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Objectives
Describe the basic Pathophysiology of Parkinsons disease Identify common signs and symptoms associated with PD Construct a pharmacotherapeutic treatment plan for a specific PD patient

disease severity other complicating factors

Mark A. Douglass, PharmD Associate Clinical Professor Northeastern University Department of Pharmacy Practice

Objectives

Parkinsons Disease
Chronic, progressive motor function disorder Primary or idiopathic Parkinsonism Epidemiology

Incidence: 446 cases/100,000 people
Neuroepidemiology 2010;34:143151

Identify common side effects (including motor fluctuations) that might be anticipated with a particular regimen
therapeutic alternatives

List monitoring parameters and treatment goals

1% prevalence - 60 yrs and older Mean age at diagnosis: 55-60 yrs.

Male gender
1.5 times greater risk than female

Etiology

Environmental factors
Rural, well water, farms/ pesticide exposure Elevated risk for PD Smoking and caffeine - protective
Recent caffeine data 2012 AAN
Protective role

Etiology

Exact underlying cause unknown Neurodegeneration

Apoptosis Neurotoxins
MPTP
MAO-B

- 3 large cups of coffee, Lewy body formation - Modest PD symptom improvement, excessive daytime somnolence

MPP+ (toxic metabolite)

Occupational factors
Copper, lead, Iron, insecticides

Free radical production

DA metabolismhydrogen peroxide

Genetic factors
first degree relatives,diagnosis before age 50 Now, 24+ identified gene mutations assoc. w/

Lewy body formation

Existence poorly understood Presence is diagnostic for PD

PD risk.

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Extrapyramidal Motor System (EPS)

Responsible for coordination of learned movement Composed of the basal ganglia

Caudate nucleus Putamen Globus pallidus

Striatum

Substantia nigra

Neuronal Communication

Neuronal communication in a normal patient

Substantia nigra Direct pathway Indirect pathway

Substantia nigra striatum

Synthesis, storage, transport DA

Striatum thalamocortical pathway

Direct and indirect pathways

Neurotransmitters
GABA (inhibitory) Glutamine (excitatory) Acetylcholine

D1 (+)

GABA, Sub. P

D2 (-)
Thalamus

SNC

GABA Enkephalins

Frontal cortex activation

Pathophysiology
Degeneration of dopaminergic cells in the substantia nigra Depletion of dopamine (DA)

5% per decade in normal adults 45% in first decade in PD

Neuronal communication in a Parkinsons patient

Substantia nigra Direct pathway Indirect pathway SNC Thalamus

Degree of DA depletion correlates with symptom severity

frontal cortex activation Inhibition of learned movement

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Pathophysiology

Several other neurotransmitters also affected by PD

acetylcholine, GABA, glutamate,

norepinephrine, serotonin
dopamine acetylcholine

worsening motor symptoms

Adapted from Dagher et. Al. Montreal Neurological Institute

Clinical Presentation
Sensory symptoms (e.g. confusion, sleep disturbances) may appear initially Classic clinical features of PD (TRAP)

Tremor at rest Rigidity Akinesia or bradykinesia Postural Instability

Resting Tremor

Typical presenting symptom on diagnosis

begins in unilateral extremity

Described as pill-rolling may cease during voluntary movement can be exacerbated by stress disappears during sleep

Rigidity

Akinesia or Bradykinesia

Cogwheel in nature
during passive range of motion of a limb muscle stiffness, weakness stop and go effect

Akinesia - absence of movement

slow to initiate movement (up out of chair) freezing

Bradykinesia - slowness of movement

Impairment of activities of daily living

getting dressed in/out of bed or vehicle

slow, shuffling gate handwriting becomes smaller decreased arm swing decreased swallowing masked faces

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Postural Instability
Symptom of advanced disease Frequent falls and injury Loss of center of gravity

tendency to fall forward/festination falling backwards/retropulsion pull test

Estimating Disease Severity

Modified Hoehn and Yahr Staging

Stage 0 - no signs of disease Stage 1 - unilateral disease Stage 1.5- unilateral with axial involvement Stage 2- bilateral disease without balance impairment Stage 2.5- mild bilateral disease with recovery on pull test Stage 3- mild to moderate bilateral disease, some postural instability; physically independent Stage 4 - severe disability; unable to live alone independantly Stage 5- unable to walk or stand without assistance

pharmacologic therapy largely ineffective

United Parkinsons Disease Rating Scale (UPDRS)

Diagnosis and Treatment

Non-pharmacologic therapy

Rule out other movement disorders

Med-induced, essential tremor, etc.

