Parkinson's Disease: Etiology, Pathophysiology, Treatment

• Parkinson's Disease (PD) is a disorder of the extrapyramidal system

Objectives

• You need to be able to explain the epidemiology and etiology of idiopathic PD
• You need to be able to explain the basic pathophysiologic mechanisms responsible for the motor features of PD
• You need to be able to list drugs that can exacerbate symptoms of PD
• You need to be able to describe the cardinal motor features and clinical presentation of PD
• You need to be able to list other conditions that may have motor features similar to PD
• You need to be able to formulate an initial treatment plan for a patient with PD based on patient-specific factors
• You need to be able to discuss the pharmacology, clinical effects, and safety of anticholinergic drugs for the management of PD
• You need to be able to discuss the pharmacology, clinical effects, and safety of amantadine for the management of PD
• *You need to be able to discuss the pharmacology, clinical effects, and safety of combined levodopa and peripheral decarboxylase inhibitors for the management of PD
• You need to be able to discuss the pharmacology, clinical effects, and safety of dopamine agonists for the management of PD
• You need to be able to discuss the pharmacology, clinical effects, and safety of catechol-O-methyltransferase (COMT) inhibitors for the management of PD
• You need to be able to discuss the pharmacology, clinical effects, and safety of monoamine oxidase-B (MAO-B) inhibitors for the management of PD
• You need to be able to compare and contrast types of levodopa motor complications based on history and symptoms
• You need to be able to formulate a treatment plan for a patient experiencing levodopa-associated motor complications
• You need to be able to formulate a treatment plan for a patient with PD who is experiencing hallucinations and psychosis

Did you know?

• In 2012, Milne met University of Edinburgh neuroscientist Tilo Kunath at an event organized by Parkinson's UK
• Using 12 T-shirts (six from people with Parkinson's and six from non-affected individuals) Milne correctly identified the disease in all six cases
• Additionally, Milne categorized the one T-shirt from a healthy person as having Parkinson's which belonged to someone who was diagnosed with the disease less than a year later

Introduction

• Hallmark motor features of idiopathic PD are bradykinesia, tremor at rest, rigidity, and postural instability

Epidemiology

• In the US, there is 1 million people affected
• Prevalence increases with age
• 0.5% of population in their 60's are affected
• 2.5% of population that are equal to or above 80 years old affected
• Males are more likely to be affected then females

Etiology

• PD occurs sporadically and the true etiology is unknown
• Cigarette smoking and caffeine consumption are consistently associated with a lower risk
• Pesticide exposure and genetic forms of parkinsonism are associated with mitochondrial dysfunction and oxidative stress
• High levels of oxidative stress in dopaminergic neurons in substantia nigra

Pathophysiology

• Degeneration of dopaminergic neurons (axons and soma) projecting from the substantia nigra pars compacta (SNc) to the striatum (caudate nucleus and putamen) are a hallmark
• The basal ganglia (composed of subcortical structures including the substantia nigra, striatum, globus pallidus, and subthalamic nucleus) regulates voluntary movement -The SNc projects to the striatum and is referred to as the nigrostriatal pathway
• The striatum conveys signals to the SNr, via the D₁ direct and the D₂ indirect pathways
• D₁ receptor activation results in stimulation of the striatal GABAergic neurons
• D₂ receptor activation results in inhibition of striatal GABAergic neurons
• Lewy bodies are Cytoplasmic filamentous aggregates composed of the protein α-synuclein.
• Reduced dopaminergic activation of D₁ and D₂ receptors and the sequential downstream effect on signaling pathways, results in a net inhibitory tone on the thalamus

Clinical Presentation

• Bradykinesia and at least one of the following: resting tremor, rigidity or postural instability are key for diagnosis
• Asymmetry of motor features is also supportive
• Motor symptoms include hypokinetic movements, decreased manual dexterity, difficulty arising from a seated position, diminished arm swing during ambulation, Dysarthria, dysphagia, festinating gait, flexed posture, hypomimia(decreased facial expression), hypophonia and Micrographia
• Nonmotor symptoms are common in PD , identify, assess, manage, and monitor
• Nonmotor symptoms can be anxiety, cognitive impairment, constipation, daytime sleepiness, depression, drooling, dysphagia, falling, fatigue, impulsivity, insomnia, orthostatic hypotension, overactive bladder, pain, hallucinations/psychosis, REM sleep behavior disorder, and restless legs syndrome
• Tremor of an upper extremity occurring at rest (and occasionally an action or postural tremor) is often the sole presenting complaint
  • Commonly presents in the hands
  • Resting tremor often begins unilaterally and becomes bilateral with disease progressio.
  • Only two-thirds of patients with PD have tremor on diagnosis, and some never develop this sign
• Rigidity is the increased muscular resistance to passive range of motion and most commonly affects the upper and lower extremities, and occasionally the neck
• Facial muscles are also affected, resulting in hypomimia that may be erroneously interpreted as apathy, depression, or unfriendliness
• Hypokinesia is decreased movement and often described as either bradykinesia (slowness of movement) or akinesia (absence of movement)
• Intermittent immobility or akinesia (freezing) is another common characteristic
• Postural instability, most common in advanced stages of PD, is one of the most disabling problems of PD because it increases the fall risk and is least amenable to pharmacotherapy
• Labs do not diagnose PD

