The document discusses acetylcholine (ACh), the first neurotransmitter discovered. ACh is synthesized in the presynaptic part of neurons from choline and acetyl-CoA. It is stored in vesicles and released into the synaptic cleft upon neuronal stimulation. In the cleft, ACh binds to cholinergic receptors on the postsynaptic membrane before being degraded by acetylcholinesterase. ACh acts as a neurotransmitter in both the central and peripheral nervous systems, including at neuromuscular junctions, autonomic ganglia, and various organs. The document outlines the synthesis, storage, release, mechanisms of action, and degradation of ACh. It also discusses cholinergic drugs that can act as

2. • The nerve endings of postganglionic parasympathetic nerves release a
neurotransmitter called acetylcholine. Such synapses are named cholinergic
synapses.
• Each synapse contains a presynaptic membrane, a synaptic gap (cleft), and a
post-synaptic membrane with cholinergic receptors

3. • Acetylcholine (ACh), the first neurotransmitter discovered, was originally
described as "vagus stuff" by Otto Loewi because of its ability to mimic the
electrical stimulation of the vagus nerve.
• It is now known to be a neurotransmitter at all autonomic ganglia, at many
autonomically innervated organs, at the neuromuscular junction, and at many
synapses in the CNS.
• In the central nervous system, ACh is found primarily in interneurons,
cholinergic projection from the nucleus basalis of Meynert (in the basal
forebrain) to the forebrain neocortex and associated limbic structures

4. • In the peripheral nervous system, ACh is the neurotransmitter at the
neuromuscular junction between the motor nerve and skeletal muscle
• In the autonomic nervous system, acetylcholine (ACh) is the neurotransmitter
in the preganglionic sympathetic and parasympathetic neurons.
In the parasympathetic, ACh is the neurotransmitter at the adrenal medulla and all the
parasympathetic innervated organs.
In the sympathetic, ACh is the neurotransmitter at the sweat glands, and at the
piloerector muscle of the sympathetic ANS.

5. • Acetylcholine is synthesized in the presynaptic part of the nerve ending
• Ach is synthesized from choline which enters the neuron via a carrier-
mediated transport
• Followed by acetylation of choline, using Acetyl-CoA as a source of acetyl
groups
• The enzyme Choline Acetyltransferase (CAT) catalyzes this reaction
• Choline + Acetyl COA ACETYLCHOLINE
• This enzyme (CAT) is found only in cholinergic neurons. It is produced in the
cholinergic cell body and transported down the axon to the nerve endings
Choline Acetyltransferase (CAT)

6. • Both CAT and Ach may be found throughout the neuron, but their highest
concentration is in axon terminals.
• The presence of CAT is the "marker" that a neuron is cholinergic, only cholinergic
neurons contain CAT.
• The rate-limiting steps in Ach synthesis are the availability of choline and acetyl-
CoA.
• During increased neuronal activity the availability of acetyl-CoA from the
mitochondria is upregulated as is the uptake of choline into the nerve ending
from the synaptic cleft. Ca2+ appears to be involved in both of these regulatory
mechanisms.

7. • The uptake of ACh into storage vesicle occurs through an energy-dependent
pump that acidifies the vesicle.
• The acidified vesicle then uses a vesicular ACh transporter (VAChT) to
exchange protons for ACh molecules.
• The majority of the ACh in nerve endings is contained in 100 um vesicles. A
small amount is also free in the cytosol.
• No useful pharmacological agents are available to modify cholinergic function
through interaction with the storage of Ach, although a drug that blocks
VAChT is a research drug vesamicol.

8. • Release of ACh occurs by Ca2+ mediated exocytosis which involves Ca2+
stimulated docking, fusion, and fission of the vesicle with the nerve terminal
membrane.
• At the neuromuscular junction, one presynaptic nerve impulse releases 100-
1500 vesicles.
• Many toxins are known that interfere with these processes and are effective
in preventing ACh secretion.
• For example botulinum toxin inhibit Ach release while black widow spider
venom (BWSV) stimulate ACh release.

