Pharmacology of Poisoining
and Drug Overdose
Mary Y. Mancao, M.D., FAAP
Cebu Doctors’ University Hospital
Cebu City, Cebu
EPIDEMIOLOGY: Philippine Perspective
(National Poison Management and Control Center)
TOXICOKINETICS
 Compartmental Toxicokinetics – exposure to a
chemical with rapid equilibration to the central
compartment followed by distribution to the
peripheral compartments
1.
2.
3.
4.
EXOGENOUS COMPOUNDS
ADVERSE EFFECT ASSOCIATED
PASSAGE THRU PHYSIOL OGICAL
ULTIMAT E FATE OF CHEMICALS
Top Ten Agents 2014
(Telephone Referrals)
Pediatrics
Adults
Kerosense
Sodium hypochlorite
Sodium hypochlorite
Methamphetamine
Silica gel
Paracetamol
Paracetamol
Hydrochloric acid
Oral contraceptive pills
Organophosphate
Isopropyl alcohol
Pyrethroid
Pyrethroid
Ferrous sulfate
Jathropa seeds
Silver jewelry cleaner
Ferrous sulfate
Chlorine granules
Paint thinner
Clonazepime
PHARMACEUTICALS
 47% of Exposures and 84% of Serious or Fatal
Poisoning
ABSORPTION: SKIN
1. Defense between dermal exposure and systemic
toxicity
2. Significant route of exposure for lipophilic
substances
3. Percutaneous absorption from skin to dermal
blood vessels
TOXICOKINETICS
• Absorption
• Distribution
• Metabolism
TOXICODYNAMICS
• Median Lethal Dose
• Median Lethal Concentration
• Threshold Level
ABSORPTION: GI TRACT
Degree of Absorption from GI tract depends on:
1. Site, time, pH dependent on the
physicochemical properties of the toxin
2. Oral Cavity/ Sublingual (first pass metabolism)
3. Esophagus
4. Presence of Food in Stomach
5. Enterohepatic circulation prolongs toxin effect
6. Colon
7. Rectum
ABSORPTION: RESPIRATORY TRACT
1. AIRBORNE
 Toxic Gases
• Aerosols
• Volatile
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2.
3.
ALVEOLI
 Large area for gas exchange and blood
perfusion
TERMINAL BRONCHIOLES
 One of the most effective surface for
absorption
 Leads to systemic
TOXICOKINETICS
DISTRIBUTION OF TOXICANT
METABOLISM
Biotransformation/ Metabolism
• is the sum of all chemical processes of the body
that modify endogenous or exogenous
chemicals
DISTRIBUTION: Factors Affecting Distribution
METABOLISM: Factors affecting Metabolism of
Toxicant
 Age
• Very young
• Elderly
• Young Adulthood
 Sex
• Hormonal Variations
 Nutritional Status
• Elderly
TOXICOKINETICS
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ELIMINATION OF THE TOXICANT
 Critical to the reduction of toxicity
 Includes all processes that lead to the decrease
in the amount of the toxicant
OVERDOSAGE
• Describes the ingestion or application of a drug
or other substance in quantities greater than are
recommended or generally practiced
• May result in a toxic state or death
GENERAL MANAGEMENT OF POISONING
Emergency Stablization
History
Physical Exam
Lab Exam
TOXICODYNAMICS
● Utilized to denote the injurious effects of toxins
on vital functions
● Response depends on the quantity of chemical
exposure or administration within a given
period
Graded Dose Response – relationship of an individual to
increasing of continuous doses of chemical
Quantal Dose Response – increasing doses in a
population of test systems
3 CONCEPTS
 Median lethal dose (LD50)
• statistically calculated dose of a chemical that
causes death in 50% of the animals tested
• used to extrapolate the toxic potential of a
compound to humans
• used with all routes of poisoning except
inhalation
 Median lethal concentration (LC50)
• smallest concentration of a given chemical that
will kill 50% of a test group of animals. It is
applicable to chemicals that are inhaled
 Threshold limit values (TLV)
• maximal amount of a chemical that is
considered safe.
