Pharmacy & Therapeutics - October 2008 - (Page 599)

Medical Management of Parkinson’s Disease continued from page 594 Adverse effects. In addition to motor fluctuations and nausea, a common and troubling adverse event with levodopa treatment is the induction of hallucinations and confusion, which are common in the elderly and in those with pre-existing cognitive dysfunction.29 The presence of these effects often limits the ability to treat parkinsonism symptoms adequately. Recently, atypical antipsychotic agents have been used in such patients, such as quetiapine (Seroquel, AstraZeneca) and clozapine (Clozaril, Novartis), although other agents can worsen PD.29 Peripheral decarboxylation of levodopa and the release of dopamine into the circulation may activate vascular dopamine receptors and produce orthostatic hypotension.29 The actions of dopamine at alpha-adrenergic or beta-adrenergic receptors may induce cardiac arrhythmias, especially in patients with pre-existing conduction disturbance. Taking levodopa with nonspecific inhibitors of MAO, such as phenelzine (Nardil, Pfizer) and tranylcypromine (Parnate, GlaxoSmithKline), accentuates the actions of levodopa and may precipitate a lifethreatening hypertensive crisis and hyperpyrexia. Levodopa is currently considered the most effective drug for controlling symptoms of PD, and for many years, it was the preferred drug for treating newly diagnosed PD. However, because its long-term use at high dosages may lead to motor complications that can be difficult to manage, many physicians switch to dopamine-receptor agonists (see next column). Approximately 40% of patients who are receiving levodopa develop motor fluctuations after four to six years of treatment.30 Table 1 shows the various levodopa drug combinations and initial dosing available in the U.S. its peripheral O-methylation and by slowing its elimination rate, without affecting the maximum plasma levodopa concentration or the time to maximum concentration.32 The same drugs that interact with carbidopa/levodopa and entacapone interact with Stalevo. Dopamine-Receptor Agonists (Bromocriptine, Ropinirole, Pramipexole, Apomorphine) Drugs acting directly on dopamine receptors may also have a beneficial effect.16 Unlike levodopa, dopamine-receptor agonists do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites, do not compete with other substances for active transport into the blood and across the blood–brain barrier, and do not depend on the functional capacities of the nigrostriatal neurons.16 In addition, drugs selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. Finally, if the hypothesis that free radical formation as a result of dopamine metabolism contributes to neuronal death is correct, dopamine-receptor agonists may be able to modify the course of the disease by reducing the endogenous release of dopamine as well as the need for exogenous levodopa. Oral Agents Three oral dopamine-receptor agonists are available for the treatment of PD: an older agent, bromocriptine (Parlodel, Novartis), and two newer, more selective compounds, ropinirole (Requip, GlaxoSmithKline) and pramipexole (Mirapex, Pfizer). Another agent, pergolide (Permax, Valeant; Par, Teva), was removed from the market in 2007. Bromocriptine. As an ergot derivative, bromocriptine is a strong agonist of the D2 class of dopamine receptors, and it is Carbidopa/Levodopa/Entacapone (Stalevo) a partial antagonist of the D1 receptors. It is available as a Stalevo (Novartis) is a combination tablet for patients who experience end-of-dose wearing-off. Even though carbidopa 2.5-mg tablet and a 5-mg capsule. It has been used with carbireduces the side effects of levodopa, entacapone (Comtan, dopa/levodopa (Sinemet) to reduce symptoms and amelioNovartis) extends the time levodopa is active in the brain (up rate the adverse reactions associated with long-term levodopa to 10% longer).31,32 Entacapone prolongs the availability of therapy. Bromocriptine is still available, but it is not as effective as other dopamine agonists early in PD, and it is not uselevodopa in the plasma, and thus to the brain, by decreasing ful in late-stage PD for reducing motor fluctuations caused by levodopa. Table 1 Levodopa Drug Combinations for the TreatRopinirole and pramipexole. These two agents have ment of Parkinson’s Disease selective activity at D2 class sites (specifically at the D2 and D3 receptor proteins) and little or no activity at D1 Medication Available Doses Initial Dosing class sites. These drugs, like bromocriptine, are well Carbidopa/levodopa 10/100 mg 25/100 mg two to absorbed orally and have similar therapeutic actions. (Sinemet) 25/100 mg three times per day Like levodopa, they can relieve the clinical symptoms of 50/250 mg PD. The duration of action of the dopamine agonists (8 to 24 hours) is often longer than that of levodopa (6 to Carbidopa/levodopa 50/250 mg 50/250 mg twice daily 8 hours), and these agents are particularly effective in controlled-release treating on/off phenomena. All three drugs may also (Sinemet CR) produce hallucinosis or confusion, similar to that Carbidopa/levodopa/ 12.5/50/250 mg 12.5/50/250 mg observed with levodopa, and they may worsen orthoentacapone (Stalevo) 25/100/250 mg static hypotension.12 37.5/150/250 mg The therapeutic effects of these agents are related to 50/200/200 mg actions at postsynaptic dopamine receptors, but they can also activate presynaptic autoreceptors found on dopaCarbidopa/levodopa 10/100 mg 25/100 mg two or mine terminals, which are mainly of the D2 class. By orally disintegrating tablet 25/100 mg three times per day stimulating presynaptic receptors, pramipexole and (Parcopa) 25/250 mg ropinirole may lower endogenous dopamine produc- Vol. 33 No. 10 • October 2008 • P&T® 599

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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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