PHA 0154 Toxicology Color 2014

PHA154:ANS/CNS Spring2014
1
General Principles of Toxicology General Principles of Toxicology
Dr. Charles Breese
Office: 204 McGlothlin Hall
DEPARTMENT OF PHARMACEUTICAL SCIENCES
cbreese@ACP.edu
Dr. Charles Breese
Office: 204 McGlothlin Hall
DEPARTMENT OF PHARMACEUTICAL SCIENCES
cbreese@ACP.edu
Resources
Required textbooks:
*Katzung BG, Basic and Clinical Pharmacology, 12e Edition. McGraw Hill, 2012
**Williams DA, Lemke TL, Foye's Principles of Medicinal Chemistry, 7e Edition, Lippincott, Williams and Wilkins, 2013
*Klaassen CD and Watkins III JB, Casarett & Doull's Essentials of Toxicology, 2e Edition. McGraw Hill, 2010
Recommended references:
*Brunton LL, Editor in Chief, Goodman & Gilmans: The Pharmacological Basis of Therapeutics, 12e Edition. McGraw Hill, 2011
* Barrett KE, Barman SM, Boitano S, Brooks H, Ganongs Review of Medical Physiology, 24e Edition. McGraw Hill, 2012
*McPhee, Hammer GD, Pathophysiology of Disease, An introduction to Clinical Medicine, 6e Edition. McGraw Hill, 2010
**Lemke TL, Review of Organic Functional Groups: Introduction to Medicinal Chemistry 5e Edition, Lippincott, Williams and
Wilkins, 2012
*Texts available on Access Pharmacy; **Texts available on LWWHealth Library
2
Introduction to Toxicology
Describe qualitative and quantitative terms used to express the
relative toxicity of a substance
Describe the effects of plasma binding proteins on toxin distribution
Describe the components which comprise the basic toxidromes
used for clinical identification of drug overdose
Compare the advantages and disadvantages of approaches to treat
the poisoned patient, particularly Gastrointestinal decontamination
Define absorption, distribution, metabolism and excretion of
toxicants
Explain the basic toxicokinetic parameters which are used to
describe a toxicant effect in the body
Explain the significance of biotransformational reactions as a
determinant of the toxicokinetic and toxicodynamic activities of
chemicals
3
What is there that is not poison?
All things are poison and nothing
[is] without poison. Solely the
dose determines that thing that
is not a poison.
PARACELSUS (1493-1541)
On the Miners Sickness and other Diseases of Miners (1567),
by Paracelsus.
Included treatment and prevention strategies for workers in the
mining and metal working industries
4
DEFINITIONS
TOXICOLOGY: The science that investigates the
adverse effects of chemicals or xenobiotics on
health
Xenobiotic: From the Greek xeno () for foreign
and bios () for life.
POISON TOXIN - TOXICANT: Any agent
capable of producing deleterious response in a
biological system, seriously injuring function,
or causing death.
Also includes plants (Phytotoxins), animals (Zootoxins),
and bacteria (Bacteriotoxins)
Ever y known chemical has the potential to be a
toxicant if present in a suf f i c i ent amount .
5
Epidemiology
Over 4 million poisonings occur annually.
10% of ED visits and EMS responses
involve toxic exposures.
70% of accidental poisonings
occur in children under
6 years of age
40% between 1-3 years of age
80% of attempted suicides
involve a drug overdose.
6
How Xenobiotics Cause Toxicity
Some xenobiotics cause toxicity by
disrupting normal cell function:
Bind and damage proteins
Structural, enzymes, receptors
Bind and damage DNA
Leading to mutations
Bind and damage lipids
React in the cell with oxygen to form
free radicals
Damages lipids, proteins, and DNA
7
Examples of Environmental and
Toxicological Health Hazards
Chemical
Pesticides, industrial discharges, household
cleaners, cosmetics, dr ugs
Physical
Fire, explosions, injuries
Biological
Microbes, poisonous plants and animals
Nuclear/Radioactive
Nuclear weapons and power plants, radon gas
8
Scope of Toxicology:
Different Branches
Biomedical:
Mechanisms of actions
Effects of exposure
Understanding biological
responses through
model toxic compounds
Public Health:
Recognition and
identification of hazards
Occupational exposure
Development and use of
pesticides
Regulatory:
Development of
exposure standards
Detection methods
Environmental:
Chemical effects on
plants, animals &
ecosystems
Clinical:
Development of
antidotes & treatments
Recognition of exposure
9
Areas for Regulatory Toxicologists
FDA - Food and Drug Administration
Responsible for drugs, cosmetics and food additives sold in
accordance with the Federal Food, Drug and Cosmetic Act (FDCA).
