Toxicology – Antidote: N-Acetylcysteine (NAC)

Indications

N-acetylcysteine is the primary antidote for acetaminophen (APAP) poisoning and can be given orally or intravenously. It may also be considered in some other toxicologic conditions involving oxidative stress or glutathione depletion.

For a known single acute acetaminophen ingestion, obtain a serum level at least 4 hours after ingestion and interpret it using the Rumack–Matthew nomogram. NAC is indicated when the level falls above the treatment threshold.

Treatment should also be strongly considered when:

• The time of ingestion is unknown
• The acetaminophen level is detectable with uncertain timing
• Liver enzymes, particularly AST/ALT, are elevated in a patient with possible acetaminophen toxicity

If the acetaminophen concentration is undetectable and liver enzymes are normal, clinically important toxicity is less likely.

Mechanism of Action

NAC helps protect the liver through several mechanisms:

• Replenishes glutathione, which detoxifies the reactive acetaminophen metabolite NAPQI
• Can act as a glutathione substitute and antioxidant
• Enhances sulfation pathways involved in acetaminophen metabolism
• After liver injury has already occurred, it may improve tissue oxygen delivery and reduce oxidative and inflammatory damage

Administration

Both oral and IV NAC are effective. IV therapy is often preferred when oral treatment cannot be tolerated or in patients with severe hepatic injury.

Common treatment protocols include:

• Oral NAC: loading dose followed by repeated maintenance doses over an extended course
• IV NAC: typically administered as a multi-stage infusion over approximately 21 hours

Treatment may need to continue beyond the standard protocol if acetaminophen remains detectable or liver injury is still progressing.

Monitoring

During treatment, follow:

• Acetaminophen concentration
• AST and ALT
• INR/coagulation studies
• Renal function
• Clinical signs of hepatic failure

NAC is generally continued until acetaminophen is no longer detectable and hepatic injury is clearly improving.

Adverse Effects

IV NAC can cause anaphylactoid reactions, including flushing, rash, wheezing, or hypotension. These are usually managed by temporarily slowing or stopping the infusion and providing symptomatic treatment before restarting when appropriate.

Key Points

• NAC is most effective when started early, but it can still provide benefit even after liver injury has developed.
• Do not delay treatment when significant acetaminophen poisoning is strongly suspected.
• The Rumack–Matthew nomogram applies only to a known, single, acute ingestion with a known time.
• Continued NAC may be necessary when liver enzymes remain markedly abnormal or acetaminophen is still detectable.

Toxicology – Hydrogen Sulfide Poisoning

Source

Hydrogen sulfide is a toxic gas produced during the breakdown of organic material. It may accumulate in sewers, manure pits, petroleum facilities, paper mills, and other poorly ventilated confined spaces. Because it is heavier than air, it can collect in low-lying areas.

Typical Presentation

Workers in a confined space may suddenly collapse after exposure to hydrogen sulfide. Rescuers who enter without proper respiratory protection can also become rapidly incapacitated.

Clinical Features

Lower-level exposure mainly causes mucous membrane and respiratory irritation, including:

• Runny nose
• Tearing
• Red or irritated eyes
• Headache
• Nausea and vomiting
• Dizziness
• Confusion

More severe exposure can produce:

• Sudden loss of consciousness
• Respiratory failure
• Cardiac dysrhythmias
• Coma
• Death
• Delayed pulmonary edema

Mechanism of Action

Hydrogen sulfide inhibits cytochrome oxidase, disrupting cellular oxygen utilization in a manner similar to cyanide. It also directly irritates the eyes and respiratory tract. At high concentrations, it can cause extremely rapid CNS depression and collapse.

Although hydrogen sulfide has a characteristic rotten-egg odor, prolonged or intense exposure can impair the sense of smell, making odor an unreliable warning sign.

Management

Treatment is mainly supportive:

• Immediate removal from the contaminated environment by appropriately protected rescuers
• Airway and respiratory support
• High-concentration oxygen
• Continuous cardiac monitoring
• Treatment of dysrhythmias and other complications as needed

Specialized therapies such as hyperbaric oxygen or hydroxocobalamin have been considered in severe cases, but supportive resuscitation remains the mainstay of treatment.

Key Points

• Hydrogen sulfide is especially dangerous in confined spaces.
• High concentrations can cause sudden collapse with little warning.
• The rotten-egg smell cannot be relied upon because olfactory fatigue may occur.
• Delayed pulmonary complications can develop even after the initial exposure.

Toxicology – Carbon Monoxide (CO) Poisoning

Source

Carbon monoxide is a colorless, odorless, nonirritating gas produced by incomplete combustion. Common sources include house fires, furnaces, heaters, grills, gasoline-powered generators, and motor vehicle exhaust. Methylene chloride exposure can also produce carbon monoxide after metabolism in the body.

