Comprehensive Guide to Levodopa: Uses, Dosage, Adverse Reactions, and Pharmacopoeia Information

Levodopa is an organic compound with the chemical formula C₉H₁₁NO₄. It is a precursor drug to dopamine (DA), with no pharmacological activity. Once it crosses the blood-brain barrier and enters the central nervous system, it is converted into DA by the enzyme dopa decarboxylase, thereby exerting its pharmacological effects.

Indications: Levodopa is highly effective in improving muscle rigidity and bradykinesia (slowness of movement). Continued use also shows effectiveness against tremors, salivation, postural instability, and difficulty swallowing. It is indicated for:

1. Parkinson’s disease (primary tremor paralysis)
2. Hepatic encephalopathy
3. Neuralgia
4. Hyperprolactinemia
5. Alopecia (hair loss)
6. Promoting growth and development in children

Dosage and Administration: Oral administration: Start with 250 mg per dose, 2-4 times daily, taken after meals. The dosage may be increased every 3-7 days, depending on the patient’s tolerance, until the optimal therapeutic effect is achieved. The maximum dosage is 6 grams per day, divided into 4-6 doses.

Adverse Reactions: Adverse reactions are relatively common and are difficult to avoid with prolonged use, primarily due to excessive dopamine produced in the peripheral system. Adjusting the dosage appropriately can reduce these adverse effects.

1. Gastrointestinal reactions: Nausea, vomiting, and loss of appetite, were observed in about 80% of patients during the initial stages of treatment. After three months of use, patients may experience restlessness, insomnia, hallucinations, and psychiatric symptoms. Other effects include orthostatic hypotension, arrhythmias, and involuntary movements. Dosage adjustment and, if necessary, discontinuation of the drug are recommended.
2. “On-off” phenomenon: This refers to a sudden increase in movement (the “on” state), followed by a return to muscle rigidity and movement difficulties (the “off” state). This phenomenon is more common in younger patients and typically occurs after more than a year of treatment. Reducing the dosage or intravenous administration of levodopa can help manage this phenomenon.
3. Diurnal fluctuations: This may be due to a narrow sensitivity threshold of dopamine receptors in the striatum to dopamine. When dopamine concentration peaks, movement disorders occur; when dopamine concentration decreases, it reverses to a state of immobility, causing significant fluctuations in motor symptoms throughout the day. Adjusting the timing and method of administration, with smaller doses taken more frequently, can alleviate diurnal fluctuations.
4. Urinary difficulties: This is more likely to occur in elderly patients.

Precautions:

1. Use with caution in patients with hypertension, arrhythmias, diabetes, bronchial asthma, emphysema, liver and kidney dysfunction, or urinary retention.
2. In elderly patients with osteoporosis who respond well to treatment with this drug, normal life should be resumed slowly to reduce the risk of fractures.
3. Regular monitoring of blood counts, liver and kidney function, and electrocardiograms is recommended during treatment.
4. This drug can be secreted into breast milk and may also reduce milk production. Animal studies have shown that this drug can cause visceral and skeletal deformities. The FDA classifies this drug as category C for pregnancy safety.
5. Use in children should be cautious.

Contraindications: Levodopa is contraindicated in patients with severe psychiatric disorders, severe arrhythmias, heart failure, glaucoma, peptic ulcers, and a history of seizures. It is also contraindicated in pregnant and lactating women.

Drug Interactions:

1. Concomitant use with non-selective monoamine oxidase inhibitors can cause an acute adrenal crisis.
2. Concomitant use of papaverine or vitamin B6 can reduce the efficacy of this drug.
3. Concomitant use with acetylspiramycin can significantly reduce the blood concentration of this drug, weakening its therapeutic effect.
4. Concomitant use with reserpine can inhibit the effect of this drug and should be avoided.
5. Concomitant use of antipsychotic drugs should be avoided as they antagonize each other.
6. Concomitant use of methyldopa can increase the adverse reactions of this drug and enhance the antihypertensive effect of methyldopa. Note: The above information is provided for reference only. Drug use must be carried out under the guidance of a qualified physician in a regular hospital.

