Transcript Toxicology - iSpatula Pharmacy

References
1.
2.
3.
4.
Casarett & Doull’s: Essentials of Toxicology, 2nd Ed.,
2010 by Curtis Klaassen and John Watkins III
Poisoning and Drug Overdose, 6th Ed., 2012 by
Kent R. Olson
Goldfrank's Toxicologic Emergencies, 10th Ed. 2014
by Lewis R. Goldfrank
Emergency Toxicology, 2nd Ed., 1998 by Peter
Viccellio
Toxicology (1203562)
(2 credit hours)
Dr. khawla abu hammour
Department of Biopharmaceutics & Clinical Pharmacy
University of Jordan
E.mail: [email protected]
INTRODUCTION:
TOXICOLOGY IN PERSPECTIVE
DEFINITIONS & TERMINOLOGY
•
Toxicology: (toxicum) & (logia)….the Study of Poisons
•
Poisons: are drugs that have almost exclusively harmful effects
•
•
•
•
However, Paracelsus (1493–1541) famously stated that “THE
DOSE MAKES THE POISON”
Toxins?? biologic origin, ie, synthesized by plants or animals, in
contrast to inorganic poisons (lead and iron)
Toxicology: is the branch of pharmacology that deals with the
undesirable effects of chemicals on living systems
Modern toxicology goes beyond this….study of molecular
biology using toxicants
TOXICOLOGY DISCIPLINES



Environmental toxicology:
•
study the effects of chemicals that are contaminants of
food, water, soil, or the atmosphere
Industrial (occupational) toxicology:
•
Toxic exposure in the work place or during product testing
Clinical (medical) toxicology: focus on the diagnosis,
management and prevention of poisoning or ADEs due to
medications, occupational and environmental toxins, and
biological agents
TOXICOLOGY DISCIPLINES



Veterinary toxicology
Forensic toxicology: is the use of toxicology to aid medical
and legal investigation of death
Nanotoxicology: is the study of the toxicity of nanoparticles
(<100 nm diameter). Because of large surface area to volume
ratio, nanomaterials have unique properties compared with
their larger counterparts
What is a Poison??
“All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy”
Paracelsus (1493-1541)
Water Intoxication?

Water poisoning….fatal disturbance in brain functions
when the normal balance of electrolytes in the body is
pushed outside of safe limits (e.g., hyponatremia) by
overhydration

Intravenous LD50 of distilled water in mouse is 44ml/kg

Intravenous LD50 of isotonic saline in mouse is 68ml/kg
What is a Poison??




Poisoning or exposure??
Many people consider that poisoning start the moment
exposure occurs
In reality, we are exposed to a wide variety of toxic
substances each day from food and water that we
ingest, and air that we breath
We do not display toxic symptoms, we are not actually
poisoned
What is Response?


Change from normal state – could be molecular, cellular, organ,
or organism level……the symptoms
The degree and spectra of responses depend upon the dose and
the organism

Immediate vs. Delayed (carcinogenic)

Reversible vs. Irreversible (liver vs. brain, teratogenic effect)

Local vs. Systemic


Graded vs. Quantal……degrees of the same damage vs. all
or none
Allergic Reactions & Idiosyncratic Reactions….ADRs
Dose

The amount of chemical entering the body

This is usually given as:
mg of chemical

/ kg of body weight = mg/kg
The dose is dependent upon:
 The environmental concentration
 The exposure pathway
 The length of exposure
 The frequency of exposure
 The properties of the toxicant
Exposure: Pathways

Routes and Sites of Exposure:
 Ingestion (GIT), (first pass effect)




Inhalation (Lungs): rapid absorption, because of large alveolar
surface area
Dermal/Topical (Skin), absorption varies with area of
application and drug formulation, but usually absorption is
slower than other routes
Injection


Ex. Lidocaine and Verapamil (antiarrhythmic drugs)
Intravenous, intramuscular, intraperitoneal
Typical response of Routes and Sites of Exposure:
i.v > inhalation > i.p > i.m > oral > topical
Exposure: Duration



Toxicologists usually divide the exposure of experimental
animals to chemicals into 4 categories……:
Acute
< 24hr
Usually 1 exposure
Sub-acute
1 month
Repeated exposure
Sub-chronic
1-3 months
Repeated exposure
Chronic
> 3 months
Repeated exposure
Over time, the amount of chemical in the body can build up, it
can redistribute, or it can overcome repair and removal
mechanisms
Lethal injection by capital punishment…..
The other time-related factor that is important in the temporal
characterization of repeated exposures is the frequency of exposure
The relationship between elimination rate and frequency of exposure
Dose Response Relationship


The magnitude of drug effect depends on the drug
concentration at the receptor site, which is in turn
determined by the dose of drug administered and by
factors of the drug pharmacokinetic profile
There is a graded dose-response relationship in each
individual and a quantal dose-response relationship in a
population
Graded-dose response relationship


The response to a drug is a graded effect, meaning that
the measured effect is continuous over a range of doses
Graded dose response curves are constructed by plotting
the magnitude of the response against increasing doses of
a drug (or log dose)
Dose-Response Relationship

As the dose of a toxicant increases, so does the response
Steep
curve….relative
small dose changes
cause large
response changes
Graded-dose response relationship

Two important properties of drugs can be determined by
the graded dose response curves:
 Potency
 Maximal toxicity
‘U’ Shape of the Dose-Response Curve
Quantal-dose response relationship

The quantal (all or none) dose-effect curve often
characterizes the distribution of responses to different doses
in a population of individual organisms



Median toxic dose(TD50): the dose at which 50% of
individuals/population exhibit a particular toxic effect
If the toxic effect is death of the animal, a median lethal
dose (LD50) may be experimentally defined
Median effective dose (ED50)
LD50