Diagnosis

• Step 1: Bradykinesia must be present with at least one of the following: resting tremor, rigidity, or postural instability
• Step 2: Exclude other types of parkinsonism or tremor disorders
• Step 3: Presence of at least three supportive positive criteria:
  • Asymmetry of motor signs/symptoms
  • Unilateral onset
  • Excellent response to carbidopa/L-dopa

Pharmacotoxicity

• Antiemetics:
  • MOA of metoclopramide is dopamine antagonist and serotonin agonist
  • Prochlorperazine
• Antipsychotics:
  • 1st generation more so than 2nd generation such as:
  • chlorpromazine, fluphenazine, haloperidol, olanzapine, risperidone and thioridazine

Treatment

• No treatments have been shown to effectively change the course of PD by slowing or halting its progression (disease modification)
• The goal: is to improve motor and nonmotor symptoms so that patients are able to maintain the best possible quality of life
• Treatment should be initiated when the disease begins to interfere with activities of daily living, employment, or quality of life
• The lowest dose of antiparkinson medication that provides satisfactory symptomatic results should be used
• Optimization of the regimen should be attempted for patients already on carbidopa/L-dopa, before adding adjunctive agents
• Initial monotherapy may be initiated for mild functional impairment through use of MAO-B inhibitor, such as rasagiline, with the addition of other therapeutic agents should PD motor symptoms progressively worsen -Dopamine agonist monotherapy provides greater symptomatic benefit for patients with mild-to-moderate impairment - Dopamine agonists are less-well tolerated, especially in older patients and for those who are cognitively impaired, intolerant of dopamine agonists, or experiencing moderate-or-severe functional impairment, than carbidopa/L-dopa
• Surgery should be considered an adjunct to pharmacotherapy when patients are experiencing frequent motor fluctuations or disabling dyskinesia or tremor despite an optimized medical regimen
• Bilateral, chronic, high-frequency electrical stimulation, also known as deep-brain stimulation (DBS), is the preferred surgical modality
  • A battery-powered neurostimulator is implanted subcutaneously below the clavicle and provides constant electrical stimulation, via electrode wires, to the targeted brain structure

Anticholergics

• Dopamine provides negative feedback to acetylcholine neurons in the striatum, the degeneration of nigrostriatal dopamine neurons also results in a relative increase of striatal cholinergic interneuron activity
• Increased cholinergic activity is believed to contribute to the tremor of PD

Treatment: Anticholinergics

• Examples: Benztropine and Trihexyphenidyl
• Especially in elderly populations intolerable side effects include blurred vision, confusion, constipation, dry mouth, memory difficulty, sleepiness, and urinary retention

Treatment: Amantadine

• NMDA-receptor antagonist
• Mechanism of action for the management of PD is not completely understood however, it may block dopamine reuptake in presynaptic neurons and increase releases from presynaptic fibers
• Renal Function:
  • Amantadine immediate-release 100 mg/day to 400 mg/day: Creatinine clearances of >50 mL/min
  • Amantadine immediate-release 100 mg/day: Creatinine clearances of 30-50 mL/min
  • 100 mg every other day: Creatinine clearances of 15-29 mL/min
  • 200 mg every 7 days: Creatinine clearances of less than 15 mL/min and patients on hemodialysis
  • Extended-release products contraindicated with CrCl < 15 mL / min
• Side effects: Confusion, dizziness, dry mouth, and hallucinations, with elderly patients being particularly prone to confusion
• Amantadine may also cause livedo reticularis, a reversible condition characterized by diffuse mottling of the skin affecting the upper or lower extremities and often accompanied by lower-extremity edema (not rare)

Treatment: Carbidopa / levodopa (L-dopa)

• L-Dopa is the immediate precursor of dopamine and, in combination with a peripherally acting L-amino acid decarboxylase inhibitor (eg, carbidopa), remains the most effective drug for the symptomatic treatment of PD
• Carbidopa reduces the unwanted peripheral conversion of L-dopa to dopamine
• increased amount of L-dopa go to the brain. Which peripherally reduces the adverse effects-dopamine such as nausea -L-dopa is converted to dopamine by the enzyme L-amino acid decarboxylase and inactivated by the enzymes MAO and COMT
• The usual initial maintenance carbidopa/L-dopa regimen is 25/100 mg three times daily
• There is no maximum allowable total daily L-dopa dose, however, in patients with severe PD, the usual maximal dose tolerated is approximately 1,000 to 1,500 mg/day; slow buildup of dose (e.g., increments of 100 mg L-dopa per week) can help minimize treatment-emergent side effects, such as drowsiness and nausea -Adverse effects include priapism but can also stain bodily fluids (i.e., brown or black) -Long-term L-dopa therapy is associated with a variety of motor complications, of which end-of-dose “wearing off” (motor fluctuations) and L-dopa peak-dose dyskinesias are the two most commonly encountered

Treatment for: Motor Complications

• “wearing off” motor fluctuation:
• Increase frequency of carbidopa/L-dopa doses
• Add either COMT inhibitor or MAO-B inhibitor or dopamine agonist
• Add or switch to extended-release carbidopa/L-dopa (ie, Rytary) Use L-dopa inhalation.
• “Delayed on”/ “no on” response” Give carbidopa/L-dopa on empty stomach
• Use carbidopa/L-dopa ODT
• Avoid carbidopa/L-dopa SR or apomorphine as a substitute
• Start hesitation Start hesitation (“freezing”):
• Increase carbidopa/L-dopa dose
• Add a dopamine agonist or MAO-B inhibitor Utilized physical therapy along with assistive walking devices or sensory cues (eg, rhythmic commands, stepping over objects)
• Peak-dose dyskinesia: Give smaller doses of cabidopa/L-dopa and add amantadine

Treatment for Caridopa/L-Dopa:

• The terms “off” and “on” refer to the periods of poor movement.
• With advancing Parkinson Dose the dosage of carbidopa/L-dopa progressively shortens therefore the patient may dose L-dopa as little as 1 hour increments during the day
  • The addition of COMT inhibitor or MAO-B inhibtor extends L-dopa so the patient should be considered -Patients can benefit from Patches and ER formulatins for"off” times overnight.
• Rapid relief: Apomorphine- subcutaneously administered
• Delayed on” or “no-on response":
• Chewing a tablet or crushing it and then drinking a full glass of water
• Or using the ODT formulation on an empty stomach can help mitigate effects * * Subcutaneously administered apomorphine may be used as rescue
• Dyskinesias: are involuntary movement, usually around the neck
• Off-period" dystonia Occuring in the early morning hours, due to decline in medication
• Patients can have "on" dyskinesia L-dopa in small amount along with with amantadine

Black Box Warning

• Carbidopa and levodopa
• Drugs Interactions
  • Contraindications can be non-selective MAO inhibitors
  • Can have antipsychotic effects

FOSCARBIDOPA/FOSLEVODOPA(VYALEV)

• Apprpoved OCT 17, 2024 AND SHOULD BE WORN 24HRS A DAY, AND DISCONNECT WHEN showering or swimming up to 1 hour(hr)
• CAN ADJUST TO high or low VYALEV
• eat what you want without AFFECTION VYELEV

MAO-B Treatment

• Selegiline- First pass metabolism is predominately done thru cypto 450 AND 2C19
• This means low bioavailability and improves absorpation from L-amphetamine
• ADVERSE EFFECTS
  • Adverse agitation can include insomnia especally when administerred at bedtime, hallucination with HTN Increases effects with and psychiatric symptoms

Side Effects

-Rasaliline is well tolerated with minimal GI

CAUTIONS

• can be MAO, but can eat avocado
• dried saurkraut

COMT

• This REDUCES L-dopa and increasing bioavailability Entacopone: 200mg that needs to be givern L-dopa 8x

Dopamine Agonist

• D1 and D2 and are adjuncts
• Patients with motor functions
• Errot comes from from Bromcriptoie
• Drugs are safer
• Nausea
• A slow dieatition is to reduce effect particularly hallucination

Patient Case: Subjective

• Declining performance Objective
• MOCA score 30/30
• General neuroligcal Exam
• Hand writing slow smaller
• Had a stool sample The End