Research Insights

Rationale for current therapies in Parkinson’s disease

Rommrell, Fernandez, & Okun Rationale for current therapies in Parkinson’s disease , 2003 Oct;4(10):1747-61

This article reviewed the rationale and strategies for the latest medical treatments in PD. The introduction of the article discussed the prevalence (approximately 1 million in the US), age of onset (~60 years), and incidence (increases with age) of PD in the United States. They also noted that with the advancing age of the baby boomer population there has been an increase in the prevalence of PD. They discussed in detail, the current medical therapies (levodopa, dopamine agonists, anticholinergics, catechol-O-methyltransferase inhibitors, selective dopamine blockers, monoamine oxidase inhibitors, Amantadine) available for patients with PD. Medications have been beneficial in the treatment of the motor and non-motor symptoms of PD however, one of the biggest challenges with this therapy is controlling the kicking "on" and wearing "off" stages of the medicine. Levodopa: Levadopa has shown the most efficacy of the PD medications by reducing morbidity and mortality of PD. However, there are controversies about this medication regarding when it should be used (initially vs. later). Patients with other Parkinsonian syndromes typically do not respond to this medication as well as patients with PD do, so it is important to monitor motor symptoms after initiating this drug to ensure appropriate treatment for each disease. The mechanism of absorption was discussed as well as how it travels to the brain to stimulate dopamine receptors (area in the brain at the neuron level involved in the uptake and release of chemicals in the brain and dopamine is a chemical that is depleted in the brain of patients with PD). One of the side effects of levodopa is nausea and vomiting so it is often combined with carbidopa or benserazide (when combined is Sinemet) to minimize those adverse effects. They listed the various dosages and release types of Sinemet as well as how it compares to generic forms of levodopa-carbidopa or benserazide. They also discussed what can happen when taking levodopa with food, on an empty stomach, and with certain foods (proteins). They suggested using the smallest amount of Sinemet that provides benefit to reduce the dyskinesias and motor fluctuations that may be seen with larger dosages. The authors noted that although there are many benefits of this medication, there are complications with long-term usage of levodopa such as, motor fluctuations, neuropsychiatric complications, and dyskinesias. They also suggested that non-motor symptoms do not respond to levodopa. Additionally, physicians and researchers are focusing on improving levodopa and minimizing the current adverse effects. Dopamine agonists (DAs): DAs (class of drugs which enhance dopaminergic function by increasing dopamine) have been around in the treatment of PD for approximately thirty years. Its involvement has fluctuated and is now considered a first line treatment for PD, as research has shown that initiating treatment with DAs may lessen long term complications (this issue is controversial in the research literature). There are multiple DAs to choose from in the event a specific drug does not provide benefit or creates adverse effects. They specifically discussed the half lives (which is the time required for half the quantity of a drug or other substance deposited in a living organism to be metabolized or eliminated by normal biological processes), titration, and recommended dosages of Bromocriptine (D2 receptor), Pergolide (D3 receptor), Pramipexole (D2 and D3 receptor), and Ropinirole (D2 and D3 receptor). They discussed that during different stages of PD there may be a need to increase or decrease the frequency of DA dosages. Common adverse effects of DAs include "nausea, vomiting, postural hypotension (drop in blood pressure when rising from a sitting position), dizziness, bradycardia (slowed heart beat), drowsiness, dyskinesia, pedal oedema, and psychiatric symptoms." Rare side effects include "erythematosus inflamed skin (redness of the skin), erythromelalgia (burning and throbbing in the extremities that comes and goes), and fibrosis (abnormal formation of tissue). Effects from long term use include retroperitoneal (mass or abnormal tissue in the abdomen), pleuropulmonary (mass or abnormal tissue in the lungs and surrounding area), and pericardial fibrosis (mass or abnormal tissue in the heart and surrounding areas). Anticholinergics: Prior to the introduction of levodopa, anticholinergics were more frequently used for PD, although the exact mechanism of action is unknown. An anticholinergic medication is a drug that inhibits or blocks the physiological action of a chemical called acetylcholine at a receptor site. Currently, anticholinergics are used to treat tremor in some patients with PD. However, quality of life may be greatly affected by this medication, because some of the adverse effects of this medication are memory loss, worsened cognitive functioning, "blurred vision, constipation, dizziness, dry mouth, impaired sweating, nausea, tachycardia, and urinary retention." Additionally, there are negative effects if this medication is abruptly stopped; as such, the authors recommend a slow gradual decline if it is necessary to discontinue the medication. Anticholinergics can also assist with urinary urgency or sialorrhea (excessive secretion of saliva. Catechol-O-methyltransferase (COMT) inhibitors: COMT is one responsible agent for metabolizing levodopa. When COMT inhibitors are given with levodopa the result is increased level-concentration of levodopa in one’s system, which results in longer lasting beneficial effects (some studies have shown increased "on," decreased "off," and improved motor scores (Baas et al, 2001; Parkinson Study Group, 1997). Some of the adverse effects of this class of medications include "harmless orange discoloration of urine," hepatic (liver) toxicity, mild or "explosive diarrhea" (5-10% of patients), and constipation. The authors suggested that research