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Treating Parkinson's Disease: Appendix
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Treating Parkinson's Disease: Appendix

 
Treating Parkinson's Disease

Appendix

Levodopa
Treatment of PD with levodopa was begun in 1960. It is still the most effective drug for the control of the symptoms of PD.

Mechanism of action
Because of the way it is metabolized, levodopa is almost always administered in combination with carbidopa. This combination is called Sinemet® and it avoids side effects of peripheral dopamine, i.e., nausea, vomiting, postural hypotension, sinus tachycardia and orange color of urine.

Timing of initiation
It was and still is the gold standard antiparkinsonian agent but the timing of its initiation remains somewhat controversial.7 Once it is absolutely necessary and when it is finally instituted, the lowest possible dose should be given. Higher dose may cause nausea, dizziness, insomnia, nervousness and vague mental symptoms (psychosis).

Side effects/complications
Complications due to levodopa therapy are usually directly proportional to the duration of treatment.

Most common serious adverse reactions are

  • Nausea, vomiting
  • Dizziness
  • Anorexia
  • Orthostatic hypotension
  • Cardiac arrhythmias
  • Paranoid ideation and psychotic episodes
  • Involuntary movements
  • Bradykinetic episodes (slowed movement) return

Controlled-Release Carbidopa/Levodopa (Sinemet®)
This drug provides prolonged levodopa concentration and is associated with much less motor disturbances. Its major drawback is slower onset of action which can be overcome by adding 1/2 of the standard dose of Sinemet® with each morning dose of Sinemet SR®. It has sedative properties.
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Direct Dopamine Agonists
They directly stimulate dopamine receptors in the brain. They are associated with fewer motor disturbances than occur with long term use of levodopa.

They are as good as levodopa for early PD and are also the second most effective class of drug after the levodopa. They may delay the need of levodopa institution. They may be more useful in younger patients who are more prone to early development of levodopa-related motor disturbances and who will have to be treated for a longer time than those with late onset.

They may be less toxic than levodopa as their metabolism does not produce free radicals.

They may delay the disability, if given in combination with the low dose of levodopa in early PD; however, this concept needs more study.

They are comparatively expensive and poorly tolerated by cognitively impaired patients.
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Pramipexole (Mirapex®)
This nonergot, benzothiazole derivative is an excellent medication for early PD and has a broader range of indication than bromocriptine and pergolide for the treatment of the sign and symptoms of PD. Its role in advanced PD is similar to that of other dopamine agonists.

Indicated both as a single agent and adjuvant to levodopa. Dose should be gradually increased to achieve maximum therapeutic effects balanced against the major side effects, i.e., motor disturbances, hallucinations, somnolence and dry mouth. Patients with renal impairment need dose reduction and the drug should be given less frequently.

Side effects
Orthostatic hypotension is rare.
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Ropinirole (Requip®)
This is a new nonergot, antiparkinsonian agent with chemical structure similar to that of dopamine. It is also claimed to be an excellent drug for early PD and may delay the need of levodopa for several years. Recommended both as a single agent and as adjuvant to levodopa, ropinirole is superior to bromocriptine and equal to levodopa in early stage disease.

No dose adjustment of ropinirole is necessary in patients with moderate renal failure. There is no study data available for its use in severe renal failure.

Side effects
  • Postural hypotension
  • Somnolence
  • Fainting
  • Dizziness
  • Nausea (well-tolerated and disappears over time)
  • Hallucinations
  • Confusion
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Pergolide (Permax®)
This is an ergot derivative and, like bromocriptine, is indicated as adjunctive treatment with carbidopa/levodopa. In comparison to bromocriptine, it has a longer duration of action.

This drug has not been frequently studied in the treatment of early PD.