9. • Cholinergic neurotransmission in the brain is responsible for a wide variety of
behavioral and cognitive processes, including attention, learning, and
memory
NOTE:
• Stimulation of nerves liberate a substance or the nerve ending activate a
receptor in the organ supplied
• This process is called chemical transmission of nerve impulses
• Following stimulation of the parasympathetic nerve a substance called
ACETYLCHOLINE is liberated at the nerve ending.
• ACh has excitatory actions at the neuromuscular junction, at autonomic
ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions
at certain smooth muscles and at cardiac muscle.

10. • ACh binds only briefly to the pre- or postsynaptic receptors.
• Following dissociation from the receptor, the ACh is rapidly hydrolyzed by the
enzyme acetylcholinesterase (AChE).
• To prevent the effect of Acetylcholine being too prolonged and powerful ,this
enzyme rapidly breaks down the Ach and terminates its effect.

11. • The inactivation of ACh is converted by its metabolism to choline and acetic acid through the
process of hydrolysis in the presence of a family of enzymes called cholinesterase (ChE).
• There are two types of ChE enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase
(BuChE)(which are pseudo cholinesterases)
• AChE is localized to the cytoplasm and outer cell membrane of blood and neural synapses (pre and
post synaptic membranes) allowing both intracellular and extracellular ACh metabolism while
• BuChE is found in plasma, liver and the CNS (neurons and glia) and differs in its substrate specificity
for ACh
• Ach is hydrolysed Choline + Acetic Acid
• Consequently much of the choline used forACh synthesis comes from the recycling of choline from
metabolized ACh.
• Another source is the breakdown of the phospholipid, phosphatidylcholine
• Vesicle-bound ACh is not accessible to degradation by Acetylcholinesterase
Acetylcholinesterase(AchE) OR Butyrylcholinesterase (BuchE)

12. • Acetylcholine is synthesized in
the presynaptic part of the
nerve ending.
• It is deposited in vesicles,
releases into the synaptic gap,
and interacts with
cholinoreceptors on the
postsynaptic membrane.
• Acetylcholinesterase produces
degradation of the
neurotransmitter in the
synaptic gap.
• Choline is taken up by the
neuron and used for the
synthesis of acetylcholine.

14. • There are two types of cholinergic receptors:
• – M-cholinoreceptors (Muscarinic) with subtypes M1, M2, M3, M4, M5
• – N-cholinoreceptors (Nicotinic) with neuronal (Nn)and muscular (Nm) subtypes.
• This classification is based on two chemical agents that mimic the effects of
ACh at the receptor site: nicotine and muscarine.
• Cholinoreceptors are located in different organs and tissues , but some of these
tissues are characterized by prevalence of M- or N-cholinergic receptors
• All autonomic ganglia have nicotinic receptors.
• All receptors at the neuromuscular junction are nicotinic receptors.
• All target organs of the parasympathetic nervous system have muscarinic receptors

16. • Nicotinic receptors
• The rapid nature of the synaptic transmission mediated by the nicotinic receptor is
consistent with its role at the neuromuscular junction (NMJ) and in the ganglion of the
ANS.
• Little is known about the role of the nicotinic receptor role in CNS behavior.
• Clearly, nicotine stimulation is related in some manner to reinforcement, as indicated by
the prevalence of nicotine addiction among humans.
• Muscarinic receptors, in contrast, are important mediators of behavior in the
CNS.
• One example is their role in modulating motor control circuits in the basal ganglia.
• A second example is their participation in learning and memory.The latter is inferred from
two types of observations:
• 1) muscarinic antagonists are amnesic agents, and
• 2) deterioration of the cholinergic innervation of the neocortex is associated with memory loss in
Alzheimer’s disease.

18. • Mechanisms of receptor signaling are formation of second messengers diacylglycerol (DAG)
and inositol-1,4,5-trisphosphate (IP3), inhibition of the formation of second messenger
cyclic-adenosine monophosphate (cAMP), and ion channel activation for sodium (Na+) influx
or potassium (K+) efflux.

