CHOLINOMIMETICS, MUSCARINIC AGONISTS,

CHOLINOCEPTIVE AGONISTS

A) Direct-acting Parasympathomimetics:
1-Choline Esters:
a- Acetylcholine b- Methacholine.
c-Carbachol. d- Bethanechol.

2-Cholinomimetic Alkaloids:
a- Pilocarpine. b-Muscarine. c-nicotine
d-Arecoline. e. oxotremorine
 B)Indirect-acting Parasympathomimetic
(Anti-Cholinesterases):
They inhibit cholinesterase enzymes ( both TRUE
and Pseudocholinesterases).

They cause accumulation of endogenous Ach.

leading to stimulation of both muscarinic and
nicotinic receptors to provide the corresponding
actions.
They are divided into: reversible and irreversible.
1-Reversible Anti-Cholinesterases:
a- Quaternary Alcohols : Edrophonium.
-is not a substrate for the Enzyme.
-is used for diagnosis of myasthenia gravis

b- Carbamate Derivatives.
Are Substrates for the Enzyme.
-Physostigmine.
-Neostigmine.
-Pyridostigmine .
2-Irreversible Anti-Cholinesterases
(Organophosphorus Compounds):
Cause 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
d- Then Ach is uptaken and stored in vesicles.This uptake is
inhibited by vesamicol.
Properties of Ach:

Very short duration of action because

of its rapid hydrolysis by
acetylcholinesterase.

Not used as a drug due to wide range

of activity.

Not given orally.

Muscarinic signalling
 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 SA-node activity
decreased heart rate (Bradycardia).
b- Negative inotropic on Atrium (decreases the
force of contraction).Decrease in refractory
period
c- Negative Dromotropic ( AV-nodal
conduction).This will reduce the cardiac
output.Incease in refractory period
B- On the blood vessels:
Ach. + non - innervated muscarinic receptors on
intact endothelium release of endothelium
derived relaxing factor (EDRF, Nitric Oxide)
increases the cGMP levels vasodilatation.
C. Blood pressure:
Causes fall in blood pressure as a result of
the bradycardia and vasodilatation.
The induced vasodilation of both peripheral
and systemic blood vessels leads to;
a- Reduction of the systemic arterial BP
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) ie accommodation for near vision.
c-opening of trabecular meshwork and outflow of
aqueous humor through canal of Schlemm.(treatment
of glaucoma).
5- Glands:
Sweat, salivary and lacrymal glands :
Stimulation to increase secretions.
6- Lungs :
a- Bronchial smooth muscles:
Contraction ( Bronchoconstriction)
b- Bronchial glands : Stimulation
(increased secretions).
Nicotinic signaling
1-Stimulation of Autonomic Ganglia
and Adrenal Medulla (Nn):
a. Acetylcholine stimulates the
autonomic ganglia, resulting in the
release of noradrenaline from the
sympathetic nerve endings .
b.Stimulation of the adrenal medulla:
release of adrenaline and noradrenalin.
This effect is blocked by the
ganglionic blockers, hexamethonium,
trimethophan.
2- Motor end plate (Nm):
Acetylcholine induces muscle
twitching.
This effect is blocked by the
neuromuscular junction blockers,
tubocurarine, decamethonium and
flaxedil.
Acetylcholine reversal:
In presence of atropine; high doses of acetylcholine
produce an increase in blood pressure instead of a
.decrease due to stimulation of autonomic ganglia
 Therapeutic uses of Ach:

Not used therapeutically because of:

a. Its multiplicity of actions,
b. Its rapid inactivation by cholinesterases.
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 to AchE.
2. More selective than Ach.
3. Have longer duration of action
4. Active orally and parentrally
They can be prepared either by:
1. -methylation, increases the
muscarinic activity.

2. Addition of carbamate increases the

stability and resist 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 due togastric acid
secretions).
c- Angina Pectoris (Hypotension
reduction of coronary blood Flow).
d- Thyrotoxicosis(Atrial Fibrillation).
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, and
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 predominent on the
eye , urinary bladder and GIT.

