Parkinson's disease, parkinsonism
Parkinsonism is characterised by tremor, rigidity and akinesia and is associated with degeneration of dopaminergic neurones in the nigro-striatal pathway.
Levodopa, a precursor of dopamine, is used as replacement therapy. Following oral administration it causes nausea, vomiting and hypotension but is usually administered in combination with a dopa-decarboxylase inhibitor such as benserazide or carbidopa to alleviate these side effects. However, after several years of levodopa therapy patients deteriorate and unpredictable fluctuations in mobility occur, particularly towards the end of the dose interval. Symptoms can be improved by increasing the dosage or by dividing the daily dose into smaller more frequent amounts. Alternatively, controlled-release preparations or adjunctive therapy may be of benefit.
Dopamine receptor agonists are used either alone or as an adjunct to a reduced dosage of levodopa in Parkinson's disease. They exert a stimulant effect at post-synaptic dopamine receptors and are therefore less dependent upon the degenerating pre-synaptic neurones. All dopamine receptor agonists carry the risk of side effects, ranging from nausea and hypotension to psychiatric disturbance. An ergot-derived dopamine receptor agonist (bromocriptine, cabergoline or pergolide) should only be considered as an adjunct to levodopa if symptoms are not adequately controlled with a non-ergot-derived dopamine receptor agonist (pramipexole, ropinirole or rotigotine). The effects of bromocriptine are similar to levodopa but its longer duration of action means a single bedtime dose may be useful for patients with severe early-morning disability. Ropinirole also has similar effects to levodopa but when used as an adjunct to levodopa, ropinirole reduces the amount of time spent 'off' and allows the total daily dose of levodopa to be reduced. Cabergoline, given as a single daily dose, decreases fluctuations in motor performance while decreasing the levodopa/dopa-decarboxylase inhibitor dose. Pramipexole can be used alone or with levodopa for the treatment of idiopathic disease, and has been shown to reduce the incidence of motor fluctuations and tremor. Rotigotine is a non-ergot dopamine agonist that is used as monotherapy in early idiopathic Parkinson's disease. It is delivered via a transdermal patch which provides continuous release of the drug over a 24 hour period and helps to avoid the GI absorption problems and first pass metabolism associated with oral routes. Subcutaneous injections of apomorphine can be used in refractory Parkinson's disease. Treatment is initiated in hospital following at least three days anti-emetic domperidone therapy, to counteract peripheral dopaminergic effects. Pergolide can be used with levodopa to reduce end of dose phenomenon. Amantadine is thought to enhance dopamine availability and is slightly more effective than anticholinergic therapy. It has few side effects but can provoke fits or confusional states at high dosage.
Monoamine oxidase B inhibitors are selective inhibitors of the B iso-enzyme of monoamine oxidase, which primarily degrades dopamine within the CNS. They prolong and potentiate dopaminergic function in the brain. They enhance the action of levodopa when given as combined therapy, allowing the dose of levodopa to be reduced and helping to alleviate end of dose fluctuations. Dietary restrictions are not necessary.
Reversible COMT inhibitors are used with levodopa and a dopa-decarboxylase inhibitor to improve symptom control, reducing the incidence of dyskinesias. Because of the risk of potentially fatal acute liver injury with tolcapone, therapy should only be initiated by a physician with experience of advanced Parkinson's disease, and liver function tests must be performed regularly.
Anticholinergics are used to relieve mild tremor and stiffness but do not improve akinesia. They are associated with peripheral parasympathomimetic side effects including glaucoma and urinary retention, and can cause confusional states, particularly among the elderly.