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Cholinergic receptors: Acetylcholine acts on two types of receptors:
Nicotinic
Site
Muscarinic
-All autonomic ganglia(NN)
-All organs supplied by
-Adrenal medulla (NN)
parasympathetic fibers.
Neuro-muscular junction(NM)
-Sweat glands supplied
by sympathetic fibers.
NN: Ganglion blockers e.g.
Blocker
hexamethonium
Atropine
NM: Neuromuscular blockers
e.g. Curare.
N.B. Endothelium of most blood vessels releases EDRF (Endothelium Derived Relaxing
Factor) =nitric oxide (NO) inducing VD through non-innervated muscarinic receptors.
*Muscarinic receptors are subdivided into M1- M5
M1
Site
Effect
M2
-Exocrine glands.
Heart
M3
-Exocrine glands.
-Parietal cells of
-Smooth muscles.
stomach.
-Vascular
-CNS.
endothelium.
-Exocrine
gland  HR and AV -Exocrine
secretion.
conduction
-HCl secretion.
gland
excretion.
-Smooth
muscle
contraction.
-Hypotension.
Selective
Pirenzipine
-Gallamine
antagonist
The exact role of M4 and M5 are not yet identified.
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Darifenacin
Removal of Acetyl choline:
Rapidly hydrolyzed by acetylcholinesterase enzyme (2 types):
*True: found at all sites of A Ch release.
*Pseudo: found in plasma and liver.
PARASYMPATHOMIMETICS
Drugs which stimulate muscarinic receptors (muscarinic agonists)
with or without nicotinic action. They are classified into:
A- Directly Acting:
1- Choline esters: A.Ch. (Natural), Methacholine, Carbachol and Bethanecol
(Synthetic)
2- Cholinomimetic Alkaloids: Pilocarpine and muscarine.
B- Indirectly Acting (Anticholinesterases):
 anticholinesterase  accumulation of endogenous A.Ch infront of
cholinergic receptors(Muscarinic & Nicotinic)  effects that mimic the
parasympathetic nervous system. They are subdivided into:
*Reversible as physostigmine, Neostigmine, Edrophonium.
*Irreversible as organophosphorous compounds.
I. Choline Esters They are quaternary amines, so can not pass to C.N.S. and
are distributed extracellular. The following table shows the main
pharmacological differences between different choline esters:
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Acetylcholine
Hydrolysis
by True
cholinesterase
Methacholine
and True only
psuedo
Nicotinic
Carbachol
Not
Bethanechol
hydrlysed
by true or
psuedo
++++

++++
---
++++
++++
++++
++++
action
Muscarinic
action
Non-specific
Specificity of
(Has the same
muscarinic
efficacy on M
action
CVS
Eye ,
and
receptors all
over the body)
Urinary bladder
Not used due Peripheral
Clinical uses
GIT
very
1- Glaucoma
short vascular
duration
action (why?)
2- Paralytic ileus
of diseases e.g.
3-Non-obstructive urine retention
Raynaud’s
disease.
II- Cholinomimetics Alkaloids: Pilocarpine
Actions: Act directly on muscarinic receptors with marked action on eye,
exocrine glands and smooth muscles.
Uses:
-Eye drops in glaucoma.
-Promotion of hair growth.
Contraindications of directly acting parasympathomimitics:
1-Bronchial asthma.
2-Peptic ulcer.
3-Coronary insufficiency, hypotension and bradycardia.
5-Never given I.M. or I.V. (produce severe bradycardia and hypotension and
Atropine is the antidote).
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Anticholinesterases
-They inhibit cholinesterase enzyme so produce accumulation of ACh. at
cholinergic sites (muscarinic and nicotinic).
-ACh. Undergoes 2 steps hydrolysis 1st binds to the active site of the
enzyme and is hydrolyzed into free choline and acetylated enzyme, the 2 nd
step is splitting of acetylated enzyme to acetic acid and free enzyme which
occurs in 150 microseconds:
1-Reversible anticholinesterases include:
*Edrophonium: It binds to the active anionic site of the enzyme for 5
minutes and then excreted in urine unchanged so it is not substrate for the
enzyme. Quaternary amine given I.V. Used for diagnosis of myasthenia
gravis.
