Drug Topics - October 22, 2007 - (Page 29)

29 stimulation (DBS) may be used to help control some of the abnormal motor movements displayed by PD patients. Pharmacotherapy Anticholinergics. Anticholinergic agents, such as benztropine and trihexyphenidyl, are believed to work by attempting to balance dopamine and acetylcholine activity. Benztropine may also inhibit the reuptake and storage of dopamine, thus prolonging the action of dopamine. Anticholinergic agents can be effective for tremors but have little benefit for other symptoms of PD. Not all patients with tremors will respond to anticholinergics. A younger Parkinson’s disease patient whose main complaint is a tremor with minimal bradykinesia or rigidity would be the best candidate for this drug class. Disadvantages in using anticholinergic agents are their adverse side effects, many of them dose-related. The common ones include dry mouth, blurred vision, constipation, tachycardia, drowsiness, memory impairment, and urinary retention. If anticholinergic therapy is to be discontinued, tapering the dose is recommended, since abrupt withdrawal may result in agitation and worsening confusion. Anticholinergic agents may be used in combination with levodopa and other antiparkinsonian agents. Amantadine. Amantadine, whose mechanism of action is unclear in Parkinson’s disease, has demonstrated usefulness in patients exhibiting pronounced akinesia or rigidity symptoms. Amantadine can be used as monotherapy for the purposes of delaying the use of levodopa, yet it is usually effective only for a short period of time (less than three months). A drug holiday for a few weeks often will restore responsiveness. As adjunctive therapy to levodopa, amantadine has been shown to be effective. Its adverse effects compared with anticholinergic agents are mild in nature. Sedation and vivid dreams may occur at the initial onset of the drug and dissipate over time. Other potential side effects include nausea, dry mouth, depression, hallucinations, anxiety, dizziness, psychosis, and confusion. Elderly patients are particularly prone to confusion at higher doses. Patients may also develop livedo reticularis, a vascular cutaneous reaction characterized by a reddishpurple, fishnet pattern mottling of the skin of the upper and lower extremities. Livedo reticularis is benign and reversible. Amantadine is eliminated renally and thus should be adjusted for those with a creatinine clearance less than 50 mL/min. To avoid withdrawal, amantadine should be gradually tapered when it is being discontinued. Dopaminergic therapy Levodopa and carbidopa/levodopa. Levodopa has long been or it will be added to the regimen as other medications begin to become ineffective. Carbidopa/levodopa is especially beneficial in those experiencing akinesia, but significant improvement has also been noted in those with tremor, rigidity, and bradykinesia. Overall, motor function can improve by greater than 50% in most PD patients. While carbidopa/levodopa is effective in PD, it is not without potential side effects, which include orthostatic hypotension, nausea, vomiting, insomnia, sleep attacks, discoloration of bodily fluids, confusion, vivid dreams, hallucinations, and psychosis. The most troubling side effects are the motor complications. In fact, approximately 40% of patients will experience involuntary motor fluctuations (“on-off” phenomena) within four to six years of initiating levodopa. Characterized by tremors, bradykinesia, and freezing episodes resulting from a decline in neuronal storage capabilities of dopamine as patients become more dependent, the “off” period ups the rate of delivery of levodopa to the brain. Typically, the “off” period occurs at the end of a dosing interval. This can be easily corrected by increasing the frequency of carbidopa/levodopa administration. Also, clinicians may choose a controlled-release dosage form, which provides a more pulsatile administration. However, some patients may continue to take the immediate-release dosage in order to have a quicker onset of action, since the controlled-release formulation may take up to one hour before effects are observed. Additionally, patients with more severe “off” periods may achieve more consistent “on” periods by using the liquid formulation of carbidopa/levodopa. Even so, the addition of an MAO-B inhibitor or a COMT inhibitor may also be considered to help extend the action of levodopa. Carbidopa/levodopa is absorbed in the small intestine via a large protein transporter, with peak plasma concentrations occurring within 30-120 minutes. Thus, diets high in protein will result in competition of the transporter receptor and interfere with absorption, ultimately affecting efficacy. Therefore, patients should adjust the timing of high-protein meals with administration of carbidopa/levodopa to help avoid this interaction. In addition, a diet high in acid content will also slow the absorption of Table 2 The Hoehn and Yahr scale for staging the severity or progression of PD Stage Symptoms 0 No clinical signs are present. 1 Functional impairment is minimal, but unilateral features of tremor rigidity or bradykinesia are evident. the mainstay of treatment in PD patients. Levodopa by itself is a precursor to dopamine. Once levodopa enters the peripheral circulation, it crosses the blood brain barrier (BBB), and is then converted to dopamine by the enzyme dopa decarboxylase and taken up by the dopaminergic neurons of the substantia nigra. In the United States, levodopa is combined with carbidopa, a peripheral dopa decarboxylase inhibitor. This component protects levodopa from being converted in the periphery, thereby increasing levodopa’s bioavailability at its intended target, the central nervous system. Additionally, carbidopa lessens the frequency of the peripheral side effects of levodopa, such as nausea, vomiting, and orthostatic hypotension. The minimum daily dose of carbidopa to overcome conversion of levodopa in the periphery is 75 mg to 100 mg. Most patients will either be initiated on carbidopa/levodopa, 2 3 Balance is not yet impaired, but the features in stage 1 become bilateral. Patients still function independently. Bilateral symptoms progress but are still mild to moderate. Postural imbalance is mild. Patients require substantial assistance. Bilateral symptoms become more severe with significant postural instability. Patients are restricted to a bed or wheelchair. Bilateral symptoms are very severe. 4 5

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Drug Topics - October 22, 2007 Contents Latebreakers Legislative Victory Builds Momentum for Pharmacy Month Letters Health-System Edition R.Ph.s Brace for Payment Denial for Hospital-Acquired Conditions Topical Human Thrombin Helps Arrest Bleeding FDA Panels Fail to Set Target Levels for Renal Patients’ Hemoglobin Warning Letters Raise Patient Safety Concerns for Fentora Ending/Reversing Weight Gain Man Given Fatal Drug Overdose at Staten Island Hospital Pharmacists Playing More Important Role in Dialysis Treatment AHA President R.Ph.'s Here's How You Can Increase Your Value Premier Launches Comprehensive Quality Improvement Project FDA Approves Dexrazoxane for Treatment of Extravasation New Federal, State Reforms to Ease Disaster Relief Kinks 150 Years of American Pharmacy Ten Tips for MTM Success Independent Superstars: The Ones to Watch The New Dynamic Duo A Parkinson's Disease Primer Classified New Products Advertisers Index Viewpoint

Drug Topics - October 22, 2007

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