The symptoms of Parkinson’s disease are due to a brain deficiency of the neurotransmitter dopamine. The most logical approach to correcting this problem is to replace the dopamine (DA). Unfortunately one cannot take dopamine orally, as it does not cross the blood brain barrier (BBB). A chemical precursor to DA, levodopa (L-dopa) can cross the BBB. L-dopa is then converted in the brain to dopamine. L-dopa was introduced for treatment of Parkinson’s disease in the late 1960’s. L-dopa therapy is the gold standard treatment for Parkinson’s disease. As a general rule, unless a patient has an exuberant response to L-dopa therapy he/she most likely has an atypical Parkinson syndrome.
L-dopa is a naturally occurring substance. It is in the chemical family of compounds known as amino acids. Amino acids are the building blocks of proteins. L-dopa can be taken orally. Its absorption can be reduced if taken with a high protein meal. Once absorbed, L-dopa is converted to DA in the blood, liver and kidneys. Some of it crosses the BBB into the brain where it is then converted to DA. Only the L-dopa that crosses the BBB has any beneficial clinical effect. A compound called carbidopa is given with L-dopa. Carbidopa inhibits the enzyme in the liver, kidneys, and blood that converts L-dopa to DA. This allows more L-dopa to pass into the brain. It also minimizes some of the side effects of L-dopa therapy. Carbidopa does not cross the BBB. Sinemet CR is a longer acting, controlled release form of carbidopa/L-dopa. Sinemet, Parcopa and Stalevo are all “regular” carbidopa/levodopa preparations.
Once a patient’s activity of daily living becomes compromised by the Parkinson symptoms, L-dopa therapy almost always improves the patient’s quality of life. The patient’s speech, gait, functional abilities and general movements are much better. L-dopa therapy is very effective in relieving the symptoms of Parkinson’s disease, particularly the symptom of rigidity. Tremor can be significantly reduced by L-dopa therapy although responses may vary from patient to patient. Early in the course of Parkinson’s disease, bradykinesia responds favorably to L-dopa. Here again patients may have a variable response to therapy. In later stages of Parkinson’s disease, bradykinesia can be a significant problem as it becomes less responsive to L-dopa. It is preferable to delay starting L-dopa therapy in early Parkinson’s disease. There are several other different medications that are effective in treating early symptoms.
L-dopa therapy can maintain this functional improvement for several years. Unfortunately this effect eventually wears off. This can be anywhere from four to ten years or more. In general, L-dopa has a useful clinical window of five to seven years. After this, patients can have significant side effects including dyskinesias and other motor fluctuations. Dyskinesias are uncontrolled involuntary head, trunk, arm and leg movements. Patients may have writhing movements of their head and extremities. They frequently have tricks to suppress some of this activity, such as sitting on their hands or crossing their arms. Development of dyskinesias is related to the duration of L-dopa therapy and the total daily dosage amount. The longer a patient is on L-dopa and the higher the daily dosage, the more likely it is that they will develop dyskinesias.
Different motor fluctuations can occur including end-of-dose (wearing off) phenomenon, on-off episodes and freezing. End-of-dose phenomenon develops toward the end of a dosing period where the effects of L-dopa wear off prior to the next dose. On-off episodes occur randomly and unexpectedly. A patient may be functioning well (on) one moment and then suddenly have change in functional status, becoming quite rigid and immobile (off). These off attacks can last anywhere from minutes to hours. Freezing occurs when a patient suddenly has the sensation that his feet are stuck to the floor. The patient may have difficulty initiating gait or passing through a doorway. Patients may also develop dystonias, which are sustained involuntary contractions of muscles. Dystonias may be painful. This most commonly affects a limb, hand, or foot.
The class of drugs known as the COMT inhibitors was developed to boost the effect of L-dopa for treatment of Parkinson’s disease. The majority of dopamine is metabolized in the brain by two enzymatic systems: MAO-B and COMT (Catechol-O–Methyl Transferase.) By inhibiting these two metabolic pathways, brain levels of dopamine can be maintained for longer periods of time. This keeps dopamine levels at a steadier level in the brain, thereby reducing motor fluctuations and sustaining longer clinical benefit. COMT inhibitors also block the break down of L-dopa outside of the brain. This makes more L-dopa available to cross the BBB for conversion to dopamine. The first COMT inhibitor available in theUnited States was tolcapone (Tasmar.) The FDA approved entacapone (Comtan) in late 1999. In general, the COMT inhibitors are well tolerated, but like many Parkinson medications, have the potential for side effects.
