You are here

Part 2: Introduction to the Pharmacotherapy of Parkinson’s Disease, With a Focus on the Use of Dopaminergic Agents

George DeMaagd PharmD, BCPS
Ashok Philip PhD

INTRODUCTION

Part 1 of this five-part series, published in the August 2015 issue of P&T, addressed the pathophysiology, diagnosis, and clinical presentation of Parkinson’s disease (PD)—a chronic, progressive neurodegenerative disorder characterized by both motor and nonmotor features.13 The key motor symptoms of PD are bradykinesia, resting tremor, and rigidity,410 whereas nonmotor symptoms can include cognitive changes, sleep disorders, and depression.11 Current PD therapies do not slow disease progression or provide a neuroprotective effect.12,13 The main goal of treatment, therefore, is to improve patients’ quality of life.14,15

In this installment, we review the pharmacotherapy of PD, with a focus on dopaminergic agents.

PHARMACOTHERAPY OF PARKINSON’S DISEASE

The use of medications in the management of PD can provide significant symptomatic improvement and allow improved mobility, functionality, and performance in the activities of daily living.1618 Current treatments focus on restoring dopaminergic activity through a variety of mechanisms. Although the short-term clinical effectiveness of pharmacotherapy in patients with PD is clear, treatment benefits wane as the disease progresses, and the use of medications in these patients becomes quite challenging.1618 The pharmacological management of PD requires careful implementation and monitoring to maintain a balance between clinical efficacy and the minimization of adverse events (AEs). Optimal control of the motor and nonmotor symptoms of PD with pharmacotherapy requires frequent dose adjustments and the appropriate use of combination therapies. Dopaminergic agents are considered to have beneficial effects on motor symptoms—referred to as improvements in “on time” or reduced “off time.”1921

Since PD medications can cause significant complications, such as dyskinesias, managing these adverse effects adds to the clinical challenge. The available pharmacotherapies increase levels of dopamine by preventing its breakdown or by activating dopaminergic receptors. An additional mechanism involves countering the imbalance that results from dopaminergic loss (e.g., a relative increase in acetylcholine function) through the use of anticholinergic medications.21,22 Although most clinicians initiate pharmacotherapy when motor symptoms are evident, the question of which dopaminergic therapy should be used is debatable and will be discussed below. Regardless of the initial treatment choice, monotherapy is usually recommended, and as the disease progresses, various combinations and individual treatment plans will be required.2127 Pharmacotherapy is beneficial in all stages of the disease, but it is most useful during the first five or six years after the patient’s diagnosis.2426 The complexity of PD and its pharmacotherapy requires knowledge of the medications used and consideration of multiple factors, such as the patient’s age, the stage of the disease, comorbidities, safety, tolerability, and cost.2329

DOPAMINERGIC AGENTS (LEVODOPA)

Pharmacology

Levodopa, a prodrug of dopamine, was introduced into clinical practice in the 1960s and has remained the mainstay in managing the motor symptoms of PD.26,30 Although levodopa has no disease-modifying effects, its use has had a significant impact on mortality rates among patients with PD.31,32 The neurotransmitter dopamine is predominantly ionized (protonated) at physiological pH and is unable to cross the blood–brain barrier (BBB). However, its prodrug, levodopa, when given exogenously, is able to cross the BBB via the large neutral amino acid transporter (LNAAT) and is then metabolized by L-aromatic amino acid decarboxylase (dopa decarboxylase) to dopamine. In addition, levodopa is extensively metabolized to dopamine in the gut, with approximately 30% of the dose reaching the systemic circulation. To counter this extensive peripheral metabolism, levodopa is administered in combination with carbidopa, a peripheral dopa decarboxylase inhibitor, which does not cross the BBB. The addition of carbidopa to levodopa results in an approximate tripling of levodopa’s bioavailability, thereby reducing the dosage requirement, improving tolerability (e.g., fewer peripheral dopaminergic adverse effects), and allowing greater passage of levodopa across the BBB, enhancing striatal availability.3234 The marketed carbidopa/levodopa products include various formulations and dosing ratios (Table 1). Approximately 75 mg to 100 mg of daily carbidopa is required in these combinations for decarboxylase enzymatic inhibition to occur. These amounts are attainable with the available dosage forms.26,32,33

A concern regarding the concurrent use of dopa decarboxylase inhibitors and levodopa is the shift in levodopa metabolism via the catechol-O-methyltransferase (COMT) system, resulting in the formation of 3-O-methyldopa (3-OMD). This metabolite, an LNAA, competes with levodopa for passage from plasma to the brain, although the clinical significance of this competition is unclear.35,36

Once in the brain, levodopa is converted by dopa decarboxylase to dopamine in the substantia nigra pars compacta and is stored in presynaptic neurons. When needed, this dopamine is released into the synaptic cleft, where it binds to postsynaptic dopamine (D1 and D2) receptors. Levodopa’s elimination half-life, even when given in combination with a dopa decarboxylase inhibitor, is short, ranging from 0.7 to 1.5 hours. In spite of this brief half-life, however, the duration of response to levodopa is relatively prolonged in patients with early PD. This may be due partly to the availability of endogenous dopamine in early stages of the disease. However, as the disease progresses, levodopa’s clinical benefit diminishes. The reduced duration of response has been attributed to pharmacodynamic changes and the loss of endogenous dopamine, as well as to the drug’s short half-life, all of which may contribute to dosing challenges.3234

Although the use of carbidopa/levodopa combinations is effective for controlling motor symptoms in the early stages of PD, the therapeutic effectiveness of treatment is hampered by complex and variable pharmacokinetic and pharmacodynamic factors as the disease progresses. As a result, motor responses fluctuate; treatment responses are unpredictable; and complications, including dyskinesias, may occur in up to 80% of patients.3234

As an LNAA, levodopa has properties that influence its kinetic profile, absorption, and response. Both intestinal and BBB absorption of levodopa occur via a saturable active transport system in the proximal duodenum and across the BBB, respectively. The significance of this process is that levodopa competes with other LNAAs, such as dietary proteins, for transport, which may affect its absorption.33 To avoid this interaction, high-protein meals should be kept separate from levodopa administration and the daily dietary protein allowance should be reduced to approximately 0.8 g/kg of body weight.34 The competition of levodopa with other LNAAs may have greater significance in patients with later-stage or advanced PD.3034

Another factor that influences the bioavailability of levodopa involves gastric emptying to the drug’s primary site of absorption, the proximal small intestine. The delayed gastric emptying seen in patients with PD may be due to multiple factors, including impaired motility.37 Reduced gastric emptying may affect the absorption of levodopa by slowing its movement into the proximal small intestine and by increasing its presystemic decarboxylation. This potential reduction in drug absorption may influence a patient’s clinical response to treatment and contribute to response fluctuations, which are often seen in patients receiving long-term levodopa therapy. Food may delay gastric emptying, while some medications, such as antacids, may promote gastric emptying by increasing gastric pH.33,37

Although the pharmacokinetic profile of levodopa undergoes minimal changes during disease progression, aging is associated with increases in the drug’s bioavailability, area under the curve (AUC), maximum plasma concentration (Cmax), and plasma elimination half-life.38,39 It is not clear how age influences these changes, but reduced systemic clearance is most likely involved. Pharmacodynamics may also play a role, with elderly patients being more sensitive to a given dose compared with younger patients (those under 65 years of age).40 These age-related changes may be significant in some elderly patients and should be considered when dosing patients older than 65 years of age.38,39

In patients with PD, carbidopa/levodopa products (i.e., Sinemet [Merck], Parcopa ODT [Mylan], generics) have recommended starting dosages of 25 mg/100 mg three times daily, a 1:4 ratio of carbidopa to levodopa (Table 1), but individual dose titration may be necessary according to the therapeutic response.40,41 Patients whose motor symptoms are well controlled but who experience significant gastrointestinal (GI) AEs, such as nausea and vomiting, may be managed with the addition of separately dosed carbidopa (Lodosyn [Aton Pharma], generics).42

Controlled-release (CR) carbidopa/levodopa products (i.e., Sinemet CR [Merck], generics) have been available for decades,43 although the advantage of these treatments over the regular-release products is debatable. The CR combinations were developed to enhance the duration of levodopa’s clinical activity, but they are poorly and inconsistently absorbed and require a 10% to 30% dose increase when replacing regular-release formulations.44 In January 2015, the Food and Drug Administration (FDA) approved an extended-release capsule formulation of carbidopa/levodopa (Rytary ER, Impax Pharmaceuticals)45 and an enteral suspension product (Duopa, AbbVie).46 Rytary ER will offer an additional advantage in patients requiring improved “on time,” usually in more advanced disease. Duopa uses a portable infusion pump for direct delivery of carbidopa/levodopa into the small intestine via a surgically placed tube. Duopa will have a role in patients with advanced PD disease.

