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Surgical treatment is for patients with persistent and disabling rigidity, tremor, or motor fluctuations despite maximizing medications. Symptoms of poor balance, akinesia, speech impairment, and freezing do not improve with surgery. There is an increased risk of depression following surgery, and long-term safety trials are in pro-gress.9 Deep-brain stimulation, the surgery of choice, involves the implantation of a high-frequency device that provides electrical stimulation of the globus pallidus and


subthalamic nucleus. Patients can expect a 40% to 75% decrease in symptoms. ' ' Pharmacologic Therapy

The best time to initiate dopaminergic therapy is controversial and patient-specific. Generally, medication is started when the patient's physical impairment affects QOL. However, some clinicians believe that starting treatment earlier may improve outcomes.

® Medication schedules should be individualized. The doses should be divided throughout the day to maximize on and minimize off periods.

Pharmacologic options include anticholinergic drugs, amantadine, monoamine oxidase type B inhibitors (MAO-B), dopamine agonists, levodopa/carbidopa, and cat-echol-O-methyltransferase (COMT) inhibitors. Medications help relieve symptoms, improve QOL, and may lengthen life expectancy, but they are not curative, and treated PD patients still die earlier than controls.1 Knowing how dopamine is metabolized and how drugs affect dopamine metabolism is important in understanding the pharmacology of PD medications (Fig. 32-2). The American Academy of Neurology and the Movement Disorder Society determined that it is reasonable to start with le-vodopa or a dopamine agonist. Starting treatment with a dopamine agonist rather than levodopa may help to delay the onset of dyskinesias and the on/off fluctuations commonly seen with long-term levodopa use. However, initiating therapy with a dopam-ine agonist instead of levodopa/carbidopa may result in less motor benefit and greater risk of hallucinations or somnolence. Levodopa results in greater motor improvement and should be used as initial therapy in the elderly (greater than 75 years of age) and in those with cognitive impairment. There is no preference for using controlled-re-lease over immediate-release levodopa as initial therapy. There are insufficient data to recommend initiating treatment with both levodopa and a dopamine agonist. Initiating treatment with anticholinergic medications, amantadine, or MAO-B inhibitors is only for patients who have mild symptoms, as they are not as effective as dopamine agonists.1,18,23-25

Carbidopa Levodopa Protein Mechanism

FIGURE 32-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopadecarboxylase, monoamine oxidase, and catechol-0-methyltrans-ferase. Carbidopa does not cross the blood-brain barrier. Large, neutral aminoacids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport into the brain (plasma compartment to brain compartment). Food and anticholiner-gics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals.

FIGURE 32-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopadecarboxylase, monoamine oxidase, and catechol-0-methyltrans-ferase. Carbidopa does not cross the blood-brain barrier. Large, neutral aminoacids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport into the brain (plasma compartment to brain compartment). Food and anticholiner-gics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals.

Medications should be started at the lowest dose and increased gradually based on symptoms (Table 32-1). When interviewing patients, ask the following questions for each scheduled dose before adjusting the dose or timing of medications:

• When did the dose start to work and how long did it last?

• How did you feel just before the dose, and during the dosing period?

If the dose did not last long enough, consider adding another dose each day, higher individual doses, an additional agent, or changing to a longer-acting dosage form. If the patient experiences side effects related to excessive dopamine concentrations (e.g., dyskinesia), consider decreasing the dose, increasing the time interval between doses, or decreasing the use of concomitant medications that augment dopamine concentrations.


Anticholinergics may minimize resting tremor and drooling, but they are not as good as other agents in controlling rigidity, bradykinesia, and gait problems. Anticholinergics should be discontinued gradually to avoid withdrawal effects or worsening of PD symptoms. Side effects of anticholinergics include dry mouth (decreased saliva), blurred vision, constipation, cognitive impairment (forgetfulness, confusion), hallucinations, urinary retention, orthostatic hypotension, temperature sensitivity, and sedation. They are usually avoided or used with caution in patients older than 70 years

1279 21 25

of age because of an increased risk of cognitive impairment. ' ' ' Use of anti-cholinergics is associated with an increased incidence of amyloid plaques and neur-ofibrillary tangles inpatients with PD that may translate to an increased risk of Alzheimer's disease.2 Anticholinergics decrease gastric motility which may decrease levodopa drug absorption.16,19

Table 32-1 Mechanism of Action and Dosing of Medications to Treat PD

Generic Name (Trade Name)

Mechanism of Action and Receptor Specificity_Dosing

Levodopa with carbcdopa (Sírveme!)

