Aricept
Aricept
Generic Name
Aricept
Mechanism
- Reversible inhibition of acetylcholinesterase (AChE) in the central nervous system (CNS) ↑ synaptic acetylcholine.
- Increases cholinergic neurotransmission, improving neuronal communication in the hippocampus and cortex.
- Selectivity for CNS over peripheral AChE reduces peripheral side effects relative to older inhibitors.
- Indirectly reduces amyloid β‑aggregation through enhanced acetylcholine‑mediated clearance.
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Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | Oral bioavailability ~70 % | Rapid absorption; peak plasma levels at ~2 h. |
| Distribution | Volume of distribution ~1.3 L/kg | CNS penetration 60–80 % of plasma concentration. |
| Metabolism | Hepatic (CYP2D6, CYP3A4) | Minor metabolites; extensive enterohepatic recirculation. |
| Elimination | Half‑life ~70 h (steady‑state) | Renal excretion 40 % unchanged; 25–30 % as metabolites. |
| Special Populations | ↓ CL in hepatic impairment; dose adjustment 5 mg q12‑24 h. | No dose change for mild–moderate renal failure. |
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Indications
- Mild‑to‑moderate Alzheimer’s disease (approved label in the U.S. and EU).
- Off‑label: mild cognitive impairment (MCI) in some countries; symptomatic management of advanced AD in selected cases.
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Contraindications
- Contraindicated in patients with known hypersensitivity to donepezil or any excipient.
- Warnings:
- Bradyarrhythmias & QT prolongation (especially with amiodarone/quinidine).
- Carcinoid syndrome: may precipitate crisis.
- Use with caution in patients with:
* Gastro‑intestinal obstruction, ileus, Crohn’s disease in steroid‑resistant patients.
* Severe hepatic disease (use 5 mg q12‑24 h, monitor).
• Drug interactions:
* Monoamine oxidase inhibitors, quinidine, verapamil, opioids, and anti‑arrhythmics can potentiate bradycardia.
* CYP3A4 inhibitors/inducers may alter plasma levels.
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Dosing
| Stage | Dose | Frequency | Notes |
| Induction | 5 mg daily | q24 h | Initiate at 5 mg to evaluate tolerance. |
| Maintenance | 10 mg daily | q24 h | Increase to 10 mg after 4–6 weeks, if tolerated. |
| Elderly/Reduced Renal Clearance | 5 mg daily | 1–2 weeks titration | Avoid rapid escalation. |
| Special | |||
| Patients on quinidine | 5 mg daily + close ECG monitoring | ||
| Patients on amiodarone | 5 mg daily | Monitor QT interval |
• Take with or without food; avoid coffee 2 h before/after dosing to reduce GI upset.
• Missed dose: Take as soon as remembered; skip if next dose <4 h away.
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Adverse Effects
| Category | Adverse Effects |
| Common (≥5 %) | Nausea, vomiting, diarrhea, anorexia, insomnia, muscle cramps, fatigue, dizziness, headache. |
| Serious (≤1 %) | Bradycardia, syncope, atrioventricular block, severe constipation (obstruction), QT prolongation, seizures in predisposed patients. |
| Rare | Hypersensitivity rash, angioedema. |
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Monitoring
- Baseline: ECG, complete blood count, liver function tests (LFTs), and serum creatinine if renal impairment suspected.
- Follow‑up:
- Every 3–4 months: ECG if on interacting drugs.
- Every 6 months: LFTs for patients with hepatic disease.
- Every 1–2 years: Cognitive assessment (ADAS‑Cog, MMSE).
- Adverse event monitoring: GI symptoms, cardiac rhythm changes, respiratory status (carcinoid crisis), and neuro‑behavioral changes.
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Clinical Pearls
- Titration is pivotal: Begin at 5 mg daily; most patients improve by *day 4–7* with tolerable side‑effect profile.
- Carcinoid crisis risk: In patients with carcinoid tumors, hold the drug until pre‑treatment with somatostatin analogues and prophylactic antihistamines.
- ECG vigilance: A baseline and follow‑up ECG should be mandatory when initiated with amiodarone, quinidine, or in those with documented conduction disease.
- Reduced dose for hepatic impairment: 5 mg daily (q12–24 h) keeps plasma levels below the upper therapeutic limit (~120 ng/mL).
- Drug–drug synergy: Donepezil can lower the effective dose of beta‑blockers; adjust accordingly.
- Non‑pharmacologic synergy: Engage cognitive stimulation therapies to maximize functional benefit; donepezil’s modest effect size (>2–3 point delay in ADAS‑Cog) is amplified with multidisciplinary care.
- Patient education: Emphasize that symptom improvement is gradual (≈3–4 weeks) and that dose increases may only occur 2–4 weeks after toleration.
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• > *Reference-friendly note*: For teaching or literature searches, use keywords such as donepezil, acetylcholinesterase inhibitor, Alzheimer’s disease, pharmacokinetics, and cardiac monitoring. This layout aligns with typical drug database entries (e.g., UpToDate, Micromedex) and supports high‑yield exam preparation.