Autonomic nervous system
Nervous system
Peripheral nervous systemCentral nervous system
ParasympatheticSympathetic
Spinal cordBrainAutonomicSomatic
Autonomic Nervous systemSyn:Involuntery N.S., Vegetative or Visceral
nervous system.
-- It innervates : + Plain or involuntery or
Smooth muscles
Exocrine glands
Visceral organs
Respiration,circulation,digestion,body
temprature,metabolism, sweating, secretion
of glands are regulated in a part and entirely
by A.N.S and its control connections
Division of autonomicnervous system
Cranial
(Brain) Parasympathetic
Thoraco-lumber
Sympathetic
Sacral region
S.C.
Divisions of the autonomic nervous system:
1- The parasympathetic division (Craniosacral):
a- Cranial outflow originates from III, VII, IX & Xcranial nerves i.e. oculomotor, facial,glossopharyngeal and vagus nerves .
b- Sacral outflow originates at 2, 3 & 4 sacralsegments of the spinal cord to supply the lowerintestine, bladder and genitalia.
Divisions of the autonomic nervous system:
• The parasympathetic fibers have a longpreganglionic fiber, the ganglia being close to orembedded in the effector organ and a shortpostganglionic fiber.
• The system is concerned with restoration ofenergy, it slows the heart, lowers the bloodpressure, increases motility and secretion in theGIT and empties the bladder and rectum.
Divisions of the autonomic nervous system:2- Sympathetic division (Thoracolumbar):
• It comes from all the thoracic and upper three lumbar
segments of the spinal cord. The nerves have a short
preganglionic fiber and long post-ganglionic ones. Ganglia
is usually located near the spinal cord in the form of a chain
(sympathetic chain). Sympathetic system makes
adjustments for body reactions to stress (fright, fight & flight)
e.g. acceleration of the heart rate, rise of blood pressure,
dilatation of the pupil and bronchioles.
• Most of the tissues and organs are innervated by both
divisions of the autonomic nervous system. In general,
activities of the two divisions produce opposite effects.
Neurotransmitters
1- Ach
❑ Synthesis:
Choline acetylase Enz
➢ Acetate + Choline Ach
➢ Ach is stored in vesicles.
❑ Metabolism:
➢ The duration of action of Ach is very short due to rapid hydrolysis into Acetate
and Choline by Cholinesterase enzyme.
Cholinesterase Enz
➢ Ach Acetate + Choline
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Types of choline-esterases
_____________________________________________
true choline-eterase Pseudocholine-
esterase
________________________________________________________
1.Specificity specific non specific
2. Site Brain, neurons,ganglia plasma,liver
t Tissues,myoneural pancreas
junction, RBCs
3. Onset o action Rapidly slowly
4. Regenration in 3 monthes in 3 weeks
2- Catecholamines:
❑ Synthesis:
▪ Tyrosine ➔ Dopa ➔ Dopamine ➔ Noradrenaline ➔ Adrenaline
▪ Catecholamines are stored in chromaffin granules.
❑ Metabolism:
1- Catechol-o-methyltransferase (COMT) converts epinephrine into metanephrine
and norepinephrine into normetanephrine.
2- Monoamine oxidase (MAO) converts metanephrine and normetanephrine into
vanilyl mandelic acid (VMA) which excreted with urine.
NOTES:
▪ Neurotransmitter of parasympathetic: Ach
▪ Neurotransmitter of sympathetic: Adrenaline, Noradrenaline and Dopamine
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AUTONOMIC RECEPTORSI. Cholinergic receptors:
1- Nicotinic receptors (Central cholinergic receptors )
• Sites of occurrence: These receptors present in the autonomic ganglia, suprarenal medulla and skeletal neuromuscular junction.
a. (NM) receptors : present in the skeletal muscles and are blocked by d- Tubocurarine
b. (NN) receptors: present in the autonomic ganglia are blocked with Hexamethonium.
Types of muscarinic receptors
• M1 neural) in the CNS, ganglia, parietal cells of the stomach responsible for the gastric secretion. Blocked by Pirenzepine (Gastrozepin ) & Telenzepine
• M2:(cardiac) in the heart
• M3:(glandular) in smooth muscles and exocrine glands
• M4 and M5: in certain areas of the brain.
II. Adrenergic receptors
They are classified according to their type and location into:
1. receptors which are classified into:
1- postsynaptic receptors
2- Presynaptic receptors
2.-adrenergic receptors which are classified into:
– 1 Receptors in the heart.
– 2 Receptors: mainly found in the blood vessels of the skeletal muscles, the bronchi and the uterus.
