CE: Treatment Options in Parkinson's Disease

Treatment Options in

Parl~inson's

Disease

Pharmacists play a key role in the medication management ofpatients with Parkinson s disease. by Judith L. Seizer, PharmD

Learnin.g Objectives Upon successful completion of this article, the pharmacist should be able to: • Describe the etiology and clinical manifestations of Parkinson's disease. • Explain the newest treatments for Parkinson's disease. • Discuss the use of levodopa in the treatment of Parkinson's disease. • Recognize the adverse effects of antiparkinsonian medications. • Counsel patients with Parkinson's disease and their families.

Program Previe'W Tilis article reviews the pathophysiology and treatment of Parkinson's disease. New trends in the use of antiparkinsonian medications are discussed. Drugs used in treating Parkinson's disease are reviewed, with a focus on their role in therapy, their dosing, and their adverse effects. Patient counseling information is also provided.

Introduction Parkinson's disease (PD), described in 1817 by James Parkinson, is a progressive neurologic disorder characterized by four classic features: tremor, rigidity, akinesia or bradykinesia, and postural abnormalities. Approximately 1% of the U.S. population over the age of 50 has PD. 1 Medications are the primary treatment for PD, and because it is a progressive disease, the doses and combinations of drugs must be frequently altered. The pharmacist can play a major role in monitoring pharmacologic treatment of PD. PK is a 55-year-old man who, at a routine physical examination, is noticed to have a resting tremor of his right hand. He relates "slowing down" a bit but Vol. NS35, No. 1

January 1995

has attributed it to getting older. He has no difficulty with activities of daily living (e.g., dressing or grooming) and is still working. His maternal uncle had Parkinson's disease.

Etiology The primary biochemical basis for PD is a dopamine deficiency in the extrapyramidal system within the basal ganglia. In 40% of cases, the onset of disease occurs in patients between the ages of 50 and 60, with only 30% of patients reporting onset at an earlier age. 1 In reality, the disease is diagnosed when patients report complaints to their physicians, but the actual biochemical onset of PD is probably much earlier. On autopsy, a loss of dopaminergic neurons from the substantia nigra is evident. The appearance of Lewy bodies, which are intraneuronal bodies within the dopaminergic cells, is a hallmark finding in PD. The extrapyramidal system is involved in the mainteCE Credit nance of posture and muscle tone and the regulation of CE Credit voluntary smooth muscles. To obtain two hours of continuing education credit (0.2 Normally, a balance exists CEUs) for completing "Treatbetween dopamine, an ment Options in Parkinson' inhibitory neurotransmitter, Disease," complete the assessment exercise and CE registraand acetylcholine, an excitation form and return it to tory neurotransmitter. With a APhA. A certificate will be decrease in dopamine, a relaawarded for achieving a passing grade of 70% or better. tive increase in cholinergic Pharmacists completing this activity occurs. This imbalarticle within two years of date ance causes symptoms of of issue can receive credit. PD, which are not usually The American Pharseen until an 80% decrease in maceutical Associadopamine occurs. tion is approved by the American Council on The cause of the nigral Pharmaceutical Education as a degeneration that leads to provider of continuing phardopamine loss is unclear. maceutical education. One theory is that oxidative ~ APhA provider number stress leads to the formation '
m

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cause mitochondrial dysfunction and nigra! damage. 2 Patients predisposed to PD may experience more oxidative injury than those who are not. Dopamine itself is metabolized by monoamine oxidase (MAO) to hydroxy free radicals. This process may explain the slight nigra! loss that occurs naturally with age. It may also explain why levodopa therapy is eventually ineffective in most patients with PD, because the conversion of levodopa to dopamine may contribute to oxidative stress. The other popular theory is that environmental factors may contribute to the development of PD. 3 This hypothesis is based on experience with 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP), a meperidine analogue. Patients who took homemade meperidine developed parkinsonism after receiving MPTP. MAO metabolizes MPTP to 1-methyl-4phenylpyridinium, which interferes with mitochondrial ftmction. Although MPTP itself is not fotmd naturally in the environment, compounds similar to it are fotmd there. Not all PD is idiopathic, however; several causes of parkinsonism are known and include head trauma, encephalitis, and drug and chemical exposure. Of most concern to pharmacists is drug-induced parkinsonism. Antipsychotic medications are the most notorious causes, but other dopamine-depleting drugs also cause this side effect, including methyldopa, metoclopramide, reserpine, and phenothiazine-type antiemetics and antihistamines, such as prochlorperazine. Elderly patients are particularly susceptible to drug-induced parkinsonism, and it may take months for the symptoms to resolve. 4

patients ftrst complain of a resting tremor of the hand. 5 Only a few patients will initially present with rigidity or bradykine. sia. The tremors usually appear ftrst in the upper body and then spread as the disease progresses. The tremors disappear during sleep and during purposeful movements. Other symptoms of PD include cogwheel rigidity (a ratchetlike movement), postural disturbances (most patients develop a flexed, or simian, posture), shuffling gait, masklike face (with decreased blinking), and micrographia (small handwrit· ing). As the disease progresses, the patient may develop dysphagia, decreased volume of voice, and in the late stages, cognitive impairment. Autonomic dysftmction also occurs in the patient with PD and causes such symptoms as drooling, heat intolerance, orthostatic hypotension, seborrhea, and sweating. Several rating scales have been developed to assess the severity of PD; the most commonly used scale is that by Hoehn and Yahr, which is based on clinical signs and functional ability (Table 1). 5 Another commonly used scale is the Unified Parkinson's Disease Rating Scale, in which the signs and symptoms are graded from 0 (normal) to 4 (most severe). 6 The points are totaled, and the maximum score is 188, which indicates severe disability. The diagnosis of PD is based on the patient's symptomatology. If the clinical features are atypical or the diagnosis is in doubt, magnetic resonance imaging may be performed to detect atrophy of the substantia nigra.

