Medical Pharmacology – Chapter 10 – Cholinergic
neurotransmission
Acetylcholine neurotransmitter is released by nerve endings of:
1. Postganglionic parasympathetic neurons and some postganglionic
sympathetic neurons (e.g. sweat glands, adrenal medulla)
2. Preganglionic parasympathetic and sympathetic neurons
3. Motor neurons in striated muscle tissue
4. Cholinergic neurons in CNS
Biosynthesis and inactivation of acetylcholine
Biosynthesis;
Acetyl-coenzyme A (synthesized in mitochondria + choline
(taken up by active transport process in nerve ending) -->
Ach (by choline acetyltransferase = CAT)
CAT is not saturated with choline, the availability of this
precursor choline is rate limiting factor.
Hemicholinium inhibits uptake of choline thus also has
inhibiting effect on cholinergic neurotransmission
Eliminated;
ACh --> choline + acetate (by acetylcholinesterase (AChE),
which is bound on the cell membrane)
Choline is taken up again and reused for acetylcholine
synthesis, so acetylcholine itself is not taken up.
In most tissues, including blood the pseudo-cholinesterase (ChE) is present. This
enzyme exhibits a much lower substrate specificity than AChE and is not directly
associated with cholinergic neurotransmission.
Acetylcholine receptors
3 different acetylcholine receptors;
1. Nicotinic acetylcholine receptor; ionotropic receptors, forms an ion
channel (ionotropic) that opens by binding with ACh. (Five subunits
that form a Na+ channel)
a. N1 (AChNm); to neuromuscular transition (overgang). Located
in motor endplates of neuromuscular synapses in skeletal
muscle
b. N2 (AChN); to postganglionic autonomic neurons. Localised in
ganglia and involved in stimulus transfer from preganglionic to
postganglionic (sympathetic and parasympathetic)
2. Muscarine acetylcholine receptor; not an inotropic
receptor but is G-protein coupled receptors
(metabotropic). G-protein performs a certain action
when ACh binds to the receptor (slower then nicotinic
acetylcholine receptor because the signal transfer must
take place via different proteins).
, 5 types (M1-M5), have different reactions on ACh. (7-transmembrane domains
that can activate the phosphatidyl inositol-route or
inhibit cAMP formation)
Involved in stimulus transfer of post-ganglionic
parasympathetic neurons (+ some postganglionic
sympathetic neurons) on the effector cells
Pharmacological control of cholinergic neurotransmission
Inhibition of acetylcholinesterase; the quantity of
(released) ACh at its receptors will increase, making it
strong and/or longer acting.
Divided cholinesterase-inhibitors into 2 groups;
1. Reversible cholinesterase inhibitors
They belong to the carbamates; physostigmine,
neostigmine and pyridostigmine
They bind to the enzyme acetylcholinesterase in
a similar manner. They dissociate slowly,
meaning that the enzyme remains bound for a
long time and thus is temporarily not available for
inactivation of ACh.
Short-acting edrophonium not belong to carbamates. It bound to
acetylcholinesterase but is not inactivated, unlike the carbamates it is a true
competitive inhibitor enzyme.
2. Irreversible cholinesterase inhibitors
Includes toxic substances belonging to the organo-phosphates. Best known
are parathion, paraoxon, soman, sarin and tabun. Strongly lipophilic, so easily
pass skin and blood-brain barrier and spread toxic effects in CNS. Attach to
acetylcholinesterase irreversible by reaction of their phosphate group with
‘active site’.
All cholinesterase inhibitors bind with the enzyme at active site in a covalent bond.
Depending on the inhibitor this bond can be more or less strong. The release of
inhibitor is called spontaneous reactivation.