Note that herbal supplements and natural products escape
regulation because they are not strictly additives.
EPA - Environmental Protection Agency
Regulates chemicals under the Federal Insecticide, Fungicide
and Rodenticide Act (FIFRA), Safe Drinking Water Act, Clean Air
Act (among lots of others)
OSHA- Occupational Safety and Health Administration
Monitors safety in the workplace
DOT - Department of Transportation
Ensures materials shipped in interstate commerce are labeled
and packaged appropriately
10
Risk Assessment
A hazard can not constitute a
risk unless there is exposure
1. Hazard identification
A hazard is a source of risk
2. Dose-response assessment
Amount of a hazard that can cause harm
3. Exposure assessment
The likelihood or possibility of exposure
4. Risk characterization
The likelihood or possibility of suffering an
injury, disease, or death from a hazard
11
Fundamental Rules of
Toxicology
Exposure must first occur for the chemical to
present a risk.
Hazard + Exposure = Risk
The magnitude of risk is proportional to both the
potency of the chemical and the extent of
exposure.
The dose makes the poison
The amount of the chemical at the target site(s)
determines the chemicals toxicity.
Route of administration, duration or frequency of
exposure, and chemical characteristics determine dose
12
Toxicokinetics & Toxicodynamics
Toxicokinetics:
How the body acts on the drug
Absorption, distribution,
excretion, and metabolism
Toxicodynamics:
How the drug affects the body
The injurious effects of these
substances on vital functions.
13
(ADME)
Reabsorbtion
Bioactivation &
Active metabolites
Detoxification
& Elimination
14
Introduction to Toxicology:
Routes of Exposure
Rapidity of Response Will Typically
Depend on the Route of Exposure
Intravenous (IV)
Inhalation
Intraperitoneally (IP)
Subcutaneous (SC)
Intramuscular (IM)
Oral (ingestion)
Topical
Most Rapid Most Toxic
Least Rapid Least Toxic
}
Underlined routes are
the most common
routes of exposure
What are some exceptions to slow toxicity with topical exposure and why?
15
Bioaccumulation and
Biomagnification
Bioaccumulation:
The ability of cells to
absorb and store
selected molecules
Biomagnification:
The toxin level
accumulates in those
organisms higher up in
the food chain (e.g. DDT)
16
Absorption, Distribution,
Metabolism, and Excretion
Once a living organism has been exposed
to a toxicant, the compound must get into
the body and to its target site in an active
form in order to cause an adverse effect.
The body has defenses:
Membrane barriers
Passive and facilitated diffusion, active transport
Biotransformation enzymes, antioxidants
Elimination mechanisms
17
Absorption:
Ability of a chemical to enter the blood
(blood is in equilibrium with tissues)
Most common routes of
toxicological exposure
Inhalation - readily absorb gases into the blood
stream via the alveoli. (Large alveolar surface, high
blood flow, and proximity of blood to alveolar air)
Ingestion - absorption through GI tract stomach
(acids), small intestine (long contact time, large surface
area--villi; bases and transporters for others)
Dermal - absorption through epidermis (stratum
corneum), then dermis; site and condition of skin
18
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, organs of
transformation, and organs of elimination
Rate of distribution (rapid) dependent upon
Lipid solubility of the drug
Ionization of the drug
Perfusion of the reactive tissue
Distribution may change over time
19
Distribution:
Storage and Binding
Storage in Adipose tissue - Very lipophilic
compounds (DDT, organophosphates) will
store in fat. Rapid mobilization of the fat
(starvation) can rapidly increase blood
concentration.
Storage in Bone - Chemicals analogous to
Calcium--Fluoride, Lead, Strontium.
Binding to Plasma proteins - Can displace
endogenous compounds. Only free toxin is
available for adverse effects or excretion.
20
Special Aspects of Toxicokinetics
Volume of Distribution (Vd):
The Vd is the ratio of the dose present in the
body and its plasma concentration
Chemicals with large Vds accumulate in tissues and
will have a relatively low plasma concentration with
regard to the administered dose.
Chemicals that accumulate in organs due to lipid solubility,
or by active transport or binding to tissue molecules
Drugs with a small Vd (<10 L) are mainly confined to
the intravascular fluid or blood.
