INTRODUCTION TO TOXICOLOGY  PHARMACOLOGY

Henri de la Cruz, MD || 06 December 2020 LT​ ​03​ ​TRANS ​10​ ​V.​01 
INSERT SPACE F

OUTLINE 
I. INTRODUCTION 1
PHARMACOKINETIC APPROACH IN
TOXICOLOGY 9
II. STEP 1: IDENTIFYING A TOXIN 1
A. DISTRIBUTION 9
A. WHICH IS A TOXIN? 1
B. METABOLISM 9
B. PHARMACODYNAMIC
EFFECT OF TOXINS 1 C. ENHANCED ELIMINATION 10
C. PHARMACODYNAMIC CLUES D. SUPPORTIVE CARE 10
2
D. PHARMACODYNAMIC VI. COMMON TOXIDROMES 11
EFFECTS OF TOXINS 2 A. PARACETAMOL OVERDOSE
E. PHARMACODYNAMIC 11
APPROACH TO POISONING 2 B. ISONIAZID POISONING 11
C. ETHANOL TOXICITY 12
III. STEP 2: HISTORY AND PHYSICAL
D. METHAMPHETAMINE
EXAM OF TOXIC EFFECTS 3
TOXICITY 12
A. CHOLINERGIC TOXIDROME 3 Figure 1​. Non-toxic, Toxic, Lethal Doses

💬
E. SODIUM HYPOCHLORITE ● To determine whether a substance will become a toxin, you have to
B. SYMPATHOMIMETIC POISONING 12
TOXIDROME 4 understand its pharmacodynamics, its mechanism of action ​
C. FACTORS AFFECTING TOXIC VII. REVIEW QUESTIONS 13 ● Examples:
EXPOSURES 4 ○ Milk Tea Poisoning (1 couple)
D. DOSE-RESPONSE VIII. REFERENCES 14 ■ Traced to oxalic acid, a cleaning agent, that was mixed
RELATIONSHIP 4 accidentally in the drink
E. CAREFUL ASSESSMENT 5 ■ Oxalic acid: can cause local burns, and acidosis that will lead
to convulsions and shock
IV. STEP 3: MANAGEMENT 6 ○ Lambanog Poisoning (111 deaths)
A. GENERAL APPROACH 6 ■ The fermentation process of lambanog produces methanol
B. DECONTAMINATION 7
■ Methanol: ​has a toxic metabolite ​(formic acid / formate) that
has direct cardiotoxic and neurotoxic effect at basal ganglia
○ Food Poisoning (237 patients)
OBJECTIVES  ■ Traced to ​Staphylococcal enterotoxins that can cause short
onset diarrhea, nausea, vomiting, and cramps
1. Determine criteria for identifying a poison.
2. Apply pharmacokinetic and pharmacodynamic principles in the
approach, management, and prevention of common toxin
exposures.
I. INTRODUCTION 
● Toxicology is the study of the adverse effects of chemical,
physical, or biological agents on living organisms and the
ecosystem, including the prevention and amelioration of such
adverse effects

○ It may be chemical, physical, or biological in form​ ​

■ Chemical: Cyanide → ​may displace oxygen
💬
● A ​toxic agent​ is anything that produces an adverse biological effect

■ Physical: Radiation → ​can alter DNA

■ Biological: Snake venom →​ causes various neurologic effects
II. STEP 1: IDENTIFYING A TOXIN 

A. WHICH IS A TOXIN? 
💬
Figure 2. ​Examples of poisoning
● Any substance can be a poison ​ B. PHARMACODYNAMIC EFFECT OF TOXINS  
● “All substances are poisons; there is none which is not a
● Known pharmacodynamic mechanisms will predict the toxic
poison. The right dose differentiates a poison and a remedy.”
effect
— Paracelcus

💬
● Alcohol​: small drink can alleviate one’s mood but higher levels may
lead to coma and death ​
exposures ​💬
○ Pharmacodynamics is an important tool in approaching toxic

○ For some toxins, the pharmacodynamic mechanism of action of

● Carbon monoxide​: small amount in the environment can be

💬
tolerated but higher doses can displace oxygen from hemoglobin
and cause death ​
immediately predictable​ ​💬
the drug may lead to augmented or extended effects that are

CNS STIMULANTS 
💬
● Sedatives, Pain relievers​: at high doses can lead to toxic exposures
● Amphetamines​ and ​Cocaine
○ Causes the direct release of neurotransmitters such as
dopamine and norepinephrine
● Antidepressants
○ Inhibits the breakdown of neurotransmitters

PHA 3.10  ​TG​ ​Aquino​, Arboleda, Arce, Arce​ño CORE Balisi​, Lopez, Salas Page 1 of ​18
● CNS Stimulation Vital Sign  Toxin 
○ Desired effects​: Abnormality 
■ elation, euphoria, and satisfaction
○ Other peripheral effects​: Hyperthermia Salicylates, Cocaine, Anticholinergics
■ ↑ motor activity, ↑ heart rate, ↑ blood pressure, ↑ body Hypothermia Opiates, Barbiturates, Sedatives
temperature
○ Toxic effects at extremes and higher doses​:
■ seizures, impairments in cognition and functioning, and even
Hypertension
Stimulation of CNS ​ 💬
Cocaine, Amphetamines, Sympathomimetics

an addiction potential
Hypotension Beta blockers and Calcium Channel Blockers
toxic effects ​ 💬
○ The effect of stimulating the CNS will lead to an extension of
Tachycardia Cocaine, Sympathomimetics
CNS DEPRESSANTS 
💬
Bradycardia Clonidine, Organophosphates, Beta Blockers
● May decrease CNS transmission ​ Tachypnea Salicylates
● Benzodiazepines​ and ​Antipsychotics
○ Sedatives and tranquilizers may increase inhibitory pathways ​💬
○ Increases activity of GABA (​inhibitory)​ : slowing brain activity
💬
Salicylate toxicity: may indicate a presence of
metabolic acidosis ​
Note: ​Know whether the toxins are uppers or downers. Know the mechanism of
● CNS Depression action.
○ Desired effects​:
D. PHARMACODYNAMIC EFFECTS OF TOXINS  
■ sedation and drowsiness
○ Depressant effects on other areas of the brain​: ● We should understand the mechanism of how drugs/toxins work ​ 💬
■ Leads to problems with movement and memory, lowered
blood pressure, slowed breathing, and altered function
ESTROGEN MIMICKERS ​   📌
● Altered function: causing confusion, poor concentration, ● Cause changes in hormone signaling or other effects:
headache, light-headedness, and dizziness ○ Estrogen Agonist ​(E.g. Bisphenol-A or BPA)
■ Overexposure to estrogens have been correlated with
augmented toxicities ​ 💬
● The mechanism of the drug may lead to extended effects,
increased ​rates of breast, uterine, and prostate cancer
○ Estrogen Antagonist​ (e.g. phthalates, triclosan)
NICE-TO-KNOW  
ANTIDEPRESSANT CLASSIFICATION 
antagonism of estrogen effects ​ 💬
■ Interrupt enzymes leading to estrogen production, causing

■ Increased risk​: heart disease and stroke

● Tricyclic antidepressants
■ Decreased​: muscle mass, sperm count, sex drive in humans
○ Imipramine, Desipramine, Amitriptyline, Nortriptyline,
Doxepin, Dothiepin
● SSRI
💬
● Exposure to: plastic bottles, beauty or cosmetic products
(phthalate), cleaning agents (triclosan) ​
○ Fluoxetine, Paroxetine, Fluvoxamine, Sertraline, Citalopram, PRODUCE DNA DAMAGE OR EPIGENETIC CHANGES 
Escitalopram ● Minamata, Japan (1950s)
● MAO-A Inhibitors ○ Increased cases of children with cerebral palsy with multiple limb
○ Clorgyline, Moclobemide abnormalities
● Atypical Antidepressants ○ Children exposed ​in utero​ were born with disabilities
○ Trazodone, Bupropion, Mianeserin, Duloxetine ○ Later traced to ​methylmercury poisoning from Union Carbide,
● Newer Antidepressants which poisoned the groundwater
○ Nefazodone, Venlafaxine, Reboxetine

C. PHARMACODYNAMIC CLUES 
damage is due to DNA or epigenetic changes ​ 💬
■ More severe mechanisms or toxic effects can happen when

DAMAGE OR DISRUPT AN ENZYME SYSTEM OR PROTEIN SYNTHESIS 

💬
● Pathways leading to the mechanism of drug action may also provide
clues as to the nature of the toxin, if other clues are unavailable​
● Vital sign abnormalities may be used to determine the nature of the
● Perchlorate​ (​fireworks, fertilizers, and industrial perchlorate​)
○ Can contaminate drinking water supplies
○ Increased​:
toxin ■ liver arginase, serum urea levels, liver and kidney glycogen
HYPERTHERMIA ​(also known as drug fever) levels, cholesterol, triglyceride, phospholipid
● Salicylates, Cocaine, Anticholinergics ○ Decreased​:
○ Induce hyperthermia by acidosis or stimulation ■ serum glucose, free fatty acid levels, activity of lipase and
● Caused by uncoupling oxidative phosphorylation, or as a phospholipase
consequence of intense skeletal muscle hypermetabolic reaction
● This reaction may lead to rapidly extensive rhabdomyolysis,
electrolyte disorders, and renal failure which may be fatal
■ Explained by disruption of enzyme systems ​ 💬
○ Resulted in: ​aplastic anemia​ or s​ evere agranulocytosis

E. PHARMACODYNAMIC APPROACH TO POISONING 

HYPOTHERMIA
● In summary, we have seen that the pharmacodynamic approach to
● Opiates, Barbiturates, Sedatives
● May result from interaction with several neurotransmitters that
regulate hypothalamic temperature setting
active ​💬
poisoning can help can help in determining or defining if a toxin is

● Important questions to ask:

○ Including: norepinephrine, dopamine, 5-hydroxytryptamine
○ What does the drug do to the body?
(serotonin), acetylcholine, prostaglandin E​1​, and other
neuropeptides.
○ How does the drug work?
○ Are effects extensions of the primary effect of the drug? ​ 💬
● Not all poisons are known
● Pharmacodynamic investigations:​ how drugs act on the body ​
○ Additive​: alcohol + sedatives
💬
○ Antagonistic​: CO + oxygen
○ Synergistic​: anesthetics + barbiturates
○ Potentiation​: cigarette smoke + radon
○ Interactions​: previous or concurrent exposures
Table 1. ​Vital sign abnormalities and related toxins
PHA 3.10 Introduction to Toxicology Page 2 of ​18
 MUST-KNOW
 
📌  
LEADING TRENDS IN THE CAUSES OF POISONING (2019) 

