Pharm - Movement disorders

Question 1

1. Describe the two components of Sinemet and their functions.

Answer 1

Sinemet is a combination of L-dopa (Levodopa) and Carbidopa. L-Dopa is the precursor to Dopamine and will increase synthesis. Carbidopa is a DOPA decarboxylase inhibitor that prevents the metabolism of L-Dopa in the periphery. Carbidopa cannot cross the BBB

Question 2

Give one reason daily doses of L-dopa are decreased over time.

Answer 2

Avoid side effects that are not present when initially taking it. These are due to the reduction of dopaminergic cells, causing an excess of L-dopa to build up.

Question 3

Explain the “on-off phenomenon” and give one treatment for it.

Answer 3

A treat patient with L-dopa exhibits two different adverse signs while on medication. “Off” periods are marked by akinesia (similar to the “wearing off” effect). Whereas “on” periods improved mobility but marked dyskinesia. The treatment for the off periods are treated with SubQ apomorphine (dopamine agonist).

Question 4

4. Give two reasons COMT inhibitors entacapone and tolcapone improve responsiveness to L-dopa.

Answer 4

They decrease metabolism of levodpa in the periphery and decrease the synthesis of 3-O-methlydopa(3OMD) which competes with L-dopa for the same transporter across the BBB

Question 5

5. Give the 3 components of Stalevo.

Answer 5

Stalevo combines levodopa (L-Dopa and carbidopa) with entacapone (peripheral COMT inhibitor)

Question 6

6. Give two advantages of DA agonists over L-dopa.

Answer 6

Dr. Esper said he’d like to prescribe these first

• Do not require the enzymatic conversion
• Have no toxic metabolites (NE metabolite in the periphery that causes cardiovascular effects)
• Do not compete with other substances to actively cross into blood and the BBB
• Have fewer adverse affects:
Lower incidence of response fluctuations and/or dysknesias

Question 7

7. Give two indications for pramipexole.

Answer 7

A specific D3 receptor agonist or a “dopamine agonist.”
Can be used as a monotherapy for mild forms of PD
Can be used as adjunctive therapy with advanced PD to lower L-dopa dosage or smooth out fluctuations.

Question 8

8. Give the specific indication for apomorphine.

Answer 8

Apomorphine is a subQ injection of a potent dopamine agonist. Given because of its quick acting (~10 min) effects on the “off” period of akinesia in patients on dopamine therapy.

Question 9

9. Give the symptoms of PD that improve with treatment with Ach blockers.

Answer 9

Will improve the tremor and rigidity but will have little effect on bradykinesia

Examples are benztropine mesylate, trihexyphenidyl

Question 10

10. Give the class of drugs given for postural tremor and one in this class not to give.

Answer 10

β- blockers can be given to alleviate postural tremor and one example is propranolol. (But not metoprolol a selective β1 receptor inhibitor). The tremor is mediate through activation of β2 receptors

Question 11

11. Give four drugs to be given for essential tremor.

Answer 11

β-blockers:
Propranolol (used with caution with patients with heart failure, heart block, asthma and hypoglycemia)
	Antiepileptics:
Primidone
Topiramate
	Anti-axiety - Benzodiazepine:
Alprazolam

Question 12

12. Give three drugs used to treat Huntington’s Disease.

Answer 12

Dopamine receptor antagonists:
Phenothiazines (perphenazine), Butyrophenones (haloperidol)

Reserpine
 Prevents intraneuronal storage of dopamine
 AE – hypotension, depression, sedation, diarrhea and nasal congestion

Tetrabenzaine
Inhibits monoamine transporter 2 to decrease central monoamines (i.e. dopamine)

Question 13

13. Give the MOA of tetrabenazine and an advantage it has over reserpine.

Answer 13

Dopamine antagonist
1. Inhibits vesicular monoamine transporter 2
1. Depletes central monoamines
2. Precise mechanism of antichorea effects are unknown
Less adverse effects compared to reserpine but patients can become depressed and suicidal

Question 14

14. Give one drug approved for ALS.

Answer 14

Riluzole only drug specifically approved for ALS

Protects motor neurons from toxic effects of excitatory amino acids (inhibits glutamate signaling)

Question 15

15. Explain the inherent difficulty in treating tardive dyskinesia.

Answer 15

Drug induced dyskinesia (from typical antipsychotics). Often trying to treat symptoms by reducing the dopamine receptor blocker often worsens the dyskinesia. You have to use drugs that interfere with dopamine signaling.

Try to switch the patient

Examples: •	Reserpine, tetrabenazine, trihexyphenidyl •	Phenothiazines, butyyophenones (last resort usage)

Question 16

16. Give one drug used to treat restless leg syndrome.

Answer 16

Unpleasant, creeping discomfort that causes the urge to move
Ropinirole a dopamine agonist

Ropinirole can also treat Wilson’s disease

Question 17

1. Describe the dosing regimen for Sinemet.

Answer 17

Doses start small x 3/day (Sinemet is carbidopa 25 mg/ L-dopa 100 mg)
Dose can be increased but can enhance side effects
Keep low and add additional drug therapies
EX: dopamine agonist/additional enzyme inhibitors
The drug Parcopa has been formulated to disintegrate in saliva.

Question 18

2. Give a class of drugs contraindicated with L-dopa and what the combination can cause.

Answer 18

Dopaminergic (dopamine antagonists) anti-emetics are NOT given as they may exacerbate the parkinsonism

 Pyridoxine enhances peripheral breakdown of L-dopa (in absence of carbidopa)
 Monoamine oxidase A inhibitors will increase dopamine levels
 When given at the same time, or within 2 weeks they may initiate a hypertensive crisis.

Question 19

3. Give a surprising population that should be careful with L-dopa treatment and describe why.

Answer 19

• Psychotic patients – exacerbates mental disturbances (remember typical anti-psychotics mostly block DA2 receptors) Dopaminergic dysregulation syndrome.
o Leads to cyclical mood disorders (hypomania/manic), tolerance, and impulse control disorders (hypersexuality and pathological gambling)
• Angle-closure glaucoma (increased IOP)
• History of melanoma/undiagnosed skin lesions
• L-dopa precursor to skin melanin -> malignant melanoma

Question 20

4. Give the indication for selegiline.

Answer 20

a. A selective irreversible inhibitor of MAO-B
b. Minor therapeutic effect when given alone
Prolongs antiparkinsonism effect of L-dopa (allowing for lower doses) for Parkinson

Question 21

5. Give the specific indication for apomorphine.

Answer 21

 SubQ injection – quickly into blood and brain
 Effect seen ~10 min and lasts for ~2 hours
 Potent dopamine agonist
 Temporary relief of off-periods of akinesia in patients on dopamine therapy
 AE – nausea; pretreatment with an antiemetic (trimethobenzamide)