ANTICHOLINESTERASANTICHOLINESTERASESES
DR.RAHULDR.RAHULASSO.PROF, RMC.ASSO.PROF, RMC.
ANTICHOLINESTERASEANTICHOLINESTERASESS
These are the agents which inhibit These are the agents which inhibit ChE, protect ACH from hydrolysis-ChE, protect ACH from hydrolysis-produce and potentiates cholinergic produce and potentiates cholinergic effects .effects .
Acetylcholinesterase Acetylcholinesterase InhibitorsInhibitors
Reversible Reversible Do not covalently modify ACHeDo not covalently modify ACHe
a)Carbamates:a)Carbamates: b)Acridineb)Acridine Physostigmine (t)Physostigmine (t) TacrineTacrine Neostigmine (q)Neostigmine (q) PyridostigminePyridostigmine EdrophoniumEdrophonium Rivastigmine, DonepezilRivastigmine, Donepezil
IrreversibleIrreversible Organophosphates & CarbamatesOrganophosphates & Carbamates
AcetylcholinesteraseAcetylcholinesterase
Cleaved
Mechanism of actionMechanism of action Acetylated enzyme reacts with Acetylated enzyme reacts with
water very rapidly and the esteretic water very rapidly and the esteretic site is freed in fraction of milli sec.site is freed in fraction of milli sec. Carbamylated enzyme reacts slowly Carbamylated enzyme reacts slowly
(reversible inhibitors)(reversible inhibitors) Phosphorylated enzyme reacts Phosphorylated enzyme reacts
extremely slowly or not at all.extremely slowly or not at all. OPPs attaches only to the esteretic site OPPs attaches only to the esteretic site
whereas drugs like Tacrine & whereas drugs like Tacrine & Endrophonium attaches to the anionic Endrophonium attaches to the anionic site.site.
Carbamate Inhibitors: Carbamate Inhibitors: PhysostigminePhysostigmine
Physostigma venenosumPhysostigma venenosum
Natural alkaloid
Tertiary amine derivative
High lipid solubility
Rapidly absorbed from git
More marked muscarinic effect
Good CNS and corneal penetration
Carbamate Inhibitors : Carbamate Inhibitors : NeostigmineNeostigmine
Neostigmine Neostigmine synthetically prepared.synthetically prepared.
Quaternary amine Less lipid soluble Pyridostigmine Pyridostigmine
resembles neostigmine resembles neostigmine but has longer DOAbut has longer DOA
Some are used as Some are used as insecticides, Carbarylinsecticides, Carbaryl
PropoxurPropoxur
FEATURES PHYSOSTIGMINE NEOSTIGMINE
1. Source
2. Chemistry
3. Oral absorption
4. CNS action
5. Corneal penetration
6. Action on Nm
7. Prominent effect
8. USE
9. DOA
Natural
Tertiary amine
Good
Present
Good
Absent
Autonomic effectors
Miotic (Glaucoma)
0.5-1mg oral/ parental
0.5-1% eye drops
4-6 hrs
Synthetic
Quaternary ammonium
Poor
Absent
Poor
Present
Skeletal muscles
Myasthenia gravis
0.5-2.5mg im/sc
15-30mg orally
3-4 hrs
Physostigmine and Physostigmine and NeostigmineNeostigmine
Competitive Inhibitors : Competitive Inhibitors : EdrophoniumEdrophonium
Alcohol bearing a Alcohol bearing a quaternary ammoniumquaternary ammonium
Very short durationVery short duration Rapidly excreted by Rapidly excreted by
the kidneysthe kidneys Resembles Resembles
neostigmineneostigmine Suitable as diagnostic Suitable as diagnostic
agent for MGagent for MG
Organophosphate Organophosphate DrugsDrugs
b. Organophosphate b. Organophosphate InsecticidesInsecticides
Mechanism of ActionMechanism of Action
Phosphorylating the active Site of serine.
Covalent modification
Duration: days
““Aging” of Aging” of Organophosphates Organophosphates
By the loss of one of the By the loss of one of the
alkyl group the alkyl group the phosporylated enzyme phosporylated enzyme may become resistant may become resistant to hydrolysis thus to hydrolysis thus causing irreversibility.causing irreversibility.