IDENTIFYING A TOXIN 
● A ​toxic agent is anything that can produce and adverse
biological effect
● Any substance can be a poison
○ Alcohol: higher levels may lead to coma and death
○ Carbon monoxide: higher doses can displace oxygen from
hemoglobin and cause death
○ Sedatives, Pain relievers: high doses can lead to toxic
exposures
 
PHARMACODYNAMICS 
● Known pharmacodynamic mechanisms will predict the toxic
effect
● CNS Stimulants
○ Amphetamines​ and ​Cocaine
■ Direct release of dopamine and norepinephrine
○ Antidepressants
Figure 3.​ 2019 Leading trends in the causes of poisoning in the Philippines
■ Inhibits the breakdown of neurotransmitters Note:​ No need to memorize, but take note of the important trends

💬
○ The effect of stimulating the CNS will lead to an extension of
toxic effects ​
● CNS Depressants
● Important information in the diagnosis may come from the leading
trends in the causes of poisoning
● In the Pediatric age group
○ ​Benzodiazepines​ and ​Antipsychotics
■ CNS depressants act on the brain by increasing activity of ○ 85%: ​Accidental poisoning
○ Accidental ingestion of toxins placed in plastic bottles: kerosene,
○ May decrease CNS transmission ​ 💬
GABA, a chemical that slows brain activity

● PD Clues: vital sign abnormalities may be used to determine

bleach, silver jewelry cleaner, ethyl/isopropyl alcohol
○ Toxin is mistaken for a normal/ common drinks ​ 💬
● Adults
the nature of the toxin
● Pharmacodynamic effects of toxins ○ Leading cause: ​drug abuse of methamphetamine
○ Second leading cause: ​methanol​.
○ Estrogen Mimickers
■ Example, from fermentation of lambanog
■ Estrogen Agonist (e.g. BPA)
○ Leading cause of ​intentional poisoning​: ​self harm or suicidal
■ Estrogen Antagonist (e.g. phthalates, triclosan)
ingestion of antidepressants
○ Produce DNA damage or epigenetic changes (e.g.
methylmercury poisoning)
○ Damage or disrupt an enzyme system or protein synthesis
acid, silver jewelry cleaner. ​ 💬
■ Aside from antidepressants: sodium hypochlorite, muriatic

(e.g. perchlorate)
● Pharmacodynamic Investigations
underlying problems that led to its ingestion ​ 💬
○ It is important to treat not only the cause of exposure but also the

○ Additive, antagonistic, synergistic, potentiation, interactions

settings ​ 💬
● Leading causes of poisoning may vary in different countries and

○ In 2018 (U.S.), 60% of the exposure are unintentional, 8% of the

CONCEPT CHECKPOINT   exposure is suicidal intent.
1. T or F: The right dose differentiates a poison and a remedy? ■ Over ingestion of : analgesics, topical preparations,
2. What is the toxic metabolite in methanol that caused 111 deaths antihistamines, vitamins, dietary supplements/ herbals/
because of drinking lambanog? homeopathic, GI preparations
3. T or F: Amphetamines and cocaine inhibit the breakdown of ○ In the Philippines, 85% came from accidental exposure related to
neurotransmitters? household items that are mistaken for drinking water.
ANSWERS:
1.T, 2. Formic acid/formate, 3. F, antidepressants inhibit the breakdown of A. CHOLINERGIC TOXIDROME 
neurotransmitters
● Toxidrome ​— A constellation of toxic effects comparing a set of
clinical fingerprints for a group of toxic chemicals ​[2022A]
III. STEP 2: HISTORY AND PHYSICAL EXAM OF TOXIC EFFECTS 
HISTORY TAKING  CLUES​:  CHOLINERGIC  TOXIDROME  IN  ORGANOPHOSPHATE
● Clues from the history can provide valuable information PESTICIDE POISONING 
● ASK: Five W’s and H’s
📌
● Associated with exposure to ​pesticides that are ​organophosphate
○ Who ​took it? in nature ​
○ What ​did they take, any other co-ingestions? ○ An excess of acetylcholine may result from the inhibition of
○ When ​did they take it? acetylcholinesterase
○ Where ​did they take it?
■ packer, stuffer, IV, PO, intranasal, transdermal, rectal?
○ Why ​did they take it ?
○ Rest and digest functions become more evident
○ Predominance of ​parasympathetic stimulation ​
■ “​DUMBBELLS​”
📌
■ suicide, occupational, accidental? ● D​iarrhea, ​U​rination, ​M​iosis, ​B​radycardia, ​B​ronchospasm,
○ How MUCH​ did they take? E​mesis,​ ​L​acrimation, ​L​imp, S
​ ​alivation and sweating
● Important to take note of the following: ■ “​SLUDGE​”
○ Where the exposure took place, time, any similar symptoms, ● S​alivation, ​L​acrimation, ​U​rination, ​D​efecation, ​G​I, upset,

💬
context clues such as unusual smell, evidences in the E​mesis

circumstances of self harm ​ 💬

surrounding environment (bottle of pills, an important note), and ● These toxidromes may point to a common etiology ​
\

💬
○ Family, patient witness, or first responder reports may give
information that may save lives.​

PHA 3.10 Introduction to Toxicology Page 3 of ​18

CLUES​:  CHOLINERGIC  TOXIDROME  WITH  OTHER  AGENTS  DEPENDS  ■ Associated with CNS excitation, sometimes hallucinations
ON THE RECEPTOR IT STIMULATES  and at a higher dose, sedation 💬
● Drugs used in myasthenia gravis, nerve gas (sarin), and
mushrooms may have cholinergic toxidrome,​ but the ​presentation
may vary depending on the receptor primarily stimulated ​
○ Muscarinic​ effects​:
💬 ● Review Of Systems
■ “SLUDGE”​, “Killer ​B​’s”, and Miosis
● S​alivation, ​L​acrimation, ​U​rination, ​D​iaphoresis (sweating),
G​I upset, ​E​mesis
● B​ronchoconstriction, ​B​ronchorrhea
○ Nicotinic​ effects​:
■ Fasciculations, muscle weakness, respiratory paralysis
sweating​ . 💬
■ Pupillary dilation, tachycardia, bronchodilation, hypertension,
○ At large doses, ​Central​ effect predominates:
■ agitation, confusion, lethargy, coma, seizure, death
further exposure that may cause deaths ​ 💬
● Recognizing the syndrome may allow us to grade and prevent
REVERSING THE CHOLINERGIC TOXIDROME 
● Cholinergic toxidrome may be reversed depending on the a ​ bility of
○ Antidote:​ ​Pralidoxime ​(​2-PAM​)​ 📌
so the usual breakdown of acetylcholine may proceed ​ 💬
an antidote to displace the binding of acetylcholinesterase enzyme,
■ 2-pyridine aldoxime methyl chloride (2-PAM) reverses the
phosphorylation of acetylcholinesterase
■ Pralidoxime separates the organophosphate
acetylcholinesterase, acetylcholinesterase can now proceed
to break down acetylcholine. ​[Cholinergic Crisis]
● Another antidote, will no longer reverse acetylcholinesterase
○ Antimuscarinic effects: ​Atropine ​ 📌
effects​ that will counter the cholinergic syndrome ​ 💬
regeneration but will ​directly act by producing sympathomimetic
■ Recall: Atropine competitively binds to the postsynaptic
■ Can also be a source of toxicity ​ 💬
muscarinic receptors preventing Ach action. ​[Cholinergic Crisis]
● Antidotes to reverse the Muscarinic and Nicotinic effects in a
cholinergic crisis ​[Cholinergic Crisis]
○ Muscarinic Effects: Atropine
○ Nicotinic Effects: Pralidoxime.
Figure 4.​ Inhibition of acetyl breakdown by Sarin in both nicotinic and muscarinic
synapses
B. SYMPATHOMIMETIC TOXIDROME 
● Although atropine can be used to reverse acetylcholine toxicity, but
in itself, sympathomimetic effects can become a source of toxicity 💬
📌
​
● Due to​ atropine overdose ​
○ REMEMBER:  ​Hot as a hare, Mad as a hatter, Red as a beet, dry as
a bone
○ Increased temperature​ (​Hot as a hare​)
■ Atropine flush increased in temperature associated with
tachycardia associated with sympathetic stimulation ​💬
○ Confusion​, ​delirium​ (​Mad as a hatter)​
PHA 3.10 Introduction to Toxicology
​
○ Flushed face​ (​Red as a beet​)
○ Decreased secretions​, t​ hirsty​ (​Dry as a bone​)
○ Eyes:​ Blurred vision - Mydriasis
○ CVS: ​Tachycardia - Presents as atropine flush
○ UT:​ Urinary retention
○ GIT:​ Constipation, paralytic ileus
○ Secretions: ​Dryness of mouth, sandy eyes, increased body
temperature
○ CNS:​ Sedation, hallucination, excitation (toxic dose)
C. FACTORS AFFECTING TOXIC EXPOSURES 
● Age,​ ​body size​, ​time of exposure​, c​ omorbid conditions may be key
💬
factors when considering the clinical and toxic effects of the
dose-response mechanism​. ​
● There can be variations in the response on the toxicant depending
on risk factors
be age-related​ ​ 💬
○ Inter-individual variations may be genetic in origin and may also
■ Very young or very old may be susceptible to poisons due to
underdeveloped, deficient or insufficient enzymes
■ Body size and distribution of fat which may bind some toxins
can affect the ability of a substance to stay and produce long
term toxicity
from ■ Comorbid conditions (E.g. T2DM, HPN) can increase the risk
for some adverse effects
■ Other key factors may depend on gender, ​timing, length of
exposure​, the duration of intake of toxin
D. DOSE-RESPONSE RELATIONSHIP 
● This type of evidence helps us determine if a toxic exposure has
occurred or is occurring
● FIGURE 5
○ At the ​NOAEL​ ​(0-1)​ part of the curve
■ This is the period wherein the symptoms do not have any
observable response
■ safe range
○ At the ​LOAEL​ ​(2-3)​ part of the curve
■ This is the point at which you can observe ​S​ymptoms
■ The curve will start to be ​S​igmoidal
● This means that ​S​maller increments of the toxicant will
produce significant exponential effects on the body
○ At the maximal response​ ​(4)
■ it is the point at which most receptors are ​saturated and no
further amount can produce an effect
Figure 5.​ A dose-response curve showing doses where the No Observed
Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level
💬
(LOAEL) occur for a substance. ​In a patient with severe symptoms, they might be
at the top of the curve​.
USING PK TO COMPARE RELATIVE TOXICITY 
● For some substances, a small increase in dose causes a large
increase in response, which is seen in Toxicant A's steep slope.
Refer to Figure 6.
○ Toxin A: more potent
○ Sigmoid curve: lower margin of safety
Page 4 of ​18
● For other substances, a much larger increase in dose is required to 6. Second- or third-degree atrioventricular block
cause the same increase in response, as indicated in Toxicant B's 7. Systolic BP ​< 80 mmHg ​(hypotension)
shallow slope. 8. QRS duration ​≥ 0.12 seconds