Elimination of Poison
EMERGENCY MANAGEMENT OF POISONING – ABDCDE
PRINCIPLE
•
•
A – Airway: Maintain adequate airway
B – Breathing: Provide oxygenation
•
•
C – Circulation: Maintain adequate circulation
D –Disturbances of the CNS: Treat seizures,
coma
E – Electrolytes: Correct electrolyte
abnormalities
•
IMPORTANT PARTS OF HISTORY TAKING
Obtain a good history which should include the following:
• Type of drug and amount ingested
• Time of intake/ingestion
• Intake of other substances
• Intentional intake of toxin or Unintentional
ingestion
• Past medical history and current medications
• Home remedies given
• Patients MUST be observed in a medical facility
even if they are asymptomatic
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IMPORTANT PARTS OF PHYSICAL EXAMINATION*
 GENERAL EXAM
• Skin
• Odor of
 AUSCULTA TE
• Lungs
• Heart
 CHECK
• Complete abdominal exam
*Watch for TOXIDROMES – groups of symptoms that
appear consistently with particular poisons
*(see separate page)
CASE 1: IRON OVERDOSE
History
• 3 year old female was brought to the local
emergency room (ER) due to abdominal pain
and vomiting.
The mother states that the
symptoms began 2 days prior to consult.
• The mother denied any other symptoms.
• On exam:
 Temp=36.5oF HR: 125/min
 RR: 30/min
 BP= 93/55mmHg
• Rest of physical exam was within normal limits
• Patient was then sent home from ER
Six hours later, the patient returned with
lethargy and pallor along with continued
vomiting and abnormal respiration
• Patient was then admitted to the ICU
• Admission lab exams were significant for: serum
bicarbonate: 5 meq/L, Arterial pH of 7.17, pO2
of 300 mm/hg on ventilator
• After 24 hours upon admission to the ICU, the
patient expired
Mechanism of Toxicity:
• Iron is corrosive to GI mucosa, leads to
hematemesis and perforation of the intestine
• Early iron-induced hypotension leads to massive
volume losses
• Iron accumulates in Kupffer cells of the liver and
myocardial cells leading to hepatotoxicity,
coagulopathy, and cardiac dysfunction
Toxic Dose
• Moderate to severe toxicity is seen with
ingestions > 60 mg/kg in children and > 40
mg/kg in adults
•
*see separate page for Elemental Iron Preparations
*see separate page for Acute Iron Intoxication Overview
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Elemental Iron Content
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IRON OVERDOSE
TOXICITY
• 20-30 mg/kg elemental iron – Abdominal pain
• 40 mg/kg elemental iron – Potentially serious
• 60 mg/kg elemental iron – Potentially fatal
6 mg/kg/day  Normal Dose in Children
 BUN=18meq/L
 creatinine 3.2 meq/L
• Patient was admitted to the Pediatric Intensive
Care Unit
Mechanism of Toxicity:
• Hepatic injury
• Renal Damage
• Fetal death and abortion
• Metabolic Acidosis and Altered Mental Status
Toxic dose:
• Acute Toxicity: more than 200mg/kg in children
and 6-7 grams in adults
A suicidal patient took 100 tablets of Ferrous fumarate
(500mg Fe/tab), weight of patient= 55kg. Calculate the
mg/kg of elemental iron ingested.
