Chapter 17. Pharmacologic Management of Parkinson's Disease and Other Movement Disorders

The major movement disorders include Parkinson‘s disease, Huntington‘s disease, Wilson‘s disease, Tourette‘s syndrome. An outline of common movement disorders is given in Table 17–1.

Several different types of abnormal movements or signs of these disorders are recognized, including athetosis, ballismus, chorea, dyskinesia, dystonia, tics and tremor as described in Table 17–2. These movements can be caused by a variety of general medical conditions and certain drugs, in addition to the neurologic disorders mentioned.

To understand how the movement disorders are treated, it is important to understand their underlying pathogenesis. Many of the movement disorders have been attributed to disturbances of the basal ganglia, but the precise function of these anatomic structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites. Furthermore, individuals with the same disease, such as Parkinson’s disease, can present very differently in terms of symptoms and may respond quite differently to drug and rehabilitative therapies. The major drug groups and representative drugs used in Parkinson’s disease and in other movement disorders are indicated in Figure 17–1.

Parkinson’s disease is a common movement disorder that involves dysfunction in the basal ganglia and associated brain structures. Signs and symptoms include rigidity of skeletal muscles, akinesia (or bradykinesia), flat facies, and tremor at rest (mnemonic RAFT). In Parkinson’s disease, there is a slow, progressive degeneration of dopaminergic neurons in the basal ganglia. The resulting clinical signs and symptoms are thought to be due to an imbalance in neurotransmitter function as a result of this neuronal degeneration.

Naturally occurring Parkinson’s disease is of uncertain origin but may be related to exposure to some unrecognized neurotoxin or to the occurrence of oxidation reactions with the generation of free radicals. Dysfunction is progressive, with increasing disability occurring more frequently from the fifth or sixth decade of life onward. Treatment, both pharmacologic and rehabilitative, may delay the disability. Pathologic characteristics include a decrease in the levels of striatal dopamine and the degeneration of dopaminergic neurons in the nigrostriatal tract that normally inhibit the activity of striatal GABAergic neurons (Figure 17–2). Most of the postsynaptic dopamine receptors on GABAergic neurons are of the D2 subclass (negatively coupled to adenylyl cyclase). The reduction of normal dopaminergic neurotransmission leads to excessive excitatory actions of cholinergic neurons on striatal GABAergic neurons; thus, dopamine and acetylcholine activities are out of balance in Parkinson’s disease (Figure 17–3). The resulting excessive excitatory action appears to be responsible for the typical signs of bradykinesia and muscle rigidity.

Certain drugs can cause reversible parkinsonian symptoms (pseudoparkinson’s disease), including the typical antipsychotic agents such as haloperidol and phenothiazines, which block brain dopaminereceptors. At high doses, reserpine causes similar symptoms, presumably by depleting brain dopamine. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a by-product of the attempted synthesis of an illicit meperidine analog (a heroin-like drug), causes irreversible Parkinson’s disease through destruction of dopaminergic neurons in the nigrostriatal tract.

Strategies for the treatment of Parkinson’s disease involve restoring dopamine activity in the brain by either increasing the activity of dopamine already available or by providing exogenous dopamine, restoring the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs, or a combination of both. The difficulty arises in finding a drug regimen that works effectively without serious adverse effects over a period of time. Since Parkinson’s disease is a progressive disorder, drug regimens must be closely monitored by all professionals involved in the care of the patient. The primary drug used in the treatment of Parkinson’s disease is levodopa. Other agents such as dopamine agonists, monoamine oxidase (MAO) inhibitors, amantadine (an antiviral agent with some dopamine-altering properties), and anticholinergic drugs can be used alone or in conjunction with levodopa, depending on the needs of the patient. An overview of the drugs used to treat Parkinson’s disease is shown in Table 17–3 and nonpharmacologic and neuroprotective therapies are discussed in Box 17–1.

