· L-dopa; Larodopa; Dopar; L-3,4-dihydroxyphenylalanine.
· Levodopa is the metabolic precursor of dopamine* and is one of the most effective agents in the treatment of Parkinsonism.
· 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.
■■ 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.
· 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.
■■ 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.
Elevation of urinary levodopa (free and total), dopamine, dihy-droxyphenylacetic acid, noradrenaline and homovanilic acid.
· 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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