Pharmacotherapy for Parkinson’s disease: Current options, promising future therapies

No current treatments can reverse or halt the progression of PD, but a combination of drugs, surgical procedures, and neuroprotective therapies may provide the key to successful treatment in the future.

Sharon S. Moser, MS, PA-C, LLP; Wendy Besler-Panos, BS

Sharon Moser is Assistant Professor in the University of Detroit Mercy College of Health Professions Physician Assistant Program, Detroit, Mich, and a clinician at the Thea Bowman Free Clinic, Highland Park, Mich. Wendy Besler-Panos is a student in the PA program. The authors have no relationships to disclose relating to the content of this article.

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Parkinson’s disease (PD) is the most common neurodegenerative, extrapyramidal movement disease in the United States, affecting approximately 1 in 200 people.¹ Onset, which is usually at age 58 to 60 years, leads ultimately to disability of overwhelming proportions. A significant percentage of patients with PD—10% to 15%—are younger than 50 years. Those who experience symptoms before age 20 are said to have juvenile-onset PD, and those in whom PD develops at age 21 to 40 are said to have young-onset PD. These statistics are unsettling, particularly for a disease of unknown etiology.²

Pathogenesis

A combination of genetic, environmental, and biochemical factors likely contributes to the development of PD. The dopamine receptor D2 appears to decline with age in brain areas related to cognition, possibly linking symptoms of depression and dementia with PD. Considering the growth of the aging population in the United States, the prevalence of PD will likely increase in the future.

The etiology is unknown. PD is characterized by a substantial depletion of the inhibitory neurotransmitter dopamine (see Figure 1). Degeneration decreases the activity of dopamine, while cholinergic activity, which is excitatory, remains normal. Thus, the balance between inhibition and excitation, which maintains normal motor function, is disturbed. This relative increase in cholinergic activity in a circuit consisting of the cerebral cortex, basal ganglia, and thalamus results in a hypertonia of tremor (usually the first symptom to appear), rigidity, and akinesia.

Signs and symptoms

The parkinsonian tremor is a regular rhythm tremor of flexion-extension contraction occurring at rest. First asymmetric and then symmetric, it often disappears with voluntary movement. Patients have rigidity, wherein all skeletal muscles contract involuntarily; muscle cramps and stiff, tired, aching limbs also occur.

The physical examination demonstrates either lead-pipe rigidity on passive movement or a jerking resistance known as cogwheel rigidity. Akinesia, a later symptom, eventually affects all skeletal muscles. The pathophysiology is unknown, but the patient cannot voluntarily produce smooth motions. Akinesia appears as movement slowness, absence of associated movements, and freezing.³

The classic features of PD-impaired postural reflexes usually occur when 80% of striatal dopamine is depleted.⁴ Additional symptoms may include micrography, rigidity, masklike facial expressions, reduced spontaneous blink rate, loss of arm swing, dementia, and depression.⁵ Manifestations are initially unilateral, then bilateral.

Diagnosis is made more complex because no definitive test for PD is available. The clinician must base the diagnosis on a careful medical history, a meticulous neurologic examination, and the elimination of other causes.

Pharmacotherapy

Medications are used to relieve the symptoms that plague patients with PD. Unfortunately, the drugs tend to become less effective over time. Table 1 lists the agents used most often to increase levels of dopamine in patients with PD.

Neuroprotection Recent studies have suggested that neuroprotection may be a new and promising approach to treatment.⁶ Neuroprotection is defined as “protecting neurons from cellular damage induced by various biochemical insults associated with the pathogenesis of PD.”⁷ Only dopamine agonist (DA) drugs—bromocriptine (Parlodel, Parlodel SnapTabs), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), apomorphine (Apokyn)—have demonstrated some ability to slow the progression of PD, possibly because they may have a neuroprotective benefit. There is considerable debate about their neuroprotective abilities, however. Neuroprotection is a complex process that is not fully understood, and clinical trials must be conducted before any of the DA drugs can be considered neuroprotective.

Because the therapies currently used for PD become less effective over time, attention has been focused on finding new ones that may defend against disability and oxidative damage, ultimately slowing disease progression. These new and unconventional therapies include potent antioxidants and bioenergetic agents that have been shown to slow the progress of the degenerative symptoms of PD. The two most promising are coenzyme Q10 and glutathione.^6,8 Their effectiveness in preliminary studies suggests that PD involves a multifactorial process, resulting in degradation of the dopaminergic system. Current thinking suggests a complex relationship among several pathogenic biochemical factors. The cascade of events leading to the eventual destruction of the nigrostriatal dopaminergic pathway may include a combination of free radicals, mitochondrial dysfunction, inflammation, and excitotoxicity.⁹ If this model is used as a guide to PD pathogenesis, it is expected that antioxidant and bioenergetic agents would serve an essential role in protecting this pathway.

