Vous êtes sur la page 1sur 2

-1Overview of drug treatment of Alzheimer’s disease.

It is believed that one of the causes of Alzheimer’s disease (AD) is the deficit in
neuronal acetylcholine function, especially in the hippocampus. Indeed, the clinical picture of
patients who has a toxic level of anticholinergic medications is relatively similar to dementia.
Therefore, to improve AD symptoms, acetylcholine (Ach) level should be boosted up.
One of the ways to improve Ach function is to block the enzyme acetylcholinesterase
that breaks down acetylcholine. This enzyme is most found in the hippocampus. The first
medication found to improve dementia is Tacrine. It is no longer used as first line of
treatment because of intolerable adverse reactions. The 3 most commonly used
anticholinesterase medications are: Donepezil/Aricept (FDA approved in 1997),
Rivastigmine/Exelon (2000), and Galantamine/Reminyl (2001). The most common side
effect of these medications is gastrointestinal disturbances (nausea, vomiting, diarrhea, loss
of appetite). They should be titrated up slowly and taken with meal to delay the absorption.
Rapid absorption may increase side effects. Some patients report that ginger improves GI
side effects.

Aricept is taken once a day while the other medications should be taken bid. The dose
range of Aricept is 5 to 10 mg/day, with better efficacy at the higher dose range. In term of
improving compliance, once a day dosage is better than bid dosage, especially in this
particular population prone to forgetfulness. In addition, it is not uncommon for the elderly
patients to receive multiple medications for different illnesses. Therefore, the simpler the
medication regimen, the better is compliance. Aricept should be taken in the morning if it
causes nightmares. Usually, patients should start with 5mg/d for a month then the dose can be
titrated up to 10mg/d.

Exelon, in addition to blocking acetyl cholinesterase, also blocks


butirylcholinesterase. It was found that in Alzheimer’s dementia, the neurons produce more
butirylcholinesterase than acetyl cholinesterase. Both of these enzymes break down
acetylcholine. Therefore, in theory, blocking both enzymes will be more effective in boosting
up the level of acetylcholine. Exelon is taken bid and the dose should be titrated up from 3mg
bid, with a monthly increment of 1.5mg bid, to 6mg bid. Some patients could not tolerate the
upper dose because of GI side effect. Patients may not fully benefit full efficacy if taken a
lower dose than 6mg bid as suggested by some studies. Exelon skin patch is in a
developmental phase. The patch can be administered once a day to improve side effects and
compliance. In theory, smooth release of the medication and bypass of the GI tract will
improve side effects.

Reminyl has a dual mechanism of action. In addition to blocking acetyl


cholinesterase, it also bind to the nicotinic receptors. It is postulated that this last action
improves cognition. Reminyl should be taken bid because of its short half life. It also needs
to be titrated up slowly like Exelon. The dose range is 8mg bid to 16 mg bid. An extended
formulation that can be taken once a day is recently approved by the FDA. It is found that it
has better tolerability than the immediate release form. Usually the peak level of medication
cause side effects, which is bypassed by using an extended release form.

Theorically, these 2 last medications may be more efficacious than Aricept.


However, in clinical settings, there is no significant difference in efficacy in few of the head
to head trials. The difference is seen more in tolerability and individual response to a
particular medication. These 3 above medications are FDA approved for mild to moderate
Alzheimer’s dementia.

A new class of medication is recently approved by the FDA. Memantine/Namenda,


the first in this class, is neuroprotective in preclinical models (rats studies) but its
neuroprotection is not conclusive in clinical trials. It is an uncompetitive antagonist at the
NMDA-receptor channel. The actual accepted mechanism of action of Namenda is that it
reduces the neuronal effect of abnormal glutamatergic neurotransmission to maintain or
improve cognition. Namenda is approved for moderate to severe dementia.

Nemanda is given bid. It is started with 5mg/d and titrated up weekly in 5mg
increments to a maintenance dose of 10mg bid. It can be taken with or without food. In
general, this medication is well tolerated. Dizziness is the most common symptom and is
reported as mild in clinical trials.

Nemanda can be combined with anticholinesterase medications safely. Studies show


that combination therapy at stable dose of both agents was well tolerated. Since these
medications have different mechanism of action, the combination may have better efficacy.
However, currently there have not yet trials that compare Nemanda versus Nemanda and
Aricept. The study that compared Nemanda and Aricept versus Aricept and placebo shows
that the former combination produced sustained improvement in cognition above baseline
during the 24 weeks of treatment.