The maximum recommended daily doses of levodopa and carbidopa in the labeling for Sinemet are 2,000 mg and 200 mg, respectively.40 Dose adjustments are recommended in patients with renal disease (i.e., creatinine clearance of less than 50 mL/min). In dialysis patients, clinicians should administer a dose post-session, with no supplemental doses. Caution is advised in patients with hepatic disease.34,39,40

Adverse Events

Commonly reported AEs associated with the use of carbidopa/levodopa products include nausea, vomiting, postural hypotension, sedation, vivid dreams, dizziness, dark urine, unusual sexual urges, and confusion. These effects are often problematic, especially in elderly patients, who comprise most of the PD population. PD patients are at risk for falls because of the motor features of the disease and because of levodopa-induced orthostatic hypotension, which may occur in up to 20% of patients.40,47 Withdrawal from or abrupt discontinuation of treatment with carbidopa/levodopa can also be problematic because of the sudden loss of dopaminergic effects, which may result in the return of symptoms or cause parkinsonism– hyperpyrexia syndrome. The latter disorder is characterized by rigidity, akinesia, decreased consciousness, acute renal failure, coagulation disorders, fever, and other complications, and requires prompt clinical attention. Treatment consists of body cooling, fluid replacement, and the resumption of dopaminergic replacement.28,29 It is important to educate patients about the risks of abruptly discontinuing carbidopa/levodopa therapy in order to avoid this serious AE.29

Dyskinesias and dystonias are also associated with carbidopa/levodopa therapy. These AEs occur in most PD patients within three to five years after the initiation of treatment.40,47,48

Drug Interactions

Numerous drug interactions are possible during carbidopa/ levodopa therapy, and appropriate clinical monitoring and dose adjustments may be necessary—especially in patients with multiple comorbidities. For example, antihypertensive agents may potentiate the postural hypotension associated with levodopa.26,49,50 Further, dopamine antagonists, including various antiemetics, phenothiazines, and antipsychotics (both first and second generation), should be avoided in PD patients receiving carbidopa/levodopa. If antipsychotic use is necessary, quetiapine or clozapine are viable treatment options. Metoclopramide may interact by increasing the bioavailability of levodopa through its influence on gastric emptying, in addition to its dopamine-antagonist properties.40 Although selective monoamine oxidase inhibitors (MAOIs) can be used concurrently with carbidopa/ levodopa, these agents should be administered with caution, and regular monitoring of blood pressure is recommended. Nonselective MAOIs (phenelzine and tranylcypromine) and other drugs with MAOI properties, such as linezolid, should be avoided because of their additive catecholamine influence and potential for hypertensive crisis.49 Caution is also recommended with the use of drugs from the tricyclic antidepressant class, while concomitant use of inhaled halogenated general anesthetics should be avoided altogether because these agents can enhance the arrhythmogenic effect of dopaminergic agents.40,49,51

Contraindications and Precautions

Contraindications to carbidopa/levodopa therapy include documented hypersensitivity to the drug, narrow-angle glaucoma, and a history of melanoma, although there is no proven correlation with the latter. Other conditions in which caution is recommended include hepatic and renal impairment, psychiatric illness, severe pulmonary disease, and cardiovascular, hematologic, and endocrine disorders.26,40,47,50,52

Role in Therapy and Clinical Updates

As noted earlier, carbidopa/levodopa is the most effective therapy for the motor symptoms of PD. The combination is approved as monotherapy and is often the first-line treatment when patients present with motor symptoms, especially in late-onset disease. The first-line use of carbidopa/levodopa in patients with PD is supported by the observation that elderly individuals (i.e., those older than 65 years of age) have shown improved tolerability with levodopa compared with other dopaminergic drugs.27,32,52 The carbidopa/levodopa combination effectively ameliorates bradykinesia and rigidity, and it is variably effective for tremor. Improvements in motor features are greater with carbidopa/levodopa compared with dopamine agonists.52,53

In PD patients, a favorable response to carbidopa/levodopa usually equates to an improvement in motor symptoms, often referred to as increased “on time” or reduced “off time.” 19,52,53 The results of the PD MED Collaborative Group Trial, published online in June 2014, support the use of carbidopa/ levodopa as initial therapy for the motor symptoms of PD, especially in patients who are older (more than 60 years of age) at disease onset. This trial compared outcomes for up to seven years in patients managed with initial MAO type-B inhibitors, dopamine agonists, or carbidopa/levodopa. The results showed a small but persistent benefit from initial therapy with carbidopa/levodopa; similar efficacy was reported with initial MAO-B inhibitor therapy or dopamine agonist therapy. Treatment options for PD patients younger than 60 years of age are not clear and require further study. The PD MED study demonstrated that, in older-onset PD, the available early treatments result in similar outcomes, although carbidopa/ levodopa may provide slightly improved mobility scores.27

Although treatment with carbidopa/levodopa can significantly improve quality of life in patients with PD, the disease is progressive, and the beneficial effects of therapy will diminish over time. The initial response to carbidopa/levodopa is usually positive because of the presence of a sufficient number of intact dopaminergic systems.54,55 In patients with early PD, these systems provide enough endogenous dopamine to act as a “buffer” for exogenous carbidopa/levodopa. However, as the disease progresses, the loss of dopaminergic neurons, receptor changes, modifications in circuitry, and desensitization of receptors result in inconsistent and unpredictable responses.54,56 The development of motor fluctuations—including wearing off, delayed onset, dyskinesias, and dystonias—will occur in most PD patients at some point in their disease.54,56 These changes will require carbidopa/levodopa dose adjustments and the use of adjunctive therapies to control fluctuations in the patient’s motor response.23,27,5759

While carbidopa/levodopa is effective for symptomatic management, the treatment cannot prevent or delay the clinical progression of PD. An important clinical diagnostic “pearl” is that the lack of a response to levodopa in a suspected PD patient may suggest an alternative diagnosis. A somewhat controversial issue that confronts the practitioner is the choice of first-line therapy in a newly diagnosed PD patient with motor features of the disease. Clinical studies have shown that patients started on carbidopa/levodopa may develop motor complications and/or dyskinesias sooner than patients who have been started on levodopa-sparing therapies.48,5861 As mentioned previously, the PD MED Collaborative Group Trial reported a small advantage for carbidopa/levodopa in terms of mobility scores compared with levodopa-sparing therapies (i.e., dopamine agonists or MAO-B inhibitors).27