Pharmacologic Treatment Clinical Manifestations of PD The goal of pharmacologic treatment of PD is to relieve symptoms and restore striatal dopaminergic activity and neurotransmitter function to as close to normal as possible. At present, no cure for PD exists, and the disease invariably progresses to a point at which medications decrease in efficacy. At diagnosis, patients should be counseled about the medications available for PD, and they should be told that the types of medications and their doses may be changed many times during the course of the disease. During follow-up visits, health professionals must listen carefully to the patient's complaints and symptoms so that the doses and schedules can be individualized. Traditionally, treatment for PD has started with an anticholinergic agent or amantadine and progressed to levodopa, with a dopamine agonist added later as the therapeutic response to levodopa decreased. This algorithm is being abandoned as we learn more about PD and the medications used to treat it. Two main questions are now asked about treatment of PD: (1) When should pharmacologic therapy begin? and (2) What agent should be prescribed ftrst? No defmitive answer exists for either question. The issue of when to start therapy stems

PD usually has a subtle onset; in fact, few patients can say exactly when their symptoms started. Approximately 70% of Table 1

The Hoehn-Vahr Stages of Parkinson's Disease Stage I

Unilateral tremor, rigidity, akinesia, or postural abnormalities only

Stage II

Bilateral tremor, rigidity, akinesia, or postural abnormalities

Stage Ill

First signs of deteriorating balance, but still fully independent

Stage IV

Requires help with some or all activities of daily living, unable to live alone without assistance

Stage V

Confined to wheelchair or bed unless assisted

Source: Reference 5.

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January 1995

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from experience with levodopa. Even though levodopa has the greatest impact on symptoms, most patients develop tolerance to it, and/or they develop fluctuations in their response to the drug, as well as dyskinesias or abnormal movements. Because of these effects, some investigators believe that levodopa treatment should be delayed as long as possible to prevent the occurrence of dyskinesias?·8 Other investigators feel that it is not the length of levodopa therapy that causes these problems, but rather the progression of the disease. 9 · 10 In the early years of levodopa therapy, Markham and Diamond followed three groups of patients who had had PD for varying amounts of time before starting levodopa. 11 After nine years of the disease, disability scores were similar for patients who had been on levodopa for one year, four years, or seven years, and no difference existed in the incidence of dyskinesias among the groups. The authors found no benefit in delaying levodopa treatment and thought that it was better to alleviate the symptoms as early as possible. Further analysis of their data found that levodopa therapy may actually decrease mortality when it is started earlier in the disease rather than later.12 The interesting point of the "early versus late" argument is that either side would agree that levodopa therapy should begin when the patient has functional difficulties.

PK's physician diagnoses Parkinson's disease and because PK has mild symptoms, prescribes selegiline 5 mg orally with breakfast and after lunch. The physician educates PK about the disease and tells him to report symptoms as they occur. When PD is diagnosed early and patients have little functional impairment, most practitioners initiate patients on selegiline

(L-deprenyl) therapy in an attempt to achieve a neuroprotective effect. Several studies have investigated the use of selegiline to slow the progression of PD_l3-l 5 In most studies, the end point was the need to initiate levodopa therapy. The Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial found a 57% decreased risk of needing levodopa for that year in patients who took selegiline for 12 months. 14 Further analysis of the selegiline studies has found that the effects of selegiline seem to be most dramatic in the first 12 months of therapy and that, besides being neuroprotective, selegiline may also reduce the symptoms of PD.15 The other option being studied and debated is the early use of dopamine agonists, either alone or in combination with levodopa. 16-I S Rinne followed three groups of patients: group 1 was started on bromocriptine therapy alone, group 2 was started on bromocriptine therapy with levodopa added later, and group 3 was started on levodopa therapy alone. 19 Fewer than 10% of patients in group 1 were able to continue taking bromocriptine alone for five to seven years, but patients taking bromocriptine alone experienced fewer fluctuations in therapeutic response than did those on levodopa and bromocriptine. Rinne suggested several strategies for starting patients on VoL NS35, No. 1

January 1995

antiparkinsonian therapy.20 One strategy starts with low doses of levodopa, and instead of increasing the dose when the patient's response decreases, adds a dopamine agonist or selegiline to the regimen. An alternative is to start with selegiline, add a dopamine agonist when clinically indicated, and then add levodopa if the patient's response is not sufficient. A second alternative is to start with a dopamine agonist and add selegiline or levodopa, or both, as necessary. A third alternative is to start with the sustained-release form of levodopa (Sinemet CR-Du Pont Pharma).

During the next nine months, PK exhibits more symptoms, with some rigidity and progression of bradykinesia. The tremor is not bothersome, but the slowness is impairing PK's daily functioning. PK also has developed prostatic hypertrophy; therefore, his physician decides not to prescribe anticholinergic agents. The physician prescribes the combination product carbidopa/levodopa 25/100 mg twice daily. W'ben filling the prescription order, you (the pharmacist) should recommend that the drug be taken with low-protein meals. The most important point made by Rinne and others is that when therapy for PD is initiated, the "cookbook method," in which everyone gets the same therapy, is no longer used. Therapy must be individualized, and realistic goals must be set for each patient. It would be impossible to alleviate all symptoms of the disease; the doses of medications needed to do so would be excessive and would cause serious side effects. Rather, the trend now is to keep medication doses as low as possible or even to undertreat patients slightly, to avoid the long-term complications that can be seen with levodopa. Table 2 lists medications used in the treatment of PD, and Table 3 (page 25) lists common drug interactions with antiparkinsonian agents.

