Transcript Mechanism of Action of AChE Inhibitors

Chapter 9
Anticholinesterase Drugs ＆
Cholinesterase Reactivators
Cao Yongxiao 曹永孝
Department of Pharmacology
029-8265 5140; [email protected]
http://pharmacology.xjtu.edu.cn
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Anticholinesterase Drugs
Cholinesterase (ChE)
inhibitors comprise
another group drugs
mimicing ACh by
inhibiting the hydrolysis
of endogenous ACh.
Cholinoceptor
agonists bind to
and activate
cholinoceptors
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西安交大医学院药理学系 曹永孝 [email protected]; 029-82655140
Mode of action of Anticholinesterase drugs
Anti-ChE agents produce
Drugs act primarily where
effects by inhibiting AChE,
ACh is physiologically
decreasing
hydrolysis of ACh,
and
increasing
［AＣh］.
released
and are
amplifiers
ACh
evoke
an
increased
of endogenous ACh.
responses.
Their primary effects are
at the active site of this
enzyme.
．
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Basic Pharmacology of
Anticholinesterase Drugs
The action of ACh is terminated by destruction
of AChE which is present
in cholinergic synapses.
Their pharmacodynamic properties are almost
identical.
The chief differences between members of the
group are chemical and pharmacokinetics.
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Chemistry
The ChE inhibitors fall into three chemical groups:
(1) simple alcohols bearing a quaternary
ammonium group, eg, edrophoniun;
(2) carbamic acid esters of alcohols bearing
quaternary or tertiary ammonium groups；
(3) organic derivatives of phosphoric acid.
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(2) carbamic acid
esters of alcohols
bearing tertiary or
quaternary
ammonium groups
(1) simple
alcohol
bearing a
quaternary
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Larger doses are
required for oral
administration than
for injection.
Absorption of the quaternary
carbamates from the conjunctiva,
skin and lungs is poor,
since their charge renders them
relatively insoluble in lipids.
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Distribution

Distribution into CNS is negligible.

Physostigmine, in contract, is well absorbed from
all sites and can be used topically in the eye.
It is distributed into CNS and is more toxic than
the more polar quaternary carbamates.

The carbamates are relatively stable in aqueous
solution but can be metabolized by ChE.

The duration of effect is determined chiefly by the
stability of the inhibitor-enzyme complex.
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Organophosphate ChE inhibitors
 are well absorbed from the skin, lung, gut, and
conjunctiva, making them dangerous to humans and
highly effects as insecticides.
 They are relatively less stable than carbamates.
 Echothiophate is the most stable organophosphates.
It can be made up in aqueous solution for
ophthalmic use and retains activity for weeks.
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9
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The dash line is the bond
that is hydrolyzed in
binding to the enzyme
The shaded ester
bond is the points of
detoxification in
mammals and birds
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The thiophosphate insecticides are lipid soluble
and rapidly absorbed. They must be activated
in the body by conversion to the oxygen analogs
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Malathion are rapidly
metabolized to inactive
products in birds and
mammals but not in
insects; they are safe.
Parathion is not detoxified effectively in
vertebrate; it is dangerous to man and not
available for general public use.
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 Malathion is the least toxic organophosphates
due to the presence of ester functions in its
molecule. Insects have much lower esterases
activity than the mammals.
13
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The thiophosphate being quite lipid-soluble is rapidly
 The thiophosphate being quite lipid-soluble is rapidly
absorbed and is activated in the body by conversion to the
absorbed and is activated in the body by conversion to the
oxygen analogy.
oxygen analogy.
Malathion are rapidly metabolized to inactive products in
 Malathion are rapidly metabolized to inactive products in
birds and mammals but not in insects; these
birds and mammals but not in insects;
agents are considered safe enough.
they are considered safe enough.
Parathion is not detoxified effectively in vertebrate; it is
 Parathion is not detoxified effectively in vertebrate; it is
considerably dangerous to humans and is not available for
considerably dangerous to humans and is not available for
general public use.
general public use.
14
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All thiophosphate-type (PS) AChE inhibitors
need to be bioactivated by the cytochrome P-450
enzymes to the corresponding phosphate esters
(PO) (i.e., the PS is not as electrophilic as
PO to allow nucleophilic attack by the Ser-OH).
Since insects appear to have more reactive
oxidative enzymes
15
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Phosphoramide-type AChE inhibitors are inactive.
The selective toxicity is due to the differences in the
biotransformations between insects and mammals
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Pharmacodynamics
Mechanism of Action
 First, ACh binds to the enzyme’s active
site and is hydrolyzed, yielding free
choline and the acetylated enzyme.
 Then, the covalent acetylenzyme bond
is split. It takes about 150 ms.
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AChE inhibitors bind to AChE active site and are hydrolyzed
Covalent bond
Ch
Electrostatically
Hydrogen bond
Irreversible
bond
Ch
Ch esters
Edrophonium
consisting
Carbamate
agents undergo a
of quaternary alcohols
two-step
bind electrostatically
and hydrolysis
sequence. However,
by hydrogen bonds to the
the covalent bond of
active site, preventing
the carbamoylated
access of ACh. The
enzyme is more
enzyme-inhibitor resistant
complexto the
second process.
is short-lived.
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Mechanism of Action of AChE Inhibitors
Organo-phosphates
also active site and are hydrolyzed
AChE
inhibitors bind to AChE
undergo initial binding
and hydrolysis by the Covalent bond
Electrostatically
enzyme,
resulting
in a
Ch
Ch
Hydrogen bond
phosphorylated active site.
The covalent phosphorusenzyme bond is extremely
stable and hydrolyzed in a
very slow rate.
Irreversible
bond
Ch
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Mechanism of Action of AChE Inhibitors
 After the initial binding-hydrolysis step,
the phosphorylated enzyme complex
may undergo a process called aging.
This process involves the breaking of
one of the oxygen-phosphorus bonds
of the inhibitor and further strengthens
the phosphorus enzyme bond.
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Organ System Effects

Central Nervous System—

In low concentrations, the lipidsoluble cholinesterase inhibitors
cause diffuse activation on the
electroencephalogram and a
subjective alerting response.

