Dopaminergic Agents

Levodopa

Levodopa is converted in the brain into dopamine, the same chemical created by substantia nigra cells and used to control movement. Levodopa was introduced as a PD therapy in the 1960s, and remains the most effective therapy for motor symptoms. It lessens and helps to control all the major motor symptoms of PD, including bradykinesia, which is generally the most disabling feature of the disease.

Carbidopa is included in the standard oral formulation to increase the effectiveness of a dose of levodopa and minimize side effects such as nausea and vomiting.

Levodopa is a type of amino acid. Amino acids, which are contained in certain foods, are the building blocks of proteins. These building blocks are transported into the blood stream through the wall of the intestines. In similar fashion, levodopa must be absorbed into the blood stream through the wall of the intestines. This requires the action of a specific "transporter" or amino acid vehicle in the intestinal lining. Because this transporter can only work so fast, an excessive amount of dietary protein can slow the transport of levodopa into the blood stream. If sufficient amounts of levodopa do not get into the blood stream and ultimately to the brain, then the dose prescribed may not be effective in treating the symptoms of PD. Once levodopa is in the blood stream, it must then cross into the brain, where it becomes active in controlling the symptoms of PD. However, the same "transport phenomenon" occurs when levodopa crosses from the bloodstream into the brain. To avoid the competition of levodopa with other dietary amino acids, patients with more advanced PD may need to time their doses to avoid meals, or reduce the protein content of certain meals.

Adverse effects
Nausea and vomiting are the most common side effects, and are due to accumulation of dopamine in the bloodstream. Orthostatic hypotension (low blood pressure upon standing) also occurs. The risk of hallucinations and paranoia increases over time. Compulsive behavior, including gambling and hypersexuality, is another risk.

Drowsiness is a common adverse effect of levodopa and other dopaminergic therapies, and sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep onset. It is important to understand this possibility, especially when levodopa therapy begins, when increasing doses, or switching agents.

The most troubling adverse effect from long-term levodopa use is dyskinesias. Dyskinesias are uncontrolled movements, including writhing, twitching, and shaking. Dyskinesias result from the combination of long-term levodopa use and continued neurodegeneration. They typically begin to develop in milder forms after 3 to 5 years of treatment, but are more severe after 5 to 10 years of treatment.

As the disease progresses, the increasing dose of levodopa required for symptom control approaches the dose at which intolerable dyskinesias occur. This limits the continuing usefulness of levodopa. At this point, surgery may be the only effective option. Because of this potential, many physicians recommend starting a younger patient on a dopamine agonist instead of levodopa, which delays the onset of dyskinesias.

Immediate-release levodopa/carbidopa is formulated in doses of 10/100, 25/100, and 25/250 milligram pills. Onset of effect is usually 20 to 40 minutes, and duration of benefit is 2 to 4 hours in more advanced stages of PD.

Dissolving the tablets in orange juice is a possible strategy for speeding the onset of effect. Patients must be sure to consult with their physician before trying this, as the duration of benefit is usually shorter as well.

Continuous infusion of levodopa into the intestine, through a feeding tube, is being studied as of mid-2004. The hope is that continuous infusion may lessen the risk for developing dyskinesias. However, this treatment approach is logistically challenging, and is reserved for only a small subset of patients with severe motor fluctuations or dyskinesias.

Dopamine Agonists

Dopamine agonists are drugs that imitate or mimic the action of levodopa in the brain by directly stimulating dopamine receptors, the same receptors that dopamine itself stimulates. While they are not quite as effective as levodopa, they provide excellent relief of symptoms and delay the onset of motor complications.

A variety of dopamine agonists are available that differ in their duration of action, chemical makeup, method of delivery, and adverse effect profile. The currently available agonists are:

Dopamine Agonists (generic name followed by trade name):

• Apomorphine (Apokyn®)
• Bromocriptine (Parlodel®)
• Pergolide (Permax®)
• Pramipexole (Mirapex®)
• Ropinirole (Requip®)

Clinical trials of several of both pramipexole and ropinirole have shown their ability to delay motor complications when used as monotherapy (the only drug given) early in the disease. Agonists tend to produce more edema and psychosis than levodopa, effects which may be more significant than mild dyskinesias, especially in older patients. Hence, in patients who are younger (less than age 70) and otherwise healthy, initiation of dopaminergic therapy with a dopamine agonist may be indicated. Older PD patients (especially those with cognitive problems) are usually treated with levodopa alone.

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. It is important to understand this possibility, which is especially likely at the commencement of therapy, when increasing doses, or switching to a different dopamine agonist.

Other significant adverse effects of dopamine agonists include nausea and vomiting, orthostatic hypotension, edema, and psychosis.

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

Apomorphine(Apokyn®) is the dopamine agonist whose symptomatic effect is most like that of dopamine. However, it cannot be taken in pill form, and must be delivered by injection beneath the skin (subcutaneously). Its duration of effect is also shorter than levodopa's.

Subcutaneously injected apomorphine is used as a "rescue" therapy for patients with "off" episodes. Its onset of effect is approximately 10 minutes, and lasts approximately 90 minutes. It can be used whenever a patient feels an off episode approaching before the next dose of levodopa takes effect, such as early in the morning, or during that day when wearing off occurs. It can be used up to 10 times per day. If a patient needs more treatment than that, alternative therapies should be considered. Injection-site reactions may occur, but are generally not a problem.

Nausea and vomiting are the principal adverse effects. An antiemetic is required at the beginning of apomorphine therapy. Trimethobenzamide is the agent usually prescribed. Many patients are able to stop taking it after several weeks of therapy.

	COMT Inhibitors