Donepezil

Usage

Donepezil is prescribed for the symptomatic treatment of mild, moderate, and severe dementia of the Alzheimer’s type. It is classified as a cholinesterase inhibitor, specifically an acetylcholinesterase inhibitor. Donepezil works by increasing the levels of acetylcholine in the brain. Acetylcholine is a neurotransmitter essential for learning and memory. In Alzheimer’s disease, there is a deficiency of acetylcholine, and donepezil helps to restore its levels by inhibiting the enzyme that breaks it down.

Alternate Names

Donepezil is also known as donepezil hydrochloride. Brand names for donepezil include Aricept, Adlarity, and various generic formulations.

How It Works

Pharmacodynamics: Donepezil selectively and reversibly inhibits acetylcholinesterase (AChE), the enzyme primarily responsible for the hydrolysis of acetylcholine (ACh) in the synaptic cleft. This inhibition leads to increased ACh concentrations at cholinergic synapses, enhancing cholinergic neurotransmission, which is crucial for cognitive functions.

Pharmacokinetics:

• Absorption: Donepezil is well-absorbed after oral administration, reaching peak plasma concentrations within 3 to 4 hours. Food does not affect its absorption.
• Metabolism: It is extensively metabolized in the liver by CYP450 enzymes, primarily CYP2D6 and CYP3A4, to several metabolites, some of which possess weak AChE inhibitory activity.
• Elimination: Donepezil is primarily eliminated through hepatic metabolism, with a small portion excreted unchanged in the urine. The elimination half-life is approximately 70 hours, resulting in once-daily dosing.

Mode of Action: Donepezil binds reversibly to AChE at the cholinergic synapse, preventing the breakdown of ACh. This increases the concentration and duration of ACh action in the synaptic cleft, enhancing cholinergic neurotransmission and improving cognitive function. It does not directly affect the synthesis or release of ACh.

Elimination Pathways: Donepezil is primarily metabolized by hepatic CYP2D6 and CYP3A4 enzymes. A small amount is excreted unchanged in the urine, and some metabolites are also excreted renally.

Dosage

Standard Dosage

Adults:

Initial dose: 5 mg orally once daily at bedtime. After 4-6 weeks, the dose may be increased to 10 mg once daily. In moderate to severe Alzheimer’s, the dose can be further increased to 23 mg once daily after 3 months on 10 mg/day, if clinically warranted.

Children:

Donepezil is not recommended for use in children. Safety and efficacy have not been established in pediatric populations for Alzheimer’s disease. Although some small studies have investigated donepezil in children with other conditions like autism spectrum disorder and Down syndrome, its use in these populations is not routinely recommended and requires specialist consultation.

Special Cases:

• Elderly Patients: No dose adjustment is generally required based on age alone. However, close monitoring for side effects is recommended, especially in frail elderly patients.

• Patients with Renal Impairment: No dosage adjustment is necessary for mild to moderate renal impairment. For patients on hemodialysis, start with 2.5 mg daily and titrate to 5 mg based on clinical response.

• Patients with Hepatic Dysfunction: No dosage adjustment is necessary for mild to moderate hepatic impairment. Donepezil is not recommended in severe hepatic impairment.

• Patients with Comorbid Conditions: Exercise caution in patients with bradycardia, sick sinus syndrome, or cardiac conduction abnormalities, as donepezil can exacerbate these conditions. Caution is also warranted in patients with peptic ulcer disease or a history of seizures.

Clinical Use Cases

Donepezil is specifically indicated for Alzheimer’s dementia and has no established role in intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations.

Dosage Adjustments

Dose modifications are primarily based on tolerability and clinical response. Start with the lowest dose and gradually titrate upwards. Consider reducing the dose or discontinuing if significant side effects occur.

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, loss of appetite, weight loss, insomnia, dizziness, headache, muscle cramps, fatigue, abnormal dreams.

Rare but Serious Side Effects:

Bradycardia, syncope, seizures, gastrointestinal bleeding, peptic ulcer disease, urinary retention, severe skin reactions (with transdermal patches), hepatotoxicity, rhabdomyolysis.

Long-Term Effects:

The long-term effects of donepezil are primarily related to its chronic use in managing Alzheimer’s disease. These effects are mostly related to its efficacy in slowing cognitive decline.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include severe vomiting, syncope, bradycardia, seizures, gastrointestinal bleeding, and urinary retention. These require immediate intervention and possibly discontinuation of therapy.

Contraindications

• Hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation.
• Severe hepatic impairment.
• Patients with known prolonged QT interval syndrome or taking other QT prolonging medications.

