Lecture 29: Parkinson's disease anti-Parkinson drugs

Question 1

What are the motor and non-motor symtoms of Parkinsons

Answer 1

Motor:

• Tremor at rest
• Rigidity (cog-wheel)- stiffness of limb with movement
• Akinesia/Bradykinesia
  
  • Movement gets slower, patient may start movement fast but then slows to a stop and have to restart the movement.
  • No arm swining
  • Don’t blink for a long time
• Postural and gait abnormalities
  
  • (tendency to take several steps to turn, falling, stooped posture)

Non-motor:

• Mood flattening
• Anosmia
• Constipation
• Pain
• Sleep distrubance
• Anxiety
• Dementia

Question 2

What are the stages of Parkinsons

Answer 2

Braak Staging

Stage 1 Motor nucleus vagal nerve àConstipation

Olfactory bulb à Loss of sense of smell

Stage 2 Reticular formation à REM sleep (Consciousness maintenance)

Stage 3 Substantia Nigra àPhysical symptoms of PD

Stage 4 Temporal cortex à Problems with memory

Stage 5 Neocortex and prefrontal cortex àDementia

Stage 6 Association areas of the cortex

Question 3

What are the criterias of Diagnosis of Parkinsons?

Answer 3

1. Two or more cardinal motor features to have Parkinson’s disease
2. Progressive course
3. Response to levodopa (Precursor is taken because Dopamine itself cannot cross the BBB and get to the brain.)
4. No alternative cause for the patient’s symptoms

Question 4

Describe the pathology of Parkinsons

Answer 4

Accumulation of abnormally folded proteins. (alpha synuclein in PD - -an “alpha-synucleinopathy”)

• Build up in different parts of the body, depending on where the build-up is, they produce different clinical syndromes.

Degeneration of dopamine secreting neurons in Substantia Nigra (paleness to SNc)à_Nigrostriatal pathway lost._ By the time you have physical symptoms you have lost most of these cells.

• Degenerating neurons contains inclusion bodies called Lewy bodies which contains alpha synuclein
• These neurons: projections to basal ganglia and cortex, use dopamine as a neurotransmitter

Question 5

What is the pathogenesis of Parkinsons

Answer 5

IDIOPATHIC

• Genetic susceptibility: gene mutation on chromosome 4 causes an early onset.

Hereditary form of Parkinson’s diseaseàRare but more common amongst young onset (<50 years of age),

Alpha synuclein gene: Parkin gene –Is the gene that makes Lewy bodies.

Triple repeat will develop Parkinson’s. Also other genes are involved.

• Toxins: MPTP (narcotic analogue)-Parkinsonism
• Infections: Von Economo’s encephalitis (encephalitis lethargica)
• Autoimmune response.

Monkey study: MPTP depletes COX 1 overnight can produce Parkinson’s diseaseà produces clinical syndrome.

Question 6

Describe the drug treatment of Parkinson’s Disease

Answer 6

Drug Treatment

1) Replacement of neurotransmitter (Dopamine)à Gold standard

• Can stimulate dopamine receptor with dopamine agonist
• Can give drugs slow break down of dopamine

NO current treatment prevents the loss of cells - condition slowly gets worse (treatment is symptomatic).

2) Drugs:

• Levodopa + DOPA decarboxylase inhibitor

Levodopa which is a supplement system can act directly on striatum or by using the remaining cells taking up the Levadopa and releasing it in physiological fashion.

Half-life of Levodopa is short (~90 minutes), blocking the breakdown of the drug can prolong the action of the drug à can have 2 medication in 1 pill Levodopa + Carbidopa which slows the peripheral conversion which decreases the peripheral side effects and increases the level in the central nervous system (allows more to brain).

• Dopamine agonists
• Anticholinesterases
• Monoamine oxidase (MAO) B inhibitor
• Catechol-o-methyltransferase (COMT) inhibitors

3) Continuous dopminergic stimulation:

• Apomorphine: Liquid absorbed from subcutaneous fat avoiding first pass metabolism
• Duodopa: Liquid levodopa absorbed from the duodenum to get around short half life

Question 7

Describe the Surgical

Answer 7

1. Stereotactic thalamotomy (for tremor)
2. Stereotactic pallidotomy (improve all features of Parkinson’s disease, including dyskinesias)
3. Transplantation of dopamine-producing tissue (e.g. fetal tissue)
4. Deep brain stimulation (inhibits overactive neurons without the need for a destructive procedure)
5. Insertion of electrodes connected to a stimulator

Can reduce involuntary movements, helps only certain aspects of the symptoms

MRI scan used to help with the surgery- Drilling hole in the skull.

Question 8

What are the late complications of parkinson’s disease

Answer 8

• Cognitive abnormalities; confusion, hallucinations, dementia
• Emotional disturbances: anxiety, depression
• Postural hypotension
• Fluctuations (50% of patients after 5 years of treatment): dyskinesia, on-off fluctuations.