Medications Used to Treat Parkinson's Disease

Properly selected medications with the correctly tailored dose form the mainstay of treatment of Parkinson's Disease.

Drugs currently used to treat Parkinson’s Disease make movement easier and can prolong function for many years. Medications aim to replace or mimic the missing chemical dopamine in the brain.

The following are the medications used in the treatment of Parkinson's Disease. Each will be considered below.

• Levodopa with carbidopa:Sinemet^TMSinemet CR^TM

• Levodopa with benserazide: Prolopa^TMin Canada and Madopar^TMin Europe

• COMT inhibitors : entacapone(Comtan^TM), Tasmar^TM)

• Dopamine agonists:pramipexoleMirapex^TM), ropinerole( Requip^TM), bromocriptine( Parlodel^TM), pergolide ( Permax^TM)

• Other medications: amantadine(Symmetrel^TM), benztropine (Cogentin^TM), trihexyphenydil(Artane^TM), deprenyl (Eldepryl^TM)

Levodopa

Considered below is:

How it works

Levodopa preparations

Side effects

How It Works

Levodopa (L-dopa for short) has been used successfully in the treatment for Parkinson’s Disease for over 30 years. It remains the most effective treatment for Parkinson’s Disease.

L-dopa is a natural chemical found in animals and plants. When L-dopa is formulated for drug use, the generic name levodopa is used.

In patients with Parkinson’s Disease the cells in the brain that produce dopamine die (for more details see what causes Parkinson’ Disease LINK). Levodopa works by being taken up by the surviving dopamine-producing cells in the brain, and is converted by these cells into dopamine.

People with Parkinson’s Disease can't simply take dopamine tablets or vegetable products containing dopamine (e.g.fava beans) to replace the missing dopamine, because dopamine taken by mouth does not get into the brain. Levodopa on the other hand does get into the brain and, once there, it converts to dopamine.

Levodopa Preparations

Levodopa is combined with carbidopa (Sinemet CR^TM, Sinemet^TM and is the main treatment for Parkinson’s Disease. (Another preparation, levodopa in combination with benserazide, is available in Canada, Europe and other parts of the world.) Combining carbidopa or benserazide with levodopa has several benefits:

• Carbidopa or benzerazide prevent levodopa from being converted to dopamine outside the brain.

• They allow more levodopa to enter the brain where it is needed.

• They help to reduce or prevent the side effects of dizziness and nausea.

The combination is usually started with low, but increasing doses, until the best effect is achieved. Levodopa never loses its effectiveness, although with increasing disability the dose required to control symptoms is also enough to precipitate unwanted side effects.

Physicians may use either the Sinemet^TM or Sinemet CR^TM preparation for their patients as soon as therapy is needed. The slow, steady release of the drug into the brain by the controlled-release Sinemet CR^TM preparation may be better for remaining dopamine cells than the abrupt delivery of the Sinemet^TM (similar to a soaker hose versus a fire hydrant).

• The immediate-release and controlled-release Sinemet^TMpreparations are best started slowly, increasing by small amounts until the required dosage is reached.

• A starting dose may be one-half of a tablet once a day increasing to three to four times a day

• This dose can be increased every four to seven days as tolerated.

• Both medications can sometimes cause nausea and dizziness when they are started.

• At high doses, they may cause involuntary movements (dyskinesias) and confusion. All side effects are dose-dependent (disappear when the drug is reduced or stopped).

• Physicians are somewhat divided as to whether anitparkinson drugs should be taken on an empty stomach or with food. Taking the tablet with food will reduce the likelihood of side effects. Sinemet CR^TM should always be taken with food for proper absorbtion. Patients should follow the recommendations of their neurologist.

Side Effects of Levodopa:

Levodopa preparations are not without side effects. The most common include nausea, vomiting, low blood pressure, involuntary movements, and, at higher doses in the elderly and frail, confusion.

• Nausea and vomiting can be a problem as the drug is being introduced. This is because the dose of carbidopa is not large enough to control these side effects. Ironically, the nausea and vomiting often get better as the levodopa/carbidopa dose is increased. The controlled-release preparation, Sinemet CR^TM, is absorbed more slowly and far less likely to cause early side effects. Taking the drug with a light meal or snack can also help these side effects.

