Droxidopa

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Droxidopa
L-DOPS.svg
Clinical data
Trade names Northera, Dops
Other names3,4-Dihydroxyphenylserine; 3,4-threo-DOPS; L-threo-Dihydroxyphenylserine; L-DOPS; L-threo-DOPS; Threo-DOPS; β,3-Dihydroxytyrosine; (–)-threo-3-(3,4-Dihydroxyphenyl)-L-serine; SM-5688
AHFS/Drugs.com Monograph
MedlinePlus a614025
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: WARNING [1] Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 90%
Metabolism Liver
Metabolites Norepinephrine
Elimination half-life 1.5 hours
Excretion Kidney
Identifiers
  • (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.215.254 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H11NO5
Molar mass 213.189 g·mol−1
3D model (JSmol)
  • N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
  • 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
   (verify)

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension (low blood pressure) and for other indications. [2] [3] It is taken by mouth. [2]

Contents

Side effects of droxidopa include headache, dizziness, nausea, and hypertension, among others. [2] Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline). [4] Hence, it acts as a non-selective agonist of the α- and β-adrenergic receptors. Unlike norepinephrine, but similarly to levodopa (L-DOPA), droxidopa is capable of crossing the protective blood–brain barrier (BBB). [4]

Droxidopa was first described by 1971. [5] [6] It was approved for use in Japan in 1989 [7] and was introduced in the United States in 2014. [2] [8]

Medical uses

Droxidopa is approved for use in the treatment of orthostatic hypotension, intradialytic hypotension (IDH; hemodialysis-induced hypotension), dizziness, and amyloid polyneuropathy. [3] For hypotension, it is specifically used in the treatment of neurogenic orthostatic hypotension (NOH) in dopamine β-hydroxylase deficiency, [7] as well as NOH associated with multiple system atrophy (MSA), [9] familial amyloid polyneuropathy (FAP), and pure autonomic failure (PAF). [10] The drug is also used off-label in the treatment of freezing of gait in Parkinson's disease.[ citation needed ]

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. [11] [12] [13]

Pharmacology

Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain. [4] 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. [14] 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. [14]

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain. [4] 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.[ citation needed ]

Chemistry

Droxidopa, also known as (–)-threo-3-(3,4-dihydroxyphenyl)-L-serine (L-DOPS), is a substituted phenethylamine and is chemically analogous to levodopa (L-3,4-dihydroxyphenylalanine; L-DOPA). Whereas levodopa functions as a precursor and prodrug to dopamine, droxidopa is a precursor and prodrug of norepinephrine.[ citation needed ]

History

Droxidopa was first described in the scientific literature by 1971. [5] [6]

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH, [7] 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. [7]

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 United States Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension. [8]

Clinical trials

A systematic review and meta-analysis conducted on clinical trials comparing the clinical use of droxidopa and midodrine have found that midodrine was more likely to cause supine hypertension than droxidopa in patients with NOH. Midodrine was also found to be slightly more effective at raising blood pressure but not statistically significantly. [15]

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. [16]

Society and culture

Names

Droxidopa is the generic name of the drug and its INN Tooltip International Nonproprietary Name and JAN Tooltip Japanese Accepted Name. [17] Brand names of droxidopa include Dops and Northera. [17] [2]

Research

Droxidopa alone and in combination with carbidopa has been studied in the treatment of attention deficit hyperactivity disorder (ADHD). [18] [19] Droxidopa was under development for the treatment of ADHD, chronic fatigue syndrome, and fibromyalgia, but development for these indications was discontinued. [3]

Related Research Articles

Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up (orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as neurogenic orthostatic hypotension. The drop in blood pressure may be sudden, within 3 minutes or gradual. It is defined as a fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg after 3 minutes of standing. It occurs predominantly by delayed constriction of the lower body blood vessels, which is normally required to maintain adequate blood pressure when changing the position to standing. As a result, blood pools in the blood vessels of the legs for a longer period, and less is returned to the heart, thereby leading to a reduced cardiac output and inadequate blood flow to the brain.

<span class="mw-page-title-main">Hypotension</span> Abnormally low blood pressure

Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is indicated by two numbers, the systolic blood pressure and the diastolic blood pressure, which are the maximum and minimum blood pressures within the cardiac cycle, respectively. A systolic blood pressure of less than 90 millimeters of mercury (mmHg) or diastolic of less than 60 mmHg is generally considered to be hypotension. Different numbers apply to children. However, in practice, blood pressure is considered too low only if noticeable symptoms are present.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

<span class="mw-page-title-main">Methyldopa</span> Medication used to treat high blood pressure

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.

<span class="mw-page-title-main">Midodrine</span> Vasopressor/antihypotensive agent

Midodrine, sold under the brand names ProAmatine and Orvaten among others, is a vasopressor or antihypotensive medication used to treat orthostatic hypotension and urinary incontinence. It is taken by mouth.

Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. It is primarily used to manage the symptoms of Parkinson's disease, but it does not slow down the disease or stop it from getting worse. It is taken by mouth. It can take two to three weeks of treatment before benefits are seen. Each dose then begins working in about ten minutes to two hours with a duration of effect of about five hours.

<span class="mw-page-title-main">Entacapone</span> Chemical compound

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

<span class="mw-page-title-main">Tolcapone</span> Chemical compound

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

<small>D</small>-DOPA Chemical compound

d-DOPA is similar to l-DOPA (levodopa), but with opposite chirality. Levo- and dextro- rotation refer to a molecule's ability to rotate planes of polarized light in one or the other direction. Whereas l-DOPA is moderately effective in the treatment of Parkinson's disease (PD) and dopamine-responsive dystonia (DRD) by stimulating the production of dopamine in the brain, d-DOPA is biologically inactive.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase(COMT) inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Norfenefrine</span> Sympathomimetic drug

Norfenefrine, also known as meta-octopamine or norphenylephrine and sold under the brand name Novadral among others, is a sympathomimetic medication which is used in the treatment of hypotension. Along with its structural isomer p-octopamine and the tyramines, norfenefrine is a naturally occurring endogenous trace amine and plays a role as a minor neurotransmitter in the brain.

<span class="mw-page-title-main">Carbidopa/levodopa/entacapone</span> Anti Parkinson medicine

Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

<span class="mw-page-title-main">Aromatic L-amino acid decarboxylase inhibitor</span>

An aromatic L-amino acid decarboxylase inhibitor is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase. It is used to inhibit the decarboxylation of L-DOPA to dopamine outside the brain, i.e. in the blood. This is primarily co-administered with L-DOPA to combat Parkinson's disease. Administration can prevent common side-effects, such as nausea and vomiting, as a result of interaction with D2 receptors in the vomiting center located outside the blood–brain barrier.

<span class="mw-page-title-main">Dopamine beta hydroxylase deficiency</span> Medical condition

Dopamine beta (β)-hydroxylase deficiency is a human medical condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<span class="mw-page-title-main">Opicapone</span> Chemical compound

Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a catechol-O-methyltransferase (COMT) inhibitor.

Supine hypertension is a paradoxical elevation in blood pressure upon assuming a supine position from a standing or sitting position. It is assumed to be a manifestation of disorders of the autonomic nervous system or due to side effects of medications such as midodrine and droxidopa.

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. 1 2 3 4 5 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203202s007lbl.pdf
  3. 1 2 3 "Sumitomo Pharma/Lundbeck". AdisInsight. 2023-11-05. Retrieved 2024-09-01.
  4. 1 2 3 4 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.
  5. 1 2 Robson RD (June 1971). "Modification of the cardiovascular effects of L-dopa in anesthetized dogs by inhibitors of enzymes involved in catecholamine metabolism". Circ Res. 28 (6): 662–670. doi:10.1161/01.res.28.6.662. PMID   4325846.
  6. 1 2 Redmond DE, Olander R, Maas JW (November 1975). "Cardiovascular effects of D,L-threo-dihydroxyphenylserine in cats". Toxicol Appl Pharmacol. 34 (2): 301–308. doi:10.1016/0041-008x(75)90035-6. PMID   1209627.
  7. 1 2 3 4 Mathias CJ (March 2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience". Clinical Autonomic Research. 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. PMID   18368304. S2CID   29861644.
  8. 1 2 "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014.
  9. ↑ Calandra-Buonaura G, Doria A, Lopane G, et al. (February 2016). "Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease". Journal of Neurology. 263 (2): 250–256. doi:10.1007/s00415-015-7961-7. PMID   26566913. S2CID   189866517.
  10. ↑ Palma JA, Kaufmann H (February 2020). "Management of Orthostatic Hypotension". Continuum. 26 (1): 154–177. doi:10.1212/CON.0000000000000816. PMC   7339914 . PMID   31996627.
  11. ↑ 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.
  12. ↑ 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. S2CID   2828467.
  13. ↑ "Highlights of prescribing information for Northeratm (droxidopa)" (PDF). Chelsea Therapeutics, Inc. 2014.
  14. 1 2 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.
  15. ↑ 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.
  16. ↑ "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 2015-11-02.
  17. 1 2 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 434. ISBN   978-3-88763-101-7 . Retrieved 1 September 2024.
  18. ↑ Buoli M, Serati M, Cahn W (2016). "Alternative pharmacological strategies for adult ADHD treatment: a systematic review". Expert Rev Neurother. 16 (2): 131–44. doi:10.1586/14737175.2016.1135735. PMID   26693882. S2CID   33004517.
  19. ↑ Adler LA, Gorny SW (January 2019). "Pilot Study of Droxidopa With Carbidopa in Adults With ADHD". J Atten Disord. 23 (2): 189–198. doi:10.1177/1087054715580393. PMID   25907673. S2CID   20990991.
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