Mirtazapine Toxicity


 

Mirtazapine

Clinical Features
  • Sedation, confusion, sinus tachycardia, & hypertension. Coma & respiratory depression are seen in severe cases or with co-ingestion of other sedatives.

ED CARE AND DISPOSITION

  1. Isolated overdose: Supportive care
  2. Single-dose activated charcoal for GI decontamination.
  3. Admit: symptomatic pt to a monitored bed.
  4. Discharge: asymptomatic pt after 6 hr

 

 

Monomine Oxidase Inhibitors

Rarely used today as first-line agent for depression due to narrow therapeutic window and drug interactionss
Examples include:
  • Phenelzine (Nardil)
  • Tranylcypromaine (Parnate)
  • St. John's Wort - an herbal preparation for depression thought to have some monoamine oxidase inhibitor action
  • MAO-B inhibitors (selegiline, rasagiline) are used to treat Parkinson disease and are much less toxic in overdose.

MECHANISM/TOXICITY

  • Inhibition of monoamine oxidase → decreased inactivation of biogenic amines, including epinephrine, norepinephrine, serotonin → excessive circulating catecholamines.
  • Monamine oxidase may take weeks to regenerate after discontinuation of MAOIs!

SYMPTOMS/EXAM

  • Characterized by excessive sympathetic activity
  • Symptoms are usually delayed 6-12 hours following overdose!
  • Agitation, mydriasis
  • Tachycardia, hyperthermia, hypertension
  • Muscle rigidity, hyperreflexia, myoclonus
  • Seizures, coma
  • Tyramine reaction - after ingestion of tyramine-containing foods (red wine, cheese, etc.)
    • Headache, hypertension, diaphoresis, palpitations, and neuromuscular excitation lasting for several hours

DIFFERENTIAL

  • Cocaine, amphetamines, PCP, ephedrine

DIAGNOSIS

  • Clinical diagnosis based on patient presentation.
  • MAOIs are usually not detected on standard toxicology screens.

ED CARE & DISPOSITION
Supportive care & Management of complications.

  1. IV access, Cardiac monitoring.
  2. Give all pts activated charcoal. Gastric lavage recommended if it can be performed within 1 hr of ingestion.
  3. Hypertension:
    • Phentolamine  2.5 - 5 mg IV q10-15 min, followed by an infusion.
    • Alternative agents: Nitroprusside or fenlodopam.
  4. Nitroglycerine for anginal chest pain & signs of myocardial ischemia.
  5. Hypotension:
    • IV Bolus, followed by norepinephrine.
  6. Ventricular Dysrhythmia:
    • Lidocaine or procainamide
  7. Bradycardia:
    • Atropine, isoproterenol, dobutamine, & pacing
  8. Seizure:
    • Benzodiazepines.
    • General anesthesia & muscle paralysis using vecuronium, with ongoing EEG monitoring, may be necessary.
  9. Hyperthermia:
    • Benzodiazepines to reduce muscle rigidity plus cooling measures. Chemical paralysis with nondepolarizing agent (Vecuronium 0.15mg/kg) may be needed for severe rigidity.
    • Dantrolene, 1.0 - 2.5 mg/kg IV q6h, is another option.
  10. Avoid:
    • Beta-Blockers (→ unopposed Alpha-adrenergic stimulation)
    • All indirect sympathomimetics (dopamine)
  11. Pt who have ingested > 1mg/kg require ICU admission. Those who ingested less can be admitted to monitored bed. Observe asymptomatic pt for 24 hr.

COMPLICATIONS

  • Serotonin syndrome
  • Sequelae of hypertensive emergency
  • Rhabdomyolysis

 

SNRI

  • Venlafexine (Effexor)
  • Duloxetine (Cymbalta)
  • Desvenlafaxine (Pristiq)

Clinical Features

  • Hypertension, diaphoresis (profuse sweating), tremor, mydriasis, sedation, & seizure.
  • ECG Changes include sinus tachycardia & QRS or QT interval widening.

