ANTICHOLINESTERASES.

/ INDIRECT
CHOLINERGIC DRUGS.

By Prof Dr Khalida Ajmal

2022
 After completion of topic,
Class students should be able to:
Learning
▫ Describe MOA, therapeutic uses of
objectives: reversible & irreversible anti-
cholinesterase. Design a management
plan for a patient of myasthenia
gravis /organophosphate poisoning.
(BLO-4)
.
 Indirect Cholinergic drugs/
Anticholinesterases/ Cholinesterase
Inhibitors
Definition: A group of drugs which inhibit
Acetylcholinesterase enzyme & indirectly provide a
cholinergic action by preventing the hydrolysis of
ACh released by cholinergic nerves.
So the increase concentration of ACh in the
synapse causes excessive stimulation of
cholinergic receptors throughout the CNS & PNS
having both muscarinic and nicotinic actions.
 I- Reversible
Classificati II- Irreversible: Organophosphorus Compounds
on I- Reversible
a. Carbamates
i) Tertiaryamines : Physostigmine
Indirect ii) Quaternary Ammonium compounds
Acting Neostigmine
Cholinergic Pyridostigmine
s Distigmine
Ambenonium
Demecarium
b. Alcohols : Edrophonium
c. Miscellaneous:
Tacrine, Donepezil, Galantamine, Rivastigmine
 Anticholinesterases/
(Organophosphorous Compounds)
II.
1) Therapeutically useful: Ecothiophate
Irrever
2) War Gases (Nerve gases): Saman,
sible Sarin
3) Insecticides: Parathion & Malathion
(pro-drugs)
Di-isopropyl Flurophosphate (DFP)
 Chemical Structure.
1.Physostigmine (Eserine): Natural compound, obtained
from CALABAR beans (physostigma venenosum).
2. Carbamate tertiary amine.—highly lipid soluble.
3. Carbamates having quaternary amines: Neostigmine
& others synthetic, charged,--- less lipid soluble.
4. Edrophonium: Simple alcohol, having Quaternary
ammonium group charged,--- less lipid soluble
5.Organophosphates: Synthetic(50000), highly lipid
soluble,
Ecothiophate is exception.
 Indirect cholinergic drugs.
 Primarily inhibit Acetylcholinesterase (AChE)
MOA of  Prevent the hydrolysis of endogenously
Anticholinesteras released Ach
es  Increase the concentration of ACh in the
synapses throughout the body
 So provoke the responses of ACh at
peripheral muscarinic & nicotinic receptors,
NMJ & CNS.
 The different agents differ in their binding
interactions-
 Reversible / irreversible differ in DOA.
 Butrylcholinesterase is also inhibited.
 .
ACh initially binds to
enzyme’s active sites & is
hydrolyzed in to free
choline + acetylated AChE
Acetylated enzyme
undergoes hydrolysis
-- Acetylated AChE + H2 O
 free AChE enzyme
Entire process occurs in 150
microseconds .
 Interaction of Anti-Cholinesterases
with AChE enzyme differs
according to chemical subgroups
1. Edrophonium: a quaternary alcohol
Inhibition of binds reversibly to the active site of
AChE by Anti- the enzyme.
◦ So hydrolysis of released
cholinesteras Acetylcholine by AChE enzyme
es is prevented & its amount
increases in the synapse
◦ AChE enzyme is set free in 2 –
10 minutes hence shortest DOA.
 A: Active site of AChE is carbamoylated,
ACh is not hydrolyzed. So they prolong
& intensify action of released
ACh .
MOA of
Their DOA differs, as the hydration
Carbama process takes 30 min – 6 hrs ,
with different carbamates.
te esters: Physostigmine --- -- 0.5- 2hrs
Neostigmine---------- 4hrs
Pyridostigmine--- -----6hrs
Ambenoniume--- ------68hrs
Demecarium--- --------4_6hrs
B: Neostigmine
also has direct agonistic effect on NM
receptors at motor end plate.
 Physostigmine