(Parcopa with phenylalanine) (S«rvemet Cfi)

(Duodopa orphan drug on fast track for approval) Apo morphine (Apokyn)

Bromocriptine (Parlodel)

Pramipexoie (Mirapex)

Standard immediate-release LO (LDis metabolized to doparrine) CD bloc*s perpheral conversion of LO to DA and increases LD CNS penetration

Rapid-dissolving LD

Sustained-release LD

Stable gel suspension oí LD

Activate postsynaptic Dl and 02 DA eceptors

Activate postsynaptic 02 and blocks Dl DA receptors

Activate postsynaptic D2 DA recept«s

Start with CSinemet) Vi tab (100 mg LD. 2S mg CD) twice daily for l week, then v> tab three times daily then, increase by v> tab daily every week, usual MD Is 300-2.000 mg daily: since the duration of LD is 2-3 hours, patients may requre doses every 2 hours

Same as Smemet

Start with I tab (100 mg I D, 2S mg CD) 2-3 times daily, as symptoms increase, use 200mg LD tab 2-4 times daily usual MD is 200-2.200 mg daily

Portable pump that continuously delivers ID 20 mg/mL and carbidopa S mg/mL via a duodenal tube

Start an antiemetic for 3 days, then gtve apomorphine 2 mg SC injection (1 mg if outpatient) while monitoring blood pressure; then increase by 1-2 mg every 2 or more hours; usual MD Is 2-6 mg 3-5 times daily for off periods

Start with 1.25 mg daily at bedtime, then 1.25 mcj twice daily on week 2. increase to 2.S mg twice daily, then increase by 2.5 mg daily every 2-4 weeks up to 15-45 mg daily divided 2-3 times daily

Start with 0.125 mg three tin*s cWy increase about weekly b/ 0.375-075 mgAJay to a MO of 0.5-1.5 mg three daily: dosage reductcn needed in patients with creatinine clearance less than 60 mlVmn


(Requip) (Requip XL)

Selegiline (Etdepiyl)

(Zelapar with phenylalanine)

Rasagalirv? (A/ilect) Tokapone (Tasmar)

Entacapone (Comtan) CtVlO/fniacapone (Stolevo)

Amantadine (Symmetrel)

Anticholinergic (various, including trihexyphenidyl, benrtropine)

Activate postsynaptic 02 DA recept«s

Immediate release Extended-release

Start with 0.2S mg three times daily; increase about weekly by 075-15 mg daily to a MD dose of 3-8 mg three times daily

Start with 2 mg once daily for I -2 weeks. Increase by 2 mgitiay in 1 week intervals; maximum dose is 24 mgrfdiy. When switching from immediate-release form use dose closest to the total dally dose

Blocks WVO-B metabolism and Start with 5 mg in the morning if symptoms continue, add 5 mg at presynaptic reuptake of DA in noon; 5 mg daily may be as clinically effective as 10 mg daily with the bran fewer side effee ts

RapiddksoMng setegrfme

Blocks MftO-8 metabolism Peripheral blocks COMT metabolism of DA; some cential activity Periphery blocks COMT

metabolism of DA See CO. 10. and entacapone

NMDA-roceptor antagonist that Weeks glutamate transmission promotes DA retease.and blocks Ach Bkxk Ach. efcerease Ach DA ratio

Start with I.2S mg every morning before breakfast; if symptoms continue after 6 weeks, increase dose to 25 mg every morning. Avoxl food or liquid for S minutes before or after the dose Start with 05 mg daily it symptoms continue. Increase to I mg dally Start with 100 mg with first Sinemet dose once daily, if symptoms continue, increase to 2 and then 3 times daily, then to 200 mg each dose: usual MD is 100-200 mg 3 times daily 200 mg tab with each Sinemet dose up to 8 tabs dafy. usual MD is 200 mg 3-4 times daily; decrease dose by 50% with hepatic impairment

Usual MD is 300-1.600 mg L0 daily the Ugest strength tab contains ISO mg 10 and 200-mg entacapone: patents requiring larger LD doses will need additional LD medication; titrate as with LD

Start with 100 mg daily at breakfast after 1 week, add 100 mq daily, decrease dose as creatinine clearance decreases less than 80 ml/minute: usual MD is 200-300 mg daily with last dose h afternoons

Ach, acetyk:hol*ve: CO, carbidopa; COMT. catechol 0 methytiransferase: Dl, a class oi dopamine receptors which includes D. and D. subtypes; D2, a class o< dopamine receptors which includes 0„ D, and D, subtypes; DA, dopamine: ID. levodopa: MAO. monoamine oxidase; MD. maintenance dose; NMDA, ft-methyl-c-aspartate. From Refs. 1.4.25.


