Cholinergic Neurotransmission
and related drugs
Asst.Prof.Gaye HAFEZ
Altınbaş University
Faculty of Pharmacy
Department of Pharmacology
2022
Cholinergic
transmission
Synthesis of acetylcholine:
• Choline is transported from the extra-cellular fluid into the
cytoplasm of the cholinergic neuron by an energy-dependent carrier
system that cotransports Na+.
• 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 in the cytosol.
Choline AcetylCoA Acetylcholine
Storage of acetylcholine in vesicles:
• The mature vesicle contains not only acetylcholine but also
adenosine triphosphate (ATP).
Release of acetylcholine:
• When an action potential propagated by the action of voltage-
sensitive sodium channels arrives at a nerve ending, voltage-sensitive
calcium channels on the presynaptic membrane open, causing an
increase in the concentration of intracellular calcium. Elevated
calcium levels promote the fusion of synaptic vesicles with the cell
membrane and release of their contents into the synaptic space. This
release can be blocked by botulinum toxin.
Binding to the receptor:
• Acetylcholine released from the synaptic vesicles diffuses across the
synaptic space, and it binds to either of two postsynaptic receptors
on the target cell or to presynaptic receptors in the membrane of the
neuron that released the acetylcholine.
• Biological response in effector cells mediated by 2nd messengers
Degradation of acetylcholine:
• The signal at the postjunctional effector site is rapidly terminated,
because acetylcholinesterase cleaves acetylcholine to choline and
acetate in the synaptic cleft
Recycling of choline:
• Choline may be recaptured by a sodium-coupled, high-affinity uptake
system that transports the molecule back into the neuron, where it is
acetylated into acetylcholine that is stored until released by a
subsequent action potential.
Cholinergic Receptors (Cholinoceptors)
Muscarinic Nicotinic
receptors receptors
Muscarinic receptors
• M1, M2, M3, M4, and M5 and subtypes
bladder, exocrine glands, and smooth muscle
gastric parietal cells
cardiac cells and smooth muscle
❑Muscarinic receptors are G protein-coupled receptors (GPCRs)
Complex Organ Control: The Eye
https://www.youtube.com/watch?v=HFNbOLTASlU
Nicotinic receptors
• Nicotinic receptors are located in the CNS, adrenal medulla,
autonomic ganglia, and the neuromuscular junction.
• Subtypes
• Ligand-gated ion channel
CHOLINOMIMETICs=parasympathomimetics=cholinergics=
cholinergic agonists
Decrease in heart rate and cardiac output
Acetylcholine
(Miochol-E®)
• Direct-Acting Decrease in blood pressure
Cholinergic Agonist
• Rarely used In the gastrointestinal tract, acetylcholine
increases salivary secretion and stimulates
• Both muscarinic and intestinal secretions and motility
nicotinic activity • Bronchiolar secretions are also enhanced
• Acetylcholine (1% In the genitourinary tract, the tone of the
solution) is instilled detrusor urinary muscle is increased, causing
into the anterior expulsion of urine
chamber of the eye to In the eye, acetylcholine is involved in
produce miosis during stimulating ciliary muscle contraction for near
vision and in the constriction of the pupillae
ophthalmic surgery sphincter muscle, causing miosis (marked
constriction of the pupil)
Bethanechol (Myocholine®)
• Direct-Acting Cholinergic Agonist
• not hydrolyzed by acetylcholinesterase
• strong muscarinic activity
• Rarely used • increases intestinal motility and tone
• stimulates the detrusor muscles of the
bladder whereas the trigone and sphincter
are relaxed, causing expulsion of urine
❖ In urologic treatment, bethanechol is used to stimulate the atonic bladder,
particularly in postpartum or postoperative, nonobstructive urinary
retention.
❖ It may also be used to treat neurogenic atony as well as megacolon.
Carbachol (carbamylcholine) (Miostat intraocular solution®)
• Direct-Acting Cholinergic Agonist
• not hydrolyzed by acetylcholinesterase
• both muscarinic as well as nicotinic actions
• rarely used
❖ Used in the eye as a miotic agent to treat
glaucoma by causing pupillary contraction
and a decrease in intraocular pressure.
