Mechanism of Action
Dopamine itself cannot cross the blood-brain barrier (BBB). Therefore, clinical practice utilizes its precursor — levodopa (Levodopa), which is the levorotatory isomer of DOPA (L-DOPA).
Levodopa is a weak acid ($ ext{p}K_a$ 2.3) that crosses the BBB via active transport, utilizing the large neutral amino acid transporter system (mimicking a natural substrate). Once inside intact CNS neurons, levodopa undergoes decarboxylation mediated by the enzyme DOPA decarboxylase. As a result, it is converted into dopamine, which is released from nerve terminals and stimulates $D_2$ receptors on cholinergic neurons of the neostriatum.
Role of Carbidopa: During levodopa monotherapy, over 90% of the dose is metabolized by DOPA decarboxylase in the intestinal wall and liver. The peripherally formed dopamine does not enter the brain, resulting in a CNS bioavailability of levodopa of only 1–3%. Carbidopa is a peripheral DOPA decarboxylase inhibitor. It prevents premature breakdown of levodopa, increases its concentration in the CNS, and dramatically reduces the frequency of peripheral adverse effects.
Pharmacological Effects and Clinical Use
Stimulation of $D_2$ receptors leads to a decrease in the pathological hyperactivity of cholinergic neurons. Clinically, this manifests as a potent antiparkinsonian effect: bradykinesia, muscle rigidity, and tremor are alleviated. The drug is considered the most effective treatment for Parkinson's disease.
Dosing Regimen: The drug is administered orally. The starting dose is $1/2$ tablet 1–2 times daily. The maximum recommended daily dose is limited to 0.2 g of carbidopa and 2.0 g of levodopa.
Clinical pearl: Levodopa is absorbed in the intestine via the aromatic amino acid transport system. Protein-rich meals compete for this carrier and significantly reduce drug absorption.
Side Effects and Complications
Adverse reactions are divided into central (related to excess dopamine in the brain) and peripheral.
- CNS: Psychoses (due to stimulation of the mesolimbic system), hallucinations, anxiety, depression, insomnia, or conversely, somnolence. For the pharmacological management of psychoses, the atypical antipsychotic clozapine (Clozapinum) is used. It predominantly blocks $D_4$ receptors while minimally affecting $D_2$ receptors, thereby preserving the antiparkinsonian efficacy of levodopa.
- Cardiovascular system: Tachycardia and arrhythmias. These occur due to the stimulation of myocardial $eta$-adrenergic receptors by peripherally formed dopamine.
- Gastrointestinal tract: Vomiting (resulting from stimulation of the chemoreceptor trigger zone of the vomiting center).
Complications of Long-Term Therapy:
- Dyskinesias: Involuntary choreiform (rapid, purposeless) movements of the face, neck, and extremities.
- "On-Off" Syndrome: Rapid fluctuations in the patient's clinical state from normal mobility to sudden symptom relapse. Attempting to increase the dose frequently leads to overdose. Sustained-release formulations are used to manage this.
Contraindications
The drug is strictly contraindicated in the following conditions:
- Narrow-angle glaucoma;
- Diabetes mellitus;
- Severe cardiac arrhythmias;
- History of psychosis;
- Severe hepatic and renal impairment;
- Pregnancy and lactation;
- Pediatric and adolescent age (under 25 years).
Principles of Combination Therapy
To potentiate the effect of levodopa and preserve endogenous dopamine, a comprehensive approach is utilized. In addition to peripheral DOPA decarboxylase inhibitors (carbidopa), the regimen may include:
- COMT inhibitors (catechol-$O$-methyltransferase inhibitors) — block an alternative metabolic pathway for levodopa.
- MAO-B inhibitors (e.g., selegiline).
- Dopamine-releasing agents (amantadine).
- Dopamine receptor agonists.