Levodopa

Mechanism of action and pharmacokinetics

Dopamine on its own is unable to cross the blood-brain barrier (BBB). Therefore, its precursor, levodopa, is used to replenish its deficiency in the central nervous system. Absorption of the drug occurs in the intestine via the active transport system for aromatic amino acids. Protein-rich foods can compete for this transport and reduce absorption efficiency.

Upon penetrating undamaged CNS neurons, levodopa is converted into dopamine by the action of the enzyme DOPA decarboxylase. Released from nerve terminals, it stimulates $D_2$ receptors on cholinergic neurons of the neostriatum. This leads to a decrease in their pathological hyperactivity and, consequently, the alleviation of parkinsonian motor symptoms.

Bioavailability issues and combination drugs

The main pharmacokinetic problem is that over 90% of a levodopa dose undergoes intensive metabolism by peripheral DOPA decarboxylase (in the intestinal wall and liver) to form dopamine, which does not cross the BBB. As a result, only 1–3% of the administered dose reaches the brain. Additional metabolism occurs via monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

To optimize therapy, levodopa is combined with DOPA decarboxylase inhibitors (carbidopa or benserazide), which do not cross the CNS. This prevents the premature conversion of the drug in the periphery, increasing its delivery to the brain up to 10%. Such a combination makes it possible to lower the therapeutic dose of levodopa and reduce the severity of peripheral side effects.

Examples of combination drugs:

• Levodopa + Carbidopa: Nakom, Sinemet, Duellin.
• Levodopa + Benserazide: Madopar.

Side effects and their management

Adverse reactions to levodopa are divided into peripheral and central:

Peripheral effects (caused by dopamine outside the CNS):

• Cardiovascular: tachycardia, arrhythmias, orthostatic hypotension.
• Gastrointestinal: nausea and vomiting due to stimulation of $D_2$ receptors in the chemoreceptor trigger zone of the vomiting center. For management, domperidone is used—a dopamine receptor blocker that does not cross the BBB and does not reduce the antiparkinsonian effect.

Central effects (associated with excess dopamine in the CNS):

• Psychoneurotic: psychoses, hallucinations, anxiety, insomnia, somnolence.
• Motor: choreiform dyskinesias (rapid, purposeless movements).

To treat psychoses, clozapine is used—an atypical antipsychotic that predominantly blocks $D_4$ receptors, thereby avoiding the exacerbation of parkinsonism symptoms.

Complications of long-term therapy and contraindications

When levodopa is taken for more than 5 years, its efficacy declines due to the progressive degeneration of dopaminergic neurons. It is hypothesized that dopamine metabolites are neurotoxic.

A specific complication is the "on-off" syndrome—sharp fluctuations in clinical state ranging from the return of symptoms to overdose with a slight increase in dose. It is managed by prescribing sustained-release formulations.

Levodopa is contraindicated in angle-closure glaucoma, diabetes mellitus, severe cardiovascular pathologies (arrhythmias), psychoses, hepatic and renal impairment, as well as in individuals under 25 years of age, pregnant, and lactating women.

Class and exam questions

What else to study on this topic

• Features of active transport of aromatic amino acids across the BBB endothelium
• The role of MAO and COMT enzymes in dopamine metabolism
• Mechanism of development of the "on-off" syndrome
• The effect of protein-rich food on the pharmacokinetics of levodopa
• Neurotoxic effects of dopamine metabolites: current hypotheses

Other topics in the section "Agents Used in Psychiatry and Neurology"

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