Dopaminergic drugs for Parkinson’s disease

Key examples

• Levodopa (as co-careldopa, co-beneldopa)
• Ropinirole
• Pramipexol

 

Common indications

• Dopaminergic drugs are used in early Parkinson’s disease, when dopamine agonists (e.g. ropinirole, pramipexol) may be preferred over levodopa.
• In later Parkinson’s disease, levodopa is an integral part of management, while dopamine agonists are an option for add-on therapy.
• Levodopa and dopamine agonists may be options for secondary parkinsonism (parkinsonian symptoms due to a cause other than idiopathic Parkinson’s disease), but addressing the underlying cause (e.g. discontinuation of an offending drug) generally takes precedence.

 

Mechanisms of action

• In Parkinson’s disease, there is a deficiency of dopamine in the nigrostriatal pathway that links the substantia nigra in the midbrain to the corpus striatum in the basal ganglia. Via direct and indirect circuits, this causes the basal ganglia to exert greater inhibitory effects on the thalamus which, in turn, reduces excitatory input to the motor cortex. This generates the features of Parkinson’s disease, such as bradykinesia and rigidity. 
• Treatment seeks to increase dopaminergic stimulation to the striatum. It is not possible to give dopamine itself because it does not cross the blood–brain barrier. By contrast, levodopa (l-dopa) is a precursor of dopamine that can enter the brain via a membrane transporter. Ropinirole and pramipexol are relatively selective agonists for the D2 receptor, which predominates in the striatum.

 

Important adverse effects

• All dopaminergic drugs can cause nausea, drowsiness, confusion, hallucinations and hypotension. A major problem with levodopa is the wearing-off effect, where the patient’s symptoms worsen towards the end of the dosage interval. This seems to get worse as duration of therapy increases. 
• It can be partially overcome by increasing the dose and/or frequency, but this can generate the opposite effect: excessive and involuntary movements (dyskinesias) at the beginning of the dosage interval. When these occur together, this is called the on–off effect.

 

Warnings

• Dopaminergic drugs should be used cautiously in the elderly and those with existing cognitive or psychiatric disease, due to the risk of causing confusion and hallucinations. 
• They should also be used cautiously in those with cardiovascular disease, because of the risk of hypotension.

 

Important interactions

• Levodopa is always given with a peripheral dopa-decarboxylase inhibitor (e.g. carbidopa) to reduce its conversion to dopamine outside the brain. 
• This desirable interaction reduces nausea and lowers the dose needed for therapeutic effect. 
• Dopaminergic agents should not usually be combined with antipsychotics (particularly first-generation) or metoclopramide because their effects on dopamine receptors are contradictory.