Parkinson’s disease

Parkinson's disease is an incurable, progressive neurodegenerative condition that is characterised by the loss of dopaminergic neurons in the substantia nigra. The disease presents with a range of

• motor-symptoms: reduced movements (hypokinesia/bradykinesia), rigidity, rest tremor, and postural instability
• non motor-symptoms: dementia, depression, sleep disturbances, bladder and bowel dysfunction, speech and language changes, swallowing problems and weight loss

The goal of therapy (both non-pharmacological and pharmacological approaches) is to control the symptoms in order to improve the patient's quality of life. Non-pharmacological approaches include physiotherapy, exercise, cognitive/behavioural, and speech and language therapies. These approaches are often used in combination with pharmacological treatments.

Deep brain stimulation is a surgical approach which should only be considered for patients with advanced stage disease, and whose symptoms are refractory to the best drug-based therapy.

Drugs used to manage motor symptoms generally aim to restore dopaminergic signalling in the brain.

Levodopa/carbidopa (co-careldopa) remains the most common and effective medical intervention for Parkinson’s disease motor symptom management. Levodopa is a dopamine precursor and it is primarily used in combination with the peripheral L-aromatic amino-acid decarboxylase (AADC) inhibitor carbidopa to functionally increase levodopa availability in the brain, whilst avoiding the conversion of levodopa to dopamine in the rest of the body which can lead to cardiovascular effects. Benserazide is an alternative AADC inhibitor in co-beneldopa. Levodopa/carbidopa is considered as the first-line option for patients in the early stages of diagnosed disease and whose quality of life is affected.

Adjuvant therapies:

Non-ergotic dopamine-receptor agonists (pramipexole, ropinirole or rotigotine), monoamine oxidase B inhibitors (rasagiline or selegiline hydrochloride) or catechol-O-methyltransferase (COMT) inhibitors (entacapone or tolcapone) can be added if dyskinesia or motor fluctuations become unmanageable with optimal levodopa therapy. A non-ergotic dopamine-receptor agonist can be replaced by an ergot-derived dopamine-receptor agonist (bromocriptine, cabergoline or pergolide), if motor-symptoms remain uncontrolled. If adjuvant dopamine-receptor agonists fail to provide benefit, amantadine can be considered to improve dyskinesia.

Levodopa, non-ergot-derived dopamine-receptor agonists (pramipexole, ropinirole or rotigotine) or monoamine oxidase B inhibitors (rasagiline or selegiline hydrochloride) can be considered for patients for whom motor-symptoms are not yet causing issue.

The choice of drugs will always be guided by symptoms, comorbidities and the individual patient’s preferences, including their ability to tolerate the possible side-effects of the different antiparkinsonian therapies.

Side-effects:

With levodopa motor complications are common, and include response fluctuations and dyskinesias that are largely a response to drug level changes (related to ‘on’ period, ‘off’ period' and ‘end-of-dose’ effects) and shortening of the duration of benefit over time. Modified-release drug formulations can help minimise ‘off’ period' fluctuations.

Motor complications are less likely to occur with long-term dopamine-receptor agonist only treatment, but these drugs are also more likely to cause non-motor complications (sleepiness, hallucinations, and impulse control disorders) than levodopa. 

Sudden withdrawal of all antiparkinsonian drugs should be avoided to reduce the risk of the emergence of acute akinesia or neuroleptic malignant syndrome.
 

Drugs used to manage advanced Parkinson's disease

The potent dopamine-receptor agonist apomorphine (given with the dopamine receptor antagonist domperidone to control nausea and vomiting caused by the apomorphine) can be considered if the benefits outweigh the cardiac risks of this option (i.e., heart problems such as QT prolongation and arrhythmia).

A formulation of levodopa/carbidopa that is administered directly into the duodenum or upper jejunum by a portable pump can be used to improve management of severe motor fluctuations and hyperkinesia or dyskinesia in patients with levodopa-responsive Parkinson's disease.

Managing non-motor symptoms in Parkinson’s disease