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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New formulation: Parcopa®, Schwarz Pharma: Carbidopa-levodopa
From Geriatrics, 11/1/04

Parkinson's tablet approved

The orally-disintegrating tablet formulation of carbidopa-levodopa was approved for the treatment of symptoms of idiopathic Parkinson's disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism. Dosage. Optimum daily dosing of carbidopa-levodopa must be carefully titrated. This formulation is available in a 1:4 ratio of carbidopa to levodopa (25/100 mg) and a 1:10 ratio (25/250 and 10/100 mg). Tablets of the 2 ratios may be given separately or combined to provide optimum dosage and should be taken at regular intervals. Ingredients will begin release within 30 minutes of placing on tongue.

Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly, although dosage adjustments may be required.

Geriatric dosage adjustments. None recommended.

Pharmacokinetics. Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and when administered with levodopa, increases plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. The plasma half-life of levodopa is about 1.5 hours when taken with carbidopa.

Abnormalities in laboratory tests may include elevations of liver function tests, such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of carbidopa-levodopa than with levodopa alone.

Safety. Nonselective MAOIs are contraindicated for use with carbidopa-levodopa tablets and must be discontinued at least 2 weeks prior to initiating therapy. Levodopa must be discontinued at least 12 hours prior to initiation of therapy with carbidopa-levodopa tablets.

CNS adverse events (eg, dyskinesias) may occur at lower dosages and sooner with carbidopa-levodopa tablets than with levodopa alone.

Cardiac function should be monitored in patients with a history of MI who have residual atrial, nodal, or ventricular arrhythmias.

A symptom complex resembling neuroleptic malignant syndrome has been reported sporadically in association with dose reductions or withdrawal of carbidopa-levodopa.

Carbidopa-levodopa tablets contain phenylalanine.

Avoid carbidopa-levodopa orally-disintegrating tablets in patients with narrow-angle glaucoma.

Rare reports exist of hypertension and dyskinesia resulting from concomitant use of tricyclic antidepressants and carbidopa-levodopa.

Symptomatic postural hypotension has occurred with carbidopa-levodopa treatment for patients already receiving antihypertensive drugs.

Adverse events. Commonly observed adverse events associated with carbidopa-levodopa therapy include nausea and dyskinesias, such as choreiform, dystonic, and other involuntary movements.

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