Levodopa, also known as L-DOPA and sold under many brand names, is a

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

which is used in the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

(PD) and certain other conditions like

dopamine-responsive dystonia Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years (variable start age). Characteristic symptoms are increased m ...

and

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD)

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication 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 levo ...

benserazide Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is on the World Health Organization's List of Essential Medicines. Medical use ...

. Levodopa is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

, by inhalation, through an intestinal tube, or by administration into fat (as

foslevodopa Foslevodopa is a medication which acts as a prodrug for levodopa, originally invented in the 1980s but not developed for medical use at that time. It is approved for use in a subcutaneous infusion as a fixed-dose combination with foscarbidopa ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of levodopa include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, the wearing-off phenomenon,

dopamine dysregulation syndrome 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 is characterized by severely disinhibited patterns of behavior, leading to ...

, and

levodopa-induced dyskinesia Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis. In the context of Parkinson's di ...

, among others. The drug is a centrally

permeable Permeability, permeable, and semipermeable may refer to: Chemistry *Drug permeability *Semipermeable membrane, a membrane which will allow certain molecules or ions to pass through it by diffusion *Vascular permeability, the movement of fluids a ...

monoamine precursor Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan (5-HTP; oxitriptan) are precursors of serotonin and melatonin, while the amino acids L-pheny ...

and

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and hence acts as a

dopamine receptor agonist A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like ...

. Chemically, levodopa is an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

, a

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

, and a

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

. The major reason for enhanced risks for levodopa induced dyskinesia (LID) and OFF phases during late PD is the progressive dying of nigrostriatal dopaminergic neurons. This results in the conversion of levodopa into dopamine in serotonergic neurons (which cannot re-uptake dopamine and have no proper regulatory capacity for dopamine synthesis) becoming the major dopamine source in the dorsal striatum, leading to the striatal dopamine concentration following the pulsatile oral administration of levodopa with large fluctuations (see the schematic graph figure). On the other hand, in a disease like Segawa disease, in which dopamine synthesis is low but without progressive degeneration of dopaminergic neurons, lifelong administration of low doses of levodopa is believed to be without serious side effects. Levodopa was first synthesized and isolated in the early 1910s. The

antiparkinsonian 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 nutr ...

effects of levodopa were discovered in the 1950s and 1960s. Following this, it was introduced for the treatment of Parkinson's disease in 1970.

Medical uses

Levodopa crosses the protective

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, whereas

itself cannot. Thus, levodopa is used to increase dopamine concentrations in the treatment of

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

and Parkinson-plus syndrome. The therapeutic efficacy is different for different kinds of symptoms.

Bradykinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...

and rigidity are the most responsive symptoms while

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

s are less responsive to levodopa therapy. Speech, swallowing disorders, postural instability, and freezing gait are the least responsive symptoms. Once levodopa has entered the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, it is converted into dopamine by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

aromatic -amino acid decarboxylase (AAAD), also known as

DOPA decarboxylase Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (), located in region 7p12.2-p12.1. Mechanism The enzyme uses pyri ...

(DDC).

Pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependen ...

( vitamin B₆) is a required cofactor in this

reaction Reaction may refer to a process or to a response to an action, event, or exposure. Physics and chemistry *Chemical reaction *Nuclear reaction *Reaction (physics), as defined by Newton's third law * Chain reaction (disambiguation) Biology and ...

, and may occasionally be administered along with levodopa, usually in the

form Form is the shape, visual appearance, or configuration of an object. In a wider sense, the form is the way something happens. Form may also refer to: *Form (document), a document (printed or electronic) with spaces in which to write or enter dat ...

pyridoxine Pyridoxine (PN) is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metaboli ...

. Because levodopa bypasses the enzyme

tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...

, 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

. Cells in the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

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 effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s seen with sole levodopa administration. To bypass these effects, it is standard clinical practice to coadminister (with levodopa) a peripheral

DOPA 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 ...

(DDCI) such as

(medicines containing carbidopa, either alone or in combination with levodopa, are branded as Lodosyn ( Aton Pharma) Sinemet ( Merck Sharp & Dohme Limited), Pharmacopa ( Jazz Pharmaceuticals), Atamet ( UCB), Syndopa and

Stalevo 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. Medical uses Carbido ...

(

Orion Corporation Orion may refer to: Common meanings * Orion (constellation), named after the mythical hunter * Orion (mythology), a hunter in Greek mythology Arts and media Fictional entities Characters and species * Orion (character), a DC Comics c ...

) or with a

(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

is not present. 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 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 ...

. It was approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) on 21 December 2018, and is marketed by

Acorda Therapeutics Acorda Therapeutics, Inc. is an American biotechnology company based in Pearl River, New York. The company develops therapies that improve neurological function in people with Parkinson's disease, multiple sclerosis and other neurological disorde ...

. Coadministration of

without a DDCI accelerates the peripheral

decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

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 Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

. 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 Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (''FOSB'') gene. The FOS gene family consists of four members: FOS, F ...

