Carbidopa/levodopa

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Carbidopa/levodopa
Combination of
Agonist Levodopa
Enzyme inhibitor Carbidopa
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Trade names Atamet, Carbilev, Sinemet, others
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MedlinePlus a601068
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Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. [1] 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. [1] It is taken by mouth. [1] It can take two to three weeks of treatment before benefits are seen. [2] Each dose then begins working in about ten minutes to two hours with a duration of effect of about five hours. [2] [3] [4]

Contents

Common side effects include movement problems and nausea. [1] More serious side effects include depression, low blood pressure with standing, sudden onset of sleepiness, psychosis, and increased risk-taking behavior. [1] [5] Carbidopa prevents the breakdown of levodopa outside the brain. [5] In the brain, levodopa is broken down into dopamine, its active form. [5] Carbidopa also helps prevent some of the nausea which levodopa causes. [6]

It is on the World Health Organization's List of Essential Medicines. [7] It is available as a generic medication. [5] In 2020, it was the 364th most commonly prescribed medication in the United States, with more than 500,000 prescriptions. [8] [9]

Medical uses

Bottle of prescription carbidopa (25 mg) / levodopa (100 mg) in Australia. Medicationlevodopa.jpg
Bottle of prescription carbidopa (25 mg) / levodopa (100 mg) in Australia.

Parkinson's disease

It is primarily used to improve the symptoms of Parkinson's disease but does not change the course of the disease. [1] It can take two to three weeks of treatment before benefits are seen. [2] Each dose then begins working in about ten minutes to two hours depending on the formulation, with a duration of effect of about five hours. [2] [3] [4]

A formulation that can be given in an intra-intestinal pump, known as Duodopa, is being developed. [10] [11]

Other

Other uses include for dopamine-responsive dystonia (DRD) and restless legs syndrome. [5] [12] [13] Using carbidopa/levodopa may lead to augmentation syndrome, with increasing persistence of restless legs syndrome, and increasing severity. [13]

There is tentative evidence that it is useful in amblyopia when used with other treatments. [14]

Side effects

Common side effects include dizziness, drowsiness, blurred vision, vomiting, nausea, dry mouth, low appetite, heartburn, diarrhea, constipation, frequent sneezing, stuffiness of the nose, any of the symptoms of ordinary common cold, cough, muscle pain, hallucinations, numbness or a tingling sensation, disturbances of sleep, skin rash, itching, and/or headache. [15]

Less common, but more serious, side effects can include very frequent blinking or twitching of the eyes, fainting, mood changes such as confusion, depression, hallucinations, thoughts of suicide, or unusual strong urges (such as increased gambling), increases in the sex-drive, delusions (strongly-felt belief in something which is obviously not true), worsening of involuntary movements or spasms, and/or other movement problems. Patients should report these to their doctors as soon as possible. [15] [1]

Mechanism of action

Levodopa is converted to dopamine via the action of a naturally occurring enzyme called DOPA decarboxylase. This occurs both in the peripheral circulation and in the central nervous system after levodopa has crossed the blood brain barrier. Activation of central dopamine receptors improves the symptoms of Parkinson's disease; however, activation of peripheral dopamine receptors causes nausea and vomiting. For this reason levodopa is usually administered in combination with a DOPA decarboxylase inhibitor (DDCI), in this case carbidopa, which is very polar (and charged at physiologic pH) and cannot cross the blood brain barrier, however prevents peripheral conversion of levodopa to dopamine and thereby reduces the unwanted peripheral side effects of levodopa. Use of carbidopa also increases the quantity of levodopa in the bloodstream that is available to enter the brain.