Important
1. CNS: Low concentrations : diffuse
pharmacologica
activation & subjective
l actions of Anti alertness
- ◦ High concentrations :
cholinesterases generalized convulsions.
:- May be followed by coma &
respiratory arrest.
1. Eye, respiratory tract, GIT, UT:
◦ Qualitatively similar to effects of
ACh.
 ↑ activity in both sympathetic &
parasympathetic ganglia: & also act on
muscarinic receptors in heart
Actions of Anti
- In the heart , PSNS predominates so bradycardia,
cholinesterases ↓ force of contraction , CO falls
In Vascular S M, sympathetic system
on CVS predominates, vasoconstriction, increased
PVR---increase in blood pressure.
The net CVS effects of moderate doses :
Bradycardia & hypertension
At toxic doses: more marked bradycardia & low

CO, hypotension .
 Physostigmine: Used in:
▫ EYE: In Glaucoma, as miotic ; in
diagnosis & treatment of Accomadative
Therapeutic esotropia (strabismus caused by
hypermetropic eye)
uses of Anti
▫ Treatment of Antimuscarinic Drug
cholinestera
Intoxication
-ses
 Physostigmine Used in
Acute Angle-closure glaucoma,
which is an emergency,
initially to lower the IOP, prior
to surgery.
▫ As eye drops in combination
with other drugs.
OOA within a few minutes.
▫ Once the raised IOP is
controlled & danger of loss of
vision is diminished, patient
can be prepared for
corrective surgery (laser
Iridotomy)
b. May be used in chronic cases (
open angle glaucoma &
some case of secondary
glaucoma)

Newer drugs like Beta blockers &

prostaglandin derivatives are
 ▫ Physostigmine is the DOC as anti-
dote for Atropine poisoning
Use in ▫ It should NOT be used in routine, as
Antimuscarinic it can also produce dangerous CNS
effects
Drug
■ Only in severe cases.
Intoxication
■ Small doses slowly I/V; 1-4mg
in adults/ 0.5-1 mg in children
may be used; after, other
measure like cold blankets & Inj
Diazepam for convulsions.
 ■ Atropine produces competitive
blockade , which is surmountable & can
Antimuscarinic be over come by increasing conc of
Ach in synapses– by giving Anti-
Drug cholinesterse.
Intoxication
■ Physostigmine --- tertiary carbamate,
lipid soluble, can reverse both peripheral
& central adverse effects of Atropine ;
which is also a tertiary compound
◦ Neostigmine/ other quaternary
compounds not used in Atropine
poisoning as they can not counter the
central adverse effects.
 Therapeutic Uses of
Neostigmine:
▫ 1. Myasthenia Gravis.
Therapeutic
Uses of ▫ 2. Reversal of NM blocking effect of
competitive Neuromuscular blockers.
Neostigmine ▫ 3. Curare poisoning.

▫ 4. Post operative abdominal

distension due to paralytic ileus
without obstruction.

