toxicity of therapeutic agents

TOXICITY OF THERAPEUTIC AGENTS

TOXICITY OF THERAPEUTIC AGENTS

C

OH

O

O C

O

CH3

Acetyl salicylic acid colorless or white in crystalline, powder, or granular form. The chemical is odorless and is soluble in water

SALICYLATE TOXICITY

SALICYLATE TOXICITY

Acetylsalicylic acid is colorless or white in crystalline, powder, or granular form. The chemical is odorless and is soluble in water

Therapeutic DoseTherapeutic Dose

• Therapeutic doses– Pediatric 10-20 mg/kg– Adults 650-1000 mg q 4-6 hrs

• Produce a serum level of 5-10 mg/dL

• Potential Toxic Acute Dose > 150 Mg/Kg

• Serious Toxicity: 300-500 Mg/Kg• Chronic Toxicity: >100 Mg/Kg/Day

• Therapeutic doses– Pediatric 10-20 mg/kg– Adults 650-1000 mg q 4-6 hrs

• Produce a serum level of 5-10 mg/dL

• Potential Toxic Acute Dose > 150 Mg/Kg

• Serious Toxicity: 300-500 Mg/Kg• Chronic Toxicity: >100 Mg/Kg/Day

Salicylates are found in hundreds of OTC medications and in numerous prescription drugs.

Salicylate ingestion is one of the most common causes of drug toxicity.

Salicylate ingestion continues to be a common cause of poisoning in children and adolescents.

The presence of aspirin-containing products as household, is a reason to be a common source of unintentional and suicidal ingestion.

The incidence in children declined due to:1-The use of alternative antipyretics. 2- Repackaging, using CRC3- Salicylates association with Reye’s syndrome

Salicylates are found in hundreds of OTC medications and in numerous prescription drugs.

Salicylate ingestion is one of the most common causes of drug toxicity.

Salicylate ingestion continues to be a common cause of poisoning in children and adolescents.

The presence of aspirin-containing products as household, is a reason to be a common source of unintentional and suicidal ingestion.

The incidence in children declined due to:1-The use of alternative antipyretics. 2- Repackaging, using CRC3- Salicylates association with Reye’s syndrome

PharmacokineticsPharmacokinetics• After ingestion, acetylsalicylic acid is rapidly

converted to salicylic acid. • Salicylic acid is readily absorbed in the stomach and small

bowel. Reach peak levels in 15-60 minutes– 90% bound to albumin in the blood at a dose of 10 mg/dL– 90% metabolized in the liver, 10% unchanged

• At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours.

• T1/2 = 15-20 minutes

• Metabolites and unchanged drug are filtered and secreted by the kidneys

• After ingestion, acetylsalicylic acid is rapidly converted to salicylic acid.

• Salicylic acid is readily absorbed in the stomach and small

bowel. Reach peak levels in 15-60 minutes– 90% bound to albumin in the blood at a dose of 10 mg/dL– 90% metabolized in the liver, 10% unchanged

• At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours.

• T1/2 = 15-20 minutes

• Metabolites and unchanged drug are filtered and secreted by the kidneys

MetabolismMetabolism

C O

OH

OH

HO

C O

O

OH

C6H9O6

C O

OH

O C6H9O6

C

NH CH2COOH

O

OH

C

OH

O

OH

C

O

CH3

O

OH

C

OH

O

O C

O

CH3

Salicyluric acid Ether glucuronide Ester glucuronide Gentisic acid

AcetylSalicylicacid

Methylsalicylate

2.5%

pHUrine

Absorbed, Proteinbinding

Salicylic acid

ToxicokineticsToxicokinetics

• 76% bound to albumin at a dose of 40 mg/dL– increased free drug in the blood

• Hepatic enzymes become saturated and elimination follows zero-order kinetics– Functional half-life can be over 20

hours

• 76% bound to albumin at a dose of 40 mg/dL– increased free drug in the blood

• Hepatic enzymes become saturated and elimination follows zero-order kinetics– Functional half-life can be over 20

hours

Saturation will change Elimination Kinetics to Zero-typeSaturation will change Elimination Kinetics to Zero-type

C O

OH

OH

HO

C O

O

OH

C6H9O6

C O

OH

O C6H9O6

C

NH CH2COOH

O

OH

C

OH

O

OH

C

O

CH3

O

OH

C

OH

O

O C

O

CH3

Salicyluric acid Ether glucuronide Ester glucuronide Gentisic acid

AcetylSalicylicacid

Methylsalicylate

2.5%

pHUrine

More ASA AbsorbedDecreased Protein

bindingSalicylic acid

SATURATED

methylsalicylate

Hydrolysis in GI tract, liver, RBC’s

2.5% excreted unchanged in urine (pH independent)

zero order kinetics once saturated

zero order kinetics once saturated

% of free SA bound to albumin decreases as the [serum] increases: 75% bound @ 40mgdL 50% bound @ 75mg/dL

Free tissue SA increases

First order kinetics

Toxicokinetic Parameters

Toxicokinetic Parameters

Therapeutic Over dose

Peak blood level 2 hrs >6 hrs

Protein binding 90% 70-90%

Vd 0.15-0.22 L/kg 0.35 L/kg

Half life 2-4 hrs 18-20 hrs

Delayed AbsorptionDelayed Absorption

Enteric coating Bezoar formation (salicylate

bollus) Salicylate-induced pylorospasm

Gastric outlet obstruction Concomitant ingestion of

sustance which decreases gastric motility

Enteric coating Bezoar formation (salicylate

bollus) Salicylate-induced pylorospasm

Gastric outlet obstruction Concomitant ingestion of

sustance which decreases gastric motility

Clinical Manifestations

Clinical Manifestations

• According to the type of toxicity: Acute toxicity or chronic toxicity– While they both encompass the same signs

and symptoms, their presentation can be clinically differentiated

• In general, the earliest signs and symptoms of toxicity include nausea, vomiting, diaphoresis, and tinnitus with or without hearing loss– Other CNS presentations include vertigo,

hyperventilation, hyperactivity, agitation, delirium, hallucinations which are usually followed by convulsions, lethargy and stupor

– A marked elevation in temperature is a sign of severe toxicity and typically preterminal condition

• According to the type of toxicity: Acute toxicity or chronic toxicity– While they both encompass the same signs

and symptoms, their presentation can be clinically differentiated

• In general, the earliest signs and symptoms of toxicity include nausea, vomiting, diaphoresis, and tinnitus with or without hearing loss– Other CNS presentations include vertigo,

hyperventilation, hyperactivity, agitation, delirium, hallucinations which are usually followed by convulsions, lethargy and stupor

– A marked elevation in temperature is a sign of severe toxicity and typically preterminal condition

Chronic SalicylismChronic Salicylism

• Most common in the elderly-unintentional

• May include any sign consistent with acute toxicity

• May also present as:– Delirium– Dementia– Encephalopathy of unknown origin– Congestive heart failure

• Most common in the elderly-unintentional

• May include any sign consistent with acute toxicity

• May also present as:– Delirium– Dementia– Encephalopathy of unknown origin– Congestive heart failure

Chronic Vs Acute Poisoning Chronic Vs Acute PoisoningAcute Chronic

Age Young Adult Elderly/Infants

Mental Status Initially Normal Altered Dehydration Moderate SevereTime To Diagnosis Short Long

Mortality 2% 25%Morbidity 16% 30%Serum ConcentrationMg/dL

40 - ≥120 30 to ≥80

Mechanism of ToxicityMechanism of ToxicitySalicylate is a metabolic substance Salicylate poisoning is manifested

clinically by disturbances of several organ systems: CNS CVS, pulmonary, hepatic, renal, & metabolic systems.

Salicylates directly or indirectly affect most organ systems in the body by uncoupling oxidative phosphorylation, inhibiting Krebs cycle enzymes, and inhibiting amino acid synthesis.

Salicylate is a metabolic substance Salicylate poisoning is manifested

clinically by disturbances of several organ systems: CNS CVS, pulmonary, hepatic, renal, & metabolic systems.

Salicylates directly or indirectly affect most organ systems in the body by uncoupling oxidative phosphorylation, inhibiting Krebs cycle enzymes, and inhibiting amino acid synthesis.

• These processes all contribute to the development of an elevated anion-gap metabolic acidosis

• Combination of a primary respiratory alkalosis and a primary metabolic acidosis is characteristic of salicylate poisoning, especially in adults

• This picture should make your suspect to the diagnosis of SALICYLATE POISONONG

• These processes all contribute to the development of an elevated anion-gap metabolic acidosis

• Combination of a primary respiratory alkalosis and a primary metabolic acidosis is characteristic of salicylate poisoning, especially in adults

• This picture should make your suspect to the diagnosis of SALICYLATE POISONONG

Normal Energy GenerationNormal Energy Generation

Glucose Pyruvate Kreb’s Cycle CO2

NADH2H2O

ATP

Glycolysis Pyruvate decarboxylase

Oxidative Phosphorelation

Salicylate UncouplingSalicylate Uncoupling

Glucose Pyruvate Kreb’s Cycle CO2

NADH2H2O

ATP

SALICYLATES

ATP

Lactate

Glycolysis Pyruvate decarboxylase

Oxidative Phosphorelation

• Catabolism secondary to the inhibition of ATP K dependent reactions leads to:

1) Increased O2 consumption2) Increased CO2 production3)Accelerated activity of glycolytic

& lipolytic pathways4)Depletion of hepatic glycogen5)Hyperpyrexia

• Catabolism secondary to the inhibition of ATP K dependent reactions leads to:

1) Increased O2 consumption2) Increased CO2 production3)Accelerated activity of glycolytic

& lipolytic pathways4)Depletion of hepatic glycogen5)Hyperpyrexia

• Adult patients with acute poisoning usually present with a mixed respiratory alkalosis & metabolic acidosis

• In children, respiratory alkalosis may be transient or metabolic acidosis may occur early in the course.

• Some patients with mixed acid-base disturbances have normal anion-gap metabolic acidosis– Normal anion-gap acidosis does not exclude

salicylate toxicity.