Selegiline Selegiline is an MAO-B inhibitor that was initially designed as an antidepressant. MAO-B is primarily found in the brain and is the enzyme principally responsible for the degradation of dopamine. In low doses (10 mg or less), selegiline does not inhibit MAO-A and thus avoids the interaction with tyraminecontaining foods, such as red wine, smoked or aged meat, and aged cheese , that is seen with nonselective MAO inhibitors. Selegiline is approved by the Food and Drug Administration (FDA) for use as an adjunct to levodopa in patients who have developed tolerance to levodopa. When selegiline is added to levodopa, the dose of levodopa can be decreased by 20 to 30%. Selegiline enhances the effect of levodopa, especially in patients whose response fluctuates from dose to dose. In a study by Elizan et al., the beneficial effects of selegiline on the wearing-off effect of levodopa lasted only 6 to 24 21 months in approximately half of the patients studied. As mentioned previously, selegiline is also being used early AMERICAN PHARMACY

Table 2

Antiparkinsonian Medications and Dosing Brand Name-Manufacturer

Oral Dosage Form (mg)

Initial Dosage

Maximum Dosage (mg/day)

Benztropine

Cogentin-Merck; generic

0.5, 1, 2

0.5 mg qd bid

6

Biperiden

Akineton-Knoll

2

2 mg qd bid

16

Diphenhydran~ine

Benadryi-Parke-Davis; generic

25,50

25 mg bid tid

200

Ethopropazine

Pa rsidoi-Pa rke-Davis

10,50

50 mg qd bid

600

Procyclidine

Kemadrin-Burroughs Wellcome

5

2.5 mg qd bid

20

Trihexyphenidyl

Artane-Lederle; generic

2,5

1 mg qd

15

An~antadine

Symmetrei-Du Pont

100

100 mg bid*

200

Bron~ocriptine

Parlodei-Sandoz

2.5, 5

1.25 mg bid

90

Carbidopa/ Levodopa

Sinemet-Du Pont Pharma

10/100, 25/100, 25/250

25/100 bid tid

200/2,000

Sinemet CR-Du Pont Pharma

25/100, 50/200

25/100 bid tid

Pergolide

Permax-Lilly

0.05, 0.25, 1

0.05 mg qd

6

Se/egiline

Eldepryi-Somerset

5

5 mg qd bid

10

Drug

Anticholinergics

Other agents

bid= twice a day; qd =every day; tid= three times a day.

*

Dose must be adjusted for renal dysfunction.

in PD therapy for its neuroprotective effect. In addition, its use in Alzheimer's disease is being studied. 22 Adverse reactions to selegiline, including confusion, hallucinations, insomnia, nausea, and orthostatic hypotension, are usually mild and occur in fewer than 10% of patients. Patients should be cautioned not to increase the dose above that prescribed by the physician. Patients taking selegiline doses of 10 mg or less do not have to avoid tyramine-containing foods, which may cause a hypertensive crisis (the tyramine reaction). However, although the reaction is unlikely to occur, its symptoms should be explained to patients. They should be told to call the physician if they experience irregular heartbeats, nausea, vomiting, photophobia, severe headache, or sweating. Patients should be advised to take selegiline early in the day to avoid insomnia. A common schedule is 5 mg at 8 am and at 2 pm.

Anticholinergic Agents Untillevodopa was developed in the 1960s, anticholinergic agents were the only treatment of PD. These agents may still be used in patients with mild symptoms and are especially AMERICAN PHARMACY

useful in treating parkinsonian tremor. Anticholinergic agents are also used to treat drug-induced parkinsonism. The main problem with the anticholinergic agents is their side effects: they are poorly tolerated, especially in elderly patients. The use of anticholinergic agents should be avoided in patients with cardiac disease, gastrointestinal or genitourinary obstruction (e.g., prostatic hypertrophy), and narrow-angle glaucoma. Anticholinergic agents may be used in combination with levodopa. When therapy with an anticholinergic agent is discontinued, the dose must be tapered to avoid a rebound effect. Trihexyphenidyl and benztropine are the anticholinergic agents used most often in PD, but diphenhydramine, an antihistamine with anticholinergic effects, is also used. Diphenhydramine may be more useful in elderly patients with tremor caused by PD because its anticholinergic effects are milder than those of a strict anticholinergic agent. Patients should be counseled about side effects of the anticholinergic agents they are taking. In particular, they should be advised to call the physician if they experience confusion, rapid heart rate, severe eye pain, or urinary retention. Patients taking anticholinergic agents should avoid the use of January 1995

Vol. NS35, No. 1

central nervous system (CNS) depressants and alcohol. They should be cautious in hot weather because they are more susceptible to heat stroke than other people are. Patients should also be advised to avoid driving until the medications' effects on mental function are seen.

Amantadine

Table 3

Common Drug Interactions with Antiparkinsonian Medications Agent

Interacts with

Effect

Anticholinergics

Narcotics

Central anticholinergic syndrome

Anti psychotics

Increased side effects

Antidepressants

Increased side effects

Antihistamines

Increased side effects

Levodopa

Decreased levodopa absorption

Digoxin Increased digoxin absorption Amantadine was and is used to prevent influenza A. Increased side effects AITiantadine Anticholinergics It was serendipitously discovCNS stimulants Increased CNS stimulation ere d to help PD when a patient with PD reported HCTZ/triamterene Decreased excretion of amantadine feeling better while taking Agitation, delirium, death Selegiline Meperidine amantadine for influenza. Amantadine blocks the reupFluoxetine Increased pressor effects take of dopamine into presyLevodopa Nonselective naptic neurons and causes MAO inhibitors Hypertension direct stimulation of postsyDecreased levodopa effect Phenytoin naptic receptors, producing an antiparkinsonian effect. Decreased levodopa effect Anti psychotics Amantadine is used to treat Decreased levodopa effect Reserpine mild PD and drug-induced Decreased levodopa effect Metoclopramide parkinsonism. The main problem with Decreased levodopa effect Benzodiazepines amantadine therapy is that Decreased levodopa effect, hypotension Methyldopa most patients develop tolerance to its effects within a Decreased levodopa bioavailability Iron few months of beginning therBroiTiocriptine & apy. Some practitioners have Decreased dopamine agonist effect Pergolide Antipsychotics had success with tapering Decreased dopamine agonist effect Reserpine amantadine therapy and then restarting it a few weeks later. Decreased dopamine agonist effect Methyldopa Adverse effects of amantaDecreased dopamine agonist effect Metoclopramide dine are not usually severe and generally occur in fewDecreased bromocriptine clearance Erythromycin er than 10% of patients. Adverse effects include CNS =central nervous system; HCTZ = hydrochlorothiazide; MAO= monoamine oxidase. some anticholinergic From: References 41 and 42; used with permission. effects, such as constipation, dry mouth, and urinary should be adjusted in patients with renal dysfunction. The retention. CNS effects include confusion, dizziness, hallucidose should be decreased when the creatinine clearance is nations, insomnia, and psychosis. Elderly patients are more < 50 mL/minute. 23 susceptible than are other patients to CNS effects. In addiPatients should be advised to take amantadine early in the tion, some patients may develop orthostatic hypotension day to avoid insomnia. Dividing the dose (using the liquid and edema. Amantadine can cause livedo reticularis, a form, if necessary) may minimize CNS effects. The drug harmless purplish mottling of the skin, which is reversible should not be stopped abruptly, and patients should call the on discontinuation of the medication. physician if adverse effects are severe. Amantadine is eliminated renally; therefore, the dose

