Historical Development of Toxicology

About This Presentation

Title:

Historical Development of Toxicology

Description:

Historical Development of Toxicology It is one of the oldest practical sciences which began with early cave dwellers who recognized poisonous plants and animals and ... – PowerPoint PPT presentation

Number of Views:779

Avg rating:3.0/5.0

Slides: 72

Provided by: pharmacy41

Category:

more less

Transcript and Presenter's Notes

Title: Historical Development of Toxicology

1
Historical Development of Toxicology

It is one of the oldest practical sciences which
began with early cave dwellers who recognized
poisonous plants and animals and used their
extracts for hunting or in warfare.
By 1500 BC, hemlock, opium, arrow poisons, and
certain metals were used to poison enemies or for
executions (Notable poisoning victims include
Socrates, Cleopatra, and Claudius)
.
The Death of Socrates, 1787 Jacques-Louis David

By the time certain concepts fundamental to
toxicology began to take shape especially by the
studies of Paracelsus (1500AD) and Orfila (1800
AD).
Paracelsus (1493 -1541)
His famous words were
"All substances are poisons there is none which
is not a poison. The right dose differentiates a
poison and a remedy."
1-He determined that specific chemicals were
actually responsible for the toxicity of a plant
or animal poison.
2-He also documented that the body's response to
those chemicals depended on the dose received
Orfila (founder of toxicology -19th century)
Spanish physician who first correlated between
the chemical and biological properties of
poisons.
The 20th century is marked by an advanced level
of understanding of toxicology. DNA (the
molecule of life) and various biochemicals that
maintain body functions were discovered. Now our
level of knowledge of toxic effects on organs and
cells is being revealed at the molecular level.

3
Scope of Toxicology

Toxicology is multidisciplinary as it entails
1-Mechanistic Toxicology
Example
Biochemical toxicology
Behavioral toxicology
Carcinogenesis
Teratogenesis
Mutagenesis
2-Applied Toxicology
Clinical Toxicology It deals with emergency
cases such as overdoses, poisonings, attempted
suicides by
Emergency care for patients.
Management of sign and symptom
Identification and quantification of the
drug ,poisons, chemicalsetc
.

Forensic Toxicology
Economic Toxicology
Environmental Toxicology
3-Analytical Toxicology
4-Regulatory Toxicology
Risk assessment
It deals with analysis of toxicological
data for the determination of Safe level of
drugs for humans , safe level of heavy metals in
water , safe levels pesticides...etc.
Legal aspect
Concerned with formulation of laws which are
intended to minimize the effect of toxic
chemicals on humans health the environment.

5
Toxicity

Def. The degree to which a substance can harm
humans or animal
Different xenobiotics cause many types of
toxicity by a variety of mechanisms. So, we have
to take an idea about
-Different types of toxic agents
-Different type of toxicity
-Different mechanisms of toxic response
Toxic Agents
Toxic agent is anything that can produce an
adverse biological effect.
-The most common terms used to describe a toxic
agent are toxicant, toxin, poison.

6
Toxic Agents

Toxic Agents are classified
1-According to their nature
1-Chemicals as alcohols, phenols heavy metals
2-Physical as radiation.
2-Bilogical Snake scorpion venoms.
2-According to their effect
i-Systemic toxicant
is one that affects the entire body or many
organs rather than a specific site.
E.g. potassium cyanide is a systemic toxicant in
that it affects virtually every cell and organ in
the body by interfering with the cell's ability
to utilize oxygen.
ii-Target organs toxicant
affect only specific tissues or organs while not
producing damage to the body as a whole.
Examples
-Arsenic paracetamol are hepatotoxic.
-Digitalis antimony are cardiotoxic.
-Mercury gentamycin are nepherotoxic
-Lead is also a specific organ toxin however,
it has three target organs (central
nervous system, kidney, and hematopoietic
system).

8
Types of poisoning

1-According to circumstances of poisoning
a-Accidental Toxicity (non-intentional
poisoning)
which occur by mistakes and usually happen to
children (below 5-years old)
E.g.With aspirin, iron preparations, pesticides,
kerosene..etc.
b-Deliberate self Toxicity (Suicidal or criminal
poisoning)
which occur when a person attempts to kill
himself or another person.
E.g. with cyanide, barbiturates,salicylates
etc
2-According to incidence of poisoning
a-Homicidal Which occurs in or around home.
E.g. pesticides, potassium hydroxide,
disinfectants.
b-Occupational This includes industrial and
agricultural poisoning.
E.g. inhalation of pesticides.

