Drugs for Parkinson's Disease Flashcards
(31 cards)
What are the symptoms of Parkinson’s disease? (4 primary symptoms, 3 secondary symptoms)
- Loss of extrapyramidal movement control -
(1) Bradykinesia
(2) Resting tremor
(3) Rigidity
(4) Postural instability
(5) Secondary symptoms include depression (~30%) dementia (~50%) and autonomic dysfunction
What is Substantia Nigra (SN) in Parkinson’s disease? (Pathology and Etiology)
- Pathology:
~ Loss of 60-80% of dopamine neurons in SN;
~ Lewy inclusion body in neurons - Etiology:
~ aging;
~ genetic origin (10-15% cases in 30’s and 40’s versus > 80% idiopathic in 60’s);
~ environmental toxins (MPTP; rotenone)
T/F Dopamine crosses the blood brain barrier.
FALSE; does NOT
What are the Pharmacologic Treatments of Parkinson’s disease?
(1) Restore dopaminergic function with Levodopa (L-DOPA)
(2) COMT inhibitors
(3) MAO-B blockers
(4) Dopamine receptor agonists
(5) Muscarinic receptor antagonists
(6) Amantadine
Biosynthesis of Dopamine: What is the rate limiting step of dopamine?
Tyrosine hydroxylase (TH)
T/F Tyrosine does not increase dopamine levels.
TRUE; because Tyrosine hydroxylase is saturated
Biosynthesis of Dopamine: What are the 2 enzymatic pathways in which Dopamine metabolizes?
(1) Monoamine oxidase (MAO)
2) Catechol O-methyltransferase (COMT
What is an important therapeutic consideration for L-DOPA?
When administered alone, the vast majority of L-DOPA is converted to dopamine by AAD in peripheral tissues before entering the brain. Therefore, L-DOPA is always administered together with CARBIDOPA, the AAD inhibitor that cannot cross the blood brain barrier.
What does Carbidopa do? (2)
- permits more L-DOPA to enter the brain, where it can be decarboxylated to dopamine by brain AAD that is not inhibited by the drug.
(1) Increases the potency of L-DOPA
(2) Decreases the production of dopamine in peripheral tissues, reducing the peripheral side effects (nausea, vomiting, postural hypotension)
What are major side effects of L-DOPA?
(1) Extrapyramidal dyskinesias
(2) Nausea and vomiting
(3) Postural hypotension
(4) Sleep disturbances
What is the on-off phenomenon? What drug does this pertain to?
L-DOPA effectiveness is on-off
- dietary reason in part
- persistent loss of DA neurons
How many patients respond to L-DOPA?
2/3; particularly effective against bradykinesia
What happens to L-DOPA with high pyridoxine (vit B6) doses?
It activates peripheral AAD which decreases L-DOPA levels
L-DOPA: Wearing off
~5 yr in use, L-DOPA loses its effectiveness; further loss of DA neurons and lack of new DA synthesis from L-DOPA
What are the COMT inhibitors?
(1) Entacapone
(2) Tolcapone
COMT inhibitors- Mechanism of Action
Inhibits L-DOPA metabolism in peripheral tissues and/or DA metabolism in the brain (striatum)
T/F COMT inhibitors are never used with L-DOPA.
FALSE; they are always used with L-DOPA
COMT inhibitors- Side effects
(1) Diarrhea
(2) Increased sensitivity to L-DOPA
Where are Tolcapone and Entacapone inhibited (central, peripheral)?
- Tolcapone: central and peripheral COMT inhibition: hepatotoxicity
- Entacapone: peripheral COMT only, shorter duration
What are the MAO-B blockers?
(1) Selegiline
(2) Rasagiline
MAO-B blockers: Mechanism of Action
Blocking dopamine metabolism by inhibiting monoamine oxidase in the striatum
MAO-B blockers: Drug interactions
(1) Contraindicated with meperidine or tricyclic antidepressants because of hyperthermic or hypertensive interactions
(2) Use with L-DOPA is complicated because of potential hypertension
What enzyme preferentially metabolizes dopamine?
MAO-B
What are the dopamine receptor agonists? What are their side effects?
(1) Older agonists: Bromocriptine
- mainly D2 agonist
- side effects: hypotension, nausea dyskinesia
(2) Newer agonists: Pramipexole & Ropinirole
- major side effects: (less severe than ergot derivatives) hypotension, nausea, dyskinesia, sleep disturbances, hallucination/confusion, risky behaviors
