SYMPTOMS AND PHARMACOLOGICAL TREATMENT OF PARKINSON’S DISEASE

Jassin Jouria, MD Dr. Jassin M. Jouria is a practicing Emergency Medicine physician, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serve as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.

ABSTRACT

There has been rapid development in the research on movement disorders and, specifically, new drugs and techniques to treat Parkinson’s Disease in recent years. Many newly diagnosed patients are candidates for pharmacological disease management, and the wide array of medications available help to improve both the length and quality of life for those with Parkinson’s Disease. The many treatment options have helped to delay the need for surgical intervention for years, if not decades, in many patients.

Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education

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requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 3 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.

Pharmacology hours include 1 hour.

Statement of Learning Need

While the cause, risks and characteristics of Parkinson’s disease are well defined in recent movement disorder diagnostic guidelines, there is no definitive test that can confirm a diagnosis of Parkinson’s disease during a person's life. The diagnosis of Parkinson’s disease remains a clinical one, confirmed only after autopsy. Clinicians treat based on clinical observation and close follow up of symptoms, and must be well informed of the changing medical options to help prolong and improve quality of life for those diagnosed with the disease. Successful pharmacotherapy of Parkinson’s disease depends on the ability of clinicians to accurately recognize characteristic signs of the disease, and to successfully function within an interdisciplinary team that includes primary care and neurology medicine to arrive at the right diagnosis. Course Purpose

To provide health clinicians with knowledge about Parkinson’s disease, its cause, risk factors and characteristics, and with an overview of the research

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and guidelines to diagnose and treat Parkinson’s disease.

Target Audience Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA

Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

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1. The Movement Disorder Society (MDS) has identified three motor manifestations of Parkinson’s disease, which are

a. dementia, micrographia, and bradykinesia. b. dyskinesia, dementia, and micrographia. c. bradykinesia, resting tremor, and rigidity. d. resting tremor, dementia, and dyskinesia.

2. When non-motor features predominate, the diagnosis classification is

a. parkinsonian syndrome. b. moderate Parkinson’s disease. c. mitochondrial complex. d. prodromal Parkinson’s disease.

3. In the later stages of Parkinson’s disease, diagnosis is based on

a. postural instability. b. dementia. c. resting tremor. d. non-motor symptoms.

4. True or False: All four signs of Parkinson’s disease (bradykinesia, resting tremor, rigidity and postural instability) must be present for a clinical diagnosis of Parkinson's disease to be made by a clinician.

a. True b. False

5. ______tremor may be observed by having the patient hold their arms out in front of themselves.

a. Resting b. Postural c. Rigid d. Non-motor

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Introduction

Parkinson’s disease is a progressive, neurodegenerative disorder that is diagnosed based on physical characteristics involving bradykinesia, rest tremor, and rigidity. In the later stages of the disease, diagnosis is based on postural instability. Diagnosis is not based on testing but is based on the clinician's ability to recognize signs and symptoms of Parkinson’s disease and to diagnose it, hopefully in the early stages of the disease. Successful pharmacotherapy of Parkinson’s disease depends on the ability of clinicians to accurately recognize characteristic signs of the disease. A diagnosis of Parkinson’s disease is difficult to make without the appropriate training and skills. Often, an interdisciplinary team effort between primary care medicine and neurology is needed to arrive at the right diagnosis. Recommended treatment are discussed.

Diagnosis Of Parkinson’s Disease: A Review

The Movement Disorder Society has identified three motor manifestations of Parkinson’s disease, which are bradykinesia, in combination with either resting tremor, rigidity, or both.1,59,68-70 The centrality of motor symptoms for clinical diagnosis of PD are generally well-defined; however, non-motor symptoms can often predominate a clinical presentation and are acknowledged. When non-motor features predominate, the diagnosis classification is prodromal Parkinson’s disease. There are four cardinal signs of Parkinson’s disease that must be identified and are defined as resting tremor, rigidity, bradykinesia, and postural instability. Postural instability is not required for a diagnosis of PD, and commonly arises later in the disease process.

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Resting Tremor

Resting tremor is assessed by having patients seated with their arms relaxed on their laps. The resting tremor may be observed without further instructions, or it may be triggered by asking the patient to count backwards from ten. Kinetic or postural tremor may be present but is not required as part of the diagnostic criteria. Kinetic tremor may be observed in the finger- to-nose test while postural tremor may be observed by having patients hold their arms out in front of themselves.

Rigidity

Rigidity is the “slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.”68 This form of rigidity is the “lead-pipe” form exemplified as velocity-independent resistance to passive movement. The cogwheel phenomenon is often present (so-named because of its cogwheel-like jerks to passive movement), but lead-pipe rigidity must be present as well to fulfill the minimum requirements of rigidity.

Bradykinesia

The bradykinesia of PD requires a slowness of movement and a decrease in amplitude or speed of movement. Limb bradykinesia must be present to establish PD. Evaluation of bradykinesia may be accomplished by finger- tapping, protonation-supination, hand movements, toe or foot tapping, and postural instability.

Postural instability, identified later in the disease process, can be tested using the retropulsion test. This test involves the patient being asked to stand with arms at their sides and eyes open. The patient is also told that this is a balance test and they will be caught if they begin to fall or unable to

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regain their balance. The examiner stands behind the patient and pulls back on the shoulders. One or two steps to regain balance are considered normal.

The Movement Disorder Society (MDS) proposed to redefine Parkinson’s disease in 2014. A number of critical issues were identified and discussed.1,59,68-70

• New findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. • The increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. • There is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. • The recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. • There is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

The MSD task force made the following proposals related to standards of diagnosis.1,59,68-70

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• The core clinicopathologic criteria of a clinical motor syndrome accompanied by SNpc neurodegeneration and synuclein deposition remain a gold standard of PD diagnosis. In the future, should reliable biomarkers of synuclein deposition be developed, these can be used to indicate a likely gold-standard clinicopathologic diagnosis.

• To incorporate genetic findings under the PD umbrella, a separate “clinicogenetic” category should be created to diagnose PD, regardless of the occurrence of synuclein deposition. This category would refer specifically to highly penetrant mutations in which the majority of affecteds meet clinical PD criteria, regardless of whether autopsy specimens of patients with this mutation find a-Syn pathology. In research studies, this diagnostic subcategory could be included or not according to the context. For example, an autopsy study validating clinical diagnostic criteria might exclude such patients, a randomized trial of symptomatic dopaminergic therapy might include them, and a neuroprotective trial may elect to include or exclude, depending upon the mechanism of the agent.

• A new scheme is likely needed to replace the current PARK classification, which is under considerable strain. This scheme should specifically differentiate between causative genes and risk factors, consider the predominant phenotype, and — in the long run — admit the incorporation of protective variants.

One-Year Rule

In the past, if dementia was diagnosed before the second year after diagnosis of Parkinson’s disease, the 1-year rule excluded PD and dementia with Lewy Bodies (DLB) was the correct diagnosis. The MDS task force

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proposed that the 1-year rule be omitted, and instead it recommends that patients be diagnosed with PD when they present with motor signs meeting full criteria for the disease, regardless of the presence or timing of dementia. In the case of DLB, the latest consensus published was that patients could be diagnosed with PD-DLB subtype. This definition did not affect patients with a DLB diagnosis not meeting criteria for parkinsonism, with no response to dopaminergic medications.1,59,68-70

Subtypes Of Parkinson’s Disease

No currently accepted subtypes of Parkinson’s disease exist even though there is a considerable variability in the appearance and progression of motor symptoms and a high prevalence on non-motor symptoms. The MDS task force proposed that:1,2,59,68-70 • Clinical subtypes should only be delineated if there are clear data that demonstrate consistent, large differences in prognosis, predicted disease manifestations, or treatment. Currently, it is unclear whether any of the current subtype classifications qualify. • The search for subtypes should not be restricted to clinical features, but should include subtypes of molecular pathogenesis.

Onset of Parkinson’s Disease

The motor symptoms of PD may sometimes be preceded by many years of non-motor symptoms, such as idiopathic rapid eye movement sleep behavior disorder (RBD), hyposmia (reduction in smelling), autonomic symptoms (constipation), depression, and a showing of abnormal neuroimaging results without any clear symptoms of PD. The MDS task force proposed that the clinical diagnosis of classic PD should remain centered on a motor

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syndrome.1,2 Further, separate research-based criteria should be developed to allow diagnosis of early PD stages.

For delineation of early stages, disease should be classified as preclinical and prodromal.1,2,109 Preclinical refers to the presence of neurodegenerative synucleinopathy without clinical symptoms (i.e., defined by biomarkers). This stage cannot be diagnosed currently because reliable biomarkers are not available. Prodromal refers to the presence of early symptoms and signs before the classical PD diagnosis is possible. This prodromal term makes no assumptions about the order in which motor versus non-motor symptoms develop.

Because one cannot determine whether any patient with prodromal neurodegenerative synucleinopathy will eventually progress to full, clinical PD, the definition of prodromal PD should center upon the likelihood of a neurodegenerative synucleinopathy being present, regardless of “conversion rate” to full clinical PD. Although PD, by definition, passes inevitably through some type of prodromal phase, there are currently no 100% reliable means to identify prodromal PD. Therefore, diagnostic criteria for prodromal PD will necessarily be variable and based on probabilities.

Two levels of certainty to diagnose PD have been proposed. Probable prodromal PD would refer to a high likelihood (i.e., >80%, sufficiently certain for neuroprotective trials). Possible prodromal PD would refer to a lower, but still substantial, likelihood of neurodegenerative synucleinopathy (i.e., 30% -80%). Prodromal PD criteria should incorporate clinical motor markers, clinical nonmotor markers, and nonclinical biomarkers. Inclusion of a marker into prodromal criteria should generally require prospective studies documenting predictive value for full clinical PD. Markers should be divided into categories of specificity, such that high specificity markers carry more

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weight than those with lower specificity. Criteria should also incorporate risk, adjusting probability estimates for persons with documented high-risk states (i.e., carriers of genetic mutations).

Key Features of the MDS Diagnostic Criteria

The MDS criteria incorporate a number of key negative and positive features in their diagnostic criteria.1,2,59,88 The negative features include red flags and absolute exclusion criteria. The positive features include supportive criteria.

Negative features involve absolute exclusion features specific for an alternative diagnosis, and red flags which are potential signs for an alternative diagnosis (but with an uncertain specificity). There is also allowance for interpretation; for example, certain drug-induced parkinsonism and critical sensory loss following a stroke can be used to “over-ride” certain criteria. Also, atypical features rarely occur early in the disease process but can occur more frequently later in the disease process. For this reason, if an atypical feature occurs outside the time window, or is absent with disease duration still less than the time window, the criterion is not applied. Clinicians should keep in mind that dementia is not considered an exclusion criterion in the MDS system.

MDS Clinical Diagnostic Criteria for PD—Executive Summary/Completion Form

The first essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at least 1 of rest tremor or rigidity. Examination of all cardinal manifestations should be carried out as described in the MDS–Unified Parkinson Disease Rating Scale. Once parkinsonism has been diagnosed:

Diagnosis of Clinically Established PD requires: 1. Absence of absolute exclusion criteria 2. At least two supportive criteria, and 3. No red flags

Diagnosis of Clinically Probable PD requires: 1. Absence of absolute exclusion criteria 2. Presence of red flags counterbalanced by supportive criteria

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Supportive criteria (Check box if criteria met) Clear and dramatic beneficial response to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. In the absence of clear documentation of initial response a dramatic response can be classified as: a) Marked improvement with dose increases or marked worsening with dose decreases. Mild changes do not qualify. Document this either objectively (>30% in UPDRS III with change in treatment), or subjectively (clearly-documented history of marked changes from a reliable patient or caregiver). b) Unequivocal and marked on/off fluctuations, which must have at some point included predictable end-of-dose wearing off. Presence of levodopa-induced dyskinesia Rest tremor of a limb, documented on clinical examination (in past, or on current examination) The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy

Absolute exclusion criteria: The presence of any of these features rules out PD: Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (eg, sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades) Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria31 within thefirst 5 y of disease Parkinsonian features restricted to the lower limbs for more than 3 y Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism Absence of observable response to high-dose levodopa despite at least moderate severity of disease Unequivocal cortical sensory loss (ie, graphesthesia, stereognosis with intact

Red flags Rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset A complete absence of progression of motor symptoms or signs over 5 or more y unless stability is related to treatment Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first 5 y Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs Severe autonomic failure in the first 5 y of disease. This can include: a) Orthostatic hypotension32—orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, in the absence of dehydration, medication, or other diseases that could plausibly explain autonomic dysfunction, or b) Severe urinary retention or urinary incontinence in the first 5 y of disease (excluding long-standing or small amount stress incontinence in women), that is not simply functional incontinence. In men, urinary retention must not be attributable to prostate disease, and must be associated with erectile dysfunction

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Recurrent (>1/y) falls because of impaired balance within 3 y of onset Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 y Absence of any of the common nonmotor features of disease despite 5 y disease duration. These include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations) Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response) Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination

Criteria Application: 1. Does the patient have parkinsonism, as defined by the MDS criteria? Yes No If no, neither probable PD nor clinically established PD can be diagnosed. If yes: 2. Are any absolute exclusion criteria present? Yes No If “yes,” neither probable PD nor clinically established PD can be diagnosed. If no: 3. Number of red flags present ____ 4. Number of supportive criteria present ____ 5. Are there at least 2 supportive criteria and no red flags? Yes No If yes, patient meets criteira for clinically established PD. If no: 6. Are there more than 2 red flags? Yes No If “yes,” probable PD cannot be diagnosed. If no: 7. Is the number of red flags equal to, or less than, the number of supportive criteria? Yes No If yes, patient meets criteria for probable PD

MDS-UPDRS Clinimetric Assessment

The MDS-UPDRX clinimetric assessment is MDS-UPDRS clinimetric divided into four parts. Part I involves non- assessment forms are available at: motor aspects of the experiences of daily http://www.movementdisor ders.org/MDS- living. The primary source of information Files1/PDFs/Rating- Scales/MDS- should be filled in by the rater (patient, UPDRS_Vol23_Issue15_200 caregiver or both). The assessment form 8.pdf

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has a specific script and patient questionnaire. The signs and symptoms are rated on a scale of “0” to “4”:61 • 0= normal • 1= slight • 2= mild • 3= moderate • 4= severe

For complex behaviors, the rating is marked and added to give a total score.

Cognitive Impairment

• 0= none • 1= mild (consistent forgetfulness with partial recollection of events with no other difficulties) • 2= moderate memory loss with disorientation and moderate difficulty handling complex problems • 3= severe memory loss with disorientation to time and often place, severe impairment with problems • 4= severe memory loss with orientation only to person, unable to make judgments or solve problems

Hallucinations and Psychosis

• 0= none • 1= mild (consistent forgetfulness with partial recollection of events with no other difficulties) • 2= moderate memory loss with disorientation and moderate difficulty handling complex problems • 3= severe memory loss with disorientation to time and often place, severe impairment with problems

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• 4= severe memory loss with orientation only to person, unable to make judgments or solve problems

Depressed Mood

• 0= not present • 1= periods of sadness or guilt greater than normal, never sustained for more than a few days or a week • 2= sustained depression for >1 week • 3= vegetative symptoms (insomnia, anorexia, abulia, weight loss) • 4= vegetative symptoms with suicidality

Motivation

• 0= normal • 1= less of assertive, more passive • 2= loss of initiative or disinterest in elective activities • 3= loss of initiative or disinterest in day to say (routine) activities • 4= withdrawn, complete loss of motivation

Other experiences of daily living in Part I include whether the patient has symptoms of anxious mood, apathy, and features of dopamine dysregulation syndrome. The patient questionnaire should address sleep issues, daytime sleepiness, pain and other sensations, urinary issues, constipation, light headedness when standing, and fatigue.

Part II involves motor aspects of the patient questionnaire. This includes assessment of the following patient functions.

