Parkinson’s disease (PD) is a progressive degenerative disorder of the central nervous system affecting over 1 million people in the United States (according to the Parkinson’s Disease Foundation and the American Parkinson Disease Association). Parkinson’s disease generally occurs in older adults and the risk of developing it increases with age. It is characterized by the degeneration of the neurons in the substantia nigra, resulting in decreased dopamine availability in the brain.
The cause of the disease is unknown and its pathophysiology is not well understood. The disease may begin with tremor, rigidity, bradykinesia, or change in posture.
These symptoms progress as the stage of PD advances. Some of the characteristic problems affecting patients include micrographia, decreased facial animation and blink rate (masked face), diminished arm swing while walking, shuffling of gait, soft or indistinct speech, and decreased dexterity in every day activities.[2] Currently, there is no cure for Parkinson’s disease.
Drug treatments do not prevent the progression of the disease, but they are used for the relief of symptoms. There have been many controversies regarding the initiation of drug therapy for Parkinson’s disease. Some practitioners advocate early treatment, while others prefer to delay treatment to minimize the risk of motor complication associated with levodopa metabolism. However, most agree that the initiation of drug treatment in PD is appropriate when patient begins to experience functional impairment.[3]
Initial treatment remains dependent on the personal preferences of physicians and patients because the progression of symptoms varies from one person to another.
Levodopa, l-dopa, is the most efficacious drug therapy available for symptoms of PD. L-dopa is decarboxylated to dopamine, thus, enhancing dopaminergic activity in the brain. It is usually administered with a decarboxylase inhibitor, carbidopa or benserazide. This prevents peripheral decarboxylation of levodopa to dopamine, allowing it to enter into the central nervous system (CNS).[1]
Levodopa/carbidopa (Sinemet) is the gold standard in the treatment of PD and have been associated with decreased morbidity and mortality.[4] The majority of PD patients respond to levodopa therapy, nonetheless, it does not treat all symptoms of PD (i.e., freezing, postural instability, autonomic dysfunction, dementia). Prolonged use of levodopa has been associated with motor fluctuation, dyskinesia, neuropsychiatric problems (more common after the first three years of therapy),and decreased its effectiveness as the disease progressed. Some practitioners are concerned about the use of levodopa in the early stage of PD. [1,3,4] New alternatives, or adjunctive therapy are required for drug therapy, especially, in advanced stage of PD.
In the early stage of PD, other drug treatments may be used to alleviate the mild motor symptoms before initiating levodopa therapy. Anticholinergic drugs such as, trihexyphenidyl and benztropine, are generally used in younger PD patients (i.e., less than 70 years old) in whom resting tremor is the predominate symptom and when cognitive impairment is not present. Although levodopa is the most effective drug for the control of tremor, some patients may respond better to anticholinergic drugs. Elderly and cognitive impaired patients are sensitive to anticholinergic agents, therefore, these agent are not recommended.[3]
Amantadine, an antiviral agent, may also be used for akinesia and rigidity symptoms of PD. However, it is less effective than anticholinergic drugs in regard to tremor. Amantadine should be used with caution in patients with renal impairment because it is mainly excreted unchanged in the urine. It also exerts anticholinergic effects, therefore it should be use with caution in the elderly.[2,3]
Dopamine agonists (i.e., bromocriptine, perolide, ropinirole, and pramipexole) may be used as adjuncts to levodopa therapy in prolonging the effective treatment period. In patients with deteriorating response to levodopa, dopamine agonists decrease the frequency of the "off" period, thus prolonging l-dopa effect.[2] Studies have shown pramipexole and ropinirole (non-ergots) to provide clinical benefits as monotherapy to previously untreated parkinsonian in the early stage, but levodopa will eventually be required.[3]
Selegiline, an MAO-B inhibitor, has been associated to show neuroprotective properties. It may decrease the generation of free radicals by reducing the metabolism of dopamine, but there is no conclusive evidence at this time.[1,2,3]
Two new drugs, tolcapone (Tasmar) and entacapone (Comtan) were approved by the FDA in 1998 and 1999, respectively. They are used as adjunctive therapy to levodopa.
Tolcapone is a selective reversible inhibitor of catechol-O-methyl transferase (COMT), which prevents the methylation of levodopa in the peripheral and CNS. Entacapone is also a selective, reversible peripheral COMT inhibitor. These drugs inhibit the metabolism of levodopa. Levodopa is methylated to 3-O-methyldopa (3-OMD by catechol-O-methyl transferase (COMT) in the peripheral and in the brain. The co-administering of levodopa with tolcapone or entacapone, will enhance the bioavailability of levodopa in the brain thus lengthening the duration of action of levodopa. Tolcapone and entacapone has no effect for PD when used alone.[5]
Both drugs extended levodopa treatment period for PD patients with wearing-off motor fluctuation. In clinical trials, tolcapone has shown to elevate hepatic transaminase blood levels (>3 times the upper limit of normal) in 1% and 3% of subjects receiving 100 mg TID and 200 mg TID, respectively.[5] Three deaths were associated with in patients treated with tolcapone. Thus, it is necessary to monitor liver function in patients taking tolcapone for the first six moths of therapy.[6]
Entacapone efficacy is slightly lesser than that of tolcapone, yet there is less adverse effect related to entacapone. In contrast to tolcapone, elevation of hepatic enzymes are not seen with entacapone treatment compared to placebo.[7]
There are different options in treating PD symptoms. The initiation of one drug before another is dependent on the patient, practitioner, and symptoms presented. However, the main drug treatment is still levodopa. Other drug treatments may be used as additional and, or adjunctive therapy to levodopa.