Levodopa long term effects

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. 

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. 

Tolerance occurs and levodopa becomes less effective with long-term use. To some extent this can be counteracted by an increase of dose. An other approach can be to stop levodopa treatment for some time and then resume again later. 

Drug Levodopa Mechanism of Action Resolves dopamine deficiency by being converted to dopamine after crossing blood-brain barrier. Special Comments Still the best drug for resolving parkinsonian symptoms long-term use limited by side effects and decreased efficacy. 

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... 

Apomorphine, a very potent non-selective dopamine agonist, which acts on both Di and D2 receptors, has been nsed with some snccess in Parkinson s disease, particn-larly in patients with severe long-term adverse effects of levodopa. Because of first-pass metabohsm it has to be used subcutaneously, sublingually, or intranasally. Its adverse effects resemble those of levodopa. 

The long-term consequences of levodopa therapy have been considered in a review by predominantly Canadian authors, but whose senior author was Oleh Homykiewicz, the doyen of the dopamine concept of Parkinson s disease (16). Their conclusions were not at aU unexpected. Levodopa was given to 42 patients (30 men, mean disease duration of 16 years, mean follow-up about 9 years). There were adverse effects in over 70% dyskinesias in 62%, on-off effects in about 17%, and end-of-dose wearing-off in about 7% (the last perhaps surprisingly low). Dyskinesia was not only the most common but also the earliest adverse effect. It should be noted that the mean levodopa dosage in this population was rather low, only 500 mg/day. 

As Parkinson s disease is associated with a loss of dopamine, it is commonly treated with drugs, which replace or supply dopamine. Since dopamine itself cannot pass the blood-brain barrier, the most commonly used therapy is levodopa (L-DOPA), a precursor of dopamine. A complication of long-term treatment with L-DOPA, however, is the development of rapid fluctuations in clinical state where the patient switches suddenly between mobility and immobility this phenomenon is known as the on-off effect .135,136 This effect might be caused by the loss of feed-back mechanisms. 

Przuntek H, Welzel D, Gerlach M, et al. Early institution of bromocriptine in Parkinson s disease inhibits the emergence of levodopa-associated motor side effects Long term results of the PRADO study. J Neurol Transm 1996 103 699-715. 

Central side effects with long-term therapy of levodopa can be serious enough for treatment to be stopped. These include dyskinesias, restlessness, anxiety, confusion, disorientation, insomnia or a schizophrenia-like syndrome. Dyskinesias can be particularly severe, involving unusual writhing movements of the limbs and grimacing and chewing movements of the face. 

About 40 years after its introduction, levodopa remains the most effective pharmacotherapy in Parkinson s disease (57). Despite controversy regarding long-term efficacy, side effects, and even potential neurotoxicity, most patients derive a substantial benefit from levodopa over the entire course of their illness. Moreover, levodopa increases life expectancy among patients with Parkinson s disease, and survival is significantly reduced if the initiation of levodopa therapy is delayed (58). 

With long-term use of levodopa, the adverse effects tend to increase and the client may develop a drug tolerance where the therapeutic effects decrease. A short hiatus from the medication (10 days) may result in beneficial effects being achieved with lower doses. 

Information appears to be limited to these single-dose and in vitro studies. The importance of this interaction in patients taking both drugs long-term awaits further study but the extent of the reductions in absorption (30 to 50%), and the hint of worsening control, suggests that this interaction may be of clinical importance. Be alert for any evidence of this. Separating the administration of the iron and levodopa as much as possible is likely to prove effective, as this appears to be an absorption interaction. More study is needed. 

Plasticity of primary motor cortex is severely impaired in Parkinson s disease and chronic dopaminergic treatment is reported not to rescue it. The effect of an acute dose of levodopa on cortical plasticity report was examined. Patients were carefully stratified based on their motor response to levodopa into stable responders (n = 17), fluctuating nondyskinetics (n=18) and fluctuating dyskinetics (n=20). Theta bm-st stimulation was applied to the motor cortex to induce long-term potentiation and long-term depression-like plasticity in both OFF and ON conditions. An... 

Clinical experience with carbidopa and levodopa has been extensive and favorable Carbidopa alone had no influence on Parkinsonian patients and is reported to be quite non-toxic. It raised plasma levels of levodopa about five-fold, thus indicating about an 80 reduction of the required levodopa alone dose. Carbidopa doses of 100-300 mg/day combined with levodopa in controlled trials resulted in a rapid onset of therapeutic effect (a few days or weeks compared with months with levodopa alone), and strikingly reduced the incidence of nausea and vomiting. Patients on long term combined therapy achieved superior relief. Combined treatment may reduce cardiac arrhythmias, but the incidence of involuntary movements is increased. Several groups foimd a 1 10 combination most useful with a daily dose of carbidopa 100 mg levodopa 1000 mg. Marsden st ggests that it may become the treatment of choice. 

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