ED CARE & DISPOSITION
There are no established guidelines for treating SNRI overdose

  1. Initiate IV access & cardiac monitoring
  2. Single-dose activated charcoal is appropriate in most cases. Gastric lavage may be beneficial with early presentation after large ingestion.
  3. Benzodiazepine are the anticonvulsants of choice.
  4. Treat hypotension w/ IV Fluids & a direct-acting Alpha-Agonist
  5. All pts require at least 6 hr observation, longer for those ingesting extended-release preparations.
  6. Admit symptomatic pts to monitored bed.

 

 

SSRI

SSRIs are widely used for depression because of their large therapeutic window. Fatal overdoses are rare.
Examples include:
  • Fluoxetine (Prozac)
  • Citalopram (Celexa)
  • Paroxetine (Paxil)
  • Lexapro
  • Fluvoxamine (Luvox)
  • Symbyax (Olanzapine/fluoxetine)
  • Vortioxetine (Brintellix)

SYMPTOMS/EXAM

  • N/V, abdominal pain, Sinus tachycardia, CNS sedation and tremor
  • Less commonly - Seizures, more serious cardiovascular toxicity
  • Serotonin syndrome may occur with overdose or routine use.
    • Autonomic dysfunction → hyperthermia (>38 C), diaphoresis.
    • CNS dysfunction → agitation and/or altered mental status.
    • Neuromuscular dysfunction → nystagmus, myoclonus, hyperreflexia, muscular rigidity (lower extremities predominantly), tremor.

ED CARE & DISPOSITION

  1. Supportive care, IV access
  2. Activated charcoal if early and no CNS depression
  3. Benzodiazepines for agitation and seizures
    • Diazepam 5-10 mg PO as single dose (may repeat in 30-60 min)
  4. Sodium bicarbonate for QRS widening >100 msec
  5. Antidote = Cyproheptadine (serotonin antagonist).
    • 12 mg PO x1, repeat at 2 hr interval. alt: 4-8 mg PO TID
    • Indicated for serotonin syndrome in the patient able to take oral medication.
  6. Observe for at least 6 hr.
  7. Admit pts who are tachycardic, lethargic, or have conduction abnormalities on ECG 6 hr after ingestion.

 

Serotonin Syndrome

Serotonin syndrome is a potentially life-threatening adverse reaction to serotoninergic medications. It cn be produced by any drug or combination of drugs that increase central serotonin neurotransmission, most commonly anti-depressants.

Clinical Features

  • Altered mental status, hyperthermia, seizure, & increased muscle tone, in particular myoclonus.
  • Hyperthermia is the most common cause of death.

Diagnosis

  • Symptoms are nonspecific, and there are no confirmatory lab tests.
  • Diagnosis criteria emphasize exposure to a serotoninergic drug, hyperreflexia & presence of myoclonus.
  • Anxiety, agitation, confusion, tremor, shivering, muscle jerking, sweating, headache, flushing

ED CARE AND DISPOSITION
Treatment is supportive. Watch pts for rhabdomyolysis & metabolic acidosis.

  1. ET intubation & Ventilatory support may be required in severe cases.
  2. Diazepam 5-10 mg PO as single dose (may repeat in 30-60 min) to decrease discomfort & promote muscle relaxation.
  3. Antiserotonergic agent: Cyproheptadine (12 mg PO x1, repeat at 2 hr interval. alt: 4-8 mg PO TID)
  4. Admit all pts until symptoms resolve.
  5. Severely ill pts require admission to an ICU.
  6. Discontinue serotonergic drugs (Do not stop abruptly).