Nutrition
protein re-distribution

Diagnosis based on clinical symptoms

Neuroimaging techniques not conclusive Presence of: Bradykinesia + tremor or rigidity

Support
Social, peer, family support

Treatment approaches
Nonpharmacologic Exercise/voice training evidence Pharmacologic Surgery

Exercise Education
family and patient

Anticholinergic Agents

Anticholinergic Agents

First widely accepted treatment of PD

before presence of levodopa

Benztropine (Cogentin)
Dosing: 0.5-1 mg PO q HS titrate to 3-6 mg/day (2-4 divided doses)

cholinergic activity in PD patients

worsening symptoms

Trihexyphenidyl (Artane)
Dosing: 1 mg PO TID with meals titrate to 6-10 mg/day (3-4 divided doses)

Efficacious for minor symptomatic control

Most effective for tremor symptoms

Current use limited

more efficacious agents significant anticholinergic side effects

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Anticholinergic Agents

Amantadine (Symmetrel)

Side effects:
significant anticholinergic side effects limit use drowsiness, confusion, memory impairment dry eyes, dry mouth, blurred vision constipation, urinary retention elderly particularly sensitive

MOA unclear
DA, anticholinergic

Modest efficacy in control of PD symptoms

tremor, bradykinesia, rigidity

Shown to improve dyskinesias

levodopa treated patients

Amantadine

Livedo reticularis

Dosing: 100 mg PO q AM with breakfast

titrate to 200-400 mg PO QD (divided BID) tachyphylaxis may develop (1-2 mos)

Side effects: generally mild (dose related)

CNS (confusion, insomnia, dizziness) Peripheral (nausea, dry mouth, dry skin) Livedo reticularis (reversible)

Adapted from McCarthy, et. al. University of Sheffield. 1996

Carbidopa/Levodopa (Sinemet)

Carbidopa/Levodopa

Most effective drug to treat PD

improvements in bradykinesia, rigidity less effective against speech/gait disturbances

Timing (early vs late) of treatment is controversial

Early treatment improves symptoms However. Earlier appearance of treatment complications

Levodopa metabolic pathways. Adapted Herfendal, et. al.

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Carbidopa/Levodopa

Carbidopa/Levodopa

Dosing:
25/100 mg PO QD, titrate to TID (800 -1000 mg Levodopa QD is usually max. dose) CR preparation- unpredictable kinetics
IPX066 investigational XR preparation Phase 3

Motor complication side effects

20-75% of patients after 3-5 yrs with Levodopa

Oral disintegrating tablets (Parcopa) Intestinal gel formulation (advanced disease) Phase 3 investigational

1.) Motor Fluctuations Wearing off gradual symptom control

toward end of dosing interval
Strategy - dosing freq., CR therapy, or adjunct

Side effects:
GI: nausea, vomiting, anorexia Most common (up to 50% incidence) avoid tx w/ Compazine, Reglan, droperidol Cardiovascular: orthostatic hypotension Neuropsychiatric: agitation, confusion, hallucinations, psychosis

therapy (COMT-I, agonist, MAOB-I)

On/Off symptoms controlled/uncontrolled

Strategy - adjunct therapy, drug holiday

all reported

Carbidopa/Levodopa
Motor complication side effects 2.) Peak Dose Dyskinesias Associated with peak levels of dopamine administration
dopaminergic cells, buffer capacity non-continuous, erratic release of DA

Motor fluctuations

Dyskinesias - abnormal, involuntary, excessive movements

orofacial lip smacking, tongue thrusting, blinking, grimacing. Speech can be effected extremity involvement spasmodic twisting of limbs posture rocking/swaying use of amantadine may help (durability?) Clozapine and olanzapine effective?

