Toxicology – Ipecac

Indication

No routine indication. Syrup of ipecac was historically kept in homes to induce vomiting after accidental poison ingestion, especially in children. It is no longer recommended for routine prehospital management of poisoning.

Mechanism of Action

Ipecac is derived from the roots and rhizomes of the Cephaelis ipecacuanha plant.

It causes vomiting through two main effects:

• Direct irritation of the stomach and intestinal lining
• Stimulation of the central chemoreceptor trigger zone

Why It Is No Longer Recommended

Inducing vomiting has not been shown to reliably improve outcomes after poisoning and can create additional problems, including:

• Aspiration
• Delayed administration of more effective treatments
• Prolonged vomiting
• Difficulty giving activated charcoal or other therapies

Adverse Effects

Repeated or chronic use can cause significant toxicity, including:

• Persistent vomiting
• Electrolyte disturbances
• Muscle weakness
• Cardiomyopathy

Key Points

• Ipecac should not be used routinely after toxic ingestion.
• It has largely been replaced by supportive care and more selective decontamination strategies.
• Chronic misuse can cause serious cardiac toxicity.
• Poisoning exposures should be discussed with a poison control center or medical professional rather than treated by inducing vomiting at home.

Toxicology – GI Decontamination: Whole Bowel Irrigation

Indications

Whole bowel irrigation (WBI) may be considered for selected poisonings in which a substance is expected to remain in the gastrointestinal tract for a prolonged period.

Examples include:

• Large ingestions of sustained-release or enteric-coated medications
• Certain slowly absorbed toxic substances
• Some iron or lead ingestions
• Ingestion of multiple transdermal patches
• Selected sustained-release drugs such as calcium channel blockers, theophylline, venlafaxine, or bupropion

Because evidence and indications vary, WBI should generally be discussed with a medical toxicologist or poison control center.

Mechanism of Action

WBI uses a polyethylene glycol–electrolyte lavage solution (PEG-ELS) to rapidly move gastrointestinal contents through the bowel.

PEG-ELS is designed to be essentially iso-osmotic, allowing large volumes to pass through the intestine with relatively little net fluid or electrolyte absorption.

The goal is to:

• Shorten gastrointestinal transit time
• Reduce continued absorption of substances still present in the bowel
• Promote elimination of intact tablets, drug packets, or poorly absorbed toxic material

Administration

PEG-ELS is given orally or through a nasogastric tube in a monitored setting and continued until bowel output is adequately cleared.

The exact rate and duration depend on factors such as:

• Patient size and age
• Substance involved
• Clinical condition
• Tolerance of the lavage

Important Limitations

WBI is not appropriate for every overdose and may be unsafe in patients with:

• Bowel obstruction or ileus
• Gastrointestinal perforation
• Significant GI bleeding
• Hemodynamic instability
• An unprotected airway or high aspiration risk

Key Points

• WBI is most useful when the toxic substance may remain in the gut for a long time.
• It is conceptually similar to bowel preparation used before colonoscopy, but in toxicology it is used for decontamination.
• Polyethylene glycol (PEG) is completely different from ethylene glycol, the toxic alcohol found in antifreeze.
• WBI should be used selectively and usually with toxicology guidance.

Toxicology – Antidote: Octreotide for Sulfonylurea Poisoning

Indication

Octreotide is used for sulfonylurea or meglitinide overdose, especially when recurrent or persistent hypoglycemia is occurring.

Mechanism of Action

Octreotide is a long-acting somatostatin analog that suppresses insulin release from the pancreas.

In sulfonylurea poisoning, giving dextrose raises the blood glucose but can also stimulate additional insulin secretion, causing another episode of hypoglycemia. Octreotide helps break this cycle by reducing pancreatic insulin release.

It is usually used together with dextrose to:

• Correct low blood glucose
• Reduce recurrent hypoglycemia
• Decrease the need for repeated dextrose administration

Administration

Octreotide is typically given by subcutaneous or IV dosing at repeated intervals, with the exact regimen adjusted for age, severity, and clinical response.

Treatment should be accompanied by close glucose monitoring, particularly because recurrent hypoglycemia can occur after the initial correction.

