Levodopa and dopa decarboxylase inhibitors

Figure 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Carbidopa, a dopa-decarboxylase inhibitor, is added to the levodopa in order to decrease the peripheral conversion of levodopa to dopamine. It does not cross the blood-brain barrier and does not interfere with levodopa conversion in the brain. Concomitant administration of carbidopa and levodopa allows for lower levodopa doses and minimizes levodopa peripheral side effects such as nausea, vomiting, anorexia, and hypotension. For most patients, at least 75 to 100 mg daily of carbidopa is required to adequately block dopamine decarboxylase in the peripheral metabolism of levodopa in most patients. Taking extra carbidopa may reduce nausea related to initiating levodopa.8,16... 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

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. 

Geriatric Considerations - Summary Levodopa is a percursor to dopamine and is converted to dopamine in the CNS. Clinical effectiveness is increased by taking in combination with carbidopa, a dopa decarboxylase inhibitor. This combination is often the initial treatment for Parkinson s disease. 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Levodopa and peripheral dopa-decarboxylase inhibitor, carbidopa or benserazide in the treatment of parkinsonism. 

There is a tendency to potassinm loss and hypokalemia. Some patients are particnlarly snsceptible to this adverse effect. In three patients with hypokalemia and five with-ont, levodopa cansed increased excretion of potassinm, and sometimes also of sodinm, in the hypokalemic bnt not in the normokalemic patients this effect was prevented by the administration of a peripheral dopa decarboxylase inhibitor (46). 

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. 

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. 

Antimuscarinics are commonly given with levodopa, and they are of established benefit. However, limited evidence suggests they might sometimes reduce levodopa efficacy. Levodopa preparations are now more usually given in conjunction with a dopa decarboxylase inhibitor to minimise metabolism in the gastric mucosa. This would be expected to minimise the effects of any interaction. However, note that one of the above studies included a dopa-decarboxylase inhibitor, yet still found an effect on levodopa absorption. There is certainly no need to avoid concurrent use, but it would be prudent to be alert for any evidence of a reduced levodopa response if antimuscarinics are added, or for levodopa toxicity if they are withdrawn. 

Twelve patients with parkinsonism on levodopa plus a dopa-decarboxylase inhibitor were additionally given baclofen. The eventual baclofen dosage was intended to be 90 mg daily, but the adverse effects were considerable (visual hallucinations, a toxic confusional state, headaches, nausea) so that only 2 patients reached this dosage, and 2 patients withdrew because they could not tolerate these adverse effects. The mean dosage for those who continued was 45 mg daily. Rigidity was aggravated by an average of 46% and functional capacity deteriorated by 21%. ... 

A 66-year-old man with idiopathic Parkinson s disease and AIDS was free of dyskinesias when taking levodopa with a dopa-decarboxylase inhibitor, although he had unpredictable fluctuations. After 1 month of starting indinavir 2400 mg daily, lamivudine and zidovudine, he developed severe peak-dose dyskinesias, and the on periods lasted all day, with no ftuctu-... 

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