Pharmacy & Therapeutics - October 2008 - (Page 594)

Medical Management of Parkinson’s Disease ever, up to 30% of patients do not have tremor; this can lead to a misdiagnosis. As the disease progresses, the tremor that affects most patients may begin to interfere with daily activities.1 Patients may not be able to hold utensils steady or may find that the shaking makes reading a newspaper difficult. The tremor may become worse when the patient is relaxed. Shaking is most pronounced a few seconds after the hands are rested on a table. sion of levodopa also elicits undesirable effects, particularly nausea. Circulating plasma concentrations of dopamine stimulate the brainstem’s chemoreceptive trigger zone to induce nausea. This effect is usually reversible with drugs that inhibit peripheral dopa-decarboxylase. Inhibition of peripheral decarboxylase elevates the fraction of administered levodopa that remains unmetabolized and available to cross the blood–brain barrier and reduces the incidence of GI adverse effects. In most individuals, a daily dose of carbidopa 75 mg is sufficient to prevent nausea. For this reason, the most commonly prescribed form of carbidopa plus levodopa (e.g., Sinemet, Bristol-Myers Squibb; Atamet, Elan) is carbidopa 25 mg/levodopa 100 mg. With this formulation, dosage schedules of three or more tablets daily provide acceptable inhibition of decarboxylase in most individuals. Occasionally, patients require larger doses of carbidopa to minimize GI adverse effects, and supplemental carbidopa (Lodosyn, Merck) alone may be beneficial. Effectiveness. Levodopa therapy can have a dramatic effect on all the signs and symptoms of PD. Early in the course of the disease, the degree of improvement in tremor, rigidity, and bradykinesia may be nearly complete. In early PD, the duration of the beneficial effects of levodopa may exceed the plasma lifetime of the drug, suggesting that the nigrostriatal dopamine system retains some capacity to store and release dopamine. A principal limitation of long-term levodopa therapy is that this apparent buffering capacity is lost over time and the patient’s motor state may fluctuate dramatically with each dose of levodopa. A common problem is the development of the “wearingoff” phenomenon; each dose of levodopa effectively improves mobility for a period of time, perhaps one to two hours, but rigidity and akinesia quickly return at the end of the dosing interval. Increasing the dose and frequency of administration can improve the situation, but this approach is often limited by the development of dyskinesia (excessive and abnormal involuntary movements). Dyskinesia is usually observed when plasma levodopa levels are high, although dyskinesia or dystonia can also be triggered when levodopa levels are rising or falling. These movements can be as disabling as the rigidity and akinesia of PD. In later stages of PD, patients may fluctuate rapidly between being “off,” or experiencing no beneficial effects from medication, and being “on,” but with disabling dyskinesias (the “on/off” phenomenon). It is still unknown whether levodopa alters the course of the underlying disease or merely modifies symptoms. Two aspects of treatment and outcomes are of concern. First, if the production of free radicals, as the result of dopamine metabolism, contributes to the death of nigrostriatal neurons, the addition of levodopa can accelerate the process, although no convincing evidence for this effect has yet been obtained. Second, the undesirable on/off and wearing-off phenomena are observed almost exclusively in patients receiving levodopa, but it is not known whether delaying treatment with levodopa delays the appearance of these effects. Because of these uncertainties, most physicians have adopted a pragmatic approach and use levodopa only when PD symptoms cause functional impairment. continued on page 599 MEDICAL TREATMENT Medications are the most common therapy for PD.12,20,23 The goal is to correct the shortage of dopamine; it is this deficiency that causes the symptoms. Pharmacological treatment is usually started when symptoms become disabling or disrupt daily activities. Treatments may differ according to the patient’s symptoms, age, and responses to specific drugs. It often takes time to find the best combination of drugs for each patient. Levodopa and Levodopa/Carbidopa Levodopa (L-dopa, L-3,4-dihydroxyphenylalanine), the metabolic precursor of dopamine, is the single most effective agent for treating PD. Levodopa itself is largely inert; both its therapeutic and adverse effects result from decarboxylation of levodopa to dopamine. When taken orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids. Drug concentrations in the plasma usually peak between 0.5 and 2 hours after an oral dose. The half-life in plasma is short (one to three hours). The rate and extent of absorption of levodopa depend on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa. Competition for absorption sites in the small bowel from dietary amino acids may also affect the absorption of levodopa; taking levodopa with meals delays absorption and reduces peak plasma concentrations. Entry of the drug into the CNS across the blood–brain barrier is also mediated by a membrane transporter for aromatic amino acids, and competition between dietary protein and levodopa may occur at this level. In the brain, levodopa is converted to dopamine by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the striatum. The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or is metabolized by the actions of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). In clinical practice, levodopa is almost always given in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa or benserazide (not available in the U.S.), which does not penetrate well into the CNS. If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites, so that relatively little unchanged drug reaches the cerebral circulation and probably less than 1% penetrates the CNS. Dopamine release into the circulation by peripheral conver- 594 P&T® • October 2008 • Vol. 33 No. 10

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - October 2008

Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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