Strategy - dose, DA agonist, MAO-I, or COMT

inhibitor

Motor fluctuations

Motor fluctuations

Dystonia
sustained, painful muscle contractions distal lower extremities (feet/toes) usually seen in morning, improvement with first

Akathisia
feeling of inner restlessness patient cant sit still pacing, shifting, tapping feet treatment with benzodiazepines (e.g. Ativan)

levodopa dose cervical dystonia responds to Botulinum toxin tx

Myoclonus
bursts of muscle activity during sleep can affect toes, ankle, knee, hip bedtime levodopa dose

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Carbidopa/Levodopa
Motor complication side effects Recent Cochrane Review

2010 Jul 7;(7):CD007166 44 trials; 8,436 patients DA agonists most effective adjunct treatment vs. COMT-I and MAOB-I Better symptom control off time and reducing levodopa dose BUT incidence of dyskinesias s/e compared to placebo in all groups

COMT Inhibitors
Periphery CNS L-DOPA
AADC COMT AADC

L-DOPA
COMT

3-OMD

dopamine

3-OMD
MAO-B

dopamine
COMT

DOPAC
COMT

3-MT
MAO-B

HVA BBB

COMT Inhibitors
Tolcapone Entacapone (Comtan) Stalevo (levodopa/carbidopa/entacapone)

Tolcapone

(Tasmar)

Improves symptomatic control with levodopa efficacious for motor fluctuations

off time, on time ~1-2 hrs/day

Longer clinical levodopa response

levodopa metabolism, BBB penetration

Dosing: 100 mg PO TID w/ Sinemet Side effects:

Dopaminergic: Nausea, dyskinesias (most

Adjunct therapy with levodopa

motor fluctuations

common)

Not indicated as monotherapy

hypotension Non-dopaminergic: diarrhea (tolerance)

hallucinations, anorexia, insomnia, orthostatic

Tolcapone

Entacapone
Improves symptomatic control, motor fluctuations in levodopa treated patients Dosing: 200 mg with each Sinemet dose

up to 8 times/day (shorter half-life)

Side effects:
Hepatotoxicity: LFT elevations and reported cases of liver failure Off the market in Europe, labeling change in US NOT recommended as first line agent unless benefit outweighs risk. AST, ALT at baseline, bi-weekly in first year, then monthly x 6mos, then every 2 months. Discontinue if AST, ALT exceed upper limit

Side effects:
Dopaminergic: nausea, dyskinesia (transient) Liver enzymes: few cases of elevations no hepatotoxicity, no monitoring required

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MAO-B Inhibitors
Periphery CNS L-DOPA
AADC COMT AADC

MAO-B Inhibitors
Selegiline (Eldepryl or Deprenyl) Irreversible substrate of MAO-B effective as monotherapy levodopa sparing

Not an FDA approved indication

L-DOPA
COMT

3-OMD

dopamine

3-OMD
MAO-B

dopamine
COMT

questionable efficacy as adjunct therapy

in Levodopa dose not associated with improved

DOPAC
COMT

3-MT
MAO-B

symptomatic control

neuroprotective?
oxidative stress

HVA BBB

Selegiline

Zydis selegiline

Dosing: 5 mg PO AM (w/ breakfast)

titrate to 5 mg PO BID

oral disintegrating tablet (ODT) formulation

Direct absorption (no first pass effect) dose, plasma concentration

Side effects:
Well tolerated, similar to placebo Dopaminergic effects when added to Levodopa Metabolized to amphetamine derivatives May have effects on cognition (confusion, insomnia)

Dosing: 1.25 mg PO QD (AM) for 6 weeks

2.5 mg QD if no benefit after 6 weeks

Side effects:
Consistent w/ levodopa treated pts in studies

Rasagiline (Azilect)
FDA approved May, 2006 Potent, irreversible MAO-B inhibitor Indicated for PD motor symptoms

Monotherapy (early disease) Adjunct therapy with levodopa (chronic)

Rasagiline (Azilect)
Dosing: 0.5-1 mg PO QD Side effects: dopaminergic, hallucinations Drug interactions: metabolized by CYP 1A2

Ciprofloxacin plasma levels of rasagiline.

Significant improvements in off time1

Compared to placebo in pts. on levodopa. Equivalent in on time, though more dyskinesias in 1mg/day rasagiline group.

