Management of Management of overdose and overdose and poisoning poisoning

Paula Jerrard-DunnePaula Jerrard-DunnePharmacology & Therapeutics Pharmacology & Therapeutics 20062006

General- evaluationGeneral- evaluation

recognition of poisoningrecognition of poisoning identification of agents involved identification of agents involved assessment of severity assessment of severity prediction of toxicity prediction of toxicity

General- managementGeneral- management

provision of supportive careprovision of supportive care prevention of poison absorptionprevention of poison absorption enhancement of elimination of enhancement of elimination of

poisonpoison administration of antidotes administration of antidotes

Supportive careSupportive care

ABCABC Vital signs, mental status, and pupil size Vital signs, mental status, and pupil size Pulse oximetry, cardiac monitoring, ECGPulse oximetry, cardiac monitoring, ECG Protect airwayProtect airway Intravenous access Intravenous access cervical immobilization if suspect traumacervical immobilization if suspect trauma Rule out hypoglycaemiaRule out hypoglycaemia Naloxone for suspected opiate poisoningNaloxone for suspected opiate poisoning

HistoryHistory

Pill bottlesPill bottles AlcoholAlcohol Drug history including accessDrug history including access Remember OTC drugsRemember OTC drugs Suicide noteSuicide note National Poisons Information National Poisons Information

Centre *Centre *

ExaminationExamination

Physiologic excitation –Physiologic excitation – anticholinergic, sympathomimetic, or central anticholinergic, sympathomimetic, or central

hallucinogenic agents, drug withdrawalhallucinogenic agents, drug withdrawal Physiologic depression –Physiologic depression – cholinergic (parasympathomimetic), cholinergic (parasympathomimetic),

sympatholytic, opiate, or sedative-hypnotic sympatholytic, opiate, or sedative-hypnotic agents, or alcohols agents, or alcohols

Mixed state –Mixed state –

polydrugs, polydrugs, hypoglycemic agents, tricyclic hypoglycemic agents, tricyclic antidepressants, salicylates, cyanideantidepressants, salicylates, cyanide

Drug detectionDrug detection

Drug levelsDrug levels

Preventing absorptionPreventing absorption

Gastric lavageGastric lavage Not in unconscious patient unless intubated (risk aspiration)Not in unconscious patient unless intubated (risk aspiration)

Flexible tube is inserted through the nose into the stomach Flexible tube is inserted through the nose into the stomach

Stomach contents are then suctioned via the tubeStomach contents are then suctioned via the tube

A solution of saline is injected into the tube A solution of saline is injected into the tube

Recommended for up to 2 hrs in TCA & up to 4hrs in Recommended for up to 2 hrs in TCA & up to 4hrs in

Salicylate ODSalicylate OD

Induced VomitingInduced Vomiting Ipecac - Not routinely recommended Ipecac - Not routinely recommended Risk of aspirationRisk of aspiration

Preventing absorptionPreventing absorption

Activated charcoalActivated charcoal Adsorbs toxic substances or irritants, thus inhibiting GI Adsorbs toxic substances or irritants, thus inhibiting GI

absorption absorption Addition of sorbitol Addition of sorbitol →→laxative effectlaxative effect Oral: 25-100 g as a single dose Oral: 25-100 g as a single dose repetitive doses useful to enhance the elimination of repetitive doses useful to enhance the elimination of

certain drugs (eg, theophylline, phenobarbital, certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products)carbamazepine, aspirin, sustained-release products)

not effective for cyanide, mineral acids, caustic alkalis, not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, organic solvents, iron, ethanol, methanol poisoning, lithium lithium

Elimination of poisonsElimination of poisons

Renal eliminationRenal elimination Medication to stimulate urination or defecation may be given to Medication to stimulate urination or defecation may be given to

try to flush the excess drug out of the body faster.try to flush the excess drug out of the body faster.