The molecule is too large to leave this compartment.
The molecule binds to plasma proteins (e.g. albumin)
Variation of Vd mainly affects the peak plasma
concentration of the drug.
21
Special Aspects of Toxicokinetics
Clearance (Cl):
Rate of drug elimination divided by plasma concentration,
giving a volume of plasma from which drug is completely
removed per unit of time
Drug elimination generally results from liver metabolism and/or
excretion by the kidneys
CL= Renal CL + Hepatic CL + other CL (minor)
In planning a detoxification strategy, it is important to
know the contribution of each organ to clearance.
If a drug is 95% cleared by liver metabolism and 5% by renal
excretion, even a large increase in urinary excretion of the drugs
metabolites will have little effect on overall elimination.
Toxicants can alter the usual pharmacokinetic processes due
to organ toxicity, changes in protein binding, etc.
Change in kinetics may markedly prolong serum half-life and
increase toxicity.
22
Target Organs:
Adverse effects dependent upon concentration
of active compound at the target site
Not all organs are affected equally
Greater susceptibility of the target organ (receptors)
Higher concentration of active compound (Vd, blood flow)
Metabolic processes that might activate toxins
Liver - high blood flow, oxidative reactions
Kidney - high blood flow, concentrates chemicals
Lung - high blood flow, site of exposure
Neurons - oxygen dependent, irreversible damage
Myocardium - oxygen dependent
Bone marrow, intestinal mucosa - rapidly divide
23
Target Sites:
Mechanisms of Action
Adverse effects can occur at the level of the
molecule, cell, organ, or organism.
Molecularly, chemicals can interact with:
Proteins Lipids DNA
Cellularly, chemicals can
Interfere with receptor-ligand binding
Interfere with membrane function
Interfere with cellular energy production
Bind to biomolecules
Perturb homeostasis (Ca
++
)
24
Metabolism:
The process by which the administered chemical or
toxin (parent compound) is modified by the organism
by enzymatic reactions:
Primary objective - make chemical agents more
water soluble and easier to excrete:
Decreased lipid solubility Decreased amount at target
Decreased toxicity
Increased ionization Increased excretion rate
Decreased toxicity
Metabolism desirable once a drug has reached the site of
action otherwise may produce its effect longer than
desired or become toxic.
Bioactivation - Biotransformation of some drugs or toxins
can result in the formation of reactive metabolites
25
Metabolic Biotransformations
Drug / Toxin Metabolism
Principal site of xenobiotic metabolism is the liver
Secondary sites include the kidneys, lungs, GI tract
Reactions include oxidation, reduction, hydrolysis,
hydration, conjugation and condensation.
Drug metabolism is divided into 2 Phases:
Phase I - which are the functionalization reactions
Introduces functional groups, often by oxygenation or hydrolysis
Makes the toxicant more water soluble
Phase II - which are the conjugation reactions
Links with a soluble endogenous agent (conjugation)
Generates highly polar derivatives (called conjugates) for excretion
Phase II reactions occur at reactive sites and phase II metabolites are usually
inactive
26
General Scheme of Xenobiotic Metabolism
Phase I: Decrease biological activity and increase excretability
Phase II: conjugation reactions to increase polarity and excretability
Kidney Excretion
UGT
H
2
O CYP
27
Phase I
Performed by the microsomal mixed-function oxidase
system (cytochrome P-450 dependent)
CYP450s are found in microsomes (endoplasmic
reticulum) of many cells (liver, kidney, lung, and
intestine) and are able to carry out different
functionalization reactions.
CYP450s represents a family of enzymes that
catalyze the same reaction on different substrates.
Catalyzes either hydroxylation or epoxidation of
various substrates.
28
Cytochrome P450s
Currently 50 known human P450s
Subdivided into families of similar gene sequences
For drug and toxin (xenobiotic) metabolism,
families 1- 4 are the most important:
CYP1: Polycyclic aromatic hydrocarbons (PAHs),
CYP2: Many drugs
CYP3: >50% of drugs in clinical use that are oxidized
CYP4: Peroxisome Proliferators
Most drugs metabolized by 5 primary
CYP450 enzymes:
CYP1A2 CYP2C CYP3A4
CYP2D6 CYP2E1
29
Metabolic Transformations:
Phase II Reactions
Conjugation reactions
Glucuronidation, Acetylation,
Sulfation, Methylation, Amino
Acid Conjugation, Glutathione
Conjugation
Generates highly polar
derivatives for excretion
Phase II reactions occur
at reactive sites
Phase II metabolites
are usually inactive
30
Metabolic Transformations:
Consequences
Body tries to remove compounds by
increasing polarity and hence facilitate
excretion
This can have several effects:
Changes in pharmacological effect of drug
Increased or decreased pharmacological action
Active or inactive metabolites
Can use metabolism to form active drug at site of action
Excretion and elimination
Toxicity
Production of toxic metabolites
31
Excretion:
Toxicants are eliminated from the
body by several routes
Urinary excretion
water soluble products are filtered out of the blood
by the kidney and excreted into the urine
Exhalation
Volatile compounds are exhaled by breathing
Biliary Excretion via Fecal Excretion
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.
