Parkinson

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Parkinsons Disease (PD) and Treatment

• Jieun Park
• Chem-5398

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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 contd

• 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 contd

• 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 Parkinsons 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 1960s, 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?vdTdW8q9hukwfeature
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 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 Parkinsons disease,
  British Medical Bulletin, 86 (2008) 109-127
• Munchau, A., Bhatia, K P. Pharmacological
  treatment of Parkinsons disease, Postgrad Med
  J, 76 (2000) 602-610
• Rao, Shobha A., Hoffman, Laura A., Shakil, Amer.
  Parkinsons Disease Diagnosis and Treatment.,
  American Family Physician, 74 (2006) 2046-2054
• Singh, N., Pillay, V., Choonara, Y. E. Advances
  in the treatment of Parkinsons disease,
  Progress in Neurobiology, 81 (2007) 29-44
• Images from Wikipedia, Google