Pharmacopoeia Information: Basic Information This product is (S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid. The content of C₉H₁₁NO₄ in the dried product should be no less than 98.0%.

• Appearance: This product is a white or off-white crystalline powder with no odor.
• It is slightly soluble in water, insoluble in ethanol, chloroform, or ether, and readily soluble in dilute acids.
• Specific Rotation: Take approximately 0.2g of the product, accurately weighed, place it in a 25ml brown volumetric flask, add 5g of urotropine, dissolve and dilute it with hydrochloric acid solution (9→100), shake well, and leave it in the dark for 3 hours. Measure the specific rotation according to the general rule (0621), which should be between -159° and -168°.
• Absorption Coefficient: Accurately weigh the product, dissolve it, and dilute it with hydrochloric acid solution (9→1000) to prepare a solution containing approximately 30μg per ml. Measure the absorbance at a wavelength of 280nm using UV-visible spectrophotometry (0401), and the absorption coefficient ( ) should be between 136 and 146.
• Identification: (1) Take approximately 5mg of the product, dissolve it in 5 ml of hydrochloric acid solution (9→1000), and add 2 drops of ferric chloride solution, which should turn green. Split the solution into two equal parts. To one part, add an excess of dilute ammonia solution, which should turn purple; to the remaining part, add an excess of sodium hydroxide solution, which should turn red.
• (2) Dissolve approximately 5mg of the product in 5 ml of water, add 1 ml of 1% ninhydrin solution, and heat the solution in a water bath. The solution should gradually turn purple.
• (3) The infrared absorption spectrum of the product should be consistent with that of the reference spectrum (Spectrum 87).
• Tests: Clarity and Color of Acidic Solution: Dissolve 0.40g of the product in 10 ml of hydrochloric acid solution (9→100). The solution should be clear and colorless; if colored, it should not be deeper than the yellow-green or yellow standard color solution No. 2 (general rule 0901, Method 1).
• Chlorides: Dissolve 0.30g of the product, and check according to the general rule (0801). The solution should not be more concentrated than the standard sodium chloride solution prepared from 6.0ml of sodium chloride solution (0.02%).
• Other Amino Acids: Test according to thin-layer chromatography (general rule 0502).
  • Test Solution: Dissolve the product in hydrochloric acid solution (9→1000) and prepare a solution containing 10mg per ml.
  • Reference Solution: Accurately measure 1ml of the test solution, place it in a 100 volumetric flask, and dilute to the mark with a hydrochloric acid solution (9→1000). Shake well.
  • System Suitability Solution: Dissolve levodopa and tyrosine in hydrochloric acid solution (9→1000) and prepare a solution containing 10mg of levodopa and 0.10mg of tyrosine per ml.
  • Chromatographic Conditions: Use a microcrystalline cellulose thin-layer plate (0.15g of microcrystalline cellulose/10cm²) and develop with n-butanol-acetic acid-water (2:1:1) as the developing solvent.
  • System Suitability Requirements: The system suitability solution should show separate spots for levodopa and tyrosine.
  • Testing Method: Apply 10μl of each of the three solutions to the same thin-layer plate, develop, evaporate the solvent in air, and spray with a mixture of 10% ferric chloride solution and 5% potassium ferricyanide solution in equal volumes (freshly prepared), then immediately observe.
  • Limits: If impurities appear in the test solution, they should not be darker than the main spot in the reference solution.
• Loss on Drying: Dry the product at 105°C to constant weight. The weight loss should not exceed 1.0% (general rule 0831).
• Residue on Ignition: Take 1.0g of the product, and check according to the general rule (0841). The residue should not exceed 0.1%.
• Heavy Metals: Check the residue from the residue on ignition test according to the general rule (0821, Method 2). The heavy metal content should not exceed 10 parts per million.

Assay: Accurately weigh approximately 0.1g of the product, dissolve it in 2ml of anhydrous formic acid, add 20ml of glacial acetic acid, shake well, add 2 drops of crystal violet indicator, and titrate