lee high georgia document

8/13/2019 lee high Georgia document

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Mark A. Douglass, PharmD

Associate Clinical ProfessorNortheastern UniversityDepartment of Pharmacy Practice

Objectives

Describe the basic Pathophysiology of

Parkinsons disease Identify common signs and symptoms

associated with PD

Construct a pharmacotherapeutic treatmentplan for a specific PD patient

disease severity

other complicating factors

Objectives

Identify common side effects (includingmotor fluctuations) that might beanticipated with a particular regimen

therapeutic alternatives

List monitoring parameters andtreatment goals

Parkinsons Disease

Chronic, progressive motor function disorder

Primary or idiopathic Parkinsonism

Epidemiology

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

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- 3 large cups of coffee, Lewy body formation

- Modest PD symptom improvement, excessive daytime somnolence

Occupational factors Copper, lead, Iron, insecticides

Genetic factors first degree relatives,diagnosis before age 50

Now, 24+ identified gene mutations assoc. w/PD risk.

Etiology

Exact underlying cause unknown

Neurodegeneration

Apoptosis

Neurotoxins MPTP MPP+ (toxic metabolite)

Free radical production

DA metabolismhydrogen peroxide

Lewy body formation

Existence poorly understood

Presence is diagnostic for PD

MAO-B


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Extrapyramidal Motor System (EPS)

Responsible for coordination of learned

movement Composed of the basal ganglia

Caudate nucleus

Putamen

Globus pallidus

Substantia nigra

Striatum

Neuronal Communication

Substantia nigra striatum

Synthesis, storage, transport DA

Striatum thalamocortical pathway

Direct and indirect pathways

Neurotransmitters

GABA (inhibitory)

Glutamine (excitatory)

Acetylcholine

Substantia

nigra

Direct

pathway

Indirect

pathway

Thalamus

Frontal cortex activation

D2 (-)GABA

EnkephalinsSNC

Neuronal communication in a normal patient

GABA,

Sub. PD1 (+)

Pathophysiology

Degeneration of dopaminergic cells inthe substantia nigra

Depletion of dopamine (DA)

5% per decade in normal adults

45% in first decade in PD

Degree of DA depletion correlates withsymptom severity

Neuronal communication in a Parkinsons patient

Substantia

nigra

Direct

pathway

Indirect

pathway

Thalamus

frontal cortex activation

Inhibition of learned movement

SNC


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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

pharmacologic therapy largelyineffective

Estimating Disease Severity

Modified Hoehn and Yahr StagingStage 0 - no signs of diseaseStage 1 - unilateral diseaseStage 1.5- unilateral with axial involvementStage 2- bilateral disease without balance

impairmentStage 2.5- mild bilateral disease with recovery on

pull testStage 3- mild to moderate bilateral disease, some

postural instability; physicallyindependent

Stage 4 - severe disability; unable to live aloneindependantly

Stage 5- unable to walk or stand without assistance

United Parkinsons Disease Rating Scale(UPDRS)

Diagnosis and Treatment Rule out other movement disorders

Med-induced, essential tremor, etc.

Diagnosis based on clinical symptoms

Neuroimaging techniques not conclusive

Presence of:

Bradykinesia + tremor or rigidity

Treatment approaches

Nonpharmacologic

Exercise/voice training evidence

Pharmacologic

Surgery

Non-pharmacologic therapy

Nutrition

protein re-distribution

Support

Social, peer, family support

Exercise

Education

family and patient

Anticholinergic Agents

First widely accepted treatment of PD

before presence of levodopa

cholinergic activity in PD patients

worsening symptoms

Efficacious for minor symptomatic control

Most effective for tremor symptoms

Current use limited

more efficacious agents

significant anticholinergic side effects


Benztropine (Cogentin)

Dosing: 0.5-1 mg PO q HS

titrate to 3-6 mg/day (2-4 divided doses)

Trihexyphenidyl (Artane) Dosing: 1 mg PO TID with meals

titrate to 6-10 mg/day (3-4 divided doses)


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Side effects: significant anticholinergic side effects limit use

drowsiness, confusion, memory impairment

dry eyes, dry mouth, blurred vision

constipation, urinary retention

elderly particularly sensitive

Amantadine (Symmetrel)

MOA unclear DA, anticholinergic

Modest efficacy in control of PD symptoms

tremor, bradykinesia, rigidity

Shown to improve dyskinesias

levodopa treated patients

Amantadine

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)

Livedo reticularis

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

Carbidopa/Levodopa

(Sinemet)

Levodopa metabolic pathways. Adapted Herfendal, et. al.

