Mary L. Wagner
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the etiology of Parkinson’s disease (PD).
2. Explain the pathologic and biochemical changes in patients with PD.
3. Identify motor and nonmotor symptoms of PD as well as symptoms that indicate disease progression.
4. Explain the desired therapeutic goals for patients with PD.
5. Recommend lifestyle modifications and pharmacotherapy interventions for treating motor symptoms of patients with PD.
6. Recommend drug and nondrug interventions for treating the nonmotor symptoms of patients with PD.
7. Develop a monitoring plan to assess effectiveness and adverse effects of nonpharmacologic therapy and pharmacotherapy for PD.
8. Educate patients about the disease state, appropriate lifestyle modifications, and drug therapy required for effective treatment.
KEY CONCEPTS
Patients with Parkinson’s disease (PD) display both motor and nonmotor symptoms. The nonmotor symptoms may precede the motor symptoms.
The most useful diagnostic tool is the clinical history, including both presenting symptoms and associated risk factors. The Unified Parkinson’s Disease Rating Scale (UPDRS) is used to define the degree of disability.
The goals of treatment are to maintain patient independence, activities of daily living (ADL), and quality of life (QOL) by alleviating the patient’s symptoms, minimizing the development of response fluctuations, and limiting medication-related adverse effects.
The treatment of PD is categorized into three phases:
• Lifestyle changes, nutrition, and exercise
• Pharmacologic intervention, primarily with drugs that enhance dopamine concentrations
• Surgical treatments for those who fail pharmacologic interventions
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 are divided throughout the day to maximize on and minimize off periods.
The treatment of nonmotor symptoms should be based on whether they are worse during an off state or if they could be related to other neurotransmitter dysfunction.
As the disease progresses, most patients develop response fluctuations. Treatment is based on optimizing the pharmacokinetic and pharmacodynamic properties of PD medications.
Patient monitoring should involve a regular systematic evaluation of efficacy and adverse events, referral to appropriate specialists, and patient education.
Parkinson’s disease (PD) is a slow, progressive, neuro-degenerative disease of the extrapyramidal motor system. Dopamine neurons in the substantia nigra are primarily affected, and degeneration of these neurons causes a disruption in the ability to generate body movements. There is no cure, and treatment is aimed at controlling symptoms and slowing disease progression.
EPIDEMIOLOGY AND ETIOLOGY
PD affects approximately one million Americans (1% of people over 60 years of age). The average age of onset is 60 years of age, and PD is fairly uncommon in those under age 40. About 15% of patients with PD have a first-degree relative with the disease. The pathogenesis of cell death (neuron degeneration) may be due to oxidative stress, mitochondrial dysfunction, increased concentrations of excitotoxic aminoacids and inflammatory cytokines, immune system disorders, trophic factor deficiency, signalmediated apoptosis, and environmental toxins. Conditions that may promote oxidative stress include increased monoamine oxidase-B metabolism or decreased glutathione clearance of free radicals which can promote cell dysfunction and death. Drugs that deplete central dopamine, such as some antipsychotics, amoxapine, antinausea drugs (e.g., prochlorperazine), and metoclopramide, worsen PD symptoms.1–4
In PD there is a loss of pigmented cells in the substantia nigra that make and store dopamine. When patients are diagnosed with PD, they have lost 50% to 60% of their dopamine neurons in the substantia nigra, and the remaining neurons may not function well, as they have lost about 80% of their activity in the striatum. There may be cortical Lewy bodies along with Lewy neurites seen in microscopic samples from the basal ganglia, cortex, brain stem, spinal cord, sympathetic ganglia, cardiac plexus, and GI system that may explain some of the nonmotor symptoms of PD.2–4
PATHOPHYSIOLOGY
The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with PD lose dopamine neurons in the substantia nigra, which is located in the midbrain within the brain stem. The substantia nigra sends nerve fibers up to the corpus striatum, which is part of the basal ganglia in the cerebrum. The corpus striatum is made up of the caudate nucleus and the lentiform nuclei that consist of the pallidum (globus pallidus) and putamen (Fig. 32–1). As dopamine neurons die, dopamine-relayed messages cannot communicate to other motor centers of the brain, and patients develop motor symptoms. A variety of chemicals are active in the basal ganglia including acetylcholine, histamine, glutamate, serotonin, dopamine, norepinephrine, epinephrine, gamma-aminobutyric acid (GABA), enkephalins, substance P, and adenosine. Some of these neurotransmitters also decrease in concentration as other brain regions degenerate resulting in degeneration of norepinephrine neurons in the locus ceruleus and acetylcholine neurons in the nucleus basalis, as well as selected neurons of the dorsal motor nucleus of the vagus, spinal cord, and peripheral autonomic system. Decreases in these neurotransmitters may explain some of the nonmotor symptoms of PD.3 For example, loss of dopamine and norepinephrine neurons in the limbic system has been associated with depression and anxiety.5 Loss of acetylcholine, dopamine, norepinephrine, and serotonin, in the substantia nigra, locus coeruleus, nucleus raphe, and limbic system is associated with cognitive impairment.6
Patient Encounter, Part 1
MW, a 65-year-old man with a 2-year history of mild depression, comes for an initial visit to evaluate his symptoms of tremor and slowness. The tremor started in his right hand about 6 months ago, and he does not remember how long he has been slower at completing his tasks. His wife reports that for the last 4 months he has been slower and that he kicks her while they are sleeping.
