PHARMCOL201 2005: Lecture 17
Learning Objectives
Lecture 17
Drugs That Enhance
Cholinergic Transmission
Rang, Dale and Ritter (5th Edition),
Chapter 10
Drugs That Enhance cholinergic
Transmission
• Increase release –aminopyridines which
block K+ channels can increase release of
Ach – not selective
• Prevent breakdown – anticholinesterases –
inhibit metabolism by acetylcholinesterase
(AchE)
Cholinesterase - Structure
• The active site of the enzyme comprises an
anionic site and an esteric site.
• The esteric site contains a histidine imadazole ring
and a serine -OH group. The acetyl group from
Ach is transferred to the serine-OH group, leaving
an acetylated enzyme molecule and a molecule of
free choline.
• Acetate is then released. The anionic site is
thought to help in aligning the two molecules.
• Rapid turnover – 10,000 molecules/second per
active site.
• Describe the means by which drugs can
enhance cholinergic transmission
• Describe (with examples) the mechanism of
action of the three classes of anti-
cholinesterase
• Describe the clinical uses and adverse
effects of anti-cholinesterases
Cholinesterases
• Two types of cholinesterase in the body – AchE
and butyrylcholinesterase (BchE).
• AchE – basement membrane of synaptic cleft at
cholinergic synapse, and cholinergic nerve
terminals – specific for Ach.
• BchE – widespread distribution, broader substrate
specificity, keeps Ach levels in the plasma
negligible, and metabolises some Ach like drugs
(suxamethonium).
Drugs That Inhibit Cholinesterase
• Short Acting – alcohols bearing a
quaternary ammonium group – form a
readily reversible ionic bond with anionic
group of enzyme e.g. edrophonium.
• Used as a diagnostic tool for myasthenia
gravis – improvement of muscle strength
by AChE is characteristic of this disease.
PHARMCOL201 2005: Lecture 17
Medium Duration AChE
• Carbamic acid esters of alcohol bearing quaternary
or tertiary amine groups (carbamates)
• Hydrolysis produces are carbamylated enzyme
(not acetylated) which is quite resistant to
hydrolysis – so enzyme is inhibited for longer, e.g.
neostigmine, pyridostigmine
Neostigmine
Irreversible Anti-Cholinesterase
Parathion – a long duration anti-cholinesterase
Used as an insecticide but commonly causes
toxicity in humans
Autonomic Effects
• What effects would increased Ach at post
synpatic parasympathetic ganglia cause?
• Why do the autonomic ganglia first become
activated and then inactivated?
Irreversible Anti-cholinesterases
• Organic derivatives of phosphoric acid
(organophosphates) e.g. isoflurophate
• Initial binding and hydrolysis results in a
phosphate covalently bound to active site of
enzyme – this is very stable and may take days to
reverse
• Some form non-hydrolysable bonds and require
resynthesis of the enzyme - may take weeks
• Most have high lipid solubility
Effects of Anti-Cholinesterase
Drugs
• At parasympathetic post ganglionic
synapses
• At autonomic ganglia
• At neuromuscular junction
• In CNS
Effects on NMJ
• Greater muscle tension.
• In myasthenia gravis transmission fails
because there are too few Ach receptors,
AchEs improve this because they give the
Ach a better chance of reaching the
receptors.
• In large doses cause twitching, and may
cause paralysis.
PHARMCOL201 2005: Lecture 17
Effects of CNS
• Those that cross the bbb.
• Initial excitation including convulsions
• Depression, unconsciousness, respiratory
failure.
• Organophosphates can also cause
demyelination leading to sensory loss.
Clinical Uses
• In anaesthesia reverse the action of non-
depolarising neuromuscular blocking drugs
– neostigmine IV
• In the treatment of glaucoma: ecthiopate as
eye drops.
Clinical Uses
• Myasthenia gravis:
– Incidence 1:2000
– Autoimmune disease – decrease Nicotinic receptors on
functional end plates
– Weakness of head, neck extremities
• Edrophonium – diagnostic test, and dose tailoring
• Neostigmine, pyridostigmine – longer term
treatment – both relatively short acting (2-6 hours)
so require frequent dosing.
• What side effects might this treatment produce?
Organophosphate Poisoning
• If treated within a few hours Pralidoxime may
reactivate enzyme.
• Has an oxime group that can attract the phosphate
group from the esteratic site of the enzyme.
• After a few hours the phosphorylated enzyme
“ages” and is no longer susceptible to reactivation.
• Pralidoxime does not enter the brain.