– 3 Receptors: present in adipose tissue.
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Autonomic Drugs
I. Cholinergic
Drugs
II. Adrenergic
Drugs
A) Peripheral
Cholinergic Drugs
B) Central
Cholinergic Drugs
1- Parasympathomimetics 1- Sympathomimetics
2- Parasympatholytics 2- Sympatholytics
I- Cholinergic Drugs
Cholinergic Agonists
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▪ Cholinergic drugs are drugs which act on the
cholinergic receptors.
▪ They are classified into 2 main classes:
A) Peripheral Cholinergic Drugs:
They acts on the peripheral cholinergic receptors
(Muscarinic R).
B) Central Cholinergic Drugs:
They acts on the central cholinergic receptors (Nicotinic
R).
A) Peripheral Cholinergic Drugs
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These are drugs which act on the peripheral cholinergic receptors (Muscarinic R)
which found on Cardiac M., Smooth Ms. & Exocrine glands.
Peripheral Cholinergic Drugs may be:
1- Muscarinic stimulants OR Parasympathomimetics.
2- Muscarinic blockers OR Parasympatholytics.
1- Parasympathomimetics (Cholinomimetics)
• These are drugs which stimulate the muscarinic receptors
➔ i.e stimulate the parasympathetic division.
MOA: Parasympathomimetics acts by 2 mechanisms:
1- Direct receptor activation: by stimulation of the muscarinic receptors.
2- Indirect receptor activation: by inactivation of cholinesterase enzyme leading
to accumulation of Ach.
Parasympathomimetics includes:
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(1) Choline
esters
(2) Choline
alkaloids
(3) Anticholinesterases
▪ ACh
▪ Methacholine
▪ Carbachol
▪ Bethanechol
▪ Pilocarpine
Reversible
(Short acting)
Irreversible
(Long acting)
▪Physostigmine
(Eserine)
▪Neostigmine
▪Organophosphates
(Diazenon, Parathion,
Malathion, Asuntol)
(1) Choline esters
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a- Ach:
It is the neurotransmitter of the cholinergic
nerves.
➢Ach acts on the Muscarinic and Nicotinic
receptors SO it has 2 types of action:
1- Muscarinic action.
2- Nicotinic action.
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Muscarinic Action Nicotinic Action
▪ It is the action of Ach on the
Muscarinic receptors which present
on Cardiac M, smooth Ms and
Exocrine glands.
▪ It is the action of Ach on the Nicotinic
receptors which present on skeletal M,
Autonomic ganglia and adrenal medulla.
▪ The action of Ach on these
receptors is similar to that produced
by Muscarine which produces
stimulation in small or large dose.
▪ The action of Ach on these receptors is
similar to that produced by Nicotine which
produce stimulation in small dose and
inhibition in large dose
▪ This action can be blocked by
atropine.
▪ This action can be blocked on skeletal M
by gallamine & tubocurarine.
Muscarinic action:
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❑ Eye:
➢ Ach binds to the muscarinic receptors in the circular muscle of the iris
(constrictor pupillae) producing pupillary constriction (miosis).
➢ In addition, it opens the angle of Schlem SO improves the drainage of aqueous
humor and reduces the intra-ocular pressure (IOP).
➢ It also increases the lacrimal secretions.
Muscarinic action:
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❑ Respiratory System:
➢ Ach binds to the muscarinic receptors in the smooth muscle of the bronchioles
producing constriction of bronchioles (bronchial asthma).
o It also increases the bronchial secretions.
❑GIT:
➢ Ach binds to the muscarinic receptors in the smooth muscle of stomach and
intestine so increases the contractions of stomach (may lead to vomiting) and
increases the motility of the intestinal muscle (may lead to spasms or
diarrhea).
o It also increases the salivary, gastric and intestinal secretions.
❑CVS:
Heart:
Ach binds to the muscarinic receptors in:
• SA node: so decreases the heart rate (bradycardia).
• AV node: so decreases conduction (block).
• Atria & Ventricles: so decreases the contractility
Blood vessels:
Ach binds to the muscarinic receptors in the smooth muscle of blood vessels so
induces vasodilatation.
Blood pressure:
Ach lowers blood pressure due to:
1- Bradycardia. 2- Vasodilatation.
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❑Urinary System:o Ach increases the contraction of smooth muscle of urinary bladder and relaxes the
sphincter.
❑ Skin: Ach increases sweating
Uses:
• Ach is not used clinically because:
o When given orally, it is rapidly hydrolyzed in the digestive tract
o When given by injections, it is rapidly metabolized by cholinesterase enzyme.
b- Methacholine:
It is a synthetic drug, destructed slowly by cholinesterase enzyme.
