Mrs. Thompson reports experiencing “on-off” episodes with her carbidopa/levodopa therapy. Explain…

➤ Why do on-off fluctuations develop with carbidopa/levodopa?
Fluctuations develop as nigrostriatal neurons decline and the brain loses dopamine storage. Levodopa’s short plasma half-life, variable absorption, peripheral metabolism, and delayed gastric emptying cause pulsatile dopamine delivery. These factors produce wearing-off and sudden “off” periods despite regular dosing.