Drug Interactions

• Cholinergic Agonists: Increased cholinergic effects.
• Anticholinergics: Reduced efficacy of donepezil.
• Non-steroidal anti-inflammatory drugs (NSAIDs): Increased risk of gastrointestinal bleeding.
• CYP2D6 and CYP3A4 inhibitors (e.g., ketoconazole, fluoxetine): Increased donepezil levels.
• CYP2D6 and CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine): Decreased donepezil levels.
• Beta-blockers: Increased risk of bradycardia.
• Neuromuscular blocking agents (e.g., succinylcholine): Prolonged neuromuscular blockade.
• QT prolonging drugs (e.g., amiodarone, thioridazine): Increased risk of QT prolongation and torsades de pointes.

Pregnancy and Breastfeeding

• Pregnancy: Donepezil is Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: It is unknown if donepezil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if donepezil is administered to a nursing woman. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Drug Profile Summary

• Mechanism of Action: Reversibly inhibits acetylcholinesterase, increasing acetylcholine levels in the brain.
• Side Effects: Nausea, vomiting, diarrhea, insomnia, dizziness, headache, muscle cramps; rarely: bradycardia, syncope, seizures, GI bleeding.
• Contraindications: Hypersensitivity, severe hepatic impairment.
• Drug Interactions: Anticholinergics, NSAIDs, CYP2D6/3A4 inhibitors/inducers, beta-blockers, QT prolonging drugs.
• Pregnancy & Breastfeeding: Category C; unknown if excreted in breast milk. Exercise caution.
• Dosage: Initial: 5 mg qHS, may increase to 10 mg qHS after 4-6 weeks; maximum 23 mg/day in moderate-severe AD after 3 months on 10mg/day, if clinically warranted.
• Monitoring Parameters: Cognitive function, behavioral changes, cardiovascular status (heart rate, ECG), gastrointestinal symptoms, liver function tests.

Popular Combinations

Donepezil is often used as monotherapy. Combination therapy with other drugs for Alzheimer’s, such as memantine (NMDA receptor antagonist), may be considered in some cases, particularly in moderate to severe disease. However, the evidence for increased benefit is limited, and the risk of side effects may be higher.

Precautions

• General Precautions: Monitor for cardiovascular, gastrointestinal, and genitourinary side effects. Assess cognitive function and behavioral changes regularly.
• Specific Populations:
  • Pregnant Women: Use with caution only if clearly needed.
  • Breastfeeding Mothers: Unknown if excreted in breast milk. Exercise caution.
  • Children & Elderly: Not recommended for children. Close monitoring in the elderly.
  • Lifestyle Considerations: Alcohol may potentiate side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Donepezil?

A: The initial dose is 5 mg orally once daily at bedtime. After 4-6 weeks, this may be increased to 10 mg daily. For moderate to severe Alzheimer’s disease, a dose of 23mg once daily can be administered if the patient has already been on 10mg once daily for 3 months, if clinically warranted.

Q2: How should Donepezil be administered?

A: Orally, once daily, preferably at bedtime due to potential for dizziness or insomnia. It can be taken with or without food. Orodispersible tablets are available and should be placed on the tongue to dissolve before swallowing.

Q3: What are the common side effects of Donepezil?

A: Common side effects include nausea, vomiting, diarrhea, loss of appetite, insomnia, dizziness, headache, muscle cramps, and fatigue.

Q4: What are the serious side effects of Donepezil?

A: Serious side effects include bradycardia, syncope, seizures, gastrointestinal bleeding, and difficulty urinating. Seek immediate medical attention if these occur.

Q5: Can Donepezil be used in patients with liver or kidney problems?

A: No dosage adjustment is needed for mild to moderate hepatic or renal impairment. Donepezil is not recommended in severe hepatic impairment. For patients on hemodialysis, a lower starting dose and careful titration are advised.

Q6: Does Donepezil interact with other medications?

A: Yes, Donepezil can interact with various medications, including anticholinergics, NSAIDs, certain antibiotics, antifungals, antidepressants, and drugs that affect heart rhythm. Always provide a complete medication history to your physician.

Q7: Can Donepezil be used during pregnancy or breastfeeding?

A: Donepezil is Pregnancy Category C. Its use during pregnancy should be carefully considered, weighing the potential benefits against the potential risks to the fetus. It is unknown if donepezil is excreted in breast milk; use with caution during breastfeeding.

Q8: Can Donepezil cure Alzheimer’s disease?

A: No, Donepezil does not cure Alzheimer’s disease. It is a symptomatic treatment aimed at improving cognitive function and slowing the progression of the disease.

Q9: How long should Donepezil be taken?

A: The duration of Donepezil treatment is determined by the physician based on the patient’s clinical response and tolerance to the medication. Regular assessments of cognitive function and overall benefit are essential to guide treatment decisions.

Q10: What should be done if a dose of Donepezil is missed?

A: If a dose is missed, skip the missed dose and take the next dose at the usual time. Do not double the dose to catch up.