Amantadine improves PD symptoms in mildly affected patients and reduces motor fluctuations and dyskinesias in patients with more advanced disease. It may minimize or delay the development of motor complications, as levodopa's pulsatile stimulation of dopamine receptors is associated with N-methyl-D-aspartate (NMDA) receptor changes and resultant motor complications. Patients who develop tolerance to amantadine's effects may benefit from a drug holiday. Doses need to be reduced in patients with renal impairment. When stopping amantadine, it should be gradually discontinued to minimize potential withdrawal effects. Side effects include nausea, dizziness, livedo reticularis (purple mottling of the skin), peripheral edema, orthostatic hypotension, hallucinations, restlessness, and anticholinergic effects. Its stimulant action may worsen insomnia, so amantadine should not be dosed in the evening.

It should be avoided in the elderly who cannot tolerate its anticholinergic ef-1 2 4 7-9 16 18 21—25

fects. ' ' ' ' ' ' It should be used cautiously with memantine, as there may be


an increased risk of psychosis and prolonged QT-interval. ' MAO-B Inhibitors

MAO-B inhibitors include selegiline and rasagiline. They may provide mild symptomatic benefit for those patients who choose to delay dopaminergic medications. Combining selegiline or rasagaline with levodopa in early treatment may delay motor complications. In patients with advanced disease, they decrease off time and improve

23 25 28

wearing-off symptoms in patients with motor fluctuations. ' '

Rasagiline may delay the progression of PD, as patients receiving rasagiline mono-therapy had higher UPDRS and QOL scores than patients who had delayed starting rasagiline for 6 months. After 1 year, patients in the delayed start group did not catch


up with those who received rasagiline earlier. Rasagiline may be neuroprotective and neurorestorative because it minimizes apoptosis and increases concentrations of 30

neurotrophic factors. The potential neuroprotective effects of selegiline may be off-

set by the neurotoxic effects of its amphetamine metabolite.

Selegiline is available in a patch formulation which should be avoided in patients with PD. The orally disintegrating tablet formulation avoids first pass metabolism which improves bioavailability and decreases serum concentrations of the amphetamine metabolite. Side effects of selegiline are minimal but include nausea, confusion, hallucinations, headache, jitteriness, and orthostatic hypotension. The amphetamines metabolite may improve fatigue but cause insomnia. Thus, selegeline should not be dosed in the late afternoon or evening. Doses are limited to 10 mg daily, as MAO-B selectivity may be lost at higher doses increasing the risk of adverse effects and drug interactions.1,23-25,28

Rasagiline is not metabolized to amphetamine; thus, there is less risk of insomnia. Side effects are primarily GI with no increased risk of vasoreactive or psychiatric effects.28 The manufacturer recommends that patients restrict the intake of tyramine-containing foods and medications that contain amines, however a recent abstract suggests that 2 mg or less of rasagiline a day may safely be administered without dietary tyramine restrictions.31 In addition, several trials were conducted without restriction

of tyramine-containing foods without any reactions.

Dyskinesias can be minimized by decreasing the levodopa dose when adding either of these agents. Patients should avoid or use these medications cautiously with narcotic analgesics, antidepressants, or sympathomimetic amines (cold and weight loss products). Rasagiline is metabolized by the CYP1A2 pathway, thus drugs that inhibit CYP1A2 (e.g., ciprofloxacin or cimetidine) increase rasagiline concentrations, and inducers (e.g., omeprazole) may reduce rasagiline concentrations. Rasagline does not induce or inhibit enzymes in the P450 system. Selegiline is metabolized by CYP2B6 and CYP3A4. It does not inhibit P450 enzymes, but CYP3A4 inducers

(e.g., phenytoin and carbamazepine) could reduce selegiline concentra-

Dopamine Agonists

Dopamine agonists are useful as initial therapy, as they can delay the need to start le-vodopa and can decrease the risk of developing motor fluctuations by two- to threefold during the first 4 to 5 years of treatment. After a few years, dopamine agonists inadequately control the patient's symptoms, and levodopa needs to be started. In advanced disease, dopamine agonists can be added to levodopa because they have a longer duration of action, minimize fluctuations in dopamine blood concentrations, decrease off time, improve wearing-off symptoms, allow a reduction in levodopa dose, and improve ADLs.1-4,16,23-25,28'1