History

In 1960 the Austrian biochemist Oleh Hornykiewicz, while at the University of Vienna, examined results of autopsies of patients who had died with Parkinson's disease. He suggested that the disease was associated with, or caused by, a reduction in the levels of dopamine in the basal ganglia of the brain. Since dopamine itself did not enter the brain, he tried treating twenty patients with a racemic mixture of dihydroxyphenylalanine (DOPA), which could enter the brain and be converted there to dopamine by the action of DOPA decarboxylase. His results were positive, as were those of another trial in Montreal run by André Barbeau. Unfortunately, other investigators were unable to replicate these early results, and the use of DOPA remained in question until 1967, when George Cotzias at the Brookhaven National Laboratories in Upton, New York, used megadoses of DOPA, up to 16 grams per day. Not long after these results became known, Curt Porter at Merck showed that L-DOPA was the active stereoisomer, thus reducing the effective dose to half. [16]

With L-DOPA identified as the active form, Alfred Pletscher and his colleagues at Hoffman-LaRoche synthesized benserazide, an inhibitor of DOPA decarboxylase, which further reduced the required dose. A drug combining L-DOPA with benserazide was marketed under the brand name of Madopar. Independent work was carried out by Victor Lotti at Merck in West Point, Pennsylvania. Merck had already synthesized and patented carbidopa, another dopa decarboxylase inhibitor in 1962, and in 1971 Lotti showed that the use of the L-form of carbidopa, further reduced the therapeutic dose of L-DOPA. The combination of L-carbidopa and L-DOPA was marketed under the brand name of Sinemet. [16]

Society and culture

Cost

It is available as a generic medication and is moderately expensive. [5]

Names

The generic name under the BAN system is Co-careldopa.

It is sold under several brand names, including Sinemet (Merck Sharp & Dohme Limited), Pharmacopa, Atamet, Apo-Levocarb, Duodopa, Kinson, and Pharmacopa, among others.

Extended-release formulations are sold as Rytary and Sinemet-CR. An extended-release enteral solution is sold as Duopa.

Shortages

In 1991, Merck licensed the rights to the manufacture and sale of Sinemet to a newly created joint venture, DuPont Merck Pharmaceutical Company. That same year, approvals for a sustained release formulation (Sinemet CR) which could be taken less frequently were also obtained. [17] DuPont purchased Merck's share in the joint venture in 1998 and began operating the company as DuPont Pharmaceuticals (DuPont Pharma), but Merck continued to manufacture the drug for DuPont. [18] Starting in late 2009 and continuing into 2011 Merck stopped manufacturing the drug while awaiting regulatory approvals due to a change in the supplier of the active ingredient. This resulted in shortages of the brand name products Sinemet and Sinemet CR, although alternative generic versions were still available. [19]

Another shortage appears to have occurred at the end of 2017. [20]

See also

Related Research Articles

<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.

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 the hands to an uncontrollable movement of the upper body or lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders that are distinguished by their underlying cause.

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

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

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

<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.

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

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">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

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

<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">Safinamide</span> Reversible monoamine oxidase B inhibitor

Safinamide is a drug used as an add-on treatment for Parkinson's disease with "off" episodes; it has multiple modes of action, including the inhibition of monoamine oxidase B.

<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.

<span class="mw-page-title-main">Parkinson's disease</span> Long-term degenerative neurological disorder

Parkinson's disease (PD), or simply Parkinson's, is a chronic degenerative disorder of the central nervous system that affects both the motor system and non-motor systems. The symptoms usually emerge slowly, and as the disease progresses, non-motor symptoms become more common. Early symptoms are tremor, rigidity, slowness of movement, and difficulty with walking. Problems may also arise with cognition, behaviour, sleep, and sensory systems. Parkinson's disease dementia is common in advanced stages.

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.

Parkinson's disease is the 2nd most prevalent neurological disorder within the United States and Europe, affecting around 1% of the population over the age of 60. While the link connecting the onset of Parkinson's disease to environmental factors is known, the link between dietary patterns and the disease is just beginning to be researched more fully. Additionally, other research has sought to examine the symptoms of the disease and propose methods on how to alleviate these symptoms through changes in diet. Current medications that work to alleviate the symptoms of Parkinson's disease can also be made more effective through changes in diet.

