Cholinergic Agonist

By: Aditya Arya

 Introduction
• Drugs affecting the autonomic nervous system
are divided into two groups according to the type
of neuron involved in their mechanism of action:

1. The cholinergic drugs: act on receptors that are

activated by acetylcholine.
2. The adrenergic drugs: act on receptors that are
stimulated by norepinephrine or epinephrine.

* Cholinergic and adrenergic drugs both act by either stimulating or blocking

receptors of the autonomic nervous system.
 The Cholinergic Neuron
• The preganglionic fibers terminating in the adrenal medulla, the
autonomic ganglia (both parasympathetic and sympathetic), and the
postganglionic fibers of the parasympathetic division use acetylcholine as
a neurotransmitter.

Sites of actions of cholinergic agonists in the autonomic and somatic nervous

systems
Neurotransmission at cholinergic neurons
Neurotransmission in cholinergic neurons involves sequential six steps:

Synthesis and release of acetylcholine from the cholinergic neuron.

AcCoA = acetyl coenzyme A
 NOTES
• Choline is transported from the extra-cellular fluid into
the cytoplasm of the cholinergic neuron by an energy-
dependent carrier system that cotransports sodium
and that can be inhibited by the drug hemicholinium.
• The uptake of choline is the rate-limiting step in
acetylcholine synthesis. Choline acetyltransferase
catalyzes the reaction of choline with acetyl coenzyme
A (CoA) to form acetylcholine an ester in the cytosol.
Acetyl CoA is derived from the mitochondria and is
produced by the Krebs cycle and fatty acid oxidation.
Acetylcholine
Neural systems where ACh is a major
neurotransmitter
ACh is broken down in the synaptic cleft by the enzyme
acetylcholinesterase (AChE)
Cholinergic Receptors (Cholinoceptors)
• Two families of cholinoceptors,
designated: 1. muscarinic and
2. nicotinic receptors, can be
distinguished from each other
on the basis of their different
affinities for agents that mimic
the action of acetylcholine
(cholinomimetic agents or
parasympathomimetics).
Types of cholinergic receptors
 A. Muscarinic receptors

• There are five subclasses of muscarinic

receptors: M1, M2, M3, M4, and M5.
• Only M1, M2 and M3, receptors have been
functionally characterized.
• These receptors, in addition to binding
acetylcholine, also recognize muscarine.
• Muscarine is an alkaloid that is present in
certain poisonous mushrooms.
1. Locations of muscarinic receptors: These receptors have
been found on ganglia of the peripheral nervous system
and on the autonomic effector organs, such as the heart,
smooth muscle, brain, and exocrine glands.

Although all five subtypes have been found on neurons,

M1 receptors are also found on gastric parietal cells, M2
receptors on cardiac cells and smooth muscle, and M3
receptors on the bladder, exocrine glands, and smooth
muscle.

* Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these

tissues, but at high concentration they may show some activity at nicotinic receptors
2.Mechanisms of acetylcholine signal
transduction:

M2 subtype on the cardiac muscle

stimulates a G protein, designated
Gi, that inhibits adenylyl cyclase2
and increases K+ conductance, to
which the heart responds with a
decrease in rate and force of
contraction.
When M1 and M3 receptors are activated,
the receptor undergoes a conformational
change and interacts with a G protein,
designated Gq, which in turn activates
phospholipase C.1 This leads to the
hydrolysis of phosphatidylinositol-(4,5)-
bisphosphate-P2 to yield diacylglycerol
and inositol (1,4,5)-trisphosphate
(formerly called inositol (1,4,5)-
triphosphate), which cause an increase in
intracellular Ca2+ . This acation can then
interact to stimulate or inhibit enzymes,
or cause hyperpolarization, secretion, or
contraction.
 B. Nicotinic receptors
.
• The nicotinic receptor is composed of five subunits, and it
functions as a ligand-gated ion channel.