Identify this patient’s motor and nonmotor symptoms of PD.
What additional information would you collect before creating this patient’s treatment plan?
FIGURE 32–1. Anatomy of the extrapyramidal system. The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with PD have a loss of dopamine neurons in the substantia nigra in the brainstem that leads to depletion of dopamine in the corpus striatum. The corpus striatum is made up of the caudate nucleus and the lentiform nuclei that are made up of the putamen and the globus pallidus.
Clinical Presentation of PD
Patients with PD display both motor and nonmotor symptoms. The nonmotor symptoms may precede the motor symptoms.
Motor Symptoms (TRAP)7
T = Tremor at rest (“pill rolling”)
R = Rigidity (stiffness and cogwheel rigidity)
A = Akinesia or bradykinesia
P = Postural instability and gait abnormalities
Nonmotor Symptoms (SOAP)
S = Sleep disturbances (insomnia, rapid eye movement sleep behavioral disorder, restless legs syndrome [RLS])
O = Other miscellaneous symptoms (problems with nausea, fatigue, speech, pain, dysesthesias, vision, seborrhea)
A = Autonomic symptoms (drooling, constipation, sexual dysfunction, urinary problems, sweating, orthostatic hypotension, dysphagia)
P = Psychological symptoms (anxiety, psychosis, cognitive impairment, depression)
Response Fluctuations (MAD)
M = Motor fluctuations (delayed peak, wearing off, random off, freezing)
A = Akathisia
D = Dyskinesias (e.g., chorea, dystonia, diphasic dyskinesia)
CLINICAL PRESENTATION AND DIAGNOSIS
Patients with PD display both motor and nonmotor symptoms. The nonmotor symptoms may precede the motor symptoms.
Motor Symptoms
The onset of PD is insidious. A thorough patient history including past and present medications, family history, environmental exposure, and a detailed description of symptom onset is essential in making an accurate diagnosis. Patients feel slowed down or trapped in their body unable to move. The tremor of PD occurs during rest and disappears with purposeful movement. Tremor usually affects the hands or feet, but may occur in other body parts such as in the lip and chin. The hand tremor can appear as if the patient is rolling a pill between their fingers. Patients describe rigidity as stiffness. Upon physical exam, it feels like uniform resistance as the muscles seem to be in a constant state of increased tone. It is defined as cogwheel rigidity when the examiner extends or flexes the patient’s extremities and feels as if they are rhythmically hitting a series of teeth on the rim of a wheel, or a gear that is meshing with another gear with teeth. Bradykinesia is noted when there is hesitancy in movement initiation, slowness in movement performance, or rapid fatiguing during movement. Patients may have a decrease in automatic movements, such as blinking, a decrease in facial expressions (often termed masked facies), or a decrease in arm swing while walking. Postural instability is a result of the loss of reflexes necessary to maintain balance when standing or ambulating. Patients may report a feeling of unsteadiness. Gait abnormalities may be evidenced by shuffling, leg dragging, festination, propulsion, retropulsion, or freezing. Rigidity and bradykinesia may make handwriting difficult as evidenced by micrographia.2,7,8
Because of a high diagnostic error rate, patients who are thought to have PD should be referred to a movement disorder specialist before starting medication. The diagnosis can often be made by history and physical. However, special imaging tests such as a MRI or single photon emissions computed tomography (SPECT) may be warranted to rule out stroke, intoxications, or other degenerative disorders.4,9
Nonmotor Symptoms
Nonmotor symptoms are due to multiple neurotransmitter abnormalities throughout the brain, and some symptoms may be aggravated by PD medications. Sleep disturbance can affect more than 70% of PD patients and includes insomnia, sleep fragmentation, rapid eye movement sleep behavioral disorder (RBD), vivid dreams, nightmares, night terrors, hallucinations, restless legs syndrome (RLS), and sleep walking. Speech problems may be exhibited as a decrease in normal volume, slurring, monotone speech, rapid speech, or stammering. Visual problems such as reading problems, double vision, perceptual changes, decreased blink, burning eyes, or itchy eyes are the result of impaired function of the muscles that move the eyeball and decreased retinal dopamine.6–11