20. By:
A) Acting on Ach receptors (muscarinic or Nicotinic)
B) Affecting release of Ach
C) Affecting destruction of Ach

21. • Cholinergic drugs are preparations acting on cholinergic neurotransmission.
• They are divided into cholinergic agonists (=cholinomimetics, cholino-positive
drugs) and cholinergic antagonists (=cholinoblockers, cholino-negative drugs)
• Cholinomimetics increase cholinergic neurotransmission.
• Cholinoblockers decrease cholinergic neurotransmission.

23. • They mimic the action of acetylcholine.
• There are two main targets of drug action: the postsynaptic receptor and the
acetylcholinesterase enzyme, which breaks down acetylcholine.
• Direct-acting cholinergic agonists have a direct action on the receptor for
acetylcholine. Some drugs are specific for the muscarinic receptor; others are
specific for the nicotinic receptor.
• The indirect-acting cholinomimetics act by blocking the metabolism of
acetylcholine by cholinesterases.These drugs effectively increase the
concentration of acetylcholine at all cholinergic synapses.

24. • M-,N-cholinomimetics
• Direct-acting
• – Acetylcholine
• – Carbachol (Carbocholinum)
• Indirect-acting (anticholinesterases)
• – Neostigmine (Proserinum)
• – Physostigmine
• – Pyridostigmine
• – Galantamine hydrobromide
• – Isoflurophate
• M-cholinomimetics
• – Pilocarpine hydrochloride
• --Bethanechol
• --Muscarine
• ---Aceclidinum
• N-cholinomimetics
• – Cytitonum
• – Lobeline hydrochloride.
• --Nicotine

25. Direct-acting agonists are divided into two groups based on
chemical structure.
• The first group consists of choline esters, esters of choline that
are structurally related to acetylcholine (indicated by “-chol-” in
their names), and typified by acetylcholine, carbachol, and
bethanechol.
• The second group includes naturally occurring alkaloids that are
not related to acetylcholine and are generally plant derivatives ,
because of their complex structure, are not metabolized by
cholinesterases such as nicotine, muscarine, and pilocarpine.
Direct acting drugs Spectrum of action Pharmacokinetics Clinical applications
Acetylcholine Muscarinic and nicotinic
Rapidly hydrolyzed by
cholinesterase (ChE);
duration of action 5–30 s;
poor lipid solubility
used to induce miosis of the iris in seconds
after delivery of the lens in cataract surgery,
in penetrating keratoplasty, iridectomy and
other anterior segment surgery where rapid
miosis may be required.
Carbachol
Muscarinic and nicotinic
(prevalently muscarinic)
Like bethanechol. It has the
chemical structure similar to
acetylcholine, but is not
destroyed by ChE;
Applied topically as eyedrops for the
treatment of glaucoma, intraocular use as a
miotic in surgery.

26. • Pharmacodynamics: all M-cholinomimetic effects on internal organs (similar to those
of carbachol and pilocarpine) cause an increase in neuromuscular transmission
resulting from the accumulation of acetylcholine at the neuromuscular junction.
• Examples: Pilocarpine hydrochloride, Bethanechol, Muscarine, Aceclidinum
Direct acting
drugs
Spectrum of
action
Pharmacokinetics Clinical applications
Bethanechol Muscarinic
Resistant to ChE, orally active, poor lipid
solubility; duration of action 30 min to 2 h
Postoperative and neurogenic ileus and
postpartum non-obstructive urinary retention.
Used to treat urinary retention, and stimulate
movement of intestinal tract
Pilocarpine Muscarinic
Is an alkaloid from Pilocarpus pinnatifolius.
Not an ester, good lipid solubility; duration
of action 30 min to 2 h
As eye drops, eye ointment, or eye membranes to
treat glaucoma, used to break iris-lens adhesions,
Sjögren’s syndrome, not used for xerostomia.
Aceclidinum muscarinic is a synthetic preparation; is administered
SC, IM, or topically (eye drops); is not
toxic; does not penetrate CNS;
It is used for the treatment of atonia of the
intestine and urinary bladder, as well as for
glaucoma

