Parkinson’s Disease Flashcards
WHAT IS THE PROBLEM IN PARKINSON’S DISEASE?
DEAD DOPAMINE NEURONS
Loss of dopamine synthesis
Loss of regulated release
PARKINSON’S DISEASE
Disease of the elderly, average onset age:
60, about 1% of people over age 60 have it
PARKINSON’S DISEASE
Genetic causes of Parkinson’s discovered in past 10 years show selective vulnerability of:
dopamine neurons
-Younger patients more likely to have genetic cause
PARKINSON’S DISEASE
People who drink ________, work with pesticides or metals like iron and copper have higher risk of Parkinson’s
well water
Tea and coffee drinkers have __________ risk of Parkinson’s
up five-times lower
________ have lower risk of Parkinson’s
Smokers
PARKINSON’S DISEASE
People who drink well water, work with pesticides or metals like _________ have higher risk of Parkinson’s
iron and copper
L-Dopa
rx- direct precursor of dopamine
Carbidopa reduces dose of L-Dopa needed
(much L-Dopa destroyed in gut w/o carbi)
Carbidopa
rx- Inhibits peripheral metabolism of L-Dopa
CAN”T cross BBB
If _____ makes you better, you have Parkinsons
L-Dopa
DRUG TREATMENT OF PARKINSON’S DISEASE
L-dopa – direct precursor of dopamine
Dopamine agonists
Dopamine “extenders”–carbidopa, MAO inhibitors and COMT inhibitors
Anticholinergic drugs
Amantadine - A glutamate antagonist
Drugs that may prevent progression
The most important drug for Parkinson’s
L-DOPA
L-DOPA
L-dopa is combined with carbidopa to block peripheral metabolism
Side effects – nausea, hypotension, depression, psychosis (up to 15%)
Long term complication – drug induced dyskinesias
Healthy brain makes about _____ of dopamine
1 g
L-Dopa dose
Typical dose 125 mg q2h 8 times/day
Taking more than 1 g of L-Dopa can cause side effects
Comtan
Keeps dopa around
Ripineral
Direct dopa agonist
Smoothes out peaks and troughs of L-Dopa w/ a short half life
L-Dopa half life
1 hour
The tremor in parkinson’s is
A rest tremor
Walking with parkinsons
Shuffling gait chasing the center of gravity
Cognitive ability of Parkinson’s
normal
Substantia Nigra name
has black pigment
Not born with pigment, it grows over time. PArk pts have no pigment
Diagnostic feature of parkinsons
Lewy Bodies
SN location
Base of skull
feeds axons to caudate and putamen (these stay normal)
Dopa deletion is worse in the Putamen
Main output of BG
GPI/SNr
Inhibitory Neurons
These dont see dopamine in PK, and they say “no movement allowed”
Amantadine
Glu Antagonist
Tyr–> L-Dopa–> Dopamine
enzyme not available in PK to do this synthesis
Dopamine Receptor Agonists
Most D2-dopamine receptor agonists
Developed for longer half lives
Often started at time of diagnosis to delay need for L-DOPA
Ropinirole (Requip)
Pramipexole (Mirapex)
Apomorphine – short acting
Dopamine Receptor Agonists ADR
TOXICITY: Nausea, hallucinations, Sudden onset of sleep* – car accidents
Pergolide – cardiac valve thickening – FDA withdrew drug
EVENTUALLY, NEARLY EVERYONE ON A DOPAMINE AGONIST NEEDS L-DOPA
Anticholinergics
Invention of antihistamines led to their use in Parkinson’s before dopamine and L-DOPA discovered
Have some limited value in treating some patients with tremor
Side effects: confusion, drowsiness, constipation, and urinary retention limit use in elderly Parkinson patients
Amantadine
Beneficial effects discovered when Parkinson patients took amantadine for influenza symptoms – Dose 300 mg/day
Mechanism uncertain
- facilitate release of endogenous dopamine - glutamate antagonist
Cost of Drugs
VERY steep
Drugs that may prevent progression of Parkinson’s
Co-enzyme Q-10 at dose of 1200 mg/day or greater has passed early double blind study
Creatine in doses of 10-20 gm/day may be beneficial
Caffeine and Adenosine A2a antagonists are being tested
Minocycline and Vitamin E have failed testing
Surgical Therapy for Parkinson’s Disease
Deep brain stimulation—reversible thalamotomy or pallidotomy
Thalamus
Internal pallidum
Subthalamic nucleus
Fetal dopamine cell transplantation
*When drugs arnt doing the trick
