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Disease
18 February 2002
Parkinson Disease
Pesticides, herbicides,
industrial chemicals - contain
substances that inhibit
complex I in the mitochondria
In Terms of Etiology and Clinical
Picture, Major Symptoms Involve:
Bradykinesia- Slowness in Initiation
and Execution of Voluntary
Movements
Rigidity - Increase Muscle Tone and
Increase Resistance to Movement
(Arms and Legs Stiff)
Tremor - Usually Tremor at Rest,
When Person Sits, Arm Shakes,
Tremor Stops When Person Attempts
to Grab Something
Postural Instability - abnormal
fixation of posture (stoop when
standing), equilibrium, and righting
reflex
Gait Disturbance - Shuffling Feet
Usually Other Accompanied
Autonomic Deficits Seen Later in
Disease Process:
Orthostatic Hypotension
Dementia
Dystonia
Ophthalmoplegia
Affective Disorders
Parkinson Disease
Neurochemistry
DA
ACh
The Dopaminergic Neurons in the Basal
Ganglia Are mainly affected
Acetylcholine within striatum is a tonically
activated neuron
It impinges on GABA Neuron by an
Excitatory Action
GABA Neuron Has an Inhibitory Action on
the Substantia Nigra from Substantia
Nigra, Has a Dopaminergic Feed Back
Loop Back to Striatum Which Gets Loss
Giving Signs and Symptoms of Parkinson
Disease
Basal Ganglia
Dopamine Decarboxylase
Converts L Dopa to
Dopamine That Gets Stored
into Secretory Vesicles and
Gets Released from Basal
Ganglia
L Dopa- Pharmacokinetics
L Dopa is readily absorbed from
GI Tract
Usually large doses must be given
since ~1% actually cross Blood
Brain Barrier enters CNS
Large amount of L Dopa has to be
given due to First Pass Effect
L Dopa metabolized by dopa
decarboxylase in liver and
periphery to dopamine
Secreted in urine unchanged or
conjugated with glucoronyl sulfate
Most of L Dopa converted in
periphery to NE and EPI
Effects of L Dopa on the
Symptoms of Parkinson
Disease
L Dopa Fairly Effective in
Eliminating Most of the Symptoms
of Parkinson Disease
Bradykinesia and Rigidity Quickly
Respond to L Dopa
Reduction in Tremor Effect with
Continued Therapy
L Dopa less Effective in
Eliminating Postural Instability and
Shuffling Gait Meaning Other
Neurotransmitters Are Involved in
Parkinson Disease
Effects of L Dopa on
Behavior
Carbidopa Is Antagonistic to
Peripheral L Dopa
Decarboxylation Carbidopa
Doesn't Cross Blood Brain Barrier
By co-administering Carbidopa,
will decrease metabolism of L
Dopa in GI Tract and Peripheral
Tissues thereby increasing L
Dopa conc into CNS; meaning we
can decrease L Dopa dose and
also control the dose of L Dopa to
a greater degree.
Drug Interactions cont
Antipsychotic Drugs -
Antipsychotic Drugs Block
Dopamine Receptor
Reserpine -Reserpine Depletes
Dopamine Storage
Anticholinergics - Used
Synergistically with L Dopa as an
Antiparkinson Agent, but
Anticholinergics Act to decrease L
Dopa absorption since
Anticholinergics have an effect on
gastric emptying time which
delays crossing of GI Membrane
by L Dopa
Drug Interactions cont
Nonspecific MAO Inhibitors -
Interfere with L Dopa Breakdown
and exaggerate the CNS effects
the Nonspecific MAO Inhibitors
Can Precipitate Hypertensive
Crisis by the tyramine-cheese
effect (Tyramine Is Found in Cheese,
Coffee, Beer, Pickles, Chocolate, and
Herring), when given to a person
taking a MAO Inhibitor Tyramine
Is not broken down therefore
producing a tremendous release
of Norepinephrine)
Other Drugs for Treating
Parkinson Disease
Glutathione peroxidase
H202 + 2 G S H ----------> G S S G + 2 H20
The evidence suggesting that oxidative
reactions may contribute to the patho-
genesis of Parkinson's disease includes the
following.
•In patients with Parkinson's disease, the iron
content is increased in the substantia nigra,
the ferritin level is decreased in the brain, and
the glutathione concentration is decreased in
the substantia nigra.
•Furthermore, although 1-methyl-4-phenyl-1,
2,3,6-tetrahydropyridine (MPTP) is not itself
toxic, when oxidized by monoamine oxidase
B to the methylphenylpyridium ion, it
becomes a selective nigral toxin that interferes
with mitochondrial respiratory mechanisms.
The toxicity of MPTP may be prevented by
pretreatment with a monoamine oxidase B
inhibitor such as selegiline.
Amphetamine for Treating
Parkinson Disease