The dose of chemical required to produce death in
50% of the organism exposed to it
LD50 is not an absolute description of the compound
toxicity in all individuals…..Variations
No. of individuals
Quantal-dose response relationship
Hyper
susceptible
Sever Response
Resistant
Majority
Mild Response
Toxicity rating chart
Rating
Oral Lethal Dose
Partially non toxic
>15 g/kg
Slightly toxic
5-15 g/kg
Moderately toxic
0.5-5 g/kg
Very toxic
50-500 mg/kg
Extremely toxic
5-50 mg/kg
Super toxic
<5 mg/kg
of
animals
Assumptions in Deriving the DoseResponse Relationship
1.
2.
3.
4.
Confirms that a chemical is responsible for a
particular effect
Establishes the lowest dose for which an effect occurs
– threshold effect (µg’s….g’s)
Individuals vary in their response to a certain dose of
xenobiotic
The magnitude of the response is related to the
dose………!!!!!
 TI = TD50 / ED50
 For non-drug
chemicals: Margin
of Safety
LD50
Shift to the left….shift to the right!!!
!!!……Molecular Target Concept
Agonist
Antagonist
Toxicodynamics & Kinetics
Toxicokinetics: Disposition (ADME)



Toxicokinetics is the quantitation of the time course of
toxicants in the body during the processes of absorption,
distribution, biotransformation, and excretion or clearance
of toxicants
In other words, toxicokinetics is a reflection of how the body
handles toxicants as indicated by the plasma concentration of
that xenobiotic at various time points
The end result of these toxicokinetic processes is a
biologically toxic concentration of the toxicant/s
Absorption



Ability of a chemical to enter the blood stream (GI tract, skin,
lungs)
Absorption: RATE & EXTENT
The rate is of toxicological importance coz is the main
determinant of the peak plasma concentration

The extent determine the total body exposure or internal dose

The fraction absorbed…..bioavailability(F)

Comparing to i.v (1 or 100%)
Absorption




Route of exposure
Inhalation: readily absorb gases into the blood via the
alveoli (large alveolar surface, high blood flow)
Particle size is the main determinant, ≤ 1μm penetrate the
alveolar sacs of the lungs (nanoparticles!!)
Enteral administration: particle size, surface area, blood
flow rate, pKa, intestinal motility??
Factors influencing Toxicity
Oral is related to:
• Solid forms? Tendency to clump together
• Presence of food: protein and fat delay absorption,
carbohydrate beverages increase absorption
• Chance to readily metabolize…and “hoped”
detoxify!! 1st pass effect
Absorption

Dermal: fortunately not very permeable
Absorption through epidermis by passive diffusion (stratum
corneum thickness, condition of skin, blood flow, small size)
…..then dermis by diffusion….systemic circulation

Parenteral: I.V, I.P, I.M, S.C

Physicochemical properties of the toxicant..


Distribution





The process in which a chemical agent translocates throughout
the body
Blood carries the agent to and from its site of action, storage
depots, organ of transformation, and organs of elimination
Storage in adipose tissue: very lipophilic compounds (DDT) will
store in fat
 Rapid mobilization of the fat (starvation) can rapidly
increase blood concentration
Liver and kidney: high binding capacity for several chemicals
Storage in bone: chemicals analogues to calcium, fluoride,
lead, strontium
Distribution: storage & binding

Rate of distribution dependent upon

Blood flow

Characteristics of toxicant (affinity for the tissue, and the partition
coefficient)

Binding plasma proteins: in equilibrium with the free portion,
displacement by another agent

Distribution may change over time

BBB……tight capillary endothelial cells
ELIMINATION =
EXCRETION + METABOLISM
Elimination

Toxicants are eliminated from the body by several routes

Urinary excretion


Exhalation


Volatile compound are exhaled by breathing
Biliary excretion via fecal excretion


Water soluble products are filtered out of the blood by the
kidney and excreted into the urine
Compounds can be extracted by the liver and excreted into
the bile. The bile drains into the small intestine and is
eliminated in the feces
Milk, Sweat, Saliva
Metabolism (biotransformation)




Toxicity depends on the concentration of active compound at
the target site over time
The process by which the administered chemical (parent
compound) are modified by the organsim by enzymatic
reactions
1st objective – make chemical agents more water soluble and
easier to excrete

Increase solubility ---- decrease amount at target

Increase ionization ---- increase excretion rate ---- decrease toxicity
Bioactivation/toxication ---- biotransformation can result in
the formation of reactive metabolites
Metabolism (biotransformation)
Can drastically affect the rate of clearance of compounds
 Can occur at any point during the compound’s journey from
absorption to excretion
 Key organs in biotrasnformation
 Liver (principal)
 Intestine,
 Lung, kidney
 Biotransformation pathways
o Phase I: make the toxicant more water soluble
o Phase II: links with a soluble endogenous agent

Factors influencing Toxicity

Poisoning do not always follow the “text-book” descriptions
commonly listed for them

S&S that are often stated as being pathognomonic for a particular
toxic episode may or may not be evident with each case of poisoning

An experimentally determined acute oral toxicity expression, such as
LD50 value, is not an absolute description of the compound’s toxicity
in all individuals

Imp. principle to be always kept in mind when evaluating a victim’s
response to a toxic chemical is that there are numerous factors that
may modify the patient’s response to the toxic agent

