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 Patients with severe disability (%)
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
- 0 +/-
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+ Non Ergot Derivatives
Apomorphine Piribedil
Pramipexole Ropinirole
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+/+++ = 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.