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Levodopa FDA approval of levodopa in 1970 literally unlocked patients with PD from their disease. Levodopa has become the mainstay of treatment, and most patients taking this drug experience an initial improvement in their symptoms. If a patient does not respond to levodopa, the diagnosis of PO should be questioned. Dopamine does not cross the blood-brain banier, but levodopa does. Levodopa is converted to dopamine by dopa decarboxylase with a cofactor of vitamin B6 . 1bis conversion occurs not only in the CNS but also in the periphery, causing such adverse effects as nausea and orthostatic hypotension. When levodopa is used alone, large doses are needed to get adequate levels of the drug into the CNS, and patients must avoid ingesting vitamin B6. All of these problems were eliminated with the development of carbidopa, a decarboxylase inhibitor. Carbidopa blocks the peripheral conversion of levodopa, but it does not cross the blood-brain barrier. When carbidopa is combined with levodopa, peripheral side effects of levodopa are minimized, lower doses of levodopa are required, and patients can ingest vitamin B6 . However, CNS effects of levodopa still occur and may even be augmented by the addition of carbidopa. Another decarboxylase inhibitor, benserazide, is available in Europe in the combination product Madopar. Today, all patients taking levodopa should be using a product containing a decarboxylase inhibitor. Approximately 50-100 mg/day of carbidopa are necessary to inhibit peripheral decarboxylation. Therefore, initial dosing of carbidopa/levodopa should be 25/100 mg (25 mg of carbidopa and 100 mg of levodopa) two or three times daily. Patients should be given this dose for 6 to 12 weeks to assess the drug's effectiveness. If the patient had been taking another antiparkinsonian medication before taking the carbidopa/levodopa, the previous medication should not be discontinued until the levodopa has taken effect. Doses of levodopa must be individualized on the basis of the patient's symptoms. The timing of doses must be determined by the patient's schedule and symptomatology. For example, some patients need a larger dose on awakening and smaller ones later in the day. In institutionalized patients, doses scheduled before physical therapy can optimize the drug's effectiveness. Levodopa is rapidly absorbed and peaks at one-three hours when it is taken on an empty stomach; this fact should be considered in timing doses. Once the dose of levodopa reaches 400-600 mg, some practitioners add another agent rather than increase the dose. 24 · 25 Other prescribers may increase the dose to 1,000 mg or more. Some patients need more than 100 mg carbidopa to block decarboxylation. Plain carbidopa tablets (Lodosyn-Merck) can be obtained from the manufacturer for these patients. Carbidopa 25 mg three times daily should be added to the regimen. For patients with severe nausea, domperidone, an investigational antiemetic, can be given. The advantage of domperidone is that it is a dopamine-receptor antagonist, but it does not cross the blood-brain barrier and AMERICAN PHARMACY

therefore does not cause extrapyramidal side effects. Although most patients have a good initial response to levodopa, more than 50% of them will develop dyskinesias or fluctuations in response, or both, in the first five years of levo. dopa therapy. 26 Two types of problems are seen: the end-of. dose effect (or wearing off) and the on-off phenomenon. In the former, the dose of levodopa does not last as long as it originally did. This problem can usually be managed by decreasing the dosing interval or switching to the sustained· release form of the drug. Wearing off may occur because few. er dopaminergic terminals are available to convert levodopa to dopamine. In the on-off phenomenon, the patient experi· ences wide fluctuations in function, ranging from freezing into position ("off') to abnormal involuntary movements or dyskinesias. In the classic on-off phenomenon, fluctuations are not related to time of dosing and can be difficult to man· age. The exact cause of the on-off phenomenon is unknown, but one theory is that sensitivity to small changes in plasma levodopa concentrations is enhanced. 27 Plasma levels may be a measure for the CNS effects of levodopa. Several options exist for the management of the on-off phenomenon. One option is to give smaller, more frequent doses of levodopa or to use the sustained-release form of the drug. Most commonly, another agent, such as a dopamine agonist or selegiline, is added, and the dose of levodopa is decreased by approximately 20%. Some support also has been given to initiating a low-protein diet. Levodopa is absorbed from the gut by a saturable active-transport process. Dietary protein can compete with levodopa for absorption. 28 Therefore, lowering dietary protein to 0.8 gram/kg/day and avoiding highprotein foods may improve drug absorption and reduce the on-off phenomenon. In the past, drug holidays were employed to treat the on-off phenomenon. 2 9 Levodopa was withdrawn for one to two weeks and then reinstituted at lower doses. The problems with drug holidays are that the effects are short-lived and the patient is severely symptomatic during drug withdrawal. Patients are virtually immobilized and at risk for thromboembolism and pneumonia. Drug holidays are no longer advocated.