Those factors are the same as those which determine a drug’s
pharmacologic action
Factors influencing Toxicity
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
COMPOSITION OF THE TOXIC AGENT
DOSE & CONCENTRATION
ROUTE OF EXPOSURE
METABOLISM OF THE TOXICANT
STATE OF HEALTH
AGE & MATURITY
NUTRITIONAL STATE
GENETICS
GENDER
ENVIRONMENTAL FACTORS
Factors influencing Toxicity
1. Composition of the toxic agent:
 A basic fallacy: responsible toxicant is the pure substance
 Physiochemical composition of toxicant: solubility, charge,
hydrophobicity, powder/dust
• Solid vs Liquid
• Poisoning is more with liquid and small particles (particle
size)
Factors influencing Toxicity
1. Composition of the toxic agent:
 E.g: Cr3+ relatively non-toxic, Cr6+ causes skin and nasal
corrosion and lung cancer
 PH: strong acids or bases vs mild acids and basics
 Stability:
paraldehyde…..acetaldehyde
pulmonary edema)
(nausea,
Factors influencing Toxicity
2. Dose and concentration:
 Most important factor: e.g. acute ethanol exposure causes
CNS depression, chronic exposure liver cirrhosis
 Diluted solutions
absorbed)
3. Route of exposure
Vs
concentrated
solution
(easily
Factors influencing Toxicity
4. Metabolism of the toxicant
 1st pass effect
• NOT ALWAYS
Ox.
• MeOH
effects
Formaldehyde + Formic acid …serious side
5. State of health:
• Hepatic, renal insufficiency
• Diarrhea or constipation may decrease or increase the time of
contact between chemical and absorptive site
• Hypertension may exacerbate response to chemical with
sympathomimetic activity
Factors influencing Toxicity
6. Age and maturity
• Chloramphenicol….grey baby syndrome
• Geriatric….generalized decrease in blood supply to
tissue…..decrease in toxicity….(not always)
• P.O drugs….absorption decrease
• Diseases (hepatic, renal, CV)….decrease detoxification, excretion,
distribution
Factors influencing Toxicity
7. Nutritional state
• Empty stomach or food contents (pH, high fat,….)
 Ca2+ in milk and tetracycline
 Fatty food increase absorption of griseofulvin
 Tyramine rich food and MAO inhibitors
 Hypoalbuminemia: greater amount of free drug
Factors influencing Toxicity
9. Gender
• Difference in absorption…..
• Difference in metabolism rate….
• Differences in quantities of muscle mass and fat tissue….in
i.m injection
Factors influencing Toxicity
8. Genetics: (Genetic toxicology….normal Gaussian curve)
• Species, strain variation, inter-individual variations
• Succinylcholine metabolized by pseudocholisterenase into
succinylmonocholine + choline then….
Esterase (liver)
Succinic acid + choline
• G6PD deficiency…..protect RBCs from oxidative damage,
may cause hemolytic anemia
Principle in management of poisoned
patient
What to do, and in what order to do it?!
“The surest poison is
time”
Ralph Waldo Emerson (1803-1882)
Poisoning in Jordan

Period during 2006-2008 at the National Drug and Poison
Information Center (NDPIC) (poisoning emergency no. 109)

The problem is underestimated and sometimes unreported

The most common reason of poisoning was unintentional
(49.39%), followed by suicidal attempts (23.94%)

The highest incidence was in children less or equal to 5 years
(34.9%), then 20-29 years (~23%)
Poisoning in Jordan

The major cause of poisoning was due to drugs (42%) of all
exposures, where acetaminophen products were responsible
for most of the cases within this category (13.4%) then
benzodiazepines, NSAID and then antihistamines

Bites and stings were relatively highly prevalent (23.7% of
exposures), which is justified by the geographical nature of
Jordan

Then household products, hydrocarbons and pesticides
How Does the Poisoned Patient Die?




Many toxins depress the central nervous system
(CNS)…coma
A comatose patients frequently lose their airway protective
reflexes and their respiratory drive
………may die as a result of airway obstruction by the
 flaccid tongue,
 aspiration of gastric contents in the tracheobronchial tree, or
 respiratory arrest
......most commonly due to overdoses of narcotics and
sedative-hypnotic drugs (eg, barbiturates and alcohol)
How Does the Poisoned Patient Die?

Cardiovascular toxicity……Hypotension may be due to depression
of cardiac contractility

Hypovolemia resulting from vomiting, diarrhea

Peripheral vascular collapse due to blockade of -adrenoceptormediated vascular tone

Lethal
cardiac
arrhythmias…….overdose
of
ephedrine,
amphetamines, cocaine, digitalis, and theophylline

Hypothermia or hyperthermia can also produce severe hypotension
How Does the Poisoned Patient Die?

Seizures may cause pulmonary aspiration, hypoxia, brain damage

Cellular hypoxia may occur in spite of adequate ventilation (poisons
that interfere with transport or utilization of oxygen cyanide, HS, CO..)

Other organ system damage may be delayed in onset…..
acetaminophen or certain mushrooms / paraquat

Finally some patients may die because the behavioral effects of the
ingested drug may result in traumatic injury (alcohol/sedative-hypnotic
drugs)

A 62-year-old woman with a history of depression is found in
her apartment in a lethargic state. An empty bottle of
bupropion is on the bedside table. In the emergency
department, she is unresponsive to verbal and painful stimuli.
She has a brief generalized seizure, followed by a respiratory
arrest. The emergency physician performs endotracheal
intubation and administers a drug intravenously, followed by
another substance via a nasogastric tube. The patient is
admitted to the intensive care unit for continued supportive
care and recovers the next morning. What drug might be used
intravenously to prevent further seizures? What substance is
commonly used to adsorb drugs still present in the
gastrointestinal tract?
Principle in management of poisoned
patient

While the majority of poisoned patients are awake and
have stable vital signs, some may present unconscious or in
shock…..so….:
1. Always assess the condition of the patients “ABCD”…clinical
evaluation
2. Decide what must be done and in what order
3. Once the patient is stabilized, and only then, try to identify
the poison, the quantity involved and how much time has
been elapsed since exposure
4. Then, proceed with decontaminating / antidoting the poison
ABCD

A
Airway

B
Breathing

C
Circulation

D
Dextrose
Airway……Ensure airway and protect cervical spine


Airway Assessment:

Consider to breath and speak to assess air entry

Signs of obstruction (flaccid tongue, vomitus….)

