Pharmacology Movement disorder - Parkinson Dr. Pond

Question 1

Characteristics of Parkinson

Answer 1

Combination of
-ridigity
-brdaykenisia
-resting tremor (when they are at rest)
-postural instability

Question 2

Which group of structures controls the body’s ability to move?

Answer 2

Basal ganglia

Question 3

What are the structures within the Basal ganglia

Answer 3

-Striatum:
caudate nucleus
putamen

-globus pallidus
internal and external part

-subthalamic nucleus (nucleus right below the thalamus)

-the substantia nigra
reticular part (SNr)
compact part )SNc)

Question 4

What is the relation between the substantia nigra and the striatum?

Answer 4

The axon terminal of dopamine neurons of the substantia nigra (pigmented) project to the striatum

Motor function ->the death of these neurons results in PD!

Nigrostriatal pathway: substantial nigra to caudate-putanem

Question 5

Which abilities are affected by the impairement of the mesolimbic and mesocortical pathways?

Answer 5

Memory
Motivation
Reward and desire
Addiction
Cognition

Question 6

Which pathway regulates the release of prolactin?

Answer 6

Dopmain release in the Tuberoinfundibular pathway

Question 7

Which dopamine receptors are involved in the Nigrostriatal pathway?

Answer 7

D1 receptor: excitatory (increasing cAMP)

D2 receptor: inhibitory (decrases cAMP)

Question 8

Which of the D receptors facilitates or inhibits movement?

Answer 8

D1 receptor: facilitates movement -> direct pathway (inhibits an inhibitory neuron by activating GABA)

D2 receptor: inhibits movement -> indirect pathway

->if the dopamine release from the substantial nigra is impaired -> we lose the stimulatory and inhibotry pathways -> missregulation of movement in PD (bradykaneisa)

Question 9

Benefit of Sinemet

Answer 9

Sinemet (L-Dopa + Carbidopa)

L-Dopa is converted to Dopamine via the dopa decarboxylase (causing side effects in the periphery)

Carbidopa is a peripheral dopa decarboxylase inhibitor -> so less L-Dopa will be present in the peripheral (toxic) -> we can give a lower dose with Sinemet

Question 10

Why don’t we use Dopamine as a drug?

Answer 10

It doesnt cross the BBB
L-Dopa does

Question 11

ADE of peripheral toxictiy of L-Dopa

Answer 11

-orthostatic hypotension
-arrhythmias
-nausea and vomiting

Question 12

Other ADEs of L-Dopa

Answer 12

Psychotic disorder: Anxiety, agitation, insomnia, hallucinations, delusions, nightmares, mood changes

-dyskinesias (too much dopamine in the nigrostatial pathway)
-compulsive behavior

Question 13

What is a significant side effect we see after long-term use of L-dopa/carbidopa

Answer 13

Wear-off effect

-predictable fluctuation of motor function
-> Increase frequency of dosing

Question 14

What represents the end-stage of L-Dopa therapy

Answer 14

On-Off phenomen

-severe, unpredictable fluctuations in motor function
-> Normal function (on) and akinesia/bradykinesia (off)

-> dyskinesia (involuntary movements) during on-period

Question 15

What is the susbtrate and product of COMT?

Answer 15

COMT converts L-Dopa (substrate) to 3-O-methyldopa

-since the dopa-decarboxlyase is inhibited with L-dopa/carbidopa -> there is more L-dopa available -> the body compensates by increasing the peripheral COMT activity

Question 16

Which drug is known to be a COMT-inhibitor?

Answer 16

-Tolcapone
-opicapone
-entacapone

doubles the half-life of L-Dopa -> more access to CNS
->limits fluctuation in L-Dopa

Question 17

Which of the COMT inhibtors dont cross the BBB?

Answer 17

opicapone
entacapone

Question 18

Which drug contains levodopa + carbidopa + entacapone and what is its side effect?