Dopamine agonists include the ergot derivatives (bromocriptine) and the nonergot derivatives (rotigotine, pramipexole, ropinirole, and apomorphine). Generally, all are equally effective except bromocriptine, which is the least effective. There are five subtypes of dopamine receptors that are divided into two classes called D1 (D1 and D5 subtypes) and D2 (D2, D3, and D4 subtypes). Receptor selectivity may result in subtle differences between the products, as pramipexole is thought to have an antidepressant effect, because it has greater D3 receptor affinity. Ropinirole may have higher D3 specificity, but less than pramipexole. Rotigotine is a once-daily skin patch that is available in Europe but has been withdrawn in the United States, until stability problems are resolved. If patients fail one dopamine agonist, another can be tried. Although not well established, it appears that bromocriptine 30 mg, ropinirole 15 mg, and pramipexole 4.5 mg are equivalent and this relationship can be a guide when switching agents.1,4,16,23-25,28,31

Common side effects include nausea, vomiting, sedation (highest with apo-morphine), pedal edema, orthostatic hypotension (highest with pramipexole and cabergoline), and psychiatric effects that are greater than with levodopa (nightmares, confusion, and hallucinations). Ergot side effects are uncommon but include painful reddish discoloration of the skin over the shins and pleuropulmonary, retroperitoneal, and cardiac fibrosis.1,16,23-25,31 Obsessive-compulsive behaviors such as pathologically excessive gambling, shopping, sexual desire, or eating may occur. Reducing or

eliminating the agonist usually resolves these problems. A questionnaire is avail-

able to help clarify potential psychiatric complications in patients with PD.

Excessive daytime sleepiness occurs in 15% to 20% of PD patients and can be aggravated by all dopaminergic drugs potentially compromising the ability to drive. Sleep attacks without warning may occur in up to 6% of patients. Patients at greatest risk of sleep attacks are those with an Epworth Sleepiness Scale34 score more than 10, long duration of PD, and those taking dopamine agonists with levodopa.10,11,35,36 Adding modafinil (100-200 mg twice daily) or possibly selegiline can improve alertness.37

All dopamine agonists are metabolized by the liver except pramipexole, which is eliminated unchanged in the urine by active tubular secretion and requires dose reduction when creatinine clearance is less than 60 mL/min. Drug interactions may occur if it is given concurrently with other agents that are eliminated by active tubular secretion, such as verapamil and cimetidine. Ropinirole is metabolized by cytochrome P450 oxidation in the liver and subject to drug-drug interactions with drugs that induce (smoking) or inhibit (ciprofloxacin, fluvoxamine, and mexiletine) CYP1A2.23-25,28

Apomorphine is approved for acute off episodes in patients with advanced stages of PD. The onset of effect is within 10 to 20 minutes, and the duration of effect is about 60 minutes. It requires premedication with an antiemetic because it causes nausea and vomiting. Patients who are allergic to sulfites may be allergic to apo-morphine 23-25,38


Although, levodopa, a dopamine precursor, is the most effective agent for PD, when to initiate therapy remains controversial. Patients experience a 40% to 50% improvement in motor function with levodopa versus 30% with dopamine agonists.1 However, some feel it best to delay starting treatment because about one-half of patients develop motor fluctuations and dyskinesias after 5 years of levodopa.1,16,25 Others feel levodopa

should be started sooner because it may normalize basal ganglia dysfunction. In support of this idea, patients from the prelevodopa era who delayed starting levodopa until it became available developed dykinesias sooner than modern era patients. In addition, patients who had a longer delay in starting levodopa treatment developed dyskinesias sooner than those who had a shorter delay.1,8,16, 3-25

Levodopa is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa absorption requires active transport by a large, neutral aminoacid transporter protein (Fig. 32-2). Levodopa competes with other aminoacids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements, and administration of iron products should be spaced by at least 2 hours from the levodopa dose.1,8,23-25

The controlled-release (CR) formulation (labeled as sustained-release or extended-

release depending on brand) is more slowly absorbed and longer acting than immediate-release tablets. With these dosage forms the total daily dose should be increased by 30%, as it is not as bioavailable as the immediate-release levodopa/

carbidopa. The CR formulation has a delayed onset (45-60 minutes) compared to the standard formulation (15-30 minutes). Thus, patients may also need to take immediate-release tablets or even a liquid formulation when they want a quicker onset

of effect, such as with the first morning dose.