As the autonomic system is disturbed in patients with PD, orthostatic hypotension and GI, urinary, sexual, and dermatologic symptoms are common. Patients with orthostatic hypotension may experience dizziness, lightheadedness, fainting upon standing, or fall-related injuries. GI symptoms include constipation and dysphagia due to a slowing of the automatic pattern of contraction and relaxation of the throat muscles. These swallowing difficulties may lead to weight loss, sialorrhea, and aspiration. Genitourinary symptoms include urinary incontinence, urgency, and frequency related to over activity of the bladder emptying reflex. Symptoms may be worse at night, causing nocturia. Sexual dysfunction includes decreased libido, erectile dysfunction, and delayed ejaculation. Skin symptoms include sweating and intolerance to heat and cold.6–8,11,12
Psychological symptoms may be exaggerated during the patient’s off periods and include psychosis, dementia, impaired cognitive function, depression, and anxiety. Psychosis occurs in nearly 30% of PD patients and is exhibited as vivid dreams, hallucinations (usually visual), paranoia, and delusions. Hallucinations may be more common when the patient is in dim light, falling asleep, or upon awakening. Dementia occurs in 20% to 44% of patients. Depression occurs in 30% to 70% of PD patients and may appear as apathy, psychomotor slowing, memory problems, irritability, sadness, agitation, and sleep disturbances. Some features of PD, such as the decreased facial expression and bradykinesia, may make the diagnosis of depression more difficult. Anxiety may present as panic attacks, phobia, or generalized anxiety, and occurs in 30% of patients. Anxiety was noted in 66% of patients with motor fluctuations and is often comorbid with depression.6–9,11,13,14
Response Fluctuations
Response fluctuations occur with disease progression, as the patient’s dopamine reserves are depleted in the brain, and as a complication of PD treatment. Motor fluctuations include delayed peak response, early wearing off, random unpredictable on-off, and freezing. Dyskinesias include chorea, dystonia, and diphasic dyskinesia. Wearing off can be visualized by imagining the therapeutic window of dopamine narrowing over time. The therapeutic window is defined as the minimum effective concentration of dopamine required to control PD symptoms (on without dyskinesia) and the maximum concentration before experiencing side effects from too much dopamine (on with dyskinesia). Early in the disease, a dose of levodopa is administered, and the plasma concentrations are supplemented by the brain’s supply of dopamine. Thus, although the plasma half-life of levodopa is 1.5 to 2 hours, the therapeutic effect lasts about 5 hours, and the patient experiences no dopamine side effects. As the disease progresses over time, the therapeutic window narrows because the brain can no longer supplement each levodopa dose with additional dopamine. Thus, during advanced disease, each dose lasts 2 to 3 hours, and patients experience dopamine side effects in order to be in an on state.4,15-16
The most useful diagnostic tool is the clinical history, including both presenting symptoms and associated risk factors. The Unified Parkinson’s Disease Rating Scale (UPDRS) is used to define the degree of disability in motor and some nonmotor symptoms.
The patient’s degree of disability should be evaluated by using the UPDRS which has six parts. The scale combines patient history and a physical examination that is performed on both sides of the body, as symptoms may appear asymmetric in early disease. It evaluates mentation, behavior, and mood (Part 1); activities of daily living (ADL, Part 2); PD motor symptoms (Part 3); complications of therapy (Part 4); modified Hoehn and Yahr stage of disease (Part 5); and Schwab and England ADL (Part 6). The modified Hoehn and Yahr staging scale defines eight stages of PD ranging from no symptoms to wheelchair or bed bound. A copy of the exam can be obtained at http://www.mdvu.org/library/ratingscales/pd/updrs.pdf.17
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
Chief Complaint
MW complains of stiffness, slow movements, and mild tremor that worsen his handwriting. The wife says that she took over the tasks that require good handwriting. She also notes that her husband is more apathetic, irritable, and kicks during the night.