In higher concentrations, they
cause generalized convulsions,
which may be followed by coma
and respiratory arrest.
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Eye, Respiratory Tract, Gastrointestinal
Tract, Urinary Tract—
 The effects of the cholinesterase inhibitors
on these organ system, all of which are well
innervated by the parasympathetic nervous
system, are quite similar to the effects of the
direct-acting cholinomimetics.
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Cardiovascular System The ChE inhibitors can
increase activation in ganglia
supplying the heart.
 In the heart, the effects on the parasympathetic
predominate. Thus, ChE inhibitors mimic the
effects of vagal nerve activation.
 Negative chronotropic, dromotropic, and inotropic
effects are produced, and cardiac output falls.
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23
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Neuromuscular Junction—

At low concentrations, the ChE inhibitors
moderately prolong and intensify the action of
ACh, increase strength of contraction.

At higher concentration, the accumulation of ACh
may result in fibrillation of muscle fibers.

Neostigmine, a quaternary carbamate
cholinesterase inhibitors, agonize N2 receptor.

This contributes to the effectiveness at therapy for
myasthenia.
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Clinical Uses
 A. The Eye
 Glaucoma is
with increasing
intraocular pressure.
Cholinesterase inhibitors reduce intraocular
pressure by increasing ACh concentration,
contracting the ciliary body and facilitating
outflow of aqueous humor.
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Gastrointestinal and Urinary Tracts
 Postoperative ileus and congenital
megacolon involve depression of smooth
muscle activity without obstruction.
 Urinary retention may occur postoperative
or postpartum or secondary to spinal cord
injury.
 Of the cholineaterase inhibitions,
neostigmine is the most widely used for
these applications.
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 Myasthenia gravis is a disease affecting
skeletal muscle neuromuscular junction.
Frequent findings are
ptosis, difficulty in
speaking and
swallowing, and
extremity weakness.
Even respiratory
muscles.
An autoimmune
process produces
antibodies that
decrease the
number of N2
receptors.
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27
 Myasthenia gravis is a disease affecting skeletal
muscle neuromuscular junction.
ChE inhibitors can
increase ACh
concentration,
excite N2 receptors,
which strengthen
contraction.
Patients are also
treated with
immunosuppressant
drugs and some
with thymectomy.
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Heart
 The short-acting
cholinesterase inhibitor
edrophonium had been
used to treat
supraventricular
tachycardia.
29
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Antimuscarinic Drug in Toxication

Atropine intoxication is potentially lethal in
children and may cause prolonged severe
behavioral disturbances in adults. The
tricyclicantidepressants in overdosage, also
cause severe muscarinic blockade.

Cholinesterase inhibitors can antagonize the
blockage of M receptors (atropine overdosage).
30
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CNS: Alzheimer’s disease
 Tacrine is a drug with anticholinesterase and other
cholinomimetic action that has been used for the
treatment Alzheimer’s disease.
 Donepezil, galantamine, and rivastigmine are more
selective AChE inhibitors that appear to have the
same modest clinical benefic as tacrine in treatment
of cognitive dysfunction in Alzheimer’s patient.
 Donepezil may be given once daily because of its
long half-life.
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Toxicity of Cholinesterase Inhibitors
 The acute toxicity:
The initial signs are those of
M symptoms: miosis, salivation,
sweating, vomiting, diarrhea,
and bronchial constriction.
CNS involvement usually follow rapidly,
accompanied by peripheral N effects, especially
depolarizing N2 blockade.
Chronic exposure to organophosphate ChE inhibitor
cause neuropathy with demyelination of axons 32
ChE Reactivators
 Cholinesterase reactivation, capable of
regenerating active enzyme from the
organophosphosphorus-cholinesterase
complex, is available to treat
organophosphorus poisoning.
 These oxime agents include pralidoxime
(PAM), diacteylmonoxime (DAM), and
others.
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Mode and Use of Action of the
Cholinesterase Reactivators
 The oxime group (NOH) has a very high affinity for the
phosphorus atom, and are able to hydrolyze the
phosphorylated enzyme.
 Pralidoxime is the most effective in regenerating ChE.
Because of its positive charge, it does not enter CNS and
is ineffective in CNS poisoning.
 Diacetylmonoxime can cross the blood brain barrier and
can regenerate cholinesterase in CNS.
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PAM reverses the effects of the organophosphate
anticholinesterase agents.
1. PAM combines with and splits off the phosphorus
from the ester site on cholinesterases in such a way that
the enzyme is restored.
2.With reactivation of the enzyme, the effects of ACh
begin to disappear.
3. The treatment must be within hours, because the
phosphorylated enzyme slowly changes to a form that
cannot be reversed.
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PAM and atropine have synergism in treating
organophosphate ChE inhibitor poisoning .
Organophosphate ChE inhibitors result in:
M effects
PAM
Atropine
+
N effects
+
-
CNS effects
+
+
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glad to share my knowledge with you,
and want you to become a master
of the subject, pharmacology
37
西安交大医学院药理学系 曹永孝
[email protected]; 029-82655140