Donepezil (Aricept)

The most-prescribed Alzheimer's drug in the world (FDA-approved 1996) — a piperidine-class reversible, highly selective AChE inhibitor with a ~70-hour half-life that lets it run once-daily and forgive missed doses. A-tier evidence is overwhelming for AD/DLB cognitive and functional benefit (Cochrane, dozens of meta-analyses). Healthy-young evidence is essentially one famous trial: Yesavage 2002, n=18 pilots in a flight simulator, 5 mg/day × 30 days, retained complex flight skills better than placebo. Real signal, but tiny, single-domain, never replicated. Side-effect profile (N/V/D early, vivid dreams + insomnia from evening dosing, bradycardia/syncope rare-serious, REM sleep behavior disorder reports, sudden-death case reports) is acceptable for an 80yo losing function — not acceptable for a 20yo MMA athlete with no cognitive deficit. For Dylan: SKIP-FOR-NOW. Cholinergic substrate (citicoline 500 mg + alpha-GPC PRN) and planned arousal/motivation drivers (modafinil, bromantane) already cover this axis without the off-target cardiac, GI, and sleep liabilities of a chronic AChEI.

Donepezil is a piperidine-class second-generation reversible acetylcholinesterase (AChE) inhibitor developed by Eisai (Japan) under code E2020 and approved by the FDA in 1996. It is the most clinically-used AChE inhibitor for Alzheimer's worldwide.

1. Highly selective AChE inhibition (no BChE)

• Donepezil is a reversible, non-competitive AChE inhibitor — binds to the peripheral anionic site of AChE, blocks acetylcholine hydrolysis, raises synaptic ACh concentration. Inhibition is reversible (binding is non-covalent), so effect tracks plasma concentration.
• ~1,000-fold selectivity for AChE over butyrylcholinesterase (BChE). This is mechanistically distinct from rivastigmine (dual AChE/BChE inhibitor) and is one reason donepezil's peripheral cholinergic side-effect profile is somewhat milder per equivalent CNS effect. BChE is more peripheral; not inhibiting it spares some peripheral cholinergic burden.
• No nicotinic activity. Unlike galantamine — which is a dual AChE inhibitor + nicotinic acetylcholine receptor allosteric potentiating ligand (APL) at α4β2 and α7 — donepezil does not directly modulate nicotinic receptors. All its CNS effect is funneled through raised synaptic ACh acting on existing M1/M2/M3/M4/M5 muscarinic and α4β2/α7 nicotinic receptors.

2. Long half-life → once-daily dosing

• Plasma half-life ~70 hours. Steady state reached in 14-21 days of daily dosing. Missed dose has minimal acute consequence — plasma level barely dips.
• High protein binding (~96%); volume of distribution ~12 L/kg. Crosses BBB readily.
• CYP2D6 + CYP3A4 substrate → metabolized to active and inactive metabolites; renal + biliary excretion.

3. Cholinergic-functional cascade (the AD rationale)

• AD pathology preferentially destroys cholinergic neurons in the nucleus basalis of Meynert — these neurons project widely to cortex and hippocampus and underwrite attention, encoding, and working memory.
• AChE inhibition raises synaptic ACh in remaining cholinergic synapses, partially compensating for the lost neurons. This is symptomatic, not disease-modifying — donepezil does not slow neurodegeneration; it props up the surviving signal.
• In healthy adults with intact cholinergic neurons, the marginal benefit is much smaller because the substrate isn't depleted to begin with — adding more ACh on top of normal ACh tone yields diminishing returns + ceiling effects.

4. Allosteric / off-target effects (debated)

• Some evidence of σ1 receptor agonism (relevance unclear; possibly contributes to mood / neuroprotective signal).
• Possible upregulation of nicotinic α7 receptor expression with chronic dosing (indirect, downstream of raised ACh tone).
• Evidence for amyloid-precursor-protein modulation in vitro — clinical relevance unclear; donepezil does not measurably reduce amyloid burden in humans.

5. Why HS (evening) dosing is standard

• Evening dosing exists because early GI side effects (nausea, vomiting, diarrhea) cluster around peak plasma concentration (3-4 hr post-dose) and are tolerated better when slept through. Trade-off: evening dosing maximizes overlap with sleep, which is why vivid dreams, nightmares, and REM-sleep disturbance are characteristic complaints. Some practitioners switch to morning dosing once the GI tolerance window passes (4-6 weeks).