Parkinsons – Page 2 – Parkinson's and Me

L-DOPA and Carbidopa

7/10/23

I’m going to begin writing about the molecular basis of Parkinson’s with a discussion of the medication used to manage the condition, the ‘gold standard’ of Parkinson’s therapy: L-DOPA/carbidopa.

L-DOPA, aka levodopa, is an amino acid whose real name is L-dihydroxyphenylalanine. For those of you who have taken organic chemistry, I’ve shown its atomic structure in the figure.

L-DOPA is actually a precursor to dopamine, which means it can be converted into dopamine in the brain. When a person takes L-DOPA, it gets absorbed into the bloodstream and eventually crosses the blood-brain barrier to reach the brain. Once in the brain, it is converted into dopamine, which helps to replenish the dopamine levels and improve the symptoms of Parkinson’s disease.

This is the description that you read on most Parkinson’s sites. However, it needs some clarification and additional information. Particularly, if you don’t have. degree in biochemistry. The first issue is a minor one. What is that ‘L’ in front of the name?

Many organic chemicals come in two forms that are mirror images. Like right and left handed gloves. And like gloves, it’s hard to convert one into the other without some serious surgery. DOPA also comes in two mirror image forms. One is called ‘L-DOPA’, the other D-DOPA. Your body makes only the L form and it is the only form that can be converted into dopamine.

The second issue has to do with the conversion of L-DOPA into dopamine. L-DOPA by itself isn’t very useful. It’s the chemical change into dopamine that’s critical for Parkinson’s relief. So why don’t we take dopamine directly? Why go through the hassle of taking something that must be converted into dopamine?

The answer is that dopamine can’t get to the brain where it’s needed. There’s something called the blood/brain barrier that prevents many chemicals from passing from the blood stream into the brain. L-DOPA can pass this hurdle. L-DOPA gets across the blood/brain barrier with the help of a special protein that transports many amino acids into the brain.

What happens when the DOPA gets to its intended target? In the brain, and in other nervous tissue, there’s a tiny chemical machine, an enzyme, that does the conversion to dopamine. It’s called ‘aromatic L-amino acid decarboxylase‘ or ‘DOPA decarboxylase’.

However, there is a challenge when using L-DOPA alone. When it is taken by itself, a significant amount of it is converted into dopamine outside the brain before it can reach its target. This can result in unwanted side effects, like diarrhea, nausea, and vomiting, and a diminution in the effectiveness of the medication.

This is where carbidopa comes in. Carbidopa is another amino acid that is often combined with L-DOPA in Parkinson’s disease treatment. Carbidopa does not convert into dopamine like L-DOPA does, but it plays a crucial role in the treatment.

Carbidopa works by inhibiting DOPA decarboxylase. You can get an idea how it does it by examining the picture below. Notice that it has infiltrated the enzyme. In that position, it interferes with the conversion of DOPA into dopamine. However, that doesn’t seem to make any sense. Why would you want to prevent the conversion of DOPA into dopamine? After all that’s why you’re taking DOPA in the first place.

The answer is that carbidopa inhibits the conversion of DOPA into dopamine only outside the brain. It, like dopamine, can’t cross the blood/brain barrier. By inhibiting DOPA decarboxylase outside of the brain, carbidopa helps to prevent the breakdown of L-DOPA into dopamine before it reaches the brain. As a result, more L-DOPA is available to cross the blood-brain barrier and be converted into dopamine specifically in the brain, where it is needed. This allows for a higher concentration of dopamine to be restored in the brain, leading to improved control of movement and reduction in Parkinson’s symptoms. At the same time, it ameliorates the unwanted side effects of dopamine when its present outside of the brain.

So, to summarize, L-DOPA is converted into dopamine in the brain, replenishing the low dopamine levels in Parkinson’s disease. Carbidopa is added to the treatment to prevent the breakdown of L-DOPA into dopamine outside the brain, ensuring more L-DOPA reaches the brain and improving its effectiveness while minimizing side effects. Together, L-DOPA and carbidopa thereby help to alleviate the symptoms of Parkinson’s disease and improve the quality of life for people living with this condition.

Confirmed

3 Comments / Parkinsons / By Bill

7/8/23

I asked my GP whether he knew of an alternative specialist. He suggested a Dr. V. I called. Again, no appointment was available for at least a month. It was not good enough. I decided to search the Web for another neurologist in Austin and found one with good credentials and positive feedback from patients. I found several, picked out one, and called. A friendly receptionist answered on the first ring. I explained my concerns.