Levodopa/carbidopa Levodopa (L-dopa), the chemical precursor to dopamine, is the most commonly used drug in patients with symptomatic PD. When administered alone, L-dopa can cause nausea, vomiting, and dyskinesias. There is a significant reduction in side effects when it is combined with carbidopa, a peripheral carbohydrate inhibitor that enables L-dopa to remain intact until it reaches the brain. The half-life of levodopa with carbidopa is usually 90 minutes.¹ It is commonly prescribed for moderate to severe symptoms and is the most effective drug currently available for treating PD.

Levodopa/carbidopa agents (such as Sinemet), also called levodopa preparations, relieve principal motor symptoms in most patients with idiopathic PD.¹⁰ However, these effects can be short-lived. Various theories exist as to why the effectiveness of levodopa preparations diminishes. The expected decline in available dopamine receptors may be responsible, or it may be that L-dopa metabolism produces an increase in reactive oxygen species, which can cause DNA, protein, and lipid damage, eventually resulting in cell death.^11-15 In progressive PD, enteral levodopa infusions (compared to oral administration) can create a more continuous level of plasma levodopa and reduce the number of off periods (marked by a significant increase in dyskinesia).¹⁶ A combination product (levodopa, carbidopa, and entacapone [Stalevo]) allows the patient to reduce the intake of other medications.¹⁰ The obvious benefit of levodopa preparations in PD treatment is marked improvement in motor skills.¹⁷

When patients first take levodopa preparations, they enter a honeymoon phase lasting 2 to 5 years, after which response to subsequent doses is erratic and marked by benign motor fluctuations.¹⁸ Patients can develop periods of impaired movement, often referred to as frozen episodes, that alternate with dyskinesia. Levodopa preparations can also be associated with irritability, anxiety, apathy, sweating, fatigue, and slow thinking. Dementia, depression, falling, and unresponsiveness are other complications associated with the therapy.¹⁸ One concern is neurotoxicity. The Parkinson’s Study Group evaluated patients who took a placebo and then levodopa. Results suggested that after levodopa was instituted, there was an accelerated decline in CNS dopaminergic activity due to decreased activity in the nigrostriatal dopamine nerve terminals. This indicates a possible worsening in the underlying pathology.¹⁹

COMT inhibitors Catechol-O-methyltransferase (COMT) inactivates dopamine. The COMT inhibitors tolcapone and entacapone can prolong the half-life of levodopa preparations by 30% to 50% by reducing levodopa catabolism.²⁰

Tolcapone is a selective COMT inhibitor approved for adjunctive therapy in PD. Chronic treatment using levodopa preparations can cause end-of-dose motor fluctuations (off phenomenon) and peak-dose dyskinesias. Using a COMT inhibitor such as tolcapone or entacapone can increase on time and permit the dosage of levodopa/carbidopa to be reduced. Tolcapone adjunct therapy can prolong the effect of levodopa preparations in the CNS.

COMT inhibitor adjunct therapy can be helpful in patients with progressive PD.²¹ Studies have shown that after tolcapone injections, plasma levodopa/carbidopa levels increased, reducing striatal dopamine turnover.^22-24 In clinical studies, tolcapone was used as an adjunctive therapy for patients who were stable or whose motor fluctuations were caused by long-term levodopa use.²⁵ Tolcapone administered with a levodopa preparation increased its effects while reducing the wearing-off and on-off phenomena.²²

Entacapone is a selective, reversible, peripheral COMT inhibitor that mediates 3-O-methyldopa (3-OMD) catabolism. Entacapone increases on time, decreases off time, improves coordinated mobility and activities of daily living (ADL),²² and helps patients with and without fluctuations.²⁶ Levodopa’s efficacy combined with entacapone reduced off time by 56.6%.²⁷

Clinical studies show that tolcapone can cause severe side effects.²⁶ Liver toxicity is one of the most frequent,²⁸ as is impaired metabolism of other drugs also metabolized by COMT (eg, alpha-methyldopa, dobutamine, and isoproterenol). Be cautious when using these agents concurrently with tolcapone, and monitor liver function frequently.²⁸ Additional adverse effects may include dystonia, nausea, sleep disturbances, hypotension, and hallucinations.

