L-Dopa

Mechanism, pharmacokinetics

Mechanism: precursor to dopamine that can be transported across BBB.  Converted to dopamine via L-amino acid decarboxylase->activates dopamine receptors.  Can also be recycled and packaged into vesicles pre-synaptically.  Benefits longer than drug's half-life.  Can treat early Parkinson's really well, but not end-stage.

Pharmacokinetics: rapidly absorbed by small intestine. Amino acids in diet can interfere with absorption. ANS dysfunction->bowel instability ->interfered absorption. Carbidopa increases fraction that passes BBB from 1-3% to 10%. COMT also metabolizes L-dopa - inhibited by entacapone and tolcapone.  Entacapone has no liver toxicity.

1. Increased dopamine ->nausea, vomiting, orthostasis, tachycardia, arrhythmias. Reduced by Carbidopa.
2. Dyskinesias, dystonias - high dose of l-dopa - chorea, athetosis, dystonia, myoclonus - can be relieved by pallidotomy. Occurs mostly in younger patients, patients who've had therapy for >5 years
3. Wearing-off - shorter and shorter L-dopa effectiveness, require higher dose
4. On-off - unpredictable fluctuations between parkinsonian symptoms and dyskinesias - later stages of disease
5. Behavioral disturbances - hallucinations, paranoia, confusion. Treat w/olanzapine.

1. Bromocriptine (D_1-5) and pergolide (D_1,2) - less effective than L-Dopa, less dyskinesias, more hallucinations and confusion. Also cause nausea, vomiting, orthostasis, pulmonary fibrosis, erythromelalgia
2. Pramipexole(D₃) and ropinirole (D₂) - more selective. Less side effects. Dyskinesias, hypotension, confusion, nausea, dizziness, somnolence. Decreases on-off in late-stage.

May affect uptake or release of dopamine, inhibits NMDA. Loses effectiveness in 6-8 weeks.

Restlessness, depression, irritability, confusion.

MAO-B

Selegiline, rasagiline

Selegiline - symptomatic benefit - used in early stages

Rasagiline - early and later stages. Neuroprotective effect and symptomatic benefit.

Help restore balance between cholinergic and dopaminergic systems.

Benztropine, trihexyphenidyl.  Decrease tremor and rigidity

-dry mouth, urinary retention, blurred vision, confusion, hallucinations.

-hyperthermia, delirium in OD