CHOLINOMIMETICS, MUSCARINIC AGONISTS,
CHOLINOCEPTIVE AGONISTS
A) Direct Parasympathomimetics:
• 1-Choline Esters:
a- Acetylcholine
c-Carbachol.
b- Methacholine.
d-Bethanechol.
2-Cholinomimetic Alkaloids:
a- Pilocarpine. b-Muscarine.
c-Arecoline.
d. oxotremorine
• B) Indirect Parasympathomimetic (AntiCholinesterases):
• They inhibit cholinesterase enzymes ( and
include both TRUE and Pseudocholinesterasea).
• They causes an accumulation of the endogenous
A.Ch. leading to the stimulation of both the
Muscarinic and Nicotinic receptors to provide
the corresponding actions.
1-Reversible Anti-Cholinesterasees:
a- Quaternary Alcohols : Edrophonium.
It is not a substrate for the Enzyme.
b- Carbamate Derivatives.
Are Substrate for the Enzyme.
-Physostigmine.
-Neostigmine.
- Pyridostigmine .
2-Irreversible Anti-Cholinesterases
(Organophosphorus Compounds):
Non-competitive Irreversible inhibition of
enzyme.
a. Di- isopropyl flurophosphate (DFP )
b. Echothiophate, used as eye drops in the
treatment of glaucoma
c. Tetraethyl pyrophosphate (TEPP)
d. Nerve gases ( Tabun, Sarin & Soman )
e. Agricultural Insecticides ( Parathion,
Malathion & Fenthion)
f. Metrifonate used in treatment of urinary
bilhaziasis
A- Choline Esters:
1- Acetylcholine :
Synthesis:
a- Active Uptake of Choline by Cholinergic Varicosity (Rate
Limiting Step)
N.B. hemicholinium Inhibits Neuronal Uptake of Choline.
b- In Mitochondria of Cholinergic Nerve Terminal (Varicosity):
Acetate + Co. A + ATP  Acetyl Co. A + ADP
c-In Cytoplasm of cholinergic Nerve Ending (Varicosity):
Choline + Acetyl Co.A  Acetylcholine + Co.A
Absorption and Fate :
a. ACh is ineffective orally and be given
parenterally.
b. Rapidly hydrolyzed in the blood and
tissues to choline and acetic acid by the
enzyme cholinesterase.
Types of cholinesterase :
There are two types of cholinesterase :
a. True cholinesterase:
- occurs in the CNS , red blood cells and
in all cholinergic structures.
- it is responsible for the hydrolysis of
ACh released at the cholinergic sites.
b. Pseudocholinesterase:
- It occurs in the liver and plasma.
- It hydrolyzes drugs with structural
similarity to Ach.
- The enzyme has two active sites, the
anionic site ( containing glutamate )
and the estratic site which contains
serine amino acid
Properties of Ach:
• Very short duration of action because
of its rapid hydrolysis by both
enzymes.
• Not used as a drug.
• Not be given orally.
Pharmacological Actions of
Acetylcholine
There are two main actions called:
1- Muscarinic actions
2- Nicotinic actions.
1 - Actions on The Cardiovascular
System:
A- On the heart :
a- Negative Chronotropic   SAN 
decreases The
heart rate (Bradycardia).
b- Negative inotropic on Atrium (decreases the
force of contraction).
c- Negative Dromotropic (  A-V
Conduction).This will reduce the cardiac
output
B- On the blood vessels:
A.Ch. + Non - innervated muscarinic receptors
on Intact Endothelium  releases Endothelium
Derived Relaxing Factor (EDRF, Nitric Oxide)
 increases the cGMP levels  vasodilatation.
C. Blood pressure:
Caues fall in blood pressure as a result of
the bradycardia and vasodilatation.
The induced vasodilatation of both
peripheral and systemic blood vessels
leads to;
a- Reduction of the systemic ABP
b- Reduction of the PVR
c- Reduction of the blood flow to some
organs e.g. kidney and the liver
2- Actions on Gastrointestinal tract:
a- Motility : Stimulation
b- Sphincters : Relaxation
c- Secretions : Increase
3- Urinary bladder: (Evacuation)
a- Detrusor Muscle : Contraction (
urination)
b- Sphincters : Relaxation
( urination)
4- Eye :
a- Circular Muscles ( M3) : Contraction (
Miosis)
b- Ciliary Muscles (M3) : Contraction for
near vision ( to see the near objects)
5- Glands:
Sweat, salivary and lacrymal :
Stimulation to increase secretions.
