Treating Dementia and Alzheimer's Disease
Current Practices of Treating Dementia and Alzheimer's Disease
What are Cholinesterase Inhibitors?
Cholinesterase inhibitors essentially work to increase the volume and activity of neurotransmitters to improve memory, thought and judgment in patients with early to moderate stages of degenerative dementia (Dementia medication, 2015). Alzheimer's disease and other forms of degenerative dementia have shown a decreased level of activity in the neurotransmitter acetylcholine, which is a key factor in several neurological processes. Cholinesterase inhibitors, also known as acetylcholinesterase inhibitors (AChEI), prevent the acetylcholinesterase enzymes from serving their function of breaking down acetylcholine, an important neurotransmitter. This preventative action increases the activity levels and duration of acetylcholine (Dementia medication, 2015).
There are currently four cholinesterase inhibitors approved by the US Food and Drug Administration (FDA) for the treatment of dementia in Alzheimer’s disease: Tacrine (brand name Cognex, which is no longer marketed); Donepezil (generic and brand name Aricept); Rivastigmine (brand name Exelon); and Galantamine (generic, formerly marketed as Razadyne and Reminyl). All of these drugs work essentially the same way, by binding to and reversibly inhibiting acetylcholinesterase, the enzyme responsible for breaking down acetylcholine in the synapse. Through this action, these drugs increase the levels of acetylcholine in the synapse of the brain (Budson & Solomon, 2016). Memantine (brand name Namenda), also a popular treatment for dementia, is the only FDA-approved drug for the treatment of Alzheimer's disease that is not a cholinesterase inhibitor (Therapeutics: Memantine, n.d.).
In cases of early to moderate degenerative dementia, cholinesterase inhibitors have proven to be effective in improving cognitive functions (Dementia medication, 2015). However, results vary from patient to patient, with some patients showing signs of improvement, some remaining in the state of when the medicine was first used, and others showing continued signs of deterioration.
Although treatment with cholinesterase inhibitors is only approved as a therapy to improve symptoms in dementia, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits (Hampel, et al., 2018). In reassessing the role of the cholinergic system in Alzheimer’s disease, a recent scientific workgroup reviewed data charting the progression of neurodegeneration which suggested cholinergic therapy may slow brain atrophy, the shrinking of brain matter (Hampel, et al., 2018).
The following provides an overview of the most common FDA approved therapies for the treatment of dementia in Alzheimer’s disease. As always, follow your provider’s direction when beginning any new medication therapy
Donepezil is used for the treatment of mild, moderate, or severe dementia associated with Alzheimer's disease. It belongs to a class of drugs called cholinesterase inhibitors. Scientists believe that Alzheimer's disease may result from a deficiency in chemicals (neurotransmitters) used by nerves in the brain to communicate with one another. Donepezil inhibits acetylcholinesterase, an enzyme responsible for the destruction of one neurotransmitter, acetylcholine. This leads to increased concentrations of acetylcholine in the brain, and the increased concentrations are believed to be responsible for the improvement seen during treatment with Donepezil. Donepezil improves the symptoms but does not slow the progression of Alzheimer's disease. Donepezil was approved by the FDA in 1996.
Brand names: Aricept, Aricept ODT
Side effects: The most common side effects associated with donepezil are: headache, generalized pain, fatigue, dizziness, nausea, vomiting, diarrhea, loss of appetite, weight loss, muscle cramping, joint pain, insomnia, and increased frequency of urination.
Dosage: Donepezil is generally taken once daily at night prior to retiring. Its absorption is not affected by food so that it may be taken with or without food. Mild to moderate disease is treated with 5 or 10 mg once daily. Moderate to severe Alzheimer's disease is treated with 10 or 23 mg daily (Saltiel, 2016).
Memantine is used for the treatment of moderate to severe dementia associated with Alzheimer's. Dementia can be categorized into three levels of severity: mild in which patients are alert and sociable, but forgetfulness begins to interfere with daily living, moderate which often is the longest stage of the disease with deterioration of intellect, logic, behavior, and function, and severe, in which there is loss of long-term memory and language skills. Patients with severe Alzheimer's may require 24-hour care and can no longer complete basic self-care tasks including washing, eating, and using the bathroom.
Memantine's effects are independent of acetylcholine and acetylcholinesterase. Glutamate is the main excitatory neurotransmitter in the brain. It is believed that too much stimulation of nerve cells by glutamate may be responsible for the degeneration of nerves that occurs in some neurological diseases such as Alzheimer's disease. Like other neurotransmitters, glutamate is produced and released by nerve cells in the brain. The released glutamate then travels to nearby nerve cells where it attaches to a receptor on the surface of the cells called the N-methyl-D-aspartate (NMDA) receptor. Memantine blocks this receptor and thereby decreases the effects of glutamate. It is thought that by blocking the NMDA receptor and the effects of glutamate, memantine may protect nerve cells from excess stimulation by glutamate. Memantine was approved by the FDA in October 2003.
Brand names: Namenda, Namenda XR
Side effects: The most common side effects of Memantine are: Fatigue, Pain, Increases in blood pressure, Dizziness, Headache, Constipation, Vomiting, Back pain, Confusion, Sleepiness (somnolence), Hallucination, Coughing, Difficulty breathing. Memantine may cause a serious skin reaction called Stevens-Johnson syndrome.