Levodopa

Dopamine does not cross the blood-brain barrier and thus has no therapeutic effect in Parkinson’s disease if given as such. However, its precursor, l-dopa (levodopa), is transported across the blood brain barrier into the brain where it is rapidly converted to dopamine by l-amino acid decarboxylase (DOPA decarboxylase), an enzyme present in many body tissues including the brain. To prevent premature conversion of levodopa to dopamine in peripheral tissue, levodopa is usually given with a DOPA decarboxylase inhibitor such as carbidopa, which does not cross the blood-brain barrier and thus prevents the conversion of levodopa to dopamine in peripheral tissues. This combination may reduce the daily requirements of levodopa by approximately 75% and results in fewer peripheral adverse effects (Figure 17–4).

Clinical Uses

Levodopa can ameliorate all the clinical features of Parkinson’s disease, but is particularly effective in relieving bradykinesia and its associated disabilities. The best results with levodopa are obtained in the first few years of treatment, and the response may be dramatic. Although it does not stop the progression of Parkinson’s disease, early initiation of treatment with levodopa lowers the mortality rate. However, responsiveness to the drug usually decreases with time, which may reflect progression of the disease. Some patients also begin to develop adverse effects at dosages previously well tolerated, which may be caused by selective denervation-induced or drug-induced supersensitivity.

After a period (usually months to years) of good or excellent clinical response, the response to the drug may begin to fluctuate quite rapidly, changing from akinesia to dyskinesia over a few hours. These fluctuations in response (the so-called on-off phenomena) may be related in part to changes in levodopa levels in the plasma or in the brain. Most patients ultimately require dosing three to four times daily, but on-off phenomena are not completely eliminated by changes in dose interval. The debilitating effects of such response fluctuations on daily activities can sometimes be reduced by including dopamineagonists in the drug regimen. Catechol-O-methyltransferase (COMT) inhibitors used adjunctively may also improve levodopa responses (see discussion below). While “drug holidays” sometimes reduce toxic effects of levodopa, they rarely affect response fluctuations and are no longer recommended.

Adverse Effects

Most adverse effects associated with levodopa are dose dependent. Gastrointestinal effects include anorexia, nausea, and emesis and occur in about 80% of the patients when the drug is given without a peripheral decarboxylase inhibitor. These adverse effects can be reduced by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly. Tolerance to the emetic action of levodopa usually occurs after several months. Centrally acting antiemetics such as phenothiazines should be avoided because they may reduce the antiParkinson’s disease effects of levodopa and exacerbate symptoms. When levodopa is given in combination with carbidopa to reduce its extracerebral metabolism, adverse gastrointestinal effects are much less common, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses.

Among cardiovascular effects, postural hypotension is common, especially in the early stage of treatment, but often is asymptomatic. Other cardiac effects include tachycardia and cardiac arrhythmias (rare). Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or when massive doses of levodopa are being taken.

Dyskinesias occur in up to 80% of patients receiving levodopa therapy for long periods. The form and nature of dyskinesias vary widely but tend to remain constant in character in individual patients. Choreo-athetosis of the face and distal extremities is the most common presentation. Chorea, ballismus, athetosis, dystonia, myoclonus, tics, and tremor may occur individually or in any combination in the face, trunk, or limbs. The development of dyskinesias is dose-related, but there is considerable individual variation in the dose required to produce them.

A wide variety of adverse mental effects have been reported including depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. Such adverse effects are more common in patients taking levodopa in combination with a decarboxylase inhibitor rather than levodopa alone, presumably because higher levels are reached in the brain. Atypical antipsychotic agents, such as clozapine and risperidone, may be helpful in counteracting the behavioral complications of levodopa. Levodopa is contraindicated in patients with a history of psychosis.

Other reported but rare adverse effects include various blood dyscrasias; hot flushes; aggravation or precipitation of gout; abnormalities of smell or taste; brownish discoloration of saliva, urine, or vaginal secretions; priapism; and mydriasis.

