Anticonvulsant Toxicity

 Mechanism of toxicity
o Main channel activity: GABA-mediated chloride channels
 Binds to barbiturate receptor on GABA-mediated chloride channels
 Increases amount of time that chloride channels remain open
• More chloride ions pass through channel
• Hyperpolarizes cell membrane to increase the refractory period
• Increases the threshold for action potential
Depresses central sympathetic tone and cardiac contractility

Can be fatal;
o CNS: lethargy, nystagmus, slurred speech, coma (>150 mcg/mL), hypothermia
o Respiratory: respiratory depression, hypoventilation, pulmonary edema
o Cardiovascular: hypotension (60-80 mcg/mL), bradycardia
o Hepatic failure
o Renal failure
o Assess ABC since it can affect all of them

o Serum phenobarbital concentration: repeat until downward trend
o Vital signs + EKG
o Urinalysis: urine pH
o CMP: renal function
o Hepatic work-up: transaminases, coagulation panel

o ABCs
o GI decontamination: activated charcoal

o Treatment of choice: enhance elimination
 Urinary alkalinization
 Hemodialysis
 Multi-dose activated charcoal (MDAC)

 Works if a drug undergoes entero-enteric or entero-hepatic recirculation

 Mechanism of action
• Forms a negative concentration gradient (interrupts recirculation)
• Pulls drug from serum into the gut lumen where it adsorbs to charcoal

 Contraindications
• Unprotected airway
• Known intestinal obstruction
• GI tract is not anatomically intact

• Prior to EVERY dose
o Verify presence of normal bowel sounds
 Do not administer if bowel sounds are hypoactive or absent
o Evaluate for aspiration risks
 Aspirated activated charcoal has been fatal
• When to discontinue MDAC
o Obtain serial serum phenobarbital levels (every 2-6 hours)
o Endpoint: reversal of life-threatening CNS, respiratory and/or CV symptoms

 Reserved for severe toxicity when unable to tolerate other methods
 Severe toxicity is defined as
• Renal or hepatic failure
• Pulmonary edema
• Coma
• Serum phenobarbital >100 mcg/mL

o Neurological
 Associated with both oral and parenteral formulations
 Mechanism is related to the drug
• Extension of its pharmacotherapy
• Increases refractory period of voltage-gated channels
o Suppresses high-frequency neuronal firing → CNS depression

o Cardiovascular and dermal
 Associated with parenteral formulation
 Mechanism is related to diluent
• Diluent = propylene glycol 40% + ethanol 10% + sodium hydroxide
• Cardiovascular: decreased peripheral vascular resistance + myocardial contractility (sodium, potassium and calcium channel blockade)
• Dermal: alkalinity leads to dermal necrosis (pH 12)

o It’s all about timing: over how long did the ingestion occur?
 Acute: ingestion occurs over <8 hours (e.g. swallow an entire bottle in a suicide attempt)
 Chronic: regularly taking the medication (e.g. incidental finding of supratherapeutic level)

 Serum phenytoin
• Free or total
• Initially obtain every 1-2 hours
• Once stable: daily
 CBC, BMP
 Albumin
 Vital signs
 Neurologic exam
 EKG

 ABCs
 GI decontamination: activated charcoal
 Treatment of choice: enhanced elimination = MDAC
• Rising or persistently elevated serial serum concentrations
• Remember contraindications and precautions!
 Cardiotoxicity (IV only)
• Typically resolves on its own within 30-60 mins
• If it does not resolve: stop the infusion + IV Fluid Bolus

o CNS depressant
 Inhibits GABA transaminase → increasing levels of GABA
 Prolongs recovery of inactivated sodium channels
o Alters metabolism of free fatty acids
 Impairs mitochondrial beta-oxidation
 Disrupts urea cycle

leads to encephalopathy
 Normally: glutamine synthetase converts ammonia + glutamate → glutamine
 Amount of ammonia overcomes ability of glutamine synthetase
• Ammonia is directly toxic to the brain tissue
• Astrocytes cannot communicate → encephalopathy

 Early
• >200 mg/L: drowsiness, confusion, disorientation, QT prolongation
• >400 mg/L: obtundation, encephalopathy, cerebral edema, hemodynamic instability
• >850 mg/L: Seizures, coma, metabolic acidosis, hypernatremia
 Late
• Late sequelae
o Optic nerve atrophy
o Non-cardiogenic pulmonary edema
o Anuria
o Hemorrhagic pancreatitis
o Pancytopenia (transient)
• Chronic ingestions
o Hepatotoxicity (asymptomatic → fatal hepatitis)
o Microvascular steatosis

 Serum valproic acid
• Repeat until trends downward
• Delayed peak with extended release
 Ammonia
 CMP, CBC
 Calcium
 Hepatic transaminases
 Coagulation panel
 EKG
 Lipase or amylase
 Serum osmolality

 ABCs
 GI decontamination: activated charcoal (if there is no C/I; typically, a good answer)
 Antidote: levocarnitine
 Enhanced elimination
• MDAC: enteric coated or extended-release products
• Hemodialysis
o Hemodynamic or neurologic instability
o Life-threatening hyperammonemia
o [VPA] >900 mg/L
o Cerebral edema

• Mechanism of action
o Restores urea cycle → reduces ammonia production
o Reduced ammonia → reduced encephalopathy
o Indicated if: ingestion of >400 mg/kg or [valproic acid] >450 mg/L
• Symptomatic: Intravenous route/dosing
o Loading dose: 100 mg/kg IV (max 6 g) over 30 mins
o Maintenance dose: 50 mg/kg IV every 8 hours (max 3 g/day)
• Asymptomatic: oral route/dosing
o 100 mg/kg PO divided every 6 hours (max 3 g/day)
• Adverse effects: nausea, vomiting, diarrhea, fishy odor
• Continue until clinical improvement and return to baseline ammonia

o Extension of pharmacology
 Prolongs inactivation of sodium channels
 Alters cerebellar-vestibular brainstem function
o Structural similarity to cyclic antidepressants
 Weak anticholinergic effects
 Cardiac conduction disturbances + seizures

o Neurological
 Confusion, agitation, drowsiness
 Nystagmus
 Ataxia
 Dysarthria
 Cyclic coma
 Seizures
o Cardiovascular
 Tachycardia, hypotension
 QRS widening, QT prolongation
o Miscellaneous
 Respiratory depression
 Hyperthermia
 Hyponatremia
 Bone marrow suppression

o Serum carbamazepine
 Repeat every 4-6 hours
 Repeat until downward trend
o CBC
o CMP
o EKG
o Can cause false positive for cyclic antidepressants

o ABCs
o GI decontamination: activated charcoal
o Enhanced elimination
 MDAC
 Hemodialysis (high-flux)
• Refractory seizures or life-threatening arrhythmias
• Prolonged coma, respiratory depression
o QRS widening: sodium bicarbonate
o Hyponatremia (seizures): hypertonic saline (3%)

o Serum concentration usually unavailable
o Based on history of ingestion/clinical suspicion

o ABCs
o GI decontamination: activated charcoal
o Symptomatic and supportive care
 QRS widening: sodium bicarbonate
 Hypotension: IV fluids, vasopressors if needed
 Seizures: benzodiazepines→ propofol → barbiturates