Donepezil for Alzheimer’s Disease

What Is Donepezil?

Donepezil is a medication from the class of cholinesterase inhibitors. This medicine works by increasing the quantity of acetylcholine (a chemical found in the brain), which plays a vital role in memory and thinking. Increased concentrations of this substance improve brain cell response, which helps to improve cognitive abilities.

Although Donepezil is prescribed for Alzheimer’s patients, it is not a cure for the disease. The principal goal for using this drug is to control dementia symptoms such as memory loss and trouble with thinking.

Is Donepezil FDA-Approved?

Donepezil was approved by the United States Food and Drug Administration (USFDA) for Alzheimer’s treatment in 1996.

Dosage and Route of Administration:

Administration:

Donepezil is usually taken once daily at night, just before going to sleep.

Available Dosages and Tablet Colors:

• 5 mg tablets- white.

• 10 mg tablets- yellowish.

• 23 mg tablets - reddish.

Initial Dose: The usual starting dose for Alzheimer’s disease is 5 mg once daily.

Dose Escalation:

• After four to six weeks of treatment, the dose may be increased to 10 mg once daily.

• After taking 10 mg daily for at least 3 months, the dose may be further increased to 23 mg once daily, if required.

Dose Based on Disease Severity:

• Mild to moderate Alzheimer’s disease: 5 mg or 10 mg once daily.

• Moderate to severe Alzheimer’s disease: 10 mg or 23 mg once daily.

Other Formulations:

• Donepezil is also available as an orally disintegrating tablet (ODT) that dissolves on the tongue with water.

• ODT strengths available: 5 mg and 10 mg.

For Patients

Why Is Donepezil Given for Alzheimer’s Disease?

Donepezil is given for Alzheimer’s disease because the brain needs a chemical called acetylcholine. It helps:

• To think, remember, and focus properly.

• Brain cells communicate with each other.

• Memory, attention, and learning.

In Alzheimer’s disease, the brain cells that make acetylcholine are damaged by harmful protein buildup. This lowers acetylcholine levels and causes problems with memory, thinking, and daily activities.

Donepezil helps by slowing the breakdown of acetylcholine, allowing more of it to remain in the brain. This can improve memory, focus, and thinking in some people. However, Donepezil does not cure Alzheimer’s disease-it only helps manage symptoms and may slow their progression for a limited time.

How Should Donepezil Be Taken?

• The dosage will be prescribed by the doctor based on the stage of Alzheimer’s disease.

• The prescribed dose should be taken once daily.

• It can be consumed with or without food. However, the tablet should not be crushed or split before consumption.

• It is also available in the form of an orally disintegrating tablet, which should be placed on the tongue and allowed to dissolve with water.

Missed Dose:

If a dose is missed, skip that particular dose and take it on the next dosing schedule. Consult a doctor before initiating the treatment if a dose is missed for more than seven days.

Overdose:

• Two tablets should not be taken at the same time.

• In case of an overdose, take them to the hospital immediately.

An overdose of Donepezil can cause

• Nausea.

• Dizziness.

• Vomiting.

• Abdominal pain.

• Extreme salivation (frothy saliva).

• Sweating.

• Reduced heart rate.

• Involuntary loss of bladder control.

• Headache.

• Confusion.

• Increased gastric motility.

• Dilated pupil.

• Tremors.

• Lowered body temperature.

In severe cases, people may have trouble breathing due to muscle spasms, a sharp fall in blood pressure, collapse, seizures, and may become life-threatening.

Drug Storage

Donepezil should be maintained at a room temperature of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit).

What Are the Side Effects of Taking Donepezil?

• Bradycardia (low heart rate) or a heart block.

• Ulcer formation in the stomach.

• Bleeding from the gastrointestinal tract.

• Nausea

• Seizures.

• Patients with an existing history of asthmatic attacks may have an acute exacerbation.

Other Minor Side Effects Noted Are:

• Diarrhea.

• Vomiting.

• Headache.

• Sleeplessness.

• Muscle cramps.

• Fatigue.

• Reduced appetite.

• Joint pain.

• Depression.

• Frequent urgency to urinate.

• Facial swelling.

• Chills.

• Fever.

• Chest pain.

• Abnormal heart rhythms.

• Bloating.

• Dry mouth.

• Mouth sores.

• Dehydration.

• Tremors.

• Irritability.

• Numbness.

• Aggression and nervousness.

• Sore throat.

• Itching.

• Skin pigmentation.

• Irritation in the eyes.

• Back pain.

• Blurred vision.

What Are the Precautions to Take Before Taking Donepezil?

• Donepezil is known to worsen existing heart problems by causing abnormal heart rhythms such as atrial fibrillation or heart block.

• It can also aggravate breathing conditions like asthma or chronic obstructive pulmonary disease (a disease that causes airway narrowing).

• Therefore, such patients should be cautious of any worsening symptoms and report them to their doctor immediately.

• Donepezil may cause noticeable weight loss, and any change in body weight after starting therapy should be recorded.

• A few patients may experience vomiting as a side effect of Donepezil.

• Donepezil can cause dizziness; caution is needed when doing tasks that require full attention.

For Doctors

Indications:

Donepezil helps manage dementia symptoms in patients with mild, moderate, or severe Alzheimer’s disease.

