Cholinergic Agonist

• 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. Adrenergic drugs act on receptors stimulated
by norepinephrine or epinephrine
 Summary of cholinergic agonist
• Direct acting
 acetylcholine MIOCHOL-E
 Bethanechol URECHOLINE
 Carbachol MIOSTAT, ISOPTO CARBACHOL
 cevimeline EVOXAC
 Pilocarpine SALAGEN, ISOPTOCARPINE

• Indirect acting (irreversible)

 Echothiophate PHOSPHOLINE IODIDE
 Cholinergic agonist
 Indirect Acting (reversible
 Ambenonium MYTELASE
 Donepezil ARICEPT
 Galantamine RAZADYNE
 Neostigmine PROSTIGMIN
 Physostigmine ANTILIRIUm
 Pyridostigmine MESTINON
 Rivastigmine EXELON
 Tacrine COGNEX
 Reactivation of acetylcholinesterase
 Pralidoxime PROTOPAM
Site of actions of cholinergic agonists
 Neurotransmission at cholinergic
neurons
 Involves six sequential steps
1.Synthesis
2.Storage
3.Release
4.Binding of Ach to a receptor
5.Degradation of the neurotransmitter in
synaptic cleft
6.Recycling of choline and acetate
Synthesis and release of acetylcholine
1 SYNTHESIS OF ACETYLCHOLINE
• Transport of choline is inhibited by hemicholinium
2 UPTAKE INTO STORAGE VESICLES
• Acetylcholine is protected from degradation in the vesicle.
3 RELEASE OF NEUROTRANSMITTER
• Release is blocked by botulinum toxin.
• Spider venom causes release of acetylcholine.
4 BINDING TO THE RECEPTOR
• Postsynaptic receptor is activated by binding of the neurotransmitter.
5 DEGRADATION OF ACETYLCHOLINE
• Acetylcholine is rapidly hydrolyzed by acetylcholinesterase in the synaptic
cleft.
6 RECYCLING OF CHOLINE
• Choline is taken up by the neuron.
 1. Synthesis of acetylcholine
• Choline is transported from the extracellular
fluid into the cytoplasm of the cholinergic
neuron by an energy-dependent carrier
system that also transports Na and can be
inhibited by a drug HEMICHOLINIUM
• The uptake of choline is the rate limiting step
in Ach synthesis
 2. Storage of acetylcholine in Vesicle
 Ach is packed and stored into presynaptic
vesicles by an active transport process
coupled to the efflux of protons
 The ,mature vesicle not only contains Ach but
also ATP and proteoglycan
 The neurotransmitter in vesicles appear as
beadlike structures known as varicoities, along
the nerve terminal of the presynaptic neuron
 3. Release of acetylcholine
 When an action potential propagated by
voltage-sensitive sodium channel arrives at a
nerve ending, voltage sensitive calcium
channel on the presynaptic membrane open
causing an increase in the concentration of
intracellular calcium
 Elevated calcium level causes the release of
their contents into the synaptic space
 This release can be blocked by botulimun
toxin
 4. Binding to the receptors
 Ach release from the synaptic vesicles diffuse
across the synaptic space and binds to either
of two post-synaptic receptors on the traget
cells, to presynaptic receptors in the
membrane of the neuron that release the Ach,
or to other targeted presynaptic receptors.
 Post synaptic cholinergic receptors on the
surface of the effector glands : muscarinic or
nicotinic
 5. Degradation of Acetylcholine
• The signal at the post junctional effector site is
rapidly terminated, because AChE cleaves Ach
to choline and acetate in the synaptic cleft
 6. Recycling of Choline
• Choline may be recaptured by sodium
coupled, high affinity uptake system that
transports the molecule back into the neuron
• There it is acetylated into ACh that is stored
until released by a subsequent action
potential
 Cholinergic Receptors
(Cholinoceptors)
 Two families of cholinoreceptors can be
distinguished on the basis of their different
affinities for agents that mimic the actions of
ACh
 They are
1.Muscarinic receptors
2.Nicotinic receptors
Types of cholinergic receptors
 Muscarinic Receptors
• Muscarinic receptors belong to the class of G
protien-coupled receptor
• the muscarinic receptors show only a weak
affinity for nicotine
• There are five subclasses of muscarinic
receptors M1 to M5
• Only M1, M2 and M3 have been functionally
characterized
 Location of muscarinic receptors
• These recptors are found on the ganglia of the
PNS and the autonomic effector organs such
as the heart, smooth muscles, brain and
exocrine glands
• M1 is found gastric parietal cells
• M2 is found on cardiac cells and smooth
muscles
• M3 is found on bladder, exocrine glands and
smooth muscles
Muscarinic Agonist and Antagonist
• Attempts are currently underway to develop
muscarinic agonist and antagonist that are
directed against specific receptor subtypes
• At present, no clinically important agents
interact solely with M4 and M5
 Nicotinic Receptors
• They bind with ACh but have only weak
affinity for muscarinic receptors
• This type of receptor is composed of five
