Levodopa On Parkinson's disease
Levodopa has been the most widely used treatment for over 30 years.
L-DOPA is converted into dopamine in the dopaminergic neurons by dopa
decarboxylase. Since motor symptoms are produced by a lack of dopamine
in the substantia nigra, the administration of L-DOPA temporarily
diminishes the motor symptoms.
Only 5–10% of L-DOPA
crosses the blood–brain barrier. The remainder is often metabolized to
dopamine elsewhere, causing a variety of side effects including nausea,
dyskinesias and joint stiffness. Carbidopa and benserazide are
peripheral dopa decarboxylase inhibitors, which help to prevent the
metabolism of L-DOPA before it reaches the dopaminergic neurons,
therefore reducing side effects and increasing bioavailability. They are
generally given as combination preparations with levodopa. Existing
preparations are carbidopa/levodopa (co-careldopa) and
benserazide/levodopa (co-beneldopa). Levodopa has been related to
dopamine dysregulation syndrome, which is a compulsive overuse of the
medication, and punding. There are controlled release versions of
levodopa in the form intravenous and intestinal infusions that spread
out the effect of the medication. These slow-release levodopa
preparations have not shown an increased control of motor symptoms or
motor complications when compared to immediate release preparations.
Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby
prolonging the effects of levodopa. It has been used to complement
levodopa; however, its usefulness is limited by possible side effects
such as liver damage. A similarly effective drug, entacapone, has not
been shown to cause significant alterations of liver function. Licensed
preparations of entacapone contain entacapone alone or in combination
with carbidopa and levodopa.
Levodopa
preparations lead in the long term to the development of motor
complications characterized by involuntary movements called dyskinesias
and fluctuations in the response to medication. When this occurs a
person with PD can change from phases with good response to medication
and few symptoms ("on" state), to phases with no response to medication
and significant motor symptoms ("off" state). For this reason, levodopa
doses are kept as low as possible while maintaining functionality.
Delaying the initiation of therapy with levodopa by using alternatives
(dopamine agonists and MAO-B inhibitors) is common practice. A former
strategy to reduce motor complications was to withdraw L-DOPA medication
for some time. This is discouraged now, since it can bring dangerous
side effects such as neuroleptic malignant syndrome. Most people with PD
will eventually need levodopa and later develop motor side effects.