Several years later, PK is taking carbidopa/levodopa 25/100 mg six times a day. He occasionally experiences wearing off but is more bothered by taking so many doses each day. The physician decides to change PK's medication to the sustained-release form of the drug at dosages of 50/200 mg at 6 am, 12 noon, and 6 pm and 25/100 mg at 10 pm. You counsel PK not to crush the tablets and not to expect a fast onset of action. Sustained-release carbidopa/levodopa was marketed several years ago; its primary goal was to reduce the number of daily doses of levodopa and to treat the wearing-off effect and possibly the on-off phenomenon. The drug was first available in a strength of 50/200 mg, and more recently, a strength of 25/100 mg was added. Because the bioavailability of this product is only 70% of that of the immediate-release form of January 1995

Vol. NS35, No. 1

carbidopa/levodopa, the dose of levodopa should be increased

melanin) and in patients taking nonselective MAO inhibitors.

by 20 to 25% when the patient's regimen is converted from the

It should be used with caution in patients with angina or

immediate-release to the sustained-release form.30 Many patients find that a dosing regimen that combines immediate-release and sustained-release levodopa is beneficial. For example, patients may need a surge of levodopa activity in the morning, so they may take the immediaterelease product on awakening and then use the sustainedrelease product throughout the day. Other patients may take the immediate-release product at night because use of the sustained-release form has caused nightmares in some patients who took it in the evening. With the sustainedrelease form, levodopa accumulates during the day, so lower doses should be given later in the day. If the patient is taking the sustained-release form to combat the wearing-off effect, the dosing interval should be four to six hours. Otherwise, the medication can be given every eight hoursY Dosage adjustments should be made every three to five days. Patients should be counseled about the effects of sustainedrelease carbidopa/levodopa. They should understand that it will not give them an immediate boost in effect and that taking an extra dose will not immediately help them if they are acutely symptomatic. In trials comparing the sustained-release and the immediate-release forms, patients experienced more "on" time and less "off' time and had no abrupt wearing-off effect.3 2 Dyskinesias were still present, and some patients continued to experience fluctuations in response . Both physicians and patients preferred the sustained-release form . Clinicians have also shown interest in using sustainedrelease carbidopa/levodopa as initial levodopa therapy.33 Some evidence indicates that fluctuations in levodopa levels lead to later problems with the drug. By preventing fluctuations in levodopa level early in the disease, perhaps the on-off and wearing-off effects can be prevented. The starting dosage of sustained-release carbidopa/levodopa would be 25/100 mg two to three times daily. Generic carbidopa/levodopa is on the market, but it is still too early to assess whether patients respond differently to the generic form. In addition to the problems associated with levodopa, other adverse effects of carbidopa/levodopa include nausea, orthostatic hypotension, arrhythmias, and CNS effects, such as hallucinations and confusion. Treating the confused or cognitively impaired patient with PD presents a clinical challenge. Typical antipsychotic agents worsen PD because of their dopamine-depleting effects on the extrapyramidal system. Atypical antipsychotic agents, such as clozapine and risperidone, cause minimal extrapyramidal side effects and may be particularly useful in this situation, although there has been little experience with either agent in patients with PD.3 4 ,35 Levodopa should be avoided in patients with narrow-angle glaucoma or malignant melanoma (levodopa is a precursor of

arrhythmias. Patients should be advised to take levodopa on an empty stomach, if possible. If gastrointestinal upset occurs, levodopa can be taken with food, but preferably with foods low in protein. Because of the risk of orthostatic hypotension, the patient should be advised to rise slowly from a sitting or lying position.

Vol. NS35, No. 1 January 1995

After several months of taking sustained-release carbidopa/levodopa, PK complains offluctuations in response that are not necessarily related to the dosing time. He also complains of abnormal movements of his head and shoulders. The physician suspects the on-off phenomenon, reduces the dose of levodopa, and adds bromocriptine 1.25 mg orally twice daily. You recommend that the new drug be taken with food and that any dizziness or lightheadedness be reported to the physician. Dopamine Agonists Bromocriptine and pergolide are the two dopamine agonists currently available in the United States. Dopa-decarboxylase activity decreases as the disease progresses; therefore, a direct dopamine agonist is needed. These agents work by stimulating supersensitive dopamine receptors in the substantia nigra. They also stimulate normosensitive receptors in other areas of the brain, which can lead to side effects. Bromocriptine primarily stimulates D 2 receptors and slightly stimulates D 1 receptors. Pergolide works on both D 1 and D2 receptors. Pergolide is more potent than bromocriptine and has a longer half-life. Goetz et al. found that patients who lost responsiveness to bromocriptine could instead be given pergolide, with good results.36 As discussed earlier, the dopamine agonists have traditionally been added to levodopa therapy when response to the latter is insufficient. Early monotherapy with the dopamine agonists has been hampered by their side effects, mainly gastrointestinal intolerance. Side effects are dose dependent, and one small study found no therapeutic advantage to the use of higher doses of bromocriptine. 17 Other side effects include CNS effects (confusion, hallucinations) and orthostatic hypotension; the latter effect is usually a greater problem early in therapy. Patients should be advised to take the bromocriptine and pergolide with meals and to rise slowly from a sitting or lying position. The dose of bromocriptine should be titrated slowly, with an increase every two to four weeks. The dose of pergolide may be increased every three days.

Investigational Agents Alpha-tocopherol has been advocated as a treatment of PD because of its antioxidant effects. In the DATATOP study, alpha-tocopherol 2,000 IU/day was studied alone and in comAMERICAN PHARMACY

bination with selegiline. 15 The results showed that use of alpha-tocopherol did not affect the probability that the patient would need treatment with levodopa. Apomorphine is an investigational injectable dopamine agonist that is being studied as a treatment of "freezing" episodes that occur in the on-off phenomenon. 37 The patient can self-inject the medication subcutaneously with a pen injector. The drug's onset of action is 5-15 minutes, and its duration of action is 90-120 minutes. The main problem with apomorphine is its potent emetic qualities. It can also cause dyskinesias, and too-frequent use may cause receptor hypersensitivity. Other dosage routes for apomorphine, such as intranasal, rectal, and sublingual administration, are being investigated. 18 Enteral infusions of levodopa are currently being evaluated. 38 The drug can be delivered directly to the duodenum or jejunum by use of a portable pump, which allows the dose to be carefully titrated. Patients can increase or decrease the rate of infusion, depending on their symptoms. Enteral infusions were found to be useful in patients with unreliable responses to orallevodopa, but it is doubtful that this dosage form will gain widespread usage. Besides being metabolized by MAO, levodopa is also metabolized by catechol-o-methyl transferase (COMn in the gastrointestinal tract, kidney, and liver. COMT inhibitors are being investigated in the treatment of PD. Glutamate antagonists are another class of agents being studied. Glutamate overactivity in the basal ganglia may play a role in PD. Partial dopamine agonists, which work only in the nigrostriatal region of the brain, are another promising class of medications for the treatment of PD. 39

