Download - Class 2 Pharmacology of Cholinergic System
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Anticholinesterases[Indirectly acting cholinomimitics]
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anti-ChE agents
[Indirectly acting cholinomimitics]
Acetylcholinesterase (AChE) terminates the action of ACh.
Inhibitors of AChE, or anti-ChE) agents, ACh to accumulate
Produce effects equivalent to excessive stimulation of cholinergic
receptors
This is the basis of clinical use and adverse effects of anti-ChE.
Since cholinergic neurotransmission is widely distributed across
animal species, anti-ChE agents are also effective toxins (e.g.,
agricultural insecticides, pesticides,
Also regrettably, chemical warfare ³nerve gases´
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Organophosphates: Carbamates:
Echothiophate Carbaryl*
Parathion* Propoxur *
Malathion*
Diazinon*
Tabun#
Sarin#
Soman#
*Insecticides# Nerve gases-
chemical warfare
Irreversible anticholinesterases
Anticholinesterases
[Indirectly acting cholinergics]
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Inactivation of acetylcholine
Acetylcholinesterase
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Carbamylation [Therapeutic]
and
Phosphorylation [Poisoning]
Reaction
Very Slow
Or
irreversible
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AChE inhibitors -Three groups
Edrophonium
Bind-Anionic
site
Termination bydiffusion
Short acting
Carbamates
Bind to both
sites
Terminationhydrolysis
Long acting
Oximes not
effective in
poisoning
O.Phosphates
Bind to
esteratic site
Terminationvery, very slow
or not at all
Oximes are
effective
[Before aging]
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AChE inhibitors ±Ph.actions
Similar to agonists
Lipid soluble[Physo, O.P]- Muscarinic
actions, CNS actions, Stimulate ganglion
and less action at NMJ
Lipid insoluble[Neostigmine]-Prominent action at NMJ, stimulate
ganglion Less muscarinic, less CNS
effects
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AChE inhibitors -PK
Physostigmine
absorbed from the GI tract, subcutaneous tissues,
and mucous membranes.
Conjunctival instillation of solutions of the drug
may result in systemic effects if measures (e.g.,
pressure on the inner canthus) are not taken toprevent absorption from the nasal mucosa.
Crosses BBB
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AChE inhibitors -PK
Neostigmine and pyridostigmine
Absorbed poorly after oral administration,
Larger doses are needed than by the parenteral
route
Organophosphorus anti-ChE-Highly lipid soluble
Absorbed from all sites
More toxic
Children lack enzymes for metabolism
Very toxic
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NeostigminePhysostigmine
Natural alakloid
Tertiary amine
Lipid soluble
Oral absorption+++CNS actions++
Penetrates cornea
No direct action on NM
RecPredominant
autonomic effects
Use-Glaucoma
Oral dose-0.5-1mg.
Synthetic
Quaternary amine
Not lipid soluble
Oral absorption-poor No CNS actions
Does not penetrte
Direct action on NM
Rec+++Predominant sk.mucle
action
Use-Myesthenia gravis
15-30mg
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REVERSIBLE
ANTICHOLINESTERASES-USES
MIOTIC
Glaucoma
Reverse the effect of mydriatics
Alternated with mydriatics-to
break irido-corneal adhesions
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REVERSIBLE
ANTICHOLINESTERASES-USES
Postoperative paralytic ileus/urinary retension
[Neostigmine]
P
ostoperative decurarization [Neostigminepreceded by Atropine]
Cobra bite [Neostigmine+Atropine]
Belladona [Atropine] poisoning-P
hysostigmine Alzheimer¶s disease-Tacrine, rivastgmine,
donepezil, galantamine [cerebroselective] Drug over dosage-e.g. TCA
Myesthenia gravis
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Some ADEs of cholinergic drugs
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Myasthenia gravis
Neuromuscular disorder characterized
by weakness and fatigability of skeletal
muscles.
Decrease in the number of available
acetylcholine receptors at NM junctions
Due to an antibody-mediated
autoimmune attack.
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MG-treatment
Anticholinesterase Medications
Thymectomy Immunosuppression
Plasmapheresis Intravenous Immunoglobulin
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Pharmacotherapy-MG
For diagnosis
Edrophonium
For treatment Pyridostigmine, neostigmine, and
ambenonium
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Pharmacotherapy-MG
Edrophonium test:
i.v.2 mg of edrophonium chloride45
seconds 8 mg if the first dose is withouteffect Brief improvement in strength
D
ecrease in strength indicates cholinergiccrisis [ Overdose of anticholinesterases in tt]
Improvement signifies myasthenic crisis
[Under dose of anticholinesterases in tt]
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Pharmacotherapy-MG««..
Pyridostigmine, neostigmine, and ambenonium
Baseline recordings are made for grip strength,
Oral pyridostigmine (30±60 mg), neostigmine
(7.5±15 mg), or ambenonium (2.5±5 mg).
After an hour or longer in the basal state, the drug
is readministered at 1.5 times the initial amount,
This sequence is continued, with increasing
increments of one-half the initial dose, until an
optimal response is obtained.
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Pharmacotherapy-MG««..
The dose may vary from day to day; physical and
emotional stress, infections,
Menstruation usually necessitate an increase inthe frequency or size of the dose.
Patients can be taught to modify their dosage
regimens according to their changing
requirements.
Pyridostigmine SR -180 mg-60 mg is released
immediately and 120 mg over several hours;
maintaining patients for 6±8-hour
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Generalized
weakness in the trunk,
arms, and legs.
Eye blink test-ptosisafter blinking for
number of minutes
Grip test-Significant
weakening of grip after
squeezing
Arm raise test
Vital parameters
Pyridostigmine
Generalized weakness in the trunk,
arms, and legs.
Eye blink test-ptosis after blinking for
number of minutes
Grip test-Significant weakening of
grip after squeezing
Arm raise test
Vital parameters
Generalized
weakness in the trunk,
arms, and legs.
Eye blink test-ptosisafter blinking for
number of minutes
Grip test-Significant
weakening of grip after
squeezing
Arm raise test
Vital parameters
Pyridostigmine 1.5 times
Return
to
baseline
Repeat tests till baseline reached
Decide adequate response reached
or notNot adequate
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Drug interactions in MG