9
Types of Toxicity

1-Systemic Toxicity
Toxicity may occur at multiple sites. This is
referred as systemic toxicity. The following are
types of systemic toxicity
a-Acute Toxicity
It occurs almost immediately (hours/days) after
an exposure to single dose or a series of doses
received within a 24 hour period. Death is a
major concern in cases of acute exposures.
Examples are
-In 1989, 5,000 people died and 30,000 were
permanently disabled due to exposure to methyl
isocyanate from an industrial accident in
Bhopal, India.
-Many people die each year from inhaling
carbon monoxide from faulty heaters.
b-Subchronic Toxicity (reversible)
It results from repeated exposure for several
weeks or months. This is a common human exposure
pattern for some pharmaceuticals and
environmental agents. Examples are
-Ingestion of coumadin tablets (blood
thinners) for several weeks as a treatment for
venous thrombosis can cause internal
bleeding.
-Workplace exposure to lead over a period of
several weeks can result in anemia.

c-Chronic Toxicity (irreversible)
It is a cumulative damage to specific organ or
system and it takes many months or years to
become a recognizable clinical disease. This
damage is so severe that the organ can no longer
function normally (irreversible) and a variety of
chronic toxic effects may result. Examples are
-Cirrhosis in alcoholics who have ingested
ethanol for several years
-Chronic bronchitis in long-term cigarette
smokers
-Pulmonary fibrosis in coal miners (black
lung disease)
d-Carcinogenicity
Carcinogenicity is a complex multistage process
of abnormal cell growth and differentiation which
can lead to cancer.
e-Developmental Toxicity
Developmental Toxicity result from toxicant
exposure to either parent before conception or to
the mother and her developing embryo-fetus.
f-Genetic Toxicity
Genetic Toxicity results from damage to DNA and
altered genetic expression. This process is known
as mutagenesis. The genetic change is referred to
as a mutation and the agent causing the change as
a mutagen.

2-Organ Specific Toxicity
Blood and Cardiovascular Toxicity
Hypoxia due to carbon monoxide binding of
hemoglobin preventing transport of oxygen
Hepatotoxicity
CCl4..metabolized by HME.CCl3 (causes lipid
peroxidation in liver lead to liver necrosis.)
Nephrotoxicity
Mercury gentamycin are nepherotoxic.
Neurotoxicity
Organophosphorus compounds (insecticides)damage
to sensory fibers.
Respiratory Toxicity
Aluminum..emphysemainflated lung
.fibrosis(aluminosis).
Dermal Toxicity
dermal irritation due to skin exposure to
gasoline
dermal corrosion due to skin exposure to sodium
hydroxide

12
Mechanism of Cellular Injury
13
Mechanism of Cellular Injury

Toxicity can result from adverse cellular,
biochemical, or macromolecular changes. Examples
are
1-Alteration of a cell membrane permeability
Toxic agents could change cell membrane
permeability through interaction with its
component as
a-SH-containing proteins
Heavy metals as As or Hg react with them
change in protein structure
change membrane permeability.
b-Lipids
-Free radicals attack fatty acids in the lipid
layer of biological membrane causing lipid
peroxidation , these peroxides are toxic to the
cell and alter membrane permeability.
E.g. CCl4..metabolized by HMECCl3
(Trichloromethyl radical causes lipid
peroxidation and finally lead to liver necrosis.)
-This is why antioxidants should be used
frequently by humans where it act as a protective
measure against many diseases(e.g.) Vit. E Vit.
C.
c-Na-K ATPase pump
Many toxicants can inhibit these pumps which are
essential for transport of major amino acids and
calcium across the cell membrane.
E.g. Hg, Cu, Pb , As and alcohol .

2-Chang in enzyme activity
a-Inhibition
E.g.1 Carbamate esters (insecticides) reversibly
inhibits anticholineserase leading to increase in
A.Ch. Level
Toxicity (SLUD are the most
characteristic symptoms of toxicity).
E.g.2 Cyanide inhibits cytochrome
oxidase enzyme no aerobic respiration
and finally cell death.
b-Activation
E.g. Barbiturates induce hepatic microsomal
enzymes increase the conversion of some non
carcinogenic agents (in cigarette smoke) into
carcinogenic ones.
3-Interferance with co-enzymes
E.g. CN- binds to essential metals as Fe3
needed for the activity of cyochrome oxidase.
4-Modification of carriers
E.g.1 CO binds with hemoglobin instead of O2
(affinity to Hb to CO is 210 times that for
O2) carboxyhemoglobin.hypoxiadeath.
E.g.2 Nitrates ,aspirin and sulfonamides oxidize
Fe2 in Hb into Fe3
Hb
MeHb
(methemoglobin) which can not

carry oxygen
NADPH-dependent
Hypoxia
MeHb
reductase Vit. C

5-Formation of reactive metabolites
E.g. Benzo(a)pyrene metabolized by HME
epoxide-7,8- dihydrodibenzo(a)

pyrene
Non-carcinogenic
Carcinogenic
In cigarette smoke
6-Reactions causing depletion of GSH
Glutathione (GSH) is an antioxidant which
protects the cell from the harmful effect of
oxidants. Reduction of GSH level into 20-30
causes impairment of cell defense mechanism .
E.g. N-acetyl-P-benzoquinone imine (NABQI) ,a
toxic metabolite of paracetamol it is
conjugated with GSH depletion of reduced
form of GSH leading to NABQI (Strong
electrophilic agent) attack liver tissues causing
liver necrosis.
-We can increase the level of GSH or overcome its
depletion by methionin (a precursor of GSH)
N-acetylcysteine (contains SH).
7- Action on nucleic acids
E.g. SO2 (air pollutant) H2O
HSO3(causing damage to DNA mutation).
E.g. Benzidine Metabolism by HME
N-hydroxybenzidine.
Non-carcinogenic
Mutagenic Carcinogenic
In cigarette smoke
8- Disruption of protein synthesis
Some toxicants either increase or decrease
protein synthesis leading to cellular injury.

