Antiparkinson Drugs Flashcards
What are the 4 main symptoms of Parkinson’s? secondary sxs?
bradykinesia, resting tremor, rigidity, postural instability. secondary: depression, dementia, autonomic dysfunction
What is the pathology?
loss of a lot of DA in neurons in the Substantia Nigra. Also Lewy inclusion bodies in neurons
What drug is used to restore dopaminergic function?
Levodopa = L-DOPA
1) what converts tyrosine to L-DOPA?
Tyrosine hydroxylase (TH)
2) what converts L-DOPA to Dopamine?
aromatic-amino acid decarboxylase (AAD)
what is the rate-limiting enzyme?
TH tyrosine hyroxylase
3) which enzymes between Dopamine and Metabolites?
MAO-B (monoamine oxidase) and COMT (catechol O-methyltransferase)
Does Dopamine cross the blood brain barrier?
no
Does tyrosine increase dopamine levels? why/why not?
no because TH (tyrosine hydroxylase) is already saturated with normal tyrosine levels
what happens when L-DOPA is administered alone?
the majority of it is converted to DA by AAD in peripheral tissues before entering the brain.
What is administered with L-DOPA and why?
Carbidopa because it inhibits peripheral AAD and can’t cross the blood brain barrier…it stops L-DOPA from being converted to dopamine by AAD in peripheral tissues before the brain
What is carbidopa?
a peripheral AAD inhibitor administered with Levodopa
What does Carbidopa do to L-DOPA levels?
it permits more L-DOPA to enter the brain where it can be converted to DA by AAD in brain
Therefore, Carbidopa (2):
1) increases the potency of L-DOPA (decreases required daily dose)
2) decreases production of DA in peripheral tissues, reducing peripheral side effects
What are the peripheral side effects?
nausea, vomiting, postural hypotension
What is the L-DOPA + Carbidopa drug?
Sinemet (like “cinema”)
What is another name for vitamin B6?
pyridoxine
What do high doses of pyridoxine do?
activates peripheral AAD which decreases L-DOPA levels
how many patients actually respond to L-DOPA?
~2/3
L-DOPA loses its effectiveness in about 5 years…why?
further loss of DA neurons and lack of new Da synthesis from L-DOPA
What is the on-off phenomenon? why?
L-DOPA effectiveness is on-off. dietary reason, persistent loss of DA neurons
What are the major side effects of L-DOPA (4)?
extrapyramidal dyskinesias, nausea and vomiting, postural hypotension, sleep disturbances
What are the COMT inhibitors?
entacapone, tolcapone
Which COMT inhibitors work in the periphery?
entacapone and tolcapone
Which COMT inhibitors work in the CNS?
tolcapone
How do COMT inhibitors work?
inhibit L-DOPA metabolism in peripheral tissues and/or DA metabolism in the brain (Tolcapone)
Are COMT inhibitors used alone?
NO! Always used in combo with L-DOPA
What are the side effects of COMT inhibitors?
diarrhea, increased sensitivity to L-DOPA
What’s special about Tolcapone?
hepatotoxicity, peripheral and central
What’s special about Entacapone?
peripheral COMT only, shorter duration
What is the Levodopa + Carbidopa + Entacapone drug?
Stalevo
What is Stalevo?
levodopa + carbidopa + entacapone
What are the MAO-B Blockers?
Selegiline, Rasagiline
Where do the MAO-B inhibitors work?
CNS (striatum)
What is the mechanism of MAO-B blockers?
block DA metabolism by inhibiting MAO in striatum
What does MAO-B do?
preferentially metabolizes DA
What are the drug interactions with MAO-B blockers (2)?
1) contraindicated with Meperidine or Tricyclid antidepressants because of hyperthermic or hypertensive interactions
2) potential hypertension if used with L-DOPA
What are the DA receptor agonists (3)?
Bromocriptine, Pramipexole, Ropinirole
What are the older DA receptor agonists?
Bromocriptine
What are the newer DA receptor agonists?
Pramipexole, Ropinirole
What are the side effects of bromocriptine?
hypotension, nausea, dyskinesia
Why are pramipexole and ropinirole better?
longer duration of action (less on and off) and good efficacy, side effects are less severe
what are the side effects of pramipexole and ropinirole?
hypotension, nausea, dyskinesia, sleep disturbance, hallucination/confusion, risky behaviors. (less severe than bromocriptine)
What are the muscarinic receptor antagonists?
Benztropine
What does DA normally do to Ach?
DA released from nigrostriatal neurons activates D2 receptors on cholinergic neurons in the striatum and inhibits the release of Ach
What does coordination of movement rely on?
balance of Ach and DA
What happens to cholinergic activity in Parkinson’s?
Reduced DA activity leads to cholinergic hyperactivity
What do muscarinic receptor antagonists do (benztropine)?
counteract cholinergic hyperactivity in PD
What are the side effects of benztropine?
anti-parasympathetic: dry mouth, reduced sweating, increased heart rate
What is benztropine especially effective against?
tremor
What antiviral agent works for Parkinsons?
Amantadine
What does Amantadine do?
increases DA release
Downsides of amantadine?
beneficial effects are not as pronounces as L-DOPA and tolerance occurs within weeks
What are the side effects of Amantadine?
(usually mild) restlessness, depression, livedo reticularis (purplish mottled skin discoloration), edema, hypotension, hallucinations
What is the DA precursor?
L-DOPA
What is the peripheral AAD inhibitor?
Carbidopa
What are the COMT inhibitors?
Entacapone, Tolcapone
What are the MAO-B inhibitors?
Selegiline, Rasagiline
What is the anti-viral agent?
Amantadine
What is the muscarinic receptor antagonist?
Benztropine
What are the DA receptor agonists?
Bromocriptine, Pramipexole, Ropinirole
