Levodopa therapy

Despite all these problems there has been considerable progress in the treatment of disease states through NT manipulation. Before the advent of levodopa therapy in Parkinsonism the treatment of neurological and psychiatric disorders had little... 

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Antimuscarinic drugs such as atropine have been used to modest effect in the treatment of PD for more than a century attenuating tremor and rigidity but with little effect on akinesia. Currently benzhexol and benztropine are sometimes added to levodopa therapy but peripheral effects such as dry mouth, blurred vision and constipation are unpleasant. They are also often used to counteract neuroleptic-induced extrapyramidal effects. 

The most important alternatives to levodopa therapy are direct-acting dopamine receptor agonists, such as ropinirole,pramipexole, or pergolide (Fig. 46-5). A number of studies have shown that use of these agents may help to delay the need for use of levodopa/carbidopa. This has... 

Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3-5 y and is followed by gradual loss of symptom control, on-off fluctuations, and development of orobuccofacial and limb dyskinesias. These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine receptor agonists. Treatment of advanced disease requires the combined administration of antiparkinsonian agents. 

Parkinson disease To treat patients with idiopathic Parkinson disease to substitute (with equivalent strength of each of the 3 components) for immediate release carbidopa/levodopa and entacapone previously administered as individual products to replace immediate release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose wearing-off (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias). 

With long term levodopa therapy the risk for the occurrence of on-off effects, periodically and paroxysmally occurring periods of the therapy becoming ineffective, increases. Decreasing the peak-trough fluctuations with slow-release levodopa/ carbidopa formulations could possibly diminish these on-off effects. 

The efficacy of anticholinergic drugs in parkinsonism is likely due to the ability to block muscarinic receptors in the striatum. In the absence of the inhibitory action of dopamine, the actions of the intrastriatal cholinergic interneurons are unopposed, yielding enhanced stimulation of muscarinic receptors. Blockade of these receptors reduces striatal activity. The muscarinic antagonists exert only modest antiparkinsonian actions and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy. 

Amantadine was originally introduced as an antiviral compound (see Chapter 50), but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and A-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning. 

Several placebo-controlled studies have demonstrated a significant delay in the need to initiate levodopa therapy in patients who receive selegiline in the early phase of the disease... 

Modeling is an analytical tool that can be used to extrapolate shorter term clinical results, such as days of improved symptoms in Parkinson s disease patients in a study over 6 months, to longer time periods. A model was developed to extrapolate the results of a 6-month trial in which patients received either levodopa alone or levodopa plus the catechol-o-methyltransferase (COMT) inhibitor entacapone. Comtan (entacapone) is designed to reduce the metabolism of levodopa in peripheral tissue and vessels so that more of the drug is available in the brain at a more constant rate than is seen with levodopa alone. The 6-month clinical trial produced clinical results that allow us to establish entacapone s effect on the OFF time associated with levodopa therapy. OFF time refers to a re-emergence of symptoms prior to the next scheduled levodopa dose. Entacapone reduces the OFF time and increases the ON time of levodopa therapy. 

Figure 9.2 illustrates the various inputs and outputs of a model built to demonstrate the 5-year results of therapy with entacapone (Comtan1 ), which represents a novel pharmacological principle used in combination with levodopa therapy. The inputs list the data fed into the model. The clinical effects of the therapy are taken from the clinical trials. The costs by disease stage are defined as costs for >25% OFF time per day (severe stage) and costs for <25% OFF time per day (less severe) and are taken from literature sources. Patient preference data (used to calculate QALYs) for these two disease stages are taken from a separate study of patient preferences. The outputs of the model list some of the more common uses of the model ... 

Miscellaneous actions Peripherally formed dopamine (converted peripherally after levodopa therapy) gains access to the CTZ (chemoreceptor trigger zone) causing nausea and vomiting. 

Levodopa with MAO inhibitors may precipitate severe rise in blood pressure (MAO inhibitors should be stopped at least two weeks before levodopa therapy). 

Dyskinesias occur in up to 80% of patients receiving levodopa therapy for long periods. The form and nature of dopa dyskinesias vary widely among patients but tend to remain constant in character in individual patients. Choreoathetosis of the face and distal extremities is the most common presentation. The development of dyskinesias is dose-related, but there is considerable individual variation in the dose required to produce them. 

In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with a COMT inhibitor or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration. 

Cardiovascular Problems. Some problems with cardiac arrhythmias may arise in a patient taking levodopa. However, these problems are usually fairly minor unless the patient has a history of cardiac irregularity. Caution should be used in cardiac patients undergoing levodopa therapy, especially during exercise. 

The reason for dyskinesias in some patients, however, may be far more complex. Certain patients, for example, may exhibit dyskinesias when plasma levodopa levels are rising or falling, or even when plasma levels are at a minimum.66 There is evidently an intricate relationship between the basal ganglia neurons that continue to release or respond to dopamine and the pharmacologic replacement of dopamine through levodopa therapy. Dyskinesias may actually be the result of functional and structural adaptations of these neurons caused by periodic fluctuations in dopamine influence supplied from exogenous sources (levodopa).7,68... 

Controversy exists as to when specific anti-Parkinson drugs should be employed.1,16 Much of the debate focuses on when levodopa therapy should be initiated. Without question, levodopa is the most effective pharmacological treatment for reducing the motor symptoms of Parkinson disease. As mentioned previously, however, long-term use of levodopa poses several risks, and the effectiveness of this drug seems to diminish after several years of use. Consequently, some practitioners question whether levodopa therapy should be withheld until the parkinsonian symptoms become severe enough to truly impair motor function. In theory, this saves the levodopa for more advanced stages of this disease, when it would be needed the most.48... 

LeWitt PA, Nyholm D. New developments in levodopa therapy. Neurology. 2004 62(suppl 1) ... 

---