9-Lysosomal changes
a-Toxicants which causes labialization of
lysosomal enzymes
E.g. Hg , Cu , silica , nicotine , bee venom ,
hypervitaminosis A , monosodium ureate crystals
deposited in gout increase lysosomal membrane
permeability release of hydrolases cell
death.
b-Toxicants which causes stabilization of
lysosomal enzymes
E.g. Corticosteroids causes indirect toxicity by
decreasing the response of the body defense
mechanism .

17
Factors Influencing Toxicity

There are many factors which can enhance,
increase or decrease toxicity. These factors are
divided into
I-Factors related to the host
A-The species.
-Rats cannot vomit and expel toxicants before
they cause severe irritation, whereas humans and
dogs are capable of vomiting.
Selective toxicity refers to species
differences in toxicity response between two
species simultaneously exposed
-an insecticide is lethal to insects but
relatively nontoxic to mammals???
malthion
Oxidation by ME

Hydrolysis
(rapid in insects slow in mammals)
(slow in insects rapid in mammals)
Malaoxone

Inactive substance
(Lethal to insects)

B-Sex
.Men traditionally weigh more than women.
Therefore, doses of a chemical in a male would be
expected to produce lower blood and tissue levels
than the same in females, simply because of the
male's larger blood volume and greater tissue
mass which dilute the chemical.
For substances that are injected
intramuscularly, lower blood levels can be
expected with those drugs in individuals (usually
men) with a greater muscle mass.
Also, drugs with a high lipid coefficient that
normally partition into fat may produce different
toxicological responses in different sexes, based
on the individual's ratio of body fat/total
weight.
C-Age
-Some chemicals are more toxic to infants or the
elderly than to adults.
Example
1)-Bounded bilirubin with p.p.Sulfonamides
replacement from P.P. binding sites.
conjugated
with glucoronyl transferase
Free bilirubin

excreted in adults
(Low activity of
GT Immature B.B.B in neonates)
Kernikterus (in newborn)
2)-Nitates(in well , s water) due to stomach
pH is high in newborn Nitrite
(oxidant)
Oxidation
Hb

MetHb

3)-Chloramphenicol conjugation by GT is low in
neonates accumulation of it ,and it
oxidizes Hb into MetHb Grey baby
syndrome (hypoxia, cyanosis , collapse and
death).
D-Genetics
I-Pharmacogentices (Idiosyncratic reaction ) An
odd response to a given normal dose of a drug on
hereditary basis.
1) Succinylcholine apnea in individuals deficient
in pseudo cholinesterase .?
2) Individuals deficient in glucose-6-phosphate
dehydrogenase suffer from hemolytic anemia upon
using sulfa drugs , aspirin or naphthalene
(oxidants)
glucose-6-phosphate NADP
2 GSH (protect RBCs from hemolysis by
oxidants)
G6PD
GSH reductase
6-phosphogluconic acid NADPH
GSSG
In case of G6PD deficiency NADPH
GSH Oxidants attack RBCs hemolysis
II-Toxicogentices An odd response to a given
toxicant on hereditary basis
smoking causes emphysema in certain
individuals deficient in a1- antitrypsin.
III-Hypersensitivity (allergic reactions)

20
Pharmacogentices (Idiosyncratic reaction)
21

Allergic reactions an immune response that
occurs after prior sensitization
-These reactions range from mild, itchy ,severe
skin rash to anaphylaxis
-Intensity is determined by degree of
sensitization and not by the dose.
Penicillin as an example
We can get sensitization from molds in the air or
from antibiotics given to animals we eat, we
dont necessarily have to be given a dose of
Penicillin to become sensitized to it.
Penicillin is not antigenic by itself because it
is too small. To become capable of eliciting an
allergic reaction, it must first be metabolized
and then one of its metabolites attaches to
endogenous protein to form a happen-protein
complex. Now, antibodies can be made to this
complex and an allergic reaction occur.
E-Dietary factors
1) Calcium and proteins increase GIT absorption
of Pb
2)Low protein in diet P.P. level decrease
free drug toxicity .
3)Food containing tyramine as old cheese ,salted
dried fish ,banana, Beer, Canned figs, Chicken
liver ,Chocolate, Sherry wines increase MAOIs
(e.g., pargyline, phenelzine) toxicity which is
severe symptoms of hypertensive crisis and even
death may occur.
4) Calcium in milk, which may bind to
tetracycline, and thus reduce its absorption.
5) Foods rich in pyridoxine may significantly
lower the pharmacological action of levodopa

F-Health factors
1)Acidosis insulin activity decrease leading to
hyperglycemia
2)Asthma patient is more liable to the effect of
air pollutants as SO2.
3)Kidney liver diseases toxicity of many drugs
increase.
End of factors
related to Host