Dosage: The usual starting dose of Memantine tablets is 5 mg once daily. The dose usually is increased to 5 mg twice daily, then 5 mg and 10 mg as separate doses daily, and finally 10 mg twice daily. Memantine can be taken with or without food. The initial recommended dose of memantine capsules is 7 mg daily. The dose may be increased weekly by 7 mg daily and the maximum dose is 28 mg daily (Ogbru, 2016).
Rivastigmine, under the brand names Exelon and Exelon Patch, is used for the treatment of mild to moderate dementia of the Alzheimer's type or mild to moderate dementia associated with Parkinson's disease. Unlike donepezil (Aricept), Exelon and Exelon Patch does not cause the blood levels of other medications to rise and increase their risk for side effects.
Brand names: Exelon, Exelon Patch
Side effects: The most common side effects Exelon and Exelon Patch are: Dizziness, Diarrhea, Headache, Stomach pain, Vomiting, Nausea, Weight loss. About one-half of patients who take Exelon and Exelon Patch develop symptoms of nausea, and about one-third vomit at least once, most commonly during the first few weeks of treatment as the dose is slowly increased. Between one in five and one in four patients lose weight during Rivastigmine therapy (about 7 to 10 pounds, on average). One in six patients experiences a loss of appetite. About one in fifty patients develops dizziness. Overall, 15 percent of patients discontinue therapy due to side effects.
Dosage: Exelon and Exelon Patch usually is taken twice daily with meals. Due to gastrointestinal side effects that can be seen early in therapy, Rivastigmine therapy is generally started at a low dose. For treating dementia associated with Alzheimer's the starting dose is 1.5 mg twice daily. It is gradually increased no more than once every two weeks. The goal usually is 3 to 6 mg twice daily. If a patient develops severe gastrointestinal side effects such as upset stomach and vomiting, he or she may need to stop taking rivastigmine for a few doses and then start taking it again at the same dose or a lower dose (Ogbru, 2018).
Galantamine is a cholinesterase inhibitor oral medication used to treat patients with Alzheimer's disease. Galantamine was approved by the FDA in 2001. The brand name of galantamine was changed in 2005 from Reminyl to Razadyne.
Brand names: Razadyne, Razadyne ER
Side effects: The most frequent side effects seen with Galantamine are: nausea, vomiting, diarrhea, and anorexia (weight loss). These side effects generally occur during the beginning of treatment or when the dose is increased. These side effects typically are mild and temporary. Taking Galantamine with food and ensuring adequate fluid intake may reduce the impact of these side effects.
Dosage: Galantamine tablets are taken twice daily, preferably with the morning and evening meals. Most often, Galantamine therapy is started with the lowest dose, 4 mg twice daily for several weeks, and then continued at 8 to 12 mg twice daily. The recommended dose when using extended release capsules is 8 to 24 mg once daily in the morning (Ogbru, 2016).
Tacrine is an cholinesterase inhibitor used to treat patients with Alzheimer's disease. Tacrine was approved by the FDA in 1993.
Brand names: Cognex
Side effects: The most common side effect of Tacrine is an increase in a liver test called alanine aminotransferase (ALT) as a result of liver damage. When a patient starts taking Tacrine, blood is drawn on a weekly basis to measure ALT. If there is an increase in blood ALT, the dosage of Tacrine can be reduced. Other side effects of Tacrine include: nausea, indigestion, vomiting, diarrhea, abdominal pain, and skin rash.
Dosage: The recommended dose is 10 to 20 mg four times daily. The maximum dose is 160 mg daily. Tacrine is usually taken on an empty stomach (one hour before, or two hours after meals) unless it causes stomach upset (Ogbru, 2016).
Namzaric (Donepezil and memantine)
Donepezil improves the function of nerve cells in the brain. It works by preventing the breakdown of a chemical called acetylcholine. People with dementia usually have lower levels of this chemical, which is important for the processes of memory, thinking, and reasoning. Memantine reduces the actions of chemicals in the brain that may contribute to the symptoms of Alzheimer's disease. Donepezil and memantine is a combination medicine used to treat moderate to severe dementia of the Alzheimer's type. Donepezil and memantine is not a cure for Alzheimer's disease. This condition will progress over time, even in people who take Donepezil.
Brand names: Namzaric, Namzaric Titration Pack
Side effects: Common side effects may include: nausea, vomiting, diarrhea, loss of appetite; headache; dizziness; or easy bruising.
Dosage: Patients stabilized on Memantine (10 mg twice a day or 28 mg ER once a day) and Donepezil 10 mg once a day: Memantine 28 mg ER-Donepezil 10 mg orally once a day in the evening. This drug should be initiated the day following the last dose of Memantine and Donepezil administered separately (Multum, 2018).
Budson, A., Solomon, P. Chapter 16 - Cholinesterase inhibitors. Memory loss, Alzheimer's Disease, and dementia (Second Edition), Elsevier, 2016, Pages 160-173. https://doi.org/10.1016/B978-0-323-28661-9.00016-0.
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Hampel, H., Mesulam, M., Cuello, A.C., Khachaturian, A.S., Vergallo, A., Farlow, M.R., Snyder, P.J., Giacobini, E., Khachaturian, Z.S. 2018. Revisiting the cholinergic hypothesis in Alzheimer’s Disease: Emerging evidence from translational and clinical research. The Journal of Prevention of Alzheimer’s Disease. http://dx.doi.org/10.14283/jpad.2018.43
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