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ANTICHOLINERGIC DRUGS. A balanced interaction exists between effects of dopamine and acetylcholine in the basal ganglia. In PD, dopamine depletion results in a state of cholinergic sensitivity, so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms.[42] Centrally acting anticholinergic drugs, such as trihexyphenidyl and benztropine, continue to occupy a useful place in the treatment of PD in the era of levodopa and dopamine agonists.[30] Although some anticholinergic drugs (e.g., benztropine) might augment the dopamine effect by inhibiting striatal presynaptic reuptake of dopamine, it is uncertain whether or not this contributes significantly to their mechanism of action. Patients <60 years of age. Anticholinergic drugs should be considered for early monotherapy in patients 60 years of age or younger. Patients with tremor-predominant parkinsonism who are not significantly disturbed by akinesia are particularly good candidates for this approach. In many early studies, anticholinergic drugs were reported to be more effective for tremor and rigidity than for akinesia. Although this differential effect of anticholinergic drugs on specific parkinsonian signs has never been adequately studied and is not universally accepted,[43] contemporary clinical experience has been that anticholinergic drugs are useful for resting tremor but of little value in the treatment of akinesia or impaired postural reflexes.[44] Trihexyphenidyl is the most widely used anticholinergic drug, but little evidence suggests that one drug in this class is superior to another in terms of either therapeutic efficacy or side effects. Trihexyphenidyl is initiated at 0.5 to 1.0 mg twice daily and increased gradually to a dosage of 2 to 3 mg three times daily. Benztropine is given in dosages of 0.5 to 1.0 mg twice daily. As with amantadine, anticholinergic drugs should be discontinued gradually to avoid acute exacerbation of parkinsonism,[45] even in patients in whom clinical response does not appear significant. Adverse side effects of anticholinergic drugs are common and often limit their use, irrespective of the patient's age. Peripheral antimuscarinic effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Particular caution should be exercised in the presence of prostatic hypertrophy or closed-angle glaucoma. Mild peripheral effects, such as dry mouth and blurred vision, often subside with continued treatment and do not limit therapy. CNS effects-such as sedation, dysphoric effects, memory impairment, acute confusion, and hallucinations-are much more troublesome and usually require discontinuation of medication.
Both advanced age and dementia are risk factors for CNS toxicity; therefore, the use of anticholinergic drugs should be limited to patients aged 60 or younger. Even in patients without obvious cognitive side effects, improvement in short-term and long-term memory has been demonstrated after withdrawal of anticholinergic drugs.[30] In summary, anticholinergic drugs are useful for the early treatment of PD in patients 60 years of age or younger in whom resting tremor is the predominant symptom. Because of the high incidence of peripheral and CNS side effects associated with these drugs, their use in patients without tremor and in patients above age 60 or with dementia is not recommended. Patients >60 years of age. As discussed previously, the routine administration of anticholinergic drugs to patients above age 60 is not recommended. Nevertheless, these agents might be useful against specific symptoms in these patients, such as resting tremor that has been resistant to other treatment. If sialorrhea is to be treated with an anticholinergic drug in this population, one which acts peripherally, such as propantheline, should be considered to avoid CNS toxicity.
