Dyskinesia, levodopa-related

In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3-7 months and were given entacapone in dosages titrated to 800-2000 mg/day after a transition period of 3-6 months with co-beneldopa, the improvements in on and off times were less impressive than they had been with tolcapone and there were more adverse effects (3). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox entacapone appears to be safer but overall causes more adverse effects. 

Silver M, Factor SA. Valproic add-induced parkinsonism levodopa responsiveness with dyskinesia. Park Relat Disord August 2013 19(8) 758-60. 

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. 

Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake, and they are then referred to as wearing-off reactions or end-of-dose akinesia. In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. The phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown. For patients with severe off-periods who are unresponsive to other measures, subcutaneously injected apomorphine may provide temporary benefit. 

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated... 

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson s disease dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. 

Untoward effects of levodopa are dyskinesia and rapid fluctuations related to rigidity, which may suddenly worsen. Psychologic effects such as confusion, disorientation, insomnia, and nightmares are common in 20% of patients. Various transplantation approaches have been tried based on the injection of dissociated fetal cells directly into the substantia nigra. An alternative approach includes the use of genetically modified nonneuronal cells (e.g., fibroblasts), so that they will secrete missing mediators such as dopamine and growth factors.62... 

Correct choice = A. Parkinsonian patients show a deficiency of dopaminergic neurons, without a decrease in cholinergic actions. Elevated levels of dopamine can lead to behavorial disorders. Levodopa and large, neutral amino acids share a transport system that is needed to enter the brain thus high protein diets may lead to elevated levels of circulating amino acids, resulting in a decrease in levodopa uptake. Dyskinesia is usually seen with longer-term therapy and is dose-related and reversible. The mechanism of action of deprenyl is not understood. 

Adverse effects Diarrhea is the most common side effect of tolcapone. As expected, /evocfopa-related adverse effects increase when tolcapone is added. These include postural hypotension, nausea, sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Baseline and frequent, regular determinations of hepatic serum enzymes are suggested by the manufacturer. Any elevations above normal are cause for discontinuation. Because of the hepatotoxicity, tolcapone should only be used as an adjunct in patients on levodopa/carbidopa who are experiencing symptom fluctuations. 

Fatigue and light-headedness or dizziness have occurred relatively frequently during oral entacapone administration in small studies (up to 60% of patients) (4). Other less frequent central nervous system effects include confusion, anxiety, syncope (related to postural hypotension), and insomnia (5,6). Mood elevation has been observed occasionally (5). The inclusion of entacapone in levodopa therapy for Parkinson s disease increases the risk of dyskinesias, possibly through enhanced brain penetration of levodopa (4,5,7). This can be adjusted by reducing the dose of levodopa. 

Toxicity Gastrointestinal effects include anorexia, nausea, and vomiting. Cardiovascular effects commonly include postural hypotension cardiac arrhythmias may also occur. Dyskinesias may occur with abnormal movements similar to those caused by levodopa. Behavioral effects include confusion, hallucinations, and delusions these occur more commonly with bromocriptine and pergolide than with levodopa. Like levodopa, bromocriptine and pergolide are contraindieated in patients with a history of psychosis. Miscellaneous ei ot-related effects with bromocriptine inelude pulmonary infiltrates and erythromelalgia. 

Toxicity Adverse effects related to increased levels of levodopa include dyskinesias, gastrointestinal distress, and posmral hj otension. Tolcapone has caused acute hepatic failure, necessitating routine monitoring of liver function tests. 

Amantadine has also been used for the treatment of PD-related dementia (Greulich and Fenger, 1995). Amantadine has been reported to reduce the duration of levodopa-induced dyskinesia and improves motor disability in PD. Although some beneficial effects are noted in patients after amantadine treatment, this drug is known to induce corneal edema that begins few months to several years after institutional therapy (Jeng et al., 2008). 

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