Treatment: Parkinson's Disease Goals are to maintain function and avoid drug-induced complications; start therapy when symptoms interfere with quality of life. Bradykinesia, tremor, rigidity, and abnormal posture respond early in illness; cognitive symptoms, hypophonia, autonomic dysfunction, and balance difficulties respond poorly (See Fig. 183-1, Table 183-3). Levodopa - Routinely administered in combination with a decarboxylase inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea and vomiting. In the United States, levodopa is combined with carbidopa (Sinemet).
- Levodopa is also available in controlled-release formulations and in with a catechol-O-methyl transferase (COMT) inhibitor (see below).
- Levodopa remains the most effective symptomatic treatment for PD, and lack of response to the medication despite an adequate trial should cause the diagnosis to be questioned.
- Side effects include nausea, vomiting, and orthostatic hypotension that can be avoided by gradual titration.
- Levodopa-induced motor complications consist of fluctuations in motor response and involuntary movements known as dyskinesias.
- When pts initially take the drug, the benefits are long-lasting; with continued treatment, the duration of benefit following an individual dose becomes progressively shorter (“wearing-off effect”).
Dopamine Agonists - A diverse group of drugs that act directly on dopamine receptors. Second-generation non-ergot dopamine agonists are commonly used (e.g., pramipexole, ropinirole, rotigotine).
- Compared with levodopa, dopamine agonists are longer acting and thus provide a more uniform stimulation of dopamine receptors; less prone to induce dyskinesias compared with levodopa.
- They are effective as monotherapeutic agents and as adjuncts to carbidopa/levodopa therapy.
- Side effects include nausea, vomiting, and postural hypotension. Hallucinations and cognitive impairment are more common than with levodopa, so caution is urged in those older than 70.
- Sedation with sudden episodes of falling asleep while driving have been reported.
- Associated with impulse-control disorders including pathologic gambling, hypersexuality, and compulsive eating and shopping.
Mao-B Inhibitors - Block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter; generally safe and well tolerated.
- Provide modest antiparkinson benefits when used as monotherapy in early disease.
- Recent work has examined whether these drugs could have a disease-modifying effect; however, long-term significance is uncertain.
Comt Inhibitors - When levodopa is administered with a decarboxylase inhibitor, it is primarily metabolized by COMT; inhibitors of COMT increase the elimination half-life of levodopa and enhance its brain availability.
- Combining levodopa with a COMT inhibitor reduces wearing-off time.
Other Medical Therapies - Anticholinergics (trihexyphenidyl, benztropine) have their major clinical effect on tremor. Use in the elderly is limited due to propensity for inducing urinary dysfunction, glaucoma, and particularly cognitive impairment.
- The mechanism of action of amantadine is unknown; it has N-methyl-D-aspartate (NMDA) antagonist properties; it is most commonly used as an antidyskinesia agent in pts with advanced PD. Side effects include livedo reticularis, weight gain, and impaired cognitive function; discontinue slowly as pts can experience withdrawal symptoms.
Surgical Treatments - In refractory cases, surgical treatment of PD should be considered.
- Deep-brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus interna (GPi) has largely replaced ablation surgery (e.g., pallidotomy or thalamotomy).
- DBS is primarily indicated for pts who suffer disability resulting from severe tremor or levodopa-induced motor complications; the procedure is profoundly beneficial to many pts.
- Contraindications to surgery include atypical PD, advanced cognitive impairment, major psychiatric illness, substantial medical comorbidities, and advanced age (a relative factor).
- Experimental surgical procedures including cell-based therapies, gene therapies, and trophic factors are under investigation.
|