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Therapeutics > Acetylcholinesterase Inhibitors > Flashcards

Acetylcholinesterase Inhibitors Flashcards

1
Q

Acetylcholinesterase

A
  • located in synapses

- substrate selectivity: Ach

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2
Q

Plasma cholinesterase

A
  • located in plasma (non-neuronal)

- substrate selectivity: Ach, succinylcholine, local anesthetics (procaine)

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3
Q

Acetylcholinesterase Inhibitors

A
  • 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)
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4
Q

Edrophonium (Tensilon)

[Acetylcholinesterase inhibitors]

A
  • Quaternary ammonium alcohol
  • Simplest structures
  • Bind to anionic site and block ACh binding
  • Reversible
  • Non-covalent
  • large phenyl ring
  • can diagnose myasthenia gravis
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5
Q

Neostigmine (Prostigmin)

Pyridostigmine (Mestinon)

Physostigmine (Antilirium)

[Acetylcholinesterase inhibitors]

A
  • 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
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6
Q

Isofluorophate; DFP Floropryl

Echothiophate (Phospholine Iodide)

[Acetylcholinesterase inhibitors]

A

-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
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7
Q

Sarin

Soman

[Acetylcholinesterase inhibitors]

A
  • 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)
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8
Q

Malathion

Diazinon

[Acetylcholinesterase inhibitors]

A
  • 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
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9
Q

Why do these drugs selectively attack the cholinergic system?

A
  • 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.
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10
Q

Antidote for AChE “poisoning”

A
  • 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
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11
Q

Edrophonium

A
  • rev
  • IM, IV
  • diagnostic for myasthenia gravis
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12
Q

Neostigmine

A
  • rev
  • IM, IV or oral
  • myasthenia gravis, post operative ileus and bladder distention, surgical adjunct
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13
Q

Physostigmine

A
  • rev
  • IM, IV or local
  • glaucoma, alzheimer’s disease, antidote to anticholinergic overdose
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14
Q

Tacrine (now banned)

A
  • rev
  • oral
  • alzheimer’s disease
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15
Q

Donepezil (current agent)

A
  • rev
  • oral
  • alzheimer’s disease
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16
Q

Isofluorophate

A
  • irrev
  • local
  • glaucoma
17
Q

Echothiophate

A
  • irrev
  • local
  • glaucoma
18
Q

Contraindications (inadvisable) to the use of parasympathomimetic drugs

A
  • asthma
  • COPD
  • peptic ulcer
  • obstruction of the urinary or GI tract
19
Q

***Cholinergic agent side effects and toxicity

A

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)
20
Q

***Anticholinergic side effects

A
  • dry mouth

- cant urinate

21
Q

Why not use anticholinergic agents for glaucoma?

A

-would close canal of schlemm and would further increase the pressure

22
Q

Alzheimer’s Disease

A
  • 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

23
Q

Treatment of Alzheimer’s Disease: Tacrine (Cognex)

A
  • 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)
24
Q

Treatment of Alzheimer’s Disease: Rivastigmine (Exelon)

A
  • 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
25
Q

Treatment of Alzheimer’s Disease: Galantamine (Razadyne)

A
  • 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
26
Q

Treatment of Alzheimer’s Disease: Memantine (Namenda)

A
  • 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
27
Q

Treatment of Alzheimer’s Disease: On the horizon (maybe disregard this)

A

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)

Therapeutics (11 decks)

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