Parkinson’s disease is the second most common neurodegenerative disease after Alzeimer’s disease. It affects 1% of the population over 65 years rising to 2% of the over 80s. Despite recent advances treatment remains palliative only. The main cost of Parkinson’s disease is the long term social care particularly in the later stages of the condition. The PD Society has estimated an annual cost of £42000 per patient
Levadopa plus a dopa-decarboxylase inhibitor (co-careldopa Sinemet or co-beneldopa Madopar) remains the most effective treatment. The benefits of Levadopa, which is a precursor of dopamine, do not last indefinitely. Within 5 to 10 years the response deteriorates. Initially the duration of response decreases (on/off) then motor complications become more severe and difficult to treat.
Other complications of late disease include neuropsychiatric effects. It is not clear if these effects are due to the disease progression or to the drug therapy.
Dopamine agonists can be used as initial treatment or as adjunctive or levadopa sparing therapy. Only bromocriptine, pramipexole and ropinirole are licensed for early treatment of PD. All the available drugs may be used as add on therapy in the later stages of the disease when motor control has become sub-optimal. This may involve a reduction in the dose of levadopa to avoid excessive dopaminergic side effects.
There have been very few trials comparing the benefits of the different dopamine agonists so it is difficult to recommend one as first choice. Their affinities for the different dopamine receptors varies but it is unclear if this is clinically significant. It is often worth changing drugs if side effects are a problem as tolerance to the different drugs varies from patient to patient.
The principle side effects are nausea and vomiting, postural hypotension, hallucinations and confusion, and exacerbation of dyskinesias.
The newer drugs have similar tolerability to bromocriptine.
One study has suggested that ropinirole is more effective then bromocriptine in early disease.
The ergot derivatives (bromocriptine, lysuride, pergolide and cabergoline) may cause pleuropulmonary fibrosis in 2 6% of patients. Other rare but serious side effects are refractory oedema of the lower limbs, Raynaud’s phenomenon, retroperineal fibrosis anderythromelalgia.
Ropinirole and pramipexole are not derived from ergotamine so are expected to be free of these problems. They have however been linked with sleep attacks. All antiparkinsons drugs can cause excessive drowsiness especially when combined with alcohol or other sedatives. There have been reports of visual abnormalities with pramipexole.
The dose of pramipexole is expressed in both salt and base (0.125mg salt = 0.088mg base).
Cabergoline can be given once daily. The other drugs require three times daily dosing.
Highly specialised and expensive dopamine agonist. Gives a reliable on effect shortly after injection which lasts for up to an hour. Continuous subcutaneous apomorphine can significantly improve dyskinesia in advanced PD as well as lessening akinesia and rigidity. The full effects can take several months to develop.
Apomorphine may cause profound nausea, vomiting and orthostatic hypotension.
Catechol-o-methyl transferase inhibitors reduce the peripheral breakdown of levadopa increasing the amount available in the brain for conversion to dopamine.
Entacapone is the only available drug of this class in the UK. Talcapone was withdrawn because of fatal toxicity.
A 200mg dose of entacapone is given with each dose of levadopa. Due to increased dyskinesias a reduction of 10 30% in the dose of levadopa may be required.
There are no comparitive studies with dopamine agonists to show which class of drug is best to use as an adjunct to levadopa or who would benefit most from therapy.
Side effects include -:
- Exacerbation of dyskinesias
- Abdominal pain
- Dry mouth
- Urine discolouration
It is best to avoid non selective MAOIs and doses of selegeline in excess of 10mg. It is also recommended that venlafaxine and other noradrenaline reuptake inhibitors should be avoided.
Entacapone may potentiate the affects of apomorphine
A selective MAOB inhibitor. It slows the breakdown of dopamine the striatum and may be neuroprotective though this is controversial.
A study published in 1995 showed an excess mortality in PD patients taking selegeline. Although the findings of this trial have been severely criticised prescribing has been much reduced.
Side effects include hallucinations and confusion.
Best avoided with SSRIs as a serotonin syndrome may develop that includes hypertension and neuropsychiatric features.
Several possible modes of action including promoting release and blocking re-uptake of dopamine, an anticholinergic effect and NMDA receptor antagonism.
Its effects in early disease are mild and short lived but it may be useful in end stage dyskinesia.