PMH: Depression for 2 years
SH: After owning a dry cleaning store for 40 years, he is thinking about retiring because he does not enjoy visiting with the customers anymore; he does not smoke or drink alcohol
Meds: Fluoxetine 10 mg every morning for 2 years
Gen: Pessimistic attitude, apathetic, looks older than stated age, slow movements, thin
PE:
VS: BP: sitting 130/80 mm Hg, standing 110/80 mm Hg (with no orthostatic symptoms); P 78 bpm, RR 16/min, wt 65 kg (143 lb)
CV: RRR, normal S1, S2; no murmurs, rubs, gallops
Abd: Soft, nontender, nondistended; (+) bowel sounds, no hepatosplenomegaly
Skin: Scalp itchy, oily, and flaky silverish scales
Exts: Tremor in right hand and foot while sitting, cogwheel rigidity in right elbow
Neuro: Steady gait, sensory function intact, alert, normal mental status,
Rating Scales:
Unified Parkinson’s Disease Rating Scale (UPDRS) = 10 while “on”
International Restless Legs Syndrome Scale (IRLS) = 5
Labs: Within normal limits
Given this additional information, what is your assessment of the patient’s condition?
Identify treatment goals for the patient.
Describe nonpharmacologic and pharmacologic treatments that are available for the patient.
TREATMENT
Desired Outcomes
The goals of treatment are to maintain patient independence, ADL, and quality of life (QOL) by alleviating the patient’s symptoms, minimizing the development of response fluctuations, and limiting medication-related adverse effects.
General Approach to Treatment
The treatment of PD is categorized into three phases:
• Lifestyle changes, nutrition, and exercise
• Pharmacologic intervention, primarily with drugs that enhance dopamine concentrations
• Surgical treatments for those who fail pharmacologic interventions
The initial therapeutic modality selected depends in part on the patient’s age, risk of psychiatric adverse effects, degree of physical impairment, and one’s school of thought on the best time to initiate therapy. The 2002 American Academy of Neurology guidelines18 and 2006 European National Institute for Health and Clinical Excellence guidelines (http://www.nice.org.uk/nicemedia/pdf/cg035fullguideline.pdf)suggest that symptomatic treatment should be delayed until the patient experiences functional disability. Preliminary data, however, suggest that earlier treatment may delay the progression of disease. Trials are in progress to compare different classes of PD drugs to determine which drug class is best for initial therapy and which agent is best in various situations.9
Nonpharmacologic Therapy
Lifestyle Modifications
Lifestyle modifications should be started early and continued throughout treatment. They may improve ADL, gait, balance, and mental health. The most common interventions include maintaining good nutrition, physical condition, and social interactions. Patients should avoid medications that block central dopamine (e.g., antipsychotics), as they may worsen PD symptoms.1,19 A multidisciplinary approach using the expertise of nutritionists, speech therapists, physical therapists, occupational therapists, and social workers may optimize care, but may not be covered by insurance. Patients should maintain regular visits with their optometrist/ophthalmologist and dentist. PD medications decrease saliva flow, increasing the risk of dental caries.
Dietary modifications improve constipation, nausea, erratic drug absorption, and minimize the risk of aspiration and weight loss. Nutritionists help with meal selection, products to boost calories, and suggestions for arranging the proper protein content of meals to maximize medication absorption. Speech therapy may improve swallowing, articulation, and the force of speech.
Physical and occupational therapy may improve a patient’s confidence, ability to stay active, and reduce the risks of falling. An exercise program and increased activity during the day should minimize daytime sleepiness, possibly improve sleep at night, and may be neuroprotective.1,8,20 Occupational therapists provide information about adaptive equipment for the home, specialized clothing, and personal training that can maximize independence, safety, and ADLs. They can help improve handwriting and train patients to use communication software.
Social workers help patients and their families handle problems related to disease progression. They provide family counseling to help keep patients engaged in family activities and to minimize family conflicts. They also arrange for special community assistance programs.