27. M-Cholinomimetics effects Clinical indications Side effects
Miosis (constriction of eye pupils)
Spasm of accommodation
(regulation of eye lens for near vision)
A decrease in intra-eye pressure
Glaucoma Hypotony
Stimulation of glands secretion
An increase in salivation
Xerostomia Sweatiness
Hyper-salivation
An increase in smooth muscles tone Atonia of the intestine and urinary
bladder after surgeries
Pain in the abdomen
Diarrhea
Frequent urination
Spasm of bronchi
Bradycardia
Blood vessels dilation
Arrhythmia Excessive Bradycardia

28. • Pharmacodynamics:They stimulate N-cholinoreceptors in zona carotis and
initiate a reflexive increase in the activity of the respiratory and vasomotor
centers resulting in the short stimulation of breathing and elevation of BP.They
also stimulate N-cholinoreceptors in the adrenal medulla, increase the secretion
of epinephrine, which causes vasoconstriction and the elevation of BP
• Examples : Cytitonum, Lobeline hydrochloride, Nicotine

29. N- cholinomimetic (direct
acting)
Pharmacological action
Nicotine It is a tobacco alkaloid with a dose-dependent action on N-cholinoreceptors.
Bind to nicotinic receptors; duration of action 1–6 h;
high lipid solubility.
Can be in form of patch, chewing gum used therapeutically to help patients stop smoking,
Cytitonum Cytitonum is the name of a cytizine solution; is administered IV, acts 3-5 min;
stimulates N-cholinoreceptors; reflexly stimulates respiration and increases BP;
Is used for emergency help in respiratory arrest and collapse;
Is an ingredient of combined tablets against tobacco abuse.
Lobeline Lobeline is an alkaloid; is administered IV and acts during 3-5 min;
the mechanism of action is similar to Cytitonum;
Is used for emergency help in the respiratory arrest, asphyxia, asphyxia of newborns;
Is used to treat tobacco abuse in the form of combined tablets “Lobesil”; I
Is not used for collapse due to its ability to provoke transitory a decrease in BP resulting from
the stimulation of n.vagus center.

30. • These are also called anticholinesterase or cholinesterase inhibitors
• By inhibiting acetylcholinesterase, indirect-acting cholinergic agonists amplify
the actions of endogenous acetylcholine at both muscarinic and nicotinic
synapses
• Indirect-acting cholinergic agonists fall into three major classes based on
chemical structure and duration of effect.
• These classes are :
• Alcohols (e.g., edrophonium),
• Carbamates (e.g., neostigmine) and
• Organophosphates (e.g., echothiophate).
• Based on the binding, all three classes may be considered pseudoirreversible
antagonists of acetylcholinesterase.

31. • The alcohol class (edrophonium) binds to the active site electrostatically and by
hydrogen bonds.The binding is short lived—on the order of minutes.
• Both the carbamate and organophosphate classes bind to acetylcholinesterase
and undergo hydrolysis. Following this enzymatic activity, the metabolite is
released slowly, preventing the binding and inactivation of acetylcholine.The
carbamates are released over a period of hours, whereas the organophosphates
require days to weeks to be released by the acetylcholinesterase
Note: Finally, some drugs in this class also have some direct-acting agonist
activity. For example, neostigmine both inhibits acetylcholinesterase and directly
activates the postsynaptic NM receptor at the neuromuscular junction.

