Treatment

Although there are a large range of drugs on the market to delay and mask many of the symptoms of Parkinson’s disease, none are able to affect the progression of the disease.

The main drugs currently in use are dopamine agonists. Levodopa is predominantly used although there are other less effective alternatives available on the market also e.g. MAO-B inhibitors (selegiline), dopamine release drugs (amantadine) and muscarinic acetylcholine receptor antagonists (benztropine).

Levodopa is the first line treatment for PD and it is usually combined with a peripheral dopa carboxylase inhibitor eg carbidopa or benserazide, which both reduce the dose needed by about 10 fold and also decrease the peripheral side effects. It is well absorbed in the small intestine and has a short plasma half life of about 2 hours. The Therapeutic effectiveness of levodopa decreases as the disease progresses, this may be due to the fact that as decreasing numbers of dopaminergic neurones are present, there is less ability to take up the levodopa and therefore less dopamine is produced via the decarboxylation reaction. On the other hand it may be that levodopa causes a ‘flooding’ of the synapse with exogenous dopamine, as synthetic dopamine agonists have the same effect as levodopa. In this instance receptor downregulation and other compensatory mechanisms may be to blame for the resistance to treatment. In either case, in order to decrease resistance to the treatment entacapone, an inhibitor of catechol-o-methyl transferase (COMT), may be applied to inhibits it’s degradation.

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Therapeutic effectiveness and unwanted effects of levodopa.

About 80% of patients show initial improvements to the treatment in particular there are decreased signs of rigidity and hypokinesia, around 20% are restored to normal motor function. Yet as time progresses the effectiveness gradually declines. Overall levodopa increases the life expectancy on PD sufferers, this is mainly due to the improved motor functions, although other symptoms such as cognitive abilities are not improved by the treatment.

Unwanted side effects to levodopa

Two main types of unwanted side effects are predominant with levodopa:

• Involuntary writhing type movements (dyskinesia), only seem to appear in patients after a period of two years after initial levodopa administration. Due to the fact levodopa is a short acting drug that has fluctuating plasma concentrations which may favour the development of dyskinesia side effects. Longer acting dopamine antagonists have proved to be less problematic in development of dyskinesia.
• Rapid changes in clinical state, rigidity and hypokinesia may become transiently worse for anything from a few minutes to a few hours, and then improve again. This is not seen in patients untreated for their PD or other non levodopa drugs. Similarly to dyskinesia this problem seems to be due to the fluctuations in plasma concentration of levodopa. As stated it is believed that as the disease progresses, the ability of neurones to take up dopamine decreases, so the therapeutic benefits of levodopa depend increasingly on formation of extraneuronal dopamine, which would require a continuous supply of levodopa. Therefore in order to prevent this symptom, the use of sustained release preparations, or co administration of COMT inhibitors eg entacapone, may be used to counter act the fluctuations in plasma concentration of levodopa.

There is also several acute side effect of the treatment, that tend to disappear in the first few weeks of treatment:

• Nausea and anorexia. Use of domperidone, which is a dopamine antagonist that works on the chemoreceptor trigger zone without gaining access to the basal ganglia, can be useful in preventing these symptoms.
• Postural hypotension is also a problem in some patients
• Psychological effects. Levodopa increases dopamine in the brain, causing schizophrenia like symptoms including delusions and hallucinations. Although more commonly patients tend to experience confusion, disorientation and insomnia.

MAO inhibitors

Selegiline is a MAO-B selective drug, this enzyme is predominantly found in the dopamine containing regions of the brain, including the substantia nigra. MAO-B acts to degrade intraneuronal, therefore by inhibiting it there is an increase in dopamine levels. Because selegiline is MAO-B selective it causes less side effects of non selective MAO inhibitors used to treat depression, and also doesn’t present with the ‘cheese reaction’. It has been proven that use of selegiline, along with levodopa, is more effective than levodopa alone in relieving symptoms and prolonging life of PD sufferers.

Dopamine receptor agonists

Bromocriptine, derived from the ergot alkaloids. Is a potent agonist at the D2 receptors in the central nervous system. It inhibits the release of prolactin from the anterior pituitary gland, but is also effective in the treatment of PD. The plasma half life is longer (6-8 hours) than levodopa, so it doesn’t require as frequent administrations. The main side effects of the drug are nausea and vomiting, more seriously peritoneal fibrosis has been reported in some cases. Newer dopamine angonists include pramipexole, lisuride, pergolide, ropinirole and cabergoline. Each is longer lasting than levodopa, and present with less tendency to cause dyskinesias and the ‘on off effects’. Main side effects of these newer drugs are confusion, delusions and sleep disturbances similar to all dopamine agonists.

Acetylcholine antagonists

It is known that muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerve terminals, therefore suppression can cause an increase in dopamine by decreasing the suppression. There are a wide variety of side effects involved with muscarinic antagonists including dry mouth, constipation, impaired vision, urinary retention. Due to this, they are now rarely used as first line treatment for PD, except to treat parkinsonian symptoms in patients receiving antipsychotic drugs (which are dopamine antagonists).

Neural transplantation

Trials in patients with PD have mainly involved the injection of midbrain neurones from aborted foetuses. It has been shown that such transplants are able to survive and establish synaptic connections, but controlled studies so far have shown little clinical benefits. Serious side effects have also been presented with such intervention, for example serious dyskinesia, possible due to dopamine overproduction. This method of treatment has also been deemed problematic, due to the fact cells from at least five foetuses are required in order for a successful transplantation to occur. Another more obvious problem is the ethical implications of the treatment. Due to the side effects and difficulties associated with the treatment method, future experiments in the field seem to be aimed towards developing preparations of immortalised neural precursor cells that can be multiplied in culture, and that will differentiate into functional post mitotic neurones after transplantation. 

Deep brain stimulation

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Deep bran stimulation (DBS) is a surgical method of treatment for PD, involving the implantation of a brain pacemaker into certain areas of the brain, which emit electrical impulses at high frequencies to control the symptoms and quality life of PD patients. Although the method of treatment is not fully understood, it is clear that by sending high frequency impulses to specific areas of the brain, the symptoms of the disease are greatly reduced. It has also been proven to decrease the common  side effects associated with typical drug treatments for PD. The most common sites for implantation are the subthalamic nucleus and globus pallidus interna (GPi), both of which are parts of the basal ganglia motor circuit. Possible side effects to the treatment include apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfunction and depression. However, these are most likely to be temporary and related to the placement of the electrodes and stimulator which can cause changes in behaviour depending on which part of the brain is being stimulated.