Toxicology – Asphyxiant Gases

Core concept

Simple asphyxiant gases cause toxicity by displacing oxygen from the surrounding atmosphere, resulting in alveolar hypoxia → systemic hypoxemia → tissue hypoxia.

They do not usually exert a specific cellular toxic effect. Their danger comes primarily from reducing the amount of oxygen available for breathing.

Examples include:

• Acetylene
• Argon
• Butane
• Carbon dioxide
• Helium
• Hydrogen
• Methane
• Natural gas
• Neon
• Nitrogen
• Propane
• Other inert gases

Carbon monoxide and pulmonary irritant gases are separate toxicologic entities.

Pathophysiology

A simple asphyxiant:

Displaces atmospheric O₂ → lowers inspired O₂ → alveolar hypoxia → hypoxemia → tissue hypoxia

Clinical effects generally become apparent when ambient oxygen falls below approximately 15% and become severe below approximately 10%.

Some liquefied or rapidly expanding gases can also cause cold injury/frostbite after direct tissue contact.

Risk Factors

Risk is increased by:

• Poorly ventilated or confined spaces
• Intentional inhalational abuse
• Significant underlying cardiac or pulmonary disease
• Advanced age
• High altitude

Patients with cardiopulmonary disease may become symptomatic with relatively small reductions in ambient oxygen.

Pregnancy

Severe maternal hypoxia can cause:

• Fetal hypoxia
• Fetal distress

Clinical Features

Symptoms correlate directly with the severity and duration of hypoxia.

Early hypoxia

• Headache
• Agitation
• Air hunger
• Tachypnea
• Hyperpnea
• Tachycardia
• Diaphoresis

Progressive hypoxia

• Cyanosis
• Lethargy
• Confusion
• Myocardial ischemia
• Dysrhythmias

Severe / preterminal hypoxia

• Respiratory depression
• Hypotension
• Bradycardia
• Mydriasis
• Coma
• Ventricular dysrhythmias
• Idioventricular rhythm
• Asystole

Diagnosis

Diagnosis is based on:

Exposure history + evidence of hypoxia + improvement after removal from exposure and oxygen

Essential investigations

• Pulse oximetry
• Arterial blood gas when clinically indicated

If another toxic exposure is possible, obtain:

• Carboxyhemoglobin level
• Methemoglobin level

Important limitation

Standard pulse oximetry may be misleading in carbon monoxide poisoning, so concurrent CO exposure must be considered in appropriate settings.

Additional investigations

Depending on clinical circumstances:

• Serum electrolytes
• BUN
• Creatinine
• Blood glucose
• ECG

In suspected overdose or unexplained altered consciousness:

• Acetaminophen level
• Salicylate level

If altered mental status persists despite adequate oxygenation, investigate alternative causes as indicated, including:

• CT brain
• Lumbar puncture
• Blood cultures
• CSF studies

Differential Diagnosis

Other causes of hypoxia or altered mental status should be considered.

Toxicologic causes

• Carbon monoxide
• Cyanide
• Hydrogen sulfide
• Methemoglobinemia

Non-toxicologic causes

• Pulmonary embolism
• Primary pulmonary disease
• Hemoglobin disorders
• Cardiovascular disease
• Other neurologic or metabolic causes of altered consciousness

Treatment

1. Remove from exposure

The patient should be immediately removed from the contaminated environment.

Rescuer safety is essential, especially in confined spaces, because rescuers can also become hypoxic.

2. Oxygen

Administer high-flow 100% oxygen.

This is the principal treatment for simple asphyxiant exposure.

3. Airway and ventilation

Provide:

• Airway support
• Assisted ventilation
• Endotracheal intubation when necessary

4. Supportive care

Monitor and treat:

• Hypotension
• Dysrhythmias
• Myocardial ischemia
• Electrolyte abnormalities
• Neurologic complications

5. Persistent altered mental status

If the patient does not rapidly improve with oxygen, evaluate for alternative or concurrent causes.

Appropriate empiric measures may include:

• Blood glucose measurement
• Dextrose if hypoglycemic
• Naloxone when opioid toxicity is possible
• Thiamine in appropriate clinical circumstances

6. Seizures

Seizures may occur because of severe hypoxia.

If they persist despite correction of oxygenation:

• Treat with benzodiazepines as first-line anticonvulsant therapy

Antidote

There is no specific antidote for simple asphyxiant gases.

The key therapy is:

Removal from exposure + 100% oxygen + airway/supportive care

Decontamination

Prehospital

• Remove from exposure
• Begin oxygen immediately

Hospital

Usually no specific decontamination is required unless another substance is also involved.

Direct contact with liquefied gases should prompt evaluation and treatment for frostbite/cold injury.

Monitoring

Symptomatic patients should receive:

• Continuous pulse oximetry
• Cardiac monitoring
• Serial neurologic assessment

Additional monitoring depends on the severity of hypoxia and suspected complications.

Admission

Hospital admission is appropriate for patients with:

• Persistent symptoms
• Persistent hypoxia despite oxygen
• Significant neurologic abnormalities
• Cardiac ischemia or dysrhythmias
• Other complications of hypoxia
• Suspected additional toxic exposure

Disposition

Patients who remain asymptomatic after removal from exposure and have no evidence of another toxic exposure may be observed for approximately 2–4 hours.

Discharge may be considered when:

• Symptoms have completely resolved
• Oxygenation is normal
• No complications of hypoxia are present
• No significant concurrent toxic exposure is suspected

Psychiatric assessment may be appropriate when exposure was intentional.

Prognosis

Prognosis depends primarily on:

Severity of hypoxia + duration of hypoxia

Prompt removal from exposure usually results in a good outcome.

Prolonged severe hypoxia can cause:

• Myocardial ischemia
• Dysrhythmias
• Anoxic brain injury
• Multiorgan injury
• Death

Important Pitfalls

1. Missing concurrent poisoning

Do not assume all hypoxia in a confined-space exposure is due to simple oxygen displacement.

Consider:

• Carbon monoxide
• Hydrogen sulfide
• Cyanide
• Pulmonary irritants

2. Rescuer injury

Entering an oxygen-deficient confined space without appropriate respiratory protection can result in multiple casualties.

3. Cold injury

Liquefied or rapidly expanding gases can cause frostbite.

4. Delayed recognition of hypoxic injury

Even after oxygenation is restored, complications such as myocardial injury or hypoxic brain injury may persist.

High-Yield Toxicology Pearls

Simple asphyxiants kill by oxygen displacement.

Think:

Confined space + low oxygen environment + neurologic/cardiopulmonary symptoms + rapid improvement with oxygen

Key points:

• Mechanism: decreased inspired oxygen
• Main toxicity: systemic tissue hypoxia
• Severe toxicity usually occurs when ambient O₂ is <10%
• Early findings: tachypnea, tachycardia, headache, agitation
• Late findings: respiratory depression, bradycardia, hypotension, coma, asystole
• Main treatment: remove from exposure + 100% oxygen
• No specific antidote
• Always consider CO, cyanide, H₂S, and methemoglobinemia
• Protect rescuers from oxygen-deficient environments
• Prognosis depends on the depth and duration of hypoxia

Toxicology – Arsine (AsH₃)

Core concept

Arsine is a potent inhaled hemolytic poison. It is a colorless, nonirritating, flammable gas that may have a garlic-like odor. Its major toxicity is rapid, severe intravascular hemolysis, which can lead to hemoglobin-induced acute kidney injury.

Exposure

Exposure is usually occupational or industrial, especially when arsenic-containing materials are exposed to strong acids or heat.

Common settings include:

• Smelting and refining of metals and ores
• Galvanizing
• Soldering
• Metal etching and plating
• Metallurgy
• Fossil-fuel combustion
• Semiconductor and microelectronics manufacturing

A major danger is that odor is unreliable, and toxic exposure may occur below the odor-detection threshold.

Mechanism

Arsine → enters RBCs → oxidative injury and glutathione depletion → severe Coombs-negative intravascular hemolysis

This may progress to:

Hemolysis → free hemoglobin → hemoglobinuria → renal tubular injury → acute kidney injury

Severe poisoning may cause multiorgan failure and death.

Toxicity

• Immediate death has been reported at approximately 150 ppm
• NIOSH IDLH: 3 ppm
• Occupational TWA historically cited: 0.05 ppm
• Clinical toxicity is often delayed by 2–24 hours

The delayed onset is an important diagnostic pitfall.

Clinical Features

Characteristic severe poisoning

A classic triad is:

Abdominal pain + dark/red urine + bronze skin discoloration

General symptoms

• Headache
• Weakness
• Chills
• Thirst
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain

Hematologic

• Severe intravascular hemolysis
• Falling hemoglobin and hematocrit
• Low haptoglobin
• Elevated markers of hemolysis
• Usually direct antiglobulin (Coombs) negative

Renal

Dark red urine commonly appears within approximately 4–12 hours and may represent:

• Hemoglobinuria
• Hematuria

Massive hemoglobinuria can cause acute tubular necrosis and acute renal failure.

Skin and eyes

Within approximately 12–36 hours:

• Dusky or bronze skin discoloration
• Reddish conjunctival discoloration

The bronze coloration is related predominantly to hemoglobin rather than bilirubin.

Cardiovascular

• Peaked T waves or other T-wave changes
• Ventricular dysrhythmias may occur
• Electrolyte disturbances associated with hemolysis and renal failure may worsen cardiac toxicity

Diagnosis

Diagnosis is based mainly on:

Exposure history + evidence of intravascular hemolysis

Essential investigations

Serial monitoring should include:

• Complete blood count
• Peripheral blood smear
• Serum haptoglobin
• Electrolytes
• BUN
• Creatinine
• Urinalysis
• ECG

Additional useful investigations include:

• LDH
• Indirect bilirubin
• Reticulocyte count
• Plasma-free hemoglobin

Blood and urine arsenic concentrations may help document exposure, but treatment should not be delayed while awaiting arsenic levels.

Treatment

1. Remove from exposure

Immediately remove the patient from the contaminated environment while ensuring appropriate protection for rescuers.

2. Oxygen

Administer supplemental oxygen. The cited source recommends 100% oxygen initially.

3. Treat hemolysis

• Monitor hemoglobin and hematocrit closely
• Provide packed red blood cell transfusion when clinically indicated
• Monitor for rapidly progressive hemolysis

4. Prevent and manage renal injury

• IV fluids when appropriate
• Maintain adequate urine output
• Monitor fluid balance carefully
• Serial potassium, electrolytes, and renal function
• Avoid additional nephrotoxins

The older source suggests maintaining urine output at approximately 1–2 mL/kg/hour, although fluid management should be individualized.

5. Hemodialysis

Hemodialysis may be necessary if acute kidney injury causes:

• Refractory hyperkalemia
• Severe metabolic acidosis
• Fluid overload
• Uremic complications

Dialysis treats the complications of renal failure rather than acting as a specific antidote to arsine.

6. Exchange transfusion

Exchange transfusion has historically been advocated in severe arsine poisoning, particularly when massive hemolysis is present.

This should be considered in consultation with toxicology, hematology, nephrology, and critical care specialists.

Antidote

There is no established specific antidote for arsine poisoning.

Dimercaprol (BAL) is not reliably effective and does not appear to prevent or reduce arsine-induced hemolysis.

This is an important distinction from some forms of inorganic arsenic poisoning, where chelation therapy may have a role.

Disposition

Patients with significant suspected arsine exposure generally require hospital admission and close monitoring, because symptoms and hemolysis may be delayed.

Severe or suspected clinically important poisoning warrants ICU-level care.

Patients should not be discharged prematurely because clinical deterioration may occur many hours after exposure.

Prognosis

Large exposures may cause:

• Rapid death
• Massive hemolysis
• Acute renal failure
• Multiorgan injury

Outcome depends largely on exposure severity and the development of hemolysis and renal complications.

High-Yield Toxicology Pearls

Arsine = hemolysis.

Think of arsine poisoning when there is:

Industrial exposure + delayed symptoms + Coombs-negative intravascular hemolysis + dark urine + acute kidney injury

Key points:

• Main route: inhalation
• Primary target: red blood cells
• Hallmark toxicity: massive intravascular hemolysis
• Classic urine finding: hemoglobinuria
• Major complication: acute kidney injury
• Symptoms may be delayed 2–24 hours
• No specific antidote
• BAL is not reliably useful
• Severe cases may require RBC transfusion, exchange transfusion, and hemodialysis

Toxicology – Arsenic Poisoning

Core Concept

Arsenic is a naturally occurring metalloid with important environmental, occupational, medicinal, and toxicologic relevance.

Toxicity depends strongly on its chemical form:

• Inorganic arsenic — most important in classic systemic poisoning
• Organic arsenic compounds — often considerably less toxic
• Arsine gas — produces a distinct syndrome dominated by massive intravascular hemolysis and should be considered separately

Acute inorganic arsenic poisoning classically causes:

Severe GI injury → capillary leak/hypovolemia → cardiovascular instability → multiorgan dysfunction

Delayed effects may include:

• Bone-marrow suppression
• Painful peripheral neuropathy
• Skin/nail changes

Chronic inorganic arsenic exposure is associated with:

• Skin abnormalities
• Peripheral neuropathy
• Cardiovascular and metabolic effects
• Increased cancer risk

Sources of Exposure

Potential sources include:

• Contaminated groundwater
• Mining and smelting
• Semiconductor manufacturing
• Glass and metal industries
• Historical pesticides and rodenticides
• Historical arsenic-containing wood preservatives
• Contaminated traditional or folk remedies
• Certain occupational processes

Many household applications described in older references are now obsolete or heavily restricted.

Seafood and Arsenic

Seafood, particularly some shellfish and seaweed, can contain substantial amounts of organic arsenic compounds.

These forms are generally much less toxic than inorganic arsenic.

However, recent seafood ingestion can markedly increase total urinary arsenic, potentially creating a misleading laboratory result.

Therefore arsenic speciation is often preferable to simply assuming an elevated total urinary arsenic concentration represents toxic inorganic exposure.

Mechanism of Toxicity

Arsenic disrupts several fundamental cellular processes.

Trivalent arsenic binds sulfhydryl groups and inhibits important enzymes.

Arsenic also interferes with:

• Cellular respiration
• Pyruvate metabolism
• Oxidative phosphorylation
• ATP generation
• Redox regulation

The result is widespread cellular dysfunction affecting:

• GI tract
• Cardiovascular system
• Nervous system
• Bone marrow
• Liver
• Kidneys

The older description of arsenic simply “uncoupling oxidative phosphorylation” is an oversimplification.

Toxic Dose

Historical texts provide specific lethal-dose ranges, but these are unreliable for bedside risk assessment.

Toxicity varies with:

• Arsenic species
• Solubility
• Formulation
• Route
• Absorbed amount
• Timing
• Patient factors
• Treatment delay

A credible significant inorganic arsenic ingestion should therefore be assessed according to the clinical syndrome and exposure circumstances, rather than relying on a single dose threshold.

Acute Arsenic Poisoning

Severe acute poisoning may evolve through several stages.

Early manifestations are predominantly:

• Burning GI discomfort
• Nausea
• Profuse vomiting
• Severe abdominal pain
• Watery diarrhea

Severe cases can resemble fulminant gastroenteritis or cholera-like illness.

Severe Gastrointestinal Toxicity

Profuse GI fluid loss can cause:

• Dehydration
• Hypovolemia
• Electrolyte abnormalities
• Metabolic acidosis
• Hypotension
• Shock

Hemorrhagic gastroenteritis can occur in severe poisoning.

This early GI syndrome may be mistaken for infectious gastroenteritis, delaying recognition of arsenic exposure.

Cardiovascular Toxicity

Severe acute arsenic poisoning can produce:

• Tachycardia
• Hypotension
• Shock
• Myocardial dysfunction
• Nonspecific ST-T abnormalities
• QT prolongation
• Ventricular dysrhythmias

Torsades de pointes has been reported.

Cardiovascular collapse may result from several mechanisms simultaneously:

GI fluid loss + capillary leak + vasodilation + direct myocardial toxicity

ECG Monitoring

Significant acute poisoning warrants:

• Initial ECG
• Continuous cardiac monitoring
• Serial ECG assessment when abnormalities are present

Particular attention should be given to:

• QRS
• QT/QTc
• Ventricular ectopy
• Rhythm

Electrolyte abnormalities can further increase dysrhythmia risk.

Pulmonary Toxicity

Severe systemic poisoning may cause:

• Dyspnea
• Hypoxemia
• Pulmonary edema
• Acute respiratory failure

Pulmonary edema may be related to systemic endothelial injury and severe shock rather than isolated primary cardiac failure.

Neurologic Toxicity – Acute

Severe poisoning can produce:

• Headache
• Weakness
• Confusion
• Delirium
• Encephalopathy
• Seizures
• Coma

These findings usually indicate substantial systemic toxicity.

Delayed Peripheral Neuropathy

One of the most characteristic delayed complications is a painful symmetric sensorimotor polyneuropathy.

It may begin days to weeks after the acute illness.

Typical pattern:

Distal symmetric “stocking-glove” neuropathy

Symptoms include:

• Burning pain
• Paresthesias
• Numbness
• Weakness
• Reduced reflexes
• Gait difficulty

Severe cases can resemble Guillain–Barré syndrome.

Arsenic Neuropathy vs Guillain–Barré Syndrome

Arsenic should be considered when a rapidly progressive neuropathy follows:

• Severe unexplained gastroenteritis
• Hypotension
• QT abnormalities
• Cytopenias
• Known environmental/occupational exposure

Electrodiagnostic studies may help characterize the neuropathy.

Recovery may require months and can be incomplete.

Hematologic Toxicity

Acute systemic poisoning can cause delayed:

• Anemia
• Leukopenia
• Neutropenia
• Thrombocytopenia
• Pancytopenia

Bone-marrow suppression may become more apparent several days after exposure.

Therefore a normal initial CBC does not exclude subsequent hematologic toxicity.

Renal Toxicity

Severe arsenic poisoning can cause AKI through several mechanisms:

• Shock/hypoperfusion
• Acute tubular injury
• Systemic toxicity
• Hemolysis in specific arsenic-related exposures such as arsine

Monitor:

• Creatinine
• Electrolytes
• Urine output
• Urinalysis

Hepatic Toxicity

Possible findings include:

• Elevated transaminases
• Hepatic dysfunction
• Rare severe hepatic injury

Liver abnormalities are generally part of severe multisystem poisoning rather than the dominant acute feature.

Dermatologic Findings – Chronic Exposure

Chronic inorganic arsenic exposure can produce characteristic skin abnormalities.

These include:

• Mottled hyperpigmentation
• Areas of hypopigmentation
• Palmar hyperkeratosis
• Plantar hyperkeratosis

A classic description is a mottled or “raindrop” pigmentation pattern.

These findings develop over time and are not useful for diagnosing a very recent ingestion.

Mees Lines

Transverse white nail bands—Mees lines—may appear weeks after substantial arsenic exposure.

Important limitation:

Mees lines are not specific for arsenic.

They can occur after other systemic illnesses or toxic exposures.

Their position as the nail grows may provide rough historical timing but should not replace exposure testing.

Garlic Odor – Poor Diagnostic Sign

A garlic-like odor has historically been associated with arsenic poisoning.

However:

• It is inconsistent
• It is subjective
• Other chemicals can produce similar odors

Its absence does not exclude arsenic poisoning, and its presence does not confirm it.

Chronic Arsenic Toxicity

Long-term inorganic arsenic exposure can produce:

• Fatigue
• Weakness
• GI complaints
• Peripheral neuropathy
• Skin pigmentation changes
• Palmar/plantar hyperkeratosis
• Hematologic abnormalities
• Cardiovascular effects

Exposure assessment is essential because these findings are individually nonspecific.

Carcinogenicity

Chronic inorganic arsenic exposure is a well-established human carcinogenic exposure.