32. • Anticholinesterases are indirect-acting M-, N-cholinomimetics.
• Mechanism of action: Anticholinesterases bind to acetylcholinesterase in the
synaptic gap, inhibit it and decrease acetylcholine destruction.The result is the
accumulation of the endogenous acetylcholine in the synaptic gap and an
increase in acetylcholine interaction with M- and N-cholinoreceptors.
These drugs can be into two groups based on type of action:
• 1. Reversible inhibitors, which are water soluble, they compete with
acetylcholine for the active site on the cholinesterase enzyme.
• This group includes the drugs with names ending in “-stigmine” and “-nium.”, and
• 2. Irreversible inhibitors (organophosphates), which are lipid soluble
phosphorylate the enzyme ChE and inactivate it.
• These cholinesterase inhibitors are widely used as insecticides and are commonly referred
to as nerve gases.
• Because the organophosphates are lipid soluble, they rapidly cross all membranes,
including skin and the blood–brain barrier

34. • These drugs have all the same actions and side effects as the direct-acting
cholinergic agonist (muscarinic). In addition, because they increase the
concentration of acetylcholine, they have effects at the neuromuscular junction
(nicotinic).
• The side effects range from tremor, anxiety, and restlessness to coma.The
organophosphates, because of their lipid solubility, rapidly cross into the CNS.
• They cause fasciculation and weakness in normal people and can improve
muscle strength in patients with myasthenia gravis.
• Myasthenia gravis is an immune disease in which there is loss of acetylcholine
receptors at the neuromuscular junction, resulting in weakness and fatigability
of skeletal muscle.

35. Reversible
anticholinesterases
Pharmacological action
Physostigmine Physostigmine is an alkaloid from Phyzostigma venenosum ; is well absorbed; penetrates CNS; has a
reversible anticholinesterase action; is used for the treatment of glaucoma, intoxication by atropine,
cholinoblockers, and tricyclic antidepressants, early stages of Alzheimer’s disease; It is toxic
Physostigmine is the specific antidote for poisoning with belladonna or other anticholinergics. It should
only be used to reverse toxic, life-threatening delirium caused by an anticholinergic agent (atropine,
scopolamine, diphenhydramine).
Galantamine Galantamine is an alkaloid from Galanthus nivalis. ; is administered SC, IM; penetrates into CNS; has a
reversible anticholinesterase action; is used for the treatment of paralysis, neuritis, early stages of
Alzheimer’s disease and other neurological diseases; is not used in glaucoma due to its irritative action
Neostigmine Neostigmine is a synthetic preparation; is administered orally, SC, IV, topically (eye drops); does not
penetrate CNS; has a reversible anticholinesterase action (4-6 hrs); it is long acting
Is used for paralysis, neuritis, myasthenia gravis, atonia of the intestine and urinary bladder, some kinds
of arrhythmia, glaucoma, poisoning with atropine, overdose of tubocurarine; may be used for
stimulation of labor activity; in dentistry is applied for xerostomia; is less toxic than physostigmine.
Edrophonium Edrophonium is a short-acting cholinesterase inhibitor that is administered intravenously to patients
suspected of having weakness caused by myasthenia gravis to dramatically improve muscle strength
Pyridostigmine Pyridostigmine acts longer, but is less potent than neostigmine; is used orally for the treatment of
neurological diseases and myasthenia gravis
Ambenonium Ambenonium are used in the treatment of myasthenia gravis.

36. • Theses group of drugs are mostly organophosphates which phosphorylate
the cholinesterase enzyme, thus inactivating it.
• Examples are malathion, parathion, echothiophate.
• There are no therapeutic uses for the irreversible cholinesterase inhibitors
except Phosphacolum which is an irreversibly acting anticholinesterase with
long-lasting action; is toxic and used only for glaucoma (eye drops).
• Signs of acute poisoning by organophosphates:
• Hyper-salivation
• Nausea,Vomiting
• Spasm Of Bronchi, Edema OfThe Lungs
• Convulsions
• Unconsciousness
• Reactivators of cholinesterase (dipyroxim, alloxim, izonitrozin), IM.
– Atropine, IM.

37. Clinical applications Indirect acting cholinomimetics
Postoperative and neurogenic ileus and urinary retention Neostigmine
Myasthenia gravis, reversal of non depolarizing
neuromuscular blockade
Neostigmine, pyridostigmine, edrophonium
Open angle Glaucoma Physostigmine, echothiophate
Alzheimer’s disease, dementia Tacrine, donepezil, galantamine, rivastigmine