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.
Forced alkaline diuresis
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
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 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
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)

In cases of alcohol induced coma exclude:
1. Coincident head injury
2. Hepatic failure
3. Meningitis
4. Wernickes encephalopathy
5. 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