Parkinson's Disease Drugs Flashcards
(36 cards)
What are the symptoms of Parkinson’s?
Three S’s : slow, stiff, shaky
Slow = bradykinesia
Stiff = rigid
Shaky = resting tremor
This presents as motor changes:
- “Pill rolling” tremor in hands
- Slow shuffling gait
- Difficulty initiating movements (e.g. getting out of chair)
- Tiny handwriting
- Reduced facial expressions
- Soft voice
Disease progression more rapid if:
-older, male patient
-rigidity is the main symptom
-other comorbidities (stroke, etc.)
Disease progression slower if:
- Younger person, tremors are the primary symptom.
What is the cause of Parkinson’s?
Cell death of dopaminergic neurons in the SUBSTANTIA NIGRA PARS COMPACTA
Eventually other neurons in other brain regions die too
(b/c it’s a progressive movement disorder)
*common for both hemispheres to be eventually affected
When do symptoms appear?
when about 70% of nigrostriatal neurons are lost
What are the Basal ganglia & motor control?
Basal ganglia are needed to INITIATE movements
At rest, the thalamus is tonically inhibited by the striatum
Outputs from the striatum lead to both activation and inhibition from the thalamus
*Dopamine from the SNpc excites the direct pathway (D1 receptors) and inhibits the indirect pathway (D2 receptors). Net result= movement
*Removes tonic inhibition
What is Parkinson’s disease?
Dopamine neuron die, so the tonic inhibition is not removed.
When dopamine is lost, the thalamus remains inhibited.
Compare the Nigrostriatal Pathway (Normal vs. Parkinson’s)
Normal:
- GABA neurons are inhibited by dopamine and stimulated by acetylcholine
Parkinson’s Disease
- Dopaminergic neurons die, leaving a relative excess of acetylcholine
*Not enough dopamine, too much acetylcholine in the striatum (main message for patho)
What are the enzymes that have ~ ability to degrade dopamine? & what is the main one?
Main one: MAOB
Other enzymes that have ~ability to degrade dopamine: MAOA, MAOB, COMT
How would you treat Parkinson’s disease? (i.e. where in the CNS would you target?)
- Replace dopamine
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
Strategies to treat Parkinson’s Disease:
- Replace dopamine
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
________ dopamine signalling in the striatum
INCREASE
What is the dopamine synthesis in substantia nigra?
1 used (a prodrug)
Levodopa (L-DOPA)
used b/c dopamine doesn’t cross BBB
What is the L-DOPA Pharmacology?
UPTAKE
- Peak plasma concentration 1-2 h after ingestion
- 1-3 h half life
L-DOPA is always given in combo with drugs that:
________ peripheral dopamine metabolism
DECREASE
What are the drugs (added to Levodopa) to increase dopamine signalling?
- Entacapone (blocks COMT)
-Carbidopa (blocks DOC)
- Benserazide (blocks DOC)
Levodopa + carbidopa =
STANDARD therapy (peripheral metab. is inhib. & more gets to brain)
Levodopa + carbidopa + entacapone =
for late stage patients
Levodopa + carbidopa CR (controlled release)
…
What are drugs to increase dopamine signalling?
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
Monoamine Oxidase A (MAOA):
Metabolizes norepinephrine (noradrenaline) and serotonin (5-HT)
Monoamine Oxidase B (MAOB):
Metabolizes dopamine
Monoamine oxidase B inhibitors:
Rasagiline, selegiline
- Rasagiline (2nd gen) - better bioavailability, fewer side effects
- Monotherapy or adjunct that enhances effects of L-DOPA
(drug to increase dopamine signalling)
Dopamine agonists:
Ropinirole (po), rotigitine (patch)
- Second generation drugs, better than first (bromocriptine)
- Act on D2 receptors (inhibitory receptors; seems to be more effective for initiating movement)
- Often preferred by young PD patients (due to less motor complications (“wearing off”) (fewer SE’s)
