Levodopa

Levodopa crosses the protective blood–brain barrier, whereas dopamine itself cannot.{{cite journal | vauthors = Hardebo JE, Owman C | title = Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface | journal = Annals of Neurology | volume = 8 | issue = 1 | pages = 1–31 | date = July 1980 | pmid = 6105837 | doi = 10.1002/ana.410080102 | s2cid = 22874032 }} Thus, levodopa is used to increase dopamine concentrations in the treatment of Parkinson's disease, parkinsonism, dopamine-responsive dystonia and Parkinson-plus syndrome. The therapeutic efficacy is different for different kinds of symptoms. Bradykinesia and rigidity are the most responsive symptoms while tremors are less responsive to levodopa therapy. Speech, swallowing disorders, postural instability, and freezing gait are the least responsive symptoms.{{cite journal | vauthors = Ovallath S, Sulthana B | title = Levodopa: History and Therapeutic Applications | journal = Annals of Indian Academy of Neurology | volume = 20 | issue = 3 | pages = 185–189 | date = 2017 | pmid = 28904446 | pmc = 5586109 | doi = 10.4103/aian.AIAN_241_17 | doi-access = free }}

Once levodopa has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B₆) is a required cofactor in this reaction, and may occasionally be administered along with levodopa, usually in the form of pyridoxine. Because levodopa bypasses the enzyme tyrosine hydroxylase, the rate-limiting step in dopamine synthesis, it is much more readily converted to dopamine than tyrosine, which is normally the natural precursor for dopamine production.

In humans, conversion of levodopa to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system perform the same task. Thus administering levodopa alone will lead to increased dopamine signaling in the periphery as well. Excessive peripheral dopamine signaling is undesirable as it causes many of the adverse side effects seen with sole levodopa administration. To bypass these effects, it is standard clinical practice to coadminister (with levodopa) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with levodopa, are branded as Lodosyn{{cite web | url=http://www.q1medicare.com/PartD-2014MedicarePlan-RetailDrugPriceprint.php?stateReg=22Tx&ndc=25010071115&formulary=00014006&contractId=S5660&planId=192&segmentId=0&zipCountyCode=0&cplanType=P&cletter=L&cmode=state | title=Medicare D | publisher=Medicare | date=2014 | access-date=12 November 2015}} (Aton Pharma){{citation |url=https://www.drugs.com/pro/lodosyn.html |title=Lodosyn |work=Drugs |date=n.d. |access-date=12 November 2012 }} Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Syndopa and Stalevo (Orion Corporation) or with a benserazide (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from levodopa). However, when consumed as a botanical extract, for example from M pruriens supplements, a peripheral DOPA decarboxylase inhibitor is not present.{{cite journal | vauthors = Cohen PA, Avula B, Katragunta K, Khan I | title = Levodopa Content of Mucuna pruriens Supplements in the NIH Dietary Supplement Label Database | journal = JAMA Neurology | volume = 79 | issue = 10 | pages = 1085–1086 | date = October 2022 | pmid = 35939305 | doi = 10.1001/jamaneurol.2022.2184 | pmc = 9361182 }}

Inbrija (previously known as CVT-301) is an inhaled powder formulation of levodopa indicated for the intermittent treatment of "off episodes" in patients with Parkinson's disease currently taking carbidopa/levodopa.{{Cite web|url=https://www.inbrija.com/prescribing-information.pdf|title=Inbrija Prescribing Information |access-date=14 February 2019}} It was approved by the US Food and Drug Administration (FDA) on 21 December 2018, and is marketed by Acorda Therapeutics.{{Cite web|url=http://ir.acorda.com/investors/investor-news/investor-news-details/2018/Acorda-Therapeutics-Announces-FDA-Approval-of-INBRIJA-levodopa-inhalation-powder/default.aspx|title=Acorda Therapeutics Announces FDA Approval of INBRIJA™ (levodopa inhalation powder)|website=ir.acorda.com|language=en-CA|access-date=14 February 2019}}

Coadministration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of levodopa to such an extent that it negates the effects of levodopa administration, a phenomenon that historically caused great confusion.

In addition, levodopa, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of restless leg syndrome.{{cite journal | vauthors = Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M | title = Levodopa for restless legs syndrome | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD005504 | date = February 2011 | volume = 2011 | pmid = 21328278 | doi = 10.1002/14651858.CD005504.pub2 | pmc = 8889887 | collaboration = Cochrane Movement Disorders Group }}

The two types of response seen with administration of levodopa are:

• The short-duration response is related to the half-life of the drug.
• The longer-duration response depends on the accumulation of effects over at least two weeks, during which ΔFosB accumulates in nigrostriatal neurons. In the treatment of Parkinson's disease, this response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.