II-Factors releated to the poison
a-Dose
It is the amount of a substance administered at
one time.
However, the number of doses, frequency, and
total time of the exposure are also very
important .
Example
b-Routes of exposure
-Ingested chemicals, when absorbed from the
intestine, distribute first to the liver and may
be immediately detoxified .
-Inhaled toxicants immediately enter the general
blood circulation and can distribute throughout
the body prior to being detoxified by the liver.
Intravenous Inhalation Interapertoneal
Intramuscular Subcutaneous Oral
Interadermal

c-Chemical structure
-Silica (amorphous) after it is
heated silica (crystalline)
has little effect on health
serious lung damage.
-Cr3 is relatively nontoxic whereas Cr6 causes
skin or nasal corrosion and lung cancer.
d-Composition and formulation ( mainly
absorption)
-Concentration .
-Lipid solubility.
-Chemicals in liquid form are more toxic than
those in solid form
-Coloring agents as tartazin yellow cause
allergy.
-Micronization increase toxicity.
-Vehicles as alcohols increase CNS depressant
action of hypnotics.
-Impurities some herbicide as 2,4,5-trichlorophen
oxy acetic acid may contain the toxic impurity
DIOXIN which is mutagenic ,teratogenic and
carcinogenic.
-pH of the preparation (high acidity or
alkalinity) cause local sever effect.
-Low stability of the compound bad storage
condition increase toxicity as food contaminants
aflatoxin ( it is a product of certain molds)
-The particle size Only particles having a small
diameter (1 mm or less) will effectively reach
the alveoli and be available for pulmonary
absorption. Larger particles may be deposited on
the walls of the throat and trachea to produce
irritation.

e-The innate chemical activity
Some toxicants can quickly damage cells causing
immediate cell death. Others slowly interfere
only with a cell's function.
-Hydrogen cyanide binds to cytochrome oxidase
resulting in cellular hypoxia and rapid death
-Nicotine binds to cholinergic receptors in the
central nervous system (CNS) altering nerve
conduction and inducing gradual onset of
paralysis
F-Temperature
-Toxic response as environmental temperature is
lowered ( but the duration of the overall
response may be prolonged)
The reasons for these are
a. Decreased rate of absorption occurring in the
colder environment
b. Lowered rate of metabolic degradatio
On the other hand, atropine-like compounds may
produce significantly greater toxicity in a warm
environment than in a colder one. Because
anticholinergic agents inhibit sweating, the body
temperature becomes elevated because the absence
of perspiration prevents cooling of the body so
the toxic effects are from hyperthermia.
End of factors
related to Toxicant

III-Toxicokinetic factors
i-Factors affecting absorption
GIT
Gastric content
-Empty stomach has higher emptying rate
Toxicity.
-Carbonated beverages increase G.E.
Toxicity.
-A full stomach with proteins fats
Toxicity.
Secretion Pepsin HCl digest peptide poisons
.
GIT flora migration of intestinal flora into the
stomach in newborns due to their high gastric pH
,this flora can convert nitrates into nitrite,
oxidizing Hb into metHb Hypoxia.
Skin (Thickness Keratin layer protect
the skin )
-Newborn (thin delicate skin).
-Lipophilicity of insecticides.
Toxicity
-Cutting , abrasions dryness of skin
Pulmonary
-Conc. Of toxicants in air.
-Solubility of the toxin in blood tissues.
-Respiration rate.

ii-Factors affecting metabolism
(biotransformation)
There are two types of metabolism detoxification
and bioactivation. Detoxification is the process
by which a xenobiotic is converted to a less
toxic form. Bioactivation is the process by which
a xenobiotic may be converted to more reactive or
toxic forms.

iii-Factors affecting distribution
Main mechanisms opposing distribution of the
toxicants are
a-Plasma proteins
-Bilirubin in neonates???.
-High affinity for binding to P.P. may cause
toxicity due to drug interaction as sulfonamide
displace tolbutamide from P.P. binding site
causing hypoglycemia.
b-Storage
-DDT is stored in fat tissues and upon short term
diet ,mobilization of fats occur leading to
release of DDT and toxicity.
-Fluoride bind to calcium in bones flurosis.
-Pb is stored in bones (non toxic to it) ,
osteoporosis mobilize Pb leading to toxicity.
c-Special barriers (B.B.B.)
-Mainly depends on lipid solubility

iv-Factors affecting excretion
-The kidney is the primary excretory organ,
followed by the gastrointestinal tract, and the
lungs (for gases). Xenobiotics may also be
excreted in sweat, tears, and milk.
-Impaired cardiac , kidney or liver function
causes slower elimination of toxicants and
increases their toxic potential.
End of
Toxicokintics factors
And
Factors related to poison

IV-Chemical Interactions
Humans are normally exposed to several chemicals
at one time rather than to an individual
chemical.
Examples are-Hospital patients on the average
receive 6 drugs daily-Home influenza treatment
consists of aspirin, antihistamines, and cough
syrup taken simultaneously-Drinking water may
contain small amounts of pesticides, heavy
metals, solvents, and other organic chemical-Air
often contains mixtures of hundreds of chemicals
such as automobile exhaust and cigarette
smoke-Gasoline vapor at service stations is a
mixture of 40-50 chemicals
-There are four basic types of interactions.

