Donepezil for Alzheimer’s Disease - A Complete Guide

Overview:

Donepezil belongs to the class of cholinesterase inhibitors and tends to increase the levels of acetylcholine neurotransmitters in the circulation. By increasing the amount of available acetylcholine, Donepezil assists in enhancing the brain’s cognitive function. This action is highly beneficial to treat the clinical features and symptoms of the neurodegenerative disorder Alzheimer’s disease. Donepezil is not indicated to cure the condition entirely but is used for managing dementia (memory loss) that is associated with Alzheimer’s disease. The approval for using Donepezil for Alzheimer’s disease was provided by the United States Food and Drug Administration (USFDA) in 1996.

Dosage and Route of Administration:

Donepezil is a drug that should be taken at night before sleeping. The dosages available for Donepezil are five, 10, and 23 mg (milligrams). Five mg tablets are white in color, 10 mg tablets are yellowish, and 23 mg tablets are reddish in color.

• The starting dose prescribed to manage Alzheimer’s disease is five milligrams once daily.

• If the patient has taken the drug for four to six weeks, the dosage of Donepezil can be escalated to 10 mg one time a day.

• The dosage of Donepezil can be increased to 23 mg once daily when the patient has taken 10 mg tablets for at least three months.

Generally, for mild to moderate Alzheimer’s disease, five or 10 milligrams are prescribed. For moderate to severe Alzheimer’s disease, a dosage of 10 or 23 mg is given.

Donepezil is also available as an orally disintegrating tablet that should be placed on the tongue and allowed to dissolve with water. The dosages available for orally disintegrating tablets are five and 10 milligrams.

For Patients:

What Is Alzheimer’s Disease?

Alzheimer’s disease manifests as a neurological disorder that causes degeneration of the neurons over time. This can lead to the loss of significant brain functions like memory and cognition. Alzheimer’s disease is considered to be the most common cause of memory loss (dementia) in geriatric people. The main cause of progressive neuronal degeneration in Alzheimer’s disease is the abnormal accumulation and deposition of proteins like beta-amyloid or tau tangles. As a result, the nerve cells degrade over time and ultimately result in neuronal death. During the progression of the condition, people may find it very difficult to manage daily tasks, remember important information, and communicate effectively with others.

What Are the Levels of Alzheimer’s Disease?

• Mild Alzheimer’s Disease: It is the stage where the symptoms of the disease are nascent, and people will find it difficult to recall recent memories and perform complex tasks. In spite of all the difficulties, patients will find it easy to carry out activities without any external assistance.

• Moderate Alzheimer’s Disease: The stage of memory loss worsens at this level, and individuals complain of difficulty in recognizing even close friends and relatives. Personality and behavior changes are noted at this level. Performing daily activities requires assistance.

• Severe Alzheimer’s Disease: In the advanced stages, individuals experience profound loss of cognitive and functional abilities. They lose both verbal and nonverbal communication. They may become completely dependent on others for their care, requiring assistance with all aspects of daily living. Physical symptoms, such as difficulty swallowing, immobility, and incontinence, may also develop. Eventually, individuals with severe Alzheimer's disease may become bedridden and are at increased risk of infections and other complications.

Why Is Donepezil Given for Alzheimer’s Disease?

For optimal cognitive functions and neural communication, neurotransmitters like acetylcholine are very important. Cognitive activities like memory, attention to detail, and recall are possible by the action of acetylcholine. It also facilitates communication between neurons in different regions of the brain, enabling the encoding and retrieval of memories, the maintenance of focus, and the processing of sensory information. In between neurons and the synaptic regions, acetylcholine acts as a messenger to aid in transferring information across various regions in the brain.

Cholinergic neurons are responsible for the synthesis and release of this neurotransmitter acetylcholine. In Alzheimer’s disease, these neurons are destroyed due to abnormal deposition of other proteins in the nerve cells. As a result, the levels of acetylcholine drop, which gradually leads to cognitive and functional abnormalities.