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Speech

• 0= normal • 1= mildly affected, no difficulty being understood • 2= moderately affected, may be asked to repeat • 3= severely affected, frequently asked to repeat • 4= unintelligible most of time

Saliva/Excessive Drooling

• 0= normal • 1= slight but noticeable increase, may have nighttime drooling • 2= moderately excessive saliva, may have minimal drooling • 3= marked drooling

Chewing and Swallowing

• 0= normal • 1= rare choking • 2= occasional choking • 3= requires soft food • 4= requires NG tube or G-tube

Eating

• 0= normal • 1= somewhat slow and clumsy but no help needed • 2= can cut most foods, some help needed • 3= food must be cut, but can feed self • 4= needs to be fed

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Dressing

• 0= normal • 1= somewhat slow, no help needed • 2= occasional help with buttons or arms in sleeves • 3= considerable help required but can do something alone • 4= helpless

Hygiene

• 0= normal • 1= somewhat slow but no help needed • 2= needs help with shower or bath or very slow in hygienic care • 3= requires assistance for washing, brushing teeth, going to bathroom • 4= helpless

Handwriting

• 0= normal, 1-slightly small or slow • 2= all words small but legible • 3= severely affected, not all words legible • 4= majority illegible

Movement in Bed

• 0= normal • 1= somewhat slow no help needed • 2= can turn alone or adjust sheets but with great difficulty • 3= can initiate but not turn or adjust alone • 4= helpless

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This would include evaluation of tremor, and how the patient gets out of a car, a chair, or bed. Walking or balance is assessed.

Falling, unrelated to freezing

• 0= none • 1= rare falls • 2= occasional, less than one per day • 3= average of once per day • 4= >1 per day

Freezing in movement

• 0= normal • 1= rare, may have start hesitation • 2= occasional falls from freezing • 3= frequent freezing, occasional falls • 4= frequent falls from freezing

Part III involves motor examination. The examiner should note any medications and the amount of time since the last dosing. It is recommended that the examiner should rate what is observed or note UR (unable to rate).

The “ON” selection indicates the typical functional state when patients are receiving medications and have a good response. Whereas, the “OFF” selection indicates the typical functional state when patients have a poor response in spite of taking medications.

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Speech

• 0= normal speech • 1= loss of modulation, diction or volume, but all words understandable • 2= loss of modulation, diction or volumes with a few words unclear, but overall understandable • 3= speech is difficult to understand with some sentences cannot be easily understood • 4= most sentences are not easily understood

Facial Expression

• 0= normal facial expressions • 1= Minimal masked facies characterized only by decreased blink frequency • 2= Decreased blink frequency plus masked facies in the lower face (masked facies may be characterized by decreased facial movements such as smiling without parting the lips, laughing without opening the mouth, decreased frequency of spontaneous smiling) • 3= Masked facies with lips parted only some of the time while the mouth is at rest • 4= Masked facies with lips parted most of the time while the mouth is at rest

Rigidity

Of the neck, right/left upper extremities and right/left lower extremities, which are each assessed: • 0= normal, no rigidity • 1= rigidity only noted with activation

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• 2= rigidity noted without activation, full range of motion (ROM) easily obtained • 3= rigidity noted without activation, full ROM obtained with some effort • 4= rigidity noted without activation, full ROM not obtained

Finger Tapping

Each hand is separately assessed. • 0= normal • 1= any of the following (of regular rhythm is broken with only one or two interruptions or hesitations, slightly decreased frequency, decreased amplitude after 10 taps) • 2= any of the following (of regular rhythm is broken with three to five interruptions or hesitations, mild decrease in frequency, decreased amplitude after 5 taps) • 3= any of the following (of regular rhythm is broken with more than five interruptions or hesitations, at least one longer hesitation or freeze, moderate slowing of taps, decreased amplitude after first tap) • 4= Can hardly tap or cannot tap at all

Hand Movements

Each hand is separately tested. The patient is instructed to make a fist. The arm is bent at the elbow and the palm of the hand should face the examiner. The patient is then asked to open and close the hand as fully and as quickly as possible. Speed, amplitude, hesitations, freezes are assessed): • 0= normal

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• 1= any of the following (of regular rhythm is broken with only one or two interruptions or hesitations, slightly decreased frequency, decreased amplitude after 10 movements) • 2= any of the following (of regular rhythm is broken with three to five interruptions or hesitations, mild decrease in frequency, decreased amplitude after 5 movements) • 3= any of the following (of regular rhythm is broken with more than five interruptions or hesitations, at least one longer hesitation or freeze, moderate slowing of movement, decreased amplitude after first movement) • 4= can hardly make or open fist or cannot perform movement at all

Pronation/Supination of Hands

Each hand is separately tested. The patient is asked to extend the arm in front of them with the palms facing down. The patient is then asked to turn the palms upward and downward 10 times as quickly and as completely as possible. • 0= normal • 1= any of the following (of regular rhythm is broken with only one or two interruptions or hesitations, slightly decreased frequency, decreased amplitude after 10 movements) • 2= any of the following (of regular rhythm is broken with three to five interruptions or hesitations, mild decrease in frequency, decreased amplitude after 5 movements) • 3= any of the following (of regular rhythm is broken with more than five interruptions or hesitations, at least one longer hesitation or freeze, moderate slowing of movement, decreased amplitude after first movement) • 4= can hardly or cannot perform movement at all

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Toe Tapping

Each foot is separately assessed. • 0= normal • 1= any of the following (regular rhythm is broken with only one or two interruptions or hesitations, slightly decreased frequency, decreased amplitude after 10 taps) • 2= any of the following (regular rhythm is broken with three to five interruptions or hesitations, mild decrease in frequency, decreased amplitude after 5 taps) • 3= any of the following (regular rhythm is broken with more than five interruptions or hesitations, at least one longer hesitation or freeze, moderate slowing of taps, decreased amplitude after first tap) • 4= can hardly tap or cannot tap at all

Leg Agility

Each leg is separately assessed. The patient is instructed to sit comfortably in a straight-backed chair with both feet flat on the floor. The patient is then asked to lift the leg and stomp as quickly as possible. The patient is also asked to lift the leg as high as possible each time. • 0= normal • 1= Any of the following (regular rhythm is broken with only one or two interruptions or hesitations, slightly decreased frequency, decreased amplitude after 10 stomps) • 2= Any of the following (regular rhythm is broken with three to five interruptions or hesitations, mild decrease in frequency, decreased amplitude after 5 stomps) • 3= Any of the following (regular rhythm is broken with more than five interruptions or hesitations, at least one longer hesitation or freeze, moderate slowing of stomps, decreased amplitude after first stomp)

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• 4= Can hardly stomp or cannot stomp at all

Getting Out of a Chair

The patient is instructed to sit comfortably in a straight-backed chair (with arms) and with both feet flat on the floor. The patient is then asked to cross their arms across their chest. Finally, the patient is instructed to stand up. This may be reattempted up to 2 more times. After the third try, have the patient move slightly forward in the chair and allow one attempt. If this is also unsuccessful, allow the patient to use their arms to push off the chair. Allow 3 attempts. If this is also unsuccessful, help the patient stand up. However, a patient gets out of the chair, use this as an opportunity to observe the patient’s posture. • 0= normal • 1= patient may need more than one attempt and may rise slower than normal. • 2= patient may need to use the arms of the chair, but accomplishes this without difficulty • 3= patient may need to push off, but has a tendency to fall back into the chair. Alternatively, may need the arms of the chair, but has difficulty getting up. • 4= patient is unable to rise without help

Gait

Gait is assessed by watching the patient walk away and towards the examiner. The patient should walk at least 30 feet (10 meters) away and then turn around and walk back towards the examiner. Observe stride length, speed, how high each foot is lifted off the floor, heel strikes and arm swing. Also observe for any signs of freezing of gait (FOG).

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• 0= normal • 1= patient can walk independently with only minor impairment of gait. • 2= patient can walk independently but has substantial impairment • 3= patient requires an assistance device such as a cane or walker for safe walking but does not need physical assistance from another person • 4= patient is unable to walk without assistance from another person

Freezing of Gait (FOG)

The examiner should limit any sensory “tricks” the patient may use, always maintaining patient safety. Assess for start hesitation or stuttering, particularly when the patient turns or reaches the end of the task. If possible, have the patient walk through a doorway. This may be accomplished during the gait assessment above. • 0= normal, no FOG • 1= patient freezes no more than 1 time when beginning, turning or walking through a doorway • 2= patient freezes with more than 1 freeze when beginning, turning or walking through a doorway. Does not freeze on a straight path. • 3= patient freezes at least once on a straight path • 4= patient freezes more than once on a straight path

Postural Stability

Examiner may use the retropulsion test. The patient is asked to stand upright with hands at their sides and eyes open. The examiner stands behind the patient. The patient is told that the examiner will pull back (gently) on their shoulders. The examiner should be ready to assist the patient to prevent a fall.

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• 0= normal, recovers stability with no more than one or two steps • 1= patient recovers with 3 - 5 steps, but does not require assistance • 2= patient recovers with more than 5 steps but does not require assistance • 3= patient is able to stand without assistance but requires assistance to avoid a fall • 4= patient is unstable or very unstable and may lose their balance even on a gentle pull. May be unable to stand without assistance

Posture

Examiner should observe posture after rising from a chair, during gait assessment and while being tested for postural stability. (Three independent observations). Examiner should also observe flexion or side-to-side leaning. • 0= normal • 1= patient is not fully erect, but has a posture appropriate to their age • 2= patient is observed with flexion, scoliosis or leaning to the side, but the patient can correct the posture when asked to do so • 3= patient is observed with a stooped posture, scoliosis or leaning to the side. Patient is unable to correct posture when asked to do so • 4= patient is observed with extreme flexion, scoliosis or leaning to the side

Body Bradykinesia

Also known as global spontaneity of movement. Combines all the examiner’s observations on slow movement, hesitations, small amplitude of movements, frequency of gestures such as hand movements, crossing the legs, animated movements, getting up, sitting down and walking.

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• 0= normal • 1= minor bradykinesia. Slight slowness and slight decreased spontaneous movement • 2= mild bradykinesia. Mild slowness and mildly decreased spontaneous movement • 3= moderate bradykinesia. Moderate slowness and moderately decreased spontaneous movement • 4= severe bradykinesia. Severe slowness and severely decreased spontaneous movement

Postural Hand Tremor

The examiner should include all forms of tremor including re-emergent rest tremor. Each hand is separately rated. The highest amplitude seen should be rated. The patient is instructed to stretch the arms out in front of them with the palms facing downward. Wrists should be straight. The observation should be held for 10 seconds. • 0= normal, no tremor • 1= tremor is present, but less than 1 cm. in amplitude • 2= tremor between 1 cm and 3 cm in amplitude • 3= tremor between 3 and 10 cm in amplitude • 4= tremor ≥ 10 cm in amplitude

Kinetic Hand Tremor

Each hand is tested. The patient is instructed to stand with arms outstretched as far as possible. The patient is then instructed to touch their nose. This is repeated at least three times and should be done slowly in order to detect tremor. • 0= normal, no tremor • 1= tremor is present, but less than 1 cm. in amplitude

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• 2= tremor between 1 cm and 3 cm in amplitude • 3= tremor between 3 and 10 cm in amplitude • 4= tremor ≥ 10 cm in amplitude

Rest Tremor Amplitude

The examiner should observe instances of rest tremor throughout the examination; during quiet sitting, walking and throughout all activities. The testing for rest tremor amplitude should be done near the end of the examination. The patient should sit in a chair with feet flat on the floor. Arms should not be in the lap, but resting on the arms of the chair. Allow at least 10 seconds to pass before assessment. Only amplitude is assessed here, with separate assessments of the four limbs, the lip/jaw. Extremities are separately assessed. • 0= normal, no tremor • 1= tremor is present, but less than 1 cm. in amplitude • 2= tremor between 1 cm and 3 cm in amplitude • 3= tremor between 3 and 10 cm in amplitude • 4= tremor ≥ 10 cm in amplitude

Lip/Jaw

• 0= normal, no tremor • 1= tremor is present, but less than 1 cm. in amplitude • 2= tremor between 1 cm and 2 cm in amplitude • 3= tremor greater than 2 and less than 3 cm in amplitude • 4= tremor ≥ 3 cm in amplitude

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Constancy of Rest Tremor

This a global, whole body assessment. • 0= normal, no tremor • 1= tremor is present during < 25% of the examination • 2= tremor is present during > 26% but less than 50% of the examination • 3= tremor is present during >51% and < 75% of the examination • 4= tremor is present during >75% of the examination

The examiner is asked if dyskinesias such as chorea or dystonia was present during the examination and if these interfered with the assessment. The Hoehn and Yahr staging of Parkinson’s disease defines five stages

Stage 1:

• Signs and symptoms only on one side • Mild symptoms • Symptoms considered inconvenient but not disabling • Limited to tremor in one extremity • Friends/caretakers may have noticed changes in posture, locomotion and facial expression Stage 2:

• Bilateral symptoms • Minimal disability • Posture and gait are affected Stage 3:

• There is a significant bradykinesia • Equilibrium dysfunction is seen both in walking and while standing • Moderately severe generalized dysfunction

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Stage 4:

• Symptoms are severe • Patient can still walk for short distances • Rigidity is present • Bradykinesia is present • Tremor may be decreased as compared to earlier stages • Patient may require in-home care, may not be able to live alone Stage 5:

• Cachexia • Patient is fully invalid • Patient cannot walk or stand • Patient requires constant nursing care

Hoehn and Yahr Stage Rating:

0= asymptomatic 1= unilateral involvement only 2= bilateral involvement without balance impairment 3= mild to moderate involvement with some postural instability (physical independence but requires help to recover from retropulsion test) 4= severe disability but able to walk and stand independently 5= wheelchair or bed-bound.

Part IV involves motor Complications. This part assesses dyskinesia and motor fluctuations including OFF-state dystonia. The questions/assessments refer to the patient’s past week.

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Dyskinesias

Ensure that the patient understands dyskinesias as involuntary movements that are random and can be stated as “jerking”, “twitching”, or “wriggling/wiggling”. This does not include “OFF-state dystonia” or tremors. The percentage of time with dyskinesia is based on the wake time; percentage age of daytime with dyskinesia. • 0= normal • 1= ≤25% of the waking day • 2= 26-50% of the waking day • 3= 51-75 % of the waking day • 4= >75% of the waking day

Impact of Dyskinesia

Functional impact on daily function is assessed here. • 0= Normal. No impact or no dyskinesia • 1= Dyskinesia affects a few activities but the patient can perform all the activities they want to and are able to interact socially. • 2= Dyskinesia impacts on many activities, but patient is still able to remain active and to interact socially • 3= Dyskinesia impacts on many activities and the patient avoids most activities and often avoids social interactions • 4= Dyskinesia impacts enough so that the patient avoids most activities and most social interactions

Motor Fluctuations

Use the number of waking hours and determine the number and percentage of “OFF-state” defined as the “Typical functional state when patients have a poor response in spite of taking medication, or the typical functional

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response when the patient is not taking medication.” This may be expressed by the patient as “bad time”, “shaking time”, or “slow time”. The “ON-state” is defined as the “Typical functional state when patients are receiving medication and have a good response”. Time spent in “OFF-state”. Record the total hours awake and the total hours “OFF”. • 0= no OFF time • 1= ≤25% of the waking day • 2= 26-50% of the waking day • 3= 51-75 % of the waking day • 4= >75% of the waking day

Impact of Motor Fluctuations

• 0= No fluctuations • 1= fluctuations affect a few activities but during the “OFF” period, the patient can perform all the activities they want to and are able to interact socially. • 2= fluctuations impact on many activities, but during the “OFF” period, patient is still able to remain active and to interact socially • 3= fluctuations impact on many activities and during the “OFF” periods, the patient avoids most activities and often avoids social interactions • 4= fluctuations impact enough so that the patient avoids most activities and most social interactions during the “OFF” periods

Complexity of motor fluctuations refers to the predictability of the OFF times irrespective of why or how the OFF time occurs (i.e., dose, time of day, triggers such as exercise or other factors). • 0= no motor fluctuations • 1= OFF times are predictable all or most of the time (>75%)

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• 2= OFF times are predictable most of the time (51-75%) • 3= OFF times are predictable some of the time (26-50%) • 4= OFF times are rarely if ever predictable (≤25%)

“OFF” Dystonia

Dystonia is a contorted posture, often a twisted posture. Patients will often recognize dystonia as “spasms” or “cramps” Painful OFF-state dystonia. Record the total hours “OFF” and the total OFF hours with dystonia. Calculate the % OFF dystonia by dividing the total OFF hours by the OFF hours with dystonia and multiplying by 100. • 0= No dystonia or no OFF time • 1= <25% of time in OFF state • 2= between 26 and 50% of time in OFF state • 3= between 51 and 75% of time in OFF state • 4= >75% in OFF state

Treatment Of Parkinson’s Disease

In 2015, the Movement Disorder Society extended their diagnostic criteria for Parkinson’s disease. Diagnosis of established Parkinson’s Disease requires absence of absolute exclusion criteria, at least two supportive criteria, no red flags. The medical management of Parkinson’s disease is largely symptomatic, providing control of signs and symptoms while, ideally, minimizing adverse reactions. Motor symptoms, motor complications and non-motor symptoms as well as psychiatric and mental health issues all need to be treated. Dopamine deficiency is addressed in early PD while non- dopaminergic effects and dopaminergic-resistance develop later in the disease process, resulting in both motor and non-motor symptoms.