▫ 5. Urinary retention without

obstruction –post op/ post partum/
after spinal cord injuries

▫ 6. Reflux esophagitis– to increase

the tone of lower esophageal
MOA of
Organophosphates
 Active site of
AChE is
phosphorylated
covalently, so it is
inhibited
irreversibly. ACh is
not hydrolyzed.
 So they intensify
action of released
ACh for prolonged
duration.
 The covalent
phosphorus
enzyme bond is
extremely stable.
 It hydrolyzes in
water very slowly
----may take
hundreds of hrs.
 Acute exposure
1. Poisoning may occur due to:
a) Inhalation of sprays or dust of pesticides.
b) Contamination of skin of agricultural
workers with pesticides.
c) Contamination of crops or food.
d) Accidental ingestion.
e) Intentional ingestion by a suicidal person
2. Poisoning may also occur due to Chemical
warfare nerve agent like Serin.
(Occurred by terrorist attack by sarin in
Tokyo subway in 1995)
 A: Initially S/S of peripheral Muscarinic excess:
◦ Abdominal cramps, Diarrhea
◦ Excessive Salivation, Lacrimation, Sweating.
Signs & ◦ Urinary frequency
Symptoms ◦
◦
Miosis,
Bronchoconstriction & increased secretions
of ◦ Hypotension, tachycardia or bradycardia
Organoph B: Peripheral Nicotinic effects:
osphate Muscle twitching, fasciculation may lead to
weakness & respiratory paralysis
Poisoning : C: CNS involvement –
Cognitive disturbances, agitation , confusion ,
seizures & coma
 1. General measures :
 Maintenance of vital signs–
ABC
Management --- respiration may particularly
be impaired
Of  Decontamination to prevent
Organophosp further absorption
 Remove from the site .
-hate  Take off the contaminated
Poisoning clothing .
 Wash the body with
alkaline solution– sodium
bicarbonate
 Blood testing may
indicate the depressed
activity of AChE---
indirect estimate of
synaptic AChE activity.
II. Specific treatment:-
 Management of Muscarinic effects:
Atropine is DOC
 It is tertiary compound, Lipid soluble
 Counteracts both the central & peripheral
effects.
• Atropine sulphate 1-2 mg I/V, every 5-15
minutes until signs of reversal i.e dry mouth,
reversal of miosis
• Atropine may have to be repeated ---- for 24-48
hrs / longer.
• In life threatening situations 1 gm /d may be
required for one month
▫ Management of Nicotinic effects (convulsions):
Inj. Diazepam 5-10mg I/V.
Management of enzyme
inhibition:-
Use of oximes /
Acetylcholinesterase Re-activators
/ Re-generators
 Pralidoxime
 Diacetylmonoxime
 Bralidoxime
▫ Oxime group (=NHO) has high
affinity for the Phosphorus atom.
▫ Oximes hydrolyze the
phosphorylated enzyme , they are
themselves phosphorylated &
AChE enzyme is set free.
◦ The AChE enzyme can then
hydrolyze the accumulated
Acetylcholine and reverses the
S/S
 Use of oximes-----
▫ Oximes should be given before
aging of the AChE -complex.
DOC: Pralidoxime by I/V infusion
gm over 15-30 min.
Pralidoxime does not cross
BBB
Diacetylmonoxime can cross
BBB
 Prevention of chemical warfare poisoning:
Pretreatment with Reversible inhibitors,
Physostigmine or Pyridostigmine may be given
along with Atropine.
Chronic Toxicity of Cholinesterase Inhibitors:
Organophosphate inhibitors can produce
Neuropathy with demyelination of axons.
(Triorthocresyl phosphate, additive in lubricating
oils)
 MCQ
Which one of the following drugs has a very high
affinity for the phosphorus atom in parathion and
is used to treat life-threatening insecticide
toxicity?
a) Atropine
b) Benztropine
c) Neostigmine
d) Pralidoxime
 ◦ An autoimmune disease affecting NMJ.
■ There is production of antibodies against the main
Myasthenia immunologic region found in Alpha subunit of NM
receptor at motor end plates of NMJ.
Gravis: ■ The antibodies reduce Nicotinic receptor function by :

