Lecture 37: Drugs of Movement Disorders

Question 1

You disrupt balance of which two NTs in indirect pathway in PD?

Answer 1

ACh and DA

Question 2

Broadly, DA activity is ___-movement. What is ACh?

Answer 2

Pro; anti-movement

Question 3

Broadly, PD drugs do one of which two things?

Answer 3

Enhance DA function or inhibit ACh function

Question 4

At first, PD disease treatment is generally what kind of therapy? Which drugs?

Answer 4

Monotherapy w/ L-DOPA, DA agonist OR MAO-B inhibitor

Question 5

Overtime, what monotherapy becomes most popular? What happens (treatment-wise) next?

Answer 5

L-DOPA; L-DOPA requires supplemental therapy

Question 6

L-DOPA is a ___-drug. Enzyme?

Answer 6

Pro-drug; DOPA decarboxylase

Question 7

Three reasons to not just give DOPA

Answer 7

Low oral bioavailability, significant peripheral effects, poor access to brain

Question 8

What drug is L-DOPA always administered with and why

Answer 8

Carbidopa; peripheral inhibitor of DOPA decarboxylase (fewere systemic effects [hypotension, arrhythmias], more L-DOPA to brain)

Question 9

What is the effect of L-DOPA on the brain?

Answer 9

Increases DA stored in remaining nigrostriatal terminals

Question 10

What symptoms of PD are relieved by L-DOPA

Answer 10

Cardinal motor symptoms (bradykinesia, resting tremor, muscular rigidity, gait/postural impairments)

Question 11

Name the two stages of loss of efficacy of L-DOPA. Which responds to dosing regimen changes?

Answer 11

1. “Wearing-off”; 2. “On-Off” effect; the first

Question 12

Three main CNS SEs of L-DOPA

Answer 12

Dyskinesias (choreoathetoid), psychiatric changes (anxiety, hallucinations, insomnia), N/V

Question 13

Recent study demonstrated what about L-DOPA?

Answer 13

Initial treatment with L-DOPA was superior to L-DOPA sparing

Question 14

When do clinicians use direct DA agonists? (2)

Answer 14

Monotherapy early in disease and as adjunct to L-DOPA + carbidopa

Question 15

Why do direct DA agonists work as adjuct therapy to L-DOPA?

Answer 15

Decrease dose, smooth out loss of efficacy fluctuations

Question 16

Two key DA agonists and their mechanism

Answer 16

Pramipexole and Ropinirole; selective D2 receptor agonist (D2&raquo_space;> D1)

Question 17

How do the SEs compare between direct DA agonists and L-DOPA?

Answer 17

Greater central effects (like impulse control disorder), similar peripheral effects

Question 18

Use of Apomorphine

Answer 18

Used as rescue drug to terminate off periods during L-DOPA therapy

Question 19

Mechanism of Apomorphine; what is a serious SE?

Answer 19

Non-selective agonist at most DA receptors; emetic (causes vomiting)

Question 20

Mechanism of MAO-B inhibitors

Answer 20

Reduce degradation of DA by MAO-B (specific to DA), irreversible inhibitor

Question 21

What is a serious concern about MAO inhibitors?

Answer 21

Interact with drugs and foods –> tyramine, resulting in hypertensive crisis (due to cross MAO-A inhibition) and can cause serotonin syndrome if given with other drugs (meperidine or SSRIs)

Question 22

Two MAO-B inhibitors

Answer 22

Selegiline and Rasagiline

Question 23

What’s important to remember about selegiline?

Answer 23

Metabolits = meth/amphetamine so it can cause anxiety and insomnia

Question 24

What are the benefits of rasagline? (3)

Answer 24

1. More selective for MAO-B; 2. Effective as a monotheraphy early on; 3. No amphetamine metabolites

Question 25

What is the mechanism of Entacapone? What is side effect?

Answer 25

Doubles t1/2 of L-DOPA in plasma via COMT inhibition; diarrhea

Question 26

Amantadine is what kind of drug normally? Describe PD treatment. SEs are mainly…

Answer 26

Anti-viral; controls mild symptoms and motor SEs of L-DOPA; psychiatric

Question 27

What role does ACh play in the striatum?

Answer 27

Provides excitatory tone to MSNs in indirect pathway via muscarinic receptors –> reduced thalamic drive to cortex (opposite of DA effect on D2 receptors)

Question 28

Name an anticholinergic used for PDs and describe its beneficial mechanism

Answer 28

Trihexyphenidyl; high ratio of central to peripheral antimuscarinic activity

Question 29

Trihexyphenidyl is best for treating what PD symptom? What SEs are significant?

Answer 29

Tremor; CNS SEs = confusion, sedation…

Question 30

How does Tetrabenazine work?

Answer 30

Catecholamine depleter –> reduces DA activity in straiatum to reduce excitatory thalamcortical drive

Question 31

What does Tetrabenazine do? SEs?

Answer 31

Improves HD motor symptoms; SEs = depression, suicidal ideation, hypotension

Question 32

What is the goal of treatment for anti-spasticity drugs?

Answer 32

Reduce excitatory output from spinal MNS

Question 33

Four drugs that treat spasticity and their mechanisms

Answer 33

1. Botulinum toxin (most effective, interferes w/ ACh release); 2. Dantrolene (interferes w/ Ca2+ release from SR, also for malignant hypothermia); 3. Baclofen (GABA-B agonist, dampens CST input to motor neurons via direct inhibition); 4. Tizanidine (alpha-2 agonist, inhibits MNs through inhibition of corticospinal inputs)

Question 34

Which two spasticity drugs act on the CNS? How about peripherally?

Answer 34

Baclofen and Tizanidine; Botulinum toxin and Dantrolene