Additivity-A tranquilizer and alcohol, often
cause depression equal to the sum of that caused
by each drug.-Chlorinated insecticides and
halogenated solvents (which are often used
together in insecticide formulations) can produce
liver toxicity with the interaction being
additive.
P.S. this same combination of chemicals
produces a different type of interaction on CNS.
Chlorinated insecticides stimulate CNS whereas
halogenated solvents cause its depression . So,
the effect of simultaneous exposure on CNS is an
antagonistic interaction.
PotentiationIt occurs when a chemical that does
not have a specific toxic effect makes another
chemical more toxic.
Example-Warfarin (a widely used anticoagulant
in cardiac disease) is bound to plasma albumin so
that only 2 of the warfarin is active (FREE).
Drugs which compete for binding sites on albumin
increase the level of free warfarin to 4
causing fatal hemorrhage.

Antagonism
It is often a desirable effect in toxicology and
it is the basis for most antidotes.
Examples include
Synergism
-Exposure to both cigarette smoke and asbestos
results in a significantly greater risk for lung
cancer-The hepatotoxicity of a combination of
ethanol and carbon tetrachloride is much greater
than the sum of the hepatotoxicity of each.
End of Factors affecting Toxicity

Sources of information on safety
1. Experimental studies
Experimental toxicology is a branch of
toxicology, which deals with toxicity studies in
experimental animals to evaluate the safety of a
new chemical (drugs, food additives, pesticides
and industrial chemicals).
2. Controlled clinical studies
Drug is tested on small number (5060) of healthy
volunteers in a controlled dose for specified
time
3. Epidemiological studies
Thalidomide its teratogenic activity was
discovered in the 1960s.
Sulphonamide elixir (1930) its vehicle was
ethylene glycol (metabolize to oxalic acid) that
resulted in titanic convulsion

Toxicity studies
Goals of toxicity studies
Predict the toxicity of chemical in human
Give information about mechanism of toxicity
Give information about toxicity of dosage used
in humans
Toxicity studies indicate the therapeutic index
which gives information about safety.
We can perform different experimental protocols
using different routes of administration. And
from this we can determine the following doses
1. No-effect dose it is the maximum dose that
produces no observable toxic effect on the
animals.
2. Minimal toxic dose it is the dose that
produces the least toxicity
3. Median lethal dose (LD50 LC50) This is the
dose that kills 50 of the animals.

35
(No Transcript)
36
How do we measure toxicity?

Toxicity is measured in numerous ways. The
classic measure is ...
LD50 Lethal Dose that kills 50 of the
population.
Dosage are measured in a mg toxin/kg body weight.
While
Drug action is measured by
ED50 Effective Dose that produces the desired
effect in 50 of the population.
Dose-Response Curves characterize the response to
different levels of a drug or toxin.

Dose Response curveThe dose-response correlates
exposures and the spectrum of induced effects.
-Generally, the higher the dose, the more severe
the response.
-The dose-response relationship is based on data
from experimental animal, human clinical, or cell
studies.
-The dose-response curve normally takes the form
of a sigmoid curve. For most effects, small doses
are not toxic.

-Knowledge of the shape and slope of the
dose-response curve is extremely important in
predicting the toxicity of a substance at
specific dose levels.
-Major differences among toxicants may exist not
only in the point at which the threshold is
reached but also in the percent of population
responding per unit change in dose (i.e., the
slope).
-As illustrated above, Toxicant A has a higher
threshold but a steeper slope than Toxicant B.

-Dose-response curves are also used to derive
dose estimates of chemical substances EDs TDs.
Toxic Doses (TDs) the doses that cause adverse
toxic effects.
-The knowledge of the effective and toxic dose
levels aides the toxicologist and clinician in
determining the relative safety of
pharmaceuticals.
-As shown above, two dose-response curves are
presented for the same drug, one for
effectiveness and the other for toxicity. In this
case, a dose that is 50-75 effective does not
cause toxicity whereas a 90 effective dose may
result in a small amount of toxicity.

The Therapeutic Index (TI) It is the ratio of
the dose producing 50 toxicity to the dose
needed to produce the 50 therapeutic response.
- For example, if the LD50 is 200 and the ED50 is
20 mg, the TI would be 10 (200/20). A clinician
would consider a drug safer if it had a TI of 10
than if it had a TI of 3.

NOAEL and LOAEL-No Observed Adversed Effect
Level (NOAEL)
-Lowest Observed Adverse Effect Level (LOAEL)
-They are the actual data points from clinical or
experimental animal studies.
-They do not necessarily imply toxic or harmful
effects ,and may be used to describe beneficial
effects of chemicals as well.

42
GENERAL MANAGEMENT OF POISONED PATIENTS
43
General Information

Remember
All chemicals have potential to be poisons if
given in a large enough dose
Poisoning occurs when exposure to a substance
adversely affects function of any organ system

44
Treatment

DECONTAMINATION! ALWAYS be sure that the patient
has been decontaminated PRIOR to doing anything
to them!
ABCs Always stabilize the patient like you
would any other patient initially.
Draw labs, obtain your EKG, get x-rays if needed,
begin fluids, and if needed.
Decrease absorption or Enhance elimination

45
Management Steps

1-Supportive
Maintain airway clean, and assure respiration.
Correct hypoxia, hypotension, dehydration, hypo-
or hyperthermia, and acidosis
Control seizures
2-Monitor
PR, BP, ECG, Oxygenation
3-History Physical examination
4-General Steps
? Absorption
? Elimination
5-Specific antidotes