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). Administration of monoamine precursors can increase the levels of monoamine neurotransmitters in the body and brain. Monoamine precursors may be used in combination with peripherally selective aromatic L-amino acid decarboxylase inhibitors such as carbidopa and benserazide. Carbidopa/levodopa is used to increase brain dopamine levels in the treatment of Parkinson's disease while carbidopa/oxitriptan (EVX-101) is under development as an antidepressant for possible use in the treatment of depression.

References

  1. 1 2 3 4 5 6 7 "Levodopa/Carbidopa". The American Society of Health-System Pharmacists. Archived from the original on 24 September 2015. Retrieved 21 August 2015.
  2. 1 2 3 4 "Chapter 15: Antiparkinson Drugs". Pharmacology and the Nursing Process. Elsevier Health Sciences. 2014. p. 246. ISBN   9780323293617. Archived from the original on 5 July 2017.
  3. 1 2 Atlee JL (2007). Complications in anesthesia (2nd ed.). Philadelphia: Elsevier/Saunders. p. 490. ISBN   9781416022152. Archived from the original on 15 March 2017.
  4. 1 2 The new Parkinson's disease treatment book : partnering with your doctor to get the most from your medications (2 ed.). Oxford University Press. 2015. p. 227. ISBN   9780190231866.
  5. 1 2 3 4 5 6 Hamilton RJ (2013). Tarascon pocket pharmacopoeia (14th ed.). Burlington, MA.: Jones & Bartlett Learning. p. 303. ISBN   9781449673635. Archived from the original on 12 January 2016.
  6. ↑ Ahlskog JE (2009). Parkinson's Disease Treatment Guide for Physicians. Oxford University Press. p. 124. ISBN   978-0-19-537177-2.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  9. ↑ "Carbidopa; Levodopa - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  10. ↑ "Fact sheet - Duodopa (levodopa/carbidopa intestinal gel)". Hc-sc.gc.ca. 11 August 2010. Archived from the original on 11 January 2013. Retrieved 5 February 2013.
  11. ↑ "Information on Duodopa". Duodopa.co.uk. Abbott Healthcare. Archived from the original on 1 January 2013. Retrieved 5 February 2013.
  12. ↑ Ramar K, Olson EJ (August 2013). "Management of common sleep disorders". American Family Physician. 88 (4): 231–238. PMID   23944726.
  13. 1 2 Gossard TR, Trotti LM, Videnovic A, St Louis EK (January 2021). "Restless Legs Syndrome: Contemporary Diagnosis and Treatment". Neurotherapeutics. 18 (1): 140–155. doi:10.1007/s13311-021-01019-4. PMC   8116476 . PMID   33880737.
  14. ↑ DeSantis D (June 2014). "Amblyopia". Pediatric Clinics of North America. 61 (3): 505–518. doi:10.1016/j.pcl.2014.03.006. PMID   24852148.
  15. 1 2 Cunha JP, ed. (26 April 2023). "Side Effects of Sinemet (Carbidopa-Levodopa), Warnings, Uses". RxList.
  16. 1 2 Scriabine A (1999). "Discovery and Development of Major Drugs Currently in Use". In Landau R, Achilladelis B, Scriabine A (eds.). Pharmaceutical Innovation: Revolutionizing Human Health. Philadelphia: Chemical Heritage Press. pp. 222–223. ISBN   978-0-941901-21-5.
  17. ↑ "Sinemet". Dupont Heritage. Archived from the original on 11 May 2011.
  18. ↑ "SINEMET". listingdrugs.com. Archived from the original on 3 May 2012.
  19. ↑ "Letter From MERCK About SINEMET Shortage". Bibmomma's Blog – Reflections of an early onset Parkinson's patient. Archived from the original on 3 July 2011.
  20. ↑ "FDA Drug Shortages". www.accessdata.fda.gov. U.S. Food and Drug Administration.
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