L-DOPA and carbidopa in the therapy of Parkinson's disease

L-DOPA and carbidopa in the therapy of Parkinson's disease

Like the transporters for the catecholamines and serotonin, those for their precursor amino acids are not of very high specificity. This has been exploited in various ways for pharmacotherapy. A very important example is the use of L-DOPA as a pre-drug to substitute dopamine to the brain in patients with Parkinson's disease (Figure 10.18a). Dopamine itself cannot cross the blood brain barrier¹³. However, L-DOPA is accepted by an amino acid carrier that normally transports aromatic amino acids. It can thus enter the brain and there be decarboxylated to dopamine.

Concurrently with its permeation into the brain, howev-er, DOPA will also be decarboxylated in the periphery to dopamine; thus, the overall fraction of DOPA that winds up in the brain is only about 2%. This means that very high dosages will be required for the desired clinical effect, and the periphery would be uselessly troubled with high amounts of dopamine and derived catecholamines. This situation can be greatly improved by the simultaneous ap-plication of an inhibitor of DOPA decarboxylase, called carbidopa (Figure 10.18b). Note that this substance will not cross the blood brain barrier, and therefore not interfere with the (necessary) decarboxylation in the brain.

Note that, since dopamine is the precursor of nore-pinephrine and epinephrine, carbidopa will inhibit the syn-thesis of all three catecholamines. One therefore might expect it to reduce blood pressure, but it in animal experi-ments it rather seems to increase it; this has been attributed to the lack of dopamine in the periphery.