Side Effects

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Side effects of anticholinergic agents are a significant clinical concern, which can limit their usefulness in the treatment of PD symptoms. Most antiparkinsonian effects are assumed to be mediated via central muscarinic acetylcholine receptors. Side effects may occur as either unintended central muscarinic effects or as incidental autonomic effects, attributed to peripheral binding to muscarinic and nicotinic acetylcholine receptors. In general, most effects are dose-dependent and respond to dose reductions.

Central Side Effects

Sedation, confusion, memory difficulties, and psychosis are well-described adverse events attributed to central nervous system anticholinergic toxicity. Scopolamine (Transderm-Scop®), an anticholinergic, was found to have effects on cognitive activities requiring rapid information processing in normal controls (83). Bedard et al. (84) found a transient induction of executive dysfunction in nondemented PD subjects with an acute subclinical dose of scopolamine. These findings underscore the necessity of being aware that, even in early PD patients with no clinical intellectual dysfunction, anticholinergics may have adverse effects on cognition. These drug-induced cognitive deficits are reversible, and persistent cognitive deficits off medications tend to be due to the progression of underlying disease rather than a direct adverse anticholinergic effect. In patients taking anticholinergics who develop psychosis, increased memory difficulties, and confusion, anticholinergic agents should be withdrawn promptly. Furthermore, in elderly parkinsonian patients, long-term use of anticholinergic medications has been associated with an increase in amyloid plaque densities and neurofibrillary tangles (85).

Peripheral Side Effects

Peripheral anticholinergic effects can produce a variety of autonomic dysfunction, including dry mouth, orthostatic hypotension, and urinary retention. Rare but potentially serious side effects such as narrow-angle glaucoma have also been described.

Similar to central effects, peripheral effects are often exacerbated in PD patients due to an underlying baseline autonomic dysfunction or an increased susceptibility due to advanced age. Concomitant dopaminergic medications may further exacerbate anticholinergic symptoms such as orthostatic hypotension, constipation, or sedation. Orthostatic hypotension is a common problem in PD and can be exacerbated by addition of anticholinergic agents. Conservative therapies begin by considering a dose reduction of either the anticholinergic or other hypotensive medications (including dopaminergic agents).

Dry mouth due to parasympathetic depression of salivary glands is a common and potentially uncomfortable side effect. In some patients with drooling, this effect may be advantageous. For excessive dry mouth, symptomatic oral moisturizing gel and other over-the-counter preparations such as specially formulated gum, mouth-wash, and toothpaste may be used. Sipping ice water and sugarless sucking candies may also be helpful. The severity of dry mouth also improves with a decrease in anticholinergic dose and may improve with prolonged exposure. The addition of pyridostigmine (Mestinon®), which does not cross the blood-brain barrier has been reported as helpful (86). Anticholinergics are often used to treat urinary frequency, a symptom of PD-associated autonomic dysfunction. These include medications such as oxybutynin (Ditropan® 5mg bid or tid), tolterodine (Detrol®1-2 mg bid), hyoscyamine (Anaspaz® 0.125-0.25 mg q4h), darifenacin (Enablex® 7.5-15 mg daily), trospium (Sanctura® 20 mg bid), flavoxate (Urispas® 100-200 mg tid/qid), and Solife-nacine (VESIcare® 5-10 mg daily). Anticholinergics can also result in urinary retention due to excess parasympathetic inhibition, so caution must be exercised. Risks are particularly great in elderly men due to bladder outlet obstruction from benign prostate hypertrophy. If there is any history of urinary hesitancy or urgency, a urology evaluation is reasonable prior to initiation of anticholinergic therapy.

Blurred vision is another common side effect with anticholinergics. This symptom is often attributed to relatively reduced accommodation due to parasympathetic blockade, and excessive dryness of the cornea may also contribute. For persistent symptoms, consultation with an ophthalmologist may be appropriate. Again, the use of pyridostigmine can be helpful. Rarely, anticholinergic therapy can precipitate narrow-angle glaucoma (closed-angle glaucoma), an ophthalmic emergency. The acute increase in intraocular pressure presents with pain and redness in the affected eye. In practice, this condition is extremely rare. Risk of narrow-angle glaucoma is minimal if there are normal pupillary responses and intact vision. Ophthalmology consultation should be sought during anticholinergic treatment if vision diminishes or pupillary responses become abnormal. In contrast, the more common open-angle glaucoma presents minimal risk for treatment with anticholinergics (73).

Careful consideration of risk-benefit analysis is needed when prescribing anticholinergic medications. Patients should be counseled about the potential for side effects and instructed to call with any problems. In younger patients without comor-bidity besides mild PD, anticholinergics are generally very well tolerated and represent a viable option for tremor-predominant symptoms. In more susceptible patients with clinically relevant autonomic dysfunction, cognitive dysfunction, or advanced age, anticholinergics should be used very sparingly.

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