Fluctuations in motor performance and dyskinesia are a common problem in the long-term management of Parkinson's disease (PD). The pharmacokinetics and pharmacodynamics of levodopa, loss of presynaptic dopamine terminals, alterations in post-synaptic dopamine receptor sensitivity, or changes in the modulatory influence of non-dopaminergic transmitter systems could play a pathogenic role. The short half-life of levodopa and its absorption and transport are also important factors. The pharmacodynamic response to levodopa changes during long-term therapy, and there appear to be an absolute threshold plasma concentration of levodopa below which patients are in the 'off' phase. The therapeutic window for levodopa becomes narrower with time, but can be widened by giving dopaminergic drugs continuously. Motor fluctuations can be ameliorated by a more physiological, continuous stimulation of the receptor site and by avoiding repeated changes in levodopa concentrations. Inhibitors of catechol-O-methyltransferase, or COMT (tolcapone, entacapone), increase the absorption and decrease the metabolism of levodopa. Pharmacokinetic studies demonstrate that tolcapone increases the area under the curve (AUC) for plasma levodopa concentrations without causing a corresponding rise in the maximal plasma concentration (C(max)). This has the advantage that levodopa is provided to the brain in a more predictable and stable fashion, avoiding peaks in plasma levodopa concentrations. This may result in a more continuous, and thus physiological, stimulation of the dopaminergic system, thus avoiding exposure of striatal dopamine receptors to alternating high and low concentrations of dopamine and minimizing the risk of motor complications. Combination with a COMT inhibitor should be considered when levodopa has been used since the very early stage of the disease.
|Number of pages||4|
|Journal||Focus on Parkinson's Disease|
|Publication status||Published - 1998|
ASJC Scopus subject areas
- Clinical Neurology