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Management of overdose and poisoning

Paula Jerrard-Dunne
Pharmacology & Therapeutics 2006

General- evaluation

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

General- management

provision of supportive care prevention of poison absorption enhancement of elimination of poison administration of antidotes

Supportive care

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

History

Pill bottles Alcohol Drug history including access Remember OTC drugs Suicide note National Poisons Information Centre *

Examination

Physiologic excitation
anticholinergic, sympathomimetic, or central hallucinogenic agents, drug withdrawal

Physiologic 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 absorption
Gastric lavage

Not in unconscious patient unless intubated (risk aspiration) Flexible tube is inserted through the nose into the stomach

Stomach contents are then suctioned via the tube


A solution of saline is injected into the tube Recommended for up to 2 hrs in TCA & up to 4hrs in Salicylate OD

Induced Vomiting

Ipecac - Not routinely recommended Risk of aspiration

Preventing absorption
Activated charcoal

Adsorbs toxic substances or irritants, thus inhibiting GI absorption Addition of sorbitol laxative effect Oral: 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 poisons
Renal elimination

Medication to stimulate urination or defecation may be given to try to flush the excess drug out of the body faster. Infusion of large amount of NS+NAHCO3 Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates Serious fluid and electrolytes disturbance may occur Need expert monitoring

Forced alkaline diuresis


Hemodialysis or haemoperfusion:

Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of distribution may also be used temporarily or as long term if the kidneys are damag 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

Opiates

Antidote naloxone MOA: 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 dependence


Elimination half-life of naloxone is only 60 to 90 minutes

Repeated administration/infusion may be necessary


S/E BP changes; arrhythmias; seizures; withdrawal

Benzodiazepines

Antidote flumazenil
MOA: Benzodiazepine antagonist IV administration 0.2 mg over 15 sec to max 3mg

S/E N&V; arrhythmias; convulsions


C/I concomitant TCAD; status epilepticus Should not be used for making the diagnosis

Benzodiazepines may be masking/protecting against other drug effects

Tricyclic antidepressants

PHARMACOLOGY
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 overdose
clinical features

Arrhythmias
- widening of PR, QRS, and QT intervals; heart block; VF/VT

Hypotension Anticholinergic toxicity - hyperthermia, flushing, dilated pupils,


intestinal ileus, urinary retention, sinus tachycardia

Confusion, delirium, hallucinations


Seizures

Diagnosis

History
Blood/urine toxicology screen

Levels not clinically useful

TCAD overdose -Treatment

ABC many require intubation Consider gastric lavage if taken < 2hrs Activated charcoal Treatment of hypotension with isotonic saline Sodium bicarbonate for cardiovascular toxicity Alpha 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 arrhythmias

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 working reasonable goal pH is 7.50 to 7.55 then taper dose S/E Volume overload, hypernatreamia, and metabolic alkalosis

Special Cautions in TCAD overdose

Class IA and IC antiarrhythmic agents are contraindicated eg quinidine;disopyramide,

flecainide; propafenone

Class IB Lignocaine, phenytoin used Phenytoin may precipitate arrhythmias

Magnesium may be useful


Flumazenil must not be given

Salicylate overdose

Aspirin (acetylsalicylic acid) Methyl salicylate (Oil of Wintergreen) 5 ml = 7g salicylic acid Herbal remedies Fatal intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children

Salicylate levels

Plasma salicylate concentration


Rapidly 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 falling Most patients show signs of intoxication when the plasma level exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L)

Salicylate overdose

Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting Direct toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopenia Activation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosis Uncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosis

Clinical features

Early 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 abnormalities

Stimulate 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 abnormalities

Metabolic acidosis increases the plasma concentration of protonated salicylate


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

Salicylate overdose - treatment

directed 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 - indications

Altered 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

Paracetamol

Widely available
Potential toxicity underestimated Toxicity 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 ingested
Excessive cytochrome P450 activity due to induction by chronic alcohol or other drug use eg carbamazepine, phenytoin, isoniazid, rifampin Decreased capacity for glucuronidation or sulfation Depletion 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 features

Stage I (0.5 to 24 hours) No symptoms; N&V Malaise Stage 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%, death

Stage IV (4 days to 2 weeks) Recovery phase that usually begins by day 4 and is complete by 7 days after overdose

Paracetamol overdose

The 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 correlation

Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparations
May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested Check level at >= 4 hrs

Paracetamol overdose treatment

Activated 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 36hrs Beyond 8 hours, NAC efficacy progressively decreases

S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse

Paracetamol overdose treatment

At 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)


1. 2. 3. 4. 5.

In cases of alcohol induced coma exclude: Coincident head injury Hepatic failure Meningitis Wernickes encephalopathy Other associated drug ingestion A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemia The airway and circulation must be maintained But glucose- containing fluids may precipitate Wernicke's encephalopathy Thiamine should given to all Intravenous naloxone has reversed coma in a proportion of cases