Table 4

Nat.i onal Organizations for Parkinson*s Disease American Parkinson Disease Association, Inc. 60 Bay St. Staten Island, NY 10301 (718) 981-8001 Parkinson's Disease Foundation William Black Medical Research Building 650 W. 168th St. New York, NY 10032 (800) 457-6676 National Parkinson Foundation, Inc. 1501 N.W. Ninth Ave. Miami, FL 33136 (800) 433-7022 United Parkinson Foundation 833 W. Washington Blvd. Chicago, IL 60607 (312) 733-1893

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Adjunctive Treatment Several adjunctive treatments may be useful in managing some of the symptoms of PD. Propranolol is approved for use in benign tremor and has been used adjunctively for the treatment of Parkinson's tremor. 40 Success with propranolol has varied, but it may be worth trying when other treatments fail. Patients need to be monitored for hypotension when propranolol is added to standard treatment of PD. Because of decreased blinking, the use of anticholinergic drugs, or both, many patients complain of dry eyes. Artificial tears may offer symptomatic relief. Patients may also suffer from constipation and may need to be counseled on proper use of laxatives.

Nonpharmacologic Treatment The most controversial treatment of PD is the transplantation of fetal tissue. In this treatment, dopamine-producing fetal cells are transplanted into the brain of the patient with PD. Because of recent changes in the regulations permitting this use of fetal tissue, large studies are now starting. In anecdotal reports, most patients improve after surgery. Rehabilitation is used to restore patients to the highest possible level of independent function. Physical and occupational therapy focuses on maintaining coordination, dexterity, flexibility, and range of motion. Therapy helps patients with ambulation, balance, and posture. Assistive devices can be used to help patients remain independent in their activities of daily living (e.g., dressing, eating, grooming). Keeping patients mobile decreases the risk of decubitus ulcers, pneumonia, and thromboembolism. Speech therapy is also useful to maintain the voice volume and to help with swallowing difficulties. Psychologically, patients and their families need support as well. Patients with PD have a high incidence of depression and social withdrawal, especially early in the disease. The family plays an important role in the patient's rehabilitation process. The patient's family can change both the physical and emotional environments to adapt to the patient's needs yet at the same time maintain the patient's self-worth and role in the family. Various support groups and organizations are available to patients with PD and their families (fable 4). With chapters in many cities, these organizations offer information and advice. Health care professionals should be aware of the resources available in their communities. Families and patients should also be encouraged to seek the assistance of home attendants and visiting nurses, when the need arises. One day, while waiting for PK's prescription medications to be refilled, his wife asks you about home health care equipment, such as a bedside commode and bathroom railings. She also tells you that PK is complaining of dry eyes and would like an artificial tear solution. You recommend an appropriate product and counsel her on how to instill eye ...... ,,, January 1995

Vol. NS35, No. 1

drops in her husband's eyes. You also take the opportunity to sit down and thoroughly review with her all of the medications PK is taking. You suggest that she call the local PD support group and encourage her to seek additional help in the house, if necessary.

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Conclusion PD is a progressive, debilitating neurologic disorder. Medications are the primary treatment of this disease, but the medications present challenges to the pharmacist, physician, and patient. Pharmacists should be active members of the teams that care for patients with PD and should be involved in ensuring the appropriate use of antiparkinsonian medications, monitoring for adverse effects, and educating patients and their families about medications. Newer therapies for PD are being developed, and newer roles for older medications are being investigated, in the hope of maximizing the function and quality of life for patients with PD. judith L. Beizer, PharmD, is associate clinical professor, Department of Clinical Pharmacy Practice, St. John's University, jamaica, N. Y

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Commonly Asked Questions Regarding Parkinson's Disease My doctor just told me that I have Parkinson's disease. What is Parkinson's disease? ,,,,,,! • Parkinson's disease occurs most often in the elderly. It is a progressive disease, which means that at ftrst, you may have mild symptoms, but as years go by, you will probably notice that your symptoms are becoming more pronounced. Parkinson's disease causes tremors-your head and limbs may shake-and stiffness-your muscles may be rigid. People with Parkinson's disease cannot start to move quickly, and they often develop a bowed posture and a shuffling gait. What causes Parkinson's disease? How did I get it? The human brain is complex. It uses many chemicals and nerve pathways to send messages to the rest of the body. Your decision to walk across the room, for example, begins as a chemical message in your brain. Doctors know that people with Parkinson's disease do not have enough of a brain chemical called dopamine, but doctors don't know why the brain may stop producing it. How is Parkinson's disease treated? Can it be cured? There is no cure for Parkinson's disease, but your doctor can turn to sevtl eral medications to control your symptoms. Most people with Parkinson's take levodopa -carbidopa; its trade name is Sinemet. In the brain, levodopa turns into dopamine, the chemical your brain needs to control movement. Your doctor will prescribe levodopa when your symptoms are severe enough to interfere with your daily activities. As your symptoms become worse, your doctor will increase the dosage of your medication or try different combinations of medicines to keep you as comfortable and active as possible. I've heard that the drug selegiline (Eldepryl) can stop the progression of Parkinson's disease. Is this true? , ~© Selegiline (formerly known as L-deprenyl) has been studied in early Parkinson's disease. Patients on selegiline have been able to keep up their normal activities for a longer period before they need to start taking levodopa. Researchers believe that selegiline may slow, but not prevent, the progression of Parkinson's disease. Selegiline is also useful in combination with levodopa later in the course of treatment. What are some of the side effects of levodopa? What is the "on-off' , phenomenon? W" The most common side effects of levodopa are dizziness when you stand up quickly and nausea. Confusion occurs in some people. Combining levodopa with carbidopa usually controls these side effects. After several years of taking levodopa, some people experience new difficulties in movement. They may have abnormal movements they cannot control, or they may freeze into one position-these difficulties are the "on" and "off' referred to as the "on-off'' phenomenon. If you develop the on-off phenomenon, your doctor may change your dose of levodopa or add another medication. What other methods, besides taking medications, are useful in the management of Parkinson's disease? Physical and occupational therapy can help you stay active and mobile. When daily activities become difficult, you can rely on devices to help you with walking, dressing, grooming, and other necessities. Dry eyes and decreased blinking can be helped with over-the-counter eyedrops. Laxatives can help manage the constipation that often accompanies the disease. In the later stages of the disease, speech therapy can help patients who have difficulty swallowing or projecting their voices. Other treatments-for example, surgical implantation of dopamine-producing fetal cells-are still in the research stage. Studies are investigating whether such treatments are safe and effective. Are there any support groups in the community for me and my family? Call one of the national organizations for Parkinson's disease and ask if there is a local chapter. Call your hospital and ask if it sponsors any programs on Parkinson's. A support group will give you emotional assistance and can be a rich source of practical information to help you and your family meet the daily challenges of living with Parkinson's disease.