• Binding of two acetylcholine molecules elicits a

conformational change that allows the entry of
sodium ions, resulting in the depolarization of the
effector cell.
• Nicotinic receptors are located in the CNS,
adrenal medulla, autonomic ganglia, and the
neuromuscular junction. Those at the
neuromuscular junction are sometimes
designated NM and the others NN.
• The nicotinic receptors of autonomic ganglia
differ from those of the neuromuscular
junction. For example, ganglionic receptors
are selectively blocked by hexamethonium,
whereas neuromuscular junction receptors
are specifically blocked by tubocurarine.
 Cholinergic Drugs
Cholinomimetics, Parasympathomimetics

• These are the drugs which produces

actions similar to that of ACh, either
by directly or indirectly interacting
with cholinergic receptors or by
increasing availability of Ach at these
sites ( anticholinesterases )
Cholinergic
Agonists
 Direct-Acting Cholinergic Agonists
• Cholinergic agonists (parasympathomimetics)
mimic the effects of acetylcholine by binding
directly to cholinoceptors.
• These agents may be broadly classified into
two groups:
1. choline esters, which include acetylcholine
synthetic esters of choline, such as carbachol
and bethanechol.
2. Naturally occurring alkaloids, such as
pilocarpine constitue the second group.
• All of the direct-acting cholinergic drugs have
longer durations of action than acetylcholine.
• Some of the more therapeutically useful drugs
pilocarpine and bethanechol preferentially
bind to muscarinic receptors and are
sometimes referred to as muscarinic agents.
• As a group, the direct-acting agonists show
little specificity in their actions, which limits
their clinical usefulness.
A. Acetylcholine: is a quaternary ammonium
compound that cannot penetrate
membranes.
it is therapeutically of no importance
because of its multiplicity of actions and its
rapid inactivation by the cholinesterases.
• Acetylcholine has both muscarinic and nicotinic activity.

Its actions include

1. Decrease in heart rate and cardiac output: The
actions of acetylcholine on the heart mimic the
effects of vagal stimulation. For example,
acetylcholine, if injected intravenously, produces
a brief decrease in cardiac rate (negative
chronotropy) and stroke volume as a result of a
reduction in the rate of firing at the sinoatrial
(SA) node.

* normal vagal activity regulates the heart by the

release of acetylcholine at the SA node
2. Decrease in blood pressure: Injection of acetylcholine
causes vasodilation and lowering of blood pressure by
an indirect mechanism of action.

Acetylcholine activates M3 receptors found on

endothelial cells lining the smooth muscles of blood
vessels

This results in the production of nitric oxide from

arginine

Nitric oxide then diffuses to vascular smooth muscle

cells to stimulate protein kinase G production, leading
to hyperpolarization and smooth muscle relaxation
• Other actions: A. In the gastrointestinal tract,
acetylcholine increases salivary secretion and
stimulates intestinal secretions and motility.
Bronchiolar secretions are also enhanced. In the
genitourinary tract, the tone of the detrusor
urinae muscle is increased, causing expulsion of
urine.
• B. In the eye, acetylcholine is involved in
stimulating ciliary muscle contraction for near
vision and in the constriction of the pupillae
sphincter muscle, causing miosis (marked
constriction of the pupil). Acetylcholine (1%
solution) is instilled into the anterior chamber of
the eye to produce miosis during ophthalmic
surgery.
B. Bethanechol: is structurally related to
acetylcholine, in which the acetate is replaced
by carbamate and the choline is methylated.
• It is not hydrolyzed by acetylcholinesterase (due
to the addition of carbonic acid), although it is
inactivated through hydrolysis by other
esterases.
• It lacks nicotinic actions (due to the addition of
the methyl group) but does have strong
muscarinic activity.
• Its major actions are on the smooth musculature
of the bladder and gastrointestinal tract. It has a
duration of action of about 1 hour.
• Actions: Bethanechol directly stimulates muscarinic
receptors, causing increased intestinal motility and tone. It
also stimulates the detrusor muscles of the bladder
whereas the trigone and sphincter are relaxed, causing
expulsion of urine.

