Drugs used in Parkinsons disease

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The discovery that dopamine was depleted in the basal ganglia of patients who suffered from Parkinsonism at the time of death led to the rational development of the therapeutic treatment, namely the use of L-dopa. Since dopamine does not cross the blood-brain barrier, and is rapidly catabolized

L-dopa in the wall of the intestinal tract by monoamine oxidase (MAO) the amine itself cannot be administered. However, L-dopa is rapidly decarboxylated in the brain to dopamine and it was found that high doses of the precursor could reverse many of the symptoms of the disease. Such high doses (up to 10 g were sometimes necessary) caused serious peripheral side effects because up to 95% of the drug was decarboxylated in the peripheral tissues and therefore never reached the brain. To prevent the peripheral catabolism of L-dopa, and to also reduce the dose of the drug that had to be given to produce a beneficial effect, a peripherally acting dopa decarboxylase inhibitor is now routinely combined with the drug. Decarboxylase inhibitors such as carbidopa or benserazide are structural analogues of L-dopa and thereby act as false substrates for dopa decarboxylase. Being charged molecules at physiological pH they cannot cross the blood-brain barrier and thereby permit parenterally administered dopa to reach the brain unchanged. The use of such inhibitors enables the dose of L-dopa to be reduced to a few grams or less, and thereby reduces the frequency and severity of the peripheral side effects which were so apparent in the early stages of its application. It should be noted, however, that an interaction occurs between dopa and pyridoxine due to the fact that pyridoxine is an essential cofactor for the enzyme metabolizing this drug. This can occasionally be a problem in patients who are concurrently taking a multi-vitamin preparation that contains pyridoxine. Despite the progress which has been made in recent years regarding the reduction in the effective dose of L-dopa that is administered, approximately 80% of patients have gastrointestinal disturbances on the drug. These take the form of

Figure 13.5. Chemical structure of dopa and two peripheral dopa decarboxylase inhibitors.

Figure 13.5. Chemical structure of dopa and two peripheral dopa decarboxylase inhibitors.

nausea and occasionally vomiting. Orthostatic hypotension is also apparent in some patients. The structure of L-dopa and the peripheral dopa decarboxylase inhibitors is shown in Figure 13.5.

Approximately 75% of patients with idiopathic Parkinsonism respond satisfactorily to L-dopa therapy with a reduction in their symptoms of at least 50%. In addition to a beneficial change in their motor symptoms, the mood changes associated with the disease also improve. In some patients, L-dopa has an alerting effect and occasionally more disturbing mental symptoms arise. These take the form of hallucinations, paranoia, mania, insomnia, anxiety and nightmares. Older patients being treated with L-dopa appear to be more prone to these effects. In addition, enhanced libido may occur in male patients, which may be socially unacceptable! Approximately 15% of patients may show such symptoms, which are often controlled by lowering the dose of the drug. The more severe psychotic episodes appear to be more frequent in those patients who are dementing.

Abnormal involuntary movements appear in approximately 50% of patients within the first few months of the commencement of L-dopa therapy, these effects being correlated with the dose of the drug and the degree of clinical improvement. The frequency of the abnormal involuntary movements increases with the duration of administration and can reach 80% of patients after 1 year of therapy. Such abnormal movements are presumed to be due to postsynaptic dopamine receptor hyperactivity and include buccolingual movements, grimacing, head-bobbing, and various choreiform and dystonic movements of the extremities. Tolerance does not appear to develop to these effects and there is no known treatment apart from reducing the dose of L-dopa, a situation which inevitably leads to the likelihood of a return of the Parkinsonian symptoms.

Other side effects involve changes in gastrointestinal function, which may be reduced by increasing the dose of the decarboxylase inhibitor and/or giving the peripheral antiemetic drug domperidone. Postural hypotension arises as a consequence of the increase in the dopamine content of the sympathetic ganglia; in these ganglia dopamine acts as an inhibitory transmitter, so that the decreased ganglionic transmission inevitably leads to reduced peripheral sympathetic tone and a drop in blood pressure.

Figure 13.6 illustrates the relationship between the efficacy of L-dopa therapy and time.

Drug-induced Parkinsonism may arise following the long-term administration of neuroleptics that block central dopamine receptors or reserpine-like drugs that deplete dopamine stores. Because of their mode of action, neuroleptics should never be coadministered to patients being treated with L-dopa or vice versa.

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    Is parkinson medication psychoactive?
    10 months ago

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