by Patricia A. Cash

Parkinson's disease affects approximately one percent of people over the age of 50 in the United States. The progression of this condition not only causes a reduction in quality of life, it often leads to a need for placement in a long-term care facility,¹ where presentation and management of the disease can become quite complicated.

By staying abreast of information about optimal drug management for residents with Parkinson's disease, consultant pharmacists can provide beneficial information to nursing staff, physicians, and other health care professionals. One encouraging development involves four new agents that are expected to be available in the near future for treating Parkinson's disease. They are: entacapone, tolcapone, pramipexole, and ropinirole.

Review of Levodopa Metabolism

Levodopa is broken down in the periphery to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC). Peripheral metabolism of levodopa can cause emesis, orthostatic hypotension, and cardiac arrhythmias. Therefore, carbidopa, a peripheral AADC inhibitor, is customarily administered with levodopa. Carbidopa does not cross the blood-brain barrier and does not affect the breakdown of levodopa in the CNS. Giving carbidopa with levodopa makes more levodopa available for transport to the brain.

However, although little dopamine is formed in the periphery, much of the levodopa that is produced undergoes O-methylation to 3-O-methyldopa, and only a small proportion of the drug reaches the brain unchanged. 3-O-Methyldopa (3-OMD) has a half life of about 15 hours, compared with levodopa's half life of one hour. This results in accumulation of the 3-OMD metabolite,⁴ which may be responsible for the "wearing off" phenomenon seen in many patients after long-term levodopa use.⁵ Because 3-OMD is also thought to compete with levodopa for transport across the blood-brain barrier,⁴ inhibition of the O-methylation of levodopa may provide increased bioavailability of levodopa and result in increased entry of levodopa into the brain.⁶ This mechanism of action is the basis of COMT inhibitors, one of the new classes of agents being developed to treat Parkinson's disease.

New Agents

Of the new agents expected to be approved soon, COMT inhibitors show some of the most promising potential. These agents work by inhibiting catechol-O-methyltransferase (COMT), one of the main enzymes responsible for both central and peripheral metabolism of catecholamines, including dopamine. When COMT is inhibited, the metabolism of levodopa to 3-O-methyldopa is reduced.⁴

While COMT inhibitors have been around for over 20 years, the first agents, often called "first generation" COMT inhibitors, were unselective, and were ineffective when taken orally. Three types of "second generation" COMT inhibitors are currently in development: peripherally acting agents; agents with better brain penetration; and agents that mimic the effects of COMT inhibitors but do not actually inhibit the enzyme.⁸

Of the COMT inhibitors under investigation, two are close to obtaining FDA approval. Entacapone, a peripherally-acting agent, has been given the trade name Comtess and will be manufactured by Novartis.⁹

Entacapone study dosage is usually 200 mg taken with each dose of levodopa. Concomitant administration of entacapone with levodopa promotes COMT inhibition in the in-testinal wall.

Roche was given an "approvable" letter from the FDA for their COMT inhibitor tolcapone (Tasmar) on June 5, 1997, and is awaiting final approval.¹⁰ Tolcapone is a second-generation COMT inhibitor that claims to have enhanced brain penetration; dosage is 200 mg three times daily.

Tolcapone will continually inhibit COMT and is given independent of levodopa administration. The significance of these different approaches in terms of adverse effects and drug interactions has yet to be determined.⁸

Both entacapone and tolcapone have been shown to increase the duration of "on" time, as well as reducing the dosage and frequency of administration of levodopa for patients with Parkinson's disease. Preliminary studies indicate a reduction of levodopa may be possible with the adjunctive use of a COMT inhibitor.^{4, 6, 11} This new class of medications appears to have synergistic activity with selegiline (Eldepryl) and carbidopa,¹¹ and in addition, agents with increased brain penetration, such as tolcapone, are thought to possess possible antidepressant properties.^4,8

Adverse effects associated with these agents appear to be mild and transient.^4,6,12 Tolcapone adverse effects include nausea, vomiting, dyspepsia, abdominal cramping, orthostatic hypotension, headache, and sedation.⁴ Dizziness, headache, fatigue, lack of appetite, epigastric pain, nausea, and loose stool are the most commonly encountered side effects seen with entacapone; this drug also causes urine to become dark yellow or orange.⁶ Rarely, dyskinesias were reported with both tolcapone and entacapone.^4,6