Forced alkaline diuresisForced alkaline diuresis Infusion of large amount of NS+NAHCO3Infusion of large amount of NS+NAHCO3 Used to eliminate acidic drug that mainly excreted by the kidney Used to eliminate acidic drug that mainly excreted by the kidney

eg salicylateseg salicylates Serious fluid and electrolytes disturbance may occurSerious fluid and electrolytes disturbance may occur Need expert monitoringNeed expert monitoring

Hemodialysis or haemoperfusionHemodialysis or haemoperfusion: : Reserved for severe poisoning Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of Drug should be dialyzable i.e. protein bound with low volume of

distributiondistribution may also be used temporarily or as long term if the kidneys are may also be used temporarily or as long term if the kidneys are

damaged due to the overdose. damaged due to the overdose.

Antidotes Antidotes

Does an antidote exist?Does an antidote exist? Does actual or predicted severity Does actual or predicted severity

of poisoning warrant its use?of poisoning warrant its use? Do expected benefits of therapy Do expected benefits of therapy

outweigh its associated risk?outweigh its associated risk? Are there contraindications? Are there contraindications?

Specific overdosesSpecific overdoses

OpiatesOpiates

Antidote – naloxoneAntidote – naloxone MOA: Pure opioid antagonist competes and MOA: Pure opioid antagonist competes and

displaces narcotics at opioid receptor sites displaces narcotics at opioid receptor sites I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg

every 2-3 minutes as needed every 2-3 minutes as needed Lower doses in opiate dependenceLower doses in opiate dependence Elimination half-life of naloxone is only 60 to 90 Elimination half-life of naloxone is only 60 to 90

minutes minutes Repeated administration/infusion may be Repeated administration/infusion may be

necessarynecessary

S/E BP changes; arrhythmias; seizures; withdrawalS/E BP changes; arrhythmias; seizures; withdrawal

BenzodiazepinesBenzodiazepines

Antidote – flumazenilAntidote – flumazenil MOA: Benzodiazepine antagonist MOA: Benzodiazepine antagonist IV administration 0.2 mg over 15 sec to max IV administration 0.2 mg over 15 sec to max

3mg3mg S/E N&V; arrhythmias; convulsionsS/E N&V; arrhythmias; convulsions C/I concomitant TCAD; status epilepticusC/I concomitant TCAD; status epilepticus Should not be used for making the diagnosisShould not be used for making the diagnosis Benzodiazepines may be masking/protecting Benzodiazepines may be masking/protecting

against other drug effectsagainst other drug effects

Tricyclic Tricyclic antidepressantsantidepressants PHARMACOLOGYPHARMACOLOGY — — TCAs have several important cellular effects, including TCAs have several important cellular effects, including

inhibition of:inhibition of:

        Presynaptic neurotransmitter reuptakePresynaptic neurotransmitter reuptake

    Cardiac fast sodium channels    Cardiac fast sodium channels

    Central and peripheral muscarinic acetylcholine receptors    Central and peripheral muscarinic acetylcholine receptors

    Peripheral alpha-1 adrenergic receptors    Peripheral alpha-1 adrenergic receptors

    Histamine (H1) receptors    Histamine (H1) receptors

    CNS GABA-A receptors    CNS GABA-A receptors

TCAD overdoseTCAD overdoseclinical featuresclinical features

Arrhythmias Arrhythmias

- widening of PR, QRS, and QT intervals; - widening of PR, QRS, and QT intervals;

heart block; VF/VTheart block; VF/VT

HypotensionHypotension

Anticholinergic toxicity Anticholinergic toxicity

- - hyperthermia, flushing, dilated pupils, hyperthermia, flushing, dilated pupils,

intestinal ileus, urinary retention, sinus tachycardiaintestinal ileus, urinary retention, sinus tachycardia