Dopamine Receptor Agonists

Dopamineagonists act directly on dopamine receptors and may have a beneficial effect additive to that of levodopa. These drugs do not require enzymatic conversion to an active metabolite and readily cross the blood-brain barrier. They are active by the oral route. The older dopamine agonists, bromocriptine and pergolide, are ergot derivatives and act as partial agonists at dopamine D2 receptors in the brain. The newer nonergot agents, pramipexole and ropinirole, are selective D3 and D2 agonists, respectively, with efficacy similar to that of the older agents. These drugs increase the functional activity of dopamine neurotransmitter pathways, including those involved in extrapyramidal functions.

Bromocriptine is absorbed to a variable extent from the gastrointestinal tract and reaches peak plasma levels within 1 to 2 hours after an oral dose. To minimize adverse effects, the dose is built up slowly over 2 or 3 months to the desired therapeutic level. Bromocriptine is excreted in the bile and feces. Pramipexole and ropinirole are rapidly absorbed after oral administration, reaching peak plasma levels in approximately 2 hours. Both pramipexole and ropinirole are usually dosed three times daily, starting with a smaller dose and building up to a therapeutic dose in approximately three to four weeks’ time. Pramipexole is excreted largely unchanged in the urine, whereas ropinirole is metabolized in the liver by CYP1A2, which also metabolizes other drugs such as warfarin and caffeine.

Clinical Use

Dopamineagonists have been used as individual drugs, in combination with levodopa and with anticholinergic drugs, and in patients who are refractory to or cannot tolerate levodopa. Bromocriptine has been widely used to treat Parkinson’s disease and the endocrine disorder hyperprolactinemia (Chapter 22). Pergolide has also been used, and in comparative studies with bromocriptine, has been shown to be more effective in decreasing response fluctuations and prolonging the effectiveness of levodopa. The newer agents, pramipexole and ropinirole, have fewer adverse effects than bromocriptine and pergolide, and are currently considered to be first-line drugs in the initial management of Parkinson’s disease. Pramipexole may be neuroprotective because it has been reported to act as a scavenger for hydrogen peroxide. Another dopamine receptoragonist, apomorphine, has been approved recently for rescue treatment of acute immobility (“off periods”) in Parkinson’s disease. Apomorphine is administered subcutaneously and necessitates pretreatment with antiemetic drugs to prevent severe nausea and vomiting.

Adverse Effects

As with levodopa, most of the adverse effects associated with dopamineagonists are dose dependent. Gastrointestinal effects include anorexia, nausea, and vomiting. These are more pronounced with initial use of the drug and can be minimized by taking the medication with meals. The most common cardiovascular effect is postural hypotension, particularly at the initiation of therapy. Cardiac arrhythmias may also occur and are an indication for discontinuing treatment. Peripheral edema has been reported. Dyskinesias similar to those caused by levodopa may occur. Behavioral effects include confusion, hallucinations, and delusions and are more common and severe with bromocriptine and pergolide than with levodopa. Like levodopa, bromocriptine and pergolide are contraindicated in patients with a history of psychosis. Ergot-related effects include pulmonary infiltrates, cardiac valvular disorders, and erythromelalgia.

Monoamine Oxidase Inhibitors

Selegiline is a partially selective inhibitor of monoamine oxidase (MAO) type B, the enzyme isoform that metabolizes dopamine in preference to norepinephrine and serotonin. Selegiline retards the breakdown of dopamine and thus may increase brain dopamine levels, both endogenous or those provided by levodopa treatment. At higher doses, it is less selective and inhibits both MAO-A and MAO–B, producing effects like those of the antidepressant MAO inhibitors (Chapter 19).

Clinical Use

Selegiline is used as an adjunct to levodopa in Parkinson’s disease and has also been used as the sole agent in newly diagnosed patients. The drug may reduce the mild on-off or wearing-off phenomena seen with levodopa therapy. Selegiline has only a minor therapeutic effect on Parkinson’s disease when given alone. Hepatic metabolism of selegiline results in the formation of desmethylselegiline (possibly neuroprotective owing to antiapoptotic mechanisms) and small quantities of both amphetamine and methamphetamine. Rasagiline, another MAO type B inhibitor recently approved for treatment of Parkinson’s disease, does not form these metabolites.