Carbidopa/Levodopa

Most effective drug to treat PD

improvements in bradykinesia, rigidity

less effective against speech/gait disturbances

Timing (early vs late) of treatment iscontroversial

Early treatment improves symptoms

However.

Earlier appearance of treatment complications


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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

Oral disintegrating tablets (Parcopa)

Intestinal gel formulation (advanced disease) Phase 3 investigational

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

all reported

Carbidopa/Levodopa

Motor complication side effects

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

1.) Motor Fluctuations

Wearing off gradual symptom controltoward end of dosing interval

Strategy - dosing freq., CR therapy, or adjuncttherapy (COMT-I, agonist, MAOB-I)

On/Off symptoms controlled/uncontrolled

Strategy - adjunct therapy, drug holiday

Carbidopa/Levodopa


2.) Peak Dose Dyskinesias

Associated with peak levels ofdopamine administration

dopaminergic cells, buffer capacity

non-continuous, erratic release of DA

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

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?

Motor fluctuations

Dystonia sustained, painful muscle contractions

distal lower extremities (feet/toes)

usually seen in morning, improvement with first

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

Motor fluctuations

Akathisia

feeling of inner restlessness

patient cant sit still

pacing, shifting, tapping feet

treatment with benzodiazepines

(e.g. Ativan)


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Carbidopa/Levodopa


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

L-DOPA

3-OMD dopamine

L-DOPA

3-OMD dopamine

DOPAC 3-MT

HVA

BBB

Periphery CNS

COMT AADC COMT AADC

MAO-B COMT

COMT MAO-B

COMT Inhibitors Tolcapone (Tasmar)

Entacapone (Comtan)

Stalevo (levodopa/carbidopa/entacapone)

Longer clinical levodopa response

levodopa metabolism, BBB penetration

Adjunct therapy with levodopa

motor fluctuations

Not indicated as monotherapy

Tolcapone

Improves symptomatic control with levodopa

efficacious for motor fluctuations off time, on time ~1-2 hrs/day

Dosing: 100 mg PO TID w/ Sinemet

Side effects: Dopaminergic: Nausea, dyskinesias (most

common)

hallucinations, anorexia, insomnia, orthostatichypotension

Non-dopaminergic: diarrhea (tolerance)

Tolcapone

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, thenmonthly x 6mos, then every 2 months.

Discontinue if AST, ALT exceed upper limit

Entacapone

Improves symptomatic control, motorfluctuations in levodopa treated patients

Dosing: 200 mg with each Sinemet dose

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

Side effects:

Dopaminergic: nausea, dyskinesia (transient)

Liver enzymes: few cases of elevations

no hepatotoxicity, no monitoring required


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MAO-B Inhibitors

L-DOPA

3-OMD dopamine

L-DOPA

3-OMD dopamine

DOPAC 3-MT

HVA

BBB

Periphery CNS

COMT AADC COMT AADC

MAO-B COMT

COMT MAO-B

MAO-B Inhibitors

Selegiline (Eldepryl or Deprenyl)

Irreversible substrate of MAO-B effective as monotherapy levodopa sparing

Not an FDA approved indication

questionable efficacy as adjunct therapy

in Levodopa dose not associated with improvedsymptomatic control

neuroprotective?

oxidative stress

Selegiline

Dosing: 5 mg PO AM (w/ breakfast)

titrate to 5 mg PO BID

Side effects:

Well tolerated, similar to placebo

Dopaminergic effects when added to Levodopa

Metabolized to amphetamine derivatives

May have effects on cognition (confusion, insomnia)

Zydis selegiline

oral disintegrating tablet (ODT) formulation

Direct absorption (no first pass effect)

dose, plasma concentration

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)

Significant improvements in off time1

Compared to placebo in pts. on levodopa.

Equivalent in on time, though more dyskinesiasin 1mg/day rasagiline group.

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

Rasagiline (Azilect)

Dosing: 0.5-1 mg PO QD

Side effects: dopaminergic, hallucinations

Drug interactions: metabolized by CYP 1A2

Ciprofloxacin plasma levels of rasagiline.