Other routes:
Milk, sweat, saliva
32
Measures of Toxicity
Toxicity of chemicals is determined in the laboratory
The normal procedure is to expose test animals
By ingestion, application to the skin, inhalation, or gavage
in order to introduce the material into the body
By placing the test material in the water or air of the test
animals environment
Toxicity is measured as clinical
endpoints which include:
Adverse reactions
Mortality (death)
Teratogenicity (ability to cause birth defects)
Carcinogenicity (ability to cause cancer)
Mutagenicity (ability to cause heritable change in the DNA)
Thalidomide
33
Measures of Acute Toxicity:
The Median Lethal Dose or
Concentration (LD
50
and LC
50
)
LD
50
The dose of a chemical
which produces death in
50% of a population of test
animals to which it is
administered by any of a
variety of methods in a
specified time frame.
Normally expressed as milligrams
per kilogram body weight
LC
50
The concentration of a
chemical in the
environment (air or water)
which produces death in
50% of an exposed
population of test animals
in a specified time frame.
Normally expressed as milligrams
per liter of air or water (or as ppm)
The primary measure of mortality LD
50
and LC
50
34
34
Measures of Toxicity: The Median Lethal
Dose / Concentration (LD
50
)
Treat test subjects to series of different dosages
of the active ingredient and each of its formulated
products
Amount of a chemical that it takes to kill 50%
of the test population
Generally expressed as milligrams of chemical per
kilogram of body weight of the test animal
The less you need to cause a toxic effect
the more toxic the substance is
Thus an LD
50
of 25 mg/kg is more toxic than is
an LD
50
of 6,000 mg/kg
HIGHER LD
50
= Lower the Toxicity
35
APPROXIMATE ACUTE LD
50
(mg/Kg) of
Representative Chemical Agents
Water 80,000
Sodium Chloride 4,000
Household bleach 2,000
Aspirin 1,700
Morphine Sulfate 900
Phenobarbital Sodium 150
Picrotoxin 5
Strychnine Sulfate 2
Nicotine 1
d-tubocurarine 0.5
Tetrodotoxin 0.10
Dioxin 0.001
Botulinum toxin 0.00001
Not very
toxic
Highly
toxic
36
Dose-Effect Curves:
Quantal Responses
Dose-Effect Curves:
Quantal Responses
Graphically expresses the frequency that a
defined effect (e.g. death) occurs in a
given population at a given dose.
Typically has a normal distribution
Also expresses the cumulative frequency
with which an effect occurs in a population
Graphically expresses the frequency that a
defined effect (e.g. death) occurs in a
given population at a given dose.
Typically has a normal distribution
Also expresses the cumulative frequency
with which an effect occurs in a population
37
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Cummulative Percent Dead at each Dose
Percent requiring a specific dose for death
Cummulative Percent Sleeping at each Dose
Percent requiring a Specific Dose for Inducing Sleep
Cumulative Frequency Distribution
For Quantal (all-or-none) Effects
Quantal
Responses
Cumulative
Percent
The quantal dose-effect
curve can define the
median effective dose
(ED50), or the dose at
which 50% of individuals
show the specified effect.
The dose required to
produce a toxic effect in
50% of animals is called
the median toxic dose
(TD50).
If the toxic effect is death
of the animal, the TD50
defines the median
lethal dose (LD50).
Shows variation in the
minimum or threshold
dose for individuals in a
population.
ED
50
TD
50
LD
50
38
Measures of Toxicity:
Usage of an LD
50
value
Effective dose (ED
50
)
Toxic Dose (TD
50
)
Lethal Dose (LD
50
)
39
Therapeutic Index
The therapeutic index is a ratio comparison
of the amount or dose of a therapeutic agent
that causes the therapeutic effect to the amount
or dose that causes drug toxicity or death.