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Symptom Progression and Medication

Medication should be instituted when patients are experiencing functional impairment or social difficulties.1,2,76 Motor symptoms can be treated with a number of different medications. The most well-established medications are reviewed in this section, and include the levodopa drugs, commonly given along with peripheral dopa decarboxylase inhibitors (PDDIs). This class includes levodopa-carbidopa and levodopa-benserazide. Other well- established classes of drugs include dopamine agonists (pramipexole, ropinirole and rotigotine), the monoamine oxidase type B inhibitors (MAOBIs such as selegiline and rasagiline) and as adjunct therapies the catechol-O- methyltransferase inhibitors (COMTIs) that include entacapone and tolcapine.75-84

Levodopa and dopamine agonists can be used to treat all motor symptoms. MAOBIs may be particularly useful with early, mild symptoms of PD as well as motor fluctuations while the COMTIs are useful for motor fluctuations.

Other medications, for which the evidence is much less established, include amantadine (used primarily for gait dysfunction and dyskinesia), β-blockers such as propranolol (to treat tremors), anticholinergics (i.e., trihexyphenidyl, Benztropine, also used to treat tremor) and the neuroleptics such as clozapine used to treat both tremor and dyskinesias.

Initially, one must determine the greatest disability - and the degree of disability - when determining treatment approaches. Often, a monoamine oxidase type B inhibitor such as selegiline or rasatiline should be considered. The use of dopamine agonists can delay the motor complications seen in younger patients. In older patients, the use of dopamine agonists is associated with a greater risk of neuropsychiatric complications.

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The European Federation of Neurological Societies (EFNS) and the Movement Disorder Societies (in Europe) have produced guidelines on the therapeutic management of Parkinson’s disease. Their recommendations for the treatment of early PD are listed below, as well as common medications and their adverse effects. The first step in defining the optimal treatment for individual PD patients is to determine the source of the greatest disability: tremors, bradykinesia with impaired dexterity or postural instability with gait impairment. Secondarily, the age of the patient is important in determining the optimal evidence-based treatment approach.

For patients who are severely impaired by their symptoms, multiple large trials have established that levodopa is associated with fewer adverse effects such as freezing, sleep difficulties, psychotic episodes or impulse control disorders as compared to other medications such as dopamine agonists. On the other hand, dopamine agonists are less likely to cause motor complications such as dyskinesia. Recent studies have indicated, in addition, that over the long term, any advantage of dopamine agonists as compared to levodopa is lost over time. In addition, there is some evidence of benefit in using MAOBIs (monoamine oxidase type B inhibitors) in early PD with mild symptoms.

Levodopa (along with a dopa decarboxylase inhibitor) is titrated slowly, starting at a low dose. A common dosage is 300-600 mg/day in divided doses (usually three to four). Higher doses are avoided as they can lead to the development of dyskinesias. If nausea is a problem, the medication can be taken with food. MAOBIs can also be added to the early treatment regimen. Selegiline is generally used as an adjunct to levodopa while rasagiline has been successfully used as monotherapy in early PD, though it is also useful as an adjunct.

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Dopamine agonists such as pramipexole and ropinirole have been suggested to delay the need for levodopa and to delay the appearance of motor symptoms. However, the early used of dopamine agonists as monotherapy is rather limited due to a higher number and sometimes degree of adverse effects such as sleepiness, hallucinations and impulse control disorders. Dopamine agonists may be more beneficial in younger patients (i.e., less than 70 years old) with no apparent cognitive difficulties. Initial low doses should be titrated slowly and cautiously to obtain symptom relief.

Anticholinergic agents may provide good control of tremor in some patients. But there is a good deal of variability in the response of individual patients to individual anticholinergic agents. In addition, the cognitive and memory side effects can be unacceptable, particularly in an elderly patient. Amantadine is an antiviral drug. It is not clear how amantadine functions in PD, but it may potentiate the dopaminergic response. Amantadine may also increase the release of stored dopamine and norepinephrine.

The choice of drug depends on the impact of improving motor disability.

Options:

• MAO-B inhibitor (selegiline, rasagiline) (Level A evidence) • Oral or transdermal dopamine agonist. Pramipexole, piribedil, ropinirole and rotigotine are effective (Level A evidence). Initial treatment with an agonist can be recommended in younger patients (Good Practice Point, GPP). • Ergot derivatives are not recommended as first-line medication because of the risk of fibrotic reactions. • Levodopa is the most effective symptomatic drug (Level A evidence). • Controlled-release formulations or adding entacapone is not effective in the delay of motor complications (Level A evidence) • Amantadine or an anticholinergic (Level B evidence) • Rehabilitation: because of the lack of evidence in early-stage disease, a recommendation cannot be made

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Practical Recommendations in patients without motor complications:

Patients not on dopaminergic therapy: If a patient has started on an MAO-B inhibitor, anticholinergic, amantadine or a combination of these, a stage will come when there is a requirement for adding levodopa or a dopamine agonist (GPP)

Patients on dopaminergic therapy: If on dopamine agonist therapy, increase the dose (GPP), switch between agonists (Level C evidence), and add levodopa (GPP). If on levodopa, increase dose (GPP), add agonist (GPP), and add COMT inhibitor (GPP).

Patients with disabling tremor: If significant tremor persists, consider anticholinergics (GPP), clozapine (Level B evidence), beta-blockers (propanolol), and deep brain stimulation.

All the medications carry some risk of adverse effects. Treatment is symptomatic and titration is recommended for levodopa. Currently, there are no definitive neuroprotective approaches or disease-modifying therapies. In some cases, shortening dose intervals and keeping individuals at the lowest dose possible may postpone motor complications while adding adjunctive treatment may improve symptomatic control.

Common Medications: Adverse Effects, Typical Dosing, Potential Adjunct Therapy

Medication Adverse Effects Typical Dosing Can be used as Adjunct Therapy Levodopa-PDDI • Nausea Initial titration to 100/25mg Y • Dyskinesia 3x/day. • Orthostatic Increase based on symptoms. hypotension Maximum ~ 1500/375 mg per day • Hallucinations Dopamine • Nausea • Pramipexole: 0.125 mg/d (tid) Y agonists • Dyskinesia • Pramipexole, ER: 0.26 mg, 0.52 • Orthostatic mg, 1.05 mg, 2.1 mg, or 3.15 hypotension mg (qd) • Hallucinations • Ropinirole: 0.25 mg (tid). Max~ • Impulse control 24 mg (qd) disorders • Ropinirole ER: 6-24 mg (qd) (ICDs) • Rotigotine: Initial dose: 2 mg/d. • Edema Max~ 24 mg/d • Sleep problems

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MAOBIs • Exacerbation of • Selegiline: 2.5 mg/day. Max~ Y levodopa’s 5mg (bid) adverse effects • Rasagiline: 1 mg/day • Stimulation • Headache Buccal selegiline and rasalinine are • Arthralgia not metabolized to amphetamine • Depression while the oral forms of these • Dizziness medications are. COMTIs • Dark urine • Entacapone: 200 mg with each Y • Exacerbation of dose of levodopa. Max 8/day levodopa • Tolcapone: 1-200 mg (tid) effects • Hepatotoxicity Levodopa/carbidopa/entacapone may shorten time of onset of dyskinesia with no wearing-off Amantadine • Hallucinations Initial dose: 100mg/d. Max~ 100 Sometimes • Confusion mg qid effective as • Blurred vision an adjunct. • Edema Evidence for • Nausea amantadine • Dry mouth is mixed. The • Constipation EFNS stated amantadine to be effective as symptomatic therapy or as an adjunct. β-blockers • Dizziness Initial dose: 40 mg (bid). Max~ Conflicting • Fatigue 320 mg/day evidence for usefulness as an adjunct treatment. Anticholinergics • Hallucinations • Trihexyphenidyl: Initial dose: Conflicting • Confusion 1mg/day. Maintenance: 2mg evidence for • Blurred vision (tid) usefulness as • Urinary • Benztropine: Initial dose: 0.5-1 an adjunct retention mg/day. treatment. • Nausea Primarily • Dry mouth anecdotal • Constipation information. Neuroleptic • Agranulocytosis Initial dose: 6.25- 12.5 mg at Possibly • Myocarditis bedtime. Max~ 150 mg/day effective for • Sedation tremor • Seizures • Orthostatic hypotension

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Dopaminergic Neurons

Dopamine is a catecholamine neurotransmitter involved in major neural functions including mood, movement and learning. Dopamine is also implicated in addictions. Dopamine is synthesized from the essential amino acid, tyrosine. Tyrosine enters the dopaminergic neuron and is hydroxylated by tyrosine hydroxylase to form L-dopa. L-dopa is then decarboxylated by l- amino acid decarboxylase to form dopamine. Dopamine is then stored in synaptic vesicles in the presynaptic neuron.

There are three main systems of the brain populated with dopaminergic neurons: the nigrostriatal system, mesolimbic system, and mesocortical system.

Nigrostriatal System

These neurons originate in the substantia nigra, terminating in the caudate nucleus and the putamen, both of which are located in the midbrain. The nigrostriatal system is an important control of movement and the area prominent in the pathology of Parkinson’s disease.

Mesolimbic System

These neurons originate in the ventral tegmental area, extending to areas of the limbic system, including the nucleus accumbens, the amygdala and the hippocampus. The mesolimbic system plays a central role in the reward system and in addictions

Mesocortical System

The mesocortical system originates in the ventral tegmental area and extends to the prefrontal cortex, impacting executive functions such as

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planning and problem solving as well as memory. Dopamine can be taken up by the post-synaptic neurons and re-taken up by the pre-synaptic neurons to be re-released. Dopamine may also be used in the synthesis of norepinephrine (via dopamine β-hydroxylase) and to epinephrine (via phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine (SAMe) as a cofactor).

Dopamine is degraded by both isoforms of monoamine oxidase (A and B) and by catechol-O-methyl transferase (COMT) followed by aldehyde dehydrogenase (ALDH). The primary end product of this degradation is homovanillic acid (HVA). HVA is excreted primarily by the kidneys. Dopamine may also be oxidized resulting in quinones and free radicals - oxidative stress may be one of the causes of cell death in Parkinson’s disease.

Main Functions of Dopamine

Dopaminergic neurons in the midbrain have a role in motivation and behavior. In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. In general, increased activity increases reward while decreased activity may induce aversion.66

Dopaminergic neurons in the substantia nigra (primarily found in the pars compacta with fewer dopaminergic neurons found in the pars reticulata) project to the dorsal striata forming the nigrostriatal pathway. Here the dopaminergic neurons play a substantial role in controlling motor function and in the learning of new motor skills. The substantia nigra along with the ventral tegmental area form the primary dopaminergic areas of the basal ganglia, informing action selection, either by releasing inhibition to allow a

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specific behavior or movement or by maintaining that inhibition, allowing other or competing behavior or movement.

Dopamine plays a critical role within the reward system involving pleasure, learning and behaviors as well as aversion. These dopaminergic neurons are found in the ventral tegmental area which expresses heterogeneous dopaminergic neuronal populations with diverse axonal projections in addition to varied anatomical, molecular and electrophysiological features. In the hypothalamus, dopaminergic neurons project into the pituitary (forming the tuberoinfundibular pathway) where these neurons influence the secretion of prolactin from the anterior pituitary gland. Dopamine inhibits prolactin secretion.

Dopamine Receptors

There are five dopamine receptor subtypes currently known (D1- D5). All five are members of the G-protein-coupled receptor (GPCR) superfamily with the canonical seven transmembrane structure. The members of the GPCR family, including all the dopamine receptor subtypes, can signal through G protein dependent and independent mechanisms. If coupled to Gαs,oif, cAMP production as a second messenger is stimulated. If coupled to Gαi/o, cAMP production is inhibited. D1 class receptors (D1 and D5) are coupled to Gαs,oif while D2 class receptors are coupled to Gαi/o. Dopamine receptors play a role in regulating voluntary movement, feeding behavior, addictions, sleep, mood, cognitive function, sense of smell, vision, reward, aversion, hormonal regulation, sympathetic regulation, parasympathetic regulation, immune response and cardiovascular, renal and gastrointestinal functions.66-70

Dopamine receptors can also utilize alternative signaling pathways. These include transactivation of brain-derived neurotrophic factor (BDNF) in

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neurons, regulation of calcium channels via direct protein-protein, via direct + + interaction with Na /K -ATPase and via IP3-mediated signaling. Additional pathways may be utilized including via the multifunctional adaptor protein β- arrestin and glucogen synthase kinase (GSK3).77,78

Dopamine receptors can function as homomers and as heteromers with several other receptors including other GPCRs, (eg. subtype D1 and D2 herterodimers) and with glutamate receptors. D1-D2 heterodimers recruits

Gαs,oif leading to calcium release. Both members of the heterodimeric group are required—dopamine or a combination of selective subtype agonists are needed to increase calcium release. However, inhibition of calcium release can be achieved with either a D1 or D2 receptor antagonist. A recent review of the function of dopamine receptors concluded that “multidimensional analysis of dopamine receptor biology will eventually provide an opportunity for the precise targeting of desired components of post-receptor intracellular processes either via receptor-related mechanisms or post-receptor signaling cascades, thereby providing an exciting opportunity to target pathological processes with minimal propensity of developing side effects. Such approaches involving ‘biased agonism’, allosteric-based targeting of receptors and heteromers and downstream intracellular signaling events could eventually result in emergence of a new generation of dopamine receptor-based therapies for a variety of dopamine-related disorders.”78

After synthesis, dopamine is transported into vesicles by vesicular monoamine transporter (VMAT)-2. Dopamine is transported into presynaptic terminals by a dopamine transporter (DAT). Both DAT and VMAT-2 are regulated by post-translational modification, protein-protein interactions and by intracellular localization.80,120,124 It is believed that α-synuclein plays a role in regulating the function of DAT: α-synuclein appears to “recruit and

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stabilize DAT at the plasma membrane and to enhance Vmax under normal conditions.”80 It is hypothesized that in Parkinson’s disease, the overexpression of α-synuclein accelerates the uptake of dopamine by DAT: this leads to oxidative stress and terminal damage. In addition, decreases in VMAT-2 have been seen in postmortem studies. Interestingly, pesticides, polychlorinated biphenyls and brominated compounds, all associated with Parkinson’s disease, also are associated with damage to DAT and VMAT-2.

Pharmacology In The Treatment Of Parkinson’s Disease

In the medical treatment of Parkinson’s disease, Levodopa has been described an effective agent for PD motor symptoms. Other medications include amantadine, anticholinergics, β-blockers, or dopamine agonists that clinicians may opt to trial first before advancing to levodopa. Clinicians may modify levodopa dosing regimen or combine it with other medications. The medical treatment of movement fluctuations and impulse control disorders are discussed in this section.62-83,144-149

Levodopa

Levodopa is a carboxylated analog to dopamine and is able to cross the blood-brain barrier where it is presumed that it is decarboxylated to dopamine, acting as replacement therapy. Carbidopa does not cross the blood brain barrier. Commonly, levodopa is given with a decarboxylase inhibitor that is active only in the periphery, allowing levodopa greater bioavailability (~30%) and decreasing the risks of peripheral dopaminergic effects on, for example, the gastrointestinal or cardiovascular systems.