Monitoring

Important monitoring includes:

• Frequent bedside blood glucose checks
• Mental status
• Oral intake when appropriate
• Recurrence of hypoglycemia after dextrose is reduced or stopped

Key Points

• Octreotide helps prevent the cycle of repeatedly “chasing the glucose” with dextrose.
• It works by inhibiting insulin secretion, rather than simply raising blood glucose.
• Children with suspected sulfonylurea ingestion require particularly cautious observation because even small exposures can cause prolonged hypoglycemia.
• Recurrent hypoglycemia may occur for many hours, so observation is often necessary even after the glucose initially normalizes.

Toxicology – Antidote: Digoxin Immune Fab

Indications

Digoxin immune Fab is the specific antidote for severe or life-threatening cardiac glycoside toxicity. It may be considered when poisoning produces findings such as:

• Hemodynamic instability or significant hypotension
• Severe symptomatic bradycardia or advanced conduction abnormalities
• Dangerous ventricular dysrhythmias
• Significant hyperkalemia in acute poisoning
• Rapidly worsening toxicity after a major exposure

It can also bind several naturally occurring cardiac glycosides found in plants such as foxglove, oleander, dogbane, milkweed, and lily of the valley.

Mechanism of Action

Digoxin immune Fab consists of antibody fragments that bind circulating digoxin and related cardiac glycosides.

Once bound:

• Free digoxin concentrations fall
• Digoxin dissociates from its tissue receptors
• Inhibition of the Na⁺/K⁺-ATPase decreases
• The digoxin–Fab complexes are subsequently cleared from the body

This can rapidly reverse serious cardiac and systemic toxicity.

Digoxin Toxicity Mechanism

Normally, digoxin inhibits the Na⁺/K⁺-ATPase pump, increasing intracellular sodium.

This reduces the activity of the Na⁺/Ca²⁺ exchanger, causing intracellular calcium to rise. More calcium becomes available for release from the sarcoplasmic reticulum, producing digoxin’s positive inotropic effect.

At toxic concentrations, however, excessive intracellular calcium promotes abnormal automaticity and dysrhythmias. Digoxin also increases vagal activity, which slows the sinus rate and conduction through the AV node.

Administration

The amount of digoxin immune Fab required depends on factors such as:

• Whether toxicity is acute or chronic
• The estimated amount of digoxin involved
• Serum digoxin concentration when appropriately timed
• Severity of the patient’s clinical findings

In severe emergencies, empiric treatment may be given without waiting for laboratory confirmation. Dosing should follow current toxicology or poison-center guidance.

Monitoring After Fab

Monitor:

• ECG and cardiac rhythm
• Potassium
• Renal function
• Blood pressure and clinical response

Potassium may decrease rapidly as toxicity reverses, so hypokalemia can develop after treatment.

Important Laboratory Point

After an acute ingestion, a digoxin concentration obtained too early—before tissue distribution is complete—can be difficult to interpret; levels are generally most useful several hours after ingestion.

After digoxin immune Fab is administered, routine digoxin assays can measure both bound and unbound drug and may therefore show a markedly elevated total digoxin concentration that does not represent ongoing toxicity.

Key Points

• Digoxin immune Fab directly binds and neutralizes circulating cardiac glycosides.
• Severe dysrhythmias, cardiovascular instability, and significant hyperkalemia are important warning signs of serious toxicity.
• Digoxin’s increased contractility comes from increased intracellular Ca²⁺, while its slowing of heart rate and AV conduction is largely related to enhanced vagal effects.
• Do not interpret routine serum digoxin levels normally after Fab has been administered.

Toxicology – Antidote: Glucagon for Beta-Blocker Poisoning

Indication

Glucagon may be used in beta-blocker overdose, particularly when significant bradycardia, hypotension, or reduced cardiac contractility is present.

Mechanism of Action

Normally, stimulation of cardiac beta receptors activates a G protein, which stimulates adenylyl cyclase. This increases cAMP, activates protein kinase A, increases calcium entry into cardiac cells, and improves heart rate and contractility.

In beta-blocker poisoning, this pathway is blocked at the beta receptor. Glucagon can bypass the blocked receptor by activating its own receptor and stimulating adenylyl cyclase through a separate pathway.

This leads to:

• Increased cAMP
• Increased intracellular calcium
• Improved cardiac contractility
• Increased heart rate

A useful way to remember this is that glucagon activates adenylyl cyclase through a “backdoor” pathway that does not depend on beta receptors.