DEFEROXAMINE TREATMENT: INDICATIONS
• Peak serum Fe concentration ≥ 500mcg/dL
• Significant clinical manifestations (lethargy,
coma, hypovolemia, coagulopathy, metabolic
acidosis)
• (+) abdominal radiograph for tablets or capsules
despite GI decontamination
• Peak serum Fe concentration between 350-500
mcg/dL AND presence of persistent vomiting,
diarrhea, severe abdominal pain
CASE 2: ACETAMINOPHEN OVERDOSE
HISTORY
• 4 day old male infant presented to the local ER
with nonprojectile vomiting, altered level of
consciousness, and poor feeding
• Infant was born at 38 weeks via spontaneous
vaginal delivery and weighed 7 lbs and 2 oz. On
the second day of life the patient underwent
circumcision
• On admission:
 Temp=37.2oF
 HR=100/min
 RR=28/ min
• Significant lab exams include:
 Serum glucose=27 mg/dL (normal 45120 mg/dL)
 sodium=149 meq/L (normal 135148meq/L)
 bicarbonate=18 meq/L
ACETAMINOPHEN OVERDOSE
Pharmacokinetics:
• Elimination half life is 1-3 hours but may be
greater than
• 12 hours in an overdose
• More toxic metabolites may be produced in high
risk
• patients such as alcoholics and those taking
isoniazid (inducers of CYP2E1). Glutathione
production is reduced in fasting and
malnourished patients.
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Diagnosis: Serum acetaminophen levels
Management: N-acetylcysteine (NAC) – restores hepatic
glutathione stores
N- ACETYLCSYSTEINE (NAC)*
Mechanism of Action
1st Stage: Prevention of NAPQI binding (w/in 8 hours)
• Precursor for Glutathione and sulfate
• Glutathione substitute
• Reduction of NAPQI to Acetaminophen
2nd Stage: Modification of NAPQI binding effects
• Antioxidant
• ↓ neutrophil accumulation
• improved microcirculatory changes
• improved tissue oxygen delivery and extraction
*NEEDS TO BE GIVEN WITH 8 – 10 HOURS FROM
INGESTION
INDICATIONS FOR NAC
• serum acetaminophen concentration drawn at
four hours or more following acute ingestion of
an immediate-release preparation is above the
"treatment" line of the treatment normogram
for acetaminophen poisoning
• A suspected single ingestion of greater than 150
mg/kg (7.5 g total dose regardless of weight) in
a patient for whom the serum acetaminophen
concentration will not be available until more
than eight hours from the time of the ingestion.
• Patient with an unknown time of ingestion and a
serum acetaminophen concentration
• >10 mcg/mL (66 μmol/L).
• Patient with a history of acetaminophen
ingestion and evidence of ANY liver injury.
• Patients with delayed presentation (>24 hours
after ingestion) consisting of laboratory
evidence of liver injury (ranging from mildly
elevated aminotransferases to fulminant hepatic
failure) and a history of excessive
acetaminophen ingestion.
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MANAGEMENT
• ABCs of life support
• Maintain vital signs
• NPO, start IVF
• NGT and gastric lavage with activated charcoal
and sodium thiosulfate after lavage.
• Give 20% NAC with premedication of
diphenhydramine to prevent anaphylactoid
reactions
• Serum AST monitoring
• Treat specific problems: acute renal failure,
bleeding tendencies, hepatic insufficiency,
metabolic disturbances
CASE 3: ORGANOPHOSPHATE POISONING
History
• 23 year old male sampaguita worker was
brought to the local ER due to headache,
shortness of breath, nausea, and vomiting of 1
day duration
• He denied any similar illness in the family.
• On admission: Temp=37.5oF HR=60/min
RR=40/min
• Significant physical examination for lethargy and
diaphoretic with bilateral wheezing of both lung
fields
• EKG revealed prolong QTC interval
Mechanism of Toxicity:
• By binding to and inhibiting
acetylcholinesterase, preventing the
degradation of acetycholine and resulting in its
accumulation in nerve synapses.
• If left untreated, organophosphates form
irreversible bond to acetylcholinesterase,
permanently inactivating the enzyme.