MUST-KNOW   📌
APPROACH TO POISONING
1. Identify the Toxin
○ Apply ​pharmacodynamic mechanisms to investigate and
explore the different manifestations that may arise as a result
of a toxic exposure
2. History and Physical Exam
○ Guided by ​pharmacokinetics and pharmacodynamics
○ Clues can guide the approach and tell us about the severity,
mechanisms, and possible complications
○ This will lead us to a better sense of what we need to manage
Figure 6.​ Comparison of the toxicity of two substances. ​LD50, dose that will 3. Management (​discussed in the next part)
cause death in 50% of a group. ED50, the median effective dose that will ○ ABC’s of Toxicology:
produce a quantal effect on 50% of a group or population.
■ Airway, Breathing, Circulation
● Comparison of the two substances: ○ Do not forget the D, E, F, G.
○ Effective dose of toxicant A is achieved at a lower dose than the ■ Drugs, Draw blood, ​Decontamination​, Exposure/examine,
effective dose to produce 50% of effects of toxicant B Full vital signs/monitoring, Give specific
○ Incremental doses of A will achieve maximal response earlier antidotes/treatment
than the effect of toxin B which gradually increases in regular ○ Decontamination:
intervals over time ■ Inhalation - remove from exposure
○ The LD​50​ of toxicant A is much lower than the LD​50​ of toxicant B ■ Eye - flush copiously with water/normal saline
● Relative toxicity of the drug​: ​Therapeutic Index ■ Skin - soap and water
○ Narrow therapeutic index is considered more toxic than a drug ■ GI
with a wider margin of safety (LD​50​ is further from ED​50​) ● Before reaching intestine (activated charcoal)
LD50 ● High index of suspicion of orally ingested toxin (gastric
○ Therapeutic index = ED50
lavage or syrup of ipecac)
USING PK TO DETERMINE A TOXIC EFFECT  ● Decontaminate large intestine (cathartics, whole bowel
irrigation)
● Figure 7 
○ Shows the relationship between effective dose response and
toxic dose response.
○ Shaded area
MUST-KNOW 📌  
HISTORY AND PHYSICAL EXAM OF TOXIC EFFECTS 
■ represents the doses at which the substance produces an ● Clues from the history can provide valuable information
effect ○ Ask the five W’s and H’s
○ Note that the toxic dose response curve remains beyond the ■ Who ​took it?
TD​50 ■ What ​did they take, any other co-ingestions?
○ The slope of a curve shows how dose increases result in ■ When ​did they take it?
responses to the effective or toxic dose. ■ Where ​did they take it?
● packer, stuffer, IV, PO, intranasal, transdermal, rectal?
■ Why ​did they take it ?
● suicide, occupational, accidental?
■ How MUCH​ did they take?
● Important information in the diagnosis may come from the
leading trends in the causes of poisoning
○ Pediatric (85%): ​accidental poisoning
○ Adults
■ Leading cause: ​drug abuse of methamphetamine
■ 2nd leading cause: ​methanol
■ Intentional poisoning: ​self harm or suicidal ingestion of
antidepressants
● It is important to treat not only the cause of exposure but also the
underlying problems that led to its ingestion
Figure 7.​ Relationship between effective dose response and toxic dose response ● Toxidrome ​- a constellation of toxic effects comparing a set of
E. CAREFUL ASSESSMENT 
● Always remember to assess for severity ​ 💬
● Severe exposures → lead to potential life-threatening complications
clinical fingerprints for a group of toxic chemicals
● Cholinergic Toxidrome
○ Clues: Cholinergic toxidrome in organophosphate pesticide
or death poisoning
CRITERIA OF SEVERE EXPOSURES ■ An excess of acetylcholine may result from the inhibition of
acetylcholinesterase
1. PaCO​2​ ​> 45 mmHg ■ Predominance of ​parasympathetic stimulation
○ PaCO​2​ is inversely proportional to pH ● “​DUMBBELLS​”
○ Respiratory alkalosis​: result of hyperventilation ○ D​iarrhea, ​U​rination, ​M​iosis, ​B​radycardia,
○ Respiratory acidosis​: result of PaCO​2 retention in patients not B​ronchospasm, ​Em
​ esis, ​L​acrimation, ​L​imp,
breathing S​alivation and sweating
2. Need for emergency intubation ● “​SLUDGE​”
3. Post-ingestion seizures ○ S​alivation, ​L​acrimation, ​U​rination, ​D​efecation, ​G​I,
4. Unresponsiveness to verbal stimuli upset, ​E​mesis.
5. Non-sinus cardiac rhythm
PHA 3.10 Introduction to Toxicology Page 5 of ​18
 ○ Clues: Cholinergic toxidrome with other agents depends on
the receptor it stimulates
●
treated as such ​ 💬
Toxin exposures are considered medical emergencies and must be

■ Muscarinic​ effects​: A. GENERAL APPROACH 

● “SLUDGE”​, “Killer ​B​’s” and miosis ABC’s OF TOXICOLOGY 
○ S​alivation, ​L​acrimation, ​U​rination, ​D​iaphoresis ● ABC, ​but with toxin exposure it is also important to remember D
​ EFG
(sweating), ​G​I upset, ​E​mesis ● A​irway
○ B​ronchoconstriction, ​B​ronchorrhea ● B​reathing
■ Nicotinic​ effects​: ● C​irculation
● Fasciculations — muscle weakness, respiratory ● D​rugs
paralysis ○ Important for antidote or resuscitation
■ At large doses, ​Central​ effect predominates: ○ Universal antidotes or resuscitation medications if needed
● agitation, confusion, lethargy, coma, seizure, death ● D​raw blood
○ Reversing the cholinergic syndrome
○ To determine the extent of poisoning
■ Antidote: Pralidoxime (2-PAM)
○ Chemistry, coagulation, blood gases, drug levels
● displace the binding of acetylcholinesterase enzyme so
● D​econtamination
the usual breakdown of acetylcholine may proceed
○ Some toxins can continue to cause effects if they are not
● Reverses nicotinic effects
removed
■ Antidote: Atropine
● E​xposure/Examine
● directly act by producing sympathomimetic effects that
will counter the cholinergic syndrome ○ All visible signs and examination of the extent of poisoning
● Reverses muscarinic effects ● F​ull vital signs and Monitoring
● Sympathomimetic Toxidrome ○ Delayed consequences of toxin exposure
● G​ive specific antidotes and treatment
○ Due to​ atropine overdose
■ Increased temperature​ (​Hot as a hare​) COMPRESSIONS, AIRWAY AND BREATHING (ABCs) 
■ Confusion​, ​delirium​ (​Mad as a hatter​) ● Modified version by the American Heart Association (AHA)
■ Flushed face​ (​Red as a beet)​ ○ This version ensures the priority of ​chest compressions in the
■ Decreased secretions​, ​thirsty​ (​Dry as a bone​) absence of pulse or heartbeat
● Factors when considering the clinical and toxic effects of the ■ Push hard and fast on the center of the victim’s chest
dose-response mechanism: ■ Restoring circulation is a priority and chest compressions can
○ Age, body size, time of exposure, comorbid conditions be life-saving
● Dose-Response Relationship ● Secure ​Airway ​by tilting the head back and chin lifted forward →
○ NOAEL examine mouth for any foreign objects
■ Symptoms have no observable response ○ Putting a tongue guard to secure the airway, if necessary.
■ Safe range ● Breathing is done by providing a single breath after 30
○ LOAEL compressions
■ Symptoms are observable ○ Give mouth-to-mouth to rescue breaths
■ Sigmoidal curve ○ Using a face mask or a “ball valve ambu bag”
○ Maximal response ■ This is more commonly known as “Bag Valve Mask” or “Ambu
■ Point at which receptors are ​saturated and no further bag”
amount can produce an effect.
● Using PK to Compare Relative Toxicity
○ Relative toxicity of the drug: ​Therapeutic Index
■ LD​50​ /ED​50
■ Narrow therapeutic index is considered more toxic than a
drug with a wider margin of safety (LD​50 is further from
ED​50​)
● Criteria of Severe Exposures
○ PaCO2 > 45 mmHg
○ Need for emergency intubation
○ Post-ingestion seizures
○ Unresponsiveness to verbal stimuli
○ Non-sinus cardiac rhythm
○ Second- or third-degree atrioventricular block
○ Systolic BP < 80 mmHg
○ QRS duration ≥ 0.12 seconds Figure 8.​ CAB of the CPR

COMMON ANTIDOTES 
CONCEPT CHECKPOINT   ● After securing ABC’s, the next step is to give the ​Dr​ ug / antidote
4. T or F: The leading cause of poisoning in adults is due to ● Many antidotes work as antagonists by competing for the receptor
accidental poisoning. sites blocking the effects of the toxin.
5. T or F: There is parasympathetic predominance in cholinergic
syndrome. Table 2. ​Common Poisons and their Antidotes ​ 📌
6. Example of an antidote for cholinergic syndrome that can Common Poisons Antidotes
displace the binding of acetylcholinesterase enzyme?
ANSWERS: Benzodiazepines Flumazenil
4.F, The leading cause of poisoning in adults is abuse of methamphetamine,
accidental poisoning is common in children. Beta Blockers Theophylline
5. T,
6.. Pralidoxime Carboxyhemoglobin 100% O2
Opioids Naloxone
IV. STEP 3: MANAGEMENT 

