Parkinsonism is defined as bradykinesia, plus tremor, rigidity or postural instability. The symptoms may be due to Parkinson's disease but can also be a side effect of medication (e.g. some neuroleptics, antipsychotics or metoclopramide use) or damage to the basal ganglia e.g. due to a vascular event. These possibilities should be investigated before a diagnosis of probable Parkinson's disease is reached, which can only definitively be diagnosed by histology (which is practice is not practical!).
Parkinson's disease is due to degeneration of the basal ganglia, which leads to a reduction of dopaminergic transmission. Signs of disease can also found in the brainstem, limbic system and frontal cortices, indicating that it is a more diffuse process. This explains the associated symptoms of Parkinson's disease such as cognitive decline, daytime somnolence and sensory symptoms.
The motor symptoms of Parkinson's disease are due to the reduced production of dopamine between the corpus striatum and substantia nigra. Normally smooth motor movements are due to the interplay between the dopamine-ergic neurones which initiate movement and the GABA-ergic neurones which suppress movement. So without dopamine to initiate movement the patient becomes hypokinetic.
Rigidity and tremor involve a more extensive neurochemical disturbance due to basal ganglia degeneration. It is due to the reduction in production of acetylcholine, noradrenaline, GABA, 5-hydroxytryptine as well as dopamine.
The aim of dopaminergic therapy is to replace dopamine levels. Dopamine cannot be given directly as it does not cross the blood brain barrier, meaning it can have no direct effect on the CNS.
There are a variety of ways to increase dopamine levels by using -
- A precursor of dopamine (e.g. Levodopa) which can cross the blood brain barrier and be converted to active dopamine. It needs to be given with a dopa-decarboxylase inhibitor stop it being used activated peripherally (which reduces side effects and increases availability for central use).
- Dopamine agonists (e.g. Ropinorole), which bind to dopaminergic post-synaptic receptors .
- MAO inhibitors (e.g. Selegiline), which protects dopamine from being degraded within neurones.
- Catechol-o-methyl transferase inhibitors (e.g. Entacapone), which reduce the breakdown of dopamine.
The decision of when to begin treatment can be a difficult one, particularly as levodopa is associated with more adverse effects the longer it is used. There are no neuroprotective medications, only drugs which treat symptoms. SIGN guidelines have identified three main drug groups to be used in early Parkinson's disease:
- Levodopa in combination with a dopa decarboxylase inhibitor
- Dopamine Receptor Agonists
- Monoamine oxidase B inhibitors
Parkinson's disease is a progressive illness and the medication given to alleviate symptoms often needs to be increased or other therapies added. 'Replacing' dopamine can cause some patients to become 'hyperkinetic' and these increased movements often present as dyskinesias. Often patients can switch between 'on' periods when the medication alleviates their symptoms or causes dyskinesias and the 'off' periods when they don't have enough dopamine and become bradykinetic. By giving short acting and longer acting Parkinson's medication the hope is that these peaks and troughs are evened out.
In those with advanced Parkinson's disease other issues will need to be taken into account - these patients may have developed cognitive issues, struggle with activities with daily living and require increasing support from family and carers. Sometimes the side effects of medication are too disabling and medication regimes need to be cut back rather than escalated.
The SIGN guidelines suggest that the following medications can be added to treatment regimes -
- MAO-B inhibitors
- Oral and transdermal dopamine receptor agonists
- Catechol-o-methyl transferase inhibitors may also be used in patients with troublesome 'off' periods.
Sign Guidelines 113:
Diagnosis and Pharmacological Management of Parkinson's Disease.
Hauser S. Harrison's Neurology in General Practice. McGraw-Hill Companies Inc. 2006.
Rang H.P, Dake M.M, Ritter J.M, Flower R.J. Rang and Dale's Pharmacology. 6th Edition.