Typical Presentation

Several people from the same household may develop headache, dizziness, nausea, and vomiting after using a fuel-burning appliance or generator in an enclosed area. Because symptoms are nonspecific, carbon monoxide poisoning can easily be mistaken for a viral illness.

Clinical Features

Common manifestations include:

• Headache
• Nausea and vomiting
• Dizziness
• Fatigue
• Confusion
• Shortness of breath
• Chest pain
• Syncope or loss of consciousness

Severe poisoning can cause neurological injury, myocardial ischemia, arrhythmias, coma, or death.

A carboxyhemoglobin (COHb) level can help confirm exposure. Pulse oximetry may appear falsely normal because standard devices cannot reliably distinguish oxyhemoglobin from carboxyhemoglobin.

Mechanism of Action

Carbon monoxide binds to hemoglobin with much greater affinity than oxygen, forming carboxyhemoglobin. This reduces oxygen-carrying capacity and also impairs release of oxygen to tissues, resulting in cellular hypoxia.

Management

• Immediately remove the patient from the source of exposure.
• Administer high-concentration oxygen.
• Monitor neurological status, ECG, and cardiac biomarkers when appropriate.
• Hyperbaric oxygen therapy may be considered in severe poisoning, especially with loss of consciousness, persistent neurological abnormalities, significant cardiac involvement, severe acidosis, or pregnancy.
• Evaluate fire victims for possible simultaneous cyanide toxicity when severe lactic acidosis or cardiovascular collapse is present.

Key Points

• Headache is the most common symptom of CO poisoning.
• Multiple people with similar symptoms in the same enclosed environment should strongly raise suspicion.
• Standard pulse oximetry can be misleadingly normal.
• Cherry-red skin is uncommon and should not be relied upon for diagnosis.
• Patients with severe smoke exposure may have both carbon monoxide and cyanide poisoning.

Toxicology – Cyanide Poisoning

Source

Cyanide exposure can occur during smoke inhalation from structural fires, especially when materials such as wool, silk, plastics, insulation, or rubber burn. It may also be encountered in certain industrial settings, some foods or plant products, and rarely from prolonged nitroprusside therapy.

Typical Presentation

A patient exposed to heavy smoke or an occupational cyanide source may rapidly develop confusion, shortness of breath, chest discomfort, seizures, or cardiovascular collapse. Cyanide toxicity should be considered in severe smoke inhalation with unexplained lactic acidosis or sudden hemodynamic deterioration.

Clinical Features

Possible findings include:

• Headache
• Nausea and vomiting
• Altered mental status
• Dilated pupils
• Rapid breathing
• Tachycardia
• Early hypertension
• Later hypotension and respiratory depression
• Chest pain
• Seizures
• Cardiovascular collapse

Laboratory abnormalities may show:

• Severe lactic acidosis
• High anion gap metabolic acidosis
• Unusually high venous oxygen content because tissues cannot effectively extract oxygen

Mechanism of Action

Cyanide inhibits cytochrome c oxidase in the mitochondrial electron transport chain. This blocks aerobic cellular respiration, preventing tissues from using oxygen despite adequate oxygen delivery and causing rapid anaerobic metabolism and lactate accumulation.

Management

Treatment requires immediate supportive care:

• High-flow oxygen and airway support
• Cardiac and hemodynamic monitoring
• Aggressive management of seizures and shock
• Hydroxocobalamin is a preferred antidotal therapy because it binds cyanide to form a less toxic compound that can be eliminated
• Sodium thiosulfate may also be used to enhance conversion of cyanide to thiocyanate

Nitrite-based antidotes induce methemoglobinemia and are generally less desirable when carbon monoxide exposure is also suspected, as commonly occurs in fire victims.

Key Points

• Think of cyanide toxicity in patients with severe smoke inhalation plus cardiovascular collapse or marked lactic acidosis.
• Cyanide prevents cells from using oxygen rather than preventing oxygen from reaching the blood.
• Hydroxocobalamin is a major antidote used in suspected cyanide poisoning.
• A markedly elevated lactate level can serve as an important indirect clue.

Toxicology – Antipsychotic Toxicity

Source

Antipsychotic medications are used to treat conditions such as schizophrenia, psychosis, severe agitation, and bipolar disorder. They include first-generation agents such as haloperidol and second-generation agents such as risperidone, olanzapine, quetiapine, clozapine, and aripiprazole.

Typical Presentation

A patient with excessive antipsychotic exposure may present with drowsiness, confusion, tachycardia, and hypotension. Severe toxicity can progress to respiratory depression, seizures, coma, or cardiac conduction abnormalities.

