Exam 6: Basal Ganglia Pharmacology

Question 1

What is an example of a hypokinetic disorder

Answer 1

Parkinson disease

Question 2

What is an example of hyperkinetic disorder

Answer 2

Huntington’s disease

Question 3

What is progressively lost in parkinson disease

Answer 3

Progressive loss of dopaminergic neurons in substantia nigra pars compacta

Question 4

What does less dopamine in the striatum result in?

Answer 4

Decreased direct pathway activity, increased indirect pathway activity, lose coordinated direct/indirect activity. Marked increase in inhibition of thalamus, reduced excitation of motor cortex

Question 5

What are the genetic components of Parkinson disease?

Answer 5

alpha-synuclein (SNCA), LRRK2, parkin, others

Question 6

What are symptoms of parkinson disease?

Answer 6

Bradykinesia, muscle rigidity, resting tremor, impair postural balance

Question 7

What is the current therapeutic strategy for parkinson’s disease?

Answer 7

treat symptoms only, restoring dopaminergic activity

Question 8

Why can’t you treat PD patients with dopamine?

Answer 8

It does not cross the BBB

Question 9

T/F: Levodopa is a prodrug

Answer 9

True

Question 10

What converts levodopa to dopamine?

Answer 10

L-aromatic amino acid decarboxylase (AAAD)

Question 11

Why does only 5% of levodopa enter the CNS?

Answer 11

Significant AAAD activity in GI tract

Question 12

What can high levels of peripheral dopamine cause?

Answer 12

nausea, orthostatic hypertension

Question 13

What is the action of carbidopa?

Answer 13

inhibits AAAD in the periphery, reducing levodopa dose by nearly 75%

Question 14

What is Levodopa and Carbidopa called in compound?

Answer 14

Sinemet

Question 15

What is the mechanism of levodopa

Answer 15

Activates D1 receptors (activates direct pathway), Acivates D2 receptors (inhibits indirect pathway)

Question 16

When is levodopa most effective in the progression of PD?

Answer 16

early in therapy

Question 17

What is the overall effect of levodopa on a PD patients disease?

Answer 17

decreased akinesia, rigidity, and tremor

Question 18

Why is levodopa less effective over time?

Answer 18

progressive loss of dopaminergic neurons

Question 19

Describe the interaction of L-DOPA and presynaptic neurons

Answer 19

store in presynaptic dopaminergic terminals of striatum and released gradually

Question 20

What can occur with treatment of L-DOPA as dopaminergic neurons are lost?

Answer 20

dyskinesia

Question 21

What are dyskinesias?

Answer 21

abnormal involuntary movements

Question 22

When do “on period dyskinesia” occur?

Answer 22

During times of peak dose (high plasma levels of levodopa) with maximal antiparkinsonian relief

Question 23

When does diphasic dyskinesia occur while dosing levodopa?

Answer 23

onset and offset of the levodopa effect coinciding rising and falling plasma levodopa levels

Question 24

What occurs in diphasic dyskinesia?

Answer 24

repetitive, slow movements of the lower limbs often coinciding with tremor in the upper limbs

Question 25

What occurs during "off" period dystonia?

Answer 25

fixed and painful postures more frequently affecting the feet

Question 26

What occurs during "on" period dyskinesia

Answer 26

brief, abrupt, irregular, unpredictable movements (chorea) predominantly involving the neck, trunk and upper limbs

Question 27

What can be done to decrease the "wearing off phenomenon"

Answer 27

increase dose, decrease dosing interval, add COMT inhibitor

Question 28

What are adverse effects of levodopa

Answer 28

confusion, anxiety, agitation, insomnia, nightmares, depression, psychotic reactions, orthostatic hypotension, nausea, vomiting, anorexia

Question 29

What drug decreases peripheral metabolism of levodopa by COMT?

Answer 29

COMT inhibitor: entacapone

Question 30

What does entacapone do in terms of levodopa effects?

Answer 30

smoother response, more prolonged "on" time

Question 31

What are adverse effects related to with entacapone treatment?

Answer 31

adverse effects are related to increased plasma L-DOPA

Question 32

What class of monoamine oxidase enzymes do we target with MAOIs. What does it do? What is an example?

Answer 32

MAO-B, which primarily metabolized dopamine. Selegiline

Question 33

When is treatment with MAOIs useful?

Answer 33

effective early in PD as monotherapy or combined with L-DOPA

Question 34

what is the benefit of using a dopamine receptor agonist?

Answer 34

bypasses the conversion of L-DOPA to dopamine

Question 35

What are the adverse effects of dopamine receptor agonists? What helps to lower these effects?

Answer 35

response fluctuations, dyskinesia, lower with L-DOPA therapy

Question 36

What are examples of dopamine receptor agonists?

Answer 36

Pramipexole, ropinirole

Question 37

T/F: muscarinic antagonists be used to treat PD? Example?

Answer 37

True; atropine

Question 38

What is the known mechanism of amantadine (symmetrel)

Answer 38

antiviral; NMDA receptor antagonist, decrease release/reuptake of dopamine, antimuscarinic

Question 39

What are adverse effects of amantadine (symmetrel)?

Answer 39

agitation, confusion, excitement, restlessness, insomnia, halucinations

Question 40

What are surgical interventions of PD?

Answer 40

pallidotomy- alleviates akinesia, rigidity, and drug-induced dyskinesia; thalamotomy- ameliorates tremor

Question 41

What are symptoms of Huntington's disease?

Answer 41

Hyperkinetic disorder; uncontrolled rapid, jerky movements

Question 42

What is the etiologic mechanism of Huntington's disease?

Answer 42

degeneration of striatal neurons projecting to GPe; leads to: increased GPe activity (GABA), decreased STN nucleus activity (glutamate), decreased GPi activity (GABA), loss of thalamic inhibition, increased thalamic excitatory drive

Question 43

What are the genetic problems of Huntington's?

Answer 43

expanded CAG (polyglutamine) repeats in huntington gene, autosomal dominant neuronal degeneration resulting in death in 10-20 years