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4 Dopamine agonists Dopamine agonists act directly on dopamine receptors, and their use in parkinsonism is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy They were previously reserved for patients who had either become refractory to levodopa or developed the on-off phenomenon However, they are now best given either before the introduction of levodopa or with a low dose of Sinemet 25/100 (carbidopa 25 mg and levodopa 100 mg), one tablet three times daily when dopaminergic therapy is first introduced; the dose of Sinemet is kept constant, while the dose of the agonist is gradually increased Bromocriptine, an ergot derivative is not widely used in the United States because of side effects, including anorexia; nausea; vomiting; constipation; postural hypotension; digital vasospasm; cardiac arrhythmias; various dyskinesias and mental disturbances; headache; nasal congestion; erythromelalgia; pulmonary infiltrates; and pericardial, pleural, or pulmonary fibrosis In 2007, the manufacturer of pergolide, another ergot derivative and dopamine agonist, withdrew the drug from the US market after two studies showed that serious cardiac valvular abnormalities developed in some patients while taking the drug Pramipexole and ropinirole are two newer dopamine agonists that are not ergot derivatives They are effective in early Parkinson s disease as well as in advanced stages of the disease In each case, the daily dose is built up gradually Pramipexole is started at a dosage of 0125 mg three times daily, and the dose is doubled after 1 week and again after another week; the daily dose is then increased by 075 mg at weekly intervals depending on response and tolerance Most patients require between 05 and 15 mg three times daily Ropinirole is begun in a dosage of 025 mg three times daily, and the total daily dose is increased at weekly intervals by 075 mg until the fourth week and by 15 mg thereafter Most patients require between 2 and 8 mg three times daily for benefit Adverse effects include fatigue, somnolence, nausea, peripheral edema, dyskinesias, confusion, and postural hypotension Less commonly, an irresistible urge to sleep may occur, sometimes in inappropriate and hazardous circumstances 5 Selective monoamine oxidase inhibitors Rasagiline, a selective monoamine oxidase B inhibitor, has a clear symptomatic benefit in a daily oral dose of 1 mg, taken in the morning; it may also be used for adjunctive therapy in patients with response fluctuations to levodopa Selegiline (5 mg orally with breakfast and lunch) is another monoamine oxidase B inhibitor that is sometimes used as adjunctive treatment for parkinsonism; by inhibiting the metabolic breakdown of dopamine, it may improve fluctuations or declining response to levodopa Tyramine-rich foods are best avoided when either of these agents is taken because of the theoretical possibility of a hypertensive ( cheese ) effect There are reasons to believe that rasagiline or selegiline may arrest the progression of Parkinson s disease Studies have failed to establish this conclusively, but this remains an important consideration for patients who are young or have mild disease 6 COMT inhibitors Catecholamine-O-methyltransferase inhibitors reduce the metabolism of levodopa to 3-O-methyl-
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side effects from antiparkinsonian agents, especially if they have no evidence of diffuse vascular disease or significant cognitive decline Surgery should generally be confined to one side because the morbidity is considerably greater after bilateral procedures Because of their morbidity, ablative procedures have generally been supplanted by deep brain stimulation, discussed in the following section Intracerebral implantation of adrenal medullary or fetal substantia nigra tissue or of stem cells is an experimental approach, and further studies are required to define the role of such cellular therapies
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dopa and thereby alter the plasma pharmacokinetics of levodopa, leading to more sustained plasma levels and more constant dopaminergic stimulation of the brain Two such agents, tolcapone and entacapone, are currently available and may be used as an adjunct to levodopa-carbidopa in patients with response fluctuations or an otherwise inadequate response and who either have failed with other adjunctive therapies or are not candidates for such therapies Treatment results in reduced response fluctuations, with a greater period of responsiveness to administered levodopa Tolcapone is given in a dosage of 100 mg or 200 mg three times daily, and entacapone is given as 200 mg with each dose of Sinemet (levodopa-carbidopa) With either preparation, the dose of Sinemet taken concurrently may have to be reduced by up to one-third to avoid side effects such as dyskinesias, confusion, hypotension, and syncope Diarrhea is sometimes troublesome Because rare cases of fulminant hepatic failure have followed its use, tolcapone should be avoided in patients with preexisting liver disease Serial liver function tests should be performed at 2-week intervals for the first year and at longer intervals thereafter in patients receiving the drug as recommended by the manufacturer Hepatotoxicity has not been reported with entacapone, which is therefore the preferred agent, and serial liver function tests are not required Stalevo is the commercial preparation of levodopa combined with both carbidopa and entacapone It is best used in patients already stabilized on equivalent doses of carbidopa/ levodopa and entacapone It is priced at or below the price of the individual ingredients (ie, carbidopa/levodopa and entacapone) and has the added convenience of requiring fewer tablets to be taken daily It is available in three strengths: Stalevo 50 (125 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone), Stalevo 100 (25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone), and Stalevo 150 (375 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone) 7 Atypical antipsychotics Confusion and psychotic symptoms, which may be iatrogenic, often respond to atypical antipsychotic agents, which have few extrapyramidal side effects and do not block the effects of dopaminergic medication Olanzapine, quetiapine, and risperidone may be tried, but the most effective of these agents is clozapine, a dibenzodiazepine derivative Clozapine may rarely cause marrow suppression, and weekly blood counts are therefore necessary for patients taking it The patient is started on 625 mg at bedtime and the dosage increased to 25 100 mg/d as needed In low doses, it may also improve iatrogenic dyskinesias
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