• Adult patients with acute poisoning usually present with a mixed respiratory alkalosis & metabolic acidosis

• In children, respiratory alkalosis may be transient or metabolic acidosis may occur early in the course.

• Some patients with mixed acid-base disturbances have normal anion-gap metabolic acidosis– Normal anion-gap acidosis does not exclude

salicylate toxicity.

Respiratory System Effects

Respiratory System Effects

• Salicylates cause direct and indirect stimulation of respiration.

• A salicylate level of 35 mg/dL or higher causes increases in rate (tachypnea) and depth (hyperpnea) of respiration.

• Salicylate poisoning may rarely cause noncardiogenic pulmonary edema (NCPE) and acute lung injury in pediatric patients.

• Pulmonary edema has extremely high mortality in both children and adults; if present, hemodialysis should be considered as soon as possible.

• Salicylates cause direct and indirect stimulation of respiration.

• A salicylate level of 35 mg/dL or higher causes increases in rate (tachypnea) and depth (hyperpnea) of respiration.

• Salicylate poisoning may rarely cause noncardiogenic pulmonary edema (NCPE) and acute lung injury in pediatric patients.

• Pulmonary edema has extremely high mortality in both children and adults; if present, hemodialysis should be considered as soon as possible.

Mechanism of ToxicityMechanism of Toxicity

• Difference between children & Adults

• Respiratory center stimulation leads to

tachypnea & hyperpnea.

• Excessive wash of CO2 leads to respiratory

alkalosis which is compensated by renal

excretion of HCO3 • Adult patients with acute poisoning

usually present with a mixed respiratory alkalosis & metabolic acidosis

• Difference between children & Adults

• Respiratory center stimulation leads to

tachypnea & hyperpnea.

• Excessive wash of CO2 leads to respiratory

alkalosis which is compensated by renal

excretion of HCO3 • Adult patients with acute poisoning

usually present with a mixed respiratory alkalosis & metabolic acidosis

Mechanism of Toxicity………Causes of Metabolic AcidosisMechanism of Toxicity………Causes of Metabolic Acidosis

1. Salicylate ion = weak acid which contributes to the acidosis.

2. Dehydration from hyperpnea, vomiting, diaphoresis and hyperthermia contributes to lactic acidosis.

3. Uncoupling of mitochondrial oxidative phosphorylation anaerobic metabolism lactate and pyruvate production.

4. Increased fatty acid metabolism (as a consequence of uncoupling of oxydative phosphorylation) lipolysis ketone formation.

5. In compensation for the initial respiratory alkalosis the kidneys excrete HCO3 which later contributes to the metabolic acidosis.

6. Increased Na & K accompany the initial renal bicarbonate diuresis hypokalemia hydrogen ion shift out of cell to maintain electrical neutrality.

7. Inhibition of liver lactate elimination.8. Renal dysfunction accumulation of SA

metabolites which are acids: sulfuric and phosphoric acids.

1. Salicylate ion = weak acid which contributes to the acidosis.

2. Dehydration from hyperpnea, vomiting, diaphoresis and hyperthermia contributes to lactic acidosis.

3. Uncoupling of mitochondrial oxidative phosphorylation anaerobic metabolism lactate and pyruvate production.

4. Increased fatty acid metabolism (as a consequence of uncoupling of oxydative phosphorylation) lipolysis ketone formation.

5. In compensation for the initial respiratory alkalosis the kidneys excrete HCO3 which later contributes to the metabolic acidosis.

6. Increased Na & K accompany the initial renal bicarbonate diuresis hypokalemia hydrogen ion shift out of cell to maintain electrical neutrality.

7. Inhibition of liver lactate elimination.8. Renal dysfunction accumulation of SA

metabolites which are acids: sulfuric and phosphoric acids.

Mechanism of Toxicity

Respiratory Acidosis

Mechanism of Toxicity

Respiratory Acidosis

Respiratory decompensation from fatigue.

SA induced acute lung injury

Inhibitory effect on respiratory center in severe toxic doses.

Respiratory decompensation from fatigue.

SA induced acute lung injury

Inhibitory effect on respiratory center in severe toxic doses.

Mechanism of Toxicity (cont.)

Mechanism of Toxicity (cont.)

Hypercative state increased energy

demand increased tissue glycolysis and gluconeogenesis

hyperglycemiaHypoglycemia is common in chronic or

late in acute toxicities (due insulin secretion)

Inhibit aminotransferase increased AA Aaciduria

Renal tubular damage lead to proteinuria with sodium and water retention

Hypercative state increased energy

demand increased tissue glycolysis and gluconeogenesis

hyperglycemiaHypoglycemia is common in chronic or

late in acute toxicities (due insulin secretion)

Inhibit aminotransferase increased AA Aaciduria

Renal tubular damage lead to proteinuria with sodium and water retention

Clinical featuresClinical features

CNS: tinnitus, decreased hearing, vertigo, hallucinations, agitation, hyperactivity, delirium, stupor, coma, lethargy, seizures, cerebral edema, SIADH

Hem: hypoprothrombinemia, platelet dysfunction and bleeding small doses inhibition of platelet aggregation

occurs BT. lasts for 4-7 days till new platelets are formed

large doses salicylates are changed in the intestine into a dicumarol like substance interferes with vit. K hepatic synthesis of prothrombin PT

GI: n/v, hemorrhagic gastritis, decreased GI motility, pylorospasm, abnormal LFTs

CNS: tinnitus, decreased hearing, vertigo, hallucinations, agitation, hyperactivity, delirium, stupor, coma, lethargy, seizures, cerebral edema, SIADH

Hem: hypoprothrombinemia, platelet dysfunction and bleeding small doses inhibition of platelet aggregation

occurs BT. lasts for 4-7 days till new platelets are formed

large doses salicylates are changed in the intestine into a dicumarol like substance interferes with vit. K hepatic synthesis of prothrombin PT

GI: n/v, hemorrhagic gastritis, decreased GI motility, pylorospasm, abnormal LFTs

Metabolic: fever, hypoglycemia, hyperglycemia, ketosis, ketonuria, rhabdomyolysis

Pulm: tachypnea, pulmonary edema

Renal: proteinuria, Na and water retention

Volume: diaphoresis and dehydration.

Metabolic: fever, hypoglycemia, hyperglycemia, ketosis, ketonuria, rhabdomyolysis

Pulm: tachypnea, pulmonary edema

Renal: proteinuria, Na and water retention

Volume: diaphoresis and dehydration.

temporal sequence temporal sequence

Early: tinnitus, n/v, diaphoresis + hearing loss (a bit later)

Vertigo, hyperventilation, hyperactivity, agitation, delirium, hallucinations, Sz, lethargy and stupor.

Late: coma (after massive ingestions levels >100mg/dL or co-ingestions)

Severe hyperthermia from uncoupling of oxidative phosphorylation is a preterminal event.

Early: tinnitus, n/v, diaphoresis + hearing loss (a bit later)

Vertigo, hyperventilation, hyperactivity, agitation, delirium, hallucinations, Sz, lethargy and stupor.

Late: coma (after massive ingestions levels >100mg/dL or co-ingestions)

Severe hyperthermia from uncoupling of oxidative phosphorylation is a preterminal event.

Fluid and ElectrolytesDehydration:vomiting & insensible

fluid losses. Hypokalemia & hypocalcemia:

respiratory alkalosis. Hypokalemia:

◦ shifting of K+ into the cells in exchange for H+

◦K loss in the urine and from vomiting with subsequent metabolic alkalosis & bicarbonaturia

CVSHypotension (vasodilatation and

hypovolemia)

Fluid and ElectrolytesDehydration:vomiting & insensible

fluid losses. Hypokalemia & hypocalcemia:

respiratory alkalosis. Hypokalemia:

◦ shifting of K+ into the cells in exchange for H+

◦K loss in the urine and from vomiting with subsequent metabolic alkalosis & bicarbonaturia

CVSHypotension (vasodilatation and

hypovolemia)

Bedside ferric chloride testing: positive test quantitative serum salicylate level.

Bedside ferric chloride testing: positive test quantitative serum salicylate level.

C

OH

O

OH

FeC

OH

O

OH

+ FeCl2Salicylic Acid (Purple colored complex)

InvestigationsInvestigationsPresence of Ketonuria & Hypoglycemia: suspicion of salicylate toxicity

Salicylate concentration: Therapeutic Levels from 15-30 mg/dL

Toxicity begin to appear beyond 30 mg/dL.

A 6-hour salicylate level >100 mg/dL is considered potentially lethal and is an indication for hemodialysis.

In significant ingestions, serum salicylate level should be monitored at least 2 hourly until a peak has been reached; then every 4-6 hrs until the peak falls into the nontoxic range.

ABG, Serum electrolytes, glucose, RFT, LFT, PT, PTT.

Presence of Ketonuria & Hypoglycemia: suspicion of salicylate toxicity

Salicylate concentration: Therapeutic Levels from 15-30 mg/dL

Toxicity begin to appear beyond 30 mg/dL.

A 6-hour salicylate level >100 mg/dL is considered potentially lethal and is an indication for hemodialysis.

In significant ingestions, serum salicylate level should be monitored at least 2 hourly until a peak has been reached; then every 4-6 hrs until the peak falls into the nontoxic range.

ABG, Serum electrolytes, glucose, RFT, LFT, PT, PTT.

TreatmentTreatmentGIT decontamination AC, some authors recommend gastric lavage in all

symptomatic patients regardless of time of ingestion. Repeated doses of charcoal may enhance salicylate elimination.

Whole bowel irrigation is more effective in reducing absorption of aspirin enteric-coated tablets.

Urinary alkalizationHaemodialysis: salicylate levels >90-100 mg/dL after acute overdose >40-50 mg/dL in chronic toxicity severe fluid or electrolyte disturbances inability to eliminate the salicylate.

Supportive treatmentCorrection of hypoglycemia in severe casesCorrection of dehydration and electrolyte disturbances Vitamin K1

GIT decontamination AC, some authors recommend gastric lavage in all

symptomatic patients regardless of time of ingestion. Repeated doses of charcoal may enhance salicylate elimination.

