levodopa
Dopar, Larodopa

Available forms
Available by prescription only
Capsules: 100 mg, 250 mg, 500 mg
Tablets: 100 mg, 250 mg, 500 mg

Indications and dosages
 Parkinsonism. Adults: Initially, 0.5 to 1 g P.O. daily, given b.i.d., t.i.d., or q.i.d. with food; increase 100 to 750 mg daily q 3 to 7 days, as tolerated. The usual optimal dosage is 3 to 6 g daily divided into three or more doses. Maximum recommended dose is 8 g daily; some patients may require more. A significant therapeutic response may not be obtained for 6 months. Larger doses require close supervision.

Pharmacodynamics
Antiparkinsonian action: Precise mechanism hasn’t been established. A small percentage of each dose crossing the blood-brain barrier is decarboxylated. The dopamine then stimulates dopaminergic receptors in the basal ganglia to enhance the balance between cholinergic and dopaminergic activity, resulting in improved modulation of voluntary nerve impulses transmitted to the motor cortex.

Pharmacokinetics
Absorption: Absorbed rapidly from the small intestine by an active amino acid transport system, with 30% to 50% reaching general circulation.
Distribution: Distributed widely to most body tissues, but not to the CNS, which receives less than 1% of dose because of extensive metabolism in the periphery.
Metabolism: 95% is converted to dopamine by l-aromatic amino acid decarboxylase enzyme in the lumen of the stomach and intestines and on the first pass through the liver.
Excretion: Excreted primarily in urine; 80% of dose is excreted within 24 hours as dopamine metabolites. Half-life is 1 to 3 hours.

Contraindications and precautions
Contraindicated in patients who have used MAO inhibitors within 14 days; in patients hypersensitive to drug; and in patients with acute angle-closure glaucoma, melanoma, or undiagnosed skin lesions.
  Use cautiously in patients with severe renal, CV, hepatic, and pulmonary disorders; peptic ulcer; psychiatric illness; MI with residual arrhythmias; bronchial asthma; emphysema; and endocrine disorders.

Interactions
Drug-drug. Amantadine, benztropine, procyclidine, trihexyphenidyl: May increase efficacy of levodopa. May be used for therapeutic benefit.
Anesthetics, hydrocarbon inhalation: May cause arrhythmias because of increased endogenous dopamine concentration. Stop levodopa 6 to 8 hours before giving anesthetics such as halothane.
Antacids that contain calcium, magnesium, or sodium bicarbonate: May increase levodopa absorption. Give antacids 1 hour after levodopa.
Anticholinergics: May produce mild synergy and increased efficacy. Gradually reduce anticholinergic dosage.
Anticonvulsants (such as hydantoins, phenytoin), benzodiazepines, haloperidol, papaverine, phenothiazines, rauwolfia alkaloids, thioxanthenes: May decrease therapeutic effects of levodopa. Monitor patient for decreased effectiveness.
Antihypertensives: Increases hypotensive effect. Monitor blood pressure.
Bromocriptine: May produce additive effects. Reduce levodopa dosage if necessary.
MAO inhibitors: May cause hypertensive crisis. Discontinue MAO inhibitors for 2 to 4 weeks before starting levodopa.
Methyldopa: May alter antiparkinsonian effect of levodopa and produce additive toxic CNS effects. Avoid use together.
Pyridoxine: A small dose (10 mg) reverses antiparkinsonian effect of levodopa. Don’t give together.
Sympathomimetics: May increase risk of arrhythmias. Dosage reduction of sympathomimetic is recommended; administration of carbidopa with levodopa reduces the tendency of sympathomimetics to cause dopamine-induced arrhythmias. Reduce levodopa dosage.
Tricyclic antidepressants: May increase sympathetic activity, with sinus tachycardia and hypertension. Avoid use together if possible.
Drug-herb. Jimsonweed: May adversely affect CV function. Discourage use together.
Kava: May increase parkinsonian symptoms. Discourage use together.
Rauwolfia: May decrease effectiveness of levodopa. Discourage use together.

Adverse reactions
CNS: aggressive behavior; choreiform, dystonic, and dyskinetic movements; involuntary grimacing; head movements, myoclonic body jerks; seizures; neuroleptic malignant syndrome; ataxia; tremor; muscle twitching; bradykinetic episodes; psychiatric disturbances; mood changes; nervousness; anxiety; disturbing dreams; euphoria; malaise; fatigue; severe depression; suicidal tendencies; dementia; delirium; hallucinations.
CV: orthostatic hypotension, cardiac irregularities, phlebitis.
EENT: blepharospasm, blurred vision, diplopia, mydriasis or miosis, activation of latent Horner’s syndrome, oculogyric crises, excessive salivation.
GI: dry mouth, bitter taste, nausea, vomiting, anorexia, constipation, flatulence, diarrhea, abdominal pain.
GU: urinary frequency, urine retention, incontinence, darkened urine, priapism.
Hematologic: hemolytic anemia, leukopenia, agranulocytosis.
Hepatic: hepatotoxicity.
Metabolic: weight loss.
Respiratory: hyperventilation, hiccups.
Skin: dark perspiration.