Confusion, delirium, hallucinationsConfusion, delirium, hallucinations

Seizures Seizures

DiagnosisDiagnosis

HistoryHistory

Blood/urine toxicology screenBlood/urine toxicology screen

Levels not clinically usefulLevels not clinically useful

TCAD overdose -TreatmentTCAD overdose -Treatment

ABC – many require intubationABC – many require intubation Consider gastric lavage if taken < 2hrsConsider gastric lavage if taken < 2hrs Activated charcoalActivated charcoal Treatment of hypotension with isotonic salineTreatment of hypotension with isotonic saline Sodium bicarbonateSodium bicarbonate for cardiovascular toxicity for cardiovascular toxicity Alpha adrenergic vasopressors (Alpha adrenergic vasopressors (

norepinephrinenorepinephrine) for hypotension refractory to ) for hypotension refractory to

aggressive fluid resuscitation and bicarbonate aggressive fluid resuscitation and bicarbonate

infusion infusion Benzodiazepines for seizuresBenzodiazepines for seizures

Sodium Bicarbonate Sodium Bicarbonate in TCA in TCA overdoseoverdose Hypertonic Hypertonic sodium bicarbonatesodium bicarbonate (NaHCO3) (NaHCO3)

- QRS widening >100 msec; ventricular - QRS widening >100 msec; ventricular

arrhythmias, and/or refractory hypotension arrhythmias, and/or refractory hypotension

↑↑ serum pH promotes protein binding and serum pH promotes protein binding and ↓↓ free drug free drug

concentrations; narrows the QRS complex, concentrations; narrows the QRS complex, ↑↑ systolic blood systolic blood

pressure, and controls ventricular arrhythmiaspressure, and controls ventricular arrhythmias

1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent 1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent

NaHCO3) rapid IV push large bore IV then infusion if workingNaHCO3) rapid IV push large bore IV then infusion if working

reasonable goal pH is 7.50 to 7.55 then taper dosereasonable goal pH is 7.50 to 7.55 then taper dose

S/E S/E Volume overload, hypernatreamia, and metabolic alkalosis Volume overload, hypernatreamia, and metabolic alkalosis

Special Cautions in TCAD Special Cautions in TCAD overdoseoverdose

Class IA and IC antiarrhythmic agents are Class IA and IC antiarrhythmic agents are

contraindicated eg quinidine;disopyramide, contraindicated eg quinidine;disopyramide,

flecainide; propafenoneflecainide; propafenone

Class IB Lignocaine, phenytoin usedClass IB Lignocaine, phenytoin used

Phenytoin may precipitate arrhythmiasPhenytoin may precipitate arrhythmias

Magnesium may be usefulMagnesium may be useful

Flumazenil must Flumazenil must notnot be given be given

Salicylate overdoseSalicylate overdose

Aspirin (Aspirin (acetylsalicylic acid)acetylsalicylic acid) Methyl salicylate (Oil of Wintergreen)Methyl salicylate (Oil of Wintergreen) 5 ml = 7g salicylic acid5 ml = 7g salicylic acid Herbal remediesHerbal remedies Fatal intoxication can occur after the Fatal intoxication can occur after the

ingestion of 10 to 30 g by adults and ingestion of 10 to 30 g by adults and as little as 3 g by childrenas little as 3 g by children

Salicylate levelsSalicylate levels

Plasma salicylate concentrationPlasma salicylate concentration

Rapidly absorbed; peak blood levels usually Rapidly absorbed; peak blood levels usually

occur within one hour but delayed in overdose 6-occur within one hour but delayed in overdose 6-

35 hrs 35 hrs

Measure @ 4 hrs post ingestion & every 2 hrs Measure @ 4 hrs post ingestion & every 2 hrs

until they are clearly fallinguntil they are clearly falling

Most patients show signs of intoxication when Most patients show signs of intoxication when

the plasma level exceeds 40 to 50 mg/dL (2.9 to the plasma level exceeds 40 to 50 mg/dL (2.9 to

3.6 mmol/L) 3.6 mmol/L)