should continue to explore the utility of this medication for patients with PD. Monoamine oxidase inhibitors (MAOIs): MAOIs affect dopamine in the brain and may have mild benefits in gait disturbance, early in PD. Research on the general utility and mortality of this medication is mixed. Side effects include insomnia and impotence. The authors suggested that more research needs to be completed on this medication to explore the efficacy and safety of these medications. Amantadine: Originally, amantadine was used to treat influenza. The benefits to patients with PD were discovered accidentally and have multiple mechanisms of action (dopamine, anticholinergic, and antiglutamatergic). It has shown benefit when started early in the course of PD and shows promise in reducing later onset "levodopa-induced dyskinesia." Adverse effects include "ankle oedema, blurred vision, confusion, dry mouth, hallucinations, insomnia, nightmares, and rash. The authors suggested that more research needs to be completed on this medication to explore the efficacy and safety of this medication. Antipsychotic Agents These medications are used to treat the psychiatric effects that can be seen with long-term dopaminergic therapy (many of the PD medications). There are two main categories of the antipsychotics, typical and atypical. There are a couple of differences between these two categories. Generally, the atypical medications are newer and they have less adverse extrapyramidal symptoms (EPS; EPS include various movement disorders suffered as a result of taking antipsychotic drugs, such as the common side effect called tardive dyskinesia, which can show itself as involuntary jerky movements of the face, tongue, jaws, trunk, and limbs). As most physicians are now using the atypical medications the authors chose to talk about the six available. 1. Clozapine (also known as Clozaril): Looking at the latest research on this medication, the authors found that most of the PD patients experiencing psychosis showed improvement (85%). They also found that low-dose Clozapine did not worsen motor symptoms and some studies actually showed it improved tremor, "rigidity, bradykinesia, drug-induced dyskinesia, and motor fluctuations." Generally, low-dose Clozapine is considered the "gold standard" in treating psychosis in patients with PD based on well designed studies from the late 90’s. However, the authors discussed that there is a study from 1990 showing poor reaction to higher dosages of Clozapine in patients with PD. It is notable that this study was the first of its kind and had methodological flaws (e.g. using too much medication) that likely contributed to the poor outcome. The main adverse effect of this medication is the possibility of developing agranulocytosis (an acute disease marked by high fever and a sharp drop in circulating granular white blood cells) and the requirement to have weekly monitoring of patient’s white blood cell (WBC) counts. In addition to weekly blood draws, many pharmacies will only dispense a week’s worth of the medication with documentation of acceptable WBC counts. 2. Risperidone (also known as Risperdal): The research on Risperidone is mixed. There is no obvious reason why the results vary, but the authors suggested that Risperidone is less like an atypical and more like a "conventional neuroleptic" (the older classes of antipsychotic medications that are not as commonly used). 3. Olanzapine (also known as Zyprexa): There have been negative and positive research outcomes on Olanzapine. The authors pointed out that a task force on evidenced-based medicine found that there was "insufficient evidence to demonstrate efficacy of Olanzapine and…it carries an unacceptable risk of motor deterioration." 4. Quetiapine (also known as Seroquel): The authors pointed out that there are no double blind trials (patients and physicians are not told what medication the patient is getting, usually compared with Clozapine) and more open label (all parties are aware what drug they are taking, which may bias the results since patients may want to please the doctor/pharmaceutical company) with Quetiapine. Of the open label studies, most patients with PD showed improvement in psychosis (81-82%). Some patients had mild worsening in motor symptoms (13-32%). It is notable that patients with PD and dementia were more likely (up to 12x greater) to have motor worsening. As there are no double blind studies, the task force on evidence based medicine considers the use of Quetiapine in patients with PD investigational, even with the large support of its use from the open label studies. 5. Ziprasidone (also known as Geodon): There isn’t any published research on Ziprasidone use in patients with PD. One drawback of this medication is that it comes in capsule form, which would preclude it from being cut in half as is done with many of the atypicals as patients with PD usually require a lower dosage than used with psychiatric patients without PD. 6. Aripiprazole (also known as Abilify): This is the newest atypical and there are no published studies looking at its use in the PD population. One of the benefits of this drug is that it increases the amount of dopamine available at receptor sites (area in the brain at the neuron level involved in the uptake and release of chemicals) in the brain. After discussing the available medications, the authors suggested a treatment algorithm. They highlight that at the onset of treatment there needs to be a discussion between the patient and physician regarding what the patient hopes to accomplish with drug therapy as well as the current areas (e.g. work, home, etc.) impacted by their PD symptoms. They discussed in detail what their recommendations would be for initial, moderate-stage disease, and severe disease treatment. In conclusion the authors suggest that although there are many medications available to treat PD symptoms, more research is necessary, as none of the aforementioned medications work without adverse effects and there are always newer medications coming out with fewer side effects.

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