Levodopa is available, alone or in combination with carbidopa, in the form of immediate-release oral tablets and capsules, extended-release oral tablets and capsules, orally disintegrating tablets, as a powder for inhalation, and as an enteral suspension or gel (via intestinal tube).{{cite journal | vauthors = Livingston C, Monroe-Duprey L | title = A Review of Levodopa Formulations for the Treatment of Parkinson's Disease Available in the United States | journal = J Pharm Pract | volume = 37 | issue = 2 | pages = 485–494 | date = April 2024 | pmid = 36704966 | doi = 10.1177/08971900221151194 | url = }}{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | archive-url=https://web.archive.org/web/20161104020633/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | url-status=dead | archive-date=November 4, 2016 | access-date=28 September 2024}} In terms of combination formulations, it is available with carbidopa (as levodopa/carbidopa), with benserazide (as levodopa/benserazide), and with both carbidopa and entacapone (as levodopa/carbidopa/entacapone). In addition to levodopa itself, certain prodrugs of levodopa are available, including melevodopa (melevodopa/carbidopa) (used orally) and foslevodopa (foslevodopa/foscarbidopa) (used subcutaneously).{{cite journal | vauthors = Nakmode DD, Day CM, Song Y, Garg S | title = The Management of Parkinson's Disease: An Overview of the Current Advancements in Drug Delivery Systems | journal = Pharmaceutics | volume = 15 | issue = 5 | date = May 2023 | page = 1503 | pmid = 37242745 | pmc = 10223383 | doi = 10.3390/pharmaceutics15051503 | doi-access = free | url = }}{{cite journal | vauthors = Fabbri M, Barbosa R, Rascol O | title = Off-time Treatment Options for Parkinson's Disease | journal = Neurol Ther | volume = 12 | issue = 2 | pages = 391–424 | date = April 2023 | pmid = 36633762 | pmc = 10043092 | doi = 10.1007/s40120-022-00435-8 | url = }}{{cite journal | vauthors = Lees A, Tolosa E, Stocchi F, Ferreira JJ, Rascol O, Antonini A, Poewe W | title = Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach | journal = Expert Rev Neurother | volume = 23 | issue = 1 | pages = 15–24 | date = January 2023 | pmid = 36729395 | doi = 10.1080/14737175.2023.2176220 | url = | hdl = 10451/56313 | hdl-access = free }}

The side effects of levodopa may include:

• Hypertension, especially if the dosage is too high
• Arrhythmias, although these are uncommon
• Nausea, which is often reduced by taking the drug with food, although protein reduces drug absorption. Levodopa is an amino acid, so protein competitively inhibits levodopa absorption.
• Gastrointestinal bleeding
• Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
• Hair loss
• Disorientation and confusion
• Extreme emotional states, particularly anxiety, but also excessive libido
• Vivid dreams or insomnia
• Auditory or visual hallucinations
• Effects on learning; some evidence indicates it improves working memory, while impairing other complex functions
• Somnolence and narcolepsy
• A condition similar to stimulant psychosis

Although many adverse effects are associated with levodopa, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.

More serious are the effects of chronic levodopa administration in the treatment of Parkinson's disease, which include:

• End-of-dose deterioration of function
• "On/off" oscillations
• Freezing during movement
• Dose failure (drug resistance)
• Dyskinesia at peak dose (levodopa-induced dyskinesia)
• Possible dopamine dysregulation: The long-term use of levodopa in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.{{cite journal | vauthors = Merims D, Giladi N | title = Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease | journal = Parkinsonism & Related Disorders | volume = 14 | issue = 4 | pages = 273–80 | year = 2008 | pmid = 17988927 | doi = 10.1016/j.parkreldis.2007.09.007 }}

Rapidly decreasing the dose of levodopa can result in neuroleptic malignant syndrome.

Clinicians try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible until absolutely necessary.

Metabolites of dopamine, such as DOPAL, are known to be dopaminergic neurotoxins. The long term use of levodopa increases oxidative stress through monoamine oxidase led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of reactive oxygen species (H₂O₂) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe²⁺ ions in striatum via the Fenton reaction and intracellular autooxidation. The increased oxidation can potentially cause mutations in DNA due to the formation of 8-oxoguanine, which is capable of pairing with adenosine during mitosis.{{cite journal | vauthors = Dorszewska J, Prendecki M, Lianeri M, Kozubski W | title = Molecular Effects of L-dopa Therapy in Parkinson's Disease | journal = Current Genomics | volume = 15 | issue = 1 | pages = 11–7 | date = February 2014 | pmid = 24653659 | pmc = 3958954 | doi = 10.2174/1389202914666131210213042 }} See also the catecholaldehyde hypothesis.