• Involuntary movements (dyskinesias) writhing, jerking, or free flowing movements and nodding can occur. The rate at which dopamine "turns over" in a person's brain cells may determine whether or not they will develop dyskinesia. Dyskinesia can only be controlled effectively by lowering the dose of levodopa or, in some severe cases, surgery.

  (Reference: R. Fuente-Fernandez, V. Sossi, Z. Huang, S. Furtado, J. Q. Lu, D. B. Calne, T. J. Ruth, and A. J.Stoessl. Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias. Brain 127 (Pt 12):2747-2754, 2004).

Other drug side effects include:

• "Wearing-off effect." This happens when Parkinson's symptoms begin to recur before the next scheduled dose of drug, due to progression of the disease. When this happens, it is easy to think that the drug is making your symptoms worse - for a while after you take the next dose, your symptoms can continue to worsen until the next dose 'kicks in'. This happens because the drug takes a while to be absorbed and reach your brain.

• These can be improved by the addition of a COMT inhibitor or a dopamine agonist

• "On-off attacks." TThese are unpredictable fluctuations in response to drug therapy that may last up to several hours. They are thought to be due to a combination of levodopa dosage and progression of symptoms. The dopamine storage cells may lose their capacity to retain the dopamine delivered by the medication.

(Reference: R. Fuente-Fernandez, and others Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model. Brain 127 (Pt 4):888-899, 2004).

These can usually be improved with lower, more frequent doses of the drug, the use of a controlled release drug or with the addition of a dopamine agonist.

COMT Inhibitors

COMT inhibitors are a new class of drug that allows even more levodopa to enter the brain, by blocking an enzyme in the body called COMT. COMT stands for Catechol-O-Methyltransferase. This enzyme is responsible for most of the levodopa in a given dose being converted to dopamine outside the brain (where it is not needed).

Entacapone (Comtan^TM) is able to inhibit one of the COMT enzymes responsible for the breakdown of dopamine in the body, resulting in greater and more sustained blood levels of dopamine when given together with carbidopa/levodopa.

Entacapone is administered together with each dose of carbidopa/levodopa. It prolongs the duration of levodopa benefit, is easy to use, and provides quick results. There is a possibility that a person will experience the side effects of too much levodopa, which can then be controlled by reducing the levodopa or entacapone dose or spacing out the dosing regimen. The primary indication for the use of entacapone is for the treatment of the wearing-off effect.

(Tasmar ^TM), is another COMT inhibitor that has proved to be very useful as an add-on medication for the treatment of Parkinson’ Disease, but had the serious side effect of fatal liver damage in a few individuals. Although it has been officially withdrawn in Europe and Canada, is still used in some patients in the U.S. and a very few in Canada who continue to do well on the medication without evidence of liver damage.

STALEVO®^TM Is a drug that contains a combination of Levodopa,/carbidopa (Sinement ®^TM) and entacapone (COMTAN®^TM)

STALEVO 50®^TM, containing 12.5 mg carbidopa, 50 mg levodopa, and 200 mg entacapone

STALEVO® 100^TM, containing 25 mg carbidopa, 100 mg levodopa, and 200 mg entacapone

STALEVO® 150^TM, containing 37.5 mg carbidopa, 150 mg levodopa, and 200 mg entacapone

STALEVO®^TM can be used instead of carbidopa/levodopa and COMTAN by patients taking those medicines as separate tablets.

Stalevo®^TM is available in the USA and other parts of the world. It is expected to be available in Canada within the next 12-18 months.

Dopamine Agonists

Dopamine agonists are medications that imitate the action of dopamine in the brain and cause nerve cells to react as if dopamine were present. Unlike levodopa, they do not require conversion to dopamine to work.

Currently there are four dopamine agonists available:

• Pramipexole (Mirapex ^TM)

• Ropinirole (Requip^TM)

• Bromocriptine (Parlodel^TM)

• Pergolide (Permax^TM)

Pramipexole dihydrochloride and Ropinirole Hydrochloride are non-ergot dopamine agonists. Bromocriptine and pergolide are ergot-derived dopamine agonists. Ergot is a fungus that grows on grasses, and rye in particular. It produces alkaloids that are used in a wide range of drugs.

