Parkinson’s disease

34 Parkinson’s disease





Questions



image What is the pathology of Parkinson’s disease?

image What drugs are used in its treatment?

Parkinson’s disease is a neurodegenerative disorder that involves selective destruction of dopaminergic neurons in the basal ganglia (Fig. 3.34.1), resulting in abnormalities of motor function including bradykinesia (slow movement), rigidity, resting tremor and disturbances in gait. These symptoms can be ameliorated by therapeutic intervention (Fig. 3.34.2); however, the neurodegeneration is not reversed.


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Fig. 3.34.1 Parkinson’s disease.


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Fig. 3.34.2 Treatment of Parkinson’s disease.



Drug treatments



Levodopa


Dopamine is synthesized in nigrostriatal neurons from the precursor levodopa by aromatic amino acid decarboxylase (dopa decarboxylase). Degeneration of dopaminergic neurons reduces dopamine levels, which can be restored with levodopa. Levodopa is administered orally and extensively metabolized to dopamine by dopa decarboxylase and to 3-O-methyldopa by the enzyme catechol-O-methyltransferase (COMT) in the periphery. Levodopa, unlike dopamine, is transported into the CNS where it is converted to dopamine, stored and released in presynaptic neurons within the nigrostriatal region.


The unwanted side-effects of levodopa result from its conversion to dopamine in the periphery. These include nausea, vomiting (stimulation of chemoreceptor trigger zone) and hypotension. These can be minimized by coadministration with a decarboxylase inhibitor (carbidopa or benserazide) that does not cross the blood–brain barrier and, therefore, prevents the conversion of levodopa to dopamine selectively in the periphery. Consequently, a lower dose of levodopa can then be administered to achieve the desired therapeutic effect. The administration of a dopamine antagonist (domperidone) that does not cross the blood–brain barrier can also be used to reduce the peripheral side-effects associated with levodopa.


The beneficial effects of levodopa declines because the capacity of the nigrostriatal dopaminergic neurons to store and release dopamine declines as neurodegeneration progresses (‘wearing off’ or ‘end of dose deterioration’). Patients also develop excessive movements (dyskinesia) with prolonged use of levodopa that appear when levodopa plasma concentration is low (the ‘on/off’ phenomenon). Under physiological conditions, nigrostriatal neurons release dopamine tonically in a continuous manner, resulting in persistent stimulation of postsynaptic dopamine receptors. The administration of levodopa in patients leads to a pulsatile release of dopamine. It is this intermittent stimulation of postsynaptic receptors that is thought to underlie dyskinesia. This unwanted effect can be delayed with the use of dopamine agonists.

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Jul 18, 2016 | Posted by in PHARMACY | Comments Off on Parkinson’s disease

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