Cholinergic Agonists

Dr. Pramod P Bhalerao (M.D.)

Asst. Professor
Dept. of Pharmacology
Parasympathetic Innervation
Cholinergic transmission
• Acetylcholine (ACh) is a major neurohumoral transmitter at
• Autonomic,
• Somatic
• Central sites.
Synthesis, storage and destruction of ACh
Metabolism of Acetylcholine-Cholinesterase
enzyme.
• Immediately after release, Ach is hydrolyzed by the enzyme
cholinesterase and choline is recycled.
Cholinesterase enzyme -Types
• A specific (Acetylcholinesterase—AChE or true cholinesterase) and a
nonspecific (Butyrylcholinesterase—BuChE or pseudocholinesterase)
type of enzyme occurs in the body.
Botulinum toxin
• Botulinum toxin A and B
are highly potent exotoxins
produced by Clostridium
botulinum.
• These neurotoxic proteins
cause long-lasting loss of
cholinergic transmission by
interacting with axonal
proteins involved in
exocytotic release of ACh.
Botulinum toxin
• Localized injection of minute quantity of botulinum toxin A (BOTOX)
can be used in the treatment of a number of spastic and other
neurological conditions due to overactivity of cholinergic
nerves, like blepharospasm, spastic cerebral palsy, strabismus,
spasmodic torticollis.
• It is increasing being employed as beauty treatment by removal of age-
related facial wrinkles.
Cholinoceptors
• Two classes of receptors for
ACh are recognized.
• Muscarinic- G protein coupled
receptor.
• Nicotinic- ligand gated cation
channel.
Muscarinic Receptors
• These receptors are selectively stimulated by muscarine and blocked
by atropine.
• They are located primarily on autonomic effector cells in heart, blood
vessels, eye, smooth muscles and glands of gastrointestinal,
respiratory and urinary tracts, sweat glands, etc. and in the CNS.
Subtypes of Muscarinic Receptor
• Muscarinic receptors have been divided into 5 subtypes: M1, M2, M3,
M4 and M5.
• The first 3 are the major subtypes that are present on effector cells as
well as on prejunctional nerve endings, and are expressed both in
peripheral organs as well as in the CNS.
• The M4 and M5 receptors are present mainly on nerve endings in
certain areas of the brain and regulate the release of other
neurotransmitters.
Nicotinic Receptor
• Location- Autonomic Ganglia(NN) and
Neuromuscular Junction(NM).
• These receptors are selectively activated by
nicotine and blocked by tubocurarine or
hexamethonium.
• They are rosette-like pentameric structures which
enclose a ligand gated cation channel: their
activation causes opening of the channel and
rapid flow of cations resulting in depolarization
and an action potential.
Nicotinic Receptor at Muscle end plate(NM)
•
CHOLINERGIC DRUGS
(Cholinomimetic, Parasympathomimetic)
• These are drugs which produce actions similar to that of ACh, either by
• Directly interacting with cholinergic receptors (cholinergic agonists) or
• By increasing availability of ACh at these sites (anticholinesterases).
• Directly acting

• Indirectly acting- Anticholinesterases (eg. Physostigmine, Neostigmine etc).

ACTIONS (of ACh as prototype)
• A. Muscarinic actions
• 1. Heart
• ACh hyperpolarizes the SA nodal cells and decreases their rate of
diastolic depolarization. As a result, rate of impulse generation
is reduced—bradycardia or even cardiac arrest may occur.
• At the A-V node and His-Purkinje fibres refractory period (RP) is
increased and conduction is slowed: P-R interval increases and partial
to complete A-V block may be produced.
• The cardiac muscarinic receptors are of the M2 subtype.
ACTIONS (of ACh as prototype)
• 2. Blood vessels
• Muscarinic (M3) receptors are
present on vascular endothelial
cells: vasodilatation is primarily
mediated through the release of
an endothelium dependent
relaxing factor (EDRF) which is
nitric oxide (NO).
ACTIONS (of ACh as prototype)
• 3. Smooth muscle
• Smooth muscle in most organs is contracted (mainly through M3 receptors).

• GIT-Tone and peristalsis in the gastrointestinal tract is increased and sphincters

relax---abdominal cramps and evacuation of bowel.