subunits and its functions as a ligand-gated
ion channel
• Binding of two ACh molecules elicit a
conforational change that allows the entry of
sodium ions resulting in depolarization of the
effector cell
 Direct acting cholinergic agonist
• Cholinergic agonist are also know as
parasympathomimetics
• Can be classified in two groups:
1. Choline esters and 2. synthetic esters of
choline
• As a group, the direct-acting agonist shows
little specificity in their actions, which limits
their clinical usefulness
 1. Acetylcholine
• Is a quaternary ammonium compound that
cannot penetrate membranes
• It lacks therapeutic importance because of its
multiplicity of actions causing a diffuse effects
and also due to rapid activation by the
cholinesterase
• ACh has both muscarinic and nicotinic activity.
 Actions of acetylcholine
• Decreases the heart rate and cardiac output
• Mimics the effect of vagal stimulation
• There is a brief decrease in cardiac rate and
stroke volume that may result in reduction of
the rate of the SA node
 Actions of Acetylcholine
• Decrease in blood pressure
• Causes vasodilation and lowering of blood
pressure by an indirect mechanism of action
• It activates the M3 receptors of the
endothelial cells lining the smooth muscle of
blood vessels
 Actions of acetylcholine
• Other actions include: GI- increase salivation
and stimulates intestinal secretions and
motility.
• It enhances bronchial secretions, increases the
tone of detrusor urinary muscle causing
expulsion of urine; stimulates ciliary muscle
contraction
 2. Bethancol
• Structurally similar to ACh in which the
acetate is replaced by carbamate and the
choline is methylated
• It lacks nicotinic activity but does not have
very strong muscarinic activity
• Major action is on the smooth musclature of
the bladder and GI tract
• Duration of action is about 1 hour
 Actions of bethanechol
• Directly stimulates muscarinic receptors
causing increase intestinal motility and tone
• It also stimulates the detrusor muscle of the
bladder, wheresas the trigons and sphincter
are relaxed
• Voiding pressure is thus increased abd bladder
capacity decreased to cause expulsion of urine
 Therapeutic implication
• Used in urologic treatment
• Stimulates atonic bladder particularly
postpartum or post operative, non-
obstructive urinary retention
• It may also be used to treat neurogenic atony
as well as megacolon
 Adverse effects of bethanechol
 Sweating
 Salivation
 Flushing
 Decreased blood pressure
 Nausea
 Abdominal pain
 Diarrhea
 Bronchospasm
*** atropine sulphate may be administered to
overcome severe cardiovascular or
bronchocontrictor responses to this agent
 3. Carbachol
• Has both muscarinic as well as nicotinic
actions
• Lacks the methyl group present in
bethanechol
• It is an ester of carbamic acid and a poor
substrate for AChE
 Actions of Carbachol
• Has profound effects on both the
cardiovascular and GI system
• It may first stimulate then depress these
systems
• It is locally instilled in eye causing miosis and
causes a constant state of contraction
 Therapeutic uses of carbachol
 Because of it’s high potency, receptor non-
selectivity and relatively long duration of
action, this drug is rarely used
 When used it can be as a miotic agent to treat
glaucoma by causing pupillary contraction and
decrease in intraocular pressure
 Onset of action for miosis is 10 to 20 minutes
 Within 4 to 8 hours intraocular pressure in
reduced
 Adverse effects of carbachol
• Little or no side effects when used
ophthalmologically
• This may be due to lack of systemic
penetration
 4. Pilocarpine
• A tertiary amine
• Far less potent than ACh but it is uncharged
and will penetrate the CNS at therapeutic
doses
• Exhibits muscarinic activity and used primarily
in ophthalmology
 Actions of pilocarpine
• Applied topically to cornea producing rapid
miosis and contraction of the ciliary muscle
• It is one of the most potent stimulators of
secretions such as sweat, tears and saliva but
its use for producing these effects has been
limited due to its lack of selectivity
 Therapeutic use of Pilocarpine
• Used to treat glaucoma
• Drug of choice for emergent lowering of
introcular pressure of both narrow-angle and
wide angle glaucoma
• Action occurs within minutes and lasts from4
to 8 hrs
• The miotic action of pilocarpine is also useful
in reversing mydriasis due to atropine
 Adervse effects of pilocarpine
• Enters the brain and cause CNS disturbances
• Poisoning with this agent is characterized by
exaggeration of various parasympathetic
effects including profuse sweating and
salivation
Adverse effects of cholinergic agonist
Some adverse effects observed with
cholinergic drugs

