Drugs For Movement Disorders DSA

Question 1

Under normal conditions how do the dopaminergic neurons of the substantia nigra work?

Answer 1

Under normal conditions, dopaminergic neurons originating in the substantia nigra inhibit
the GABAergic output from the striatum (caudate and putamen) while cholinergic neurons
exert an excitatory effect on GABAergic neurons

Question 2

Which neurons are lost in PD patients and what does this result in?

Answer 2

The selective loss of dopaminergic neurons in patients with PD results in disinhibition of
GABAergic neurons and disturbed movement

Question 3

Levodopa uses which amino acid transporter?

Answer 3

Levodopa enters the CNS via an L-amino
acid transporter (LAT); dopamine does not
cross the blood-brain barrier

Question 4

MOA of Levodopa

Answer 4

agonist at dopamine receptors

Question 5

absorption of levodopa and halflife

Answer 5

Rapidly absorbed from the small intestine
with a peak plasma concentration usually
between 1-2 hours after an oral dose
(plasma half-life is usually between 1-3
hours)

Question 6

how much levodopa actually makes it to the brain unaltered?

Answer 6

Only 1-3% of administered levodopa
actually enters the brain unaltered (the
remainder is metabolized extracerebrally,
predominantly by decarboxylation to
dopamine)

Question 7

Coadministration of levodopa with carbidopa does what?

Answer 7

Coadministration of levodopa with a DOPA
decarboxylase inhibitor that does not cross
the blood-brain barrier (carbidopa) results
in reduced peripheral metabolism,
increased plasma levels, increased half-
life, and increased levodopa available for entry into the brain

Question 8

Coadmin of levodopa + carbidopa reduces the daily requirements by?

Answer 8

Coadministration of levodopa and carbidopa may reduce the daily requirements of
levodopa by approximately 75%

Question 9

what is the wearing off phenomenon

-when does it occur and how is it characterized

Answer 9

A ‘wearing-off’ phenomenon can occur during long-term treatment, where each dose of
levodopa effectively improves mobility for a period of time (1-2 hours), but rigidity and
akinesia return rapidly at the end of the dosing interval; increasing the dose and
frequency of administration can improve symptoms, but this is often limited by the
development of dyskinesias (distortion or impairment of voluntary movement)

Question 10

adverse gi effects of levodopa

Answer 10

Gastrointestinal effects: Levodopa given in the absence of a peripheral decarboxylase
inhibitor causes anorexia, nausea, and vomiting (due to activation of the chemoreceptor trigger zone) in roughly 80% of patients; the combination of levodopa/carbidopa causes less frequent and less troublesome GI side effects

Question 11

adverse cardiovascular effects of levo

Answer 11

often diminishes with continuing treatment. Hypertension can occur when taking large doses of levodopa or levodopa in combination with nonselective monoamine oxidase inhibitors or sympathomimetics.
Cardiovascular effects: Postural hypotension (frequently asymptomatic) can occur but

Question 12

when does levo cause hypertension?

Answer 12

can occur when taking large doses of levodopa or levo in combo w/ nonselective mao inhibitors or sympathomimetics

Question 13

Dyskinesias associated with levo therapy

Answer 13

Dyskinesias can occur in 80% of patients. Choreoathetosis (movement of intermediate
speed, between the quick, flitting movements of chorea and the slower, writhing
movements of athetosis) of the face and distal extremities is the most common
presentation

Question 14

Behavioral effects of levodopa

Answer 14

Behavioral effects: depression, anxiety, agitation, insomnia, somnolence, confusion,
delusions, hallucinations, nightmares, euphoria, other changes in mood or personality
have been reported. Atypical antipsychotic agents (clozapine, olanzapine, quetiapine,
risperidone) are able to help counteract behavioral complications

Question 15

What is the on-off phenomenon

-what provides relief during these periods?

Answer 15

Fluctuations in response and the ‘on-off phenomenon’: Fluctuations in response can
occur due to the timing of the dose (wearing off phenomenon, see above) or due to
reasons unrelated to dose timing (on-off phenomenon). In the on-off phenomenon, off-
periods of marked akinesia alternate over the course of a few hours with on-periods of
improved mobility but often marked dyskinesia (exact mechanism is unknown).
Subcutaneous injections of apomorphine may provide temporary benefit to those
patients with severe off-periods.

Question 16

Drug interaction with MOA inhibitors

Answer 16

Patients taking monoamine oxidase A inhibitors (or within 2 weeks of discontinuation)
may experience hypertensive crisis when combined with levodopa

Question 17

Levodopa is contraindicated in which patients?

Answer 17

• psychotic patients
• angle closure glaucoma (can be given to patients with well controlled open)
• history of melanoma or suspicious skin lesions (levodopa is precursor of skin melanin)
• patients w/ active peptic ulcer due to possible gi bleeding

Question 18

What is the purpose of a dopamine receptor agonist?

Answer 18

Lower incidence of the response fluctuations and dyskinesias that occur with long-term
levodopa therapy, although patients who don’t respond well to levodopa generally don’t respond well to dopamine agonists

Question 19

when is it administered with levodopa?

Answer 19

Can be administered in addition to levodopa/carbidopa and in patients who are taking
levodopa and who have end-of-dose akinesia or on-off phenomenon

Question 20

Three dopamine receptor agonists

Answer 20

bromocriptine, pramipexole, ropinirole

Question 21

Bromocriptine:

• alkaloid derivative of ?
• agonist at which site?
• CYP?

Answer 21

(1) Ergot alkaloid derivative that is a D2 agonist; also approved for treatment of endocrine
disorders (e.g., hyperprolactinemia, prolactin secreting adenomas, acromegaly) (2) Bioavailability 28% (extensive first pass metabolism with CYP3A4) with peak plasma
concentration usually attained within 1–3 hours; 15-hour half-life

Question 22

Pramipexole:

• which active site
• also commonly used to treat what?
• metabolism

Answer 22

Pramipexole
(1) Preferential affinity for D3 receptors; also approved for the treatment of moderate-to-
severe primary Restless Leg Syndrome (RLS) (2) Peak plasma concentration reached in 2 hours with a half-life of 8 hours; 90% excreted
unchanged in the urine (renal insufficiency may require dose adjustment)

Question 23

Ropinirole:

• active site
• also treat which disorder?
• cyp, metabolism

Answer 23

Ropinirole

(1) Preferential affinity for D2 receptors; also approved for the treatment of RLS
(2) CYP450 metabolism (primarily CYP1A2); peak plasma concentration reached in 1-2 hours with a half-life of 6 hours

Question 24

Adverse effects of dopamine receptor agonists.
Gi:
CV:
MSK:
Psych:

Answer 24

GI: Gastrointestinal effects: anorexia, nausea, and vomiting can occur (reduced if agents
are taken with meals); constipation, dyspepsia, and symptoms of reflux esophagitis
CV:Cardiovascular effects: postural hypotension may occur (more common early in
therapy); digital vasospasm during long-term treatment; presence of peripheral edema
and cardiac arrhythmias may indicate the need to discontinue therapy
MSK: