Exam 2 Lecture 19, Anti-PD II Flashcards
L-DOPA + Carbidopa
Drugs which increase dopamine synthesis in brain
Decrease DA metabolism, prolong DA effect
MAO inhibitors: selegeline (deprenyl) and rasagiline
COMT inhibitors: Tolcapone and entacapone
Stimulate DA receptors (DA agonists)
D2 agonist: bromocriptine
D2/D3 agonist: pramipexole, ropinirole, rotigotine
Block muscarinic receptors, re-establish DA/Ach balance
benztropine mesylate
trihexiphenidyl
procyclidine
Increase DA synthesis or release
amantidine
Treat Parkinson’s disease psychosis
pimavanserin
over activation of D2 = psychosis…since D2 agonists used to treat Parkinson’s it can lead to psychosis.
Levodopa (L-Dopa)
Dopamine has poor BBB penetration thus L-DOPA
converted to DA by L-AAAD
Given with Carbidopa to prevent being metabolized in peripheral system. Carbidopa is a peripherally active decarboxylase inhibitor…doesnt enter brain
Alleviates all clinical symptoms of PD
Sinemet
Combo carbidopa: L-DOPA in 1:10 or 1:4 ratio
Levodopa Side effects (short term)
Gastrointestinal
Cardiovascular
Behavioral - anxiety, depression, delusions, hallucinations
Levodopa Limitations long-term use
Loss of response Induction of involuntary movements (dyskinesias) "Freezing" episodes "on-off" fluctuations Parkinson's disease psychosis
Drug Holidays
may cause acute, dramatic worsening of parkinsonian symptoms, but drug can usually be reinstated at lower dose with better control of symptoms afterward
ie T break
Strategy behind L-DOPA + carbidopa combo
by using carbidopa, prevents L-DOPA from being turned into DA in the peripheral system so you need less of a dose to get a greater effect in the brain.
Without carbidopa 1-3%, with carbidopa 10%
Selegiline
selective MAO-B inhibitor (MAO-B metabolizes DA but NOT NE, 5-HT)
Used in combination with L-DOPA for its ability to breakdown of DA, thereby prolonging L-DOPA effect
Drug was thought to slow progression of Parkinson’s disease by preventing formation of neurotoxic species like MPP+ (MAO-B plays role) but not supported in clinical studies
Rasagiline
Selective, irreversible MAO-B inhibitor approved in 2006
Used as monotherapy in early PD, in adjunct with L-DOPA in later stages….reduces “off time” and increases “on time”
Once daily, well-tolerated
Tolcapone
Selective COMT inhibitor
Used in combination with L-DOPA + carbidopa to inhibit peripheral L-DOPA metabolism so that more reaches the brain
Therapeutic benefit: may prevent end-of-dose wearing off and fluctuations in efficacy due to L-DOPA pharmacokinetics; extends “on time”
WARNING ISSUED NOV 1998: drug associated with hepatic injury and liver failure
Entacapone
Newer selective COMT inhibitor without hepatoxicity problem of tolcapone
reduces peripheral O-methylation of L-DOPA so that more reaches brain, reduces end of dose wearing off
Shorter ~2 hours duration of action
Bromocriptine (Parlodel)
D2 selective DA agonist
Reserved for patients with “on/off” symptoms caused long-term L-DOPA
used in combo with L-DOPA at sub maximal doses of each
Side effects (hallucinations, postural hypotension) similar to L-DOPA
Causes nausea and fatigue upon starting therapy, increase dose to minimize problem
Used to treat hyperprolactinemia caused by prolactin-secreting tumors of the pituitary
Pramipexole (Mirapex)
D3 agonist, non-ergot agonist at D2 like family of DA receptors
more widely used than ergot derivatives, can be used with or without L-DOPA and useful all stages PD
Generally well-tolerated, therapy can be started more quickly than ergots but still same side effects
Side effects: sleep attacks, compulsive behaviors
Approved for treatment of RLS
Ropinirole (Requip)
non-ergot D2 like receptor agonist
used as initial therapy early PD, or with L-DOPA late state, similar to pramipexole
Side effects: nausea, hallucinations, sleep attacks
Also approved for RLS treatment
Rotigotine (Neupro)
New non-ergo D3/D2/D1 agonist
Administered transdermally
Continuous delivery for 24hrs
Side effects: postural hypotension, nausea, sleep attacks, hallucinations
Anticholinergic drugs
Muscarinic receptor antagonists
Benzotropine mesylate (Cogentin)
Trihexyphenidyl (Artane)
Procyclidine (Kemadrin)
Diphenhydramine (Benadryl)
Anticholinergic Drug info
Block effects of ACh in striatum, restoring balance between DA and ACh
Modest anti-parkinsonian action, improve tremor and rigidity
Useful in early stages of disease, sometimes used in combo
Side effects: Peripheral antimuscarinic effects like dry mouth, blurred vision. CNS effects
Amantadine
Antiviral found to have antiparkinson effects
May increase DA synthesis and or release from surviving neurons. Interacts NMDA receptor
Less effective than L-DOPA, more effective anticholinergics
Effectiveness modest and short lived so used in early stage or intermittently with other drugs
side effects mild and readily reversible once stop drug
ER form released for levodopa induced dyskinesia, taken at bedtime, reduces symptoms
Pimavanserin (Nuplazid)
Approved 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis without worsening motor symptoms
Acts as inverse agonist/antagonist at 5HT2A…..does not block D2 receptors