In addition to its use as monotherapy, carbidopa/levodopa may be administered in combination with dopamine agonists and other adjunctive agents, including COMT inhibitors, MAO-B inhibitors, and amantadine. In patients initially started on carbidopa/levodopa, adjunctive treatments may be added prior to maximization of the carbidopa/levodopa dose. Patients with advanced PD will usually require various combinations to manage the progression of motor disability. Patients initially started on amantadine or an MAO-B inhibitor for mild-to-moderate symptoms usually require the addition of carbidopa/levodopa or a dopamine agonist as the disease progresses.27,6265 Patients who were initially treated with carbidopa/levodopa may benefit from a COMT inhibitor or an MAO-B inhibitor. In general, the addition of agents that extend the duration of action of levodopa, especially the COMT inhibitors, usually requires a reduction in the levodopa dose of approximately 20% to 30% to avoid additive AEs and complications.35,36 Patients who initially receive dopamine agonist monotherapy will eventually require carbidopa/levodopa as an adjunctive treatment.65

In summary, although various combinations of PD medications can be used with carbidopa/levodopa and can help improve motor responses, they all require dose adjustments in the event of AEs or complications.66,67

DOPAMINE RECEPTOR AGONISTS

Overview

An alternative first-line pharmacotherapeutic option for PD patients with motor symptoms is the use of dopamine receptor agonists (Table 2). These drugs may be administered as monotherapy in patients with early disease or in combination with carbidopa/levodopa in those with advanced disease.23,27 Dopamine receptor agonists compensate for hypodopaminergic function through their direct activation of central post-synaptic dopamine receptors in the caudate-putamen region, thereby enhancing dopaminergic effects.68,69

Pharmacology

The dopamine agonists are classified as ergot or nonergot types, with the differences primarily related to receptor affinities. The ergot derivatives include bromocriptine (Parlodel, Validus Pharmaceuticals)70 and cabergoline (Dostinex, Pharmacia & Upjohn)71—compounds rarely used for the treatment of PD, although they are beneficial in patients with acromegaly, hyperprolactinemia, neuroleptic malignant syndrome, and other conditions. Bromocriptine is approved for the treatment of patients with PD, but cabergoline is not.70,71 The ergot class of dopamine agonists are non–receptor-specific (nonselective) and interact with both inhibitory D2 and excitatory D1 receptors, as well as with serotonin and adrenergic receptors. Dopamine agonists in the ergot class, however, have the potential to cause fibrosis as a result of their high affinity for serotonin (5-HT2B) receptors, which are expressed in heart valves and other organ systems.68,69,72,73

The nonergot class of dopamine agonists consists of ropinirole (Requip and Requip XL, GlaxoSmithKline)74,75 and pramipexole (Mirapex and Mirapex ER, Boehringer Ingelheim),76,77 along with the rotigotine transdermal patch (Neupro, UCB, Inc.).78 These products have demonstrated clinical efficacy as well as improved safety and tolerability in patients with PD as a result of their selective D2 and D3 receptor profiles. The low affinity of these drugs for 5-HT2B receptors is clinically important and contributes to their positive safety profile compared with that of the ergot agents. The clinically advantageous pharmacokinetic properties of the nonergot oral formulations include good GI absorption and effective passage across the BBB. Since no conversion to active drug is required for these agents to become active, they have a longer half-life compared with that of levodopa and, therefore, an extended duration of action.68,72

The dopamine agonists have a variety of dosing regimens (Table 2). As PD progresses, dose adjustments require careful monitoring with individualized approaches. Doses should be titrated slowly to minimize AEs and to maximize the clinical response.20,68 The extended-release (ER) and transdermal formulations offer convenience and improved compliance.79,80 In addition, the ER products may avoid the pulsatile receptor stimulation associated with dyskinesias, although this potential benefit requires further research.80,81

The rotigotine transdermal patch is an ER dosing system that releases active drug for 24 hours after application to intact skin. This product has a role in PD patients with dysphagia or in other situations where oral therapy is restricted.79,80,82 The absolute bioavailability of rotigotine is approximately 37%, which may vary among application sites, although the differences do not appear to affect the treatment’s clinical efficacy. When the patch is applied to the trunk, rotigotine is detected in plasma after approximately three hours, with maximum levels reached at 15 to 27 hours. Daily application of the patch provides predictable release and absorption of rotigotine, with steady-state concentrations reached within one to two days.80

Rotigotine has a large volume of distribution (84 L/kg), along with 92% binding to plasma proteins. The drug is extensively metabolized via conjugation and N-dealkylation by CYP 450 isozymes and other enzyme systems. The multiple pathways involved in the metabolism of rotigotine make it unlikely that the inhibition of any one pathway would alter drug concentrations. Metabolites are primarily eliminated in the urine, with an elimination half-life of three to seven hours. Although dosage adjustments of rotigotine appear to be necessary in PD patients with renal impairment, it is not known whether such adjustments are necessary in patients with hepatic disease.80 The safety and tolerability of subcutaneous rotigotine appear to be similar to that of the oral nonergot dopamine agonists.83,84 When dispensing the rotigotine transdermal patch, pharmacists should educate patients regarding the patch’s proper use. This includes the application process, application-site location and rotation, and contraindications, such as magnetic resonance imaging (MRI) procedures.84,85

Apomorphine (Apokyn, US WorldMeds) is another nonergot dopamine agonist. It is administered as a subcutaneous injection for the treatment of acute, intermittent hypomobility in PD patients, including use in rescue situations (e.g., severe freezing episodes or related immobility crises).86 As PD progresses, nonresponders to other medications (about 10% of patients) may be candidates for the intermittent administration of apomorphine. The beneficial effects of this agent are limited, however, by its short duration of action, by extensive first-pass metabolism (which precludes oral formulations), and by potential tolerance. Clinical studies of apomorphine infusions have been fraught with technical difficulties and cutaneous AEs, which limit its clinical use.8789 If the drug is used for the acute management of PD, test doses and careful monitoring are recommended. In addition, the severe nausea associated with apomorphine requires pretreatment with an antiemetic, typically trimethobenzamide. It is important that apomorphine not be administered in the presence of a 5-HT3 receptor antagonist because of the potential for profound hypotension and loss of consciousness.80,90,91

Adverse Events

Dopamine agonists are associated with a number of potential AEs that may be particularly troublesome in elderly patients. Overall, the adverse drug reaction (ADR) profile of the dopamine agonists is similar to that of carbidopa/levodopa and is related to their dopaminergic effects, although clinical data suggest that carbidopa/levodopa is better tolerated. The ergot derivatives, such as bromocriptine, are rarely used in PD patients because of their vasoconstrictive properties and are associated with serious fibrotic complications. Retroperitoneal fibrosis, Raynaud’s phenomenon, pulmonary infiltrates, pleural thickening and effusions, cardiac valvulopathy, pericarditis, myocardial infarction, arrhythmias, heart failure, and hypertension have been reported. Although these complications usually resolve when the ergot derivatives are discontinued, they can cause permanent damage. Fibrotic complications are usually not associated with the nonergot dopamine agonists, but close monitoring is still necessary.9294

AEs commonly associated with dopamine agonists include somnolence, sleep attacks, dizziness, vivid dreams, nausea, constipation, edema of the lower extremities, chest pain, sweating, flushing, pallor, dyskinesia, rhinorrhea, and orthostatic hypotension. The latter disorder is concerning because of its association with falls and fractures, especially in elderly patients. Sudden sleep attacks are another AE that may affect patients during waking activities (e.g., during driving), resulting in potentially harmful consequences. Sleep attacks have been reported primarily with the newer dopamine agonists, such as ropinirole, pramipexole, and rotigotine.50,68,69,72

Psychiatric AEs reported with the dopamine agonists include confusion, cognitive changes, hallucinations, delusions, and impulse-control disorders (ICDs). The challenge in identifying these effects is that they need to be differentiated from the nonmotor symptoms of PD. The management of severe delusions and hallucinations may require the use of second-generation antipsychotic agents.50,68,69,72

