Benserazid: Peripheral DOPA Decarboxylase Inhibitor in Madopar (with Levodopa)

Benserazid is a peripheral inhibitor of aromatic L amino acid decarboxylase (DOPA decarboxylase). It is used exclusively in fixed combination with levodopa as Madopar (Roche) for the treatment of Parkinson's disease. In the US and some other countries, carbidopa is used as the decarboxylase inhibitor combined with levodopa instead (Sinemet, Stalevo).

The levodopa plus benserazid combination was approved in 1973 and revolutionized Parkinson therapy. Pure levodopa is metabolized to dopamine in the periphery before reaching the brain, which weakens the onset profile in the brain and increases peripheral side effects such as nausea, vomiting, and hypotension. Through peripheral decarboxylase inhibition, more levodopa reaches the central nervous system unchanged across the blood-brain barrier, where it can then be converted to dopamine. This reduces the required dose by approximately 75 percent and significantly improves tolerability.

Mechanism of Action

In Parkinson's disease, dopaminergic neurons in the substantia nigra degenerate, resulting in dopamine deficiency in the striatum. Since dopamine itself cannot cross the blood-brain barrier, the precursor levodopa is used, which is converted to dopamine in the brain by DOPA decarboxylase.

The problem is that the enzyme DOPA decarboxylase is also present peripherally in many tissues (intestine, liver, kidney, blood vessels). Without an inhibitor, approximately 95 percent of the oral levodopa dose is converted to dopamine in the periphery, which causes useless peripheral side effects and greatly reduces the cerebral available amount. Benserazid selectively inhibits peripheral DOPA decarboxylase but cannot cross the blood-brain barrier and does not affect cerebral decarboxylase activity.

The result is significantly higher cerebral availability of levodopa and thus better antiparkinson effect at a much lower dose. Pharmacokinetically, benserazid itself is only partially absorbed and metabolized almost completely in the periphery, so the cerebral effect relies solely on the levodopa substance.

Indications

• Idiopathic Parkinson's disease: in combination with levodopa as standard therapy from moderate symptomatology onwards
• Symptomatic parkinsonism: in secondary Parkinson forms (post-encephalitic, vascular, traumatic)
• Restless legs syndrome: off-label, short-term therapy only with caution due to augmentation risk
• Atypical Parkinson syndromes: multiple system atrophy, progressive supranuclear palsy with often limited response

Dosage and Administration

Madopar standard form: fixed ratio 4:1 levodopa to benserazid. Usual initial dose 50/12.5 mg three times daily, gradual increase by 50/12.5 mg every 3 to 7 days until effective dose (usually 200 to 800 mg levodopa per day, higher in advanced disease).

Madopar sustained-release form: delayed release for maintenance phase and nocturnal symptoms. Madopar dispersible: effervescent tablets with rapid onset of action for on-off phenomena or morning akinesia.

Administration: at least 30 minutes before or 60 minutes after protein-rich meals, as amino acids from food compete for absorption at the blood-brain barrier and can weaken the effect. Too rapid dose escalation can cause nausea, vomiting, and orthostatic hypotension.

In renal insufficiency and hepatic insufficiency: cautious titration. In severe hepatic insufficiency use with caution.

Side Effects

Very common (especially at the beginning): nausea, vomiting, loss of appetite, orthostatic hypotension, dizziness, headaches, sleep disturbances.

Common: dyskinesias (involuntary movements), motor fluctuations with on-off phenomena, especially after several years of therapy; sleep attacks (sudden sleep especially while driving), psychiatric symptoms (hallucinations, confusion, depression, anxiety), impulse control disorders (gambling, hypersexuality, eating disorder, compulsive shopping), reddish discoloration of urine and sweat.

Serious, rare: malignant neuroleptic-like syndrome upon abrupt discontinuation, hemolytic anemia, leukopenia, hyperpigmentation of skin, worsening of narrow-angle glaucoma.

Important: Patients and relatives should be informed about impulse control disorders because these can be recognized late and have serious consequences (financial ruin, relationship breakdown). Sleep attacks can make driving dangerous.

Drug Interactions

• MAO inhibitors (non-selective such as tranylcypromine): hypertensive crisis, combination contraindicated
• Selective MAO B inhibitors (selegiline, rasagiline): permitted and often combined
• Antipsychotics (classical and some atypical): antagonism via D2 blockade, loss of effect and worsening of Parkinson symptoms
• Metoclopramide: antagonistic effect at D2, contraindicated
• Iron preparations: reduce levodopa absorption through complex formation, take at separate times
• Protein-rich meals: reduce levodopa efficacy
• Antihypertensives: additive hypotension

Special Precautions

Pregnancy and lactation: Data limited, in pregnancy only with clear indication. In young patients, therapy planning should be individualized.

Discontinuation of therapy: taper slowly, never stop abruptly, as malignant neuroleptic-like syndrome with fever, muscle rigidity, and impaired consciousness may occur.

Driving ability: Due to sleep attacks, confusion, and hypotension, driving ability must be assessed individually. If sleep attacks occur, driving ban until stabilization.

Eye examination: with prolonged therapy, regular ophthalmological monitoring due to rare narrow-angle glaucoma worsening.

Wearing off and dyskinesias: after several years of therapy, the duration of action of individual doses shortens (wearing off) and dyskinesias may develop. Strategies include more frequent smaller doses, sustained-release formulations, combination with dopamine agonists, MAO B or COMT inhibitors.

You might also be interested in

• Levodopa, the main active ingredient for Parkinson's
• Carbidopa, alternative DOPA decarboxylase inhibitor (Sinemet)
• Entacapon, COMT inhibitor in Stalevo
• Rasagilin, MAO B inhibitor
• Pramipexol, dopamine agonist

Frequently Asked Questions

Sources

• EMA Product Information Madopar
• DGN Guideline Idiopathic Parkinson Syndrome
• Gelbe Liste, Benserazid and Madopar active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices