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Parkinson’s Disease Drug Therapy: The Role of
Levodopa and Carbidopa in Treating Disease
Symptoms
By: Nicole Hume
Overview of Parkinson’s Disease: Common
Symptoms and Manifestations
Parkinson’s Disease is a nervous system disease that affects
movement. The symptoms of this disease are progressive, possibly
beginning with a small tremor of the hand, slowing of movements, or
stiffness. Slurred speech is another symptom of the disease, and
symptoms become worse as the disease progresses. Although these
symptoms seem like a problem with muscle, the root cause of the
disease is in the nervous system. The nervous system is the network of
neurons in our body responsible for transmitting nerve impulses so we
can carry out actions such as muscle movement and contraction.
Unfortunately, there is no cure today for Parkinson’s Disease, but the
symptoms can be treated with drugs Levodopa (L-Dopa) and
carbidopa. Figure 1 shows the common symptoms of Parkinson’s
Disease.
Figure 1: Common symptoms of Parkinson’s Disease
Development of Parkinson’s Disease through Loss of Dopaminergic Signaling
Parkinson’s Disease arises as a result of nerve cells called neurons gradually breaking down or dying in the
brain. These nerve cells are located in the substantia nigra region of the midbrain. The substantia nigra is a
part of the brain that plays a role in movement and requires the neurotransmitter dopamine, a chemical
responsible for signaling connections in the brain that lead to outward changes such as movement. In
patients with Parkinson’s Disease, these dopaminergic
neurons (neurons that produce dopamine and transmit
dopamine signals) are destroyed. Therefore dopamine
is no longer produced in this area of the brain and
cannot signal to control body movements. Figure 2
compares a normal neuron and a Parkinson’s affected
neuron. It is estimated that 70% of neurons in the
substantia nigra are destroyed at the time of first
symptoms. As more neurons die, the symptoms
become worse. It is not understood how these neurons
die, but Parkinson’s Disease drug therapy involves
promoting an increase in dopamine levels in the brain
to promote dopaminergic signaling in the substantia
nigra, ultimately leading to body movements.
Figure 2: Comparison dopamine signaling in a normal neuron
compared to a Parkinson’s Disease affected neuron
Figure 1 image from http://spinalstenosis.org/blog/pain-parkinsons-disease/
Figure 2 image from http://healthlifemedia.com/healthy/what-is-parkinsons-disease/
Mechanism of Parkinson’s Disease Drug Therapy
The most common therapy involves levodopa (L-Dopa), which is taken in combination with carbidopa.
Both drugs work together to decrease the symptoms of Parkinson’s disease.
L-Dopa
L-Dopa has been the most effective treatment for
Parkinson’s for the last thirty years. This drug is a dopamine
precursor; it is a molecule that is converted to dopamine by
an enzymatic reaction once it is inside the body. L-Dopa is
taken orally, absorbed in the blood stream, and crosses the
blood-brain barrier. The blood-brain barrier (BBB) is a filter
that selectively allows the passage of certain substances from
the periphery into the brain and vice versa. L-Dopa can cross
the blood-brain barrier while dopamine cannot, which is why
L-Dopa is given as the drug instead of dopamine. Once LDopa crosses the blood-brain barrier, it is converted to
dopamine by an enzyme called DOPA Decarboxylase
(DDC). This enzymatic reaction increases dopamine levels
in the brain so signaling for movement in the substantia
nigra can occur. Figure 3 depicts the action of L-Dopa once
is has entered the neuron. L-Dopa is converted to dopamine
inside the neuron, where it is packaged into a vesicle. The
vesicle travels to the end of the neuron and enters the
synapse, where it releases dopamine. The dopamine can then
bind to a receptor on the receiving cell to pass on the
message. These messages consist of electrical signals
Figure 3: The Mechanism of L-Dopa Inside the Neuron to
that ultimately lead to muscle movement.
promote dopaminergic signaling
Carbidopa
Only 1-3% of oral L-Dopa reaches the brain before it is
metabolized to another substance that is neither a
dopamine precursor nor cross the blood-brain barrier,
which means that when taking L-Dopa alone, only a
small percentage of the drug taken is effectively
alleviating symptoms of Parkinson’s Disease. This
problem arises because DDC exists in the peripheral
tissues as well and converts L-Dopa to dopamine before
it is able to cross the blood-brain barrier. When this
reaction occurs, no dopamine is able to reach the brain
and produce dopaminergic signaling needed for
movement. To avoid this problem, carbidopa is given
with L-Dopa. The mechanism of action of carbidopa
involves the inhibition of DDC. The drug binds to the
enzyme outside of the BBB and prevents it from
Figure 4: General Overview of Levodopa/Carbidopa
interacting with L-Dopa, therefore no conversion to
Therapy in the Peripheral and Central Nervous System
dopamine occurs. Carbidopa is effective because it is not
able to cross the blood-brain barrier and only inhibits DDC in the periphery. By inhibiting DDC in the
periphery, absorbed L-Dopa can cross the blood-brain barrier and enter the brain where it is converted to
dopamine by the DDC enzymes in the brain that are not inhibited. Figure 4 depicts this process, showing
that the conversion of L-Dopa to dopamine is inhibited by carbidopa, then L-Dopa can cross the BBB, enter
the brain, and be converted to Dopamine by the enzyme DDC.
Figure 3 image from http://www.nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html
Figure 4 image from http://m.blog.daum.net/ni-co2/15005700
Conclusion
Parkinson’s Disease is a nervous system disease that leads to tremors, slowed movement, and slurred
speech. These symptoms occur as a result of dopaminergic neuron degeneration in the substantia nigra
region of the brain. This region of the brain is responsible for movement and relies on dopamine to send
these movement signals. Drug therapy for Parkinson’s Disease is aimed at alleviating symptoms by
increasing the amount of dopamine in the brain. To do so, Levodopa (L-Dopa) is administered along with
carbidopa. L-Dopa is taken orally, is absorbed into the blood stream, and crosses the blood brain barrier.
Once the drug is inside the brain, DOPA Decarboxylase converts L-Dopa to dopamine to increase the
amount of dopamine for signaling in the substantia nigra. As a result, the physical symptoms of Parkinson’s
Disease are alleviated. However, only a small percentage of L-Dopa can reach the site of action in the brain
because it is metabolized in the periphery. Carbidopa is used to inhibit the conversion of L-Dopa to
dopamine before it reaches its site of action. This inhibition allows L-Dopa therapy to be more effective
and allow people with Parkinson’s Disease to control their muscle movements. In the future, an ideal drug
therapy would be to target the degenerated neurons in the substantia nigra. However, alleviating the
symptoms is the most effective treatment today.