Apnea, dysphonia, cyanosis, airway distress
Management Goals:

Optimize the airway position……force the flaccid tongue
forward and maximize the airway opening

Prevent aspiration

Permit adequate oxygenation
Airway……Ensure airway and protect cervical spine

The following techniques are useful:.





Caution: Do not perform neck manipulation if you suspect a neck
injury.
Place the neck and head in the “sniffing” position, with the neck
flexed forward and the head extended….(chin lift to open the
airway)
Apply the “jaw thrust” maneuver to create forward movement of
the tongue without flexing or extending the neck.
https://www.youtube.com/watch?v=r3ckgEQEE_o
Place the patient in a head-down, left-sided position…..allows the
tongue to fall forward and secretions or vomitus to drain out of the
mouth….(lateral decupitus position)
Oral axis
Pharyngeal axis
Tracheal axis
Airway


The airway can also be maintained with artificial
oropharyngeal or nasopharyngeal airway devices
Placed in the mouth or nose to lift the tongue and push it
forward.
Airway



Endotracheal intubation: attempted only by those with training
Complications: vomiting with pulmonary aspiration; local trauma to
the oropharynx, nasopharynx, and larynx; inadvertent intubation of
the esophagus or a main-stem bronchus; and failure to intubate the
patient after respiratory arrest has been induced by a
neuromuscular blocker
Indications:

Unable to protect airway

Inadequate spontaneous ventilation
Arterial blood gases (pCO2 > 60%)

Profound shock

GCS (Glasgow Coma Scale) ≤ 8

Orotracheal or nasotracheal
intubation
Two routes for endotracheal intubation.
A: Nasotracheal intubation. B: Orotracheal intubation.
13-15 mild injury, 9-12 moderate injury, 8 or less severe injury
Breathing



Pulse Oximetry
By observation and oximetry (monitor the saturation of pt’s Hb)
Ventilatory failure…..most common cause of death in poisoned
patients:
Hypoxia……brain damage, cardiac arrhythmias, and cardiac
arrest

Hypercarbia…...acidosis (may contribute to arrhythmias)

LOOK for mental status, chest movement, respiratory rate

LISTEN for air escaping during exhalation, sound of obstruction

FEEL for the flow of air, chest wall for crepitus

ASSESS tracheal position, auscultation of all lung fields
Circulation

Check skin color, temperature, capillary refill

Check blood pressure and pulse rate and rhythm

Management: stop major external bleeding

Begin continuous ECG monitoring
Altered mental status





A decreased level of consciousness is the most common
serious complication of drug overdose or poisoning
Coma sometimes represents a postictal phenomenon after a
drug- or toxin-induced seizure
Coma may also be caused by brain injury associated with
infarction or intracranial bleeding
Coma frequently is accompanied by respiratory depression,
which is a major cause of death
May be complicated by hypotension, hypothermia,
hyperthermia, and rhabdomyolysis
Disability

Assess level of consciousness by AVPU method
 A…..ALERT
 V…..responds to VERBAL stimuli
 P…..responds to PAINFUL stimuli
 U…..UNRESPONSIVE

Size and reactivity of pupils

Movement of upper and lower extremities
The DONT Cocktail


Administer supplemental oxygen
Dextrose: All patients with depressed consciousness should
receive concentrated dextrose unless hypoglycemia is ruled out

Adults: 50% dextrose, 50 mL (25 g) IV.

Children: 25% dextrose, 2 mL/kg IV
Thiamine: is a cofactor in a number of metabolic pathways
allowing aerobic metabolism to produce ATP and,
 Important in normal neuronal conduction

The DONT Cocktail


Given to prevent or treat Wernicke's syndrome resulting from
thiamine deficiency in alcoholic patients (poor diet) and others
with suspected vitamin deficiencies (100 mg, in the IV bottle or
intramuscularly)
Naloxone: All patients with CNS depression and respiratory
depression should receive naloxone!

If artificially ventilated…..not immediately necessary

Caution: may precipitate abrupt opioid withdrawal
The DONT Cocktail

DOSE:

0.4 mg IV (may also be given intramuscularly)

If there is no response within 1–2 minutes, give naloxone, 2
mg IV

If there is still no response and opioid overdose is highly
suspected give naloxone, 10–20 mg IV
Exposure

Remove clothes and other items that interferes with
a full evaluation
1. History




Historical data should include the type of toxin
Route of exposure
intravenous)
(e.g.
ingestion,
inhalation,
Also ask about prior suicide attempts or psychiatric
history
If the patient is a female in reproductive years, ask
about pregnancy and obtain pregnancy test
Identify the toxicant

SAMPLE



S: substance, amount, time, correlate symptom
A: allergies, age, gender, wt
M: medication (including prescription drugs, OTC
medication, vitamins, and herbal preparation)



P: past diseases, substance abuse or intentional
ingestion
L: last meal….influence absorption
E: events leading to current condition
ODORS
Acetone
Garlic
• Isopropyl alcohol
• Ethanol
• Arsenic
• Organophosphates
Bitter almonds
Rotten eggs
• Cyanide
• Sulfide
 Not absolute… the odor may be subtle and may be obscured by
the smell of emesis or by other ambient odors. In addition, the
ability to smell an odor may vary
Blood Pressure
HYPERTENSION

Sympathomimetics

Amphetamines

Cocaine

MAOI

Nicotine
HYPOTENSION

Antipsychotic

Nitrates

Beta blockers

Opioids

Calcium channel blockers

Sedative-hypnotics

Ethanol

Tricyclic antidepressants
(with tachycardia)
Pulse
TACHYCARDIA

Amphetamines

Atropine

Antihistamines

Caffeine

Cyanide

Nitrates
BRADYCARDIA

Beta blockers

Calcium channel blockers

Clonidine

Digitalis

Mushrooms

Organophosphates

Sedative hypnotics
RESPIRATION
HYPERVENTILATION

Rapid respirations are typical of toxins that produce
metabolic acidosis or cellular asphyxia..

Salicylates

Carbon monoxide

Ethylene glycol

Hydrocarbons
HYPOVENTILATION

Anesthetics

Cyanide

Ethanol

Sedative hypnotics

Opioids
TEMPERATURE

HYPERTHERMIA (>40°C):

Sympathomimetics

Amphetamines

MAOI

Anticholinergic

Drugs producing seizures or muscular rigidity
TEMPERATURE

HYPOTHERMIA (<32°C):

CNS depressants (barbiturates, opioids, ethanol)

Hypoglycemic agents

Drugs that cause vasodilation

…..(especially if accompanied by cold environment)

N.B:
commonly
bradycardia
accompanied
by
hypotension
and
EYE FINDINGS
Miosis:

Cholinergic

Clonidine

Insecticides

Narcotics

Phenothiazines
EYE FINDINGS
Mydriasis:



Anticholinergic
Sympathomimetic
Withdrawal states
Nystagmus:


Horizontal……phenytoin, alcohol, barbiturates
Both vertical & horizontal: strongly suggest
phencyclidine poisoning
OTHERS




Absent bowel sounds: paralytic ileus……anticholinergic
intoxication or perforation coz of acid ingestion
Hyperactive bowel sounds, abdominal cramping and
diarrhea….organophosphates, A muscaria
Determine if bladder distention and urinary retention
exist…..anticholinergic intoxication
Skin appearance: red, white, blue, warm, cool, dry, moist,
piloerection (opioid withdrawal)
Decontamination

Gastric exposure
Inhalation exposure


Dermal exposure

Ocular exposure
The decision to perform GI
decontamination is based upon




the specific poison(s) ingested, the time from
ingestion to presentation, presenting symptoms, and
the predicted severity of poisoning. GI
decontamination is most likely to benefit patients
who:
●Present for care soon after ingestion (usually within
one to two hours)
●Have ingested a poison and amount suspected to
cause toxicity
●Do not have clinical factors that make
decontamination dangerous
Inhalation exposure



Irritant gases exposure!! mainly in industry, but also after
mixing cleansing agents at home, or smoke inhalation in
structural fires
Health care providers should protect themselves from
contamination
Eg.: “organophosphate, fumes of H2S, cyanide, ammonia,
formaldehyde”
Inhalation exposure
Treatment:

Immediate removal from hazardous environment

100% humidified O2

Assisted ventilation

Bronchodilators


Observe for noncardiogenic pulmonary edema. Early signs
and symptoms include “dyspnea, tachypnea, hypoxemia”
Monitor arterial blood gases or oximetry, chest x-ray, and
pulmonary function
Dermal exposure





Attendant should wear protective gear “gloves, goggles,
shoe cover”
Remove contaminated clothes, contact lenses and jewelry
and place them in a plastic bag
Gently rinse and wash skin with copious amount of water
for at least 30min….start with lukewarm water
“vasoconstriction”
Use soap to remove oily substances
Caustic contamination may need prolonged irrigation


Some substances may react with water, should be
brushed off e.g. chlorosulfonic acid, Ca oxide, titanium
tetrachloride
For some substances, local application of certain
chemical compound as soaks may be useful
 Hydrofluoric acid…calcium gluconate 2.5%
 Oxalic acid…calcium gluconate
 Phenol…mineral oil or other oil
 White phosphorous…copper sulfate 1%
Ocular exposure




At least 15-20min irrigation with fully retracted
eyelids
Don’t neutralize acid or alkali; continue irrigation until
pH of the tear is neutral
After irrigation examine the eye for corneal damage
Ophthalmogist consultation:

Ophthalmogist may instill topical cycloplegic agent, e.g. 5%
homatropine or 2% scopolamine to prevent spasm of ciliary body

Topical antibiotic (sulfisoxazole or gentamicin)

Apply a sterile patch
Decontamination




Gastric Decontamination
Inhalation exposure
Dermal exposure
Ocular exposure
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
Gastric Decontamination



Controversy about the roles of emesis, gastric lavage, activated
charcoal, and cathartics to decontaminate the gastrointestinal
tract
Little medical support for gut-emptying procedures, especially
after a delay of 60 minutes or more very little of the ingested
dose is removed by emesis or gastric lavage
Moreover, simple oral administration of activated charcoal
without prior gut emptying seems to be as effective as the
traditional sequence of gut emptying followed by charcoal
Gastric Decontamination


However,
in
some
circumstances,
aggressive
gut
decontamination may potentially be life saving, even after
more than 1–2 hours
Examples: ingestion of highly toxic drugs (eg, calcium
antagonists, colchicine), ingestion of massive amounts of a drug
(eg, 150–200 aspirin tablets), and ingestion of sustainedrelease or enteric-coated products
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
DILUTION

Must
acidic
or
alkaline
substances
be
neutralized..??.........NEVER!!!...heat!

55-ml
of
sulfuric
water……temperature
acid,
mixed
solution
of
with
54ml
79ºC;
with
1000ml…still 14ºC

“To dilute or no dilute…this is the question!”
DILUTION


Dilution of the poison:
1.
1-2 cupfuls of water to children
2.
2-3 cupfuls of water to adult
3.
A better rule to give a quantity comfortable swallowed
Water??
1. Reduce gastric irritation
2. Add bulk to the stomach needed later for emesis

Carbohydrated beverages??....NO!!


CO2 distension of the stomach….opening pyloric sphincter
Milk??....NO!!