Surgery
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 progress.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.2,21,22
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 catechol-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 levodopa 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 dopamine 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-release 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
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-O-methyltransferase. 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 anticholinergics 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
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 of age because of an increased risk of cognitive impairment.1,2,7-9,21-25 Use of anticholinergics is associated with an increased incidence of amyloid plaques and neurofibrillary tangles in patients with PD that may translate to an increased risk of Alzheimer’s disease.26 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
Amantadine
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 effects.1,2,4,7–9,16,18,21–25 It should be used cautiously with memantine, as there may be an increased risk of psychosis and prolonged QT-interval.19,27
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 wearing-off symptoms in patients with motor fluctuations.23,25,28
Rasagiline may delay the progression of PD, as patients receiving rasagiline monotherapy 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.28,29 Rasagiline may be neuroprotective and neurorestorative because it minimizes apoptosis and increases concentrations of neurotrophic factors.30 The potential neuroprotective effects of selegiline may be offset by the neurotoxic effects of its amphetamine metabolite.29
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.28
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 concentrations.1,2,7,8,16,22–25,28
Dopamine Agonists
Dopamine agonists are useful as initial therapy, as they can delay the need to start levodopa and can decrease the risk of developing motor fluctuations by two- to three-fold 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.1–4,16,23-25,28,31
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 apomorphine), 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.32 A questionnaire is available to help clarify potential psychiatric complications in patients with PD.33
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.10,11,35,36Adding 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 apomorphine.23–25,38
Levodopa/Carbidopa
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.1,16,25Others feel levodopa should be started sooner because it may normalize basal ganglia dysfunction.39 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.1,8,16,23–25
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.1,8,23-25
Levodopa is usually administered as a combination product with carbidopa, a dopa-decarboxylase inhibitor, in order to decrease the peripheral conversion of levodopa 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.1,8,23-25
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 levodopa 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.23–25,40
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 hallucinations. Dyskinesias should improve with a decrease in the levodopa dose.23–25,28,31 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.23–25,28,31
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.8,42,43
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
TREATMENT OF NONMOTOR SYMPTOMS
The treatment of nonmotor symptoms should be based on whether they are worse during an off state or if they could be related to other neurotransmitter dysfunction.
The treatment of nonmotor symptoms, such as psychological conditions, sleep disorders, and autonomic dysfunction, should include both pharmacologic and nonpharmacologic approaches. Patients should be given suggestions for maintaining ADLs, a positive self-image, family communication, and a safe environment.
Psychological Symptoms
Vivid dreams or nightmares may herald psychosis. Other potential causes of psychosis, dementia, or depression, such as infections, metabolic changes, electrolyte disturbances, or toxic exposures should be ruled out. Confusion may be alleviated by the presence of a night light or correction of vision and hearing deficits. PD therapy should be adjusted to decrease off periods when depression and anxiety may be more likely to occur. Low-efficacy PD medications should be gradually decreased and stopped in patients with psychosis. Patients should be encouraged to participate in tasks that improve cognition, such as puzzles or reading. Some patients and their families may benefit from professional counseling. Some antidepressants may be used for anxiety, panic, or depression. Low-dose quetiapine (12.5-200 mg) at bedtime can improve psychosis. Dementia symptoms may improve with an acetylcholinesterase inhibitor or memantine. Consider electroconvulsive therapy in depressed patients who fail medications.2,7-9,11,13,14,46,47
Sleep Problems
Sleep problems and fatigue are common in PD and may be due to medications, uncontrolled PD symptoms, or many other medical and psychological causes. The patient’s bed partner can provide useful information on the patient’s quality of sleep. Patients may benefit from instruction on good sleep hygiene, adjustment of therapy to control nighttime PD symptoms, or cognitive behavioral therapy. Referral to a sleep specialist may be necessary. Amantadine and selegiline may worsen insomnia; selegiline and tricyclic antidepressants may worsen RBD; and some antidepressants and antipsychotics may worsen RLS. Short-acting benzodiazepines (e.g., zaleplon, zolpidem), and sedating antidepressants (e.g., trazodone) are used for short periods to improve insomnia. However, benzodiazepines may increase the risk of falling. Antidepressants may worsen cognition and hypotension. Ramelteon may prove beneficial in patients with circadian sleep disorders (study in progress). Pramipexole, melatonin, and clonazepam are recommended for RBD. In addition to dopaminergic medications, iron and gabapentin are recommended for RLS. However, iron may decrease the absorption of levodopa and increase constipation. A nighttime dose of a COMT inhibitor may help RLS.2,6,10,11,46,47
