Indication |
For the treatment of idiopathic Parkinson's disease (Paralysis
Agitans), postencephalitic parkinsonism, symptomatic parkinsonism which
may follow injury to the nervous system by carbon monoxide intoxication,
and manganese intoxication. |
Pharmacodynamics |
Levodopa (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. |
Mechanism of action |
Striatal dopamine levels in symptomatic Parkinson's disease are
decreased by 60 to 80%, striatal dopaminergic neurotransmission may be
enhanced by exogenous supplementation of dopamine through administration
of dopamine's precursor, levodopa. A small percentage of each levodopa
dose crosses the blood-brain barrier and is decarboxylated to dopamine.
This newly formed dopamine then is available to stimulate dopaminergic
receptors, thus compensating for the depleted supply of endogenous
dopamine. |
Absorption |
Levodopa is rapidly absorbed from the proximal small intestine by the large neutral amino acid (LNAA) transport carrier system. |
Volume of distribution |
Not Available |
Protein binding |
High |
Metabolism |
95% of an administered oral dose of levodopa is pre-systemically
decarboxylated to dopamine by the L-aromatic amino acid decarboxylase
(AAAD) enzyme in the stomach, lumen of the intestine, kidney, and liver.
Levodopa also may be methoxylated by the hepatic
catechol-O-methyltransferase (COMT) enzyme system to 3-O-methyldopa
(3-OMD), which cannot be converted to central dopamine. |
Route of elimination |
Not Available |
Half life |
50 to 90 minutes |
Clearance |
Not Available |
Toxicity |
Oral, mouse: LD50 = 2363 mg/kg; Oral, rabbit: LD50 = 609 mg/kg; Oral, rat: LD50 = 1780 mg/kg. |