Motor symptoms, the main symptom of Parkinson’s disease, are caused by damage to dopaminergic nerves that control movement in the substantia nigra part of the brain. When motor symptoms appear and Parkinson’s disease is diagnosed, 50% of dopaminergic nerves in this area are usually damaged, and the dopamine content of nerve endings is reduced by 80%.
There is still no drug that prevents nerve damage and cures Parkinson’s disease. Currently used drugs are administered for the purpose of improving quality of life by alleviating motor symptoms. Levodopa is the most central drug in the treatment of Parkinson’s disease.
Levodopa was first administered to patients with Parkinson’s disease in the 1960s, and was approved by the US FDA in 1970. To date, there is no drug that can compete with levodopa in Parkinson’s disease. Levodopa is a precursor to dopamine. In order for a drug to reach the brain, it must cross the blood-brain barrier. Since dopamine cannot penetrate the blood-brain barrier, levodopa is administered. Levodopa works by being absorbed into the brain and then converted to dopamine.
Neurons transmit information to adjacent nerves by excitation. Dopaminergic neurons use dopamine as a neurotransmitter. Dopaminergic neurons make dopamine, pack it into a package, store it in the nerve endings, and release it when excited.
Excitation is propagated as the released dopamine stimulates receptors on adjacent nerves. In the case of Parkinson’s disease, dopaminergic nerves are damaged so that dopamine is not produced and released, so that the transmission of excitability between nerves does not occur. Levodopa is converted into dopamine in nerve cells to facilitate the transmission of nerve impulses.
Although levodopa is a very effective drug, patients gradually develop dyskinesia with prolonged administration. The ups and downs of the ‘on’ state in which the drug is effective and the ‘off’ state in which the drug does not appear to the patient are irregularly displayed, the period of ineffectiveness gradually increases, involuntary movement is exaggerated, and dystonia appears. .
Depending on the patient, symptoms may appear suddenly, such as turning a light on and off. Among the patients who used levodopa for more than 5 years, half of the patients who used levodopa for more than 10 years, most of them showed dyskinesia. Dysmotor symptoms appear not simply in proportion to the duration of levodopa administration, but in relation to the degree of damage to the dopaminergic nerve. Therefore, even if the administration of levodopa is intentionally delayed, the onset of dyskinesias cannot be delayed.
Dyskinetic symptoms appear not because levodopa is toxic, but because it is unstable. In other words, it is a phenomenon that occurs when the instability of levodopa and the loss of dopaminergic neurons work together. Levodopa is so unstable that its blood concentration is reduced by half within 50 minutes after administration, and only 1% of the administered drug is absorbed into the brain.
In the early stages of Parkinson’s disease, dopaminergic nerves remain to some extent, so levodopa is converted to dopamine and stored, and then dopamine is continuously released. As Parkinson’s disease progresses and dopaminergic nerves decrease, the storage capacity of levodopa/dopamine is also depleted, and the dopamine supply in the brain is completely dependent on blood levodopa concentration and becomes unstable. Dyskinesia or catatonia occurs when blood levodopa is excessively high or low.
Maintaining a continuous and stable level of levodopa in the blood is important for the management of motor symptoms and dyskinesias in Parkinson’s disease. Levodopa is converted to dopamine by dopa decarboxylase while present in the blood.
When carbidopa, a dopa decarboxylase inhibitor, is administered together, the half-life of levodopa is increased to 90 minutes, and at the same time, the amount of levodopa that crosses the blood-brain barrier and is absorbed into the brain increases by more than 5 times, thereby reducing the administered dose of levodopa. . The levodopa/carbidopa sustained-release form further prolongs the half-life of levodopa, but instead the efficacy of levodopa is delayed.
Levodopa/carbidopa for inhalation (Inbriza) is a fast-acting agent, and is used when a patient who has lost efficacy urgently needs recovery. Improvements in sustained release formulations and fast-acting formulations are still ongoing.
