Carbidopa/levodopa

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Carbidopa/levodopa
Combination of
Agonist Levodopa
Enzyme inhibitor Carbidopa
Clinical data
Trade names Atamet, Carbilev, Sinemet
AHFS/Drugs.com monograph
MedlinePlus a601068
Licence data US FDA:link
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Identifiers
ATC code N04BA02
PubChem CID: 104778
ChemSpider 94585 YesY
 YesY (what is this?)  (verify)

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 improve the symptoms of Parkinson's disease but does not change the course of the disease. It is taken by mouth.[1] It can take two to three weeks of treatment before benefits are seen.[2] Each dose than begin working in about ten minutes with a duration of affect of about five hours.[2][3]

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 the desire to gamble.[1][4] Carbidopa prevents the breakdown of levodopa outside of the brain. In the brain levodopa is broken down into dopamine by which it has its affects.[4]

It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[5] It is avaliable as a generic medication and is moderately expensive.[4] Globally the wholesale price of the medication is about 1.80 to 3.00 USD a month.[6] In the United States a months supply is about 50 to 150 USD.[1]

Medical uses[edit]

Parkinson's disease[edit]

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 than begin working in about ten minutes with a duration of affect of about five hours.[2][3]

A formulation that can be given in a intra-intestinal pump, know as Duodopa is being developed.[7][8]

Other[edit]

Other uses include for dopamine-responsive dystonia (DRD) and restless legs syndrome.[4]

There is tentative evidence that it is useful in amblyopia when used with other treatments.[9]

Side effects[edit]

Common side effects include movement problems, and nausea.[1] More serious side effects include depression, low blood pressure with standing, sudden onset of sleepiness, and the desire to gamble.[1]

Mechanism of action[edit]

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[edit]

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.[10]

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 into the range of 1 to 2 grams per day. The combination of L-carbidopa and L-DOPA was marketed under the brand name of Sinemet.[10]

In 1991 the manufacture and sale of Sinemet was taken over by a new 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.[11] Dupont purchased Merck's share in the joint venture in 1998 and began operating the company as Dupont Pharmaceuticals (later Dupont Pharma), but Merck continued to manufacture the drug for Dupont.[12] 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.[13]

Society and culture[edit]

Cost[edit]

It is avaliable as a generic medication and is moderately expensive.[4] Globally the wholesale price of the medication is about 1.80 to 3.00 USD a month.[6] In the United States a months supply is about 50 to 150 USD.[1]

Names[edit]

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

It is sold under several brand names, including Sinemet, Pharmacopa, Atamet, Apo-Levocarb, Duodopa, Kinson, and Parcopa among others.

A extended-release formulation is sold as Rytary.

See also[edit]

References[edit]

  1. ^ a b c d e f g h i "Levodopa/Carbidopa". The American Society of Health-System Pharmacists. Retrieved Aug 21, 2015. 
  2. ^ a b c d Pharmacology and the Nursing Process. Elsevier Health Sciences. 2014. p. 246. ISBN 9780323293617. 
  3. ^ a b Atlee, John L. (2007). Complications in anesthesia (2nd ed.). Philadelphia: Elsevier/Saunders. p. 490. ISBN 9781416022152. 
  4. ^ a b c d e Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia. (14th ed.). Burlington, MA.: Jones & Bartlett Learning. p. 303. ISBN 9781449673635. 
  5. ^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015. 
  6. ^ a b "Levodopa + Carbidopa". International Drug Price Indicator Guide. Retrieved 22 August 2015. 
  7. ^ "Fact sheet - Duodopa (levodopa/carbidopa intestinal gel)". Hc-sc.gc.ca. 2010-08-11. Retrieved 2013-02-05. 
  8. ^ "Abbott Healthcare - Information on Duodopa". Duodopa.co.uk. Retrieved 2013-02-05. 
  9. ^ DeSantis, D (June 2014). "Amblyopia.". Pediatric clinics of North America 61 (3): 505–18. PMID 24852148. 
  10. ^ a b Scriabine, Alexander (1999). "Discovery and Development of Major Drugs Currently in Use", pp. 222–223 in Pharmaceutical Innovation: Revolutionizing Human Health, edited by Ralph Landau, Basil Achilladelis, and Alexander Scriabine. Philadelphia: Chemical Heritage Press. ISBN 978-0-941901-21-5.
  11. ^ Sinemet at Dupont Heritage.
  12. ^ SINEMET at listingdrugs.com[dead link]
  13. ^ Letter From MERCK About SINEMET Shortage at Bibmomma's Blog – Reflections of an early onset Parkinson's patient.

External links[edit]