The speed of reactivation is high for most carbamates – reversible bond
The speed of reactivation is low for most organo-phosphates – irreversible bond
4 classes of drugs cause effect by direct interaction with ACh receptors
1. Direct parasympathomimetic (agonists of the AChM receptor); mimic
(nabootsen) the effects of stimulation of the parasympathetic nerves
2. Direct parasympathicolytics (antagonists of the AChM receptor);
counteract/reduce effects of stimulation of parasympathetic nerves
3. Ganglion-inhibitors (antagonists of the AChN receptor); hinder or inhibit
ganglionic neurotransmission
4. Neuromuscular inhibitors (either antagonist or agonists) and bind to AChM
receptors in skeletal muscle
neurotransmission
Acetylcholine neurotransmitter is released by nerve endings of:
1. Postganglionic parasympathetic neurons and some postganglionic
sympathetic neurons (e.g. sweat glands, adrenal medulla)
2. Preganglionic parasympathetic and sympathetic neurons
3. Motor neurons in striated muscle tissue
4. Cholinergic neurons in CNS
Biosynthesis and inactivation of acetylcholine
Biosynthesis;
Acetyl-coenzyme A (synthesized in mitochondria + choline
(taken up by active transport process in nerve ending) -->
Ach (by choline acetyltransferase = CAT)
CAT is not saturated with choline, the availability of this
precursor choline is rate limiting factor.
Hemicholinium inhibits uptake of choline thus also has
inhibiting effect on cholinergic neurotransmission
Eliminated;
ACh --> choline + acetate (by acetylcholinesterase (AChE),
which is bound on the cell membrane)
Choline is taken up again and reused for acetylcholine
synthesis, so acetylcholine itself is not taken up.
In most tissues, including blood the pseudo-cholinesterase (ChE) is present. This
enzyme exhibits a much lower substrate specificity than AChE and is not directly
associated with cholinergic neurotransmission.
Acetylcholine receptors
3 different acetylcholine receptors;
1. Nicotinic acetylcholine receptor; ionotropic receptors, forms an ion
channel (ionotropic) that opens by binding with ACh. (Five subunits
that form a Na+ channel)
a. N1 (AChNm); to neuromuscular transition (overgang). Located
in motor endplates of neuromuscular synapses in skeletal
muscle
b. N2 (AChN); to postganglionic autonomic neurons. Localised in
ganglia and involved in stimulus transfer from preganglionic to
postganglionic (sympathetic and parasympathetic)
2. Muscarine acetylcholine receptor; not an inotropic
receptor but is G-protein coupled receptors
(metabotropic). G-protein performs a certain action
when ACh binds to the receptor (slower then nicotinic
acetylcholine receptor because the signal transfer must
take place via different proteins).
, 5 types (M1-M5), have different reactions on ACh. (7-transmembrane domains
that can activate the phosphatidyl inositol-route or
inhibit cAMP formation)
Involved in stimulus transfer of post-ganglionic
parasympathetic neurons (+ some postganglionic
sympathetic neurons) on the effector cells
Pharmacological control of cholinergic neurotransmission
Inhibition of acetylcholinesterase; the quantity of
(released) ACh at its receptors will increase, making it
strong and/or longer acting.
Divided cholinesterase-inhibitors into 2 groups;
1. Reversible cholinesterase inhibitors
They belong to the carbamates; physostigmine,
neostigmine and pyridostigmine
They bind to the enzyme acetylcholinesterase in
a similar manner. They dissociate slowly,
meaning that the enzyme remains bound for a
long time and thus is temporarily not available for
inactivation of ACh.
Short-acting edrophonium not belong to carbamates. It bound to
acetylcholinesterase but is not inactivated, unlike the carbamates it is a true
competitive inhibitor enzyme.
2. Irreversible cholinesterase inhibitors
Includes toxic substances belonging to the organo-phosphates. Best known
are parathion, paraoxon, soman, sarin and tabun. Strongly lipophilic, so easily
pass skin and blood-brain barrier and spread toxic effects in CNS. Attach to
acetylcholinesterase irreversible by reaction of their phosphate group with
‘active site’.
All cholinesterase inhibitors bind with the enzyme at active site in a covalent bond.
Depending on the inhibitor this bond can be more or less strong. The release of
inhibitor is called spontaneous reactivation.
The speed of reactivation is high for most carbamates – reversible bond
The speed of reactivation is low for most organo-phosphates – irreversible bond
4 classes of drugs cause effect by direct interaction with ACh receptors
1. Direct parasympathomimetic (agonists of the AChM receptor); mimic
(nabootsen) the effects of stimulation of the parasympathetic nerves
2. Direct parasympathicolytics (antagonists of the AChM receptor);
counteract/reduce effects of stimulation of parasympathetic nerves
3. Ganglion-inhibitors (antagonists of the AChN receptor); hinder or inhibit
ganglionic neurotransmission
4. Neuromuscular inhibitors (either antagonist or agonists) and bind to AChM
receptors in skeletal muscle
