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Drug update: Parkinson's disease.

Levodopa has been the mainstay treatment of Parkinson's disease for more than 30 years, but it no longer reigns supreme. The dopamine precursor has had to make room for the dopamine agonists, a class that historically has had an adjunctive role but increasingly is seen as first-line treatment, especially for initial therapy.

Levodopa is more effective than the dopamine agonists for controlling the symptoms of Parkinson's disease, particularly bradykinesia and rigidity. But the dopamine agonists have a longer duration of action and thus are not plagued by the troubling "on-off" effect that is common with levodopa, particularly when the efficacy of levodopa fades as the disease progresses. The dopamine agonists also avoid development of dyskinesias, a disturbing effect of long-term levodopa use.

In 2002, the American Academy of Neurology issued new treatment guidelines and said that levodopa is still the best first-choice treatment for many patients (Neurology 5811]:11-17, 2002). The guidelines also said that the dopamine agonists are first-line therapy for selected patients, especially younger patients, to delay the long-term motor complications of prolonged levodopa therapy.

Other drug classes are generally used as adjuncts. Experts add an anticholinergic drug to minimize tremor in the early stages, but these agents may increase the risk of dementia later. Anticholinergic drugs are not advised for elderly patients because of potential adverse cognitive and cardiovascular events. Agents in this class include benztropine, ethopropazine, and trihexyphenidyl. The antiviral agent amantadine has anticholinergic properties; it can be effective for the motor symptoms of Parkinson's and may reduce dyskinesia. Tricyclic antidepressants with mild anticholinergic effects, such as amitriptyline and doxepin, can also help, particularly for associated depression. The side effect of dry mouth can minimize drooling.

In general, therapy for Parkinson's disease should not be withheld because of pregnancy. Dopaminergic agents can cause teratogenicity and dose-related toxicity in animals, but limited data in humans have not shown these effects. Treatment with MAO-B inhibitors, which are embryotoxic and fetotoxic at high doses in animals, should be avoided during pregnancy. Amantadine therapy should be delayed until beyond the first trimester because of limited reports of congenital abnormalities in humans. Breast-feeding is generally not recommended because all of the drugs are excreted in breast milk and some act to suppress lactation.
Drug Dosage Cost/Day *

DOPAMINE PRECURSOR

carbidopa/levodopa 75 mg/300 $3.55
 mg to 250 (25 mg/100
 mg/2,500 mg mg, five times
 daily a day)

DOPAMINE AGONISTS

Directly stimulate dopamine receptors. Affect all Parkinson's symptoms
except postural reflexes. Start with a low dose and titrate
over several weeks. Nonresponse to one agent in class does not
preclude response to another. Class poses risk of short-term side
effects; some of these can be controlled medically. Patients over 65
years of age are particularly susceptible to dopamine agonist-related
confusion and hallucinations, and thus are not prime candidates for
these agents. Adding a dopamine agonist to levodopa therapy early in
the disease among stable, nonfluctuating patients slows loss of
dopamine-producing brain cells, lessening the potential for
dosing-related "on-off" periods. Also, in combination therapy,
dosages of levodopa and dopamine agonist can be reduced because
of complementary effects, delaying long-term motor complications and
reducing severity of short-term side effects. Dopamine agonists can
also be used late in the disease in combination with levodopa.

ropinirole 9-24 $6.21
(Requip) mg/day (5 mg t.i.d.)
pramipexole 1.5-4.5 $6.75
(Mirapex) mg/day (1 mg t.i.d.)
pergolide 0.5-1.5 $5.64
(Permax) mg/day (0.25 t.i.d.)
bromocriptine 15-50 $22.44
(Parlodel) mg/day (15 mg b.i.d.)

CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS

Useful adjuncts to levodopa, greatly reducing "on-off" fluctuations.
No clinical effect in the absence of levodopa. Starting one of these
agents usually requires reduction in the levodopa dosage because of
potential to increase associated dyskinesias.

entacapone 200 mg with $8.40 (five
(Comtan) each dose of times a day)
 levodopa
tolcapone 100-200 $7.29
(Tasmar) mg t.i.d (100 mg t.i.d)

MONOAMINE OXIDASE TYPE B INHIBITOR

selegiline 5 mg once or $3.88
 twice daily (5 mg b.i.d.)