Salicylate overdoseSalicylate overdose

Inhibition of cyclooxygenase results in decreased synthesis of Inhibition of cyclooxygenase results in decreased synthesis of

prostaglandins, prostacyclin, and thromboxanesprostaglandins, prostacyclin, and thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla Stimulation of the chemoreceptor trigger zone in the medulla

causes nausea and vomitingcauses nausea and vomiting Direct toxicity of salicylate species in the CNS, cerebral edema, Direct toxicity of salicylate species in the CNS, cerebral edema,

and neuroglycopenia and neuroglycopenia  Activation of the respiratory center of the medulla results in Activation of the respiratory center of the medulla results in

tachypnea, hyperventilation, respiratory alkalosistachypnea, hyperventilation, respiratory alkalosis Uncoupled oxidative phosphorylation in the mitochondria Uncoupled oxidative phosphorylation in the mitochondria

generates heat and may increase body temperature generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosisInterference with cellular metabolism leads to metabolic acidosis

Clinical featuresClinical features

Early symptoms of Early symptoms of aspirinaspirin toxicity include toxicity include

tinnitus, fever, vertigo, nausea, tinnitus, fever, vertigo, nausea,

hyperventilation, vomiting, diarrhoeahyperventilation, vomiting, diarrhoea

More severe intoxication can cause altered More severe intoxication can cause altered

mental status, coma, non-cardiac pulmonary mental status, coma, non-cardiac pulmonary

oedema and deathoedema and death

Metabolic Metabolic abnormalitiesabnormalities Stimulate the respiratory center directly, early fall in the PCO2 Stimulate the respiratory center directly, early fall in the PCO2

and and respiratory alkalosis respiratory alkalosis

An anion-gap An anion-gap metabolic acidosismetabolic acidosis then follows, due to the then follows, due to the

accumulation of organic acids, including lactic acid and accumulation of organic acids, including lactic acid and

ketoacidsketoacids

Mixed Mixed respiratory alkalosis and metabolic acidosisrespiratory alkalosis and metabolic acidosis with with ↑ anion ↑ anion

gapgap

Arterial Ph variable depending on severityArterial Ph variable depending on severity

Metabolic Metabolic abnormalitiesabnormalities Metabolic acidosis Metabolic acidosis increases the increases the

plasma concentration of plasma concentration of protonated salicylate protonated salicylate

thus worsening toxicity by thus worsening toxicity by allowing easy diffusion of the allowing easy diffusion of the drug across cell membranesdrug across cell membranes

Salicylate overdose - Salicylate overdose - treatmenttreatment

directed toward increasing systemic pH by the directed toward increasing systemic pH by the administration of sodium bicarbonate administration of sodium bicarbonate

IV fluids +/- vasopressorsIV fluids +/- vasopressors

Avoid intubation if at all possible (Avoid intubation if at all possible (↑ acidosis)↑ acidosis)

Supplemental glucose (100 mL of 50 percent dextrose Supplemental glucose (100 mL of 50 percent dextrose in adults) to patients with altered mental status in adults) to patients with altered mental status regardless of serum glucose concentration to regardless of serum glucose concentration to overcome neuroglycopaeniaovercome neuroglycopaenia

HemodialysisHemodialysis

Alkalinization of plasma and Alkalinization of plasma and

urineurine Alkalemia from a respiratory alkalosis is not a Alkalemia from a respiratory alkalosis is not a

contraindication to sodium bicarbonate therapy contraindication to sodium bicarbonate therapy

A urine pH of 7.5 to 8.0 is desirableA urine pH of 7.5 to 8.0 is desirable

Blood gas analysis every two hours Blood gas analysis every two hours

Avoid severe alkalemia (arterial pH >7.60)Avoid severe alkalemia (arterial pH >7.60)

Haemodialysis - indicationsHaemodialysis - indications

Altered mental statusAltered mental status

Pulmonary or cerebral edemaPulmonary or cerebral edema

Renal insufficiency that interferes with salicylate excretionRenal insufficiency that interferes with salicylate excretion

Fluid overload that prevents the administration of sodium Fluid overload that prevents the administration of sodium bicarbonatebicarbonate

A plasma salicylate concentration >100 mg/dL (7.2 mmol/L)A plasma salicylate concentration >100 mg/dL (7.2 mmol/L)