Autonomic and Other Problems
Drooling may be accompanied by speech problems and dysphagia. Anticholinergics, botulinum toxin injections, and sublingual atropine can decrease drooling. Speech therapists perform swallowing studies to assess the risk of aspiration, and nutritionists optimize diet. Patients at high risk of aspiration or poor nutrition may require placement of a percutaneous endoscopic gastrostomy tube. Nausea improves if patients take their PD medications with meals or pharmacologic therapy (domperidone [in Canada] or trimethobenzamide). Sexual dysfunction or urinary problems may require a urologic evaluation. Adjustment of PD therapy to increase on time, removal of drugs that decrease sexual response, and pharmacologic therapy (sildenafil or yohimbine) may help treat sexual dysfunction. Patients with urinary frequency may find a bedside urinal along with a decrease in evening fluids helpful. Improvement in PD symptom control can improve urinary frequency, but worsening symptoms may require catheterization or pharmacologic measures (oxybutynin, tolterodine, propantheline, imipramine, hyoscyamine, or nocturnal intranasal desmopressin). Anticholinergic drugs could cause urinary retention and constipation. Constipation can be improved by increased fluid intake, a fiber-rich diet, and physical activity. Patients should generally avoid cathartic laxatives and use stool softeners, osmotic or bulk-forming laxatives, glycerin suppositories, or enemas. Dyskinesia-related sweating may respond to PD therapy adjustment or β-blockers. Orthostasis may respond to removal of offending drugs (tricyclic antidepressants, PD medications, alcohol, and antihypertensives) increasing carbidopa doses, or addition of salt or fluids to the diet, compression stockings, fludrocortisone, indomethacin, or mitodrine. Seborrhea usually responds to over-the-counter dandruff shampoos or topical steroids.2,6–8,11,12,46,47
Treatment of Response Fluctuations
As the disease progresses, most patients develop response fluctuations. Treatment is based on optimizing the pharmacokinetic and pharmacodynamic properties of Parkinson’s disease medications.
Treatment includes adjusting or adding medications to maximize the patient’s on time, minimize the time on with dyskinesia, and minimize off time (Table 32–2). Use various dosage plans to minimize suboptimal or delayed peak levodopa concentrations by adding longer-acting medications to minimize wearing-off periods, adding or adjusting medications to stop an unpredicted off period, and providing treatments that decrease freezing episodes. It also involves adjusting or adding medications to decrease chorea, dystonia, diphasic dyskinesias, or akathisia. Patients should schedule activities when they are on. Patients can also keep an extra dose of medication with them when they are away from home in case their medication wears off.2,6,15,16,46–48
Table 32–2 Management of Motor Complications in Advanced PD
|
I. Motor fluctuations |
|
A. Suboptimal or delayed peak response |
|
1. Take Sinemet on an empty stomach |
|
2. Decrease dietary protein and fat around the dose that is delayed |
|
2. Use rapid-dissolving tablet (Parcopa), crush Sinemet, or make liquid Sinemet |
|
3. Substitute standard Sinemet for some of the Sinemet CR |
|
4. Minimize constipation |
|
5. Withdraw drugs with anticholinergic properties |
|
6. Add intermittent subcutaneous apomorphine |
|
B. Optimal peak but early wearing off |
|
1. Decrease dose and increase frequency of standard Sinemet |
|
2. Substitute Sinemet CR for some of the standard Sinemet |
|
3. Add other PD medications (dopamine agonist, MAO-B inhibitor, amantadine, or COMT inhibitor) |
|
C. Optimal peak but unpredictable offs |
|
1. Adjust time of medications with meals and avoid high-protein meals or redistribute the amount of protein in diet |
|
2. Substitute or add rapid-dissolving tablet form or liquid form of Sinemet |
|
3. Add COMT inhibitor |
|
4. Add or try a different dopamine agonist |
|
5. Consider continuous infusion of levodopa (Duodopa), apomorphine, or lisuride |
|
6. Deep-brain stimulation procedure |
|
D. Freezing |
|
1. Gait modifications (use visual cues such as walk-over lines, tapping, rhythmic commands, rocking; use rolling walker) |
|
2. Difficult to treat, so adjust current medication up or down based on other PD symptoms |
|
a. On freezing—reduce dopamine medications, inject botulinum toxin |
|
b. Off freezing, increase Sinemet dose or add dopamine agonists |
|
3. Treat anxiety if present |
|
II. Dyskinesias |
|
A. Peak dose chorea |
|
1. Evaluate the value of adjunctive PD medications |
|
2. Decrease risk by lowering Sinemet dose when adding other PD medications |
|
3. Adjust levodopa formulation, dose, or frequency |
|
4. Add amantadine |
|
5. Add propranolol, fluoxetine, buspirone, or clozapine |
|
6. Deep-brain stimulation |
|
B. Off period dystonia in the early morning (e.g., foot cramping) |
|
1. Add Sinemet CR or dopamine agonist at bedtime if having nighttime offs |
|
2. Morning Sinemet dose should be immediate-release with or without CR |
|
3. Selective denervation with botulinum toxin |
|
4. Add lithium or baclofen |
|
C. Diphasic dyskinesia |
|
1. Avoid controlled-release preparations; consider liquid Sinemet |
|
2. Add dopamine agonist, amantadine, or COMT inhibitor |
|
3. Increase Sinemet dose and frequency |
|
4. Deep brain stimulation |
|
III. Akathisia |
|
1. Benzodiazepine |
|
2. Propranolol |
|
3. Dopamine agonists |
|
4. Gabapentin |
COMT, catechol-O-methyltransferase.
