Exam 2 Lecture 19, Anti-PD II

Question 1

L-DOPA + Carbidopa

Answer 1

Drugs which increase dopamine synthesis in brain

Question 2

Decrease DA metabolism, prolong DA effect

Answer 2

MAO inhibitors: selegeline (deprenyl) and rasagiline

COMT inhibitors: Tolcapone and entacapone

Question 3

Stimulate DA receptors (DA agonists)

Answer 3

D2 agonist: bromocriptine

D2/D3 agonist: pramipexole, ropinirole, rotigotine

Question 4

Block muscarinic receptors, re-establish DA/Ach balance

Answer 4

benztropine mesylate
trihexiphenidyl
procyclidine

Question 5

Increase DA synthesis or release

Answer 5

amantidine

Question 6

Treat Parkinson’s disease psychosis

Answer 6

pimavanserin

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

Question 7

Levodopa (L-Dopa)

Answer 7

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

Question 8

Sinemet

Answer 8

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

Question 9

Levodopa Side effects (short term)

Answer 9

Gastrointestinal
Cardiovascular
Behavioral - anxiety, depression, delusions, hallucinations

Question 10

Levodopa Limitations long-term use

Answer 10

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

Question 11

Drug Holidays

Answer 11

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

Question 12

Strategy behind L-DOPA + carbidopa combo

Answer 12

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%

Question 13

Selegiline

Answer 13

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

Question 14

Rasagiline

Answer 14

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

Question 15

Tolcapone

Answer 15

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

Question 16

Entacapone

Answer 16

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

Question 17

Bromocriptine (Parlodel)

Answer 17

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

Question 18

Pramipexole (Mirapex)

Answer 18

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

Question 19

Ropinirole (Requip)

Answer 19

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

Question 20

Rotigotine (Neupro)

Answer 20

New non-ergo D3/D2/D1 agonist

Administered transdermally

Continuous delivery for 24hrs

Side effects: postural hypotension, nausea, sleep attacks, hallucinations

Question 21

Anticholinergic drugs

Answer 21

Muscarinic receptor antagonists

Benzotropine mesylate (Cogentin)
Trihexyphenidyl (Artane)
Procyclidine (Kemadrin)
Diphenhydramine (Benadryl)

Question 22

Anticholinergic Drug info

Answer 22

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

Question 23

Amantadine

Answer 23

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

Question 24

Pimavanserin (Nuplazid)

Answer 24

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

Question 25

Tissue Transplantation

Answer 25

DA cell grafts into corpus striatum

Involves transplantation of substantia infra tissue from aborted human fetus, not widely adopted form of therapy

Major impediments: poor survival of cells, need large amount of fetal tissue and immunosuppressant therapy, ethical issues

Question 26

Surgical lesions

Answer 26

goal to prevent excessive inhibition of motor neurons

Question 27

Pallidotomy (Surgical Lesions)

Answer 27

ablation of globes pallidus interns, GPi.

Prevents excessive inhibition of thalamus, performed in US with apparently high success rate

Controversial, but in demand…how long does it work for?

Question 28

Autografts

Answer 28

involve surgical removal of cells capable of making dopamine from the patient and surgically injecting them into the striatum of same patient

been performed using adrenal medulla cells, but cells did not reliably release dopamine or improve Parkinson’s disease

Question 29

Deep brain stimulation

Answer 29

stimulation of sub thalamic nucleus (STN) or GPi via chronically implanted electrodes

Believe to quite STN, lessen its “drive” of GPi, and prevent excessive inhibition of thalamus. Can also implant directly into GPi

Highly effective therapy without risks of creating new brain lesion (safer than pallidotomy). Can be programmed to deliver titrated stimulus

Question 30

Induced pluripotent stem cells (iPSCs)

Answer 30

Health DA neurons cultured and grafted into midbrain to restore DA transmission

iPSCs derived from already differentiated somatic cells, can be differentiated into DA neuron via transcription factors and used for grafting

Rodent model showed it can reverse Parkinsonism.

Used to use embryonic stem cells, but iPSCs more ethical

Question 31

COMT inhibitors

Answer 31

Tolcapone and entacapone

Question 32

MAO inhibitors

Answer 32

selegeline (deprenyl) and rasagiline

Question 33

D2 agonist

Answer 33

Bromocriptine

Question 34

D3/D2 agonist

Answer 34

Pramipexole
Ropinirole
Rotigotine