Parkinson's disease: dopaminergic therapy
Parkinson's disease (PD) has been linked to a deficiency of dopamine in the nigrostriatal system of the brain. As a consequence, most drug treatment has focused on either dopamine replacement therapy or dopamine agonists, drugs which stimulate the receptors involved in the action of dopamine. Since dopamine is involved in many of the interactions between neurotransmitters (brain messenger chemicals) and other chemicals deep in the brain, research is also focused on the area of dopamine uptake into the brain.
Dopamine is a neurotransmitter which carries nerve impulses between neurones [a type of brain cell that carries electrical impulses] across the synapse (the gap between 2 neurones), stimulating the dopamine receptors and allowing the impulse to reach its destination.
Dopamine is a monoamine found mainly in the neurones of the substantia nigra [a part of the brain], whose axons [part of the nerve fibres] terminate in the corpus striatum [a grey and white striped area of the brain]. The striatonigral neurones are involved in regulating the activity of dopaminergic (dopamine producing) neurones in the substantia nigra via a feedback mechanism. This feedback system involves the transfer of dopamine between neurones to carry messages eventually to the muscles.
In PD, this action of dopamine is severely affected by the loss of dopaminergic neurones, diminishing the body's control of smooth movement.
Dopamine replacement therapy
Dopamine is not directly passed into the brain from the blood supply, as the human brain has a protective mechanism known as the blood-brain barrier that prevents chemicals such as dopamine from entering the brain. In the treatment of Parkinson's disease (PD), that protective mechanism forces the use of an alternative chemical (i.e. a dopamine precursor), which can enter the brain. That substance is levodopa (also written as l-dopa), an amino acid which is converted into dopamine. When l-dopa is administered orally, however, it is rapidly converted into dopamine in the body, with only a small portion reaching the central nervous system. So if l-dopa is used alone it must be used in high dosages to get the required effect. Therefore, other methods have been developed to administer the l-dopa so that it is only converted to dopamine after it is in the cells of the brain.
The drug Sinemet uses a peripheral enzyme (a decarboxylase inhibitor), carbidopa, to inhibit the breakdown of l-dopa in the body. Carbidopa cannot cross the blood-brain barrier, which allows l-dopa to enter the brain, where it is converted into dopamine. This makes more dopamine available to the brain where it is needed. It also reduces the dosage required to achieve maximum dopamine levels in the brain.
Another drug which combines l-dopa with a decarboxylase inhibitor is Madopar, which uses benserazide to assist with the transposition of l-dopa across the blood-brain barrier. Like carbidopa, benserazide cannot cross the barrier but inhibits the conversion of l-dopa into dopamine until it reaches the cells of the brain, where it becomes available to the target cells in the corpus striatum.
Replacement of dopamine with l-dopa remains the most effective way of controlling Parkinsonian symptoms, particularly bradykinesia [slowness of movement] and rigidity and, to a lesser extent, tremor. Initially it can improve symptoms in more than 80 per cent of cases in 6-8 weeks.
After long-term l-dopa treatment (average 5-10 years), side effects such as dystonia (twisting postures) and dyskinesia (other involuntary movements) may occur in patients treated with the usual doses of l-dopa therapy. The involuntary movements occur when the drug is at high dosage levels in the blood and the dystonia is more common when the drug levels are low in the body.
Peak-dose dyskinesia is best treated by lowering the l-dopa dose or using smaller, more frequent doses. Partial replacement of l-dopa by a dopamine agonist such as bromocriptine or pergolide may be helpful.
The 'on-off' phenomenon (sudden episodes of being unable to move) may also develop after several years of therapy. These fluctuations do not always correspond to drug levels and can be very distressing and unpredictable.
Long-acting (slow-release) forms of Sinemet and Madopar have been developed which reduce some of the problems associated with long-term therapy. They are sometimes used in combination with conventional carbidopa/l-dopa to provide longer 'on' time, fewer 'off' periods, better function, and less dystonia. Some studies of taking controlled-release tablets in halves for the first morning dose show less delay in response.
Several important factors influence the action of l-dopa.
- Absorption: related to dissolution, the pattern of gastric emptying and the rate of uptake from the small intestine.
- Distribution: determined by the rate of l-dopa transported from gut to blood and from blood to brain (which can be influenced by competition with dietary amino-acids).
- Bio-transformation: peripheral degradation of l-dopa reduced by use of a catechol-O-methyltransferase (COMT) inhibitor.
COMT inhibitors
Catechol-O-methyltransferase (COMT) is an enzyme that metabolises l-dopa and dopamine. Inhibitors to this enzyme improve the availability of l-dopa by blocking the breakdown of l-dopa and dopamine and subsequently boosting l-dopa activity. COMT inhibitors such as Entacapone have dose-sparing effects and prolong the plasma half-life of l-dopa and thus its clinical effects.
Entacapone (Comtan)
Comtan is a different form of treatment than the current range of agonist but it still must be taken with levodopa (Madopar, Sinemet).
It is a COMT inhibitor, effectively knocking an enzyme out of your liver. This enzyme inhibits the levodopa from doing its work and the result can be the person with Parkinson's can reduce the amount of levodopa, sometimes by as much as half, and avoid the side effects that plague many people. It also can sustain the 'on' periods, in some cases by 30 minutes to an hour. It must be taken at the same time as the levodopa and no less than 200 mg.