Strong associations include increased risk of:

• Skin cancer
• Lung cancer
• Bladder cancer

Associations with additional internal malignancies have also been reported, but strength of evidence varies by cancer site and exposure setting.

The risk relates primarily to chronic inorganic arsenic exposure rather than ordinary dietary organic arsenic from seafood.

Arsine Gas – Important Distinction

Arsine is a gaseous arsenic compound encountered mainly in industrial settings.

Its defining acute toxicity is:

Massive intravascular hemolysis

Possible consequences include:

• Rapid anemia
• Hemoglobinuria
• Jaundice
• AKI
• Hyperkalemia
• Cardiovascular instability

This syndrome differs substantially from classic inorganic arsenic ingestion.

Diagnosis

Ask specifically about:

• Contaminated drinking water
• Well-water use
• Occupation
• Mining/smelting
• Semiconductor work
• Pesticides
• Traditional remedies
• Supplements
• Recent intentional or accidental exposure
• Other exposed household/workplace members

A careful environmental and occupational history is particularly important in chronic toxicity.

Urine Arsenic – Preferred Exposure Test

For many suspected exposures, urinary arsenic is more useful than blood arsenic because arsenic clears relatively rapidly from blood.

A timed urine collection or appropriately interpreted spot urine may be used depending on the clinical setting.

However, interpretation requires attention to arsenic species.

Arsenic Speciation

When total urine arsenic is elevated, speciation can distinguish toxicologically important inorganic arsenic and its metabolites from less-toxic seafood-derived organic species.

This is especially useful when the patient has recently eaten seafood.

A high total urinary arsenic result should therefore not automatically trigger a diagnosis of inorganic arsenic poisoning.

Seafood Before Testing

Older teaching recommended avoiding seafood for several days before urinary testing.

That can still help reduce dietary interference when testing is nonurgent.

However, in a clinically significant suspected poisoning:

Do not delay necessary testing or treatment simply to wait for seafood-derived arsenic to clear.

Instead, obtain appropriate samples and request speciation when available.

Blood Arsenic

Blood arsenic can be elevated soon after a substantial exposure but falls relatively rapidly.

Therefore:

• It may support a recent exposure
• A normal later blood concentration does not exclude poisoning
• It is generally less useful than urine testing for many exposure investigations

Other Laboratory Evaluation

In significant acute poisoning, consider:

• CBC with differential
• Electrolytes
• Glucose
• Bicarbonate
• BUN/creatinine
• Magnesium
• Calcium
• Liver tests
• Urinalysis

For severe illness:

• Blood gas
• Lactate
• Coagulation studies
• CK

Serial CBC and renal/electrolyte testing may be necessary because toxicity can evolve.

Imaging

Some arsenic-containing compounds can be radiopaque.

Abdominal imaging may occasionally identify retained radiopaque material after a substantial ingestion.

However:

• A normal radiograph does not exclude arsenic ingestion
• Imaging is not required for every exposure

It should be used when the formulation and exposure circumstances make retained material plausible.

Initial Management

For significant acute poisoning:

Airway/breathing → circulation → aggressive treatment of fluid loss/shock → ECG/electrolytes → confirm exposure → consider GI decontamination when appropriate → early toxicology consultation → chelation when indicated

Treatment should not be delayed while waiting for confirmatory arsenic concentrations in a severely symptomatic patient with a convincing exposure.

Fluid Resuscitation

Severe vomiting and diarrhea can cause profound intravascular depletion.

Management includes:

• Appropriate isotonic crystalloid
• Frequent reassessment of perfusion
• Electrolyte correction
• Monitoring urine output

Persistent shock requires vasopressor support according to hemodynamic physiology.

For persistent vasodilatory shock, norepinephrine is generally preferred.

Trendelenburg positioning and routine dopamine-first therapy are outdated.

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is not recommended.

Activated charcoal has limited and uncertain effectiveness for metals/metalloids such as arsenic and should not be assumed to provide reliable adsorption.

Management should prioritize resuscitation and toxicology-directed care.

Whole-Bowel Irrigation

Whole-bowel irrigation may occasionally be considered after a substantial ingestion when:

• Radiopaque arsenic-containing material remains in the GI tract
• A poorly soluble preparation is suspected
• There is concern for continued GI absorption

It is not routine treatment for every arsenic exposure.

Contraindications include situations such as bowel obstruction, ileus, perforation, severe hemodynamic instability, or an unprotected airway.

Chelation

Chelation is considered for significant inorganic arsenic poisoning, especially when the patient is symptomatic or has evidence of substantial systemic exposure.

Important agents include:

• Dimercaprol (BAL)
• Succimer (DMSA)
• DMPS where available

Selection depends on:

• Clinical severity
• Ability to tolerate oral medication
• Arsenic species
• Timing
• Availability
• Toxicology expertise

Dimercaprol – BAL

Dimercaprol has historically been used for severe acute arsenic poisoning, particularly in critically ill patients who cannot take oral therapy.

Important adverse effects include:

• Hypertension
• Tachycardia
• Nausea/vomiting
• Headache
• Fever
• Pain with IM administration

It can also cause hemolysis in susceptible patients, including those with G6PD deficiency.

Because administration and toxicity are significant, its use should be guided by a medical toxicologist.

Succimer – DMSA

Succimer is an orally administered chelator that can bind arsenic.

It may be considered in selected patients who:

• Have clinically significant inorganic arsenic poisoning
• Are stable enough for oral therapy

It is generally better tolerated than BAL.

Potential adverse effects include:

• GI upset
• Rash
• Mild transaminase elevation

DMPS

DMPS is another sulfhydryl-containing chelator with activity against arsenic.

It is used in some countries and specialist settings.

Availability varies geographically.

Evidence and regulatory status differ by jurisdiction, so use should be coordinated with a poison center or medical toxicologist.

Chelation Should Not Be Based on a Number Alone

Modern management should not automatically continue chelation until urine arsenic falls below a single historical cutoff.

Decisions should integrate:

• Clinical improvement
• Exposure source
• Arsenic speciation
• Serial urinary measurements when useful
• Organ injury
• Toxicologist recommendations

This is especially important because total urinary arsenic may be distorted by dietary organic arsenic.

Timing of Chelation

In severe symptomatic poisoning with a credible exposure:

Do not wait for laboratory confirmation before obtaining specialist advice and initiating appropriate chelation.

Chelation is most useful when started early in substantial poisoning.

However, unnecessary chelation should also be avoided when exposure evidence is weak or the elevated laboratory result represents nontoxic organic arsenic.

Seizures

For toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic therapy.

Correct:

• Hypoglycemia
• Hypoxia
• Electrolyte abnormalities
• Severe acid–base disturbances

QT Prolongation and Ventricular Dysrhythmia

Management includes:

• Continuous ECG monitoring
• Correction of potassium and magnesium abnormalities
• Treatment of shock and hypoxia
• IV magnesium for torsades when indicated
• Electrical therapy for unstable malignant rhythms

Avoid adding unnecessary QT-prolonging medications.

Hemodialysis

Hemodialysis is not a substitute for chelation in ordinary arsenic poisoning.

Its role in removing arsenic is limited and depends on factors such as:

• Renal function
• Timing
• Arsenic species
• Whether chelation has altered circulating complexes

Dialysis may nevertheless be required for conventional indications such as:

• Severe AKI
• Refractory electrolyte abnormalities
• Severe acid–base disturbance

Specialist guidance is appropriate.

Monitoring

Significant acute arsenic poisoning may require serial monitoring of:

• Hemodynamics
• ECG
• Electrolytes
• Renal function
• CBC
• Liver function
• Neurologic status
• Urine output

Remember that:

GI/cardiovascular toxicity may be early, while marrow suppression and neuropathy may appear later.

Admission

Hospital admission is appropriate for patients with:

• Significant symptomatic acute exposure
• Severe vomiting or diarrhea
• Dehydration
• Hypotension/shock
• ECG abnormalities
• Significant electrolyte disturbance
• AKI
• Encephalopathy
• Seizures
• Cytopenias
• Need for chelation
• Significant uncertainty about an ongoing exposure source

ICU care is appropriate for:

• Shock
• Respiratory failure
• Malignant dysrhythmia
• Severe encephalopathy
• Status epilepticus
• Multiorgan failure

Chronic Exposure Management

The most important intervention is:

Identify and eliminate the arsenic source.

This may require:

• Testing drinking water
• Occupational investigation
• Removing contaminated remedies/supplements
• Public-health involvement
• Assessment of other exposed people

Chelation is not automatically indicated for every chronically exposed asymptomatic person and should be individualized.

Safeguarding

Historical rules assigning intentional poisoning or neglect according to rigid childhood age cutoffs are outdated.

Assess:

• Developmental capability
• Access to the substance
• Exposure environment
• Consistency of the history
• Recurrent unexplained illness
• Whether other household members are affected
• Broader safeguarding concerns

Prognosis

Mild exposures can resolve completely.

Severe acute poisoning can cause:

• Refractory shock
• Dysrhythmias
• Multiorgan failure
• Encephalopathy
• Death

Delayed complications may include:

• Persistent painful polyneuropathy
• Weakness
• Hematologic abnormalities
• Residual neurologic impairment

Neuropathy can take months to improve and may not resolve completely.

Important Modernization of the Older Source

• Arsenic is a metalloid, although often grouped clinically with heavy-metal poisonings.
• Toxicity depends strongly on arsenic species; inorganic arsenic is much more clinically important than most seafood-derived organic forms.
• Seafood can markedly elevate total urine arsenic without representing dangerous inorganic arsenic exposure.
• Arsenic speciation is therefore important when interpreting elevated urinary concentrations.
• Blood arsenic falls relatively rapidly and is less useful than urine for many exposure assessments.
• Garlic odor is neither sensitive nor specific.
• Mees lines are delayed and not specific for arsenic.
• Acute poisoning classically produces severe GI toxicity, shock, QT abnormalities, and multiorgan dysfunction.
• Painful sensorimotor peripheral neuropathy may emerge days to weeks later and can mimic Guillain–Barré syndrome.
• Serial CBC monitoring may be necessary because marrow suppression can be delayed.
• Chronic inorganic arsenic exposure is strongly associated with skin, lung, and bladder cancers.
• Arsine gas is a separate syndrome characterized primarily by massive intravascular hemolysis.
• Activated charcoal does not reliably adsorb arsenic and should not be considered standard metal decontamination.
• Ipecac and routine gastric lavage are obsolete.
• Whole-bowel irrigation is reserved for selected substantial exposures with retained GI material.
• BAL, succimer, and DMPS are potential chelators depending on severity and availability.
• Severe symptomatic poisoning may justify chelation before laboratory confirmation after specialist consultation.
• Chelation should not be started or stopped solely according to one historical urinary arsenic threshold.
• Trendelenburg and routine dopamine-first shock management are outdated.
• Hemodialysis is not a routine substitute for chelation.
• Chronic poisoning requires source identification and removal, often involving occupational or public-health assessment.
• Rigid age-based assumptions about intentional poisoning or neglect are obsolete.

Key Points

• Acute inorganic arsenic → severe gastroenteritis + fluid loss/shock + cardiac toxicity.
• QT prolongation and ventricular dysrhythmias can occur in severe poisoning.
• Delayed painful stocking-glove sensorimotor neuropathy is characteristic.
• Bone-marrow suppression may appear several days after acute poisoning.
• Chronic exposure can cause mottled pigmentation, palmar/plantar hyperkeratosis, neuropathy, and increased cancer risk.
• Urinary arsenic with speciation is generally more informative than relying on blood arsenic alone.
• Recent seafood can falsely suggest toxic exposure if only total urine arsenic is measured.
• BAL, DMSA, or DMPS may be used for clinically significant inorganic arsenic poisoning with specialist guidance.
• Do not delay appropriate chelation in a severely symptomatic patient solely while awaiting arsenic levels.
• Arsine gas poisoning is different: think intravascular hemolysis and AKI.

Toxicology – HIV Reverse Transcriptase Inhibitors

Core Concept

Reverse transcriptase inhibitors are major components of combination antiretroviral therapy (ART) for HIV.

The older source focuses on:

Nucleoside/nucleotide reverse transcriptase inhibitors – NRTIs

• Zidovudine
• Lamivudine
• Didanosine
• Stavudine
• Zalcitabine

Modern practice also commonly includes:

• Tenofovir
• Emtricitabine
• Abacavir

Non-nucleoside reverse transcriptase inhibitors – NNRTIs

• Nevirapine

Other NNRTIs include:

• Efavirenz
• Etravirine
• Rilpivirine
• Doravirine

Several drugs emphasized in the older chapter—particularly zalcitabine, stavudine, and didanosine—are now obsolete or rarely used because safer antiretroviral regimens are available.

Acute isolated overdose is usually mild, but clinically important toxicity can result from mitochondrial injury, hepatic injury, metabolic acidosis, marrow suppression, pancreatitis, renal injury, hypersensitivity, or agent-specific CNS/cardiac effects.

Mechanism of Antiviral Action

Reverse transcriptase converts viral RNA into DNA.

NRTIs

After intracellular activation, NRTIs mimic normal nucleosides/nucleotides.

Their incorporation into viral DNA interferes with continued DNA synthesis and inhibits reverse transcription.

NNRTIs

NNRTIs bind directly to HIV-1 reverse transcriptase at an allosteric site and alter enzyme function.

They do not require incorporation into viral DNA.

Why Older NRTIs Cause Mitochondrial Toxicity

Several older NRTIs inhibit human mitochondrial DNA polymerase-γ to varying degrees.

This can impair mitochondrial DNA replication and oxidative phosphorylation.

The resulting toxicity may include:

• Lactic acidosis
• Hepatic steatosis
• Peripheral neuropathy
• Myopathy
• Pancreatitis

The older “d-drugs”—particularly didanosine and stavudine—have substantially greater mitochondrial toxicity than most modern NRTIs.

Acute Overdose

A single acute ingestion of many NRTIs produces limited immediate toxicity.

Possible symptoms include:

• Nausea
• Vomiting
• Diarrhea
• Headache
• Fatigue
• Dizziness
• Somnolence

Serious toxicity is more often associated with:

• Chronic treatment
• Repeated dosing errors
• Drug interactions
• Renal/hepatic impairment
• Older, more toxic NRTIs

1. Zidovudine – AZT

Zidovudine was one of the earliest effective antiretroviral drugs.

Its most important toxicities include:

• Bone-marrow suppression
• Anemia
• Neutropenia
• Myopathy
• Mitochondrial toxicity
• Lactic acidosis in severe chronic toxicity

Zidovudine Bone-Marrow Toxicity

Clinically important findings may include:

• Macrocytic anemia
• Neutropenia
• Leukopenia

Macrocytosis is common during zidovudine treatment and does not by itself establish dangerous toxicity.

Severe anemia or neutropenia requires assessment of both the medication and other potential causes.

Zidovudine Myopathy

Long-term exposure can produce mitochondrial skeletal-muscle injury.

Possible manifestations include:

• Proximal weakness
• Myalgia
• Exercise intolerance
• Elevated CK in some patients

This is primarily a chronic toxicity rather than the expected consequence of an isolated overdose.

2. Lamivudine – 3TC

Lamivudine generally has a relatively favorable toxicity profile.

Acute overdose is usually mild.

Possible effects include:

• Nausea
• Vomiting
• Headache
• Fatigue
• GI discomfort

Serious mitochondrial toxicity is much less characteristic than with didanosine or stavudine.

Lamivudine and Renal Function

Lamivudine is substantially renally eliminated.

Reduced kidney function can increase exposure, so dosing may require adjustment depending on the formulation and treatment regimen.

Lamivudine and Hepatitis B

Lamivudine also has activity against hepatitis B virus (HBV).

An important clinical issue is that stopping HBV-active therapy in a person with HBV infection can lead to hepatitis exacerbation.

Therefore, abnormal liver tests after discontinuation should not automatically be interpreted as direct lamivudine hepatotoxicity.

3. Didanosine – ddI

Didanosine is now rarely used because of significant toxicity.

Important adverse effects include:

• Pancreatitis
• Peripheral neuropathy
• Lactic acidosis
• Hepatic injury
• Noncirrhotic portal hypertension

Didanosine Pancreatitis

Pancreatitis was one of the most important dose-limiting complications.

Possible findings include:

• Severe epigastric pain
• Nausea/vomiting
• Elevated lipase
• Systemic inflammatory complications in severe disease

Lipase is generally more useful than amylase alone when pancreatitis is suspected.

Didanosine Peripheral Neuropathy

Mitochondrial toxicity can produce a painful, predominantly distal sensory neuropathy.

Symptoms include:

• Burning
• Tingling
• Numbness
• Distal pain

Toxicity may be increased when combined with other neurotoxic medications.

Didanosine Hepatic/Vascular Toxicity

Chronic didanosine exposure has been associated with noncirrhotic portal hypertension.

This may lead to:

• Splenomegaly
• Thrombocytopenia
• Esophageal varices
• Portal hypertensive bleeding

This is an important later-recognized toxicity absent from many older references.

4. Stavudine – d4T

Stavudine is another older NRTI now rarely used because of substantial mitochondrial toxicity.

Major complications include:

• Peripheral neuropathy
• Lactic acidosis
• Hepatic steatosis
• Pancreatitis
• Lipodystrophy

Stavudine and Lactic Acidosis

Stavudine is among the NRTIs most strongly associated with mitochondrial dysfunction and severe hyperlactatemia.

Possible manifestations include:

• Progressive weakness
• Nausea/vomiting
• Abdominal discomfort
• Dyspnea
• Tachypnea
• Hepatic dysfunction
• High anion-gap metabolic acidosis
• Elevated lactate

Severe cases may progress to multiorgan dysfunction.

5. Zalcitabine – ddC

Zalcitabine is an obsolete antiretroviral agent.

Its historical toxicities included:

• Painful peripheral neuropathy
• Pancreatitis
• Oral/esophageal ulceration
• Hepatic injury
• Cytopenias

It has essentially no role in contemporary HIV therapy.

6. Tenofovir

Tenofovir is highly relevant to modern ART.

Two major prodrug formulations are:

• Tenofovir disoproxil fumarate – TDF
• Tenofovir alafenamide – TAF

TDF produces greater systemic tenofovir exposure and has greater renal and bone toxicity than TAF.

Tenofovir Nephrotoxicity

Tenofovir can injure proximal renal tubular cells.

Possible manifestations include:

• Rising creatinine
• Proteinuria
• Normoglycemic glycosuria
• Phosphate wasting
• Hypophosphatemia
• Bicarbonate wasting
• Fanconi syndrome
• AKI

Long-term tubular phosphate wasting may contribute to bone disease.

TDF vs TAF

TAF generally has less renal and bone toxicity than TDF because it achieves lower circulating tenofovir concentrations while delivering active drug intracellularly.

This distinction is important when evaluating modern antiretroviral toxicity.

7. Emtricitabine – FTC

Emtricitabine is structurally related to lamivudine and is generally well tolerated.

Acute toxicity is usually limited.

A characteristic benign adverse effect during therapy can be:

• Skin hyperpigmentation, particularly involving palms or soles

Like lamivudine and tenofovir, it also has activity against HBV, making treatment interruption relevant in patients with hepatitis B.

8. Abacavir

Abacavir has an important distinctive toxicity:

Potentially severe hypersensitivity reaction

Risk is strongly associated with HLA-B*57:01.

Abacavir Hypersensitivity

Possible manifestations include combinations of:

• Fever
• Rash
• Malaise
• GI symptoms
• Respiratory symptoms

The reaction can worsen rapidly with continued administration.

Patients are therefore screened for HLA-B*57:01 before starting abacavir.

Critical Abacavir Principle

If true abacavir hypersensitivity is suspected:

Abacavir should be stopped and must not be restarted.

Rechallenge can provoke a rapid, potentially life-threatening reaction.

This is not an overdose phenomenon but is one of the most important safety issues involving an NRTI.

9. Nevirapine

Nevirapine is an NNRTI.

Acute overdose experience is limited, and isolated exposure often produces relatively mild effects.