Answer 18

-Stalevo

-higher risk of dyskinisia
-also nausea, confusion, diarrhea, fatigue, drowsiness, hallucinations

-discoloration of urine - may be seen with levodopa

Question 19

Which receptors contribute to the indirect “STOP” pathway inhibiting movement controlled by the motor cortex?

Answer 19

Adenosine receptors (A(2A))

Question 20

Which drug is used to combat higher levels of adenosine receptors in the basal ganglia?

Answer 20

-Istradefylline (Adenosine receptor antagonist)

ADE: Dyskinesias; constipation and nausea;
dizziness, insomnia; abnormal behaviors, hallucinations,
delusions, impulse control disorder

Question 21

What is the role of Monoamine oxidase and MOA-inhibitors?

Answer 21

Monoamine oxidase causes intracellular degradation of Monoamines

MOA-A: degrade NE and 5-HT
MOA-B: degrades Dopamine

MOA-B inhibitor: will increase the level of dopamine in the neuron -> recycled -> counteracts the PD

Question 22

Cheese effect DDI with MAO-inhibitors

Answer 22

hypertensive crisis resulting from interaction
with sympathomimetic agents
-> less seen with MAO-B inhibitors

Question 23

DDI with MAO inhibitors - Serotonin syndrome

Answer 23

Caution when using: SSRIs, TCA, other MAO inhibitors

hyperthermia, rigidity, myoclonus (muscle jerks),
mental and vital sign changes, seizures, coma with 5-HT drugs

Question 24

DDI with MAO inhibitors and Dextromethorphan

Answer 24

psychosis, bizarre behavior

Question 25

DDI with MAO inhibitors and opioids

Answer 25

potentiate CNS/respiratory depression

Question 26

Which drug is a reversible MAO-B inhibitor?

Answer 26

-Safinamide

-Add on treatment for patients experiencing “off” episodes

Question 27

MOA Dopamine agonists

Answer 27

-mimics the effect of dopamine

-Pramipexole (D3 agonist)
-Ropinirole (D2 agonist)
-Rotigotine (D3, D2, D1 agonist)
-> newer agents with less side effects

-Apomorphine - helpful in “off-periods”

Question 28

Muscarinic receptor antagonists

Answer 28

-Benztropine
-trihexyphenidyl

ACh neuron causing overaction of the GABA neuron in the nigrostriatal pathway
-> blocking the muscarinic receptor

treats the tremor and rigidity better than bradykinesia

ADE: dry mouth, flush, increased heart rate, dilated pupils, constipation, urinary retention, delirium

Question 29

MOA of Amantadine

Answer 29

not fully understood

-influences levels of dopamine in the synapsis
-may increase D2 receptor expression

Question 30

What determines if someone carries Huntington’s disease?

Answer 30

more than 36 glutamine residues on a gene on the Chromosome 4
-> production of an abnormal protein

Question 31

Which structures of the brain are involevd in Huntington’s disease?

Answer 31

degeneartion of neurons within

-striatum (movement) -> dyskinesia (chorea - dance uncontrolled)
-cortex (thought, perception, memory)

Question 32

MOA of Reserpine and tetrabenazine

Answer 32

in the disease, GABA neurons are degenerated
-> so we want to inhibit dopamine neurons that inhibit the remaining GABA neurons

-depletion of dopamine and other monoamines by preventing interneural storage - blocking vMAT -> so dopamine doesn’t get into vesicles but stays in the cytosol -> and will be degraded by MAO-B (mitochondria)

-may also use dopamine receptor antagonists or BZ

Question 33

What is the BBW for tetrabenazine?

Answer 33

Depression and suicidal thoughts

-> since all monoamides (dopamine, NE, serotonin) are depleted it causes severe depression, may also cause Parkinson due depleting dopamine

Question 34

Drugs indicated for Restless leg syndrome

Answer 34

-dopamine agonists: Ropinirole, Rotigotine

-levadopa

-GABA enhancing drugs

-Gabapentin

-opioids

-iron supplementation may work - there is a link between patients with iron deficiency and anemia and having the symptomes