 

TCA

TCAs are associated with life-threatening CNS and cardiovascular toxicity. Safer medications, such as SSRIs, have decreased the use of TCAs for depression, and they are now more commonly used at lower doses for treatment of chronic pain syndromes, migraine prophylaxis, and enuresis.
Examples include:
  • Amitriptyline (Elavil)     [Max Dose: 300mg/day ]
  • Nortriptyline (Aventyl) [Max Dose: 150 mg/day]
  • Imipramine (Tofranil)   [Max Dose: 300 mg/day]

MECHANISM/TOXICITY

  • TCAs have seven pharmacologic effects that contribute to toxicity, including:
Histamine receptor blockade  → CNS excitation/Coma
Muscarinic receptor inhibition
(anticholinergic effects)
→ Dry, flushed skin
→ Mydriasis
→ Hyperthermia
→ Seizures
→ Tachycardia
→ Urinary retention
→ CNS excitation ↔ coma
Alpha-Adrenergic receptor blockade → Reflex tachycardia
→ Orthostatic hypotension
→ Miosis
GABA receptor antagonism → seizures
Na channel blockade → prolongation of phase 0 (rapid depolarization) → Quinidine-like effects.
 -- Worsened by acidosis (respiratory or metabolic))

QRS widening
→ Decreased contractility
→ Hypotension

K+ channel antagonism QT prolongation
Inhibition of amine uptake Initial hypertension
CNS excitation ↔ coma

SYMPTOMS/EXAM

  • Table above summarizes the clinical findings in TCA poisonings.
    • Early poisoning → Reflex sinus tachycardia and hypertension.
    • Life-threatening toxicity → Na channel blockade → hypotension with QRS widening >100 msec.
    • Seizuress are typically self-limited, but are associated with acidosis, which in turn worsens the Na++ channel blockade.
    • Rapid deterioration can occur.

DIFFERENTIAL DIAGNOSIS

  • False-positive serum TCA screen may occur with carbamazepine, cyclobenzaprine, diphenhydramine, and phenothizines.
  • Antidysrhythmic overdose
  • Cocaine toxicity

DIAGNOSIS

  • Suspect based on history and presentation.
  • ECG findings of Na channel blockade:
    • Rightward deviation of the terminal 40 msec of the QRS = terminal R in lead aVR of >3 mm and S wave in lead I.
  • Prolongation of PR interval
  • QRS widening
    • QRS >100 msec is associated with increased risk of seizuress.
    • QRS >160 msec is associated with increased risk of wide-complex dysrhythmias.
  • Plasma TCA level
    • Serious intoxications are generally >1000 ng/mL.
  • Urine tox screen for TCAs.
    • False positives include diphenhydramine, carbamazepine.

