- These are the agents which inhibit ChE, protect ACH from hydrolysis-produce and potentiates cholinergic effects .
- Reversible: Do not covalently modify ACHe
- Physostigmine (t)
- Neostigmine (q)
MECHANISM OF ACTION:
- Acetylated enzyme reacts with water very rapidly and the esteretic site is freed in fraction of milli sec.
- Carbamylated enzyme reacts slowly (reversible inhibitors)
- Phosphorylated enzyme reacts extremely slowly or not at all.
- OPPs attaches only to the esteretic site whereas drugs like Tacrine & Endrophonium attaches to the anionic site.
- 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.
|Chemistry||Tertiary amine||Quaternary ammonium|
|Action on Nm||Absent||Present|
|Prominent effect||Autonomic effectors||Skeletal muscles|
|USE||Miotic (Glaucoma)0.5-1mg oral/ parental
0.5-1% eye drops
5-2.5mg im/sc15-30mg orally
|DOA||4-6 hrs||3-4 hrs|
- 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:
- Phosphorylating the active
- Site of serine.
- Covalent modification
- Duration: days
- Act at both muscarinic and nicotinic synapses
- They potentiates synaptic transmission both parasympathetic and sympathetic
- Central nervous system:
- Ache inhibitors are Lipid soluble (Physostigmine and Ops) Cross BBB
- Low doses: CNS activation
- High: coma and respiratory arrest
- Eye, respiratory tract, GI & urinary tract:
- The same as muscarinic agonists (regulated by parasympathetic neurons)
- Bradycardia, decrease contraction, cardiac output
- Neuromuscular junction:
- Increase force of contraction (low dose)
- Muscle fasciculation and depolarizing blockade (high dose) weakness and paralysis(Neostigmine)
- Miosis and constriction of the ciliary muscle, and are used to treat glaucoma
- GI and urinary tract: Neostigmine 0.5-1mg s.c.
- Paralysis of the stomach and intestines(paralytic illeus)(Neostigmine)
- Postpartum urinary retention(Neostigmine)
- Neuromuscular junction:
- Myastenia Gravis----Neostigmine 0.5-2mg i.v.
- Post operative decurarization induced by NMB
- Cobra bite
- 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 phenothiazides, TCAs
- As d-TC & Panduronium, both are non-depolarizing muscle relaxant, so neostigmine is used to reverse the drugs.
- Rivastigmine (cholinesterase inhibitor) should not be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA) as the combination is counter productive
- 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