DOPAMINE AGONISTS. Dopamine agonists offer the theoretic advantage of exerting a direct action on striatal dopamine receptors, which does not require presynaptic uptake and synaptic release by degenerating dopaminergic nerve terminals. In addition, they do not require metabolic conversion to exert their effects, and their absorption and transport into the brain are not influenced by circulating plasma amino acids. Traditionally, dopamine agonists have been developed and used largely for the treatment of patients with declining response to levodopa, motor fluctuations, dyskinesias, or other adverse levodopa effects. The early use of dopamine agonists as a levodopa-sparing strategy-to reduce or delay long-term levodopa complications-recently has been suggested.[46] In a widely cited, uncontrolled, retrospective study, patients treated with bromocriptine and levodopa showed equivalent therapeutic benefit with fewer motor fluctuations and dyskinesias than patients treated with levodopa alone.[47] A prospective trial from the same center, comparing patients treated with lisuride, lisuride plus levodopa, or levodopa also showed fewer fluctuations in lisuride-treated patients than patients receiving levodopa alone.[48] However, a double-blind, randomized, prospective study of a small number of patients-comparing early combination therapy with levodopa monotherapy-showed no significant differences in frequency of long-term levodopa fluctuations after 4 years of treatment.[49] Results of a similar but larger prospective study comparing levodopa with combination therapy have not yet been published. Despite the lack of definitive data on the comparative advantages of levodopa and combination therapy,[50] the early use of dopamine agonists is increasingly advocated as a levodopa-sparing strategy, to delay or reduce the incidence and severity of long-term levodopa fluctuations and dyskinesias,[51-52] and possibly to reduce oxidative stress from free radicals generated by high-dose levodopa replacement therapy.[53]
Bromocriptine and pergolide are the only dopamine agonists currently available for use in the United States. Bromocriptine has both presynaptic and postsynaptic effects and stimulates D2 receptors. It is started in low doses with close monitoring for such side effects as hypotension, nausea, vomiting, hallucinations, peripheral vasoconstriction, and erythromelalgia. Bromocriptine is initiated at 1.25 mg daily and titrated slowly, according to response, to a level of 10 to 25 mg daily. Some patients, however, might require dosages as high as 50 to 75 mg daily. As bromocriptine is titrated upward, the dosage of levodopa is usually lowered to reduce dopaminergic toxicity. Pergolide does not have presynaptic effects and stimulates both D1 and D2 receptors. It is more potent than bromocriptine by a factor of 10 and has a longer duration of action. It is initiated with 0.05 mg daily and titrated slowly over several weeks to a dose of 2 to 3 mg daily. Further increases in dosage might be considered, if needed, to a maximum of 5 mg daily. Although pergolide's therapeutic efficacy is similar to that of bromocriptine, pergolide may be beneficial for some patients in whom bromocriptine therapy fails because it does not produce a clinical response or cause intolerable side effects.[54,55] Patients <60 years of age. Dopamine agonist monotherapy may be considered for mild parkinsonian symptoms in patients aged 60 years and below, but it produces suboptimal benefit in many patients. Even when it is effective, its benefit might wane after several months.[47-49,51] We therefore recommend that in most cases, dopamine agonists be held in reserve until after initiation of levodopa, when they can be used instead of increasing levodopa dosages for management of increased parkinsonian disability. [51,52,54] It is not yet known whether this approach will reduce or delay the incidence of long-term levodopa fluctuations, but the issue is expected to be resolved by studies currently in progress. Patients >60 years of age. The rationale for dopamine agonists in patients over age 60 is similar to that for its use in younger patients. The aim is to reduce cumulative exposure to levodopa and thereby possibly reduce long-term side effects. Controversy remains, however, as to whether cumulative levodopa exposure over the long term has any adverse consequences. It is recommended that levodopa be initiated first and that when the levodopa requirement exceeds 600 mg daily, a dopamine agonist be added according to the regimen described previously.