6- Lung :
a- Bronchial Muscles: Contraction (
Bronchoconstriction)
b- Bronchal glands : Stimulation (
Increased secretions)
1-Stimulation of Autonomic Ganglia
and Adrenal Medulla (Nn)
a. Acetylcholine stimulates the
autonomic ganglia, resulting the
release of noradrenaline from the
sympathetic nerve endings .
b. Stimulation of the adrenal medulla
release of adrenaline and
noradrenaline .
This effect is blocked by the
ganglionic blockers, hexamethonium
2- Motor end plate (Nm):
Acetylcholine induces muscle
twitching.
This effect is blocked by the
neuromuscular junction blocker
decamethonium and flaxedil.
Acetylcholine reversal:
In presence of atropine; high doses of acetylcholine
produce an increase in blood pressure instead of a
decrease.
Therapeutic uses of Ach:
Not used therapeutically because of:
a. Its multiplicity in action,
b. Its rapid inactivation by cholinesterase
enzymes.
c. Being ineffective orally.
• Except during cataract , it produces
immediate brief miosis
2- Synthetic Cholinomimetic
esters :
They are characterized by
1. More stable than ACh
2. More selective than Ach
3. Have longer duration of action
4. Active orally and parentrally
They can be prepared either by
1. B-methylation, increases the
muscarinic activity.
2. Addition of carbamate increases the
stability and resist the enzymatic
hydrolysis.
Properties:
1- ALL are quaternary ammonium
compounds
2- More specific.
3- Less metabolised: Hence have longer
duration of action and Effective Orally.
4- NEVER be injected I.V. or I.M.  toxicity is
abolished by ATROPINE.
Contraindicated in:
a- Bronchial asthma (Bronchospasm
and increased secretion).
b- Peptic Ulcer
Secretions).

(Gastric Acid
c- Angina Pectoris  (Hypotension 
reduction of coronary blood Flow).
d- Thyrotoxicosis
Fibrillation).

(Atrial
Therapeutic Uses of methacholine
1. Paroxysmal atrial tachycardia
2. Raynaud's disease
3.Diagnosis of atropine (Belladonna) toxicity
How? Because Normally when injected,
It causes colics, salivation, lacrimation,
sweating.
These symptoms do not appear in case of
atropine toxicity
Uses of carbachol:
Used for treatment of Glaucoma and
cataract extraction.
Uses of Bethanechol ( Urecholine )
1. Paralytic ileus
2. Post operative retention of urine, in
absence of mechanical obstruction
3. Gastric atony
4. Glaucoma
A- Methacholine :
a- Its nicotinc actions are not clear
b- It has longer duration of action
c- Its muscarinic actions are more
prodominent on the cardiovascular
system than on GIT and urinary
bladder.
B- Carbamylcholine ( Carbachol):
a- It has a longer duration of action
b- Its nicotinc action is nearly similar to Ach
c- Its muscarinic actions are more prodominent
on the eye , urinary bladder and GIT.
C-Bethanechol ( Urecholine) :
It is completely similar to that of carbachol , but
the main difference is that it does not have
nicotinic actions.
II- Cholinomimetic Alkaloides :
Pilocarpine
Pilocarpine is a direct prasympathomimetic
tertiary amine.
a. It is a naturally occurring alkaloid
obtained from Pilocarpus jaborandi leaf.
b. It is readily absorbed from the GIT.
c. Inactivated by cholinesterase enzyme .
d. It has longer duration of action.
e- Passes the B.B.B (Avoids in
Parkinsonism).
f- Excreted in urine.
Pharmacological actions
A. Eye:
Locally in the eye as eye drops, it produces:
a. Miosis
b. Contraction of the ciliary muscle
leading to accomodation for near
objects
c. Decreases the intra-ocular pressure.
B. Exocrine glands
Increases the secretion of the exocrine
glands especially salivary (sialagogue
action) and sweat (diaphoretic action)
Smooth muscles . C
It increases the tone and motility of the
GIT, urinary bladder and
bronchoconstriction.