New Dopamine Agonists

Dopamine and dopamine agonists exert a pharmacological effect by binding to a dopamine receptor. Five dopamine receptor subtypes have been identified; however, because of the similarities between dopamine D1 and D5 receptors and dopamine D2, D3, and D4 receptors, new nomenclature has been proposed that will group the dopamine receptors into two main categories, D1 receptors and D2 receptors. Receptors formerly designated D1 and D5 receptors are now designated D1a and D1b; D2, D3, and D4 receptors are designated D2a, D2b, and D2c, respectively. The D2 receptors are responsible for the control of dopaminergic activity in the nigrostriatal and mesolimbic-mesocortical pathways.^13-16

Ropinirole and Pramipexole

Approval of two new dopamine agonists-ropinirole (reQuip) and pramipexole (Mirapex)-is anticipated shortly from the FDA (see below). Pramipexole will be manufactured by Pharmacia & Upjohn. SmithKline Beecham is awaiting final approval for ropinirole.

Parkinson's disease was identified in 1817 by James Parkinson when he characterized the primary symptom as an "involuntary tremulous motion." Today the classic triad of symptoms includes not only tremor, but also rigidity and bradykinesia. Since the arrival of levodopa in 1967, Parkinson's disease management has greatly improved. However, adverse effects, drug interactions, food-drug interactions, and reduced efficacy over time have all reduced the impact of levodopa therapy. Although levodopa remains the "drug of choice" in treating Parkinson's disease, other antiparkinson agents have proven beneficial in early stages of the disorder, as adjunctive therapy, and when levodopa is contraindicated. These agents include anticholinergics, dopamine agonists, amantadine, and selegiline.

Anticholinergic agents work by blocking the action of acetylcholine. Trihexyphenidyl (Artane) and benztropine (Cogentin) are two of the more commonly used anticholinergic agents for treating Parkinson's disease. They are particularly beneficial in reducing tremor and when used in mild to moderate stages of Parkinson's disease. In the older adult, the adverse effects of anticholinergic agents (dry mouth, constipation, urine retention) often prohibit their use.

Currently available dopamine agonists include bromocriptine and pergolide. Bromocriptine is an ergot alkaloid with agonist activity at postsynaptic D2 receptors. Pergolide is also an ergot alkaloid with activity at both D1 and D2 receptor sites. These agents have been shown to be helpful in the treatment of Parkinson's disease both as monotherapy and as adjunctive treatment. Dopamine agonists are less likely to cause dyskinetic side effects compared with levodopa. Adverse effects of bromocriptine and pergolide include nausea, vomiting, postural hypotension, confusion, and visual hallucinations. Ergot alkaloids can cause adverse effects, including pleuropulmonary and retroperitoneal fibrosis, erythromyalgia, and digital vasospasm.³

Amantadine (Symmetrel) is used in mild to moderate cases of Parkinson's disease and is usually beneficial for short periods. Selegiline (Eldepryl) blocks the breakdown of dopamine and can be used at any stage of Parkinson's disease.³

Therapeutic effectiveness can be seen with pramipexole in three weeks, compared to the older dopamine agonists, whose effectiveness is seen in 6 to 10 weeks.^13-14,17

Ropinirole is a nonergoline D2 agonist with little or no affinity for other receptor sites.^18-28 The drug binds to all three of the D2 subtypes: D2a, D2b, and D2c. Study dosages have ranged from starting doses of 0.25 mg three times daily to 8 mg three times daily.^25,27 Tolerance of the common dopamine agonist side effect, orthostatic hypotension, has been documented.¹⁶

Pramipexole and ropinirole are not ergot alkaloids like bromocriptine and pergolide and may, therefore, cause fewer adverse effects. Pleuropulmonary and retroperitoneal fibrosis, erythromyalgia, and digital vasospasm, which are associated with ergot alkaloids, have not been reported with these newer agents. Adverse effects for both agents are, however, similar to those seen with earlier dopamine agonists, and include orthostatic hypotension, nausea, dry mouth, dizziness, insomnia, and visual hallucinations.^14,17,28 Orthostatic hypotension is a result of stimulation of peripheral dopamine receptors; with ropinirole, studies indicate tolerance developing peripherally to the agent, thus reducing the incidence of orthostatic hypotension with continued use of the drug.¹⁶

