Levodopa/carbidopa adverse effects

During early treatment witii levodopa and carbidopa, adverse reactions are usually not a problem. But as the disease progresses, die response to die drug may become less, and the period of time tiiat each dose is effective begins to decrease, leading to more frequent doses, and more adverse reactions. 

Levodopa interacts with many different drugs. When levodopa is used with phenytoin, reserpine, and papaverine, there is a decrease in response to levodopa The risk of a hypertensive crisis increases when levodopa is used with the monoamine oxidase inhibitors (see Chap. 31). Foods high in pyridoxine (vitamin B6) or vitamin B6 preparations reverse the effect of levodopa However, when carbidopa is used with levodopa, pyridoxine has no effect on the action of levodopa hi fact, when levodopa and carbidopa are given together, pyridoxine may be prescribed to decrease the adverse effects associated with levodopa... 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone fComtan). They are used in combination with levodopa-carbidopa. In patients with motor fluctuations, they increase the on time. Adverse effects are similar to those observed with levodopa-carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver enzymes for signs of hepatic changes. 

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. 

Adverse effects Diarrhea is the most common side effect of tolcapone. As expected, /evocfopa-related adverse effects increase when tolcapone is added. These include postural hypotension, nausea, sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Baseline and frequent, regular determinations of hepatic serum enzymes are suggested by the manufacturer. Any elevations above normal are cause for discontinuation. Because of the hepatotoxicity, tolcapone should only be used as an adjunct in patients on levodopa/carbidopa who are experiencing symptom fluctuations. 

Minimisation of unwanted effects. Combining levodopa with benserazide (Madopar) or with carbidopa (Sinemet) slows its metabolism outside the central nervous system so that smaller amounts of levodopa can be used this reduces adverse effects. 

In a double-blind, placebo-controlled, crossover study, 10 patients with probable progressive supranuclear palsy took single oral doses of zolpidem (5 and 10 mg), co-careldopa (levodopa 250 mg plus carbidopa 25 mg), or placebo in four separate trials in random order (10). Zolpidem, unlike levodopa or placebo, reduced voluntary saccadic eye movements, and the 5 mg dose produced a statistically significant improvement in motor function. The adverse effects of zolpidem included drowsiness and... 

Parkinson s disease is caused by the oxidative stress-induced loss of dopaminergic neurons and can be effectively treated with levo-dopa in combination with dopa decarboxylase inhibitors such as carbidopa or catechoi-0-methyltransferase inhibitors such as tolca-pone. Levodopa is well known to increase the life spans of patients with Parkinson s disease. It may do this by enhancing brain dopamine levels and inhibiting tyrosine hydroxylase, which produces oxygen radicals. Several dopamine receptor agonists are available for use in Parkinson s disease and are extensively used in patients suffering from the adverse effects of levodopa. Anticholinergics such as trihexyphenidyl are also used in Parkinson s disease. 

Two COMT inhibitors are available for this use, tolcapone (tasmar) and entacapone (comtan). Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. The duration of action of entacapone is short, around 2 hours, so it usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those observed in patients treated with levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An adverse effect associated with tolcapone is hepatotoxicity tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring of hepatic transaminases. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo). 

Levodopa can pass the blood-brain barrier (unlike dopamine), where it is converted into dopamine, and thus acts by topping up the CNS dopaminergic system. Levodopa is most usually given with carbidopa or benser-azide (dopa-decarboxylase inhibitors), which prevent the wasteful peripheral metabolism of levodopa. This allows lower doses of levodopa to be given, which results in fewer adverse effects. 

Donepezil 5 mg daily for 15 days eaused a modest 30% increase in the AUCq oflevodopa in a placebo-controlled study in 23 patients with Parkinson s disease taking levodopa/carbidopa. There was no change in car-bidopa pharmacokinetics, and the pharmacokinetics of donepezil did not differ between the patients with Parkinson s disease and a control group of healthy subjects. There was no obvious difference in adverse effects between patients with Parkinson s disease and the control subjects, and no evidence that donepezil significantly altered motor activity in those treat-... 

Entacapone and tolcapone have been shown to increase the AUC and prolong the elimination half-life of levodopa (as levodopa/benser-azide or levodopa/carbidopa) without altering the maximum levodopa level. COMT inhibitors can therefore improve the clinical condition of patients with Parkinson s disease, which is mainly seen as a decrease in off time. However, as levodopa levels are raised, there may be an accompanying increase in the adverse effects oflevodopa (e.g. dyskinesias, nausea, vomiting, orthostatic hypotension, hallucinations). " ... 

Carbidopa and benserazide, two agents which are potent aromatic amino acid decarboxylase inhibitors in vitvo and in vivo, have been extensively studied in patients and have been found effective in lowering the clinically required levodopa dose and are neeuring approval for broad availability. They do not enter the brain and thus selectively decrease the peripheral destruction of levodopa, decreasing exposure to some of the adverse effects of dopamine, and proportionately enhance the levodopa-induced dopamine increase in the brain, especially in the extrapyramidal centers >... 

CNS effects Certain adverse CNS effects (eg, dyskinesias) will occur at lower dosages and sooner during therapy with levodopa and carbidopa than with levodopa alone. 

The manufacturer of rotigotine reports that levodopa and carbidopa had no effect on the pharmacokinetics of rotigotine and similarly, rotigotine had no effect on tiie pharmacokinetics of either levodopa or carbidopa. However, as with other dopamine agonists, rotigotine may cause and/or exacerbate dyskinesia in patients taking levodopa and may potentiate the dopaminergic adverse reactions of levodopa. ... 

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