Levodopa and dopamine agonists (together called "dopaminergic drugs")
are the main tools used for the treatment of Parkinson's disease. But
they are not the only tools in the tool chest—several other types of
drugs may each be useful in the right patient. These agents are
discussed in this article. A future article will look at the
dopaminergic drugs in detail.

Anticholinergics
The anticholinergics include trihexyphenidyl (Artane®), benztropine
(Cogentin®), and ethopropazine (Parsitan®). This class of drugs has
been used to treat Parkinson's disease since at least the 19th
century, when an extract of the belladonna plant, which had
anticholinergic properties, was used for quieting parkinsonian
tremor. Anticholinergics are believed to work by rebalancing the two
principal brain systems that control movement—the dopaminergic system
(which uses the neurotransmitter dopamine) and the cholinergic system
(which uses acetylcholine). In PD, the dopaminergic system is
impaired, leading to a relative overactivity of the cholinergic
system. By dampening the activity of the cholinergic system,
anticholinergics restore some balance between the two systems.

Anticholinergics are mainly effective against tremor and rigidity,
but not other PD symptoms such as slowed movements or postural
instability. Common side effects include dry mouth, sedation,
delirium, confusion, hallucinations, constipation, and urinary
retention. These side effects are often intolerable in older patients
and, for this reason, anticholinergics are rarely used in more
elderly PD patients. For the same reason, they are also usually the
first drugs to be withdrawn in younger patients on multiple
medications who begin to develop confusion, hallucinations, or other
drug-related problems.

Amantadine
Amantadine was originally developed as an antiviral treatment, and
was coincidentally discovered to have a beneficial effect on the
three major motor symptoms of PD: tremor, rigidity, and bradykinesia.
Its effects are not strong, but its side effects, which are similar
to the anticholinergics, are relatively mild; therefore, amantadine
is often prescribed early in the disease course. Side effects may
also include patchy discoloration of the skin and orthostatic
hypotension. Patients with kidney disorders require a much lower
dose, since amantadine is removed from circulation by the kidneys. As
with anticholinergics, amantadine is often reduced or eliminated when
cognitive side effects become intolerable.

Low doses of amantadine have been shown to effectively reduce (though
not eliminate) dyskinesias, the unwanted movements that are a
consequence of long-term use of levodopa. Thus, amantadine becomes a
potentially useful treatment for more advanced PD as well as in
patients who can tolerate the side effects.

MAO-B Inhibitors: Selegiline and Rasagiline
Selegiline (Eldepryl®) and rasagiline inhibit the action of monoamine
oxidase B (MAO-B), an enzyme that breaks down dopamine in the brain.
By inhibiting this enzyme, these drugs prolong the activity of
dopamine, thus improving PD symptoms. Selegiline is an FDA-approved
treatment for PD. Rasagiline has proven effective in clinical trials
but is not yet commercially available. Their effects against PD
symptoms are relatively weak compared to dopaminergic drugs.
Selegiline is typically used either early in the disease, or later as
an add-on to dopaminergic therapy.

Much research and even more discussion have surrounded the question
of whether selegiline is neuroprotective; that is, whether it slows
the loss of brain cells in PD. A pivotal trial begun in 1987 called
the DATATOP study examined this question. The initial results
suggested selegiline may have a neuroprotective effect, but later
analysis contradicted this, and suggested that selegiline's
symptomatic effects were responsible for all the benefit seen in the
trial. The difficulty of separating symptomatic benefits from real
neuroprotection is a problem common to many neuroprotection trials in
PD. Follow-up on patients from the DATATOP study continues today,
with the most recent results indicating no clear effect of selegiline
on disease progression or mortality.

Finding the Right Balance
Finding the right mix of drugs and the right doses for each is one of
the greatest challenges for the PD physician and patient. There is a
continual balancing act between improving symptoms and minimizing
side effects, against the backdrop of disease progression and
treatment of other conditions affecting the person with PD. As
scientists develop a better understanding of the brain in both health
and disease, new treatments should become available to make that
balancing act a bit easier.

Glossary

neurotransmitter:
a chemical used by one brain cell to send a signal to another; the
basis of all brain activity

motor symptoms:
tremor, slowed movements, rigidity, postural instability and other
movement-related symptoms

orthostatic hypotension:
a sudden fall in blood pressure upon standing, often causing
dizziness or lightheadedness
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WE MOVE
Editor: Richard Robinson