*Carbamates (Physostigmine, Neostigmine) undergo 2 step hydrolysis as
ACh., but the carbamylated enzyme is resistant to hydrolysis (prolonged to
0.5 - 6 hours). They are substerate for the enzyme.
Physostigmine (Eserine)
Neostigmine
Source
Natural
Synthetic
Chemistry
Tertiary amine (-N-) i.e. Quaternary amine (-N-)
non-ionized
i.e. ionized
Oral absorption
Complete
Incomplete
Passage through
Can pass
Can’t pass
BBB
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Actions
*Muscarinic: more on eye
*Muscarinic: more on
*Nicotinic.
GIT
*CNS
stimulation
 *Nicotinic.
*Direct skeletal muscle
convulsions.
stimulation.
Uses
1-Glaucoma.
1-Diagnosis
and
2-Antidote to atropine i.e. treatment of Myasthenia
used
in
treatment
of Gravis.
atropine or atropine like 2-Antidote to curare.
drugs e.g. TCAs poisoning. 3.post-operative
urine
retention and paralytic
ileus.
Neostigmine Substitutes:
•Pyridostigmine: used in treatment of myasthenia gravis.
•Demecarium: Local long acting miotic in glaucoma.
•Tacrine has anticholinesterase activity and is used in treatment of
Alzheimer's disease. It is hepato-toxic.
•Donepezil,
Galantamine
and
rivastagmine
are
more
selective
cholinesterase inhibitor in treatment of Alzheimer’s disease and are not
hepatotoxic
Myasthenia Gravis
Disease of neuromuscular junction characterized by weakness on
repetition of
movement. It is an autoimmune process, which cause production of
antibodies that decrease the number of functional nicotinic (NM) receptors on
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the motor end plate. It is diagnosed by neostigmine or by edrophonium
(muscle weekness is improved).
It is treated by cholinesterase inhibitors as Neostigmine (give atropine
before)
or
neostigmine
substitutes
(pyridostigmine),
also
immunosuppressants (cordcosteroids) may be tried and surgical removal of
thymoma if present.
2- Irreversible anticholinesterases:
They combine with the active site of the enzyme but the
phosphorylated enzyme is stable (needs hundreds of hours for hydrolysis).
This phosphorylated enzyme may undergoes aging process, which
strengthens the bond, and induces complete and permanent enzyme
inactivation and so they have long duration until new enzyme synthesis.
Organo-Phosphorus Compounds
They are non-competitive irreversible inhibitors for cholinesterase
enzyme. Most of them are highly lipid soluble. They are used as:
1-Insecticides: Parathion and Malathion..
2-War gas: Tabun, Sarin and Soman.
Organophosphorus Poisoning:
It is due to inhalation of sprays or dusts of insecticides or
contamination of skin or food. It may be caused as a result for chemical
wars. Death is due to respiratory failure (central or peripheral).
* Treatment:
1-Care of respiration by artificial respiration and suction of secretions.
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1-Atropine 2 mg. I.V. or I.M./10 minutes until pupil dilates and skin dries. It
antagonizes the muscarinic effects central and peripheral.
2-Cholmesterases reactivators (oximes) as Pralidoxime (PAM), diacetyl
monoxime (DAM). They combine with the poison in blood and may
dephosphorylate the enzyme if given early before aging of the enzyme. They
reverse muscle weakness and are used with atropine. PAM can not pas to
C.N.S. but DAM. crosses blood brain barrier.
3-Symptomatic treatment e.g. anticonvulsants as diazepam.
Muscarinic Receptor Antagonists (Parasympathetic depressants)
They produce competitive reversible blockade of the actions of A.Ch.
at muscarinic (M) receptors. They are classified into:
I. Natural Belladonna alkaloids which include Atropine and Hyoscine. They
are tertiary amine compounds.
II. Synthetic derivatives.
ATROPINE
Actions:
1-Eye: Local atropine application lasts for 7-10 days.
*Block of M receptors in constrictor pupillae muscle:
Passive Mydriasis & Loss of reaction to light (-ve light reflex).