To raise the levels of acetylcholine and improve the symptoms, cholinesterase inhibitors like Donepezil are given. Donepezil aids temporarily by impeding the degradation of acetylcholine to improve cognitive function, including memory, attention, and reasoning, in some individuals with Alzheimer's disease. Donepezil does not provide a permanent cure for the underlying condition. It just helps to slow down the progression of symptoms.

How Should Donepezil Be Taken?

The dosage of Donepezil necessary will be prescribed by the doctor based on the stage of Alzheimer’s disease. The prescribed dose of Donepezil should be taken one time daily. Donepezil is suitable to be consumed with or without food. However, the tablet should not be crushed or split before consumption.

Donepezil is also offered 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 of Donepezil is missed, patients should skip that particular dose and take it on the next dosing schedule. The prescribing doctor must be consulted before initiating the treatment if a dose is missed for more than seven days.

Overdose:

Two Donepezil tablets should not be taken at the same time. In case of an overdose of Donepezil, patients should be taken to the hospital immediately.

Overdose of Donepezil can result in a cholinergic crisis and cause manifestations like

• 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 advanced cases, people experience respiratory depression (ineffective breathing due to spasms of respiratory muscles), severe drop in blood pressure, collapse, convulsions or seizures, and ultimately death.

Drug Storage:

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

What Are the Side Effects of Taking Donepezil?

• Donepezil is known to cause bradycardia (low heart rate) or a heart block as a result of stimulation of parasympathetic activity by the vagus nerve. This occurs in individuals with or without any previous medical history of cardiac diseases.

• Ulcer formation in the stomach is a common side effect of Donepezil. In advanced stages, bleeding from the gastrointestinal tract is reported.

• Nausea is noted when individuals are prescribed an increased dosage of Donepezil.

• In some individuals, seizures (abnormal activity of neurons) are noted after Donepezil intake.

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

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 exacerbate existing cardiac issues by causing abnormal heart rhythms (atrial fibrillation or heart block) and respiratory issues like asthma or chronic obstructive pulmonary disease (disease with airway construction). So, such patients should be cautious about the symptoms of exacerbation and report to their doctors at once when the clinical features are noted.

• Donepezil can cause significant weight loss. Any changes in weight after Donepezil therapy should be informed.

• There can be episodes of vomiting after taking Donepezil.

• Donepezil can cause dizziness. So, use caution when performing tasks that require alertness.

For Doctors:

Indications:

• Donepezil is indicated to manage dementia associated 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, mannitol, and silicon dioxide.

Half-Life:

The half-life of Donepezil is around 70 hours.

Clinical Pharmacology:

Donepezil, a reversible blocker of acetylcholinesterase, is a key therapeutic agent in the management of Alzheimer's disease. By stopping acetylcholine degradation (a neurotransmitter crucial for cognitive function), Donepezil enhances cholinergic neurotransmission in the brain. This mechanism of action leads to temporary improvements in cognitive function.

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, 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. By inhibiting acetylcholinesterase (an enzyme that fragments acetylcholine), Donepezil prolongs the action of acetylcholine at the synaptic receptors, thereby enhancing cholinergic neurotransmission. This leads to temporary improvements in cognitive function, like memory and reasoning, in some individuals with Alzheimer's disease. 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 optimal response.

Drug Interactions:

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

• Drugs that enhance cholinergic activity, such as cholinesterase inhibitors (for example, Rivastigmine) or direct-acting cholinergic agonists (for example, Bethanechol), may potentiate the effects of Donepezil and increase the incidence of adverse reactions. Concurrent use of multiple acetylcholinesterase inhibitors, such as Donepezil and Rivastigmine, may increase the risk of cholinergic side effects, including bradycardia, syncope, and gastrointestinal symptoms.

• When non-steroidal anti-inflammatory agents are given with Donepezil, the incidence of gastrointestinal bleeding is very high.

• Some beta-blockers, particularly those with intrinsic sympathomimetic activity, like Pindolol, may interact with Donepezil and increase the risk of bradycardia or heart block due to additive effects on heart rate and conduction.

Guidelines for Specific Population:

Pregnancy and Lactation

Donepezil is a category C drug and is not indicated for pregnant ladies 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 only. 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.