As with sleep attacks, ICDs are more common with the newer dopamine agonists (nonergot agents). These disorders may be related to a phenomenon known as dopamine dysregulation syndrome. The association of ICDs with dopamine agonists in the treatment of PD is supported by reports of this AE in patients receiving dopamine agonists for other indications, such as restless legs syndrome.9597 ICDs include hypersexuality, binge eating, excessive gambling or shopping, and pathological collecting. Risk factors for ICDs include higher drug doses, single marital status, and being younger than 65 years of age.98102 Reduced doses are recommended in high-risk patients.76 ICDs are burdensome for both the family and caregivers, especially when they must deal with embarrassing and socially unacceptable behaviors. Although ICDs have been reported with carbidopa/levodopa, they are more common in patients taking dopamine agonists.97 The mechanism of ICDs is thought to be related to dopaminergic transmission along the mesocorticolimbic pathway.98,99

The management of ICDs related to dopamine agonist therapy usually involves reducing the dose of the drug or discontinuing it, which may require the adjustment of adjunctive therapies as well. In addition, nonpharmacological interventions for patients with ICDs include caregiver support and education, behavioral therapy, and self-help groups. The use of adjunctive pharmacotherapy in severe cases may include antidepressants for compulsive behaviors and antipsychotic agents, such as quetiapine or clozapine, for behavioral problems.100102

The rotigotine transdermal patch has a systemic ADR profile similar to that of the oral dopamine agonists, and clinical trials in patients with both early and advanced PD have reported good tolerability.83 Application-site reactions have been observed, however, with approximately 3% described as severe (e.g., anaphylactic). These reactions may be related to the patch’s sodium metabisulfite component; therefore, use of the patch should be avoided in patients with a sulfite allergy.78,84 Serious AEs were more common in asthmatic patients. In addition, the patch contains aluminum, which can cause skin burns if the patient is exposed to magnetic imaging or cardioversion procedures. Both patients and health care professionals should understand the importance of removing the patch before these procedures are performed.78,84

Drug Interactions

The dopamine agonists are prone to numerous drug interactions, and it is essential that all concurrent medications be evaluated. Ropinirole is metabolized by CYP1A2; therefore, inhibitors of this enzyme, such as ciprofloxacin, may increase plasma levels of ropinirole, and adjustments may be necessary. Pramipexole, on the other hand, is not significantly metabolized by the liver and is devoid of CYP-related drug interactions. Inhibitors of renal tubular secretion, specifically the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, cisplatin, and quinidine), may decrease the clearance of pramipexole by approximately 20%, although the clinical relevance of this interaction is unclear.76 In addition, drugs with dopamine-antagonist properties, phenothiazines, butyrophenones (e.g., haloperidol), thioxanthenes, and other antipsychotics should be avoided in PD patients treated with dopamine agonists. The antiemetic agent metoclopramide may decrease the effectiveness of dopamine agonists and should be avoided as well.74,76,78,86

Treatment with apomorphine may cause severe nausea. In addition, severe hypotension may occur if the drug is administered concurrently with 5-HT3 receptor antagonists, including ondansetron, dolasetron, granisetron, palonosetron, and alosetron. If the patient requires an antiemetic during treatment with apomorphine, an alternative agent, such as trimethobenzamide, is recommended. Arrhythmias may occur when apomorphine is coadministered with thioridazine, quinidine, sotalol, erythromycin, or dofetilide. In addition, since apomorphine is metabolized by COMT, the concurrent use of entacapone may reduce its elimination.86,88

Precautions and Contraindications

Postural hypotension requires evaluation in PD patients treated with dopamine agonists, especially if the patients report symptoms of dizziness when going from a supine position to standing, which can increase their risk of falls. Caution is also advised for patients who drive while being treated with these drugs. GI bleeding and ulceration have also been reported and require subsequent monitoring.74,76,78,86

A recent drug safety communication from the FDA reported a possible increased risk of heart failure with pramipexole. Although the data are not conclusive, monitoring for this complication is recommended, along with educating patients to report any signs of heart failure.103 Other precautions include use in patients with renal and/or hepatic impairment and a history of ulcers or GI bleeds, psychosis, or dementia.74,76,78 The potential for pro-arrhythymic effects secondary to QT prolongation has been reported with apomorphine, and caution in this regard is recommended in high-risk patients.86

Contraindications to the use of dopamine agonists include patients with documented hypersensitivity or a sulfite allergy.78 The use of ergot derivatives is contraindicated in patients with cardiovascular disease because of the fibrotic changes described earlier.73,74,76 Epidemiological studies have reported that patients with PD have a sixfold greater risk of developing melanoma.104 Therefore, both patients and clinicians are advised to monitor for signs of melanoma on a regular basis, including periodic evaluation by a dermatologist. The abrupt withdrawal of any dopaminergic agent, or a rapid dosage reduction, may precipitate hyperpyrexia syndrome, a condition that resembles neuroleptic malignant syndrome. In addition to emergent hyperpyrexia, hyperpyrexia syndrome is characterized by confusion, muscular rigidity, rhabdomyolysis, and akinetic crises. Appropriate drug tapering is therefore required in patients who develop this disorder.74,76,78,86

Role in Therapy and Clinical Updates

The dopamine agonists, both oral and transdermal formulations (Table 2), are approved for monotherapy in patients with early PD and may offer an initial treatment option for younger patients (under 65 years of age) with mild-to-moderate motor symptoms. A dopamine agonist should be initiated at low doses with slow titration to minimize AEs.105108 Clinical studies also support once-daily extended-release products as options for monotherapy in some patients.80,109 The use of dopamine agonists as first-line therapy rather than carbidopa/levodopa in patients with PD is controversial, and experts in the field have differing opinions. Those who advocate delaying carbidopa/ levodopa and starting a dopamine agonist as first-line treatment have expressed concern with the earlier onset of motor complications, such as “wearing off” and dyskinesias, related to carbidopa/levodopa use. Although this concern may be valid in younger patients (those under 65 years of age), most PD patients will develop these complications within five to 10 years regardless of the drug therapy that is used.67,110115 A recent study (discussed in the carbidopa/levodopa section) reported a small but persistent benefit in mobility scores with the initial use of carbidopa/levodopa compared with dopamine agonists or MAO-B inhibitors.27 A concern that levodopa might be toxic to neurons was not supported by data from recent clinical studies.116,117

Those who advocate the early use of carbidopa/levodopa focus on the progressive nature of PD and on the importance of early treatment for maintaining activities of daily living and employment. Practice parameters support carbidopa/levodopa as being more effective than dopamine agonists in treating the motor features of PD.61,65,118,119 In addition, the more-tolerable ADR profile of carbidopa/levodopa compared with that of the dopamine agonists supports its earlier use in PD, especially in elderly patients.120 Elderly PD patients started on dopamine agonists have an increased risk of serious AEs, including orthostatic hypotension, hallucinations, and confusion.120,121

Clinical trials also support the role of dopamine agonists in combination with carbidopa/levodopa or other adjunctive therapies in patients with advanced PD and motor complications. Dopamine agonists, when added to carbidopa/levodopa, reduce the frequency of “off periods” and may allow a reduction in carbidopa/levodopa dosing. Dopamine agonists may also be used in combination with MAO-B inhibitors in PD patients with advanced disease, which can result in some patients receiving triple therapy. PD patients receiving multiple therapies must be closely monitored for efficacy, additive AEs, and the need for dose adjustments.122126

SUMMARY

The use of medications in the management of PD can alleviate symptoms in addition to improving mobility, functionality, and performance in the activities of daily living.1618 Levodopa, a prodrug of dopamine, is the mainstay in managing the motor symptoms of PD.26,30 The addition of carbidopa to levodopa triples levodopa’s bioavailability, thereby allowing greater passage of levodopa into the brain.3234 Carbidopa/levodopa is approved as monotherapy in PD and is often the first-line treatment when patients present with motor symptoms.27,32,52 Controlled-release carbidopa/levodopa products have been available for decades,43 although the advantage of these treatments over the regular-release formulations is unclear. The newer ER product Rytary, released this year, may offer advantages over the previous CR product.

