Management of overdose and poisoning Paula Jerrard-DunnePharmacology & Therapeutics 2006

General- evaluationrecognition of poisoningidentification of agents involved assessment of severity prediction of toxicity

General- managementprovision of supportive careprevention of poison absorptionenhancement of elimination of poisonadministration of antidotes

Supportive careABCVital signs, mental status, and pupil size Pulse oximetry, cardiac monitoring, ECGProtect airwayIntravenous access cervical immobilization if suspect traumaRule out hypoglycaemiaNaloxone for suspected opiate poisoning

HistoryPill bottlesAlcoholDrug history including accessRemember OTC drugsSuicide noteNational Poisons Information Centre *

ExaminationPhysiologic excitation anticholinergic, sympathomimetic, or central hallucinogenic agents, drug withdrawalPhysiologic depression cholinergic (parasympathomimetic), sympatholytic, opiate, or sedative-hypnotic agents, or alcohols Mixed state polydrugs, hypoglycemic agents, tricyclic antidepressants, salicylates, cyanide

Drug detection

Drug levels

Preventing absorptionGastric lavageNot in unconscious patient unless intubated (risk aspiration)Flexible tube is inserted through the nose into the stomach Stomach contents are then suctioned via the tubeA solution of saline is injected into the tube Recommended for up to 2 hrs in TCA & up to 4hrs in Salicylate OD Induced VomitingIpecac - Not routinely recommended Risk of aspiration

Preventing absorptionActivated charcoalAdsorbs toxic substances or irritants, thus inhibiting GI absorption Addition of sorbitol laxative effectOral: 25-100 g as a single dose repetitive doses useful to enhance the elimination of certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products)not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, lithium

Elimination of poisonsRenal elimination Medication to stimulate urination or defecation may be given to try to flush the excess drug out of the body faster.Forced alkaline diuresisInfusion of large amount of NS+NAHCO3Used to eliminate acidic drug that mainly excreted by the kidney eg salicylatesSerious fluid and electrolytes disturbance may occurNeed expert monitoringHemodialysis or haemoperfusion: Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of distributionmay also be used temporarily or as long term if the kidneys are damaged due to the overdose.

Antidotes Does an antidote exist?Does actual or predicted severity of poisoning warrant its use?Do expected benefits of therapy outweigh its associated risk?Are there contraindications?

Specific overdoses

OpiatesAntidote naloxoneMOA: Pure opioid antagonist competes and displaces narcotics at opioid receptor sites I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg every 2-3 minutes as needed Lower doses in opiate dependenceElimination half-life of naloxone is only 60 to 90 minutes Repeated administration/infusion may be necessaryS/E BP changes; arrhythmias; seizures; withdrawal

BenzodiazepinesAntidote flumazenilMOA: Benzodiazepine antagonist IV administration 0.2 mg over 15 sec to max 3mgS/E N&V; arrhythmias; convulsionsC/I concomitant TCAD; status epilepticusShould not be used for making the diagnosisBenzodiazepines may be masking/protecting against other drug effects

Tricyclic antidepressantsPHARMACOLOGY TCAs have several important cellular effects, including inhibition of:

Presynaptic neurotransmitter reuptake Cardiac fast sodium channels Central and peripheral muscarinic acetylcholine receptors Peripheral alpha-1 adrenergic receptors Histamine (H1) receptors CNS GABA-A receptors

TCAD overdoseclinical featuresArrhythmias - widening of PR, QRS, and QT intervals; heart block; VF/VTHypotensionAnticholinergic toxicity - hyperthermia, flushing, dilated pupils, intestinal ileus, urinary retention, sinus tachycardiaConfusion, delirium, hallucinationsSeizures

DiagnosisHistoryBlood/urine toxicology screenLevels not clinically useful

TCAD overdose -TreatmentABC many require intubationConsider gastric lavage if taken < 2hrsActivated charcoalTreatment of hypotension with isotonic salineSodium bicarbonate for cardiovascular toxicityAlpha adrenergic vasopressors (norepinephrine) for hypotension refractory to aggressive fluid resuscitation and bicarbonate infusion Benzodiazepines for seizures

Sodium Bicarbonate in TCA overdose Hypertonic sodium bicarbonate (NaHCO3) - QRS widening >100 msec; ventricular arrhythmias, and/or refractory hypotension serum pH promotes protein binding and free drug concentrations; narrows the QRS complex, systolic blood pressure, and controls ventricular arrhythmias1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent NaHCO3) rapid IV push large bore IV then infusion if workingreasonable goal pH is 7.50 to 7.55 then taper doseS/E Volume overload, hypernatreamia, and metabolic alkalosis

Special Cautions in TCAD overdose

Class IA and IC antiarrhythmic agents are contraindicated eg quinidine;disopyramide, flecainide; propafenoneClass IB Lignocaine, phenytoin usedPhenytoin may precipitate arrhythmiasMagnesium may be usefulFlumazenil must not be given

Salicylate overdoseAspirin (acetylsalicylic acid)Methyl salicylate (Oil of Wintergreen)5 ml = 7g salicylic acidHerbal remediesFatal intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children