Administration

Glucagon is given intravenously, often as an initial bolus followed by a continuous infusion if the patient responds.

Because relatively large doses may be required in toxicologic emergencies, treatment should be directed by a poison center or medical toxicologist.

Adverse Effects

The most common adverse effect is:

• Nausea and vomiting

Antiemetic therapy may therefore be useful. Hyperglycemia can also occur.

Key Points

• Glucagon can bypass beta-receptor blockade and increase intracellular cAMP.
• It may improve bradycardia and myocardial contractility in beta-blocker poisoning.
• Vomiting is common after administration.
• In severe beta-blocker toxicity, glucagon is usually one part of a broader resuscitation strategy that may also include vasopressors and hyperinsulinemic euglycemia therapy.

Toxicology – Antidote: Hyperinsulinemic Euglycemia (HIE) Therapy

Indications

Hyperinsulinemic euglycemia therapy is used for severe calcium channel blocker (CCB) and beta-blocker poisoning, especially when there is significant myocardial depression, hypotension, or shock.

Mechanism of Action

In severe CCB and beta-blocker toxicity, the heart becomes less able to use its usual fatty-acid energy pathway and relies more heavily on glucose.

High-dose insulin helps by:

• Increasing myocardial glucose uptake
• Improving cellular energy production
• Producing a positive inotropic effect
• Improving cardiac contractility and circulation

In calcium channel blocker overdose, pancreatic insulin release may also be suppressed, producing hyperglycemia with relative hypoinsulinemia.

Administration

HIE therapy uses high-dose IV insulin together with glucose supplementation as needed to maintain normal blood glucose.

Treatment typically involves:

• An initial IV insulin dose
• A continuous high-dose insulin infusion
• Dextrose supplementation when necessary
• Gradual adjustment based on blood pressure, cardiac function, and metabolic response

Because this therapy uses insulin doses far above those used routinely for diabetes, it should be managed in a closely monitored critical-care setting.

Monitoring

Frequent laboratory and bedside monitoring is essential, especially:

• Blood glucose
• Potassium
• Other electrolytes
• Blood pressure
• Heart rate and rhythm
• Cardiac perfusion and overall hemodynamic response

Major Risks

The most important complications are:

• Hypoglycemia
• Hypokalemia

Both require active monitoring and correction during therapy.

Key Points

• HIE is an important treatment for severe CCB and beta-blocker toxicity.
• Its main benefit is improved myocardial energy utilization and contractility.
• CCB poisoning often causes hyperglycemia because calcium-channel blockade reduces pancreatic insulin secretion.
• A useful memory aid is that the poisoned myocardium is energy-starved and benefits from increased glucose utilization.
• HIE should be performed with intensive glucose, electrolyte, and cardiovascular monitoring.

Toxicology – Antidotes: Chelating Agents

Overview

Chelators bind specific toxic metals and form complexes that can be eliminated from the body, usually through the urine. The appropriate agent depends on the metal involved and the severity of poisoning.

Succimer (DMSA)

Binds: Lead, arsenic, and mercury.

Mechanism of Action

• Water-soluble compound related to dimercaprol (BAL)
• Contains sulfhydryl groups that bind toxic metals
• The resulting complexes are primarily excreted in urine
• Has only limited effectiveness for cadmium removal

Succimer is commonly used as an oral chelator, particularly for selected cases of lead poisoning.

DMPS (2,3-Dimercapto-1-Propanesulfonic Acid)

Binds: Mercury and arsenic; it can also bind lead.

Mechanism of Action

• Water-soluble dimercaprol-related chelator
• Sulfur-containing groups bind metal ions
• Metal-chelator complexes are eliminated mainly through the kidneys

Availability and approved indications vary by country.

Penicillamine

Binds: Primarily copper; it has also been used in selected cases involving other metals.

Mechanism of Action

• A penicillin-related compound without antibacterial activity
• Acts as a thiol-containing chelator
• Binds free copper and reduces its ability to participate in damaging oxidation-reduction reactions
• Excreted in urine

It is particularly associated with treatment of copper overload, including Wilson disease.

Calcium Disodium EDTA (CaNa₂EDTA)

Binds: Lead.