More important therapeutic toxicities are:

• Hepatotoxicity
• Severe cutaneous hypersensitivity

Nevirapine Hepatotoxicity

Nevirapine can cause clinically significant hepatitis, sometimes associated with systemic hypersensitivity.

Possible findings include:

• Fatigue
• Nausea
• Abdominal discomfort
• Elevated transaminases
• Jaundice
• Severe hepatic injury

Risk is particularly important during the early phase of treatment.

Nevirapine Severe Cutaneous Reactions

Possible reactions include:

• Maculopapular rash
• SJS
• TEN
• DRESS-like systemic hypersensitivity

Warning findings include:

• Painful skin
• Blistering
• Mucosal involvement
• Facial edema
• Fever
• Eosinophilia
• Internal-organ involvement

These require immediate drug cessation and urgent evaluation.

10. Efavirenz

Efavirenz is an NNRTI with characteristic CNS and psychiatric adverse effects.

Possible manifestations include:

• Dizziness
• Abnormal dreams
• Insomnia
• Impaired concentration
• Ataxia
• Confusion
• Hallucinations

These effects are most prominent early during treatment.

11. Rilpivirine

Rilpivirine generally has a favorable toxicity profile but can affect cardiac repolarization at excessive exposure.

Potential concern:

• QT prolongation

Risk increases with interacting medications or other QT-prolonging drugs.

Mitochondrial Toxicity Syndrome

The classic severe NRTI toxicity syndrome consists of:

Mitochondrial dysfunction → impaired oxidative phosphorylation → lactate accumulation ± hepatic steatosis

Possible findings include:

• Malaise
• Weakness
• Nausea
• Vomiting
• Abdominal pain
• Weight loss
• Dyspnea/tachypnea
• Hepatomegaly
• Metabolic acidosis

This is much more strongly associated with older NRTIs than with most current regimens.

Lactic Acidosis

Suspected severe mitochondrial toxicity warrants assessment of:

• Lactate
• Electrolytes
• Bicarbonate
• Anion gap
• Blood gas when clinically indicated
• Glucose
• Renal function
• Liver function

Marked lactate elevation should not automatically be attributed to an NRTI.

Also consider:

• Sepsis
• Shock
• Seizures
• Hypoxia
• Metformin
• Cyanide
• Other mitochondrial toxins

Peripheral Neuropathy

The older NRTIs most strongly associated with toxic neuropathy include:

• Didanosine
• Stavudine
• Zalcitabine

Symptoms are usually:

• Distal
• Symmetric
• Sensory
• Painful

Modern NRTIs have a substantially lower neuropathy burden.

Pancreatitis

Historically important agents include:

• Didanosine
• Stavudine

If pancreatitis is suspected, evaluate:

• Symptoms
• Lipase
• Hydration
• Electrolytes
• Organ dysfunction

Other causes of pancreatitis should also be considered.

Hepatotoxicity

Liver injury can occur through several different mechanisms:

• Direct drug toxicity
• Mitochondrial toxicity
• Hypersensitivity
• HBV flare after withdrawal of HBV-active therapy
• Drug interactions
• Underlying viral hepatitis

The mechanism therefore matters when interpreting elevated liver enzymes.

Bone-Marrow Toxicity

Most strongly associated historically with zidovudine.

Monitor for:

• Anemia
• Neutropenia
• Other cytopenias

CBC abnormalities in a person with HIV have a broad differential and should not automatically be attributed to ART.

Drug Interactions

Reverse transcriptase inhibitors vary considerably in interaction potential.

NNRTIs may induce or inhibit CYP enzymes, while many NRTIs have relatively fewer CYP-mediated interactions.

Always review:

• Complete ART regimen
• Antimicrobials
• Antiseizure medications
• Psychiatric medications
• Cardiovascular drugs
• Supplements
• Recreational substances

Modern fixed-dose combination tablets make identification of every active ingredient particularly important.

Diagnosis

Determine:

• Exact drug or combination product
• Amount
• Timing
• Acute vs chronic/repeated exposure
• Renal function
• Hepatic function
• Other ART
• Coingestants
• Drug interactions
• HBV coinfection when relevant

Symptoms may overlap with HIV itself, opportunistic infections, and adverse effects from other medications.

Laboratory Evaluation

Minor asymptomatic acute exposures may need little investigation.

For significant or symptomatic exposure, testing can include:

• CBC
• Glucose
• Electrolytes
• Bicarbonate
• BUN/creatinine
• Liver tests

Depending on the suspected agent or syndrome:

• Lactate
• Blood gas
• Lipase
• CK
• Phosphate
• Urinalysis

ECG

Routine cardiac monitoring is not required for every NRTI exposure.

Obtain an ECG when there is:

• Syncope
• Palpitations
• Significant overdose
• Electrolyte disturbance
• Suspected QT-active NNRTI
• Relevant coingestant

The older recommendation for universal cardiac monitoring of nucleoside analog toxicity is unnecessarily broad.

Serum Drug Concentrations

Routine serum NRTI/NNRTI concentrations generally do not guide acute overdose treatment.

Management is based primarily on:

• Clinical status
• Acid–base findings
• Renal/hepatic function
• CBC
• Agent-specific complications

Initial Management

General approach:

Airway/breathing → circulation → identify every ART component → evaluate renal/hepatic function → assess metabolic toxicity → identify coingestants/interactions → supportive care

Most isolated acute ingestions require conservative treatment.

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a clinically important recent ingestion when the expected benefit exceeds aspiration risk and the airway is safe.

Routine decontamination is unnecessary for most minor exposures.

Seizures

Seizures are uncommon with uncomplicated NRTI overdose.

If they occur:

Benzodiazepines are first-line.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic treatment.

Correct:

• Hypoglycemia
• Hypoxia
• Electrolyte disturbances
• Severe acid–base abnormalities

Also investigate coingestants and CNS disease.

Hypotension

Significant hypotension is not a characteristic uncomplicated reverse transcriptase inhibitor toxidrome.

If present, consider:

• Dehydration
• Sepsis
• Lactic acidosis
• Anaphylaxis/hypersensitivity
• Coingestants
• Other medication toxicity

Use isotonic fluid when appropriate.

Persistent vasodilatory shock generally favors norepinephrine rather than routine dopamine-first treatment.

Trendelenburg positioning is outdated.

Enhanced Elimination

There is no universal role for extracorporeal removal.

Dialyzability varies substantially between drugs.

The older suggestion that didanosine dialysis should routinely be used after overdose is not supported as a general management strategy.

Renal replacement therapy remains appropriate for conventional indications such as:

• Severe renal failure
• Refractory electrolyte disturbance
• Severe acid–base disturbance

Agent-specific toxicology guidance should determine whether extracorporeal drug removal adds meaningful benefit.

No Universal Antidote

There is no general antidote for NRTI or NNRTI poisoning.

Management consists of:

Stop further exposure + supportive care + correct metabolic abnormalities + manage agent-specific organ toxicity

Observation and Follow-Up

A universal observation period is inappropriate.

Acute symptoms may resolve quickly, while other toxicities can be delayed or result from cumulative treatment.

Follow-up may require:

• CBC
• Liver tests
• Renal function
• Lactate
• Lipase
• Neurologic examination

depending on the implicated drug.

Admission

Hospitalization may be appropriate for:

• Significant lactic acidosis
• Hepatic failure
• Pancreatitis
• Severe cytopenias
• AKI/Fanconi syndrome
• Severe peripheral neurologic toxicity
• Seizures
• Persistent altered mental status
• SJS/TEN or systemic hypersensitivity
• Hemodynamic instability

ICU care is appropriate for severe metabolic acidosis, shock, respiratory failure, status epilepticus, fulminant hepatic failure, or multiorgan dysfunction.

Pregnancy and Breastfeeding

The historical FDA pregnancy letter categories are obsolete.

Modern HIV care strongly emphasizes maintaining effective ART during pregnancy because viral suppression protects both:

• Maternal health
• The fetus/newborn from perinatal HIV transmission

Drug selection depends on:

• Current treatment guidelines
• Resistance profile
• Previous ART
• Viral suppression
• Drug interactions
• Pregnancy pharmacokinetics
• Maternal/fetal safety data

Older blanket Category B/C descriptions should not guide modern therapy.

Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are outdated.

Assess pediatric exposures according to:

• Developmental ability
• Access to medication
• Circumstances
• Consistency of history
• Recurrent unexplained exposures
• Broader safeguarding concerns

Prognosis

Most isolated acute NRTI/NNRTI overdoses have a favorable outcome.

Serious morbidity is more likely from:

• Mitochondrial lactic acidosis
• Severe hepatotoxicity
• Pancreatitis
• Profound marrow suppression
• Severe hypersensitivity
• Renal tubular injury
• Chronic peripheral neuropathy

The older NRTIs account for many of the historically severe mitochondrial complications and are now rarely used.

Important Modernization of the Older Source

• Modern reverse transcriptase inhibitors include many agents absent from the historical chapter, especially tenofovir, emtricitabine, and abacavir.
• Didanosine, stavudine, and zalcitabine are obsolete or rarely used because of toxicity.
• NRTI mitochondrial toxicity results partly from inhibition of mitochondrial DNA polymerase-γ.
• Older NRTIs can cause lactic acidosis, hepatic steatosis, neuropathy, myopathy, and pancreatitis.
• Zidovudine → anemia/neutropenia and chronic myopathy.
• Didanosine → pancreatitis, neuropathy, mitochondrial toxicity, and noncirrhotic portal hypertension.
• Stavudine → neuropathy, lactic acidosis, hepatic steatosis, and lipodystrophy.
• Tenofovir, particularly TDF → proximal tubular injury/Fanconi syndrome and bone toxicity.
• TAF generally has less renal and bone toxicity than TDF.
• Abacavir → HLA-B*57:01-associated hypersensitivity; suspected true hypersensitivity means no rechallenge.
• Nevirapine → severe hepatotoxicity and serious cutaneous hypersensitivity.
• Efavirenz is particularly associated with CNS/neuropsychiatric adverse effects.
• Rilpivirine can contribute to QT prolongation at excessive exposure.
• Stopping lamivudine, emtricitabine, or tenofovir in a patient with HBV can precipitate a hepatitis B flare.
• Universal cardiac monitoring is unnecessary for uncomplicated NRTI exposure.
• Serum antiretroviral concentrations rarely guide acute overdose management.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and routine dopamine-first shock management are outdated.
• Routine dialysis is not a universal treatment for these drugs.
• Historical FDA pregnancy categories are obsolete.
• Modern ART toxicity must be interpreted in the context of fixed-dose combinations, drug interactions, HIV itself, and coinfections.

Key Points

• Reverse transcriptase inhibitors are divided into NRTIs and NNRTIs.
• Acute isolated overdose is usually relatively mild; important toxicity is often agent-specific or cumulative.
• Older NRTIs → mitochondrial toxicity, including lactic acidosis, neuropathy and hepatic injury.
• Zidovudine → marrow suppression.
• Didanosine → pancreatitis + neuropathy.
• Stavudine → neuropathy + lactic acidosis.
• Tenofovir → proximal renal tubular toxicity/Fanconi syndrome, especially TDF.
• Abacavir → potentially life-threatening hypersensitivity; never rechallenge after true hypersensitivity.
• Nevirapine → hepatotoxicity + severe cutaneous reactions.
• There is no universal specific antidote.
• Management is primarily supportive, agent-specific, and guided by metabolic, hepatic, renal, hematologic, and neurologic complications.

Toxicology – HIV Protease Inhibitors

Core Concept

HIV protease inhibitors (PIs) are antiretroviral drugs that inhibit the viral protease required for maturation of infectious HIV particles.

Older agents include:

• Ritonavir
• Indinavir
• Saquinavir

Other important PIs include:

• Darunavir
• Atazanavir
• Lopinavir
• Fosamprenavir

Some older agents such as indinavir and saquinavir are now rarely used in contemporary HIV treatment.

Acute isolated PI overdose is usually mild to moderate, with GI symptoms predominating. More clinically important toxicity often results from:

• Drug–drug interactions
• Hepatic dysfunction
• Chronic metabolic effects
• Agent-specific cardiac toxicity
• Renal complications
• Toxicity of another drug whose concentration has been increased by a pharmacokinetic booster

There is no specific antidote for PI overdose.

Mechanism

HIV initially produces large viral polyproteins.

HIV protease normally cleaves these precursor proteins into functional viral components.

Protease inhibitors block this process:

Protease inhibition → failure of viral protein processing → immature, noninfectious viral particles

They are generally administered as part of combination antiretroviral therapy rather than alone.

Pharmacokinetic Boosting

A major modern concept is the use of pharmacokinetic boosters.

Ritonavir

At low doses, ritonavir is commonly used primarily to inhibit drug metabolism and increase exposure to another PI.

Cobicistat

Cobicistat is another commonly used pharmacokinetic enhancer, although it has no useful anti-HIV activity by itself.

This makes drug interactions one of the most important clinical issues in PI toxicity.

Ritonavir and CYP3A

Ritonavir is a potent inhibitor of CYP3A and several drug transport pathways.

It can dramatically increase concentrations of susceptible medications.

Therefore, in a patient taking ritonavir, toxicity may arise not from ritonavir itself but from accumulation of another medication.

Drug Interactions – Major Toxicology Issue

Potentially important interacting drug groups include:

• Certain sedatives
• Opioids
• Antiarrhythmics
• Calcium-channel blockers
• Some statins
• Corticosteroids
• Anticoagulants
• Antiseizure medications
• Immunosuppressants
• Antimicrobials
• Other antiretroviral drugs

The exact interaction depends on the specific PI and accompanying medication.

Interaction Pattern

A useful approach is:

PI/booster + CYP3A substrate → reduced metabolism → increased substrate concentration → secondary toxicity

Possible secondary syndromes include:

• Excessive sedation
• Respiratory depression
• Hypotension
• Bradycardia
• Dysrhythmia
• Bleeding
• Myopathy/rhabdomyolysis
• Endocrine abnormalities

Ritonavir and Corticosteroids

An important modern interaction involves corticosteroids metabolized through CYP3A.

Ritonavir or cobicistat can markedly increase systemic corticosteroid exposure.

This can cause:

• Iatrogenic Cushing syndrome
• Adrenal suppression
• Metabolic complications

This interaction can occur even with some inhaled, injected, or intranasal corticosteroids.

Ritonavir and Statins

Some statins depend heavily on CYP3A metabolism.

Markedly increased exposure can cause:

Myopathy → rhabdomyolysis → hyperkalemia/AKI

Not every statin has the same interaction potential, so drug-specific interaction checking is required.

Rifampin Interaction – Correction

The older source suggests rifampin may increase PI concentrations.

This is generally backwards.

Rifampin is a potent enzyme inducer and can markedly reduce concentrations of many protease inhibitors.

This can result in:

• Loss of antiviral efficacy
• Virologic failure
• Resistance concerns

Many rifampin–PI combinations are therefore contraindicated or require an alternative regimen.

Acute Overdose

Isolated oral PI overdose most commonly causes:

• Nausea
• Vomiting
• Diarrhea
• Abdominal discomfort
• Headache
• Dizziness

Serious toxicity from a single isolated ingestion is uncommon, although the specific agent, formulation, comorbidities, and coingestants matter.

1. Gastrointestinal Toxicity

GI adverse effects are common during both therapeutic use and excessive exposure.

Possible symptoms include:

• Nausea
• Vomiting
• Diarrhea
• Abdominal discomfort
• Reduced appetite

Severe vomiting or diarrhea can produce:

• Dehydration
• Electrolyte abnormalities
• AKI

2. Hepatotoxicity

Protease inhibitors can produce elevations in liver enzymes and, less commonly, clinically significant hepatic injury.

Risk may be increased by:

• Preexisting liver disease
• Viral hepatitis coinfection
• Other hepatotoxic medications
• Complex multidrug therapy

Evaluation of significant toxicity may include:

• AST/ALT
• Bilirubin
• Alkaline phosphatase
• Coagulation studies if severe

3. Cardiac Toxicity

Cardiac electrophysiologic effects vary substantially between agents.

Potential abnormalities include:

• PR prolongation
• QT prolongation
• Bradyarrhythmia
• Ventricular dysrhythmia

These are not uniform class effects.

Atazanavir

Atazanavir can produce PR-interval prolongation and AV conduction abnormalities.

It also commonly causes indirect hyperbilirubinemia during therapy.

Saquinavir

Saquinavir has been associated with both:

• QT prolongation
• PR prolongation

Its use has declined considerably.

A significant overdose or interacting-drug exposure warrants ECG assessment.

ECG

Obtain an ECG when there is:

• Significant overdose
• Syncope
• Palpitations
• Bradycardia
• Hypotension
• Known QT/PR-active PI
• Other QT-prolonging drugs
• Significant electrolyte disturbance

Routine prolonged cardiac monitoring is unnecessary after every small asymptomatic exposure.

4. Renal Toxicity

The older source incorrectly attributes a common stone risk to ritonavir.

The classic PI associated with nephrolithiasis is indinavir.

Indinavir Nephrolithiasis

Indinavir can crystallize in urine and cause:

• Flank pain
• Hematuria
• Dysuria
• Crystalluria
• Nephrolithiasis
• Obstructive uropathy
• AKI

Adequate hydration during therapeutic use reduces risk.

Atazanavir can also rarely contribute to urinary calculi.

Cobicistat and Creatinine

Although not itself a protease inhibitor, cobicistat is frequently encountered with modern PI regimens.

It can inhibit tubular secretion of creatinine.

Therefore:

Serum creatinine may rise without a true reduction in glomerular filtration.

As with trimethoprim, this laboratory effect must be distinguished from genuine AKI.

5. Metabolic Toxicity

Long-term PI therapy can contribute to:

• Insulin resistance
• Hyperglycemia
• New or worsening diabetes
• Dyslipidemia
• Altered body-fat distribution

These are primarily chronic treatment effects, not characteristic findings after a single acute overdose.

Lipodystrophy

Older PI-containing antiretroviral regimens were particularly associated with metabolic and body-composition changes.

Possible findings included:

• Peripheral fat loss
• Central fat accumulation
• Dyslipidemia
• Insulin resistance

Modern antiretroviral regimens have substantially changed this toxicity profile.

6. Hyperbilirubinemia

Atazanavir inhibits bilirubin conjugation and can produce:

• Elevated unconjugated bilirubin
• Scleral icterus
• Jaundice

This can occur without significant hepatocellular injury.

Therefore:

Jaundice during atazanavir therapy does not automatically mean hepatitis.

Liver enzymes and the bilirubin pattern help distinguish the two.

7. Pancreatitis

Pancreatitis has occasionally been reported during antiretroviral therapy.

However, causation may be difficult to assign because patients often receive several medications with overlapping metabolic effects.

Symptoms include:

• Epigastric pain
• Nausea/vomiting
• Pain radiating to the back

Lipase is generally preferred over relying on amylase alone when pancreatitis is suspected.

8. Neurologic Effects

Possible adverse effects include:

• Headache
• Dizziness
• Paresthesias
• Taste disturbance

Severe:

• Confusion
• Seizures
• Coma

are not typical findings of uncomplicated isolated PI overdose.

When they occur, evaluate carefully for:

• Coingestants
• Drug interactions
• Metabolic disturbances
• CNS infection
• Other neurologic disease

The older source overstates peripheral neuropathy as a defining PI class toxicity.

9. Hematologic Effects

Cytopenias may occur in patients receiving HIV therapy, but attribution is often complicated by:

• HIV itself
• Opportunistic infections
• Other antiretroviral agents
• Bone-marrow suppressive medications
• Nutritional disease

CBC testing should therefore be clinically directed rather than assuming marrow suppression is a characteristic acute PI toxidrome.

Diagnosis

Determine:

• Exact PI
• Whether ritonavir or cobicistat is present
• Amount and timing
• Acute vs chronic exposure
• Complete medication list
• Renal function
• Hepatic function
• Coingestants

Because interactions are so important, medication reconciliation is often more informative than the PI dose alone.