1. PRESTO Study. Parkinson Study Group. Arch Neurol. 2005;62:241-248

1. Parkinson Study Group. Arch Neurol. 2004;61:561-566

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Safinamide

Dopamine Agonists

Investigational MAO-B inhibitor

Phase 3 study (016, 018 extension)
Mid-advanced disease patients Improvements in on time with no or minor dyskinesias

Ergot derivatives (older agents)

Pergolide (Permax) Bromocryptine (Parlodel)

Non-ergot derivatives (newer agents)

Pramipexole (Mirapex) Ropinirole (Requip)

Dopamine Agonists

Dopamine Agonists

Rotigotine (Neupro)
Transdermal delivery system (2, 4, 6 mg) FDA approved, 2007
Recalled, 2008 crystals in the patches UPDATE:

Apomorphine
dopamine agonist SC formulation - Apokyn penfill for injection Indicated for acute, unpredictable off episodes May cause significant nausea/vomiting Better response in patients w/ early disease Inhaled formulation Investigational, small study (n=55) Better tolerated

- Transdermal patches reformulated and available - 2012

off time, levodopa dose/fluctuations Modest improvements in UPDRS scores as Adjunct w/ levodopa in advanced disease Patches contain metabisulfite Do not use in sulfite allergic patients

monotherapy in patients with early stage disease.

Dopamine Agonists

Dopamine Agonists

Effects on striatal DA receptors

ergots: D1, D2, and 5 HT non-ergots: D2 and D3

Dosing: ergot derivatives

Pergolide:
withdrawn from the market due to cardiac valve

Shown to be efficacious:
monotherapy, symptomatic disease adjunct therapy with Levodopa improved parkinsonian symptoms motor fluctuations in Levodopa patients prevention of motor complications
Levodopa nave patients with PD

dysfunction.
Bromocryptine: 30 mg/day (dose TID)
slow titration; start 1.25 mg QD or BID by 1.25-2.5 mg/day weekly to 10-50 mg/day note: pergolide is ~10-13 times more potent

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Dopamine Agonists

Dopamine Agonists

Dosing: non-ergot derivatives

Pramipexole: 3 - 4.5 mg/day (three divided doses) 0.125 mg TID, every 5-7 days to target dose renally eliminated, dose adjust Ropinirole: 6 - 9 mg/day (three divided doses) 0.25 mg PO TID to start, titrate weekly hepatically metabolized Generic formulations

Side effects: ergot and non-ergot

Dopaminergic: nausea (50%), vomiting,

orthostatic hypotension
similar frequency in ergot and non-ergot

agents despite receptor affinity

CNS: somnolence (sleep attacks),

dizziness, confusion, psychosis

(hallucinations) dose limiting especially problematic for the elderly

ER formulations
Recently studied, available - ropinirole

Dopamine Agonists

Dopamine Agonists
Side effects: ergot derivatives
Pleuropulmonary disease (PPD) Retroperitoneal fibrosis Cardiac valve dysfunction

Side effects: ergot and non-ergot Recent Cochrane review

ISSN 1464-780X DA agonists in early PD 29 trials, 5,247 patients agonists vs. levodopa Dyskinesia incidence Non-motor side effects

Rare but potentially serious (2-5%) Dose/duration of therapy Reversible upon discontinuation Baseline CXR recommended

DiPiro Figure 68-4: PD treatment algorithm

Dopamine Agonists

Side effects: Impulse Control Disorders (ICDs)

reported frequency past several yrs. Incidence: ~6% (1.5% in gen. population) Younger PD patients, underlying history. Pathologic gambling, hypersexuality

Compulsive shopping, binge eating, etc. DOMINION study: Neurology 2010;67:589-595 ICD in pramipexole patients vs. placebo
17.1% vs 6.9% (odds ratio, 2.72; 95% confidence interval,

2.08 3.54; P < .001)

$8.3 million judgment against Boehringer Ingelheim

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Parkinsons Resources

Surgery

National Parkinson Foundation

www.parkinsons.org

Deep Brain Stimulation (DBS)

most promising, non-ablative drug refractory tremors

American Parkinson Disease Assn.

http://www.apdaparkinson.com

CNS lesions (thalamotomy, pallidotomy,

subthalamic nucleus lesions)
improves rigidity, tremor, and akinesia

World Parkinson Disease Association

www.wpda.com

Grafting, transplantation
investigational

Controversy still exists, despite studies:

initiation with levodopa? Gold standard" but long term risks (e.g. motor fluctuations) initiation with selegiline? Slow disease progression? initiation with dopamine agonists? onset of motor fluctuations as monotherapy not as efficacious as levodopa adjunct therapy with selegiline, agonist, or COMT