Therapeutic uses :
1. Treatment of glaucoma, the drug of
choice in the emergency of the
increased IOP in both open and closed
angel glaucoma.
2. To counteract the mydriatic effect of
atropine, homatropine and eucatropine .
3. Alternately with mydriatics to break
adhesions between the iris and lens
4. To stimulate salivation in dry mouth
( xerostomia)
5. Treatment of atropine overdosage.
They are indirectly acting cholinomimetics.
They block the enzymatic hydrolysis of
acetylcholine, by inhibition of acetylcholinesterase and plasma pseudocholinesterase.
They increase the local acetylcholine
concentrations and Accumulation of the
endogenous A.Ch. inducing both the
Muscarinic and Nicotinic actions.
1-Reversible Anti-Cholinesterasees:
They weakly inhibit acetylcholinesterase by
reversible association with the anionic site and
hindering access to acetylcholine
2-Irreversible Anti-Cholinesterases:
(Organophosphorus Compounds):
These agents act by covelantly phosphorylating
the hydroxyl group of serine on the enzyme.
1. Reversible anticholinesterases:
a. Short acting:
Edrophonium:
it is mainly used for diagnostic purposes
b. Medium acting:
- Physostigmine:
- It is a natural alkaloid). (tertiary amine).
- Absorbed from the GIT and pass the BBB
producing central stimulation.
- Neostigmine (prostigmine), has a direct
stimulant effect on skeletal muscles.
- Pyridostgmine
- Tacrine, Donepezil, Rivastgmine,
galantamine ( 3ary amines in Alzheimer)
- Ambenomium , - Demecrium and Benzyrinium.
Mechanism of action
A. Short acting:
• Compete with ACh for the active sites on
the true and pseudocholinestrases .
• Bind to the anionic site of the enzyme with
ionic bond so they have brief and short
duration.
B.Medium acting
- They bind to the anionic site and estratic
site of the enzyme.
- The carbamylated enzyme has a slower
rate of hydrolysis and recovery.
- The duration of action of these drugs is
relatively longer.
Neostgmine: 2-4 h, Pyridostgimine: 3-6 h.
2. Irreversible anticholinesterases:
(Organic phosphate esters)
a. Diisopropylflurorophosphate (DFP)
(Isoflurophate)
b. Tetraethylpyrophosphate
c. Ecothiophate
d. Insecticides e.g. parathion
e. Nerve gases e.g. sarin, tabun and soman.
Mechanism of action
1. They bind to the serine OH group in the
estratic site .
2. The inactivated phopshorylated enzyme is
very stable.
3. The recovery of the enzyme activity
depends on the synthesis of new one.
It takes few weeks ( Reactivation of the nonaged enzyme may be occurred by
cholinesterase reactivator. pralidoxime
(PAM).
4. War gases and pesticides interact only
with the estratic site of the enzyme and
have no anionic.
Ecothiophate which binds also to the anionic
site.
Pharmacological actions
I. Muscarinic actions
1. Cardiac muscles: bradycardia and decrease
conductivity
2. Smooth muscles
a. Eye: iris: miosis due to contraction of circular
muscles
ciliary muscles: contraction and accommodation
for near vision.
b. Bronchi: bronchoconstriction and stimulation
of secretion
c. GIT: increase tone and motility and
stimulation of gastric secretions
d. Urinary bladder: evacuation of the bladder
and urination.
3. Exocrine glands: Stimulation of sweat, salivary
and lacrymal secretions.
II. Nicotinic actions:
1. Skeletal muscles:
These drugs potentiate the action of
Ach on the muscle by their
anticholinesterase activity.
2. Autonomic ganglia: no marked effect.
III. Effect on the CNS
Tertiary compounds as physostigmine,
tacrine and donepezil pass the blood
brain barrier.
They produce symptoms of CNS
stimulation as restlessness, insomnia,
tremors and convulsions followed by
depression.
These effects are:
- Due to the activation of the
muscarininc receptors.
- Antagonized by atropine.
- Greater with irreversible
anticholinesterase compounds.