PHA 3.10 Introduction to Toxicology Page 6 of ​18

 📌
💬
Table 3.​ Other Mechanisms on How Antidotes Counter Toxins ​ ○ Common byproducts of industrial processes or vehicular
Toxin Antidotes Mechanism ​ exposures
● Removing the patient from this environment may immediately
Organophosphates Pralidoxime Regenerates reverse​ the effects of these pollutants
acetylcholinesterase → restores
acetylcholine in EYE 
organophosphate poisoning ● In ocular toxicities, it is important to move quickly
Cyanide Nitrite, Bind nitrogen → renders ● Remove contact lens
Sodium cyanide ineffective ● Flush copiously with​ water or normal saline​ for 15-30 minutes
Thiosulfate ● Use local anesthetic drops
○ Helps to reduce irritation but you must ​continue irrigation until pH
Arsenic, Mercury, Chelators: Chelators can bind arsenic, is normal or irritation subsides
Gold Dimercaprol mercury, and gold ● Refer the patient for a​ slit lamp and fluorescein exam
Digoxin Digoxin Antibodies target digoxin ○ To determine if there are corneal abrasion, ulceration or other
Antibodies deeper eye problems.
Calcium Channel Calcium Provide needed element SKIN 
Block blocked by calcium channel ● Might not be evident immediately
blockers
● Soap and water​ enhances elimination of local irritants
Heparin Protamine Bind heparin → interfere with ● The alkali nature of soap neutralizes pesticide absorption
anticoagulant abilities
GASTROINTESTINAL 
Warfarin Vitamin K Replaces factors blocked by
● Goal of GI Decontamination: limit the absorption of the toxin into
warfarin
the systemic circulation of the body.
● Methods include using activated charcoal, gastric lavage, syrup of
NICE-TO-KNOW​ ​[2022A trans]  ipecac, use of cathartics and whole bowel irrigation.
NOTE​:​ This was not discussed by the lecturer ● Activated Charcoal
MANAGEMENT PROTOCOLS ​[2022 A]  ○ Given within the first 60 minutes of ingestion
■ Before the drug is absorbed by the small intestine
● Careful history and Physical exam
■ Patient must be either awake or intubated
● Decontamination ○ Activated Charcoal ​limits drug absorption in the GI tract
○ Prevent decontamination in ​absorption phase ■ The adsorbing surface of activated charcoal is 1000x more
● Enhance elimination than ordinary charcoal, limiting the availability of the drug to
● Supportive Care the systemic circulation
● Psychiatric Support ○ Contraindication:
○ Especially, in those involved in suicidal intakes ■ vomiting, aspiration, bezoar formation, bowel obstruction or
● Dose defines the effect ileus with distention
○ Determine the bioavailability of the toxin to predict the effect ○ 1 gram/kg PO or GT
○ Ineffective against ​some substances that cannot be adsorbed​:
PHARMACOKINETIC EFFECTS BASED ON DRUG DISTRIBUTION  
PHAILS
● Blood carries the agent to and from its site of action, storage, ■ P​esticides
depots, organs of transformation and organs of elimination ■ H​ydrocarbons
● Rate of distribution is dependent on: ■ A​lcohols/Caustics
○ Blood flow ■ I​ron
○ Characteristic of the toxicant ■ L​ead/Lithium
■ Affinity for the tissue and partition coefficient ■ S​ustained release/Enteric coated ingestions
● Distribution may change over time ● Pesticides and hydrocarbons are very volatile and may not
be adsorbed → may cause damage if it’s made to stay in
the stomach
B. DECONTAMINATION 

exposure ​ 💬
● It is important to decontaminate, and remove additional source of

○ Some toxins can continue to cause effects if they are not

NICE-TO-KNOW ​ ​[2022 A, Uptodate: ​Gastrointestinal decontamination of the poisoned patient​]
● There are 2 kinds of dosage for activated charcoal:
○ Single-Dose Activated Charcoal (SADC)
removed ■ Recommended as first-treatment
● Goal: ​prevent absorption and distribution of toxin ■ Used for virtually any toxic ingestion to limit drug
○ Protect yourself and others absorption from the GIT
○ Remove ​both​ rescuer and victim from source of exposure ○ Multi-Dose Activated Charcoal (MDAC)
■ This requires the physician to look at various routes of ■ Considered only in patients with suspected or confirmed
exposure life-threatening carbamazepine, dapsone, phenobarbital,

💬
● Decontamination measures aim to reduce the amount of toxin quinine, or theophylline ingestions
absorbed depending on the route of exposure.​ ■ Data gives evidence of enhanced elimination
■ Not routinely indicated with Salicylate poisoning
INHALATION 
● Quickest routes to produce effect ​
● Carbon monoxide / Cyanide
💬 ■ CI: ​Unprotected Airway and Intestinal Obstruction

● Gastric Lavage
○ Can easily displace oxygen causing ​cellular hypoxia within ○ Does not reliably remove pills and pill fragments
minutes​ of inhalation ○ However, if used within 30-60 minutes after ingestion
● Other respiratory pollutants causes local irritation → systemic ■ A nasogastric tube can be used to remove pills or pill
effects fragments
○ 98% of air pollutants contain: Nitrogen Dioxide (NO​2​), Ozone, ○ Useful after caustic liquid ingestion prior to endoscopy
Sulfur Dioxide (SO​2​), Hydrocarbons ■ To remove gastric contents

PHA 3.10 Introduction to Toxicology Page 7 of ​18

 ○ Contraindicated in:
■ Any sign of perforation, nasal injuries, active vomiting, and ■ CO/Cyanide - can easily displace oxygen causing cellular
risk of aspiration hypoxia within minutes of inhalation
■ Loss of protective airway (ex. patient is obtunded, comatosed ■ Other pollutants: Nitrogen Dioxide, Ozone, Sulfur Dioxide,
or convulsing)​[2022A] Hydrocarbons
■ Ingestion of caustic or hydrocarbon ​[2022A] ○ EYE
■ Underlying risk of hemorrhage ​[2022A] ■ Important to move quickly
● Syrup of Ipecac ■ Remove contact lens
○ Emetic agent to induce ​vomiting​ within minutes of ingestion ■ Flush copiously with​ water or normal saline​ for 15-30 min
■ Use local anesthetic drops and continue irrigation until pH
tear, drowsiness, or existing problems in the GIT
○ Nowadays, it is rarely used
💬
○ Contraindicated with risk of​: aspiration, gastritis, Mallory-Weiss
is normal
■ Refer for​ slit lamp and fluorescein exam
● Gastric lavage and emetic agents are only used if there is a high ○ SKIN
index of suspicion of an orally ingested toxin. ■ Might not be evident immediately
● NOTE: ​The route of a toxic exposure is NOT always immediately ■ Soap and water​ enhances elimination of local irritants
known to the physicians ■ The alkali nature of soap neutralizes pesticide absorption
● Cathartics ○ GASTROINTESTINAL
○ May be used when the toxic substance has ​passed beyond the ■ Goal : limit the absorption of the toxin into the systemic
stomach (when the substance is theorized to be in the small circulation of the body.
intestine already) ■ Activated Charcoal
○ Will hasten the passage of ingested substances by ​inducing ● Given within the ​first 60 minutes of ingestion before
diarrhea the drug is absorbed by the small intestine
○ 10% Magnesium citrate 3ml/kg or 70% Sorbitol 1-2 ml/kg may be ● Patient must be awake or intubated
used ● Limits drug absorption in the GI tract → limited
■ Sorbitol - osmotic agent availability to the systemic circulation
○ Side effects​: ● Contraindicated in patients with: vomiting, aspiration,
■ Severe fluid loss, hypernatremia, hyperosmolarity bezoar formation, bowel obstruction or ileus with
○ Contraindication​: distention
■ bowel obstruction, intestinal paralysis or ileus with distention ● Ineffective against:​ PHAILS
● Whole Bowel Irrigation ○ P​esticides
○ Introduce water in an enema ○ H​ydrocarbons
○ Indicated for: ○ A​lcohols/Caustics
■ large ingestions and SR (slow release) or EC (enteric coating) ○ I​ron
tablets, packers (ex. cocaine) ○ L​ead/Lithium
○ Contraindication​:​ bowel obstruction or ileus with distention ○ S​ustained release/Enteric coated ingestions
○ May cause: aspiration, nausea, may decrease effectiveness of ■ Gastric Lavage
charcoal ● Does not reliably remove pills and pill fragments

MUST-KNOW
MANAGEMENT
📌  
● A nasogastric tube may be used to remove pills or pill
fragments if used within 30-60 minutes after ingestion
● Useful after caustic liquid ingestion prior to endoscopy
● General approach: ABC’s of toxicology to remove gastric contents
○ A​irway ● Contraindicated if there are signs of: perforation, nasal
■ Tilt the victims head back and lift the chin to open the injuries, active vomiting, and risk of aspiration
airway ​[AHA modification] ■ Syrup of Ipecac
○ B​reathing ● Emetic agent to induce vomiting within minutes of
■ Give mouth-to-mouth to rescue breaths ​[AHA modification] ingestion
○ C​irculation ● Contraindicated with risk of​: aspiration, gastritis,
■ Compression by pushing hard and fast on the center of the Mallory-Weiss tear, drowsiness, or existing problems in
victim’s chest ​[AHA modification] the GIT
○ D​rugs ● Rarely used
■ Important for antidote or resuscitation ■ Cathartics
○ D​raw blood ● May be used when the toxic substance has passed
■ To determine extent of poisoning beyond the stomach
○ D​econtamination ● Hasten the passage of ingested substances by inducing
■ Some toxins can continue to cause effects if they are not diarrhea
removed ● Use 10% Magnesium citrate 3ml/kg or 70% Sorbitol 1-2
○ E​xposure/examine ml/kg
■ All visible signs and examination of the extent of poisoning ● Side effects​: Severe fluid loss, hypernatremia,
○ F​ull vital signs and Monitoring hyperosmolarity
■ Delayed consequences of toxin exposure ● Contraindication​: bowel obstruction, intestinal paralysis
○ G​ive specific antidotes and treatment or ileus with distention
● Decontamination
○ Some toxins can continue to cause effects if remained ■ Whole Bowel Irrigation
○ Goal: ​prevent absorption and distribution of toxin ● Indicated for​: large ingestions of SR (slow release) or
■ Protect yourself and others EC (enteric coated) tablets, packers (Ex. Cocaine)
■ Remove ​both ​rescuer and victim from source of exposure ● Contraindication​: bowel obstruction or ileus with
● Require physician to look at various routes of exposure distentionObstruction of ileus
○ Aim: ​reduce the amount of toxin absorbed depending on ● May cause​: aspiration, nausea, may decrease
the route of exposure effectiveness of charcoal
○ INHALATION
■ Quickest route of exposure

