Parkinson's Disease

Dopaminergic Agents

Levodopa
Levodopa was introduced as a PD therapy in the 1960s, and remains the most effective therapy for motor symptoms. It alleviates all the cardinal motor symptoms of PD, including bradykinesia, which is generally the most disabling motor feature of the disease.

Carbidopa (in the United States) or benserazide (not available in the US) are included in the standard oral formulation to inhibit conversion of levodopa to dopamine outside of the brain (in the periphery). Carbidopa does not cross the blood-brain-barrier.

Levodopa is a large neutral amino acid, which is absorbed in the gut and transported across the blood-brain barrier by the large neutral amino acid transporter. Thus, it competes with dietary amino acids for transport, and patients with advanced PD may need to schedule the administration of their doses far from meal times, or reduce the protein content of their meals.

Legend: Levodopa Metabolism

BBB = Blood brain barrier AADC = amino acid decarboxylase COMT = catechol O-methyltransferase MAO = monoamine oxidase

Adverse effects
Nausea and vomiting are the most common side effects, and are due to accumulation of dopamine in the blood stream (periphery). Orthostatic hypotension also occurs. The risk of hallucinations and paranoia increases over time, especially with advanced age. Compulsive behavior, including gambling and hypersexuality, is a rare adverse effect.

Drowsiness is a common adverse effect of levodopa and other dopaminergic therapies, and daytime somnolence and sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep onset; when such therapy is prescribed by a physician, patients need to be counseled and warned about this possibility of sudden sleep onset. In addition, patients should be reminded of this warning when doses are increased or when switching agents. No one agent appears to be more likely than others to cause these effects.

The most troubling adverse effect from long-term levodopa use is dyskinesias, or uncontrolled movements. These typically begin to develop in a relatively mild form after three to five years of treatment and become more severe after five to 10 years of treatment. As the disease progresses, the dose required for symptomatic control approaches that which induces intolerable dyskinesias, thus narrowing the therapeutic window and limiting the continuing utility of levodopa. At this point, surgery may be the only effective option. Delaying commencement of levodopa therapy may be an appropriate strategy in younger patients, as discussed in the section entitled "Approaches to Treatment."

Early concern that levodopa may be neurotoxic in vivo does not seem to be borne out by clinical experience or recent research.

Dosing and Other Formulations
Theoretical and experimental evidence suggests that continuous, versus pulsatile, delivery of levodopa may reduce or delay the risk for dyskinesias. While controlled-release preparations have not proven effective, newer formulations, including duodenal delivery, may hold promise in this regard.

Immediate-release levodopa/carbidopa is formulated in doses of 10/100, 25/100, and 25/250 milligram pills. Onset of action is usually 20 to 40 minutes. Early-stage PD patients typically experience a smooth and sustained benefit from intermittent dosing. In more advanced PD patients, duration of benefit is 2 to 4 hours.

An orally disintegrating tablet of levodopa and carbidopa (Parcopa®) is also available in the same doses as the swallowed pill. This formulation does not need to be taken with water.

Dissolving the tablets in orange juice is a possible strategy for speeding the onset of effect, although this reduces the duration of benefit.

Dopamine Agonists
A variety of dopamine agonists are available; these differ in their duration of action, method of delivery, and adverse effect profile. The currently available agonists are listed in the table below.

Dopamine Agonists: Half-lives and Monotherapy Dosages
Name	T1/2	Dosage (monotherapy)
Apomorphine (Apokyn®)	30 min	2-100 mg/day
Bromocriptine (Parlodel®)	6 hr	7.5-30 mg/day
Pramipexole (Mirapex®)	8 hr	1-4.5 mg/day
Ropinirole (Requip®)	4 hr	3-24 mg/day
Rotigotine (Neupro®)	5-7 hr	4-6 mg/day
Cabergoline (not approved in US)	65+ hr	2-5 mg/day
Lisuride (not approved in US)	2-4 hr	1-5 mg/day

Dopamine agonists directly stimulate dopamine receptors, and do not require metabolic conversion within the degenerating cells of the substantia nigra. Despite this theoretical advantage, dopamine agonist monotherapy is not an effective substitute for levodopa in the long-term, with the possible exception of apomorphine infusion.

Clinical trials of both pramipexole and ropinirole have shown their ability to delay motor complications when used as monotherapy early in the disease. These trials have also shown that the dopamine agonists provide less complete symptomatic control than levodopa, although it is possible this difference is simply an artifact of the evaluation tools used. Dopamine agonists tend to produce more edema and psychosis than levodopa, effects which may be more clinically significant than mild dyskinesias, especially in older patients.

The reason for the delay in motor complications has been the subject of much study and controversy. While some preclinical evidence supports the possibility that dopamine agonists are neuroprotective, no unequivocal clinical evidence for this effect exists. In the agonist-levodopa trials, intensity of neuroimaging markers declined less quickly on the agonists. While neuroprotection is one possible explanation, there is also evidence that differential pharmacological effects on the remaining cells, such as upregulation by the agonist or downregulation by levodopa, may play a part.

Adverse Effects
Drowsiness is a common adverse effect of dopamine agonists and levodopa, and sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep onset, and should be warned about this possibility at the commencement of therapy, when increasing doses, or switching agents.

Other significant adverse effects of dopamine agonists include nausea, vomiting, and orthostatic hypotension. A rare but potentially serious adverse effect is development of impulse control disorders, most often manifested as hypersexuality, excessive gambling, compulsive shopping, or obsessive hobby activity.

Fibrosis is a risk from the ergot-derived dopamine agonists, which are pergolide, bromocriptine, cabergoline, and lisuride. Pulmonary and retroperitoneal fibrosis are rare, while recent studies suggest fibrosis of the heart valves may be common enough to warrant monitoring of all patients on ergot-derived agonists, and switching to a non-ergot agonist when possible. Pergolide was withdrawn from the US market in March 2007 over concern for this effect.

Apomorphine Rescue Therapy
The receptor activation profile of apomorphine most closely matches that of levodopa, and it can provide a quality of symptomatic benefit that is equivalent to that of levodopa. It is not orally available, and must be administered parenterally.

Subcutaneously injected apomorphine (Apokyn®) is used as a "rescue" therapy for patients with off episodes. Its onset of effect is approximately 10 minutes, and lasts approximately 90 minutes. Guidelines from frequent prescribers indicate it can be used up to 10 times per day; if more frequent dosing is needed, continuous infusion is recommended if the patient is to remain on apomorphine. Injection-site reactions may occur, but are generally well tolerated.

Continuous subcutaneous apomorphine infusion is possible as an alternative to other forms of therapy. This continuous delivery has been shown to reduce dyskinesias in clinical trials. Skin nodules at the infusion site are a major complication, but may be minimized by regular rotation of the needle site.

Nausea and vomiting are the principal adverse effects. An antiemetic is required at the commencement of apomorphine therapy. Domperidone (not available in US) is used widely outside the United States, while trimethobenzamide is the agent of choice within the US. Many patients can be tapered from it after several weeks of therapy.