General Guidelines

Several issues should be considered before prescribing a medication for a recently diagnosed PD patient, as follows.

Does a recently diagnosed patient need medications and, if so, what should be the goal of treatment?

Since no definite neuroprotective agent is yet available, there is no rush to begin pharmacotherapy. Physical exercises should be encouraged if the patient does not experience significant functional disability. The therapeutic strategy should be discussed with the patient as well as the expectations from treatment in terms of benefit or adverse events. The major goal of treating PD remains symptomatic treatment tailored individually in order to maintain maximal function, with minimal short-term and long-term complications.

Which agents should be prescribed for which symptoms?

Most antiparkinsonian agents have a similar effect on the parkinsonian symptoms. Bradykinesia and rigidity respond better than tremor or postural disturbances. Age, cognitive function and degree of disability are the three major factors taken into consideration while choosing a drug. Other clinical characteristics, such as compliance, comorbid disorders and the presence of autonomic symptoms, affect the choice as well.

Which agents should be taken first?

In younger patients (those below 70), it is common practice to initially withhold levodopa therapy, and start with amantadine, selegiline or anticholinergics. Patients may enjoy symptomatic improvement with these drugs for several months. Only when disability becomes significant should one consider adding dopamine agonists (DAs) or levodopa. For elderly patients, levodopa may be the first choice for maximizing rapid benefit and minimizing side-effects.

When and how to escalate with therapy?

Since a chronic progressive illness is dealt with, one should consider milder medications and lowest doses early in the course of the disease and escalate slowly, trying to prescribe minimal dosages with maximal benefit. 'Using up' all the 'ammunition' at early stages is not advisable.

SPECIFIC AGENTS Anticholinergics

Drugs that block the muscarinic receptor have a modest place in PD pharmacotherapy. They are mildly beneficial mostly for rest tremor and rigidity, with little effect on other cardinal symptoms.

Their use in PD has been limited because of the common occurrence of both peripheral (dry mouth, constipation, urinary hesitancy and visual blurring) and central (memory loss and confusion) side-effects. The latter are especially problematic in the elderly, and anticholinergics should therefore be avoided in elderly patients.

Medications such as trihexyphenidyl (Artane), procyclidine (Kemadrin), biperiden (Dekinet) and benztropine (Cogentin) can be used, starting at a low dose and increasing slowly.

Anticholinergics may be the initial therapy for early stages when rest tremor is a dominant symptom.

Amantadine

The mechanism of action of amantadine is not completely clear. There is evidence for various mechanisms, such as enhancing dopamine release, blockage of dopamine reuptake, anticholinergic effect and glutamate-n-methyl-D-aspartate (NMDA) receptor blockage.2,3 Many patients have some symptomatic benefit, especially in the early stages, but also in the late stages of PD.

Apart from its effect on the cardinal features of parkinsonism, amantadine has been shown to decrease drug-induced dyskinesias (DID), and was suggested to have a positive effect on longevity and to improve lethargy.4,5 Side-effects of amantadine are common and include leg edema, livedo reticularis (mottled skin on the legs), urinary retention and hallucinations.

The possible neuroprotective effect of amantadine through its NMDA antagonistic properties have made it a commonly used drug throughout the course of the disease. Memantine is another NMDA receptor antagonist related to amantadine, and which shows antiparkinsonian activity in animal models and in Parkinson's patients. Its role as a symptomatic or neuroprotective agent for PD has not yet been established.

MAO-B inhibitors

Selegiline (Eldepryl) is the only agent from this group which has been approved for PD. It is an irreversible inhibitor of monoamine oxidase B (MAO-B), is known to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkin-sonism in animal models, and has been shown in vitro to possess unique anti-apoptotic properties that could have neuroprotective implications.6 Unfortunately, the evidence for slowing of PD progression is sparse, and, in addition, selegiline does not delay the development of dyskinesias or fluctuations associated with chronic levodopa therapy.7

Selegiline has a mild symptomatic effect in the early stages and is also beneficial for the later stages in fluctuating patients as a dopa-sparing drug, which allows a reduction of about 20% of levodopa dose.8 The side-effects of selegiline when given in combination with other antiparkinsonian agents are those of increased dopaminergic stimulation and insomnia, which have also been seen with monother-apy. The insomnia may be attributed to the metabolism of selegiline to amphetamine. For this reason, it is recommended to take selegiline no later than at noon. The recommended dose is 5 mg twice-daily (morning and noon).

Other MAO-B inhibitors are being developed (see later).

Levodopa

Levodopa in combination with a peripheral dopa-decarboxylase inhibitor (DDI) is the most effective symptomatic medication for PD. In the brain, levodopa is converted to dopamine and both act to stimulate the monoaminergic system. The peripheral DDIs, carbidopa and benserazide, are combined with levodopa in order to increase its bioavailability in the brain and to reduce peripheral side-effects.

Despite an excellent response, most PD patients will develop levodopa-induced side-effects within 5 years of levodopa treatment.9 These include motor fluctuations (wearing off) and/or dyskinesias (choreiform movements) as well as psychiatric or autonomic disturbances. It has become common practice to delay the use of levodopa, especially in young-onset patients, who are more prone to develop response fluctuations.

