What are Cholinesterase Inhibitors (ChE-Is)?

ChE-Is are a group of drugs that are used as a part of the treatment plan for mild to moderate Alzheimer's disease. The three most commonly used ChE-Is are donepezil (Aricept, Eisai, Inc), rivastigmine (Exelon, Novartis Pharmaceuticals), and galantamine (Reminyl, Janssen Pharmaceuticals). Tacrine (Cognex, First Horizon Pharmaceutical Corp.) was the first ChE-I approved for treatment of dementia ³. However, it is not recommended for use anymore due to its negative effects on the liver. These medications can provide modest and temporary improvements in memory or slow down the rate of decline in memory, improve thinking (decision making), and improve behavior ⁴.

How ChE-I's work?

In Alzheimer's disease there is too little of acetylcholine in the brain; these drugs help build up acetylcholine in the brain ⁴.

Other Uses

ChE-Is are being tested in other conditions such as vascular dementia, lewy body dementia, Down's syndrome, and multiple sclerosis ⁶. This is not a complete list just some examples.

What does it mean for Caregivers: Improvement in memory leads to improvement in behavior and thinking and improves activities of daily living. This can decrease the time and the effort needed to care for the person.

Patient	Caregiver
Slow the progression of disease Cognitive Improvement: memory, decision making Behavior improvement Activities of Daily living improvement: toileting, washing, cleaning Delay placement in the nursing home	Reduce Burden Save Time

It is important to remember that Cholinesterase inhibitors are not a cure for Alzheimer's disease. Even if a person does not get better, it does not mean that they haven't slowed down the rate at which they are declining. Studies have shown that things like memory, thinking, and behavior may improve, get better in small ways or stay the same, or get worse over time, but slower than expected. If symptoms stay the same or get worse over time but slower than expected, it can still mean that the medication is working ².

How does the doctor decide which ChE-I to use?

• No clear difference in efficacy between the three.
• Individual variation: each individual is different, no way to pick out which drug will work best for which patient ⁶.
• If one drug doesn't work, trying different drug may help ⁶.
• Main difference is the administration schedule (how often a day the drug must be taken)/compliance and drug interactions
• Decision usually based on individual patient case. Drug interactions are taken into consideration.

What does it mean for Caregivers: There is no way to decide which one will work better for the person you take care of. Thus, one may have to try using more than one drug. Dosing schedule may be important for caregivers; Aricept is the only one with once a day dosing.

Dosing and Side Effects

• Start Low, Go Slow!
• The side effects for all ChE-Is are decreased by slowly increasing the dose to the desired final dose, this is also called Titration ⁶.

Symptom	week 1 Titration	week 6 Titration
Nausea	19%	6%
Vomiting	8%	3%
Diarrhea	15%	9%

* ⁷ Table taken from MD Consult, Aricept 10 mg

On the left, the three most common side effects, nausea, vomiting, and diarrhea, which people experience while starting cholinesterase inhibitors are listed. Week 1 titration refers to people whose Aricept dose was increased over 1 week period, while Week 6 titration refers to the group of people whose Aricept dose was slowly increased over a 6 week period. In week 1 titration, 19% of the people had nausea, while in week 6 titration group with a much slower increase in dose, only 6% reported having nausea. Similarly, the percent of people reporting vomiting also decreased from 8% to 3% from week 1 titration to a much slower week 6 titration schedule. And lastly, 15% of the patient complained of Diarrhea in week 1 titration, but in a slower titration over 6 weeks only 9% reported diarrhea.

More drug is not necessarily better. Make sure not to exceed the prescribed dose.

Side Effects of Cholinesterase Inhibitors ³

Report to your prescriber or health care professional as soon as possible:

• changes in vision or balance
• diarrhea, if it is severe or does not stop
• dizziness, fainting spells, or falls
• increase in frequency of passing urine, or incontinence
• nervousness, agitation, or increased confusion
• skin rash or hives
• slow heartbeat, or difficulty breathing
• stomach pain
• sweating
• uncontrollable movements
• unusual bleeding or bruising, red or purple spots on the skin
• vomiting, if severe or does not stop
• weight loss

Usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):

• mild diarrhea, especially when starting treatment
• drowsiness
• headache
• indigestion or heartburn
• loss of appetite
• nausea/vomiting
• joint pain
• muscle cramping
• trouble sleeping
• tiredness

Nausea/vomiting, Diarrhea, and indigestion can be severe especially when the medication is first started. These can be reduced if the medications are taken WITH food.