➔ So produce a prolonged duration of action than Ach.
Actions:
1- Muscarinic: ……………………
➔ It has a selective action on Cardiac M.
Uses:
Used for Tachycardia.
c- Carbachol:
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It is a synthetic drug, destructed slowly by cholinesterase
enzyme.
➔ So produce a prolonged duration of action than Ach.
Actions:
1- Muscarinic:……………………
It has a selective action on smooth muscle of GIT and urinary
bladder.
2- Nicotinic.
Uses:
➢ Paralytic ileus
➢ Non-obstructive urinary retention like that resulting from
general anesthetics.
d- Bethanechol:
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It is a synthetic drug, hydrolyzed slowly by cholinesterase
enzyme.
➔ So produce a long duration of action than Ach.
Actions:
1- Muscarinic:……………………
It has a selective action on smooth M of GIT and urinary
bladder.
Uses:
➢ Paralytic ileus.
➢ Non-obstructive urinary retention like that resulting from
general anesthetics.
(2) Choline alkaloids
CHOLINOMIMETIC ALKALOIDS
Pilocarpine:
➢ It is a naturally occurring alkaloid obtained from jaborandi leaves.
➢ It is readily absorbed from the GIT.
➢ Not inactivated by cholinesterase enzyme.
➔ So produce a prolonged duration of action than Ach.
Action:
Muscarinic………………………
It has a selective action on eye pupil & gland secretions.
Uses:
1- In the form of eye drops for Glaucoma (miosis reduces IOP).
2- It is a powerful diaphoretic, so used to remove edema.
3- It is a powerful sialagogue, so used in dryness of mouth following use of
atropine.
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(3) Anticholinesterases:
These are drugs which inhibit the cholinesterase enzyme so prolong the
muscarinic and nicotinic actions of Ach.
Classes of anticholinesterases:
1- Reversible (Short acting):
➢ Physostigmine (Eserine)
➢ Neostigmine
2- Irreversible (Long acting):
➢ Organophosphates (Diazenon, Parathion, Malathion, Asuntol)
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1- Reversible
(Short acting)
2- Irreversible
(Long acting)
Binding to
cholinesterase enz
Loose Firm
Duration of action Short Long
Examples • Physostigmine (Eserine)
• Neostigmine
Organophosphates (Diazenon,
Parathion, Malathion, Asuntol)
MOA
They react with
cholinesterase enzyme
forming carbamylated
enzyme which hydrolysed
slowly, so Ach released,
accumulate and prolong its
action.
They react with cholinesterase
enzyme forming
phosphorylated enzyme which
not hydrolysed, so Ach
released, accumulate and
prolong its action.
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1- Reversible anticholinesterases (Short acting):Physostigmine Neostigmine
Source Natural alkaloid obtained from the
seeds of Calabar beans.
Synthetic
Oral route Complete absorption from GIT Incomplete
Distribution Pass through BBB Cannot pass
Actions
1- Muscarinic: ……………..
Mainly eye
2- Nicotinic:
Muscle twitches.
3- CNS stimulation.
1- Muscarinic: ……………….
Mainly GIT, Urinary tract
2- Nicotinic:
.aMuscle twitches.
.bDirect skeletal M stimulation
a + b = Powerful M stimulation
Uses
1- In the form of eye drops for
Glaucoma (miosis reduces IOP).
2- Atropine poisoning:
It antagonizes the actions of
Atropine.
1- Paralytic ileus
2- Post operative urine retention.
3- Myasthenia gravis (given with
atropine to block the muscarinic
action)
2- Irreversible anticholinesterases (Long acting):
Ex: Organophosphates (Diazenon, Parathion, Malathion, Asuntol)
• They are highly soluble in lipids, so:
➔ Absorbed from all sites, even the intact skin.
➔ Distributed to all tissues, even CNS (pass through BBB).
Actions: 1- Muscarinic. 2- Nicotinic.
Uses: Used as insecticide.
Toxicity of organophosphates:
Symptoms:
1- Muscarinic symptoms:
▪ Lacrimation, salivation, sweating.
▪ Miosis, bronchial asthma, vomiting, diarrhea, colic, urination.
2- Nicotinic symptoms: Skeletal muscle twitches followed by paralysis.
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Treatment:
1- Atropine:
➢ Given to block the muscarinic receptors, so antagonize the action of ACh on the
muscarinic receptors in cardiac M, smooth m and exocrine glands.
➢ Given IV or IM (2 mg) every 5-10 min till:
➔ Dilatation of eye pupil. ➔ Dryness of mouth.
