Autonomic nervous system introduction and cholinergic system

INTRODUCTION
TO ANS AND
CHOLINERGIC
DRUGS

There are two systems in our body
A. CENTRAL NERVOUS SYSTEM (CNS)
B. PERIPHERAL NERVOUS SYSTEM OR
AUTONOMIC NERVOUS SYSTEM (ANS)

 The ANS controls the functioning of viscera, and innervates
almost all the tissues of the body except the voluntary
muscles.
 The ANS thus regulates the vital functions in the body
including
 RESPIRATORY SYSTEM,
 BLOOD PRESSURE,
 BODY TEMPERATURE,
 WATER BALANCE,
 URINATION,
 DIGESTION AND
 MANY METABOLIC FUNCTIONS.

The ANS comprises of three major subdivisions:-
a) PARASYMPATHETIC NERVOUS SYSTEM
b) SYMPATHETIC NERVOUS SYSTEM AND
c) ENTERIC NERVOUS SYSTEM (ENS).

ACETYLCHOLINE (ACH)
Acetylcholine (ACh) is the neurotransmitter
i. All somatic motor neurons to skeletal muscle
(NMJ),
ii. All pre ganglionic parasympathetic and
sympathetic fibers(including adrenal medulla),
iii. Postganglionic parasympathetic fibers of neuro
effector junction (NEJ) and
iv. Post ganglionic fibers to sweat glands of palm
and sole are cholinergic in character.
They act through cholinergic receptors.

NOREPINEPHRINE
All postganglionic sympathetic fibers release
norepinephrine at NEJ except-
 sweat gland,
fibers supplying to arteriole of skeletal muscles
and
some postganglionic sympathetic neurons of
splanchnic and renal blood vessels.
They act through adrenergic receptors

The major receptor systems in the ANS
include-
I. CHOLINERGIC RECEPTORS
II. ADRENERGIC RECEPTORS
III.DOPAMINE RECEPTORS

NON-ADRENERGIC NON CHOLINERGIC
TRANSMISSION (NANC)
Some nerve fibers in autonomic effector tissues
does not show the histochemical characteristics of
either cholinergic or adrenergic fibers.
Some of these are motor fibers that cause the
release of ATP and other purines related to it.
Purine evoked responses have been identified in
the bronchi, gastrointestinal tract vas deferens and
urinary tract.
Other motor fibers release peptides as the primary
transmitters. These peptides are potent agonist in
many autonomic effector tissues.

CHOLINERGIC RECEPTORS
 Muscarinic receptors-
 These receptors respond to muscarine as well as to
acetylcholine. The effects of activation of these receptors
resemble those of postganglionic parasympathetic nerve
stimulation.
 Muscarinic receptors are located primarily on autonomic
effector cells including -
 heart,
 vascular endothelium,
 smooth muscle,
 pre synaptic nerve terminals, and
 exocrine glands.
They are of 5 subtypes, of which 3 appear to be important in
peripheral autonomic transmission.

NICOTINIC RECEPTORS
 These receptors are parts of ion channels and
respond to acetylcholine and nicotine, but not to
muscarine
 The two major nicotinic subtypes are
 located in ganglia (Nn type)
 in skeletal muscle end plates (Nm type).

LOCATION AGONIST ANTAGONIST MECHANIS
M
MAJOR FUNCTION
Muscarinic
(M1)
Autonomic
ganglia,
CNS, GIT
Oxotremori
ne
Atropine,
Pirenzepine,
Telenzepine
Gq-coupled Increased IP3,
DAG cascade
Muscarinic
(M2)
Heart S.A.
node
Atrium, AV
node
Ventricles
Smooth
muscles
Methacholin
e
Methoetramin
e
Tripitramine
Gi-coupled Decrease cAMP,
activates K+
channels
Muscarinic
(M3)
Smooth
muscles
secretary
glands
Bethanecol Darifenacin
Tolterodine
Gq-coupled Increase IP3, DAG
cascade

LOCATION AGONIST ANTAGONIST MECHANIS
M
MAJOR
FUNCTIO
N
Nicotinic
(Nm)
Muscle
Neuromuscular
junction
Nicotine,
PTMA
Succinyl
choline
d-
Tubocuararine
Intrinsic
ion channel
Depolari
zes,
evokes
action
potential
,
contracti
on of
skeletal
muscle