Drug Interactions

• Some drug interactions are specific to each of the three ChE-Is, thus, the doctor may choose one over the other based on what other medications the person is taking.
• There are many potential drug interactions that can occur with both prescription and over-the-counter or non prescription medications. Two common over-the-counter medications that can interact with ChE-Is are ³:
  1. Benadryl (diphenhydramine): used for insomnia (difficulty sleeping), allergies, and cough
  2. St. John's Wart: herbal supplement used to improve mood

What does it mean for Caregivers: Do not start, stop, or change drug, dosage, or frequency without consulting the doctor of pharmacist. Before a new medication is started, always make sure the doctor is aware of all the other medications the person you take care of is taking. Even though over-the-counter medications and herbal supplements are available without prescription they still can interfere with the way prescription medications work. Always check with the pharmacist before taking any new over-the-counter medication and herbal supplement.

Cautions

Before starting a ChE-I, tell your doctor if the person you are caring for has any of the following conditions ³:

• asthma or other lung disease
• difficulty passing urine
• head injury
• heart disease, or irregular or slow heartbeat
• liver disease
• kidney disease
• low blood pressure
• tobacco smoker

• Parkinson's disease
• seizures (convulsions)
• severe headaches
• stomach or intestinal disease, ulcers or stomach bleeding
• a prior unusual or allergic reaction to donepezil, galantamine, rivastigmine, or other medicines, foods, dyes, or preservatives

What does it mean for Caregivers: It is important to tell the health care provider of any of the above mentioned conditions because they may interfere with the way ChE-Is work or may cause harm to the one you are taking care of.

Starting, Interrupting or Switching ChE-Is

• Start early: start ChE-Is as soon as diagnosis is made
• Must use the medication for at least 6 months to see if it is working or not ⁴.
• Length of Therapy: not known right now. Studies show being used for 3-5 years
• Problems with interruption of treatment: lost ground may have to start from a lower dose.
  1. Aricept has long lasting affect (hours/days) so not a problem.
  2. If Reminyl therapy has been interrupted for 3 days or more, the patient should be restarted at the lowest dose and the dose should be titrated up to the current dose 10.
  3. If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) are severe and unbearable d uring Exelon treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, treatment should be started again with the lowest daily dose and titrated properly ⁸.
• Switching drugs: Be cautious. Start at the lowest dose and increase dose slowly.

What does it mean for Caregivers: once diagnosis is made, start the treatment early.

Dosage Forms and Administration Recommendations ^{3, 8}

• Take with food to decrease side effects
• Crushing tablet: Not all tablets can be crushed.
  • Aricept: 5mg and 10 mg tablet are film coated so they should be taken whole and NOT be broken in half or crushed.
  • Reminyl: 4mg, 8mg, and 12 mg tablet. Reminyl tablets have a film coating as well, therefore, it is recommended to take them whole.
  • Exelon: 1.5mg, 3mg, 4.5mg, and 6mg capsule. Exelon comes in a capsule form and thus the contents can be sprinkled on food such as apple sauce or yogurt.
• Reminyl (4mg/mL) and Exelon (2mg/mL)are available as liquid form.

What does it mean for Caregivers: If the person you are taking care of cannot swallow a tablet whole there are two options: Reminyl and Exelon are available in liquid formulation or Exelon capsule that can be sprinkled.

Using Cholinesterase Inhibitor with Namenda

• Namenda ⁹
  1. approved in October 2003 in USA for use in moderate to severe Alzheimer's disease (ChE-Is are approved for mild to moderate Alzheimer's)
  2. different action on the brain than ChE-Is: NMDA receptor blocker and therefore can be used with ChE-Is
  3. for more detailed information see Namenda presentation in the "Medication Management and Information" section of the AlzOnline Classroom:
     Namenda presentation: http://alzonline.phhp.ufl.edu/en/classes/class_view.php?cid=61
     Namenda Fact Sheet: http://alzonline.phhp.ufl.edu/en/reading/mmi_namenda.php
• Studies done only with Aricept
• In studies when Namenda was added to patients already on Aricept , patients showed major improvement over when they were on Aricept alone. Significant improvements were seen in memory, behavior, activities of daily living, and patients tolerated the drugs well ⁵. The two side effects that were seen more in patients taking Namenda and Aricept (they had been on Aricept already) were confusion and headache ⁹.

What does it mean for Caregivers: Since Namenda works by a different mechanism than ChE-Is, when added to the treatment it can further improve memory than ChE-I alone. Improvement in memory can mean improvements in behavior and activities of daily living. This can further decrease the number of hours the caregivers work spend and the effort it takes for the caregivers.

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Page updated: 8/1/05