Levodopa

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Levodopa
3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
Skeletal formula of levodopa
L-DOPA-from-xtal-view-2-3D-bs-17.png
Ball-and-stick model of the zwitterionic form of levodopa found in the crystal structure [1]
Clinical data
Pronunciation /ˌɛlˈdoʊpə/ , /ˌlɛvoʊˈdoʊpə/
Trade names Larodopa, Dopar, Inbrija, others
Other namesL-DOPA
AHFS/Drugs.com Professional Drug Facts
MedlinePlus a619018
License data
Pregnancy
category
Routes of
administration 		By mouth, inhalation, enteral (tube), subcutaneous (as foslevodopa)
Drug class Dopamine precursor; Dopamine receptor agonist
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only (some forms are OTC)
  • EU:Rx-only
Pharmacokinetic data
Bioavailability 30%
Metabolism Aromatic-l-amino-acid decarboxylase
Metabolites • Dopamine
Elimination half-life 0.75–1.5 hours
Excretion Renal 70–80%
Identifiers
  • (S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C9H11NO4
Molar mass 197.190 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H](N)Cc1cc(O)c(O)cc1
  • InChI=1S/C9H11NO4/c10-6(9(13)14)3-5-1-2-7(11)8(12)4-5/h1-2,4,6,11-12H,3,10H2,(H,13,14)/t6-/m0/s1 Yes check.svgY
  • Key:WTDRDQBEARUVNC-LURJTMIESA-N Yes check.svgY
   (verify)

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat (as foslevodopa).

Contents

Side effects of levodopa include nausea, the wearing-off phenomenon, dopamine dysregulation syndrome, and levodopa-induced dyskinesia, among others. The drug is a centrally permeable monoamine precursor and prodrug of dopamine and hence acts as a dopamine receptor agonist. Chemically, levodopa is an amino acid, a phenethylamine, and a catecholamine.

The antiparkinsonian effects of levodopa were discovered in the 1950s and 1960s. Following this, it was introduced for the treatment of Parkinson's disease.

Medical uses

Levodopa crosses the protective blood–brain barrier, whereas dopamine itself cannot. [3] 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. [4]

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 [5] (Aton Pharma) [6] 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. [7]

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. [8] It was approved by the United States Food and Drug Administration on 21 December 2018, and is marketed by Acorda Therapeutics. [9]

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. [10]

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

Available forms

Levodopa is available, alone and/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). [11] [12] 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). [11] [12] [13] [14] In addition to levodopa itself, certain prodrugs of levodopa are available, including melevodopa (melevodopa/carbidopa) (used orally) and foslevodopa (foslevodopa/foscarbidopa) (used subcutaneously). [15] [16] [17]

Side effects

The side effects of levodopa may include:

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:

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. [19] See also the catecholaldehyde hypothesis.

Pharmacology

Pharmacodynamics

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).

Pharmacokinetics

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 hours. It is excreted 70 to 80% in urine.

Chemistry

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.

History

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, [20] published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered levodopa in patients. [21] This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers, [22] who used greatly increased oral doses, for which they won the 1969 Lasker Prize. [23] [24] 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. The first study reporting improvements in patients with Parkinson's disease resulting from treatment with levodopa was published in 1968. [25]

Society and culture

Names

Levodopa is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, DCIT Tooltip Denominazione Comune Italiana, and JAN Tooltip Japanese Accepted Name. [26] [27] [13] [14]

Research

Novel formulations and prodrugs

New levodopa formulations for use by other routes of administration, such as subcutaneous administration, are being developed. [28] [29]

Levodopa prodrugs, with the potential for better pharmacokinetics, reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed. [30] [31]

Depression

Levodopa has been reported to be inconsistently effective as an antidepressant in the treatment of depressive disorders. [32] [33] However, it was found to enhance psychomotor activation in people with depression. [32] [33]

Motivational disorders

Levodopa has been found to increase the willingness to exert effort for rewards in humans and hence appears to show pro-motivational effects. [34] [35] Other dopaminergic agents have also shown pro-motivational effects and may be useful in the treatment of motivational disorders. [36]

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 years. The authors state that significant effects were obtained for both dry and wet AMD. [37] [ non-primary source needed ]

Related Research Articles

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

l-DOPA, also known as l-3,4-dihydroxyphenylalanine and used medically as levodopa, 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.

