Pharmacological Basis of OFF Episodes in Parkinson's Disease

EP: 1.OFF Episodes in Parkinson's Disease: Terminology and Patient Experience

EP: 2.Manifestation of OFF Episodes and Impact on Quality of Life in Patients with Parkinson’s Disease

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EP: 3.Pharmacological Basis of OFF Episodes in Parkinson's Disease

EP: 4.Current Treatment Paradigm for Management of OFF Episodes

EP: 5.Future Outlook for Parkinson’s Disease

Stuart Isaacson, MD, FAAN: Levodopa remains our cornerstone therapy. It becomes dopamine, the essential neurotransmitter that our patients don’t make enough of. Not having enough dopamine results in motor symptoms and some nonmotor symptoms. Initially, the brain has a robust ability to compensate for the very short half-life of oral immediate-release levodopa in the bloodstream. In the circulating plasma, the elimination half-life is approximately 90 minutes. But the benefit from each individual dose is longer than that. We have what we would call the long-duration response that reflects the compensatory mechanism of the brain and the robust buffering capacity of the striatum to uptake levodopa, convert it to dopamine, release it at the synaptic level, and then reuptake it to the dopamine transporter and recycle it. Each dose lasts in this long-duration fashion. But after a couple of years—sometimes a year or 2, sometimes 3 or 5, or sometimes even out to 7 years—patients begin to recognize that an individual dose of oral levodopa no longer provides a long-duration benefit. The benefit becomes shorter and symptoms return after 4 or 5 hours and eventually 3 or 4 hours. As time goes on, and as progressive striatal denervation with degeneration in Parkinson disease, the duration of benefit from each dose of levodopa begins to approximate its plasma elimination half-life getting closer to 2 hours and less. It’s a big problem.

On top of the problem of central degeneration, striatal denervation, and loss of buffering capacity are altered other chemicals, like glutamate and adenosine. They limit the benefit from each dose of medication, increase the amount of time that patients don’t have benefit and have these OFF episodes, and increase OFF time throughout the day. On top of that, there are peripheral problems affecting this short half-life of levodopa. The plasma is the variability in the absorption of oral doses that have to go from the laryngeal-pharyngeal border through the esophagus, which we know has dysmotility in Parkinson’s disease into the stomach and is dysmortal. Gastroparesis results in delayed emptying of food and medications.

Of course, levodopa is not absorbed until it exits the stomach into the small intestine, where it’s actively transported by the large neutral aminoacidic transporter into the plasma. There can be variable delay reflecting esophageal and gastric dysmotility. Protein in the diet can go into the gut and compete at the transporter level for levodopa absorption from the gut into the plasma, and from the plasma into the brain across the blood-brain barrier—the same transporter brings levodopa into the brain. There’s so much variability of oral levodopa to get from the mouth into the brain. Coupled with the short half-life in the plasma on top of the progressive loss of buffering capacity in the striatum, we get patients who don’t always know when a dose is going to work with a delayed onset from protein effect, dysmotility in the gut, how long the duration of benefit will reflect the short half-life in the plasma, differential amounts being absorbed from the gut, and derivation and loss of buffering capacity in the brain. When they’re OFF, what do they do? We have to translate all the information we have on the causes of OFF into how it impacts patients’ daily activities and ultimately the quality of their daily lives.

Transcript edited for clarity