Primidon (Mysoline)

Clinical Effects:

BARBITURATES-LONG ACTING
  • USES: Sedative hypnotics are used for sedation and the treatment of epilepsy, including status epilepticus (phenobarbital). Long acting barbiturates include mephobarbital, primidone, and phenobarbital. PHARMACOLOGY: Barbiturates cause depression of neuronal activity via alternation of gamma-aminobutyric acid (GABA) mediated chlorine currents. Specifically, barbiturates increase the duration of opening of the ligand gated chloride channel. TOXICOLOGY: Toxicology is the extension of the pharmacology. Central nervous system depression due to enhanced GABA activity is the primary effect, and may be accompanied by hypotension secondary to direct myocardial depression. CNS and respiratory depression may be exacerbated by co-ingestion of other sedatives. EPIDEMIOLOGY: Poisoning is uncommon; however, toxicity may be severe and may occur via oral or parenteral routes. MILD TO MODERATE TOXICITY: Somnolence, slurred speech, nystagmus, confusion, and ataxia may occur. SEVERE TOXICITY: Severe effects may include coma, hypotension, decreased myocardial contractility, hypothermia and respiratory failure. Blisters may occur secondary to prolonged immobilization from coma. Patients may have small to midpoint pupils and have very diminished reflexes. Death is most commonly caused by respiratory depression and cardiovascular collapse. Patients that present after prolonged coma are at risk for aspiration pneumonia, rhabdomyolysis, and renal failure. ADVERSE EFFECTS: Mild sedation, dizziness, and impaired coordination develop in some patients.

Range of Toxicity:

BARBITURATES-LONG ACTING
  • TOXICITY: The toxic dose varies depending on route and speed of administration as well as patient tolerance. Ingestion of 8 mg/kg phenobarbital generally causes some CNS depression in non-tolerant individuals. THERAPEUTIC DOSE: PHENOBARBITAL: ADULT: (Oral) 30 to 200 mg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. CHILDREN: (Oral) 5 to 8 mg/kg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. PRIMIDONE: ADULT: 500 mg/day divided. CHILDREN: less than 8-years-old, 10 to 25 mg/kg/day divided; more than 8-years-old, 750 to 1500 mg/day divided.

Treatment:

BARBITURATES-LONG ACTING
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Activated charcoal may be given if patients present shortly after ingestion, and are awake and alert with a protected airway. MANAGEMENT OF SEVERE TOXICITY: Orotracheal intubation for airway protection should be performed if patient is increasingly drowsy or comatose. Administer activated charcoal (GI decontamination should be performed only in patients who can protect their airway or who are intubated). Severe hypotension and hypothermia may develop; aggressive supportive care is the mainstay of treatment including passive rewarming, administration of normal saline, and in severe cases vasopressors. Clinical manifestations may be prolonged due to long half-life of drug. Tetanus and routine wound care for blisters. A burn surgeon should be consulted for extensive skin blistering.
  • Decontamination: PREHOSPITAL: Not recommended because of potential for somnolence and loss of airway protection. HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway, or if intubated.
  • Airway management: Perform early in patients with severe intoxication (i.e., coma, respiratory depression, hypotension).
  • Antidote: None
  • Hypotensive episode: Secure intravenous access. Initiate treatment with intravenous fluids. Initiate vasopressors and titrate to a mean arterial pressure of at least 60 mmHg. Insert a bladder catheter and monitor urine output.
  • Coma: Treat symptomatically and supportively. Perform orotracheal intubation to protect airway.
  • Hypothermia: Monitor core temperature with rectal or bladder probe. Initiate external rewarming with warm blankets, IV fluids, and warm humidified oxygen until temperature is greater than 32.2 degrees C. For severe hypothermia, provide gastric or peritoneal lavage with warm fluids, consider warm fluids via chest tubes, and for very severe cases associated with cardiac arrest, perform rewarming with cardiopulmonary bypass.
  • Bradycardia: Place on cardiac monitor. Correct hypothermia, if present, prior to initiating other treatment for bradycardia. Do not treat sinus bradycardia unless patient is symptomatic/hypotensive. Follow ACLS protocol including use of atropine, and, if necessary, epinephrine.
  • Monitoring of patient: Monitor vital signs, and mental status. Routine monitoring of electrolytes, renal function, glucose, pulse oximetry and blood gases may be helpful. Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Phenobarbital may be detected on urine immunoassays. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity. Monitor creatinine phosphokinase in patients with prolonged immobilization from coma; monitor renal function and urine output in patients with rhabdomyolysis. Monitor urine output and pH in patients treated with alkalinization. Other causes of coma and hypotension should be ruled out.
  • Enhanced elimination procedure: Urinary alkalinization can enhance the elimination of phenobarbital. Administer 1 to 2 mEq/kg (2 to 3 ampules in an adult) of bicarbonate IV initially followed by an infusion of 3 ampules of sodium bicarbonate mixed in 1 liter of D5W given at 1.5 to 2 times maintenance fluid rates. Goal urine pH is 7.5 to 8. Do not allow serum pH to exceed 7.55. Follow urine pH, serum pH and serum potassium carefully. Add potassium chloride to IV bicarbonate if the serum potassium is low. Repeat dose activated charcoal decreases the half life of phenobarbital but has not been shown to improve outcome; it should not be administered routinely. Charcoal 0.25 to 0.5 g/kg given every 2 to 4 hours (multiple dose charcoal should NOT be administered to any patient with ileus as it may cause bowel obstruction or infarction). End points include decreasing serum drug level and clinical improvement, this usually takes 24 hours. Hemodialysis or hemoperfusion should be performed in patients who have hemodynamic instability not responding to symptomatic supportive care. In addition, hemodialysis or hemoperfusion should be considered in symptomatic patients who are in renal failure or cannot tolerate a fluid load, such as patients with congestive heart failure.
  • Patient disposition: HOME CRITERIA: Phenobarbital doses as low as 8 mg/kg may produce toxicity in non-tolerant patients. Therefore, any child that ingests a phenobarbital dose of 8 mg/kg or greater should be evaluated by a healthcare professional. OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 6 to 8 hours. Anyone that ingests 8 mg/kg or greater of phenobarbital and is non-tolerant should be observed. Patients who do not develop more than mild drowsiness and have phenobarbital concentrations that have peaked and are clearly declining may be discharged following psychiatric evaluation. ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (i.e., CNS depression, confusion or ataxia), or rising phenobarbital concentrations should be admitted. Patients with coma, hypotension, respiratory depression, or hypothermia should be admitted to an intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., coma, respiratory depression, hypotension, or hypothermia), or in whom the diagnosis is not clear. Consult a nephrologist for hemodialysis in patients with severe poisoning not responding to supportive care.
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