Droxidopa, also known as L-threo-dihydroxyphenylserine and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth. Technically, droxidopa is a synthetic amino acid analog that functions as a norepinephrine precursor and is converted enzymatically by aromatic L-amino acid decarboxylase to norepinephrine in peripheral tissues and the central nervous system. It is formulated as the L-threo stereoisomer to maximize pharmacologic activity. Oral dosing is typically given two to three times daily with a recommended titration to balance efficacy and the risk of supine hypertension. Pharmacokinetic characteristics include rapid absorption, a plasma elimination half-life on the order of a few hours, renal excretion of metabolites, and considerable impact of peripheral decarboxylation on systemic exposure. Concomitant use of peripheral decarboxylase inhibitors or monoamine oxidase inhibitors alters exposure and clinical effect and should be managed clinically.
Parent: Droxidopa
Parent: Droxidopa
Parent: Droxidopa
Manufactures control droxidopa drug substance and drug product using validated chromatographic and chiral assays to monitor related substances, enantiomeric purity, and degradants. Typical related compounds observed by HPLC or LC-MS include the D-threo enantiomer, the erythro diastereomer, low level decarboxylation products such as norepinephrine and its conjugates, and minor oxidative degradants arising from the catechol moiety. Typical quality specifications used in production and release testing set individual related-compound limits at or below 0.2 percent of the active substance and a total impurities limit at or below 1.0 percent, with reporting and identification thresholds commonly in the 0.05 to 0.10 percent range; chiral purity is monitored separately and is expected to meet tight limits to ensure stereoisomeric consistency. Residual solvents, inorganic counterions, and water content are controlled to pharmacopeial and ICH guideline limits and characterized during stability testing.
Droxidopa is used primarily to raise blood pressure in symptomatic neurogenic orthostatic hypotension caused by autonomic failure conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure. It may also be used off label in other forms of symptomatic hypotension when a norepinephrine precursor is clinically appropriate and other measures are insufficient.
Droxidopa is a metabolic precursor that is converted in vivo to norepinephrine and increases endogenous catecholamine levels, producing vasoconstriction and improved orthostatic tolerance. Midodrine is an alpha-1 adrenergic receptor agonist prodrug whose active metabolite directly stimulates peripheral alpha-1 receptors to cause vasoconstriction. Clinically the two have different onset, duration, and side effect profiles and their effects on supine hypertension and heart rate differ, so choice between them is based on patient comorbidities and response.
Droxidopa is taken up by tissues and decarboxylated by aromatic L-amino acid decarboxylase to form norepinephrine. The resulting increase in norepinephrine availability at sympathetic nerve terminals and in circulation enhances vasoconstriction through adrenergic receptor activation, raising standing blood pressure and improving symptoms of orthostatic intolerance.
Droxidopa is contraindicated or should be avoided in patients with a known hypersensitivity to the drug and used with caution or not used in patients with uncontrolled supine hypertension, acute coronary ischemia, severe cardiac arrhythmias, or pheochromocytoma. Patients receiving monoamine oxidase inhibitors or certain other sympathomimetic agents require careful assessment because of interaction risks. Clinical judgment is required for patients with significant cardiovascular disease or cerebrovascular disease.
