Drug update: Parkinson's disease.
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.
|Printer friendly Cite/link Email Feedback|
|Publication:||Internal Medicine News|
|Date:||Sep 1, 2003|
|Previous Article:||Whites more likely to get narcotics for pain: insurance status, age also factors.|
|Next Article:||FDA okays rosuvastatin for hypercholesterolemia: most potent statin to date.|