Clinical deterioration despite aggressive and appropriate Clinical deterioration despite aggressive and appropriate supportive caresupportive care

ParacetamolParacetamol

Widely availableWidely available

Potential toxicity underestimatedPotential toxicity underestimated

Toxicity unlikely to result from a single dose of less Toxicity unlikely to result from a single dose of less

than 150 mg/kg in child or 7.5 to 10 g for adult than 150 mg/kg in child or 7.5 to 10 g for adult

Toxicity is likely with single ingestions greater than 250 Toxicity is likely with single ingestions greater than 250

mg/kg or those greater than 12 g over a 24-hour period mg/kg or those greater than 12 g over a 24-hour period

Virtually all patients who ingest doses in excess of 350 Virtually all patients who ingest doses in excess of 350

mg/kg develop severe liver toxicity unless mg/kg develop severe liver toxicity unless

appropriately treatedappropriately treated

Factors influencing Factors influencing toxicitytoxicity Dose ingestedDose ingested

Excessive cytochrome P450 activity due to induction Excessive cytochrome P450 activity due to induction

by chronic alcohol or other drug use eg by chronic alcohol or other drug use eg

carbamazepine, phenytoin, isoniazid, rifampin carbamazepine, phenytoin, isoniazid, rifampin

Decreased capacity for glucuronidation or sulfationDecreased capacity for glucuronidation or sulfation

Depletion of glutathione stores due to malnutrition or Depletion of glutathione stores due to malnutrition or

chronicchronic alcohol ingestion alcohol ingestion

Acute alcohol ingestion is not a risk factor for Acute alcohol ingestion is not a risk factor for

hepatotoxicity and may even be protective by hepatotoxicity and may even be protective by

competing with acetaminophen for CYP2E1 competing with acetaminophen for CYP2E1

Clinical featuresClinical features Stage I (0.5 to 24 hours)Stage I (0.5 to 24 hours)

No symptoms; N&V MalaiseNo symptoms; N&V Malaise

Stage II (24 to 72 hours)Stage II (24 to 72 hours)

Subclinical elevations of hepatic aminotransferases (AST, ALT) Subclinical elevations of hepatic aminotransferases (AST, ALT)

right upper quadrant pain, with liver enlargement and tenderness. right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident renal function abnormalities may become evident

Stage III (72 to 96 hours)Stage III (72 to 96 hours)

Jaundice, confusion (hepatic encephalopathy), a marked elevation in Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, deathhypoglycemia, lactic acidosis, renal failure 25%, death

Stage IV (4 days to 2 weeks)Stage IV (4 days to 2 weeks)

Recovery phase that usually begins by day 4 and is complete by 7 days Recovery phase that usually begins by day 4 and is complete by 7 days after overdose after overdose

Paracetamol overdoseParacetamol overdose

The risk of toxicity is best predicted by relating the time The risk of toxicity is best predicted by relating the time of ingestion to the serum of ingestion to the serum paracetamolparacetamol concentration concentration

The dose history should not be used as studies have The dose history should not be used as studies have found no correlationfound no correlation

Peak serum concentrations reached within 4 hrs Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparationsfollowing overdose of immediate-release preparations

May be delayed with extended releases preparations or May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingestedanticholinergic agents) are coingested

Check level at >= 4 hrsCheck level at >= 4 hrs

Paracetamol overdose Paracetamol overdose treatmenttreatment

Activated charcoal within four hours of Activated charcoal within four hours of

ingestion ingestion

May reduce absorption by 50 to 90 May reduce absorption by 50 to 90

percent percent

Single oral dose of one gram per Single oral dose of one gram per

kilogram kilogram

Inhibits absorption of oral methionineInhibits absorption of oral methionine

N-acetylcysteine N-acetylcysteine

Antidote – MOA: Antidote – MOA: a glutathione precursor a glutathione precursor

Limits the formation and accumulation of NAPQI Limits the formation and accumulation of NAPQI

