Pharmacotherapy for Movement Disorders

Question 1

under normal conditions the SNc favors the which pathway?

Answer 1

direct pathway

Question 2

in PD the activity of which pathway predominates?

Answer 2

indirect pathway

Question 3

___________ receptor activation appears to be most important in gating the balance of the direct and indirect pathways

Answer 3

D2

Question 4

what are the 5 main strategies for PD pharmacotherapy?

Answer 4

1. replace DA
2. Stimulate DA receptors
3. Enhance DA release
4. Inhibit DA metabolism
5. Alter DA/ACh

Question 5

which drug is the single most effective treatment for PD?

Answer 5

L-DOPA

Question 6

Which drug can completely ameliorate all the symptoms of PD, particularly during initial treatment?

Answer 6

L-DOPA

Question 7

what is the MOA of L-DOPA?

Answer 7

replenishes DA Stores in the remaining DA terminals in the striatum

Question 8

L-DOPA is converted in the periphery and brain to dopamine by what enzyme?

Answer 8

L-aromatic aminoacid decarboxylase (L-AAD)

Question 9

99% of systemically administered L-DOPA is converted to dopamine in the periphery, and is principally excreted in the urine as what two substances?

Answer 9

HVA & DOPAC

Question 10

L-DOPA has to be co-administered w/ what drug?

Answer 10

carbidopa

Question 11

what is the MOA of cabidopa?

Answer 11

inhibits L-aromatic amino acid decarboxylase (L-AAD)
-prevents metabolism of L-DOPA to dopamine in the periphery (you want L-DOPA to remain unchanged so it can cross the BBB)

Question 12

what are the two main benefits of using carbidopa with L-DOPA?

Answer 12

reduces the amount of L-DOPA needed by up to 75% & reduces side effects due to reduced level of peripheral DA

Question 13

the GI and CV adverse effects of L-DOPA are due to what?

Answer 13

due to the response to L-DOPA monotherapy

Question 14

what are the GI adverse effects of L-DOPA monotherapy?

Answer 14

anorexia, N/V, tend to decrease w/ repeated use

Question 15

what are the CV adverse effects of L-DOPA monotherapy?

Answer 15

arrhythmias, tachycardia, ventricular extrasystoles, Afib, incidence tends to be low except in those predisposed, also orthostatic hypotension

Question 16

the behavioral and dyskinesias are adverse effects of L-DOPA therapy with what other drug?

Answer 16

carbidopa

Question 17

what are the behavioral adverse effects of L-DOPA combo therapy w/ carbidopa?

Answer 17

depression, anxiety, delusion, agitation, insomnia, hallucinations, nightmares, euphoria. (antipsychotics are used to alleviate this problem)

Question 18

what are the dyskinesias associated with L-DOPA combo therapy with carbidopa?

Answer 18

chorea, myoclonus, tics, tremor

Question 19

the adverse effects for which drug have fluctuations in response like a “on-off phenomenon”?

Answer 19

L-DOPA

Question 20

what is the main drug interaction with L-DOPA, that causes an increase in L-DOPA metabolism?

Answer 20

vitamin B6 (pyridoxine)

Question 21

why is it not ok to give L-DOPA to pts on MAO-A inhibitors?

Answer 21

hypertensive crisis

Question 22

what are some of the contrindications for L-DOPA therapy?

Answer 22

psychotic pts, glaucoma (angle-closure), cardiac disease, peptic ulcer, melanoma

Question 23

Therapy with L-DOPA is often effective for how many years?

Answer 23

3-5 yrs (often delayed until symptoms of PD yield functional impairment)

Question 24

What is the rationale behind dopamine agonist therapy?

Answer 24

to activate D2 receptors to reduce the activation of the indirect pathway?

Question 25

what are the advantages to dopamine agonist therapy?

Answer 25

- doesn't have to be converted to active compound - no toxic metabolites - doesn't compete w/ other substances for GI absorption or crossing BBB - may be more selective (reducing adverse effects)

Question 26

what kind of drugs are considered the preferred therapeutic strategy for early PD?

Answer 26

dopamine agonists

Question 27

which kind of drugs may be used in combo w/ L-DOPA in advanced PD to reduce the "on-off" phenomenon?

