Introduction
The greatest concentration of dopamine in the brain is found within the basal ganglia. Clinical interest in dopamine began with the observation that brain dopamine is profoundly depleted in Parkinson's disease. We now know that the loss of dopamine is not simply the result of a metabolic defect, but is due to loss of the terminals of dopaminergic nerves from the mid-brain, principally the nigrostriatal tract. The basis of this degeneration remains unknown, but is not simply due to ageing. Surviving nigral neurons show changes of increased oxidative activity. Within the basal ganglia, the principle target for dopaminergic innervation is the neostriatum (caudate and putamen) and here the principle receptors are the D1 and D2 subtypes.
Excess dopaminergic stimulation leads to involuntary movements (principally choreiform). Conversely, blocking dopaminergic transmission reduces movement and, even in normal subjects, may lead to a parkinsonian-like state of bradykinesia and rigidity.
Parkinson's disease is the main indication for treatments which increase the effectiveness of dopaminergic neurotransmission. Levodopa, a prodrug, remains the mainstay of treatment, but the seemingly inevitable development of response fluctuations and involuntary movements has led to consideration of adjunctive therapy. Practitioners should be aware of the treatment options available, the stage at which the various options should be introduced and the possibility that treatment may accelerate or retard the course of Parkinson's disease.
Treatment options in Parkinson's disease
Levodopa
Dopamine does not penetrate the central nervous system. However, levodopa crosses the blood-brain barrier and is then decarboxylated to form dopamine. Levodopa is now always given with a peripherally-acting decarboxylase inhibitor to reduce the peripheral formation of dopamine. Blocking peripheral decarboxylation reduces adverse effects (nausea, vomiting and postural hypotension) and maximises the amount of levodopa available for transfer into the brain. Levodopa enters the brain via a saturable carrier system shared with large neutral amino acids. Competition for the carrier system may occur if high concentrations of amino acids are present e.g. after a high protein meal. Ideally, levodopa preparations should be taken either 30 minutes before or an hour after meals.
Delayed release formulations are now available. Their bioavailability is less than for conventional levodopa preparations e.g. one 200/50 levodopa carbidopa controlled release tablet releases about the same amount of levodopa as a conventional 100/25 tablet.
Dopamine agonists (drugs which act directly on dopamine receptors)
Bromocriptine stimulates D2 receptor subtypes and is usually prescribed with levodopa preparations to try to reduce the development of involuntary movements and response fluctuations. It is best tolerated if begun in low dosage (1.0-2.5 mg/day) and built up gradually to 10-40 mg/day.
Apomorphine, which directly stimulates both D1 and D2 receptor subtypes, was recently reintroduced into the treatment of Parkinson's disease. The nausea which limited its usefulness previously can be controlled with domperidone. Currently, apomorphine is only available as a parenteral preparation, but its rapid onset of action gives it a role in advanced Parkinson's disease to shorten unpredictable 'off' periods. However, prospective patients do require hospital admission for instruction in self-injection and determination of appropriate dosages. Apomorphine may prove to have an important role in parkinsonian patients undergoing surgery or those who are unable to take their usual oral medication.
Monoamine oxidase (MAO) inhibitors
Selegiline slows the metabolic breakdown of dopamine by selectively inhibiting the enzyme MAO-B1, thereby prolonging the action of levodopa. Interest in selegiline was generated by the DATATOP trial finding that it could delay the introduction of levodopa treatment. It was speculated that this was due to slower loss of nigral cells ('neuro protection'). However, limitations in the trial design mean that selegiline has not been proven conclusively to slow the progress of Parkinson's disease.
Adverse effects
All antiparkinsonian medications can cause confusion and hallucinations: monotherapy with a levodopa/decarboxylase inhibitor preparation is preferable in these circumstances. Both bromocriptine and levodopa can cause orthostatic hypotension. Selegiline may exacerbate the adverse effects of levodopa, particularly dyskinesias. There is theoretical concern about the role of dopamine itself as a cause of additional oxidative damage to remaining nigral cells because both metabolism by MAO and auto-oxidation of dopamine can generate free oxyradicals. At present, it seems prudent to minimise the dose of levodopa if this is possible without compromising patients' symptomatic benefits.
An approach to the treatment of Parkinson's disease
Most clinicians would defer starting drug treatment until there was clear evidence of functional disability. Isolated parkinsonian tremor may run a more benign course than other forms of the disease. Once significant bradykinesia becomes evident, levodopa should be begun in modest dosage (e.g. 100/25 tablets 3 or 4 times a day). Should the response to this dose decline, one approach, before increasing the dosage further, is to add either bromocriptine or selegiline, particularly if patients begin to notice 'wearing off' effects. Once stabilised on these additional therapies, levodopa can be given in larger or more frequent doses as necessary if 'wearing off' or peak dose dyskinesias become evident. Nocturnal rigidity responds to the use of delayed release preparations at bedtime. Patients with advanced disease (typically about 10 years from initial diagnosis) and apparently unpredictable fluctuations are best assessed if they complete a treatment diary documenting the times of their medications and their clinical state, either 'off' (rigid) or 'on' (mobile). Patients with resistant 'off' periods should be considered for apomorphine injections. Patients with persistent disabling tremor may benefit from stereotactic thalamotomy. Even in advanced disease, patients should continue to show a definite clinical response to adequate dopaminergic stimulation.
Conclusion
As long as the pathogenesis of Parkinson's disease remains unknown, there is likely to be uncertainty about its optimum treatment. In the future, we can expect existing treatments to be supplemented by more specific drug therapy targeted at specific receptor subtypes, clarification of the issue of neuro protection to retard disease progression and the selective use of neurosurgical procedures (stereotactic lesions and nigral transplantation) in suitable patients.
