Transcript PPT

Parkinson’s Disease (PD):
Levodopa Drug Treatment
Presenter: Pedro Da Silva
Date: February 27, 2007.
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Celebrities with PD
Michael J. Fox
Muhammad Ali
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History of PD
• James Parkinson was the first to collect certain
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symptoms such as ataxia, paralysis, and tremor
into a common syndrome which formed a
distinctive condition. He published a treatise
called “An Essay on the Shaking Palsy” in 1817
which contained different sections outlining the
symptoms, diagnoses, causality, and possible
treatments.
These speculations were made by watching the
movements of six elderly males along the streets
of London.
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History Continued…..
• It was not until 1861 that Jean-Martin Charcot added
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more symptoms to James Parkinson’s clinical description
and attached the name Parkinson’s Disease to the
syndrome. Charcot added to the list of symptoms the
mask face, various forms of contractions of hands and
feet, and rigidity.
The drug used in the emmergence stage of this
syndrome was the alkaloid drug hyoscine (or
scopolamine) derived from the Datura plant. A century
later, a new drug was prescribed to sustain some of the
symptoms, one known by the name levodopa, more
commonly known as L-Dopa.
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Structure of L-Dopa
• Levodopa (L-Dopa)
Formula: C9H11NO4
Molecular Weight: 197.19 g/mol
Metabolism: Aromatic-L-amino acid decarboxylase
Half-life: 0.75-1.5 hours
Administration: Oral
Legal Status: Prescription only
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Treatment with L-Dopa
• The drug Levodopa has been the most effective
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drug treatment for PD and remains the gold
standard treatment for those afflicted with this
syndrome.
L-(Dopa) was first isolated from legumes in 1913
but declared biologically inactive. However, in
1938, it was found that an enzyme L-Dopa
decarboxylase was able to convert human body
L-Dopa into dopamine (DA).
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L-Dopa continued…..
• These conclusions set the bar for the beginning
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of DA studies in the brain of patients with
Parkinson’s Disease.
In 1960, the severe DA deficit in the brain, the
major etiology of this syndrome, was discovered
and a year later, L-Dopa was shown to have a
strong therapeutic effect in these patients.
Now it is recognized as a classic example of a
brain neurotransmitter replacement therapy.
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How does L-Dopa work?
• Levodopa is the precursor of dopamine and its use
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replaces the deficient neurotransmitter.
Levodopa is absorbed from the duodenum and
penetrates to a certain degree the brain through the
blood-brain barrier. In the brain, it is converted to
dopamine by the enzyme L-Dopa decarboxylase located
in neuronal compartments.
To prevent episodes of nausea or vomitting, levodopa is
combined with the peripheral dopa decarboxylase
inhibitors such as carbidopa. This inhibits the conversion
of levodopa to dopamine at a peripheral level which is
responsible for vomitting episodes.
Levodopa has a short half-life of about 60 to 90 minutes.
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How does L-Dopa work
continued…..
• Failure to respond to L-Dopa ultimately
suggests that the disease may not be
Parkinson’s Disease and could just be a
Parkinson-like disorder.
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Chemical reaction in the brain
• Conversion of L-Dopa
to dopamine
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Neurobiology of Parkinson’s
disease
• The main symptoms from Parkinson’s disease arise from the
deterioration of the part of the brain that monitors motor
functioning. This region is called the substantia nigra which is found
deep within the brain stem and contains neuronomelanin, pigment
cells, which synapse to cells of the striatum. The striatum deals
with balance, control of movements, and walking. Dopamine which
is produced in the substantia nigra, passes messages between the
striatum and the substantia nigra. In Parkinson’s disease, the cells
of the substantia nigra actually deteriorate causing there to be a
decrease in the amount of dopamine produced between the cells.
This decrease in the levels of dopamine causes the neurons of the
striatum to fire excessively, leading the patient to refrain from
proper movement.
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Neurobiology continued…
• These alterations in the neural circuit within the basal ganglia
causes irregular movements by inhibiting the direct pathway and
exciting the indirect pathway.
• The direct pathway is responsible for movement and the indirect
pathway inhibits movement. This ultimately leads to movements
related to hypokinesia.
• There are four major dopamine pathways in the brain: 1.) The
nigrostriatal pathway which mediates movement 2.) Mesocortical
pathway which deals with emotional responsiveness 3.) Mesolimbic
pathway which is responsible for desire and initiative and 4.)
Tuberoinfundibular pathway which is involved with sensory
processes.
• As a result, disruption of dopamine along these pathways explains
much of the symptomology associated with this disease.
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Parkinson’s Disease
SUBSTANTIA NIGRA
Decrease Dopamine
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PET SCAN
A PET scan will automatically
tell a physician if a patient is
diagnosed with Parkinson’s
Disease. Here, a radiolabelled
amino acid called F-DOPA
(analogue of L-DOPA) is used
with PET to see if there is a
deficiency in dopamine
synthesis. Note the reduced
uptake of DOPA in the basal
ganglia. Following treatment
involving transplanting
dopamine synthesizing cells
into the striatum, there is more
uptake of DOPA in the patient.
