When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly. Antacids taken 30–60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brainstem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. If not, an additional dose of carbidopa (Lodosyn; 25 mg) taken with the regular carbidopa-levodopa dose is often helpful, even though the usual maximum requirement of carbidopa is 75 mg daily. Domperidone (not available in the USA) may also relieve persistent nausea. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease.
When levodopa is given in combination with carbidopa, adverse gastrointestinal effects are much less frequent and troublesome, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses.
Metabolism Peripheral in the tissues GI tract (toxicity)
Levodopa with carbidopa
Metabolism Peripheral in the tissues GI tract (toxicity)
FIGURE 28–4 Fate of orally administered levodopa and the effect of carbidopa, estimated from animal data. The width of each pathway indicates the absolute amount of the drug at each site, whereas the percentages shown denote the relative proportion of the administered dose. The benefits of co-administration of carbidopa include reduction of the amount of levodopa required for benefit and of the absolute amount diverted to peripheral tissues and an increase in the fraction of the dose that reaches the brain. GI, gastrointestinal. (Data from Nutt JG, Fellman JH: Pharmacokinetics of levodopa. Clin Neuropharmacol 1984;7:35.)
B. Cardiovascular Effects
A variety of cardiac arrhythmias have been described in patients receiving levodopa, including tachycardia, ventricular extrasystoles, and rarely, atrial fibrillation. This effect has been attributed to increased catecholamine formation peripherally. The incidence of such arrhythmias is low, even in the presence of established cardiac disease, and may be reduced still further if the levodopa is taken in combination with a peripheral decarboxylase inhibitor.
Postural hypotension is common, but often asymptomatic, and tends to diminish with continuing treatment. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken.
C. Behavioral Effects