2- Cholinestrase reactivators (Oximes):
➢ They are effective only in early stages (within 12 h).
➢ Oximes react with the phosphorylated enzyme to free the active unit.
➢ Example of oximes: Pralidoxime (PAM).
3- Anticonvulsants as Diazepam (IV).
4- Other measures:
➔ Stomach wash (gastric lavage) ➔ Skin wash
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Contraindications of parasympathomimetics
1- Bronchial asthma
2- Peptic Ulcer
3- Angina Pectoris → (Hypotension → reduction of coronary
blood flow).
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2- Parasympatholytics
Antimuscarinic• These are drugs which prevent the access of Ach to the muscarinic receptors, so
inhibit the muscarinic actions of Ach.
MOA:
They act by blocking the muscarinic receptors on cardiac M, smooth Ms and
exocrine glands.
Parasympatholytics include:
(1) Natural alkaloids
• Atropine, Hyoscine
(2) Atropine substitutes
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(1) Natural alkaloids
a- Atropine: It is an alkaloid obtained from Atropa bella-dona.
Actions:
❑ Eye:
➢ Atropine blocks the muscarinic receptors in the circular muscle of the iris
(constrictor pupillae) producing pupillary dilatation (myderiasis).
➢ Duration of action of atropine on the eye ; 7-10 days
➢ In addition, it increases the intra-ocular pressure (IOP).
➢ It also reduces the lacrimal secretions.
❑ Respiratory:
➢ It relaxes the smooth M of bronchi (bronchodilatation).
➢ Reduce bronchial secretion.
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❑ GIT:
➢ It relaxes the smooth M of stomach (anti-emetic) and intestine (antispasmodic,
spasmolytic) and constrict sphincters.
➢ Reduce salivary secretion (dry mouth).
➢ Reduce GI secretions (antisecretory) leading to constipation.
❑ CVS: It increase the heart rate (Tachycardia).
❑ Urinary:
➢ It relaxes the smooth M and constrict the sphincter of urinary bladder leading to
urine retention.
❑ Sweat glands: Reduce sweating.
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Uses:
1- Used locally on the eye for eye examination (Cyclopentolate andTropicamide as eye drops are better derivatives ).
2- Bronchial asthma (Ipratropium by inhalation is a betterderivative)
3- Pre-anesthetic medication before volatile anesthesia.
➔ Reduce respiratory tract secretions, so avoid suffocation.
4- Vomiting, Spasmodic colic, diarrhea.
5- Used as antidote in case of toxicity by organophosphates &digitalis.
6-Hyperhidrosis (excessive sweating)
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2. Action On The Central Nervous System:
• Stimulant Actions:
• Stimulation of the respiratory center causingrespiratory stimulation
• High doses stimulate the Cerebral cortex leading torestlessness, hallucinations and delirium. This centralexcitation is followed by depression
• Depressant Actions:
• Decreased tremors and rigidity, so used in parkinsonism
• Inhibits vomiting centers : Antiemetic action
3. Cardiovascular system:• Heart: Small doses produce bradycardia due to blockade of M1
receptors on the inhibitory prejunctional neurons thus increaseacetylcholine release.
• Large doses produce tachycardia due to blocking of the M2
receptors
Atropine poisoning (Adverse Effects)
after frequent application, but it rarely produces death
because it has a wide safety margin.
symptoms of poisoning include mouth dryness, dilation of
the eye pupil, tachycardia, constipation, urine retention,
flushing , hyperthermia and muscular in coordination.
• Treatment of atropine poisoning:
– Administration of Physostigmine slowly I.V. to antagonize both
central and peripheral effects of atropine.
– Neostigmine can be used to antagonize peripheral actions only.
– Respiratory stimulant, CNS stimulant and cold fomentation.
•Synthetic Atropine substitutesThere are five chief classes of synthetic atropinesubstitutes:1-Mydriatic Atropine substitutes They have shorterduration of action. Homatropine•Eucatropine2- Antisecretory – Antispasmodic Atropine substitutes
- Propantheline - Hyoscine butylbromideThey are used for treatment of spasms of the GIT, bileduct and urinary tract•Pirenzepine & telenzepine: these drugs are selective M1
receptor antagonists, used in the treatment of peptic ulcer( decrease HCl)
3. Antiparkinsonism – atropine substitutes
- Trihexphenidyl - Biperiden
4. Atropine substitutes used in bronchial asthma
• Ipratropium
• It has more selective bronchodilators effectwith a lesser action on sputum viscosity, itcan be used in combination with 2 agonists
• Ipratropium has no significant CNS effects .