Whole bowel irrigation is more effective in reducing absorption of aspirin enteric-coated tablets.

Urinary alkalizationHaemodialysis: salicylate levels >90-100 mg/dL after acute overdose >40-50 mg/dL in chronic toxicity severe fluid or electrolyte disturbances inability to eliminate the salicylate.

Supportive treatmentCorrection of hypoglycemia in severe casesCorrection of dehydration and electrolyte disturbances Vitamin K1

ACETAMINOPHEN

TOXICITY

ACETAMINOPHEN

TOXICITY

• Widely used in adults & commonly used drug in pediatrics.

• Chemical structure is N-acetyl-p-aminophenol

• Maximum daily dose is 4 g in adults & 90 mg/kg in children.

• A single ingestion of 7.5 g (adult) or more than 150 mg/kg in a child is a potentially toxic dose of APAP.

• Widely used in adults & commonly used drug in pediatrics.

• Chemical structure is N-acetyl-p-aminophenol

• Maximum daily dose is 4 g in adults & 90 mg/kg in children.

• A single ingestion of 7.5 g (adult) or more than 150 mg/kg in a child is a potentially toxic dose of APAP.

Mechanism of ActionMechanism of Action

Central prostaglandin synthetase inhibitor

• analgesic• antipyretic with weak anti-inflammatory

properties.

Central prostaglandin synthetase inhibitor

• analgesic• antipyretic with weak anti-inflammatory

properties.

Metabolic PathwaysMetabolic Pathways

Hepatic glucuronide conjugation(40-65%) 90%

Hepatic sulfate conjugation(20-45%) inactive metabolites excreted in the urine.

Excretion of unchanged APAP in the urine (5%).

Oxidation by Cytochrome oxidase P450 (CYP 2E1, 1A2,

and 3A4) to NABQ (5-15%)

GSH combines with NAPQI nontoxic cysteine/mercaptate conjugates excreted in urine.

Hepatic glucuronide conjugation(40-65%) 90%

Hepatic sulfate conjugation(20-45%) inactive metabolites excreted in the urine.

Excretion of unchanged APAP in the urine (5%).

Oxidation by Cytochrome oxidase P450 (CYP 2E1, 1A2,

and 3A4) to NABQ (5-15%)

GSH combines with NAPQI nontoxic cysteine/mercaptate conjugates excreted in urine.

Hepatic glucuronide conjugation(40-65%)Hepatic sulfate conjugation(20-45%)

Factors affecting Acetaminophrn metabolism

Factors affecting Acetaminophrn metabolism

Upregulation (i.e. induction) of CYP 2E1 enzyme activity lead to more production of NABQ: smoking, barbituates, rifampin, carbamazepine,

phenytoin, INH, + ethanol

Decreased glutathione stores: age, diet, liver disease, and medical conditions such as fasting, gastroenteritis, chronic alcoholism, or HIV disease.

Frequent dosing interval of APAP.Prolonged duration of excessive dosing.

Upregulation (i.e. induction) of CYP 2E1 enzyme activity lead to more production of NABQ: smoking, barbituates, rifampin, carbamazepine,

phenytoin, INH, + ethanol

Decreased glutathione stores: age, diet, liver disease, and medical conditions such as fasting, gastroenteritis, chronic alcoholism, or HIV disease.

Frequent dosing interval of APAP.Prolonged duration of excessive dosing.

In children, sulfation is the primary pathway until age 10-12 years; glucuronidation predominates in adolescents and adults.

In children, sulfation is the primary pathway until age 10-12 years; glucuronidation predominates in adolescents and adults.

Gluthione StoresGluthione Stores

Glutathione stores are determined by:◦ age◦ diet◦ liver disease◦ fasting prior

ingestion◦ chronic

malnutrition (anorexia)

◦ gastroenteritis◦ chronic alcoholism◦ HIV

Glutathione stores are determined by:◦ age◦ diet◦ liver disease◦ fasting prior

ingestion◦ chronic

malnutrition (anorexia)

◦ gastroenteritis◦ chronic alcoholism◦ HIV

Glutathione replacement by sulfhydryl compounds: eating NAC

Glutathione replacement by sulfhydryl compounds: eating NAC

Clinical FeaturesClinical FeaturesPhase 1 (up to 24 hours): Patients typically experience anorexia,

nausea, & vomitingRarely neurologic, respiratory, and cardiac

symptomsPhase 2 (24-48 hours) Rt upper quadrant pain with transaminase

elevation.Phase 3 (3-4 days) Symptoms of hepatic failure with jaundice,

bleeding, or encephalopathy. Only about 3.5% of patients who develop

hepatotoxicity develop fulminant hepatic failure.

Phase 4 (4-14 days)Patients may have complete recovery of liver

function or death.

Phase 1 (up to 24 hours): Patients typically experience anorexia,

nausea, & vomitingRarely neurologic, respiratory, and cardiac

symptomsPhase 2 (24-48 hours) Rt upper quadrant pain with transaminase

elevation.Phase 3 (3-4 days) Symptoms of hepatic failure with jaundice,

bleeding, or encephalopathy. Only about 3.5% of patients who develop

hepatotoxicity develop fulminant hepatic failure.

Phase 4 (4-14 days)Patients may have complete recovery of liver

function or death.

InvestigationsInvestigations

1- Acetaminophen serum concentration:– A history of potentially toxic ingestion.– An unknown amount of APAP.– Altered mental status.– Suicidal attempt

2- LFT: transaminase above 1,000 U/L.

3- RFT: may show evidence of renal failure, which often occurs with hepatic failure. In rare circumstances, renal failure may occur without hepatic failure.

1- Acetaminophen serum concentration:– A history of potentially toxic ingestion.– An unknown amount of APAP.– Altered mental status.– Suicidal attempt

2- LFT: transaminase above 1,000 U/L.

3- RFT: may show evidence of renal failure, which often occurs with hepatic failure. In rare circumstances, renal failure may occur without hepatic failure.

Rumack and Matthew Nomogram


mcg/ml 4 8 12 16 20 24

Hours After Acetaminophen Ingestion

150

5

10

50

500


100

Late

Not valid after 24 hours

Abnormal VIII/V ratio:Factor VIII is produced by endothelial cells

and its production is not impaired by APAPFactor V is produced by hepatocytes and its

production diminishes with hepatocellular necrosis.

Metabolic acidosis may result from:Intravascular volume depletion and lactic acidosis

from dehydration/hypoperfusion.ARFLactic acidosis without evidence of FHF from a direct

effect of acetaminophen inhibition of hepatic lactic acid uptake and metabolism.

Fulminant Hepatic Failure (FHF)

Abnormal VIII/V ratio:Factor VIII is produced by endothelial cells

and its production is not impaired by APAPFactor V is produced by hepatocytes and its

production diminishes with hepatocellular necrosis.

Metabolic acidosis may result from:Intravascular volume depletion and lactic acidosis

from dehydration/hypoperfusion.ARFLactic acidosis without evidence of FHF from a direct

effect of acetaminophen inhibition of hepatic lactic acid uptake and metabolism.

Fulminant Hepatic Failure (FHF)

Poor Prognostic IndicatorsPoor Prognostic Indicators

• pH <7.3

• Hepatic encephalopathy• PT >1.8 times normal.• Serum creatinine >

300mmol/L• Coagulation factor VIII/V

ratio of >30

• pH <7.3

• Hepatic encephalopathy• PT >1.8 times normal.• Serum creatinine >

300mmol/L• Coagulation factor VIII/V

ratio of >30

TreatmentTreatment Gastric lavage: should be done to patients with recent (within

1h) and life-threatening toxicity. Activated charcoal adsorbs APAP, but not with oral NAC

N-Acetyl Cysteine is the antidote:1-Precursor for glutathione. NAC is converted to cysteine, which can

replenish glutathione stores.2- NAC also directly detoxifies acetaminophen toxic metabolite to nontoxic metabolites. 3-NAC can provide a substrate for sulfation

a) Oral NAC: It is effective in preventing hepatotoxicity regardless of the initial acetaminophen level if it is started within 8 hrs of ingestion.

b) Intravenous NAC: IV administration of NAC is recommended for selected patients, including those with GIT bleeding or obstruction, potential fetal toxicity, or an inability to tolerate oral NAC.

Gastric lavage: should be done to patients with recent (within 1h) and life-threatening toxicity.

Activated charcoal adsorbs APAP, but not with oral NAC

N-Acetyl Cysteine is the antidote:1-Precursor for glutathione. NAC is converted to cysteine, which can

replenish glutathione stores.2- NAC also directly detoxifies acetaminophen toxic metabolite to nontoxic metabolites. 3-NAC can provide a substrate for sulfation

a) Oral NAC: It is effective in preventing hepatotoxicity regardless of the initial acetaminophen level if it is started within 8 hrs of ingestion.

b) Intravenous NAC: IV administration of NAC is recommended for selected patients, including those with GIT bleeding or obstruction, potential fetal toxicity, or an inability to tolerate oral NAC.

IRON TOXICI

TY

IRON TOXICI

TY

One of the expected common poisonings in young children. The potential severity is based on the amount of elemental iron ingested.

Iron exerts both local and systemic effects: =Iron is corrosive to the GI mucosa and affects the lungs and liver. =Excess free iron is a mitochondrial toxin leading to disturbances in energy metabolism.

Serum iron levels are useful in predicting the clinical course of the patient.

One of the expected common poisonings in young children. The potential severity is based on the amount of elemental iron ingested.

Iron exerts both local and systemic effects: =Iron is corrosive to the GI mucosa and affects the lungs and liver. =Excess free iron is a mitochondrial toxin leading to disturbances in energy metabolism.

Serum iron levels are useful in predicting the clinical course of the patient.

Clinical Manifestations Clinical Manifestations

Phase I: GIT effects: first 6hrs as hemorrhagic vomiting, diarrhea, and abdominal pain.

Hypovolemia may result from GI losses and contribute to tissue hypoperfusion and metabolic acidosis.

