5. Drugs for Movement Disorders

Question 1

GO TO DRUGS

Answer 1

1. Levodopa
2. Carbidopa
3. Levodopa + carbidopa

Question 2

Dopamine R AGO

Answer 2

1. Apomorphine
2. Bromocriptine
3. Pramipexole
4. Ropinirole

Question 3

MAO-I

Answer 3

1. Rasagiline
2. Selegiline
3. Safinamide

Question 4

Catechol-O-methyltransferase inhibitors

Answer 4

COMT breaks down Levodopa => 3-O methyldopa, which competes for Levodopa for transport ancross the intestinal mucosa and BBB. COMT-I prevent metabolism of Levodopa=> prolong activity of Levodopa => ⬆︎ bioavailability and ⬇︎ clearance.

1. Entacapone
2. Tolcapone

Question 5

Anticholinergic drugs (5)

Answer 5

Central-acting mAChR ANT => improve tremor and rigidity in those with PD, but l_ittle effect on Bradykinesia._

• 1. Benztropine
• 2. Biperiden
• 3. Orphenadrine
• 4. Procyclidine
• 5. Trihexyphenidyl

Question 6

Miscellaneous Drugs for Movement Disorders

Answer 6

1. Riluzole
2. Reserpine
3. Tetrabenazine

Question 7

Pathological Hallmark of Parkinsons Disease

Answer 7

1. Loss of pigmented, dopaminergic neurons in the substantia nigra
2. Lewy bodies (intracellular inclusions)

Question 8

How does our brain regulate movement?

Answer 8

1. CTX sends messages to the Basal Ganglia, specifically the key processing center, the striatum (caudate + putamen).
2. Striatum then sends [stimulatory/inhibitory messages] to CTX.
3. However, dopaminergic neurons in the SNPc (Substantia Nigra Pars Compacta) release DA and inhibit GABAergic output in the striatum via the nigrostriatal pathway.

Question 9

Under normal conditions, dopaminergic neurons in the substantia nigra inhibit the GABAergic output from the _________

Answer 9

Striatum

Question 10

_______ neurons excite GABAergic neurons of the striatum.

Answer 10

Cholinergic

Question 11

What is the problem in Parkinsons?

Answer 11

KO if DA neurons in the SNPc ➜ GABAeric neurons not inhibited ➜

↑ inhibition to the CTX ➜ movement disorders

Question 12

Based on the pathology, how do we treat those with PD?

Answer 12

1. DA AGO
2. Anticholinergic agents

Question 13

Levodopa (L-Dopa)

1. What is Levodopa?
2. MOA?
3. Use?
4. Absorption?

Answer 13

1. Immediate metabolic precursor to DA that crosses the BBB (DA does NOT cross BBB)
2. Dopamine AGO
3. PD, does not stop progression but ⬇︎ mortality.
4. Taken orally and peaks in plasma after 1-2 hours. Only 1-3% enters the brain unaltered. Thus, it is taken with Carbidopa (DOPA decarboxylase inhibitor), which does not cross the BBB and ⬇︎ peripheral metabolism ➜ ⬆︎plasma levels, 1/2 life, and Levodopa that reaches the brain and ⬇︎ the daily requirement for Levodopa.

Question 14

In order to ⬇︎ peripheral metabolism of Levodopa and ⬆︎ the amount that reaches the brain, what is taken with it?

Answer 14

Levodopa + Carbidopa

Question 15

What kind of drug is Carbidopa?

Answer 15

DOPA decarboxylase inhibitor

Question 16

How does Levodopa + Carbidopa alter the symptoms, compared to Levodopa alone?

Answer 16

• Significantly ⬇︎ the adverse peripheral effects of: nausea, vomiting, and postural hypotension!
• But may ⬆︎ the adverse behavioral effects

Question 17

Levodopa SE?