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


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Safinamide

Investigational MAO-B inhibitor

Phase 3 study (016, 018 extension) Mid-advanced disease patients

Improvements in on time with

no or minor dyskinesias

Dopamine Agonists

Ergot derivatives (older agents) Pergolide (Permax)

Bromocryptine (Parlodel)

Non-ergot derivatives (newer agents)

Pramipexole (Mirapex)

Ropinirole (Requip)

Dopamine Agonists

Rotigotine (Neupro) Transdermal delivery system (2, 4, 6 mg)

FDA approved, 2007 Recalled, 2008 crystals in the patches

UPDATE:

- Transdermal patches reformulated and available - 2012

off time, levodopa dose/fluctuations

Modest improvements in UPDRS scores asmonotherapy in patients with early stage disease.

Adjunct w/ levodopa in advanced disease

Patches contain metabisulfite Do not use in sulfite allergic patients

Dopamine Agonists

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

Dopamine Agonists

Effects on striatal DA receptors

ergots: D1, D2, and 5 HT

non-ergots: D2 and D3

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

Dopamine Agonists

Dosing: ergot derivatives

Pergolide:

withdrawn from the market due to cardiac valvedysfunction.

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

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

ER formulations

Recently studied, available - ropinirole

Dopamine Agonists

Side effects: ergot and non-ergot

Dopaminergic: nausea (50%), vomiting,orthostatic hypotension

similar frequency in ergot and non-ergotagents despite receptor affinity

CNS: somnolence (sleep attacks),dizziness, confusion, psychosis(hallucinations)

dose limiting

especially problematic for the elderly

Dopamine Agonists

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

Dopamine Agonists

Side effects: ergot derivatives Pleuropulmonary disease (PPD)

Retroperitoneal fibrosis

Cardiac valve dysfunction

Rare but potentially serious (2-5%)

Dose/duration of therapy

Reversible upon discontinuation

Baseline CXR recommended

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

DiPiro Figure 68-4: PD treatment algorithm


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Parkinsons Resources

National Parkinson Foundation

www.parkinsons.orgAmerican Parkinson Disease Assn.

http://www.apdaparkinson.com

World Parkinson Disease Association

www.wpda.com

Surgery

Deep Brain Stimulation (DBS)

most promising, non-ablative drug refractory tremors

CNS lesions (thalamotomy, pallidotomy,subthalamic nucleus lesions)

improves rigidity, tremor, and akinesia

Grafting, transplantation

investigational

Controversy still exists, despite studies: initiation with levodopa?

Gold standard" but long term risks (e.g. motorfluctuations)

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 COMTinhibitor? very few studies with direct comparisons between

classes

Drug Therapy InitiationWhen 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

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

Early PD Treatment

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

Other agents studied for neuroprotective benefits:

Levodopa Inconclusive evidence to date Acceleration of neurologic destruction

Dopamine agonists

Retards oxidative stress in vivo?

Investigational agents

Exanatide

Creatine

Isradipine

Early PD Treatment

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.

Levodopa/Carbidopa

elderly (or poor cognition), functionally impaired

Advanced PD Treatment

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

Non-motor symptoms of PD

Sleep disorders

incontinence

constipation

dysphagia

drooling

sweating

temperatureintolerance

Erectile dysfunction

paresthesias

dementia

anxiety

depression

seborrheic dermatitis

visual deficits

orthostatic hypotension

Non-motor PD symptoms

Under recognized and under treated

Medication side effects vs. diseasecomplications

Recent AAN guidelines released Neurology. 2010;74:924-931

Evidence supports:

Sildenafil for ED

Levodopa/carbidopa for RLS.

Dementia and Psychosis in PD patients

Complication of disease progression

up to 40% incidence in advanced disease

Drug induced

Simplify drug regimen

discontinue meds of least likely clinicalbenefit, highest risk of psychosis

1) anticholinergics 4) amantadine

2) selegiline 5) COMT inhibitors

3) dopamine agonists


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Dementia and Psychosis Treatment in PD

Psychosis

Second generation antipsychotics mostfrequently 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)

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 musclestiffness 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

SH: negative Allergies: NKDA

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 excessivesomnolence/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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