Mechanism of Action

• Primarily acts in the extracellular compartment
• Binds circulating lead and promotes its urinary elimination
• As circulating lead decreases, additional lead can redistribute from tissues into the blood and become available for chelation

The calcium disodium form is used for lead poisoning; plain disodium EDTA can cause dangerous hypocalcemia.

Deferoxamine (DFO)

Binds: Iron.

Mechanism of Action

• Chelates free ferric iron
• Forms the water-soluble complex ferrioxamine
• Mainly targets free or loosely bound iron rather than iron incorporated into hemoglobin
• The complex is eliminated through urine

Deferoxamine is an important antidote for significant acute iron poisoning.

Dimercaprol (BAL – British Anti-Lewisite)

Binds: Arsenic, mercury, and lead; historically developed for the arsenical warfare agent Lewisite.

Mechanism of Action

• Contains sulfhydryl (–SH) groups that bind toxic metals
• Prevents metals from interacting with sulfhydryl-containing cellular proteins
• Metal-chelator complexes are eliminated primarily through urine

Key Points

• Lead: Succimer or CaNa₂EDTA; dimercaprol may be added in severe cases.
• Arsenic/Mercury: Dimercaprol, succimer, or other specialist-selected thiol chelators.
• Copper: Penicillamine.
• Iron: Deferoxamine.
• Chelation should be guided by the specific metal, blood concentration, clinical severity, and toxicology consultation.

Toxicology – Antidote: Intravenous Lipid Emulsion (ILE)

Indications

Intravenous lipid emulsion may be considered as a rescue therapy for severe cardiovascular toxicity caused by highly lipophilic drugs, particularly when standard resuscitative measures are failing.

The strongest evidence is for local anesthetic systemic toxicity, especially with agents such as bupivacaine. It has also been used in selected severe poisonings involving drugs such as:

• Tricyclic antidepressants
• Calcium channel blockers
• Beta-blockers
• Bupropion
• Lamotrigine
• Some antipsychotics and other lipophilic toxins

Its use outside local anesthetic toxicity is generally based on case reports and specialist toxicology judgment.

Mechanism of Action

The exact mechanism is not fully established. Proposed effects include:

• Lipid shuttle/sink effect: Lipophilic toxins redistribute from target tissues into the intravascular lipid phase, potentially reducing drug availability at the heart and other organs.
• Metabolic support: Fatty acids may provide an additional energy source for cardiac muscle and improve myocardial performance.

Administration

A 20% lipid emulsion is typically used. Exact dosing depends on the clinical situation and local toxicology protocols, and treatment should ideally be guided by a medical toxicologist or poison center.

Management Considerations

ILE is generally reserved for:

• Severe hypotension
• Malignant dysrhythmias
• Cardiovascular collapse
• Cardiac arrest associated with a suspected lipophilic toxin

It should be used alongside standard airway management, cardiac monitoring, and advanced resuscitative care rather than as a replacement for them.

Risks

Potential complications include:

• Hypertriglyceridemia
• Pancreatitis
• Interference with laboratory testing
• Pulmonary complications
• Thrombosis or impaired microcirculatory flow with very large lipid loads

Key Points

• ILE is best established for severe local anesthetic systemic toxicity.
• Evidence for many other poisonings is limited and often case-based.
• It is generally considered a rescue therapy, not first-line treatment for most overdoses.
• Specialist toxicology consultation is strongly recommended when considering its use.

Toxicology – Antidotes for Toxic Alcohols: Fomepizole, Ethanol & Hemodialysis

Metabolic Pathways

Methanol and ethylene glycol become dangerous mainly after they are metabolized by alcohol dehydrogenase (ADH) into toxic metabolites.

• Methanol → formaldehyde → formic acid
• Ethylene glycol → glycolaldehyde → glycolic acid → glyoxylic acid → oxalic acid
• Ethanol → acetaldehyde → acetic acid

Ethanol

Ethanol has a higher affinity for ADH than methanol or ethylene glycol. By occupying the enzyme, it slows formation of their toxic metabolites and allows more of the parent alcohol to be eliminated unchanged.

Disadvantages include:

• CNS depression
• Nausea and vomiting
• Hypoglycemia
• Need for frequent serum concentration monitoring

Because of these limitations, ethanol is generally less convenient than fomepizole.