LEVODOPA. Levodopa is the most effective drug available for the treatment of early PD, and patients who fail to respond to it are highly unlikely to respond to dopamine agonists.[52] Despite a good initial response, however, approximately 50% of patients experience motor fluctuations, such as "wearing-off" effect, unpredictable "on-off" effects, dyskinesias, and dystonias within 6 years of levodopa's initiation. Patients <60 years of age. The treatment of patients with young-onset PD, who show earlier and more frequent appearance of severe motor fluctuations and involuntary movements, is particularly problematic with regard to the adverse effects of long-term levodopa use.[56,57] Some practitioners have expressed the concern that levodopa fluctuations and dyskinesias are related more to the duration of levodopa treatment than to the duration and severity of the disease,[56,58,59] Therefore, proponents of this theory have recommended that levodopa treatment be withheld until the appearance of significant limitations in activities of daily living and job performance. Other clinicians, however, contend that because no evidence proves that levodopa therapy is directly responsible for these late effects, delay of treatment unnecessarily deprives patients of improved function during the early phase of the disease.[60] Despite this unresolved controversy, most practitioners agree that treatment with levodopa should be initiated when the disease markedly impairs job performance or activities of daily living.[61]
Another possibility is that the form of levodopa delivery plays a role in the development of fluctuations and dyskinesias.[61] In experimental animals, continuous and intermittent administration of dopamine agonists exert different and frequently opposite effects on dopamine-mediated behavior.[62] In several recent studies, chronic, intermittent levodopa administration produced greater dopamine-mediated behavioral supersensitivity than continuous treatment, although this has not been confirmed by all studies.[63,64] Some research has suggested that chronic intermittent therapy is less physiologic than continuous treatment and might result in postsynaptic changes that affect the response to levodopa treatment.[64] These dopamine receptor changes might then cause a narrowing of the therapeutic window and steepening of the dose-response curve, resulting in a fluctuating levodopa response.[65] Dopamine replacement treatments that provide stable stimulation of dopamine receptors might possibly avoid the appearance of motor fluctuations.[65,66] For this reason, the use of sustained-release formulations of levodopa for initiation of therapy has been advocated increasingly, although their ability to produce predictably smooth plasma levodopa levels[66] and prevent motor fluctuations has not been proven.[67] In Europe, the sustained-release benserazide-levodopa formulation utilizes the decarboxylase inhibitor benserazide rather than carbidopa. The drug is sold under the trade name Madopar. One randomized, double-blind study comparing sustained-release benserazide-levodopa with standard benserazide-levodopa in a relatively small number of patients showed fewer fluctuations and dyskinesias in patients on the sustained-release preparation 2 years after treatment began.[68] More definitive information on the potential advantage of the early use of sustained-release carbidopa-levodopa should emerge from an ongoing clinical trial, in which patients are randomized to either immediate, or sustained-release carbidopa-levodopa.[67] We typically introduce levodopa therapy in the form of sustained-release carbidopa-levodopa in patients who are beginning to experience significant disability in activities of daily living or professional activities. Determination of what constitutes significant disability must be made on a case-by-case basis. Once this decision has been reached, the issue of dosage must be addressed. No available prospective, controlled studies have compared low-dose with higher-dose levodopa treatment, and uncontrolled studies have yielded conflicting results regarding the effect of dosage on incidence of fluctuations.[69,70] Experimental studies of alternate-day[71] and oral-pulse[72] levodopa therapy in early FD have been carried out in an effort to reduce total levodopa exposure. These approaches, however, are of unproven long-term benefit arid expose the patient to the potential adverse effects of intermittent rather than continuous treatment, which might be less desirable. Sustained-release carbidopa-levodopa should be initiated at 25/100 mg or 50/200 mg twice daily given early morning and early to midafternoon. If delayed onset of effect ("kick-in" time) and lack of sufficient peak effect are problematic, then standard carbidopa-levodopa may be introduced. A relatively low dose of 200 to 400 mg of levodopa should be maintained until progressively disabling symptoms require an increase in dosage or dosing frequency. When a daily dose of 500 to 800 mg of levodopa is reached, the addition of a dopamine agonist is favored over further increases in the levodopa dosage. Patients >60 years of age. The concern for long-term adverse effects of levodopa are not as great for patients above age 60, in whom the incidence and severity of motor fluctuations and dyskinesias appears to be diminished.[57] Since anticholinergic drugs are discouraged in patients older than age 60 and dopamine agonist monotherapy is unlikely to be of sufficient long-term benefit, carbidopa-levodopa is likely to be required earlier in this age group. As in patients 60 years or younger, sustained-release carbidopa-levodopa is recommended, but an early trial with standard carbidopa-levodopa should be considered if the response to the sustained-release preparation is suboptimal. The incidence of CNS side effects, such as hallucinations, confusion, and psychosis, is higher among patients in this age group, and appropriate caution should be exercised in determining dosage and in combining carbidopa-levodopa with other medications that exert CNS effects.
