Download Parkinson’s Disease

Drugs Used to Treat Parkinson’s Disease
By Jasmine and Morgan
11/13/03
Parkinson’s Disease subtypes
• Idiopathic Parkinson’s disease – Primary
(unknown origin)
•Parkinsonism – Secondary (known origin) –
drugs, stroke, trauma
•Familial – (genetic origin)
Subclinical hypodopaminergic state - loss
of 80-90% of DA neurons before
symptoms present (roughly 20 years)
DA neuronal loss not from Basal Ganglia loss of dopaminergic input to Striatum
Neuronal death observed in Substantia Nigra
(Pars Compacta) and the Nigrastriatal bundle
A9 DA System
DA content decrease in extra pyramidal
motor areas of basal ganglia
Caudate and putamen
Substantia Nigra, Normal. Pigment
Loss Is Seen In Parkinson's
Disease
Rodent Brain A9 System
• 1 % Prevalence in Adult Population- Age
65 and Older
• As many as 10% aged 60 and older may
have undiagnosed early stages of the
disease
• Increased onset due to
– Transitory Ischemic Attacks (TIA)
– Brain Damage
– Drug Abuse
•1 ½ times more prevalent in women
Cardinal Symptoms
Bradykinesia - Slowness and poverty of
movement
Muscle “Cogwheel” rigidity
Resting tremor
Abates during voluntary movement
Shuffling gait
Impairment of postural balance
Secondary Symptoms
Dementia
Visuospatial deficits, impaired attention and
executive function
Anxiety
Sleep disturbances
Sexual dysfunction
Abnormal theromregulation
Therapy
see table18.2 pg534
Levodopa (L-dopa)
Rapid oral absorption – 95% converted
to DA in plasma
DA doesn’t cross BBB from plasma
into CNS
Precursor L-dopa does cross BBB
via active transport system (about 5%)
Most effective current treatment
Problems Associated with L-Dopa
Decrease high levels of DA in periphery
that can cause nausea
by inhibiting dopa decarboxylase
which converts
dopa to DA
Carbidopa – Peripheral decarboxylase
inhibitor
Carbidopa/ levodopa combo reduces the
amount necessary for therapeutic level of
L-Dopa by 75%
Problems Associated with L-Dopa
Even with carbidopa, much of L-Dopa converted by
COMT (in GI tract and Liver) to inactive metabolic byproduct
Recent addition of peripheral COMT inhibitors to
standard treatment – Talcapone and Entacapone
Increase the half-life and prolong the effects of LDopa
– A few cases of serious liver toxicity attributed
to Talcapone (1998) – Entacapone too new to
say (2000)
Limitations to L-dopa Therapy
Becomes less effective as time goes on
“on-off”/ “wearing off” effect
between 1-5 yrs patients on L-dopa therapy
gradually become less responsive
Results in hypermovement, then
hypomovement, then no movement (akinesia)
Taking doses more often, or taking large
doses results in dyskinesias (uncontrolled
movements) and may result in psychiatric
complications.
On-off effect possibly related to DA neurons
inability to synthesize and store DA
DA Receptor Agonists
Bind to postsynaptic striatal neurons
Possible use for early and late stages
Four currently available
Bromocriptine (1978) and Pergolide (1989)
Derived from lysergic acid, structurally similar
to DA
– Marginally effective with numerous side
effects
– Affinity for D2 receptors (Inhibitory)
DA Receptor Agonists
Pramipexole and Ropinirole (1997)
Affinity for D3 receptors (Inhibitory)
Indicated for use in early onset
Increased safety and efficacy over older agonists
(although risk of sleep attacks)
Long half lives may partially explain reduction in
on-off effect
Side effects: hallucinations, insomnia, nausea,
somnolence and dizziness.
Long term use of DA agonists results in increased
sensitivity of DA receptors (sensitization)
Additional Therapies
Selegiline
Selectively inhibits MAO-B (preferential affinity for
DA neurons)
Used in newly diagnosed, younger patients
Appears to slow disease progression and delay need
for L-Dopa
Metabolized to several by-products, including
amphetamine and methamphetamine
In combo with L-Dopa, may result in increased
morbidity after 5 years
Additional Therapies
Muscarinic Receptor Antagonists
Widely used before L-Dopa
Still used as an adjunct to L-Dopa for severe tremors
Cognitive dysfunction limits their use
Experimental Brain Surgery
Lesions (thalamus and GPi)
Neural tissue implants (fetal substantia nigra neurons)
Transplantation of carotid body glomus cells (secrete
DA) to the putamen
Dopaminergic substantia nigra
neurons continue to die, until they’re all
gone.
Thank You
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Q&A!!!