Peak plasma levels are achieved within 1-2 hours but less than 1% of dose reaches the brain. Levodopa undergoes first-pass hepatic metabolism but

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carbidopa is not extensively metabolized. Levodopa has a t1/2 of 60-90 minutes. Initial loading dose is generally 50 mg along with 12.5 mg of a decarboxylase inhibitor such as carbidopa or benserazide) with dosing intervals of 8 to 12 hours. Maintenance doses can range from 100-200 mg (with 25-50 mg of a decarboxylase inhibitor) every 4 to 8 hours.

The positive value of levodopa treatment slowly decreases as adverse effects multiply both quantitatively and qualitatively. Adverse effects may be decreased by using adjunct therapy such as bromocriptine or selegilin. Early adverse effects include nausea, hypotension and extrasystoles. Long- term adverse effects include involuntary movement, dyskinesias, motor fluctuations, sleep disturbances, depression, anxiety, confusion, hallucinations and paranoid delusions. Rare adverse effects include hemolytic anemias and exanthemas.

Levodopa effects can be diminished by interactions with anticholinergic drugs, benzodiazepines and pyridoxine (Vitamin B6). Non-specific MAO inhibitors and sympathomimetic drugs when used with levodopa can induce hypertensive reactions. Levodopa is contraindicated in narrow-angle glaucoma, psychoses and melanoma. Patients should be maintained at the lowest dose possible for symptom relief and to minimize any adverse reactions.

Sinemet

Sinemet immediate release should be initiated at 25 mg/100 mg every eight hours or 10 mg/100 mg every six to eight hours. The levodopa can be increased by up to 100 mg every 1-2 days but the carbidopa portion should be maintained between 70-100/day. The maximum recommended levodopa dose is 800mg/day while the maximum recommended carbidopa dose is 200

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mg/day. If the extended release formula (Sinemet CR) is used, it should be initiated at 50mg/200mg every 12 hours. Doses may be increase to 1600 mg per day, but must be given at least 6 hours apart. To convert from immediate release (IR) to extended release (CR), the following conversions may be used. • 300-400 mg/day IR = 200 mg ER every 12 hours • 500-600 mg/day IR = 300 mg ER q12hr or 200 mg ER every 8 hours • 700-800 mg/day IR = 800 mg ER divided every 8 hours • 900-1000 mg/day IR = 1000 ER divided every 8 hours

Rytary contains both immediate-release and extended release forms. For patients never having taken levodopa, the dose is initially 23.75mg/95mg. On the fourth day of treatment, that dose can be increased to 36.25mg/145mg three times a day with a maximum recommended dose of 97.5mg/390 mg three times a day. If more frequent dosing is needed, it may be increased to five times a day up to a maximum of 612.5 mg/2450 mg per day. To convert from an immediate-release preparation (Sinemet or Parcopa) to Rytary, the following conversions may be used. • 400-549 mg IR: 3 caps 23.75mg/95mg three times a day • 550-749 mg IR: 4 caps 23.75mg/95mg three times a day • 750-949 mg IR: 3 caps 36.25mg/145mg three times a day • 950-1249 mg IR: 3 caps 48.75 mg/195 mg three times a day • ≥1250 mg IR: 4 caps 48.75 mg/195 mg three times a day, OR 3 caps 61.25 mg/245 mg three times a day

Duopa

Duopa (carbidopa/levodopa), the extended-release enteral solution, is administered by intrajejunal infusion over 16 hours. The daily dose may be individualized by bearing in mind the morning dose, the continuing dose and

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any doses the patient may be taking. Maximum recommended dose is 2000 mg (1 cassette/day) over 16 hours. The patient may also be taking a nightly dose of carbidopa/levodopa. To “convert” a patient to Duopa, the patient is first maintained on immediate-release carbidopa/levodopa.143-148

With Duopa, “off” symptoms can be managed using an extra dose function— this should be set at 1 mL initially and adjusted with 0.2mL increments. This should be limited to 1 extra dose every 2 hours. Health clinicians should be aware that use of the extra dose function can either cause or worsen dyskinesia. To determine the initial dose (Day 1) of Duopa, clinicians should pursue the following steps.

• Determine the total milligrams of levodopa that was taken by the patient on the previous day in their first, morning dose. • To convert the oral dose, multiply the oral dose by 0.8 and then divide by 20 mg/mL. This provides the morning dose of Duopa in mL. • Add 3 mL to the number of mL obtained in the previous calculation (morning dose) and use this volume to fill or prime the intestinal tube. This total morning dose is usually administered over 10-30 minutes. • Program the pump to deliver the total morning dose.

To calculate the continuous dose for Day 1:

• Determine the amount of orally-dosed, immediate-release carbidopa/levodopa that the patient received the entire (16 hours) previous day in mg. The nightly dose is not included in this amount. • Subtract the first oral morning levodopa dose (in mg) taken by the patient on the previous day. Divide this number by 20 mg/mL. The result is the dose of Duopa (in mL) administered as an continuous dose over 16 hr. The hourly infusion rate (in mL/hr): Take the continuous

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dose just calculated and divide by 16 hours. The result is programmed into the pump as the as the continuous rate. • If there are numerous “Off” periods occur during the 16-hr infusion, consider increasing the continuous dose or using the Extra Dose function. Conversely, if dyskinesia or other levodopa-related adverse reactions occur, consider decreasing the continuous dose. Also, consider stopping the infusion until the adverse reactions subside sufficiently. • Duopa can be titrated by adjusting the morning dose and/or the continuous dose. If the clinical response is suboptimal or inadequate on the previous day, to adjust the morning dose by increasing by 1mL if the morning dose on the preceding day was ≤ 6mL, increase the new morning dose by 1 mL. If the morning dose on the preceding day was > 6mL, increase the new morning dose by 2 mL. If dyskinesia or other adverse effects are noted within 1 hour of the morning dose, the next day, decrease the morning dose by 1 mL. The continuous dose may also be adjusted due to adverse reactions. If the adverse reactions lasted longer than 1 hour, decrease the continuous dose by 0.3mL/hr. If the adverse reactions lasted for more than 2 periods of longer than 1 hour, decrease the continuous dose by 0.6mL/hr.143-148

Contraindications and Interactions

Carbidopa/Levodopa use with medications that act synergistically with levodopa and may cause an acute hypertensive episode include isocarboxazid, phenelzine, procarbazine, selegiine (oral or transdermal) tranylcypromine. Alternative medications should be used in place of those listed here. Also, high fat meals may inhibit the absorption of levodopa.

Pharmacodynamic antagonists (decreases effect of levodopa):

• Aripiprazole

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• Chlorpromazine • Clozapine • Droperidol • Fluphenazine • Haloperidol • Iloperidone • Loxapine • Loxapine (Inhaled) • Olanzapine • Paliperidone • Perphenazine • Pimozide • Prochlorperazine • Promethazine • Quetiapine • Risperidone • Thioridazine • Thiothixene • Trifluoperazine • Ziprasidone (increases serotonin levels synergistically with levodopa) • Desvenlafaxine, • Linezolid • Methylene blue • Procarbazine

Adverse Effects

The frequency of the adverse effects has not been determined. Post marketing reports have included suicide attempts and suicidal ideation, among other physiological, cognitive and psychological effects.

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Contraindications

• Hypersensitivity • Narrow-angle glaucoma (tablets) • Concurrent administration of nonselective monoamine oxidase inhibitors (MAOIs) or use within last 14 days

Cautions

• Use caution in history of MI with residual atrial, nodal, or ventricular arrhythmias, peptic ulcer, or seizure. • Use caution in severe cardiovascular, respiratory disease, renal, hepatic, or endocrine disease; monitor disease parameters. • Use caution in bronchial asthma patients taking sympathomimetics. • Levodopa may cause patients to fall asleep while engaging in activities of daily living; caution regarding use of machinery and driving. • Avoid use in patients with a major psychotic disorder; therapy may exacerbate psychosis; increases risk for hallucinations and development of psychosis; other psychiatric symptoms include decreased impulse control and compulsive behaviors, depression, and suicidality; observe patients for symptoms of depression with concomitant suicidal tendencies. • May exacerbate dyskinesia; reduce dose to control symptoms. • Peripheral neuropathy reported with use; evaluate patients for history of neuropathy and known risk factors prior to initiating therapy; assess patients for peripheral neuropathy periodically during therapy. • Orthostatic hypotension may occur (more common with immediate- release formulation). • Use caution in patients with glaucoma; monitor intraocular pressure carefully; some formulations are contraindicated in patients with narrow- angle glaucoma.

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• Observe patients carefully if discontinued abruptly; risk of syndrome resembling neuroleptic malignant syndrome. • Controlled-release formulation is less bioavailable than conventional formulation. • Gastrointestinal complications from PEG-J or naso-jejunal tube can occur (i.e., bezoar, ileus, intussusception, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum, and post- operative wound infection); these complications may result in serious outcomes (i.e., need for surgery, death). • Parkinson’s patients are at increased risk of developing melanoma; monitor patients closely and perform periodic skin examinations. • Pregnancy category C. • Inhibits lactation: Use with caution.

Early Parkinson’s Disease and Dopamine Agonists

Dopamine agonists may be used as monotherapies in early PD or as adjuncts to levodopa in those patients who are deteriorating or who may be experience fluctuations to levodopa. Current dopamine agonists bind to the D2 family of receptors. Levodopa is a dopamine agonist, but is generally considered apart from the alternative dopamine agonists because levodopa is directly converted to dopamine whereas the dopamine agonist groups bind as structural analogs to the dopamine receptor.

Apomorphine

Apomorphine is a non-ergoline dopamine agonist thought to activate the postsynaptic D2 receptors. It is recommended for use in patients with either unpredictable “on/off” episodes ore with end-of-dose wearing off episodes. Apomorphine is given as a subcutaneous injection. Initial dose is 2mg (0.2

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mL) and the dose is titrated to an effective dose (maximum 6mg), commonly given three times a day. It is provided as a subcutaneous injection at 10 mg/mL or at 30mg/3mL as a pen injector. Apomorphine can be titrated to effectiveness and tolerance up to the maximum dose.

Apomorphine is associated with nausea and vomiting. An antiemetic such as trimethobenzamide may be initiated up to 3 days before giving the initial dose of apomorphine. Contraindicated with 5HT3 antagonists such as ondansetron, granisetron, dolasetron and palonosetron. Dosage must be modified in cases of renal or hepatic impairment. Peak plasma time is within

10-60 minutes with a t1/2 of 30-60 minutes. Apomorphine is primarily excreted in the urine and undergoes first pass metabolism with sulfation, oxidation, glucuronidation, demethylation and catalysis by cetechol-O methyltransferase (COMT).

Testing of the apomorphine dose should be initiated with the patient in an “off” state in a medical setting where supine and standing blood pressure and pulse (at 20, 40 and 60 minutes) can be monitored. Those patients experiencing significant hypotension after the initial dose (2 mg) in response to the test dose should be considered for alternative treatments. Dosing is initiated at 2 mg if patient responds and may be increased by 1 mg every 2- 4 days as needed for symptom control.

If the patient does not respond to a 2 mg test dose, a 4 mg test dose may be administered while monitoring blood pressure and pulse during the next “off” period. If responsive to the 4mg test dose, the patient may be maintained on a 3mg dose for “off” periods. If the patient does not tolerate the 4 mg test dose, a 3 mg test dose may be administered at least 2 hours after the 4 mg test dose. If tolerated, recommended maintenance in this case would be 2 mg to treat “off” periods.

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Contraindications and Interactions

Apomorphine is contraindicated with 5HT3 antagonists such as alosetron, dolasteron, granisetron, palonosetron and ondansetron. The mechanism of interaction is not known. Alternative medications for patients taking apomorphine should be sought for the following. Pharmacodynamic antagonists (decreasing the effect of apomorphine) include: • Aripiprazole • Chlorpromazine • Clozapine • Droperidol • Fluphenazine • Haloperidol • Ilopericone • Loxapine (including inhaled form) • Olanzapine • Paliperidone • Perphenazine • Quetiapine • Risperidone • Saquinavir • Thioridazine • Thiothixene • Trifluoperazine • Ziprasidone

Interference with CYP3A4 metabolism, increasing serum levels of apomorphine:

• Idelalisib

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• Ivacaftor (has a reciprocal effect with apomorphine, i.e., use of one or the other medication will increase serum levels of the other)

Interact to increase QTc interval:

• Panobinostat • Toremifene • Umeclidinium bromide/vilanterol inhaled • Vandetanib • Vemurafenib • Vilanterol/fluticasone (inhaled)

Causing CNS depression:

• Sodium oxybate

Adverse Effects

Greater than 10% of patients report the following adverse effects: • Dizziness or postural hypotension (20%) • Dyskinesia (35%) • Injection site reaction (26%) • Nausea or vomiting (30%) • Somnolence (35%) • Yawning (40%)

Between 1-10% of patients report the following adverse effects: • Anxiety • Arthralgia • Back pain • CHF • Confusion (10%)

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• Depression • Edema (10%) • Hallucinations (10%) • Headache • Injection site pain • Insomnia • Limb pain • Rhinorrhea (10%) • UTI

Contraindications

• Hypersensitivity to apomorphine • Sulfite or sulfur allergies

• 5-HT3 antagonist anti-emetic agents (i.e., dolasetron and alosetron) due to risk of severe hypotension with resultant loss of consciousness

Cautions

• Apomorphine is for subcutaneous injection only; intravenous use may result in thrombus and embolus formation. • Severe nausea and vomiting are possible even at lower doses. Avoid

using 5-HT3 antagonists. Trimethobenzamide is recommended to reduce nausea and vomiting. However, patients using trimethobenzamide experience and increased incidence of somnolence and an increased frequency of falls, so treatment with trimethobenzamide should be short-term only. • Increased risk of: - Somnolence - Syncope - Hypotension

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- Orthostatic hypotension - Hallucinations - Psychoses or psychotic behavior - Dyskinesia - Loss of impulse control - Coronary events including angina, MI, cardiac arrest, prolonged QT interval, torsades de pointes - Confusion associated with withdrawal - Hyperpyrexia associated with withdrawal

There is currently insufficient data on the use of apomorphine in pregnancy.

Pramipexole

Pramipexole may be used as a monotherapy early in the disease process and as an adjunct to levodopa therapy in more advanced disease. Pramipexole is a non-ergot dopamine agonist that is believed to stimulate D2 receptors. The immediate release tablet is available as 0.125, 0.25, 0.5, 0.75, 1.0 and 1.5 mg. The extended release as available as 0.375, 0.75, 1.5, 2.25, 3.0, 3.75 and 4.5 mg tablets. The immediate release tablet is generally begun at the lowest dose (0.125 mg) every 8 hours with gradual weekly titration towards a target range of 1/5 – 4.5 mg every 8 hours. The extended release is begun at 0.375mg with weekly increases (by 0,75mg/day) until symptom relief is obtained. The dose should not exceed 4.5 mg/day.

The immediate release tablet reaches peak plasma levels within 2 hours while the extended release tablet reaches peak plasma levels with 6 hours. Bioavailability is greater than 90% with about 15% protein bound. The elimination t1/2 is 8.5 hours—this is somewhat longer in the elderly at 12 hours. Less than 10% is metabolized with 90% excreted in the urine.

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Contraindications and Interactions

Currently, there are no known medications contraindicated for use with pramipexole. There are, however, a number of medications with serious interactions. These include pharmacodynamic antagonists (decreasing the effect of apomorphine): • Aripiprazole • Chlorpromazine • Clozapine • Droperidol • Fluphenazine • Haloperidol • Ilopericone • Loxapine (including inhaled form) • Metoclopamine • Olanzapine • Paliperidone • Perphenazine • Pimozide • Prochlorperazine • Promethazine • Quetiapine • Risperidone • Thioridazine • Thiothixene • Trifluoperazine • Ziprasidone

Close monitoring should be adopted if pramipexole is used with any of the following medications.