PHA 3.10 Introduction to Toxicology Page 8 of ​18

 ○ Increase ionization = Increase excretion rate → Decrease
NICE-TO-KNOW ​[2022 A]  toxicity
● Intravenous Entry of Substances ○ Brought about by phase I and II metabolic reaction
○ Considered as the most important route of entry
○ Risk of Injectables → 100% Entry into the systemic circulation
○ Most lethal route of toxic exposure
💬
■ Some cases lead to an inactive metabolite but in other cases
it can lead to bioactivation like in paracetamol ​  
■ Recall: ​Biotransformation Pathways
● Phase I ​→ Make the toxicant more water soluble.
CONCEPT CHECKPOINT   ● Phase II → Links with a soluble endogenous agent
7. What is the quickest route of exposure? (conjugation)
8. What is the emetic substance used for GI Decontamination? ● Bioactivation: Biotransformation can result in the formation of
9. What is the MOA of common antidotes? reactive metabolites
ANSWERS:
7. Inhalation BIOTRANSFORMATION (METABOLISM) 
8. Syrup of Ipecac
Table 4.​ Biotransformation (metabolism)
9. . Most common antidotes act by competitively binding to the receptor sites of the toxin
Without Metabolism With Metabolism
Compound
V. PHARMACOKINETIC APPROACH IN TOXICOLOGY  (Hepatic insufficiency) (Normal)
A. DISTRIBUTION  Ethanol 4 weeks 10mL/hr

for storage and binding.​ 💬

● Limiting absorption will decrease the amount of drug for distribution

● Distribution is also dependent on protein binding

Phenobarbital
DDT pesticide
5 months
Infinity
8hrs
Days to weeks
○ Highly protein bound substances do not go into the tissue → safe ● Metabolism can facilitate the natural excretion of drugs.
○ Free substances accumulate in tissues and exert toxic effects ● In hepatic insufficiency, metabolism is delayed → drug stays in the
STORAGE AND BINDING  body
● Metabolism
These factors may be taken into consideration when determining ○ Can drastically affect the rate of clearance of compounds
relative toxicity of a drug ○ Can occur at any point during the compound’s absorption to
● Storage in Adipose tissue
○ Very lipophilic compounds will be stored in fat
○ Examples: ​DDT pesticides
excretion
○ Adjust dosages if metabolism is impaired to avoid toxicity
○ Altered metabolism is responsible for some toxic effects of drugs
💬
■ used in mass spraying in malaria endemic regions like in paracetamol and isoniazid poisoning
■ Now banned
● Storage in Bone NICE-TO-KNOW ​ ​[2022A Trans]
○ Can occur in exposure to substances analogous to ​Calcium that ● If you have drugs that are eliminated by hepatic metabolism, the
may bind to the bone presence of a co-morbid liver impairment will drastically affect the
○ Examples: ​Fluoride, Lead and Strontium clearance
● Binding to Plasma Proteins ● For chronic alcoholics, your metabolism will be much delayed
○ Can displace endogenous compounds. ○ the effect will be smaller

effects or excretion.​ 💬
○ Can limit the amount of free drug available to cause adverse ● Key organs in biotransformation
○ LIVER (high)
○ Lung, kidney, intestine (medium)
DISTRIBUTION TO TARGET ORGANS 
○ Others (low)
Absorbed toxins may have higher toxicity in organs with high blood

susceptible. ​ 💬
flow. Such as the liver, kidney, lungs, and myocardium, these are very

● Not all organs are affected equally

C. ENHANCED ELIMINATION 
● Urinary manipulation: Increase excretion
○ Forced diuresis​: osmotic diuresis using mannitol
○ Greater susceptibility of the target organ ○ Alkalinization:​ using sodium bicarbonate for weak acids
○ Higher concentration of active compound ■ Example of weak acid is ​aspirin
● Liver ○ Acidification:​ using ascorbic acid for weak bases
○ High blood flow, oxidative reactions ■ Example of weak base is​ amphetamine
● Kidney ● Repeat-dose activated charcoal
○ High blood flow, concentrates chemicals ○ Very large ingestions of toxic substance
● Lung ○ Used in ingestion of sustained release and enteric coated
○ High blood flow, site of exposure preparations
● Neurons ■ Carbamazepine, phenobarbital, phenytoin
○ Oxygen dependent, irreversible damage
○ Susceptible to injury because of its non-dividing nature​
● Myocardium
💬 ●
●
■ Salicylate, theophylline, digitoxin
Hemodialysis, Hemoperfusion
Peritoneal dialysis, Hemofiltration
○ Oxygen dependent ● Plasmapheresis
○ Susceptible due to non-regenerating tissues → irreversible ○ Severe intoxication / toxic exposure with a deteriorating
damage condition despite maximal supportive care
● Bone marrow, intestinal mucosa ○ Filtering blood from the plasma, treating the plasma, and
○ Rapid division returning viable the plasma for patients who are resistant to other
B. METABOLISM  means of elimination
○ Mechanically remove the toxin
A pharmacokinetic factor which can be manipulated to decrease toxic ○ Used when the usual route of ​elimination is impaired
effects ○ A known lethal dose or lethal blood level

💬
● First objective​: Make chemical agents ​more water soluble and ○ Underlying medical conditions that can increase complications
easier to excrete ○ Expensive but life saving ​
○ Decreasing the lipid solubility → Decrease amount at target ● Absorption to excretion

PHA 3.10 Introduction to Toxicology Page 9 of ​18

 NICE-TO-KNOW ​ ​[2022A Trans]
● Mannitol - sugar; causes high osmolarity, attracts water and the
■ Expensive but life saving​
○ Increase Excretion through several routes
💬
toxin, which is then eliminated via diuresis ■ Urinary manipulation
● Two major pathways of excreting drugs: renal and fecal excretion ● Use of diuretics
● Neutralize weak bases and weak acids through
EXCRETION 
📌
acidification and alkalinization respectively
● Most common route: ​renal ​ ■ Exhalation: Improving the environment oxygenation and

💬
● Toxicants are eliminated from the body by several routes increasing ventilation may relieve the patient
● Used to enhance elimination​ ■ Biliary and Fecal Excretion: Given cathartics → increases
● Exhalation​: Improving the environment oxygenation and increasing peristalsis
ventilation may relieve the patient ■ Others : Milk, Sweat, Saliva
○ Used for volatile compounds are exhaled by breathing ● Supportive Care
● Biliary and Fecal Excretion: ​Giving cathartics → will increase ○ Used when drugs have no specific antidotes
peristalsis ○ Can be life saving
○ Compounds can be extracted by the liver and excreted into the ○ Includes
bile. The bile drains into the small intestine and is eliminated in ■ Treating electrolyte abnormalities, correcting any osmolar
the feces. gap
● Others : Milk, Sweat, Saliva ■ assess & manage circulation : hypo/hypertension
■ provide airway / breathing support - manage agitation
D. SUPPORTIVE CARE 

💬
● Used when drugs have ​no specific antidotes
● Can be life saving​ ​
toxicity​ 💬
○ Can be the only way to handle some of the toxins in Ethanol

● Supportive care includes:

CONCEPT CHECKPOINT  
○ Treating electrolyte abnormalities
10. T or F: ​Phase I and Phase II metabolic reactions ​only leads to
○ Correcting any osmolar gap
Bioactivation
○ Assess & manage circulation
11. Plasmapheresis is used for during what scenario?
■ addressing hypo/hypertension
12. Is managing hypertension a part of supportive care?
○ Provide airway or breathing support
○ Manage agitation ANSWERS:

💬
● Can be the only way to handle some of the toxins in Ethanol toxicity

○ Used in ethanol and methamphetamine toxicity​ 📌

10. F it can lead to either bioactivation or an inactive metabolite depending on the case
11.Severe intoxication/toxic exposure, where the patient has either impaired elimination or
underlying medical conditions that can increase complications
12.Yes

MUST-KNOW 📌  
PHARMACOKINETIC APPROACH IN TOXICOLOGY
VI. COMMON TOXIDROMES 
● Distribution A. PARACETAMOL OVERDOSE 
○ Not all organs are affected equally
■ Greater susceptibility of the target organ
■ Higher concentration of active compound
○ Storage in Adipose tissue
■ Very lipophilic compounds will be stored in fat
■ Examples: ​DDT pesticides
○ Storage in Bone
■ Can occur in exposure to substances analogous to
Calcium
■ Examples: ​Fluoride, Lead and Strontium
○ Binding to Plasma Proteins
■ Can displace endogenous compounds.

💬
■ Can limit the amount of free drug available to cause
adverse effects or excretion.​
● Metabolism
○ Make chemical agents more water soluble and easier to
excrete through phase I and II metabolic reaction Figure 9.​ Hepatic paracetamol metabolism.
○ Can lead to either inactive metabolite or bioactivation ● Overview​ (Refer to Figure 9)
○ BIOTRANSFORMATION (METABOLISM)  ○ Overdose of paracetamol (acetaminophen) overwhelms its
■ Drastically affects clearance rates natural breakdown by conjugation into non-toxic glucuronides or
💬
■ Adjust dosages if metabolism is impaired to avoid
toxicity​
● Enhanced Elimination
sulfates
○ This results to activation of alternate breakdown by cytochrome
P450 enzymes
○ Repeat-dose activated charcoal
■ Very large ingestions of toxic substance (NAPQI) ​ 📌
■ Shunted into production of ​N-acetyl-p-benzoquinone imine

■ Sustained release and enteric coated preparations
● Carbamazepine, phenobarbital, phenytoin, salicylate,
theophylline, digitoxin
○ Hemodialysis, Hemoperfusion
○ Peritoneal dialysis, Hemofiltration
○ Plasmapheresis
■ For ​severe intoxication/toxic exposure, ​when ​usual
route of ​elimination is impaired
📌
■ NAPQI as the toxic byproduct/metabolite; hepatotoxic
● Treatment: ​N-Acetyl Cysteine (NAC) ​
○ Toxic dose is equivalent to 20 tablets
○ NAPQI is broken down into cysteine and mercapturic acid
(non-toxic) in the presence of ​glutathione​ supplied by NAC

PHA 3.10 Introduction to Toxicology Page 10 of ​18

 NICE-TO-KNOW​ ​[2022A Trans 💬]
● When you take paracetamol/acetaminophen, it is normally
conjugated and is excreted. Its hepatic metabolism makes the
metabolite inactive and excretable. In cases of overload and
toxicity, all the enzymes for conjugation are consumed thus
metabolism goes to an alternate pathway. Cytochrome p450
becomes overwhelmed which stimulates production of a toxic
metabolite, ​NAPQI​.
○ NAPQI is the toxic metabolite that accumulates that causes
hepatic necrosis.
■ The presence of NAPQI happens because it was ​shunted
to an alternate pathway​. The antidote to this will be ​NAC​.
So by giving this, you provide the source of conjugates to
make it easily metabolize.
● The ​glutathione ​from NAC provides the needed substrate
Figure 10.​ Isoniazid metabolism in the liver ​[PPT]

are non-toxic metabolites.​ 📌

(glutathione) to produce Cysteine and mercapturic acid, which Note: I​ n the liver, INH is metabolized to acetylisoniazid via N-acetyltransferase 2
(NAT2), this is followed by hydrolysis to acetylhydrazine. Acetylhydrazine is
oxidized by CYP2E1 to form hepatotoxic intermediates. The major enzymes
STAGES OF PARACETAMOL TOXICITY  involved in this pathway are indicated in boxes.

