By combining l-dopa with a decarboxylase inhibitor (carbidopa or benserazide), which is unable to penetrate the central nervous system (CNS), decarboxylation of l-dopa to dopamine is greatly diminished in peripheral tissues. This permits a greater proportion of l-dopa to reach nigral neurons and, at the same time, reduces the peripheral side effects of l-dopa and dopamine (nausea, hypotension, confusion). Combinations of carbidopa-levodopa are available in a 1:10 or 1:4 ratio and the benserazide-levodopa combination is available in a 1:4 ratio. The initial dose of carbidopa-levodopa is typically one-half to one of a 25/100-mg tablet given bid or tid and increased slowly until optimum improvement is achieved, usually up to 4 tablets administered 5 or more times daily as the disease advances, or a similar dose of the 25/250-mg combination.
A class of catechol-O-methyltransferase (COMT) inhibitors, typified by entacapone, extends the plasma half-life and the duration of l-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability, as in the case of carbidopa). A combination of l-dopa, carbidopa, and a COMT inhibitor is available in a single pill.
Long-acting preparations of levodopa-carbidopa may provide slightly longer effect and reduce dyskinesias in some patients (Hutton and Morris) in the advanced stages of disease, but our experience with these drugs given earlier in the course of disease has given less-predictable results. The absorption of the long-acting drug is approximately 70 percent and may be inconsistent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be given late in the previous evening.
For patients who require very frequent but small doses of the drug because of severe motor fluctuations and dyskinesias, an oral suspension may be formulated that allows precisely measured doses to be delivered orally or through a nasogastric tube. The typical composition is 500 mg l-dopa (of carbidopa-l-dopa 10/100 or 25/100), 500 mg of ascorbic acid to stabilize the drug, and 250 mL of water, resulting in a concentration of l-dopa of 2 mg/mL, which is administered in small amounts. A gel preparation is also available for delivery through a duodenal tube.
Each patient requires empirical adjustment of the dose and timing of medication and then generally does well by maintaining a relatively regular medication schedule, supplemented by small intercalated doses when needed. The effect of l-dopa may be virtually immediate (i.e., after absorption, which occurs over 30 to 40 min) but there is a further cumulative effect over several days of consistent dosing. The principles that guide the adjustment of dosing (end-of-dose wearing off, dyskinesias, freezing, confusion) are discussed further on.