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References 1. Hoehn MM. The natural history of Parkinson's disease in the prelevodopa and post-levodopa eras. Neural C/in. 1992;10:331-9. 2. Olanow CW. Oxidation reactions in Parkinson's disease. Neurology. 1990;40(suppl3):32-7. 3. Tanner CM, Langston JW. Do environmental toxins cause Parkinson's disease? A critical review. Neurology. 1990;40(suppl3):17-30. 4. Stephen PJ, Williamson J. Drug-induced parkinsonism in the elderly. Lancet. 1984;ii:1082-4. 5. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;17:427-42. 6. Lang AE, Fahn S. Assessment of Parkinson's disease. In: Munsat TL, ed. Quantification of Neurologic Deficits. Boston : Butterworths; 1989:285-309. 7. Melamed E. Initiation of levodopa therapy in parkinsonian patients should be delayed until the advanced stages of the disease. Arch Neural. 1986;43:402-5. 8. Fahn S, Bressman SB. Should levodopa therapy for parkinsonism be started early or late? Evidence against early treatment. Can J Neural Sci. 1984;11:20
32. Hutton JT, Morris JL, Bush OF, et al. Multicenter controlled study of Sinemet CR vs. Sinemet (25/100) in advanced Parkinson's disease. Nei!' rology. 1989;39(suppl2):67-72. 33. Olanow CW, Nakano K, Nausieda P, et al. An open multicenter trial of Sinemet CR in levodopa-naive Parkinson's disease patients. Clin Neuro. pharmaco/. 1991 ;14:235-40. 34. Ostergard K, Dupont E. Clozapine treatment of drug-induced psychotic symptoms in late stages of Parkinson's disease. Acta Neurol Scand. 1988;78:349-50. 35. Friedman JH, Max J, Swift R. Idiopathic Parkinson's disease in a chronic schizophrenic patient long-term treatment with clozapine and L-dopa. Cfin Neuropharmacol. 1987;10:470-3. 36. Goetz CG, Tanner CM, Glantz RH, et al. Chronic agonist therapy for Parkinson 's disease: a five year study of BCT and PERG . Neurology. 1985;35:749-51 . 37. Frankel JP, Lees AJ, Kempster PA. et al. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neuro/ Neurosurg Psychiatry. 1990;53:96--101 . 38. Lewitt PA. Treatment strategies for extension of levodopa effect. Neural Clin. 1992;10:511-25. 39. Riederer P, Lange KW, Youdim MBH. Recent advances in pharmacologi· cal therapy of Parkinson's disease. Adv Neural. 1993;60:626--35. 40. Tyrer PJ. Use of beta -blocking drugs in psychiatry and neurology. Drugs. 1980;20:300-8. 41. Hansten PO, Horn JR, eds. Drug Interactions and Updates. Vancouver: Applied Therapeutics; 1993. 42. Olin BR, ed. Drug Facts and Comparisons. St. Louis: Facts and Compar· isons; 1994.

12. Diamond SG, Markham CH, Hoehn MM. et al. Multi-center study of Parkinson mortality with early versus late dopa treatment. Ann Neurol. 1987;22:8-12.

Assessment Questions

13. Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science. 1989;245:519-22. 14. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Eng/ J Med. 1989;321 :1364-71. 15. The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Eng/ J Med. 1993;328: 176--83. 16. Kurian R. International symposium on early dopamine agonist therapy of Parkinson's disease. Arch Neural. 1988;45:204-8. 17. The Bromocriptine Multicentre Trial Group. Bromocriptine as initial therapy in elderly parkinsonian patients. Age Ageing. 1990;19:62-7.

Instructions: For each question, blacken the letter on the answer sheet corresponding to the answer you select as being the correct one. Please review all of your answers to be sure you have blackened the proper spaces. There is only one correct answer for each question. 1.

The primary neurotransmitter disorder in Parkinson's disease is: a. Dopamine excess b. Acetylcholine deficiency c. Dopamine deficiency d. Serotonin excess e. Norepinephrine deficiency

2.

Which of the following medications does not cause drug-induced parkinsonism? a. Reserpine b. Propranolol c. Haloperidol d. Prochlorperazine e. Metoclopramide

3.

All of the following are symptoms of Parkinson 's disease except: a. Diarrhea b. Resting tremor c. Cogwheel rigidity d. Shuffling gait e. Micrographia

4.

Which of the following statements concerning the treatment of Parkinson's disease is true? a. Most patients can be maintained on amantadine with no loss in efficacy. b. Dopamine agonists should never be used alone. c. Antiparkinsonian therapy should be initiated in all patients being given an anticholinergic agent. d. Sustained-release carbidopa/levodopa should not be used as initial therapy. e. Selegiline is used early in the disease for its neuroprotective effect.