Combination Products

Modern antiretroviral therapy frequently uses fixed-dose combinations.

Always identify every active ingredient.

Toxicity attributed to a “protease inhibitor tablet” may actually arise from:

• Another antiretroviral
• Pharmacokinetic booster
• Interacting medication
• Coingestant

Laboratory Evaluation

Small asymptomatic isolated exposures may require no laboratory investigation.

For symptomatic or clinically significant exposures, consider:

• Glucose
• Electrolytes
• BUN/creatinine
• Liver tests

Depending on presentation:

• CBC
• Bilirubin fractionation
• Lipase
• CK
• Urinalysis
• Potassium
• Magnesium

Rhabdomyolysis

If an interacting medication such as a susceptible statin is involved, assess for:

• Muscle pain
• Weakness
• Dark urine
• Elevated CK
• Hyperkalemia
• AKI

This represents interaction-mediated toxicity, not necessarily direct PI muscle toxicity.

Serum Protease-Inhibitor Levels

Routine serum PI concentrations are generally not useful in acute poisoning.

Treatment is based on:

• Symptoms
• ECG
• Organ function
• Identification of interacting drugs

Initial Management

General approach:

Airway/breathing → circulation → exact drug/formulation → complete medication reconciliation → ECG when indicated → renal/hepatic/metabolic assessment → supportive care

Most isolated acute ingestions require only symptomatic management.

GI Decontamination

Do not induce vomiting.

Ipecac has no role.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The exposure is clinically important
• The drug is adsorbable
• Airway protection is adequate
• Aspiration risk is acceptable

Most small uncomplicated exposures need no decontamination.

Hypotension

Significant hypotension is unusual after isolated PI ingestion.

If present, investigate:

• Dehydration
• Interacting cardiovascular medications
• Dysrhythmia
• Sepsis
• Anaphylaxis
• Coingestants

Treat appropriate volume depletion with isotonic crystalloid.

Persistent vasodilatory shock generally favors norepinephrine rather than a routine dopamine-first strategy.

Trendelenburg positioning is outdated.

Seizures

Seizures are unusual in uncomplicated PI poisoning.

If they occur:

• Consider coingestants and metabolic causes
• Check glucose and electrolytes
• Treat hypoxia

Benzodiazepines are first-line for toxicologic seizures.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic therapy.

Dysrhythmias

Management is based on:

• Exact rhythm
• PR interval
• QRS duration
• QT interval
• Electrolytes
• Hemodynamic status
• Interacting medications

Correct potassium and magnesium abnormalities and discontinue relevant interacting/QT-active medications when possible.

There is no PI-specific universal antiarrhythmic regimen.

Enhanced Elimination

Hemodialysis generally has little role in removing protease inhibitors because many have:

• High protein binding
• Large distribution characteristics

Dialysis may still be required for conventional indications, such as severe renal failure or refractory electrolyte abnormalities.

No Specific Antidote

There is no specific antidote for PI overdose.

Treatment consists primarily of:

Supportive care + stopping further exposure + identifying interactions + treating secondary drug toxicity

Observation and Disposition

A universal observation period is unnecessary.

Disposition depends on:

• Exact PI
• Amount
• Symptoms
• ECG
• Coingestants
• Drug interactions
• Renal/hepatic function
• Clinical trajectory

Patients with a minor isolated exposure who remain well generally have a favorable course.

Admission

Hospitalization may be appropriate for:

• Persistent severe vomiting/dehydration
• AKI
• Significant hepatotoxicity
• Pancreatitis
• Rhabdomyolysis
• Significant PR/QT abnormality
• Dysrhythmia
• Hypotension
• Severe interaction-mediated toxicity
• Seizures or persistent altered mental status

ICU care is reserved for severe cardiovascular, respiratory, neurologic, or multiorgan toxicity.

Pregnancy and Breastfeeding

Historical FDA pregnancy letter categories are obsolete.

Antiretroviral therapy during pregnancy is important for both maternal health and prevention of perinatal HIV transmission.

Selection of a PI-containing regimen depends on:

• Current HIV treatment guidelines
• Resistance history
• Maternal viral suppression
• Drug interactions
• Pharmacokinetic changes during pregnancy
• Maternal and fetal safety data

The older blanket Category B description is therefore inadequate.

Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are outdated.

Pediatric exposure should instead be assessed according to:

• Developmental capability
• Medication accessibility
• Circumstances
• Consistency of history
• Recurrent unexplained exposure
• Broader safeguarding concerns

Prognosis

Most isolated acute PI overdoses have a favorable prognosis.

More serious outcomes are usually related to:

• Major drug interactions
• Cardiac conduction abnormalities
• Severe dehydration
• Renal injury
• Hepatic dysfunction
• Rhabdomyolysis
• Significant coingestants

Important Modernization of the Older Source

• Modern HIV treatment uses combination antiretroviral therapy; older agents such as indinavir and saquinavir are now rarely used.
• Acute isolated PI overdose is generally GI-predominant and relatively mild.
• Drug interactions are one of the major toxicologic concerns.
• Ritonavir is now commonly encountered as a pharmacokinetic booster because of potent CYP3A inhibition.
• Cobicistat is another important modern booster.
• Severe symptoms may reflect toxicity from an interacting drug rather than the PI itself.
• Ritonavir/cobicistat can markedly increase systemic exposure to certain corticosteroids, causing Cushing syndrome and adrenal suppression.
• Interactions with susceptible statins can produce rhabdomyolysis and AKI.
• Rifampin generally reduces, rather than increases, concentrations of many PIs through enzyme induction.
• Indinavir, not ritonavir, is the classic PI associated with nephrolithiasis/crystalluria.
• Atazanavir may cause benign unconjugated hyperbilirubinemia without hepatocellular injury.
• Cobicistat can increase creatinine by inhibiting tubular secretion without necessarily lowering true GFR.
• Cardiac toxicity is agent specific; atazanavir may prolong PR, while saquinavir has been associated with PR and QT abnormalities.
• Peripheral neuropathy is not a defining acute class toxicity.
• Severe CNS depression or seizures should trigger a search for coingestants, interactions, metabolic disease, or CNS pathology.
• Serum PI concentrations are generally not useful for acute management.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and routine dopamine-first shock management are outdated.
• Hemodialysis does not meaningfully enhance elimination of most PIs.
• Historical FDA pregnancy categories are obsolete.
• Fixed observation periods are unnecessary; disposition should be individualized.

Key Points

• Protease inhibitors block HIV protease and prevent viral maturation.
• Acute isolated overdose is usually mild and GI-predominant.
• Ritonavir is a potent pharmacokinetic booster and major source of drug interactions.
• Always review the entire medication list in suspected PI toxicity.
• Ritonavir/cobicistat + interacting drug can produce toxicity far more important than the PI exposure itself.
• Indinavir → crystalluria/nephrolithiasis/obstructive renal injury.
• Atazanavir → unconjugated hyperbilirubinemia and possible PR prolongation.
• Some older PIs can affect cardiac conduction and repolarization.
• There is no specific antidote.
• Most treatment consists of supportive care, recognition of interactions, and targeted management of complications.

Toxicology – Selected Antiviral Drugs

Core Concept

This older chapter combines several pharmacologically unrelated antiviral drugs:

• Acyclovir / valacyclovir
• Famciclovir
• Amantadine / rimantadine
• Cidofovir
• Foscarnet
• Ganciclovir / valganciclovir
• Ribavirin

They do not produce a common antiviral toxidrome. Toxicity is best remembered by the characteristic organ injury of each drug:

• Acyclovir/valacyclovir → crystal nephropathy + neurotoxicity
• Amantadine → CNS + cardiac toxicity
• Cidofovir → proximal tubular nephrotoxicity/Fanconi syndrome
• Foscarnet → nephrotoxicity + major electrolyte disturbances
• Ganciclovir/valganciclovir → bone-marrow suppression + renal accumulation
• Ribavirin → hemolytic anemia

There is no universal antidote for this group.

1. Acyclovir and Valacyclovir

Acyclovir inhibits viral DNA polymerase after activation within infected cells.

Valacyclovir is the oral prodrug of acyclovir and has substantially greater oral bioavailability.

Famciclovir is similarly converted to the active antiviral penciclovir.

Acute uncomplicated oral overdose is often mild, but excessive systemic exposure—especially with renal dysfunction—can cause important renal and neurologic toxicity.

Acyclovir Crystal Nephropathy

Acyclovir has limited urinary solubility.

High tubular concentrations can result in:

Acyclovir precipitation → intratubular obstruction → crystal nephropathy → AKI

Risk is greatest with:

• High systemic exposure
• Rapid IV administration
• Dehydration
• Preexisting renal impairment
• Inadequate dose adjustment

Clinical Features of Acyclovir Nephrotoxicity

Possible findings include:

• Rising creatinine
• Reduced urine output
• Hematuria
• Crystalluria
• Flank discomfort
• AKI

Renal dysfunction then reduces acyclovir elimination, potentially increasing systemic exposure further.

Acyclovir/Valacyclovir Neurotoxicity

Accumulation can cause:

• Confusion
• Agitation
• Hallucinations
• Tremor
• Myoclonus
• Dysarthria
• Ataxia
• Somnolence
• Seizures
• Coma

The risk is particularly important in patients with renal impairment.

Acyclovir Neurotoxicity vs Viral Encephalitis

This distinction can be difficult because acyclovir is often being administered specifically for suspected CNS herpes infection.

Features favoring drug accumulation include:

• Development after acyclovir/valacyclovir exposure
• Renal dysfunction
• Myoclonus or prominent neuropsychiatric abnormalities
• Improvement after withdrawal and clearance of the drug

However, these findings are not sufficiently specific to exclude active viral encephalitis.

Clinical context, CSF studies, imaging, renal function, and treatment history must be integrated.

Acyclovir Management

Important measures include:

• Stop or appropriately reduce further exposure
• Correct dehydration when present
• Monitor renal function and urine output
• Avoid additional nephrotoxins
• Adjust future dosing for kidney function
• Treat neurologic complications supportively

Routine forced diuresis is inappropriate.

Hemodialysis and Acyclovir

Acyclovir is substantially dialyzable.

Hemodialysis can be useful in selected patients with:

• Severe renal failure
• Marked drug accumulation
• Severe or persistent neurotoxicity

It is not routinely required after a minor ingestion with normal renal function.

2. Famciclovir

Famciclovir is converted to penciclovir.

Acute overdose experience is limited, but uncomplicated exposures generally produce relatively mild effects such as:

• Nausea
• Headache
• GI discomfort
• Dizziness

Because active drug is eliminated renally, renal dysfunction can increase exposure.

Severe toxicity is considerably less characteristic than with drugs such as amantadine or foscarnet.

3. Amantadine

Amantadine deserves separate attention because its toxicity is substantially different from that of nucleoside antiviral agents.

Although historically used against influenza A, amantadine is no longer recommended for routine influenza treatment because of widespread viral resistance.

It remains clinically relevant primarily for neurologic indications such as Parkinsonian syndromes and drug-induced movement disorders.

Amantadine Toxicity

Amantadine overdose can produce severe:

• CNS excitation or depression
• Delirium
• Hallucinations
• Seizures
• Cardiac conduction abnormalities
• Ventricular dysrhythmias

It also has antimuscarinic-like properties.

Antimuscarinic Features

Possible findings include:

• Mydriasis
• Dry mouth
• Tachycardia
• Reduced bowel motility
• Urinary retention
• Agitation
• Hallucinations
• Hyperthermia

However, amantadine poisoning should not be reduced to a pure anticholinergic syndrome because cardiac and neurologic toxicity can dominate.

Cardiotoxicity

Severe amantadine poisoning can produce:

• Tachycardia
• QRS abnormalities
• QT abnormalities
• Ventricular ectopy
• Ventricular tachyarrhythmias
• Hypotension
• Cardiac arrest

Electrolyte disturbances can worsen electrical instability.

Hypokalemia

Hypokalemia has been described in severe amantadine poisoning and can contribute to ventricular dysrhythmias.

Therefore significant poisoning warrants careful monitoring of:

• Potassium
• Magnesium
• ECG

Amantadine and Renal Function

Amantadine is predominantly eliminated through the kidneys.

Renal impairment can therefore produce substantial accumulation even during apparently conventional treatment.

Older adults with declining kidney function are particularly vulnerable to:

• Hallucinations
• Confusion
• Myoclonus
• Delirium
• Other CNS toxicity

Amantadine Withdrawal

Abrupt discontinuation after chronic use can occasionally produce a withdrawal syndrome with:

• Delirium
• Agitation
• Worsening Parkinsonism

Rare severe syndromes resembling neuroleptic malignant syndrome have also been reported.

This is distinct from acute amantadine overdose.

Rimantadine

Rimantadine is another adamantane antiviral historically used for influenza A.

Because of widespread resistance, it is also no longer recommended for routine influenza therapy.

Its toxicity can include:

• CNS effects
• Antimuscarinic-like findings
• GI symptoms

Severe cardiac toxicity is generally more strongly associated with amantadine.

Physostigmine – Important Update

The older recommendation to consider physostigmine broadly for severe amantadine toxicity requires substantial caution.

Amantadine overdose can involve:

• QRS/conduction abnormalities
• Ventricular dysrhythmias
• Seizures

Therefore physostigmine is not a routine antidote.

It should only be considered in highly selected predominantly antimuscarinic delirium after ECG and seizure-risk assessment and with expert toxicology guidance.

Dialysis and Amantadine

Despite renal elimination, conventional hemodialysis removes relatively little amantadine because of its pharmacokinetic characteristics.

Thus the older claim that dialysis meaningfully lowers amantadine concentrations is misleading.

Management is primarily supportive.

4. Cidofovir

Cidofovir is a nucleotide analog historically important in treatment of selected severe viral infections, particularly CMV in immunocompromised patients.

Its defining toxicity is:

Dose-dependent proximal tubular injury

Cidofovir Nephrotoxicity

Proximal tubular dysfunction can produce:

• Rising creatinine
• Proteinuria
• Glycosuria despite normal blood glucose
• Phosphate wasting
• Bicarbonate wasting
• Electrolyte abnormalities
• Fanconi syndrome
• AKI

Cidofovir Risk Factors

Risk increases with:

• Preexisting renal dysfunction
• High exposure
• Other nephrotoxic drugs
• Inadequate renal-protective measures

Renal function and urinalysis are central to monitoring.

Probenecid and Cidofovir

Probenecid reduces active tubular uptake of cidofovir and is used with IV cidofovir to reduce nephrotoxicity.

Hydration is also part of standard nephroprotection.

However, probenecid should be understood primarily as a preventive component of prescribed cidofovir therapy, not as a universally established antidote after an overdose has already occurred.

5. Foscarnet

Foscarnet directly inhibits viral DNA polymerase without requiring intracellular phosphorylation.

Its major toxicities are:

• Nephrotoxicity
• Electrolyte disturbances

These can interact to produce severe neurologic and cardiac complications.

Foscarnet Nephrotoxicity

Foscarnet can cause:

• Rising creatinine
• Reduced GFR
• AKI
• Renal tubular dysfunction

Risk increases with:

• Dehydration
• High exposure
• Preexisting renal dysfunction
• Other nephrotoxins

Adequate hydration and renal dose adjustment are important during therapy.

Foscarnet Electrolyte Toxicity

Foscarnet can chelate divalent cations and disturb mineral metabolism.

Possible abnormalities include:

• Hypocalcemia
• Hypomagnesemia
• Hypokalemia
• Hypophosphatemia
• Sometimes hyperphosphatemia

Clinical Effects of Hypocalcemia

Patients may develop:

• Perioral tingling
• Paresthesias
• Muscle cramps
• Tetany
• Seizures
• QT prolongation
• Dysrhythmias

Ionized calcium can be particularly useful because total serum calcium may not accurately reflect the physiologically active fraction.

Foscarnet Monitoring

Significant toxicity warrants:

• Creatinine
• Potassium
• Magnesium
• Calcium, preferably ionized when clinically relevant
• Phosphate
• ECG

Correct clinically important electrolyte abnormalities carefully.

Dialysis and Foscarnet

Foscarnet can be removed to some extent by dialysis, but evidence supporting extracorporeal treatment specifically for overdose remains limited.

Renal replacement therapy should be considered according to:

• Renal failure
• Severe electrolyte abnormalities
• Conventional dialysis indications
• Overall clinical toxicity

6. Ganciclovir and Valganciclovir

Ganciclovir inhibits viral DNA synthesis and is particularly important against CMV.

Valganciclovir is its orally bioavailable prodrug and should be included in a modern discussion.

The defining toxicity is:

Bone-marrow suppression

Ganciclovir Hematologic Toxicity

Possible abnormalities include:

• Neutropenia
• Thrombocytopenia
• Anemia
• Pancytopenia

Severe neutropenia increases the risk of serious infection.

This toxicity is particularly important during prolonged therapeutic exposure.

Ganciclovir and Renal Function

Ganciclovir is substantially renally eliminated.

Renal impairment increases drug exposure and therefore increases the risk of:

• Marrow suppression
• Neurologic toxicity

Dose adjustment according to renal function is essential.

Ganciclovir Neurotoxicity

Less commonly, excessive exposure can cause:

• Confusion
• Tremor
• Seizures

A severe presentation warrants evaluation for renal accumulation and other neurologic causes.

Hemodialysis and Ganciclovir

Ganciclovir is dialyzable.

Dialysis may be useful in selected severe accumulation, particularly when renal failure is present.

Routine dialysis is not indicated after minor exposure.

7. Ribavirin

Ribavirin is a nucleoside analog with uses that have changed considerably since the older source.

Its most characteristic systemic toxicity is:

Hemolytic anemia

Ribavirin Hemolysis

Systemic ribavirin accumulates within erythrocytes and can produce oxidative/metabolic injury.

Possible findings include:

• Falling hemoglobin
• Fatigue
• Pallor
• Dyspnea
• Indirect hyperbilirubinemia
• Compensatory reticulocytosis

Patients with significant underlying cardiac disease may tolerate anemia poorly.

Aerosolized Ribavirin

The severe respiratory events described historically largely relate to specific clinical circumstances involving aerosolized therapy and severely ill infants.

They should not be generalized as the expected syndrome after an ordinary oral exposure.

Ribavirin and Pregnancy

Ribavirin has important embryotoxic and teratogenic potential.

Pregnancy-related precautions are particularly important because systemic ribavirin and its metabolites may persist for a prolonged period.

The old FDA pregnancy letter system is obsolete, but the reproductive risk remains clinically important.

Diagnosis

Because these drugs have very different toxicities, first identify the exact antiviral.

Acyclovir/valacyclovir

Focus on:

• Renal function
• Hydration
• Mental status

Amantadine

Focus on:

• Mental status
• ECG
• Potassium/magnesium
• Renal function

Cidofovir

Focus on:

• Creatinine
• Urinalysis
• Proximal tubular function

Foscarnet

Focus on:

• Renal function
• Calcium
• Magnesium
• Potassium
• Phosphate
• ECG

Ganciclovir/valganciclovir

Focus on:

• CBC
• Renal function

Ribavirin

Focus on:

• Hemoglobin
• Evidence of hemolysis

Laboratory Evaluation

Small uncomplicated exposures may require little or no testing.

For clinically important exposure, testing is agent specific rather than using one universal antiviral panel.

Possible studies include:

• CBC
• Glucose
• Electrolytes
• Creatinine/BUN
• Magnesium
• Calcium
• Phosphate
• Liver tests
• Urinalysis

ECG is particularly important for amantadine toxicity and significant foscarnet-associated electrolyte abnormalities.

Serum Antiviral Concentrations

Routine serum concentrations of these agents are generally not useful for emergency overdose management.

Clinical status, renal function, CBC, ECG, and electrolytes usually provide more actionable information.

