A 72-year-old man with a history of Parkinson disease comes to the office for follow-up. The patient has been taking levodopa/carbidopa since being diagnosed 5 years ago, and has required increasing doses of medication to control his symptoms. He is currently on a maximum dose, but for the past several months has experienced bothersome motor fluctuations. The patient also reports worsening stiffness and difficulty moving before his next scheduled dose, which improves after taking the medication. Entacapone is added to his treatment regimen. This drug most likely improves this patient's symptoms by which of the following mechanisms?

Question

A 72-year-old man with a history of Parkinson disease comes to the office for follow-up.  The patient has been taking levodopa/carbidopa since being diagnosed 5 years ago, and has required increasing doses of medication to control his symptoms.  He is currently on a maximum dose, but for the past several months has experienced bothersome motor fluctuations.  The patient also reports worsening stiffness and difficulty moving before his next scheduled dose, which improves after taking the medication.  Entacapone is added to his treatment regimen.  This drug most likely improves this patient's symptoms by which of the following mechanisms?

Quizplus · Accepted Answer

11ec160b_3c17_8ba7_9249_b3a56e171db5_MD0001_00 Levodopa is the immediate precursor of dopamine, a neurotransmitter that is absent in the nigrostriatum of patients with Parkinson disease. Dopamine itself cannot be administered directly due to its inability to cross the blood-brain barrier; however, levodopa can cross this barrier. Levodopa is rapidly metabolized in the peripheral tissues to dopamine (via DOPA decarboxylase) and 3-O-methyldopa (via catechol-O-methyltransferase [COMT]). Therefore, only a small percentage of levodopa reaches the brain. Consequently, levodopa is typically administered with carbidopa, a peripheral DOPA decarboxylase inhibitor, but even then only 5%-10% of levodopa reaches the brain. Entacapone is a COMT inhibitor that increases the bioavailability of levodopa by inhibiting its peripheral methylation. Combining levodopa with entacapone helps increase the plasma half-life of levodopa, producing more stable levodopa plasma concentrations and prolonging the therapeutic effect of each dose. COMT inhibitors are currently used to treat Parkinson disease patients with motor fluctuations who are experiencing end-of-dose "wearing off" periods with levodopa/carbidopa therapy. COMT inhibitors should only be used in combination with levodopa, as they are otherwise ineffective. (Choice B) Dopamine agonists (eg, bromocriptine, pramipexole, ropinirole) preferentially stimulate dopamine 2 receptors. (Choice C) Amantadine likely enhances the effect of endogenous dopamine by increasing dopamine synthesis/release and inhibiting the reuptake of dopamine. (Choice D) Anticholinergics such as trihexyphenidyl and benztropine inhibit central muscarinic receptors. These drugs are mainly used for drug-induced parkinsonism, but patients with tremor as the predominant symptom also respond well. (Choice E) Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) increase the amount of acetylcholine in the central nervous system. These drugs are commonly used in patients with dementia to increase cholinergic activity in the prefrontal cortex. However, they should be used cautiously in patients with Parkinson disease as higher levels of acetylcholine in the basal ganglia can exacerbate symptoms. 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 to the brain. __________ References: Pharmacological treatment of Parkinson disease: A review. (http://www.ncbi.nlm.nih.gov/pubmed/24756517)

A 72-Year-Old Man with a History of Parkinson Disease Comes