• Therapeutic applications: In urologic treatment,

bethanechol is used to stimulate the atonic bladder,
particularly in postpartum or postoperative, nonobstructive
urinary retention. Bethanechol may also be used to treat
neurogenic atony ( poor muscular condition ). as well as
megacolon (Hypertrophy and dilation of the colon
associated with prolonged constipation).

• Adverse effects: Bethanechol causes the effects of

generalized cholinergic stimulation. These include
sweating, salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm.
C. Carbachol (carbamylcholine): has both
muscarinic as well as nicotinic actions (lacks a
methyl group present in bethanechol.

• Like bethanechol, carbachol is an ester of

carbamic acid and a poor substrate for
acetylcholinesterase.
• It is biotransformed by other esterases, but at
a much slower rate.
• Actions: Carbachol has profound effects on
both the cardiovascular system and the
gastrointestinal system because of its
ganglion-stimulating activity, and it may first
stimulate and then depress these systems. It
can cause release of epinephrine from the
adrenal medulla by its nicotinic action. Locally
instilled into the eye, it mimics the effects of
acetylcholine, causing miosis and a spasm of
accommodation in which the ciliary muscle of
the eye remains in a constant state of
contraction.
• Therapeutic uses: Because of its high potency,
receptor nonselectivity, and relatively long
duration of action, carbachol is rarely used
therapeutically except in the eye as a miotic
agent to treat glaucoma by causing pupillary
contraction and a decrease in intraocular
pressure.

• Adverse effects: At doses used

ophthalmologically, little or no side effects
occur due to lack of systemic penetration
(quaternary amine).
D. Pilocarpine: is alkaloid with a
tertiary amine and is stable to
hydrolysis by
acetylcholinesterase.

• Compared with acetylcholine and

its derivatives, it is far less
potent, but it is uncharged and
penetrate the CNS at therapeutic
doses.

• Pilocarpine exhibits muscarinic Actions of pilocarpine

and atropine on the iris
activity and is used primarily in and ciliary muscle of
ophthalmology. the eye
 Glaucoma
- What is it?
- Types of Glaucoma
1) Closed-Angle Glaucoma
2) Open-Angle Glaucoma
3) Normotensive (Low Tension) Glaucoma
- Who’s at risk
1) > age 55
2) family history
3) having diabetes
4) being very nearsighted
5) African American
- Effects of Glaucoma
1) Tunnel Vision
2) Blindness
 Types of Glaucoma

Open-Angle Glaucoma Closed-Angle Glaucoma

Blocked drainage of aqueous Blocked drainage of aqueous
Anterior chamber open Anterior Chamber
Blockage at trabecular angle closure
meshwork

Cassel, Billig, Randall Fig 8-4 Cassel, Billig, Randall Fig 8-3
Effect of Glaucoma
 Cause of Blindness
- Cupping of Optic Nerve

Cassel, Billig, Randall

 Pilocarpine

-Origin of the Drug

-South American Shrub
- Pilocarpus jaborandi
-Isolated in 1875
-Chemical Structure

- Cholinergic Parasympathomimetic agent

 Reaction Mechanism
- Pilocarpine binds to muscarinic receptor
- Activates receptor binds G-protein
- Removal of GDP and addition of GTP to G-protein
- Dissociation of G-protein from muscarinic receptor
- Separation of G-protein into alpha and beta-gamma
subunits
- Alpha subunit interacts with and activates Phospholipase C -
Phosphatidyl inositol biphosphate (PIP) complex
- Phospholipase breaks down PIP into inositol
1,4,5-triphosphate (IP3)and diacylglycerol (both 2o)
- IP3 interacts with ER membrane which releases Ca2+
 Muscle Action