Levodopa is a dopamine precursor and prodrug of dopamine and hence acts as a non-selective dopamine receptor agonist, including of the D₁-like receptors (D₁, D₅) and the D₂-like receptors (D₂, D₃, D₄).

The bioavailability of levodopa is 30%. It is metabolized into dopamine by aromatic-L-amino-acid decarboxylase (AAAD) in the central nervous system and periphery. The elimination half-life of levodopa is 0.75 to 1.5{{nbsp}}hours. It is excreted 70–80% in urine.

Levodopa is an amino acid and a substituted phenethylamine and catecholamine.

Analogues and prodrugs of levodopa include melevodopa, etilevodopa, foslevodopa, and XP-21279. Some of these, like melevodopa and foslevodopa, are approved for the treatment of Parkinson's disease similarly to levodopa.

Other analogues include methyldopa, an antihypertensive agent, and droxidopa (L-DOPS), a norepinephrine precursor and prodrug.

6-Hydroxydopa, a prodrug of 6-hydroxydopamine (6-OHDA), is a potent dopaminergic neurotoxin used in scientific research.

Levodopa was first synthesized in 1911 by Torquato Torquati from the Vicia faba bean. It was first isolated in 1913 by Marcus Guggenheim from the V.{{nbsp}}faba bean. Guggenheim tried levodopa at a dose of 2.5{{nbsp}}mg and thought that it was inactive aside from nausea and vomiting.

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering levodopa to animals with drug-induced (reserpine) Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960 or 1961 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease,{{cite journal | vauthors = Ehringer H, Hornykiewicz O | title = [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system] | journal = Klinische Wochenschrift | volume = 38 | issue = 24 | pages = 1236–9 | date = December 1960 | pmid = 13726012 | doi = 10.1007/BF01485901 | s2cid = 32896604 }} published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered levodopa in patients.{{cite journal | vauthors = Birkmayer W, Hornykiewicz O | title = [The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia] | journal = Wiener Klinische Wochenschrift | volume = 73 | pages = 787–8 | date = November 1961 | pmid = 13869404 }} This treatment was later extended to manganese poisoning and later parkinsonism by George Cotzias and his coworkers,{{cite journal | vauthors = Cotzias GC, Papavasiliou PS, Gellene R | title = L-dopa in parkinson's syndrome | journal = The New England Journal of Medicine | volume = 281 | issue = 5 | pages = 272 | date = July 1969 | pmid = 5791298 | doi = 10.1056/NEJM196907312810518 }} who used greatly increased oral doses, for which they won the 1969 Lasker Prize.{{cite web | url = http://www.laskerfoundation.org/awards/1969_c_description.htm | title = Lasker Award | date = 1969 | archive-url = https://web.archive.org/web/20160105102139/http://www.laskerfoundation.org/awards/1969_c_description.htm| archive-date= 5 January 2016}}, retrieved 1 April 2013{{cite book | vauthors = Simuni T, Hurtig H | chapter = Levadopa: A Pharmacologic Miracle Four Decades Later | url = https://books.google.com/books?id=zUp54Dm-Y7MC | title = Parkinson's Disease: Diagnosis and Clinical Management | via = Google eBook | veditors = Factor SA, Weiner WJ | publisher = Demos Medical Publishing | date = 2008 | isbn = 978-1-934559-87-1 }} The first study reporting improvements in patients with Parkinson's disease resulting from treatment with levodopa was published in 1968.{{cite journal | vauthors = Cotzias GC | title = L-Dopa for Parkinsonism | journal = The New England Journal of Medicine | volume = 278 | issue = 11 | pages = 630 | date = March 1968 | pmid = 5637779 | doi = 10.1056/nejm196803142781127 }}

Levodopa was first marketed in 1970 by Roche under the brand name Larodopa.

The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his 1973 book Awakenings, upon which the 1990 movie of the same name is based.

Carbidopa was added to levodopa in 1974 and this improved its tolerability.

Levodopa is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|USAN|United States Adopted Name}}, {{Abbrlink|USP|United States Pharmacopeia}}, {{Abbrlink|BAN|British Approved Name}}, {{Abbrlink|DCF|Dénomination Commune Française}}, {{Abbrlink|DCIT|Denominazione Comune Italiana}}, and {{Abbrlink|JAN|Japanese Accepted Name}}.{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA54 | access-date=28 September 2024 | page=54}}{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA164 | access-date=28 September 2024 | page=164}}{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA699 | access-date=28 September 2024 | page=699}}{{cite web | title=Levodopa (International database) | website=Drugs.com | date=2 September 2024 | url=https://www.drugs.com/international/levodopa.html | access-date=28 September 2024}}