ED Care & Disposition

  1. Supportive care
    • Early intubation to avoid respiratory acidosis
  2. Obtain IV Access & initiate cardiac rhythm & ECG monitoring.
  3. Activated charcol  1g PO. This may be preceded by gastric lavage in pt presenting < 1hr after a large ingestion (> 1g ingestion).
  4. IV fluid boluses for hypotension. If no response, administer NaHCO3 1-2 mEq/kg IV Bolus, repeated until the pt improves or until pH 7.50-7.55. A continuous IV infusion (150 mEq added to 1L of D5W) may be used at rate of 2-3 ml/kg/h.
    • Sodium bicarbonate, indications:
      • Rightward deviation of the terminal 40 msec of the QRS
      • QRS >100 msec
      • Ventricular dysrhythmiass
      • Hypotension unresponsive to fluids
      • Administer boluses of 1-2 mEq/kg until improvement, then start drip (3 ampules in 1 L of D5W at maintenance rate).
  5. Norepinephrine (levophed) for hypotension unresponsive to fluid and sodium bicarbonate
  6. Treat conduction disturbances & ventricular dysrhytmias with NaHCO3. Synchronized cardioversion may be indicated for unstable pt.
    • Torsades de pointes: Magnesium sulfate 2g IV
  7. Seizures: Benzodiazepines
    • Phenobarbital, starting at 15mg/kg IV, may be required for refractory seizures.
    • Sodium bicarbonate is NOT indicated for seizures (seizures are not due to Na channel blockade!).
  8. Pt who remain asymptomatic after 6 hr do not need admission for toxicologic reasons. Admit symptomatic pt to monitored bed or ICU
  9. Avoid:
    • Physostigmine (no treatment benefit and may cause seizures)
    • Respiratory and/or metabolic acidosis (worsens Na channel blockade))
    • Class IA and IC antidysrhythmics (fast Na channel blockers)
    • Class III antidysrhythmics (K channel blockers)
    • Phenytoin (no treatment benefit)
  Receptor Activity    
Agent a1 b1 b2 DA  
Effects
Indication
Phenylephrine
40-180 mcg/min
+++ 0 0 0 SVR ↑↑
CO ↔/↑
Sepsis,
Neurogenic shock
(Levophed)
Norepinephrine
1-30 mcg/min
+++ ++ 0 0 SVR ↑↑
CO ↔↓↑
Sepsis
Epinephrine +++ +++ ++ 0 CO ↑↑
SVR ↓ (L)
SVR ↔/↑ (H)
Anaphylaxis,
ACLS,
Sepsis
Dopamine (mcg/kg/min)
Low-dose (0.5-2) 0 + 0 ++ CO ↑
SVR ↑↓
Sepsis,
Cardiogenic shock
Mid-dose(5-10) + ++ 0 ++ CO ↑
High-dose(10-20) ++ ++ 0 ++ SVR ↑↑
Doubutamine
2.5-20 mcg/kg/min
0/+ +++ ++ 0 CO ↑
SVR ↓
Cardiogenic shock
Isoproterenol
2-10 mcg/min
0 +++ +++ 0 CO ↑
SVR ↓
Cardiogenic shock w/
bradycardia
Vasopressin
(Adjunct)
0.01-0.04 U/min
        V2 receptors Vasoconstriction
Augments catecholamine

COMPLICATIONS

  • Aspiration
  • Hypoxic brain injury
  • Cardiovascular collapse

 

Trazodone

Clinical Features
  • CNS depression, ataxia, dizziness, seizures, orthostatic hypotension, vomiting, & abdominal pain.
  • ECG abnormalities include QT interval prolongation, sinus bradycardia & tachycardia, & torsades de pointes

ED CARE AND DISPOSITION
Supportive care is generally sufficient in isolated overdose.

  1. Initiate cardiac rhythm monitoring & obtain a 12-Lead ECG
  2. Single-dose activated charcoal is recommended. Gastric lavage followed by activated charcoal may be beneficial for ingestion > 2 g if early after ingestion.
  3. Hypotension: IV fluids, followed by norepinephrine.
  4. Torsades de pointes: Magnesium Sulfate 2g IV
  5. Discharge pt who remain asymptomatic for at least 6 ht, with psychiatric evaluation as indicated.
  6. Admit those with neurologic and/or cardiac symptoms for > 6 hrs after ingestion to a monitored bed.

 

Wellbutrin (Bupropion)

Clinical Features
  • Agitation, dizziness, tremor, vomiting, drowsiness, & tachycardia.
  • Seizures are more common than with other atypical anti-depressants.
  • ECG changes include sinus tachycardia, QRS interval widening, & QT interval prolongation.

ED CARE & DISPOSITION
Seizures should be anticipated. Cardio-toxicity unlikely in isolated overdose.

  1. Start peripheral IV line & initiate cardiac rhythm monitoring.
  2. GI Decontamination if done within 1 hr of ingestion. Consider whole-bowel irrigation in overdoses of sustained-release products.
  3. Treat seizures with benzodiazepines, followed by phenobarbital.
  4. Observe asymptomatic pt for 8 hrs. Monitor pts ingesting > 450 mg of sustained-release bupropion for up to 24 hrs.
  5. Admit those with seizures, persistent tachycardia, or lethargy.