How do levodopa medications work?
We look at the science behind the levodopa based medications that are available today, and find out how you can help develop better medications.
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Levodopa was first discovered in the 1960s, today it is still one of the main drugs used to treat Parkinson’s symptoms at all stages of the condition. But when levodopa was originally discovered there were a number of issues with the drug. While the medication could work to alleviate some of the motor symptoms of Parkinson’s, it had to be taken in very large doses and caused people to feel very nauseous. So much so that taking the medication was unbearable and the untreated symptoms of Parkinson’s were preferable.
As levodopa is the gold standard in Parkinson’s medication, how have researchers overcome these issues? What has been done to improve the way this drug works in the last 50 years?
Getting more levodopa into the brain
Levodopa works by replacing the chemical messenger dopamine, which the brain cells in the substantia nigra are no longer making. So the first question is why can people not just take dopamine? The answer involves a barrier, called the blood brain barrier, that helps to protect the brain from nasty bacteria and viruses that may have got into our blood. This barrier stops dopamine from passing, which means it cannot get into the brain.
Fortunately, levodopa can cross the blood brain barrier and, as it is a ‘precursor’ to dopamine, the body can turn it into dopamine. When someone takes tablet of levodopa, the idea is that it travels to the brain where cells can turn it into dopamine.
But, when a tablet of levodopa is swallowed, the drug doesn’t make its way directly to the brain where it is needed. It is absorbed in the small intestine and makes its way into the blood stream. From there, the blood takes the drug all around the body. And it is here that the early levodopa tablets had their unwanted effects.
Outside the brain, our bodies contain proteins that break down levodopa. This means much of the drug (around 60–80%) is deactivated before it even has the chance to get into the brain. The first of these proteins, called DOPA decarboxylase, is the protein that turns levodopa into dopamine. Inside the brain this protein vital for the drug to work, but when levodopa is turned into dopamine outside the brain it causes people to feel nauseous.
To counteract this, today’s medications for Parkinson’s combine levodopa with other drugs — such as carbidopa, which blocks DOPA decarboxylase outside the brain— that stop this break down, allowing more of the levodopa to get into the brain and reducing the side effects from having dopamine in our bodies outside the brain.
Levodopa was first combined with other drugs in the 1970s, and the first levodopa-carbidopa medications (trade name Sinemet) were made commercially available in 1975. Later attention was turned to COMT, another protein that breaks down levodopa outside the brain, and drugs like entacapone (trade name Comtess) and tocapone (trade name Tasmar) were developed to block COMT and allow more levodopa to get into the brain.
Randomised control trials showed that levodopa-carbidopa tablets taken with entacapone or tocapone can help to reduce motor symptom fluctuations, although they weren’t without side effects, and these individual drugs have been on the market since the late 1990s. Entacapone has since been made into combined medications where this drug is in the same tablet as levodopa and carbidopa (e.g. Stalevo or Sastravi).
Making dopamine stick around
Once levodopa is in the brain it can be converted to dopamine. Dopamine plays a vital function allowing brain cells in the substantia nigra to communicate, to do this the brains cells release this ‘neurotransmitter’ into a space between the cells called the synapse. Another trick to treating Parkinson’s is to make sure the dopamine sticks around as long as possible in this space where it can continue to work. To do this researchers have developed drugs that stop dopamine that has been released into the synapses being recycled.
The protein COMT, as well as being outside the brain stopping levodopa getting in, is also found in the brain. Here is has an additional function to recycle dopamine. As tocapone can cross the blood brain barrier, this drug can also block COMT in the brain and allow the dopamine to stick around longer.
The second type of protein that recycles dopamine is MAO-B. While drugs that act to block MAO date back to the 1950s, it wasn’t until the 1970s that researchers in Vienna worked out that a drug called selegiline, could be used in Parkinson’s. Selegiline specifically blocked one of the two types of MAO (the B variety) and, in 1975, the first paper on the effect of selegiline in Parkinson’s was published. It was 1993, when this drug (trade name Eldepryl) became the first MAO-B inhibitor drug to be made available in the UK for the treatment of Parkinson’s, 3 years before it was made available in the US.
Developing new and better drugs
The levodopa based medications we have today are better than ever before. In addition to combination drugs we have extended release tablets that work longer, while formulations like Duodopa can help to control the symptoms of advanced Parkinson’s when all other treatments have stopped working.
Despite its limitations, researchers have found ways to maximise the benefit of levodopa, getting better symptom control for longer, while limiting its side effects. However, as more brain cells are lost over time, larger doses and more drugs are needed to achieve the same symptom control, and this means more side effects. And none of these medications can slow the progression of Parkinson’s.
But researchers all around the world are working to change that. And there are a number of clinical trials of new and potentially better treatments happening at the moment, which you can read about here:
With focused effort, alongside the guidance and support of the Parkinson’s community, we are making headway. But to make these new treatments a reality, we need everyone to get involved.
From shaping research to taking part in research studies to becoming a Research Volunteer, there is a role for anyone in the Parkinson’s community to get involved in research. And if you’re interested in finding out about these opportunities, or just want to stay connected with the latest research the Research Support Network is for you.
You can find out more about Parkinson’s treatments and therapies on the Parkinson’s UK website. If you have any concerns about your medication not working, please speak your medical team.
This blog is not meant as health advice. You should always consult a qualified health professional or specialist before making any changes to your medications or lifestyle.
