Selegiline (Eldepryl; Somerset) and Rasagiline (Azilect, TEVA) are irreversible, selective inhibitors of MAO-B at the recommended doses of up to 5 mg twice a day and 1 mg every day, respectively. Zelapar (Zydis selegiline; Valeant) is an orally disintegrating formulation of selegiline, taken at 2.5 mg per day.

Adverse effects of selegiline are relatively infrequent when the drug is used early in the disease. Occasional patients report insomnia related to its amphetaminelike metabolite. To minimize insomnia, selegiline should not be used late in the afternoon or evening. Rasagiline, on the other hand, does not produce amphetamine-like metabolites. Although a restricted low-tyramine diet has been recommended by the American Food and Drug Administration to minimize the “cheese effect,” such effect is not expected at the recommended doses, designed to maintain selectivity of MAO-B receptors.

Patients taking MAO-B inhibitors should not be given meperidine (Demerol; Sanofi) for pain control or dextromethorphan. Although serotonin syndrome has been reported in patients taking selegiline with selective serotonin reuptake inhibitors (SSRIs), many patients are on this combination without adverse effects.

Amantadine (Symmetrel; Endo Pharmaceuticals) is used in the management of mild to moderate PD and is most helpful in addressing tremor and levodopainduced dyskinesias. The various mechanisms of action include N-methyl-Daspartate receptor antagonism, blockade of dopamine reuptake, stimulation of dopamine receptors, and promotion of dopamine release.

Amantadine is excreted unchanged in the urine. The usual dosage range is 100 mg two or three times a day (Table 41.1). Elderly patients and those sensitive to the effects of medications should probably start with 25 mg per day for a few days, using a syrup formulation.

Adverse effects of amantadine may be mild but some are intolerable. The most common are leg edema and livedo reticularis, a mottling discoloration of the lower limbs, as well as effects associated with its anticholinergic properties, such as disorientation and hallucinations, as well as dry mouth and blurry vision, especially in older patients.

Anticholinergic drugs have been used for many years in the management of PD. Dopamine depletion in the striatum causes a relative “hypercholinergic” state that responds to the use of anticholinergic drugs. Many centrally acting anticholinergic drugs are available, but the two most commonly used in the United States are trihexyphenidyl (Artane; Lederle) and benztropine (Cogentin; Merck). Biperiden (Akineton; Knoll), orphenadrine (Norflex; 3M Pharmaceuticals), and procyclidine (Kemadrin; GlaxoSmithKline) are rarely used.

Anticholinergics may be used early in the course of PD. Tremor remains the only practical indication for their use given the poor side-effect profile (see below). Typically, trihexyphenidyl is started at doses of 1 mg per day and increased weekly up to 2 mg four times per day until symptomatic control is obtained or side effects develop. Benztropine usually is started at 0.5 mg per day and titrated up to 4 mg per day. If anticholinergics are to be discontinued, this should be done gradually to avoid withdrawal effects.

Adverse effects of anticholinergic medications include both peripheral antimuscarinic side effects (e.g., dry mouth, impaired visual accommodation, urinary retention, constipation, tachycardia, and impaired sweating) and central effects (e.g., sedation, dysphoria, memory difficulties, confusion, and hallucinations).

Dopamine receptor agonists directly stimulate dopamine receptors. The currently commercially available dopamine agonists in the United States are pramipexole (Mirapex; Boehringer-Ingelheim), ropinirole (Requip; GlaxoSmithKline), apomorphine (Apokyn, Ipsen), and bromocriptine (Parlodel; Novartis). The long-acting ergot derivative bromocriptine and cabergoline are rarely used for the treatment of PD. Their use in North America has been largely restricted to the treatment of hyperprolactinemia. The transdermally delivered rotigotine (Neupro; UCB/Schwarz Pharma) is temporarily off the market due to the development of crystals in the patch system. Pergolide (Permax; Elan) was withdrawn from the US market due to increased risk of cardiac valvulopathy. Lisuride and piribedil are available in other countries.

