Acetylcholinesterase Inhibitors Flashcards
Acetylcholinesterase
- located in synapses
- substrate selectivity: Ach
Plasma cholinesterase
- located in plasma (non-neuronal)
- substrate selectivity: Ach, succinylcholine, local anesthetics (procaine)
Acetylcholinesterase Inhibitors
- Tetraalkylammonium ions
- Simplest structures
- Bind to anionic site and block ACh binding
- Reversible
- Non-covalent (cation, Pi interaction)
- potency “caps out” at propyl group (~C3H7)
Edrophonium (Tensilon)
[Acetylcholinesterase inhibitors]
- Quaternary ammonium alcohol
- Simplest structures
- Bind to anionic site and block ACh binding
- Reversible
- Non-covalent
- large phenyl ring
- can diagnose myasthenia gravis
Neostigmine (Prostigmin)
Pyridostigmine (Mestinon)
Physostigmine (Antilirium)
[Acetylcholinesterase inhibitors]
- Carbamates
- Quaternary or tertiary ammonium groups
- Reversible (harder to reverse than typical ester)
- Covalent modification to AChE
- harder to cleave (more nitrogen rich)
- Physostigmine (structure has no charged atom, how interact with anionic site?), @ physiological pH, one N is basic enough to pick up a proton, but because not always protonated = can get into BBB easier
- The regeneration step w/ the water is slower
Isofluorophate; DFP Floropryl
Echothiophate (Phospholine Iodide)
[Acetylcholinesterase inhibitors]
-Organophosphates
IRREVERSIBLE (NO ESTER. PHOSPHONIC GROUP ATTACHED TO FLUORINE, electron deficient due to inductive effect of fluorine, nucleophilic attack on the P)
- Covalent modification to AChE
- Longer acting
- Used in the treatment of glaucoma
- irreversible not great for drugs, only use in the eye because can be administered locally, for example, treat glaucoma, acts until enzyme is recycled
Sarin
Soman
[Acetylcholinesterase inhibitors]
- Organophosphates
- Nerve gases
- IRREVERSIBLE
- Covalent modification to AChE
- Sarin, lipophilic = can enter thru skin, can age (covalent modification breaks down, portion of the modification leaves a negatively charge = harder for water or any antidote to regenerate it)
Malathion
Diazinon
[Acetylcholinesterase inhibitors]
- Organophosphates
- Insecticides (specific to insects, PRODRUGS, P in the center is bound to S, the S is more electron rich and donates electrons into phosphorus to make it a worse electron center = in insects, converted into a more electrophilic form, metabolize S into an O, easier to attack by serine, is selectively modified in insects, not mammals = not humans)
- IRREVERSIBLE
- Covalent modification to AChE
- Rapidly inactivated in mammals
- During mechanism, left with a negatively charged covalent modification to the serine, bad electrophilie, not good at receiving a nucleophilic attack by water
Why do these drugs selectively attack the cholinergic system?
- these drugs are lipophilic, nothing about the molecule will make it interact with the residues specifically, why does it attack acetylcholinesterase?
- the receptors are UBIQUITOUS in the body, catalysis occurs FAST, these molecules are not really selective for acetylcholinesterase, but acetylcholinesterase is the first to pick it up.
Antidote for AChE “poisoning”
- Pralidoxime Chloride (Protopam; 2-pyridine aldoxime methyl chloride; 2-PAM)
- Antidote for pesticide or nerve gas poisoning
- Most effective if given within a few hours of exposure
- hydroxyl group attacks like the water for catalyst regeneration, cleaves the group and allows the catalyst to be regenerated
Edrophonium
- rev
- IM, IV
- diagnostic for myasthenia gravis
Neostigmine
- rev
- IM, IV or oral
- myasthenia gravis, post operative ileus and bladder distention, surgical adjunct
Physostigmine
- rev
- IM, IV or local
- glaucoma, alzheimer’s disease, antidote to anticholinergic overdose
Tacrine (now banned)
- rev
- oral
- alzheimer’s disease
Donepezil (current agent)
- rev
- oral
- alzheimer’s disease
Isofluorophate
- irrev
- local
- glaucoma
Echothiophate
- irrev
- local
- glaucoma
Contraindications (inadvisable) to the use of parasympathomimetic drugs
- asthma
- COPD
- peptic ulcer
- obstruction of the urinary or GI tract
***Cholinergic agent side effects and toxicity
SLUD:
- salivation
- lacrimation
- urination
- defecation
Also:
- increased sweating
- decreased heart rate
- pupils constricted
- CNS activation
Treatment:
- cholinergic receptor antagonist (atropine)
- If irreversible AChE inhibitor, 2-PAM (Pralidoxime)
***Anticholinergic side effects
- dry mouth
- cant urinate
Why not use anticholinergic agents for glaucoma?
-would close canal of schlemm and would further increase the pressure
Alzheimer’s Disease
- Most common cause of dementia after age 50
- Atrophy of brain
- Widening of sulci and thinning of gyri
- Improper processing of b-amyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis
- On pathological exam:
- **Senile plaques: b-amyloid
- **Neurofibrillary tangles
-Loss of cholinergic neurons in brain
Treatment of Alzheimer’s Disease: Tacrine (Cognex)
- not positively charged, can enter BBB, no cation portion therefore does a pi - pi interaction in the anionic portion
- Bind to anionic site and block ACh binding
- Reversible
- Non-covalent
- Enhances cognitive ability
- Does NOT slow progression of disease, now banned
- Newer agent: Donepezil (Aricept)
Treatment of Alzheimer’s Disease: Rivastigmine (Exelon)
- Reversible carbamate AChE inhibitor
- Enhances cognitive ability by increasing cholinergic function
- Loses effectiveness as disease progresses
- Side Effects: Nausea, vomiting, anorexia, and weight loss
- Newer long-acting carbamate: Eptastigmine
Treatment of Alzheimer’s Disease: Galantamine (Razadyne)
- Reversible competitive AChE inhibitor
- natural extract from daffodil, no ester that participates covalently, blocks the zone, permeates BBB (no charged group)
- Extract from daffodil (Narcissus pseudonarcissus) bulbs
- Loses effectiveness as disease progresses
- May be a nicotinic receptor agonist
- Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability
Treatment of Alzheimer’s Disease: Memantine (Namenda)
- N-methyl-D-aspartate (NMDA) receptor antagonist
- NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory
- Neuronal loss in Alzheimer’s may be related to increased activity of glutamate
- May slow progression of the disease (not true)
- Favorable adverse effect profile
Treatment of Alzheimer’s Disease: On the horizon (maybe disregard this)
Acetyl-L-carnitine - neuroprotective agent
- beta-amyloid fibrillogenesis inhibitor (Alzhemed) - disease-modifying inhibitor of beta-amyloid fibril formation
- Cerebrolysin – neurotrophic and neuroprotective agent
- Phenserine – acetylcholinesterase and beta-amyloid precursor protein inhibitor
- Xaliproden – neurotrophic agent (failed trials)