(Nn)
Neuronal
Autonomic
ganglia
Adrenal
medulla
DMPP,
nicotine
Hexamethoniu
m
Trimetharphan
Ion
channel
Depolarizes,
evokes
action
potential ,
secretion of
NE and E

CHOLINERGIC DRUGS
(PARASYMPATHOMIMETIC DRUGS)
Acetylcholine (ACh) an ester of choline, is the
neurotransmitter of the parasympathetic system.
The nerves that synthesize, store and release ACh
are called 'cholinergic nerves.
 Acetylcholine is synthesized from acetyl CoA and
choline and released into the synaptic cleft.
This ACh binds to and activates the cholinergic
receptor on the postsynaptic membrane leading to
the depolarization of the membrane.

 ACh released into the
synaptic cleft is rapidly
destroyed by the
enzyme acetyl
cholinesterase (AChE).
There are two types of AChE
present:
a) True cholinesterase –It
present at neurons,
ganglia and
neuromuscular junction.
b) Pseudo cholinesterase – It
present in plasma, liver
and intestine.
Acetyl cholinesterase (AChE).

CHOLINERGIC DRUGS
A. Esters of choline – Acetylcholine, Methacholine, Carbachol,
Bethanechol
B. Cholinomimetic alkaloids- Pilocarpine, Muscarine,
Arecoline
C. Anticholinesterases-
a) Reversible: Physostigmine, Neostigmine, Pyridostigmine, Donepezil,
Edrophonium, Ambenonium, Demecarium, Rivastigmine.
b) Irreversible:
 Organophosphates e.g. - Echothiophate, Malathion, Sumithion,
Diazinon. ,
 Carbamates e.g.- Carbaryl (SEVIN), Propoxure (BAYGON), Aldicarb
(TEMIK), toxic nerve gases( Sarin, Tabun).

ACTIONS OF
ACETYLCHOLINE
 Muscarinic actions
 Heart -
Depresses the SA node and thereby
Reduces the heart rate and force of contraction,
Decreases rate of diastolic depolarization and increase
refractory period (through M2 receptors).
 Blood vessels –
ACh relax the vascular smooth muscles and dilate the blood
vessels of the skin and mucous membrane.
The BP falls due to a fall in total peripheral resistance and
reflex tachycardia (arteries have no parasympathetic
innervations, but have M3 receptors which release EDRF).

MUSCARINIC
ACTIONS(CONT.)
 Smooth muscle ACh increases the tone of all other
(non-vascular) smooth muscle tone.
Intestinal -peristalsis is enhanced, sphincters are
relaxed, resulting in rapid forward propulsion of
intestinal contents. (M1 and M3 receptors).
Urinary bladder- detrusor contracts and trigonal
sphincter relaxes thus promotes voiding of urine. (M3
receptors)
Bronchial smooth muscle- contraction of bronchial
muscle resulting in bronchospasm. (M3 receptors).

MUSCARINIC
ACTIONS(CONT.)
 Secretory glands-
Enhances the secretions of all glands; salivary, lacrimal,
nasopharyngeal, tracheo-bronchial, gastric (M1-receptor) and
intestinal secretions are increased. (M3 receptors).
 Eye –
constriction of pupil (miosis) by contracting the circular
muscles of the iris.
Drainage of aqueous humor is facilitated and intraocular
pressure falls.
Ciliary muscle contracts resulting in spasm of
accommodation.

NICOTINIC ACTIONS
Neuromuscular junction (NMJ): Contraction of
skeletal muscles by stimulating Nm receptors
present in the neuromuscular junction. Large doses
cause paralysis.
Autonomic ganglia: Acetylcholine stimulates both
sympathetic and parasympathetic ganglia and the
adrenal medulla and causes rise in BP.
CNS: IV injection of ACh does not penetrate BBB
and no central effect are seen but direct injection
into brain produce stimulation followed by
depression.