TI (clinical) = TD50 / ED50
TI = LD50 / ED50
40
LD
50
and the Therapeutic Index (TI)
Quantal dose effect curves
permit an analysis of the
margin of safety for a
specific drug.
In animal studies, the
therapeutic index is
generally defined as the
ratio of the LD50 (lethal) to
ED50 (effective).
TI = LD50 / ED50
TI = LD50 / ED50 = 8.5 / 2.5 = 3.4
In human studies the
clinical TI is defined as
the ratio of the TD50 (toxic)
to ED50 (effective).
Clinical TI = TD50 / ED50
t
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20
40
60
80
100
Cummulative Percent Dead at each Dose
Percent requiring a specific dose for death
Cummulative Percent Sleeping at each Dose
Percent requiring a Specific Dose for Inducing Sleep
Quantal
Responses
ED
50
TD
50
LD
50
What happens to the TI if the LD50 or TD50 curve shifts to the right? or Left?
Cumulative
Percent
41
Important Notice
Measures of acute lethality may not accurately
reflect the full spectrum of toxicity, or hazard,
associated with exposure to a chemical.
Some chemicals with low acute toxicity may have
carcinogenic effects at doses that produce no
evidence of acute toxicity.
But one can get very, very sick without dying. Does
this mean the compound is not toxic?
Noit only means that dose wont kill you!
It is important to know what the definition
means. The LC
50
is often a measure of acute
(short-term) toxicity.
42
Exposure: Duration
Acute < 24hr usually 1 exposure
Subacute 14 d-1mo repeated doses
Subchronic 1-3mo repeated doses
Chronic > 3mo repeated doses
Over time, the amount of chemical in the
body can build up, redistribute, and
overwhelm repair and removal mechanisms,
increasing the long-term toxicity of the agent.
Bioaccumulation
43
Toxidromes
Physiologic fingerprints that occur in the form of
clinical syndromes or groups of symptoms which
typically occur together in response to exposure to
one of a pharmacologically similar group of agents.
Useful in determining the class of agents involved in
an unknown poisoning.
The most important clinical toxidromes:
Cholinergics
Anticholinergics
Sympathomimetics
Sedative/ Hypnotics
Opiates
Tricyclics (TCAs)
Acetaminophen
and Salicylates
44
Scenario
A mother tells you that she arrived home last Wednesday to discover
that the lawn care company had sprayed. There was a strong odor,
and liquid could be seen on the grass and furniture. After playing
outdoors that afternoon with her child, the child developed nausea
and vomiting, with sweating, but no fever and mild skeletal muscle
tremor. Her pediatrician diagnosed her child with flu (due to a GI
virus). However, the mother is asking if the pesticides may have had
something to do with her childs illness.
Do you think that pesticide poisoning (or poisoning by other environmental
toxicants) could be misdiagnosed?
What is the toxidrome observed in this child?
If the child in this scenario did develop illness from the pesticides, why didnt her
mother get sick?
What types of environmental health effects may mimic other conditions.
What types of child behavior may increase susceptibility to environmental
toxicants.
45
Oxidative Stress and Diseases
Associated with Free-Radical Injury
Cells has defenses against
damage by ROS (Reactive oxygen
species) and RNOS (Reactive
nitrogen-oxygen species), such as
Antioxidants and enzymes
Amyotrophic lateral
sclerosis (ALS)
Ischemia/reperfusion injury
Alzheimers disease
Parkinsons disease
OXPHOS diseases
(mitochondria)
Diabetes
Aging
46
Oxidative Stress and Free Radicals
A free radical is any species capable of
independent existence that contains one or
more unpaired electrons.
Free radicals extract e
-
from other molecules
Free Radicals can be formed by the:
Loss of a single electron from the non-radical:
X e
-
+ X
. +
Gain of a single electron by the non-radical:
Y + e
-
Y
. -
47
Oxygen Free Radicals (ROS)
Reactive Oxygen Species (ROS) are a
natural occurrence:
Accidental products of nonenzymatic and
enzymatic processes
Deliberate production by immune cells for
killing pathogens
UV irradiation, pollutants
Spontaneous or enzymatic
Oxygen is an important free radical
generator
It has a tendency to form toxic
reactive oxygen species (ROS)
Superoxide (O
2
-
)
Hydrogen peroxide (H
2
O
2
),
Hydroxyl radical (OH)
48
Conversion of
Cellular Oxygen
Oxygen is reduced
cellularly to water in
4 sequential steps
Free radicals can be
generated in several
placing during this
process (in red).
