Movement Disorders

Question 1

Levodopa (D2) - PD

Answer 1

• enter via LAT (note: dopamine can’t cross BBB)
• decarboxylated to dopamine; 1-3% enters brain unaltered
• rapidly absorbed from SI (peaks at 1-2 hrs; half life 1-3 hrs)
• “wearing off” phenomenon - long term treatment

Question 2

Levodopa + Carbidopa (dopa decarboxylase inhibitor)

Answer 2

• decrease peripheral metabolism
• increase plasma levels
• increase half life
• increase levodopa availability to enter brain
• reduced daily requirement for levodopa by 75%

Question 3

Adverse effects - Levodopa

Answer 3

GI - anorexia, nausea, vomiting (chemo receptor trigger zone in brain stem activated) in 80%
CV - postural hypotension, get HTN with LARGE DOSES (or in combo with MAO inhibitor)
rare - cardiac arrhythmias (inc peripheral catecholamine)
Dyskinesis - choreoathetosis of face + extremities in 80%
Behavior - depression, anxiety, hallucinations, confusion etc.

Question 4

Antipsychotic drugs 
(due to adverse effects of levodopa)

Answer 4

1. Clozapine
2. Olanzepine
3. Quetiapine
4. Risperidone

Question 5

“On-off phenomenon” - levodopa

Answer 5

Fluctuation due to:
1. Timing of day (WEARING OFF phenomenon)
2. Unrelated to dose timing (ON-OFF phenomenon)
Severe OFF periods –> APOMORPHINE

Question 6

Apomorphine

Answer 6

• D2 agonist Rc in caudate/putamen
• give subcutaneously (only one that’s injectable)
• quick/temp relief when experiencing “off” periods
  Adverse effect - nausea, sweating, hypotension, drowsiness

Question 7

If giving Apomorphine, what anti-memetic should you pretreat patient with?

Answer 7

Trimethobenzamide (helps with the adverse effects experienced by Apomorphine)

Question 8

Levodopa contraindications

Answer 8

1. If given with MAO-A inhibitor –> HTN crisis

2. Psychosis, closed-angle glaucoma (OK with open-angle tho), melanoma, peptic ulcer/GI bleed

Question 9

Bromocriptine

Answer 9

• D2 Rc agonist; alkaloid
• used for endocrine disorders too
• high 1st pass metabolism - CYP 3A4
• 28% bioavailability
  Adverse effect - digital vasospasm, peripheral edema, heart arrhythmia; Retroperitoneal fibrosis
  Contraindications - peripheral vascular disease

Question 10

Pramipexole

Answer 10

• D3 Rc agonist
• treats RLS
• 90% excreted unchanged

Question 11

Ropinirole

Answer 11

• D2 Rc agonist
• treats RLS
• metabolized by CYP 1A2 in liver

Question 12

Dopamine agonists - Adverse effects/contraindications

Answer 12

GI - constipation, dyspepsia, vomiting, nausea
CV - postural hypotension,
Dyskinesis - similar to levodopa
Mental - hallucinations, confusion, MORE SEVERE than levodopa
Misc. - headache, nasal congestion, pulmonary infiltration, inc arousal
Contraindications - psychosis, MI, peptic ulcer

Question 13

MAO types

Answer 13

1. MAO-A = metabolizes NE + serotonin
2. MAO-B = metabolizes phenylethylamine + benzylamine
3. MAO-A + MAO-B = dopamine + tryptamine

Question 14

MAO inhibitors

Answer 14

1. Selegiline

2. Rasagiline

Question 15

Selegiline (deprenyl)

Answer 15

• IRREVERSIBLE
• MAO-B inhibition (MAO-A inhibition at HIGH doses)
• slows dopamine breakdown
  Contraindications - meperidine, tricyclic depressants, serotonin reuptake inhibitors (can get serotonin syndrome!!)

Question 16

Rasagiline

Answer 16

• IRREVERSIBLE
• MAO-B inhibition (more potent)
• neuroprotective
• early trt of PD
• BUT combined levodopa and nonselective MAO inhibitor can lead to HTN crisis!!

Question 17

COMT inhibitors

Answer 17

metabolizes levodopa –> 3-O methyldopa
1. Tolcapone (CENTRAL + PERIPHERAL effects) - increase in liver enzyme levels causing hepatotoxicity
2. Entacapone (PERIPHERAL effects only)
Side effects of both- orange discoloration of urine, diarrhea, abdominal pain, sleep disturbances

Question 18

Amantadine

Answer 18

• MOA unknown
• short lived benefits
• used in PD
• livedo reticularis - vascular condition: purplish mottled discoloration of skin (legs usually)
• can cause hallucinations, restlessness, confusion, GI/heart failure

Question 19

mAcH Rc antagonists

Answer 19

Improve tremor/rigidity but little effect on bradykinesia

1. Benztropine
2. Biperden
3. Orphenadrine
4. Procyclidine
5. Trihexyphenidyl

Question 20

Other disorders - Tremor

Answer 20

• Metoprolol, Propranolol: b1
• Primidone: anti-epileptic drug
• Topirimate: serotonin Rc agonist (Broad spectrum drugs)
• Alprazolam: benzodiazepines
• Botulinum toxin A: intramuscular injection

Question 21

Other disorders - Huntington

Answer 21

• GABA, GAD, choline acetyltransferase decreased in basal ganglia
  1. Reserpine - IRRVERSIBLE - block vesicular monoamine transporter/deplete dopa
  2. Tetrabenazine - REVERSIBLE (shorter duration) - block VMT/deplete dopa
  3. Olanzapine
  4. Perphenazine - Phenothiazines
  5. Haloperidol - Butyrophenones
  6. Fluoxetine - depression + irritability
  7. Carbamazepine - depression (generalized onset + partial onset)

Question 22

Other disorders - Tics

Answer 22

1. Antipsychotics - Tetrabenzaine, Haloperidol, Pimozide (cause extrapyramidal syndrome, weight gain)
2. Alpha adrenergic - Clonidine, guanfacine
3. Injection of botulinum toxin A

Question 23

Other disorders: RLS

Answer 23

1. 1st line trt - Pramipexole, Ropinirole

2. Dopamine agonists - correction of coexisting iron deficiency anemia corrects this too

Question 24

Other disorders - ALS

Answer 24

Riluzole - inhibits glutamate, blocks NMDA and kainite-type glut Rc and inhibits VG Na channels

Question 25

Other disorders - Wilson disease

Answer 25

Copper metabolism disorder - dec ceruloplasmin, inc Cu in brain and viscera, hepatic/neurological dysfunction 1. Penicillamine - (chelating) forms complex with Cu --> excreted Adverse effects - nausea, vomiting, nephrotic syndrome, optic neuropathy, blood disorders, myasthenia 2. Potassium disulfide - decrease absorption of Cu (give with 1.) 3. Others - Trientine (chelating), Zinc acetate (fecal excretion of Cu), Zinc sulfate (fecal excretion of Cu)