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Increase dopaminergic effects:

• Apomorphine • Bromocriptine • Cabergoline • Levodopa • Methyldopa • Ropinirole

Decrease renal clearance:

• Tenofovir

Competition for renal clearance (cationic):

• Cimetidine • Digoxin • Procainamide • Quinidine • Ranitidine

Increased CNS effects:

• Clobazam • Lurasidone

Adverse Effects

Greater than 10% of patients report the following adverse effects: • Somnolence • Dyskinesia • Hallucinations • Insomnia • Dizziness

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• Postural hypotension • Nausea • Constipation

Between 1-10% of patients report the following adverse effects: • Abnormal dreams, thoughts, or vision • Amnesia • Confusion • Paranoia or delusion • Akathisia • Asthenia • Dry mouth • Urinary frequency

Post-marketing reports include: • Neurologic adverse effects: abnormal behavior, abnormal dreams, compulsive shopping, fatigue, hallucinations (all kinds), headache, pathologic gambling • Cardiovascular effects: - Syncope - Postural hypotension • Metabolic effects: - Increased eating (binge eating, compulsive eating, hyperphagia) - Weight gain - SIADH • Dermatologic effects: - skin reactions (erythema, rash, pruritus, urticarial) - Gastrointestinal effects (vomiting)

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- Genitourinary effects (increased or decreased libido, and hypersexuality)

Warnings and Cautions

The sole known contraindications to pramipexole is hypersensitivity. Cautions include: • Sudden sleep attacks and sleep disorders • Orthostatic hypotension • Unusual behavior patterns - Impulse disorders - Hallucinations - Psychotic behavior - Augmentation or rebound of restless leg syndromes - Elderly patients may be more susceptible to adverse effects - Fibrotic complications - Increased risk of melanoma - May cause or exacerbate dyskinesia - Possible neuroleptic malignant syndrome with rapid dose reduction (elevated temperature, muscular rigidity, altered consciousness. autonomic instability).

There is currently insufficient data on the use of pramipexole in pregnant or lactating women.

Ropinirole

Ropinirole may be used as a monotherapy both early in the disease process and as an adjunct to levodopa/carbidopa in more advanced disease. It has a higher affinity for the D3 receptor than either for D2 or D4 receptors. It is also a nonergot dopamine agonist and comes as an immediate release and extended release tablet.

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Ropinirole comes in 0.25, 0.5, 1 and 2 mg doses. It is usually initiated at 0.25 mg every eight hour, and increased as needed by 0.25 mg in weekly intervals. It can be increased up to 9 mg/day and in some cases, up to 24 mg/day. The extended release form is usually initiated at 2 mg every 24 hours and increases as needed by 2 mg/day — the recommended maximum dose is 24 mg/day, though no additional benefit has been shown at these higher levels. The doses that appear to be most effective are less than or equal to 12 mg/day in early Parkinson’s disease and less than or equal to 8 mg/day in more advanced cases.

Contraindications and Interactions

Currently, there are no known medications contraindicated for use with ropinirole. There are several medications with serious interactions, however. These include the following characteristics.

Pharmacodynamic antagonism:

• Aripiprazole • Chlorpromazine • Clozapine • Droperidol • Fluphenazine • Haloperidol • Ilopericone • Loxapine (including inhaled form) • Metoclopamine • Olanzapine • Paliperidone • Perphenazine

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• Pimozide • Prochlorperazine • Promethazine • Quetiapine • Risperidone • Thioridazine • Thiothixene • Trifluoperazine • Ziprasidone

Inhibition of CYP1A2 (increases effect/plasma level of ropinirole)

• Fluvoxamine

Adverse Effects

Greater than 10% of patients report the following adverse effects: • Nausea (40-60%) • Dizziness (6-40%) • Somnolence (11-40%) • Syncope (1-12%) • Vomiting (12%) • Fatigue (8-11%) • Viral infection (11%) • Dyspepsia (10%) • Falls (10%)

Between 1-10% of patients report the following adverse effects: • Hypertension (5%) • Flushing (3%)

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• Orthostasis (1-6%) • Chest pain (4%) • Palpitation (3%) • Extrasystoles (2%) • Tachycardia (2%) • Hyperhidrosis (3%) • Abnormal pain (3-7%) • Anorexia (4%) • Flatulence (3%) • Malaise (3%) • Hypoesthesia (4%) • Urinary tract infection (5%) • Impotence (3%) • Alkaline phosphatase (3%) • Abnormal vision (6%) • Xerophthalmia (2%) • Increased diaphoresis (3-6%)

Less than 1% of patients reported the following effects:

• Agitation • Aneurysm • Aphasia • Bradycardia • Cardiac arrest • Valvulopathy • Cellulitis • Colitis • Delusion • Delirium

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• Diaphoresis • Dyspnea • Ulceration • Glaucoma • Psychotic-like behavior • Impulse control/compulsive behavior • Withdrawal-emergent hyperpyrexia and confusion • Melanoma • Fibrotic complications

There are post-marketing reports of unspecified retinal pathology.

Warnings and Cautions

Hypersensitivity reactions include urticaria, angioedema, rash and pruritus. Cautions include: • Psychoses, psychotic behaviors, paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. These risks may be increased in the elderly. • Erratic behavior including compulsive behavior, gambling, increased sexual urges. • There is an increased risk of orthostatic hypotension with the extended release formula. • There is an increased risk of hypertension, changes in heart rate in patients with concomitant cardiovascular disease and the extended release formula. • Use with caution in patients with a history of hepatic or renal impairment. • Dyskinesia • Increased risk of melanoma.

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• Possible neuroleptic malignant syndrome with rapid dose reduction (elevated temperature, muscular rigidity, altered consciousness, autonomic instability).

There is currently insufficient data on the use of pramipexole in pregnant or lactating women.

Amantadine

Amantadine is approved for the treatment of Parkinson’s disease, symptomatic parkinsonism (i.e., post-CO poisoning), medication-induced extrapyramidal symptoms and for parkinsonism associated with cerebral arteriosclerosis in the elderly. Amantadine comes in a 100 mg tablet. It is believed that the mechanism of action includes indirect stimulation of the release of dopamine from presynaptic neurons possibly as a response to its antiviral actions. Amantadine may also prevent re-uptake of dopamine. Peak plasma levels are obtained within 2-4 hours with a bioavailability of about 90%. Approximately 70% of amantadine is protein bound with minimal hepatic metabolism. T1/2 is 16 hours and excretion is primarily renal.

Contraindications and Interactions

Currently, there are no known medications contraindicated for use with amantadine. Amantadine has significant interactions with mefloquine — mefloquine increases the QT interval and increases the risk of amantadine toxicity.

Adverse Effects

Greater than 10% of patients report the following adverse effects: • Agitation • Anorexia

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• Anxiety • Ataxia • Confusion • Constipation • Depression • Diarrhea • Dizziness • Dream abnormality • Dry nose • Fatigue • Hallucinations • Headache • Insomnia • Irritability • Livedo reticularis • Nausea • Nervousness • Orthostatic hypotension • Peripheral edema • Somnolence • Xerostomia

Less than 1% of patients report the following adverse effects: • Amnesia • CHF • Decreased libido • Dyspnea • Eczematoid dermatitis • Euphoria

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• Hyperkinesis • Hypertension • Instances of convulsions • Leukopenia • Neutropenia • Oculogyric episodes • Psychosis • Rash • Slurred speech • Urinary retention • Visual disturbances • Vomiting • Weakness

Warnings and Cautions

Contraindications to amantadine use include hypersensitivity to amantadine and/or rimantadine, untreated narrow-angle glaucoma and breastfeeding. Cautions include that the CDC does not recommend the use of amantadine for the treatment or prophylaxis of influenza; and caution should be used with amantadine administration if there is concomitant: • Congestive heart failure • Peripheral edema • Orthostatic hypotension • Renal or hepatic impairment • History of seizures, eczematoid rash, and severe psychosis or psychoneurosis • If patient is on anticholinergics, consider decreasing the dose of the anticholinergics before initiating amantadine treatment

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• Avoid abrupt withdrawal: risk of neuroleptic malignant syndrome (NMS) with dosage reduction or withdrawal • Increased risk of impulse control disorders (uncontrolled sexual, gambling, buying, OCD) • May be linked to higher risk of melanomas

Amantadine is Pregnancy Category C and amantadine is secreted into breast milk. Amantadine is not recommended for pregnant or lactating women.

Rotigotine

Rotigotine stimulates D1, D2 and D3 receptors, but is thought to be primarily active via D2 receptors in the caudate putamen. Rotigotine is available as a transdermal patch at 1, 2, 3, 4, 6 and 8 mg/24 hours. Rotigotine may be increased by 2 mg every week until symptom relief is achieved. Dose should also be reduced gradually if needed (2mg/24 hours every 2 days). Applications should be rotated to intact skin on the abdomen, high, hip, flank, shoulder, or upper arm with no site re-used more than every 14 days.

Rotigotine is a non-ergot dopamine agonist, stimulating the D2 receptors primarily, but the precise mechanism of action is not well understood. Approximately 90% of rotigotine is protein bound with 37% bioavailability and peak plasma levels at 15-18 hours. The metabolic t1/2 is biphasic with the first phase within 3 hours and the second (terminal) phase by 5-7 hours. Hepatic metabolism includes dealkylations and conjugation. Primary route of excretion is via the kidneys, but approximately 23% is excreted via feces.

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Contraindications and Interactions

Currently, there are no known medications contraindicated for use with rotigotine. Rotigotine has significant interactions with inhaled loxapine, which demonstrated pharmacodynamic antagonism and with sodium oxybate, which may synergistically depress the CNS. Patients on rotigotine should be monitored closely with concomitant use of:

• Buprenophine, enflurane, ketotifen (ophthalmic), inhaled loxapine. All these medications may interact with rotigotine to increase sedation. • Ephedrine and phenylephrine (oral) may interact with rotigotine to decrease sedation. • Clobazam use may increase the potential for CNS depression.

Adverse Effects

The following adverse effects are seen in >10% of early-stage Parkinson’s disease patients using rotigotine. • Nausea (34-48%) • Application site reactions (21-46%) - Erythema - Pruritus - Irritation - Burning - Dermatitis - Inflammation - Papular rash - Vesicle formation - Pain

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• Dizziness (14-22%) • Somnolence (12-20%) • Vomiting (10-20%) • Fatigue (6-18%) • Insomnia (5-11%) • Hyperhidrosis (3-11%)

The following adverse effects are seen in 1-10% of early-stage Parkinson’s disease patients using rotigotine: • Abnormal dreams (2-7%) • Erythema (3-6%) • Anorexia (2-6%) • Depression (2-5%) • Edema peripheral (2-4%) • Dyspepsia (2-3%) • EKG, T- wave abnormalities (2-3%) • Weight loss (2-3%) • Balance disorder (2-3%) • Tinnitus (2-3%) • Hiccups (2-3%) • Pruritic rash (2-3%) • Erectile dysfunction (2-3%) • Lethargy (1-2%) • Orthostatic hypotension (1-2%)

The following adverse effects are seen in >10% of advanced-stage Parkinson’s disease patients using rotigotine: • Application site reactions (36-46%) • Somnolence (32%)

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• Nausea (22-28%) • Dizziness (14-23%) • Dyskinesia (14-17%) • Edema peripheral (9-14%) • Insomnia (9-14%) • Hallucinations (7-14%) • Arthralgia (8-11%)

The following adverse effects are seen in 1-10% of advanced-stage Parkinson’s disease patients using rotigotine: • Vomiting (8-10%) • Headache (8-10%) • Constipation (5-9%) • Diarrhea (5-7%) • Hypertension (3-5%) • Nightmares (3-5%) • Paraesthesias/Dysesthesias (3-4%) • Tremor (3-4%) • Asthenia (3-4%) • Cough (3%) • Nasal Congestion (3%) • Sinus congestion (2-3%) • Erythema (2-3%) • Hyperhidrosis (1-3%) • Musculoskeletal pain (2%)

Warnings and Cautions

Do not use rotigotine if patient is hypersensitive. Cautions include those outlined below.

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May cause: • Sudden drowsiness • Compulsive disorders - Gambling - Punding (repetitive meaningless actions) - OCD - Hypersexuality or increased libido • Hallucinations • Psychotic-like behaviors • Hypotension or hypertension • Syncope • Increased heart rate • Exacerbate dyskinesia • Weight gain (dose dependent) • Water retention (dose dependent) • Increased risk or melanoma • Abrupt withdrawal should be avoided to avoid the risk of neuroleptic malignant syndrome (elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, autonomic instability).

Rotigotine is Pregnancy Category C. It is not known if rotigotine is expressed in breast milk, but it may inhibit lactation. Rotigotine is not recommended for pregnant or lactating women.

Anticholinergic Drugs

Anticholinergic medications are used either as monotherapy or as adjuncts to treat symptoms of Parkinson’s disease, particularly tremor. These agents are generally used in PD patients under the age of 70 who do not have significant dyskinesia or gait difficulties.

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Trihexyphenidyl

Trihexyphenidyl is a synthetic tertiary amine with direct inhibition of the parasympathetic nervous system and thereby, anti-spasmotic actions. Trihexyphenidyl also has weak mydriatic, anti-secretory, and positive chronotropic activities. It is also believed that trihexylphenidyl also inhibits dopamine reuptake. It is commonly used as an adjunct with other anti-PD medications. Excretion is via the urine and bile with a t1/2 of 33 hours. Peak effects are seen by 1.5 hours with an onset within 1 hour of dosing. The availability of Trihexyphenidyl is 2 and 5 mg tablet or as a 0.4 mg/mL elixir. It is commonly initiated at 1 mg on the first day with 2 mg increases every 3-5 days for symptom relief. Maintenance dosage is 5-15 mg per day every 6-8 hours.

Contraindications and Interactions

Currently, there are no known medications contraindicated or medications with significant interactions with trihexyphenidyl. However, there are significant numbers of drugs that require close monitoring of patients taking them with trihexyphenidyl. These include those that may increase or decrease the effectiveness of trihexyphenidyl. Agents that decrease cholinergic effects/cholinergic transmission include: • Abobotulinumtoxin • Aclidinium • Amitriptyline • Amoxapine • Anticholinergic and sedative cmbinations • Atropine (IV or IM) • Belladonna alkaloids • Benztropine • Clomipramine

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• Cyclizine • Cyclobenzaprine • Darifenacin • Desipramine • Dicyclomine • Diphenhydramine • Doxepin • Edrophonium • Fesoterodine • Flavoxate Glycopyrrolate (oral and inhaled forms) • Homatropine • Hyoscyamine (oral and spray forms) • Imipramine • Incobotulinutoxin A • Ipratropium • Maprotiline • Meclizine • Methscopolamine • Nortriptyline • Onabotulinumtoxina • Orphenadrine • Oxybutin (oral, topical, transdermal) • Physostigmine • Propantheline • Protriptyline • Rimabotulinumtoxin B • Scopolamine • Solifenacin • Tiotropium

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• Tolterodine • Trimipramine • Trospium chloride

Agents that interact with pharmacodynamic synergism, potentially increasing the effect of trihexyphenidine: • Amantadine • Chlorpromazine • Droperidol • Dimenhydrinate • Fluphenazine • Haloperidol • Loxapine (oral and inhaled form) • Olanzapine • Perphenazine • Pimozide • Pramlintide • Prochlorperazine • Promethazine • Quetiapine • Risperidone • Thiothexene • Thioridazine • Trifluoperazine

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Agents that interact with pharmacodynamic antagonism, potentially decreasing the effect of trihexypehidine: • Donezepil • Galantamine • Tacrine

Other: Tranylcypromine may cause severe reactions.

Adverse Effects

The following adverse effects are seen in >10% of Parkinson’s disease patients using trihexypehidyl.

Anticholinergic side effects (30-50%) • xerostomia • blurry vision • constipation • drowsiness • sedation • hallucinations • memory impairment • difficulty urinating • confusion • delirium • hypohydrosis • decreased saliva • rash

The following adverse effects are seen in >1% of Parkinson’s disease patients using trihexypehidyl.

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• Suppurative parotitis • Hallucination • Paralytic ileus

Warnings and Cautions

Contraindications include hypersensitivity, narrow angle glaucoma and existing cardiovascular disease.

