Droxidopa

MECHANISM OF ACTION

Droxidopa is a synthetic amino acid prodrug that is metabolized to norepinephrine by the enzyme L-aromatic amino acid decarboxylase. By increasing norepinephrine levels in the peripheral nervous system, Droxidopa enhances vascular tone and blood pressure, helping to reduce symptoms of dizziness, lightheadedness, and fainting in patients with neurogenic orthostatic hypotension. Its action is particularly effective in patients with autonomic failure, where endogenous norepinephrine release is insufficient to maintain blood pressure upon standing.

PHARMACOKINETICS

Absorption

Droxidopa is well absorbed after oral administration, reaching peak plasma concentrations within approximately one hour. Its oral bioavailability is moderate, and while food may slightly delay the time to peak concentration, it does not significantly reduce overall drug exposure. Droxidopa can be taken with or without food, although administration with meals may improve gastrointestinal tolerability in some patients.

Distribution

Droxidopa has a volume of distribution of approximately 0.6 L/kg, indicating moderate distribution throughout body tissues, primarily in the extracellular fluid. This distribution allows sufficient tissue availability for conversion to norepinephrine, which is essential for its therapeutic effect in improving blood pressure and reducing symptoms of neurogenic orthostatic hypotension.

Metabolism

Droxidopa is primarily metabolized by the enzyme L-aromatic amino acid decarboxylase into norepinephrine, which is responsible for its therapeutic effects in raising blood pressure. It is also converted to an inactive metabolite, 3-O-methyl-DOPS, via catechol-O-methyltransferase (COMT).

Elimination

Droxidopa is primarily eliminated through renal excretion, with most of the drug and its metabolites excreted in the urine within 24 hours. Its elimination half-life is approximately 2–3 hours, which allows for multiple daily dosing to maintain therapeutic blood pressure levels.

PHARMACODYNAMICS

Droxidopa is a synthetic prodrug that is converted in the body to norepinephrine, a key neurotransmitter in the sympathetic nervous system. By increasing peripheral norepinephrine levels, it enhances vascular tone and blood pressure, helping to reduce dizziness, lightheadedness, and fainting in patients with neurogenic orthostatic hypotension (nOH).

ADMINISTRATION

Droxidopa is administered orally, typically three times daily morning, midday, and late afternoon to manage symptoms of neurogenic orthostatic hypotension. The dose is individualized and titrated gradually based on patient response and blood pressure measurements. To minimize supine hypertension, the last daily dose should be taken at least 3–4 hours before bedtime.

DOSAGE AND STRENGTH

Droxidopa is typically administered orally, starting at a dose of 100 mg three times daily morning, midday, and late afternoon. The dose may be gradually increased by 100 mg every 24–48 hours based on the patient’s symptomatic response and blood pressure, with a maximum dose of 600 mg three times daily. It is available in 100 mg, 200 mg, and 300 mg capsules.

DRUG INTERACTIONS

Droxidopa can interact with several medications that affect norepinephrine levels or blood pressure. Concomitant use with monoamine oxidase inhibitors (MAOIs) can significantly increase norepinephrine, raising the risk of hypertensive crisis. It may counteract antihypertensive agents, reducing their effectiveness, and its conversion to norepinephrine can be impaired by dopamine β-hydroxylase inhibitors such as disulfiram.

FOOD INTERACTIONS

Droxidopa has minimal food interactions. While food may slightly delay the time to peak plasma concentration, it does not significantly reduce overall absorption or effectiveness. The drug can be taken with or without meals, and taking it with food may help reduce gastrointestinal discomfort in some patients.

CONTRAINDICATIONS

Droxidopa is contraindicated in patients with known hypersensitivity to the drug or any of its components. It should not be used in individuals with pheochromocytoma, due to the risk of hypertensive crises, or in those with severe supine hypertension. Caution is required in patients with recent myocardial infarction, stroke, unstable angina, or significant cardiac arrhythmias, as increased norepinephrine levels may worsen cardiovascular conditions.

SIDE EFFECTS

• Headache 

• Dizziness 

• Nausea and vomiting 

• Fatigue 

• Hypertension, especially supine hypertension

OVER DOSAGE

Droxidopa overdosage occurs when doses exceed the recommended regimen, potentially leading to severe hypertension, headache, palpitations, nausea, vomiting, and dizziness. Serious cardiovascular events, including arrhythmias or hypertensive crises, may occur in susceptible patients.

TOXICITY

Droxidopa toxicity can occur when excessive doses are taken or in patients particularly sensitive to norepinephrine. Clinical manifestations may include severe hypertension, headache, palpitations, nausea, vomiting, and arrhythmias. Supine hypertension is a major concern and can lead to cardiovascular complications if not managed promptly. Toxicity management is primarily supportive, involving blood pressure monitoring, dose adjustment, or temporary discontinuation of the drug.