Answer 17

1. GI symptoms:
   
   1. Levodopa alone (80% of pts): anorexia, N/V
   2. Levodopa + Carbidopa: ⬇︎ SE
2. CV effects
   
   1. Postural hypotension at first, but ⬇︎ with use.
   2. If take large amounts with MOA-I or sympathomimetics: Hypertension
3. Dyskinesias
   
   1. ​Choreoathetosis (80% of pts): movement of intermediate speed of face and distal extrememties
4. Behavioral effects

Question 18

When does using Levodopa produce the BEST results and why?

Answer 18

• First few years of using
• Long-term usage => “wearing-off phenomenon”: every does only proves sx for 1-2 hours, but rigidity and akinesia rapidly return. Increasing the dose and frequency is not the best idea bc ⬆︎ dyskinesias

Question 19

What is the “on-off phenomenon” associated with Levodopa?

Answer 19

• Off-periods (not taking drug) = marked akinesia alternate over the course of a few hours
• On-periods = improved mobility but often marked dyskinesia

Question 20

What drug and via what route, may provide temporary benefit to those patients with severe off-periods while taking Levodopa?

Answer 20

SQ injection of Apomorphine: ⬇︎ akinesia

Question 21

Levodopa CI

Answer 21

1. MAO-I (or within 2 weeks of DQ): HTN crisis
2. Psychotic patients
3. Close-angle glaucoma
4. Melanoma and undiagnosed skin lesions
5. Active peptic ulcer => GI bleeding

Question 22

Why are Dopamine-R AGO preferred over Levodopa?

Except in who?

Answer 22

• ⬇︎ response flucations and ⬇︎ dyskinesias that occur with long-term usage of Levodopa
• Dont respond well to Levodopa = dont respond well to DA-R AGO.

Question 23

How are DA-R AGO given?

Answer 23

• Alone
• + levodopa + carbidopa
• In patients taking Levodopa and who have end-of-dose akinesia or on-off phenonemon.

Question 24

Which DA-Receptor AGO is an D2-R AGO and ergot alkaloid derivative?

• Name its other uses
• Metabolism
• Peak concentration and 1/2 life

Answer 24

• Bromocriptine
• Treats = endocrine disorders (hyperprolactinemia, prolactin-secreting adenoma, acromegaly)
• Metabolized by: CYP3A4
• Peak concentration: 1-3 hours
• 1/2 life = 15 hours

Question 25

**_Ropinirole_** 1. MOA 2. Name other uses 3. Metabolism

Answer 25

1. **D2-R AGO** 2. **RLS** 3. **CYP450 (CYP1A2)**

Question 26

Which DA-Receptor AGO has preferential affinity for **D3 receptors?** ## Footnote - Name other uses - How is it excreted?

Answer 26

**_Pramipexole_** * - **Treats**: Restless Leg Syndrome (RLS) * - **90% excreted by kidney**; so adjust dose if kidney problems.

Question 27

**_DA-R AGO_** ## Footnote **Side Effects**

Answer 27

1. **GI:** 1. anorexia, N/V (decrease if taken with meals), constipations, dyspepis 2. **CV:** 1. Postural HTN at first. 2. Digital vasospam with long term use 3. If develops peripheral edema/cardiac arrhythmias = DQ 3. **Dyskinesias**: reverse by ⬇︎ total dose 4. **Mental disturbances**: confusion, hallucination, psych reactions that are MORE severe than Levodopa

Question 28

**_DA-R AGO_** ## Footnote **Contraindications**

Answer 28

1. **Psychotic patients** 2. **Active peptic ulcer** 3. **Recent MI** 4. **Periperal vascular disease (vasoconstricting effects)**

Question 29

What is the difference between **MAO-A** and **MAO-B?** ## Footnote **Similarities?**

Answer 29

* **MAO-A:** breaks down **NE** and **5HT** * **MAO-B:** breaks down **phenylethylamine** and **benzylamine** * **Both equally break down Dopamine** and **Tryptamine.**

Question 30

**_Selegiline_** * Type of drug * MOA * Uses

Answer 30

* **Selective MOA-B inhibitor,** but non-selective at high doses. * **MAO-B-I**; slows down the breakdown of DA * Uses * 1. Prolongs antiparkinsonian effects of levodopa * 2. Reduce on-off/wearing-off phenomenom * 3. Adjunct to ppl not responding well to Levodopa

Question 31

**_Selegiline_** * CI

Answer 31

* CI in ppl taking * **1. Meperidine** * **2. TCAs** * **3. SSRIs** * bc increase risk of **serotonin syndrome**

Question 32

What drugs act similar to **Selegiline**?