Reactivation time of Reactivation time of carbamylated enzyme is carbamylated enzyme is less(30mins) whereas less(30mins) whereas phospory. E is more phospory. E is more than regeneration time.than regeneration time.
c. Organophosphate c. Organophosphate WeaponsWeapons
Chemical warfare agents-nerve Chemical warfare agents-nerve gasesgases
TabunTabun
Serin Serin
SomanSoman
Pharmacology of AChE Pharmacology of AChE InhibitorsInhibitors
Act at both muscarinic and Act at both muscarinic and nicotinic synapsesnicotinic synapses
They potentiates synaptic They potentiates synaptic transmission both transmission both parasympathetic and sympathetparasympathetic and sympatheticic
PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL ACTIONS
a.a. Central nervous system Central nervous system: : Ache inhibitors are Lipid soluble Ache inhibitors are Lipid soluble
(Physostigmine and Ops) Cross (Physostigmine and Ops) Cross BBBBBB
Low doses: CNS activationLow doses: CNS activation High: coma and respiratory arrestHigh: coma and respiratory arrest
b.b. Eye, respiratory tract, GI & urinary Eye, respiratory tract, GI & urinary tract:tract:
The same as muscarinic agonists The same as muscarinic agonists (regulated by parasympathetic (regulated by parasympathetic neurons)neurons)
PHARMACOLOGICAL PHARMACOLOGICAL ACTIONSACTIONS
c. c. Cardiovascular:Cardiovascular: ComplexComplex Bradycardia, decrease contraction, Bradycardia, decrease contraction,
cardiac outputcardiac output Blood vessels? No effectBlood vessels? No effect
d. d. Neuromuscular junction:Neuromuscular junction: Increase force of contraction (low Increase force of contraction (low
dose)dose) Muscle fasciculation and depolarizing Muscle fasciculation and depolarizing
blockade (high dose) weakness and blockade (high dose) weakness and paralysisparalysis
Therapeutic UsesTherapeutic Uses
A. Eye: A. Eye: Miosis and constriction of the ciliary Miosis and constriction of the ciliary
muscle, and are used to treat glaucomamuscle, and are used to treat glaucoma
B. GI and urinary tractB. GI and urinary tract: : Neostigmine 0.5-Neostigmine 0.5-1mg s.c1mg s.c..
Paralysis of the stomach and intestines Paralysis of the stomach and intestines (paralytic illeus)(paralytic illeus)
Postpartum urinary retentionPostpartum urinary retention
C. Neuromuscular junctionC. Neuromuscular junction:: Myastenia Gravis----Neostigmine 0.5-Myastenia Gravis----Neostigmine 0.5-
2mg i.v.2mg i.v. Post operative decurarization induced Post operative decurarization induced
by NMBby NMB Cobra biteCobra bite
D. CNSD. CNS:: Belladona poisoningBelladona poisoning Alzheimer’s diseaseAlzheimer’s disease Overdose of phenothiazides, TCAsOverdose of phenothiazides, TCAs
GlaucomaGlaucoma
Group of disease characterized by Group of disease characterized by progressive optic nerve damage ass. with progressive optic nerve damage ass. with raised IOT raised IOT
Treatment aims:Treatment aims:
Lower IOT by Lower IOT by :1.Reducing aqueous secretion :1.Reducing aqueous secretion
2. Promoting its drainage.2. Promoting its drainage.
TypesTypes-- Open angle glaucoma Open angle glaucoma (wide angle, chronic simple)(wide angle, chronic simple)
Closed angle glaucoma Closed angle glaucoma (narrow angle, acute (narrow angle, acute congestive)congestive)
Drugs used in glaucomaDrugs used in glaucoma Open angle glaucomaOpen angle glaucoma1.Beta adrenergic 1.Beta adrenergic
blockers-blockers-Timolol(B1+B2)Timolol(B1+B2)Betaxolol (B1)Betaxolol (B1)LevobunololLevobunolol
2.Miotics-2.Miotics-PilocarpinePilocarpinePhysostigminePhysostigmine
3.Alpha agonists3.Alpha agonistsAdrenaline, Dipivefrine, Adrenaline, Dipivefrine, apraclonidine, apraclonidine,
4.Carbonic anhydrase 4.Carbonic anhydrase inhibitorsinhibitors
5.latanoprost-PG analogue5.latanoprost-PG analogue
Angle closure Angle closure glaucomaglaucoma
Narrow iridocorneal angle and Narrow iridocorneal angle and shallowshallow
ant. Chamberant. Chamber
1.Beta adrenergic blockers1.Beta adrenergic blockers`Timolol(B1+B2)`Timolol(B1+B2)
2.Miotics2.Miotics-Pilocarpine-Pilocarpine
3.iv.20% Mannitol3.iv.20% Mannitol
4.Acetazolamide 4.Acetazolamide
Myasthenia GravisMyasthenia Gravis
Myasthenia Gravis is an autoimmune Disease that ischaracterized by a decrease in number of AChR
Myasthenia GravisMyasthenia Gravis
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction
Myasthenia Gravis – Effect Myasthenia Gravis – Effect on the Neuromuscular on the Neuromuscular
JunctionJunction
NormalNormal Myasthenia gravisMyasthenia gravis
Myasthenia GravisMyasthenia GravisSymptoms: Symptoms:
Specific muscle weakness, and not Specific muscle weakness, and not of generalized fatigue. Ocular of generalized fatigue. Ocular motor disturbances, ptosis or motor disturbances, ptosis or diplopia, Oropharyngeal muscle diplopia, Oropharyngeal muscle weakness, difficulty chewing, weakness, difficulty chewing, swallowing, or talking, limb swallowing, or talking, limb weakness. weakness.
