(20) Cholinesterase Inhibitors & NMDA Receptor Antagonists

Alzheimer’s:

• Loss of cholinergic pathways → ↓ acetylcholine

  • ACh is important for memory/mood

• Glutamate/NMDA receptor

  • Glutamate = excitatory neurotransmitter important for learning + memory

  • NMDA receptor = type of glutamate receptor

  • Normal NMDA activation → important for synaptic plasticity + neuron survival

  • Dysregulated glutamate/NMDA signaling → neuronal injury/excitotoxicity

Alzheimer’s diagnosis

Impairment in 2 of these:

• Memory

• Communication/language

• Focus/attention

• Reasoning/judgment

Alzheimer’s Pathology

Plaques + tangles

Alzheimer’s Cure

No cure. Treatment is aimed at slowing/helping symptoms rather than curing Alzheimer’s.

Alzheimer drugs

Drug	Class / structure to recognize	Main action
Donepezil	Benzylpiperidine	AChE inhibitor
Rivastigmine	Aryl/phenyl carbamate	AChE inhibitor
Galantamine	Benzazepine	AChE inhibitor
Memantine	Adamantane cage + primary amine + essential 2 methyl	NMDA antagonist

Why AChE inhibitors work

• Normally:

  • Acetylcholinesterase breaks down ACh

• Drug: AChE inhibitor

  • → ↓ ACh breakdown

  • → ↑ ACh stays around in CNS

  • → helps cognitive function

• Important:

  • AChE = the esterase we particularly want to inhibit in the CNS.

DONEPEZIL

• Benzylpiperidine

• 6-O-desmethyl ACTIVE metabolite

  • long DOA/once daily

• Higher affinity for AChE

• Greater selectivity for the brain

• Can cause sleep disturbances

  • may be taken in the morning

• Metabolism: CYP2D6 + CYP3A4

RIVASTIGMINE

• PHENYL/ARYL CARBAMATE

  • → pseudo-irreversible inhibition

  • → DOA (because of inhibition and NOT active metabolte) + delayed onset

GALANTAMINE

• BENZAZEPINE

• essential OH + tertiary amine

  • OH is essential for enzyme binding

  • Modifying the structure → ↓ activity

• Metabolism

  • Extensive metabolism - CYP2D6 + CYP3A4

  • Metabolites are inactive

  • Some drug is excreted unchanged

• Used for mild–moderate Alzheimer's

MEMANTINE

• Adamantane cage + primary amine + 2 essential methyl

• Can be combined with donepezil

  • combination = Namzaric

• Used for moderate–severe AD

DONEPEZIL - draw

RIVASTIGMINE - draw

GALANTAMINE - draw

MEMANTINE - draw