Clinical Features

Possible findings include:

• Sedation or agitation
• Ataxia
• Confusion
• Seizures
• Coma
• Respiratory depression
• Orthostatic hypotension

Some agents may also produce anticholinergic findings, including:

• Dilated pupils
• Dry skin and mucous membranes
• Tachycardia
• Urinary retention
• Reduced bowel sounds
• Agitation

ECG abnormalities may include:

• QRS widening
• QT prolongation
• Cardiac dysrhythmias in severe cases

Mechanism of Action

Most antipsychotics block dopamine D2 receptors to varying degrees. First-generation drugs generally produce stronger D2 blockade and therefore more extrapyramidal adverse effects. Many second-generation agents also affect serotonin receptors. Additional blockade of α1-adrenergic, histamine, and muscarinic receptors contributes to hypotension, sedation, and anticholinergic effects.

Management

Treatment is primarily supportive:

• Airway and respiratory support when necessary
• Continuous ECG and cardiac monitoring
• IV fluids for hypotension
• Vasopressors may be required for persistent hypotension
• Treat significant QRS widening or QT-related dysrhythmias according to toxicology and resuscitation guidance
• Benzodiazepines may be used for seizures or severe agitation

Key Points

• Antipsychotics can cause extrapyramidal symptoms, dystonia, neuroleptic malignant syndrome, anticholinergic effects, and orthostatic hypotension.
• Clozapine is associated with agranulocytosis.
• Seizures are uncommon overall but are more strongly associated with clozapine.
• Cardiac monitoring is important because some agents can prolong the QT interval or impair conduction.

Toxicology – Phenytoin & Fosphenytoin Toxicity

Source

Phenytoin is an anticonvulsant used for seizure control. Fosphenytoin is a water-soluble prodrug of phenytoin that is commonly used intravenously because it is better tolerated.

Typical Presentation

A patient taking phenytoin may present with unsteady gait, slurred speech, lethargy, and altered mental status. Neurological findings usually become more pronounced as the serum concentration rises.

Clinical Features

Acute toxicity is dominated by neurological symptoms, including:

• Nystagmus
• Nausea and vomiting
• Ataxia and poor coordination
• Slurred speech
• Lethargy
• Extrapyramidal movements
• Altered mental status
• Coma in severe cases

IV phenytoin can also cause:

• Hypotension
• Ventricular dysrhythmias
• Cardiovascular collapse

Chronic therapy may be associated with:

• Gingival hyperplasia
• Coarsening of facial features
• Chronic ataxia
• Liver injury

Mechanism of Action

Phenytoin inhibits voltage-gated sodium channels in neurons, reducing repetitive neuronal firing. Excessive concentrations produce predominantly cerebellar and CNS dysfunction.

Management

Treatment is mainly supportive:

• Airway and respiratory support when necessary
• Neurological monitoring
• Cardiac monitoring after IV phenytoin toxicity
• Activated charcoal may be considered in appropriate recent oral exposures
• Manage hypotension, dysrhythmias, or other complications supportively

There is no specific antidote for phenytoin toxicity.

Key Points

• Nystagmus, ataxia, and slurred speech are classic findings of phenytoin toxicity.
• Neurological toxicity generally worsens as drug levels rise.
• IV phenytoin formulations can cause significant cardiovascular toxicity.
• Fosphenytoin is generally safer for IV administration because it does not contain the propylene glycol vehicle used in traditional IV phenytoin.
• IV phenytoin may cause severe local tissue injury, sometimes referred to as purple glove syndrome.

Toxicology – Carbamazepine Toxicity

Source

Carbamazepine is an anticonvulsant used for seizure disorders, trigeminal neuralgia, neuropathic pain, and bipolar disorder.

Typical Presentation

A patient, often after accidental or intentional ingestion, may develop marked drowsiness, unsteady gait, slurred speech, and altered mental status. Severe poisoning can progress to seizures, respiratory depression, coma, and cardiac conduction abnormalities.

Clinical Features

Possible findings include:

• Sedation and confusion
• Ataxia
• Dysarthria
• Nystagmus
• Anticholinergic features
• Respiratory depression
• Seizures
• Coma

ECG abnormalities may include:

• QRS widening
• QT prolongation
• Cardiac dysrhythmias in severe toxicity

Mechanism of Action

Carbamazepine blocks voltage-gated sodium channels, accounting for both its therapeutic anticonvulsant activity and many of its toxic effects. It is structurally related to tricyclic antidepressants and also has anticholinergic and sedating properties.

Management

Treatment is primarily supportive:

• Airway and respiratory support when needed
• Continuous cardiac monitoring and serial ECGs
• Benzodiazepines for seizures
• Sodium bicarbonate for clinically significant sodium-channel blockade with QRS widening
• Serial carbamazepine concentrations may be useful because absorption can be delayed and levels may continue to rise
• Multiple-dose activated charcoal may enhance elimination in selected significant poisonings
• Hemodialysis or hemoperfusion may be considered in severe or refractory toxicity with specialist guidance

Key Points

• Although carbamazepine treats seizures, overdose can itself cause seizures.
• Ataxia, nystagmus, sedation, and anticholinergic findings are common neurological clues.
• Sodium-channel blockade can produce dangerous cardiac conduction abnormalities.
• Chronic carbamazepine therapy may be associated with hyponatremia.

