Pharmacy & Therapeutics - October 2008 - (Page 601)

Medical Management of Parkinson’s Disease of the drug is catabolized and does not reach the brain. Most is converted by aromatic L-amino acid decarboxylase (AAD) to dopamine, which causes nausea and hypotension. Target MainThe addition of an AAD-inhibitor such as Medication Available Doses Initial Dosing tenance Dose carbidopa reduces the formation of dopamine Apomorphine HCl 0.02–0.06 mL 0.02 mL during 3–6 mg three but increases the amount of levodopa, which is (Apokyn injection) “off” periods times per day methylated by COMT. The principal therapeutic action of the COMT-inhibitors is to block this Rotigotine 2 mg every 24 hours One 2-mg 4–6 mg every peripheral conversion to levodopa to 3-O-methyltransdermal system 4 mg every 24 hours patch per day 24 hours dopa, elevating both the plasma half-life of levo(Neupro) 6 mg every 24 hours dopa as well as the fraction of each dose that Pramipexole 0.125 mg 0.125 mg three 1.5–4.5 mg/day reaches the CNS. (Mirapex) 0.25 mg times per day Two COMT-inhibitors are presently marketed 0.5 mg in the U.S.: tolcapone (Tasmar, Valeant) and en1 mg tacapone (Comtan). Both agents reduce the clin1.5 mg ical symptoms of “wearing off” in patients taking levodopa/carbidopa.41,42 Although the magniRopinirole 0.25 mg 0.25 mg twice 5 mg twice tude of their clinical effects and their mecha(Requip) 0.5 mg daily daily nisms of action are the same, their pharmaco1 mg kinetic properties and adverse events differ. 2 mg Tolcapone has a relatively long duration of action 3 mg (two or three times a day) and acts by both cen4 mg tral and peripheral inhibition of COMT. It signif5 mg icantly reduces “off” time an average of 40% and increases total “on” time by about 25% at all dose levels. Levkinetic drug–drug interactions. odopa/carbidopa dosage and frequency can be decreased. Adverse effects. Frequently reported adverse events in Entacapone’s duration of action is short (approximately two clinical trials were nausea, application-site reactions, somnohours), and it is usually taken simultaneously with each dose lence, dizziness, headache, vomiting, and insomnia. Other of levodopa/carbidopa. The drug’s action is attributable mainly adverse effects included peripheral edema, fluid retention, to its peripheral inhibition of COMT. hallucinations, symptomatic orthostatic hypotension, weight Table 3 shows the initial dosing schedule for these two gain, elevated heart rate, elevated BP, and syncope.40 COMT inhibitors. Despite the agent’s benefits, the manufacturer informed health providers and patients that by the end of April 2008, the Adverse effects. The effects of tolcapone and entacapone are patch would not be available from pharmacies in the U.S. The similar to those observed with levodopa/carbidopa alone and recall was based on reports of the possibility of reduced clininclude nausea, orthostatic hypotension, vivid dreams, confuical performance because of rotigotine crystals forming in the sion, and hallucinations.43,44 Both agents have been known to patches, resulting in less drug absorption through the skin and cause increases in serum alanine aminotransferase and asparin the potential for lower efficacy. tate transaminase (ALT and AST). A notable adverse effect is diarrhea. Hepatotoxicity may occur with tolcapone, and a warning label is included in the prescribing information. TolCatechol-O-Methyltransferase Inhibitors capone should be used with extreme caution. Because of the (Tolcapone and Entacapone) risk of potentially fatal, acute fulminant liver failure, tolcapone COMT-inhibitors are a relatively new class of drugs for should usually be used in patients taking levodopa/carbidopa treating PD.24 COMT and MAO are responsible for the catabwho are experiencing symptom fluctuations and who are not olism of levodopa as well as dopamine. COMT transfers a responding satisfactorily to or are not appropriate candidates methyl group from the donor S-adenosyl-L-methionine, producfor other adjunctive therapies. Entacapone has not been assoing the pharmacologically inactive compounds 3-O-methylciated with hepatotoxicity. dopa (from levodopa) and 3-O-methoxytyramine (from In placebo-controlled trials associated with tolcapone, the dopamine). When levodopa is administered orally, nearly 99% most commonly observed adverse events in more Table 3 Catechol-O-Methyltransferase (COMT)– than 5% of patients but not seen at an equivalent freInhibitors for the Treatment of Parkinson’s Disease quency among placebo-treated patients were dyskinesia, nausea, sleep disorders, dystonia, excessive Medication Available Doses Initial Dosing dreaming, anorexia, muscle cramps, orthostatic comEntacapone (Comtan) 200 mg 200 mg with levodopa; plaints, somnolence, diarrhea, confusion, dizziness, maximum 8 per day headache, hallucination, vomiting, constipation, fatigue, upper respiratory tract infection, falling, inTolcapone (Tasmar) 100 mg 100 mg three times per creased sweating, urinary tract infections, xerosto200 mg day mia, abdominal pain, and urine discoloration.43 Table 2 Dopamine Agonists for the Treatment of Parkinson’s Disease Vol. 33 No. 10 • October 2008 • P&T® 601

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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