The severity of weakness fluctuates The severity of weakness fluctuates during the day, usually being least during the day, usually being least severe in the morning and worse as severe in the morning and worse as the day progresses, especially after the day progresses, especially after prolonged use of affected muscles.prolonged use of affected muscles.
Prognosis:Prognosis:With treatment, most MG patients With treatment, most MG patients will have excellent improvement of will have excellent improvement of their muscle weakness.their muscle weakness.
Drugs Used in Myasthenia Drugs Used in Myasthenia GravisGravis
Diagnosis: Diagnosis: EdrophoniumEdrophoniumiv (improvement)iv (improvement) 5-15 min5-15 min
TreatmentTreatment: : ANTICHOLINESTERASESANTICHOLINESTERASES
Neostigmine Neostigmine 0.5-2 hours0.5-2 hours
Pyridostigmine Pyridostigmine 3-6 hours3-6 hours
CORTICOSTEROIDS AND THYMECTOMYCORTICOSTEROIDS AND THYMECTOMY
Alzheimer’s Disease - Alzheimer’s Disease - SymptomsSymptoms
AD is a neurodegenerative AD is a neurodegenerative disorder Charcterized by disorder Charcterized by progressive dementia progressive dementia primarily affecting cholinergic primarily affecting cholinergic neurones in the brain.neurones in the brain.
Alzheimer’s Disease PathologyAlzheimer’s Disease Pathology
Cholinergic NeuronsCholinergic Neurons
AChE Inhibitors Used to AChE Inhibitors Used to Treat Alzheimer’s DiseaseTreat Alzheimer’s Disease
The first to The first to become available become available
The first to The first to become passbecome passéé
AChE Inhibitors Used to AChE Inhibitors Used to Treat Alzheimer’s DiseaseTreat Alzheimer’s Disease
Are They Worth It?Are They Worth It?
Effect of Rivastigmine in Alzheimer’s Effect of Rivastigmine in Alzheimer’s DiseaseDisease
RivastigmineRivastigmine Placebo Placebo
ImprovedImproved 37%37% 20% 20%
Adverse EffectsAdverse Effects 23%23% 7% 7%
Toxicity of AChE Toxicity of AChE InhibitorsInhibitors
Organophosphorous Organophosphorous poisoningpoisoningAutonomic Nervous System:Autonomic Nervous System:
Eye: Eye: Miosis, blurred visionMiosis, blurred vision
Cardiovascular: Cardiovascular: Bradycardia, hypotensionBradycardia, hypotension
Glands: Glands: Extreme salivation, lacrimation, Extreme salivation, lacrimation, sweatingsweating
Gastrointestinal:Gastrointestinal: Anorexia, nausea, vomiting, Anorexia, nausea, vomiting, diarrheadiarrhea
Respiratory: Respiratory: Bronchoconstriction, Bronchoconstriction, bronchial secretion bronchial secretion
Organophosphorous Organophosphorous poisoningpoisoning
Skeletal MuscleSkeletal Muscle:: Fasciculations, weakness, paralysis Fasciculations, weakness, paralysis
CNSCNS:: Ataxia, confusion, convulsions, coma, Ataxia, confusion, convulsions, coma,
paralysisparalysis
Death:Death:
Respiratory depression due to Respiratory depression due to
bronchoconstriction, bronchoconstriction, increased secretions, increased secretions,
paralysis of diaphragm and paralysis of diaphragm and intercostal muscles intercostal muscles
and central respiratory depressionand central respiratory depression
Treatment of AChE Treatment of AChE PoisoningPoisoning
Atropine:Atropine:Reverses muscarinic but not Reverses muscarinic but not
nicotinicnicotinic 2 mg i.v. repeated every 10 mins 2 mg i.v. repeated every 10 mins
till signs of full atropinization i.e till signs of full atropinization i.e dilatation of pupils ,tachycardia.dilatation of pupils ,tachycardia.
Pralidoxime (2-PAM):Pralidoxime (2-PAM):
Mechanism of Action of Mechanism of Action of PralidoximePralidoxime
Clinical pharmacology of Clinical pharmacology of acetylcholinesterase inhibitorsacetylcholinesterase inhibitors
DrugType ofinhibition
Route ofadministrationClinical Use
Edrophonium Rev IM or IV Diagnostic for Myasthenia GravisNeostigmine Rev IM, IV, or oralMyasthenia Gravis, post-operative ileus and
bladder distention, surgical adjunctPhysostigmine Rev IM, IV, or localGlaucoma, Alzheimer’s disease, antidote to
anticholinergic overdoseTacrine Rev Oral Alzheimer’s diseaseDonepezil Rev Oral Alzheimer’s diseaseIsofluorophate Irrev Local GlaucomaEchothiophate Irrev Local Glaucoma
