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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Anticonvulsants and Antiparkinsonian Drugs

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Levodopa - Antiparkinsonian Drug

Synonyms · L-dopa; Larodopa; Dopar; L-3,4-dihydroxyphenylalanine­.

Levodopa

Synonyms

·              L-dopa; Larodopa; Dopar; L-3,4-dihydroxyphenylalanine­.

Uses

·              Levodopa is the metabolic precursor of dopamine* and is one of the most effective agents in the treatment of Parkinsonism.

Toxicokinetics

·              On oral administration, levodopa is rapidly absorbed and peak plasma levels are usually achieved in ½ hour to 2 hours. Over one-half of the oral dose is decarboxylated in the gastroin- testinal wall. Absorption of intact levodopa is via a saturable transport system. Erratic gastric emptying may account for multiple peak levels after single oral doses.

·              In the brain, levodopa is converted to dopamine by decar- boxylation, mainly within the presynaptic terminals of dopaminergic neurons in the striatum, subsequently, the action of dopamine is terminated by the sequential actions of the enzymes catechol-O-methyl-transferase (COMT) andmonoamine oxidase (MOA), or by reuptake of dopamine into the terminal.

·     Levodopa is metabolised by decarboxylation (via levodopa decarboxylase) to dopamine in the gut, liver, and kidney and by o-methylation, transamination, and oxidation. 70 to 80% of levodopa is excreted in the urine in the form of metabo-lites (dopamine, norepinephrine, vanillinemandelic acid, homovanillic acid, dihydroxyphenylacetic acid, vanillpyru-vate, vanillactate, etc.) within 24 hours.

·     To prevent decarboxylation of levodopa after adminis-tration, it is always combined with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase such as carbidopa or benzeraside. This enables a large amount of levodopa to remain unmetabolised and therefore available to cross the blood-brain barrier, and also minimises the incidence of gastrointestinal side effects.

Adverse Effects

■■  Postural hypotension (especially severe in the elderly), anorexia, nausea, vomiting, cardiac arrhythmias, delirium, hallucinations, depression, leukopenia, and thrombocyto-penia. GI bleeding can occur in patients with peptic ulcer.

■■  Dyskinesias (facial tics, grimacing, head bobbing, torti-collis and choreoathetosis) have been reported following chronic therapy.

■■  Hallucinations were reported in 5.6% of patients given levodopa in one study, and insomnia was reported in 23.6%.

■■  Sudden withdrawal after prolonged use may precipitate neuroleptic malignant syndrome, convulsions, agitation, paranoia, mania, hypoventilation and myoglobinuria.

Drug Interactions

·              Effects are enhanced by amantadine, anticholinergics, and amphetamines.

·              Effects are reduced by phenothiazines, haloperidol, reser- pine, benzodiazepines, and phenobarbitone.

·              Hypertensive crisis can be precipitated by con­comitant administration of furazolidone or MAOIs. 

Clinical (Toxic) Features

■■   Clinically, the most prominent signs/symptoms seen following acute overdose include confusion, agitation, insomnia, and excessive motor activity.

■■   Other effects reported after acute overdose have included nausea, vomiting, sinus tachycardia, postural hypotension, restlessness, hypertension and dyskinesias.

■■   Bilateral maximally dilated pupils, with absent light reac-tion, were reported in one case.

■■   Respiratory dyskinesias have been reported following therapeutic use and include dyspnoea, hypoventilation, diaphragm myoclonic jerks, and respiratory alkalosis.

Diagnosis

Elevation of urinary levodopa (free and total), dopamine, dihy-droxyphenylacetic acid, noradrenaline and homovanilic acid.

Treatment

·      Supportive measures.

·      Pancuronium may have to be administered in severe cases.

·      Specific treatment for dyskinesias has primarily included reduction of dosage and supportive care.

·      Other treatments which have been tried, but have not been proven clinically efficacious, include deanol (100 mg three times daily) and pyridoxine (10 to 15 mg IV).

·      Hypertension is usually transient and frequently followed by hypotension, and, therefore, should not be treated with medications unless severe or symptomatic.

For hypotension: infuse 10 to 20 ml/kg of isotonicfluid and place in Trendelenburg position. If hypoten-sion persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·      Neuroleptic malignant syndrome due to levodopa with-drawal may be successfully managed with oral dantrolene sodium (Adult and child: 1 mg/kg orally every 12 hours up to 50 mg/dose), oral bromocriptine mesylate 5 mg 3 times a day, or reinstitution of levodopa.

 

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