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.

Available forms

Levodopa is available, alone or in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

with

, in the form of

immediate-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets and capsules,

extended-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

oral tablets and capsules,

orally disintegrating tablet An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be ...

s, as a powder for

inhalation Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

, and as an

enteral Enteral administration is food or drug administration via the human gastrointestinal tract. This contrasts with parenteral nutrition or drug administration (Greek ''para'', "besides" + ''enteros''), which occurs from routes outside the GI tract, ...

suspension Suspension or suspended may refer to: Science and engineering * Car suspension * Cell suspension or suspension culture, in biology * Guarded suspension, a software design pattern in concurrent programming suspending a method call and the calling ...

or gel (via intestinal tube). In terms of combination formulations, it is available with

(as levodopa/carbidopa), with

(as levodopa/benserazide), and with both carbidopa and

entacapone 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 lo ...

(as levodopa/carbidopa/entacapone). In addition to levodopa itself, certain

s of levodopa are available, including

melevodopa 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 250times the water solubil ...

( melevodopa/carbidopa) (used orally) and

( foslevodopa/foscarbidopa) (used

subcutaneously The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, or superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and m ...

Side effects

The

s of levodopa may include: *

Hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, especially if the dosage is too high *

Arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

s, although these are uncommon *

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, which is often reduced by taking the drug with food, although

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

reduces drug absorption. Levodopa is an amino acid, so protein competitively inhibits levodopa absorption. * Gastrointestinal bleeding * Disturbed

respiration Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenance respiration, the amount of cellul ...

, which is not always harmful, and can actually benefit patients with upper airway obstruction *

Hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

Disorientation Orientation is a function of the mind involving awareness of three dimensions: time, place and person. Problems with orientation lead to ''dis''orientation, and can be due to various conditions. It ranges from an inability to coherently understand ...

and

confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

* Extreme

emotion Emotions are physical and mental states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavior, behavioral responses, and a degree of pleasure or suffering, displeasure. There is ...

al states, particularly

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, but also excessive

libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

* Vivid

dream A dream is a succession of images, ideas, emotions, and sensation (psychology), sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around ...

s or

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

* Auditory or

visual hallucinations A visual hallucination is a vivid visual experience occurring without corresponding external stimuli in an awake state. These experiences are involuntary and possess a degree of perceived reality sufficient to resemble authentic visual perception. ...

* Effects on learning; some evidence indicates it improves

working memory Working memory is a cognitive system with a limited capacity that can Memory, hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term m ...

, while impairing other complex functions *

Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

and

narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

* A condition similar to

stimulant psychosis Stimulant psychosis is a mental disorder characterized by psychotic symptoms such as hallucinations, paranoid ideation, delusions, disorganized thinking, and grossly disorganized behaviour. It typically occurs following an overdose or several ...

Although many adverse effects are associated with levodopa, in particular psychiatric ones, it has fewer than other

antiparkinsonian agent 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 nutr ...

s, such as

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

s and

s. 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 Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...

) *

Dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...

at peak dose (

) * Possible dopamine dysregulation: The long-term use of levodopa in Parkinson's disease has been linked to the so-called

. Rapidly decreasing the dose of levodopa can result in

neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...

. 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 neurotoxin A monoamine neurotoxin, or monoaminergic neurotoxin, is a drug that selectively damages or destroys monoaminergic neurons. Monoaminergic neurons are neurons that signal via stimulation by monoamine neurotransmitters including serotonin, dopamine ...

s. The long term use of levodopa increases oxidative stress through

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(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 Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

. See also the catecholaldehyde hypothesis.

Pharmacology

Pharmacodynamics

Levodopa is a

dopamine precursor Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan (5-HTP; oxitriptan) are precursors of serotonin and melatonin, while the amino acids L-phenyl ...

and

and hence acts as a non-selective

, including of the D₁-like receptors ( D₁, D₅) and the D₂-like receptors ( D₂, D₃, D₄).

Pharmacokinetics

The

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of levodopa is 30%. It is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

into

by aromatic--amino-acid decarboxylase (AAAD) in the

and periphery. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of levodopa is 0.75 to 1.5hours. It is

excreted Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific ...

70–80% in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

Chemistry

Levodopa is an

and a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and

. Analogues and prodrugs of levodopa include

etilevodopa Etilevodopa (developmental code name TV-1203) is a dopaminergic agent which was developed as a treatment for Parkinson's disease. It is the ethyl ester of levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopami ...

, and

XP-21279 XP-21279 is a sustained-release levodopa (L-DOPA) prodrug and hence a dopamine precursor and non-selective dopamine receptor agonist which was under development for the treatment of Parkinson's disease. It is taken by mouth. Pharmacology Th ...

. Some of these, like melevodopa and foslevodopa, are approved for the treatment of

similarly to levodopa. Other analogues include

methyldopa Methyldopa, also known as α-methyl-L-DOPA and 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 blo ...

