Lec 36 Drugs for Movement Disorders

Question 1

What is the pathophysiology of parkinsons?

Answer 1

• substantia nigra degenerates –> striatum deprived of dopamine input
• causes less excitation of direct path and less inhibition of indirect path
• this leads to greater activity of GPi –> more inhibition of thalamus sending info to corte

Question 2

What are the direct and indirect paths via which dopamine from substantia nigra effects globus pallidus interna [GPi] inhibition of thalamus

Answer 2

direct:
substantia nigra DA –> activate striatum GABA –> inhibit GPi

indirect:
substantia nigra DA –> inhibits striatum GABA –> which is inhibiting GPe –> which is inhibiting STN –> activates GPi

thus if you increase direct path you get inhibition of GPi

if you increase indirect path you get excitation of GPi

Question 3

What are roles of ACh vs DA in the path from striatum to thalamus? the balance in parkinsons?

Answer 3

more ACh = more inhibition of thalamus
more DA = less inhibition of thalamus

–> in parkinsons more ACh than DA = imbalance –> more inhibition of thalamus

Question 4

Why administer L-dopa instead of dopamine itself?

Answer 4

• dopamine has poor access to brain from periphery, not good at crossing BBB

Question 5

What are the two enzymes that act on L-Dopa in the periphery?

Answer 5

COMT –> product is inactive

DOPA decarboxylase –> product is dopamine

Question 6

What is side effect of dopamine?

Answer 6

arrhythmias

after long term us: dyskinesia after dose + akinesia between doses

Question 7

What is reason for giving carbidopa with Ldopa?

Answer 7

decrease systemic conversion of L-dopa to dopamine –> increase bioavailability of L-dopa in brain

Question 8

What is MAO-B? where is it found?

Answer 8

• metabolizes DA but not NE or 5HT
• predominant isoform in striatum

vs MAO-A metabolizes DA, NE, and 5HT

Question 9

What is effect of COMT inhibitors?

Answer 9

• give as adjunct to LDOPA to decrease response fluctuations

- inhibits COMT in periphery and CNS

Question 10

Which drugs can induce parkinsonism?

Answer 10

• antipsychotics [paticularly older tones that strongly block D2]
• MPTP poisoning = contaminant of designer opioid MPPP

Question 11

What is the first aid mneumonic for parkinsons treatment?

Answer 11

BALSA

• bromocriptine [DA agonist]
• amantadine [increase DA]
• levodopa
• selegiline [and COMT inhibitors]
• Antimuscarinics [benzotropine = park your benz]

Question 12

WHat is action of cholinergic interneurons of striatum in PD?

Answer 12

• provide excitatory tone to indirect pathway via muscarinic receptors –> reduced thalamic drive, opposite to inhibitory effect of DA on D2 receptors

Question 13

What treatments for the non-motor symptoms of PD?

Answer 13

• central acting anticholinesterases for dementia
• antidepressants
• anxiolytics

Question 14

What is pathophysiology of huntingtons?

Answer 14

• degeneration of striatum
• cholinergic interneurons die off
• indirect path to thalamuc more affected than direct
• excessive excitatory to cortex
• -> chorea

Question 15

What is spasticity?

Answer 15

excessive resting tone of skeletal muscle

• exaggerated stretch reflex response
• due to abnormal function spinal cord or higher CNS center