Levodopa
Levodopa
Generic Name
Levodopa
Mechanism
- Precursor to dopamine: Levodopa crosses the blood‑brain barrier via the large neutral amino acid transporter and is decarboxylated by aromatic L‑amino acid decarboxylase (AADC) to produce dopamine.
- Reduces mesencephalic dopamine deficit: Restores dopaminergic tone in the nigrostriatal pathway, improving motor symptoms.
- Peripheral inhibition with carbidopa: Co‑administration with carbidopa (an AADC inhibitor) prevents peripheral conversion, increasing central availability and minimizing peripheral side effects (nausea, vomiting).
Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | Oral; peak plasma 30–60 min (with carbidopa). Limited by acidic pH, food (especially protein). | High‑fat meals delay absorption by ~30 min. |
| Distribution | Volume ~300 mL/kg; extensive CNS penetration >70 % of administered dose. | Highly protein‑bound (~70 %). |
| Metabolism | Decarboxylated to dopamine via AADC; catechol-O-methyltransferase (COMT) in liver and intestine. | COMT inhibitors (entacapone, tolcapone) prolong action. |
| Half‑life | 1–1.5 h (with carbidopa), 0.5–1 h alone. | Variable with comedications and renal function. |
| Elimination | Urine (≈80 % unmetabolized); renal clearance ~0.5 mL/min/kg. | Renal impairment does not greatly affect clearance due to hepatic metabolism. |
Indications
- Idiopathic Parkinson’s disease (early, moderate, and advanced stages).
- Parkinsonian disorders: multiple system atrophy, progressive supranuclear palsy (symptomatic relief).
- Post‑operative parkinsonism and acute sedation in certain neurosurgical contexts (off‑label use).
Contraindications
- Contraindications:
- Known hypersensitivity to levodopa, carbidopa, or excipients.
- Severe cardiovascular disease (e.g., uncontrolled hypertension, tachyarrhythmias).
- Warnings:
- Psychosis: May precipitate mania, hallucinations; caution in patients with psychiatric history.
- Cardiovascular: Acute orthostatic hypotension; avoid in decompensated heart failure.
- Drug interactions:
- Monoamine oxidase inhibitors (MAO‑I) – risk of serotonin syndrome.
- Anticholinergics – may potentiate dry mouth, constipation.
- Antihypertensives – additive hypotensive effect.
Dosing
| Formulation | Initial Dose | Titration | Typical Daily Dose* | Notes |
| Carbidopa/Levodopa (1.5/50 mg) PO | 1–2 tablets BID | Increase 1 tablet after 3–5 days if tolerated | 600–800 mg/day (divided) | Start at low dose; avoid maxing early. |
| Extended‑release (LCIG, St. Jude) | 200 µg/kg/h infusion | Titrated by 25 µg/kg/h increments | 800–1,200 µg/kg/h | For motor fluctuations. |
| Sustained‑release (Carbidopa/Levodopa 200 mg + 50 mg) | 1 tablet QID | Increment 1 tablet QID if needed | 600–1,200 mg/day | Splits dose to minimize nausea. |
| Combination with COMT inhibitor | Add entacapone 200 mg TID | Match levodopa intake | ± 180 mg/day | Reduces motor “off” periods. |
*Daily dose ranges refer to total levodopa across all administrations.
Adverse Effects
- Common:
- Nausea, vomiting, dyspepsia.
- Orthostatic hypotension.
- Hypersalivation, sweating.
- Dyskinesias (early, peak‑dose, and dopamine agonist‑induced).
- Serious:
- Hallucinations/Delirium (especially >10 mg/kg/day).
- Psychosis requiring haloperidol or atypical antipsychotics.
- Severe cardiovascular arrhythmias (rare).
- Irreversible dopamine agonist–induced dyskinesias if over‑titrated.
Monitoring
- Motor function: Unified Parkinson’s Disease Rating Scale (UPDRS) every 4–6 weeks.
- Blood pressure: Baseline and orthostatic BP at each visit.
- Weight & nutritional status: Monitor for weight loss due to nausea.
- Adverse effect log: Dyskinesia score, falls risk.
- Drug interactions: Review concomitant medications at each visit; adjust doses accordingly.
Clinical Pearls
1. Low‑dose, high‑frequency strategy: Begin with mini‑doses (1–2 tablets) every 2–3 h during the day; titrate slowly to reduce nausea and dyskinesia.
2. Timing with meals: Administer Levodopa 30 min before breakfast or 2 h after meals to avoid peak‑plasma delay from protein competition.
3. Carbidopa‑only dosing: For patients unable to tolerate nausea, add carbidopa alone for 30 min before levodopa to reduce peripheral side effects.
4. COMT inhibitors: Use entacapone instead of tolcapone except when contraindicated; watch for hepatotoxicity (tolcapone) and liver enzyme monitoring.
5. Extended‑release (ER) vs. multiple-dose: ER formulations improve compliance but may mask peak‑off times; consider LCIG for refractory motor fluctuations.
6. Dyskinesia management: Introduce dopamine agonists only after adequate response to levodopa and consider reducing levodopa dose or adding entacapone.
7. Elderly & renal impairment: Dose reduction by 25% until tolerability improves; monitor for orthostatic hypotension.
8. Drug‑drug interactions: Avoid MAO‑I use < 2 weeks after stopping levodopa; monitor for serotonergic syndrome if combined with SSRIs or tricyclics.
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• References (for quick verification):
• Hoehn & Yahr, *Neurology* 1987;
• Pahwa, R. et al., *Clinical Pharmacology & Therapeutics* 2022;
• 2022 American Academy of Neurology guidelines on Parkinson’s disease therapy.
*This card aims to provide a concise, professional overview suitable for medical students and clinicians seeking rapid pharmacology insight into Levodopa.*