Entacapone works similarly but without the hepatic toxicity of tolcapone. Side effects include dyskinesia, nausea, abdominal pain, diarrhea, and, rarely, hallucinations.²¹

Dopamine agonists These agents exert their effects mainly by stimulating postsynaptic striatal dopamine receptors.²⁶ DAs can be effectively utilized before administering a levodopa preparation or as an additional therapy to avoid increasing the dose of levodopa in later stages of PD. The best known are the ergot DAs, bromocriptine and pergolide, and the nonergot preparations, pramipexole, ropinirole, and apomorphine.¹¹ The nonergot agents have fewer side effects and may also be neuroprotective. They are usually used in patients with newly diagnosed PD where adding a DA can reduce concurrent L-dopa therapy by 20%.²⁹ Studies show that with the introduction of a DA, PD can be managed with a reduced risk of dyskinesia for 3 to 5 years before introducing L-dopa therapy.³⁰

Bromocriptine and pergolide can be prescribed as monotherapy and are effective with levodopa preparations to reduce freezing episodes, although they cause mental confusion and delusions.²⁹ Ropinirole is a nonergoline, selective D2-type DA. It can reduce the risk of dyskinesia for up to 5 years before levodopa is added and has fewer side effects than ergot DAs.¹¹ Both nonergoline DAs can be used in patients with early PD and as supplements in advanced cases.

Apomorphine, a D1/D2 dopamine receptor agonist, differs from other nonergoline therapies in that it has a higher affinity for D2 presynaptic autoreceptors at low doses. Activation of these receptors is essential for producing smooth voluntary movement. Doses starting at 0.2 mL stimulate postsynaptic D2 receptors; doses higher than 0.6 mL are not recommended. Apomorphine is indicated for the treatment of acute, intermittent hypomobility associated with advanced PD. Expect severe nausea and vomiting with dosages of 0.2 mL to 0.6 mL; an antiemetic is necessary starting 3 days before apomorphine therapy is instituted.³¹

The most common side effects with all DAs are postural hypotension, nausea, and dizziness. Ropinirole and pramipexole cause significantly fewer side effects than the older nonergoline DAs. Additional frequent side effects of apomorphine are dyskinesia, yawning, and injection site reactions.³²

Amantadine This antiviral medication is a noncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist that reduces some symptoms in early-stage PD. It apparently works through NMDA receptor antagonism and by slightly increasing dopamine release.³³ It is an early therapy because of its weak anti-PD effects, which are most evident in reducing rigidity and bradykinesia. Amantadine alone has diminished effectiveness after about 1 year in some patients;³⁴ however, it can be given with an anticholinergic drug to enhance its action.

Amantadine can reduce L-dopa-induced dyskinesias by 50%.³⁵ Although its greatest effect is seen in the first month of therapy, studies that have followed patients for 4 years have suggested that L-dopa can also be added to a stable dose of amantadine to produce modest beneficial effects for 3 years or more.

Amantadine causes edema, usually in the lower limbs, and livedo reticularis (localized purple blotches). Side effects occur twice as often in female patients.³⁵ Starting doses of 200 mg can cause confusion and hallucinations.¹¹ Reduce the dose in patients with renal impairment. Rimantadine is an amantadine alternative for patients experiencing these peripheral side effects.³⁵ In some elderly patients, amantadine can cause depression, irritability, or anxiety, but these side effects can be managed by reducing the starting dose.

Selegiline An irreversible monoamine oxidase-B (MAO-B) inhibitor, selegiline decreases dopamine catabolism, allowing increased dopaminergic activity. Independent of its MAO-B inhibition, selegiline is believed to protect against a toxic metabolite produced by the MAO-B enzyme.³⁵ It has been hypothesized that inhibiting this toxin can retard the progression of neuronal loss and thereby offer a neuroprotective effect.

Selegiline slows the disabling deficits in PD, although its mechanism for doing so remains unclear.³⁶ It is used in treating early PD and delays the need for levodopa/carbidopa therapy for 6 to 9 months.³⁷ After PD has progressed, selegiline may augment the action of levodopa/carbidopa.

When combined with other serotonergic agents such as selective serotonin reuptake inhibitors or tricyclic antidepressants, selegiline can induce serotonin syndrome in rare cases.¹¹ Selegiline should not be used with meperidine or fluoxetine.²¹ The most common side effects are nausea, dizziness, abdominal pain, confusion, and hallucinations. When combined with levodopa/ carbidopa, selegiline may cause elderly patients to experience loss of balance, mental confusion, nausea, and orthostatic hypotension.

Rasagiline The FDA recently approved rasagiline (Azilect) for initial single-drug therapy in early PD and as an adjunct to standard levodopa treatment in more advanced cases. Rasagiline is an irreversible selective MAO-B inhibitor with a proposed potency 5 to 10 times that of selegiline.³⁸ In laboratory studies, rasagiline reduced cell death through various neuroprotective pathways, suggesting it may be useful in all stages of PD and in other neurodegenerative diseases.³⁹ Clinical trials have demonstrated its efficacy in treating early-onset PD and in levodopa-treated patients with concurrent motor fluctuations.^40,41 In the latter study, patients’ daily off time was reduced by 29% on 1 mg of rasagiline daily. At this dosage, tyramine restriction in food choices is not necessary. Considering the neurotoxic potential of levodopa treatment, concurrent rasagiline therapy may offer measurable neuroprotective properties.

Anticholinergics These were among the earliest classes of PD drugs and can be used in early stages, especially in patients who present with mild tremor as their primary symptom. In these cases, a low-dose anticholinergic may be beneficial, since by blocking the cholinergic excess, these medications diminish tremor and help restore balance. Four of the most common anticholinergics are benztropine, trihexyphenidyl, biperiden, and procyclidine.^11,42 In later stages of PD, anticholinergics may be used to enhance the effects of levodopa/carbidopa therapy.

Unfortunately, anticholinergics must be used with caution, as they can cause memory impairment, disorientation, constipation, extreme dry mouth, and tachycardia.¹¹ Anticholinergics should be avoided in the elderly, especially those beginning to have cognitive symptoms.

Glutathione A relatively new therapy for PD, glutathione has received attention as a neuroprotective antioxidant. It is an essential catalyst, reductant, and reactant that is naturally produced in almost every cell. Glutathione defends against reactive oxygen species, disposes of peroxides, increases cellular dopamine sensitivity, and acts as a detoxifying agent.¹¹ Its production is dependent on cysteine, which is relatively scarce in food.

Glutathione has been found to be severely deficient in patients with PD.^43,44 Studies show that the substantia nigra of patients with PD has been subjected to oxidative stress, indicated by increased lipid peroxidation and decreased glutathione.¹ This finding correlates positively with PD severity. There is evidence of reduced glutathione, peroxidase, and catalase activity, implicating impaired antioxidant defense mechanisms. Considering the pathogenic cascade of events starting with oxidative stress, the deficiency of glutathione may lead to neuronal damage in PD, and supplementation might be useful in PD treatment.⁹ In one study, GSH-treated patients had a 42% reduction in disability. The therapeutic effect lasted 2 to 4 months.⁴³ GSH therapy studies are currently ongoing in the United States.

There are no known adverse effects with GSH therapy. It can be given only by intravenous injection, but research is being conducted on additional routes of administration.

Coenzyme Q10 This potent antioxidant seems to be significantly depleted in patients with PD. Also known as ubiquinone, coenzyme Q10 is the electron acceptor for complexes I and II in the mitochondrial electron transport chain. Multiple studies have confirmed a decrease in complex I activity in PD patients.⁹ A recent study using high dosages of coenzyme Q10 suggested that this treatment can reduce the progression and significantly slow the worsening of PD.¹ Additional studies combining coenzyme Q10 with PD treatment, including a phase 2 clinical trial, are under way.⁴⁵

Coenzyme Q10 is well tolerated at high doses.⁸ It may decrease the action of anticoagulant drugs, so laboratory parameters should be monitored carefully if these agents are used concurrently.

OTC medications and interactions Patients with PD should be warned of possible interactions with OTC medications containing scopolamine and antihistamines. Many of these are used as sedatives. They may interact with some PD pharmacotherapies, causing duplicate effects and possible toxic responses.

Surgical treatments

Surgical procedures for PD have been developed largely because medical therapies are not effective over the long term. They include ablation, deep brain stimulation (DBS), and cell transplantation.

Surgical ablation techniques, first introduced 50 years ago, are more successful now because of the accuracy of image-guided neurosurgery and microelectrode recording techniques. DBS is a nonpermanent alternative to ablative procedures. A stimulating lead is implanted deep in the brain to the desired target (usually the subthalamic nucleus).⁴⁶ An extension cable connects it to a generator, which acts as a pacemaker, sending electrical signals to the targeted structures to regulate their activity. Although the procedure carries substantial adverse effects, it produces a 63% to 95% improvement in motor activity, enabling most patients to greatly reduce medication use.⁴⁷ Cell transplantation uses fetal tissue, which is hypothesized to grow and secrete dopamine. The procedure is still experimental and in clinical trials.⁴⁸

On the horizon

A phase 1 clinical trial is under way using a viral vector (nonpathogenic adeno-associated virus, or AAV) to transfer a gene that codes for glutamic acid decarboxylase, an enzyme that produces GABA, a major CNS inhibitory neurotransmitter. At the 1-year mark, patients exhibited a statistically significant improvement of 27% (P=.04) in ipsilateral motor function on the treated side of the brain, while the untreated side showed no significant improvement. Self-reported ADL levels tended toward statistical improvement (P=.06). Positron emission tomography scans also showed a significantly decreased rate of abnormal brain metabolism, indicating that the introduced GABA was functioning.⁴⁸ Gene therapy administered through viral vectors may be the next breakthrough in PD treatment.  

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