Droxidopa

Droxidopa
Names
Pronunciationdrox" i doe' pa[1]
Trade namesNorthera
Other namesβ,3-Dihydroxytyrosine, L-DOPS,L-threo-dihydroxyphenylserine, L-threo-DOPS, SM-5688
IUPAC name
  • (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Clinical data
Main usesNeurological causes of low blood pressure with standing[1]
Side effectsHeadache, dizziness, nausea, high blood pressure[1]
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    Typical dose100 to 600 mg TID[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa614025
    Legal
    License data
    Legal status
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability90%
    MetabolismLiver
    Elimination half-life1.5 hours
    ExcretionKidney
    Chemical and physical data
    FormulaC9H11NO5
    Molar mass213.189 g·mol−1
    3D model (JSmol)
    SMILES
    • C1=CC(=C(C=C1[C@H]([C@@H](C(=O)O)N)O)O)O
    InChI
    • InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1
    • Key:QXWYKJLNLSIPIN-JGVFFNPUSA-Na

    Droxidopa, sold under the brand name Northera, is a medication used to treat neurological causes of low blood pressure with standing.[1] These causes may include Parkinson disease, autonomic neuropathy, and multiple systemic atrophy.[1][2] It is taken by mouth.[1]

    Common side effects include headache, dizziness, nausea, and high blood pressure.[1] Other side effects may include neuroleptic malignant syndrome or worsened heart failure.[1][2] Safety in pregnancy is unclear.[2] It works after being converted in the body to norepinephrine (noradrenaline).[1]

    Droxidopa was approved for medical use in the United States in 2014.[2] It is not approved in either Europe or the United Kingdom.[3] It is available as a generic medication.[4] In the United States a month of medication at a dose of 300 mg per day costs about 740 USD as of 2021.[4]

    Medical uses

    A systematic review comparing the use of droxidopa and midodrine have found that midodrine was more likely to cause supine hypertension in NOH. Midodrine was also found to be slightly more effective at raising blood pressure but not significantly so.[6]

    Dosage

    The typical initial dose is 100 mg three times daily, with subsequent increases based upon efficacy and tolerance to as much as 600 mg three times daily.[1]

    Side effects

    With over 20 years on the market, droxidopa has proven to have few side effects of which most are mild. The most common side effects reported in clinical trials include headache, dizziness, nausea, hypertension and fatigue.[7][8][9]

    Pharmacology

    Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).[10] Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier (BBB).[10]

    It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.[11] Droxidopa works by increasing the levels of norepinephrine in the peripheral nervous system (PNS), thus enabling the body to maintain blood flow upon and while standing.

    Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain.[10] Increased levels of norepinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine concentrations while minimizing increases of peripheral levels.

    History

    Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,[5] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asian areas for these indications since 1989. Following a merger with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed droxidopa to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan. In February 2014, the Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.[12]

    Chelsea Therapeutics obtained orphan drug status (ODS) for droxidopa in the US for NOH, and that of which associated with PD, PAF, and MSA. In 2014, Chelsea Therapeutics was acquired by Lundbeck along with the rights to droxidopa which was launched in the US in Sept 2014.[13]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 "Droxidopa". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 15 May 2021. Retrieved 27 December 2021.
    2. 1 2 3 4 "Droxidopa Monograph for Professionals". Drugs.com. Archived from the original on 26 September 2020. Retrieved 27 December 2021.
    3. ↑ "Droxidopa". SPS - Specialist Pharmacy Service. 5 January 2016. Archived from the original on 11 January 2022. Retrieved 27 December 2021.
    4. 1 2 "Droxidopa Prices and Droxidopa Coupons - GoodRx". GoodRx. Archived from the original on 8 May 2016. Retrieved 27 December 2021.
    5. 1 2 Mathias CJ (March 2008). "L-Dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience". Clinical Autonomic Research. 18 Suppl 1 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. PMID 18368304. S2CID 29861644.
    6. ↑ Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K (December 2018). "Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials". The Annals of Pharmacotherapy. 52 (12): 1182–1194. doi:10.1177/1060028018786954. PMID 29972032. S2CID 49674644.
    7. ↑ Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, et al. (July 2014). "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial". Neurology. 83 (4): 328–35. doi:10.1212/WNL.0000000000000615. PMC 4115605. PMID 24944260.
    8. ↑ Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G (April 2015). "Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B)". Movement Disorders. 30 (5): 646–54. doi:10.1002/mds.26086. PMID 25487613.
    9. ↑ "Highlights of prescribing information for Northeratm (droxidopa)" (PDF). Chelsea Therapeutics, Inc. 2014. Archived (PDF) from the original on 2021-04-02. Retrieved 2021-01-31.
    10. 1 2 3 Goldstein DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovascular Drug Reviews. 24 (3–4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596.
    11. ↑ Robertson D (March 2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clinical Autonomic Research. 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0. PMID 18368300. S2CID 15693501.
    12. ↑ "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014. Archived from the original on November 23, 2020. Retrieved January 31, 2021.
    13. ↑ "Lundbeck Announces Availability of NORTHERATM (droxidopa) Capsules in the U.S. for Symptomatic Neurogenic Orthostatic Hypotension" (PDF). Lundbeck NA Ltd. Archived from the original (PDF) on 2018-09-20. Retrieved 2021-01-31.
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