Exam 2 Lecture 19, Anti-PD II

Drugs which increase dopamine synthesis in brain

MAO inhibitors: selegeline (deprenyl) and rasagiline COMT inhibitors: Tolcapone and entacapone

D2 agonist: bromocriptine D2/D3 agonist: pramipexole, ropinirole, rotigotine

benztropine mesylate trihexiphenidyl procyclidine

amantidine

pimavanserin over activation of D2 = psychosis…since D2 agonists used to treat Parkinson’s it can lead to psychosis.

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

Combo carbidopa: L-DOPA in 1:10 or 1:4 ratio

Gastrointestinal Cardiovascular Behavioral - anxiety, depression, delusions, hallucinations

Loss of response Induction of involuntary movements (dyskinesias) "Freezing" episodes "on-off" fluctuations Parkinson's disease psychosis

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

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%

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

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

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

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

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

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

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

New non-ergo D3/D2/D1 agonist Administered transdermally Continuous delivery for 24hrs Side effects: postural hypotension, nausea, sleep attacks, hallucinations

Muscarinic receptor antagonists Benzotropine mesylate (Cogentin) Trihexyphenidyl (Artane) Procyclidine (Kemadrin) Diphenhydramine (Benadryl)

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

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

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