Adverse Effects

The most prominent adverse effect associated with selegiline use is insomnia, which can be minimized by taking the medication early in the day. Other less prominent effects include mood changes, dyskinesias, gastrointestinal distress, and hypertension. Rasagiline is reported to cause fewer central nervous system (CNS) stimulatory effects. Selegiline should not be taken by patients receiving meperidine, tricyclic antidepressants, or serotonin reuptake inhibitors because of the risk of acute toxic interactions.

Amantadine

Amantadine, an antiviral agent, was by chance found to have antiParkinson’s disease properties. Amantadine inhibits the N-methyl-d-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine release in rat striatum. In addition to this anticholinergic effect, amantadine may enhance dopaminergic neurotransmission by increasing synthesis or release of dopamine or by inhibiting dopamine reuptake.

Clinical Use

Amantadine has limited but favorable influence on the bradykinesia, rigidity, and tremor of Parkinson’s disease. It is less potent than levodopa and usually effective for only a few weeks.

Adverse Effects

Amantadine has a number of undesirable CNS effects such as restlessness, agitation, insomnia, confusion, and acute toxic psychosis, all of which can be reversed by discontinuing the drug. Peripheral edema is another well-recognized complication, and it responds to diuretics. Livedo reticularis (a dermatologic reaction) sometimes occurs and usually clears within a month after the drug is withdrawn.

Catechol-O-Methyltransferase Inhibitors

Entacapone and tolcapone are selective inhibitors of COMT, the enzyme that converts levodopa to 3-O-methyldopa (3OMD). Inhibition of dopa decarboxylase (by carbidopa) is associated with compensatory activation of other pathways of levodopa metabolism, especially COMT. Increased plasma levels of 3OMD are associated with poor therapeutic response to levodopa, partly because the compound competes with levodopa for active transport into the CNS. Such selective COMT inhibitors prolong the action of levodopa by increasing the amount transported into the brain and diminishing its peripheral concentration.

Clinical Use

These agents may be helpful in patients receivinglevodopa who have developed response fluctuations, improving response and prolonging “on” time. They may also provide the option of reducing the total daily levodopa dose. Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity.

Adverse Effects

Tolcapone has been associated with hepatotoxicity requiring routine monitoring of liver function tests. Other adverse effects of both medications relate to increased levels of levodopa and include dyskinesias, hypotension, confusion, and gastrointestinal distress.

Acetylcholine-Blocking Drugs (Antimuscarinic Drugs)

These drugs decrease the excitatory actions of cholinergic neurons on cells in the striatum by blocking muscarinic receptors. Antimuscarinic drugs used in Parkinson’s disease include benztropine, orphenadrine, procyclidine, and trihexyphenidyl.

Clinical Use

Antimuscarinic drugs may improve the tremor and rigidity of Parkinson’s disease in 50% of patients but have little effect on bradykinesia. Treatment is usually started with low doses and gradually increased until benefit occurs or adverse effects limit further increments. If a patient does not respond to one drug, a trial with another drug may prove more successful. In some patients, antimuscarinic agents may decrease the effects of levodopa. These drugs have value in attenuating the parkinson-like extrapyramidal adverse effects of typical antipsychotic drugs such as haloperidol.

Adverse Effects

Antimuscarinic medications have both CNS and peripheral adverse effects. CNS toxicity includes drowsiness, inattention, confusion, delusions, and hallucinations. Peripheral adverse effects are typical of atropine-like drugs and include dry mouth, blurred vision, mydriasis, urinary retention, nausea, constipation, and tachycardia. These agents also exacerbate tardive dyskinesias that result from prolonged use of antipsychotic drugs. Withdrawal of medication should be accomplished gradually in order to prevent acute exacerbation of tremor.

