Levodopa adverse effects

It is an ergot preparation which has a specific dopamine receptor agonist action (acts mainly on receptors) and capable of crossing the blood brain barrier. It is less active than levodopa and used only in late cases as a supplement to levodopa. Adverse effects are vomiting hallucinations, hypotension, nasal stuffiness. 

A patient (who was very sensitive to levodopa) found that he was only able to prevent the involuntary movements of his tongue, jaw, neck and limbs caused by levodopa, by taking frequent small doses (125 mg) of levodopa. He was able to suppress the levodopa adverse effects with phenylbutazone. However, the phenylbutazone also lessened the therapeutic effect of the levodopa. The reason is not understood. This interaction has not been confirmed, and its general importance is not known. 

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... 

Dopamine receptor agonists. Deficient dopaminergic transmission in the striatum can be compensated by ergot derivatives (bromocriptine p. 114], lisu-ride, cabergoline, and pergolide) and nonergot compounds (ropinirole, prami-pexole). These agonists stimulate dopamine receptors (D2, D3, and D sub-types), have lower clinical efficacy than levodopa, and share its main adverse effects. 

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. 

These drugs were developed before levodopa which has largely replaced them, probably because of a lack of modern clinical research. Actually, the adverse effects of anticholinergic drugs (confusion, memory disorders, peripheral anticholinergic effects) and the interindividual variability of their effects considerably limit their use, particularly in subjects over 65 years of age. These compounds are considered to be effective against tremor and are... 

All four exert similar therapeutic effects and can produce the same adverse effects seen with levodopa. The differences between the ergot derivatives and the... 

Amantadine was originally introduced as an antiviral compound (see Chapter 50), but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and A-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning. 

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. 

At least as effective as bromocriptine in the treatment of advanced parkinsonian patients with levodopa-related motor fluctuations adverse effects similar in incidence and severity appears to lack some of the toxicity seen with bromocriptine, pergolide, and cabergoline (e.g., pleuropulmonary disease) may be a useful alternative in patients with intolerable adverse effects due to ergot derivatives... 

Adverse effects are postural hypotension, nausea, confusion, increased levodopa induced involuntary movements and confusion. 

The treatment of Parkinson s disease is often an exercise in polypharmacy, since no single agent is fully effective over the course of the disease. Most antimuscarinic drugs promoted for this application (see Table 28-1) were developed before levodopa became available. Their use is accompanied by all of the adverse effects described below, but the drugs remain useful as adjunctive therapy in some patients. 

The best results of levodopa treatment are obtained in the first few years of treatment. This is sometimes because the daily dose of levodopa must be reduced over time to avoid adverse effects at doses that were well tolerated initially. 

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 brain stem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease. 

A drug holiday (discontinuance of the drug for 3-21 days) may temporarily improve responsiveness to levodopa and alleviate some of its adverse effects but is usually of little help in the management of the on-off phenomenon. Furthermore, a drug holiday carries the risks of aspiration pneumonia, venous thrombosis, pulmonary embolism, and depression resulting from the immobility accompanying severe parkinsonism. For these reasons and because of the temporary nature of any benefit, drug holidays are not recommended. 

Neither selegiline nor rasagiline should be taken by patients receiving meperidine. They should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa may be increased by these drugs. 

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated... 

Dicyclomine (Bentyl) [Anrimuscarinic, GI Anrispasmodic/ Anticholinergic] Uses Functional IBS Action Smooth-muscle relaxant Dose Adults. 20 mg PO qid T to 160 mg/d max or 20 mg EM q6h, 80 mg/d - qid then T to 160 mg/d, max 2 wk Feds. Infants >6 mo 5mg/dose tid-qid Children 10 mg/dose tid-qid Caution [B, -] Contra Infants <6 mo, NAG, MyG, severe UC, BOO Disp Caps, tabs, syrup, inj SE Anticholinergic SEs may limit dose Interactions T Anticholinergic effects W/ anticholinergics, antihistamines, amantadine, MAOIs, TCAs, phenothiazides T effects OF atenolol, digoxin X effects H7 antacids X effects OF haloperidol, ketoconazole, levodopa, phenothiazines EMS Avoid procainamide usage, may T adverse effects may T effects of digoxin, monitor... 

Disruption of diurnal cortisol rhythm has been detected and could explain some of the sleep disturbances and psychic adverse effects that levodopa can have (SEDA-8, 143). 

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