“Yes, Dr. W. has an opening in two weeks,” she told me.

I figured that would have to do. I didn’t like it but I’d have to wait. Then, to my surprise, that evening I got a call from her. There had been a cancellation.

“Could I come to Dr. W’s office on Monday, three days hence?”

“Yes,” I said. “No problem. I’ll be there.”

When I arrived at Dr. W’s modest facility, I told her of my symptoms. She had me walk a few yards up and down the corridor. She did me do a few other movement tests and asked me a lot of questions.

“You probably have Parkinson’s,” she finally announced. “We’ll start you on a regimen of L-Dopa right away.”

She explained that a lot of patients don’t tolerate the medicine very well. They get nauseous. For that reason, she suggested that I ramp us the dose and, at first, take the medication with a meal. She started me with a formulation of 25mg carbidopa and 100 mg levodopa. I hadn’t the faintest idea of what that was.

“Start with one a day for 5 days, then two for another five days, and finally, three a day.”

I filled the prescription that afternoon and began my journey with Parkinson’s.

I’m a molecular biologist. Or at least I used to be one before I retired. (You can read more about me in the ‘Memoir’ section of this site.) That meant that I was able to better understand the basic biochemistry, genetics, and molecular biology of Parkinson’s better than most laymen. In this blog, my intention is to do two things: First, describe in real time the progression of my symptoms. And second, given my background, to try to explain the molecular and cellular basis of the disease and it therapy. Since, I’m going to start out knowing little about the disease, I’ll be learning as well as explaining along the way. Anyone who reads these posts with more expertise can put corrections and suggestions in the comments box.

Two other points. Keep in mind that if you have Parkinson’s, or if you’re looking after someone with the disorder, both the symptoms and rate of progression may be quite different than my own. It seems like Parkinson’s has a wide range of effects.

And most important, it’s critical to understand that I’m not a doctor and will not offer medical advice because I’m not competent to do so. That’s the function of a physician.

By the way, there are other websites with similar goals. The best one that I’ve come across is this one: https://journeywithparkinsons.com/ The author,Frank Church, like me, is a retired professor. A biochemist. He’s had Parkinson’s since 2012 and his blog is quite extensive.

Parkinson’s

1 Comment / Parkinsons / By Bill

5/14/23 – Discovery

The thumb on my left hand started to tremble while I was seated in my favorite chair watching TV. Then it happened again. Over the next few weeks, its frequency increased to five or six times a day. Always when I was relaxed.

So, I went to my GP.

“Probably nothing,” he said after examining me. “But if it continues to bother you, here’s the name of a neurologist.”

It didn’t bother me enough for me to make the call. So I ignored it. The frequency of the trembling increased to a dozen times a day. I still was in denial. A month later, while at the dentist getting my teeth cleaned, my jaw began to shake. It lasted only a few seconds, the hygienist ;didn’t even notice, but it made me wary. Could it be a sign of something more serious? Parkinson’s? Muscular Dystrophy? Or something worse?

I googled ‘Parkinson’s’. I found out that there’s no definitive diagnostic test for the condition, although there are some being developed. In the absence of a good diagnostic tool, doctors currently look for a set of characteristic symptoms. I found a list. Did any of the symptoms on the list match what was happening to me?

Constipation? Yes, I had been uncharacteristically constipated for the last six months. Speaking softly? Yes, my friends often asked me to speak up. Phlegm in my throat? Yes, when I lay on my back mucus accumulated back there. Slow gait? Check. Stooped over when walking? So my wife ways.

Then there were other bothersome symptoms not on the list. Slower golf swing? I had been hitting the ball of the tee some 50 yards short of where I had been hitting a year previously. Difficulty in moving around in bed? Yes. And subsequent reading also indicated that this was a typical symptom. Trouble typing? Another sign of the disease. But I’m over 80 years old. Could these symptoms be just other indications of advancing age?

I needed to find out. I called for an appointment with the neurologist that my doc recommended. Her first opening to see a new patient was in December, six months away. That was clearly unacceptable. I needed answer sooner. Many sites on the Web said that people with Parkinson’s should start therapy as soon as possible.I didn’t know what to do.