ACTIONS OF
ACETYLCHOLINE
CVS Decrease HR, decrease BP
Non-vascular
smooth muscle
Contraction, increase gut peristalsis, promotes urine
voiding.
bronchospasm
Glands Increase secretion
Eye Miosis, spasm of accommodation, decrease IOP
Ganglia Stimulation
NMJ Muscle contraction

USES
 Acetylcholine is not used therapeutically.
 Carbachol and bethanechol are resistant to both pseudo and true
cholinesterases and have a longer duration of action. Carbachol is
sometimes used in glaucoma.
 Bethanechol is used to
1. Reverse post-operative atony of bladder
2. GIT atony (without obstruction)
3. Xerostomia as an alternative to pilocarpine.
4. Cevimeline s a new drug used nowadays. It is long acting and
less toxic to pilocarpine.
5. Alzheimer’s disease .

CONTRAINDICATIONS OF
CHOLINE ESTERS
1. Hyperthyroidism,
2. Bronchial asthma
3. Peptic ulcer
4. Myocardial infarction

CHOLINOMIMETIC
ALKALOIDS
Pilocarpine - Its muscarinic actions are prominent
(M3 receptor), with mild action at Nn receptor. It is
too toxic for systemic use. Main therapeutic uses
are -
Open angle glaucoma (ocusert)
Used alternately with mydriatics like homatropine
to break the adhesions between the iris and the
lens
It is used to counter dryness of mouth that is seen
following radiation of head and neck and after
laryngeal surgery.

ANTI CHOLINESTERASES
Anti cholinesterases (anti ChEs) or cholinesterase
inhibitors are drugs which inhibit the enzyme
cholinesterase
The actions of all these drugs are due to this
accumulated Ach in synaptic cleft. Hence the actions
are similar to cholinergic agonists
As their structure resembles that of ACh, they bind
to acetyl cholinesterases and inactivate them. Thus
ACh is not hydrolyzed and it accumulates.

ANTICHOLINESTERASES
a) Reversible: Physostigmine, Neostigmine, Pyridostigmine,
Donepezil, Edrophonium, Ambenonium, Demecarium,
Rivastigmine.
b) Irreversible:
 Organophosphates e.g. - Echothiophate, Malathion,
Sumithion, Diazinon. ,
 Carbamates e.g.- Carbaryl (SEVIN), Propoxure
(BAYGON), Aldicarb (TEMIK), toxic nerve gases( Sarin,
Tabun).

Acetyl choline is metabolized with ChE enzyme
Two sites on enzyme-
Anionic site(-ve charged)
Esteritic site
Similar sites are there on cholinergic receptors.
Acetylation of enzyme (esteritic site)with Ach
resulting into splitting off choline and acetyl CoA

REVERSIBLE ANTI
CHOLINESTERASES
 They bear the structural resemblance to ACh and
combined with both anionic and the esteratic sites
of AChE
 which hydrolyze slowly and causes temporary
inhibition and accumulation of ACh at synaptic cleft
 Lipid soluble drugs have more marked CNS effects
as they crosses BBB
 Non lipid soluble drugs have more marked effect on
skeletal muscles

Edrophonium is rapid and short acting (as it
binds with anionic site only).
 It is used for diagnosis of the myasthenia gravis
and in snake bite and in curare poisoning
(intravenously).
Physostigmine- it is a tertiary ammonium
compound, has better penetration into tissues
and also cross the BBB.
 It is used in glaucoma and in atropine
poisoning.

Neostigmine is a synthetic quaternary ammonium
compound, poorly absorbed from the gut and it
does not cross the BBB.
 It is used in myasthenia gravis. The mechanism
to improve muscle power in myasthenia gravis is –
Its anti ChE activity (accumulate Ach at motor
end plate).
Increase the amount of ACh released during each
nerve impulse.
Directly stimulate cholinoceptive receptor sites
on motor end plate, so act as partial agonist.