Patients with advanced Parkinson’s disease have irregular gastrointestinal motility due to autonomic symptoms, and food also inhibits drug absorption, so absorption of orally administered drugs is irregular. A formulation (duodopa enteric gel) that directly administers levodopa/carbidopa to the small intestine has been developed.
For intestinal administration of Duodopa, there is a burden of inserting an administration tube into the jejunum of the small intestine, so research to improve the administration method is in progress. A method of continuously administering levodopa through a skin patch has been tried for a long time, but the absorption efficiency of levodopa has become a problem. Recently, the development of a formulation in which levodopa is continuously injected subcutaneously is being developed.
Another metabolizing enzyme for levodopa is COMT. When co-administered with entacapone, a COMT inhibitor, it has the effect of stabilizing the action of levodopa and reducing the dose of levodopa, just like dopa decarboxylase inhibitors. Starevo is a combination drug of levodopa, a dopa decarboxylase inhibitor, and a COMT inhibitor.
Instead of levodopa, drugs that act directly on dopamine receptors can be administered to replace the function of dopamine. Inhibitors of the dopaminerase MAO are also used for the same purpose. These drugs are used instead of levodopa in the early stages of Parkinson’s disease, administered in combination with levodopa, or used as substitute drugs for levodopa dyskinesia.
Although these drugs are more stable than levodopa, each has its own side effects. In particular, drugs that act on dopamine receptors increase impulsivity, and patients may show behavioral changes such as impulse buying, gambling, and hypersexuality. First of all, these drugs are less effective than levodopa.
Amantadine is the only drug approved for relieving levodopa dyskinesia. Although it has been used for a long time, amantadine does not sufficiently relieve dyskinesia and may exhibit side effects such as psychiatric symptoms and hypotension.
Relatively recently approved drugs to aid in the effects of levodopa include safinamide, an MAO inhibitor, israpedilin, which acts on the adenosine receptor, and opicafone, a COMT inhibitor.
If dyskinesia is severe but cannot be controlled with drugs, deep brain stimulation (DBS) is used. Because motor circuits in the brain work independently of cognitive memory circuits, they stimulate motor circuits in a manner similar to the way a pacemaker works on the heart without affecting the cognitive memory capacity of the brain.
Deep brain stimulation does not replace levodopa, but aims to stabilize the action of levodopa and alleviate dyskinesia. If Parkinson’s disease is so severe that levodopa does not work, deep brain stimulation is also invalid.
Currently, drugs used for motor symptoms of Parkinson’s disease can be summarized as symptom relievers, dopamine nerve targets, and levodopa. This trend is likely to continue for some time to come. As of January 2022, three-quarters of drug development for Parkinson’s disease in the phase 3 clinical trial is to alleviate symptoms by acting on dopaminergic nerves, and a significant number is related to the development of formulations of levodopana or dopaminergic drugs. are things
However, Parkinson’s disease drug development is gradually shifting toward using various mechanisms and targeting various targets. The development of drugs aimed at improving motor symptoms and alleviating dyskinesias through other nervous systems and targets other than dopaminergic neurons is active, and these are the mainstay of phase 2 clinical trials.
In addition, over the past 20 years, many studies have been made on the cause and progression mechanism of Parkinson’s disease, and information on biomarkers related to Parkinson’s disease has been accumulated, which is the basis for drug development. Beyond simple symptom improvement, ‘therapeutic’ drugs with various mechanisms that try to slow or prevent the progression of Parkinson’s disease are in the clinical trial stage.
△ Biography of Dr. Seong-ah Seong-ah
Bachelor of Pharmacy, Ewha Womans University
PhD, State University of New Jersey, USA
1998-2011 Vanderbilt University/Yale University- A study on drug mechanism of action on the brain nervous system
2011-2015 Korea Institute of Science and Technology-Crain neural transmission circuit research
2018-2022, Medi-Helpline Co., Ltd. drug development research, Medi-Helpline Senior Researcher