The major classes of anti-Parkinson medication include carbidopa-levodopa (often referred to as Sinemet), catechol-o-methyltransferase inhibitors or COMT inhibitors, monoamine oxidase type B inhibitors, dopamine agonists, amantadine, and anticholinergics. Many of these medications are used in combinations although some of these may be used by themselves (in monotherapy) for treatment of symptoms of Parkinson’s disease.
Levodopa is the main and most effective symptomatic treatment for Parkinson’s disease and acts to directly replace the brain dopamine deficiency that occurs as a result of loss of dopamine cells. Levodopa is a precursor to dopamine that can cross between the bloodstream and the brain, unlike dopamine. Once levodopa is in the brain, it can be converted by dopamine-producing cells to dopamine. Typically dopamine is stored in small vesicles within dopamine cells and then released as needed by the brain. Dopamine acts on cells in the striatum (where dopamine-producing cells project) and binds to receptors on these cells to mediate the improvement in movement and other symptoms seen with levodopa.
Almost all patients who have Parkinson’s disease demonstrate significant improvement with an adequate dose of levodopa. Bradykinesia (slowness) and rigidity (stiffness) tend to respond better than tremor. Improvement can be seen within a few days but gradually builds up, typically over several weeks. The dose of levodopa used must be highly customized as the effective dose varies tremendously from patient to patient.
The most common adverse effects of levodopa are nausea, orthostatic hypotension (reduction in blood pressure when changing position from lying to sitting or standing resulting in dizziness), vivid dreams, and hallucinations. Hallucinations typically occur in patients who have advanced Parkinson’s disease or have significant cognitive impairment and as a result are uncommon early in the disease.
There are two major types of motor complications: motor fluctuations and dyskinesias. These motor complications are associated with levodopa therapy and typically begin after months or more commonly, years of treatment. Motor fluctuations are variations in mobility associated with the effectiveness of levodopa. As the disease progresses and with chronic levodopa therapy, the beneficial effect of each individual dose of levodopa may become shorter. Levodopa may have to be dosed more frequently (4, 5, or even 6 times a day) compared to 3 times a day when initially started. The term “on” is used to describe the period during which medications are working and mobility is good while the term “off” is used to describe episodes in which medication is working poorly and mobility is poor.
Dyskinesias refer to excess involuntary squirming and rocking-type movements which may occur as an adverse effect of chronic levodopa. These usually occur during the “on” state. They can be mild and not troublesome, but can also be severe and interfere with day-to-day activities. The other form of dyskinesias is called dystonia, which refers to sustained abnormal fixed posturing. Dystonia more commonly occurs in the “off” state and often occurs in the foot, causing pain and interfering with walking.
Patients are often mislead by information in the lay literature which scares them about the development of dyskinesias and may this may dissuade them from using levodopa. It should be emphasized that levodopa is the most effective drug for motor features of Parkinson’s and that, in general, undertreatment of Parkinson’s disease thus increased Parkinson’s symptoms is a greater source of disability in the vast majority of patients than is dyskinesia.
Patients are sometimes confused, believing that dyskinesias are due to an increased rate of disease progression. There is no convincing clinical evidence that levodopa speeds up or hastens the progression of Parkinson’s disease, and the issues of dyskinesias and drug toxicity are largely unrelated. Some older reports suggested that high doses of levodopa applied to dopamine cells in vitro may cause cell death. However, more recent data using physiologic doses of levodopa applied to dopamine cells in conjunction with the normal supporting cells in the brain, does not suggest that levodopa causes dopamine cell death and there is even some data that levodopa may have a protective affect on dopamine neurons.
Levodopa is broken down outside of the brain by an enzyme called dopamine decarboxylase which converts it to dopamine. Dopamine outside of the brain is responsible for many of the side effects of levodopa, especially nausea and vomiting.
Levodopa is almost always given in combination with carbidopa, marketed as Sinemet. Carbidopa inhibits the enzyme DDC and markedly reduces the peripheral production of dopamine and greatly reduces the incidence of nausea and vomiting. Another DDC inhibitor, benserazide, is commonly used in Europe.
Levodopa can also be metabolized by the enzyme catechol-o-methyltransferase in the periphery or outside of the brain. Dopamine may also be metabolized by the same enzyme within the brain.
There are two different medications that can be administered to inhibit or block COMT. Entacapone is the most commonly used such medication and extends the duration of an individual dose of levodopa by blocking COMT. When there are motor fluctuations this increases the amount of “on” time with an individual dose of levodopa. There is a second COMT inhibitor, tolcapone, which inhibits COMT both outside of the brain (like entacapone), but also within the brain, and as a result is even more effective in improving the amount of “on” time. COMT inhibitors are only effective when given in conjunction with levodopa and by themselves do not improve parkinsonism.
Dopamine within the brain may also be broken down by another enzyme called monoamine oxidase type B.
Blocking MAOB with rasagiline or selegiline can improve symptoms of parkinsonism directly when taken alone, by reducing the breakdown of one’s endogenously produced dopamine. These medications may also be given in combination with levodopa to improve wearing off or motor fluctuations.
Dopamine agonists are artificial dopamine-like chemicals which directly cross over into the brain and can replace the dopamine deficiency by directly binding to dopamine receptors. These medications are approved by the FDA for treatment of parkinsonism by themselves or can be used in combination with levodopa to reduce motor fluctuations. Compared to levodopa, dopamine agonists are less potent. These medications have a lower tendency to produce dyskinesias compared to levodopa when given in early Parkinson’s disease. However they have significantly more side effects such as hallucinations, swelling of the feet, and sleepiness. The main medications in this class are ropinirole, pramipexole, and rotigotine, also known as Requip, Mirapex, and Neupro patch respectively.
Anticholinergic medications are amongst the oldest sorts of medications used for the treatment of Parkinson’s disease and were the main treatment prior to the discovery of levodopa. These medications predominantly improve resting tremor and have a relatively minor effect on slowness and gait. The main medications in this class are trihexyphenidyl (Artane) and benztropine (Cogentin). They commonly cause difficulties with memory, especially when given in older individuals. They may also cause other adverse effects including dry mouth, blurry vision, and constipation.
Amantadine is also an older medication which was first used to help prevent influenza Type A. It was subsequently found to have a mild but definite effect on Parkinson’s symptoms. More recently, it has been found to be helpful in reducing levodopa-induced dyskinesias and now is predominantly used in advanced Parkinson’s disease for this purpose. Adverse effects with amantadine are not uncommon and include swelling of the feet, dry mouth, constipation, vivid dreams, and hallucinations.