46
I-Emergency stabilization

First priorities are ABCs
Vital sign including pulse ,oxygen and
hypoglycemia must be corrected
Only in very rare incidences does administration
of antidote precede stabilizing ABCs and vital
signs
Unresponsive pts treated empirically with coma
cocktail Oxygen, naloxone, glucose, and thiamine

47
(No Transcript)
48

Airway
If the victim loss airway protective reflexes
..Airway obstruction by flaccid tongue, or
aspiration of gastric contents.Respiratory
arrest
.Death
-If reflexes were lost or the victim is comatos
----do endotracheal intubation
Endotracheal intubations
Not easy--------requires expertise
1-Nasotracheal intubations
-requires local anaesthetic(
lidocaine) ----reduces pain
-vasoconstrictor
(phenylephrine) ----reduces bleeding
2-Orotracheal intubations
-requires neuromuscular
blocker e.g. suxamethonium
( is contraindicated in
children so pancuronium is recommended in
children)

BREATHING
Breathing difficulties major cause of morbidity
and death.
Complications
1. Ventilatory failure
2. Hypoxia
3. Bronchospasm
A-Ventilatory failure
CAUSES OF VENTILATORY FAILURE
a) Failure of respiratory muscles e.g,
Neuromuscular blockers, Snake bite
b) Depression of respiratory center e.g. by
barbiturates, alcohols, opioids
c) Severe pneumonia.
d) Pulmonary oedema

HYPOXIA
CAUSES OF HYPOXIA
A.Insufficient oxygen in air (e.g. displacement
of oxygen by inert gases).
B.Disruption of oxygen absorption by the lung
resulting from
1- pneumonia The most common cause of pneumonia
in overdosed patients is pulmonary aspiration of
gastric contents.
Pneumonia may also be caused by intravenous
injection of foreign material or bacteria,
aspiration of petroleum distillates or inhalation
of irritant gases.
2-Pulmonary edema
-Cardiogenic pulmonary edema caused by Beta
blockers, Cyclic antidepressants, Quinidine
-Non-cardiogenic pulmonary edema caused by
aspiration of hydrocarbons (e.g. petroleum)
C- Cellular hypoxia
methemoglobinemia, by oxidizing agents which
limit binding of oxygen to hemoglobin, and
cyanide, which blocks oxygen utilization.

Bronchospasm
Examples
1.Direct irritant injury from inhaled gases or
pulmonary aspiration of petroleum distillates or
stomach contents.
2.Pharmacologic effects of toxins, e.g.
organophosphate or carbamate insecticides or
beta-adrenergic blockers.
Treatment
1. Assist breathing manually with a
bag-valve-mask device
2. Perform endotracheal intubation
3.Use oxygen (usually 3035 to start).
-Administer 100 oxygen in carbon monoxide
poisoning
4.Give cyanide antidote kit for cyanide
poisoning.
5.Remove the patient from the source of exposure
to any irritant gas.
6.Administer bronchodilators in case of
bronchospasm
a.
salbutamol inhaler
b. If
this is not effective, give aminophylline, IV.
For patients with bronchospasm and bronchorrhea
caused by organophosphate or other
anticholinesterase poisoning, give atropine.

CIRCULATION
General assessment
Check blood pressure and pulse rate and rhythm.
Perform cardiopulmonary resuscitation (CPR) if
there is no pulse
perform continuous (ECG) for monitoring of
arrhythmias
1-Examples of drugs and toxins causing
bradycardia or AV block
Beta blockers, Cholinergic ,Digitalis glycosides
and Organophosphates.
Treatment
1.Administer supplemental oxygen.
2.Rewarm hypothermic patients.
3.Administer atropine or an emergency pacemaker.
2-Examples of drugs and toxins causing
hypotention
-Beta blockers , TCA ,Barbiturates ,Calcium
antagonists ,Cyanide ,Opiates ,Organophosphates
and carbamates
Hypotension usually responds readily to
empirical therapy with intravenous fluids and low
doses of presser drugs (eg, dopamine)

3-Examples of drugs and toxins causing
tachycardia
Amphetamines ,Caffeine, Cocaine ,Agents causing
cellular hypoxia Carbon monoxide ,Cyanide
,Oxidizing agents (methemoglobinemia) and
Anticholinergic agents
Treatmente.g.For sympathomimetic-induced
tachycardia, give propranolol, or esmolol,
For anticholinergic-induced tachycardia, give
physostigmine, or neostigmine.
4-Examples of drugs and toxins causing
hypertention
Amphetamines ,Antihistamines ,Cocaine ,Atropine
,Epinephrine ,LSD (lysergic acid diethylamide)
,Ethanol and drug withdrawal (Marihuana )
,Nicotine , Monoamine oxidase inhibitors
,Organophosphates, and TCA.
Treatment
For hypertension with little or no tachycardia,
use nifedipine or nitroprusside.
For hypertension with tachycardia, add to the
above treatment propranolol, or esmolol , or
labetalol.
Caution Do not use propranolol or esmolol alone
to treat hypertensive crisis beta blockers may
paradoxically worsen hypertension if it is caused
primarily by alpha stimulation.