Initial Management

General approach:

Airway/breathing → circulation → identify exact antiviral → determine renal function → ECG/electrolytes when indicated → evaluate CNS and hematologic toxicity → supportive care

Because several of these drugs are renally eliminated, renal function is particularly important.

GI Decontamination

Do not induce vomiting.

Ipecac has no modern role.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent oral exposure when:

• The drug is adsorbable
• Airway protection is adequate
• Aspiration risk is acceptable
• Expected benefit justifies treatment

Many minor exposures need no GI decontamination.

Seizures

For toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic therapy.

Always correct contributing abnormalities such as:

• Hypoglycemia
• Hypocalcemia
• Hypomagnesemia
• Hypokalemia
• Hypoxia
• Acid–base disturbance

This is particularly important with foscarnet.

Hyperthermia

If severe hyperthermia occurs:

• Control agitation/seizures
• Use active external cooling
• Correct dehydration and metabolic complications
• Monitor for rhabdomyolysis and organ injury

Antipyretics do not treat toxicologic hyperthermia unless fever from a hypothalamic set-point change is actually present.

The older term “malignant hyperthermia” should not be casually applied to amantadine toxicity.

Amantadine Dysrhythmias

Management should be based on:

• Rhythm
• QRS
• QT
• Potassium/magnesium
• Blood pressure
• Acid–base status

Avoid medications likely to worsen the existing conduction or repolarization abnormality.

The older blanket statement to avoid class IA drugs remains directionally reasonable, but modern management should be physiology- and ECG-directed rather than based on one antiarrhythmic class alone.

Enhanced Elimination – Summary

Acyclovir

Hemodialysis can meaningfully enhance elimination in selected severe accumulation.

Amantadine

Poorly removed by conventional hemodialysis; supportive care predominates.

Cidofovir

No routine extracorporeal antidotal strategy.

Foscarnet

Some dialysis removal is possible, but clinical overdose evidence is limited.

Ganciclovir

Dialyzable; may be useful in selected severe accumulation with renal dysfunction.

Ribavirin

Dialysis is not an effective routine antidotal strategy.

Monitoring and Observation

A universal 4–6 hour observation period is inappropriate.

Monitoring depends on:

• Exact antiviral
• Dose
• Route
• Symptoms
• Renal function
• ECG
• Electrolytes
• CBC
• Clinical trajectory

Some toxicities are delayed.

For example:

• Ganciclovir marrow suppression may evolve later.
• Ribavirin anemia is not excluded by a normal early hemoglobin.
• Acyclovir accumulation can persist when renal function is impaired.

Admission

Hospitalization may be appropriate for:

• Significant AKI
• Severe acyclovir neurotoxicity
• Amantadine delirium or seizures
• QRS/QT abnormalities
• Ventricular dysrhythmia
• Significant foscarnet electrolyte disturbances
• Symptomatic hypocalcemia
• Severe cytopenias
• Serious hemolytic anemia
• Persistent altered mental status
• Respiratory compromise
• Hemodynamic instability

ICU care is appropriate for malignant dysrhythmia, shock, status epilepticus, respiratory failure, or severe electrolyte-driven cardiac instability.

Pregnancy and Breastfeeding

The historical FDA pregnancy letter categories are obsolete.

Risk assessment should be drug specific.

Important considerations include:

• Maternal infection
• Gestational age
• Expected therapeutic benefit
• Alternative therapies
• Drug-specific fetal effects

Ribavirin remains particularly important because of its reproductive toxicity.

A blanket category-based approach should not replace contemporary drug-specific guidance.

Safeguarding

Rigid age cutoffs for assuming neglect, abuse, or intentional poisoning are outdated.

Assess pediatric exposures using:

• Developmental capability
• Access to medication
• Exposure circumstances
• Consistency of history
• Recurrent events
• Broader safeguarding concerns

Prognosis

Most minor antiviral exposures have favorable outcomes.

Important exceptions include:

• Severe amantadine cardiotoxicity
• Acyclovir/valacyclovir neurotoxicity with renal failure
• Persistent cidofovir-associated proximal tubular injury
• Severe foscarnet renal/electrolyte toxicity
• Profound ganciclovir-associated marrow suppression
• Clinically important ribavirin-associated hemolytic anemia

Outcome depends more on the specific antiviral and affected organ system than on the broad label “antiviral poisoning.”

Important Modernization of the Older Source

• These antivirals should not be treated as one toxicologic class.
• Valganciclovir belongs with ganciclovir in a modern discussion.
• Acyclovir/valacyclovir can cause crystal nephropathy plus neurotoxicity, especially with renal impairment.
• Hemodialysis can enhance acyclovir elimination in selected severe accumulation.
• Amantadine is no longer routinely used for influenza because of widespread resistance but remains relevant in neurologic practice.
• Amantadine toxicity includes CNS, antimuscarinic-like, and potentially severe cardiac effects.
• Renal impairment markedly increases amantadine toxicity.
• Physostigmine is not a routine amantadine antidote, particularly when conduction abnormalities or seizure risk exist.
• Conventional hemodialysis removes relatively little amantadine.
• Cidofovir → proximal tubular injury/Fanconi syndrome.
• Probenecid is principally preventive nephroprotection during cidofovir therapy, not a proven universal rescue antidote after overdose.
• Foscarnet → nephrotoxicity plus calcium, magnesium, potassium, and phosphate disturbances.
• Ionized calcium can be particularly informative during symptomatic foscarnet toxicity.
• Ganciclovir/valganciclovir → neutropenia, thrombocytopenia, anemia, with increased toxicity during renal impairment.
• Ribavirin → hemolytic anemia and important reproductive toxicity.
• The historical FDA pregnancy categories are obsolete.
• Ipecac and routine gastric lavage are obsolete.
• A fixed 4–6 hour observation period is inappropriate because several toxicities may be delayed.
• There is no universal antiviral antidote; management is agent-specific and complication-directed.

Key Points

• Acyclovir/valacyclovir → AKI/crystal nephropathy + neurotoxicity.
• Amantadine → delirium/seizures + potentially dangerous ventricular dysrhythmias.
• Cidofovir → proximal tubular injury/Fanconi syndrome.
• Foscarnet → AKI + major electrolyte disturbances, especially hypocalcemia and hypomagnesemia.
• Ganciclovir/valganciclovir → bone-marrow suppression.
• Ribavirin → hemolytic anemia.
• Renal dysfunction is a major amplifier of toxicity for several antiviral agents.
• Hemodialysis is useful for selected severe acyclovir or ganciclovir accumulation, but not as a universal antiviral treatment.
• There is no single specific antidote for this group.
• Treatment is primarily withdrawal of the offending drug, supportive care, correction of organ-specific complications, and appropriate renal dose adjustment.

Toxicology – Antiprotozoal Medications

Core Concept

This older grouping focuses on three very different drugs:

• Chloroquine
• Hydroxychloroquine
• Metronidazole

They should not be treated as a single toxicologic class.

The most important distinction is:

• Chloroquine/hydroxychloroquine overdose → potentially rapid, life-threatening cardiotoxicity
• Metronidazole overdose → usually GI and neurologic toxicity, generally much less acutely cardiotoxic

Chloroquine and hydroxychloroquine poisoning can deteriorate extremely quickly, with hypotension, conduction abnormalities, ventricular dysrhythmias, seizures, and cardiac arrest.

1. Chloroquine

Chloroquine is an antimalarial and antiprotozoal medication that also has important cardiac electrophysiologic effects.

In overdose it behaves partly as a potent membrane-stabilizing/sodium-channel–blocking toxin.

It can also interfere with other cardiac ion channels.

The result can be:

Rapid conduction slowing + myocardial depression + vasodilation + electrolyte disturbance → cardiovascular collapse

Chloroquine Has a Narrow Safety Margin

Chloroquine is unusual because relatively modest multiples of therapeutic exposure can cause severe poisoning.

Historical fixed gram-based toxicity thresholds should not be used as the sole basis for risk assessment, particularly in children.

Any credible significant chloroquine overdose should be treated as a medical emergency.

Rapid Onset

Serious chloroquine toxicity generally develops early.

Possible progression:

GI symptoms → dizziness/agitation → hypotension → QRS/QT abnormalities → ventricular dysrhythmia → seizure/coma → cardiac arrest

A patient can deteriorate rapidly despite appearing relatively well initially.

Cardiovascular Toxicity

Major manifestations include:

• Hypotension
• Tachycardia
• QRS widening
• QT prolongation
• AV/intraventricular conduction abnormalities
• Ventricular ectopy
• Ventricular tachyarrhythmias
• Severe myocardial depression
• Cardiac arrest

Continuous ECG and hemodynamic monitoring are essential in significant poisoning.

Hypokalemia – Key Feature

A characteristic feature of severe chloroquine poisoning is hypokalemia.

This is largely caused by an intracellular shift of potassium rather than necessarily reflecting true whole-body potassium depletion.

Severe poisoning may therefore produce:

• Low serum potassium
• Muscle weakness
• Increased electrical instability

Potassium Replacement – Important Caution

Hypokalemia should be monitored carefully, but overly aggressive potassium replacement can be dangerous.

As chloroquine toxicity resolves:

Intracellularly shifted K⁺ can move back extracellularly → rebound hyperkalemia

Therefore potassium correction should be carefully titrated with frequent reassessment.

Neurologic Toxicity

Severe chloroquine poisoning may cause:

• Headache
• Agitation
• Confusion
• Seizures
• CNS depression
• Coma

Seizures can worsen:

• Hypoxia
• Acidosis
• Cardiovascular instability

Rapid control is therefore important.

Respiratory Toxicity

Respiratory compromise may result from:

• CNS depression
• Seizures
• Severe shock
• Cardiac arrest

Early airway control may be necessary in severe poisoning, especially when cardiovascular deterioration is progressing.

2. Hydroxychloroquine

Hydroxychloroquine is closely related to chloroquine.

Although widely used for autoimmune diseases rather than protozoal infection in contemporary practice, its overdose syndrome resembles chloroquine toxicity.

Important acute effects include:

• Hypotension
• Hypokalemia
• QRS widening
• QT prolongation
• Ventricular dysrhythmias
• Seizures
• CNS depression
• Cardiovascular collapse

A significant hydroxychloroquine overdose should therefore be approached as a potentially severe cardiotoxic poisoning.

Chloroquine vs Hydroxychloroquine

Both drugs can produce rapid cardiovascular toxicity.

Chloroquine has the strongest historical evidence base for classic severe poisoning management, while hydroxychloroquine overdose is generally managed using similar toxicologic principles because of their pharmacologic similarities.

Chronic Retinal Toxicity

Both chloroquine and hydroxychloroquine can cause retinal injury during chronic therapy.

Features may include:

• Reduced visual acuity
• Paracentral or central visual-field defects
• Difficulty reading
• Altered color vision
• Progressive retinopathy

This is primarily a cumulative therapeutic toxicity, not the expected manifestation of acute overdose.

Hydroxychloroquine Retinopathy

Risk relates to factors such as:

• Daily exposure relative to body size
• Duration of therapy
• Cumulative exposure
• Renal dysfunction
• Concurrent retinal risk factors

Retinal injury may continue to progress after the drug has been stopped because of prolonged tissue retention.

Ophthalmologic Monitoring

Long-term hydroxychloroquine treatment requires appropriate retinal screening using modern ophthalmologic methods.

These may include:

• Automated visual-field testing
• Spectral-domain OCT
• Other specialized retinal tests when indicated

Routine acute overdose management does not depend on an immediate retinal examination unless visual symptoms or another indication exists.

Other Chronic Chloroquine/Hydroxychloroquine Toxicity

Long-term therapy can rarely cause:

• Skeletal myopathy
• Neuropathy
• Cardiomyopathy
• Conduction disease
• Hearing abnormalities
• Skin pigmentation changes

These should be distinguished from the rapid cardiovascular syndrome of acute overdose.

3. Metronidazole

Metronidazole is a nitroimidazole antimicrobial used against:

• Anaerobic bacteria
• Trichomonas
• Giardia
• Entamoeba and other susceptible organisms

Acute overdose is generally much less dangerous than chloroquine or hydroxychloroquine poisoning.

Acute Metronidazole Toxicity

Common effects include:

• Nausea
• Vomiting
• Abdominal discomfort
• Metallic taste
• Headache
• Dizziness
• Drowsiness
• Ataxia

Most isolated acute exposures are managed supportively.

Metronidazole Neurotoxicity

Prolonged or excessive exposure can produce clinically important neurologic toxicity.

Manifestations include:

• Ataxia
• Dysarthria
• Confusion
• Encephalopathy
• Peripheral neuropathy
• Seizures

Metronidazole-Induced Encephalopathy

Characteristic findings may include:

• Gait instability
• Dysarthria
• Altered mental status
• Cerebellar dysfunction

MRI can show characteristic abnormalities, including lesions involving the dentate nuclei and other CNS structures.

Symptoms frequently improve after discontinuation, although recovery can take time.

Peripheral Neuropathy

Prolonged metronidazole exposure can cause:

• Numbness
• Tingling
• Burning sensations
• Distal sensory impairment

Risk is more closely related to cumulative exposure than to a single modest ingestion.

Metronidazole and Alcohol

Older literature commonly states that metronidazole reliably causes a classic disulfiram-like reaction with ethanol.

Modern evidence is less convincing.

Although avoidance of alcohol during treatment is still commonly recommended in product guidance, the mechanism and consistency of a true disulfiram-like interaction are uncertain.

Therefore, flushing or vomiting after alcohol plus metronidazole should not automatically be assumed to prove an acetaldehyde-mediated disulfiram reaction.

Metronidazole Drug Interactions

Important interactions include:

Warfarin

Metronidazole can increase anticoagulant effect, potentially raising INR and bleeding risk.

Lithium

Lithium concentrations may increase in some patients, particularly when renal function changes.

Enzyme-inducing antiseizure medications

Some can increase metronidazole metabolism and reduce exposure.

A severe or atypical presentation should therefore include a complete medication review.

Dark Urine

Metronidazole can occasionally cause dark or reddish-brown urine due to metabolites.

This finding alone does not necessarily indicate hematuria or renal failure.

Hematologic Effects

Rare effects include:

• Leukopenia
• Neutropenia
• Thrombocytopenia

These are more relevant to therapeutic or prolonged exposure than uncomplicated acute overdose.

Hepatic Considerations

Metronidazole is metabolized hepatically.

Significant hepatic dysfunction can reduce clearance and increase systemic exposure.

Rare clinically important hepatotoxicity can also occur.

Diagnosis

The first priority is determining the exact drug.

For chloroquine/hydroxychloroquine

Assess immediately:

• Amount and timing
• Symptoms
• Blood pressure
• ECG
• Potassium
• Glucose
• Other electrolytes
• Acid–base status when severely ill
• Coingestants

For metronidazole

Assess:

• Acute vs cumulative exposure
• Neurologic findings
• Hepatic function when relevant
• Interacting medications
• Coingestants

ECG in Chloroquine/Hydroxychloroquine Poisoning

Obtain an ECG early and monitor serially.

Assess:

• Heart rate
• Rhythm
• PR interval
• QRS duration
• QT/QTc
• Ventricular ectopy

Progressive conduction abnormalities may precede cardiovascular collapse.

Laboratory Evaluation

For significant chloroquine/hydroxychloroquine exposure, consider:

• Potassium
• Magnesium
• Calcium
• Sodium
• Glucose
• Renal function
• Blood gas/lactate in severe poisoning

Frequent potassium reassessment may be required because concentrations can change rapidly during recovery.

Drug Concentrations

Routine serum chloroquine, hydroxychloroquine, or metronidazole concentrations are generally not sufficiently available or actionable to guide acute emergency management.

Treatment should be driven by:

• Clinical severity
• ECG
• Hemodynamics
• Electrolytes

Management of Chloroquine/Hydroxychloroquine Poisoning

Priorities are:

Airway → continuous ECG → circulation → potassium/electrolytes → seizures → aggressive treatment of shock and dysrhythmia

Early toxicology/poison-center consultation is strongly appropriate for any significant exposure.

Airway Management

Severe chloroquine poisoning may deteriorate abruptly.

Early controlled airway management should be considered when there is:

• Severe CNS depression
• Recurrent seizures
• Progressive shock
• Respiratory failure

Peri-intubation cardiovascular collapse is a major concern in severely poisoned patients, so resuscitation must proceed concurrently.

Epinephrine

Epinephrine has an important role in severe chloroquine poisoning with hypotension and myocardial depression.

It can improve:

• Blood pressure
• Cardiac output
• Contractility

Vasopressor therapy should be titrated to clinical response under intensive monitoring rather than according to rigid historical dose targets.

High-Dose Diazepam – Important Historical Therapy

Older literature describes high-dose diazepam as a central treatment for severe chloroquine poisoning.

Modern interpretation is more nuanced.

Benzodiazepines are clearly appropriate for:

• Seizures
• Agitation
• Sedation when required

Historical observational evidence suggested benefit from high-dose diazepam combined with epinephrine in severe chloroquine poisoning, but the evidence is limited and does not establish diazepam as a universal antidote.

Very high-dose diazepam regimens should therefore be undertaken only with specialist toxicology guidance and intensive airway/hemodynamic monitoring.

Sodium Bicarbonate

Because chloroquine can produce sodium-channel blockade and QRS widening, sodium bicarbonate may be considered in selected severe conduction toxicity.

However, this requires caution because alkalemia can further reduce serum potassium.

Treatment should therefore be guided by:

• ECG
• Potassium
• Acid–base status
• Hemodynamics
• Toxicology expertise

It is not a routine treatment for every chloroquine ingestion.

Ventricular Dysrhythmias

Priorities include:

• Optimize oxygenation
• Correct severe acidemia
• Carefully manage potassium
• Correct magnesium when indicated
• Treat shock
• Address sodium-channel blockade when appropriate

Antiarrhythmic selection requires caution because some agents can worsen conduction or QT abnormalities.

Seizures

Benzodiazepines are first-line.

Persistent seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic therapy

Correct:

• Hypoglycemia
• Hypoxia
• Electrolyte abnormalities
• Acid–base disturbance

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is not standard management.

Because chloroquine/hydroxychloroquine can become life-threatening rapidly, airway and cardiovascular stabilization take priority over GI decontamination.

Activated charcoal may be considered after a clinically important recent ingestion when:

• The airway is protected
• Aspiration risk is acceptable
• Administration will not delay resuscitation

Metronidazole Management

Most acute metronidazole overdoses require:

• Supportive care
• Fluids if clinically dehydrated
• Antiemetic therapy when appropriate
• Neurologic observation
• Seizure treatment if required

For chronic neurotoxicity:

Stop metronidazole and provide supportive neurologic care.

There is no specific antidote.

Enhanced Elimination

Routine enhanced elimination is not recommended for chloroquine, hydroxychloroquine, or metronidazole poisoning.

Chloroquine and hydroxychloroquine have extensive tissue distribution, making conventional dialysis ineffective for meaningful toxin removal.

Extracorporeal life support such as VA-ECMO may be considered as circulatory rescue in selected refractory cardiogenic/cardiotoxic collapse, but this supports the patient while toxicity resolves—it does not meaningfully eliminate the drug.

Observation

A universal fixed observation period is inappropriate.

Chloroquine/hydroxychloroquine

Significant exposures require monitored medical evaluation because severe toxicity can develop rapidly.

Disposition depends on:

• Exposure magnitude
• Symptoms
• ECG
• Potassium
• Blood pressure
• Mental status
• Clinical trajectory

Metronidazole

Minor asymptomatic exposures generally require much less intensive monitoring.

Prolonged exposure requires assessment for delayed neurologic toxicity.

Admission

Hospitalization is appropriate for chloroquine/hydroxychloroquine poisoning with:

• Significant or uncertain overdose
• Hypotension
• Hypokalemia
• QRS/QT abnormality
• Ventricular ectopy/dysrhythmia
• Seizure
• Altered mental status
• Respiratory compromise

ICU care is appropriate for clinically significant cardiotoxicity.