Increase absorption of lipophilic toxicant…&....delay emetic action of
ipecac
General consideration


Fluids should not be forced
Excessive liquid may distend the stomach…premature
evacuation

In case of solid form do not dilute

Household products….dilution

Nothing administered orally to unconscious patient or if
gag reflux absent
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
EMESIS




Emesis can be induced with ipecac syrup
Chemically induced emesis is no more approved as a 1st
line procedure for antidoting poisons….activated
charcoal
Decrease absorption
dangerous….?
Precautions!!!!
of
drug
but
sometimes
EMESIS


Do not induce vomiting if the poison is a:

Convulsant, or sedative-hypnotic

Hydrocarbon

Corrosive acid or alkali
Do not induce vomiting if the patient:

Unconscious or comatose

Absence of gag reflex

Have severe CVD extremely weakened blood vessels

< 6 months in age (poorly developed gag reflex)
SYRUP OF IPECAC (1648)

Indications:




Children that recently ingested known substances that are not well
adsorbed by activated charcoal
for whom transport time to a healthcare facility is delayed….save
time
Less traumatic than gastric lavage
Remove particles of material too large to pass through the
opening of a lavage tube
Recommended dose of syrup of Ipecac
AGE
QUANTITY
< 1 yr
5-10 ml
<5 yr
15 ml
Adult
30 ml
After 10–15 minutes, give 2–3 glasses
of water
SYRUP OF IPECAC



Ipecac induce vomiting has 2 phases:
Early: within 15-20 min….direct stimulation of GIT
Late: after 20 min….direct stimulation of medullary
chemoreceptor trigger zone

The dose may be repeated once if no response within 15-20 min

Repeat the fluid administration


Have the patient sit up or move around, because this sometimes
stimulates vomiting
If the second dose of ipecac does not induce vomiting, use an
alternative method of gut decontamination
Syrup of Ipecac: side effects






Drowsiness occurs in about 20% and diarrhea in 25% of
children
Persistent vomiting may delay administration of activated
charcoal or oral antidotes
Protracted forceful vomiting may result in hemorrhagic gastritis
Intracerebral bleeding in elderly patients, diaphragmatic
rupture, aspiration pneumonia
Repeated daily use (bulimic patients) may result in cardiac
arrhythmias owing to accumulation of cardiotoxic alkaloids
Convulsion, skeletal muscle weakness
SYRUP OF IPECAC


Collect vomits and inspect for fragments of pills, note
appearance, color and odor
In emergency and no ipecac syrup: 2-3 tablespoons of liquid
detergent (not powdered or concentrated) in a glass of water
(direct stimulation of gastric mucosa within 10 min.)

No other acceptable alternative…..!

Never salt water….fatal hypernatremia

Manual digital stimulation, copper sulfate, apomorphine, and
other emetics are unsafe and should not be used
SYRUP OF IPECAC

Contraindications:

Loss of airway protection reflexes

Caustic or corrosive

Toxicant produce abrupt loss of conscious (ethanol, ultrashort BZDs,
short acting barbiturate, heterocyclic antidepressant)

Seizures (amphetamine, cocaine, ibuprofen >400mg/kg)

Petroleum distillate

Infant <6 months age

Prior significant vomiting or hematoemesis

Absence of bowel sound…gastric lavage

Special situations (late pregnancy, elderly, HTN)
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
GASTRIC LAVAGE





Process of washing out the stomach with various solutions
including lukewarm water, saline, sodium bicarb.
Indicated when emesis is contraindicated
Preferred method for adult (co-operative) already in
medical facility
Effective within 30–60 minutes of the ingestion….
Usefulness decrease with time
Still useful several hours after ingestion of agents that
slow gastric emptying (eg. anticholinergic drugs)

Gastric lavage
Indications
The American Association of Poison Centers
(AAPC) and the European Association of
Poisons Centres and Clinical Toxicologists
(EAPCCT) have issued a joint statement that
gastric lavage should not be employed
routinely, if ever, in the management of
poisoned patients
The patient is placed
on the left lateral
decubitus position
(pylorus pointed up) to
permit pooling of
gastric contents with
head lower than the
rest of the body. The
largest catheter is
inserted into the
stomach
GASTRIC LAVAGE





Attempt to aspirate as much of the stomach content as
possible then…
Lavage fluids should be introduced into the stomach (50100ml aliquots for children) and (200- to 300-ml
aliquots for adults)
Lavage till clear
Complication (3%) aspiration pneumonia, esophageal
perforation, electrolyte imbalance
Advantages: dilute and remove corrosive liquids and
prepare the stomach for endoscopy
GASTRIC LAVAGE




Do not perform in any patient with an impaired level
of consciousness unless the airway is protected by a
cuffed endotracheal tube….prevent aspiration
In patients < 2 years, no cuff is needed because the
endotracheal tube fits snugly
A specific antidote is then given if available; otherwise,
a slurry of activated charcoal is given
Do not perform if ingestion of tablets (especially big in
size)
GASTRIC LAVAGE

CONTRAINDICATION:
 Caustic or corrosive*….perforation
 Uncontrolled convulsion….aspiration
 HC & petroleum distillate
 Comatose….endotracheal intubation
 Cardiac dysrhythmia….must be first controlled
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
ACTIVATED CHARCOAL
 Is a highly adsorbent powdered material produced by the
superheating of wood pulp
 Form of carbon that has been processed in order to make it
very porous with a large surface area to adsorb chemicals
 ……it is highly effective in adsorbing most toxins when given in
a ratio of approximately 10 to 1 (charcoal to toxin)
 Only a few toxins are poorly adsorbed to charcoal and in
some cases this requires a higher ratio (eg, for cyanide a ratio
of about 100:1 is necessary)
ACTIVATED CHARCOAL
 Indications: whenever an emetic cannot be used, following
successful chemical induction of emesis, or when the patient is
unconscious
 In ED, compliance is assumed after emesis, during or after
lavage
 Given even if the offending substance is not well adsorbed to
charcoal in case other substances have been co-ingested
 Give activated charcoal aqueous suspension orally or by
gastric tube. Initial dose (1 g/kg)
 Then 0.5g/kg every 2-6hrs
ACTIVATED CHARCOAL
 Within 30-60 min of ingestion
 Should not be given within 30-60 min of syrup of ipecac
unless the victim has already vomited (adsorbed on charcoal)
 In the stomach and intestine, poisons diffuse through the
numerous pores on the charcoal surface and form tight
chemical bonds
 This charcoal-chemical complex then passes out of the body
 Risk: pulmonary aspiration due to loss of airway reflex
Substances poorly adsorbed by
activated charcoal