Pramipexole and ropinirole have been found to be beneficial in the treatment of early, moderate, and advanced Parkinson's disease. Both agents have a longer duration of action and greater effectiveness as solo treatments for tremors and other parkinsonian symptoms. ^9,26 Both appear beneficial as adjunct therapy with levodopa.^17,28,29 In addition, pramipexole is thought to affect D2b receptors in the mesolimbic pathways, which may result in antidepressant activity. More extensive study is needed to confirm this effect.

Studies indicate both agents can reduce the "wearing-off" phenomenon often seen with levodopa in advanced Parkinson's disease.^23,24,29 A reduction in the dose of levodopa may be possible when one of the dopamine agonists is added.^15,27 Fewer side effects have been reported with pramipexole and ropinirole compared to currently available dopamine agonists.^14,16,17

All four of these new agents show great promise in providing additional benefit and less troubling side effects for patients with Parkinson's disease. As these therapies become more widely available, caregivers, families, and residents can look forward to yet another set of treatment options to improve quality of life for those living with this condition.

While most residents with Parkinson's disease are not candidates for surgical intervention, as these procedures become more common, chances are that in the not-too-distant future consultant pharmacists will encounter more residents who have had surgery to treat this disorder.

Unfortunately, drug treatment often loses its effectiveness; this is the point at which surgical treatment may be considered. The most frequently encountered surgical interventions include pallidotomy, thalamotomy, chronic thalamic stimulation, and fetal tissue transplantation.

Pallidotomy: This procedure, which is becoming widely available in the United States, involves making a stereotactic lesion to the posteroventral medial pallidum. Pallidotomies were common procedures in the 1950s and 1960s but results were inconsistent, and the procedure was abandoned until the early 1990s.

Benefits of pallidotomy include an immediate or nearly immediate symptomatic and functional improvement. Levodopa-induced dyskinesias can be completely eliminated by pallidotomy. Rigidity and bradykinesia is also often relieved. Other benefits may include reduction in tremor, improved gait and balance, and improvement in the "off" period.

Complications of a pallidotomy can include bleeding, infaction, facial paresis, and hemiparesis. Except for bleeding, these side effects appear to be extremely rare.

Thalamotomy and Subthalamotomy: During a thalamotomy, a lesion is made on the ventrolateral thalamus. A subthalamotomy involves lesions applied both to the thalamus and the zona incerta.

When the primary symptom is tremor, thalamotomy can provide effective long-term treatment. Both tremor and rigidity may be improved with subthalamotomy. Like pallidotomies, the effect is immediate or nearly immediate.

Complications of these procedures include hemiparesis and ataxia. Other transient side effects include confusion and postural instability.

Chronic Thalamic Stimulation: Also referred to as deep brain stimulation, this procedure, which is currently in clinical trials in the United States, involves insertion of an electrode into the thalamus and subcutaneous implantation of a pulse generator, which causes chronic high frequency stimulation of the thalamus.

Results are immediate or near immediate, producing improvement in tremor and abnormal involuntary movements such as dyskinesias. Some improvement in rigidity may occur, but no change in bradykinesia has been reported. The side effects of chronic thalamic stimulation are mild and include paresthesias, dystonia and dysarthia.

Neurotransplantation: Neurotransplantation involves grafting dopamine-producing cells from fetal nigral tissue into the striatum. Fetal tissue is used because it can survive for long periods of time in the patient's striatum and can form synapses and produce dopamine.

This procedure raises complex ethical concerns and continues to undergo clinical studies. Moderate improvement and reduction in levodopa dosage has been reported one to three months after neurotransplantation. Complications include intracerebral hemorrhage and the risk of transmission of infectious diseases.

Krauss JK, Jankovic J. Surgical treatment of parkinson's disease. Am Fam Phys 1996;54:1621-1628.

Pramipexole Gains FDA Approval