Pilocarpine (Pilosed ophtalmic®, Salagen tb®)
• stable to hydrolysis by acetylcholinesterase
• muscarinic activity and is used primarily in ophthalmology
• Pilocarpine is one of the most potent stimulators of secretions
(secretagogue) such as sweat, tears, and saliva.
❖Beneficial in promoting salivation in patients with xerostomia
resulting from irradiation of the head and neck.
❖Sjögren syndrome, which is characterized by dry mouth and lack of
tears, is treated with oral pilocarpine tablets
In glacoma,
• 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.
Physostigmine
Neostigmine
Reversible
Pyridostigmine and
ambenomium
Anticholinesterases
(acetylcholineesterase
inhibitors) Edrophonium
Irreversible Organophosphates
Physostigmine
• Indirect-Acting Cholinergic Agonist:
Anticholinesterases (Reversible)
• increases intestinal and bladder
motility
• produces miosis and spasm of
accommodation, as well as a
lowering of intraocular pressure.
❖ It is also used in the treatment of
overdoses of drugs with
anticholinergic actions, such as
atropine, phenothiazines, and
tricyclic antidepressants.
Neostigmine
• Indirect-Acting Cholinergic Agonist: Anticholinesterases (Reversible)
• It is used to stimulate the bladder and GI tract
• An antidote for tubocurarine and other competitive neuromuscular
blocking agents
❖ Symptomatic treatment of myasthenia gravis
Pyridostigmine (Mestinon®)
• used in the chronic management of myasthenia gravis
Edrophonium
• rapidly absorbed and has a short duration of action of 10 to 20 minutes
• used in the diagnosis of myasthenia gravis
Indirect-Acting Cholinergic Agonsists: Anticholinesterases
(Irreversible)
• Organophosphate compounds
• Echothiophate: covalently binds via its phosphate group to the
active site of acetylcholinesterase
• An ophthalmic solution of the drug is
used directly in the eye for the
chronic treatment of open-angle
glaucoma. LIMITED USE IN CLINIC
Reactivation of acetylcholinesterase
• Pralidoxime can reactivate inhibited
acetylcholinesterase.
???
Botulinum toxin blocks the release of acetylcholine from cholinergic
nerve terminals. Which is a possible effect of botulinum toxin?
A. Skeletal muscle paralysis
B. Improvement of myasthenia gravis symptoms
C. Increased salivation
D. Reduced heart rate
???
If an ophthalmologist wants to dilate the pupils for an eye
examination, which drug/class of drugs is theoretically useful?
A. Muscarinic receptor activator (agonist)
B. Muscarinic receptor inhibitor (antagonist)
C. Pilocarpine
D. Neostigmine
???
In Alzheimer disease, there is a deficiency of cholinergic neuronal
function in the brain. Theoretically, which strategy is useful in treating
symptoms of Alzheimer disease?
A. Inhibiting cholinergic receptors in the brain
B. Inhibiting the release of acetylcholine in the brain
C. Inhibiting the acetylcholinesterase enzyme in the brain
D. Activating the acetylcholinesterase enzyme in the brain
?????
• A patient with an acute attack of glaucoma is treated with
pilocarpine. The primary reason for its effectiveness in this
condition is its:
A. Action to terminate acetylcholinesterase
B. Selectivity for nicotinic receptors
C. Ability to inhibit secretions, such as tears, saliva, and sweat
D. Ability to lower intraocular pressure
E. Inability to enter the brain
???
A 60-year-old female who had a cancerous growth in the neck region
underwent radiation therapy. Her salivary secretion was reduced due
to radiation and she suffers from dry mouth (xerostomia). Which drug
would be most useful in treating xerostomia in this patient?
A. Acetylcholine
B. Pilocarpine
C. Echothiophate
D. Atropine
???
A 40-year-old male presents to his family physician with drooping
eyelids, difficulty chewing and swallowing, and muscle fatigue even
on mild exertion. Which agent could be used to diagnose myasthenia
gravis in this patient?
A. Atropine
B. Edrophonium
C. Pralidoxime
D. Echothiophate
Van Gogh
The garden of the
asylum at Saint-Rémy