Alkali
Iron
Lithium
Ethylene glycol
Mineral acids
Fluoride
Potassium
Heavy metals
Cyanide*
Rapid onset
ACTIVATED CHARCOAL
 ADDITIONAL USES:
 Long acting sustained release (9-10hr later ingestion)
 Enterohepatic circulation
 Fecal discoloration frequently occurs. Black stools
may be utilized as a diagnostic sign of
gastrointestinal transit
 Can be given at home?? Available in pharmacies?
Substances with enterohepatic circulation
Chloral hydrate
NSAIDS
Colchicine
Phencyclidine
Digitalis
Salicylates
INH
TCA
ACTIVATED CHARCOAL

CONTRAINDICATION:
 Absence of bowel sounds
 Sign of intestinal obstruction
 Lack of airway protection
 Child less that 1year…cathartic effect
 May decrease the absorption of the antidote
given later
Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
Cathartics
Whenever contact time between the
poison and absorption site is
reduced, the potential for toxicity is
likewise less
Cathartics





Controversy remains over the use of cathartics to hasten
elimination of toxins from the gastrointestinal tract
Few data exist to support their efficacy…..some toxicologists
still use cathartics routinely when giving activated charcoal
even
To enhance GI transit of the charcoal-toxin complex
Administer the cathartic (Mg citrate, Na phosphate, sorbitol)
along with activated charcoal or mixed together as a slurry
The evacuation action of saline cathartics may require several
hours for completion
Contraindications
Patient has electrolyte disturbance
 Bowel sound absent
 Evidences for bowel obstruction
 Sodium- and magnesium-containing cathartics should not be
used in patients with fluid overload or renal insufficiency
respectively
 Evidence of GI bleeding
 Patient with diarrhea
 <1yr (electrolyte disturbances)

Decontamination

Gastric decontamination (decrease absorption)






Dilution
Emesis
Gastric lavage
Activated charcoal
Cathartics
Whole bowel irrigation
Whole Bowel Irrigation

WBI: aggressive form of GIT decontamination attempt to
cleanse the bowel by the enteral administration of large
volume
of
an
osmotically
balanced
nonabsorbable
polyethylene glycol electrolyte solution (PEG-ES) which
induces a liquid stool

Contains the osmotically active sugar (PEG) with sodium
sulfate, sodium chloride, sodium bicarb and potassium
chloride to maintain electrolyte balance
Whole Bowel Irrigation

Rarely performed because risk-benefit analysis reserves this
intervention for life-threatening indication:

Ingestion of sustained-release or enteric coated preparations (valproic
acid, verapamil or diltiazem)

Agent that do not bind to charcoal (iron, other heavy metals, lithium)

No good clinical outcome is expected with antidote administration and
the patient presents before established severe toxicity

Complications such as: N, V
Whole Bowel Irrigation

TECHNIQUE:
Use nasogastric tube

Dose:



Adult 2L/hr,
< 5yrs 35ml/kg/hr

Continue irrigation until rectal effluent is clear (~6hr)

Administer metoclopramide to minimize vomiting

Stop if abdominal distension or loss of bowel sounds are
noted
Contraindications

Good outcome assured with antidote therapy

Uncooperative patient….inability to place a nasogastric tube

Uncontrolled vomiting (extensive hematomesis)

Ileus and bowel obstruction

Perforation or peritonitis
Gastrointestinal decontamination
METHODS TO ENHANCE
ELIMINATION OF TOXIC
AGENT
Urinary manipulation
 Extracorporeal methods




Peritonial dialysis
Hemodialisis
Hemoperfusion
Enhanced Elimination
3 critical questions must be answered:
A. Does the patient need enhanced removal?
1. Severe or critical intoxication with a deteriorating condition
despite maximal supportive care (eg, phenobarbital
overdose with intractable hypotension)
2. The normal or usual route of elimination is impaired (eg,
lithium overdose in a patient with renal failure)
3. The patient has ingested a known lethal dose or has a lethal
blood level (eg, theophylline or methanol)
4. The patient has underlying medical problems that could
further complicate the situation

Enhanced Elimination
B. Is the drug or toxin accessible to the removal procedure?
The drug ‘poison’ should be located primarily within the
bloodstream or in the extracellular fluid…..If extensively
distributed to tissues, it is not likely to be easily removed
1.
The volume of distribution (Vd) provides info on the
accessibility of the drug:
 Very large Vd……Small Vd
2.
Protein binding……highly protein-bound drugs have low
free drug concentrations……difficult to remove by dialysis
Enhanced Elimination
C. Will the method work?.......Does the removal procedure
efficiently extract the toxin from the blood?
1.
The clearance (CL) is the rate at which a given volume of
fluid can be "cleared" of the substance
 CL = extraction ratio x blood flow rate
 Extraction ratio across the dialysis machine or hemoperfusion
column and the blood flow rate through the following system
2.
Total clearance…..If the contribution of dialysis is small
compared with the total clearance rate, the procedure will
contribute little to the overall elimination rate
Urinary manipulation:
These methods require that the renal route be a
significant contributor to total clearance

Forced diuresis



Increase GFR, used in conjugation with ion trapping to
prevent reabsorption
Administration of enough fluids to establish a renal flow
of 3-5ml/kg/hr
Dangerous due to fluid overdose:
CHF
 RF
 Electrolyte disturbances
 SIADH
 Pulmonary edema
 Cerebral edema