18. Montrastruc JL, Rascal 0, Senard JM. Current status of dopamine agonists in Parkinson's disease management. Drugs. 1993;46:384-93. 19. Rinne UK. Early combination of bromocriptine and levodopa in the treatment of Parkinson's disease: a 5-year follow-up. Neurology. 1987;37 :826--8. 20. Rinne UK. Strategies in the treatment of early Parkinson's disease. Acta Neural Scand [Supp/}. 1993;87(suppl146):50-3. 21 . Elizan TS, Yahr MD, Moros DA. et al. Selegiline as an adjunct to conventional levodopa therapy in Parkinson 's disease. Arch Neural. 1989; 46:1280-3. 22. Knoll J . (-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system . JAm Geriatr Soc. 1992;40:839-47. 23. Du Pont Pharmaceuticals. Symmetrel. Wilmington, Del: Du Pont, April 1992.Packageinsert. 24. Standaert DG, Stern MB. Update on the management of Parkinson's disease. Med Clin North Am. 1993;77:169-83. 25. Koller WC . Initiating treatment of Parkinson's disease. Neurology. 1992;42(suppl 1):33-8. 26. Poewe WH, Lees AJ, Stern GM. Low-dose L-dopa therapy in Parkinson's disease: a 6-year follow-up study. Neurology. 1986;36:28-30. 27 . Juncos JL. Levodopa: pharmacology, pharmacokinetics, and pharmacodynamics. Neurol Clin. 1992;10:487-509. 28. Nutt JG, Woodward WR, Hammerstad JP, et al. The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N Eng/ J Med. 1984;310:483-8. 29. Friedman JH. " Drug holidays" in the treatment of Parkinson's disease. A brief review. Arch Intern Med. 1985;145:913-5. 30. Merck & Co., Inc. Sinemet CR. West Point, Pa: Merck & Co., Inc. : Decem ber 1992. Package insert. 31 . Rodnitsky RL. The use of Sinemet CR in the management of mild to moderate Parkinson's disease. Neurology. 1992;42(suppl1):44-50.

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5.

All of the following statements concerning selegiline are true except: a. In dosages of< 10 mg/day, selegiline selectively inhibits monoamine oxidase-B. b . Patients taking selegiline do not have to avoid tyraminecontaining foods. c. Selegiline should be taken early in the day to avoid insom nia.

d. Selegiline should not be used in combination with levodopa. e. Selegiline is being studied in the treatment of Alzheimer's disease.

12. All of the following should be told to patients taking carbidopa/levodopa except: a. Do not crush the sustained-release form. b. Do not expect a surge in effect with the sustained-release form. c . It may cause central nervous system effects like confusion and hallucinations. d. Take it with a high-protein diet. e. Rise slowly from a sitting position.

13. Which of tlte following statements about dopamine agonists is true? a. They rarely cause nausea. b. Pergolide and bromocriptine are tlte only ones available in the United States. c. Bromocriptine is more potent than pergolide. d. The dose of bromocriptine can be rapidly increased. e. They are converted to dopamine in tlte brain.

6. Which of the following statements concerning anticholinergic agents is true? a. Therapy can be discontinued abruptly. b. Side effects are usually well tolerated. c. Men with prostatic hypertrophy should avoid taking anticholinergic agents. d. Anticholinergic agents are safe in patients with narrowangle glaucoma. e. Anticholinergic agents are most useful for treating bradykinesia. 7.

8.

9.

14. All of tlte following statements about apomorphine are true except: a. It is a dopamine agonist. b . It is given subcutaneously. c. It is useful to treat "freezing" episodes that occur in the on-off phenomenon. d . It has potent emetic properties. e. It is currently available in the United States.

Which of the following is not a side effect of amantadine? a. Constipation b . Dyskinesias c . livedo reticularis d. Orthostatic hypotension e. Confusion

15. Investigational treatments for Parkinson's disease include all of tlte following except: a. L-deprenyl. b. Enteral infusions of levodopa. c. Catechol~methyl transferase inhibitors. d. Glutamate antagonists. e. Partial dopamine agonists.

Which of the following statements concerning carbidopa/ levodopa is true? a. Patients on carbidopa/levodopa should avoid taking vitaminB6. b . Carbidopa works by enhancing the blood-brain barrier's permeability to levodopa. c. The incidence of nausea is increased when carbidopa is added to levodopa. d. Plain carbidopa is not available. e. To achieve a therapeutic effect, 50-100 mg/day of carbidopa is needed.

16. Adjunctive treatment of Parkinson's disease includes all of the

following except: a. Propranolol b . Chlorpromazine c. Artificial tears

d. Laxatives e. Domperidone 17. Which of the following statements about the Hoehn-Yahr scale is false? a. Stage V is the severest stage. b. It is based on clinical signs and functional ability. c. It is based on the number of years tlte patient has had Parkinson's disease. d. It assesses the severity of Parkinson's disease. e. Patients witlt stage I disease usually have unilateral symptoms.

An appropriate starting dosage of carbidopa/levodopa would be: a. 10/100 mg three times a day. b. 25/100 mg three times a day. c . 25/250 mg three times a day. d. 25/250 mg every day. e. 10/100 mg five times a day.

10. Which of the following is not an acceptable option for the management of the on-off phenomenon? a. Drug holiday. b. Use of sustained-release carbidopa/levodopa. c. Use of smaller, more frequent doses of carbidopa/ levodopa. d . Addition of a dopamine agonist and decrease in the dose of carbidopa/levodopa. e. Addition of selegiline and decrease in the dose of carbidopa/levodopa.

18. Newer treatment options in Parkinson's disease include all of the following except: a. Initiation of therapy with a dopamine agonist. b . Initiation oftlterapy with low-dose combination therapy. c. Initiation of therapy with selegiline. d. Initiation of therapy with high-dose levodopa. e. Maintenance of the levodopa dosage at 400-600 mg/day. 19. Traditionally, levodopa should be started: a. At the onset of symptoms. b . When the patient complains of functional impairment. c. Two years after onset of the disease. d. Five years after disease onset. e. When all other agents fail.

ll . When the patient's regimen is converted from immediaterelease carbidopa/levodopa to the sustained-release form, the dose should be: a. Increased by 20-25% b . Decreased by 20-25% c . The same d. Increased by 70% e. Decreased by 70%

Vol NS35, No. 1 January 1995

20. Which of the following medications does not interact with levodopa? a. Digoxin b . Methyldopa c. Diazepam d . Phenytoin e. Phenelzine

ED

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