided into two
groups (cholinergic and adrenergic) based on the
chemical nature of the NT released.
Acetylcholine(ach): If transmission is mediated by
ach, the neuron is termed cholinergic
Norepinephrine and Epinephrine: When NE or E is the
transmitter, the fiber is termed adrenergic
NE and E produce their actions on effector organs
by acting on:
and adrenoceptors
Which one of the following is characteristic of
parasympathetic stimulation?
A. Decrease in intestinal motility.
B. Inhibition of bronchial secretion.
C. Contraction of sphincter muscle in the iris of
the eye (miosis).
D. Contraction of sphincter of urinary bladder.
E. Increase in heart rate.
 Cholinergic Agonists
Drugs affecting the ANS are divided into two
groups according to the type of neuron
involved in their mechanism of action
The cholinergic drugs, act on receptors that
are activated by Ach.
The adrenergic drugs act on receptors that are
stimulated by NE or E
Cholinergic and adrenergic drugs both act by
either stimulating or blocking receptors of the
ANS
Cholinergic Drugs
 Neurotransmission at cholinergic neurons
sequential six steps:
synthesis,
storage,
release,
binding of acetylcholine to a receptor
degradation of Ach in the synaptic gap
recycling of choline
 Cholinergic Receptors (Cholinoceptors)

Two families of cholinoceptors, designated

Muscarinic and Nicotinic receptors
on the basis of their different affinities for agents
that mimic the action of acetylcholine
(cholinomimetic agents or
parasympathomimetics).
Toxicity/Mycetism

Mushrooms of Amanita species

contain muscarine, which if ingested
can cause intoxication
30-60 minutes, salivation, lacrimation, excessive
sweating, nausea, vomiting diarrhea, bronchospasm,
headache, visual disturbances, abdominal colic,
bradychardia, hypotension, shock
ALL SYMPTOMS REVERTED BY ATROPINE
 five subclasses of
muscarinic receptors: M1,
M2, M3, M4, and M5.
only M1, M2 and M3,
receptors have been
functionally characterized.
Location
M1 -- found on gastric parietal
cells, --- pirenzepine
M2 receptors on cardiac cells
and smooth muscle, and
M3 receptors on the bladder,
exocrine glands, and smooth
muscle
Nicotinic receptors
functions as a ligand-
gated ion channel
Nicotinic receptors are
located in:
CNS, adrenal medulla,
autonomic ganglia, and
the neuromuscular
junction
Those at the NMJ are
designated NM and the
others NN
M1 Secretory salivation, stomach acid, sweating, lacrimation
glands
M2 Heart Decreases heart rate bradycardia
M3 Smooth Contraction of smooth muscles (some)
muscle diarrhea, bronchospasm, urination
(GI/GU/Resp)
M3 Pupil and Contracts Miosis
ciliary Increased flow of aqueous humor
muscle
Nm Skeletal Contraction of skeletal muscle
muscle end
plate
Nn Autonomic Secretion of Epinephrine
ganglia, Controls ANS
Adrenal
Medulla
 Direct-Acting Cholinergic Agonists

Cholinergic agonists (also known as

parasympathomimetics) mimic the effects of
acetylcholine by binding directly to
cholinoceptors.
These agents may be broadly classified into
two groups:
choline esters, which include acetylcholine and
synthetic esters of choline, such as carbachol and
bethanechol.
Naturally occurring alkaloids, such as pilocarpine
constitue the second group
 Acetylcholine

A quaternary ammonium compound

Cannot penetrate membranes
Neurotransmitter of parasympathetic and somatic
nerves as well as autonomic ganglia,
Therapeutically -- no importance because of
its multiplicity of actions and
its rapid inactivation by the cholinesterases.
Acetylcholine has both muscarinic and nicotinic
activity.
 Acetylcholine
Its actions include:
Decrease in heart rate and cardiac output: The
actions of Ach on the heart mimic the effects of
vagal stimulation
Decrease in blood pressure: Injection of Ach causes
vasodilation and lowering of blood pressure by an
indirect mechanism of action
Other actions:
In GIT, Ach increases salivary secretion, stimulates
intestinal secretions and motility.
Bronchiolar secretions are also enhanced.
In the genitourinary tract, the tone of the detrusor
urinae muscle is increased, causing expulsion of urine.
In the eye, acetylcholine is involved in stimulating ciliary
muscle contraction for near vision and in the constriction
of the pupillae sphincter muscle, causing miosis
 What is the effect of high IV dose of Ach given
after atropine on the heart rate and BP of an
experimental animal?
 Carbachol (carbamylcholine)

Ester of carbamic acid ---- > poor substrate for

acetylcholinesterase (acetate vs carbamate)
Has both muscarinic as well as nicotinic actions
profound effects on both the CVS and GI system
because of its ganglion-stimulating activity
Therapeutic uses: as a miotic agent to treat
glaucoma
Adverse effects: At doses used ophthalmologically,
little or no side effects occur due to lack of systemic
penetration (quaternary amine).
 Bethanechol

Not hydrolyzed by acetylcholinesterases

It has strong Muscarinic action & no Nicotinic action
Actions
Directly stimulates M receptors causing increased intestinal motility
& tone
It stimulates detrusor muscle of the bladder while trigone &
sphincters are relaxed causing expulsion of urine
Therapeutic Uses:
Paralytic ileus
Urinary retentions
(C H 3)3 N + (C H 2)2 O O (C H 3)3 N + CH 2 CH O O
C C
CH 3
A c e t y lc h o lin e CH 3
CH 3
M e t h a c h o lin e

