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Chapter 13: Drug Therapy of Neurodegenerative Diseases

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A 72-year-old man with Parkinson’s disease is being treated with selegiline. Over the past 2 weeks he has noticed an increase in insomnia and anxiety. It is likely these symptoms are due to

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a. dopamine.

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b. ephedrine.

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c. amphetamine.

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d. serotonin.

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e. caffeine.

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Answer is c. Metabolites of selegiline include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms. Unlike selegiline, rasagiline does not give rise to undesirable amphetamine metabolites.

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A 75-year-old woman with Parkinson’s disease is being treated with the combination of levodopa/carbidopa. Entacapone is added. This patient is treated with this combination of drugs to increase the amount of which of the following substance to reach the CNS?

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a. Carbidopa

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b. Levodopa

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c. Entacapone

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d. Acetylcholine

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e. Dopamine

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Answer is b. Drugs for the treatment of PD include inhibitors of the enzyme COMT, which, together with MAO, metabolize levodopa and DA. COMT transfers a methyl group from the donor S-adenosyl-l-methionine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from DA; see Figure 13-5). When levodopa is administered orally, nearly 99% of the drug is metabolized in the periphery and does not reach the brain. Most is converted by aromatic l-amino acid decarboxylase (AADC) to DA, which causes nausea and hypotension. Addition of an AADC inhibitor such as carbidopa reduces the peripheral formation of DA but increases the fraction of levodopa that is methylated by COMT. The principal therapeutic action of the COMT inhibitor entacapone is to block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t1/2 of levodopa as well as the fraction of levodopa that reaches the CNS.

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Figure 13-5. Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (L-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AADC, aromatic l-amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-O-MD, 3-O-methyl DOPA.

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