Levodopa is a drug that can be changed into dopamine in the body and in the brain. Therefore, it directly supplies the brain with more dopamine (see Figure 5).

Levodopa is always prescribed with other drugs such as dopa-decarboxylase inhibitors (DDIs) and COMT inhibitors, which prevent it from being broken down before it reaches the brain. Combination with these other drugs reduces the dose of levodopa needed, and prevents some unpleasant side effects.

Levodopa is a well-established treatment for PD, and is thought of as the ‘gold standard’ treatment. Most people with PD will be prescribed levodopa at some point during their therapy.

Levodopa is very effective at preventing slow movements and stiffness, especially in the early stages of PD.It is also used to reduce tremor.

Levodopa may cause side effects including nausea, vomiting, low blood pressure upon standing, sleepiness, hallucinations and vivid dreams.

Those people who have received levodopa therapy for a number of years will begin to experience changes in its effectiveness – freezing, and ‘wearing off’ and ON–OFF fluctuations. In addition, dyskinesias (restless movements) may begin to appear.

Some of the side effects of levodopa (e.g., vomiting) may disappear over time, while others may be improved by a reduction in dose. Medication can be prescribed to help relieve nausea, and this should be discussed with a doctor or PD nurse.

In the brain, a chemical called MAO-B breaks down dopamine, thus preventing its action (a normal control mechanism). MAO-B inhibitors stop MAO-B from working, and this raises the levels of dopamine in the brain (Figure 6).

Therefore, in PD, MAO-B inhibitors (e.g., rasagiline, selegiline) can be given to prevent dopamine being broken down – thereby prolonging the action of dopamine in the brain (including the dopamine provided by treatment with levodopa).

MAO-B inhibitors are useful in the very early stages of PD, and may be used as a first treatment – delaying the need for levodopa. Eventually, levodopa is usually required, and MAO-B inhibitors can be added to the regimen, allowing a lower dose of levodopa to be used, and therefore helping to delay the start of the motor fluctuations that appear with long-term levodopa treatment.

There has been some discussion as to whether the MAO-B inhibitors protect brain cells and can slow down the progression of PD. This is currently being investigated in clinical trials.

Another practical advantage of the new MAO-B inhibitor, rasagiline, is that it is taken in a single daily dose, requiring no titration (gradual increase to find the most effective dose), thus providing a more convenient administration schedule than most other PD medications.

Rasagiline is generally well tolerated, with the most common side effects including headache (as monotherapy), dyskinesia, vomiting, constipation, accidental injury, and low blood pressure upon standing (when taken together with levodopa).

Selegiline is also generally well tolerated, with dry mouth and sleeping disorders being some of the most common side effects. However, as it helps to increase the action of levodopa, selegiline also increases some of levodopa’s side effects such as dyskinesia, nausea, confusion, hallucinations, low blood pressure on standing, and vertigo. The increase in levopdopa-related side effects may be alleviated by adjusting the levodopa dosage. Side effects of selegiline relating to the central nervous system (hallucination, confusion and changes in blood pressure) may be due to its amphetamine metabolite (a breakdown product).

Dopamine agonists (e.g., ropinirole, cabergoline, bromocriptine, pergolide, pramipexole) imitate the action of dopamine in the brain. The brain cells respond as if more dopamine was present (see Figure 7).

There are several types of dopamine agonist, and they each work in a slightly different way.

Dopamine agonists are useful in the early stages of PD, and may be used as a first treatment – delaying the need for levodopa. Eventually, levodopa is usually required, and dopamine agonists can be given with levodopa, allowing a lower dose of levodopa, and therefore helping to delay the start of the motor fluctuations that appear with long-term levodopa treatment.

Long-term treatment with dopamine agonists tends to cause fewer dyskinesias and ON–OFF fluctuations than levodopa.

Dopamine agonists can sometimes cause nausea, vomiting, low blood pressure on standing, confusion the side effects? and hallucinations, constipation, vivid dreams, and fatigue. However, some of these can be reduced by gradual introduction of the drug, or by reduction of the dose.

Because of the way they work, different dopamine agonists tend to be associated with different side effects.

COMT inhibitors (e.g., entacapone, tolcapone) are given with levodopa. This is because they prevent levodopa from being broken down before it gets to the brain (Figure 8).

When people begin to experience end of dose wearing off with levodopa treatment, a COMT inhibitor can be added to decrease OFF time, and reduce fluctuations – improving the response to levodopa. In such cases, the levodopa dose may need to be reduced.

COMT inhibitors generally produce few side effects, and those that do occur are usually caused by the increasing dopamine levels produced by the drugs. Entacapone may cause dyskinesia, nausea, hallucination, urine discolouration, diarrhoea, and stomach pain. However, these effects are often reduced by lowering the levodopa dose. Diarrhoea lasting longer than 2 weeks should be reported to a doctor.

Tolcapone has been associated with adverse effects on the liver (hepatotoxicity), and therefore liver monitoring is required while taking this medication.