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.

pharmacology

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.

toxicity

Oral, mouse: LD₅₀ = 2363 mg/kg; Oral, rabbit: LD₅₀ = 609 mg/kg; Oral, rat: LD₅₀ = 1780 mg/kg.

biotransformation

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.

absorption

Levodopa is rapidly absorbed from the proximal small intestine by the large neutral amino acid (LNAA) transport carrier system.

half life

50 to 90 minutes

drug interactions

Fosphenytoin: The hydantoin decreases the effect of levodopa

Iron Dextran: Iron decreases the absorption of dopa derivatives

Isocarboxazid: Possible hypertensive crisis

Methyldopa: Methyldopa increases the effect and toxicity of levodopa

Metoclopramide: Levodopa decreases the effect of metoclopramide

Paliperidone: The atypical antipsychotic agent, paliperidone, may decrease the therapeutic effect of the anti-Parkinson's agent, levodopa. This interaction may be due to the dopamine antagonist properties of paliperidone. Consider an alternate antipsychotic in those with Parkinson's disease or consider using clozapine or quetiapine if an atypical antipsychotic is necessary.

Phenelzine: Possible hypertensive crisis

Phenytoin: The hydantoin decreases the effect of levodopa

Tetrabenazine: Tetrabenazine may cause Parkinsonian symptoms and neutralize the effect of Levodopa.

Thiothixene: Thiothixene may antaonize the effects of the anti-Parkinsonian agent, Levodopa. Consider alternate therapy or monitor for decreased effects of both agents.

Tranylcypromine: Levodopa may increase the adverse effects of Tranylcypromine. Risk of severe hypertension. Concomitant therapy should be avoided or monitored closely for adverse effects of Tranylcypromine.

Ziprasidone: The atypical antipsychotic, ziprasidone, may antagonize the effect of the dopamine agonist, levodopa. Consider alternate therapy or monitor for worsening of movement disorder.

Zuclopenthixol: Antagonism may occur between zuclopenthixol, a dopamine D2 receptor antagonist, and levodopa, a dopamine agonist. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if concurrent therapy is initiated, discontinued or dose(s) changed.