A 72-year-old man with a history of Parkinson disease comes to the office for follow-up. The patient has been taking carbidopa-levodopa since being diagnosed 5 years ago and has required increasing doses to control his symptoms. He is now taking the maximum dose but has experienced bothersome motor fluctuations for the past several months. The patient also reports worsening stiffness and difficulty moving between his scheduled doses; these symptoms improve after he takes the medication. Entacapone is added to his treatment regimen. This drug is most likely to improve this patient's symptoms through which of the following mechanisms?
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Parkinson disease is caused by degeneration of the dopaminergic neurons in the substantia nigra, leading to a progressive deficiency of dopamine in the brain. Direct dopamine replacement is impossible because dopamine cannot cross the blood-brain barrier, so levodopa (ie, L-DOPA), the immediate precursor of dopamine, is used. Once levodopa crosses the BBB, it is taken up by nigrostriatal neurons and converted to therapeutic dopamine in the brain.
Levodopa is rapidly metabolized in the peripheral tissues to dopamine (via aromatic D-amino acid [DOPA] decarboxylase) and 3-O-methyldopa (via catechol O-methyltransferase [COMT]). Therefore, only a small percentage of levodopa reaches the brain. Both COMT inhibitors (eg, entacapone, tolcapone) and DOPA decarboxylase inhibitors (eg, carbidopa) decrease peripheral levodopa degradation and increase the amount of levodopa available to cross the blood-brain barrier.
Patients are nearly always prescribed carbidopa with levodopa. The progression of Parkinson disease leads to an increasingly narrow therapeutic window, as seen in this patient with bothersome "wearing off" periods. In these patients, entacapone can be added to further increase the bioavailability of levodopa, produce more stable levodopa plasma concentrations, and prolong the therapeutic effect of each dose.
(Choice B) Dopamine agonists (eg, pramipexole, bromocriptine) directly activate dopamine receptors in the brain without the need for metabolism to the active form (unlike levodopa). Entacapone has no direct effect on dopamine receptors and does not cross the blood-brain barrier.
(Choice C) Amantadine enhances the effect of endogenous dopamine by increasing dopamine release and inhibiting its reuptake. It is also thought to cause anticholinergic effects (reduces tremor), as well as antagonism of N-methyl D-aspartate receptors (reduces glutamine-induced neurotoxicity).
(Choices D and E) The dopamine insufficiency of Parkinson disease upsets the normal balance between dopamine and acetylcholine in the basal ganglia, resulting in cholinergic hypersensitivity. Anticholinergic medications (eg, trihexyphenidyl) counteract this effect by inhibiting central muscarinic receptors. Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) would increase the amount of acetylcholine in the CNS, which could worsen symptoms of Parkinson disease.
Educational objective:
Parkinson disease is typically treated with levodopa (immediate precursor of dopamine), which crosses the blood-brain barrier. Levodopa is administered with DOPA decarboxylase inhibitors (eg, carbidopa) and sometimes catechol O-methyltransferase inhibitors (eg, entacapone) to reduce the peripheral metabolism of levodopa, resulting in increased levodopa bioavailability within the brain.