Fomepizole

Fomepizole directly inhibits alcohol dehydrogenase, preventing methanol and ethylene glycol from being converted into their harmful metabolites.

Advantages include:

• Predictable dosing
• Less CNS depression than ethanol
• No need to maintain an intoxicating serum alcohol concentration
• Can be used together with hemodialysis when necessary

Possible adverse effects include:

• Headache
• Nausea
• Dizziness
• Drowsiness
• Altered taste
• IV-site irritation

Hemodialysis

Hemodialysis can rapidly remove both the parent toxic alcohol and important toxic metabolites.

It may be needed in severe poisoning associated with:

• Significant metabolic acidosis
• Kidney failure
• Severe clinical deterioration
• High toxic-alcohol concentrations
• Visual symptoms in methanol poisoning

In ethylene glycol poisoning, dialysis is particularly useful when kidney injury or severe acidosis develops.

In methanol poisoning, dialysis removes both methanol and formate, the metabolite responsible for much of its ocular and systemic toxicity.

Additional Supportive Therapy

For ethylene glycol toxicity:

• Thiamine and pyridoxine may help direct metabolism toward less toxic products

For methanol toxicity:

• Folate or folinic acid may enhance metabolism of formate into less harmful compounds

Key Points

• Fomepizole is the preferred ADH inhibitor in most toxic alcohol poisonings.
• Ethanol works by competing for alcohol dehydrogenase but requires close monitoring and causes more adverse effects.
• Hemodialysis is used for severe methanol or ethylene glycol poisoning, especially with major acidosis or organ dysfunction.
• The major goal of antidotal therapy is to prevent formation of toxic metabolites, not simply to remove the parent alcohol.

Toxicology – Antidotes for Cyanide Poisoning

Indications

Cyanide poisoning should be suspected in patients with severe smoke inhalation or occupational exposure who develop findings such as:

• Altered mental status
• Dyspnea
• Seizures
• Coma
• Cardiovascular collapse
• Severe tissue hypoxia and lactic acidosis

Because confirmatory testing is often too slow to guide emergency care, treatment may need to begin based on the clinical picture.

Hydroxocobalamin

Hydroxocobalamin is generally the preferred antidote, especially in smoke-inhalation cases.

Mechanism

• Contains a cobalt atom that binds cyanide
• Forms cyanocobalamin (vitamin B12)
• The resulting compound is then eliminated by the kidneys

Advantages

• Does not induce methemoglobinemia
• Can be used when concurrent carbon monoxide poisoning is suspected
• Does not typically cause significant hypotension

Adverse Effects

• Red discoloration of the skin
• Red urine (chromaturia)
• Headache
• Nausea or vomiting
• Itching

Sodium Thiosulfate

Sodium thiosulfate provides sulfur that the enzyme rhodanese uses to convert cyanide into the much less toxic compound thiocyanate, which is eliminated through the kidneys.

It can be used in smoke-inhalation patients because it does not create methemoglobinemia.

Possible adverse effects include:

• Nausea
• Vomiting
• Hypotension

Nitrites – Amyl Nitrite and Sodium Nitrite

Nitrites convert normal hemoglobin into methemoglobin. Cyanide preferentially binds to methemoglobin rather than mitochondrial cytochrome oxidase, helping remove cyanide from its cellular target.

However, methemoglobin cannot effectively carry oxygen. For this reason, nitrites are generally avoided or used very cautiously when carbon monoxide poisoning or significant smoke inhalation is also present.

Rapid IV administration of sodium nitrite may also cause:

• Marked vasodilation
• Hypotension
• Tachycardia

Mechanism Summary

Cyanide antidotes work mainly by:

• Binding cyanide directly: hydroxocobalamin
• Enhancing detoxification to thiocyanate: sodium thiosulfate
• Creating an alternative cyanide-binding target: nitrites

Key Points

• Hydroxocobalamin is particularly useful in smoke-inhalation cyanide poisoning.
• Sodium thiosulfate assists the body’s natural cyanide-detoxifying pathway.
• Nitrites induce methemoglobinemia and may worsen oxygen delivery when carbon monoxide poisoning is also present.
• Cyanide treatment should not be delayed in a critically ill patient when the clinical suspicion is high.