• Genitourinary tract-Peristalsis in ureter is increased. The detrusor muscle

contracts while the bladder trigone and sphincter relaxes --- voiding of bladder.

• Respiratory system-Bronchial muscles constrict, asthmatics are highly sensitive -

-- bronchospasm, dyspnoea, precipitation of an attack of bronchial asthma.
ACTIONS (of ACh as prototype)
• 4. Exocrine Glands
• Secretion from all parasympathetically innervated glands is increased
via M3 receptors:
• sweating,
• salivation,
• lacrimation,
• increased tracheobronchial and gastric secretion.
ACTIONS (of ACh as prototype)
• 5. Eye
• Contraction of ciliary muscle--- spasm
of accommodation, increased outflow
of aqueous humour ,
• Reduction in intraocular tension
(especially in glaucomatous patients).
ACTIONS (of ACh as prototype)- Eye
ACTIONS (of ACh as prototype)
• 5. Eye
• Contraction of circular muscle of iris---Miosis.
ACTIONS (of ACh as prototype)
• B. Nicotinic actions
1. Autonomic ganglia
• Both sympathetic and parasympathetic ganglia are stimulated. This
effect is manifested at higher doses.
• High dose of Ach given after atropine causes tachycardia and rise in
BP due to stimulation of sympathetic ganglia and release of
catecholamines.
ACTIONS (of ACh as prototype)
• B. Nicotinic actions
• 2. Skeletal muscles
• Acetylcholine released from nerve endings stimulates NM receptors
resulting in skeletal muscle contraction
• But i.v. injection is generally without any effect (due to rapid
hydrolysis of ACh).
• Interactions
• Anticholinesterases potentiate Acetylcholine markedly.
• Atropine and its congeners competitively antagonize muscarinic
actions.
Choline esters-Uses
• Choline esters are rarely, if ever, clinically used.
• ACh is not used because of transient and nonselective action.
Choline esters-Uses
• Bethanechol
• Used in postoperative/postpartum nonobstructive urinary retention,
neurogenic bladder to promote urination.

• Side effects are prominent: belching, colic, involuntary

urination/defecation, flushing, sweating, fall in BP, bronchospasm.
Choline esters-Uses
• Methacoline
• Can be administered by inhalation for the diagnosis of bronchial
airway hyperreactivity.
• Fall in FEV1 by 20% is suggestive of Bronchial Asthma.
Cholinomimetic alkaloids
• Pilocarpine
• It is obtained from the leaves of Pilocarpus
microphyllus and other species.
Pilocarpine
• Applied to the eye, it penetrates cornea and promptly causes miosis,
ciliary muscle contraction and fall in intraocular tension lasting 4–8
hours.
• Pilocarpine is used only in the eye as 0.5–4% drops.
• It is a third-line drug in open angle glaucoma.
• An initial stinging sensation in the eye and painful spasm of
accommodation(due to contraction of ciliary muscle) are frequent side
effects.
Pilocarpine- site of action (M3 Receptor in
iris and ciliary muscles)
Pilocarpine
• Other uses as a miotic are—
• to counteract mydriatics after
they have been used for testing
refraction.
Pilocarpine
• Other uses as a miotic are—
• To prevent/break adhesions of iris
with lens or cornea by alternating it
with mydriatics.
Muscarine
• It occurs in poisonous mushrooms Amanita muscaria and Inocybe
species and has only muscarinic actions.
• It is not used therapeutically but is of toxicological importance.
Mushroom poisoning
• Depending on the toxic principle present in the particular species, at
least 3 types of mushroom poisoning is known.
• Muscarine type (Early mushroom poisoning)
• Hallucinogenic type
• Phalloidin type (Late mushroom poisoning)
Early mushroom poisoning
• Muscarine type due to Inocybe and related
species.
• Symptoms characteristic of muscarinic actions
appear within an hour of eating the mushroom,
• Symptoms- salivation, lacrimation, abdominal
colic, diarrhea, visual disturbances and
bronchospasm.
• Treatment- Atropine(1-2 mg intramuscularly
every 30 minutes).
Inocybe
Thank
You