The dopamine agonists are classified as ergot or nonergot types. The ergot derivatives include bromocriptine and cabergoline (compounds rarely used for the treatment of PD), and the nonergot derivatives include oral ropinirole and pramipexole, along with the rotigotine transdermal patch.69,72 Both the oral and transdermal forms of the nonergot derivatives are approved for monotherapy in patients with early PD and may offer an initial treatment option for younger patients (under 65 years of age) with mild-to-moderate motor symptoms.105108 Dopamine agonists are also used in combination with carbidopa/levodopa and other PD agents in more advanced disease.122126

In the next issue of P&T, part 3 of this five-part series will discuss additional therapeutic options and the management of motor complications in patients with PD.

Tables

Carbidopa/Levodopa Products2224,26,3034,4048,50

Product
Manufacturer
Dosinga Mechanism/Pharmacokinetics Potential Adverse Events Monitoring Parameters
Sinemet (carbidopa/levodopa tablet)b
Merck
Parcopa ODT (carbidopa/levodopa ODT)c
Mylan
10/100 mg
25/100 mg
25/250 mg
Starting dosage: usually 25/100 mg TID; weekly titration based on response
  • Levodopa = dopamine prodrug; crosses BBB; converted to dopamine by dopa decarboxylase.
  • Adding carbidopa blocks peripheral conversion of levodopa to dopamine; more levodopa crosses into CNS, with fewer peripheral adverse events and less levodopa needed.
  • Absorption: proximal small intestine (food may delay); saturable; competes with LNAAs
  • Metabolism: GI tract, kidney, liver
  • Excretion: 70% in urine; half-life: approximately 1 hour
  • CNS: confusion, sedation, vivid dreams, dizziness, hallucinations, psychosis, depression
  • GI: nausea, vomiting, changes in bowel habits
  • Other: orthostasis, leg edema, dyskinesia, dystonia, hemolytic anemia, leukopenia
  • Blood pressure
  • Pulse
  • Changes in
  • mental status
  • Clinical response Note: May turn urine dark or brown/black.
Sinemet CR (carbidopa/levodopa sustained-release tablet)b
Merck
25/100 mg
50/200 mg
Starting dosage: 50/200 mg BID
Rytary ER (carbidopa/levodopa ER tablet)
Impax Pharmaceuticals
23.75/95 mg
36.25/145 mg
48.75/195 mg
61.25/245 mg
Dosing is TID and may be increased to five times daily in advanced disease
Duopa (carbidopa/levodopa enteral suspension)
AbbVie
4.63/20 mg/1 mL (100-mL cassettes); suspension delivered via infusion pump in small intestinee (PEG-J tube)
Stalevo (carbidopa/levodopa/entacapone)b,d
Novartis
Combines carbidopa/levodopa with COMTI
12.5/50/200 mg
18.75/75/200 mg
25/100/200 mg
31.25/125/200 mg
37.5/150/200 mg
50/200/200 mg

aA daily carbidopa dose of 75–100 mg is required to inhibit peripheral conversion of levodopa to dopamine. Dose reductions of 10% to 30% may be needed when carbidopa/levodopa is used with other agents, e.g., COMTIs/Stalevo, dopamine agonists, monamine oxidase Binhibitors.

bGeneric available.

cParcopa ODT contains phenylalanine; avoid in patients with phenylketonuria.

dDo not split tablets.

eAdministered into the jejunum via a percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) with an infusion pump.

BBB = blood–brain barrier; BID = twice daily; CNS = central nervous system; COMTI = catechol-O-methyltransferase inhibitor; GI = gastrointestinal; CR = controlled release; ER = extended release; LNAA = large neutral amino acid; ODT = orally disintegrating tablets; TID = three times daily.

Dopamine Receptor Agonist Products3,20,2224,27,50,64,6889,92103

Product
Manufacturer
Dosing Mechanism/Pharmacokinetics Potential Adverse Events Monitoring Parameters
Parlodel (bromocriptine mesylate)*
Validus Pharmaceuticals
Approved for PD, but rarely used. Other indications: hyperprolactinemic states, acromegaly
  • Strengths: 2.5-mg tablet; 5-mg capsule
  • Initial dose in PD: one-half of 2.5-mg tablet (1.25 mg) BID with meals
  • Dosage may be increased every 14 to 28 days by 2.5 mg/day with meals
  • Safety has not been demonstrated in dosages exceeding 100 mg/day
  • Hepatic metabolism; CYP3A4 substrate
  • Excretion: 82% in feces; 6% in urine
  • 90% to 96% bound to serum albumin
  • Half-life: 5–15 hours
  • Pulmonary: pleural thickening (fibrosis) after long-term treatment
  • GI: nausea, vomiting, abdominal discomfort
  • CNS: abnormal involuntary movements, ataxia, hallucinations, confusion, “on-off” phenomenon, dizziness, syncope, drowsiness, insomnia, depression
  • Other: visual disturbance, hypotension, shortness of breath, constipation, vertigo, asthenia
  • Pulmonary function
  • Blood pressure
  • Daytime alertness
  • Weight
  • Heart rate
Requip, Requip XL (ropinirole)*
GlaxoSmithKline
Approved for PD and restless legs syndrome (IR) or for idiopathic PD (XL)
  • IR strengths: 0.25-mg, 0.5-mg, 1-mg, 2-mg, 3-mg, 4-mg, 5-mg tablets
  • XL strengths: 2-mg, 4-mg, 8-mg, 12-mg tablets
  • IR starting dose: 0.25 mg TID; titrate weekly to maximum of 24 mg/day
  • XL starting dose: 2 mg QD for 1–2 weeks; titrate weekly to maximum of 24 mg/day
  • Hepatic metabolism; CYP1A2 substrate (inactive metabolites)
  • Excretion: > 88% of radiolabeled dose in urine (IR); < 10% in urine as unchanged drug (XL)
  • Half-life: about 6 hours (IR/XL)
  • GI: nausea, vomiting, dyspepsia, abdominal pain, constipation
  • CNS: dizziness, somnolence, headache, syncope, confusion, hallucinations, impulse control disorders, sleep attacks
  • Other: fatigue, asthenia, dependent/leg edema, viral infection, pain, increased sweating, orthostatic symptoms, pharyngitis, abnormal vision, UTIs
  • Blood pressure
  • Daytime alertness
  • Weight
  • Heart rate
Mirapex, Mirapex ER (pramipexole)*
Boehringer Ingelheim
Approved for PD and restless legs syndrome (IR) or for PD (ER).
Overnight switch from IR to ER successful in 80% of patients
  • IR strengths: 0.125-mg, 0.25-mg, 0.5-mg, 0.75-mg, 1-mg, 1.5-mg tablets
  • ER strengths: 0.375-mg, 0.75-mg, 1.5-mg, 2.25-mg, 3.0-mg, 3.75-mg, 4.5-mg tablets
  • IR starting dose: 0.125 mg TID; titrate weekly to 0.25–1.5 mg TID; BID dosing not approved
  • ER starting dose: 0.375 mg QD; titrate weekly to maximum of 4.5 mg QD
  • Negligible metabolism (< 10%)
  • Excretion: 90% in urine as unchanged drug (via renal tubules)
  • Half-life: about 8 hours in young, healthy subjects; about 12 hours in elderly subjects (IR)
  • Dose adjustment required in renal impairment
  • GI: nausea, abdominal pain/discomfort, constipation
  • CNS: dizziness, somnolence, headache, hallucinations, impulse control disorders, sleep attacks
  • Other: dyskinesia, orthostatic hypotension, xerostomia, peripheral edema, muscle spasms
  • Blood pressure
  • Daytime alertness
  • Weight
  • Heart rate
Neupro (rotigotine)
UCB, Inc. Transdermal patch; indicated for PD and restless legs syndrome
  • Strengths: 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, 8 mg/24 hours
  • Initial dose: 2 mg/24 hours (early PD) or 4 mg/24 hours (advanced PD); may be increased at weekly intervals to maximum of 6 mg/24 hours or 8 mg/24 hours, respectively
  • Apply QD to healthy skin; do not use same site more than once every 2 weeks
  • Extensive metabolism
  • Excretion: 71% in urine (inactive conjugates); about 23% in feces
  • Initial half-life: 3 hours
  • Terminal half-life: 5 to 7 hours after patch removal
  • GI: nausea, vomiting
  • CNS: somnolence, dizziness
  • Other: application-site reactions, dyskinesia, anorexia, hyperhidrosis, visual disturbance, peripheral edema
  • Avoid in patients with sulfa allergy
  • Remove patch prior to MRI (burn risk): patch contains aluminum
  • Blood pressure
  • Daytime alertness
  • Weight
  • Heart rate
  • Skin reactions
Apokyn (apomorphine)
US MedWorlds
Subcutaneous injection into abdominal wall, upper arm, or upper leg (rotate sites); indicated for hypo mobility, “off” episodes associated with PD
  • Strength: 30 mg/3 mL (10 mg/mL) glass cartridge
  • Initial dose: 0.2 mL (2 mg) under medical supervision; can be titrated to maximum dose of 0.6 mL
  • Reduce starting dose in patients with renal impairment
  • Treatment with concomitant antiemetic (e.g., trimethobenzamide) is recommended, starting 3 days before first Apokyn dose and continuing for at least first 2 months of therapy
  • Extensive first-pass metabolism
  • Terminal half-life: about 40 min
  • GI: nausea, vomiting
  • CNS: drowsiness, somnolence, dizziness, postural hypotension, hallucinations, confusion
  • Other: dyskinesia, rhinorrhea, edema/ swelling of extremities
  • Avoid use with serotonin blockers (may cause profound hypotension)
  • Blood pressure (supine/standing)
  • Drowsiness