Salicylate levelsPlasma salicylate concentrationRapidly absorbed; peak blood levels usually occur within one hour but delayed in overdose 6-35 hrs Measure @ 4 hrs post ingestion & every 2 hrs until they are clearly fallingMost patients show signs of intoxication when the plasma level exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L)

Salicylate overdoseInhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanesStimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomitingDirect toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopeniaActivation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosisUncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosis

Clinical featuresEarly symptoms of aspirin toxicity include tinnitus, fever, vertigo, nausea, hyperventilation, vomiting, diarrhoea

More severe intoxication can cause altered mental status, coma, non-cardiac pulmonary oedema and death

Metabolic abnormalitiesStimulate the respiratory center directly, early fall in the PCO2 and respiratory alkalosis

An anion-gap metabolic acidosis then follows, due to the accumulation of organic acids, including lactic acid and ketoacids

Mixed respiratory alkalosis and metabolic acidosis with anion gap

Arterial Ph variable depending on severity

Metabolic abnormalitiesMetabolic acidosis increases the plasma concentration of protonated salicylate

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

Salicylate overdose - treatmentdirected toward increasing systemic pH by the administration of sodium bicarbonate

IV fluids +/- vasopressors

Avoid intubation if at all possible ( acidosis)

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

Alkalinization of plasma and urine Alkalemia from a respiratory alkalosis is not a contraindication to sodium bicarbonate therapy

A urine pH of 7.5 to 8.0 is desirable

Blood gas analysis every two hours

Avoid severe alkalemia (arterial pH >7.60)

Haemodialysis - indicationsAltered mental status

Pulmonary or cerebral edema

Renal insufficiency that interferes with salicylate excretion

Fluid overload that prevents the administration of sodium bicarbonate

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

Clinical deterioration despite aggressive and appropriate supportive care

ParacetamolWidely availablePotential toxicity underestimatedToxicity unlikely to result from a single dose of less than 150 mg/kg in child or 7.5 to 10 g for adult Toxicity is likely with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity unless appropriately treated

Factors influencing toxicity Dose ingestedExcessive cytochrome P450 activity due to induction by chronic alcohol or other drug use eg carbamazepine, phenytoin, isoniazid, rifampin Decreased capacity for glucuronidation or sulfationDepletion of glutathione stores due to malnutrition or chronic alcohol ingestion Acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for CYP2E1

Clinical featuresStage I (0.5 to 24 hours) No symptoms; N&V MalaiseStage II (24 to 72 hours) Subclinical elevations of hepatic aminotransferases (AST, ALT) right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident Stage III (72 to 96 hours) Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, deathStage IV (4 days to 2 weeks) Recovery phase that usually begins by day 4 and is complete by 7 days after overdose

Paracetamol overdoseThe risk of toxicity is best predicted by relating the time of ingestion to the serum paracetamol concentration The dose history should not be used as studies have found no correlationPeak serum concentrations reached within 4 hrs following overdose of immediate-release preparationsMay be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingestedCheck level at >= 4 hrs

Paracetamol overdose treatmentActivated charcoal within four hours of ingestion May reduce absorption by 50 to 90 percent Single oral dose of one gram per kilogram Inhibits absorption of oral methionine

N-acetylcysteine Antidote MOA: a glutathione precursor Limits the formation and accumulation of NAPQI Powerful anti-inflammatory and antioxidant effects IV infusion or oral tablets (also oral methionine)150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg over next 16 hrs up to 36hrsBeyond 8 hours, NAC efficacy progressively decreases S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse

Paracetamol overdose treatmentAt the end of NAC infusion, a blood sample should be taken for determination of the INR, plasma creatinine and ALT. If any is abnormal or the patient is symptomatic, further monitoring is required and advice sought from the NPIS

Patients with normal INR, plasma creatinine and ALT and who are asymptomatic may be discharged from medical care. They should be advised to return to hospital if vomiting or abdominal pain develop or recur

Indications for liver transplantation

Liver transplantation is life-saving for fulminant hepatic necrosis The indications for liver transplantation are: 1 - Acidosis (pH < 7.3), or 2 - PT > 100 sec 3 - Creatinine > 300 mcg/l 4 - Grade 3 encephalopathy (or worse)It is better to contact the local liver transplant centre earlier than this. Grossly abnormal prothrombin times should trigger referral:PT > 20 sec at 24 hr PT > 40 sec at 48 hr

Alcohol poisoning

Clinical features of acute alcohol poisoning include:Ataxia and anaesthesia leading to accidental injury Dysarthria and nystagmus Drowsiness which may progress to coma Inhalation of vomit which can be fatal & should be prevented Hypoglycaemia in children and some adults Check BM stix and give 50% glucose i.v. if required

Coma (alcohol induced)

In cases of alcohol induced coma exclude:Coincident head injuryHepatic failure MeningitisWernickes encephalopathy Other associated drug ingestionA blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemiaThe airway and circulation must be maintainedBut glucose- containing fluids may precipitate Wernicke's encephalopathyThiamine should given to allIntravenous naloxone has reversed coma in a proportion of cases