Dopamine receptor agonists may relieve all of the cardinal manifestations of PD. Despite the theoretical advantages over levodopa by acting directly on striatal dopamine receptors while circumventing the degenerating dopaminergic neurons, dopamine agonists are less effective than levodopa, yielding a lower risk of dyskinesia and motor fluctuation compared with it, and have an extensive list of potential side effects. Agonists can be used both as monotherapy and as adjuncts to levodopa. To minimize side effects, the dosage of a dopamine agonist should be increased gradually until the desired effect is obtained. Table 41.1 shows common dosages for different antiparkinsonian drugs. Apomorphine can only be administered subcutaneously as a rescue treatment for intractable and disabling wearing off. An apomorphine challenge is required to determine the correct dose of the drug while the patient is pretreated with an antiemetic, such as domperidone or trimethobenzamide.

Dopaminergic adverse effects of dopamine agonists include nausea, vomiting, postural hypotension, and excessive daytime sleepiness and psychiatric manifestations including visual hallucinations and impulse-control disorders. Elderly and cognitively impaired patients are more prone to psychiatric side effects. Impulse control disorders (excessive shopping, compulsive gambling, and hypersexuality, among others) may develop 20 months after the onset of therapy, which demands regular monitoring. Also in the long term, dopamine agonists can cause leg edema and livedo reticularis. Older ergot-derived dopamine agonists such as bromocriptine and cabergoline in rare instances cause pulmonary and retroperitoneal fibrosis, cardiac valvulopathy, vasospasm, and erythromelalgia and can exacerbate angina and peptic ulcer disease.

Levodopa is the most effective antiparkinsonian medication. It is mainly absorbed in the proximal small intestine by a carrier-mediated process for neutral amino acids and is similarly transported across the blood-brain barrier. Once in the brain, it is converted to dopamine by the enzyme aminoacid dopa decarboxylase.

Levodopa is administered in combination with a peripheral dopa decarboxylase inhibitor (carbidopa in North America or benserazide in Europe). Inhibition of peripheral dopa decarboxylase markedly reduces the required total daily dose of levodopa and minimizes the gastrointestinal side effects and hypotension caused by peripheral conversion of levodopa to dopamine.

Available preparations of levodopa include immediate-release carbidopalevodopa (Sinemet; Dupont), an orally disintegrating tablet (Parcopa; Azur Pharma), and a controlled-release preparation (Sinemet CR, Dupont). A minimum of 75 mg per day of carbidopa is required for appropriate peripheral decarboxylation. Carbidopa-levodopa preparations are available as 10 per 100, 25 per 100, and 25 per 250 tablets (carbidopa milligrams per levodopa milligrams) and as 25 per 100 and 50 per 200 tablets in the controlled-release preparation. Sustainedrelease preparations are 30% less bioavailable and substantially more erratic in its pharmacokinetics than the immediate-release forms. Because of the latter, Sinemet CR is no longer recommended for the control of daytime symptoms, and its use is reserved for reemergence of night-time or early-morning symptoms.

Levodopa generally relieves all of the cardinal signs of PD—bradykinesia, tremor, and rigidity. Delaying levodopa in any patient older than 70 years of age or in younger individuals insufficiently treated with dopamine agonists or MAO-B inhibitors is no longer recommended. Unlike the core deficits of tremor, bradykinesia, and rigidity, axial deficits, such as impaired postural reflexes, hypophonia, and dysphagia, are less reliably improved. A lack of response to levodopa may suggest a diagnosis of one of the atypical parkinsonisms, but an adequate trial with doses up to 1,500 mg of levodopa should be tried before considering anyone nonresponder. Treatment with carbidopa-levodopa usually is initiated using 25 per 100 immediate-release tablets titrating slowly upward to minimize acute side effect.

As the disease progresses, patients may develop motor complications in the form of motor fluctuations with wearing off toward the end of a dose cycle (reemergence of parkinsonian deficits or appearance of end-of-dose or early-morning dystonia) or choreic or choreathetoid movements (dyskinesia). Wearing off can be improved by decreasing the interdose interval of levodopa, increasing the individual levodopa doses, adding a catechol-O-methyltransferase (COMT) or MAO-B inhibitor, or considering apomorphine subcutaneous injections. Choreic movements of the upper body predominantly head and neck is often indicative of peak-dose dyskinesia and requires lowering the levodopa doses, increasing the interdose interval, or adding amantadine. Choreic movements predominantly of the lower body, especially legs, feet, and pelvis, may occur at the beginning of or at the end of a dose cycle of levodopa and are referred to as diphasic dyskinesia. Unlike peak-dose dyskinesias, diphasic dyskinesias are treated by increasing the dose of levodopa or decreasing the interdose interval. In general, motor complications, particularly dyskinesia, begin after 2 to 10 years of levodopa therapy. Younger patients are more prone to dyskinesia and motor fluctuations earlier in the course of the disease. When medication adjustments do not improve these motor complications, deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal pars of the globus pallidus (GPi) may be considered (see section 3, below).