For metronidazole, admission may be appropriate for:

• Persistent encephalopathy
• Severe ataxia
• Seizures
• Significant dehydration
• Serious coingestion or interaction

Pregnancy and Breastfeeding

Historical FDA pregnancy letter categories are obsolete.

The statement that metronidazole should simply be avoided throughout pregnancy is also outdated.

Modern decisions consider:

• Drug
• Infection
• Gestational age
• Maternal benefit
• Fetal risk
• Available alternatives

Chloroquine and hydroxychloroquine have established therapeutic uses during pregnancy in appropriate clinical circumstances.

Breastfeeding recommendations should similarly be drug- and indication-specific.

Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are inappropriate.

Evaluate pediatric exposures according to:

• Developmental capability
• Medication accessibility
• Circumstances
• Consistency of history
• Recurrent events
• Broader safeguarding concerns

Prognosis

Chloroquine/Hydroxychloroquine

Outcome depends heavily on the severity of early cardiovascular toxicity.

Poor prognostic features include:

• Severe hypotension
• Marked conduction abnormalities
• Ventricular dysrhythmias
• Severe hypokalemia
• Seizures
• Cardiac arrest

Patients who survive the acute cardiotoxic phase may recover substantially, although hypoxic injury can cause persistent deficits.

Metronidazole

Most acute exposures have a favorable prognosis.

Chronic neurotoxicity often improves after discontinuation, although peripheral neuropathy may recover slowly or occasionally persist.

Important Modernization of the Older Source

• Chloroquine and hydroxychloroquine overdose should be separated toxicologically from metronidazole.
• Chloroquine/hydroxychloroquine poisoning is a rapidly developing cardiotoxic emergency.
• Sodium-channel blockade contributes to QRS widening and ventricular dysrhythmias.
• Hypokalemia is a characteristic marker of severe chloroquine toxicity, largely reflecting intracellular redistribution.
• Potassium replacement requires caution because rebound hyperkalemia can occur during recovery.
• Significant hydroxychloroquine overdose can produce a syndrome similar to chloroquine poisoning.
• Chronic retinal toxicity should not be confused with the acute overdose syndrome.
• Epinephrine remains an important vasopressor/inotropic therapy in severe chloroquine poisoning.
• High-dose diazepam is historically associated with severe chloroquine treatment, but evidence is limited; it should not be described as a universally proven antidote.
• Sodium bicarbonate may have a role for selected significant sodium-channel blockade but requires careful potassium and acid–base monitoring.
• Dialysis is ineffective for meaningful chloroquine/hydroxychloroquine elimination.
• VA-ECMO can be considered as rescue support for refractory cardiovascular collapse; it is not an elimination technique.
• Metronidazole overdose is usually much less severe.
• Prolonged metronidazole exposure can cause encephalopathy, cerebellar dysfunction, and peripheral neuropathy.
• The classic metronidazole–ethanol “disulfiram reaction” is less firmly established than older teaching suggested.
• Metronidazole can interact importantly with warfarin and lithium.
• Ipecac is obsolete and routine gastric lavage is not standard.
• Fixed 2-, 4-, or 8-hour discharge rules are too rigid.
• Historical FDA pregnancy categories and blanket metronidazole pregnancy avoidance are outdated.

Key Points

• Chloroquine/hydroxychloroquine → rapid, potentially fatal cardiotoxicity.
• QRS widening + hypotension + hypokalemia are particularly concerning in chloroquine poisoning.
• Severe cases can progress quickly to ventricular dysrhythmia, seizure, shock, and cardiac arrest.
• Epinephrine has an important role in severe chloroquine-associated cardiovascular collapse.
• Benzodiazepines treat seizures; historical high-dose diazepam therapy requires specialist guidance.
• Potassium must be corrected cautiously because rebound hyperkalemia can occur.
• Metronidazole → GI symptoms and, with substantial/cumulative exposure, neurotoxicity.
• Metronidazole-induced encephalopathy often features cerebellar dysfunction and may have characteristic MRI abnormalities.
• There is no universal specific antidote for these agents.
• Significant chloroquine or hydroxychloroquine exposure warrants rapid monitored evaluation and early toxicology/poison-center involvement.

Toxicology – Benzimidazole Antiparasitic Drugs

Core Concept

This older “antiparasitic drugs” entry mainly describes the benzimidazole anthelmintics:

• Albendazole
• Mebendazole
• Thiabendazole

These drugs are used against various helminth infections. Thiabendazole is now much less commonly used systemically because newer agents generally have better tolerability.

Acute isolated overdose is usually mild and self-limited. More important toxicity tends to occur during prolonged or high-dose therapy and includes:

• GI symptoms
• Hepatotoxicity
• Rare bone-marrow suppression
• Hypersensitivity reactions
• Neurologic symptoms

There is no specific antidote.

Mechanism

Benzimidazoles bind parasite β-tubulin and disrupt microtubule formation.

This interferes with:

• Glucose uptake
• Intracellular transport
• Secretory processes
• Energy production
• Parasite survival

The older description that all these drugs are simply poorly absorbed is too broad.

Mebendazole

Generally has limited systemic bioavailability.

Albendazole

The parent drug is poorly absorbed but is rapidly converted to albendazole sulfoxide, an active systemically available metabolite.

Systemic exposure is important when treating tissue parasites such as neurocysticercosis or echinococcosis.

Thiabendazole

Is considerably better absorbed and therefore produces more systemic adverse effects.

Acute Overdose

Most acute exposures produce:

• Nausea
• Vomiting
• Abdominal discomfort
• Diarrhea
• Headache
• Dizziness
• Drowsiness

Serious acute poisoning is uncommon.

Thiabendazole historically produces more adverse effects than albendazole or mebendazole.

1. Gastrointestinal Toxicity

GI symptoms are the most common adverse effects.

Possible manifestations include:

• Anorexia
• Nausea
• Vomiting
• Abdominal pain
• Diarrhea

These effects are usually managed supportively.

Persistent vomiting can occasionally result in:

• Dehydration
• Electrolyte abnormalities
• Orthostatic symptoms

2. Hepatotoxicity

Albendazole and mebendazole can cause elevations in liver enzymes, particularly during prolonged systemic therapy.

Rare clinically important liver injury may occur.

Possible manifestations include:

• Nausea
• Fatigue
• Right-upper-quadrant discomfort
• Elevated AST/ALT
• Jaundice

Risk is more relevant during repeated or prolonged therapy than after a small accidental ingestion.

Monitoring During Prolonged Therapy

When albendazole is used for prolonged systemic treatment, monitoring commonly includes:

• Liver function tests
• CBC

Significant abnormalities may require interruption or reassessment of therapy.

A normal initial liver panel after an acute exposure does not predict all delayed adverse reactions from prolonged treatment.

3. Bone-Marrow Suppression

Rare hematologic toxicity has been reported with systemic benzimidazole therapy, particularly prolonged albendazole treatment.

Possible abnormalities include:

• Leukopenia
• Neutropenia
• Thrombocytopenia
• Pancytopenia

Severe marrow toxicity is uncommon but potentially serious.

Patients receiving prolonged treatment may therefore require serial CBC monitoring.

4. Neurologic Effects

Possible CNS effects include:

• Headache
• Dizziness
• Drowsiness
• Confusion
• Rare hallucinations

Seizures have occasionally been reported, but they are not the expected manifestation of uncomplicated benzimidazole overdose.

If seizures occur, consider:

• Large or mixed exposure
• Metabolic abnormalities
• CNS infection
• Underlying neurologic disease
• Treatment of a CNS parasitic infection
• Other medications

Neurocysticercosis – Important Clinical Distinction

Neurologic deterioration after albendazole treatment for neurocysticercosis does not necessarily represent direct drug poisoning.

Destruction of intracranial parasites can provoke an inflammatory response, potentially worsening:

• Headache
• Cerebral edema
• Seizures
• Focal neurologic abnormalities

This is a treatment-associated inflammatory phenomenon rather than conventional albendazole overdose.

Seizure Management

For toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic management.

Also correct:

• Hypoglycemia
• Hypoxia
• Electrolyte abnormalities
• Acid–base disturbances

5. Hypersensitivity

Benzimidazoles can rarely cause:

• Rash
• Urticaria
• Pruritus
• Angioedema
• Severe cutaneous reactions

SJS/TEN has been reported rarely.

A severe mucocutaneous eruption requires immediate discontinuation and urgent medical evaluation.

6. Thiabendazole

Thiabendazole is considerably more likely than albendazole or mebendazole to produce systemic adverse effects.

Reported effects include:

• Nausea/vomiting
• Dizziness
• Drowsiness
• Headache
• Visual disturbances
• Tinnitus
• Hypotension
• Neuropsychiatric symptoms
• Hepatic dysfunction

Its unfavorable adverse-effect profile is one reason systemic thiabendazole has largely been replaced by better-tolerated therapies for many infections.

7. Drug Interactions

Mebendazole

Cimetidine can inhibit metabolism and increase systemic mebendazole exposure, although the clinical importance depends on the treatment setting.

A particularly important modern interaction is:

Mebendazole + metronidazole

This combination has been associated with an increased risk of severe cutaneous adverse reactions such as SJS/TEN and is generally avoided.

Thiabendazole

Thiabendazole can inhibit the metabolism of theophylline.

Theophylline accumulation can produce:

• Nausea/vomiting
• Tremor
• Tachycardia
• Agitation
• Seizures
• Dysrhythmias

A severe presentation in a patient taking both drugs should therefore raise concern for secondary theophylline toxicity.

Albendazole

Albendazole is converted to active albendazole sulfoxide.

Some medications can alter concentrations of its active metabolite.

The older source contains spelling errors such as “abendaxole” and “dexamethadone”; these refer to albendazole and dexamethasone.

Drug interactions are usually more relevant during systemic treatment than during a single accidental exposure.

8. Renal Effects

The older source lists hemolytic-uremic syndrome as though it were a characteristic class effect.

This is not a defining toxicity of modern benzimidazole poisoning.

If AKI develops, evaluate for alternative or contributing causes such as:

• Dehydration
• Sepsis
• Hemolysis
• Other nephrotoxins
• Underlying illness

Routine renal failure is not expected after an uncomplicated benzimidazole overdose.

9. Pregnancy

The historical FDA pregnancy letter categories are obsolete.

Pregnancy recommendations are now agent- and indication-specific.

Albendazole and mebendazole may be used in selected circumstances when treatment benefits justify exposure, including in public-health deworming programs under appropriate guidance.

Therefore, the older statement that all these agents are simply “relatively contraindicated” throughout pregnancy is too broad.

Consider:

• Specific parasite
• Severity of infection
• Gestational stage
• Expected treatment benefit
• Available alternatives

Breastfeeding

Breastfeeding recommendations should also be drug specific.

Albendazole and mebendazole generally produce relatively limited infant exposure with commonly used regimens, but the indication and treatment duration should still be considered.

A blanket class-wide prohibition is not appropriate.

Diagnosis

Determine:

• Exact antiparasitic
• Amount
• Timing
• Single vs repeated exposure
• Treatment duration
• Underlying parasitic infection
• Liver disease
• Coingestants
• Interacting medications

When neurologic deterioration occurs during treatment of a CNS parasite, distinguish direct drug toxicity from inflammation caused by parasite destruction.

Laboratory Evaluation

No laboratory tests may be required after a small, asymptomatic acute ingestion.

For significant symptoms or prolonged/high-dose therapy, consider:

• CBC
• Electrolytes
• Glucose
• BUN/creatinine
• Liver function tests

Additional testing should be directed by the presentation.

Drug Concentrations

Routine serum albendazole, mebendazole, or thiabendazole concentrations have no established role in managing most acute overdoses.

Clinical findings and organ-function testing are more useful.

ECG

Routine continuous cardiac monitoring is unnecessary after every uncomplicated exposure.

Obtain an ECG when there is:

• Significant hypotension
• Palpitations
• Syncope
• Major systemic toxicity
• Suspected theophylline interaction
• Relevant coingestion

This replaces the older blanket recommendation for cardiac monitoring after poisoning.

Initial Management

General priorities are:

Airway/breathing → circulation → identify exact drug → assess neurologic status → evaluate GI losses → consider liver/marrow toxicity when relevant → identify interactions/coingestants

Most acute exposures require only supportive treatment.

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is also obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The exposure is clinically important
• The drug is adsorbable
• The airway is safe
• Aspiration risk is acceptable

Most minor accidental benzimidazole ingestions do not require decontamination.

Hypotension

Significant hypotension is unusual.

If present, consider:

• Dehydration from vomiting
• Hypersensitivity/anaphylaxis
• Thiabendazole toxicity
• Coingestants
• Other illness

Treat clinically significant volume depletion with appropriate isotonic fluid.

Persistent shock should be managed according to its physiology rather than with a rigid historical vasopressor sequence.

Anaphylaxis

For true anaphylaxis:

IM epinephrine is first-line therapy.

Airway, oxygenation, and circulatory support should be provided as required.

Antihistamines are adjuncts and must not delay epinephrine.

Enhanced Elimination

There is no established routine role for:

• Hemodialysis
• Hemoperfusion
• Multiple-dose activated charcoal

in uncomplicated benzimidazole overdose.

Renal replacement therapy may still be required for conventional indications if unrelated severe organ failure develops.

No Specific Antidote

There is no specific antidote for:

• Albendazole
• Mebendazole
• Thiabendazole

Treatment consists mainly of:

Stopping exposure + supportive care + managing complications

Observation

The historical fixed 8-hour observation rule is unnecessarily rigid.

Observation should instead depend on:

• Exact drug
• Amount
• Symptoms
• Coingestants
• Interactions
• Liver function when relevant
• Clinical trajectory

Most acute effects develop relatively early, but delayed marrow or hepatic toxicity associated with prolonged therapy cannot be excluded by a short ED observation period.

Admission

Hospitalization may be appropriate for:

• Persistent altered mental status
• Seizures
• Significant hypotension
• Severe vomiting/dehydration
• Clinically important hepatic injury
• Significant cytopenias
• Severe hypersensitivity
• SJS/TEN
• Serious interacting-drug toxicity

ICU care is reserved for severe neurologic, respiratory, or hemodynamic complications.

Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are outdated.

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Medication accessibility
• Circumstances of exposure
• Consistency of history
• Recurrent unexplained events
• Broader safeguarding concerns

Prognosis

Most isolated acute benzimidazole exposures have an excellent prognosis.

Potentially important complications are more likely with:

• Prolonged systemic treatment
• Significant hepatic dysfunction
• Drug interactions
• Rare severe hypersensitivity
• Significant marrow suppression

Most uncomplicated acute symptoms resolve with supportive care.

Important Modernization of the Older Source

• This entry specifically concerns benzimidazole anthelmintics, not antiparasitic drugs as a whole.
• Albendazole, mebendazole, and thiabendazole disrupt parasite microtubules.
• The statement that all are poorly absorbed is inaccurate: thiabendazole is systemically absorbed, while albendazole forms an active systemic metabolite.
• Acute overdose is generally mild and GI-predominant.
• Thiabendazole has more systemic adverse effects and is now much less commonly used.
• Prolonged albendazole therapy can cause hepatotoxicity and bone-marrow suppression.
• Neurologic worsening during neurocysticercosis treatment may result from inflammation around dying parasites rather than direct albendazole poisoning.
• Mebendazole plus metronidazole is an important interaction because of severe cutaneous reaction risk.
• Thiabendazole can increase theophylline exposure.
• Hemolytic-uremic syndrome is not a defining class toxicity.
• Serum benzimidazole concentrations generally do not guide acute toxicology management.
• Routine cardiac monitoring is unnecessary after every minor exposure.
• Ipecac and routine gastric lavage are obsolete.
• There is no specific antidote or routine role for extracorporeal removal.
• A fixed 8-hour observation period is unnecessary.
• Historical FDA pregnancy categories and blanket pregnancy contraindications are outdated.
• Pediatric safeguarding should not use rigid age cutoffs.

Key Points

• Albendazole, mebendazole, and thiabendazole are benzimidazole anthelmintics.
• Acute overdose is usually mild, with GI symptoms, headache, or dizziness.
• Thiabendazole produces the most systemic adverse effects of these older agents.
• Prolonged albendazole/mebendazole exposure can rarely cause hepatotoxicity and marrow suppression.
• Albendazole’s active metabolite achieves systemic exposure and is important in treatment of tissue parasites.
• CNS symptoms during neurocysticercosis treatment may reflect an inflammatory response to parasite death, not poisoning.
• Mebendazole + metronidazole should be avoided because of severe cutaneous reaction risk.
• Thiabendazole can increase theophylline concentrations.
• There is no specific antidote.
• Management of acute overdose is predominantly supportive and symptom-directed.

Toxicology – Antineoplastic Medications

Core Concept

Antineoplastic drugs comprise many pharmacologically unrelated agents used to treat malignancy. Some, particularly methotrexate, are also used for nonmalignant diseases.

Unlike many medication ingestions, antineoplastic overdose is potentially serious because toxicity may be:

• Delayed
• Multisystem
• Prolonged
• Dose- and route-dependent
• Associated with profound myelosuppression
• Complicated by renal, hepatic, cardiac, neurologic, or pulmonary injury

A patient can initially appear well and subsequently develop severe toxicity days or even weeks later.

Management therefore requires identification of the exact drug, route, dose, timing, and treatment protocol, usually with early toxicology and oncology involvement.

Major Antineoplastic Classes

Important groups include:

Antimetabolites

• Methotrexate
• 5-fluorouracil (5-FU)
• Cytarabine

Alkylating agents

• Cyclophosphamide
• Ifosfamide
• Melphalan
• Chlorambucil
• Mechlorethamine
• Carmustine
• Lomustine

Platinum compounds

• Cisplatin
• Carboplatin
• Oxaliplatin

Anthracyclines

• Doxorubicin
• Daunorubicin

Vinca alkaloids

• Vincristine
• Vinblastine

Topoisomerase inhibitors

• Etoposide

Microtubule-stabilizing agents

• Paclitaxel and related taxanes

Other cytotoxic agents

• Bleomycin
• Dactinomycin
• Mitomycin
• Asparaginase

Modern oncology also includes targeted therapies, monoclonal antibodies, immune checkpoint inhibitors, antibody-drug conjugates, and other agents whose toxicity differs substantially from traditional cytotoxic chemotherapy.

Why Antineoplastic Toxicity Is Different

Many cytotoxic drugs preferentially injure rapidly dividing cells.

Consequently, major target tissues include:

• Bone marrow
• GI epithelium
• Oral mucosa
• Hair follicles
• Reproductive tissues

Individual drugs additionally have characteristic organ toxicities.

A useful framework is:

Exposure → early GI/mucosal toxicity → delayed marrow suppression ± agent-specific organ injury

Delayed Toxicity

A critical toxicology principle is that absence of early symptoms does not exclude severe poisoning.

Delayed complications may include:

• Neutropenia
• Thrombocytopenia
• Anemia
• Mucositis
• Infection
• Sepsis
• Bleeding
• Organ failure

Some agents, particularly nitrosoureas, can cause marrow suppression substantially later than the classic first 1–2 weeks.

1. Methotrexate

Methotrexate inhibits dihydrofolate reductase, impairing tetrahydrofolate production and nucleotide synthesis.

Major toxicities include:

• Mucositis
• Myelosuppression
• GI injury
• Hepatotoxicity
• Nephrotoxicity
• Neurotoxicity
• Pulmonary toxicity

High-dose therapy is particularly dangerous when renal elimination becomes impaired.

Methotrexate Nephrotoxicity

Methotrexate and its metabolites may precipitate within renal tubules.

This can produce:

Crystal nephropathy → reduced clearance → rising methotrexate concentration → further toxicity

This creates a potentially dangerous positive-feedback cycle.

Risk increases with:

• High-dose therapy
• Dehydration
• Acidic urine
• Preexisting renal impairment
• Interacting medications

Methotrexate Drug Interactions

Medications that interfere with renal clearance can increase toxicity.