Levodopa is usually administered as a combination product with carbidopa, a dopa-decarboxylase inhibitor, in order to decrease the peripheral conversion of le-vodopa to dopamine. Carbidopa does not cross the blood-brain barrier and does not interfere with levodopa conversion in the brain. Concomitant administration of carbidopa and levodopa allows for lower levodopa doses and minimizes levodopa peripheral side effects such as nausea, vomiting, anorexia, and hypotension. Generally 75 to 100 mg daily of carbidopa is required to adequately block peripheral dopamine decarboxylase. Taking extra carbidopa may reduce nausea related to initiating levodopa.8,23-25

Initial levodopa side effects include orthostatic hypotension, dizziness, anorexia, nausea, vomiting, and discoloration of urine/sweat. Most of these effects can be minimized by taking levodopa with food and using a slow dose titration. Postural hypotension may worsen as the autonomic symptoms of PD worsen, or with coadministration of other medications that lower blood pressure. Side effects that develop later in therapy include dyskinesias, sleep attacks, impulse control disorders, and psychiatric effects (confusion, hallucinations, nightmares, and altered behavior). Dyskinesias caused by adding other PD drugs to levodopa may be improved by decreasing the levodopa dose.1,8, 3-25

Patients with severe dyskinesias and off periods may achieve more constant blood concentrations (lower peak and higher trough concentrations) by taking a liquid formulation of levodopa with carbidopa. Each day patients may make a 1 mg/mL le-

vodopa solution made with water and ascorbic acid or with a carbonated beverage,

which allows patients to take a precisely adjusted dose every 30 to 90 minutes. COMT Inhibitors

COMT inhibitors are used in conjunction with levodopa/carbidopa. They minimize peak and trough levodopa fluctuations by prolonging the half-life and area under the curve of levodopa. They may allow for a decrease in daily levodopa doses while increasing on time by 1 to 2 hours, decreasing wearing off, and improving ADLs in patients with motor fluctuations. Some clinicians believe that a COMT inhibitor should be added when levodopa is first introduced in an effort to promote more continuous dopamine stimulation, potentially minimizing long-term complications associated with the more pulsatile effect of intermittent levodopa administration. However, starting multiple drugs at the same time increases the risk of side effects. Side effects include diarrhea (worse with tolcapone), nausea, vomiting, anorexia, dyskinesias, urine discoloration, daytime sleepiness, sleep attacks, orthostatic hypotension, and hallucin-

ations. Dyskinesias should improve with a decrease in the levodopa dose. ' ' Entacapone inhibits P4502C9; thus drugs like warfarin may have increased effects.19

Tolcapone is associated with three cases of severe liver failure, including fatalities, and has been removed from the market in some countries. Thus, it should be used only in patients who cannot take or do not respond to entacapone. When starting therapy, patient informed consent should be documented. Serum alanine aminotransferase and aspartate aminotransferase concentrations should be monitored at baseline, then every 2 to 4 weeks for 6 months, and then periodically for the remainder of therapy. Patients who fail to show symptomatic benefit after 3 weeks should discontinue tolcapone. Entacapone has not been associated with liver damage, so monitoring of liver

enzymes is not currently recommended. Herbs and Supplements

Clinicians should ask patients if they take any herbs and supplements. There is very little support for using creatine, gingko, ginseng, green tea, ginger, yohimbine, or St John's wort in patients with PD. Patients should be cautioned that supplements and herbs are not well controlled by the FDA and may not contain the active ingredient or amounts indicated on the label. Melatonin and valerian may improve insomnia, but there are insufficient data on their use in PD patients.41

Patients should eat a balanced diet and take a multivitamin with minerals, but there is generally no need to supplement with specific vitamins. Some clinicians recommend vitamins C and E for their antioxidant properties; however, no significant improvements have been documented. Encourage patients to eat a diet rich in vitamin C and E (i.e., bright colored fruits and vegetables, nuts, and whole grains). Metabolism of levodopa may elevate homocysteine concentrations that may be associated with an increased risk of vascular disease, dementia, and depression. Administering levodopa with a COMT inhibitor may minimize the increase in homocysteine. Vitamin B is involved in maintaining normal homocysteine concentrations; thus PD patients may have a greater requirement for B vitamins than patients not receiving levodopa. Eating foods rich in B vitamins (i.e., wheat gram, beans, and whole grains) should be sufficient; however, B vitamin supplements may be warranted in patients with elevated homocysteine concentrations. Excess pyridoxine (vitamin B6) may decrease the


effect of levodopa, so limit doses to less than 50 mg per day. ' '

Coenzyme Q10 is an antioxidant essential for mitochondrial function. Patients taking 1,200 mg daily had a slower decline in UPDRS scores than patients not receiving coenzyme Q10. Lower doses were no better than placebo. Many formulations contain vitamin E, and patients should not exceed recommended daily allowances of this vitamin, as bleeding times may be prolonged.44,45

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