Effects on lab test results
• May increase BUN, ALT, AST, alkaline phosphatase, LDH, and bilirubin levels.
• May decrease hemoglobin and WBC and granulocyte counts.

Overdose and treatment
Signs and symptoms of overdose include spasm or closing of eyelids, irregular heartbeat, and palpitations.
 Treatment includes immediate gastric lavage, maintenance of an adequate airway, and judicious administration of I.V. fluids and may include antiarrhythmics, if needed. Pyridoxine 10 to 25 mg P.O. has been reported to reverse toxic and therapeutic effects of levodopa. (Its usefulness hasn’t been established in acute overdose.)

Special considerations
• Levodopa is indicated in treating idiopathic, postencephalitic, arteriosclerotic parkinsonism, and symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide intoxication and manganese intoxication.
• Give drug between meals and with low-protein snack to maximize drug absorption and minimize GI upset. Foods high in protein appear to interfere with transport of drug.
• Tablets and capsules may be crushed and mixed with applesauce or pureed fruit for patients who have difficulty swallowing pills.
• Maximum effectiveness of drug may not occur for several weeks or months.
• Monitor patient for muscle twitching and blepharospasm (twitching of eyelids), which may be an early sign of drug overdose.
• Test patients on long-term therapy regularly for diabetes and acromegaly; check blood tests and liver and kidney function studies periodically for adverse effects. Leukopenia may require cessation of therapy.
• Monitor serum laboratory tests periodically. Coombs’ test occasionally becomes positive during extended use. Expect uric acid elevation with colorimetric method but not with uricase method.
• Alkaline phosphatase, AST, ALT, LDH, bilirubin, BUN, and protein-bound iodine levels show transient elevations in patients receiving levodopa; WBC count, hemoglobin level, and hematocrit show occasional reduction.
• Because of risk of precipitating a symptom complex resembling neuroleptic malignant syndrome, observe patient closely if levodopa dosage is reduced abruptly or discontinued.
• If restarting therapy after a long period of interruption, adjust drug dosage gradually to previous level.
• Patients undergoing surgery should continue levodopa as long as oral intake is permitted, usually 6 to 24 hours before surgery. Resume drug as soon as patient is able to take oral medication.
• Although controversial, a medically supervised period of drug discontinuance may reestablish the effectiveness of a lower dose regimen.
• Combination of levodopa-carbidopa usually reduces amount of levodopa needed, thus reducing risk of adverse reactions.
• Levodopa also has been used to relieve pain of herpes zoster, to manage bone pain in metastatic disease, and to manage hepatic coma.
• Protect drug from heat, light, and moisture. If preparation darkens, it has lost potency and should be discarded.
• Coombs’ test occasionally becomes positive during extended therapy. Colorimetric test for uric acid has shown false elevations. False-positive results have been noted on tests for urine glucose using the copper-reduction method; false-negative results have occurred with the glucose oxidase method. Levodopa also may interfere with tests for urine ketones, urine norepinephrine, and urine protein determinations.
Breast-feeding patients
• Drug may inhibit lactation and shouldn’t be used by breast-feeding women.
Pediatric patients
• Safety of levodopa in children younger than age 12 hasn’t been established.
Geriatric patients
• Smaller doses may be required because of reduced tolerance to effects of drug. Geriatric patients, especially those with osteoporosis, should resume normal activity gradually, because increased mobility may increase risk of fractures. Geriatric patients are more likely to develop adverse effects, such as anxiety, confusion, or nervousness; those with heart disease are more susceptible to cardiac effects of levodopa.

Patient education
• Warn patient and family not to increase drug dose without specific instruction. (They may be tempted to do this as parkinsonian symptoms progress.)
• Explain that therapeutic response may not occur for up to 6 months.
• Advise patient and family that multivitamin preparations, fortified cereals, and certain OTC products may contain pyridoxine (vitamin B₆), which can reverse the effects of levodopa.
• Warn patient of possible dizziness and orthostatic hypotension, especially at start of therapy. Tell patient to change position slowly and dangle legs before getting out of bed. Instruct patient in use of elastic stockings to control this adverse reaction if appropriate.
• Inform patient of signs and symptoms of adverse reactions and therapeutic effects; instruct him to report changes.
• Tell patient to take a missed dose as soon as possible; skip dose if next scheduled dose is within 2 hours, but don’t double the dose.
• Advise patient not to take drug with food, and that eating about 15 minutes after administration may help reduce GI upset.
• Warn patient of possible darkening of urine, sweat, and other body fluids.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use