 As a miotic (in glaucoma)
 Myasthenia gravis
 Alzheimer's disease
 Poisoning due to anticholinergic drugs, TCA,
 Curare poisoning
 Postoperative paralytic ileus and urinary retention
 Cobra bite(with atropine)
 Post operative decurarization
 Paroxysmal atrial and SVT(nowadays CCBs are preferred)

TREATMENT OF
MYASTHENIA GRAVIS
Myasthenia gravis is an acquired auto-immune
disorder causing skeletal muscle fatigability and
weakness, which worsen after exercise.
Associated with formation of IgG antibodies which
bind with nicotinic receptors
Decrease in number of receptors leads to decrease
amplitude of the end plate potential
Diagnosis-anti Ach receptor titer and edrophonium
test

DRUG USED ARE
Anti cholinesterase (Reversible)
A. Neostigmine- 15-30 mg/6hrly
B. Pyridostigmine 60-120mg
C. Ambenonium -5-25mg (with atropine to
minimize muscarinic adverse effects)

A. Glucocorticoids – Prednisolone which may
inhibit antibodies production.
B. Immunosuppressants - Azathioprine,
Cyclosporine.
C. Thymectomy
D. Plasmapheresis – To remove antibodies

Drugs which aggravate myasthenia gravis are-
aminoglycosides,
Morphine,
Procainamide,
Quinidine
dTc,
Lithium etc.

TREATMENT OF
ALZHEIMER’S DISEASE
It is a neuro-degenerative disorder characterized by
progressive loss of memory (dementia).
Pathology-
Amyloid plaque deposit in selective areas of brain
Intraneuronal neurofibrillary tangles which may
cause neurodegeneration
Marked decrease in choline-acetyl transferase and
loss of cholinergic neurones in the brain (also DA,
5HT, somatostatin)

Tacrine – long acting anti ChE. This facilitate
release of Ach, NA, DA and 5HT and inhibits
MAO, GABA release may cause hepato toxicity.
Donepezil, Rivastigmine, Galantamine are the
other drugs nowadays preferred and have better
CNS penetration ,less toxic, better tolerated
Other supplement drugs -Vitamin E, Vitamin A,
Zn, Acetyl-L-carnitine, DHEA (dehydro-epi
androsterone).

IRREVERSIBLE
ANTICHOLINESTERASES
Organophosphorus (OP) compounds are powerful
inhibitors of AChE enzyme, they bind only to the
esteratic site (except echothiophate, which bound
with anionic site) and the enzyme is phosphorylated.
This phosphorylated complex hydrolyses very slowly
or sometimes does not hydrolyze.
So recovery takes very long time. Organophosphates
are highly lipid soluble and hence are absorbed from
all routes including intact skin.
Since they are very toxic, so, they are not used.

ACUTE ORGANOPHOSPHORUS
COMPOUND POISONING
 Occupational
 Accidental
 Suicidal
S/S
1. Nicotinic effects-twitching, fasciculation
2. Glandular secretion
3. CNS effects- excitation, convulsion followed by depression
4. Neurotoxicity –peripheral nerve damage
5. Eye- miosis
6. Cardio vascular- fall in BP, tachycardia, arrhythmais

ACUTE ORGANOPHOSPHORUS
COMPOUND POISONING
Treatment
Remove/ Termination of further exposure
Gastric lavage- activated charcoal.
Purgative (sodium sulphate/ magnesium
sulphate)
Maintain BP and patent airway.

SPECIFIC THERAPY
A. Atropine : IV, high doses-2-4mg IV slow repeat
after every 15 min
B. Cholinesterase reactivators-
Pralidoxime,
Obidoxime,
Diacetylmonoxime.

These oxime compounds combine with
cholinesterase enzyme by attaching themselves on
anionic site and form complex with phosphate
group which is soluble.
Thus set free the binding and AChE enzyme.
Thus they reactivate the cholinesterase enzyme.
They should be given within minutes after
poisoning preferably immediately, because the
complex undergoes 'aging' (strengthening of
phosphate enzyme) and the enzyme cannot be
released.

A)Pralidoxime-
Dose- 1-2gm
20-50mg/kg(<12 years of age)
Dissolve in 250ml of 5% dextrose IV infusion over 30
mins
B)Diacetyl monooxime.
Only diacetyl monoxime crosses BBB
They are ineffective in carbamate poisoning

Autonomic nervous system introduction and cholinergic system

Autonomic nervous system introduction and cholinergic system

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Autonomic nervous system introduction and cholinergic system