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Acetylcholinesterase (Ache) Inhibitors

Renu Maurya

ACETYLCHOLINESTERASE (AchE) INHIBITORS

ACETYLCHOLINESTERASE (AchE) INHIBITORS/ANTI-CHOLINESTERASES

  • Drugs inhibiting Anti-cholinesterase enzyme (Anti-ChE).
  • Thereby,
    • Protects Ach from hydrolysis potentiating cholinergic effects.
    • Increases it’s availability.
    • Prolongs acetylcholine (Ach) actions.

DRUGS & CLASSIFICATION:

Classified into reversible & irreversible grp. of drugs.

  • Reversible: Do not covalently modify ACh’esterase.

Carbamates: 

  • Physostigmine (t)  
  • Neostigmine (q)
  • Pyridostigmine
  • Edrophonium
  • Rivastigmine
  • Donepezil
  • Acridine
  • Tacrine
  • Irreversible
    • Organophosphates 
    • Carbamates 

MECHANISM OF ACTION:

  • Anticholinesterases act by inhibiting acetylcholinesterase enzyme action.
    • Acetylcholinesterase enzyme degrades acetylcholine by hydrolyzing.
    • Thus increasing acetylcholine level at NMJ.
PROPERITIES:
FEATURES PHYSOSTIGMINE NEOSTIGMINE
source
 Natural Synthetic
Chemistry
 Tertiary amine Quaternary ammonium
Oral absorption Good  Poor
CNS action Present – Crosses BBB – Due to high lipid solubility Absent – Poor CNS penetration.
Corneal penetration Good  Poor
Action on Nm Absent  Present
Prominent effect Autonomic effectors Skeletal muscles
USE Miotic (Glaucoma)

0.5-1% eye drops

0.5-1mg oral/ Parental

 

Used as specific antidote in belladona poisoining.

 

Post-operative paralytic ileus.

Postoperative urinary retention.

 Myasthenia gravis

0.5-2.5mg m/sc.

15-30mg orally

Cobra bite – Due to direct Nm receptor agonist action.

Atrophine combination therapy preferred – Counteract adverse effects due to muscarinic receptor stimulation.

Reversal of non-depolarizing muscle relaxants.
DOA 4-6 hrs  3-4 hrs

COMPETITIVE INHIBITORS:

EDROPHONIUM:

  • Alcohol bearing a quaternary ammonium.
  • Resembles neostigmine
  • Very short duration
  • Rapidly excreted by kidneys
  • Suitable as diagnostic agent for Myasthenia Gravis – Tensilon test:
    • 1-2 mg i.v. – Improves skeletal muscle activities if it myasthenia gravis, worsens if due to cholinergic actions.

PYRIDOSTIGMINE:

  • Longer acting than neostigmine.

TACRINE:

  • DOC for Alzhemier’s disease.
  • More limitations (frequent drug dosing requirements, hepatotoxicity, diarrhea) makes it less preferrable.

RIVASTIGMINE:

  • Approved for dementia treatment in Alzhemier’s & Parkinson’s Disease.

ORGANOPHOSPHATE (OPP) Drugs:

MECHANISM OF ACTION:

  • Phosphorylating the active
  • Site of serine.
  • Covalent modification

PHARMACOLOGY:

  • Act at both muscarinic and nicotinic synapses.
  • They potentiate synaptic transmission both parasympathetic & sympathetic.

ACTIONS:

Central nervous system: 

  • Ache inhibitors are lipid soluble (Physostigmine & OPP) – Hence, easily cross BBB
  • Low doses: CNS activation
  • High: Coma & respiratory arrest

Eye, respiratory tract, GI & urinary tract:

  • Used as muscarinic agonists
  • Regulated by parasympathetic neurons.

Cardiovascular:   

  • Complex
  • Bradycardia, decrease contraction, cardiac output 

Neuromuscular junction:

  • Low dose – Increase force of contraction.
  • High dose – Muscle fasciculation, depolarizing blockade, weakness and paralysis (Neostigmine)

THERAPEUTIC USES:

Eye:

  • Miosis & ciliary muscle constriction.
  • Used to treat glaucoma

GI & urinary tract: 

  • Neostigmine 0.5-1mg s.c.
  • Paralysis of stomach & intestines – Paralytic ileus- Neostigmine)
  • Postpartum urinary retention (Neostigmine)

Neuromuscular junction:

  • Myasthenia Gravis – Neostigmine 0.5-2mg i.v.
  • Post operative decurarization induced by NMB
  • Cobra bite

 CNS:

  • Belladona poisoning
  • Alzheimer’s disease (Donepezil )
    • Rivastigmine, Donepezil, Galantamine and tacrine all are central cholinesterase inhibitors and are used in senile dementia of Alzheimer’s desease.
  • Overdose of phenothiazines, TCAs
  • As d-TC & Pancuronium, both are non-depolarizing muscle relaxant, hence neostigmine used for drug reversal effect.

CONTRAINDICATIONS:

  • Rivastigmine (cholinesterase inhibitor) not to be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA), since combination is counter-productive.

Exam Important

  • Positive edrophonium test is most sensitive test for diagnosis of myasthenia gravis.
  • Neostigmine is a quaternary ammonium compound.
  • Neostigmine antagonizes nondepolarizing blockade by decreasing acetylcholine breakdown at motor end plate, preventing K+ efflux from cell & depolarization of 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 treatment of alzheimer dementia.
  • Rivastigmine (cholinesterase inhibitor) should not be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA) as combination is counterproductive.
  • Neostigmine is used for reversing adverse effect of DTC + pancuronium.
  • Shortest acting anticholinesterase is Edrophonium.
  • Rivastigmine & Donepezil are drugs used predominantly in management of dementia.

 

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