1. Cross linking receptors that stimulates

their internalization & degradation.
2. Causing lysis of postsynaptic membrane.
3. Binding to receptor & inhibiting their
function
There is accelerated degradation of NM , so ACh has only
a few NM receptors to bind .
 Sign & Frequent findings are:
Symptoms ◦ Ptosis
◦ Diplopia
◦ Difficulty in speaking & swallowing
◦ Weakness of extremities.
▫ Severe disease can affect all
muscles, including respiratory
muscles.
▫ The disease resembles NM
paralysis produced by
competitive NM blockers--- so
they are C/I.
 1. Drugs
a. Anticholinesterases : Neostigmine
Treatment Pyridostigmine , Distigmine ,
of Ambenonium
myasthenia b. Immunosuppressants ----
gravis Corticosteroids, cyclosporin &
Azathioprine
2. Thymectomy: removal of thymus
in severe cases
3. Plasmapheresis/
Immunoglobulins: in severe
cases
 ▫ Long term Therapy is done by
Neostigmine
Treatment Pyridostigmine , Ambenonium, alone. DOA
short:
of MG with
Neostigmine---------- 4 hrs
Anticholin Pyridostigmine--- --- 6 hrs
esterases Ambenoniume--- ---- 6 hrs
▫ Frequent dosing required., but the dose
requirement changes so rapidly that these short
acting drugs are better.
▫ Sustained release prep should only be given at
night.
▫ If muscarinic effects are troublesome,
Atropine may be added. Generally tolerance
develops to these effects.
 ▫ To assess the adequacy of R/
with longer acting anti
Differentiatio –cholinesterases & to
n between differentiate between
cholinergic & cholinergic & myasthenic
crisis.
myasthenic
Edrophonium may be used.
crisis ▫ In very ill pts during treatment
there may be severe
myasthenia, which may be due
to :
▫ Myasthenic crisis or Cholinergic
crisis.
 ▫ To assess the adequacy of R/
with longer acting
Therapeutic anti –cholinesterases & to
Uses of differentiate between
Edrophoniu cholinergic & myasthenic crisis
(as discussed)
m
▫ For diagnosis of myasthenia
gravis
▫ Previously for
Supraventricular tachycardia,
now Adenosine or CCBs are
used.
 Drugs that precipitate
Myesthenia Gravis
The disease resembles the neuromuscular paralysis
produced by d-tubocurarine and similar
nondepolarizing neuromuscular blocking drugs
Patients with myasthenia are exquisitely sensitive to the
action of curariform drugs and other drugs that
interfere with neuromuscular transmission, eg,
aminoglycoside antibiotics.
 Treatment of Alzheimer’s disease.
Use of Anti cholinesterases: The first drug
Miscellaneous used Tecrine. (Hepatotoxic), no
longer used.
Anticholinesteras Newer drugs Donepezil, Galantamine
es , Rivastigmine are useful

Orally effective .good penetration into

CNS
Memantine: NMDA blocker is also
added after patient is better with
Anti cholinesterases.
 The only organophosphate
compound, therapeutically
Echothiophat useful
e DOA of Ecothiophate----1
week.
Used previously for Chronic
treatment of open angle
Glaucoma.
▫ Not used now due to cataract
formation
 MCQ
Which of the following drug is useful in
management of Alzheimer’s disease?

a) Edrophonium
b) Pyridostigmine
c) Physostigmine
d) Rivastigmine
 MCQ
A patient of myasthenia gravis is well controlled with anti-
cholinesterase for several yrs; presents with muscle
weakness that could reflect either a cholinergic crisis or
myasthenic crisis.
Which of the following agent is used to differentiate between
cholinergic crisis or myasthenic crisis?
a) Edrophonium
b) Neostigmine
c) Pyridostigmine
d) Physostigmine
 Many cholinomimetics are useful
clinically in conditions related to
:
Eye: Glaucoma & Accomodative
Clinical Uses ▫
esotropia, miotic
of ▫ Gastrointestinal & Urinary Tract:
Atony of gut or UB , Sialogogue, reflux
Cholinomimeti esophagitis
▫ Neuromuscular Junction: Myasthenia
c agents: Gravis
▫ Paroxysmal supraventricular
tachycardia\
▫ Antimuscarinic Drug Intoxication
▫ Reversal of NM blocking effect of
competitive NMB-
▫ Treatment of Alzheimer’s disease
▫ Cessation of smoking