Convulsions, shock, and coma may complicate this phase.

Phase I: GIT effects: first 6hrs as hemorrhagic vomiting, diarrhea, and abdominal pain.

Hypovolemia may result from GI losses and contribute to tissue hypoperfusion and metabolic acidosis.

Convulsions, shock, and coma may complicate this phase.

Diarrhoea Vomiting

Fe

Bloody diarrhoea(Melena)

Bloody vomitus(Hematemesis)

Irritation

Corrosion

Irritation Corrosion

Stage I: 1 -6 hrs

GIT

Fluid Loss

Blood Loss

Stage I: 1 -6 hrs

CVS

Reflex tachycardia

GIT

Released from

damaged GIT tissue

↓ B.P hypoperfusion hypoxia anaerobic lactic à.

Fe →uncoupling oxidation phosphorylation →↓ ATP production.

CNS Lethargy, severe coma or seizures.

Lactic acidosis

Hyperglycemia (at early stage).

RS↑Medullary respiratory

center

Acidosis H+ + HCO3- H2CO3 H2O + CO2 BBB

↑R.R Tachypnea

Phase 2: • 6-12 hrs, may be associated with a

period of "apparent recovery" that may be confusing. – In mild cases, the recovery may

represent true recovery. – In serious ingestions, this phase may

not occur at all. • This phase may represent the time

of iron distribution throughout the body to cause systemic injury.

Phase 2: • 6-12 hrs, may be associated with a

period of "apparent recovery" that may be confusing. – In mild cases, the recovery may

represent true recovery. – In serious ingestions, this phase may

not occur at all. • This phase may represent the time

of iron distribution throughout the body to cause systemic injury.

Phase 3: 12-24 hrs: ferrous ferric iron + unbuffered H+

Mitochondrial accumulation disturbs oxidative phosphorylation metabolic acidosis and cell death.

GIT fluid losses hypovolemic shock and acidosis.

Cardiovascular symptoms: decreased heart rate, myocardial activity, cardiac output.

High anion-gap metabolic acidosis results from: (1)Rise of H+ during conversion of free plasma iron to ferric

hydroxide(2)Free radical damage to mitochondrial lactic acidosis(3)Hypovolemia and hypoperfusion.

Coagulopathy: may be due to• inhibitory effect of free iron on the formation of thrombin• reduced levels of clotting due to hepatic failure.

Phase 3: 12-24 hrs: ferrous ferric iron + unbuffered H+

Mitochondrial accumulation disturbs oxidative phosphorylation metabolic acidosis and cell death.

GIT fluid losses hypovolemic shock and acidosis.

Cardiovascular symptoms: decreased heart rate, myocardial activity, cardiac output.

High anion-gap metabolic acidosis results from: (1)Rise of H+ during conversion of free plasma iron to ferric

hydroxide(2)Free radical damage to mitochondrial lactic acidosis(3)Hypovolemia and hypoperfusion.

Coagulopathy: may be due to• inhibitory effect of free iron on the formation of thrombin• reduced levels of clotting due to hepatic failure.

Uncoupling oxidative phosphorylation

Excretion of

HCO3-

Metabolic

AcidosisFe

↓

Stage III

Phase 4: 2 – 6 Weeks

Phase 4: 2 – 6 Weeks

Hepatic cirrhosis.

Pyloric stricture (pyloric

stenosis) → corrosive action.

Hepatic cirrhosis.

Pyloric stricture (pyloric

stenosis) → corrosive action.

Investigations

Investigations• Serum iron levels.

• TIB (is not important)• Abdominal x-ray: may show

radiopaque tablets.• Deferoxamine challenge test: bind

free iron to be excreted in the urine as ferrioxamine complex, changing the urine to reddish (vin rosé) color, indicating the need for chelation.

• Serum iron levels.• TIB (is not important)• Abdominal x-ray: may show

radiopaque tablets.• Deferoxamine challenge test: bind

free iron to be excreted in the urine as ferrioxamine complex, changing the urine to reddish (vin rosé) color, indicating the need for chelation.

TreatmentTreatment• Appropriate supportive care.• Deferoxamine:

1-Shock 2- Altered mental status 3- Persistent GI symptoms 4- Metabolic acidosis 5- Positive radiographs6-Serum Fe >500 μg/dL or estimated dose greater than 60 mg

elemental iron/kg7-Serum iron level is not available with presence of symptoms.

Deferoxamine may be administered IM or IV infusion but IM is not recommended because it is painful and less iron is excreted. Indications for cessation include significant resolution of shock and acidosis, and acute RDS.

• Patients with acute poisoning may develop Yersinia enterocolitica infection. Yersinia requires iron as a growth factor. Infection can be manifested by abdominal pain, fever, and diarrhea following resolution of iron toxicity.

• Appropriate supportive care.• Deferoxamine:

1-Shock 2- Altered mental status 3- Persistent GI symptoms 4- Metabolic acidosis 5- Positive radiographs6-Serum Fe >500 μg/dL or estimated dose greater than 60 mg

elemental iron/kg7-Serum iron level is not available with presence of symptoms.

Deferoxamine may be administered IM or IV infusion but IM is not recommended because it is painful and less iron is excreted. Indications for cessation include significant resolution of shock and acidosis, and acute RDS.

• Patients with acute poisoning may develop Yersinia enterocolitica infection. Yersinia requires iron as a growth factor. Infection can be manifested by abdominal pain, fever, and diarrhea following resolution of iron toxicity.

BARBITURATE

TOXICITY

BARBITURATE

TOXICITY

Barbiturates are commonly used drugs.

Majority of barbiturate poisonings in adults are suicidal attempts.

In children, the poisoning is usually accidental.

Barbiturate abuse is a common problem and the commonly abused barbiturates

Barbiturates are commonly used drugs.

Majority of barbiturate poisonings in adults are suicidal attempts.

In children, the poisoning is usually accidental.

Barbiturate abuse is a common problem and the commonly abused barbiturates

Clinical Presentation

Clinical Presentation

Grade I: Mild Intoxication1.The patient is drowsy. Impaired judgment,

slurred speech, drunken-like gait, incoordination, nystagmus, & ataxia.

2.Reflex activity and vital signs are not affected.

3.This condition resembles alcohol intoxication without flushed face, and no smell.

4.EEG changes include appearance fast activity of 20-30 c/s (prominent over frontal regions).

Grade I: Mild Intoxication1.The patient is drowsy. Impaired judgment,

slurred speech, drunken-like gait, incoordination, nystagmus, & ataxia.

2.Reflex activity and vital signs are not affected.

3.This condition resembles alcohol intoxication without flushed face, and no smell.

4.EEG changes include appearance fast activity of 20-30 c/s (prominent over frontal regions).

Grade II: Moderate Intoxication1. Depression of consciousness

level. Superficial and deep reflexes are depressed.

2. Pupils may be normal, or small and reactive. Severe hypoxia may produce mydriasis.

3. Respiration is slow but not shallow.

4. EEG changes: fast waves become less regular interspersed with slow activity of 3-4 c/s.

Grade II: Moderate Intoxication1. Depression of consciousness

level. Superficial and deep reflexes are depressed.

2. Pupils may be normal, or small and reactive. Severe hypoxia may produce mydriasis.

3. Respiration is slow but not shallow.

4. EEG changes: fast waves become less regular interspersed with slow activity of 3-4 c/s.

Grade III. Severe Intoxication1.Severe impairment of consciousness level.

Absence of deep tendon reflexes then brainstem reflexes.

2.Respiratory depression. Slow, shallow or irregular respiration. Pulmonary edema and cyanosis.

3.Hypotension. Shock.4.Hypothermia is a frequent finding.5.Paralytic ileus.6.Renal failure (hypotension, anoxia, hypothermia,

direct toxicity on renal tubules.)7.Barbiturate blisters: helpful in the diagnosis of

comatose patient. Clear vesicles and bullae on an erythematous base, skin areas at other pressure sites. In about 5% of acute intoxication, and 50% of deaths.

8.EEG: all electrical activity ceases.

Grade III. Severe Intoxication1.Severe impairment of consciousness level.

Absence of deep tendon reflexes then brainstem reflexes.

2.Respiratory depression. Slow, shallow or irregular respiration. Pulmonary edema and cyanosis.

3.Hypotension. Shock.4.Hypothermia is a frequent finding.5.Paralytic ileus.6.Renal failure (hypotension, anoxia, hypothermia,

direct toxicity on renal tubules.)7.Barbiturate blisters: helpful in the diagnosis of

comatose patient. Clear vesicles and bullae on an erythematous base, skin areas at other pressure sites. In about 5% of acute intoxication, and 50% of deaths.

8.EEG: all electrical activity ceases.

ManagementManagement1- Stabilization of vital functions2- Prevention of absorption.3- Enhancing elimination: a) Forced alkaline diuresis. long-

acting barbiturates.b) Hemodialysis: Indications include: • Abnormal vital signs despite

therapy. • Prolonged coma with clinical

deterioration or complications.• Potentially fatal dose or blood level.c) Hemoperfusion with charcoal is

more efficient than hemodialysis.

1- Stabilization of vital functions2- Prevention of absorption.3- Enhancing elimination: a) Forced alkaline diuresis. long-

acting barbiturates.b) Hemodialysis: Indications include: • Abnormal vital signs despite

therapy. • Prolonged coma with clinical

deterioration or complications.• Potentially fatal dose or blood level.c) Hemoperfusion with charcoal is

more efficient than hemodialysis.

TRICYCLIC

ANTIDEPRESSANT

TOXICITY

TRICYCLIC

ANTIDEPRESSANT

TOXICITY

Uses of TCAsUses of TCAs• Depression• OCD• ADD• panic/phobia/anxiety/eating

d/o, • chronic pain• peripheral neuropathies• nocturnal enuresis• migraine prophylaxis• drug withdrawal

• Depression• OCD• ADD• panic/phobia/anxiety/eating

d/o, • chronic pain• peripheral neuropathies• nocturnal enuresis• migraine prophylaxis• drug withdrawal

• Well absorbed from the GIT, rapidly distributed, and quickly bound to body tissue.