Examples may include:

• NSAIDs
• Certain antibiotics
• Proton-pump inhibitors in some high-dose settings
• Other nephrotoxic or renally competing medications

Medication review is therefore essential when methotrexate elimination is delayed.

Methotrexate – Leucovorin Rescue

Leucovorin (folinic acid) bypasses the folate pathway blocked by methotrexate and is a central rescue therapy for clinically important systemic methotrexate toxicity.

The amount and duration of leucovorin depend on:

• Methotrexate concentration
• Time since administration
• Renal function
• Evidence of delayed elimination
• Clinical toxicity

Historical fixed concentration cutoffs should not substitute for the appropriate treatment protocol or nomogram.

Glucarpidase

A major modern addition is glucarpidase.

It rapidly metabolizes circulating methotrexate through a pathway independent of renal clearance.

It may be indicated in selected patients with:

High-dose methotrexate + delayed elimination + significant renal dysfunction

Leucovorin therapy remains important, but its timing relative to glucarpidase matters and should follow specialist protocols.

Methotrexate Hydration and Urinary Alkalinization

High-dose methotrexate toxicity is managed with carefully controlled:

• IV hydration
• Urinary alkalinization
• Serial methotrexate concentrations
• Serial renal function
• Leucovorin rescue

The aim is to improve methotrexate solubility and renal elimination.

Exact fluid and bicarbonate regimens are protocol-specific rather than universal overdose formulas.

Methotrexate Routes Matter

Toxicity differs markedly between:

• Single acute oral exposure
• Repeated low-dose dosing errors
• High-dose IV chemotherapy
• Intrathecal exposure

A particularly important modern problem is accidental daily instead of weekly methotrexate dosing in patients prescribed low-dose therapy.

Repeated dosing errors can cause severe:

• Mucositis
• Pancytopenia
• Infection
• Bleeding
• Renal/hepatic injury

Intrathecal Methotrexate

Excessive intrathecal exposure can cause severe neurotoxicity, including:

• Headache
• Meningeal irritation
• Encephalopathy
• Seizures
• Motor deficits
• Leukoencephalopathy

This is a specialized emergency requiring immediate consultation with oncology, toxicology, neurology/neurosurgery, and other appropriate specialists.

Historical invasive CSF-exchange procedures should not be treated as routine bedside instructions.

2. 5-Fluorouracil – 5-FU

5-FU interferes with pyrimidine metabolism, particularly through inhibition of thymidylate synthase, while metabolites can also become incorporated into RNA and DNA.

Major toxicities include:

• Severe mucositis
• Diarrhea
• Myelosuppression
• Neurotoxicity
• Cardiotoxicity

5-FU Cardiotoxicity

5-FU can produce:

• Coronary vasospasm
• Chest pain
• Myocardial ischemia
• Dysrhythmia
• Cardiomyopathy
• Rare cardiogenic shock

Cardiac symptoms during infusion require prompt evaluation and cessation of the offending therapy.

5-FU and DPD Deficiency

A major modern concept is dihydropyrimidine dehydrogenase (DPD) deficiency.

DPD is crucial for fluoropyrimidine metabolism.

Reduced DPD activity can result in unexpectedly severe toxicity even with standard treatment.

Possible manifestations include:

• Profound diarrhea
• Mucositis
• Neutropenia
• Encephalopathy
• Multiorgan toxicity

Uridine Triacetate

Another major modernization is uridine triacetate, a specific emergency antidotal therapy for severe fluoropyrimidine toxicity.

It is used for selected:

• 5-FU overdoses
• Capecitabine overdoses
• Early severe/life-threatening fluoropyrimidine toxicity

Benefit is highly time dependent, so suspected serious fluoropyrimidine overdose warrants immediate specialist/poison-center consultation.

The historical suggestion that allopurinol prevents 5-FU overdose-related marrow suppression is not modern standard antidotal management.

3. Cytarabine

Cytarabine is a cytidine analog that inhibits DNA synthesis.

High systemic exposure can cause:

• Myelosuppression
• Mucositis
• Hepatic dysfunction
• Neurotoxicity

A characteristic complication of high-dose therapy is cerebellar toxicity.

Cytarabine Neurotoxicity

Possible findings include:

• Dysarthria
• Nystagmus
• Ataxia
• Dysmetria
• Confusion
• Encephalopathy

Risk increases with:

• Older age
• Renal dysfunction
• High-dose therapy

Serial neurologic examination is therefore important during high-dose treatment.

4. Cisplatin and Carboplatin

Platinum agents produce DNA cross-linking.

Cisplatin

Particularly associated with:

• Nephrotoxicity
• Ototoxicity
• Peripheral neuropathy
• Severe nausea/vomiting
• Electrolyte wasting

Carboplatin

More prominently associated with:

• Myelosuppression, especially thrombocytopenia

while generally being less nephrotoxic than cisplatin.

Cisplatin Electrolyte Toxicity

Renal tubular injury can produce:

• Hypomagnesemia
• Hypokalemia
• Hypocalcemia
• Other electrolyte abnormalities

Monitor:

• Creatinine
• Magnesium
• Potassium
• Calcium

Ototoxicity may manifest as tinnitus or high-frequency sensorineural hearing loss.

5. Cyclophosphamide and Ifosfamide

These alkylating agents generate toxic metabolites capable of injuring the urinary tract.

A classic complication is:

Hemorrhagic cystitis

Manifestations include:

• Dysuria
• Hematuria
• Bladder irritation

Mesna

Mesna binds urotoxic metabolites within the urinary tract and is used to prevent hemorrhagic cystitis associated particularly with ifosfamide and high-risk cyclophosphamide regimens.

Adequate hydration is also important.

This is more specific and clinically useful than relying on extremely high fixed fluid volumes from older toxicology references.

Ifosfamide Encephalopathy

Ifosfamide can cause:

• Confusion
• Somnolence
• Hallucinations
• Agitation
• Seizures
• Coma

Renal tubular dysfunction and metabolic abnormalities can also occur.

Selected severe cases of ifosfamide encephalopathy may be treated with methylene blue, although evidence is limited and specialist guidance is appropriate.

Cyclophosphamide Cardiotoxicity

High systemic exposure can cause:

• Myocardial injury
• Arrhythmia
• Heart failure
• Hemorrhagic myocarditis in severe cases

This is primarily associated with intensive treatment regimens rather than ordinary low-dose exposure.

6. Anthracyclines – Doxorubicin and Daunorubicin

Anthracyclines interfere with topoisomerase II, DNA function, and oxidative cellular pathways.

Important toxicities include:

• Myelosuppression
• Mucositis
• Cardiotoxicity
• Severe tissue injury after extravasation

Anthracycline Cardiotoxicity

Cardiac toxicity may be:

Acute

• ECG abnormalities
• Dysrhythmia
• Myopericarditis
• Transient ventricular dysfunction

Chronic

• Progressive cardiomyopathy
• Reduced ejection fraction
• Heart failure

Chronic risk generally rises with cumulative exposure but cannot be represented by a single universal dose cutoff because risk depends on the specific anthracycline and patient factors.

Dexrazoxane

Dexrazoxane can reduce anthracycline-related cardiac injury in selected treatment settings.

It also has an important modern role as an antidotal treatment for anthracycline extravasation.

Its use is indication- and timing-specific and should follow oncology/extravasation protocols.

7. Vinca Alkaloids

Vincristine

Toxicity is predominantly neurologic.

Possible manifestations include:

• Peripheral neuropathy
• Paresthesias
• Weakness
• Reduced reflexes
• Autonomic dysfunction
• Ileus
• Cranial neuropathies
• SIADH
• Severe neurotoxicity after excessive exposure

Vinblastine

Produces relatively more:

• Myelosuppression

although neurologic toxicity can also occur.

Vincristine – Intrathecal Exposure

Intrathecal vincristine is a catastrophic medical error and can be fatal.

Vincristine must never be administered intrathecally.

This requires immediate specialist emergency management.

Older descriptions of specific CSF-perfusion procedures should not be treated as a standard or universally effective antidote.

Prevention through safe chemotherapy systems is critical.

Vincristine Interactions

Vincristine neurotoxicity can be substantially increased by medications that impair its metabolism.

Clinically important interactions include some strong CYP3A inhibitors, particularly certain azole antifungals.

Medication reconciliation is therefore essential.

8. Etoposide

Etoposide inhibits topoisomerase II.

Major adverse effects include:

• Myelosuppression
• Nausea/vomiting
• Mucositis
• Hepatic injury at high exposure
• Hypersensitivity

Rapid IV administration can produce hypotension.

9. Paclitaxel

Paclitaxel stabilizes microtubules and prevents normal mitotic function.

Important adverse effects include:

• Neutropenia
• Peripheral neuropathy
• Hypersensitivity reactions
• Myalgias/arthralgias
• Cardiac conduction abnormalities in selected patients
• Mucositis

Acute overdose can produce severe marrow and neurologic toxicity.

10. Bleomycin

Bleomycin causes DNA strand injury.

Its characteristic dose-limiting organ toxicity is:

Pulmonary injury

Possible manifestations include:

• Dry cough
• Dyspnea
• Interstitial pneumonitis
• Pulmonary fibrosis

Bleomycin and Oxygen – Important Nuance

Older teaching sometimes implied that oxygen should simply be avoided in anyone previously exposed to bleomycin.

That is too absolute.

Hypoxemia must be treated.

However, unnecessary prolonged exposure to excessive inspired oxygen should be avoided when lower concentrations adequately maintain oxygenation, particularly in patients with established bleomycin lung injury.

11. Asparaginase

Asparaginase reduces circulating asparagine and interferes with protein synthesis in susceptible malignant cells.

Major toxicities include:

• Hypersensitivity/anaphylaxis
• Pancreatitis
• Hepatic dysfunction
• Hyperglycemia
• Thrombosis
• Bleeding/coagulopathy

Coagulation abnormalities reflect disruption of hepatic synthesis of both procoagulant and anticoagulant proteins.

12. Nitrosoureas

Carmustine and lomustine can produce particularly delayed myelosuppression.

Important effects include:

• Thrombocytopenia
• Leukopenia
• Pulmonary toxicity
• Hepatic injury
• Renal injury
• CNS effects at high exposure

Marrow nadir may occur several weeks after treatment.

Therefore, short ED observation cannot exclude serious toxicity.

13. Procarbazine

Procarbazine has weak monoamine oxidase-inhibiting properties.

Potential adverse effects include:

• Myelosuppression
• GI symptoms
• Neuropathy
• CNS disturbances

Clinically important medication and dietary interactions should be considered during therapy, although the interaction profile should not simply be extrapolated from classic irreversible MAO inhibitors.

14. Extravasation

Several antineoplastic drugs can cause substantial local tissue injury if they escape from the vein.

Possible manifestations include:

• Burning
• Pain
• Swelling
• Erythema
• Blistering
• Ulceration
• Tissue necrosis

Vesicants

Important vesicant drugs include:

• Anthracyclines
• Vinca alkaloids
• Mechlorethamine
• Mitomycin
• Several other cytotoxic agents

Management is drug specific.

Extravasation Management

General priorities include:

• Stop the infusion immediately
• Leave vascular access available initially when appropriate for aspiration/antidotal management
• Avoid flushing the infiltrated line
• Identify the exact drug
• Elevate the affected limb when appropriate
• Follow the agent-specific cold/warm compress protocol
• Obtain oncology/pharmacy/extravasation specialist guidance

The older recommendation to inject saline into the site to “dilute” the drug is not a universal modern approach and may spread the vesicant further.

Extravasation Antidotes

Depending on the drug, modern antidotal strategies may include:

• Dexrazoxane for anthracycline extravasation
• Hyaluronidase for selected vinca alkaloid/taxane extravasations
• Sodium thiosulfate for selected mechlorethamine-related injuries

Antidote choice, compress temperature, and technique are drug specific.

Routine corticosteroid infiltration is not a universal treatment.

Myelosuppression

Myelosuppression is one of the most important delayed complications of cytotoxic chemotherapy.

It can cause:

• Neutropenia → infection/sepsis
• Thrombocytopenia → bleeding
• Anemia → fatigue, dyspnea, tissue hypoxia

The timing of nadir differs substantially between agents.

Neutropenic Fever

Fever in a significantly neutropenic patient after chemotherapy is an oncologic emergency.

Management includes:

• Immediate clinical assessment
• Blood cultures and appropriate infection evaluation
• Prompt empiric antimicrobial therapy according to febrile-neutropenia protocols

Treatment should not be delayed while waiting for culture results.

Growth Factors

Granulocyte colony-stimulating factors such as filgrastim may be used in selected chemotherapy-associated neutropenia or overdose situations.

Use depends on:

• Agent involved
• Severity and expected duration of neutropenia
• Infection status
• Oncology/toxicology recommendations

A single historical neutrophil threshold is insufficient to determine use.

Laboratory Evaluation

Important baseline studies after significant antineoplastic overdose may include:

• CBC with differential
• Platelet count
• Electrolytes
• Glucose
• BUN/creatinine
• Liver tests

Additional studies depend on the drug.

Agent-Specific Testing

Methotrexate

• Serial methotrexate concentrations
• Creatinine
• Urine pH when high-dose toxicity is relevant

Cisplatin/carboplatin

• Magnesium
• Potassium
• Calcium
• Renal function
• Audiometry when indicated

Cyclophosphamide/ifosfamide

• Urinalysis
• Renal function
• Electrolytes
• Acid–base status

Anthracyclines

• ECG
• Cardiac biomarkers when clinically indicated
• Echocardiography for suspected myocardial dysfunction

Bleomycin

• Oxygenation
• Pulmonary imaging/function assessment when symptomatic

Serial CBC Is Essential

A normal initial CBC does not exclude future severe marrow suppression.

Repeat testing must be scheduled according to:

• Drug
• Dose
• Expected nadir
• Clinical condition

This is one of the most important follow-up principles in antineoplastic poisoning.

GI Decontamination

Do not induce vomiting.

Ipecac is obsolete.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a clinically important recent oral exposure when:

• The agent is adsorbable
• Airway protection is adequate
• Aspiration risk is acceptable
• Expected benefit outweighs risk

Many antineoplastic overdoses occur through parenteral medication errors, where GI decontamination has no role.

Seizures

For toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic therapy for refractory status epilepticus

Correct contributing:

• Hypoglycemia
• Electrolyte abnormalities
• Hypoxia
• Acid–base disturbances

Hypotension

Identify the mechanism, such as:

• Volume depletion
• Rapid infusion reaction
• Anaphylaxis
• Cardiogenic shock
• Sepsis
• Coingestant

Use appropriate isotonic fluid when indicated.

Vasopressor selection should be based on shock physiology; norepinephrine is generally preferred for persistent vasodilatory shock.

Trendelenburg positioning and routine dopamine-first therapy are outdated.

Dysrhythmias

There is no universal antineoplastic-associated dysrhythmia treatment.

Management depends on:

• Exact drug
• Rhythm
• QRS duration
• QT interval
• Electrolytes
• Myocardial function
• Hemodynamic stability

The older routine sequence of bicarbonate → lidocaine → bretylium is not a modern universal chemotherapy-overdose algorithm.

Bretylium is obsolete in routine contemporary resuscitation.

Dialysis and Extracorporeal Treatment

Extracorporeal removal is highly agent dependent.

It cannot be generalized across antineoplastic drugs.

For example, severe delayed methotrexate elimination is now approached with:

• Leucovorin
• Hydration
• Urinary alkalinization
• Glucarpidase when indicated

rather than assuming conventional dialysis is the optimal method of drug removal.

Renal replacement therapy remains appropriate for conventional severe renal/metabolic indications.

Monitoring

Significant antineoplastic overdose may require monitoring for:

• Delayed cytopenias
• Infection
• Bleeding
• Mucositis
• Renal failure
• Hepatic injury
• Electrolyte abnormalities
• Cardiac dysfunction
• Neurotoxicity
• Pulmonary toxicity

The monitoring period can extend for days to weeks depending on the agent.

Disposition

A universal “6-hour observation then discharge” approach is inappropriate.

Disposition depends on:

• Exact drug
• Dose
• Route
• Time since exposure
• Renal/hepatic function
• Initial symptoms
• Expected delayed toxicity
• Ability to obtain serial laboratory testing
• Reliability of oncology/toxicology follow-up

A clinically well patient may still require carefully scheduled outpatient CBC and organ-function monitoring.

Admission

Hospitalization is appropriate for clinically important exposures associated with:

• Significant methotrexate accumulation
• Severe mucositis
• Neutropenia
• Febrile neutropenia
• Thrombocytopenia/bleeding
• Severe anemia
• AKI
• Major electrolyte abnormalities
• Hepatic failure
• Encephalopathy
• Seizures
• Cardiac toxicity
• Pulmonary toxicity
• Serious extravasation
• Significant fluoropyrimidine overdose

ICU care may be necessary for shock, respiratory failure, malignant dysrhythmia, status epilepticus, severe sepsis, or multiorgan failure.

Pregnancy

The historical FDA pregnancy letter categories are obsolete.

Many traditional cytotoxic antineoplastics can cause:

• Embryotoxicity
• Fetotoxicity
• Teratogenicity
• Fetal growth effects

However, cancer treatment during pregnancy is highly dependent on:

• Specific drug
• Gestational age
• Cancer type
• Disease urgency
• Treatment alternatives

Pregnancy is therefore not appropriately summarized by a single class-wide prohibition.

Safeguarding and Medication Error

Antineoplastic overdose is frequently iatrogenic, making systems analysis important.

Potential causes include:

• Wrong dose
• Wrong route
• Wrong infusion rate
• Wrong schedule
• Confusion between daily and weekly dosing
• Intrathecal/intravenous route errors
• Pump programming errors

Prevention and rapid recognition of chemotherapy medication errors are major components of toxicology care.

Rigid age cutoffs for assuming abuse or intentional poisoning are outdated.

Prognosis

Outcome varies enormously by drug and exposure.

Important causes of morbidity and mortality include:

• Neutropenic sepsis
• Severe thrombocytopenic bleeding
• Multiorgan failure
• AKI
• Cardiomyopathy
• Pulmonary fibrosis
• Severe neurotoxicity
• Catastrophic wrong-route administration

Some complications may be permanent, including:

• Peripheral neuropathy
• Hearing loss
• Cardiac dysfunction
• Pulmonary fibrosis
• CNS injury
• Renal impairment

Important Modernization of the Older Source

• Antineoplastic poisoning is highly agent- and route-specific.
• Early asymptomatic appearance does not exclude serious delayed toxicity.
• Serial CBC monitoring is crucial because myelosuppression may be delayed.
• Methotrexate toxicity requires protocol-guided leucovorin rescue, hydration, urinary alkalinization, and serial concentrations.
• Glucarpidase is an important modern treatment for selected high-dose methotrexate toxicity with renal dysfunction and delayed elimination.
• Repeated accidental daily methotrexate dosing is an important modern poisoning pattern.
• Uridine triacetate is the specific emergency antidotal therapy for selected 5-FU/capecitabine overdoses and early severe fluoropyrimidine toxicity.
• DPD deficiency can produce catastrophic fluoropyrimidine toxicity at otherwise therapeutic exposure.
• Mesna prevents urothelial injury from ifosfamide and selected cyclophosphamide regimens.
• Ifosfamide can cause severe encephalopathy.
• Dexrazoxane has roles in anthracycline cardioprotection and anthracycline extravasation.
• Intrathecal vincristine is a catastrophic, potentially fatal wrong-route error.
• Extravasation treatment is drug specific; saline injection to dilute a vesicant is not a universal modern recommendation.
• Bleomycin exposure does not mean withholding oxygen from a hypoxemic patient.
• Fever with significant chemotherapy-induced neutropenia requires urgent empiric infection management.
• G-CSF decisions should be individualized rather than based on one historic cell-count threshold.
• The historical bicarbonate/lidocaine/bretylium sequence is not a universal treatment for chemotherapy-related dysrhythmia; bretylium is obsolete.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and dopamine-first shock management are outdated.
• Fixed 6-hour observation is inadequate for drugs with delayed marrow or organ toxicity.
• Historical FDA pregnancy categories are obsolete.

