Continuing Education Activity
Carbidopa is a medication used in the management and treatment of Parkinson disease (PD). It is in the decarboxylase inhibitor class of drugs. This activity reviews the indications, mechanism of action, and contraindications for carbidopa as a valuable agent in managing PD symptoms. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the interprofessional team in the management of patients with PD and related conditions.
- Identify the mechanism of action of carbidopa.
- Describe the potential adverse effects of carbidopa.
- Review the appropriate monitoring for patients receiving carbidopa.
- Summarize interprofessional team strategies for improving care coordination and communication to advance carbidopa and improve outcomes.
Carbidopa is indicated for combination use with levodopa (L-dopa) for the treatment of motor symptoms encountered in Parkinson disease (PD), post-encephalitic parkinsonism, and parkinsonism symptoms resulting from intoxication by carbon monoxide or manganese.
Parkinson’s disease is a disorder of decreased dopamine secreting neurons of the substantia nigra, causing several motor symptoms, including bradykinesia, cogwheel rigidity, resting tremor, shuffling gait postural instability. Levodopa is a precursor of dopamine that can cross the blood-brain barrier, thus increasing dopamine production in the brain, helping to manage parkinsonism symptoms. Carbidopa is added to levodopa formulations to decrease the peripheral conversion of L-dopa to dopamine to reduce gastrointestinal side effects, and increase levodopa bioavailability in the central nervous system (CNS).
More recently, there have been suggestions that carbidopa has potential anticancer properties through its role as a selective aryl hydrocarbon receptor modulator (SAhRM). At this time, carbidopa has no FDA-approved uses in the treatment of cancer.
Mechanism of Action
Carbidopa, 1-α-methyldopahydrazine, acts by irreversibly binding pyridoxal 5′-phosphate (PLP), inhibiting l-aromatic amino acid decarboxylase (AADC), a PLP-dependent enzyme. AACD acts to metabolize 5-HTP to serotonin and L-dopa to dopamine. Whereas levodopa is taken up by the central nervous system, carbidopa cannot cross the blood-brain barrier, and therefore its effects on enzymatic activity act only peripherally.
Decreasing levodopa metabolism peripherally allows for more L-dopa to be taken up by the CNS. This increased potency reduces the dose of levodopa necessary for the effective treatment of parkinsonian motor symptoms by up to 75%.
Additionally, the lack of peripheral conversion of levodopa to dopamine decreases gastrointestinal (GI) absorption, preventing excess dopamine in the GI tract, decreasing levodopa side effects, including diarrhea, nausea, and/or vomiting.
There are several formulations and routes of administration for combinations of levodopa and carbidopa. The basis for dosing is weight, with a ratio of 10 to 1 or 4 to 1, levodopa to carbidopa. “Off time” and “on time” refer to common motor fluctuations occurring with levodopa administration, and therefore also with carbidopa/levodopa coadministration. “Off time” refers to the periods where patients experience parkinsonian motor symptoms, i.e., the medication working ineffectively. In comparison, “on-time” refers to the relief of symptoms or the potential emergence of dyskinesias, involuntary, erratic movements. This fluctuation of symptoms is likely due to the stimulation of the dopamine receptors in a pulsatile, non-physiological fashion. The severity of Parkinson disease can affect the stability of dopamine concentrations despite fluctuating levodopa concentrations. More advanced disease states may require different formulations of the drugs.
- There are formulations of both immediate release and sustained release of carbidopa/levodopa and a combination of carbidopa/levodopa and entacapone, a peripheral inhibitor of catechol-O-methyltransferase.
- Extended-release capsule formations of carbidopa/levodopa are designed with beads that release medication at a constant rate for 4 to 5 hours after administration. The extended-release version has been shown to decrease “off-time” in more advanced PD patients when compared to immediate-release formulations.