Rarely tolcapone can cause a severe liver problem, which can be fatal. For this reason, Comtan has become the preferred COMT inhibitor. However, for patient’s that have not benefited from Comtan or other dopamine boosting agents, Tasmar would be a reasonable medication to consider. COMT inhibitors act in conjunction with L-dopa and must be given with this drug. COMT inhibitors will not improve Parkinson’s disease if taken alone. Stalevo is a combination tablet containing Comtan, levodopa and carbidopa.
Dopamine agonists are chemical agents that mimic the action of dopamine. Unlike L-dopa, dopamine agonists do not need to undergo enzymatic transformation to exert their clinical effects. These agents can be taken orally. They cross the blood-brain barrier and act directly on the dopamine receptor sites. Bromocriptine was the first dopamine agonist. It has been available for Parkinson disease treatment since 1970, but was not widely used due to the high doses required for clinical benefit, difficulty in titration of dosing, cost and side effects. Newer dopamine agonists have been developed. These medications have a more specific action on specific dopamine receptors than bromocriptine. Current agents include pramipexole (Mirapex), ropinirole (Requip) and rotigotine patches (Neupro.) Permax (pergolide) was voluntarily removed from the market due to risk of cardiac valvular disease.
Apokyn (apomorphine) is an injectable dopamine agonist. It is quite useful in Parkinson disease for patients that have recurrent, prolonged off times during the day or night. This medication is rapidly acting with duration of effect for about 90 minutes. This helps patients by allowing them to function during a time that they would otherwise be incapacitated, until their other medications take effect. This medication can be particularly useful in the morning, when PD patients more commonly have significant off time.
The dopamine agonists have been viewed by many clinicians to be a more appropriate first line treatment for Parkinson’s disease. The idea is to delay starting L-dopa therapy for as long as possible while maintaining a patient’s functional level. Dopamine agonists are also used as additive therapy with Ldopa. They can smooth out the motor fluctuations that occur with L-dopa therapy. This is particularly true for patients with on-off or wearing off episodes. The dopamine agonists have a relatively prominent side effect profile including nausea, low blood pressure, drowsiness, leg swelling, hallucinations, paranoia, nightmares, confusion, and psychosis. It is usually these side effects that limit the usefulness of this class of drugs.
Amantidine (Symmetral) is a drug that can be helpful in Parkinson’s disease therapy. Amantidine is thought to help promote dopamine-containing neurons to more easily release their dopamine thereby helping to alleviate Parkinson symptoms. This however is still a matter of dispute. Amantidine is generally safe to use and is commonly started early in the course of treatment of Parkinson’s disease. Generally, it loses its effectiveness over a few months, although some patients continue to get lasting benefit.
A class of drugs known as “anticholinergics” is frequently used in combination with L-dopa therapy. Acetylcholine is a major neurotransmitter in the brain. Dopamine helps to suppress the effects of acetylcholine. Since there is a brain dopamine deficiency in Parkinson patients, the effects of acetylcholine become more pronounced. The use of anticholinergic compounds can help to control the effects of acetylcholine. Anticholinergics may help to relieve the tremor, rigidity, excessive salivation and sweating that Parkinson patients experience. The anticholinergics can have significant side effects including dry mouth, blurred vision, constipation, difficulty urinating, hallucinations, forgetfulness and confusion. The two most commonly used anticholinergic drugs are trihexyphenidyl (Artane) and benztropine mesylate (Cogentin.)
Selegiline (Eldepryl) is a selective monoamine oxidase-B (MAO-B) inhibitor. Dopamine is broken down (metabolized) in the brain by MAO-B. Selegiline can be used for enhancing the effect of L-dopa by slowing the metabolism of dopamine. This has the effect of raising brain dopamine levels. By doing so, the total daily dosage of L-dopa can frequently be reduced. This, in combination with a dopamine agonist and/or Comtan, can reduce or eliminate some of the troublesome side effects seen with higher doses of L-dopa such as confusion, dyskinesias and dystonias. It can also help by smoothing out end-of-dose phenomenon and on-off episodes. The MAO-B inhibitors can occasionally be effective as a first line treatment in early Parkinson’s disease. Newer MAO-B inhibitors are being developed. Zelepar is a newly developed, faster acting form of selegiline. The tablet dissolves rapidly in the mouth and is absorbed through the oral tissues, bypassing stomach adsorption.
Azilect (Rasagiline) is the newest MAO-B inhibitor approved by the FDA for clinical use beginning August 2006. Azilect has been shown in studies to be of significantly better benefit, even when used as initial therapy for Parkinson disease, over selegiline. For patients taking Azilect, they must be made aware of the potential for Serotonin Syndrome. This condition may present clinically as a wide range of clinical symptoms. Mild symptoms may consist of rapid heart rate, sweating, twitching or increased tremor. More severe symptoms can include marked blood pressure elevation and body temperature elevations 102-104°. In the most severe cases, patients may go into shock. Fortunately, Serotonin Syndrome is very rare.