*Generic version available

BID = twice daily; CNS = central nervous system; CYP = cytochrome P450; ER = extended release; GI = gastrointestinal; IR = immediate release; MRI = magnetic resonance imaging; PD = Parkinson’s disease; PO = by mouth; QD = once daily; SC = subcutaneous; TID = three times daily; UTI = urinary tract infection.

Author bio: 
Dr. DeMaagd is the Associate Dean of Academic Administration and a Professor of Pharmacy Practice at the Union University School of Pharmacy in Jackson, Tennessee. Dr. Philip is an Associate Professor of Pharmaceutical Sciences at the Union University School of Pharmacy.

References

  1. Parkinson J. An Essay on the Shaking Palsy London: Sherwood, Neely, and Jones. 1817;1–16.
  2. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord 2003;18:19–31.
  3. National Institute for Health and Care Excellence (NICE). Parkinson’s disease: diagnosis and management in primary and secondary care. NICE clinical guidelines 35 June 2006;Available at: http://www.nice.org.uk/guidance/cg35/resources/guidance-parkinsons-disease-pdf. Accessed April 28, 2015
  4. Baumann CR. Epidemiology, diagnosis and differential diagnosis in Parkinson’s disease tremor. Parkinsonism Relat Disord 2012;18;(suppl 1):S90–S92.
  5. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013;20:16–34.
  6. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–376.
  7. Reichmann H. Clinical criteria for the diagnosis of Parkinson’s disease. Neurodegenerative Dis 2010;7:284–290.
  8. Munhoz RP, Werneck LC, Teive HA. The differential diagnosis of parkinsonism: findings from a cohort of 1528 patients and a 10 year comparison in a tertiary movement disorders clinic. Clin Neurol Neurosurg 2010;112:431–435.
  9. Wickremaratchi MM, Knipe MD, Sastry BS, et al. The motor phenotype of Parkinson’s disease in relation to age of onset. Mov Disord 2011;26:457–463.
  10. Suchowersky O, Reich S, Perlmutter J, et al. Practice parameter: diagnosis and prognosis of new-onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:968–975.
  11. Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 2015;1:57–64.
  12. MontgomeryEBJrPractice parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007;68:164
  13. Sozio P, Cerasa LS, Abbadessa A, et al. Designing prodrugs for the treatment of Parkinson’s disease. Expert Opin Drug Discov 2012;7:385–406.
  14. Simonson W, Hauser RA, Schapira AHV. Role of the pharmacist in the effective management of wearing-off in Parkinson’s disease. Ann Pharmacother 2007;41:1842–1849.
  15. Van der Marck MA, Bloem BR. How to organize multispecialty care for patients with Parkinson’s disease. Parkinsonism Relat Disord 2014;20;(suppl 1):S167–S173.
  16. Jankovic J, Poewe W. Therapies in Parkinson’s disease. Curr Opin Neurol 2012;25:433–447.
  17. Smith Y, Wichmann T, Factor SA, DeLong MR. Parkinson’s disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacology 2012;37:213–246.
  18. Grosset DG, Macphee GJA, Nairn M, et al. Diagnosis and pharmacological management of Parkinson’s disease: summary of SIGN guidelines. BMJ 2010;340:b5614
  19. Xia R, Mao ZH. Progression of motor symptoms in Parkinson’s disease. Neurosci Bull 2012;28:39–48.
  20. Fernandez HH. Updates in the medical management of Parkinson disease. Cleve Clin J Med 2012;79:28–35.
  21. Giroux ML. Parkinson disease: managing a complex, progressive disease at all stages. Cleve Clin J Med 2007;74:313–314.317–318.320–322.
  22. Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 2008;4:743–757.
  23. Fox SH, Katzenschlager R, Lim SY, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2011;26;(suppl 3):S2–S41.
  24. Gárdián G, Vécsei L. Medical treatment of Parkinson’s disease: today and the future. Int J Clin Pharmacol Ther 2010;48:633–642.
  25. Schapira AH, Olanow CW. Drug selection and timing of initiation of treatment in early Parkinson’s disease. Ann Neurol 2008;64;(suppl 2):S47–S55.
  26. Schapira AH, Emre M, Jenner P, Poewe W. Levodopa in the treatment of Parkinson’s disease. Eur J Neurol 2009;16:982–989.
  27. PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014;384:1196–1205.
  28. Arora A, Fletcher P. Parkinsonism hyperpyrexia syndrome caused by abrupt withdrawal of ropinirole. Br J Hosp Med 2013;74:698–699.
  29. Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care 2009;10:136–140.
  30. Abbott A. Levodopa: the story so far. Nature 2010;466:S6–S7.
  31. Poewe W, Antonini A, Zijlmans JC, et al. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clin Interv Aging 2010;5:229–238.
  32. Pezzoli G, Zini M. Levodopa in Parkinson’s disease: from the past to the future. Expert Opin Pharmacother 2010;11:627–635.
  33. Contin M, Martinelli P. Pharmacokinetics of levodopa. J Neurol 2010;257;(suppl 2):S253–S261.
  34. Fernandez N, Garcia JJ, Diez MJ, et al. Effects of dietary factors on levodopa pharmacokinetics. Expert Opin Drug Metab Toxicol 2010;6:633–642.
  35. Müller T. Entacapone. Expert Opin Drug Metab Toxicol 2010;6:983–993.
  36. Müller T. Levodopa/carbidopa and entacapone in the treatment of Parkinson’s disease: efficacy, safety and patient preference. Patient Prefer Adherence 2009;3:51–59.
  37. Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson’s disease. Mov Disord 2014;29:23–32.
  38. Contin M, Riva R, Martinelli P, et al. Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson’s disease. Eur J Clin Pharmacol 1991;41:463–466.
  39. Nagayama H, Ueda M, Kumagai T, et al. Influence of aging on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease. Parkinsonism Relat Disord 2011;17:150–152.
  40. Sinemet (carbidopa/levodopa) prescribing information White-house Station, New Jersey: Merck & Co Inc.. July 2014;Available at: https://www.merck.com/product/usa/pi_circulars/s/sinemet/sinemet_pi.pdf. Accessed May 1, 2015
  41. National Institutes of Health. Parcopa ODT (carbidopa and levodopa tablet, orally disintegrating): drug label information. November 2007;Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e1ff4c1f-5d6f-44a6-a0f6-d7ca2a94adb9. Accessed May 1, 2015
  42. Food and Drug Administration. Lodosyn (carbidopa). March 192014;Available at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm388773.htm. Accessed May 1, 2015
  43. National Parkinson Foundation. Lessons from the 2001 Sinemet shortage. 2012;Available at: https://www.parkinson.org/Nation-alParkinsonFoundation/files/ae/aea8377b-cf22-46d0-bdc6-3922290efb60.pdf. Accessed May 1, 2015