- There is an intestinal gel infusion formulation of carbidopa/levodopa that is a suspension of levodopa (20 mg/ml) and carbidopa (5 mg/ml) in 2.95% carboxymethylcellulose gel. This route of administration is typically first performed via a portable pump that runs through a naso-duodenal tube and later through a percutaneous endoscopic gastrostomy (PEG) tube following titration of the proper dose. This route of administration is reserved for the most severe cases of PD.
Overall, the variety of routes of administration and drug combinations demonstrate the balance between making the drug fast-acting, long-lasting, stable, and effective at treating the symptoms without causing unnecessary risk or adverse effects to the patient.
Because of the irreversible binding of AADC, carbidopa can decrease or deplete peripheral levels of serotonin, dopamine, norepinephrine, and epinephrine. Additionally, research has demonstrated that the irreversible binding of PLP causes nutritional deficiencies of vitamins B3 and B6. Specific carbidopa-induced dyskinesias, including “facial twitching and head bobbing,” have also been described.
It is also essential to recognize the adverse effects associated with carbidopa/levodopa combinations. In addition to dyskinetic movements, there are reports of psychiatric problems, autonomic dysfunction, and sensory/pain symptoms with levodopa use. These non-motor symptoms range from euphoric mood, hallucinations, and worsening cognition, to poor thermoregulation, dysphagia, and peripheral neuropathy and can vary depending on the “on/off” fluctuations of levodopa.
Carbidopa alone has few contraindications; however, because its administration is always in combination with levodopa, it shares the same risks. Because of limited data, carbidopa should not be used in those under 18 years old and should be avoided in pregnancy. It is contraindicated to give carbidopa/levodopa capsules along with nonselective monoamine oxidase inhibitors due to a risk of hypertension. These include but are not limited to phenelzine, isocarboxazid, and tranylcypromine. Any nonselective MAO inhibitor should be stopped at least two weeks prior to beginning treatment with carbidopa/levodopa.
The use of carbidopa alone does not call for any specific monitoring. Monitoring all PD patients for motor symptoms is necessary for creating drug schedules that align with disease progression. Co-prescribing carbidopa/levodopa with specific drugs may require monitoring for potential adverse effects. Using carbidopa/levodopa with selective MAO-B inhibitors and certain antihypertensives poses a risk for postural hypotension and should be monitored appropriately. Additionally, concomitant use with tricyclic antidepressants may have some association with hypertension and dyskinesias.
There is little data to suggest a possibility for or symptoms of carbidopa toxicity. However, reported data indicate that carbidopa/levodopa intestinal gel infusion can cause significant damage to small nerve fibers leading to pain and sensory discomfort.
Enhancing Healthcare Team Outcomes
sIt is important to understand the indications and use of carbidopa along with levodopa for the treatment of Parkinson’s disease and parkinsonism motor symptoms. Determining patient-specific formulations and dosage is key to its effective use. Carbidopa can decrease peripheral side effects and lower the effective dose of levodopa, but it is essential to recognize adverse effects and toxicity to adjust dosages and medication combinations as needed.
Carbidopa/levodopa is among the most effective medical treatments for PD patients, but because of the “on/off” fluctuations and wearing off that occurs, it is often reserved for later in the disease course. For example, a patient may be started on an MAO-B inhibitor for early disease symptoms and transitioned to a dopamine agonist once there is noticeable functional impairment. When additional therapy is required, carbidopa/levodopa is a therapeutic option. From that point, determining the proper administration methods and drug combinations are crucial to providing the patient with the most effective care. This is where the prescriber would do well to have a pharmacist consult, particularly with a board-certified pharmacotherapy specialist, who can guide agent selection, dosing, and counsel the patient on adverse events and side effects. It is also relevant to note that deep brain stimulation can be another option when medication alone is not enough to control symptoms. As an interprofessional health care team, it is crucial to understand treatment algorithms and allow patients to know their options, particularly as their disease progresses, which is why interprofessional collaboration and communication are vital to optimal patient outcomes. [Level 5]