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

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Pramipexole Delays Complications Longer Than Levodopa - Brief Article - Statistical Data Included
From Family Pratice News, 6/15/00 by Betsy Bates

SAN DIEGO -- The dopamine agonist pramipexole staved off three key motor complications longer than levodopa in a double-blind, placebo-controlled trial in patients with early Parkinson's disease.

But the new drug produced more somnolence, particularly in the dose-escalation phase of the 24-month study, Dr. Robert Holloway reported at the annual meeting of the American Academy of Neurology.

Dr. Holloway, a neurologist at the University of Rochester (N.Y.), presented data on behalf of the Parkinson Study Group, a group of researchers at 22 clinical centers. The research was sponsored by Pharmacia & Upjohn, makers of pramipexole.

Initially, 301 patients were randomized to receive active pramipexole and placebo levodopa or active levodopa and placebo pramipexole. In the first 10 weeks, investigators were permitted to individualize dosages based on patients' needs, with maintenance dosages ranging at 1.5-4.5 mg/day of pramipexole, 75-150 mg of carbidopa, or 300-600 mg of levodopa. During the maintenance phase of the study open-label levodopa could be started as a supplemental agent if a patient had continuing or emerging disability.

Pramipexole clearly came out ahead in delaying complications. One of three dopaminergic motor complications (wearing off, on-off motor fluctuations, or dyskinesias) developed in 28% of patients receiving that drug, compared with 51% of patients receiving only levodopa.

Patients on levodopa were significantly more likely to develop dyskinesias or wearing off. Also, more patients in that group developed on-off symptoms, but that difference was nor statistically significant.

About 48% of patients on pramipexole eventually required supplemental 1evodopa, compared with just 36% of those originally assigned to the levodopa group.

In all, 42 targeted motor complications occurred in patients receiving pramipexole, 24 of them before supplemental 1evodopa was initiated. Patients who first received levodopa experienced a total of 76 motor complications, with 61 of those events occurring before more levodopa was added to their maintenance regimens.

Although pramipexole's superior ability to delay a dopaminergic complication was "highly significant," patients receiving 1evodopa had significantly more improvement in mean total scores on the Unified Parkinson's Disease Rating Scale, he said.

More adverse events occurred among patients taking pramipexole. Most notably, 32% of patients in that group experienced somnolence, compared with 17% of patients taking levodopa. Three patients fell asleep while driving during the course of the study; two were taking pramipexole. One patient from each group had a motor vehicle accident.

Dr. Holloway noted that somnolence posed a problem for some pramipexole patients during the escalation phase, when nearly one in four recounted it as a problem. Once dosages were stabilized, rates of somnolence were almost identical at about 9%-10% of patients in each study arm.

Peripheral edema was more common in the pramipexole group, occurring in 15% of patients, compared with 4% in the 1evodopa arm. Hallucinations were seen in 9% of pramipexole patients and 3% of 1evodopa patients, he reported.

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