L-DOPA
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L-DOPA (levodopa, 3,4-dihydroxy-L-phenylalanine). As a drug it is used to treat Parkinson's disease.
Therapeutic use
L-DOPA is used to replace dopamine lost in Parkinson's disease because dopamine itself cannot cross the blood-brain barrier where its precursor can. However, L-DOPA is converted to dopamine in the periphery as well as in the CNS, so it is administered with a peripheral DDC (dopamine decarboxylase) inhibitor such as carbidopa, without which 90% is metabolised in the gut wall, and with a COMT inhibitor if possible; this prevents about a 5% loss. The form given therapeutically is therefore a prodrug which avoids decarboxylation in the stomach and periphery, can cross the blood-brain barrier, and once in the brain is converted to the neurotransmitter dopamine by the enzyme aromatic-L-amino-acid decarboxylase.
Side Effects
Possible side effects 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. It can reveal dementia that was previously subclinical.
- 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 side-effects associated with L-DOPA, particularly psychiatric ones, it has fewer than other Parkinson's drugs, including anticholinergics, selegiline, amantadine, and dopamine agonists.
More serious are the effects of chronic L-DOPA 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 L-DOPA dosages as far as possible until absolutely necessary.
Synthesis
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).
History
In work that earned him a Nobel Prize, Swedish scientist Arvid Carlsson first showed in the 1950s that administering L-DOPA to animals with Parkinson's Disease-like symptoms would cause a reduction of the symptoms. The neurologist Oliver Sacks describes this treatment in human patients in his book Awakenings on which the movie of the same name is based.