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Neurobiology Continued...
• In order to compensate for the loss of dopamine and the
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destroyed cells of the substantia nigra, the brain may
boost the level of activity in the pigment cells, or
increase the sensitivity of the cells of the striatum. In
the normal process of aging, these mechanisms can
compensate for neuronal degeneration in the substantia
nigra. However, in Parkinson’s disease, this mechanism
can only account for 75% of the loss of DA. This is
where the treatment of L-Dopa comes into the picture.
L-Dopa crosses the blood-brain barrier, gets converted to
dopamine, and increases the overall levels of DA. Due
to the large deficiencies of dopamine though, large
doses are required which can cause many side effects.
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Side Effects (Disadvantages)
• Levodopa causes what is known as “dopaminergic” side
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effects, which basically means that they derive from
mimicking the action of dopamine.
These effects include the following:
Nausea and vomitting
Orthostatic hypotension
Excessive sleepiness
Hallucinations
Dyskinesias
Short half-life
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Advantages of using L-Dopa
• L-Dopa alleviates bradykinesia, rigidity, and tremor.
• Allows patients to improve in activities in daily life.
• L-Dopa is readily combined with carbidopa which reduces the side
effects experienced.
• L-Dopa preparations are available in pill form as well as liquid form
allowing for patients to have options in selecting the form of
administration.
• L-Dopa is also good for the proper diagnosis of PD. If a patient
takes levopoda and shows a significant improvement in the
symptoms experienced, then that concluded that the individual has
Parkinson’s Disease. If the contrary happens and the individual
feels no difference, then he/she does not have PD.
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Case Study #1
• One hundred patients (63 men and 37 women
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with an age ranging between 40 to 78) with
Parkinson’s Disease were treated with Levodopa
for more than a year at UCLA Medical Centre.
They were examined at given intervals and their
improvement was graded.
At the end of the first year, 60 percent of the
patients improved 50 percent or better, and 10
percent were symptom-free. (symptoms in this
study analyzed were rigidity, akinesia, and
tremors.)
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Case Study #1 continued…
• More than one-fourth of the patients had improved 50
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percent or more by the end of the first trimester. At the
end of six months, more than half had improved 50
percent or better, and by end of the first year, 62 percent
of patients had attained this improvement.
At the end of all this, 10 percent were symptom-free.
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Case Study #1 Continued…
• Table illustrating the symptoms experienced by patients with Parkinson’s disease and
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the overall improvement.
Limitations: Average Levodopa dose for group which responded poorly was much
greater than for the entire study group or select symptom-free group. Since all the
patients had the levodopa dosage pushed to a high level, this indicates that these
individuals were able to tolerate larger than usual amounts of the drug.
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Case Study #2
• In this study, 32 patients (18 men and 14 women with an average
age of 61 years) with Parkinson’s Disease were treated with L-Dopa.
• There was no selection of patients because of age or severity of
affection, but those who showed forms of dementia were excluded
from the trial.
• Features such as tremor, rigidity, and hypokinesis were graded
respectively in each patient as “marked,” “moderate,” “slight,” or
“absent.” All of the patients were assessed clinically before
treatment as well as during the assessment.
• Other features associated with Parkinson’s Disease were also
measured such as postural defects, impassivity of the face,
salivation, and mood.
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Case Study #2 Continued…
• Table illustrating how Levodopa significantly helped the patients to perform an
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activity with a much faster response.
After the study was complete, 9 were markedly and 14 moderately improved. Such
marked improvement does not imply restoration to normality but rather a restoration
of function to a socially and economically acceptable level. Two patients though
achieved virtual normality after treatment for six months. The rest of the patients
still showed amelioration.
Limitations: Some individuals responded to levodopa with more side effects and
could have discontinued the use of the drug treatment as a result.
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Evaluation/Conclusion
• Overall, Levodopa Therapy has revolutionized the treatment of
Parkinson’s Disease and remains the “gold standard” after so many
years.
• It definitely provides dramatic benefits in terms of alleviating many
symptoms thus allowing patients afflicted with this disease to enjoy
their routine activities as well as prolong their life span.
• In the early stages of PD, levodopa is excellent in responding to the
disease and even if a dose is missed, the benefits persist. Not
effective on every patient. Usually more successful in patients with
an early onset of the disease.
• On the other hand, with progression of this disease, the benefit of
the drug begins to wear off. Over time, the duration of the motor
response to a given dose of L-Dopa becomes shorter and begins to
reflect the half-life of the drug itself (60-90 minutes). As a result,
more research needs to be conducted to find a longer-lasting
effective drug.
• In the end, above the side effects experienced, I think it is an excellent
treatment with many benefits since it extinguishes many of the pains both
psychological and physical when dealing with such a debilitating disease.
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THE END
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