• In overdose, they are absorbed slowly because they are ionized in the acid stomach and they slow the peristalsis dramatically; the drug may remain in the stomach for 12 hours or more.

• Gastric dilatation had been reported.

• They are cathecolamine and serotonin RI

• Well absorbed from the GIT, rapidly distributed, and quickly bound to body tissue.

• In overdose, they are absorbed slowly because they are ionized in the acid stomach and they slow the peristalsis dramatically; the drug may remain in the stomach for 12 hours or more.

• Gastric dilatation had been reported.

• They are cathecolamine and serotonin RI

• Most fatalities ingest more than 1 gram

• Fatalities occur in initial hours usually before arrival to hospital

• Desipramine–Most potent Na-channel blocker–Twice the fatality rate of other

TCA’s–May precipitate cardiotoxicity

without significant antimuscarinic symptoms

• Most fatalities ingest more than 1 gram

• Fatalities occur in initial hours usually before arrival to hospital

• Desipramine–Most potent Na-channel blocker–Twice the fatality rate of other

TCA’s–May precipitate cardiotoxicity

without significant antimuscarinic symptoms

EPIDEMIOLOGYEPIDEMIOLOGY

• TCA Toxicity is nearly 25% of drug toxicities in developed countries

• Amitriptyline (TRIPTIZOL)- 40%• Imipramine (TOFRANIL)- 17%• Doxepin (SINEQUAN, ADAPIN)-14%• Nortriptyline (PAMELOR, AVENTYL)-

12%• Desipramine (NORPRAMINE, PERTOFRANE)-

6%

• TCA Toxicity is nearly 25% of drug toxicities in developed countries

• Amitriptyline (TRIPTIZOL)- 40%• Imipramine (TOFRANIL)- 17%• Doxepin (SINEQUAN, ADAPIN)-14%• Nortriptyline (PAMELOR, AVENTYL)-

12%• Desipramine (NORPRAMINE, PERTOFRANE)-

6%

Mechanisms of Action & Toxicity

Mechanisms of Action & Toxicity

Main effectMain effect Other effectsOther effects

PathophysiologyPathophysiology

• All TCA’s structurally similar

• Multiple toxicologic effects–Anticholinergic (Antimuscarinic)

–α adrenergic blockade–Sodium channel blockage–Antihistaminic–GABA-A receptor antagonist

• All TCA’s structurally similar

• Multiple toxicologic effects–Anticholinergic (Antimuscarinic)

–α adrenergic blockade–Sodium channel blockage–Antihistaminic–GABA-A receptor antagonist

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

• Antimuscarinic

– Central: agitation, delirium, confusion, amnesia, hallucinations, slurred speech, ataxia, sedation, coma

– Peripheral: dilated pupils, blurred vision, ↑HR, ↑temp, ↑BP, ↓oral/bronchial secretions, dry skin, ileus, urinary retention, ↑muscle tone, tremor

• Antimuscarinic

– Central: agitation, delirium, confusion, amnesia, hallucinations, slurred speech, ataxia, sedation, coma

– Peripheral: dilated pupils, blurred vision, ↑HR, ↑temp, ↑BP, ↓oral/bronchial secretions, dry skin, ileus, urinary retention, ↑muscle tone, tremor


• α-Adrenergic inhibition– α1>α2 CNS sedation, orthostatic

hypotension, pupillary constriction*

• *NOTE: may present with constricted, dilated or mid-sized

pupils

• α-Adrenergic inhibition– α1>α2 CNS sedation, orthostatic

hypotension, pupillary constriction*

• *NOTE: may present with constricted, dilated or mid-sized

pupils


• Amine reuptake inhibition– NE:

• Cardiac dysrhythmias• Sympathomimetic

– 5-HT: • Serotonin syndrome• Myoclonus• Hyperreflexia

• Amine reuptake inhibition– NE:

• Cardiac dysrhythmias• Sympathomimetic

– 5-HT: • Serotonin syndrome• Myoclonus• Hyperreflexia


• Na-channel blockade– Inhibits influx of Na+ during

depolarization– EKG:

• PR & QRS prolongation• RAD (↑height R wave in lead AVR, S wave

in lead I)

–

• Na-channel blockade– Inhibits influx of Na+ during

depolarization– EKG:

• PR & QRS prolongation• RAD (↑height R wave in lead AVR, S wave

in lead I)

–

PathophysiologyPathophysiology• Sodium Channel Blockade

– Quinidine-like effect– Inhibits influx of Na+ during

depolarization– Most important factor of mortality in

TCA toxicity– Inhibits fast sodium channels in His-

Purkinje cells– Impairs sodium entry into myocardial

cells– Prolongs depolarization (Phase 0),

decreases contractility–

• Sodium Channel Blockade– Quinidine-like effect– Inhibits influx of Na+ during

depolarization– Most important factor of mortality in

TCA toxicity– Inhibits fast sodium channels in His-

Purkinje cells– Impairs sodium entry into myocardial

cells– Prolongs depolarization (Phase 0),

decreases contractility–

-100

-80

-60

-40

-20

0

20

Phase 0

Phase 1

Phase 2

Phase 3

Phase 4

Na+ ca++

ATPase

mv Cardiac Action Potential

Resting membrane Potential

Na+

m

Na+

Na+Na+Na+Na+

h

K+ca++

K+K+K+

ca++ca++

)Plateau Phase(

K+K+K+ Na+

K+

Dep

olar

izat

ion

Sodium Channel Blockade– Prolonged PR– Widens QRS– Right axis deviation

– Bradycardia- May be attenuated by antimuscarinic effect- Indicates profound sodium channel blockade

Sodium Channel Blockade– Prolonged PR– Widens QRS– Right axis deviation

– Bradycardia- May be attenuated by antimuscarinic effect- Indicates profound sodium channel blockade


• Antihistaminic–Central CNS sedation, coma

• GABA-A receptor antagonist–Seizures

• Antihistaminic–Central CNS sedation, coma

• GABA-A receptor antagonist–Seizures

Clinical FeaturesClinical Features

• Varies from mild antimuscarinic to severe cardiovascular collapse

• Up to 70% will have coingestants

• May have rapid progression of coma and cardiovascular collapse

• Varies from mild antimuscarinic to severe cardiovascular collapse

• Up to 70% will have coingestants

• May have rapid progression of coma and cardiovascular collapse

Clinical FeaturesClinical Features• Anticholinergic effects tachycardia, hypertension, fever

mydriasis. Dry red skin, dry mouth. Decreased bowel sounds. Urinary retention. Respiratory depression.

• Central nervous system effects Disorientation. Agitation. Hallucinations.

Pyramidal signs: clonus, positive Babinski sign, hyperreflexia. Myoclonic jerks. Seizures. Coma.

• Effects on cardiac conduction and contractility

Hypotension. Bradychardia. AV block. Cardiac

arrest. ECG prolongation of QRS

• Anticholinergic effects tachycardia, hypertension, fever

mydriasis. Dry red skin, dry mouth. Decreased bowel sounds. Urinary retention. Respiratory depression.

• Central nervous system effects Disorientation. Agitation. Hallucinations.

Pyramidal signs: clonus, positive Babinski sign, hyperreflexia. Myoclonic jerks. Seizures. Coma.

• Effects on cardiac conduction and contractility

Hypotension. Bradychardia. AV block. Cardiac

arrest. ECG prolongation of QRS

• Poorer Prognosis:

–QRS >100ms•Greater likelihood of seizures

–QRS >160ms•Greater likelihood of ventricular dysrhythmias

• Poorer Prognosis:

–QRS >100ms•Greater likelihood of seizures

–QRS >160ms•Greater likelihood of ventricular dysrhythmias

ManagementManagement Assessment and Stabilization: The mainstays:prevention of absorbtion of the

drug & respiratory support.

The first 6 hoursAny patient must be placed immediately on a

cardiac monitor.Stomach emptying: Putting charcoal down the

lavage tube before lavage may further limit the amount of drug absorbed. AC effectively binds TCA and can decrease plasma levels. Late gastric lavage should be performed.

Ventilatory support and careful monitoring of acid-base status

ECG should be obtained quickly to detect changes as tachycardia and QRS prolongation.

Hemoperfusion with AC helps to remove the drug

Assessment and Stabilization: The mainstays:prevention of absorbtion of the

drug & respiratory support.

The first 6 hoursAny patient must be placed immediately on a

cardiac monitor.Stomach emptying: Putting charcoal down the

lavage tube before lavage may further limit the amount of drug absorbed. AC effectively binds TCA and can decrease plasma levels. Late gastric lavage should be performed.

Ventilatory support and careful monitoring of acid-base status

ECG should be obtained quickly to detect changes as tachycardia and QRS prolongation.

Hemoperfusion with AC helps to remove the drug

Indications of Sodium Bicarbonate Therapy

Indications of Sodium Bicarbonate Therapy

• Widened QRS >100ms• Refractory hypotension• Ventricular dysrhythmias

–Improves ▪ Conductivity ▪ Contractility▪ Suppresses ventricular ectopy

• Widened QRS >100ms• Refractory hypotension• Ventricular dysrhythmias

–Improves ▪ Conductivity ▪ Contractility▪ Suppresses ventricular ectopy

Treatment of Specific Complications Coma:35%- supportive care. Physostigmine.

Seizures and Myoclonic Jerks in 10%, they may trigger dysrhythmias. Diazepam. Phenytoin can be used for seizures & conduction problems but not myoclonic jerks. Alkalinization in any patient who is in seizure to minimize CV toxicity.

Cardiovascular Toxicity: Sinus tachycardia is universal in TCA overdose. No reason to treat it unless patient is hypotensive or complicated by HF. Alkalinization of the blood to a pH of 7.5 is probably the best treatment available for tachycardia and other forms of cardiotoxicity.

Treatment of Specific Complications Coma:35%- supportive care. Physostigmine.

Seizures and Myoclonic Jerks in 10%, they may trigger dysrhythmias. Diazepam. Phenytoin can be used for seizures & conduction problems but not myoclonic jerks. Alkalinization in any patient who is in seizure to minimize CV toxicity.