54
History of poisoning

1-History is key to the approach of the poisoned
patient.
2-Establish an exposure time , Estimate the dose.
3-Determine other factors that may be present and
affecting your treatment.
What type of exposure was this?
Environmental, industrial, accidental,
homicidal, suicidal, or unknown? (Empty bottles ,
if he was taken from garage.?,a factoryetc).
Establish the dose if known. Number of pills in
the bottle, time ingested/exposed, or have they
vomited since ingestion?
The patient's psychological profile This is
difficult because the poisoned individual may be
unconscious, unresponsive or confused.
Information usually obtained from relatives or
friends.
Identify if the patient performed any self
treatment or took any medication?

B-Physical examination
Physical exam should include all body systems.
Many clues may be obtained from the physical
exam.
Some poisons produce clinical characteristics
which strongly suggest the type of the poison
1-Presence of characteristic odour
phenol, alcohol, kerosene, bitter almond odour
of cyanide
2-Skin manifestation
a- Changes in the skin Color
- Red in carbon monoxide poisoning.
- Pale and dry in atropine poisoning.
- Flushed and sweaty in LSD and cocaine.
- Cyanosed in cyanide, nitrites.
-Yellow Jaundice in acetaminophen, carbon
tetrachloride
b- Needle markers Indicate addiction by
intravenous route e.g. cocaine.
c- Alopecia in Thallium.
d-Burns corrosion Acids alkali
e-Fingernails may hold many lines in a variety of
poisonings. Brittle fingernails in thalidomide
ingestion. Lines/Grooves in sodium fluoride.
Heavy metals may cause staining or other
abnormalities of the nails.

3-Eye
manifestation
a- Eye globe
i- Lacrimation In organic phosphorous
ii- Nystagmus In barbiturates.
b- Pupils
i- Dilated reactive pupils In alcohol and
cocaine.
ii- Dilated fixed pupils In atropine.
iii- Constricted pupils In phenol and opium.
iv- Miosis clonidine, carbamates, opiates,
organophosphates
v-Mydriasis anticholinergics or sympathomimetics
4-Gastro-intestinal manifestations
a- Mouth
i- Salivation In organophosphorous compounds.
ii- Dry mouth In atropine and other
anticholinergic drugs.
iii- Corrosion With corrosives.
iv- Gum discoloration Lead causes blue line.
Cadmium causes yellow line. Mercury causes grey
line.
b- Vomiting

5-Cardio-vascular manifestations
a- Tachycardia In alcohol, atropine.
b- Bradycardia In digitalis ,opium, cyanide ß
blockers.
c- Rise in blood pressure Lead,amphetamine, and
tricyclic antidepressant.
d- Hypotension In barbiturates.
6-Respiratory manifestations
-Acute respiratory failure in barbiturates.
-Pulmonary edema due to inhalation of
petroleum and arsenic fumes.
7-Central nervous system manifestation
a- Coma Barbiturates, Paraldehyde, and
ethylene glycol.
b-Convulsions Amphetamines, camphor, chlorinated
hydrocarbons, lead, strychnine, cocaine, alcohol,
anticholinergic, antihistaminic.
c-Hyperpyrexia Salicylates, amphetamine and
theophyline.
d-Hypothermia Clonidine and tricyclic
antidepressants.
e-Muscle fasciculations With nicotine,
strychnine and camphor.
f-Tremors Occurs with amphetamines, carbon
monoxide, hallucinogenic drugs, xanthines
(theophylline) and tricyclic antidepressants.
8. Skeletal muscle muscle paralysis is produced
by lead, curare and flaxedil.

C- Analytical toxicological laboratory screening
These give the correct diagnosis and could be
done on biological fluids .This usually include
-CBC
-Serum electrolyte level.
-BUN
-Blood glucose, prothrombin time.
-Urine analysis.
-X-ray on the chest.
-Spinal tap (meningitis (coma, fever)
Once emergency procedures have been performed and
the poisoned patient is stabilized, or at least
is out of immediate danger, additional steps can
be taken to remove the poison, prevent a delay
absorption, enhance excretion, or administer a
specific antidote.

59
III-Prevent absorption and removal of poison
60
A)-Topical decontamination

Prior to the assessment of the patient, you MUST
be
sure the toxin is not toxic to you.
If the patient needs to be decontaminated, do
this PRIOR
to your assessment. No need for 2 or more
patients.
-Generally achieved by undressing patients and
washing them thoroughly with copious amounts
of water
-Should occur outside of ER (Pt should initially
be in isolated area)
-All towels and clothing should be put into
hazardous waste bags
1- Skin decontamination
Rapid decontamination is needed specially if the
poison is a corrosive or is easily absorbed from
the skin.
-Wash contaminated areas as well as exposed areas
with warm water or saline , with careful washing
of the skin, behind ears, under nails, and skin
folds.
1-Phenol Can apply olive oil .
2-Oxalic acid Soak the affected area with
solution of calcium gluconate.
3-Organophosphorus Soap water

61
(No Transcript)
62

2-Eye decontamination
i- Irrigation of the eyes with large
amounts of water.
ii- The eye is usually affected by a
corrosive apply anesthetic drops
e.g. cocaine HCI (Xylocaine)
iii-After first aid treatment the patient
should be referred to an
ophthalmologist in order to asses and treat any
inflammation.
3- Demulcents
Many plants and chemicals cause oral and gastric
mucosa irritation but no serious toxicity.
Management for these acute ingestion may include
ice cream or milk. Egg whites, which serve as a
source of readily available protein, have been
given for corrosive intoxications.

