Levodopa – Karbidopa

Levodopa is an indirect central dopamine agonist due to its central conversion to dopamine. Levodopa is used in combination with carbidopa, which is a decarboxylase inhibitor that prevents peripheral destruction of levodopa. These drugs are most often used in the symptomatic treatment of Parkinson’s disease.

Clinical Effects:

0.2.1) SUMMARY OF EXPOSURE

A) USES: Levodopa and carbidopa combination is used to treat symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.
B) PHARMACOLOGY: Levodopa, the metabolic precursor of dopamine, has the capacity to cross the blood brain barrier thus providing dopamine to the corpus striatum. Carbidopa is an inhibitor of aromatic acid decarboxylation which prevents the rapid decarboxylation of levodopa in extracerebral tissues making more levodopa available for transport to the brain.
C) TOXICOLOGY: Cardiovascular and CNS effects are probably due to levodopa’s immediate metabolite dopamine. This compound at low serum levels causes hypotension and tachycardia due to stimulation of the dopaminergic and beta receptors. At higher levels alpha receptor stimulation overrides and hypertension is the result. Dysrhythmias may occur due to stimulation of beta receptors in the heart. CNS effects due to excessive dopamine may be expected to include dyskinesias.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE

1) COMMON: Nausea, dyskinesia (eg, choreiform, dystonia, facial tics, grimacing, head bobbing, torticollis, and choreoathetosis). OTHER EFFECTS: Anorexia, vomiting, somnolence, agitation, diaphoresis, insomnia, anxiety, confusion, postural hypotension, dizziness, hypertension, rash, delirium, hallucinations, psychosis, respiratory dyskinesias, and Henoch-Schonlein purpura. A constellation of symptoms resembling neuroleptic malignant syndrome has been described following withdrawal of levodopa/carbidopa. Symptoms reported include fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, mental status changes, autonomic dysfunction, tachycardia, tachypnea, sweating, and hyper- or hypotension.

F) WITH POISONING/EXPOSURE

1) The most common signs/symptoms seen following acute overdose include confusion, agitation, diaphoresis, insomnia, anxiety, and excessive motor activity. Other effects reported after acute overdose have included nausea, vomiting, sinus tachycardia, postural hypotension, restlessness, hypertension, dyskinesias, confusion, delirium, hallucinations, psychosis, xerostomia, urinary retention, mydriasis, increased CK, myoglobinuria, rhabdomyolysis, and respiratory dyskinesias.

0.2.3) VITAL SIGNS

A) WITH THERAPEUTIC USE

1) Malignant hyperthermia has occurred following withdrawal of therapy.

0.2.21) CARCINOGENICITY

A) Preliminary data from a randomized controlled trial have shown an increased incidence of prostate cancer with the combination of carbidopa/levodopa/entacapone compared with carbidopa/levodopa in male Parkinson’s disease patients. The data review is ongoing and recommendations on drug use have not been made.
Range of Toxicity:
A) TOXICOLOGY: Ingestions of 15 to 100 grams in adults have not been associated with severe toxicity; however, a woman died after ingesting up to 11 grams of levodopa.
B) THERAPEUTIC DOSES: IMMEDIATE RELEASE TABLETS: Initial, 1 carbidopa/levodopa combination tablet (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg) orally 3 to 4 times daily; titrated up to 8 tablets daily. SUSTAINED RELEASE TABLETS: Initial, 1 carbidopa/levodopa combination tablet (50 mg/200 mg) orally twice daily; titrated to 400 to 1600 mg of levodopa daily.
Treatment:
0.4.2) ORAL/PARENTERAL EXPOSURE

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Control agitation and confusion with benzodiazepines.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat dystonias and dyskinetic movements with diazepam, diphenhydramine, or benztropine. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. Treat neuroleptic malignant syndrome with benzodiazepines, bromocriptine, consider dantrolene, as well as cooling and supportive measures.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended.
2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe toxicity (eg, excessive drowsiness, severe delirium, or hyperthermia).

E) ANTIDOTE

1) None.

F) DYSTONIA

1) Dystonias may respond to diazepam, diphenhydramine or benztropine. ADULT: Benztropine is dosed at 1 to 4 mg IV or IM, maximum 6 mg/day. Diphenhydramine is dosed at 25 to 50 mg IV over 2 minutes. PEDIATRIC: Diphenhydramine: 1.25 mg/kg/dose IV over 2 minutes.

G) HYPERTENSIVE EPISODE

1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.

H) HYPOTENSIVE EPISODE

1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.

I) PSYCHOMOTOR AGITATION

1) Sedate with benzodiazepines as needed; large doses may be required. Provide a quiet environment.

J) NEUROLEPTIC MALIGNANT SYNDROME

1) Oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider IV dantrolene in severe cases.

K) RHABDOMYOLYSIS

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.

L) ENHANCED ELIMINATION PROCEDURES

1) No data are currently available, however, due to the large volume of distribution of levodopa and rapid metabolism, it is doubtful that significant amounts would be removed by dialysis.

M) PATIENT DISPOSITION

1) HOME CRITERIA: Patients who are asymptomatic after inadvertent ingestion can be managed at home.
2) OBSERVATION CRITERIA: Symptomatic patients and those with deliberate ingestions should be sent to a medical facility for evaluation and treatment. Peak concentrations of sustained-release formulation is reached 2 hours after ingestion as compared with 0.5 hours after an immediate-release formulation. Patients that have ingested a sustained-release product have the potential to manifest symptoms in a delayed/prolonged fashion and should be observed for 4 to 8 hours.
3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

N) PITFALLS

1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.

O) PHARMACOKINETICS

1) Bioavailability: immediate release: 80% to 90%; sustained release: 70% to 75%. Tmax: Immediate-release: mean, 0.5 hours. Tmax: Sustained-release tablets: mean, 2 hours. Protein binding: not bound to plasma proteins. Vd: 0.6 L/kg (elderly subjects). Metabolism: Levodopa is metabolized by decarboxylation (via levodopa decarboxylase) to dopamine in the gut, liver, and kidney and by o-methylation, transamination, and oxidation. Excretion: 70% to 80% of levodopa is excreted in the urine in the form of metabolites, within 24 hours. Elimination half-life: 1.5 hours; metabolite 3-O-methyldopa: 15 hours.

P) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that may cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), hypertension (eg, amphetamine), dystonia or dyskinesias (eg, antipsychotics, neuroleptics), or neuroleptic malignant syndrome (eg, antipsychotics, neuroleptics).
Monitoring:
A) No specific laboratory tests are necessary unless otherwise clinically indicated.
B) Monitor vital signs and mental status following significant overdose.
C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
E) Serum concentrations are not widely available or clinically useful in managing overdose.