Huntington’s Disease and Other Choreas

Huntington’s disease (Table 17–1) is characterized by progressive chorea and dementia. The development of chorea seems to result from a loss of GABA transmitter functions and enhanced dopaminergic activity (Figure 17–2). There may also be a cholinergic deficit because choline acetyltransferase is decreased in the basal ganglia of patients with this disease. Drug therapy involves the use of dopamine-depleting drugs (e.g., reserpine, tetrabenazine) or dopamine receptorantagonists (e.g., haloperidol). Pharmacologic attempts to enhance brain GABA and acetylcholine activities have not been successful in patients with this disease. However, rehabilitative techniques may be helpful to develop appropriate strategies to help the patient minimize or control the excessive movement in functional situations. When chorea occurs as a complication of general medical disorders or due to a specific drug, treatment is directed to the underlying cause or withdrawal of the offending substance, respectively.

Tourette’s Syndrome

Tourette’s syndrome (Table 17–1) is a disorder of unknown cause that is characterized by chronic multiple involuntary tics involving sudden violent or repetitive movements and loud, obscene, or hostile vocalizations. The disease often occurs in adolescence or young adulthood and may, if severe, have a significant impact on the patient’s life. The most effective pharmacologic approach currently available is with haloperidol, a D2 receptor blocker (Chapter 18). (Note that haloperidol causes a high incidence of drug-induced Parkinson’s disease.) If this drug is not successful, other medications can be tried, including pimozide (another D2 receptor blocker), carbamazepine (a Na+ channel blocker), clonazepam (a benzodiazepine), and clonidine (an α2 agonist).

Wilson’s Disease

A recessively inherited disorder of copper metabolism, Wilson’s disease is characterized pathologically by deposits of copper salts in the liver and other tissues, including the brain, and clinically by signs of hepatic and neurologic dysfunction, which may be severe or fatal. Treatment involves use of the chelating agents penicillamineandtrientine, which remove the excess copper. Toxic effects of penicillamine include gastrointestinal distress, myasthenia, optic neuropathy, and blood dyscrasias. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients, but it may be less effective.

Drug-Induced Dyskinesias

Parkinson’s disease symptoms caused by antipsychotic agents are usually reversible by lowering drug dosage, changing the therapy to a drug that is less toxic to extrapyramidal function, or treating with a muscarinic blocker (benztropine). Acute dystonias caused by antipsychotic drugs are usually treated with an antihistamine (diphenhydramine), often given parenterally, or a benzodiazepine (diazepam). Levodopa and bromocriptine are not useful because dopaminereceptors are blocked by the antipsychotic drugs.

Tardive dyskinesias are a special form of movement disorders that develop from long-term neuroleptic therapy with the traditional antipsychoticdrugs. They may represent a form of denervation supersensitivity. They are usually irreversible and no specific drug therapy is available. Unfortunately, patients with tardive dyskinesias also do not respond well to rehabilitative intervention for minimization of the abnormal movements.

Rehabilitation is a very important component of the overall medical care of patients with movement disorders, especially degenerative diseases such as Parkinson’s disease. For patients with general movement disorders, teaching simple strategies for minimizing and managing their abnormal movements can mean tremendous improvements in their daily quality of life and overall self-esteem. Therapies can include, but are not limited to, traditional gait training, gait training with body weight support, balance training, stretching, proprioceptive training, and strength training. With our emerging understanding of the importance of maintaining the physiologic system (muscle force, muscle length, joint integrity, receptor integrity) in patients with neurologic disorders, rehabilitative therapy may reduce the patient’s need for rapid escalation of antiparkinson medications. Evidence suggests there is a synergistic effect of early physical rehabilitation intervention and medication in providing improved functional outcomes across all levels of body function and structure, activity, and participation.

Adverse Drug Reactions

• Nausea
• Anorexia
• Orthostatic hypotension
• Dyskinesia

Effects Interfering with Rehabilitation

• Weakness due to anorexia and weight loss
• Severe orthostatic hypotension
• Therapy occurring during “off” time of medication

Possible Therapy Solutions

• Combination drug therapies that reduce adverse effects such as hypotension and weight loss
• Aggressive therapeutic rehabilitation intervention to maximize potential
• Coordinate rehabilitative therapy with the peak effects of drug therapy for maximum benefit

Potentiation of Functional Outcomes Secondary to Drug Therapy

• Increase in movement velocity
• Increase in muscle strength
• Possible reduction in tremor
• Possible reduction in rigidity

Brief History: The patient is a 78-year-old male of small stature who was referred to physical therapy after a progressive reduction in his physical capabilities secondary to Parkinson’s disease. The patient stated he had been diagnosed with Parkinson’s disease 7 years ago.

