Download Choline Esters

Munir Gharaibeh, MD, PhD, MHPE
[email protected]
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Sites of Origins
Length of Preganglionic and Postganglionic
neurons.
Ratio of preganglionic: postganglionic
Function
Heart rate
Blood vessels
Sympathetic
Increased
Constricted
Parasympathetic
Slowed
Dilated
Stomach and
Decreased activity
intestine
and secretions
Salivary and bronchial Decreased secretion
glands
Increased activity and
secretions
Increased secretion
Urinary bladder
Body contracted,
sphincter relaxed
Contracted
Bronchial muscle
Body relaxed,
sphincter constricted
Relaxed
Blood sugar
Eye
Raised
Pupils dilated
Munir Gharaibeh
Pupils constricted,
accommodation for
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near vision
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Choline is transported into the presynaptic nerve
terminal by a sodium-dependent choline
transporter (ChT). This transporter can be
inhibited by hemicholinium drugs.
In the cytoplasm, acetylcholine is synthesized
from choline and acetyl Co-A (AcCoA) by the
enzyme choline acetyltransferase (ChAT).
Acetylcholine is then transported into the
storage vesicle by a second carrier, the vesicleassociated transporter (VAT), which can be
inhibited by vesamicol.
Peptides (P), adenosine triphosphate (ATP), and
proteoglycan are also stored in the vesicle.
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Release of transmitter occurs when voltagesensitive calcium channels in the terminal
membrane are opened, allowing an influx of
calcium. The resulting increase in intracellular
calcium causes fusion of vesicles with the surface
membrane and exocytotic expulsion of
acetylcholine and cotransmitters into the junctional
cleft. This step can be blocked by botulinum toxin.
Acetylcholine's action is terminated by metabolism
by the enzyme acetylcholinesterase.
Receptors on the presynaptic nerve ending
modulate transmitter release.
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ACh released from the motor nerve
terminal interacts with subunits of the
pentameric nicotinic receptor to open it,
allowing Na +influx to produce an
excitatory postsynaptic potential (EPSP).
The EPSP depolarizes the muscle
membrane, generating an action potential,
and triggering contraction.
Acetylcholinesterase (AChE) in the
extracellular matrix hydrolyzes ACh.
The ENS receives input from both the sympathetic and the parasympathetic
systems and sends afferent impulses to sympathetic ganglia and to the
central nervous system.
 Many transmitter or neuromodulator substances have been identified in the
ENS.
AC: absorptive cell
CM: circular muscle layer
EC: enterochromaffin cell
EN: excitatory neuron
EPAN: extrinsic primary afferent neuron
IN: inhibitory neuron
IPAN: intrinsic primary afferent neuron
LM: longitudinal muscle layer
MP: myenteric plexus
NP: neuropeptides
SC: secretory cell
SMP: submucosal plexus
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Definition:
 Drugs which produce effects similar to those observed
during the stimulation of postganglionic
parasympathetic nerve fibers or have actions similar
to acetylcholine.
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Choline Esters.
Alkaloids.
Cholinesterase Inhibitors or Anticholinesterases.
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Choline Esters:
 Acetylcholine:
▪ Naturally released ACh from the cholinergic nerve endings.
▪ Very short acting because of rapid hydrolysis by AChase
enzyme.
▪ Used only in experimentation.
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 Methacholine:
 Used in in the diagnosis of bronchial asthma ”Methacholine
Challenge”
 Carbachol: not used clinically because of nicotinic
activity
 Bethanechol:
 Works mainly on M3( smooth muscles and glands), but weak
at M2, so minimal cardiac effects.
▪ Synthetic, long acting, used orally or s.c..
▪ Used in gastric and bladder atony, when there is no
obstruction.
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Choline Esters.
Alkaloids: produce similar actions to ACH but inconsistent
 Muscarine: present in some species of mushroom
(Amanita muscaria), can cause poisoning.
 Pilocarpine:
▪ not hydrolyzed by cholinesterase
▪ works mainly on M3 receptors.
▪ used topically in glaucoma.
 Nicotine
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▪ Uses: Non medical use( smoking and as an insecticide) and medical use in
smoking cessation
▪ Kinetics:
▪ Rapidly absorbed through skin, lungs, and gut
▪ For smoking cessation, used orally as a gum or topically as a patch.
▪ Works on the ganglia, parasympathetic, sympathetic, motor end plate, CNS).
▪ Dependence: due to activation of nicotinic receptors on neurons in the brain’s
dopaminergic reward pathway(venrtal tegument area).
▪ Nm stimulation can lead to fasiculations, spasms, and depolarizing blockade.
▪ Nn stimulation can lead to:
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High heart rate
Vsoconstriction
High gastric motility and secretions.
Increased respiratory rate, due to chemoreceptor activation.
Medullary emetic chemoreceptor stimulation, so nausea and vomiting.
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Partial nicotinic agonist.
Highly effective in supporting smoking
cessation.
May be associated with psychiatric
symptoms, including suicidal ideation.
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Choline Esters.
Alkaloids.
Cholinesterase Inhibitors or Anticholinesterases:
 Reversible
▪ Alcohols: e.g. Edrophonium
▪ Carbamic acid esters: e.g. Neostigmine, Carbaryl.
 Irreversible( Organophosphates): e.g. Echothiophtae,
Soman, Malathion
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Mechanism of Action:
 Inhibit cholinesterase enzyme leading to
accumulation of acetylcholine at
neuromuscular junctions and synapses
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Very potent agricultural insecticides and lethal
war weapons.
Very easily absorbed through all parts of the
skin.
Inhibit the enzyme and cause accumulation of
ACh at all sites.
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Tissue or System
Effects
Skin
Sweating
Visual
Lacrimation, miosis, blurring, spasm
Digestive
Salivation, increased secretions, tone, and motility
(cramps, vomiting, diarrhea, and defecation)
Urinary
Frequency and incontinence
Respiratory
Increased secretions, bronchoconstriction, weakness of
muscles
Skeletal muscle
Fasiculation, weakness, paralysis
Cardivascular
Bradycardia, decreased cardiac output, hypotension.
CNS
Tremor, anxiety, restlessness, confusion, convulsions,
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coma
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Stop the exposure, wash extensively, very lipid
soluble.
Atropine, a parasympatholytic drug, in very
large doses, until the appearance of Atropine
Poisoning.
Pralidoxime, when given very early after the
poisoning, can regenerate the enzyme.
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