Therapeutic uses:
1. Diagnosis and treatment of myasthenia gravis
2. Treatment of glaucoma (eserine, demecarium)
3. Teatment of postoperative paralytic ileus and
urine retention (benzpyrinium)
4. Antidote for atropine poisoning
5. Alzheimer (tacrine and donepezil)
6. To counteract the mydriatic effect of
homatropine and eucatropine
7. Alternatively with mydriatic to break adhesion
between iris and lens.
1. Diagnosis and treatment of myasthenia
gravis
What is myasthenia gravis?
Myasthenia Gravis mean "Grave muscle
weakness."
Myasthenia gravis is a auto-immune disorder,
characterized by progressive muscle fatigue
and weakness.
Usually involves muscles around the eyes,
mouth, throat and limbs.
A. A disease of impaired neuromuscular
transmission.
B. Characterized by weakness and rapid
fatigability of the skeletal muscle, drooping
of the upper eye lid (ptosis).
C. Usually occurs between age group of 20
and 40, and more common in women.
D. This disease affects 1:2000 individuals,
100,000 case in USA.
Etiology:
1. Autoimmune disease, due to the presence
of antibodies against Ach receptor protein.
2. The presence of circulating curare-like
substances.
3. A defective rate of synthesis of
acetylcholine.
4. Excessive amount of acetylcholinesterase
in the neuromuscular junction.
Myasthenia gravis occurs when the immune
system makes antibodies that damage or
block many of the muscle's acetylcholine
(ACh) receptors on the surface of muscle
cells.
This prohibits ACh from binding to the
damaged receptors and acting on the muscle,
which reduces muscle contractions, leading
to weakness and fatigue.
There are enough number
of acetylcholine receptor
transmitting the signal from
the nerve to the muscle.
Antibody (Y-shaped) binds
and reduces the number of
acetylcholine receptor
and makes the transmission
of the signal difficult
A.Diagnosis of Myasthenia gravis
• Administration of edrophonium (IV) which
is a short acting anticholinesterase.
B.Treatment of Myasthenia gravis
a. Anticholinesterases
• Neostigmine:
• It has a direct action on the muscle. It is
used in combination with atropine to block
the unwanted muscarinic effects.
• Pyridostgmine (Neostgmine substitutes,
mestinone)
• Ambenonium: More selective on the skeletal
muscles, effective orally, longer duration of action
(advantage over neostgmine)
b. Azathioprine ( immunosuppressant agent).
c. Thymectomy
d. Plasma exchange
e. Prednisolone ( as corticosterids)
2. Treatment of glaucoma (eserine, demecarium)
3. Teatment of postoperative paralytic ileus and urine
retention (benzpyrinium)
4. Antidote for atropine poisoning
5. Alzheimer (tacrine and donepezil)
6. To counteract the mydriatic effect of homatropine
and eucatropine
7. Alternatively with mydriatic to break adhesion
between iris and lens.
. These are drugs that block the peripheral
muscarinic receptors.
. They inhibit the muscarinic actions of acety
-lcholine and other parasympathomimetics.
They include:
a-Naturally occurring Belladonna alkaloids
e.g. Atropine, Hyoscine ( Scopolamine)
b- Atropine substitutes
I. Atropine
Pharmacological Actions of Atropine :
1. Actions on the smooth muscles
A. Eye:
B. Bronchi:
C. Gastrointestinal tract:
D. Urinary tract:
E. Blood vessels
F. Exocrine Glands:
A. Eye:
• Local application of atropine in the eye or its
systemic administration produces:
a. Mydriasis due to paralysis of the constrictor
pupillae muscle containing M3 receptors (
passive mydriasis)
b. Paralysis of the ciliary muscle (cycloplegia)
leading to loss of accomodation to near
objects.
c. Increased intra-ocular tension due to closure
of the canal of Schlemm and obstruction of
the spaces of Fontana
d. Loss of the light reflex
e. Inhibition of lacrimation
• The duration of action of atropine following
its local application to the eye is 7 – 10 days.
B. Bronchi:
Bronchodilation and reduction of bronchial
secretion
C. Gastrointestinal tract:
a. Reduction of tone and motility of the GIT
b. Reduction of gastric secretion (volume and
total acid content)
D. Urinary tract:
a. Ureter: antispasmodic
b. Urinary bladder: relaxation of the
detrusor muscle, contraction of the
sphincter and trigone leading to retention
of urine.