Cardiovascular Toxicity: Sinus tachycardia is universal in TCA overdose. No reason to treat it unless patient is hypotensive or complicated by HF. Alkalinization of the blood to a pH of 7.5 is probably the best treatment available for tachycardia and other forms of cardiotoxicity.

• Conduction Blocks: dose dependent, and QRS prolongation becomes greater the more severe doses. RBBB is also common. QT interval may be prolonged. Alkalinization is the first choice treatment, and QRS will narrow and conduction improves with this therapy.

• Hypotension in 14% of patients, usually accompanied by ventricular blocks and cardiac dysrhythmias. Alkalinization and IV fluid loading are effective. If these fail, epinephrine is desirable, because TCA produce strong -adrenergic blockade. Isoproterenol may worsen hypotension by unopposed -adrenergic effect. Dopamine is effective in high doses, but in low doses gives effects similar isoproterenol.

• Conduction Blocks: dose dependent, and QRS prolongation becomes greater the more severe doses. RBBB is also common. QT interval may be prolonged. Alkalinization is the first choice treatment, and QRS will narrow and conduction improves with this therapy.

• Hypotension in 14% of patients, usually accompanied by ventricular blocks and cardiac dysrhythmias. Alkalinization and IV fluid loading are effective. If these fail, epinephrine is desirable, because TCA produce strong -adrenergic blockade. Isoproterenol may worsen hypotension by unopposed -adrenergic effect. Dopamine is effective in high doses, but in low doses gives effects similar isoproterenol.

DIGITALIS

TOXICITY

DIGITALIS

TOXICITY

• Derived from Digitalis lanata & D.

purpurea.

Used in the treatment of HF & SV

arhythmia (particularly atrial fibrillation &

atrial flutter).

• Digitalis poisoning continues to be a

serious problem in infants and

children due to its wide availability &

narrow therapeutic index.

• Derived from Digitalis lanata & D.

purpurea.

Used in the treatment of HF & SV

arhythmia (particularly atrial fibrillation &

atrial flutter).

• Digitalis poisoning continues to be a

serious problem in infants and

children due to its wide availability &

narrow therapeutic index.

PathophysiologyPathophysiology• Bind to cell membrane reversible inhibition of Na+-K+

ATPase pumpElevated intracellular Na+ increased intracellular Ca++ enhanced cardiac contractions (delayed

after depolarizations & manifest clinically as aftercontractions, such as premature ventricular contractions).

• Digitalis increase phase 4 action potential in myocardial tissue reduction of CV with increased automaticity & ectopic activity.

• It has a negative chronotropic action that is partly a vagal effect and partly a direct effect on the sinoatrial node.

– Digitalis has vagotonic effects, resulting in bradycardia & heart blocks.

• Inhibition of Na+-K+-ATPase in skeletal muscle results in increased extracellular potassium and contributes to hyperkalemia.

• Bind to cell membrane reversible inhibition of Na+-K+

ATPase pumpElevated intracellular Na+ increased intracellular Ca++ enhanced cardiac contractions (delayed

after depolarizations & manifest clinically as aftercontractions, such as premature ventricular contractions).

• Digitalis increase phase 4 action potential in myocardial tissue reduction of CV with increased automaticity & ectopic activity.

• It has a negative chronotropic action that is partly a vagal effect and partly a direct effect on the sinoatrial node.

– Digitalis has vagotonic effects, resulting in bradycardia & heart blocks.

• Inhibition of Na+-K+-ATPase in skeletal muscle results in increased extracellular potassium and contributes to hyperkalemia.

Remember that………..Remember that………..

• Heart rate (chronotropic)

• Contractility (inotropic)

• Conductivity (dromotropic)

• Excitability (bathmotropic).

• Heart rate (chronotropic)

• Contractility (inotropic)

• Conductivity (dromotropic)

• Excitability (bathmotropic).

Clinical Features Clinical Features 1-Cardiovascular Manifestations:Sinus bradycardia and AV blocks are more in

childrenVentricular ectopy is more common in

adults. If automaticity is increased and conduction

is depressed, we must think about digitalis toxicity.

2-CNS Manifestation: Lethargy or drowsiness, or

confusion.Headaches.Hallucinations.Visual changes: chromatopsia & xanthopsia,

transient amblyopia or scotomata, and decreased visual acuity (chronic toxicity).

Seizures (rare).3-Gastrointestinal Manifestations:Nausea, vomiting, Diarrhea, Anorexia/weight

loss or failure to thrive, Abdominal pain

1-Cardiovascular Manifestations:Sinus bradycardia and AV blocks are more in

childrenVentricular ectopy is more common in

adults. If automaticity is increased and conduction

is depressed, we must think about digitalis toxicity.

2-CNS Manifestation: Lethargy or drowsiness, or

confusion.Headaches.Hallucinations.Visual changes: chromatopsia & xanthopsia,

transient amblyopia or scotomata, and decreased visual acuity (chronic toxicity).

Seizures (rare).3-Gastrointestinal Manifestations:Nausea, vomiting, Diarrhea, Anorexia/weight

loss or failure to thrive, Abdominal pain

Factors Increasing Toxicity Hypokalemia or hyperkalemia:

Hypokalemia observed with chronic toxicity or with diuretics. Hyperkalemia is a complication of acute toxicity. The large bulk of skeletal muscles is the source of hyperkalemia.

Hypomagnesemia and hypercalcemia. Drugs: Quinidine, procainamide, amiodarone, Ca+

+ channel blockers, and beta-blockers, diuretics including spironolactone.

Erythromycin & tetracycline inactivatie Eubacterium, which is present in 10% of the population and inactivates digoxin in the GIT.

Renal dysfunction. Hypothyroidism. Hypoxemia. Alkalosis. Myocardial disease.

Factors Increasing Toxicity Hypokalemia or hyperkalemia:

Hypokalemia observed with chronic toxicity or with diuretics. Hyperkalemia is a complication of acute toxicity. The large bulk of skeletal muscles is the source of hyperkalemia.

Hypomagnesemia and hypercalcemia. Drugs: Quinidine, procainamide, amiodarone, Ca+

+ channel blockers, and beta-blockers, diuretics including spironolactone.

Erythromycin & tetracycline inactivatie Eubacterium, which is present in 10% of the population and inactivates digoxin in the GIT.

Renal dysfunction. Hypothyroidism. Hypoxemia. Alkalosis. Myocardial disease.

InvestigationsInvestigations Electrolytes, BUN/creatinine,

magnesium, and calcium: initial K+ levels have better prognostic correlation than either ECG changes or initial serum digoxin level

ECG: Sinus bradycardia and AV conduction blocks are the most common ECG changes in children.

Electrolytes, BUN/creatinine, magnesium, and calcium: initial K+ levels have better prognostic correlation than either ECG changes or initial serum digoxin level

ECG: Sinus bradycardia and AV conduction blocks are the most common ECG changes in children.

Therapeutic Serum Digoxin Level = 0.5-2 ng/mL

Neonates and small infants rarely will develop toxicity at levels less than 4-5 ng/mL

Children without CV disease may tolerate levels up to 10 ng/mL …..may have bradyarrhythmias or conduction delays on ECG

General rule: the smaller the infant, the higher the levels may be before observing toxic effects

Therapeutic Serum Digoxin Level = 0.5-2 ng/mL

Neonates and small infants rarely will develop toxicity at levels less than 4-5 ng/mL

Children without CV disease may tolerate levels up to 10 ng/mL …..may have bradyarrhythmias or conduction delays on ECG

General rule: the smaller the infant, the higher the levels may be before observing toxic effects

Endogenous Digoxinlike Immunoreactive Substance (DLIS)

cause false-positive or elevated digoxin level.

DLIS is observed in:1. Neonates2. Patients with renal insufficiency3. Liver disease or hyperbilirubinemia4. Subarachnoid hemorrhage5. Congestive heart failure6. Diabetes M7. Acromegaly8. Pregnancy9. Spironolactone use. 10.Studies have shown preterms with positive

assays up to age 3 months.

Endogenous Digoxinlike Immunoreactive Substance (DLIS)

cause false-positive or elevated digoxin level.

DLIS is observed in:1. Neonates2. Patients with renal insufficiency3. Liver disease or hyperbilirubinemia4. Subarachnoid hemorrhage5. Congestive heart failure6. Diabetes M7. Acromegaly8. Pregnancy9. Spironolactone use. 10.Studies have shown preterms with positive

assays up to age 3 months.

Treatment Treatment General supportive careIV fluid hydration, oxygenation and

support of ventilation, and correction of electrolyte imbalances.

Forced diuresis is not recommended will not increase renal excretion and can worsen electrolyte abnormalities.

General supportive careIV fluid hydration, oxygenation and

support of ventilation, and correction of electrolyte imbalances.

Forced diuresis is not recommended will not increase renal excretion and can worsen electrolyte abnormalities.

Gastrointestinal decontamination1. Activated charcoal is the preferred

method. – Multiple charcoal doses may be

beneficial.

2. Induced emesis is not recommended because of increased vagal effect.

3. Gastric lavage may be useful early but also can increase vagal effects.

4. Whole bowel irrigation may be useful, but clinical data are lacking.

5. Cholestyramine can interrupt enterohepatic circulation especially in patients with renal insufficiency.

Gastrointestinal decontamination1. Activated charcoal is the preferred

method. – Multiple charcoal doses may be

beneficial.

2. Induced emesis is not recommended because of increased vagal effect.

3. Gastric lavage may be useful early but also can increase vagal effects.

4. Whole bowel irrigation may be useful, but clinical data are lacking.

5. Cholestyramine can interrupt enterohepatic circulation especially in patients with renal insufficiency.

Digoxin-specific antibodies (Fab fragments) 1) Life-threatening arrhythmias

2nd. or 3rd.-degree heart blockventricular tachycardia/fibrillation).

2) Initial potassium level > 5 mEq/l.3) Digoxin serum levels >10 ng/mL at 6-8 h 4) Digoxin serum levels >15 ng/mL in an

acute ingestion5) Ingestion >10 mg in healthy adults or

>4 mg in children.