● Stage I: ​(0-24 hrs)

○ Nausea and vomiting, but mostly asymptomatic
MUST-KNOW 📌 
● Stage II: ​Latent stage (24-48 hrs) PARACETAMOL OVERDOSE
○ Subclinical increase in liver enzymes and biomarkers: ● Paracetamol overdose leads to an alternative metabolic pathway
■ aspartate aminotransferase (AST) that produces hepatotoxic metabolites called
■ alanine aminotransferase (ALT) N-acetyl-p-benzo-quinone imine (NAPQI).
■ bilirubin ○ Antidote: NAC
● Stage III: ​Hepatic stage (3-4 days) ○ There are 4 stages of Paracetamol overdose.
○ Liver failure, right upper quadrant pain, jaundice, coagulopathy ■ Nausea and Vomiting (0-24 hrs) but mostly asymptomatic
vomiting, hypoglycemia, renal failure, metabolic acidosis stage
■ Latent stage (24-48 hrs)
patient in paracetamol toxicity 💬
○ May lead to liver failure that is why it is important to observe the

● Stage IV: ​Recovery stage (4 days to 2 weeks)

■ Hepatic stage (3-4 days)
■ Recovery stage (4 days to 2 weeks)
ISONIAZID POISONING
○ Resolution of hepatic dysfunction
● Isoniazid poisoning leads to an alternative metabolic pathway
B. ISONIAZID POISONING  that produces hepatotoxic metabolites called hydroxylamine &
● Isoniazid (INH) is a first-line anti-TB drug acetylhydrazine
○ In large doses of INH, pyridoxine is depleted. Decrease of
💬
● Similar to paracetamol, toxicity in INH results from bioactivation of a
hepatotoxic metabolite​.   GABA can precipitate seizures
● Normal breakdown of INH is dependent on pyridoxine (Vitamin B6), ○ Treatment: Pyridoxine
a co-factor of ​gamma-aminobutyric acid (GABA)  
○ Pyridoxine with ​N-acetyltransferase converts INH into CONCEPT CHECKPOINT  
acetylisoniazid and acetylhydrazine which are non-toxic 13. Paracetamol overdose is equivalent to how many doses?
metabolites and can be readily excreted. 14. What hepatotoxic metabolite is produced due to paracetamol
● In INH overdose, an alternative breakdown pathway is shunted to overdose?
CYP2E1 metabolism → production of ​hepatotoxic metabolites 15. T or F: ​The third stage of paracetamol overdose is the recovery
(​hydroxylamine and ​acetyl isoniazid derivatives: acetyl hydrazine, stage
hydroxylamines, acetylonium ions) which decreases inhibitory 16. Which hepatotoxic metabolites are produced from Isoniazid
GABA poisoning?
○ Toxic metabolites consumes pyridoxine → decreased GABA 17. What is the drug for treatment for Isoniazid poisoning?
production → decrease inhibition → seizures → life threatening
■ Recall: GABA is an inhibitory neurotransmitter. So a decrease ANSWERS:
in causes overstimulation that may result to intractable 13. 20 tablets
14. NAPQI

● Treatment: Pyridoxine ​ 📌
seizures ​(presenting sign of INH toxicity) 15. F. It’s the fourth.
16. hydroxylamine and acetyl isoniazid derivatives
17. Pyridoxine
○ By restoring the pathway using pyridoxine, normal breakdown by
hydrolysis in the presence of acetyltransferases will lead to
normal metabolites which are quickly excreted in the kidney. ​💬

PHA 3.10 Introduction to Toxicology Page 11 of ​18

 C. ETHANOL TOXICITY 
See ​Figure 12​ in appendix for clinical spectrum of ethanol intoxication antidepressants ​ 💬
■ If in a state of depression, don’t use this but instead use

Table 5. Standard practices for treating acute methamphetamine intoxication and

withdrawal ​[PPT]
Symptom Acute intoxication Acute withdrawal
Supportive care
Agitation
Benzodiazepines
Supportive care
Anxiety
Benzodiazepines
Sedating antipsychotics,
Insomnia
antidepressants
Psychosis Antipsychotics
Depression Not applicable Antidepressants
Note: ​Supportive management may vary according to the presenting symptoms
E. SODIUM HYPOCHLORITE POISONING 
● Common term:​ Bleach, Clorox
Figure 11.​ Schema of acute ethanol toxicity ● Sodium hypochlorite is very simple but highly ionized molecule ​[PPT]

💬
● The basis of alcohol toxicity is the mechanism of how it stimulates
the CNS​
○ Stimulation is limited when you have normal amounts
● Normally, ethanol is broken down to ​aldehyde by alcohol
dehydrogenase. Aldehyde, through aldehyde dehydrogenase, is
💬
converted to ​acetate​ which further broken down to​ H​2​O and CO​2​ ​
○ In excess, you will have consumption of aldehyde
● Mechanism of injury
dehydrogenases
■ This will lead to the accumulation of:
● Lactic acids
○ A major constituent of many bleaching agents (especially laundry
bleach).
○ It is also used in wastewater treatment as a disinfectant, and as
a sanitizer of food process equipment.
○ It can easily dissolve the mucosa of the esophagus​ 💬
○ Causes vomiting and corrosive injury to the gastrointestinal tract
○ Household bleaches (3 to 6% sodium hypochlorite) usually
cause ​esophageal irritation, but rarely cause strictures or
serious injury such as perforation

💬
● Keto acids ● Signs and symptoms
● And other byproducts of intermediate metabolism coming Degree of poisoning depends on the dose ​
from alternate pathways ○ Breathing difficulties, if fumes of the solution are inhaled
○ Chest pain and gagging sensation; coughing
MANAGEMENT OF ETHANOL TOXICITY ​[PPT]
💬📌
○ Burning and associated pain in the mouth, throat, and food-pipe
● All treatments are supportive​ ​ ​ (even the stomach may be burnt)
○ Preventing aspiration ○ Speaking and swallowing difficulties
○ Allowing rehydration ○ Skin irritation and burns (blister formation)
○ IV fluids and supportive care ○ Eye irritation, burning sensation, redness and pain, if the
■ Vitamin B, D50W compound spills into one’s eye
● Confirm that the airways are protected, ensure breathing and the ○ Irregular heartbeat and decrease in blood pressure
presence of a pulse (hypotension)
● If the individual is sleepy, try gently to wake him/her and place them ○ Stomach pain
in a comfortable sleep position ○ Shock
● In case the individual is vomiting, turn sideways to avoid choking on ○ Coma
their own vomit ● Management of secondary effects
● Unless instructed by a healthcare professional, ​DO NOT induce ○ Rapid decontamination is critical
vomiting in the affected individual ■ Remove clothing; wash patient with tepid water; irrigate eye

💬 💬
● Watch for respiratory depression → need for intubation and with plain NSS
■ Soap alone can neutralize the organophosphate​
ventilation
■ Since it is caustic, so we want to dilute it​
💬
● Chronic drinkers can have ​Wernicke-Korsakoff Syndrome (Vit B
deficiency) and may be hypoglycemic ​
D. METHAMPHETAMINE TOXICITY 
damage​ ​ 💬
■ We don’t induce vomiting because it will cause more harm or

■ Conscious patients able to swallow can be asked to take 4-8

● Known as shabu ​ 💬 glasses of water; ​defer if there are any signs of perforation
■ Secure airway and respiration via endotracheal intubation
● Mechanism: ​Produces euphoria and causes stimulant effects that
promote the release of monoamine neurotransmitters like
dopamine​, ​serotonin​, and ​norepinephrine within central (CNS) and
📌
■ ER: ​Flexible endoscopy to determine perforation; ​no
antidote​!​ ​  
■ Patient may require urgent surgery to correct perforation
peripheral nerve endings

💬
● One of the methamphetamine derivatives is used on a late study
night but causes rapid memory loss. Don’t try this. ​
MUST-KNOW 📌 
● Treatment: supportive care ETHANOL TOXICITY
● Management of ethanol toxicity is primarily ​supportive
NICE-TO-KNOW​ ​[2022A Trans]
💬
○ Confirm that the airways are protected, ensure breathing and
● Management: ​Is always supportive care​ ​ the presence of a pulse
○ Benzodiazepine​ (Valium) may be given ○ If the individual is sleepy, try gently to wake him/her and place
■ Has a mild sedating effect them in a comfortable sleep position
■ Helpful in an overdose of shabu/methamphetamine

PHA 3.10 Introduction to Toxicology Page 12 of ​18

 1. What is the drug of choice for organophosphate poisoning?
○ In case the individual is vomiting, turn sideways to avoid a. Atropine
choking on their own vomit b. Glycopyrronium bromide
○ Unless instructed by a healthcare professional, DO NOT c. Ivermectin
induce vomiting in the affected individual d. Salbutamol
○ Watch for respiratory depression 2. Mechanism of death due to paracetamol toxicity is
METHAMPHETAMINE TOXICITY a. Renal failure
● Methamphetamine toxicity produces euphoria, and promotes the b. Hepatic necrosis
release of monoamine neurotransmitters (dopamine, serotonin, c. Brain edema
norepinephrine).
○ Treatment: Benzodiazepine is the drug of choice ​ 📌
(in early
stages) if the patient is already in a state of depression, use
d. Cardiac toxicity
3. Which of the following is an antidote for Paracetamol
poisoning?
antidepressants a. N-Acetylcysteine
SODIUM HYPOCHLORITE POISONING b. Pralidoxime
● Bleach ​causes vomiting and corrosive injury to the c. Atropine
gastrointestinal tract d. Deferoxamine
● Signs and symptoms mainly include: 4. Fatima experienced seizure, severe metabolic acidosis and
○ Breathing difficulties, if fumes of the solution are inhaled coma after overdosing in Isoniazid. The following can be
○ Chest pain and gagging sensation; coughing used to manage the patient except
○ Burning and associated pain in the mouth, throat, and a. Activated charcoal
food-pipe b. 1g of parenteral Pralidoxime for every 1 g of INH ingested
c. 500 mg IC Paracetamol q6h
📌
● Management include:
○ Rapid decontamination​ d. 10 mg/mL Furosemide
■ Soap to neutralize
■ Dilution with water
Answer Key: 1.A, 2.B, 3.A, 4.C
■ Secure airway and respiration via endotracheal intubation
■ No antidote!
2021 Feedback (different lecturer)
1. For a patient with acute poisoning from an unidentified
CONCEPT CHECKPOINT   poison. Which of the following should be done FIRST?
18. Sodium hypochlorite is usually known as what product and what a. Complete the history and PE
are its adverse health effects? b. Ensure the patency of the airway
19. What drug is used to treat Methamphetamine toxicity? c. Determine blood sugar level
d. Administer the acetylcysteine antidote
2. The effective dose of activated charcoal to estimated toxin
ANSWERS:
18. Bleach/Clorox; causes vomiting and GI tract injury
by weight is:
19.. Benzodiazepine (Valium) a. 1:10
b. 1:100
VII. REVIEW QUESTIONS  c. 10:1
 
d. 100:1
2022 SAMPLEX
3. In which situation will a quantitative laboratory exam be
1. Which of the following provide enhanced excretion by most helpful in terms of therapy?
producing cathartic effect? a. All cases of poisoning
a. Syrup of ipecac b. All cases of acute poisoning and unconscious patient
b. Magnesium citrate c. Post N-acetylcysteine in acetaminophen poisoning
c. Sodium Bicarbonate d. A case of paracetamol poisoning in stage IV
d. Atropine 4. Which of the following is a correct “poison” antidote pair?
2. Which of the following is the treatment for warfarin a. Isoniazid: thiamine
overdose? b. Iron: hydroxocobalamin
a. Vit K c. Tricyclic antidepressant: naloxone
b. Fresh Frozen plasma d. Carbon monoxide: oxygen
c. Protamine sulfate
d. Desmopressin Acetate
3. Isoniazid toxicity results from? Answer Key: 1.B, 2.C, 3.C, 4.D
a. Breakdown through alternate pathways producing hepatotoxic
metabolite, acetylhydrazine
b. Activation of metabolite diacetylhydrazine which inhibits VIII. REFERENCES 
metabolism of isoniazid Henri​ de​ ​la​ ​Cruz. (2020). Introduction to Toxicology. [lecture powerpoint +
c. Alternative metabolic pathway that produces large amounts of annotations].
the metabolite NAPQI 2022A Trans
d. Hyperproduction of GABA leading to central nervous system 2020A Trans.
Adeyinka A, Kondamudi NP. Cholinergic Crisis. [Updated 2020 Sep 11]. In:
depression
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.
4. Which symptom is expected in anticholinergic overdose? Available from: ​https://www.ncbi.nlm.nih.gov/books/NBK482433/
a. Miosis Robert G Hendrickson, MDShana Kusin, MD​. Gastrointestinal decontamination of
b. Bronchodilation the poisoned patient. Available from:
c. Diarrhea https://www.uptodate.com/contents/gastrointestinal-decontamination-of-the-poiso
d. Lacrimation ned-patient?search=activated%20charcoal&source=search_result&selectedTitle
=2~148&usage_type=default&display_rank=1#H18993853