The side effects are sudden diarrhoea, which for some reason that can't be explained, strikes without warning at about 5 weeks. Also it has no effect at all on 30 per cent of users but 70 per cent are assisted by this medication.
Dopamine agonists
Dopamine receptors are membrane-bound proteins of as yet unknown structure. There are 2 classes of dopamine receptor: type 1 and type 2. Dopamine receptor stimulation has become increasingly important as it seems that by stimulating the receptors, anti-parkinsonian effects can be achieved.
Drugs which stimulate these receptors are known as dopamine agonists and have a number of advantages over l-dopa. They directly stimulate dopamine receptors without requiring neuronal storage or release and do not produce toxic metabolites (end products).
Theoretically, dopamine agonists may slow the nigral cell loss by reducing the amount of l-dopa required, which is an advantage to patients who experience fluctuations. There is evidence that early treatment with dopamine agonists, together with a lower dose of l-dopa, delays the onset of dyskinesias and fluctuations. (Rinne, 1987; Olanow 1990; Worm-Peterson 1990; Morris 1991.)
Bromocriptine
Bromocriptine (e.g. Parlodel) was the first dopamine agonist to become available in Australia. While it stimulates the activity of the receptors in the corpus striatum, it cannot replace l-dopa for most patients.
Almost all patients commenced on bromocriptine alone eventually also need l-dopa to help control the disease. In patients with mild or moderate PD, low-dose bromocriptine, either alone or with l-dopa, is effective.
Because bromocriptine is a long-acting drug and has a half-life of 3 hours, this results in longer 'on' periods for the patient. However, it must be introduced slowly to avoid side effects. Studies have shown that some patients already treated with l-dopa, who have fluctuations, can decrease these with the introduction of bromocriptine. The introduction of bromocriptine some time after the commencement of l-dopa probably prolongs the trouble-free period before the development of fluctuations and dyskinesias. Another benefit that bromocriptine can provide is that it reduces the l-dopa dosage needed, thus decreasing the side effects caused by l-dopa use.
Pergolide
Pergolide (Permax) is one of the most recent dopamine agonists to become available in Australia. Clinical studies have found pergolide to be more effective than bromocriptine (Pezzoli 1994) and may have an advantage in terms of l-dopa-sparing capacity (Boas 1996). Some clinicians believe that pergolide's activity at both D1 and D2 receptors (bromocriptine is a D1 agonist only) may be the reason for its better efficacy.
Pergolide is a long-acting agonist and also results in longer 'on' periods for the patient. When given to people who have a fluctuating response to l-dopa, pergolide helps smooth out the response and reduce motor fluctuations. It, too, must be introduced slowly to avoid side effects.
Cabergoline (e.g. Cabaser)
Cabaser is an ergot-based dopamine agonist. Generically known as cabergoline, Cabaser is a long-acting dopamine agonist that after careful and slow titration can be taken once a day. Cabaser can provide continuous and sustained dopamenergic stimulation primarily to the D2 receptors of the brain and offers particular benefits when used as an adjunct therapy to existing levodopa therapy (e.g. Madopar or Sinemet).
It is one of the ergot group of drugs (others include Permax and Parlodel) so if you have had a bad reaction to either of these drugs it is likely you will experience a similar reaction. Consult with your neurologist as always but remember it has a half-life of about 60 hours so follow the instructions carefully. Those who can tolerate it report a smooth reaction and an increase in 'on' time. One tablet a day beats remembering to take another tablet.
There may be some evidence that it could be advantageous to start new patients on Cabaser instead of levodopa. Once again, anything as controversial as this should be discussed with your doctor.
Dopamine agonists do have side effects, which include nausea and vomiting, confusion and drowsiness, cardiac problems and dizziness due to hypotension (low blood pressure). However most of these are alleviated by maintaining patients at the lowest necessary dosage. Psychiatric side effects should initially be managed by changing the anti-Parkinsonian treatment before resorting to anti-psychotic drugs.
Cabergoline is another agonist and may have similar effects and side effects.
Studies have been done on sources of l-dopa in broad bean pods, but natural sources cannot compete with tablet formulation for convenience and predictable bioavailability.
Apomorphine
Apomorphine is also a D1 and D2 receptor agonist, but is given subcutaneously by injection or in-dwelling catheter to treat severe 'freezing'; that is, it is used as a rescue therapy and may only last up to one hour. A nasal spray of apomorphine is being developed in the UK for the same purpose. As it tends to cause nausea, domperidone is needed to combat this. Possible other side effects are as for l-dopa with the addition of yawning, drowsiness and local skin reactions or abscesses at the injection site(s).
Selegiline
Other neuroprotective strategies include monoamine oxidase inhibition (MAO). MAO inhibitors (MAOIs) such as selegiline are free radical scavengers and are neurotropic agents with nerve protection factors.
Summary
Dopamine replacement therapy and dopamine agonist treatment are 2 ways that effective dopamine levels can be restored in PD patients. Scientists are continually testing drugs for their effects on dopamine levels and stimulation of dopamine receptors. It is through more research and clinical trials that the most effective therapy will be perfected. As it stands, l-dopa therapy, either on its own or with a dopamine agonist, remains the most effective therapy.
Last Reviewed: 24 July 2002