Digoxin-specific antibodies (Fab fragments) 1) Life-threatening arrhythmias

2nd. or 3rd.-degree heart blockventricular tachycardia/fibrillation).

2) Initial potassium level > 5 mEq/l.3) Digoxin serum levels >10 ng/mL at 6-8 h 4) Digoxin serum levels >15 ng/mL in an

acute ingestion5) Ingestion >10 mg in healthy adults or

>4 mg in children.

Dysrhythmia control1. Fab fragment is considered first line

treatment 2. Phenytoin is the drug of choice for

digoxin-induced arrhythmia. It is effective against SV ectopics as well as ventricular arrhythmias.

– Lidocaine is alternative but is not effective against SV arrhythmias.

3. Quinidine and procainamide are not used as they intensify the AV block.

4. IV calcium is contraindicated absolutely due to increased intracellular Ca in digoxin-toxic patients.

Dysrhythmia control1. Fab fragment is considered first line

treatment 2. Phenytoin is the drug of choice for

digoxin-induced arrhythmia. It is effective against SV ectopics as well as ventricular arrhythmias.

– Lidocaine is alternative but is not effective against SV arrhythmias.

3. Quinidine and procainamide are not used as they intensify the AV block.

4. IV calcium is contraindicated absolutely due to increased intracellular Ca in digoxin-toxic patients.

CALCIUM CHANNEL BLOCKER TOXICITY

CALCIUM CHANNEL BLOCKER TOXICITY

CCB are used for AnginaHypertensionArrhythmiasmigraine prophylaxis.

CCB toxicity is one of the most lethal prescription drug ingestions.

CCB are used for AnginaHypertensionArrhythmiasmigraine prophylaxis.

CCB toxicity is one of the most lethal prescription drug ingestions.

Calcium Channel BlockersCalcium Channel Blockers

• Phenylalkylamines– Verapamil

• Benzothiazepines– Diltiazem

• Dihydropyridines– Nifedipine (Adalat) , felodipine,

nimodipine, nicardipine, amlodipine, lercanidipine

• Phenylalkylamines– Verapamil

• Benzothiazepines– Diltiazem

• Dihydropyridines– Nifedipine (Adalat) , felodipine,

nimodipine, nicardipine, amlodipine, lercanidipine


• All existing CCBs function by binding to the L-subtype, voltage-sensitive, slow calcium channels in cell membranes.

• The L-type CCBs decrease the flow of calcium into the cells of the cardiac conduction pathway, which leads to an inhibition of the phase 0 in cardiac pacemaker cells and slows the phase 2 plateau in Purkinje cells, cardiac myocytes, and vascular smooth muscle cells.

• In cardiac muscle and vascular smooth muscle rapid calcium influx causes myosin and actin binding and contraction.

• CCBs inhibit calcium influx leading to decreased myocardial contractility and peripheral arterial vasodilation.

• All existing CCBs function by binding to the L-subtype, voltage-sensitive, slow calcium channels in cell membranes.

• The L-type CCBs decrease the flow of calcium into the cells of the cardiac conduction pathway, which leads to an inhibition of the phase 0 in cardiac pacemaker cells and slows the phase 2 plateau in Purkinje cells, cardiac myocytes, and vascular smooth muscle cells.

• In cardiac muscle and vascular smooth muscle rapid calcium influx causes myosin and actin binding and contraction.

• CCBs inhibit calcium influx leading to decreased myocardial contractility and peripheral arterial vasodilation.

Calcium channels The drugs act from the inner side of the membrane and bind more effectively to open channels.-Drugs act by binding to the alpha-1 subunit

Calcium channels The drugs act from the inner side of the membrane and bind more effectively to open channels.-Drugs act by binding to the alpha-1 subunit

Subunit structure of CaV1 channels (L-type channels)

Pathophysiology Pathophysiology • CCB have 4 cardiovascular effects:

1)Peripheral vasodilatation 2)Negative chronotropy (decreased

heart rate)3)Negative inotropy (decreased

cardiac contractility)4)Negative dromotropy (prolonged

cardiac conduction)

• CCB have 4 cardiovascular effects:

1)Peripheral vasodilatation 2)Negative chronotropy (decreased

heart rate)3)Negative inotropy (decreased

cardiac contractility)4)Negative dromotropy (prolonged

cardiac conduction)

Calcium channel blockersCalcium channel blockers

• Block calcium channels (L-type) in heart and blood vessels– prolong depolarisation

• ↑QRS width– block SA and AV node conduction

• heart block• asystole

– vasodilators– cerebral protection

• Block calcium channels (L-type) in heart and blood vessels– prolong depolarisation

• ↑QRS width– block SA and AV node conduction

• heart block• asystole

– vasodilators– cerebral protection

Calcium Channel BlockersCalcium Channel Blockers

• Hypotension–peripheral vasodilatation and myocardial depression

• Bradycardia–AV and SA node block

• Hypotension–peripheral vasodilatation and myocardial depression

• Bradycardia–AV and SA node block

Other Important Effects

Other Important Effects

• Suppression of insulin release & decreased free fatty acid utilization by the myocardium.

These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.

• Suppression of insulin release & decreased free fatty acid utilization by the myocardium.

These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.

CLINICAL PICTURECLINICAL PICTURE• Children can become symptomatic with

as little as one tablet. In young children, calcium channel blockers have the potential to be fatal with single tablet ingestions.

• Delayed onset of hypotension has been reported in children with extended-release tablet ingestion.

• All children with suspected calcium channel blocker ingestions of any amount should be evaluated in a health care facility and monitored in an ICU setting for signs of delayed toxicity.

• Children can become symptomatic with as little as one tablet. In young children, calcium channel blockers have the potential to be fatal with single tablet ingestions.

• Delayed onset of hypotension has been reported in children with extended-release tablet ingestion.

• All children with suspected calcium channel blocker ingestions of any amount should be evaluated in a health care facility and monitored in an ICU setting for signs of delayed toxicity.

• Hypotension• Bradycardia, with variable

degrees of heart block• Altered mental status or

seizures secondary to hypotension

• Occasional cases of bowel infarction caused by mesenteric underperfusion

• Hypotension• Bradycardia, with variable

degrees of heart block• Altered mental status or

seizures secondary to hypotension

• Occasional cases of bowel infarction caused by mesenteric underperfusion

INVESTIGATIONSINVESTIGATIONS• Blood sugar• ABG• Blood levels are generally not

available.• ECG• Cardiac biomarkers, such as

troponin I, may help differentiate drug-induced bradycardia from ischemic causes.

• Blood sugar• ABG• Blood levels are generally not

available.• ECG• Cardiac biomarkers, such as

troponin I, may help differentiate drug-induced bradycardia from ischemic causes.

Management Management Prehospital Care: • Rapid transport before the patient

deteriorates is crucial. Empiric use of glucagon (5-15 mg IV) may be warranted for patients with an unknown overdose presenting with bradycardia or hypotension.

• Consider using calcium only if a witness confirms a calcium channel blocker overdose.

• Treat hypotension with fluid boluses. If profound hypotension fails to respond to fluid resuscitation, administer a dopamine or norepinephrine drip. If the patient deteriorates to cardiac arrest from a calcium channel blocker overdose, perform prolonged cardiopulmonary resuscitation (CPR) in the field because patients have survived neurologically intact after an hour of CPR.

• Establish ABCs, obtain IV access, provide oxygen, and monitor closely.

Prehospital Care: • Rapid transport before the patient

deteriorates is crucial. Empiric use of glucagon (5-15 mg IV) may be warranted for patients with an unknown overdose presenting with bradycardia or hypotension.

• Consider using calcium only if a witness confirms a calcium channel blocker overdose.

• Treat hypotension with fluid boluses. If profound hypotension fails to respond to fluid resuscitation, administer a dopamine or norepinephrine drip. If the patient deteriorates to cardiac arrest from a calcium channel blocker overdose, perform prolonged cardiopulmonary resuscitation (CPR) in the field because patients have survived neurologically intact after an hour of CPR.

• Establish ABCs, obtain IV access, provide oxygen, and monitor closely.

• Avoid ipecac syrup.• Administer IV glucagon if hypotension is

present. Administer fluid bolus of normal saline if no evidence of decompensated congestive heart failure exists.

• Atropine may be tried if significant bradycardia occurs; however, heart block is usually resistant to atropine in calcium channel blocker toxicity. Mid-dose dopamine (5-10 mcg/kg/min) may improve heart rate and contractility.

• Administer IV calcium chloride (up to 4 g) and/or glucagon (up to 15 mg) if hypotension persists.

• Consider dopamine or norepinephrine infusion if a long transport time is likely, as permitted by local prehospital care protocols.

• Avoid ipecac syrup.• Administer IV glucagon if hypotension is

present. Administer fluid bolus of normal saline if no evidence of decompensated congestive heart failure exists.

• Atropine may be tried if significant bradycardia occurs; however, heart block is usually resistant to atropine in calcium channel blocker toxicity. Mid-dose dopamine (5-10 mcg/kg/min) may improve heart rate and contractility.

• Administer IV calcium chloride (up to 4 g) and/or glucagon (up to 15 mg) if hypotension persists.

• Consider dopamine or norepinephrine infusion if a long transport time is likely, as permitted by local prehospital care protocols.

• Gastric decontamination

–Gastric lavage –Activated charcoal –Completely asymptomatic patients may be treated with activated charcoal and close observation.

–Whole bowel . To be careful that ileus, bowel obstruction, and bowel ischemia have not occurred.

• Gastric decontamination

–Gastric lavage –Activated charcoal –Completely asymptomatic patients may be treated with activated charcoal and close observation.

–Whole bowel . To be careful that ileus, bowel obstruction, and bowel ischemia have not occurred.

