Levodopa is standard, and often initial, therapy for patients with Parkinson's disease; however, with continued treatment and as the disease progresses, up to 80% of patients experience wearing-off symptoms, dyskinesias and other motor complications.
These Levodopa-associated problems may become disabling and profoundly affect quality of life.
Medications commonly used to manage these symptoms include MAO-B inhibitors, COMT inhibitors, the NMDA receptor antagonist Amantadine and dopamine receptor agonists.

Agents that block MAO-B, such as Rasagiline ( Azilect ) and Selegiline ( Eldepryl ), are used as both initial and adjunctive therapy in patients with Parkinson's disease.
These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase on time and improve symptoms of Parkinson's disease.
Adverse events with these agents can include confusion, hallucination and orthostatic hypotension.
MAO-B inhibition may elicit drug-drug interactions if administered with tricyclic antidepressants, selective serotonin reuptake inhibitors ( SSRIs ) or serotonin and norepinephrine reuptake inhibitors ( SNRIs ).
Conventional oral Selegiline is associated with potentially harmful plasma concentrations of three major amfetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet ( ODT ) Selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral Selegiline.

COMT mediates peripheral catabolism of Levodopa. Therefore, agents that block COMT, such as Tolcapone ( Tasmar ) and Entacapone ( Comtan ), increase the elimination half-life of Levodopa. Given adjunctively with Levodopa, COMT inhibitors can decrease off time and increase on time, as well as lower the daily Levodopa dose.
Although more potent than Entacapone, Tolcapone requires monitoring for hepatotoxicity.

Amantadine ( Symmetrel ) is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with Levodopa.

Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease off time purportedly through direct stimulation of dopamine receptors.
Current dopamine agonists include Bromocriptine ( Parlodel ), Pergolide ( Permax ), Cabergoline ( Cabaser ), Lisuride ( Dopergin / Revanil ), Apomorphine ( Apokyn ), Pramipexole ( Mirapex ), Ropinirole ( Requip ) and Rotigotine ( Neupro ).
Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility.

Source: CNS Drugs, 2007

XagenaMedicine2007


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