The short half-life of immediate-release levodopa is believed to be a major factor in the development of motor complications. A gel formulation of levodopa continuously administered intrajejunally is under investigation and expected to become available in the United States in 2012. A similar preparation has been available in Europe for over a decade (Duodopa; Abbott).

Adverse effects of levodopa can be classified into acute and chronic. In the short term, nausea, vomiting, and hypotension-related lightheadedness can be addressed by adding extra carbidopa (Lodosyn; Bristol-Myers Squibb), 25 to 75 mg three times per day, to enhance the peripheral decarboxylation and minimize bioavailability of dopamine outside the brain, where is typically toxic. Another option is to use a peripheral dopamine receptor blocker such as domperidone in doses of 10 to 20 mg three times a day. Domperidone is not currently available in the United States but can be readily obtained from Canadian online pharmacies. In the long term, patients may develop changes in behavioral complications in the form of psychosis, paranoia, sexual preoccupation, impulse control disorder, mania, or agitation. Visual hallucinations can be quite vivid in the form of people or animals. Mental status changes usually are dose-dependent and typically lessen with medication reduction, although at the expense of deterioration of motor function. Quetiapine (Seroquel; Astra-Zeneca) or clozapine (Clozaril; Novartis) may be considered in these cases, as the only antipsychotics safe to use in PD. Reports of accelerated melanoma growth in PD patients taking levodopa have been published. However, melanoma seems to be more prevalent among PD patients regardless of their exposure to levodopa or other PD drugs.

COMT inhibitors are used as adjuncts to levodopa. By blocking the peripheral conversion of levodopa to 3-O-methyldopa, COMT inhibitors increase the bioavailability of levodopa. Two COMT inhibitors are available—tolcapone (Tasmar; Valeant) and entacapone (Comtan; Novartis). A carbidopa-levodopa-entacapone
preparation (Stalevo; Novartis) is also available. Tolcapone is used in doses of 100 to 200 mg three times a day, and entacapone 200 mg is given with each dose of levodopa up to 2,000 mg per day. If tolcapone is used, liver function tests should be monitored periodically at least for the first 6 months because of earlier reports of rare cases of tolcapone-induced liver failure, some fatal. Side effects of COMT inhibitors are related to increased bioavailability of levodopa. In addition, diarrhea and a brownish-orange discoloration of the urine may occur.

Visual hallucinations and psychosis are adverse effects that can occur in association with any antiparkinsonian medication. Any potential triggering event, such as infections or metabolic derangements, should be actively sought and treated, if present. Otherwise, decreasing or discontinuing the dose of dopaminergic medications is warranted, in the following order if hallucinations persist: anticholinergics, amantadine, selegiline/rasagiline, and dopamine agonists. If worsening of motor symptoms make such a reduction impossible, the judicious use of one of the safe atypical antipsychotics quetiapine or clozapine, or an acetylcholinesterase inhibitor, such as rivastigmine, may be necessary. Clozapine is started at a dose of usually 6.25 mg at bedtime. Because 1% to 2% of patients taking clozapine may experience agranulocytosis, patients should be monitored with weekly blood counts. Quetiapine is effective in the management of dopaminergic-induced psychosis at doses of 12.5 mg to 300 at night without worsening parkinsonism.

Constipation is a common problem among PD patients. Management should include dietary modifications, increasing fluid and fiber intake, exercise, and minimizing or eliminating the use of anticholinergic medications. Psyllium (Metamucil; Procter & Gamble) 1 tsp (5 ml) two to four times a day may be added. Osmotic agents such as sorbitol and lactulose are often helpful. Agents that stimulate intestinal motility such as bisacodyl (Dulcolax; Novartis) could be added. Some patients may need enemas.

Other potential problems of patients with PD include nocturia, urinary urgency and frequency, erectile dysfunction, dysphagia, orthostatic hypotension, and sleep problems (see Chapters 7, 9, 18, and 31). Depression requires special mention as it affects about 50% of patients with PD and may respond to antidepressant medications such as SSRIs and SNRIs, given the involvement of serotonin but importantly of norepinephrine in PD.