Side effects
  • Diarrhea
  • Nausea
  • Constipation
  • Indigestion
  • Insomnia
  • Motor disturbances
  • Hallucinations
  • Somnolence
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Bromocriptine (Parlodel®)
This is an ergot alkaloid now approved as an adjunctive therapy with carbidopa/levodopa for those patients who develop tolerance and end-of-dose failure to levodopa.10 After addition of bromocriptine, dose of levodopa should be reduced. Bromocriptine can be used as a single agent in the treatment of early or mild PD.
Contraindications
  • History of mental illness
  • Recent heart attack
  • Peptic ulcer disease (bleeding from pergolide has been reported)
  • History of peripheral vascular disease
Side Effects
  • Hallucinations
  • Confusion
  • Nausea
  • Postural hypotension
  • Motor disturbances
  • Mental changes
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COMT Inhibitors
With the addition of carbidopa to levodopa, greater amount of levodopa is available to reach the brain. The rest of the levodopa is then metabolized in the gut and liver. COMT inhibitors prevent this breakdown, thus increasing the amount of levodopa available to reach the brain.
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Tolcapone (Tasmar®)
Tolcapone is advocated as an adjunctive therapy with carbidopa/levodopa for both early and mild PD and for advanced disease complicated by levodopa-related motor disturbances.
Side effects
  • Motor disturbances
  • Nausea, vomiting
  • Diarrhea
  • Increase in liver enzyme (ALT)
  • Sedation
  • Headache
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Entacapone (Comtan®)
This is an investigational drug in America.

Generally well tolerated, except for transient motor disturbances and mild nausea that are much more common with entacapone.

Side effects
  • Headache
  • Constipation
  • Hypotension
  • Sedation
  • Diarrhea
  • Nausea, vomiting
  • Motor disturbances
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Anticholinergics
Effective for the control of tremor and drooling in PD patients, rigidity and slow movements are not much altered.

Should be used with caution in older persons.

Side effects
  • Memory impairment
  • Glaucoma
  • Dry mouth
  • Confusion
  • Hallucinations
  • Urinary retention
  • Constipation
return

Others
Selegiline (Eldepryl®);
This is an irreversible inhibitor of MAO-B, used in patients when there is a deterioration in response to levodopa. Selegiline may have some possible neuroprotective effects; however, it remains to be proven.

Cognitively impaired patients are also poor candidates for this drug.

Selegiline as single agent therapy
Reasonable medication for early-stage patients without disabling symptoms.

Can be used in young patients (<65 years of age).

Selegiline as adjunctive therapy
Can be given in combination with levodopa/benserazide but it will need more clinical studies to establish its efficacy.
Side effects
  • Psychosis
  • Cognitive decompensation
  • May aggravate the side effects of levodopa
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Amantadine (Symmetrel®)
An antiviral agent, its mechanism of action is not known. As more direct dopamine agonists become available, this drug appears to be less appropriate for general use.

Other reported mechanism of action is

  • Anticholinergic actions
  • Delay of dopamine uptake by neural cells
  • Release of dopamine from central neurons
  • Blockade of N-methyl-D-aspartate (NMDA) receptors.
  • It has only minimal effect on tremor; tolerance develops in 6-8 months.
  • It is advocated to substitute or add when patient's early symptoms do not respond to anticholinergics.
  • When given as a monotherapy for early minor symptoms, it reportedly results in a 20% to 40% global improvement in two third of patients.
  • It is also effective in late stages of PD; patients who are getting maximal response from levodopa usually derive some additional benefits because of additive action of the two drugs.
Side effects
  • Leg swelling (particularly in elderly)
  • Hallucinations
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Vitamin E (Tocopherol)
High dietary intake of vitamin E may delay the occurrence of PD. There is little evidence supporting its use at present.
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Hormone Replacement Therapy (HRT)
According to recent reports, hormone replacement therapy may be effective in preventing the onset of PD and such therapy could be used to alleviate some symptoms of the disorder.

Researchers at the Mayo Clinic and Mayo Foundation in Rochester, Minnesota, studied 144 postmenopausal women, half of whom had PD. They found that 10% of the Parkinson's patients had been on hormone replacement therapy (HRT) for at least six months, compared to 14% of the patients without the disease.

In a related study from University of Utah, researchers found that, of postmenopausal women with PD, those undergoing HRT scored an average of 16% higher on test of long-term verbal memory, compared to their counterparts not taking the therapy.
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October 1, 1999






 
 
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