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Parasympathetic nervous system
Dr.asaad
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Classification of neurons (nervecells) by transmitter released
1. Adrenergic: release
1. norepinephrine (NE)
2. epinephrine (EPI)
3. dopamine (DA)
2. Cholinergic: release acetylcholine (ACh)
3. Other (non-adrenergic, non-cholinergic,NANC)
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Cholinergic - release acetylcholine
1. pre-ganglionic (SNS and PSNS)
2. post-ganglionic (PSNS)
3. post-ganglionic SNS to sweat glands4. neuromuscular junction (NMJ)
5. CNS (99% muscarinic)
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Cholinergic transmission
(terminal of the cholinergic neuron)
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Synthesis, Storage, Release, and
Removal of Acetylcholine
Synthesis and storage:
Acetylcholine is synthesized in the cholinergic nerve terminal fromacetyl CoA and choline. The formed acetylcholine is stored intovesicles.
Release:
Conduction of an action potential through the terminal branches ofan axon causes entry of calcium into the nerve terminal resulting inthe release of acetylcholine
molecules outside the nerve terminal.
Interaction with cholinergic receptors:
Once in the junctional extracellular space , acetylcholine interactsreversibly with cholinoreceptors.
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Termination of action of acetylcholine:
The length of time that the molecules of acetylcholine interactwith receptors is short because acetylcholinesterase, anenzyme that rapidly hydrolyzes acetylcholine, is highly
concentrated on the outer surfaces of both the prejunctional(neuronal) and postjunctional (effector cell) membranes. Arapid hydrolysis of acetylcholine by the enzyme results in alowering of the concentration of free acetylcholine and a rapiddissociation of receptor-bound acetylcholine from its
receptors.Little or no acetylcholine escapes into the circulation.
Any acetylcholine that reaches the circulation is immediatelyinactivated by plasma esterases.
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Cholinergic receptors
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Action of acetylcholine at cholinergic receptorsOrgan Receptor Action
Eye
Circular muscle of
the iris
M3 Contracts
Ciliary muscle M3 Contracts
Heart
Sino-atrial node M2 Slows
Myocardium M2 Negative inotropic action (more in
atria) and negative chronotropic action
Blood vessels Endothelium M3 Vasodilatation
Bronchioles M3 Contraction
GIT
Smooth muscle
walls
M3 Contraction
Sphincters M3 Relax
Glands M3 Secretion
Urinary bladderWall M3 Contracts
Sphincter M3 Relax
Pregnant uterus M3 Contracts
Glands M3 Secretion
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Parasympathomimetics = Cholinoceptor stimulants:bind to acetylcholine receptors and stimulatesthem.
Parasympatholytics (cholinergic antagonistsanticholinergic drugs): bind to acetylcholinereceptors and reduce the effects of parasympathetic
stimulation by preventing endogenous acetylcholinefrom binding to them.
Modifying Autonomic Nervous System
Function
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Parasympathomimetics
(Cholinoceptor stimulants)
Cholinoceptor
stimulants
Direct
Esters of choline
Alkaloids
Indirect Cholinesterase inhibitors
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Cholinoceptor stimulants
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Direct cholinoceptor stimulants
Alkaloids
Nicotine
Lobeline
Muscarine
Pilocarpine
Esters of choline
Acetylcholine
Methacholine
Bethanechol
Carbachol
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NicotineSite of action:
A) nicotinic receptors (small doses stimulate and large doses
inhibit)1- NN at autonomic ganglia and adrenal medulla
2- NM at the motor end plate (Affinity is greater for NNsitesthan NM sites)
B) CNS 15
Acetylcholine (ACh) has no therapeutic
applications because of its diffuse action and its
rapid hydrolysis by both AChE and plasma
butyrylcholinesterase.
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Actions of nicotine
Action at autonomic ganglia (both sympatheticand parasympathetic):
1. Small doses stimulate autonomic ganglia
leading to:
a) sympathetic effect on the cardiovascularsystem with tachycardia and hypertension
b)parasympathetic effect on the GIT - withnausea, vomiting and diarrhoea and urinary
bladder with voiding of urine2. Large doses or prolonged occupancy at
nicotinic receptors inhibit autonomic ganglia
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Actions of nicotine
Action at the neuromuscularjunction:
1. Small doses stimulate leading toeither fasciculation or strongmuscle contraction
2. Large doses inhibit leading todepolarization blockade.
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Actions of nicotine
Action at the CNS:
Used as an insecticide
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Small doses (tobacco smoke) Mild alerting action
Larger doses Tremors
Very large doses Convulsions and death
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Indirect cholinoceptor stimulants
(agents that inhibit acetylcholinesterase)
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Cholinesterase inhibitors
Types of cholinesterases:
1- Acetylcholinesterase (true cholinesterase): Found at:
I. Cholinergic neurons
II. Cholinergic synapses
III. Neuromuscular junction
IV. Red blood cells
2- Butyrylcholinesterase (pseudocholinesterase):
- Found at:
Plasma and liver
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Acetylcholinesterase inhibitors
Three chemical groups:
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Alcohols Esters Organophosphates
1- Edrophonium 1- Neostigmine
2- Physostigmine
1- Echothiophate
Neostigmine is not absorbed
and does not enter CNS
Physostigmine is absorbed
from all sites including
conjunctiva and enters CNS
All organophosphorous
compounds are well
absorbed from all sites of
administration and enter the
CNS except echothiophate
Reversible inhibition after 2-10 min.
Reversible inhibition after 30min to 6 hours
Irreversible inhibition (can bereversed by pralidoxime)
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Action of acetylcholinesterase
inhibitors:
Inhibit acetylcholinesterase and to a lesser
extent butyrylcholinesterase leading to
increase the concentration of endogenous
acetylcholine at cholinergic receptors
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Organ system effects of acetylcholinesterase
inhibitors
CNS Low concentrations cause alertness
High concentrations cause convulsions followed by coma
Eye, GIT,
Bronchioles and
urinary bladder
Similar to acetylcholine (increase the effect of acetylcholine at
muscarinic receptor)
Cardiovascular
system
Effect is due to :
1- Stimulation of sympathetic and parasympathetic autonomic ganglia
2- Stimulation of cholinergic receptors at the heart and blood vessels
Effect on the heart:
Similar to acetylcholine leading to decreased cardiac output
Effect on the blood vessels:
Vasodilatation (less than direct cholinoceptor stimulants) with only
little hypotension
Neuromuscular
junction
Therapeutic doses increases strengh of contraction
Higher concentrations cause muscle fibrillation
Higher concentration cause neuromuscular blockade and paralysis
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Therapeutic uses of cholinoceptor
stimulantsDisease Mechanism of action Drug
1- Glaucoma Contraction of the ciliary
muscle and increasing the
outflow of the aqueous
humor
Pilocarpine
Physostigmine
echothiophate
2- Postoperative ileusBethanechol or
neostigmine3- Reflux esophagitis
4- Urinary retention
5- Myasthenia gravis neostigmine,
pyridostigmine, or
ambenonium.
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Myasthenia gravis
Definition:
Myasthenia gravis is a disease affecting skeletalmuscle neuromuscular junctions. An autoimmune
process causes production of antibodies thatdecrease the number of functional nicotinicreceptors on the motor end plates.
Frequent findings are ptosis, diplopia, difficulty in
speaking and swallowing, and extremity weakness.Severe disease may affect all the muscles, includingthose necessary for respiration.
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Myasthenia gravis
Diagnosis: Edrophonium test:
A dose is injected intravenously. If the patient has myastheniagravis, an improvement in muscle strength that lasts about 5minutes will usually be observed.
Edrophonium is also used to assess the adequacy of treatment with
the longer-acting cholinesterase nhibitors in patients withmyasthenia gravis. If excessive amounts of cholinesterase inhibitorhave been used, patients may become paradoxically weak becauseof nicotinic depolarizing blockade of the motor end plate. Smalldoses of edrophonium (12 mg intravenously) will produce
no relief or even worsen weakness if the patient is receiving
excessive cholinesterase inhibitor therapy. On the other hand, if thepatient improves with edrophonium, an increase in cholinesteraseinhibitor dosage may be indicated.
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Myasthenia gravis
Treatment:
Long-term therapy for myasthenia gravis is
usually accomplished with neostigmine,
pyridostigmine, or ambenonium.
If muscarinic effects of such therapy are
prominent, they can be controlled by the
administration of antimuscarinic drugs such as
atropine.
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Toxicity of cholinoceptor stimulantsDirect acting muscarinic
stimulants (ex. Pilocarpine)
meiosis, nausea, vomiting, diarrhea, salivation,
sweating, cutaneous vasodilation, and bronchialconstriction. These effects are all blocked by
atropine.
Direct-Acting Nicotinic
Stimulants
Acute toxicity (treatment symptomatic)
(1) central stimulation, which cause convulsions and
may progress to coma and respiratory arrest;
(2) skeletal muscle paralysis
(3) hypertension and cardiac arrhythmias.
Cholinesterase inhibitors Acute toxicity: Treated by atropine and pralidoxime)
1- meiosis, nausea, vomiting, diarrhea, salivation,
sweating, cutaneous vasodilation, and bronchial
constriction2- These manifestations are followed by:
(1) central stimulation, which cause convulsions and
may progress to coma and respiratory arrest;
(2) skeletal muscle paralysis
(3) hypertension and cardiac arrhythmias.
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