Cautions include: • GI obstruction • Urinary retention • Myesthenia gravis • Hypotension • Benign prostatic hypertrophy • Hepatic or renal impairment

Trihexyphenidyl is Pregnancy Category C and may inhibit lactation. Its use is not recommended in pregnant or lactating women.

Benztropine mesylate

Benztropine mesylate may be used as an adjunct in the treatment of PD to aid in the treatment of tremor. Benztropine acts both as an anticholinergic and an antihistamine and may inhibit the reuptake of dopamine. Bioavailability is relatively low and is approximately 29%; 95% of Benztropine is protein bound. Oral onset is within an hour, lasting for up to 48 hours. The metabolism is uncertain, with trace amounts of unmetabolized Benztropine found in the feces.

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Benztropine is available as a tablet in doses of 0.5, 1 and 2 mg. It is also available as a 1 mg/mL injectable 1mg/mL solution (iv or im). In Parkinson’s disease, treatment is initiated with 0.5-1 mg given nightly at bedtime. The doses are titrated in 0.5 mg increments every five to six days. Dosage should not exceed 6 mg per day.

Contraindications and Interactions

Currently, there are no known medications contraindicated or medications with significant interactions with benztropine. However, there are significant numbers of drugs that require close monitoring of patients taking them with benztropine. These include that that may increase or decrease the effectiveness of benztropine. These include agents that interact with pharmacodynamic synergism, potentially increasing the anticholinergic effects of benztropine. • Abobotulinumtoxina • Aclidinium • Amitriptyline • Amoxapine • Anticholinergic and sedative combinations • Atropine (IV or IM) • Belladonna alkaloids • Benztropine • Clomipramine • Cyclizine • Cyclobenzaprine • Darifenacin • Desipramine • Dicyclomine • Diphenhydramine

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• Doxepin • Edrophonium • Fesoterodine • Flavoxate • Glycopyrrolate (oral and inhaled forms) • Homatropine • Hyoscyamine (oral and spray forms) • Imipramine • Incobotulinutoxin A • Ipratropium • Maprotiline • Meclizine • Methscopolamine • Nortriptyline • Onabotulinumtoxina • Orphenadrine • Oxybutin (oral, topical, transdermal) • Physostigmine • Propantheline • Protriptyline • Rimabotulinumtoxin B • Scopolamine • Solifenacin • Tiotropium • Tolterodine • Trimipramine • Trospium chloride

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Agents that interact with pharmacodynamic synergism, potentially increasing the effect of benzoprine include: • Amantadine • Chlorpromazine • Droperidol • Dimenhydrinate • Fluphenazine • Haloperidol • Loxapine (oral and inhaled form) • Olanzapine • Perphenazine • Pimozide • Pramlintide • Prochlorperazine • Promethazine • Quetiapine • Risperidone • Thiothexene • Thioridazine • Trifluoperazine

Agents that interact with pharmacodynamic antagonism, potentially decreasing the effect of benztropine: • Donezepil • Galantamine • Tacrine

Other • Tranylcypromine; severe reactions have been reported

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Adverse Effects

Adverse effects with unknown frequency include the following: • Blurred vision • Confusion • Constipation • Disorientation • Dry mouth or throat • Hyperthermia • Mydriasis • Nausea • Paralytic ileus • Psychosis • Tachycardia • Urinary retention • Visual hallucinations • Vomiting

Warnings and Cautions

Benztropine should not be used in hypersensitive individuals or patients less than 3 years old.

Cautions include: • May cause anhydrosis which may become severe particularly in hot weather and during strenuous exercise • May cause hyperthermia which may become severe particularly in hot weather and during strenuous exercise • Common anticholinergic adverse effects such as constipation, xerostomia, blurred vision and urinary retention occur frequently

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• In some patients, benztropine may cause CNS depression—they should be cautioned about impaired abilities • Higher doses are associated with increased risk of confusion, visual hallucinations or hyper-excitement. In patients with existing psychiatric disorders, symptoms of psychosis may increase or intensify. • In some patients, higher doses may cause paralysis of certain muscles • Use with caution in patients with: - GI obstruction - Tachycardia - Benign prostatic hypertrophy (BPH) or prostatic hyperplasia - Urinary stricture - Glaucoma • Initiate using lower doses in elderly patients, increasing as needed for symptom relief. Assess for adverse effects. • May exacerbate symptoms of tardive dyskinesia

Benztropine is not currently characterized regarding pregnancy category. It has been associated with paralytic ileus in newborn. It is not known if Benztropine is excreted in breast milk.

Monoamine Oxidase-B Inhibitors

Monoamine oxidase (MAO) is a widely distributed mitochondrial enzyme, with particularly high levels in the GI tract, the liver and neuronal tissues. MAO catalyzes the oxidative deamination of both endogenous and exogenous monoamines and plays a critical role in the catabolism of various neurotransmitters, including dopamine. The action of MAO produces aldehydes and hydrogen peroxide (H2O2) and are further catabolized by aldehyde reductases. Aldehyde formation along with peroxide formation can generate reactive oxygen species (ROS) - these ROS may, in turn, cause

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oxidative stress and damage (see above) and may be central in the pathogenesis of Parkinson’s disease. MAO inhibitors (MAOIs) can reduce the degree of oxidative stress by reducing the products of the enzymatic reaction.

There are two isoforms of MAO: MAO-A and MAO-B. These are encoded by a gene located on the X-chromosome (Xp1 123). MAO-A and MAO-B have over 70% homogeneity and differ by their substrate and inhibitor specificities. The A isoform has a greater affinity for hydroxylated amines (i.e., noradrenaline, serotonin) while the B isoform has a greater affinity for non- hydroxylated amines (benzylamine, beta-phenylethylamine). Dopamine has similar affinities for either the A or the B isoforms. While the specific locations of the different isoforms within the brain are not clear, treatment with an MAO-B inhibitor increases levels of DA in the Parkinsonian brain with partial depletion of dopaminergic neurons in the substantia nigra pars compacta and in resulting anti-Parkinsonian action.

Selegiline

Selegiline has been approved as an adjunct therapy for PD patients not responding well to levodopa/carbidopa or whose response to those medications has deteriorated. Selegiline may improve motor function, reduce the amount of “off” time and, important for those patients experiencing levodopa adverse effects, can potentially reduce the dosage of levodopa given. Selegiline effectively increases the duration of action of levodopa.

Selegiline is available as a 1.25 and a 5mg capsule form. It is given twice a day, not to exceed 10 mg. Levodopa can be tapered by increments (10- 30%) 2-3 days after selegiline is initiated. The capsule is often given at breakfast and at noon. Selegiline is also available as an orally-disintegrating

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tablet, beginning at 1.25mg per day, increasing after 6 weeks. The tablet should not be taken with food or drink.

Selegiline reaches peak plasma levels in 0.5 to 0.9 hours. The oral disintegrating tablet reaches peak levels within 15-40 minutes. The t1/2 is 10 hours with an onset of action within 1 hour and lasting up to 72 hours. Approximately 90% of selegiline is protein bound and it is metabolized (CytP450) to L-amphetamine, L-desmethylselegiline, L-methamphetamine. Excretion is primarily through the urine.

Contraindications and Interactions

There are a large number of medications contraindicated with selegiline. These include agents that may increase serotonin levels and induce serotonin syndrome. The following should not be used with 14 days of selegiline discontinuation: • Amitryptyline • Amoxapine • Citalopram • Clomipramine • Desipramine • Desvenlafaxine • Dextroamphetamine • Dextromethorphan • Doxepin and Doxepin topical • Duloxetine • Escitalopram • Fluoxetine • Fluvoxamine • Imipramine • Isocarboxazid

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• Levodopa (reduce dose of levodopa after selegiline is initiated) • Levomilnacipran • Meperidine • Mirtazapine • Nortriptyline • Paroxetine • Phenelzine • Procarbazine • Protriptyline • Rasagiline • Safinamine • Sertraline • St John’s wort • Tramalol • Tranylcypromine • Venlafaxine • Vilazodone • Vortioxetine

Pharmacodynamic synergism with increased risk of acute hypertension:

• Atomoxetine • Dimethylphenidate • Ephedrine • Lisdexamfetamine • Methamphetamine • Methylphenidate • Phenylephrine • Pseudophedrine • Tapentadol

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• Tetrabenazine

Increased dopaminergic effects: • Bupropion

Unknown mechanisms: • Apraclonidine • Brimonidine • Carbamazepine • Methadone

Potentiation of MAO inhibition: • Fentanyl

Adrenergic effects: • Deutetrabenazine

Increased adrenergic effects: • Cyproheptadine

Serious interactions have been reported for the following drugs. Alternative medications should be considered. • Buprenorphine, Buprenorphine buccal • Buspirone • Desflurane • Difenoxin hcl • Diphenoxylate hcl • Dolasetron • Granisetron

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• Hydromorphone • Ketamine • Linezolid • Lorcaserin • Maprotiline • Metformin • Methylene blue • Midodrine • Milnacipran • Nefazodone • Netupitant/palonosetron • Ondansetron • Opium tincture • Palonosetron • Phendimetrazine • Phentermine • Propofol • Reserpine • Sevoflurane • Tedizolid • Trazodone • Umeclidinium bromide/vilanterol inhaled • Valbenazine • Vilanterol/fluticasone furoate inhaled • Yohimbine

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Adverse Effects

Greater than 10% of patients report dyskinesia and nausea (20%) with selegiline use. 1-10% report abdominal pain and dry mouth. Other adverse effects with no defined frequency include: • Arrhythmias • Confusion • EPS • Generalized pain • Hallucinations • Headache • Hypertension • Insomnia • Mood changes • Orthostatic hypotension • Syncope • Urinary retention • Vomiting

At higher doses of selegiline, selectivity for MAO-B receptors decreases. Other cautions include reports of increased sleepiness and diminished impulse control. Patients and caregivers report increased and sometimes intense urge to gamble, spend money, buy, binge eat and engage in sexual activity. Also, Selegiline is a Pregnancy Category C.

Rasagiline

Rasagiline is a selective MAO inhibitor, inhibiting the depletion of dopamine. It may be used as an initial monotherapy, starting at 1 mg daily, or as an adjunct to levodopa therapy, starting at 0.5 mg daily. Bioavailability is 36%

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(88-94% protein bound) with a peak plasma time of 1 hour. Onset of action is within 1 hour as well. Rasagiline is primarily metabolized by the CYP1A2 system and excreted via the urine and feces; T1/2 is 1.3 to 3 hours. Rasagiline is provided as a 0.5 or a 1 mg tablet and should not be given with CYP1A2 inhibitors.

Contraindications and Interactions

There are a significant number of contraindicated medications for use with rasagiline. These include those acting to increase serotonin levels. • Desvenlafaxine • Dextromethorphan • Isocarboxazid • Levomilnacipran • Meperidine • Milnacipran • Mirtazapine • Phenelzine • Procarbazine • Safinamide • Selegiline • St John’s wort • Tramadol • Tranylcypromine • Vilazodone • Vortixetine

Increased dopaminergic effects: • Bupropion

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Pharmacodynamic synergism:

• Atomoxetine • Dexmethylphenidate • Dextroamphetamine • Ephedrine • Lisdexamfetamine • Methamphetamine • Methylphenidate • Phenylephrine • Pseudophedrine

Unknown mechanism: • Apraclonidine • Brimonidine • Methadone • Tapentadol

Other mechanisms: • Cyproheptadine: anticholinergic effect is increased with MAOIs • Deutetrabenazine: Increased adrenergic cardiovascular effects • Opioids such as fentanyl (oral, spray, transdermal, transmucosal). Severe and acute potentiation of MAOI action • Tetrabenazine: Increased risk of acute hypertensive episode

Alternative medications for patients on rasagiline should be investigated for the following.

Increase serotonin levels: • Almotriptan

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• Amoxipine • Citalopram • Clomipramine • Desipramine • Dolsetron • Doxepin • Duloxetine • Eletriptan • Escitalopram • Fluoxetine • Frovatriptan • Granisetron • Imipramine • Linzolid • Lorcaserin • Maprotiline • Methylene blue • Naratriptan • Nefazodone • Netupitant/Palonosetron • Nortriptyline • Ondansetron • Palonosetron • Paroxetine • Protriptyline • Rizatriptan • Selegiline • Sertraline • Sumatriptan

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• Trazodone • Trimipramine • Valbenazine • Venlafaxine • Zolmitriptan

Pharmacodynamic synergism: • Buspirone • Desflurane • Ketamine • Midodrine • Phendimetrazine • Phentermine • Propofol • Sevflurane • Tedizolid • Yohimbine

Unknown mechanism: • Alfentanil • Buprenorphine • Butophanol • Codeine • Diphenoxylate • Hydrocodone • Hydromorphone • Levophanol • Morphine • Nalbuphine

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• Oxycodone • Oxymorphone • Pentazocine • Sufentanil

Other: • Tetrabenazine (risk of acute hypertensive episodes)

There are a large number of medications which, when used with rasagiline, require monitoring. These are listed below. • Altretamine • Armodafinil • Benazepril • Buprenorphine subdermal implant • Caffeine • Captopril • Cimetidine • Cocaine • Cyclobenzaprine • Deferasirox • Diethylpropion • Difenoxin hcl • Dihydroergotamine • Dihydroergotamine intranasal • Dobutamine • Dopamine • Enflurane • Epinephrine • Ergotamine

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• Erythromycin ethylsuccinate • Erythromycin lactobionate • Erythromycin stearate • Ethinylestradiol • Glipizide • Green tea • Insulin aspart • Insulin detemir • Insulin glargine • Insulin glulisine • Insulin lispro • Insulin nph • Isoniazid • Isoproterenol • l-tryptophan • Levodopa • Lurasidone • Metformin • Mexiletine • Modafinil • Norepinephrine • Norfloxacin • Opium tincture • Peginterferon alfa 2a • Phenobarbital • Phenylephrine • Primidone • Rifampin • S-adenosyl methionine (SAMe)

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• Sumatriptan intranasal • Tacrine • Tapentadol • Teriflunomide • Tyramine • Zileuton

Adverse Effects

The following adverse effects are reported with greater than a 10% frequency rate. • EPS (dyskinesia/dystonia) (18%) • Headache (14%) • Nausea (10-12%)

These adverse effects are reported with between 1-10% frequency: • Postural hypotension (6-9%) • Constipation (4-9%) • Weight loss (2-9%) • Arthralgia (7%) • Dyspepsia (7%) • Xerostomia (2-6%) • Depression (5%) • Fall (5%) • Flu-like syndrome (5%) • Hallucination (4-5%) • Conjunctivitis (3%) • Fever (3%) • Gastroenteritis (3%) • Rhinitis (3%)

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• Arthritis (2%) • Bruising (2%) • Malaise (2%) • Neck pain (2%) • Parasthesia (2%) • Vertigo (2%)

Cardiovascular accidents, myocardial infarcts, bundle branch blocks and gastrointestinal hemorrhages are reported with a less than 1% frequency.

Warnings and Precautions

As listed above, coadministration of rasagiline with any other MAOI, meperidine, tramadol, methadone or opioid is contraindicated. Wait at least 14 days between discontinuing rasagiline until beginning treatment with any of the medications. In addition, rasagiline should not be used with St John’s wort, cyclobenzaprine or dextromethorphan.

Cautions include:

• Rasagiline may cause hypertension at recommended doses. This included severe hypertensive syndromes. • Rasagiline can exacerbate hypertension or cause hypotension, particularly orthostatic hypotension. Antihypertensive drugs may need appropriate dosage adjustment • Rasagiline may cause serotonin syndrome when used with antidepressants • Rasagiline may cause daytime drowsiness and somnolence. These have been reported during activities of daily living • Rasagiline may cause or exacerbate dyskinesia. Decreasing the dose of levodopa given may lessen or eliminate the dyskinesia.

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• Rasagiline may induce hallucinations and psychotic-like behavior • Rasagiline use has resulted in reports of impulse control and/or compulsive behaviors. This can include intense urges to gamble, increased sexual urges, intense urges to spend money, or binge eating • Rasagiline can induce withdrawal-emergent hyperpyrexia and confusion if rapidly reduced. The hyperpyrexia is characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability • Because PD patients have a 2-6 fold increased risk of melanoma, monitor for melanomas frequently and on a regular basis

Rasagiline is Pregnancy Category C.