Ion trapping

Alteration of urine pH prevent renal reabsorption of
poison that undergo glomerular filtration and active
tubular secretion

Many substance are reabsorbed in the nonionized form

Urine alkalization (pH= 7.5-8)


NaHCO3 ± acetazolamide
Urine acidification (PH= 4.5-6)

Ascorbic acid, NH4Cl, HCl
Alkalinization

NaHCO3 1-2 mEq/kg mix with 5% dextrose/0.5 N saline
15ml/kg

Infuse i.v over 3-4hrs

Check urine PH every hour, maintain at pH7.5-8

Has limited role in Tx of weak acids…the acidic toxin is much
less likely to cross the cell membrane leaving the serum to enter the cell

Reserved for phenobarbital, salicylate
Acidification

Ammonium (preferred agent):



Monitoring is mandatory of electrolyte status, acid-base status
and complication
HCl (alternative agent):


75mg/kg/24hr given either i.v. as 2% solution or P.O. in 4-6
divided doses
0.1M HCl solution 0.2 mEq/kg/h i.v.
Ascorbic acid (controversial)

2g i.v., 6g p.o.
Ion trapping


Acidification of the urine is not recommended by
many poison centers, may cause metabolic
acidosis….
May cause rhabdomyolysis & myoglobinurea
Acidification
Phencyclidine
Amphetamine
Quinidine
Strychnine
Phosphorous
Cocaine
Urine PH alteration
Alkalinization
Salicylates
Phenobarbital
Arsenic
INH
Lithium
Meprobamate
Naphthalene
Indications:

Renal elimination is the 1º route of excretion

Significant renal tubular reabsorption of toxin

Small Vd

Low protein binding
Contraindications

Renal dysfunction…fluid overload

Cardiac insufficiency…pulmonary edema

Uncorrected fluid deficit

Electrolyte abnormality

NH4Cl..hepatic insufficiency
Urinary manipulation
 Extracorporeal methods




Peritonial dialysis
Hemodialisis
Hemoperfusion
Extracorporeal methods

Peritoneal dialysis, hemodialysis, hemoperfusion,
hemofiltration, and plasmapheresis are not ED
procedure

Shouldn’t replace specific antidote
Dialysis
•
•
•
Is a process for removing waste and excess water from the
blood, and is used primarily to provide an artificial
replacement for lost kidney function in people with renal failure
Diffusion
of
solutes
across
a
semi-permeable
membrane….substances tend to move from an area of high
concentration to an area of low concentration
Smaller solutes and fluid pass through the membrane, but the
membrane blocks the passage of larger substances (for
example, red blood cells, large proteins)
Dialysis
•
Considered for patients intoxicated with:
 Dialyzable toxin (table)
 Who are not responding or is deteriorating in spite
of good medical care
 Vd < 1L/kg (phenobarbital, salicylate, theophylline)
 Protein binding <50%
 Water soluble
 Low Mol. Wt. < 500 Da
 Long elimination T1/2
Drugs and Toxins for Which Dialysis Is effective
Amphetamines
MAO inhibitors
Antibiotics
Antihistamines
Boric acid
Tricyclic antidepressants
Calcium
Lirium
Chloral hydrate
Digitalis
Fluorides
ethanol
Iodides
Hallucinogens
Isoniazid
Heroin/opiates
Paraldehyde
Carbon monoxide
Phenobarbital
Phenothiazines
Potassium
Eucalyptus oil
Quinidine
Iron
Salicylates
Lead
Strychnine
Lithium
Thiocyanate
Belladonna compounds
HEMOdialysis

Blood is taken from a large vein (usually a femoral vein) and is
pumped through the hemodialysis system
Drugs and toxins flow passively across the semipermeable
membrane down a concentration gradient into a dialysate
(electrolyte and buffer) solution
Removal of drug is dependent on flow rate—insufficient flow
(ie, due to clotting) will reduce clearance proportionately
Should be considered immediately if:

The patient is stable and has a MeOH or ethylene glycol conc. >50mg/dl

Neurological manifestations or Lithium conc.> 4mEq/L




Complication: hemorrhage
hypocalcemia, and infection
(heparin),
hypotension,
hypoglycemia,
BAGELS:
• Bromide
• Alcohols
• Glycols
• Electrolytes
• Lithium/longacting
barbiturates
• Salicylate
Hemoperfusion





Significantly more effective than hemodialysis
Same procedure as hemodialysis including anticoagulant, but
the blood is pumped directly through a column containing
adsorbent material (charcoal or resin)
Even if the toxin is lipid soluble, protein bound, or high Mol.
Wt.
Factors: adsorbability of resin or charcoal, (short acting
barbiturates, theophylline, phenytoin), low Vd, plasma conc.
of the toxin
Similar complications….thrombocytopenia (hemorrhage),
hypotension, hypoglycemia, infection and
PERITONEAL dialysis




Elimination of toxic metabolites from the blood, using the
peritoneum as semipermeable membrane for dialysis
Dialysate fluid (1-2 L) introduced into the cavity through
transcutaneous catheter after local anesthesia, allow to
equilibrate for 1-2hrs and then cleaned off
Water soluble toxins, poorly protein bound, low MW, low Vd
Easiest performed method…(at home), does not require
anticoagulation


Lowest risk for causing complications
Least effective (10-15% as effect as hemodialysis)
•
CL of toxin depends on dialysate flow rate, Mol. Wt. of the toxin &
surface area of the peritoneum
PERITONEAL dialysis





Effectiveness may be increased by certain
drugs…dipyridamole…increases vascular permeability
and may increase peritoneal clearance
NO if Severe or threatening absorption of toxin for which
peritoneal dialysis will need to much time
The presence of hypotension, vasoconstriction
Not dialyzable toxin
Complication: intestine perforation, electrolyte imbalance,
infections