Medical Medical

1)Correction of acidosis 2)Calcium loading 3)Glucagon 4)Insulin-dextrose 5)Atropine 6)Inotropic agents 7)Cardiac pacing

1)Correction of acidosis 2)Calcium loading 3)Glucagon 4)Insulin-dextrose 5)Atropine 6)Inotropic agents 7)Cardiac pacing

Correction of acidosisCorrection of acidosis

–acidosis enhances the effect of verapamil and decreases the effect of calcium

–sodium bicarbonate significantly improved myocardial contractility and cardiac output in a swine model of verapamil poisoning

–acidosis enhances the effect of verapamil and decreases the effect of calcium

–sodium bicarbonate significantly improved myocardial contractility and cardiac output in a swine model of verapamil poisoning

Calcium LoadingCalcium Loading

• Calcium loading appears to be the most effective agent to use in calcium channel blocker poisoning

• It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem)

• Calcium loading appears to be the most effective agent to use in calcium channel blocker poisoning

• It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem)

GlucagonGlucagon

• Glucagon is a well-accepted antidote for beta-blocker poisoning

• The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux

• Clinical experience suggests it is less effective in this setting than in beta-blocker poisoning

• Glucagon is a well-accepted antidote for beta-blocker poisoning

• The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux

• Clinical experience suggests it is less effective in this setting than in beta-blocker poisoning

Insulin-dextrose euglycaemia

Insulin-dextrose euglycaemia

• Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia

• Insulin-dextrose euglycaemia is more effective in animal models than calcium, adrenaline or glucagon

• Effective in a case series of clinically serious poisonings

• Hypotension that is refractory to volume loading, correction of acidosis and calcium salts

• Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia

• Insulin-dextrose euglycaemia is more effective in animal models than calcium, adrenaline or glucagon

• Effective in a case series of clinically serious poisonings

• Hypotension that is refractory to volume loading, correction of acidosis and calcium salts

AtropineAtropine

• Vagal tone is increase by vomiting and gastrointestinal decontamination

• Atropine should be given to all patients who are vomiting or having GI decontamination

• Atropine should be given to all patients with bradycardia

• A response may only occur after calcium loading

• Vagal tone is increase by vomiting and gastrointestinal decontamination

• Atropine should be given to all patients who are vomiting or having GI decontamination

• Atropine should be given to all patients with bradycardia

• A response may only occur after calcium loading

Inotropic agentsInotropic agents

• Dopamine is the initial pressor agent of choice (75% response) for diltiazem overdose

• Isoprenaline produces a therapeutic response in 50% of patients

• Action is predominantly through increasing the frequency of impulses originating in the SA node

• These agents are often ineffective as chronotropic agents when there is a high degree of conduction block

• Dopamine is the initial pressor agent of choice (75% response) for diltiazem overdose

• Isoprenaline produces a therapeutic response in 50% of patients

• Action is predominantly through increasing the frequency of impulses originating in the SA node

• These agents are often ineffective as chronotropic agents when there is a high degree of conduction block

Cardiac pacingCardiac pacing

• Ventricular rather than atrial pacing

• In severe poisoning the heart may fail to capture and pharmacological therapy will still be required

• Ventricular rather than atrial pacing

• In severe poisoning the heart may fail to capture and pharmacological therapy will still be required

LITHIUMLITHIUM

Back Ground & Pharmacokinetics

Back Ground & Pharmacokinetics• Lithium was an additive in 7 Up till American

beverage makers were forced to remove lithium in 1948.

• Lithium is used in the treatment of depressive and bipolar affective disorders.

• The CNS is the major organ system affected, although the renal, GIT, endocrine, and CVS also may be involved.

• Absorbed from the GI tract. • Peak levels occur 2-4 hours postingestion• Lithium intoxication may occur because of its

narrow therapeutic index. • Poisoning may be intentional or unintentional

• Lithium was an additive in 7 Up till American beverage makers were forced to remove lithium in 1948.

• Lithium is used in the treatment of depressive and bipolar affective disorders.

• The CNS is the major organ system affected, although the renal, GIT, endocrine, and CVS also may be involved.

• Absorbed from the GI tract. • Peak levels occur 2-4 hours postingestion• Lithium intoxication may occur because of its

narrow therapeutic index. • Poisoning may be intentional or unintentional

PharmacokineticsPharmacokinetics

• Half-life of a single dose of Li is 12-27 hrs

• The half-life increases to approximately 36 hrs in elderly

• Half-life may be longer with chronic lithium use.

• An estimated 10,000 toxic exposures occur per year. These data indicate a gradual increase over the past 10 years*

• Half-life of a single dose of Li is 12-27 hrs

• The half-life increases to approximately 36 hrs in elderly

• Half-life may be longer with chronic lithium use.

• An estimated 10,000 toxic exposures occur per year. These data indicate a gradual increase over the past 10 years* * From USA

Mode of Action

Mode of Action

• Lithium is similar to sodium• In addition, lithium may inhibit the release of

monoamines from nerve endings and increase their uptake.

• The exact mode of action of lithium in affective disorders is unknown.

• Lithium has a narrow therapeutic ratio.• Blood concentration must be carefully monitored to

avoid toxicity. • Early signs of lithium toxicity are vomiting and

severe diarrhoea followed by tremor, ataxia, renal impairment and convulsions

• Lithium is similar to sodium• In addition, lithium may inhibit the release of

monoamines from nerve endings and increase their uptake.

• The exact mode of action of lithium in affective disorders is unknown.

• Lithium has a narrow therapeutic ratio.• Blood concentration must be carefully monitored to

avoid toxicity. • Early signs of lithium toxicity are vomiting and

severe diarrhoea followed by tremor, ataxia, renal impairment and convulsions

Types of Poisoning Types of Poisoning

131

1. Acute poisoning - Voluntary or accidental ingestion in a previously untreated patient

2. Acute-on-chronic - Voluntary or accidental ingestion in a patient currently using lithium

3. Chronic poisoning - Progressive lithium toxicity in a patient on lithium therapy

Clinical PictureClinical PictureMild-to-moderate toxicity• Generalized weakness• Fine resting tremor• Mild confusion

Moderate-to-severe toxicity• Severe tremor• Muscle fasciculations• Choreoathetosis• Hyperreflexia• Clonus• Opisthotonos• Stupor• Seizures• Coma• Signs of cardiovascular collapse

Mild-to-moderate toxicity• Generalized weakness• Fine resting tremor• Mild confusion

Moderate-to-severe toxicity• Severe tremor• Muscle fasciculations• Choreoathetosis• Hyperreflexia• Clonus• Opisthotonos• Stupor• Seizures• Coma• Signs of cardiovascular collapse

Lithium Toxicity Effects

Lithium Toxicity Effects

133

ACUTE CHRONIC

GI (nausea, vomiting & diarrhoea)

42% 20%

CNS (seizures) delayed Common > 2.mmol/L

Renal Usualy non signifiant

Universal

ECG Normal QT prolongation usual

Thyroid none Hypothyroidism 20%

Recovery Usual, rapid Disability 10% delayed

Level correlation poor Good

Hypertox. 2007

DosingDosing

• Lithium toxicity is dose related• Lithium is minimally protein bound • The therapeutic dose is 300-2700 mg/d with

desired serum levels of 0.7-1.2 mEq/L.• Lithium clear via kidneys. • Most filtered lithium is reabsorbed in the PCT• Reabsorption of lithium is increased and

toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

• Lithium toxicity is dose related• Lithium is minimally protein bound • The therapeutic dose is 300-2700 mg/d with

desired serum levels of 0.7-1.2 mEq/L.• Lithium clear via kidneys. • Most filtered lithium is reabsorbed in the PCT• Reabsorption of lithium is increased and

toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

Tubular Lithium handling

Li+

Li+

THIAZIDES

LOOPAGENTS

Effects of Furosemide (an example)Effects of Furosemide (an example)

• Loop diuretics may increase serum lithium levels and potentiate the risk of lithium toxicity.

• The exact mechanism is unknown but may be related to the sodium loss induced by loop diuresis, which produces a compensatory increase in proximal tubular reabsorption of sodium along with lithium.

• Loop diuretics may increase serum lithium levels and potentiate the risk of lithium toxicity.

• The exact mechanism is unknown but may be related to the sodium loss induced by loop diuresis, which produces a compensatory increase in proximal tubular reabsorption of sodium along with lithium.

Li+

Li+X

Tubular lithium handling:

Effect of Furosemide

TreatmentTreatmentPrehospital Care• Stabilize life-threatening conditions

and initiate supportive therapy.• Obtain IV access with isotonic sodium

chloride solution.• Monitor cardiac function to assess

rhythm disturbances.

Prehospital Care• Stabilize life-threatening conditions

and initiate supportive therapy.• Obtain IV access with isotonic sodium

chloride solution.• Monitor cardiac function to assess

rhythm disturbances.

Treatment (continued...)


• Gastric decontamination• Gastric lavage• Activated charcoal (for

possible other drugs)• Consider whole bowel

irrigation.• Hypokalemia.

• Gastric decontamination• Gastric lavage• Activated charcoal (for

possible other drugs)• Consider whole bowel

irrigation.• Hypokalemia.



• Avoid onset of hypernatremia.• Hemodialysis In general, consider dialysis in

patients with chronic toxicity and serum lithium concentrations higher than 4mEq/L; also consider dialysis in unstable chronic patients with lithium levels higher than 2.5 mEq/L.

Change in mental status assists in determining need for dialysis

• Avoid onset of hypernatremia.• Hemodialysis In general, consider dialysis in

patients with chronic toxicity and serum lithium concentrations higher than 4mEq/L; also consider dialysis in unstable chronic patients with lithium levels higher than 2.5 mEq/L.

Change in mental status assists in determining need for dialysis

Complications & Prognosis

Complications & Prognosis

• Truncal and gait ataxia• Nystagmus• Hypertonicity• Short-term memory deficits• Dementia (rare)Prognosis• Most cases of lithium toxicity

result in a favourable outcome; however, up to 10% of individuals with severe toxicity

• Truncal and gait ataxia• Nystagmus• Hypertonicity• Short-term memory deficits• Dementia (rare)Prognosis• Most cases of lithium toxicity

result in a favourable outcome; however, up to 10% of individuals with severe toxicity

toxicity of therapeutic agents

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