AChE inhibitors

ANTICHOLINESTERASES:
  • These are the agents which inhibit ChE, protect ACH from hydrolysis-produce and potentiates cholinergic effects .
ACETYLCHOLINESTERASE INHIBITORS:
  • Reversible: Do not covalently modify ACHe
  1. Carbamates:
  2. Physostigmine (t)
  3. Neostigmine (q)
  4. Pyridostigmine
  5. Edrophonium
  6. Rivastigmine,
  7. Donepezil
  8. Acridine
  9. Tacrine
  • Irreversible
  1. Organophosphates
  2. Carbamates

MECHANISM OF ACTION:
  • Acetylated enzyme reacts with water very rapidly and the esteretic site is freed in fraction of milli sec.
  1. Carbamylated enzyme reacts slowly (reversible inhibitors)
  2. Phosphorylated enzyme reacts extremely slowly or not at all.
  3. OPPs attaches only to the esteretic site whereas drugs like Tacrine & Endrophonium attaches to the anionic site.
  4. Anticholinestrases act by inhibiting the action of acetylcholinesterase (an enzyme that degrades acetylcholine by causing its hydrolysis).
  • Anticholinesterases thus increase the level of acetylcholine at the neuromuscular junction.
  • Neostigmine also has some additional direct action on cholinergic receptors i.e., it depolarizes motor end plate.
  • It does not increase the release of ACH. Accumulated ACH acts on prejunctional muscarinic autoreceptors and inhibits the release of ACH.
PROPERTIES:

FEATURES PHYSOSTIGMINE NEOSTIGMINE
source Natural Synthetic
Chemistry Tertiary amine Quaternary ammonium
Oral absorption Good Poor
CNS action Present Absent
Corneal penetration Good Poor
Action on Nm Absent Present
Prominent effect Autonomic effectors Skeletal muscles
USE Miotic (Glaucoma)0.5-1mg oral/ parental
0.5-1% eye drops
Myasthenia gravis0.
5-2.5mg im/sc15-30mg orally
DOA 4-6 hrs 3-4 hrs
COMPETITIVE INHIBITORS :
EDROPHONIUM:
  • Alcohol bearing a quaternary ammonium
  • Very short duration
  • Rapidly excreted by the kidneys
  • Resembles neostigmine
  • Suitable as diagnostic agent for Myasthenia Gravis(proximal weakness of muscles, ptosis and easy fatigability)
  • Organophosphate Drugs:
MECHANISM OF ACTION:
  • Phosphorylating the active
  • Site of serine.
  • Covalent modification
  • Duration: days
PHARMACOLOGY :
  • Act at both muscarinic and nicotinic synapses
  • They potentiates synaptic transmission both parasympathetic and sympathetic
PHARMACOLOGICAL ACTIONS:
  • Central nervous system:
  1. Ache inhibitors are Lipid soluble (Physostigmine and Ops) Cross BBB
  2. Low doses: CNS activation
  3. High: coma and respiratory arrest
  • Eye, respiratory tract, GI & urinary tract:
  1. The same as muscarinic agonists (regulated by parasympathetic neurons)
  2. Cardiovascular:
  3. Complex
  4. Bradycardia, decrease contraction, cardiac output
  • Neuromuscular junction:
  1. Increase force of contraction (low dose)
  2. Muscle fasciculation and depolarizing blockade (high dose) weakness and paralysis(Neostigmine)
THERAPEUTIC USES:
  • Eye:
  1. Miosis and constriction of the ciliary muscle, and are used to treat glaucoma
  2. GI and urinary tract: Neostigmine 0.5-1mg s.c.
  3. Paralysis of the stomach and intestines(paralytic illeus)(Neostigmine)
  4. Postpartum urinary retention(Neostigmine)
  5. Neuromuscular junction:
  6. Myastenia Gravis----Neostigmine 0.5-2mg i.v.
  7. Post operative decurarization induced by NMB
  8. Cobra bite
  • CNS:
  1. Belladona poisoning
  2. Alzheimer’s disease(Donepezil )
  3. Rivastigmine, Donepezil, Galantamine and tacrine all are central cholinesterase inhibitors and are used in senile dementia of Alzheimer's desease.
  4. Overdose of phenothiazides, TCAs
  5. As d-TC & Panduronium, both are non-depolarizing muscle relaxant, so neostigmine is used to reverse the drugs.
CONTRAINDICATIONS:
  • Rivastigmine (cholinesterase inhibitor) should not be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA) as the combination is counter productive
Exam Question
  • Positive edrophonium test is the most sensitive test for the diagnosis of myasthenia gravis
  • Neostigmine is a quartarnary amounium compound
  • Neostigmine antagonizes nondepolarizing blockade by Decreasing the breakdown of Acetylcholine at the motor end plate, Preventing K+ efflux from the cell, Depolarization of the motor end plate
  • Neostigmine Helps in urinary retention
  • Neostigmine is Given to reduce post operative paralytic ileus
  • Neostigmine is Given to reduce effect of depolarising muscle relaxation
  • Donepezil is used in the treatment of Alzheimer dementia
  • Rivastigmine (cholinesterase inhibitor) should not be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA) as the combination is counter productive.
  • Neostigmine is used for reversing the adverse effect of dTC + pancuronium
  • Shortest acting anticholinesterase is Edrophonium
  • Rivastigmine & donepezil are drugs used predominantly in the management of Dementia
Don't Forget to Solve all the previous Year Question asked on AChE inhibitors