From Refs. 2, 15, 16, 44–46.
Patient Encounter, Part 3: Creating a Care Plan
Considering the goals of therapy, treatment options, and your assessment of each of the patient’s problems in part 2, create a care plan for MW that includes:
a. Nondrug and drug therapy for each problem
b. A protocol for monitoring efficacy and adverse effects
When the disease progresses, describe how you would help a family member make the decision to hire more home help versus move the patient into an assisted living facility or nursing home.
Patient Encounter, Part 4: Evaluation of the Outcomes
At the last visit, MW’s fluoxetine was changed to bupropion, pramipexole was started and gradually increased to 0.5 mg three times daily, and a dandruff shampoo was started. Since that time, his skin condition, attitude, apathy, stiffness, rigidity, handwriting, tremor, slowness, and kicking have improved. The UPDRS is 5 while “on”.
Do you agree with this therapeutic plan?
Have therapeutic goals been achieved?
OUTCOME EVALUATION
Patient monitoring should involve a regular systematic evaluation of efficacy and adverse events, referral to appropriate specialists, and patient education.
Evaluate the clinical outcomes of treatment by using the UPDRS. In addition, periodically ask patients to record the amount of on and off time they have with and without dyskinesias in a diary. There are a variety of scales that can be used to assess QOL, depression, anxiety, and sleep disorders. Patients with PD cannot be cured; but treatment can delay the progression of symptoms and improve QOL. Delaying the patient’s admission into a nursing home is a good outcome.
Patient Care and Monitoring
Patient monitoring should involve a regular systematic evaluation of efficacy and adverse events, referral to appropriate specialists, and patient education.
1. Determine type of symptoms, frequency, and exacerbating factors. Assess for PD treatment-related complications? Assess the patient’s symptoms to determine if therapy should be adjusted or maintained, or if referral for more extensive evaluation is needed.
2. Review any available diagnostic data to determine status, motor ability, dyskinesias, and nonmotor symptoms.
3. Obtain a thorough history of prescription, nonprescription, and complementary/alternative medication use. Determine what treatments have been helpful to the patient in the past. Is the patient taking any medications that may increase PD symptoms?
4. Educate the patient about lifestyle modifications that will improve symptoms and sustain independence.
5. Is the patient taking the appropriate dose of PD medication to maximize on time and minimize adverse effects? If not, why?
6. Determine if polytherapy treatment is necessary and/or adequate.
7. Assess improvement in QOL measures.
8. Evaluate the patient for the presence of drug adverse reactions, allergies, and interactions.
9. Recommend a therapeutic regimen that is easy for the patient to follow. Educate the patient on how to use medications, and allow the patient to adjust medications for fluctuations in response.
10. Educate patients regarding PD, including lifestyle modifications and drug therapy, including:
• When and how to take medications
• The potential adverse effects that may occur
• Which drugs may interact with therapy (give patients a list)
• Warning signs to report to the physician
• Where they can obtain further information such as books and Web sites (e.g., http://www.apdaparkinson.org; http://www.parkinson.org)
11. Refer patients to a local PD support group where they can obtain educational materials as well as empathy and social support from fellow PD patients. Support groups that include patients with advanced disease may upset patients with early disease; therefore, the advantages and disadvantages of attending should be explained to the patient.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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