  44. Sinemet CR (carbidopa/levodopa sustained-release tablets) prescribing information Whitehouse Station, New Jersey: Merck & Co Inc.. July 2014;Available at: http://www.merck.com/product/usa/pi_circulars/s/sinemet_cr/sinemet_cr_pi.pdf. Accessed May 1, 2015
  45. Impax Pharmaceuticals. Impax Pharmaceuticals announce FDA approval of Rytary (carbidopa and levodopa) extended-release capsules for the treatment of Parkinson’s disease. January 82015;Available at: https://investors.impaxlabs.com/Media-Center/Press-Releases/Press-Release-Details/2015/Impax-Pharmaceuticals-Announce-FDA-Approval-of-RYTARY-Carbidopa-and-Levodopa-Extended-Release-Capsules-for-the-Treatment-of-Parkinsons-disease/default.aspx. Accessed May 1, 2015
  46. AbbVie Inc. AbbVie announces U.S. FDA approval of Duopa (carbidopa and levodopa) enteral suspension for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. January 122015;Available at: http://news.abbvie.com/2015-01-12-AbbVie-Announces-U-S-FDA-Approval-of-DUOPA-carbidopa-and-levodopa-Enteral-Suspension-for-the-Treatment-of-Motor-Fluctuations-in-Patients-with-Advanced-Parkinsons-Disease. Accessed May 1, 2015
  47. Barbeau A. The clinical physiology of side effects in long-term L-DOPA therapy. Adv Neurol 1974;5:347–365.
  48. Calabresi P, Di Filippo M, Ghiglieri V, et al. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol 2010;9:1106–1117.
  49. Pfeiffer RF. Antiparkinsonian agents: drug interactions of clinical significance. Drug Saf 1996;14:343–354.
  50. Chen JJ, Swope DM. Parkinson’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach 9th edNew York, New York: McGraw-Hill. 2014;
  51. Burton DA, Nicholson G, Hall GM. Anaesthesia in elderly patients with neurodegenerative disorders: special considerations. Drugs Aging 2004;21:229–242.
  52. Olanow CW, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 2004;19:997–1005.
  53. Katzenschlager R, Head J, Schrag A, et al. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 2008;71:474–480.
  54. Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson’s disease?. Eur Neurol 2010;63:257–266.
  55. Warren Olanow C, Kieburtz K, Rascol O, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord 2013;28:1064–1071.
  56. Müller T. Motor complications, levodopa metabolism and progression of Parkinson’s disease. Expert Opin Drug Metab Toxicol 2011;7:847–855.
  57. Gershanik OS. Clinical problems in late-stage Parkinson’s disease. J Neurol 2010;257;(suppl 2):S288–S291.
  58. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983–995.
  59. Melamed E, Ziv I, Djaldetti R. Management of motor complications in advanced Parkinson’s disease. Mov Disord 2007;22;(suppl):S379–S384.
  60. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351:2498–2508.
  61. Hauser RA New considerations in the medical management of early Parkinson’s disease: impact of recent clinical trials on treatment strategy. Parkinsonism Relat Disord 2009;15;(suppl 3):S17–S21.
  62. Thobois S, Delamarre-Damier F, Derkinderen P. Treatment of motor dysfunction in Parkinson’s disease: an overview. Clin Neurol Neurosurg 2005;107:269–281.
  63. Salat D, Tolosa E. Levodopa in the treatment of Parkinson’s disease: current status and new developments. J Parkinson Dis 2013;3:255–269.
  64. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014;311:1670–1683.
  65. Simola N, Pinna A, Fenu S. Pharmacological therapy of Parkinson’s disease: current options and new avenues. Recent Pat CNS Drug Discov 2010;5:221–238.
  66. Khan TS. Off spells and dyskinesias: pharmacologic management of motor complications. Cleve Clin J Med 2012;79;(suppl 2):S8–S13.
  67. Stowe R, Ives N, Clarke CE, et al. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson’s disease. Mov Disord 2011;26:587–598.
  68. Perez-Lloret S, Rascol O. Dopamine receptor agonists for the treatment of early or advanced Parkinson’s disease. CNS Drugs 2010;24:941–968.
  69. Bonuccelli U, Del Dotto P, Rascol O. Role of dopamine receptor agonists in the treatment of early Parkinson’s disease. Parkinsonism Relat Disord 2009;15;(suppl 4):S44–S53.
  70. Parlodel (bromocriptine mesylate) prescribing information Parsippany, New Jersey: Validus Pharmaceuticals. April 2014;Available at: https://parlodel.us.com/wp-content/uploads/sites/3/2014/05/parlodel_fullPI.pdf. Accessed May 11, 2015
  71. Dostinex (cabergoline) prescribing information New York, New York: Pfizer Inc.. July 2011;Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020664s011lbl.pdf. Accessed May 11, 2015
  72. Jenner P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr Opin Neurol 2003;16;(suppl 1):S3–S7.
  73. Elenkova A, Shabani R, Kalinov K. Increased prevalence of sub-clinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment. Eur J Endocrinol 2012;167:17–25.
  74. Requip (ropinirole) prescribing information Research Triangle Park, North Carolina: GlaxoSmithKline. August 2014;Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmith-Kline/US/en/Prescribing_Information/Requip/pdf/REQUIP-PIPIL.PDF. Accessed May 11, 2015
  75. Requip XL (ropinirole extended-release tablets) prescribing information Research Triangle Park, North Carolina: GlaxoSmithKline. August 2014;Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Requip_XL/pdf/REQUIP-XL-PI-PIL.PDF. Accessed May 11, 2015
  76. Mirapex (pramipexole dihydrochloride) prescribing information Ridgefield, Connecticut: Boehringer Ingelheim Pharmaceuticals, Inc.. March 2015;Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Mirapex/Mirapex.pdf. Accessed May 11, 2015
  77. Mirapex XR (pramipexole dihydrochloride extended-release tablets) prescribing information Ridgefield, Connecticut: Boehringer Ingelheim Pharmaceuticals, Inc.. March 2015;Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Mirapex+ER/MirapexER.pdf. Accessed May 11, 2015
  78. Neupro (rotigotine transdermal system) prescribing information Smyrna, Georgia: UCB, Inc.. February 2015;Available at: https://www.neupro.com/pdf/Neupro-PI.pdf. Accessed May 11, 2015
  79. Mizuno Y, Nomoto M, Kondo T, et al. Transdermal rotigotine in early stage Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Mov Disord 2013;28:1447–1450.
  80. Schapira AH, Barone P, Hauser RA, et al. Neurology 2011;77:767–774.
  81. Stocchi F, Giorgi L, Hunter B, et al. PREPARED: comparison of prolonged and immediate-release ropinirole in advanced Parkinson’s disease. Mov Disord 2011;26:1259–1265.
  82. Wullner U, Kassubek J, Odin P, et al. Transdermal rotigotine for the perioperative management of Parkinson’s disease. J Neurol Transm 2010;117:885–889.