Drug Therapy Initiation

When to start, what to use?

patient age
younger vs. elderly (>65) patients

early vs. advanced disease

previous PD therapy

symptoms present
severity cognitive or functionally impaired

inhibitor?
classes

very few studies with direct comparisons between

Early PD Treatment

Early PD Treatment

Several studies support early treatment

Delayed treatment patients Progressive symptom deterioration Early treatment patients Stabilization of symptoms and QOL ELLDOPA (levodopa vs. placebo) Symptoms but uptake - imaging DATATOP (selegiline, vitamin E) delayed need for levodopa TEMPO CALM-PD, REAL-PET

Neuroprotection
Currently a very hot research area Rasagiline TEMPO study
functional decline in early vs. delayed start patients

Minimize formation of free radicals ADAGIO study (NEJM 2009;361:1268) Similar to TEMPO design, larger N, 1.5 years Early (1or 2 mg/d) vs. delayed (placebo1 or 2mg/d) Early treatment with 1mg/d (but not 2mg) superior

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Early PD Treatment

Early PD Treatment

Other agents studied for neuroprotective benefits:

Levodopa Inconclusive evidence to date
Acceleration of neurologic destruction

Anticholinergics and Amantadine

younger, minor PD symptom (e.g. tremor)

Evolving role of DA agonists vs. levodopa

Pros/cons of early agonist vs. levodopa use Dopamine Agonists
younger, no functional or cognitive impairment.

Dopamine agonists Retards oxidative stress in vivo? Investigational agents

Exanatide Creatine Isradipine

Levodopa/Carbidopa elderly (or poor cognition), functionally impaired

Advanced PD Treatment

Non-motor symptoms of PD

Agonist monotherapy, worsening symptoms

dose add levodopa/carbidopa no evidence for adding selegiline, COMT-I

Motor fluctuations with levodopa/carbidopa

add dopamine agonist OR add COMT-I ? selegiline

Sleep disorders incontinence constipation dysphagia drooling sweating temperature intolerance

Erectile dysfunction paresthesias dementia anxiety depression seborrheic dermatitis visual deficits orthostatic hypotension

Non-motor PD symptoms

Dementia and Psychosis in PD patients

Under recognized and under treated

Medication side effects vs. disease

Complication of disease progression

up to 40% incidence in advanced disease

complications

Recent AAN guidelines released

Neurology. 2010;74:924-931

Drug induced
Simplify drug regimen discontinue meds of least likely clinical

Evidence supports:
Sildenafil for ED Levodopa/carbidopa for RLS.

benefit, highest risk of psychosis

1) anticholinergics 2) selegiline 3) dopamine agonists 4) amantadine 5) COMT inhibitors

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Dementia and Psychosis Treatment in PD

Patient Case
CC/HPI: WB is a 75 year old male evaluated in clinic today for worsening Parkinsonian symptoms. Within the past several weeks, he reports worsening tremor and increased muscle stiffness which has made it more difficult for him to ambulate. He also notes that his symptoms seem to be the worst just before his next dose of Sinemet, which leads him to complain that the medicine isnt working as well anymore. PMH: Parkinsons disease (diagnosed 1988) - Stage 3 Allergies: NKDA

Psychosis
Second generation antipsychotics most

frequently used
clozapine: 6.25 mg q HS (max: 50 mg QD) superior to olanzapine in studies lower doses, risk of hematologic effects low quetiapine: newer agent, very little data

Dementia
Rivastigmine - EXPRESS study ( n/v) Memantine recent, small, Phase II study (6/09)

SH: negative MPTA:

Carbidopa/Levodopa 25/100 mg tabs 2 tabs PO q 6 h (started 1998)

Patient Case
Past meds: Selegiline 10 mg PO QD (1988-1998, off ~ 5 yrs) Ropinirole 2 mg PO TID (1998) discontinued after 1-2 mos due to excessive somnolence/drowsiness

Describe WBs signs and symptoms associated with Parkinsons disease

Describe a possible explanation for WBs concerns that Sinemet is no longer working as well

List a potential therapeutic intervention(s) that may alleviate his symptoms and address his concerns noted above.

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