Answer Key: 1.B, 2.A, 3.A, 4.B

2020A&B TRANS REVIEW QUESTIONS

PHA 3.10 Introduction to Toxicology Page 13 of ​18

 IX. SUMMARY 
MUST KNOW CONCEPTS 
IDENTIFYING A TOXIN  ○ S​alivation, ​L​acrimation, ​U​rination, ​D​efecation, ​G​I,
● A ​toxic agent is anything that can produce and adverse biological upset, ​E​mesis
effect ○ Clues: Cholinergic toxidrome with other agents depends on the
● Any substance can be a poison receptor it stimulates
○ Alcohol: higher levels may lead to coma and death ■ Muscarinic​ effects​:
○ Carbon monoxide: higher doses can displace oxygen from ● “SLUDGE”​, “Killer ​B’​ s” and miosis
hemoglobin and cause death ○ S​alivation, ​L​acrimation, ​U​rination, ​D​iaphoresis
○ Sedatives, Pain relievers: high doses can lead to toxic exposures (sweating), ​G​I upset, ​E​mesis
○ B​ronchoconstriction, ​B​ronchorrhea
PHARMACODYNAMICS ■ Nicotinic​ effects​:
● Known pharmacodynamic mechanisms will predict the toxic effect ● Fasciculations — muscle weakness, respiratory paralysis
● CNS Stimulants ■ At large doses, ​Central​ effect predominates:
○ Amphetamines​ and ​Cocaine ● agitation, confusion, lethargy, coma, seizure, death
■ Direct release of dopamine and norepinephrine ○ Reversing the cholinergic syndrome
○ Antidepressants ■ Antidote: Pralidoxime (2-PAM)
■ Inhibits the breakdown of neurotransmitters ● displace the binding of acetylcholinesterase enzyme so the
● CNS Depressants usual breakdown of acetylcholine may proceed
● Reverses nicotinic effects
○ ​Benzodiazepines​ and ​Antipsychotics
■ Antidote: Atropine
■ CNS depressants act on the brain by increasing activity of
● directly act by producing sympathomimetic effects that will
GABA, a chemical that slows brain activity
counter the cholinergic syndrome
● PD Clues: vital sign abnormalities may be used to determine the
● Reverses muscarinic effects
nature of the toxin
● Sympathomimetic Toxidrome
● Pharmacodynamic effects of toxins
○ Due to​ atropine overdose
○ Estrogen Mimickers
■ Increased temperature​ (​Hot as a hare)​
■ Estrogen Agonist (e.g. BPA)
■ Confusion​, ​delirium​ (​Mad as a hatter)​
■ Estrogen Antagonist (e.g. phthalates, triclosan)
■ Flushed face​ (​Red as a beet)​
○ Produce DNA damage or epigenetic changes (e.g.
■ Decreased secretions​, t​ hirsty​ (​Dry as a bone)​
methylmercury poisoning)
● Age,​ b
​ ody size​, ​time of exposure​, c​ omorbid conditions may be key
○ Damage or disrupt an enzyme system or protein synthesis (e.g.
factors when considering the clinical and toxic effects of the
perchlorate)
dose-response mechanism
● Pharmacodynamic Investigations
● Dose-Response Relationship
○ Additive, antagonistic, synergistic, potentiation, interactions
○ NOAEL
■ Symptoms have no observable response
HISTORY AND PHYSICAL EXAM OF TOXIC EFFECTS 
■ Safe range
● Clues from the history can provide valuable information
○ LOAEL
○ Ask the five W’s and H’s
■ Symptoms are observable
■ Who ​took it?
■ Sigmoidal curve
■ What ​did they take, any other co-ingestions?
○ Maximal response
■ When ​did they take it?
■ Point at which receptors are ​saturated and no further amount
■ Where ​did they take it?
can produce an effect
● packer, stuffer, IV, PO, intranasal, transdermal, rectal?
● Using PK to Compare Relative Toxicity
■ Why ​did they take it ?
○ Relative toxicity of the drug: ​Therapeutic Index
● suicide, occupational, accidental?
■ LD​50​ /ED​50
■ How MUCH​ did they take?
■ Narrow therapeutic index is considered more toxic than a
● Important information in the diagnosis may come from the leading
drug with a wider margin of safety (LD​50​ is further from ED​50​)
trends in the causes of poisoning
● Criteria of Severe Exposures
○ Pediatric (85%): ​accidental poisoning
○ PaCO2 > 45 mmHg
○ Adults
○ Need for emergency intubation
■ Leading cause: ​drug abuse of methamphetamine
○ Post-ingestion seizures
■ 2nd leading cause: ​methanol​ from lambanog
○ Unresponsiveness to verbal stimuli
■ Intentional poisoning: ​self harm or suicidal ingestion of
○ Non-sinus cardiac rhythm
antidepressants
○ Second- or third-degree atrioventricular block
● It is important to treat not only the cause of exposure but also the
○ Systolic BP < 80 mmHg
underlying problems that led to its ingestion
QRS duration ≥ 0.12 seconds
● Toxidrome ​- a constellation of toxic effects comparing a set of
clinical fingerprints for a group of toxic chemicals MANAGEMENT
● Cholinergic Toxidrome ● General approach: ABC’s of toxicology
○ Clues: Cholinergic toxidrome in organophosphate pesticide ○ A​irway
poisoning ■ Tilt the victims head back and lift the chin to open the airway
■ An excess of acetylcholine may result from the inhibition of
[AHA modification]
acetylcholinesterase ○ B​reathing
■ Predominance of ​parasympathetic stimulation ■ Give mouth-to-mouth to rescue breaths ​[AHA modification]
● “​DUMBBELLS​” ○ C​irculation
○ D​iarrhea, ​U​rination, ​M​iosis, ​B​radycardia, ■ Compression by pushing hard and fast on the center of the
B​ronchospasm, ​E​mesis, ​L​acrimation, ​L​imp, ​S​alivation victim’s chest ​[AHA modification]
and sweating ○ D​rugs
● “​SLUDGE​” ■ Important for antidote or resuscitation
○ D​raw blood
PHA 3.10 Introduction to Toxicology Page 14 of ​18
 ■ To determine extent of poisoning ● May be used when the toxic substance has passed
○ D​econtamination beyond the stomach
■ Some toxins can continue to cause effects if they are not ● Hasten the passage of ingested substances by inducing
removed diarrhea
○ E​xposure/examine ● 10% Magnesium citrate 3ml/kg or 70% Sorbitol 1-2 ml/kg
■ All visible signs and examination of the extent of poisoning may be used
○ F​ull vital signs and Monitoring ● Side effects​: Severe fluid loss, hypernatremia,
■ Delayed consequences of toxin exposure hyperosmolarity
○ G​ive specific antidotes and treatment ● Contraindication​: bowel obstruction, intestinal paralysis or
● Decontamination ileus with distention
○ Some toxins can continue to cause effects if they are not ■ Whole Bowel Irrigation
removed ● Indicated for​: large ingestions of SR (slow release) or EC
○ Goal: ​prevent absorption and distribution of toxin (enteric coating) tablets, packers (Ex. Cocaine)
■ Protect yourself and others ● Contraindication​: bowel obstruction or ileus with
■ Remove ​both ​rescuer and victim from source of exposure distentionObstruction of ileus
● Require physician to look at various routes of exposure ● May cause​: aspiration, nausea, may decrease
○ Aim: ​reduce the amount of toxin absorbed depending on the effectiveness of charcoal
route of exposure
○ INHALATION PHARMACOKINETICS
■ Quickest route of exposure ● Distribution
■ CO/Cyanide - can easily displace oxygen causing cellular ○ Not all organs are affected equally
hypoxia within minutes of inhalation ■ Greater susceptibility of the target organ
■ Other pollutants: Nitrogen Dioxide, Ozone, Sulfur Dioxide, ■ Higher concentration of active compound
Hydrocarbons ○ Storage in Adipose tissue
○ EYE ■ Very lipophilic compounds will be stored in fat
■ Important to move quickly ■ Examples: ​DDT pesticides
■ Remove contact lens ○ Storage in Bone
■ Flush copiously with​ water or normal saline​ for 15-30 min ■ Can occur in exposure to substances analogous to ​Calcium
■ Examples: ​Fluoride, Lead and Strontium
■ Use local anesthetic drops and continue irrigation until pH is
○ Binding to Plasma Proteins
normal
■ Can displace endogenous compounds.
■ Use of slit lamp and fluorescein exam - to determine if
■ Can limit the amount of free drug available to cause adverse
there are corneal abrasion, ulceration or ​other eye problems. effects or excretion.
○ SKIN ● Metabolism
■ Might not be evident immediately ○ Make chemical agents more water soluble and easier to excrete
■ Soap and water​ enhances elimination of local irritants through phase I and II metabolic reaction
■ The alkali nature of soap neutralizes pesticide absorption ○ Can lead to either inactive metabolite or bioactivation
○ GASTROINTESTINAL ○ Biotransformation (Metabolism)
■ Goal is to limit the absorption of the toxin into the systemic ■ Drastically affects clearance rates
circulation of the body. ■ Adjust dosages if metabolism is impaired to avoid toxicity
■ Activated Charcoal ● Enhanced Elimination
● Given within the ​first 60 minutes of ingestion before the ○ Repeat-dose activated charcoal
drug is absorbed by the small intestine ■ Very large ingestions of toxic substance
● Patient must be awake or intubated ■ Sustained release and enteric coated preparations
● Limits drug absorption in the GI tract → limited availability ● Carbamazepine, phenobarbital, phenytoin
to the systemic circulation ● Salicylate, theophylline, digitoxin
● Contraindicated in patients with: vomiting, aspiration, ○ Hemodialysis, Hemoperfusion
bezoar formation, bowel obstruction or ileus with distention ○ Peritoneal dialysis, Hemofiltration
● Ineffective against:​ PHAILS ○ Plasmapheresis
○ P​esticides ■ For ​severe intoxication/toxic exposure, ​when ​usual route of
○ H​ydrocarbons
○ A​lcohols/Caustics
○ I​ron
elimination is impaired
💬
■ Expensive but life saving​
○ Increase Excretion through several routes
○ L​ead/Lithium ■ Urine
○ S​ustained release/Enteric coated ingestions ● Use of diuretics
■ Gastric Lavage ● Neutralize weak bases and weak acids through
● Does not reliably remove pills and pill fragments acidification and alkalinization respectively
● A nasogastric tube may be used to remove pills or pill ■ Exhalation: Improving the environment oxygenation and
fragments if used within 30-60 minutes after ingestion increasing ventilation may relieve the patient
● Useful after caustic liquid ingestion prior to endoscopy to ■ Biliary and Fecal Excretion: Given cathartics → increases
remove gastric contents peristalsis
● Contraindicated if there are signs of: perforation, nasal ■ Others : Milk, Sweat, Saliva
injuries, active vomiting, and risk of aspiration ● Supportive Care
■ Syrup of Ipecac ○ Used when drugs have no specific antidotes
● Emetic agent to induce vomiting within minutes of ○ Can be life saving
ingestion ○ Includes
● Contraindicated with risk of​: aspiration, gastritis, ■ Treating electrolyte abnormalities, correcting any osmolar gap
Mallory-Weiss tear, drowsiness, or existing problems in the ■ assess & manage circulation : hypo/hypertension
GIT ■ provide airway / breathing support - manage agitation
● Nowadays, it is rarely used ○ Can be the only way to handle some of the toxins in Ethanol
■ Cathartics toxicity