  83. Naidu Y, Oertel W, LeWitt P, Giladi N. Treatment of patients with early and advanced Parkinson’s disease with rotigotine transdermal system: age-relationship to safety and tolerability. Parkinsonism Relat Disord 2013;19:37–42.
  84. Sprenger FS, Seppi K, Poewe W. Drug safety evaluation of rotigotine. Expert Opin Drug Saf 2012;11:503–512.
  85. Schnitzler A, Leffers KW, Hack HJ. High compliance with rotigotine transdermal patch in the treatment of idiopathic Parkinson’s disease. Parkinsonism Relat Disord 2010;16:513–516.
  86. Apokyn (apomorphine hydrochloride injection) prescribing information Louisville, Kentucky: US WorldMeds, LLC. August 2014;Available at: https://www.apokyn.com/assets/APOKYN_PI.pdf. Accessed May 22, 2015
  87. Poewe W, Mahlknecht P, Jankovic J. Emerging therapies for Parkinson’s disease. Curr Opin Neurol 2012;25:448–459.
  88. Factor SA. Literature review: intermittent subcutaneous apomorphine therapy in Parkinson’s disease. Neurology 2004;62;(suppl 4):S12–S17.
  89. Vaamonde J, Flores JM, Weisser R, et al. The duration of the motor response to apomorphine boluses is conditioned by the length of a prior infusion in Parkinson’s disease. Mov Disord 2009;24:762–765.
  90. Schapira AH. The management of Parkinson’s disease: What is new?. Eur J Neurol 2011;18;(suppl 1):1–2.
  91. Hickey P, Stacy M. Available and emerging treatments for Parkinson’s disease: a review. Drug Des Devel Ther 2011;5:241–254.
  92. Perez-Lioret S, Rey MV, Crispo J, et al. Risk of heart failure following treatment with dopamine agonists in Parkinson’s disease patients. Expert Opin Drug Saf 2014;13:351–360.
  93. Antonini A, Poewe W. Fibrotic heart-value reactions to dopamine-agonist treatment in Parkinson’s disease. Lancet Neurol 2007;6:826–829.
  94. Andersohn F, Garbe E. Cardiac and noncardiac fibrotic reactions caused by ergot- and non-ergot-derived dopamine agonists. Mov Disord 2009;24:129–133.
  95. Martinkova J, Trejbalova L, Sasikova M, et al. Impulse control disorders associated with dopaminergic medication in patients with pituitary adenomas. Clin Neuropharmacol 2011;34:179–181.
  96. Dang D, Cunnington D, Swieca J. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome. Clin Neuropharmacol 2011;34:66–70.
  97. Calandrella D, Antonini A. Pathological gambling in Parkinson’s disease: disease related or drug related?. Expert Rev Neurother 2011;11:809–814.
  98. Vilas D, Pont-Sunyer C, Tolosa E. Impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord 2012;18;(suppl 1):S80–S84.
  99. Wu K, Politis M, Piccini P. Parkinson disease and impulse control disorders: a review of clinical features, pathophysiology, and management. Postgrad Med J 2009;85:590–596.
  100. Villa C, Pascual-Sedano B, Pagonabarraga J, et al. Impulse control disorders and dopaminergic treatments in Parkinson’s disease. Rev Neurol 2011;167:827–832.
  101. Okai D, Askey-Jones S, Samuel M, et al. Trial of CBT for impulse control behaviors affecting Parkinson patients and their caregivers. Neurology 2013;80:792–799.
  102. Claassen DO, van den Wildenberg WP, Ridderinkhof KR, et al. The risky business of dopamine agonists in Parkinson disease and impulse control disorders. Behav Neurosci 2011;125:492–500.
  103. Renoux C, Dell’Aniello S, Brophy JM, Suissa S. Dopamine agonist use and the risk of heart failure. Pharmacoepidemiol Drug Saf 2012;21:34–41.
  104. Olsen JH, Jorgensen TL, Rugbjerg K, et al. Parkinson disease and malignant melanoma in first-degree relatives of patients with early-onset melanoma. Epidemiology 2011;22:109–112.
  105. Kieburtz K. Twice-daily, low-dose pramipexole in early Parkinson’s disease: a randomized, placebo-controlled trial. Mov Disord 2011;26:37–44.
  106. Hauser RA, Schapira AH, Rascol O, et al. Randomized, double blind, multicenter evaluation of pramipexole extended-release once daily in early Parkinson’s disease. Mov Disord 2010;25:2542–2549.
  107. Giladi N, Boroojerdi B, Korczyn AD, et al. Rotigotine transdermal patch in early Parkinson’s disease: a randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord 2007;22:2398–2404.
  108. Watts RL, Jankovic J, Waters C, et al. Randomized, blinded, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007;68:272–276.
  109. Stocchi F, Hersh BP, Scott BL, et al. Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson’s disease: a randomized, double-blind, non-inferiority crossover study. Curr Med Res Opin 2008;24:2883–2895.
  110. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61:1044–1053.
  111. Hauser RA, Rascol O, Korczyn AD, et al. Ten-year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov Disord 2007;22:2409–2417.
  112. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484–1491.
  113. Watts RL, Lyons KE, Pahwa R, et al. Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson’s disease. Mov Disord 2010;25:858–866.
  114. Goudreau JL. Medical management of advanced Parkinson’s disease. Clin Geriatr Med 2006;22:753–772.
  115. Batla A, Stamelou M, Mencacci N, et al. Ropinirole monotherapy induced severe reversible dyskinesias in Parkinson’s disease. Mov Disord 2013;28:1159–1160.
  116. Rajput AH. Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 2001;8:95–100.
  117. Parkkinen L, O’Sullivan SS, Kuoppamäki M, et al. Does levodopa accelerate the pathologic process in Parkinson disease brain?. Neurology 2011;77:1420–1426.
  118. Hayes MW, Fung VS, Kimber TE, O’Sullivan JD. Current concepts in the management of Parkinson disease. Med J Aust 2010;192:144–149.
  119. Chen JJ, Swope DM. Pharmacotherapy for Parkinson’s disease. Pharmacotherapy 2007;27;(12 Pt 2):161S–173S.
  120. Shulman LM, Minagar A, Rabinstein A, et al. The use of dopamine agonists in very elderly patients with Parkinson’s disease. Mov Disord 2000;15:664–668.
  121. Tarrants ML, Denarié MF, Castelli-Haley J, et al. Drug therapies for Parkinson’s disease: a database analysis of patient compliance and persistence. Am J Geriatr Pharmacother 2010;8:374–383.
  122. Moller JC, Oertel WH, Koster J, et al. Long-term efficacy and safety of pramipexole in advanced Parkinson’s disease: results from a European multicenter trial. Mov Disord 2005;20:602–610.
  123. Mizuno Y, Abe T, Hasegawa K, et al. Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkinson’s disease: STRONG study. Mov Disord 2007;22:1860–1865.
  124. LeWitt PA, Lyons KE, Pahwa R. Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology 2007;68:1262–1267.
  125. Poewe WH, Rascol O, Quinn N, et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurol 2007;6:513–520.
  126. Trenkwalder C, Kies B, Rudzinska M, et al. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord 2011;26:90–99.