PARKINSON'S DISEASE

1. Levodopa is a dopamine precursor and enhances dopaminergic transmission
2. Carbidopa potentiates the levodopa and reduces some side effects
3. More effective than dopamine agonists for controlling badykinesia and rigidity
4. However, duration of action is short (t-1/2 = 2h) and there is an "on-off" effect; this tends to worsen with prolonged use with progressive loss of dopaminergic neurons
5. Dyskinesias and dystonias can be seen with long-term use
6. Effect of levodopa/carbidopa on disease progression in Parkinson's
   1. 361 pts with early Parkinson's randomized to levodopa/carbidopa 50-200/12.5-50 TID vs. placebo x 40wks; at 42wks, standardized measures of Parkinson's severity, all active-tx groups had sig. less deterioration than the placebo groups (NEJM 351:2498, 2004--JW)
7. Absorption of levodopa can be adversely affected by Helicobacter Pylori infection of the upper GI tract, including subclinical infection.
   1. In a study in 34 pts with Parkinson's, motor fluctuations on levodopa, and endoscopy-confirmed H. pylori infection randomized to anti-H. pylori anitibiotic therapy vs. no tx, a sig. greater proportion of the active-tx group had clinical improvement (prologation of clinical response to levodopa) at 3mos. 

1. Don't affect the altered postural reflexes of Parkinson's
2. Less risk of "on-off" effect and dyskinesias than levodopa
3. Often used in combination with levodopa
4. Lack of response to one agent doesn't preclude response to another in the same class
5. Can cause confusion and hallucinations, particularly in pts > 65yo
6. Can cause edema
7. Specific agents
   1. Ropinirole (Requip) .75-3mg/d divided TID; can cause sudden somnolence
   2. Pramipexole (Mirapex) 1.5-4.5mg/d divided TID; can cause sudden somnolence
   3. Pergolide (Permax) 0.5-1.5mg/d divided TID; higher incidence of adverse effects than pramipexole and ropinirole (including retroperitoneal, pleural, and pericardial fibrosis; also possibly pulmonary hypertension and restrictive cardiac valvular disease; faster onset of action than bromocriptine
   4. Bromocriptine (Parlodel) 15-40mg/d divided BID; higher incidence of adverse effects than pramipexole and ropinirole

1. COMT metabolizes levodopa
2. Used ONLY as adjuncts to levodopa (no clinical effect w/o it) to reduce "on-off" fluctuations
3. May increase dyskinesias from levodopa and also nausea and somnolence
4. Specific agents
   1. Entacapone (Comtan) 200mg with each dose of levodopa
      1. Entacapone + levodopa/carbidopa is marketed as "Stalevo" in the US; has different doses of levodopa/carbidopa combined with 200mg entacapone.
   2. Tolcapone (Tasmar) 100-200mg TID; lower potency but longer duration of action than entacapone; may cause hepatotoxicity

1. Selegiline (Eldepryl) 5mg PO QD-BID or transdermal 6-12mg/24h
2. Rasagiline (Azilect) 0.5-1mg QD
3. Inhibits dopamine breakdown, thus prolonging action of levodopa
4. May increase dyskinesias from levodopa
5. In a meta-analysis of 17 randomized trials involving 3,525 pts, comparing an MAO-B inhibitor vs.placebo, levodopa, or both, no sig. diff. was found in mortality with MAOBIs vs. placebo; MAOBIs were ass'd with sig. better Parkinson's disease rating scales at 3mos c/w placebo (BMJ 329:593, 2004--JW)

1. Generally used as adjunts in early stages, to minimize tremor
2. May increase eventual risk of dementia
3. Can cause adverse cognitive and cardiovascular effects in elderly patients
4. Benztropine, ethopropazine, trihexylphenidyl

1. Mild anticholinergic
2. May reduce dyskinesia and tremor

1. Mildly effective for motor sx
2. Can also minimize drooling because of reduced salivary production

III. Choice of medications for Parkinson's

1. A systematic review in 2005 found no compelling evidence of an advantage of one medication regimen over another when initiating treatment early in the disease, but evidence that all improved symptoms and quality of life.

IV. Other treatments for Parkinson's:

1. High-frequency low-voltage epidural stimulation over motor cortex has shown promise in animal models of Parkinson's (Neuron 44:769, 2004--JW)
2. Deep brain stimulation
   1. High-frequency continuous electrical stimulation to subthalamic nucleus--In one randomized trial in 156 pts with advanced Parkinson's and severe motor sx, receipt of this treatment (vs. medication only) was associated with sig. greater symptomatic and functional improvement at 6mos (NEJM 355:896, 2006--JW)
   2.  

V. Medications for Parkinson's-associated dementias

1. Rivastigmine
   1. 541 pts with Parkinson's-associated dementia randomized to rivastigmine vs. placebo; after 24wks, mean improvement in cognitive function scores was sig. greater in the active-treatment group (NEJM 35:2509, 2004--JW)