Safinamide

Currently, safinamide is recommended as an adjunct treatment for patients on levodopa/carbidopa experiencing “off” periods. It does not appear to be effective as a monotherapy nor has over 100 mg/day shown to have any additional benefits. Safinamide is available as 50 and 100 mg tablets and is generally initiated at 50 mg per day.

Peak plasma time is achieved within 2-3 hours with a high bioavailability (95%) due to the lack of protein binding. Elimination is primarily through the urine with the majority (>75%) excreted as inactive metabolites after hydrolysis and oxidative cleavage. Safinamide has a t1/2 of 20-26 hours and reaches a steady state within 3-5 days.

Contraindications and Interactions

There are a significant number of contraindicated medications for use with safinamide.

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Increased serotonin levels: • Amitriptyline • Amoxapine • Amphetamine • Clomipramine • Cyclobenzaprine • Desipramine • Desvenlafaxine • Dexmethylphenidate • Dextromethophan • Diethylpropion • Doxepin • Duloxetine • Fentanyl (intranasal, oral, transdermal, transmucosal) • Imipramine • Isocarboxazid • Levomilnacipran • Linezolid • Lisdeamfetamine • Maprotiline • Meperidine • Methadone • Methamphetamine • Methylphenidate • Milnacipran • Morphine • Nefazodone • Nortriptyline • Phendimetrazine

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• Phenelzine • Protriptyline • Rasagiline • Selegiline • St John’s wort • Tapentadol • Tranylcypromine • Trazodone • Trimipramine • Venlafaxine

Increased adrenergic effects

• Deutetrabenazine

Other

• Cyproheptadine

Caution should be used when using safinamide with any of the following medications.

Pharmacologic antagonism: • Aripiprazole • Asenapine • Cariprazine • Clozapine • Deuteterabenazine • Fluphenazine • Haloperidol • Iloperidone • Loxapine

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• Lurasidone • Metoclopramide • Olanzapine • Paliperidone • Perphenazine • Pimavanserin • Pimozide • Prochlorperazine • Quetiapine • Risperidone • Tetrabenazine • Thiothixene • Trifluoperazine • Ziprasidone

Increased serotonin levels:

• Methylene blue • Valbenazine

Patients on safinamide should be closely monitored if taking any of the following medications. Statin levels may be increased while on safinamide. Safinamide and its major metabolite may inhibit an intestinal transport protein Breast Cancer Resistant Protein (BCRP). • Atorvastatin • Fluvastatin • Pitavastatin • Rosuvastatin

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Other drugs utilizing intestinal BRCP as a transporter may be increased with concomitant use of safinamide:

• Chlorothiazid • Cimetidine • Daunorubicin • Dipyridamole • Doxorubicin • Glyburide • Imatinib • Irinotecan • Lapatinib • Ledipasvir/sofosbuvir • Leflunomide • Lenvatinib • Methotrexate • Mitoxantrone • Nitrofurantoin • Osimertinib • Pantoprazole • Pazopanib • Riociguat • Selexapag • Sofosbuvir • Vepatasvir • Sulphasalazine • Tenfovir (AF and DF) • Topotecan • Vemurafenib

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Increased serotonin levels:

• Buprnophine (Subdermal implant) • Citalopram • Escitalopram • Fluoxetine • Fluvoxamine • Isoniazid • Paroxetine • Sertraline

Increased adrenergic effects including prescription or OTC sympathomimetics:

• Midodrine • Naphazoline (including ophthalmic preparations) • Oxymetazoline (intranasal and ophthalmic preparations) • Phenylephrine • Pseudophedrine • Tetrahydrozoline • Xylometazoline

Other: Safinamide increases GI absorption

• Tyramine • Foods that are aged, fermented, cured, smoked or pickled may contain high levels of amines that can cause norepinephrine release and reactive hypertension (tyramine reactions)

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Adverse Effects

More than 10% of patients using safinamide report dykinesias (17-21%). Between 1-10% of patients using safinamide report the following adverse effects: • Hypertension (5-7%) • ALT or AST increased to >ULN (5-7%) • Fall (4-6%) • Nausea (3-6%) • Insomnia (1-4%) • Orthostatic hypotension (2%) • Anxiety (2%) • Cough (2%) • Dyspepsia (2%)

After marketing reports include swelling of the gingiva and tongue, dyspnea and rash.

Warnings and Precautions

Severe hepatic impairment is considered a contraindication for safinamide use. Safinamide should not be used with MAOIs (which can result in a hypertensive crisis), opioids, Serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants, cyclobenzaprine, methylphenidate, amphetamine, and their derivatives; or St John’s wort. The concomitant use of these could result in serotonin syndrome. MAOIs should not be used in combination with dextromethorphan due to the risk of psychosis or abnormal behavior.

Cautions for the use of safinamide include:

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• Safinamide may cause or worsen existing hypertension. Patients should be closely monitored. Adjustment of medication may be necessary if blood pressure elevation is sustained • Safinamide may cause serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs • Safinamide may cause sleepiness during activities of daily living • Safinamide may cause or exacerbate dyskinesia. Consider reducing levodopa dose to lessen the dyskinesia • Safinamide may cause hallucinations and psychotic behavior. Consider reducing or stopping dosage • Safinamide may cause problems with impulse control and/or compulsive behaviors. Consider reducing or stopping dosage • Safinamide may cause withdrawal-emergent hyperpyrexia and confusion • Safinamide may cause retinal degeneration and loss of photoreceptor cells. These have been observed in animal studies. Patients should be periodically monitored for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy

There are no current pregnancy or lactation recommendations.

Acetylcholinesterase Inhibitors

As a class, acetylcholinesterase inhibitors may improve the symptoms of dementia in PD patients by increasing cholinergic function on pathways from the forebrain, the cerebral cortex and the hippocampus. This increase is due to the inhibition of the enzymatic breakdown of acetylcholine thereby increasing the local available levels of the neurotransmitter.

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Donepezil

Donepezil is provided as a 5, 10, and 23 mg tablet and as a 5 and 10 mg oral disintegrating tablet (ODT). It is recommended for treatment of mild to moderate Alzheimer’s type dementia. Donepezil is an acetylcholinesterase inhibitor that increases the available concentrations of acetylcholine neurotransmitter, presumably making more neurotransmitter available increases the efficiency of signal transmission. 96% of donepezil is protein bound and it is 100% bioavailable, reaching peak plasma levels with 3-4 hours. T1/2 is 70 hours and excretion is by urine and feces. Donepezil is metabolized by hepatic CYP2D6 and CYP3A4.

Contraindications and Interactions

There are no medications currently contraindicated with donepezil use. There are serious interactions (pharmacologic synergism) with ambenonium, where alternative medications should be sought. Patients on donepezil should be closely monitored if concurrently on the following medications:

Medications decreasing cholinergic effects: • Abobotulinumtoxina • Aclidinium • Amitriptyline • Amoxapine • Anticholinergic and sedative combinations • Atracurium • Atropine • Belladonna alkaloids • Buclizine • Carbamazapine • Cisatracurium

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• Clomipramine • Cyclizine • Cyclobenzaprine • Darifenacin • Dichlorphenamide • Dicyclomine • Diphenhydramine • Dosulepin • Doxepin • Fesoterodine • Flavoxate • Glycopyrrolate • Henbane (derived from Hyocyamus niger. Also known as stinkingnightshade) • Homatropine • Hyoscyamine • Imipramine • Incobotulinumtoxina • Ipratropium • Lofepramine • Maprotiline • Meclizine • Mepenzolate • Methscopolamine • Mianserin • Nortriptyline • Onabotulinumtoxina • Orphenadrine • Oxybutynin

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• Pancuronium • Pradidoxime • Propantheline • Protriptyline • Rapacuronium • Rifabutin • Rifampin • Rimabotulinumtoxinb • Rocuronium • Scopolamine • Solifenacin • St John’s wort • Tiotropium • Tolterodine • Trihexyphenidyl • Trimipramine • Trospium • Tubocurarine • Vecuronium

Medications increasing cholinergic effects:

• Ambenonium • Artemther/lumefantrine (inhibits CYP2D6) • Bethanechol • Carbachol • Cevimeline • Cimetidine (inhibits CYP3A4) • Clarithromycin (inhibits CYP3A4) • Desvenlafaxine (inhibits CYP2D6 at >400 mg)

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• Distigmine • Echothiophate • Edrophonium • Erythromycin (inhibits CYP3A4) • Fluoxetine (inhibits CYP2D6) • Galantamine • Huperizine A • Itraconazole (inhibits CYP3A4) • Ketoconazole (inhibits CYP3A4) • Lumefantrine (inhibits CYP2D6) • Neostigmine • Paroxetine (inhibits CYP2D6) • Physostigmine • Pyridostigmine • Quinidine (inhibits CYP2D6) • Rivastigmine • Succinylcholine • Tacrine

Pharmacologic antagonism:

• Benztropine action is decreased in combination with Donepezil

Unknown:

• Ramelteon action is increased in combination with donepezil

Adverse Effects

More than 10% of patients report the following adverse effects:

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• Nausea (3-19%) • Diarrhea (5-15%) • Insomnia (2-14%) • Accident (7-13%) • Infection (11%)

Between 1-10% of patients report the following adverse effects: • Headache (3-10%) • Vomiting (3-8%) • Cramping (3-8%) • Fatigue (3-8%) • Anorexia (2-8%) • Hypertension (3%) • Abnormal dreams (3%) • Hallucinations (3%) • Confusion (2%) • Syncope (2%)

Post marketing reports include additional adverse effects. These include abdominal pain, agitation, aggressive behavior, cholecystitis, convulsions, all types of heart block, hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, Stevens Johnson syndrome, toxic epidermal necrolysis, torsade de pointes and QT elongation.

Warnings and Precautions

Hypersensitivity to donepezil or piperidine derivatives constitutes a contraindication for donepezil use. Cautions include the following: • There is an increased risk of GI bleed, particularly in patients with history of gastric ulcer or those on NSAIDs

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• Cholinesterase inhibitors such as donepezil are likely to amplify succinylcholine-type muscle relaxation during anesthesia • Cholinesterase inhibitors such as donepezil may have vagotonic effects on the sinoatrial (SA) and atrioventricular (AV) nodes. This effect can manifest as bradycardia or heart block • Donepezil can cause vomiting. There is a higher risk with doses of 23 mg/day • Donepezil may cause a dose-dependent anorexia and/or weight loss • Cholinomimetics, including donepezil, may cause bladder outflow obstructions • Cholinomimetics, including donepezil, have the potential to cause generalized convulsions • Cholinesterase inhibitors, including donepezil, should be cautiously prescribed in patients with a history of asthma or obstructive pulmonary disease • Donepezil should be used with caution in those patients with a history of seizure disorders, urinary tract obstruction, peptic ulcer disease, cardiac conduction abnormalities, and respiratory disease including COPD or asthma. • Donepezil use may be associated with QT prolongation and torsades de pointes. Donepezil should be used with caution in patients at risk of cardiac repolarization • Donepezil has been associated with rare cases of neuroleptic malignant syndrome (NMS) reported. Consider discontinuing therapy if symptoms of NMS occur • Donepezil has been associated with rare cases of rhabdomyolysis. These have been reported after a few months of therapy or following initiation of including donepezil. Donepezil should be used with caution in patients with rhabdomyolysis risk factors, including medications associated with

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rhabdomyolysis (discontinuing therapy with donepezil should be considered if marked elevation of CPK levels is found or if symptoms suggesting rhabdomyolysis appear). • Low weight patients (weighing <55 kg) may experience more weight loss, nausea, and vomiting than patients weighing more than 55 kg.

Donepezil is Pregnancy Category C. The status of donepezil in breastmilk is not known.

Rivastigmine

Rivastigmine is provided as a capsule (1.5, 3, 4.5, 6 mg) or a transdermal patch (4.6, 9.5, 13.3 mg/24 hour). It is indicated for mild-to-moderate Alzheimer’s type dementia. Dosage should not exceed 6 mg (by mouth) every 12 hours or 13.3 mg.24 hours. The patch should be replaced every 24 hours. For patients with Parkinson’s disease, initial dose is 1.5 mg every 12 hours, increasing after 4 weeks as tolerated. To switch from an oral dose to the patch, doses of the capsule less than 6 mg should be switched to the 4.6 mg patch. For switching an oral dose of greater than 6 mg, switch to the 9.5 mg patch.

Contraindications and Interactions

There are no medications contraindicated for use with rivastigmine. There are several serious interactions for which alternative medications are recommended. These include medications which interact by pharmacodynamic synergism. • Atenolol • Betaxolol • Bisoprolol • Emolol

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• Levobunolol • Metoprolol • Nadolol • Nebivolol • Propranolol • Sotalol • Timolol

Antidopaminergic effects:

• Metoclopramide

There are a significant number of medications for which close monitoring is essential when used in combination with rivastigmine. These include decrease cholinergic effects.

• Abobotulinumtoxina • Aclidinium • Amitriptyline • Atropine • Clomipramine • Darifenacin • Doxepin • Fesoterodine • Glycopyrrolate • Hyoscyamine • Incobotulinumtoxina • Maprotiline • Oxybutynin • Pralidoxime

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• Protriptyline • Rimaboutulinumtoxinb • Solifenacin • Tolterodine • Trospium

Increase cholinergic effects:

• Ambenonium • Bethanchol • Carbachol • Cevimeline • Donepezil • Echothiophate • Edrophonium • Galantamine • Neostigmine • Physostigmine • Pilocarpine • Pyridostigmine • Succinylcholine • Tacrine

Pharmacodynamic Synergism

Increased toxicity when combined with rivastigmine by synergistic mechanisms

• Aspirin • Celecoxib • Diclofenac

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• Diflunisal • Etodolac • Fenoprofen • Flurbiprofen • Ibuprofen • Indomethacin • Ketoprofen • Ketorolac • Meclofenamate • Mefenamic acid • Meloxicam • Nabumetone • Naproxen • Oxaprozin • Piroxicam • Non-aspirin salicylaters • Salsalate • Sulindac • Tolmetin

Increase serum potassium levels:

• Dichlorphenamide and rivastigmine can both increase serum K+ levels

Adverse Effects

More than 10% of patients on rivastigmine report the following adverse effects: • Nausea (PO 47%; patch 21%) • Vomiting (PO 31%; patch 6-19%) • Dizziness (PO 21%; patch 2-7%)

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• Diarrhea (PO 19%; patch 6-10%) • Headache (PO 17%; patch 3-4%) • Anorexia (PO 17%; patch 3-9%) • Abdominal pain (PO 13%; patch 2-4%)

From 1-10% of patients on rivastigmine report the following adverse effects: • Decreased weight (3-8%) • Insomnia (PO 9%; patch 1-4%) • Anxiety (PO 5%; patch 3%) • Asthenia (PO 6%; patch 2-3%) • Vertigo (2%) • Fatigue (2%)

Post marketing reports indicate additional adverse effects. These include: • Hepatobiliary: Abnormal liver function tests, hepatitis • Nervous System: Seizure • Psychiatric: Aggression, nightmares • Cardiac: Tachycardia • Skin: Allergic dermatitis, application site hypersensitivity, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticarial rash

Warnings and Precautions

Rivastigmine should not be used in individuals with a history of: • Skin reactions to patches • Active or past GI bleeds, peptic ulcer • Hypersensitivity to rivastigmine or carbamates • Anorexia • Sick sinus syndrome • Asthma or COPD

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• Extrapyramidal symptoms: rivastigmine may exacerbate these symptoms • Combination with NSAID

Significant number of serious adverse effects have been caused by failure to remove old patches. Rivastigmine is Pregnancy Category B but it is unknown if rivastigmine or its metabolites are secreted into breast milk. Use in lactating women is not recommended.