• Pramipexole (Mirapex ®) ^TM or Ropinirole ^TM(Requip®) may be used as a "first line" treatment, that is, as the main treatment, particularly for people with young onset (under 50) Parkinson’s Disease.

Dopamine agonists are now frequently added to levodopa early in treatment, before levodopa side effects first occur, to extend the duration of benefit between each dose.

• These drugs may also be used to replace some levodopa if its side effects have become unmanageable.

• When given together with levodopa, symptom control between doses lasts longer, and wearing-off reactions, on-off effects , and dyskinesias can be reduced.

• Side effects: Dopamine agonists can cause stomach upset, nausea and vomiting, and dizziness from lowered blood pressure when first started and, at high doses, confusion or hallucinations. These side effects are dose-dependent and reversible.

The best results are achieved when the agonist is started in a low dose, increasing by half a tablet until the required dose is reached. These drugs should be taken with food to minimize side effects and can be taken at the same time as other antiparkinson drugs.

Pergolide has recently been associated with cardiac valve disease in patients taking the drug for a long time. If you are on this drug discuss whether you should switch to another with your physician

(Reference: J. Horvath and others Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord. 19 (6):656-662, 2004).

Bromocriptine and pergolide can both cause fibrotic changes in the lungs after prolonged use but these symptoms are reversible if the drug is stopped. They also can cause a condition in the lower legs that makes them red, hot, and painful (erythromelalgia).

At the time ropinerole and pramipexole were first marketed there were reports of patients falling asleep while driving when taking one of these drugs. Some countries banned people taking the drugs from driving. Two major published studies have since shown that in certain people any drug used to treat Parkinson's disease can produced daytime sleepiness and so everyone should be aware of this possibility whatever treatment they are on.

(Reference: C. C. Sanjiv, and others Daytime somnolence in patients with Parkinson's disease. Parkinsonism and Related Disorders 7 (4):283-287, 2001.

D. E. Hobson, and others. Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. J American Medical Association 287 (4):455-463, 2002).

• The antibiotic CIPRO ®^TM should be used with caution by patients taking ropinerol.

Other Medications Useful In Parkinson’s Disease

Other medications that are useful in treating Parkinson’s Disease include the following:

• Amantadine (Symmetrel ^TM) is available as a 100 mg soft red gelatin capsule or a syrup. This drug can be used as early treatment for rigidity. For many years, the action of amantadinewas not understood. It has recently been shown to be a glutamate antagonist and to be effective at reducing dyskinesias. This is now its major role in the treatment of Parkinson’s Disease

  (Reference: P. J. Blanchet, L. V. Metman, and T. N. Chase. Renaissance of amantadine in the treatment of Parkinson's disease. Adv.Neurol. 91:251-257, 2003).

  Side effects:Amantadine can cause lightheadedness and confusion and a red "spider's web" mottling on the legs (lividoreticularis). It should be used with caution in the elderly and those with urinary problems. It should not be stopped abruptly after prolonged use.

• Anticholinergic drugs (such as benztropineCogentinor^TMtrihexyphenidyl Artane ^TM) or antihistamines used in the treatment of allergy symptoms (such as diphenhydramine) may be used alone in the early stages of treatment, if tremor is the major problem. These medications are more useful in treating tremor than the slowness and stiffness.

  Side effects: In older, frail individuals, side effects that include confusion, blurred vision, and urinary retention often limit the usefulness of these drugs.

• Selegiline (Eldepryl^TM) The use of this drug has declined in the last five years. This drug has a modest action. It works by slowing the breakdown of dopamine in the brain by inhibiting one of the enzymes responsible for the breakdown of dopamine (called monoamine oxidase B). It comes in 5 mg tablets and the daily dose must not exceed 10 mg. If used as initial treatment, selegiline may delay use of levodopa by about a year but should be stopped when more treatment is needed. There are reports suggesting that it should not be used in conjunction with levodopa. It can have a mild antidepressant effect.

  Side effects: The major side effect is insomnia (because it converts to amphetamine in the brain), and lack of sleep is extremely detrimental to a person with Parkinson’s Disease. Even though selegiline has few side effects, it has the potential to enhance side effects associated with levodopa if they are taken together.

Many of the drugs described above are now available in generic forms.