Current Medical Status and Drug Therapy: The patient stated that he did not require medication initially. He was started on a combination of levodopa and carbidopa 6 months ago when his signs and symptoms had worsened and his neurologist felt it was time to begin medication.

Rehabilitation Setting: The patient’s chief complaints are generalized stiffness, slow movement, and tremors of his hands and arms at rest. He also feels that he has gotten very weak over the last several months. Posture evaluation showed the patient has a minimal stoop posture. He also had limited passive and active range of motion in bilateral hips and in bilateral upper extremities in flexion, abduction, and external rotation. His overall functional strength was diminished for his age and he had extremely poor endurance. Upon interview by the therapist, the patient revealed that he had lost 25 pounds over the last 6 months and that his appetite had diminished drastically.

Problem/Clinical Options: The physical therapist hypothesized that the patient’s weight loss was due to diminished appetite, as a result of the levodopa medication. Although he was taking levodopa with carbidopa, which has been shown to reduce the gastrointestinal side effects associated with levodopa, he still had lost significant lean muscle mass. The physical therapist contacted the referring health-care provider who had initially prescribed the medication and informed him of the patient’s physical status. The practitioner subsequently met with the patient and made a few changes in his drug regimen: lowering his dose of levodopa, adding pramipexole (a dopamine agonist), and having the patient take his medication immediately following meals. The patient began a rehabilitative program consisting of neuromuscular reeducation, therapeutic exercise, and patient education concurrent with this new drug regimen. The patient stated after several weeks he felt stronger and he made objective improvements in strength. He also began to gain back some of the weight he has lost. He continued with his rehabilitation program.

Amantadine (Symmetrel, others)

Oral: 100-mg capsules; 10 mg/mL syrup

Benztropine (Cogentin, others)

Oral: 0.5-, 1-, 2-mg tablets

Parenteral: 1 mg/mL for injection

Biperiden (Akineton)

Oral: 2-g tablets

Parenteral: 5 mg/mL for injection

Bromocriptine (Parlodel)

Oral: 2.5-mg tablets; 5-mg capsules

Carbidopa (Lodosyn)

Oral: 25-mg tablets

Carbidopa/levodopa (Sinemet)

Oral: 10-mg carbidopa and 100-mg levodopa, 25-mg carbidopa and 100-mg levodopa, 25-mg carbidopa and 250-mg levodopa tablets

Oral sustained release (Sinemet CR): 25-mg carbidopa and 100-mg levodopa; 50-mg carbidopa and 200-mg levodopa

Entacapone (Comtan)

Oral: 200-mg tablets

Levodopa (Dopar, Larodopa)

Oral: 100-, 250-, 500-mg tablets, capsules

Orphenadrine (various)

Oral: 100-mg tablets

Oral sustained release: 100-mg tablets

Parenteral: 30 mg/mL for injection

Penicillamine (Cuprimine, Depen)

Oral: 125-, 250-mg capsules; 250-mg tablets

Pergolide (Permax)

Oral: 0.05-, 0.25-, 1-mg tablets

Pramipexole (Mirapex)

Oral: 0.125-, 0.25-, 1-, 1.5-mg tablets

Procyclidine (Kemadrin)

Oral: 5-mg tablets

Ropinirole (Requip)

Oral: 0.25-, 0.5-, 1-, 2-, 5-mg tablets

Selegiline (Deprenyl) (generic, Eldepryl)

Oral: 5-mg tablets

Tolcapone (Tasmar)

Oral: 100-, 200-mg tablets

Trientine (Syprine)

Oral: 250-mg capsules

Trihexyphenidyl (Artane, others)

Oral: 2-, 5-mg tablets; 2 mg/5 mL elixir

Oral sustained release (Artane Sequels): 5-mgcapsules