63
B)-If the poison was ingested

Three general methods involve removing toxin from
stomach via the mouth, binding it inside gut
lumen, or mechanically flushing it through GIT.
Each method has benefits and risks. However, we
usually begin with dilution
1- Dilution
- By using water milk immediately after
poisoning.
- This reduce the gastric irritation induced by
many ingested poisons.
- Milk provides dilution and is also a demulcent.

2- Delay gastric emptying
a)-Emesis
induced by
i-Syrup of Ipecac orally administered
ii- Apomorphine given by s.c. injection
(most rapid) ,but cause CNS depression
iii- Liquid detergent 30-45 ml in 120-240 ml
juice or water.
Contraindications
1- Ingestion of a strong acids ,alkalis or
hydrocarbon e.g. kerosene????????
2-Do not induce vomiting if the patient is
Unconscious or comatose, convulsant , has sever
cardiovascular disease or, emphysema or under 6
months of age??
b)-Gastric lavage
Gastric lavage is only effective when
ingestion of the poison is discovered within 1
hours except salicytates may be within 4-6 hours
(it sticks to the mucous membrane).This procedure
is often reserved for patients with impaired
consciousness and uncooperative or when ipecac
failed to produce emesis.
Solutions used sodium bicarbonate, saline,
tannic acid or water.
Indicated for
Heavy metals
Iron
Lithium
Sustained or delayed release formulations
Contraindications

3-Adsorbents
activated charcoal, starch and flour .
Activated charcoal is administered orally to
adsorb or bind toxins and allows them to pass
from the GIT without being absorbed into the
systemic circulation.
Contraindications
1- Absence of the bowel sounds .
2- Intestinal obstruction.
3- Many preparation add sorbitol to the mixture
,so repeated dose lead to diarrhea,
dehydration, hypernatraemia in children and
elderly.
4-DO NOT give with syrup of ipecac because it
will bind it .
4-Cathartic Agents
Such as Magnesium citrate, sodium sulfate ,
polyethylene glycol and sorbito1. Careful
monitoring of the fluid and electrolyte status is
necessary.
Contraindications
-Catharsis should not be attempted when the
poison is strongly corrosive, the patient has
electrolyte disturbance or bowel sounds are
absent.
-Magnesium containing cathartics-should not be
used in cases of renal failure because of the
possibility of causing CNS depression due to
accumulation of high concentration of magnesium
in the serum.
-Sodium containing cathartics are, likewise, best
avoided by persons with congestive heart failure
-Oil cathartics e.g. castor oil may increase the
absorption of fat-soluble poisons such as
pesticides.

66
IV-Enhance Excretion
67

IV-Enhancement of Excretion
1-Forced Diuresis its useful to enhance renal
elimination of poisons. Saline to expand fluid
volume and furosemide may be used to enhance
diuresis.
2-Acid Diuresis with ammonium chloride can
enhance the elimination of weak bases e.g.
phencyclidine, amphetamine, strychnine and
quinidine.
3-Alkaline Diuresis with Sodium bicarbonate can
remove weak acids (e.g. salicylates and
Phenobarbital).
4-Dialysis and Hemoperfusion
-As adjuncts for management of severely
intoxicated
patients.
-Dialysis and hemoperfusion should never replace
more
specific antidotes.
-These procedures would be of little value in
treating acute
ingestions of cytotoxic poisons such as cyanide
which produce
toxic effects very rapidly.
Dialysis reserved for specific toxins
salicylates, methanol,
ethylene glycol, lithium, theophylline, amanita
(mushrooms)
Benefits removal of toxins already absorbed by
gut

68
V-Antidote
69

V- Specific Antidote
Chemical antidotes
In oxalic acid poisoning, absorption produces
renal damage. Calcium salts react with oxalic
acid to yield a poorly soluble compound, calcium
oxalate, which passes through the intestine
without being absorbed.
Antidotes such as dimercaprol (BAL) and
deferoxamine form chemical chelates with heavy
metals. Chelated complexes are water soluble and
readily excreted by the kidney.
Receptor antidotes
Compete with the poison for receptor sites.
-Naloxone reversal of morphine-induced
respiratory depression
-Cholinergic blockade by atropine (parathion
poisoning).
-For atropin or other anticholinergic poisons,
physostigmine is a specific antidote.
Dispositional antagonism
In acetaminophen overdose, a toxic metabolite is
conjugated with glutathione(a sufhydryl
( sH group donor). When glutathione reserves are
depleted..hepatotoxicity.
N-acetylcysteine is also a source of sulfhydryl
groups which serve the same function as
endogenous glutathione. Acetaminophen and its
toxic metabolite are therefore detoxified and the
liver cells are not subjected to prolonged
toxicity.
Function (physiologic) antagonist
Epinephrine reverses the bronchoconstriction due
to anaphylactic reaction following administration
of certain drugs.