- Ca2+ binds to calmodulin forming a complex

- This complex binds to caldesmon
- When caldesmon is bound by Ca2+/calmodulin complex
this allows myosin-actin interactions to occur
-The muscle (pupil)contracts

Marieb Fig 16-7

 Reaction Sequence
Phospholipase C
Phosphatidyl inositol
G- Protein biphosphate (PIP) complex
subunits , , 

GDP\

Inositol 1,4,5 - triphosphate (IP3) + diacylglycerol

GTP
Myosin-actin interactio
Muscarinic Receptor (Muscle Contraction)

caldesmon

Endoplasmic Reticulum Ca2+ Calmodulin/ Ca2

• Actions: Applied topically to the cornea, pilocarpine
produces a rapid miosis and contraction of the ciliary
muscle.
Pilocarpine is one of the most potent stimulators of
secretions (secretagogue) such as sweat, tears, and saliva,
but its use for producing these effects has been limited due
to its lack of selectivity.
The drug is beneficial in promoting salivation in patients
with xerostomia resulting from irradiation of the head and
neck.
Sjgoren's syndrome: which is characterized by dry mouth
and lack of tears, is treated with oral pilocarpime tablets
and cevimeline, a cholinergic drug that also has the
drawback of being nonspecific.
The opposing effects of atropine, a muscarinic blocker, on
the eye.
• Therapeutic use in glaucoma: Pilocarpine is the
drug of choice in the emergency lowering of
intraocular pressure of both narrow-angle (also
called closed-angle) and wide-angle (also called
open-angle) glaucoma.
Pilocarpine is extremely effective in opening the
trabecular meshwork around Schlemm's canal,
causing an immediate drop in intraocular
pressure as a result of the increased drainage of
aqueous humor.
• Adverse effects: Pilocarpine can enter the brain
and cause CNS disturbances. It stimulates profuse
sweating and salivation.
 Anticholinesterases:
Anticholinesterases are the agents which inhibit
ChE, protect Ach from hydrolysis- produce
cholinergic effects and potentiates Ach.
Reversible:
Carbamates: Physostigmine, Neostigmine,
Pyridostigmine, Edrophonium, Rivastigmine,
Donepeizil, Galantamine
Acridine: Tacrine
 USES:
• As miotic
• Myasthenia gravis
• Postoperative paralytic ileus/urinary retention
• Postoperative decurarization
• Cobra bite
• Belladona poisoning
• Alzheimer’s diseases
• Other drug overdosages
Indirect-Acting Cholinergic Agonists
Anticholinesterases (Reversible)

Mechanisms of action of indirect (reversible)

cholinergic agonists
A. Physostigmine: is a nitrogenous
carbamic acid ester found
naturally in plants and is a
tertiary amine.
1. Actions: Physostigmine has a
wide range of effects as a result
of its action, and not only the
muscarinic and nicotinic sites of
the autonomic nervous system
but also the nicotinic receptors
of the neuromuscular junction
are stimulated.

Physostigmine can enter and

stimulate the cholinergic sites
in the CNS.
Some actions of
physostigmine
 Therapeutic uses: The drug increases intestinal and
bladder motility, which serve as its therapeutic action
in atony of either organ.

• Placed topically in the eye, it produces miosis and

spasm of accommodation, as well as a lowering of
intraocular pressure.It is used to treat glaucoma, but
pilocarpine is more effective.

• Physostigmine is also used in the treatment of

overdoses of drugs with anticholinergic actions, such as
atropine, phenothiazines, and tricyclic antidepressants.
 Adverse effects: The effects of physostigmine on the
CNS may lead to convulsions when high doses are
used.

• Bradycardia and a fall in cardiac output may also occur.

• Inhibition of acetylcholinesterase at the skeletal

neuromuscular junction causes the accumulation of
acetylcholine and, ultimately, results in paralysis of
skeletal muscle.

• These effects are rarely seen with therapeutic doses.