E. Blood vessels
a. Therapeutic doses do not produce
significant action on the blood vessels and
blood pressure
b. Toxic doses: dilatation of cutaneous blood
vessels especially those in face area
(Atropine flush).
F. Exocrine Glands:
- Reduction of salivary secretions
producing dry mouth
- Reduction of the Lachrymal secretion
- Reduction of sweating producing dry
skin and arise of body temperature
(atropine fever) and is usually observed
after toxic doses of atropine.
2. Action On The Central Nervous
System:
Stimulant Actions :
a. Stimulation of the respiratory center causing
respiratory stimulation
b. High doses stimulate the Cerebral cortex
leading to restlessness, hallucinations and
delirium.
This central excitation is followed by
depression
Depressant Actions:
a- Decreased tremors and rigidity, so
can be used in treatment of
parkinsonism
b- Inhibits vomiting centers : Antiemetic
action
3. Cardiovascular system:
Heart:
a. Small doses: bradycardia due to
blockade of M1 receptors on the
inhibitory prejunctional neurons thus
increasing the release acetylcholine.
b. Large doses produce tachycardia due to
blocking of the postsynaptic M2
receptors
Therapeutic uses:
1- Preanesthetic medication:
Half an hour before general anesthesia :
a. Decrease salivary and bronchial secretions
b. Protect the heart from excessive vagal tone
c. Counteract the inhibitory effect of
morphine on the respiratory center
2- Antispasmodic in cases of intestinal ,
biliary and renal colics
3- In case of Heart block due to myocardial
infarction , over dose of digitalis or
propranolol.
4- Treatment of severe bradycardia
6- Hyperhidrosis (excessive sweating)
7- locally in the eye:
a. In cases of iris and corneal ulcer to
prevent the adhesions
b. In alternations with miotics to
breakdown recent adhesions between
the iris and lens
8- Antidote to parasympathomimetics
poisoning e.g. organophosphorus
poisoning.
9- In case of Parkinsonism
10- To treat Peptic ulcer
11- Bronchial asthma: however, it has the
disadvantage that the sputum becomes
viscid and more difficult to expel.
12- Nocturnal enuresis
Side Effects:
1. Dryness of mouth , blurred vision and
tachycardia
2. Retention of urine may occur in patients
with enlarged prostate
3. Acute glaucoma may be precipitated
4. In children, cutaneous vasodilatation with
flushing of the skin and elevation of body
temperature
Contraindications
1. It can precipitate an acute attack of
glaucoma.
2. Patients with enlarged prostate as
atropine may precipitate urine retention.
2. Hyoscine (Scopolamine):
1. It has a CNS depressant effect and usually
causes drowsiness and euphoria.
2 .It has a depressant action on vestibular
function and is useful in the management
of motion sickness and Meniere disease.
3. It produces amnesia and was used with
morphine to produce a state of twilight
sleep during delivery.
4. In parkinsonism, hyoscine has
antitremor activity therefore reducing
tremors
Synthetic Atropine substitutes
1- Mydriatic Atropine substitutes:
They have shorter duration of action
• 1. Homatropine
• 2. Eucatropine
• 3. Cyclopentolate
• 4. Tropicamide
2- Antisecretory – Antispasmodic Atropine
substitutes:
– Propantheline,
– Oxyphenonium,
– Hyoscine butylbromide
– Glycopyrrolate,
– Dicyclomine
• They are used for treatment of spasms
of the GIT, bile duct and urinary tract
Pirenzepine & telenzepine : these drugs
are selective M1 receptor antagonists ,
used in the treatment of peptic ulcer.
3- Antiparkinsonism – atropine substitutes
1. Trihexphenidyl
2. Benztropine (cogentin)
3. Biperiden
4- Decreasing urinary bladder activity
A. Oxybutynin: to relieve bladder spasm after
urologic surgery and to reduce involuntary
voiding in patients with neurologic disease.
B. Tolterodine, an M3- selective
antimuscarinic, is used in adults with
urinary incontinence.
C. Propiverine
5- Atropine substitutes used in bronchial
asthma
• Ipratropium
• It has more selective bronchodilators effect
with a lesser action on sputum viscosity.
• It can be used in combination with 2
agonists as a bronchodilators in asthma.