Key Points

• Antineoplastic toxicity is drug-, dose-, route-, and time-dependent.
• Delayed myelosuppression is one of the most important dangers.
• Methotrexate → leucovorin rescue; glucarpidase for selected severe delayed elimination with renal dysfunction.
• 5-FU/capecitabine → uridine triacetate for qualifying overdose or early severe toxicity.
• Cisplatin → nephrotoxicity, electrolyte wasting, ototoxicity, neuropathy.
• Cyclophosphamide/ifosfamide → hemorrhagic cystitis; mesna is protective.
• Ifosfamide → encephalopathy.
• Anthracyclines → cardiotoxicity and severe extravasation injury.
• Vincristine → neurotoxicity; intrathecal administration is catastrophic.
• Bleomycin → pulmonary toxicity.
• Asparaginase → pancreatitis, coagulopathy/thrombosis, hyperglycemia, hypersensitivity.
• A normal early CBC does not rule out later severe toxicity.
• Significant exposures require early toxicology, oncology, pharmacy, and poison-center coordination with prolonged follow-up when indicated.

Toxicology – Sulfonamides

Core Concept

Sulfonamides include several antimicrobial drugs and related compounds. Important examples include:

• Sulfamethoxazole, most commonly combined with trimethoprim as TMP-SMX
• Sulfadiazine
• Sulfadoxine
• Sulfacetamide
• Silver sulfadiazine
• Mafenide
• Sulfasalazine — primarily used for inflammatory bowel disease and some rheumatologic conditions

Many older sulfonamides are now rarely used.

Acute isolated overdose is usually relatively mild. More clinically important toxicity generally occurs as an adverse reaction during therapeutic use, particularly:

• Hypersensitivity
• Severe cutaneous adverse reactions
• Hematologic toxicity
• Renal injury
• Hepatotoxicity
• Hyperkalemia from the trimethoprim component of TMP-SMX
• Hypoglycemia in susceptible patients
• Rare methemoglobinemia or hemolysis

There is no universal specific antidote for sulfonamide poisoning.

Mechanism of Antimicrobial Action

Sulfonamide antibiotics inhibit bacterial folate synthesis by competing with para-aminobenzoic acid (PABA) and inhibiting dihydropteroate synthase.

Trimethoprim acts at a different step by inhibiting dihydrofolate reductase.

Therefore, TMP-SMX produces sequential inhibition of microbial folate metabolism.

Acute Overdose

Most isolated acute sulfonamide ingestions produce either no symptoms or relatively nonspecific GI effects such as:

• Nausea
• Vomiting
• Abdominal discomfort

Severe acute toxicity is uncommon.

Importantly, many of the most serious sulfonamide reactions are not directly related to the size of an overdose.

1. Hypersensitivity

Sulfonamide antimicrobials can cause immune-mediated reactions at therapeutic doses.

Possible manifestations include:

• Fever
• Maculopapular rash
• Urticaria
• Angioedema
• Drug fever
• Rare anaphylaxis

A susceptible individual can react after relatively small exposure, so there is no meaningful “safe overdose threshold” for allergic reactions.

Severe Cutaneous Adverse Reactions

Sulfonamide antibiotics are important causes of severe drug eruptions, including:

• Stevens–Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• DRESS
• AGEP

These are primarily delayed adverse drug reactions rather than manifestations of acute overdose.

SJS/TEN

Warning features include:

• Fever
• Malaise
• Painful skin
• Blistering
• Epidermal detachment
• Oral erosions
• Ocular involvement
• Genital mucosal involvement

Suspected SJS/TEN requires:

Immediate discontinuation of the causative drug + urgent hospital assessment + supportive specialist care

Simply treating the eruption as an uncomplicated “sulfa allergy” can miss a life-threatening syndrome.

DRESS

Drug reaction with eosinophilia and systemic symptoms may produce:

• Fever
• Extensive rash
• Facial edema
• Eosinophilia
• Lymphadenopathy
• Hepatitis
• Nephritis
• Other organ involvement

Symptoms may continue or evolve even after the medication has been discontinued.

“Sulfa Allergy” – Important Clarification

A history of allergy to a sulfonamide antimicrobial does not automatically mean that the patient will cross-react with every medication containing a sulfonamide chemical group.

Non-antimicrobial sulfonamide-containing drugs are structurally different.

Therefore:

“Sulfa allergy” should not automatically be interpreted as allergy to all sulfur-containing or sulfonamide-containing medications.

Elemental sulfur, sulfates, and sulfites are also chemically distinct from sulfonamide antibiotics.

2. Renal Toxicity

Sulfonamides are substantially eliminated through the kidneys, and renal impairment can increase systemic exposure to some agents.

Renal complications include:

• Crystalluria
• Crystal nephropathy
• Hematuria
• Acute interstitial nephritis
• Acute kidney injury

Crystalluria

Some sulfonamides or their metabolites have limited urinary solubility.

Precipitation within the urinary tract can produce:

Crystalluria → tubular obstruction/injury → hematuria → AKI

Risk may increase with:

• High exposure
• Dehydration
• Concentrated urine
• Preexisting renal dysfunction

Modern agents are generally less prone to severe crystalluria than some older sulfonamides, but the complication remains possible.

Acute Interstitial Nephritis

Sulfonamides can cause immune-mediated interstitial nephritis.

Possible findings include:

• Rising creatinine
• Hematuria
• Pyuria
• Proteinuria

Fever, rash, and eosinophilia may occur but are not reliably present.

TMP-SMX and Creatinine – Important Pitfall

Trimethoprim can inhibit tubular secretion of creatinine.

Therefore, serum creatinine may rise even without a true fall in GFR.

This can create an apparent AKI.

However, TMP-SMX can also cause genuine renal injury, so a creatinine increase should not automatically be dismissed as a benign laboratory effect.

Interpret:

• Creatinine trend
• Urine output
• Urinalysis
• Electrolytes
• Overall clinical condition

3. Hyperkalemia

A major modern toxicity omitted from many older sulfonamide discussions is trimethoprim-associated hyperkalemia.

Trimethoprim can act similarly to the potassium-sparing diuretic amiloride in the distal nephron.

This decreases renal potassium excretion.

Therefore:

Trimethoprim → reduced K⁺ excretion → hyperkalemia

Risk Factors for TMP-SMX Hyperkalemia

Risk increases with:

• Renal impairment
• Older age
• High trimethoprim exposure
• Baseline hyperkalemia
• ACE inhibitors
• ARBs
• Potassium-sparing diuretics
• Other medications that impair potassium elimination

Severe hyperkalemia can cause:

• Weakness
• Conduction abnormalities
• Ventricular dysrhythmia
• Cardiac arrest

Hyperkalemia Management

Clinically important hyperkalemia should be managed according to severity and ECG findings.

Priorities include:

• Stop contributing medications
• Cardiac stabilization when indicated
• Shift potassium intracellularly
• Promote potassium elimination
• Consider dialysis for severe refractory hyperkalemia or major renal failure

The serum potassium level and clinical/ECG picture are more important than the size of the original antibiotic exposure.

4. Hematologic Toxicity

Sulfonamides can rarely cause:

• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Pancytopenia
• Hemolytic anemia

These are generally complications of therapeutic exposure rather than isolated acute ingestion.

Hemolysis and G6PD Deficiency

Sulfonamide antimicrobials can produce oxidative stress.

Patients with G6PD deficiency may be more susceptible to hemolysis.

Possible findings include:

• Fatigue
• Pallor
• Jaundice
• Dark urine
• Falling hemoglobin
• Elevated bilirubin
• Elevated LDH
• Reduced haptoglobin

The risk varies by drug, dose, and individual susceptibility.

5. Methemoglobinemia

Methemoglobinemia is an uncommon but recognized complication of some sulfonamide exposures.

Oxidation converts hemoglobin iron:

Fe²⁺ → Fe³⁺

Methemoglobin cannot effectively carry oxygen.

Clinical Features of Methemoglobinemia

Possible findings include:

• Cyanosis
• Headache
• Dizziness
• Dyspnea
• Fatigue
• Tachycardia

Severe cases may cause:

• Altered consciousness
• Myocardial ischemia
• Seizures
• Dysrhythmias
• Cardiovascular collapse

Diagnosis of Methemoglobinemia

A characteristic clue is:

Low pulse oximetry that improves little despite supplemental oxygen

Blood may appear unusually dark or brownish.

Diagnosis is confirmed using co-oximetry.

Standard pulse oximetry alone cannot accurately quantify methemoglobin.

Treatment of Methemoglobinemia

Management includes:

• Stop the oxidizing drug
• Supplemental oxygen
• Support airway and circulation
• Treat clinically significant symptomatic methemoglobinemia with an appropriate reducing agent such as methylene blue

Treatment decisions depend on:

• Symptoms
• Methemoglobin concentration
• Comorbid disease
• Evidence of tissue hypoxia

A rigid concentration alone should not determine treatment.

Methylene Blue – Important Caution

Methylene blue requires particular caution in patients with G6PD deficiency because:

• Response may be reduced
• Hemolysis may worsen

It can also contribute to serotonergic toxicity because it has monoamine oxidase-inhibiting properties.

Severe cases in which methylene blue is ineffective or unsuitable require specialist toxicology/hematology input.

6. Hypoglycemia

Sulfonamide antimicrobial therapy, especially TMP-SMX, can occasionally cause hypoglycemia.

Risk increases with:

• Renal impairment
• Malnutrition
• Older age
• High systemic exposure
• Concurrent glucose-lowering medications

Manifestations include:

• Sweating
• Tremor
• Confusion
• Altered consciousness
• Seizures

Check bedside glucose in patients with neurologic symptoms.

7. Hepatotoxicity

Sulfonamide antibiotics can cause drug-induced liver injury.

Patterns may include:

• Hepatocellular injury
• Cholestatic injury
• Mixed injury

Liver involvement can also occur as part of systemic hypersensitivity or DRESS.

Clinical Features of Liver Injury

Possible findings include:

• Fatigue
• Nausea
• Right-upper-quadrant discomfort
• Pruritus
• Dark urine
• Jaundice

Evaluation may include:

• AST/ALT
• Bilirubin
• Alkaline phosphatase
• Coagulation studies when severe

8. Pulmonary Hypersensitivity

Rare pulmonary reactions include:

• Drug-induced pneumonitis
• Eosinophilic pulmonary reactions
• Other hypersensitivity lung injury

Symptoms may include:

• Cough
• Dyspnea
• Fever
• Hypoxemia

Alternative infectious and cardiopulmonary causes must also be considered.

9. Sulfasalazine

Sulfasalazine deserves separate consideration because it is metabolized in the colon to:

• 5-aminosalicylic acid
• Sulfapyridine

Therefore, its toxicity is not identical to ordinary sulfonamide antimicrobial poisoning.

Possible adverse effects include:

• Nausea
• Vomiting
• Abdominal discomfort
• Headache
• Rash
• Hepatotoxicity
• Hematologic toxicity
• Rare hemolysis
• Rare severe hypersensitivity

Large exposures may also have features related to its salicylate-derived component, although classic severe salicylate poisoning should not automatically be assumed.

10. Topical Sulfonamides

Silver Sulfadiazine

Used particularly for selected burn/wound indications.

Systemic absorption can occur when applied to large areas of damaged skin.

Potential complications include:

• Leukopenia
• Hypersensitivity
• Rare systemic sulfonamide effects

Mafenide

Mafenide is particularly important because it can inhibit carbonic anhydrase.

Systemic absorption from large treated burn areas can contribute to:

Bicarbonate loss → hyperchloremic metabolic acidosis

This is an important agent-specific toxicity not emphasized in older general sulfonamide summaries.

11. Neonates and Bilirubin

Sulfonamides have historically raised concern for displacement of bilirubin from albumin binding.

Neonates—particularly premature infants or those with significant hyperbilirubinemia—require special caution because excessive unbound bilirubin can contribute to bilirubin encephalopathy/kernicterus.

This concern is primarily relevant to systemic therapeutic exposure in susceptible neonates rather than typical accidental overdose in older children.

Pregnancy and Breastfeeding

The old FDA pregnancy letter categories are obsolete.

Use during pregnancy should be individualized according to:

• Specific drug
• Gestational timing
• Infection
• Maternal condition
• Folate considerations
• Available alternatives

TMP-SMX deserves particular consideration because trimethoprim interferes with folate metabolism.

Near delivery, neonatal bilirubin-related considerations may also influence drug selection.

Breastfeeding

Sulfonamide use during breastfeeding should consider:

• Infant age
• Prematurity
• Hyperbilirubinemia
• G6PD status
• Specific medication

A blanket statement that all sulfonamides are either completely safe or universally contraindicated during breastfeeding is inappropriate.

Diagnosis

Determine:

• Exact product
• Whether trimethoprim is also present
• Amount
• Timing
• Acute vs prolonged exposure
• Renal function
• Other medications
• Allergy history
• Coingestants

The distinction between isolated sulfonamide exposure and TMP-SMX is particularly important because trimethoprim contributes additional renal and electrolyte effects.

Laboratory Evaluation

Small asymptomatic exposures may require no testing.

For significant or symptomatic toxicity, consider:

• Bedside glucose
• CBC
• Electrolytes
• Potassium
• Bicarbonate
• BUN/creatinine
• Urinalysis
• Liver tests

Depending on presentation:

• Co-oximetry for suspected methemoglobinemia
• Hemolysis studies
• ECG for hyperkalemia or significant systemic illness
• Blood gas when severe acid–base disturbance is suspected

Serum Sulfonamide Concentrations

Routine serum sulfonamide concentrations are generally not clinically useful.

Management should be guided by:

• Symptoms
• Renal function
• Electrolytes
• Hematologic findings
• Organ injury

Initial Management

General priorities are:

Airway/breathing → circulation → identify exact drug → glucose → electrolytes/renal function → evaluate hypersensitivity and organ toxicity → supportive care

Most isolated acute ingestions do not require aggressive intervention.

GI Decontamination

Do not induce vomiting.

Ipecac has no modern role.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The drug is adsorbable
• The airway is safe
• Aspiration risk is acceptable
• Expected clinical benefit justifies treatment

Many uncomplicated exposures require no decontamination.

Anaphylaxis

If true anaphylaxis occurs:

IM epinephrine is first-line therapy.

Provide:

• Airway support
• Oxygen when required
• Appropriate IV fluid resuscitation
• Additional supportive treatment

Antihistamines may help skin symptoms but must not delay epinephrine.

Seizures

For toxicologic seizures:

Benzodiazepines are first-line.

Persistent seizures may require additional benzodiazepines, phenobarbital, or appropriate anesthetic management.

Correct accompanying:

• Hypoglycemia
• Electrolyte abnormalities
• Hypoxia
• Acid–base disturbances

Hypotension

Determine whether hypotension reflects:

• Anaphylaxis
• Dehydration
• Severe hypersensitivity
• Coingestion
• Other illness

Treat appropriate volume depletion with isotonic crystalloid.

Persistent vasodilatory shock generally favors norepinephrine.

Trendelenburg positioning and routine dopamine-first therapy are outdated.

Renal Management

When crystalluria or renal injury is suspected:

• Stop further exposure
• Correct dehydration appropriately
• Monitor renal function
• Monitor urine output
• Correct electrolyte abnormalities
• Avoid additional nephrotoxins where possible

Aggressive forced diuresis is not routinely appropriate.

Enhanced Elimination

Hemodialysis is not routine treatment for uncomplicated sulfonamide overdose.

It may become relevant when severe toxicity occurs in the setting of:

• Major renal failure
• Severe refractory electrolyte abnormalities
• Other conventional indications for renal replacement therapy

The decision should be individualized.

Monitoring

Monitoring should match the toxicity.

Renal toxicity

• Creatinine
• Electrolytes
• Potassium
• Urine output

Hematologic toxicity

• CBC
• Hemolysis studies when indicated

Hepatotoxicity

• Liver tests
• Coagulation studies if severe

Methemoglobinemia

• Clinical oxygenation
• Co-oximetry

Severe hypersensitivity

• Skin/mucosal progression
• Airway
• Hemodynamics
• Organ involvement

Observation and Disposition

There is no universal observation period.

Disposition depends on:

• Exact drug
• Amount
• Symptoms
• Renal function
• Potassium/glucose abnormalities
• Coingestants
• Clinical trajectory

Importantly, delayed immune reactions such as SJS/TEN, DRESS, cytopenias, or hepatitis cannot be excluded by a few hours of emergency observation.

Admission

Hospitalization may be required for:

• Anaphylaxis
• SJS/TEN or other severe cutaneous reaction
• DRESS with organ involvement
• Significant methemoglobinemia
• Hemolysis
• Severe cytopenia
• AKI
• Significant hyperkalemia
• Severe hypoglycemia
• Hepatic injury
• Persistent seizures
• Hemodynamic instability

ICU or specialized burn/critical-care management may be necessary for severe SJS/TEN, shock, respiratory failure, or major methemoglobinemia.

Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are outdated.

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Medication accessibility
• Circumstances
• Consistency of history
• Recurrent unexplained exposures
• Broader safeguarding concerns

Prognosis

Most isolated acute sulfonamide ingestions recover with supportive care.

Prognosis is more serious when toxicity involves:

• SJS/TEN
• DRESS
• Severe anaphylaxis
• Agranulocytosis
• Severe hemolysis
• Methemoglobinemia
• Significant AKI
• Hyperkalemia
• Severe hepatic injury

Important Modernization of the Older Source

• Acute sulfonamide overdose is usually mild, while serious toxicity more often represents therapeutic adverse reactions.
• Hypersensitivity is not reliably dose dependent; severe reactions can occur at therapeutic doses.
• Sulfonamide antimicrobials are important causes of SJS/TEN and DRESS.
• “Sulfa allergy” does not automatically imply cross-allergy to every non-antibiotic sulfonamide, sulfate, sulfite, or sulfur-containing substance.
• TMP-SMX must be considered as a two-drug exposure.
• Trimethoprim can cause clinically important hyperkalemia.
• Trimethoprim may raise serum creatinine by reducing tubular creatinine secretion without necessarily reducing true GFR.
• Sulfonamides can also cause true AKI through crystal nephropathy or interstitial nephritis.
• G6PD deficiency may increase susceptibility to oxidative hemolysis.
• Methemoglobinemia is rare but potentially serious; diagnosis is by co-oximetry.
• Methylene blue requires special caution in G6PD deficiency and can interact with serotonergic medications.
• Mafenide can cause hyperchloremic metabolic acidosis through carbonic-anhydrase inhibition.
• Neonatal kernicterus concerns are primarily relevant to susceptible premature or hyperbilirubinemic infants.
• Ipecac and routine gastric lavage are obsolete.
• Forced diuresis is not routine treatment for crystalluria.
• Trendelenburg and dopamine-first shock management are outdated.
• Historical FDA pregnancy letter categories are obsolete.
• Delayed hypersensitivity, marrow, liver, and renal complications cannot be excluded by a short observation period.

Key Points

• Sulfonamides → hypersensitivity, renal, hematologic, and hepatic toxicity.
• TMP-SMX → remember trimethoprim-associated hyperkalemia and creatinine elevation.
• SJS/TEN and DRESS are major delayed adverse reactions.
• Crystalluria, interstitial nephritis, and true AKI can occur.
• G6PD deficiency increases concern for oxidative hemolysis.
• Rare methemoglobinemia is confirmed with co-oximetry.
• Mafenide → hyperchloremic metabolic acidosis.
• Sulfonamide allergy does not equal allergy to all sulfur-containing drugs.
• There is no single specific antidote for sulfonamide poisoning.
• Management is primarily withdrawal of the offending drug, supportive care, and targeted treatment of complications.