PHA 3.10 Introduction to Toxicology Page 15 of ​18

 ○ In case the individual is vomiting, turn sideways to avoid choking
on their own vomit
PARACETAMOL OVERDOSE ○ Unless instructed by a healthcare professional, DO NOT induce
● Paracetamol overdose leads to an alternative metabolic pathway vomiting in the affected individual
that produces hepatotoxic metabolites called ○ Watch for respiratory depression
N-acetyl-p-benzo-quinone imine (NAPQI).
○ Antidote: NAC METHAMPHETAMINE TOXICITY
○ There are 4 stages of Paracetamol overdose. ● Methamphetamine toxicity produces euphoria, and promotes the
■ Nausea and Vomiting (0-24 hrs) but mostly asymptomatic release of monoamine neurotransmitters (dopamine, serotonin,
stage norepinephrine).
■ Latent stage (24-48 hrs) ○ Benzodiazepine is the drug of choice (in early stages) if the
■ Hepatic stage (3-4 days) patient is already in a state of depression, use antidepressants
■ Recovery stage (4 days to 2 weeks)
SODIUM HYPOCHLORITE POISONING
ISONIAZID POISONING ● Bleach ​causes vomiting and corrosive injury to the gastrointestinal
● Isoniazid poisoning leads to an alternative metabolic pathway that tract
produces hepatotoxic metabolites called hydroxylamine & ● Signs and symptoms mainly include:
acetylhydrazine ○ Breathing difficulties, if fumes of the solution are inhaled
○ In large doses of INH, pyridoxine is depleted. Decrease of GABA ○ Chest pain and gagging sensation; coughing
can precipitate seizures ○ Burning and associated pain in the mouth, throat, and food-pipe
○ Breakdown of isoniazid is dependent on Pyridoxine (treatment ● Management include:
drug), a cofactor for GABA. ○ Rapid decontamination
■ Soap to neutralize
ETHANOL TOXICITY ■ Dilution with water
● Management of ethanol toxicity is primarily supportive ■ Secure airway and respiration via endotracheal intubation
○ Confirm that the airways are protected, ensure breathing and the ■ No antidote!
presence of a pulse
○ If the individual is sleepy, try gently to wake him/her and place
them in a comfortable sleep position
CONCEPT CHECKPOINT 

IDENTIFYING A TOXIN PHARMACOKINETICS

1. T or F: The right dose differentiates a poison and a remedy? 10. T or F: ​Phase I and Phase II metabolic reactions ​only leads to
○ T Bioactivation
2. What is the toxic metabolite in methanol that caused 111 deaths ○ F it can lead to either bioactivation or an inactive metabolite
because of drinking lambanog? depending on the case
○ Formic acid/formate 11. Plasmapheresis is used for during what scenario?
○ Severe intoxication/toxic exposure, where the patient has either
PHARMACODYNAMICS impaired elimination or an underlying medical conditions that can
3. T or F: Amphetamines and cocaine inhibit the breakdown of increase complications
neurotransmitters? 12. Is managing hypertension a part of supportive care?
○ F, antidepressants inhibit the breakdown of neurotransmitters ○ Yes

HISTORY AND PHYSICAL EXAM OF TOXIC EFFECTS COMMON TOXIDROMES

4. T or F: The leading cause of poisoning in adults is due to accidental 13. Paracetamol overdose is equivalent to how many doses?
poisoning? ○ 20 tablets
○ F, The leading cause of poisoning in adults is abuse of 14. What hepatotoxic metabolite is produced due to paracetamol
methamphetamine overdose?
5. T or F: There is parasympathetic predominance in cholinergic ○ NAPQI
syndrome? 15. T or F: ​The third stage of paracetamol overdose is the recovery
○ T stage
6. Example of an antidote for cholinergic syndrome that can displace ○ F, it’s the fourth
the binding of acetylcholinesterase enzyme? 16. Which hepatotoxic metabolites are produced from Isoniazid
○ Pralidoxime poisoning?
○ hydroxylamine and acetylisoniazid
MANAGEMENT 17. What is the drug for treatment for Isoniazid poisoning?
7. What is the quickest route of exposure? ○ Pyridoxine
○ Inhalation 18.Sodium hypochlorite is usually known as what product and what are
8. What is the emetic substance used for GI Decontamination? its adverse health effects?
○ Syrup of Ipecac ○ Bleach / Clorox; Vomiting and GI injury
9. What is the MOA of common antidotes? 19. What drug is used to treat Methamphetamine toxicity?
○ Most common antidotes act by competitively binding to the ○ Benzodiazepine (Valium)
receptor sites of the toxin.

PHA 3.10 Introduction to Toxicology Page 16 of ​18

 APPENDIX 

Figure 12.​ Clinical spectrum of ethanol toxicity

Table 6. ​Common Poisons and their Antidotes ​ 📌

Common Poisons Antidotes
Benzodiazepines Flumazenil
Beta Blockers Theophylline
Carboxyhemoglobin 100% O2
Opioids Naloxone

Table 7.​ Other Mechanisms on How Antidotes counter toxins ​📌

Toxin Antidotes
Organophosphates Pralidoxime
Cyanide Nitrite, Na Thiosulfate
Arsenic, Mercury, Gold Chelators: Dimercaprol
Digoxin Digoxin Antibodies
Calcium Channel Block Calcium
Heparin Protamine
Warfarin Vitamin K

PHA 3.10 Introduction to Toxicology Page 17 of ​18

Table 8.​ Summary of Common Toxidromes ​📌
Common Toxidromes Mechanism of Action
Paracetamol Overdose Overdose of paracetamol overwhelms
its natural breakdown → activation of
alternate pathway using by P450
enzymes → shunted into production of
N-acetyl-p-benzoquinone imine
(NAPQI)​, ​a​ ​toxic byproduct
Accumulation of NAPQI causes hepatic
necrosis.
Isoniazid Poisoning Abnormally high amounts of isoniazid Intractable seizures, peripheral neuropathy
will activate an alternate metabolic
pathway → shunted to CYP2E1
metabolism → production of hepatotoxic
metabolites (​hydroxylamine and ​acetyl
isoniazid derivatives: acetyl hydrazine,
hydroxylamines, acetylonium ions)
which decreases GABA
These metabolites decrease GABA
which in turn decreases breakdown of
isoniazid since isoniazid breakdown is
dependent on pyridoxine which is a
cofactor of GABA. This leads to further
accumulation of isoniazid and
hepatotoxic metabolites
Toxic metabolites consumes pyridoxine
→ decreased GABA production →
decrease inhibition → seizures
Ethanol Toxicity Excess in ethanol will lead to
deficiencies in aldehyde dehydrogenase
and accumulation of lactic acids, keto
acids, and other byproducts of
intermediate metabolism coming from
alternate pathways will occur.
Methamphetamine Toxicity Produces euphoria and stimulant
effects. It also promotes the release of
monoamine neurotransmitters like
dopamine, serotonin, and
norepinephrine within central (CNS) and
peripheral nerve endings.
Sodium Hypochlorite Highly corrosive. It causes tissue
Poisoning damage via liquefaction necrosis.
Causes vomiting and corrosive injury to Dermal: burning pain, inflammation, blisters
the gastrointestinal tract. Usually
esophageal irritation, but rarely cause Ocular: necrosis and chemosis of the
strictures or serious injury such as cornea
perforation
PHA 3.10 Introduction to Toxicology
Clinical Manifestations Antidotes
Stage 1 (0-24 hrs) - Nausea and vomiting N-Acetyl Cysteine (NAC)
but mostly asymptomatic
Stage 2 (24-48 hrs) - Latent stage.
Subclinical increase in AST/ALT/Bilirubin
Stage 3 (3-4 days) - Hepatic stage. Liver
failure, RUQ pain, vomiting, hypoglycemia,
renal failure, metabolic acidosis.
Stage 4 (4 days - 2 weeks) - Recovery
stage. Resolution of hepatic dysfunction.
Pyridoxine
Mild impairment: mild speech, memory, All treatments are supportive.
attention, coordination, balance
impairment; sleepiness; relaxation IV fluids and supportive care:
vitamin B, D50W
Severe impairment: mild speech, memory,
attention, coordination, balance severely
impaired; driving-related skills dangerously
impaired; judgement and decision-making
severely impaired; blackouts
(amnesia);vomiting; loss of consciousness
Agitation, anxiety, insomnia, psychosis, and Supportive case:
depression Benzodiazepine
Note: If the patient has
depression, use an
antidepressant instead.
GI: pharyngeal pain, esophagogastric injury, No antidote.
dysphagia, vomiting, odynophagia
Management: Rapid
decontamination through water
intake (defer if signs of
perforation); remove clothing
and wash patient with tepid
water; irrigate eye with plain
NSS
Perforation may be determined
through flexible endoscopy.
Urgent surgery to correct
perforation
Page 18 of ​18