Drugs for Parkinson's

Question 1

Three cardinal features of Parkinson’s

Answer 1

tremor
rigidity
akinesia (bradykinesia)

Question 2

Increased risk of Park

Answer 2

• age (1% of ppl over 60)
• genetic (esp for younger): alpha synuclein aa mutation–>AD form
• drink well water, work with pesticides or metals like iron and copper have higher risk
• lower risk if drink coffee and tea
• lower risk for smokers

Question 3

Final common pathology of Park

Answer 3

destruction of DA cells in pars compacta of Substantia Nigra

and loss of NT DA in caudate and putamen

Question 4

Metabolism of DA

Answer 4

synth: tyrosine –(TH)–>L-DOPA–(DDC)–>Dopamine

Breakdown:
DA–(MAO)–>DOPAC–(COMT)–>HVA

Question 5

Most important drug for treating Park

Answer 5

L-DOPA (500-1500 mg): crosses BBB and converted to DA by aromatic L-amino acid decarboxylase in surviving DA nerve terminals.
(combine with peripheral decarboxylase inhibitor carbidopa (250mg, doesn’t cross BBB) to reduce dosage of L-DOPA)
Ex of combo: Sinemet

SE: GI; dyskinesia @ peak blood levels (long term); psychosis, nausea, hypotension, depression

Question 6

Dopamine receptor agonists

Answer 6

• direct stim of caudate and putamen DA recep
• most are D2 dopamine receptor agonists
• developed for longer half lives to blunt on/off L-DOPA response
• often started at diagnosis to delay need for L-DOPA

a. Bromocriptine (Parlodel), dose 2-60 mg/day
b. Pergolide (Permax), dose 0.25 to 3 mg/day–>OFF MARKET (heart valve defects)
c. Pramipexole (Mirapex), D2 + D3 agonist, dose 1-5 mg/day
d. Ropinirole (Requip), D2 agonist, dose 0.5-10 mg/day
e. Cabergoline (Dostinex), D2 agonist, very long half-life, approximately 65 hours.
Dose 0.5-2mg/week.

Question 7

Dopamine Receptor Agonist Toxicity

Answer 7

nausea, hallucinations, sudden onset of sleep,

*eventually nearly all need L-DOPA

Question 8

Drugs that extend L-DOPA

Answer 8

Carbidopa (blocks DOPA decarboxylase in int, liver, others, delivers 90% to brain; 10-25 mg w/ each 100mg L-DOPA

MAO inhibitor–blocks breakdown of DA : Selegiline (eldepryl) 10mg/d
SE: worse postural hypotension
(Rasagiline)

COMT inhibitors: blocks metabolism of L-DOPA and DA

Question 9

COMT inhibitors

Answer 9

blocks metabolism of L-DOPA and DA:

Tolcapone(300-600 mg/d)
–>hepatotox in some

Entacapone (Comtan) 200mg w/ each dose of L-DOPA/Carbidopa

Question 10

MAOIs

Answer 10

Selegiline

Rasagiline

Question 11

Anticholinergics

Answer 11

less effective than L-DOPA
-sometimes initial therapy for tremor.
(dopamine is inhibitory to cholinergic interneurons onto medium spiny neurons that project to GP)
-these block muscarinic receptors
-SE: dry mouth, constip, urinary retention

a. Trihexyphenidyl (Artane) Dose 2-8 mg/day
b. Benztropine (Cogentin) Dose 1-2 mg/day
c. Diphenhydramine (Benadryl) Dose 75-200 mg/day

Question 12

Amantadine

Answer 12

• beneficial effects discovered when Park pts took it for flu sx
• uncertain mech
• facilitate release of endogenous DA
• Glutamate antagonist

Question 13

Surgical therapy for Park

Answer 13

Thalamotomy: relieves tremor
Pallidotomy: relieves drug-induced dyskinesias
DBS-reversible thalamotomy or pallidotomy (thal, internal pallidum, STN)
Fetal DA cell transplantation

?stem cells.

Question 14

Pathway pic

Answer 14

(phone)