Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (–)-3-(3,4-dihydroxyphenyl)-l-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an l-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6–5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows.
Dopamine receptors are discussed in detail in Chapters 21 and 29. They exist in five subtypes. D1 and D5 receptors are classified as the D1 receptor family based on genetic and biochemical factors; D2, D3, and D4 are grouped as belonging to the D2 receptor family. Dopamine receptors of the D1 type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra. The D2 receptors are located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia. The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors. However, D1-receptor stimulation may also be required for maximal benefit, and one of the newer drugs is D3 selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are powerful stimulators of the D2 receptors have antiparkinsonism properties, whereas certain dopamine blockers that are selective D2 antagonists can induce parkinsonism.
Dopa is the amino acid precursor of dopamine and norepinephrine (discussed in Chapter 6). Its structure is shown in Figure 28–3. Levodopa is the levorotatory stereoisomer of dopa.
Levodopa is rapidly absorbed from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Ingestion of food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain. Plasma concentrations usually peak between 1 and 2 hours after an oral dose, and the plasma half-life is usually between 1 and 3 hours, although it varies considerably among individuals. About two thirds of the dose appears in the urine as metabolites within 8 hours of an oral dose, the main metabolic products being 3-methoxy-4-hydroxyphenyl acetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC). Unfortunately, only about 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Accordingly, levodopa must be given in large amounts when used alone. However, when given in combination with a dopa decarboxylase inhibitor that does not penetrate the blood-brain barrier, the peripheral metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain (Figure 28–4). Indeed, concomitant administration of a peripheral dopa decarboxylase inhibitor such as carbidopa may reduce the daily requirements of levodopa by approximately 75%.
The best results of levodopa treatment are obtained in the first few years of treatment. This is sometimes because the daily dose
FIGURE 28–3 Some drugs used in the treatment of parkinsonism.