The possibility that levodopa may be toxic to dopaminergic neurons through enhancement of oxidative stress10 raises some concern, but currently there is no convincing evidence in animal models or in humans that levodopa is toxic. When mild disability persists despite the initial antiparkinsonian treatment (anticholinergics, amantadine and selegiline), and certainly when disability increases, more potent dopaminergic therapy should be initiated. For older patients it is safer to begin levodopa. At a younger age, DAs should be introduced first, since they may result in less motor complications (see section on DAs). An alternative is to begin with low-dose levodopa combined with a low-dose DA, while further augmentation of the antiparkinsonian effect is achieved by increasing the dosage of the agonist. When the patient develops occupational or social disability despite other dopaminergic therapy, levodopa therapy should be installed or increased.

Levodopa should be given at the lowest effective dose. The maximal carbidopa or benserazide blockage effect is reached at or above 75 mg/day. If nausea is bothersome, higher doses of carbidopa can be given, or domperidone (a peripheral dopamine receptor antagonist) can be supplemented.

If the response to levodopa is unclear, the dosage should be gradually escalated until benefit or side-effects are reached. A patient that does not respond to 500 mg levodopa in a single dose is unlikely to have primary PD.

Some recommend commencing therapy with the controlled-release formulations of levodopa and a DDI, in order to provide more stable concentrations of levodopa in the brain and, as a result, to cause less long-term side-effects.11 However, a long-term prospective study, comparing standard versus controlled-release formulations of levodopa, could not confirm this hypothesis.12

When motor response fluctuations develop, it becomes a real art to keep the patient in a good functional state for most of the waking hours. Manipulation of the levodopa dose and type of levodopa given is usually the first step in treating 'wearing-off' fluctuations. Increasing the number of levodopa dosages may be necessary to provide continuous coverage throughout the waking day. Changing from immediate-release to sustained-release levodopa (e.g. Sinemet CR) is another option. These formulations enable slower and more sustained levodopa absorption. Levodopa bioavail-ability is lower (about 70%), so the actual total dose of levodopa must be increased by about one-third. Since the peak effect is also delayed, in order to get a 'kick-in' effect patients add a small dose of the regular levodopa formulation, especially in the morning. Another approach is to add amantadine, selegiline and/or DAs.

It has been suggested that delayed gastric emptying and competition with dietary amino acids over the amino acid transporters in the small intestine and the blood-brain barrier may contribute to the development of a delayed effect to levodopa (delayed 'on') or its absence (dose failure). Therefore, in patients with motor fluctuations, levodopa should be taken on an empty stomach at least 60 min prior to meals. Dietary protein should be minimized during the day and eaten predominantly in the evening.

One may form a 'liquid levodopa' formulation, by crushing 1000 mg levodopa and 100 mg of a DDI with 1 l of water and 2 g ascorbic acid (creating a solution that contains 1 mg levodopa = 1 ml solution). This may be a solution for patients with long delayed 'on' and others who need fast absorption or very small adjustments in dosage that cannot be achieved by breaking the pills. Nocturnal akinesia can be eased by a bedtime dose of a controlled-release formulation of levodopa.

Drug-induced choreiform dyskinesias may resolve with a reduction in the daily levodopa dose. As the disease progresses, the levodopa dosage needed to produce an adequate motor response approaches the dosage that causes dyskinesia, and eventually any 'on' is accompanied by dyskinesia. Other alternatives for treating drug-induced dys-kinesias are mentioned later.

Dopamine agonists

The DAs are a group of antiparkinsonian agents acting directly on the dopamine receptors. There are currently six commercially available DAs: bromocriptine (Parlodel), lisuride (Dopergin), pergolide (Permax), pramipexole (Mirapex), ropini-role (Requip) and cabergoline (Cabaser).

The DAs have a longer half-life than levodopa, and are thought to cause less response fluctuations. In addition, they do not increase oxidative stress, and may have neuroprotective effects on dopamin-ergic neurons. As a result of all the above and their established efficacy in parkinsonism, they are being used increasingly in the treatment of PD. DAs are given as monotherapy early in the course of disease, in order to delay the introduction of levodopa. It has recently been shown that early PD can be managed successfully for up to 5 years with a reduced risk of dyskinesia by initiating treatment with ropinirole alone and supplementing it with levodopa if neces-

sary.13

DAs work in concert with levodopa at all stages, ameliorating the symptoms and enabling lower levodopa dosage. DAs are commonly given to PD patients with levodopa-induced motor fluctuations in order to smoothen the fluctuations by decreasing the patient's 'off' periods.

One of the disadvantages of DA therapy is the long and complex titration period needed to reach effective doses. In addition, their side-effect profile is more complex and frequent. The most frequent adverse effects of DAs are nausea and vomiting, postural hypotension, drowsiness, constipation and mental disturbances (hallucinations and confusion). The latter are more common in elderly and demented patients. Serious but rare adverse events associated with the ergoline DAs (bromocriptine, pergolide, lisuride and cabergoline) include pulmonary and retroperitoneal fibrosis as well as erythromelalgia, which are unlikely with the newer non-ergot DAs (pramipexole and ropinirole). Recently, it has been reported that DAs may cause in addition to somnolence sudden bouts of sleep that are often unpredictable.14 Therefore, DAs should be taken with caution when driving.

Table 31.1

In vitro receptor binding affinities of

dopamine agonists

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