C. Pyridostigmine and ambenomium: are other
cholinesterase inhibitors that are used in the
chronic management of myasthenia gravis.
Adverse effects of these agents are similar to
those of neostigmine.
D. Demecarium: is another cholinesterase inhibitor
used to treat chronic open-angle glaucoma
(primarily in patients refractory to other agents)
closed-angle glaucoma after irredectomy. It is
also used for the diagnosis and treatment of
accommodative esotropia.
Mechanisms of actions and side effects are
similar to those of neostigmine.
E. Edrophonium: The actions of edrophonium
are similar to those of neostigmine, except
that it is more rapidly absorbed and has a
short duration of action.
used in the diagnosis of myasthenia gravis.
Intravenous injection of edrophonium leads to
a rapid increase in muscle strength.
Caution: Care must be taken, because excess
drug may provoke a cholinergic crisis. Atropine
is the antidote.
F. Tacrine, donepezil, rivastigmine, and galantamine:

patients with Alzheimer's disease

have a deficiency of cholinergic neurons in the CNS

led to the development of anticholinesterases as possible

remedies for the loss of cognitive function

• Tacrine was the first to become available, but it has been

replaced by the others because of its hepatotoxicity.
• Despite the ability of donepezil, rivastigmine, and
galantamine to delay the progression of the disease, none
can stop its progression. Gastrointestinal distress is their
primary adverse effect
Indirect-Acting Cholinergic Agonists:
Anticholinesterases (Irreversible)

A number of synthetic organophosphate

compounds have the capacity to bind
covalently to acetylcholinesterase.

Many of these drugs are extremely toxic and

were developed by the military as nerve
agents. Related compounds, such as
parathion, are employed as insecticides.
 Irreversible:
Organophosphates: Carbamates:
Dyflos ( DFP ) Carbaryl
Echothiophate Propoxur
Parathion
Malathion
Diazinon
Tabun, Sarin, Soman
A. Echothiophate

Mechanism of action:

Echothiophate is an organophosphate that covalently

binds via its phosphate group to the serine-OH group at
the active site of acetylcholinesterase.

Once this occurs, the enzyme is permanently inactivated,

and restoration of acetylcholinesterase activity requires
the synthesis of new enzyme molecules.

Following covalent modification of acetylcholinesterase,

the phosphorylated enzyme slowly releases one of its
ethyl groups.

The loss of an alkyl group, which is called aging, makes it

impossible for chemical reactivators, such as
pralidoxime, to break the bond between the remaining
drug and the enzyme.
• Actions: include generalized cholinergic
stimulation, paralysis of motor function
(causing breathing difficulties), and
convulsions.
Echothiophate produces intense miosis and,
thus, has found therapeutic use.
Atropine in high dosage can reverse many of
the muscarinic and some of the central effects
of echothiophate.
• Therapeutic uses: An ophthalmic solution of
the drug is used directly in the eye for the
chronic treatment of open-angle glaucoma.

* Echothiophate is not a first-line agent in the

treatment of glaucoma. In addition to its other
side effects, the potential risk for causing
cataracts limits the use of echothiophate.
 Reactivation of acetylcholinesterase
• Pralidoxime can reactivate inhibited
acetylcholinesterase. However, it is unable to
penetrate into the CNS.
• The presence of a charged group allows it to
approach an anionic site on the enzyme, where it
essentially displaces the phosphate group of the
organophosphate and regenerates the enzyme.
• If given before aging of the alkylated enzyme
occurs, it can reverse the effects of
echothiophate, except for those in the CNS.
• With the newer nerve agents, which produce
aging of the enzyme complex within seconds,
pralidoxime is less effective.
• Pralidoxime is a weak acetylcholinesterase
inhibitor and, at higher doses, may cause side
effects similar to other acetylcholinsterase
inhibitors .
 Summary

Some adverse effects observed

Summary of actions of some cholinergic agonists with cholinergic drugs
Thank you