CHAPTER 2-3: AMANTADINE

INTRODUCTION

Amantadine (Symmetrel) is an antiviral agent whose dopaminergic properties make it effective in the treatment of Parkinson's disease and for prophylaxis against the parkinsonian side effects of neuroleptic agents. Although amantadine is no longer recommended for the treatment or prophylaxis of influenza because of resistance, it has been studied as a potential treatment for hepatitis C, Huntington's disease, brain injury or encephalopathy, and cocaine dependence. Its effects in acute overdose have been associated with seizures, arrhythmias, and death. Withdrawal from amantadine has also been linked to neuroleptic malignant syndrome.

MECHANISM OF TOXICITY

1. Amantadine is thought to increase dopamine levels in the peripheral and central nervous systems by enhancing the release of dopamine and preventing dopamine reuptake. It also acts as a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. It blocks potassium and sodium channels in cardiac myocytes, leading to QT prolongation and widened QRS intervals. In addition, it has anticholinergic properties, especially in overdose.

2. Pharmacokinetics. Peak absorption 1–4 hours; volume of distribution (Vd) 4–8 L/kg. Eliminated renally with a half-life of 7–37 hours (see also Table II–66).

TOXIC DOSE

The toxic dose has not been determined. Because the elimination of amantadine depends almost entirely on kidney function, patients with renal insufficiency may develop intoxication with therapeutic doses. Ingestion of an estimated 800–1,500 mg caused status epilepticus in a 2-year-old child.

CLINICAL PRESENTATION

1. Amantadine intoxication causes agitation, visual hallucinations, nightmares, disorientation, delirium, slurred speech, ataxia, myoclonus, tremor, and sometimes seizures. Anticholinergic manifestations include dry mouth, urinary retention, and mydriasis. Obstructive acute renal failure due to urinary retention has also been reported. Interval changes on the ECG, such as QT prolongation and QRS widening, may be seen. Ventricular arrhythmias, including torsade de pointes (Ventricular dysrhythmias) and premature ventricular contractions, may occur. Amantadine has also been reported to cause heart failure and acute respiratory distress syndrome (ARDS).

2. Amantadine withdrawal, either after standard therapeutic use or in the days after an acute overdose, may result in hyperthermia and rigidity (similar to neuroleptic malignant syndrome).

DIAGNOSIS

Is based on a history of acute ingestion or is made by noting the aforementioned constellation of symptoms and signs in a patient taking amantadine.

1. Specific levels are not readily available. When available, serum amantadine levels above 1.5 mg/L have been associated with toxicity.

2. Other useful laboratory studies include electrolytes, BUN, creatinine, creatine kinase (CK), and ECG.

TREATMENT

1. Emergency and supportive measures

   1. Maintain an open airway and assist ventilation if necessary.

   2. Treat coma, seizures, arrhythmias, and hyperthermia if they occur.

   3. Monitor an asymptomatic patient for at least 8–12 hours after acute ingestion.

2. Specific drugs and antidotes. There is no known antidote. Although some of the manifestations of toxicity are ...