Acetylcholinesterase Inhibitors Flashcards
What are the 2 types of Acetylcholinesterase?
AChE
BChE - Butyrylcholinesterase
What is ACh broken down into?
Its broken down by hydrolysis
Into Acetic Acid & Choline
What are the different chemical classes of AChE inhibitors?
Tetraalkylammonium ions
Quaternary ammonium alcohol - Edrophonium
Carbamates - Neostigmine
Organophosphates - Isoflurophate; DFP = Irreversible
How do Tetraalkylammonium ions work?
Non-covalent reversible inhibitors
Bind to anionic site of AChE and block activity
Not used Therapeutically
Its used Diagnostically
How does Quaternary Ammonium Alcohol work?
Short acting inhibitor
Reversible non-covalent interaction
Not used Therapeutically
Clinically used in diagnosis of MG
How do Carbamates work?
Carbamoyl esters inactivate the enzyme by transferring Carbamoyl group
They compete with ACh for active site on AChE
Reversible inhibitors
Intermediate duration of action - 0.5 - 2 hours
What class does Physostigmine belong to, and how does it work?
Carbamate
Primarily acts at the Postganglionic presynaptic synapse
Medium duration of action
Used in treatment of Glaucoma - aids in intraocular fluid drainage
Also used to treat atropine poisoning = esp in children
Used for treatment of MG & Alzheimers
How does Neostigmine work?
Medium duration of action
Acts on Neuromuscular junction
Used orally to treat MG
Can act on PNS but NOT CNS - since its too polar to cross BBB
How do Organophosphates work?
Long lasting irreversible inhibitors of AChE
Covalent attachment with AChE
Used to treat Glaucoma
Also presents as poison & nerve gas
What are some examples of bad Organophosphates?
Malathion, Diazinon
Both Highly toxic
Long acting
Covalent modification of AChE
Irreversible
Serine
Irreversible Phosphorylation
P-O bond = Very stable
What are the antidotes for Organophosphates and how do they work?
A strong nucleophile is required to cleave the P-O bond
Hydroxylamine - however too toxic for clinical use
Pralidoxime
- 1 million times more effective that Hydroxylamine
- Non-toxic
- Can’t act in CNS as can’t cross BBB
Thus ProPAM is used
- Prodrug for Pralidoxime
- Passes through BBB
- Oxidised in CNS to Pralidoxime
What are some clinically used AChE inhibitors?
Physostigmine Tacrine Donepezil Galantamine Neostigmine Pyridostigmine Edrophonium Rivastigmine
How is Glaucoma treated?
Inhibtion of AChE
Increased drainage of fluid from eye - thus relieving intra-ocular pressure
Only used as symptomatic treatment
Drugs used:
- Ecothiophate
- Physostigmine
Systemic Side effects:
- Sweating
- Blurred vision
- GI pain
- Respiratory difficulty
- Bradycardia
- Hypotension
What is MG and how is it treated?
Its the Auto-immune depletion of ACh receptors
Characterised by:
- Weakness of face, tongue
- Double vision OR drooping eyelids
- Difficulty chewing, swallowing and talking
Inhibition of AChE - increases life-time of ACh at NM junction - thus enhancing stimulation of muscle
Drugs used:
Neostigmine
Pyridostigmine
What is Alzheimer’s disease (AD) and how is it treated?
Neurodegenerative disease
Characterised by:
- Progressive cognitive impairment
- Neuropsychiatric & behavioural disturbances
- Loss of neurons in cerebral cortex
- Reduced cholinergic activity
AChEI - used to slow breakdown of ACh - thus an increased ACh compensates for loss of cholinergic neurons
Drugs used:
First gen:
- Physostigmine
- Tacrine
Second gen:
- Donepezil
- Rivastigmine
- Galantamine
ALL CAN CROSS BBB