Powerful anti-inflammatory and antioxidant effects Powerful anti-inflammatory and antioxidant effects

IV infusion or oral tablets (also oral methionine)IV infusion or oral tablets (also oral methionine)

150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg 150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg

over next 16 hrs up to 36hrsover next 16 hrs up to 36hrs

Beyond 8 hours, NAC efficacy progressively decreases Beyond 8 hours, NAC efficacy progressively decreases

S/Es nausea, flushing, urticaria, bronchospasm, S/Es nausea, flushing, urticaria, bronchospasm,

angioedema, fever, chills, hypotension, hemolysis and angioedema, fever, chills, hypotension, hemolysis and

rarely, cardiovascular collapse rarely, cardiovascular collapse

Paracetamol overdose Paracetamol overdose treatmenttreatment

At the end of NAC infusion, a blood sample should be At the end of NAC infusion, a blood sample should be

taken for determination of the INR, plasma creatinine taken for determination of the INR, plasma creatinine

and ALT. If any is abnormal or the patient is and ALT. If any is abnormal or the patient is

symptomatic, further monitoring is required and symptomatic, further monitoring is required and

advice sought from the NPIS advice sought from the NPIS

Patients with normal INR, plasma creatinine and ALT Patients with normal INR, plasma creatinine and ALT

and who are asymptomatic may be discharged from and who are asymptomatic may be discharged from

medical care. They should be advised to return to medical care. They should be advised to return to

hospital if vomiting or abdominal pain develop or recurhospital if vomiting or abdominal pain develop or recur

Indications for liver Indications for liver transplantationtransplantation

Liver transplantation is life-saving for fulminant hepatic Liver transplantation is life-saving for fulminant hepatic necrosis necrosis

The indications for liver transplantation are:The indications for liver transplantation are:

1 - Acidosis (pH < 7.3), or 1 - Acidosis (pH < 7.3), or

2 - PT > 100 sec 2 - PT > 100 sec

3 - Creatinine > 300 mcg/l 3 - Creatinine > 300 mcg/l

4 - Grade 3 encephalopathy (or worse)4 - Grade 3 encephalopathy (or worse) It is better to contact the local liver transplant centre earlier It is better to contact the local liver transplant centre earlier

than this. than this. Grossly abnormal prothrombin times should trigger referral:Grossly abnormal prothrombin times should trigger referral: PT > 20 sec at 24 hr PT > 20 sec at 24 hr PT > 40 sec at 48 hr PT > 40 sec at 48 hr

Alcohol poisoningAlcohol poisoning

Clinical features of acute alcohol poisoning include:Clinical features of acute alcohol poisoning include:

Ataxia and anaesthesia leading to accidental injury Ataxia and anaesthesia leading to accidental injury

Dysarthria and nystagmus Dysarthria and nystagmus

Drowsiness which may progress to coma Drowsiness which may progress to coma

Inhalation of vomit which can be fatal & should be prevented Inhalation of vomit which can be fatal & should be prevented

Hypoglycaemia in children and some adults Hypoglycaemia in children and some adults

Check BM stix and give 50% glucose i.v. if requiredCheck BM stix and give 50% glucose i.v. if required

Coma (alcohol induced)Coma (alcohol induced) In cases of alcohol induced coma exclude:In cases of alcohol induced coma exclude:

1.1. Coincident head injuryCoincident head injury

2.2. Hepatic failure Hepatic failure

3.3. MeningitisMeningitis

4.4. Wernicke’s encephalopathy Wernicke’s encephalopathy

5.5. Other associated drug ingestionOther associated drug ingestion A blood test will confirm substantial levels of alcohol A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemiaRule out alcoholic hypoglycaemia The airway and circulation must be maintainedThe airway and circulation must be maintained But glucose- containing fluids may precipitate Wernicke's But glucose- containing fluids may precipitate Wernicke's

encephalopathyencephalopathy Thiamine should given to allThiamine should given to all Intravenous naloxone has reversed coma in a proportion of Intravenous naloxone has reversed coma in a proportion of

casescases