Managing Motor Fluctuations In Parkinson’s Disease

Motor fluctuations are a common adverse effect to dopaminergic medications and may take months or years to develop. “On” periods can be defined as those times when a patient is experiencing good control of symptoms by the medication. “Off” periods can be defined as those times when the medication is wearing off or if symptoms are resurfacing. The most common approaches to increasing “on” times and/or decreasing “off” times are to increase the dose of the dopaminergic agents, adding a second dopaminergic medication, levodopa dose fractionation, where the levodopa dosage is decreased but given more frequently or with the addition of either a catechol-O- methyltransferase inhibitor (COMTI) or an MAOBI which inhibit the catabolism of levodopa and dopamine. The evidence for the use of entacapone and tocapone indicates that these COMTIs can significantly reduce “off” time, but have similar adverse effects including nausea, diarrhea, dyskinesia and orthostatic hypotension. More recently, evidence has been produced that a novel COMTI, opicapone, as an adjunct to either dopamine agonists or MAOBIs, improved motor fluctuations in PD patients over 60 years of age.74-84

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Summary

Parkinson’s disease is a progressive, neurodegenerative disorder that is diagnosed based on physical characteristics involving bradykinesia, rest tremor, and rigidity. In the later stages of the disease, diagnosis is based on postural instability. Diagnosis is not based on testing but is based on the clinician's ability to recognize signs and symptoms of Parkinson’s disease and to diagnose it, hopefully in the early stages of the disease.

Successful pharmacotherapy of Parkinson’s disease depends on the ability of clinicians to accurately recognize characteristic signs of the disease. A diagnosis of Parkinson’s disease is difficult to make without the appropriate training and skills. Motor symptoms, motor complications and non-motor symptoms as well as psychiatric and mental health issues all need to be treated for the patient diagnosed with Parkinson’s disease. Medication should be instituted when patients are experiencing functional impairment or social difficulties. Motor symptoms can be treated with a number of different medications. The most well-established medications include the levodopa drugs. Levodopa and dopamine agonists can be used to treat all motor symptoms. MAOBIs may be particularly useful with early, mild symptoms of PD as well as motor fluctuations while the COMTIs are useful for motor fluctuations.

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1. The Movement Disorder Society (MDS) has identified three motor manifestations of Parkinson’s disease, which are

a. dementia, micrographia, and bradykinesia. b. dyskinesia, dementia, and micrographia. c. bradykinesia, resting tremor, and rigidity. d. resting tremor, dementia, and dyskinesia.

2. When non-motor features predominate, the diagnosis classification is

a. parkinsonian syndrome. b. moderate Parkinson’s disease. c. mitochondrial complex. d. prodromal Parkinson’s disease.

3. In the later stages of Parkinson’s disease, diagnosis is based on

a. postural instability. b. dementia. c. resting tremor. d. non-motor symptoms.

4. True or False: All four signs of Parkinson’s disease (bradykinesia, resting tremor, rigidity and postural instability) must be present for a clinical diagnosis of Parkinson's disease to be made by a clinician.

a. True b. False

5. ______tremor may be observed by having the patient hold their arms out in front of themselves.

a. Resting b. Postural c. Rigid d. Non-motor

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6. ______is the slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.

a. Bradykinesia b. Supination c. Retropulsion d. Rigidity

7. The bradykinesia of Parkinson's disease requires a slowness of movement and

a. an increase of amplitude of movement. b. the presence of cartwheel-like, jerking motions. c. a decrease in amplitude or speed of movement. d. persistent foot tapping.

8. Evaluation of bradykinesia may be accomplished by which of the following?

a. Breathing exercises b. Slow, passive movement of major joints by a clinician c. Finger-tapping, protonation-supination, hand movements d. Velocity-independent resistance

9. The ______test involves the patient being asked to stand with arms at their sides and eyes open.

a. instability b. passive movement c. retropulsion d. velocity

10. In the retropulsion test, the examiner

a. stands behind the patient and pulls back on the shoulders. b. stands behind the patient and pushes lightly to test balance. c. manipulates the patient's limbs and neck. d. measures ability of a patient's ability to elevate his or her arms.

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11. True or False: An increasing recognition of dementia in Parkinson's disease may mean that dementia should be removed as an exclusion criterion for a Parkinson's disease diagnosis.

a. True b. False

12. Under the “one-year rule,” if dementia was diagnosed before the second year after diagnosis of Parkinson’s disease, the correct diagnosis was

a. Alzheimer’s disease. b. parkinsonian syndrome. c. dementia with Lewy Bodies (DLB) d. Parkinson’s disease.

13. When classifying the disease in the early stages, the disease should be classified as preclinical in the presence of

a. neurodegenerative synucleinopathy, without clinical symptoms. b. reliable biomarkers. c. early symptoms and signs of Parkinson’s disease. d. synucleinopathy, with one or more clinical symptoms of Parkinson’s disease.

14. Patients with prodromal neurodegenerative synucleinopathy

a. may be tested to determine if they will progress to full, clinical Parkinson’s disease. b. will have parkinsonian symptoms but will not progress to Parkinson’s disease. c. will eventually progress to full, clinical Parkinson’s disease. d. will acquire dementia but will not progress to Parkinson’s disease.

15. In Parkinson’s disease, the MDS-UPDRX clinimetric assessment is used to evaluate a patient’s

a. non-motor skills used in daily living. b. motor skills used in daily living. c. complications associated with motor skills. d. All of the above

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16. True or False: The Movement Disorder Society (MDS) proposed to redefine Parkinson’s disease by removing dementia as an exclusion criterion for PD diagnosis.

a. True b. False

17. Nondopaminergic effects and dopaminergic-resistance develop ______in the disease process, resulting in both motor and non-motor symptoms.

a. early b. later c. at the end-stage d. during the preclinical stage

18. The most well-established medications for treating motor symptoms in early Parkinson’s disease include

a. amantadine. b. β-blockers such as propranolol. c. anticholinergics. d. the levodopa drugs.

19. Which of the following medications is used in early Parkinson’s disease to treat gait dysfunction?

a. Amantadine b. β-blockers such as propranolol c. Benztropine d. Trihexyphenidyl

20. In managing motor symptom fluctuations in Parkinson’s disease patients, the ______periods can be defined as those times when a patient is experiencing good control of symptoms by the medication.

a. prodromal b. “Off” c. synucleinopathic d. “On”

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CORRECT ANSWERS:

1. The Movement Disorder Society (MDS) has identified three motor manifestations of Parkinson’s disease, which are

c. bradykinesia, resting tremor, and rigidity.

"The Movement Disorder Society (MDS) has identified three motor manifestations of Parkinson’s disease, which are bradykinesia, in combination with either resting tremor, rigidity, or both."

2. When non-motor features predominate, the diagnosis classification is

d. prodromal Parkinson’s disease.

"When non-motor features predominate, the diagnosis classification is prodromal Parkinson’s disease."

3. In the later stages of Parkinson’s disease, diagnosis is based on

a. postural instability.

"Parkinson’s disease is a progressive, neurodegenerative disorder that is diagnosed based on physical characteristics involving bradykinesia, rest tremor, and rigidity. In the later stages of the disease, diagnosis is based on postural instability."

4. True or False: All four signs of Parkinson’s disease (bradykinesia, resting tremor, rigidity and postural instability) must be present for a clinical diagnosis of Parkinson's disease to be made by a clinician.

b. False

"There are four cardinal signs of Parkinson’s disease that must be identified and are defined as resting tremor, rigidity, bradykinesia, and postural instability. Postural instability is not required for a diagnosis of PD, and commonly arises later in the disease process."

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5. ______tremor may be observed by having the patient hold their arms out in front of themselves.

b. Postural

"Resting tremor is assessed by having patients seated with their arms relaxed on their laps. The resting tremor may be observed without further instructions, or it may be triggered by asking the patient to count backwards from ten. Kinetic or postural tremor may be present but is not required as part of the diagnostic criteria. Kinetic tremor may be observed in the finger-to-nose test while postural tremor may be observed by having the patient hold their arms out in front of themselves."

6. ______is the slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.

d. Rigidity

"Rigidity is the 'slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.'"

7. The bradykinesia of Parkinson's disease requires a slowness of movement and

c. a decrease in amplitude or speed of movement.

"The bradykinesia of PD requires a slowness of movement and a decrease in amplitude or speed of movement. Limb bradykinesia must be present to establish PD."

8. Evaluation of bradykinesia may be accomplished by which of the following?

c. Finger-tapping, protonation-supination, hand movements

"Evaluation of bradykinesia may be accomplished by finger-tapping, protonation-supination, hand movements, toe or foot tapping, and postural instability."

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9. The ______test involves the patient being asked to stand with arms at their sides and eyes open.

c. retropulsion

"Postural instability, identified later in the disease process, can be tested using the retropulsion test. This test involves the patient being asked to stand with arms at their sides and eyes open."

10. In the retropulsion test, the examiner

a. stands behind the patient and pulls back on the shoulders.

"Postural instability, identified later in the disease process, can be tested using the retropulsion test. This test involves the patient being asked to stand with arms at their sides and eyes open. The patient is also told that this is a balance test and they will be caught if they begin to fall or unable to regain their balance. The examiner stands behind the patient and pulls back on the shoulders. One or two steps to regain balance are considered normal."

11. True or False: An increasing recognition of dementia in Parkinson's disease may mean that dementia should be removed as an exclusion criterion for a Parkinson's disease diagnosis.

a. True

"The increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis."

12. Under the “one-year rule,” if dementia was diagnosed before the second year after diagnosis of Parkinson’s disease, the correct diagnosis was

c. dementia with Lewy Bodies (DLB)

“In the past, if dementia was diagnosed before the second year after diagnosis of Parkinson’s disease, the 1 year rule excluded PD and dementia with Lewy Bodies (DLB) was the correct diagnosis.”

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13. When classifying the disease in the early stages, the disease should be classified as preclinical in the presence of

a. neurodegenerative synucleinopathy, without clinical symptoms.

“For delineation of early stages, disease should be classified as ‘preclinical’ and ‘prodromal.’ Preclinical refers to the presence of neurodegenerative synucleinopathy without clinical symptoms (i.e., defined by biomarkers). This stage cannot be diagnosed currently because reliable biomarkers are not available. Prodromal refers to the presence of early symptoms and signs before the classical PD diagnosis is possible. This prodromal term makes no assumptions about the order in which motor versus non-motor symptoms develop.”

14. Patients with prodromal neurodegenerative synucleinopathy

c. will eventually progress to full, clinical Parkinson’s disease.

“Because one cannot determine whether any patient with prodromal neurodegenerative synucleinopathy will eventually progress to full, clinical PD, the definition of prodromal PD should center upon the likelihood of a neurodegenerative synucleinopathy being present, regardless of “conversion rate” to full clinical PD. Although PD, by definition, passes inevitably through some type of prodromal phase, there are currently no 100% reliable means to identify prodromal PD. Therefore, diagnostic criteria for prodromal PD will necessarily be variable and based on probabilities.”

15. In Parkinson’s disease, the MDS-UPDRX clinimetric assessment is used to evaluate a patient’s

a. non-motor skills used in daily living. b. motor skills used in daily living. c. complications associated with motor skills. d. All of the above [correct answer]

“The MDS-UPDRX clinimetric assessment is divided into four parts. Part I involves non-motor aspects of the experiences of daily living. The primary source of information should be filled in by the rater (patient, caregiver or both). Part II involves motor aspects of the patient questionnaire. Part III involves motor examination. Part IV involves motor complications.”

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16. True or False: The Movement Disorder Society (MDS) proposed to redefine Parkinson’s disease by removing dementia as an exclusion criterion for PD diagnosis.

a. True

“The MDS proposed to redefine Parkinson’s disease ... removing dementia as an exclusion criterion for PD diagnosis.”

17. Nondopaminergic effects and dopaminergic-resistance develop ______in the disease process, resulting in both motor and non-motor symptoms.

b. later

“Dopamine deficiency is addressed in early PD while nondopaminergic effects and dopaminergic-resistance develop later in the disease process, resulting in both motor and non-motor symptoms.”

18. The most well-established medications for treating motor symptoms in early Parkinson’s disease include

d. the levodopa drugs.

“Medication should be instituted when patients are experiencing functional impairment or social difficulties. Motor symptoms can be treated with a number of different medications. The most well- established medications include the levodopa drugs, commonly given along with peripheral dopa decarboxylase inhibitors (PDDIs).”

19. Which of the following medications is used in early Parkinson’s disease to treat gait dysfunction?

a. Amantadine

“Other medications, for which the evidence is much less established, include amantadine (used primarily for gait dysfunction and dyskinesia), β-blockers such as propranolol (to treat tremors), anticholinergics (i.e., trihexyphenidyl, Benztropine, also used to treat tremor) and the neuroleptics such as clozapine used to treat both tremor and dyskinesias.”

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20. In managing motor symptom fluctuations in Parkinson’s disease patients, the ______periods can be defined as those times when a patient is experiencing good control of symptoms by the medication.

d. “On”

“Managing Motor Fluctuations: ‘On’ periods can be defined as those times when a patient is experiencing good control of symptoms by the medication. ‘Off’ periods can be defined as those times when the medication is wearing off or if symptoms are resurfacing.”

Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. [References are for a multi-part series on Parkinson's Disease.]

1. Berg, Daniela, et al. (2014). Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Movement Disorders. 29(4);454-462. 2. Pringsheim T, et al. (2014). The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014 Nov;29(13):1583-90. 3. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at https://ghr.nlm.nih.gov/condition/parkinson- disease#genes 4. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at Uhttps://ghr.nlm.nih.gov/gene/LRRK2 5. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at https://ghr.nlm.nih.gov/gene/PARK7 6. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at https://ghr.nlm.nih.gov/gene/PINK1#conditions 7. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at https://ghr.nlm.nih.gov/gene/PRKN#location 8. https://ghr.nlm.nih.gov/ U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at gene/PRKN#conditions

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9. U.S. National Library of Medicine (2017). Genetics Home Reference. NIH. Retrieved online at https://ghr.nlm.nih.gov/gene/SNCA#synonyms 10. Sidransky E. and Lopez, G. (2012). The link between the GBA gene and parkinsonism. Lancet Neurol. 2012 Nov; 11(11): 986–998. 11. Todorova A, et al. (2014). Non-motor Parkinson's: integral to motor Parkinson's, yet often neglected. Pract Neurol. Oct;14(5):310-22. 12. Rodnitzky, R. (2017).Cognitive impairment and dementia in Parkinson disease. UpToDate. Retrieved online at https://www.uptodate.com/contents/cognitive-impairment-and- dementia-in-parkinson- disease?source=search_result&search=lewy%20body%20and%20park inson&selectedTitle=1~150. 13. Nalls, Mike A., et al. (2014). Large-scale meta-analysis of genome- wide association data identifies six new risk loci for Parkinson's disease. Nature genetics. 46(9); 989-993. 14. Campdelacreu, J. (2014). Parkinson's disease and Alzheimer disease: environmental risk factors. Neurología. 29(9); 541-549. 15. Kieburtz, Karl, and Kathryn B. Wunderle (2013). Parkinson's disease: evidence for environmental risk factors. Movement Disorders. 28(1); 8-13. 16. Chin-Chan, Miguel, et al. (2015). Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Frontiers in cellular neuroscience. 9; 124. 17. Marras, C. et al (2014). Systematic review of the risk of Parkinson's disease after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. Mar, 95(3 Suppl): S238-44. 18. Ong, E. L., et al (2014). Differential risks of cancer types in people with Parkinson’s disease: a national record-linkage study. European journal of cancer. 50(14); 2456-2462. 19. Tan, L. et al. (2014). Parkinson's disease and risk of fracture: a meta- analysis of prospective cohort studies. PLoS One.9(4). 20. Fairfield, K.M. (2017). Vitamin supplementation in disease prevention. UpToDate. Retrieved online at https://www.uptodate.com/contents/vitamin-supplementation-in- disease- prevention?source=search_result&search=vitamin%20d%20and%20al zheimers&selectedTitle=2~150. 21. Broen, MP., et al. (2016). Prevalence of anxiety in Parkinson's disease: A systematic review and meta-analysis. Mov Disord. 31(8); 1125-33. 22. Tarsy, D. (2017). Pharmacologic treatment of Parkinson disease. UpToDate. Retrieved online at https://www.uptodate.com/contents/pharmacologic-treatment-of-

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