*Block of M receptors in Cilliary muscle
Relaxation of ciliary muscle (cycloplegia)  loss of accommodation for
near vision.
Impair aqueous humor drainage   IOP.
* lacrimation.
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2-Secretions:  salivary, bronchial, gastric, and sweat secretion.
3-Bronchi: Bronchodilatation and dryness of secretions.
4-C.V.S:.
*small doses I.V.  initial bradycardia due to stimulation of C.I.C. (central
effect) and blockade of presynaptic M receptors, followed by tachycardia
due to block of M2 receptors.
*large dose I.V. or orally it produce tachycardia from the start.
*It  A.V. conduction.
*On blood vessels it has no effect in therapeutic doses as most of vessels
have no parasympathetic supply (unninnervated M 3). However, toxic doses
especially in children cause cutaneous V.D. especially in the face (Atropine
flush).
5-GIT: Decrease motility and secretions.
6-Urinary tract: Relax wall and contract sphincters (urine retention).
7-C.N.S:.
*Stimulate R.C. and C.I.C.
*Inhibit vomiting centre and basal ganglia.
*large doses on cortex produce excitation, agitation, hallucination and
coma.
Therapeutic Uses:
a- Preanesthetic medication to:
*Decrease salivary and bronchial secretions and prevent bronchospasm.
*Antagonize respiratory center depressants.
*Protect heart from bradycardia induced by some general anaesthetics.
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*Prevent vomiting .But its disadvantages are urine retention and intestinal
hypomotility following surgery.
b- To measure errors of refraction in uncooperative patient (e.g. children).
Also for fundus examination and to prevent formation of adhesions in iritis
c- Heart block, marked bradycardia and carotid sinus syndrome.
d- Bronchial asthma (but secretions become viscid so better use
Ipratropium).
e- Peptic ulcer, colics and gut hypermotility: In traveler's diarrhea, it is
combined with diphenoxylate (opioid anti-diarrheal drug).
f- Nocturnal enuresis and urinary urgency to reduce bladder motility.
g. Parkinsonism.
h. Motion sickness but hyoscine is better
i- Hyperhidrosis (excessive sweating).
j- Cholinergic poisoning to antagonize the muscarinic effects as in
organophosphorus poisoning or physostigmine poisoning.
Adverse Effects:
Dry mouth, blurred vision, tachycardia, urine retention, glaucoma, flush and
hyperthermia (especially in children).
Contraindications:
-Prostatic hypertrophy
-Glaucoma.
HYOSCINE = SCOPOLAMINE
*It has a shorter duration with more potent effect on eye and secretions, but
less effect on heart.
*It is a tertiary amine as atropine, so stimulate R.C. and C.I.C. and inhibit
vomiting centre and basal ganglia, also produces sedation & amnesia.
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*Used as Atropine and preferred in preanesthetic medication of cardiac
patients, in obstetric (with Meperidme to produce sedation and amnesia), in
motion sickness, to abort vertigo in Meniere's disease, antispasmodic.
Synthetic Atropine Substitutes
1-Mydriatic
Group:
Homatropine
hydrobromide,
Eucatropme,
Cyclopentolate and Tropicamide. All of them produce cycloplegia except
eucatropine. They are preferred over atropine in fundus examination and
measuering errors of refraction. They are contraindicated in glaucoma.
2-Antisecretory Antispasmodic Group: They
*Block M receptors especially on GIT.
*They include: Probanthelene and Oxyphenonium and Hyoscine butyl
bromide (Buscopan).They are used in peptic ulcer and colics.
Pirenzepine and telenzepine are selective M1 blockers, used in peptic ulcer.
*They are contraindicated in glaucoma and prostatic hypertrophy as
Atropine.
3-Ipratropium and Tiotropium
produce bronchodilatation without
dryness of secretions. Given by inhalation in prophylaxis of bronchial
asthma.
4-Anti-Parkinsonian group: Benzhexol= Trihexphenedyle, Benztropine
and Caramiphen (which has also central antitussive action).
5-Emepronium: is similar to Probanthelene and used to reduce bladder
motility in incontinence and nocturnal enuresis.
* Tolterodine is M3 blockers for treatment of urinary incontinence.
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