Answer 32

1. **Rasagiline** 2. **Safinamide**

Question 33

What drug should not be taken with **nonselective MAO-I?**

Answer 33

Levodopa + non-selective MAO-I = **_NO_** **_=\>_** **HTN crisis**

Question 34

**_COMT-I_** 1. Use 2. How are the two COMT-I different? 3. SE?

Answer 34

1. Pts taking Levodopa who have developed **response fluctuations** 2. **Tolcapone =\>** central and peripheral acting; **Entacapone =\>** peripheral acting only. 3. SE are **mostly due to Levodopa**, but can cause 1. Yellow pee 2. Diarrhea/ Abdominal pain 3. Sleep problems

Question 35

**_Apomorphine_** 1. MOA 2. Use 3. AE

Answer 35

1. MOA: **D2-R AGO** 2. Use: **SQ injection for quick, temporary relief of off-periods of akinesia in patients that take DA ➜ works in 10 minutes** 3. AE= **Nausea**, dyskinesias, drowsiness, hypotension

Question 36

What can be used to prevent **nasuea** that **Apomorphine** causes?

Answer 36

**Trimethobenzamide**

Question 37

**AE** of **Anticholinergic Drugs** (mAChR ANT) used to treat PD (tremor and rigity)

Answer 37

1. **Sedation** 2. **Confusion** 3. **Constipation/urinary retention** 4. **Blurred vision**

Question 38

What drugs are good for **tremors**?

Answer 38

_B1-R blockers_ 1. **Metaprolol** 2. **Propanolol** _Antiepileptic drugs_ 1. **Primidone** _Other_ 1. **Topirimate** = 5HT AGO 2. **Alprazolam** = benzo 3. **Botulinum toxin A (IM injections)**

Question 39

What drugs are good to alleviate **chorea** seen in **Huntingtons Disease?**

Answer 39

Drugs that **impair** dopaminergic neurotransmission 1. **Reserpine** 2. **Tetrabenazine**

Question 40

What drug/class is the **most predictive and effective** pharmacologic approach for treating **Tics**? **Adverse effects**?

Answer 40

* - Neuroleptic antipsychotics: **pimozide** * - Cause **extrapyramidal syndromes,** **WG**, **sedation**, **irritability**, and various phobias

Question 41

Which drugs are effective in the treatment of **Tics** and have **less adverse effects?**

Answer 41

**- α-adrenergic agents**: _clonidine_ and _guanfacine_ - Injection of **botulinum toxin A** at tic site is beneficial in some cases

Question 42

Symptoms are **Restless Leg Syndrome** may resolve with correction of which co-existing deficiency?

Answer 42

**Iron-deficiency anemia**

Question 43

Which drug is the **only drug** to have any impact on survival in **ALS** and may **prolong survival by a few months?** **- MOA** and **AE?**

Answer 43

**_Riluzole_** 1. **Inhibits glutamate release** and **blocks postsynaptic NMDA- and kainite-type glutamate receptors** 2. **Inhibits VGNa+ channels** * - Adverse effects: **nausea** and **weakness**

Question 44

Which drugs may be used in the treatment of **Wilson disease?** How does each drug work?

Answer 44

* **Penicillamine**, * **Potassium Disulfide**, * **Trientine, Zinc acetate, Zink sulfate** 1. **Penicillamine**: chelating agent, forms stable complex w/ copper and is readily excreted by kidney 2. **Potassium disulfide:** reduces intestinal absorption of copper 3. **Trientine (chelating agent); zinc acetate** and **zinc sulfate** (increase fecal excretion of copper by decreasing GI absorption)