Pharmacodynamics of levodopa in Parkinson's disease

1. Levodopa markedly reduces parkinsonism during the first years of treatment. However, with continued therapy the response to levodopa becomes erratic and is complicated by involuntary movements. To improve the therapy of parkinsonism, the challenge is to understand why fluctuations in response develop and, once developed, what controls the moment to moment motor status. 2. In patients with a fluctuating response to levodopa, three distinct responses can be recognized: a short-duration response, a long-duration response and a negative response. 3. The short-duration response, measured in minutes to hours, has a steep concentration-response relationship such that the response appears 'all or nothing.' The duration of effect is dose-responsive. The short-duration response becomes shorter during chronic therapy, possibly because of tolerance. The onset to effect becomes briefer and the magnitude of the response becomes larger during chronic therapy, possibly because of sensitization. 4. The long-duration response, measured in days to weeks, develops and decays slowly. The rate of decay is proportional to the severity of the parkinsonism and therefore this response may relate to dopamine storage capacity of remaining nerve terminals. 5. The negative response, measured in minutes, is a worsening of motor function as the short-duration improvement wears off. It may reflect a biphasic concentration-response relationship. 6. The response to levodopa in parkinsonian patients is a complex interplay between responses with different time courses and variably affected by sensitization, tolerance and disease progression.