Several synthetic preparations of anticholinergic drugs are available, the most widely used ones being trihexyphenidyl (beginning with 1 to 2 mg/d and increased up to 6 to 8 mg over several weeks) and benztropine mesylate (1 to 4 mg/d in divided doses). When it has been available, we have also had success with the related agent ethopropazine (50 to 200 mg daily in divided doses; but it has become difficult to obtain). The effects on tremor are cumulative and may not be evident for several days. To obtain maximum benefit from the use of these drugs, they should be given in gradually increasing dosage to the point where toxic effects appear: dryness of the mouth (which can be beneficial when drooling of saliva is a problem), blurring of vision from pupillary mydriasis, constipation, and urinary retention as mentioned (especially with prostatism). The presence of angle closure glaucoma is a contraindication to its use. Tremor abates in several days and most of our patients have become tolerant to the dry mouth after several weeks. Pyridostigmine, propantheline, or glycopyrrolate can be given to reduce the oral dryness.
With higher dose ranges, mental slowing, confusional states, hallucinations, and impairment of memory in elderly patients—specifically if there is already some degree of forgetfulness—are side effects that limit usefulness. Occasionally, further benefit may accrue from the addition of another antihistaminic drug, such as diphenhydramine or phenindamine.
The antiviral agent amantadine (100 mg bid) has mild or moderate benefit for tremor, hypokinesia, and postural symptoms. In some patients, it reduces l-dopa–induced dyskinesias (see further on). Its mechanism of action is unknown but antagonism of NMDA or release of stored dopamine has been proposed. It should be noted that amantadine commonly causes leg swelling, may worsen congestive heart failure, and can have an adverse effect on glaucoma, as well as exaggerate the cognitive changes associated with anticholinergic medications. The use of the centrally acting anticholinesterase, donepezil, is being explored for a possible effect on improving gait stability but requires further study. Finally, the monoamine oxidase-B inhibitors, described just below as putative neuroprotective agents, have a beneficial effect on motor fluctuations induced by l-dopa and may have a slight beneficial effect on the main Parkinson symptoms as described in several trials, such as the one reported by Rascol and colleagues (2000 and 2005).
Neuroprotective agents An additional approach has been to initiate treatment early in the course of the disease with a monoamine oxidase-B inhibitor (MAO-B inhibitor), with the aim of reducing oxidative stress in dopaminergic neurons. The DTAATOP trial conducted by The Parkinson Study Group (1989) reported a slowing of disease progression but later followup showed little difference between treated and untreated groups. Other agents in this class, notably rasagiline, have given similar mixed results in brief studies including the ADAGIO trial reported by Olanow and coworker. The difficulty in assessing the benefit of these agents has to do with their mild but definite symptomatic benefit on motor function. A long-term study has reported that early initiation of treatment with bromocriptine (now little used) did not reduce mortality or motor disability over 14 years and that any reduction in motor complications was unsustained (Katzenschlager et al). Nonetheless, we often institute one of these MAO-B inhibitors in many patients.