Drug Comment **

DOPAMINE PRECURSOR

carbidopa/levodopa Decreases the amount of levodopa needed and
 lessens some side effects. In tablets with this
 formulation, first dose listed is carbidopa and
 the second is levodopa. Treatment begins with
 one 25 mg/100 mg tablet t.i.d. Most patients
 require 400-1,000 mg of levodopa per day in
 divided doses every 2-5 hours. Controlled-re-
 lease formulation available; minimizes
 variations in plasma levodopa levels. When
 levodopa is first-line treatment, maximizing
 efficacy while minimizing or delaying long-term
 adverse effects requires careful dosing. Short
 half-life (less than 2 hours) becomes a problem
 over time as dopaminergic brain cells die,
 reducing storage capacity for chemical. As the
 duration of action for each dose decreases,
 patients need more frequent and/or higher
 doses.

DOPAMINE AGONISTS

ropinirole Nonergot derivative, as is pramipexole. These
(Requip) two relatively new agents have fewer adverse
 effects than bromocriptine and pergolide, but
 "sleep attacks" have been reported, which means
 patients must be educated regarding driving and
 operating machinery. No studies have compared
 all agents within class, but for now ropinirole
 and pramipexole are considered safer and more
 effective. Ropinirole has additional
 advantages: somewhat more experience, compared
 with pramipexole, and some evidence that
 ropinirole slows loss of dopamine function. In
 addition, there is concern that pramipexole may
 exacerbate neuropsychiatric problems.
pramipexole Nonergot derivative, as is ropinirole.
(Mirapex) Considered roughly similar to ropinirole in
 safety and efficacy, but pramipexole has
 somewhat less experience in studies than
 ropinirole, and serotonergic properties may
 exacerbate neuropsychiatric problems. Also,
 ropinirole may have ability to slow loss of
 dopamine function.
pergolide Ergot derived; greater potential for adverse
(Permax) effects than pramipexole and ropinirole, which
 makes pergolide a less attractive option.
 Similar in efficacy and safety to bromo-
 criptine, but with faster onset of action.
 This may make pergolide the favored option.
 Dosage given here is what's commonly effective,
 but larger dosages possible. In combination
 therapy, dosages greater than 5 mg/day increase
 adverse effects without increasing benefit.
bromocriptine Ergot derived; greater potential for adverse
(Parlodel) effects than pramipexole and ropinirole, which
 makes bromocriptine a less attractive option.
 Similar in efficacy and safety to pergolide,
 but with slower onset of action.

CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS

entacapone May allow reduction of levodopa dose by 20%-
(Comtan) 30%. Somewhat higher potency but shorter
 duration of action, compared with tolcapone.
tolcapone Inhibits COMT for longer periods than enta-
(Tasmar) capone, but not as effective for reducing
 levodopa dose. Potential for liver toxicity
 requires weekly monitoring of liver enzymes.

MONOAMINE OXIDASE TYPE B INHIBITOR

selegiline Inhibits dopamine breakdown, so prolongs and
 enhances action of levodopa. May also have mild
 anti-Parkinson's activity. Occasionally can
 stimulate the adverse mental and motor function
 effects of levodopa, prompting a reduction in
 the levodopa dosage. Morning and noon dosing
 can prevent potential sleep problems. In some
 patients with mild "on-off" levodopa
 fluctuations, lessens the effect when a
 levodopa dose wears off.

* Cost/day is based on the average wholesale price for a 100-unit
container or closest available size of the generic formulation,
unless otherwise indicated, in the 2002 Red Book.

** Comments reflect the opinions and expertise of the following
sources: Gerald G. Briggs, B.Pharm., pharmacist clinical specialist,
Women's Hospital, Long Beach (Calif.) Memorial Medical Center.
Dr. William C. Kolter, director, Movement Disorders Program,
Mount Sinai Medical Center, New York.
Dr. Kenneth Marek, Institute for Neurodegenerative Disorders, New
Haven.
Dr. Ray Watts, professor of neurology, Emory University, Atlanta.
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No portion of this article can be reproduced without the express written permission from the copyright holder.
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Author:Mahoney, Diana
Publication:Internal Medicine News
Date:Sep 1, 2003
Words:1250
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