Article: Levodopa

Levodopa
Systematic (IUPAC) name
(S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid
Identifiers
CAS number	59-92-7
ATC code	N04BA01
PubChem	6047
DrugBank	APRD00055
Chemical data
Formula	C9H11NO4
Mol. weight	197.19 g/mol
Pharmacokinetic data
Bioavailability	30%
Metabolism	Aromatic-L-amino-acid decarboxylase
Half life	0.75–1.5 hours
Excretion	renal 70–80%
Therapeutic considerations
Pregnancy cat.	B3(AU) C(US)
Legal status	℞ Prescription only
Routes	oral

Levodopa (INN) or L-DOPA (3,4-dihydroxy-L-phenylalanine) is an intermediate in dopamine biosynthesis. Clinically, levodopa is used in the management of Parkinson's disease.

Therapeutic use

Levodopa is used as a prodrug to increase dopamine levels for the treatment of Parkinson's disease, since it is able to cross the blood-brain barrier whereas dopamine itself cannot. Once levodopa has entered the central nervous system (CNS), it is metabolised to dopamine by aromatic-L-amino-acid decarboxylase. However, conversion to dopamine also occurs in the peripheral tissues, causing adverse effects and decreasing the available dopamine to the CNS, so it is standard practice to co-administer a peripheral DOPA decarboxylase inhibitor – carbidopa or benserazide – and often a catechol-O-methyl transferase (COMT) inhibitor.

Adverse effects

Possible adverse drug reactions include:

• Hypotension, especially if the dosage is too high.
• Arrhythmias, although these are uncommon.
• Nausea, which is often helped by taking the drug with food, although protein interferes with drug absorption.
• Gastrointestinal bleeding.
• Disturbed respiration. This is not always harmful, and can actually benefit patients with upper airway obstruction.
• Hair loss.
• Confusion.
• Extreme emotional states, particularly anxiety, but also excessive libido.
• Vivid dreams and/or fragmented sleep.
• Visual and possibly auditory hallucinations.
• Effects on learning. There is some evidence that it improves working memory, while impairing other complex functions.
• Sleepiness and sleep attacks.
• a condition similar to amphetamine psychosis.

Although there are a number of adverse effects associated with levodopa, particularly psychiatric ones, it has fewer than other anti-Parkinson's drugs, including anticholinergics, selegiline, amantadine, and dopamine agonists.

More serious are the effects of chronic levodopa administration, which include:

• End-of-dose deterioration of function.
• On/off oscillations.
• Freezing during movement.
• Dose failure (drug resistance).
• Dyskinesia at peak dose.

Clinicians will try to avoid these by limiting levodopa dosages as far as possible until absolutely necessary.

Biosynthesis

L-DOPA is produced from the amino acid tyrosine by the enzyme tyrosine hydroxylase. It is also the precursor molecule for the catecholamine neurotransmitters dopamine and norepinephrine (noradrenaline), and the hormone epinephrine (adrenaline). Dopamine is formed by the decarboxylation of L-DOPA.

The prefix L- references its property of levorotation (compared with dextrorotation or D-dopa).

History

In work that earned him a Nobel Prize, Swedish scientist Arvid Carlsson first showed in the 1950s that administering levodopa to animals with Parkinsonian symptoms would cause a reduction of the symptoms. The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his book Awakenings on which the movie of the same name is based.

The 2001 Nobel Prize in Chemistry was also related to L-DOPA: the Nobel Committee awarded one-fourth of the prize to William S. Knowles for his work on chirally catalysed hydrogenation reactions, the most noted example of which was uses for the synthesis of L-DOPA.

Adhesion

DOPA is a key molecule in the formation of marine adhesive proteins, such as those found in mussels. It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible substrate.

References

• Waite, J. Herbert, et al. (2005). "Mussel Adhesion: Finding the Tricks Worth Mimicking". J Adhesion 81: 1-21.
• Messersmith, Phillip B., et al. (2006). "Rapid Gel Formation and Adhesion in Photocurable and Biodegradable Block Copolymers with High DOPA Content". Macromolecules 39: 1740-1748.