PHARMACODYNAMICS OF LEVODOPA IN PARKINSONS-DISEASE

1. Levodopa markedly reduces parkinsonism during the first years of tr eatment. However, with continued therapy the response to levodopa beco mes erratic and is complicated by involuntary movements, To improve th e therapy of parkinsonism, the challenge is to understand why fluctuat ions 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-duratio n response, a long-duration response and a negative response. 3. The s hort-duration response, measured in minutes to hours, has a steep conc entration-response relationship such that the response appears 'all or nothing.' The duration of effect is dose-responsive. The short-durati on response becomes shorter during chronic therapy, possibly because o f tolerance, The onset to effect becomes briefer and the magnitude of the response becomes larger during chronic therapy, possibly because o f sensitization. 4. The long-duration response, measured in days to we eks, develops and decays slowly. The rate of decay is proportional to the severity of the parkinsonism and therefore this response may relat e to dopamine storage capacity of remaining nerve terminals. 5. The ne gative response, measured in minutes, is a worsening of motor function as the short-duration improvement wears off. It may reflect a biphasi c concentration-response relationship. 6. The response to levodopa in parkinsonian patients is a complex interplay between responses with di fferent time courses and variably affected by sensitization, tolerance and disease progression.