New levodopa formulations for use by other routes of administration, such as subcutaneous administration, are being developed.{{cite journal | vauthors = Doggrell SA | title = Continuous subcutaneous levodopa-carbidopa for the treatment of advanced Parkinson's disease: is it an improvement on other delivery? | journal = Expert Opin Drug Deliv | volume = 20 | issue = 9 | pages = 1189–1199 | date = 2023 | pmid = 37634938 | doi = 10.1080/17425247.2023.2253146 | url = | hdl = 10072/425143 | hdl-access = free }}{{cite journal | vauthors = Urso D, Chaudhuri KR, Qamar MA, Jenner P | title = Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies | journal = CNS Drugs | volume = 34 | issue = 11 | pages = 1149–1163 | date = November 2020 | pmid = 33146817 | doi = 10.1007/s40263-020-00769-7 | url = }}

Levodopa prodrugs, with the potential for better pharmacokinetics, reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed.{{cite journal | vauthors = Cacciatore I, Ciulla M, Marinelli L, Eusepi P, Di Stefano A | title = Advances in prodrug design for Parkinson's disease | journal = Expert Opin Drug Discov | volume = 13 | issue = 4 | pages = 295–305 | date = April 2018 | pmid = 29361853| doi = 10.1080/17460441.2018.1429400 | url = }}{{cite journal | vauthors = Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R | title = Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease | journal = Molecules | volume = 23 | issue = 1 | date = December 2017 | page = 40 | pmid = 29295587 | pmc = 5943940 | doi = 10.3390/molecules23010040 | doi-access = free | url = }}

Levodopa has been reported to be inconsistently effective as an antidepressant in the treatment of depressive disorders.{{cite journal | vauthors = Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M | title = Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology | journal = Brain | volume = 139 | issue = Pt 5 | pages = 1325–1347 | date = May 2016 | pmid = 27189581 | pmc = 5839596 | doi = 10.1093/brain/aww050 | url = }}{{cite journal | vauthors = Brown AS, Gershon S | title = Dopamine and depression | journal = J Neural Transm Gen Sect | volume = 91 | issue = 2–3 | pages = 75–109 | date = 1993 | pmid = 8099801 | doi = 10.1007/BF01245227 | url = }} However, it was found to enhance psychomotor activation in people with depression.

Levodopa has been found to increase the willingness to exert effort for rewards in humans and hence appears to show pro-motivational effects.{{cite journal | vauthors = Webber HE, Lopez-Gamundi P, Stamatovich SN, de Wit H, Wardle MC | title = Using pharmacological manipulations to study the role of dopamine in human reward functioning: A review of studies in healthy adults | journal = Neurosci Biobehav Rev | volume = 120 | issue = | pages = 123–158 | date = January 2021 | pmid = 33202256 | pmc = 7855845 | doi = 10.1016/j.neubiorev.2020.11.004 | url = }}{{cite journal | vauthors = Zénon A, Devesse S, Olivier E | title = Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost | journal = J Neurosci | volume = 36 | issue = 37 | pages = 9516–9525 | date = September 2016 | pmid = 27629704 | pmc = 6601940 | doi = 10.1523/JNEUROSCI.4467-15.2016 | url = }} Other dopaminergic agents have also shown pro-motivational effects and may be useful in the treatment of motivational disorders.{{cite journal | vauthors = Salamone JD, Correa M | title = The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine | journal = Annu Rev Psychol | volume = 75 | issue = | pages = 1–32 | date = January 2024 | pmid = 37788571 | doi = 10.1146/annurev-psych-020223-012208 | url = | hdl = 10234/207207 | hdl-access = free }}

In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking levodopa found that the drug delayed onset of AMD by around 8{{nbsp}}years. The authors state that significant effects were obtained for both dry and wet AMD.{{cite journal | vauthors = Brilliant MH, Vaziri K, Connor TB, Schwartz SG, Carroll JJ, McCarty CA, Schrodi SJ, Hebbring SJ, Kishor KS, Flynn HW, Moshfeghi AA, Moshfeghi DM, Fini ME, McKay BS | title = Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration | journal = The American Journal of Medicine | volume = 129 | issue = 3 | pages = 292–8 | date = March 2016 | pmid = 26524704 | pmc = 4841631 | doi = 10.1016/j.amjmed.2015.10.015 }}{{Primary source inline|date=December 2016}}

{{Reflist}}

• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/levodopa | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Levodopa }}

{{Antiparkinson agents}}

{{Supplements}}

{{Dopamine receptor modulators}}

{{Phenethylamines}}

{{Portal bar | Medicine}}

Category:Alpha-Amino acids

Category:Antiparkinsonian agents

Category:Aromatic amino acids

Category:Carbonic anhydrase activators

Category:Catecholamines

Category:Dopamine agonists

Category:Monoamine precursors

Category:Phenethylamines

Category:Pro-motivational agents

Category:Prodrugs