Products
Levodopa is marketed exclusively as combination products together with a peripheral decarboxylase inhibitor (carbidopa or benserazide) or a COMT inhibitor (entacapone). It has been approved in many countries since 1973 and is commercially available in tablet, capsule, suspendable tablet, and sustained-release tablet forms, among others.
Structure and properties
Levodopa (C9H11NO4, Mr = 197.2 g/mol) exists as a white crystalline powder that is sparingly soluble in water. It is a derivative of the amino acid tyrosine. Levodopa is a prodrug of the neurotransmitter dopamine, which is activated in the central nervous system by decarboxylation.
Effects
Levodopa (ATC N04BA01) compensates for the lack of dopamine in the brain, which in the case of Parkinson’s disease results from the loss of function and demise of dopaminergic neurons in the black matter of the brain. Symptoms of Parkinson’s disease such as slowed movement and rigidity respond well to therapy with levodopa. In contrast, tremors, speech and swallowing disorders, and a rigid gait are resistant to dopaminergic therapy. The antiparkinsonian effect is enhanced by combining levodopa with a decarboxylase inhibitor. Decarboxylase inhibitors cannot cross the blood–brain barrier, resulting in inhibition of peripheral conversion of levodopa to dopamine. This combination results in the ability to decrease the dose of levodopa and reduce side effects attributable to the peripheral formation of dopamine.
Mechanism of action
The effects are due to the interaction of dopamine with postsynaptic dopaminergic receptors D1 and D2.
Indications
For the treatment of Parkinson’s disease and restless legs syndrome. Other indications exist, such as the rarely occurring Segawa syndrome (off-label).
Dosage
According to the drug label. Daily dose is determined on an individual basis. Taking levodopa after meals may prolong the duration of action and reduce adverse effects such as movement disorders.
Contraindications
Levodopa is contraindicated in hypersensitivity, in patients with narrow-angle glaucoma or a history of melanoma, and in concomitant use of nonselective MAO inhibitors and metoclopramide. The latter blocks dopamine receptors in the brain, exacerbating PD symptoms. For complete precautions, see the drug label.
Interactions
Concomitant ingestion of a high-protein meal or administration of antacids, dopamine antagonists (neuroleptics), and iron may decrease the effects of levodopa. When combined with MAO-A inhibitors, a crisis increase in blood pressure may occur. These should be discontinued two weeks before starting therapy with levodopa. Together with antihypertensive drugs, orthostatic hypotension may occur. Other interactions have been described with phenytoin and papaverine, which may attenuate the antiparkinsonian effects of levodopa.
Adverse effects
Common adverse effects include nausea, vomiting, and cardiovascular disturbances. They are due to the central effects of dopamine. They usually occur with the first dose and may increase with increasing doses. Combination with decarboxylase inhibitors can reduce these adverse effects. Several years of therapy with levodopa often cause fluctuations in effect and disturbances in movement. The most pronounced form is the on-off phenomenon, which is characterized by alternating phases of good mobility and complete rigidity. It is probably due to an insufficiently constant extracellular dopamine concentration in the basal cells. Such fluctuations in effect can be reduced with sustained-release tablets or by combination with dopamine agonists.
