Download Parkinson`s Disease (PD) and Treatment

Jieun Park
Chem-5398
Outline
Overview
 Diagnosis
 Treatment

 Physical Therapy
 Drug Therapy
 Surgery

New Research
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Overview
Second most common human
neurodegenerative disorder.
 Prevalence of 1 out 272 in U.S.
 Increases to 4 to 5% for ages 85 and over.


Degeneration of dopaminergic neurons in
the substantia nigra.
Dopamine
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Overview cont’d

Symptoms caused by insufficient dopamine.

3 main symptoms:
 Tremors
 Rigidity
 Slowed motion (Bradykinesia)

Other symptoms include:
 Dementia, sleep disturbances, depression, etc.
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Overview cont’d
Common cause of chronic progressive
parkinsonism.
 Exact causes still yet unknown.

 Gene mutation
 Toxins
 Trauma
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Diagnosis
No definitive tests for PD. PET scans
can aid to determine levels of dopamine.
 Difficult to diagnose, many symptoms
shared with other disorders.
 Medical history and neurological tests
are conducted to diagnose.

 Usually, if two of the cardinal symptoms are
present.
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Treatment – Parkinson’s Disease
No cure for PD.
 Treatment can be divided into two stages.

 Early and Later stages

Early stage
 Onset of symptoms, treated with physical therapy and
medications (Levodopa, dopamine agonists, etc)

Later stage
 Usually after having received 5+ years of levodopa
treatment.
 “Wearing-off” and “On/Off” effect develops, other
medication in conjunction levodopa is commenced.
 MAO-B and COMT inhibitors.
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Treatment – Physical Therapy

Regular exercise
 Recommended throughout the life of disorder.
 Helps maintain and improve mobility and strength.
 Physical exercise aids in rigidity relief, muscle
strength and flexibility, balance, etc.
 Caution is advised to avoid sudden movements or
strenuous activities – fall could result in serious
injury.
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Treatment – Drug Therapy

Levodopa (L-DOPA)
 Preferred medication to control major symptoms.
 Usually administered at the early onset of disorder.
 Drug is well tolerated and side affects are limited.
Levodopa
Dopamine
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Drug Therapy – L-DOPA

L-DOPA is converted to Dopamine by
enzyme DOPA decarboxylase (DDC).
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Drug Therapy – L-DOPA
 Used with Carbidopa, which blocks the early
conversion of L-DOPA into dopamine.
Carbidopa
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Drug Therapy – L-DOPA
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Drug Therapy – L-DOPA

Side effects include
 Psychiatric symptoms; linked to depression
 Nausea and vomiting

Prolonged use can cause “wearing-off” effect.
 Leads to other motor complications, such as
dyskinesia.
Still the preferred treatment for symptoms.
 Drug brand name: Sinemet ®

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Drug Therapy – L-DOPA
L-DOPA can cross blood-brain barrier, when
dopamine cannot. This led to the idea of
using L-DOPA as treatment for PD.
 First used in the 1960’s, with daily increase
dosage program.
 L-DOPA used in combination with Carbidopa
in 1967.

 Increases potency of L-DOPA up to 4-fold.
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Treatment – Drug Therapy

Dopamine Agonists
 Acts directly on the dopamine receptors.
 Initially was used with L-DOPA.
 Today, sometimes prescribed before L-
DOPA, to delay “wearing-off” effect and
other motor complications brought on by
prolonged use of L-DOPA.
Pramipexole
Dopamine
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Drug Therapy - DOPA agonists

Triggers dopamine receptors in place of
depleted dopamine neurotransmitters.
http://www.youtube.com/watch?v=dTdW8q9hukw&feature=related
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Drug Therapy – DOPA agonists

Adverse side effects
 Nausea, dizziness, hallucinations
 Sleep attacks, hypotension
 Permax ® (pergolide) pulled after direct link
to fibrosis of cardiac valves that can lead to
death. Unavailable in U.S. since 2007.
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Treatment – Drug Therapy

Monoamine Oxidase B (MAOB) Inhibitors
 Delays or reduces breakdown of dopamine by
MAO-B.
 Used as monotherapy or in conjunction with
L-DOPA, it can reduce the dosage of L-DOPA by
15%.
Selegeline
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Drug therapy – MAO-B Inhibitors
MAO-B is an enzyme that metabolizes
dopamine.
 From the breakdown of dopamine,
hydrogen peroxide is produced, which the
oxidative stress can damage
dopaminergic neurons in the substantia
nigra. (Possibly neuroprotective)
 MAO-B inhibitor delays or reduces the
metabolism of dopamine.

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Drug therapy – MAO-B Inhibitors
Side effects of L-DOPA may be
enhanced by selegeline.
 Nausea and dizziness.

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Treatment – Drug Therapy

Catechol O-Methyl Transferase (COMT)
Inhibitors
 Inactivates and degrades neurotransmitters,
such as dopamine.
 Mainly used in combination with L-DOPA, it
increases the half-life of L-DOPA.
 Delays “wearing-off” effect of L-DOPA and
other motor complications such as dyskinesia
Tolcapone(Tasmar ®)
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Drug therapy – COMT Inhibitors
COMT catalyses methylation of L-DOPA.
 Addition of COMT inhibitor along with LDOPA and carbidopa prolongs the half-life
of L-DOPA and increases the amount in
the CNS.

 This increases “on” time for L-DOPA.
Tasmar ® are hepatotoxic.
 Diarrhea and sleep disturbances

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Treatment – Drug Therapy

Amantadine
 Antiviral agent.
 Known to aid in reducing dyskinesia.

Anticholinergics
 Improve tremors and stiffness
 Cause impairment and constipation
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Treatment - Surgery
Before commerciality of levodopa, surgical
treatment were preferred.
 Early surgeries were successful with
tremors, but failed to relieve other symptoms.
 “Means of last resort” due to high risk of
potential complications.
 Recent advances in neurosurgical
procedures allow for better treatment.

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Surgery 
Deep Brain Stimulation
 Brain pacemaker, sends electrical impulses to
brain to stimulate the subthalamic nucleus.
 Improves motor functions and reduce motor
complications.
 Complications include: brain
hemorrhage, seizures, death.
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New Researches

Nicotine
 Intake of nicotine has shown to slow the
degeneration of neurons.
 Acts similar to levodopa.

Melatonin
 Serotonin derivative that helps insomnia.
 Also shown to cause a reduction in
production of neurodegenerative radicals.
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Assigned Reading
Jankovic, Joseph; Aguilar, L. Giselle. Current
approaches to the treatment of Parkinson's
disease. Neuropsychiatric Disease and
Treatment (2008), 4(4), 743-757.
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Homework Problems
1.
2.
3.
Which medicinal treatment is generally
started for younger patients with mild
symptoms in early-stage treatment?
Levodopa is used with which drug and why?
Describe “wearing-off” and “on-off” effect.
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References
Davie, C. A. “A review of Parkinson’s disease”, British
Medical Bulletin, 86 (2008): 109-127
Munchau, A., Bhatia, K P. “Pharmacological treatment
of Parkinson’s disease”, Postgrad Med J, 76
(2000): 602-610
Rao, Shobha A., Hoffman, Laura A., Shakil, Amer.
“Parkinson’s Disease: Diagnosis and Treatment.”,
American Family Physician, 74 (2006): 2046-2054
Singh, N., Pillay, V., Choonara, Y. E. “Advances in the
treatment of Parkinson’s disease”, Progress in
Neurobiology, 81 (2007): 29-44
Images from Wikipedia, Google
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