<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">Benserazide</span> Chemical compound often used as medication

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

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">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<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.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

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

A catechol-O-methyltransferase 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">Melevodopa</span> Chemical compound

Melevodopa, also known as levodopa methyl ester (LDME) and sold under the brand name Levomet, is a dopaminergic agent. It is the methyl ester of levodopa. It is used in oral tablet form as an effervescent prodrug with 250 times the water solubility of tablet levodopa. In combination with carbidopa, as melevodopa/carbidopa, it is approved for use in the treatment of Parkinson's disease.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

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 and for other indications. It is taken by mouth.

<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.

Aromatic <small>L</small>-amino acid decarboxylase inhibitor

An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC, AAAD, or DOPA 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 (or cheomoreceptor trigger zone) located outside the blood–brain barrier.

<span class="mw-page-title-main">Dopamine dysregulation syndrome</span> Medical condition

Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dopamine agonist medications for an extended period of time. It is characterized by problems such as addiction to medication, gambling, or sexual behavior.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

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.

<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).

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

Foslevodopa is a drug which acts as a prodrug for levodopa, originally invented in the 1980s but not developed for medical use at that time. It has more recently attracted renewed interest due to its improved pharmacokinetics compared to levodopa itself, and is now approved for use in a subcutaneous infusion as a fixed-dose combination with foscarbidopa for the treatment of Parkinson's disease, under the trade name Vyalev.

<span class="mw-page-title-main">Melevodopa/carbidopa</span> Combination dopaminergic medication

Melevodopa/carbidopa, sold under the brand name Sirio, is a combination of melevodopa, a prodrug of the dopamine precursor and hence non-selective dopamine receptor agonist levodopa (L-DOPA), and carbidopa, a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor, which is used in the treatment of Parkinson's disease in Italy. It is taken orally in the form of tablets.

References

  1. ↑ Howard ST, Hursthouse MB, Lehmann CW, Poyner EA (1995). "Experimental and theoretical determination of electronic properties in Ldopa". Acta Crystallogr. B . 51 (3): 328–337. Bibcode:1995AcCrB..51..328H. doi:10.1107/S0108768194011407. S2CID   96802274.
  2. ↑ "Levodopa Use During Pregnancy". Drugs.com. 12 July 2019. Retrieved 27 September 2020.
  3. ↑ Hardebo JE, Owman C (July 1980). "Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface". Annals of Neurology. 8 (1): 1–31. doi:10.1002/ana.410080102. PMID   6105837. S2CID   22874032.
  4. ↑ Ovallath S, Sulthana B (2017). "Levodopa: History and Therapeutic Applications". Annals of Indian Academy of Neurology. 20 (3): 185–189. doi: 10.4103/aian.AIAN_241_17 . PMC   5586109 . PMID   28904446.
  5. ↑ "Medicare D". Medicare. 2014. Retrieved 12 November 2015.
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  35. ↑ Zénon A, Devesse S, Olivier E (September 2016). "Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost". J Neurosci. 36 (37): 9516–9525. doi:10.1523/JNEUROSCI.4467-15.2016. PMC   6601940 . PMID   27629704.
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  37. ↑ Brilliant MH, Vaziri K, Connor TB, Schwartz SG, Carroll JJ, McCarty CA, et al. (March 2016). "Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration". The American Journal of Medicine. 129 (3): 292–8. doi:10.1016/j.amjmed.2015.10.015. PMC   4841631 . PMID   26524704.
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