+ O (C H 3)3 N + CH CH O O
(C H 3)3 N (C H 2)2 O 2
C
C
CH 3
NH NH 2
C a rb ac h o l 2 B e th a n e c h o l
 Pilocarpine
An alkaloid, lipid soluble & is stable to hydrolysis by
cholinsterases. It has Muscarinic activity only .
Actions-
When applied locally to cornea, Produces rapid moisis &
contraction of ciliary muscle. Produces accommodation for
near vision
Therapeutic Use : In Glaucoma (emergency)
It opens trabecular meshwork around schlemms canal
causes drainage of aqueous humor
IOP immediately decreases.

Carbonic anhydrase inhibitors, such as acetazolamide, as well as

the 2-adrenergic blocker timolol, are effective in treating
glaucoma chronically but are not used for emergency
lowering of intraocular pressure
Some adverse effects observed with cholinergic drugs
Indirect Cholingeric Agonists (Anticholinesterases)
Cholinesterase inhibitors. Can be reversible or
irreversible.
Reversible:
Neostigmine
Physostigmine
Edrophonium
Tacrine
Danopezil
Irreversible
Malathion and Parathion
Sarin
Ecothiopate
AchE Inhibitors (quaternary alcohols and carbamates)
 Uses of Indirect Cholinergic agonists
Neostigmine in M.gravis
Physostigmine in Glaucoma, atropine overdose

Ecothiopate in glaucoma
Edrophonium in M.gravis to test
Tacrin, Danopezil in Alzheimer's
Malathion, Parathion as insecticides
 Anticholinesterases (Reversible)
AchE is an enzyme that cleaves acetylcholine to
acetate and choline and, thus, terminates its actions
Inhibitors of AchE indirectly provide a cholinergic
action by prolonging the lifetime of acetylcholine
This results in the accumulation of acetylcholine in
the synaptic space
 Physostigmine
a nitrogenous carbamic acid ester found
naturally in plants and is a tertiary amine
Can enter and stimulate the cholinergic sites
in the CNS.
Therapeutic uses
Glaucoma, atropine overdose
 Neostigmine
Unlike physostigmine, neostigmine has a
quaternary nitrogen;
hence, it is more polar and does not enter the CNS.
No CNS side effects
Used in symptomatic treatment of myasthenia
gravis
it is not used to overcome toxicity of central-
acting antimuscarinic agents such as atropine.
 QQQQQ
Physostigmine is better as an antidote for
atropine overdose compared to neostigmine.
Why?????
 Edrophonium

Actions similar to those of neostigmine, except:

has a short duration of action of 10 to 20 minutes
(prototype short-acting agent).
quaternary amine
used in the diagnosis of myasthenia gravis.
Intravenous injection of edrophonium leads to a
rapid increase in muscle strength.
Care must be taken, because excess drug may
provoke a cholinergic crisis.
Atropine is the antidote.
 QQQQQQ
Neostigmine is used in the treatment of
myasthenia gravis but is not employed in its
diagnosis. Why????
 Tacrine, donepezil, rivastigmine, and galantamine

patients with Alzheimer's disease have a deficiency

of cholinergic neurons in the CNS
This observation led to the development of AchEs
Tacrine was the first to become available, but it has
been replaced by the others because of its
hepatotoxicity.
none can stop the disease progression.
 Anticholinesterases (Irreversible)
A number of synthetic organophosphate compounds
bind covalently to AchE.
The result is a long-lasting increase in Ach at all sites
where it is released.
Many of these drugs are extremely toxic and were
developed by the military as nerve agents.
Related compounds, such as parathion, are employed
as insecticides.
 Terminal oxygen vs. terminal sulfur

Thiophosphoryl compounds, those bearing the P=S

functionality, are much less toxic than related
phosphoryl derivatives. Thiophosphoryl compounds are
not active inhibitors of acetylcholinesterase in either
mammals or insects; in mammals, metabolism tends to
remove lipophilic side groups from the phosphorus
atom while in insects it tends to oxidize the compound,
thus removing the terminal sulfur and replacing it with
a terminal oxygen, which allows the compound to more
efficiently act as an acetylcholinesterase inhibitor.
Organophosphates
The loss of an alkyl group, which is called aging,
makes it impossible for chemical reactivators, such
as pralidoxime, to break the bond between the
remaining drug and the enzyme
Reactivators of ChE used for the treatment
of intoxication with organophosphates
Mechanism of action
 Summary of actions of some cholinergic agonists
Thanks
 Paraoxonase (PON1) is a key enzyme involved in OP pesticides and has
been found to be critical in determining an organism's sensitivity to OP
exposure.
PON1 can inactivate some OPs through hydrolysis. PON1 hydrolyzes the
active metabolites in several OP insecticides such as chlorpyrifos oxon,
and diazoxon, as well as, nerve agents such as soman, sarin, and VX
Paraoxonase (PON1) is a key enzyme in the metabolism of
organophosphates
The higher the concentration of PON1 the better the protection
provided.
PON1 activity is much lower in neonates, so neonates are more
sensitive to OP exposure