Answer 27

dopamine agonists

Question 28

name the drug: D2 agonist/D1 partial agonist

Answer 28

bromocriptine

Question 29

name the drug: D1/D2 agonist

Answer 29

apomorphine

Question 30

name the drug: D2 selective, may also act as a free radical scavenger

Answer 30

pramipexole

Question 31

name the drug: D2 selective, metabolized by CYP1A2

Answer 31

Ropinirole

Question 32

which drug is an antiviral agent that was found to alleviate parkinsonian symptoms?

Answer 32

Amantadine

Question 33

how long do the effects of amantadine last?

Answer 33

effects are modest and short-lived

Question 34

how is amantadine excreted?

Answer 34

urine

Question 35

what are the adverse effects of amantadine?

Answer 35

``` restlessness depression agitation irritability insomnia excitement hallucinations confusion overdose may produce psychosis other adverse effects similar to L-DOPA and dopamine agonists ```

Question 36

which drug is contraindicated in pts w/ history of seizures or heart failure?

Answer 36

amantadine

Question 37

which drug is a selective MAO-B inhibitor that retards the breakdown of dopamine?

Answer 37

Selegiline

Question 38

metabolites of selegiline include what two drugs that increase dopamine release?

Answer 38

amphetamine & methamphetamine

Question 39

what is the indication for selegiline?

Answer 39

used primarily in pts whose responsiveness to L-DOPA has declined (little effect when administered alone)

Question 40

what are some of the drug interactions of selegiline?

Answer 40

don't take w/ meperidine, TCAs, or SSRIs

Question 41

what are the adverse effects of selegiline?

Answer 41

May potentiate the adverse effect of L-DOPA

Question 42

name the drug: a new more potent inhibitor of MAO-B approved for combo therapy w/ levodopa in late-stage or alone in early PD?

Answer 42

rasagiline

Question 43

name the two drugs that are selective inhibitors of COMT?

Answer 43

entacapone, tolcapone

Question 44

what is the MOA of entacapone and tolcapone?

Answer 44

prolongs the action of L-DOPA, reduces the production of 3OMD which may compete w/ L-DOPA for transport carriers in GI and BBB -increases the bioavailability of L-DOPA

Question 45

What is the indication for enacapone, tolcapone?

Answer 45

helpful in reducing fluctuation responses to L-DOPA

Question 46

name the inhibitors of DA metabolism that are both rapidly absorbed, highly bound to protein, half-life about 2 hrs?

Answer 46

entacapone, tolcapone

Question 47

which COMT inhibitor has both central and peripheral effects?

Answer 47

tolcapone

Question 48

which COMT inhibitor has only peripheral effects?

Answer 48

entacapone

Question 49

which COMT inhibitor is preferred b/c the other one may result in increased liver enzymes and hepatic failure (requires pt consent)

Answer 49

entacapone is preferred | tolcapone (causes increased liver enzymes and hepatic failure, requires pt consent)

Question 50

what are the muscarinic antagonists used to block cholinergic activation in the striatum (3)

Answer 50

benztropine diphenhydramine trihexyphenidyl

Question 51

what are the adverse effects of the muscarinic antagonists used to treat PD?

Answer 51

drowsiness, mental slowness, inattention, confusion, delusions, hallucinations, and mood changes

Question 52

using muscarinic antagonists to treat PD are contraindicated in pts with what conditions?

Answer 52

prostatic hyperplasia OBD glaucoma (avoid concomitant use of drugs with antimuscarinic effects-like TCAs or antihistamines)

Question 53

what is the trinucleotide repeat found in huntington's?

Answer 53

CAG (glutamine, polyglutamine expansion)

Question 54

the huntingtin gene is located on what chromosome?

Answer 54

4

Question 55

Huntington's disease has a loss of cholinergic neurons in the striatum but a greater and earlier loss is observed in WHICH NEURONS that project to the external globus pallidus (indirect pathway) thus decreasing the output (STN) of the indirect pathway?

Answer 55

loss is observed in the striatal medium spiny GABAergic neurons which project to GPe

Question 56

what are the 2 main drugs used to treat HD associated depression?

Answer 56

Fluoxetine | carbamazepine

Question 57

what are the central dopamine depleting agents drugs used to treat HD associated chorea?

Answer 57

reserpine and tetrabenazine

Question 58

what are teh dopamine antagonists that are used to treat HD associated chorea?

Answer 58

chlorpromazine and haloperidol

Question 59

what is the proposed MOA of the drugs used to treat HD associated chorea?

Answer 59

thought to be able to block D2 receptors