Since the advent of levodopa therapy for PD in the 1960s, the usefulness and popularity of anticholinergics waned dramatically. However, an evidence-based review by the Cochrane Collaboration concluded that anticholinergics are effective in improving motor function in parkinsonian patients as monotherapy and adjunct therapy. Current data are not sufficient to allow comparison in efficacy or tolerability between individual anticholinergic medications (76).
Tremor Predominant Parkinson's Disease
The most recognized use of anticholinergics is to treat tremor in early- or young-onset PD representing a levodopa-sparing strategy. In general, it appears that anti-cholinergics help tremor, but do not significantly affect bradykinesia or rigidity of PD. Anticholinergic agents may be used as initial therapy of tremor predominant PD (72). Schrag et al. (77) found equivalent reductions in tremor with a single dose of either a dopamine agonist (apomorphine) or an anticholinergic (biperiden), but only apomorphine reduced rigidity and akinesia. Although anticholinergics do not appear to have significant effects on akinesia and rigidity as therapy, deterioration of all parkinsonian symptoms has been described following abrupt withdrawal (78).
Anticholinergics are useful in the early treatment of tremor predominant PD in young or mild patients if the primary indication for symptomatic therapy is tremor, and there are relatively minimal associated signs of rigidity or bradykinesia. Anticholinergics should be avoided in patients with baseline cognitive deficits, significant orthostatic hypotension, or urinary retention, as they are at higher risk for exacerbation of these symptoms.
Parkinson's Disease-Associated Dystonia
Dystonia can occur in several clinical circumstances in association with PD. Anti-cholinergics can play an adjunctive role in managing such dystonia. Most PDassociated dystonia occurs in the context of motor complications, but can occur even in levodopa-nai've patients. Most commonly, an off-period dystonia characteristically causes painful foot- and toe-posturing when dopaminergic medication wears off in the morning. Levodopa-induced on-period dystonia can follow either biphasic or peak-dose patterns. Poewe et al. suggest that anticholinergics can play a role in helping relieve the severity of episodic dystonia in PD. However, limb dystonia as an early symptom in levodopa-naive patients tended not to respond as well compared to dystonia associated with motor fluctuations (79).
In practice, dopamine agonists seem more useful in treating most forms of PDassociated dystonia. Anticholinergics can be used as adjunctive therapy if dystonia persists despite dopaminergic therapy. Theoretically, on-period dystonia may be more amenable to anticholinergics, as dopaminergic agents risk prolonging peak-dose effects.
TABLE 1 Common Anticholinergics Used in Parkinson's Disease
Trihexyphenidyl Central 2, 5 mg tablets;
(Artane®) antimuscarinic 2mg/5mL elixir
Central 0.5, 1, 2mg tablets;
antimuscarinic injection 1 mg/mL
Central 2 mg tablets;
antimuscarinic 5mg/mL ampules
Ethopropazine Central 50 mg tablets
1 mg qd-bid
0.5 mg bid
1 mg bid
Increase to tid; every 3-4 days increase by 0.5-1 mg each dose Increase to tid; every 3-4 days increase by 0.5-1 mg each dose Increase to tid; every 3-4 days increase by 0.5-1 mg each dose Increase to tid; every 3-4 days increase by 12.5mg each dose
2-3 mg tid
50 mg tid-qid
First synthetic anticholinergics
Also available parenteral ly
Also available parenteral ly
Not available in the United States
Secondary anticholinergic effects
Diphenhydramine Antihistamine (Benadryl®)
12.5, 25 mg tablets;
12.5 mg liquid 10, 25, 50, 75, 100, 150 tablets; injection 10 mg/mL 25 mg tablets
25 mg qhs 12.5mg qhs
Increase by 25mg every 3-4 days Increase by 12.5mg every 2-3 nights
Increase by 6.25-12.5mg every 2-3 nights
25 mg tid or 25-100 mg qhs 150mg
H1 blocker, also available parenterally
May cause increased salivation
Often anticholinergic agents can be used to treat miscellaneous indications. In this setting, agents are often chosen on the basis of secondary anticholinergic side effects. For example, if antidepressants are needed, a tricyclic antidepressant such as amitriptyline might be chosen for its anticholinergic properties to assist with insomnia or PD-related tremor. Diphenhydramine is an antihistamine commonly prescribed for allergies or insomnia, and possesses mild anticholinergic side effects that can be used for PD-associated sialorrhea and may help reduce tremor. Regarding sialorrhea, atropine drops in 1% solution administered sublingually twice daily has been reported as beneficial with no significant mental state changes (80).
Another class of medications commonly used in PD is the atypical antipsychotics. Quetiapine (Seroquel®), olanzapine (Zyprexa®), and clozapine (Clozaril®) all have anticholinergic properties that may contribute to side effects and may be of only modest benefit. Clozapine, in particular, has significant anticholinergic-attributed sedation, but also can reduce tremor (81) and produce increased salivation and drooling. Amantadine also has modest anticholinergic properties, although its antiparkinsonian use is commonly chosen on its own merits (82). A partial list of commonly used medications with either primary or secondary anticholinergic properties and their use is shown in Table 1.
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