•Diarrhea

•Diaphoresis

•Miosis

•Nausea

•Urinary urgency
Indirect acting cholinergic agonist: acetylcholinesterase
inhibitors (reversible)

• AChE is an enzyme that specifically cleaves

ACh to acetate and choline and thus
terminates its action
• Located both in presypnatic and post synaptic
nerve terminals
• These drugs can provoke a response at all
cholinoreceptors
• These drugs can be classified as short-acting
or intermediate acting agents
 1. Endrophonium
 It is a short-acting AChE inhibitor
 Rapidly absorbed and has a short duration of
action about 10 to 20 minutes
 Used in the diagnosis of myasthenia gravis
 Must be careful when use cause excess may
provoke a cholinergic crisis in which case,
atropine is the antidote
 Due to availability of other drugs this is rarely
used
 2. Physostigmine
• It is a nitrogenous carbamic acid ester found
naturally in plants
• It is a tertiary amine
• It is a substrate for AChE
 Action of physostigmine
• Actions: stimulates not only the muscarinic
and nicotinic sites of the ANS but also the
nicotinic receptors of the neuro-muscular
junction
• Duration of action is 2 to 4 hrs
• Can enter and stimulate the cholinergic sites
in the CNS
 Therapeutic uses of
Physostigmine
 Increases intestinal and bladder motility which
serves as its therapeutic action in atony of
either organ
 It produces miosis and spasm accomodatiom
as well as lowering of intraocular pressure
 Used to treat glaucoma
 Used to treat overdoses of drugs with
anticholergic actions such as atropine,
phenothiazines,tricyclic antidepressants
 Adverse effects of physostigmine
• Convulsion if high doses are used
• Bradycardia and a fall in cardiac output
• Inhibition of AChE at the skeletal
Neuromuscular junction causes accumulation
of ACh which may result in paralysis of
skeletal muscle
 3. Neostigmine
• Has a quartenary nitrogen
• Absorbed poorly in the GI tract and does not
enter the CNS
• Has greater effect on skeletal muscle than
physostigmine
• Has an intermediate duration of action usually
30 minutes to 2 hrs
 Therapeutic uses of Neostigmine
• Used to stimulate the bladder and GI tract
• Antidote for tubocurarine and other
competitive neuromuscular blocking agents
• Used to sympthomatically treat myasthenia
gravis
 Adverse effects of neostigmine
• Include those of generalized cholinergic
stimulation such as salivation, flushing,
decreased blood pressure, nausea, abdominal
pain, diarrhea and bronchospasm
• Containdicated when intestinal or bladder
obstruction is present
 4. Pyridostigmine and ambenonium
• Used in chronic management of myasthenia
gravis
• Duration of action are intermidiate but longer
than neostigmine
• Pyridostigmine: 3 to 6 hrs
• Ambenonium : 4 to 8 hrs
• Adverse effects are similar to those of
neostigmine
 5. Tacrine, donepezil, rivastigmine,
and galantamine
• Patients with alzheimers have a deficient of
cholinergic neurons
• Tacrine was the first to treat this condition but
due to its high toxicity was rapidly replaced by
donepezil, rivastigmine and galantamine
• the primary adverse effect is GI distress
 Indirect acting cholinergic agonist: anticholinesterase
(irreversible

• A number of organic synthetic

organophosphate compounds have the
capacity to bind covalently to AChE.
• The result is a long lasting increase of ACh at
all sites released
• These drugs are extremely toxic
• Related compounds such as parathoin are
used as insecticide
 1. Echothiophate
• Is an organophosphate that covalently binds
via its phosphate group to the active site of
AChE
• The enzyme becomes permanently
deactivated and restoration of enzyme activity
requires the synthesis of a completely new
enzyme molecule
 Actions of Echothiophate
• Include generalized cholinergic stimulation,
paralysis of motor function and convulsion
• Produces intense miosis
• Intraocular pressure falls from the
fascilatation of outflow of aqeous humor
• Atropine in high doses can reverse many of
the muscarinic and some effects of
echothiophate
Therapeutic uses of echothiophate
• Applied topically to the eye for chronic
treatment of open-angle glaucoma
• Not the first line agent
• It has a potential risk for causing cataracts
thus not first line
 Toxicology of acetylcholinesterase
inhibitors
• AChE inhibitors are used as insecticides in the
US because of high toxicity
• Reactivation of acetylcholinesterase can be
done through the use of Pralidoxime but this
drug cannot cross into the CNS
• Atropine may also be used to prevent
muscarinic side effects of these agents