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.

Dopamine
Pramipexole

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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 16
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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20
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 L-
DOPA 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. Which medicinal treatment is generally
started for younger patients with mild
symptoms in early-stage treatment?
2. Levodopa is used with which drug and why?
3. 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 30