Contraindications:

Patients who have an allergy to Donepezil or other piperidine derivatives are contraindicated.

Drug Ingredients:

Active Ingredient: Donepezil hydrochloride.

Inactive Ingredients:

• Donepezil tablets contain lactate monohydrate, cellulose, polyethylene glycol, and magnesium stearate.

• Orally disintegrating tablets of Donepezil contain mannitol, polyvinyl alcohol, and silicon dioxide.

Half-Life:

Donepezil has a long half-life of about 70 hours.

Clinical Pharmacology:

Donepezil acts by reversibly inhibiting the enzyme acetylcholinesterase. This enzyme is responsible for the degradation of acetylcholine, a neurotransmitter that plays a vital role in memory and thinking. Acetylcholine, therefore, would not be broken down in the brain, and this would temporarily enhance the brain functioning in patients suffering from Alzheimer's.

Pharmacokinetics:

• Absorption: After taking orally, Donepezil is absorbed by the gastrointestinal tract, and the peak plasma concentration of Donepezil is reached within three to four hours.

• Metabolism: Donepezil undergoes metabolism in the liver, and after hydrolysis and glucuronidation, the active metabolite 6-O-desmethyl Donepezil is formed.

• Distribution: Donepezil exhibits a high volume of distribution and easily crosses the blood-brain barrier to exert its effects on the brain. Thus, the activity of cholinesterase is inhibited.

• Excretion: Donepezil and its metabolites are excreted through urine, and about 17 percent of Donepezil excreted is unchanged in the urine.

Pharmacodynamics:

Donepezil exerts its pharmacodynamic effects by increasing the concentration of acetylcholine in the synaptic cleft. Alzheimer's disease involves acetylcholine deficiency resulting from neuronal degeneration of cholinergic neurons.

Acetylcholinesterase, an enzyme responsible for the degradation of acetylcholine, can be prevented by Donepezil's action, resulting in prolonged activity of acetylcholine at the junction of nerve cells. The memory and cognitive abilities will temporarily improve as a result of improved nerve cell interactions in the brain. Also, Donepezil may modulate other neurotransmitter systems, such as glutamate and norepinephrine, which could contribute to its therapeutic effects.

Clinical Toxicity

• Gastrointestinal manifestations seen after Donepezil intake are nausea and profuse vomiting, especially after the dose is increased from 10 mg to 23 mg. Some patients may experience peptic ulcer and upper gastrointestinal bleeding as a result of elevated cholinergic activity on the stomach, leading to excessive gastric acid secretion.

• The impact of the tenth cranial nerve (vagus nerve) on the sinoatrial and atrioventricular nodes also changes after intake of Donepezil. The parasympathetic fibers of the vagus nerve are activated to release acetylcholine. This acts on the nodes of the heart and causes a delay in the production and conduction of electrical impulses. Thus, the heart rate slows down (bradycardia), and a heart block results. This is common, especially in individuals with a previous history of abnormal heart rhythms or other cardiac diseases.

• Convulsions and seizures are noted after taking Donepezil.

• Patients may also lose weight when the dose of Donepezil is increased.

• In some patients, there can be episodes of asthmatic attacks and worsening of chronic obstructive pulmonary disease.

Donepezil can have varied actions on different individuals. While some patients may tolerate and respond well to Donepezil, some people may have adverse effects or exacerbation of existing conditions after therapy with Donepezil. So, the clinical manifestations of such adverse effects should be checked frequently.

When an overdose of Donepezil is noted, intravenous administration of Atropine sulfate should be done immediately. The dose of Atropine sulfate prescribed is one to two milligrams initially. This can be increased if the initial dose fails to achieve an optimal response.

Drug Interactions

• Donepezil interacts with other drugs, causing anticholinergic action like antihistamines and resulting in severe gastric symptoms.

• Drugs that boost cholinergic activity, such as direct-acting cholinergic agonists (like Bethanechol) or cholinesterase inhibitors (like Rivastigmine), may aggravate the effects of Donepezil and increase the risk of side effects. Using more than one acetylcholinesterase inhibitor at the same time, such as Donepezil and Rivastigmine, can raise the risk of cholinergic side effects. These may include a slow heart rate, fainting, and stomach-related problems such as nausea, vomiting, or diarrhea.

• When NSAIDs (non-steroidal anti-inflammatory drugs) are taken along with Donepezil, the likelihood of bleeding from the gastrointestinal tract increases.

• Certain beta-blockers, especially those with intrinsic sympathetic activity(a drug that mimics the fight-or-flight response), such as Pindolol, may interact with Donepezil and raise the risk of heart block or reduced heart rate.

Guidelines for Specific Population

• Pregnancy and Lactation: Donepezil is a category C drug and is not indicated for pregnant women, as there is no available data on the effects of Donepezil on fetuses. Similarly, Donepezil is also not given to lactating mothers.

• Pediatric Population: The use of Donepezil has not yet been studied for the child population.

• Geriatric Individuals: Donepezil is primarily indicated for this age group, as Alzheimer’s disease is frequently prevalent among the geriatric population. The pharmacological properties of Donepezil have been established after studying its effect only on the geriatric population. However, the comorbidities of these individuals should be assessed thoroughly before initiating Donepezil therapy to prevent adverse events.