• Carbamates form a temporary bond to the
enzyme, allowing reactivation of
acetylcholinesterase within 24 hours
Organophosphates: Malathion, Dursban (Chlorpyrifos
can be found in Raid)
Carbamates: Aldicarb, Methomyl
*see nest page for neurologic effects of
organophosphate and carbamate agents
ORGANOPHOSPHATE POISONING
A. Muscarinic Effects
DUMBBELS
• Diarrhea/
• Defecation
• Urination
• Miosis
• Bronchorrhea
• Bronchospasm
• Bradycardia
• Emesis /excitation of muscles
• Lacrimation
• Salivation
B. Nicotinic Effects
• muscle fasciculations
• cramping
• weakness
• diaphragmatic failure
• hypertension
• tachycardia
• mydriasis
• pallor
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CHOLINERGIC TOXIDROME
*see next page for organophosphate and carbamate
poisoning: Rapid overview
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CASE 4: TRICYCLIC ANTIDPRESSANT
OVERDOSE
History
• A 36-year old female was admitted to the local
ER for generalized tonic clonic movement of 1hour duration.
• The family denies any prior illness or symptoms
• On examination: the patient is lethargic and
confused
• Vital signs: Temp=38.9oF HR=108/min BP=80/60
• First EKG: Sinus tachycardia
• Second EKG: Ventricular tachycardia, Ventricular
Fibrillation
Mechanism of Toxicity
• Achieve their desired antidepressant effects via
blockade or norepinephrine and serotonin
reuptake
• Antagonism at muscarinic ACH receptors leads
to anticholinergic toxidrome
• Antagonism at peripheral alpha receptors lead
to hypotension and syncope
• Toxicity of TCAs due to ability to block sodium
channels leading to impaired cardiac conduction
and arrythmias
Toxic Dose: 10 -20 mg/kg is potentially life threatening
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)
• In overdose, SSRIs are considerably less toxic
than TCA
• Mechanism of toxicity: SSRI selectively block
uptake of serotonin in the central nervous
system. In contrast to TCAs, SSRIs do not directly
interact with receptor types
• Clinical and Lab Manifestations:
 Sertonin syndrome is a triad of altered
mental status, autonomic instability, and
neuromuscular hyperactivity (hyperreflexia,
tremors, clonus in the lower extremities
 ECG shows prolonged QTc prolongation
• Treatment: Supportive care, Cyproheptadine
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CASE 5: ISONIAZID OVERDOSAGE
History
• A 62-year old male was found by relative
wandering the streets of Lahug saying in Bisaya
“Repent-the world is at its end”
• His relatives state he had been well until two
hours prior to admission to the local ER. They
also stated that he had been regularly going to
the health department
• Upon arrival to the ER, he was noted with a 30minute generalized tonic clonic seizure
Mechanism of Toxicity
• INH produces acute toxic effects by reducing
brain pyridoxal 5-phosphate, which is the active
form of vitamin B6 and an essential cofactor for
the enzyme glutamic acid decarboxylase. This
results in lower CNS levels of
gammaaminobutyric acid (GABA), an inhibitory
neurotransmitter, which leads to uninhibited
electric activity manifested as seizures.
• INH may also inhibit the hepatic conversion of
lactate to pyruvate, exacerbating the lactic
acidosis resulting in eizures.
ISONIAZID OVERDOSE: ACUTE TOXICITY
ISONIAZID OVERDOSE
Mechanism of Toxicity
• Peripheral neuropathy, presenting in a stockingglove distribution, is thought to be related to
pyridoxine deficiency. It is the most common
complication of chronic INH therapy.
• The mechanism of INH-induced hepatitis
involves two pathways: an autoimmune
mechanism and, more commonly, direct hepatic
injury by INH and its metabolites. Hepatocellular
necrosis is the most alarming adverse effect of
chronic therapeutic INH.
INH TOXICITY
Toxic Dose
• Acute ingestion of as little as 15–40 mg/kg can
produce toxicity. Doses larger than this often
cause seizures. Ingestion of 80–150 mg/kg is
associated with increased mortality.
