PARKINSON’S

DISEASE

Parkinson’s Disease

Parkinson’s disease (PD) is a progressive

neurodegenerative disorder of the basal

ganglia characterized by tremor, muscular

rigidity, difficulty in initiating motor activity,

and loss of postural reflexes.

Parkinson’s Disease

It is now clear that PD can be defined in biochemical terms as primarily a

dopamine-deficiency state resulting from degeneration or injury of

dopamine neurons. The most striking degenerative loss of dopamine neurons is

observed in the nigrostriatal system.

Pathogenesis of Parkinson’s disease

Substantia nigra

Pathology of PD

Striatum (PET scan)

Reduced striatal fluorodopa uptake in PD patients

Substantia Nigra

Visible neuronal loss in the substantia nigra of PD patients

Normal PD

substantia nigra

The Extrapyramidal system

Alexander et al. Prog Brain Res, 1990

CLINICAL FEATURES

Four cardinal signs:

Tremor

Bradykinesia

Rigidity

Postural instability

Features of Parkinson’s disease

Neuropsychiatric

Behavioral: psychosis

Cognitive: dementia

Affective: depression

Sleep disorders

Autonomic dysfunction

Motor features Non-Motor features

Motor complications Fluctuations

Dyskinesias

Non-motor features of

Parkinson’s disease

These non-motor features are of crucial importance to people since they have a major impact on quality of life.

Non-motor features comprise:

anxiety, apathy, psychosis

depression and dementia

falls and potential fractures

sleep disturbance (RIS, nocturnal akinesia etc.)

autonomic disturbance (constipation, urinary urgency, salivation, hypotension,

sweating)

pain

Royal College of Physicians

THERAPY I

Treatment Options

• Preventive treatment – No definitive treatment available

• Symptomatic treatment – Pharmacological

– Surgical

Restorative ??—experimental only

– Transplantation

– Neurotrophic factors

Drug Classes in PD

• Dopaminergic agents

– Levodopa

– Dopamine agonists

• COMT inhibitors

• MAO-B inhibitors

• Anticholinergics

• Amantadine

Sites of Action of PD Drugs

DA GABA

ACh

Striatum

Substantia Nigra

levodopa

Amantadine

selegiline Dopamine agonists

bromocriptine

pergolide

pramipexole

ropinirole

baclofen

trihexiphenidyl

BBB

carbidopa

benserazide

tolcapone

entacapone

Levodopa

• Most effective drug for parkinsonian symptoms

• First developed in the late 1960s; rapidly became the drug of choice for PD

• Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers

• Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide)

• Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations

Mechanism of action of L-dopa

Reduced disability after Levodopa

was introduced for PD treatment

Years since diagnosis

Pati

en

ts w

ith

severe

dis

ab

ilit

y (

%)

0

20

40

60

80

100

1–5 6–10 11–15

Untreated patients

Treated patients

Hoehn and Yahr, 1967; Hoehn, 1983

Levodopa – dopamine metabolism

Response to levodopa changes

with PD progression

Obeso and Olanow, 2000

• Smooth, extended duration of target clinical response

• Low incidence of dyskinesia

• Diminished duration of target clinical response

• Increased incidence of dyskinesia

• Short duration of target clinical response

• ‘On’ time is associated with dyskinesia

Levodopa-Induced Dyskinesias

• Manifestation of excessive dopaminergic stimulation

• Typically late effect, and with higher doses

• Narrowing of therapeutic window

• Rare in LD-naive patients on DA monotherapy

• Most common is “peak dose” dyskinesia – disappears with dose reduction

• Choreiform, ballistic and dystonic movements

• Most patients prefer some dyskinesias over the alternative of akinesia and rigidity

Therapeutic Options for

Levodopa-induced Dyskinesias

Add amantadine

Reduce levodopa

Add/increase dopamine agonist and reduce levodopa

Switch to dopamine agonist monotherapy

Use continuous drug delivery

(duodenal levodopa, s.c. apomorphine)

GPi pallidotomy, GPi stimulation, STN stimulation

THERAPY II

Anticholinergics

• Dopaminergic depletion cholinergic overactivity

• Initially used in the 1950s

• Effective mainly for tremor and rigidity

• Start low, go slow:

• Side effects: – Dry mouth, sedation, delirium, confusion,

hallucinations, constipation, urinary retention

Available anticholinergic agents

• Benzhexol

• Benztropine

• Biperiden

• Orphenadrine

• Procyclidine

• Trihexylphenidyl

• Tropatepine

Anticholinergics

• Anticholinergics are used to reduce the production

of excessive saliva and urinary incontinence in PD

• Can be used adjunctively with dopaminergic agents

• Caution is advised for use in elderly, as they can

cause confusion, hallucinations and memory

disturbance

• Dry mouth, constipation and urinary retention can

also be caused

Amantadine

• Antiviral agent; PD benefit found accidentally

• Tremor, bradykinesia, rigidity & dyskinesias

• Exact mechanism unknown; possibly:

– enhancing release of stored dopamine

– inhibiting presynaptic reuptake of catecholamines

– dopamine receptor agonism

– NMDA receptor blockade

• Side effects —autonomic, psychiatric

• 200-300 mg/day

Monoamine oxidase-B (MAO-B)

inhibitors • Monoamine oxidase (MAO) is an enzyme that

breaks down amines

• MAO exists as two major isoforms: – MAO-A

– MAO-B

• Isoforms are distinguished by the compounds that inhibit them, and by the substances that they act on: – MAO-A metabolises serotonin and dietary amines

– MAO-B metabolises dopamine

Mechanism of action

Selegiline

• Irreversible MAO-B inhibitor

• Clinically active by inhibiting dopamine metabolism in

brain; dosage: 5 mg at breakfast and lunch

• Side effects: insomnia, hallucinations, nausea (rarely),

OH

• Potential interactions with tricyclics and SSRI

antidepressants

COMT Inhibitors

• Newest class of antiparkinsonian drugs: tolcapone,

entacapone

• Potentiate LD: prevent peripheral degradation by inhibiting

catechol O-methyl transferase

• Reduces LD dose necessary for a given clinical effect

• Helpful for both early and fluctuating Parkinson’s disease

• May be particularly useful for patients with ―brittle‖ PD, who

fluctuate between off and on states frequently throughout the

day

Entacapone

• Dosage: 200 mg w/each levodopa dose

• Parkinson’s Study Group 1997: Increased on time

by 5%, more in pts w/least on time

• Rinne et al., 1998: Increased on time by ~10%;

decreased levodopa

• Diarrhea, dopaminergic SEs

Dopamine Agonists:

Distinguishing Features

• Directly stimulate dopamine receptors

• No metabolic conversion; bypasses nigrostriatal neurons

• No absorption delay from competition with dietary amino acids

• Longer half-life than levodopa

• Monotherapy or adjunct therapy

• May delay or reduce motor fluctuations & dyskinesias associated with levodopa

DA-agonists D1 D5 D2 D3 D4 5HT

Ergot Derivatives

Bromocriptine

Cabergoline

Dihydroergocriptine

Lisuride

Pergolide

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Non Ergot Derivatives

Apomorphine

Piribedil

Pramipexole

Ropinirole

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D1-like D2-like

+/+++ = agonist; - = antagonist; 0 = unactive

DAs: Common Adverse Effects

• Nausea, vomiting

• Dizziness, postural hypotension

• Headache

• Dizziness

• Drowsiness & somnolence

• Dyskinesias ??

• Confusion, hallucinations, paranoia

• Erythromelalgia; pulmonary & retroperitoneal fibrosis; pleural effusion & pleural thickening; Raynaud’s phenomena. May be more common with ergotoline DAs

Apomorphine

• D1/D2 agonist

• Parenteral delivery (s.c., i.v., sublingual, intranasal, rectal)

• Rapid ―off‖ period rescue – 2-5 mg s.c.; pen injection systems

• Treatment of unpredictable, frequent motor fluctuations – continuous s.c. infusion via mini-pump

• SE: nausea, vomiting, hypotension – trimethobenzamide 250 mg t.i.d.

– domperidone 20 mg t.i.d.; not available in U.S.

Non Pharmacological intervention

Pallidotomy

– Small lesions (ablations) are made with the use of radio waves

– Dramatically improves dyskinesia caused by PD medications

– Risk factors include slurred speech, disabling weakness and vision problems

• Thalamotomy

– A small part of the thalamus is destroyed