C-Bethanechol ( Urecholine) :
Actions similar to that of carbachol except that it lacks
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. Has longer duration of action

e. Passes BBB,avoid in parkinsonism

 :Pharmacological actions
A. Eye:
In the eye as eye drops, it produces:
a. Miosis, due to contraction of circular muscles of
iris.
b. Contraction of the ciliary, muscle leading to
accomodation for near objects
c. Decreases the intra-occular pressure due to
facilitation of drainage of aqueous humor as a result
of opening trabecular mesh and canal of Schelem.
B. Exocrine glands
Increases the secretion of exocrine
glands especially salivary (sialagogue ),
sweat (diaphoretic),and bronchi.
C. Smooth muscles
Increases tone and motility of GIT,
urinary bladder and bronchial muscle.
Therapeutic uses :
1. Treatment of glaucoma, the drug of choice
in the emergency control of increased IOP
in both open and closed angel glaucoma.

2. To counteract the mydriatic effect of

atropine, homatropine and tropicamide .
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.

- are indirectly- acting cholinomimetics.

- block the enzymatic hydrolysis of Ach by

inhibition of acetylcholinesterase and plasma
pseudocholinesterase.

- increase local Ach concentrations and

accumulation of endogenous ACh. inducing
both muscarinic and nicotinic .
1-Reversible Anti-Cholinesterases:
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 covalantly phosphorylating
the hydroxyl group of serine on the enzyme.
1. Reversible anticholinesterases:
a. Short acting:
Edrophonium: mainly used for diagnostic
purposes ,eg diagnosis of myasthenia gravis.

b. Medium acting:
- Physostigmine:
- It is a natural alkaloid (tertiary amine).
- Absorbed from the GIT and passes the BBB
producing central stimulation.
- Neostigmine (prostigmine), has a direct
stimulant effect on skeletal muscles.
- Pyridostgmine
- Tacrine, Donepezil, Rivastgmine, galantamine
( tertiary amines used in Alzheimer diseae)
- 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,malathion.
e. Nerve gases e.g. sarin, tabun and soman.
Mechanism of action
1. They bind covalently 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 non-
aged enzyme may be achived by
cholinesterase reactivator. pralidoxime
(PAM).

4. War gases and pesticides interact only with

the estratic site of the enzyme and have no
anionic activity.

Ecothiophate which binds also to the anionic

site.
 Pharmacological actions
I. Muscarinic actions
1. Cardiac muscles: bradycardia and decrease conductivity and
contractility.

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 secretions

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
:AchE inhibitors
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 means "Grave muscle
weakness, is an autoimmune disorder in which
antibodies are formed against nicotinic receptors
in the neuromuscular junction.
characterized by progressive muscle fatigue and
weakness drooping of the upper eye lid(ptosis).
Usually involves muscles around the eyes, mouth,
diaphragum, throat and limbs.
A disease of impaired neuromuscular
transmission.
Usually occurs between age group of 20 and
40 years, and more common in women.
This disease affects many individuals
worldwide.
Etiology:
1. An autoimmune disease, due to the
presence of antibodies against Ach nicotinic
receptor proteins.
2. The presence of circulating curare-like
substances.
3. A defective rate of synthesis of Ach
4. Excessive amount of acetylcholinesterase
in the neuromuscular junction.
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 (2mgIV) 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 ( corticosterids)
2. Treatment of glaucoma (eserine, demecarium)
3. Teatment of postoperative paralytic ileus and urine
retention (benzpyrinium)
4. Antidote for atropine poisoning
5. Alzheimer disease (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 or
nicotinic receptors.
Antimuscarinics:
. Inhibit the muscarinic actions of acetylcholine and other
parasympathomimetics.
They include:
a-Naturally occurring alkaloids
e.g. Atropine(hyoscyamine), Hyoscine ( scopolamine)
b- Atropine substitutes
 I. Atropine(hyoscyamine)
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 out flow of aqueous humor.
d. Loss of light reflex
e. Inhibition of lacrimation(dry sandy eyes).
The duration of action of atropine following
its local application to the eye is 7 10 days.
Effect of topical scopolamine on
pupil diameter&accommodation
B. Bronchi:
Bronchodilation and reduction of bronchial
secretions
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.
b. 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 Lachrymal secretions
leading to dry sandy eyes.
- Reduction of sweating producing dry
skin and a rise in body temperature
(atropine fever) , 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(eg scopolamine).
3. Cardiovascular system:
Heart:
a. Small doses: bradycardia due to
blockade of prejunctional 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 to :
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( mainly benztropine and
trihexyphendyl are the agents used).
 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 and COPD:
Ipratropium
It has more selective bronchodilator effect
with a lesser action on sputum viscosity.
It can be used in combination with 2-
agonists as a bronchodilators in asthma.