Toxicology – Monoamine Oxidase Inhibitor (MAOI) Toxicity

Source

Monoamine oxidase inhibitors are antidepressants now used mainly for atypical or treatment-resistant depression. Certain MAO-inhibiting drugs are also used in Parkinson disease.

Typical Presentation

A patient taking an MAOI may present with severe agitation, hypertension, sweating, tachycardia, and altered mental status. In overdose, symptoms can be significantly delayed and may later progress from a hyperadrenergic state to profound hypotension and cardiovascular collapse.

Clinical Features

MAOI toxicity can appear in several forms:

• Hyperadrenergic crisis: Headache, flushing, diaphoresis, dilated pupils, tachycardia, severe hypertension, and agitation. This may occur after consumption of high-tyramine foods while taking an MAOI.
• Acute overdose: Similar hyperadrenergic findings plus hyperthermia, vomiting, diarrhea, psychosis, myoclonus, seizures, and marked altered mental status. Severe cases may progress to coma, hypotension, and cardiovascular collapse.
• Serotonin syndrome: May occur when MAOIs are combined with other serotonergic medications and is characterized by altered mental status, autonomic instability, and neuromuscular hyperactivity.

Symptoms after overdose may not appear for many hours and can persist for several days.

Mechanism of Action

MAOIs inhibit monoamine oxidase, the enzyme responsible for breaking down serotonin, norepinephrine, and dopamine. This causes accumulation of these neurotransmitters and excessive adrenergic and serotonergic activity.

Management

Treatment is primarily supportive:

• Airway and respiratory support when necessary
• Continuous cardiac and blood pressure monitoring
• Benzodiazepines for agitation and seizures
• Rapid cooling for significant hyperthermia
• Short-acting IV antihypertensive therapy may be required for severe hypertension
• IV fluids and vasopressors may be necessary if cardiovascular collapse develops
• Gastrointestinal decontamination may be considered in appropriate recent exposures

Because toxicity can be delayed, significant MAOI overdoses generally require prolonged monitored observation.

Key Points

• MAOI overdose can have a markedly delayed onset.
• Early toxicity often produces a hyperadrenergic state with hypertension and agitation.
• Severe poisoning may later progress to hypotension, coma, and cardiovascular collapse.
• Combining MAOIs with serotonergic drugs can precipitate serotonin syndrome.

Toxicology – Tricyclic Antidepressant (TCA) Toxicity

Source

Tricyclic antidepressants were once widely used for depression but are now also prescribed for conditions such as neuropathic pain, migraine prevention, OCD, and nocturnal enuresis. Examples include amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline.

Typical Presentation

A patient with TCA overdose may present with altered mental status, anticholinergic findings, seizures, hypotension, or ECG abnormalities, especially a widened QRS complex.

Clinical Features

Toxicity commonly affects the nervous and cardiovascular systems.

Anticholinergic findings:

• Dilated pupils
• Dry skin and mucous membranes
• Flushing
• Hyperthermia
• Tachycardia
• Urinary retention
• Confusion

Other important findings include:

• Sedation progressing to coma
• Seizures
• Orthostatic hypotension
• Cardiac arrhythmias

ECG abnormalities may include:

• Sinus tachycardia
• PR prolongation
• QRS widening
• QT prolongation
• Potentially fatal ventricular dysrhythmias

Mechanism of Action

TCAs have several pharmacologic actions, including:

• Anticholinergic activity
• Antihistamine effects
• α-adrenergic blockade
• Inhibition of serotonin and norepinephrine reuptake

Their most dangerous cardiac effect results from voltage-gated sodium channel blockade, which slows cardiac conduction and widens the QRS. Potassium-channel effects may also contribute to QT prolongation.

Management

Treatment requires rapid supportive care:

• Airway and respiratory support as needed
• Continuous cardiac monitoring and serial ECGs
• Benzodiazepines for seizures
• IV fluids for hypotension
• Sodium bicarbonate is the key therapy when significant QRS widening, ventricular dysrhythmias, or persistent hypotension is present
• Vasopressor support, typically norepinephrine, may be required if hypotension persists
• IV lipid emulsion may be considered in severe refractory toxicity with specialist guidance

Key Points

• QRS widening is an important marker of severe TCA toxicity.
• Increasing QRS duration is associated with a greater risk of seizures and ventricular arrhythmias.
• Cyclobenzaprine is structurally similar to TCAs and may produce a similar overdose pattern.
• Some TCAs, particularly desipramine, may produce prominent cardiotoxicity even without obvious anticholinergic findings.