, an

antihypertensive agent Antihypertensives are a class of medication, drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myo ...

, and

droxidopa 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 in ...

(L-DOPS), a norepinephrine precursor and prodrug.

6-Hydroxydopa 6-Hydroxydopa (6-OH-DOPA; 6-OHDOPA) is a catecholaminergic neurotoxin that damages noradrenergic and dopaminergic neurons and is used in scientific research. It is a precursor and prodrug of 6-hydroxydopamine (6-OHDA). The drug is a derivative ...

, a prodrug of

6-hydroxydopamine Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a synthetic monoaminergic neurotoxin used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. The main use for ox ...

(6-OHDA), is a potent

used in

scientific research The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...

History

Levodopa was first synthesized in 1911 by Torquato Torquati from the ''

Vicia faba ''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Vari ...

'' bean. It was first isolated in 1913 by Marcus Guggenheim from the ''V.faba'' bean. Guggenheim tried levodopa at a dose of 2.5mg and thought that it was inactive aside from

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

. In work that earned him a

Nobel Prize The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...

in 2000,

Swedish Swedish or ' may refer to: Anything from or related to Sweden, a country in Northern Europe. Or, specifically: * Swedish language, a North Germanic language spoken primarily in Sweden and Finland ** Swedish alphabet, the official alphabet used by ...

scientist

Arvid Carlsson Arvid Carlsson (25 January 1923 – 29 June 2018) was a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. For his work on dopamine, Carlsson was awarded the Nob ...

first showed in the 1950s that administering levodopa to animals with drug-induced (

reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...

) Parkinsonian

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s 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, published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered levodopa in patients. This treatment was later extended to manganese poisoning and later parkinsonism by

George Cotzias George Constantin Cotzias (June 16, 1918 – June 13, 1977) was a Greek scientist who together with his coworkers developed L-Dopa treatment, currently the most commonly used treatment for Parkinson's disease. Early life Cotzias was born in Cha ...

and his coworkers, who used greatly increased oral doses, for which they won the 1969 Lasker Prize. The first study reporting improvements in patients with Parkinson's disease resulting from treatment with levodopa was published in 1968. Levodopa was first marketed in 1970 by Roche under the brand name Larodopa. The

neurologist Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the ...

Oliver Sacks Oliver Wolf Sacks (9 July 1933 – 30 August 2015) was a British neurology, neurologist, Natural history, naturalist, historian of science, and writer. Born in London, Sacks received his medical degree in 1958 from The Queen's College, Oxford ...

describes this treatment in human patients with

encephalitis lethargica Encephalitis lethargica (EL) is an atypical form of encephalitis. Also known as "von Economo Encephalitis", "sleeping sickness" or "sleepy sickness" (distinct from tsetse fly–transmitted sleeping sickness), it was first described in 1917 by ne ...

in his 1973 book ''

Awakenings ''Awakenings'' is a 1990 American biographical drama film written by Steven Zaillian, directed by Penny Marshall, and starring Robert De Niro, Robin Williams, Julie Kavner, Ruth Nelson, John Heard, Penelope Ann Miller, Peter Stormare and Max ...

'', upon which the 1990 movie of the same name is based.

Carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication 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 levo ...

was added to levodopa in 1974 and this improved its

tolerability In pharmacology, tolerability refers to the degree to which overt adverse effects of a drug can be tolerated by a patient. Tolerability of a particular drug can be discussed in a general sense, or it can be a quantifiable measurement as part of a ...

Society and culture

Names

''Levodopa'' is the generic name of the drug and its , , , , , , and .

Research

Novel formulations and prodrugs

New levodopa formulations for use by other

routes of administration In pharmacology and toxicology, a route of administration is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance ...

, such as

subcutaneous administration Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, colle ...

, are being developed. Levodopa

s, with the potential for better

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

, reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed.

Depression

Levodopa has been reported to be inconsistently effective as an

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

in the treatment of

depressive disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental disorder, mental and Abnormal behavior, behavioral Disorder (medicine), disorder where the main underlying characteristic is a disturbance in the per ...

s. However, it was found to enhance psychomotor activation in people with depression.

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. Other

dopaminergic agent Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related ...

s have also shown pro-motivational effects and may be useful in the treatment of

motivational disorder Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions. Many different terms have been used to refer to diminished motivation. Often however, a spectrum is defined encompassing a ...

Age-related macular degeneration

In 2015, a retrospective analysis comparing the incidence of

age-related macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Some people experien ...

(AMD) between patients taking versus not taking levodopa found that the drug delayed onset of AMD by around 8years. The authors state that significant effects were obtained for both dry and wet AMD.

References

External links

* {{Portal bar , Medicine Alpha-Amino acids Antiparkinsonian agents Aromatic amino acids Carbonic anhydrase activators Catecholamines Dopamine agonists Monoamine precursors Phenethylamines Pro-motivational agents Prodrugs