Neurodegenerative Diseases

1
Neurodegenerative Diseases

• Gerianne R. Bliss, M.D.
• Chuck Hensley, R.Ph.

2
Parkinsons Disease

• Resting tremor, rigidity, and bradykinesia
• Degeneration of dopaminergic neurons in the
  substantia nigra and project to the basal
  ganglia-smooth coordination of the body
• Treated with drugs that either increase
  dopaminergic activity or inhibit cholinergic
  activity in the basal ganglia

3
Drugs that Increase Dopamine Levels

• Levodopa-precursor of dopamine
• Converted by dopaminergic neurons to dopamine
• Absorbed from the duodenum
• Metabolized by two pathways
• Large first-pass effect, only 1 reaches brain
  tissue
• Wearing-off effect-end of dosage interval
• On-off phenomenon-severe motor fluctuations

4
Drugs that Increase Dopamine Levels

• Levodopa-Adverse Effects
• N/V, orthostatic hypotension, cardiac
  arrhythmias-administer with carbidopa
• Dyskinesias due to excess dopamine in the
  striatum
• Psychoses
• Interactions MAOIs, antipsychotic drugs

5
Drugs that Increase Dopamine Levels

• Carbidopa
• Inhibits the conversion of levodopa to dopamine
  in peripheral tissues and increases the amount of
  levodopa that enters the brain
• Does not cross the blood-brain barrier
• Reduces GI and CV side effects

6
Drugs that Increase Dopamine Levels

• Amantadine
• Increases the release of dopamine form
  nigrostriatal neurons
• Treat early or mild disease
• Livido reticularis

7
Drugs that Increase Dopamine Levels

• Selegiline
• Prevents oxidation of dopamine
• ? Inhibit disease progression
• Treat early or mild disease
• Adjunct for advanced disease

8
Drugs that Increase Dopamine Levels

• Tolcapone
• Increases half-life of dopamine by inhibiting
  metabolism of levodopa in gut and liver
• Increase dopamine level in the striatum

9
Dopamine Receptor Agonists

• Activate dopamine receptors in the striatum
• Good for advanced disease
• Bromocriptine and pergolide
• Ergot alkaloids
• Adjunct to levodopa
• Pramipexole and ropinirole
• Selective D2 receptor agonists

10
Acetylcholine Receptor Antagonists

• Benztropine and trihexyphenidyl
• Anticholinergic
• Reduce tremor
• Reduce symptoms caused by dopamine receptor
  antagonists

11
Huntingtons Disease

• Autosomal dominant hereditary
• Choreoathetoid movements of the limbs , tongue,
  and face with mental decline
• Degeneration of GABA neurons in the
• Treat by blocking dopamine receptors-haloperidol
  or potentiate GABA with diazepam

12
Alzheimers Disease

• Progressive dementia-destruction of cholinergic
  neurons in the cortex and limbic structures
• Treat with cholinesterase inhibitor
• Donepezil
• Long half-life, causes diarrhea, N/V
• Tacrine
• Short half-life, liver toxicity, urinary
  incontinence

13
Multiple Sclerosis

• Demyelination of neurons
• Spasticity-treat with baclofen
• Acute exacerbations-treat with steroids
• Interferon beta-1b halt and reverse progression
  of disease

14
Amyotrophic Lateral Sclerosis

• Progressive disease of the motor neurons
• Muscle wasting, weakness, and respiratory failure
• ? Defect in superoxide dismutase
• Treatment
• Spasticity-baclofen, muscle strength-gabapentin
• Riluzole-prevent anoxia-related death of cortical
  neurons