• With chronic use, 10–20% of patients will
develop hepatic toxicity when the dose is 10
mg/kg/d, but fewer than 2% will develop this
toxicity if the dose is 3–5 mg/kg/d. Older
persons are more susceptible to chronic toxicity.
Diagnosis: Triad of Metabolic Acidosis, Seizures, and
Coma
Treatment: Supportive, Vitamin B6, Sodium Bicarbonate
in Severe Metabolic Acidosis, Benzodiazepines
LABORATORY
• Plasma INH levels
• Urine test for metabolite
• Other examinations
 CBC, ABG, Random Blood Sugar
 serum electrolytes
 BUN, creatinine
 liver function tests
 Protime, CPK MM
 urine pH
MANAGEMENT
 ABCs of life support
 Maintain vital signs
 NPO, start IVF
 NGT and gastric lavage with activated charcoal
and add sodium thiosulfate after lavage
 Alkalinization therapy with Na bicarbonate at
1mEq/kg IV q6h until urine pH ≥ 7.5 to enhance
excretion
 Vitamin B6 (either as pure or in combination),
avoid
 phenytoin
 Treatment of specific problems: metabolic
acidosis, rhabdomyolysis, pulmonary edema,
renal failure, seizures
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CASE 6: BENZODIAZEPINE OVERDOSAGE




Enhance action of inhibitory neurotransmitter
gammaaminobutyric acid (GABA)
Anxiolytic, muscle relaxant, anticonvulsant and
hypnotic properties
Kinds of benzodiazepines: long-acting,
intermediate acting and short-acting
• Diazepam (long acting)-t1/2= 24-48 h
• Midazolam (short-acting)-t1/2= 2 hours
Rapidly and nearly completely absorbed in the
GI tract
BENZODIAZEPINE OVERDOSE
Toxic Dose
• In general, the toxic-therapeutic ratio for
benzodiazepines is very high. For example, oral
overdoses of diazepam have been reported in
excess of 15–20 times the therapeutic dose
without serious depression of consciousness.
• Respiratory arrest has been reported after
ingestion of 5 mg of triazolam and after rapid IV
injection of diazepam, midazolam, and many
other benzodiazepines.
• Ingestion of another drug with CNS-depressant
properties (eg, ethanol, barbiturates, opioids)
probably will produce additive effects.
• Determination of benzodiazepine levels in the
blood is NOT useful
• Urine benzodiazepine level can be obtained but
interpreted with caution since only the
metabolites of 1,4-benzodiazepine such as
oxazepam can be detected by the urine drug
test. It may not detect lorazepam, alprazolam,
and midazolam.
• Other diagnostic tests
 Random Blood Sugar, BUN, creatinine
 Serum electrolytes
 ABG, 12 lead EKG
 Pregnancy test (pregnancy risk
category D)
•
•
•
Flumazenil – competitive antagonist with weak
agonist properties at the benzodiazepine
receptors
Indications:
 pure benzodiazepine overdose
 CNS depression
 normal Vital Signs, including O2
saturation
 normal ECG
 otherwise normal neurologic exam
Expected response: improvement of level of
consciousness
Specific Precautions
• It may take several days to achieve recovery
• Benzodiazepine abstinence syndrome may
occur around 5 days after discontinuation of
the drug
• Benzodiazepines exert a synergistic effect with
other CNS depressants
• Flumazenil has NO ROLE in unknown poisoning
presenting with coma
• Forced diuresis and hemodialysis are not
effective – Benzodiazepines are highly proteinbound!
Management
• ABCs of life support
• O2 inhalation
• IV fluids
• Insert NGT and do gastric lavage with activated
charcoal
• Give sodium thiosulfate (Adult: 15g in 100ml
water; Pediatric:
• 250mg/kg in water to make a 10% solution)
• If (-) respiratory depression: observe for 24
hours
• If (+) respiratory depression: Give Flumazenil
(adult: 0.1mg/min to total dose of 1mg;
Pediatric: 0.01mg/kg to total dose of 1mg)
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