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In Parkinson disease there is loss of the dopamine-containing neurons in the substantia nigra (Figure 22–1). These neurons normally project to the caudate putamen (one piece of the basal ganglia) where the dopamine inhibits firing of the cholinergic neurons. These cholinergic neurons form excitatory synapses onto other neurons that project out of the basal ganglia. The result of the loss of dopamine-containing neurons is that the cholinergic neurons are now without their normal inhibition. This is a bit like a car going down a hill without any brakes.


Diagram of projections into and out of the striatum. In Parkinson disease, there is a loss of the dopamine (DA)-containing neurons that project from the substantia nigra to the striatum where they inhibit cholinergic (ACh) neurons (dashed line).


  1. Dopamine replacement therapy

  2. Dopamine agonist therapy

  3. Anticholinergic therapy

The goals of therapy are to correct the imbalance of the cholinergic neurons in the striatum. All of the therapeutic approaches to Parkinson disease make sense. Given the loss of dopamine-containing neurons, you could replace the dopamine or give dopamine agonists (to mimic the action of the lost dopamine). Because many of the cholinergic neurons are uninhibited, you could give an anticholinergic drug to try to restore inhibition. If you can remember this much, you are well on your way to a good grasp of this area.


It would be nice if we could just give dopamine itself. However, dopamine does not cross the blood-brain barrier.

LEVODOPA (L-dopa) is a metabolic precursor of dopamine that crosses the blood–brain barrier (Figure 22–2).


Structures of dopamine, levodopa, and carbidopa.

Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery. All this dopamine floating around peripherally causes side effects.

CARBIDOPA is a dopamine decarboxylase inhibitor that does not cross the blood–brain barrier. It reduces the peripheral metabolism of levodopa, thereby increasing the amount of levodopa that reaches the brain.

Carbidopa and levodopa are used today in combination. This is a prime example of a beneficial drug interaction that is logical based on the mechanisms of action of the two drugs. Side effects of levodopa and carbidopa are related to the dopamine that is generated by peripheral decarboxylation.

Tolcapone, entacapone, and opicapone are plasma catechol-O-methyltransferase (COMT) inhibitors that prolong the half-life of levodopa. Much lower on the trivia list is a new drug approved in 2020—istradefylline. Istradefylline is an oral adenosine A2A receptor antagonist for use as an adjunct in patients with “off” episodes.


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