49
Oxygen Radicals
Hydroxyl radical (OH
.
)
Most reactive of biologically important radicals and can
readily oxidize cellular macromolecules
Generated by ionizing radiation
H
2
O 2 OH + H
Generated from hypochlorous acid (HOCl) reacting with O
2
-
HOCl + O
2
-
O
2
+ Cl
-
+ OH
Produced from H
2
O
2
by neutrophils to destroy invading organisms
Generated by reactions with transitional metals such as Fe
and Fe containing proteins
Superoxide radical (O
2
-
)
Less reactive than OH
.
and can be both reducing and oxidizing.
Generated by uncoupling of mitochondrial electron transport,
cytochrome P450 metabolism
Cannot diffuse far from the site of origin
Important in the generation of more reactive oxidants such
as OH from H
2
O
2
(Haber-Weiss and Fenton reactions)
50
Formation of the reactive oxygen species OH
H
2
O
2
(Hydrogen peroxide) is not a free radical, but
generates free radicals by two nonenzymatic reactions
which can form OH by transfer a of single e
-
Using superoxide via the Haber-Weiss reaction
Transition metals (e.g. Fe2
+
) via the Fenton reaction
H
2
O
2
diffuses freely into and through cell membrane
51
Nitrogen Containing Radicals (RNOS)
Nitric oxide (NO) and
Peroxynitrite
NO is formed by the enzymes
nitric oxide synthase which
converts L-arginine to NO
and L-citrulline.
NO is not very reactive with
non-radical species but
rapidly reacts with O
2
- to form
the strong oxidant
peroxynitrite (ONOO-)
NO + O
2
- ONOO-
52
Nitrogen Containing Radicals (RNOS)
Peroxynitrite (ONOO-)
ONOO- is thought to form
through NO reaction with O
2
-
ONOO- produces damage by
decomposing at physiological
pH to reactive species with
reactivity similar to OH and NO
2
.
ONOO- is a good nitrating agent
and able to remove protons to
create carbon centered radicals
Strong oxidizing agents that are
not free radicals can generate
NO
2
(nitrogen dioxide), which is
a radical
53
Phagocytes use free radicals
Phagocytic cells of the immune system release reactive
oxygen species as part of antimicrobial defense:
NADPH oxidase forms O
2
-
H
2
O
2
and OH (1,2,4)
Myeloperoxidase forms HOCl OCl
-
(3)
iNOS activated, makes NO RNOS (5,6)
Phagocytes also
mediate immunological
responses by releasing
lysozymes, peroxidases,
and elastases to
damage invading
microorganisms.
54
Cellular Consequences of ROS/RNOS
Oxygen radicals react
with cell components:
Lipid peroxidation of
membranes
Increase Ca
2+
permeability
mitochondrial damage
Cys SH and other amino
acids of proteins are
oxidized and degraded
DNA oxidized breakage
55
Lipid Peroxy
Radicals
Lipid peroxidation
Free-radical chain reaction:
A. Initiation by OH attack of
polyunsaturated lipid lipid
B. Free-radical chain reaction by
reaction with O
2
C. Lipid peroxy radical propagates,
lipid peroxide degrades
Major contributor to
ROS-induced injury
56
ROS attack proteins, peptides, DNA
Proteins
Pro, his, arg, cys, & met most
susceptible amino acids
Protein fragment, cross-link,
may aggregate, and will also
be degraded
Glutathionine (-glu-cys-gly) is
an anti-oxidant, cell defense
DNA
DNA oxidized bases mispair at
replication (G-C T-A)
DNA backbone broken
Repair mechanisms do exist
57
Cell death
Necrosis
Organelle and cell swelling, loss of integrity of mitochondrial
and plasma membranes and breakdown of cell
Necrotic also death affects the surrounding cells by the
release of lysosomal enzymes
Apoptosis
Condensation and fragmentation of chromatin, fragmentation
of cell into apoptotic bodies without rupture of mitochondrial
and lysosomal membranes
Calcium metabolism dysregulation
Damage to mitochondria by ROS/RNOS can cause calcium
release
Consequences of
Oxidative Stress
58
Oxygen Free Radicals
E.T.C.producesSuperoxideRadical,O
2
10,000percellperday!
DamagesDNAandmembranesofmitochondria
Normallythesuperoxideradicalis
deactivated:
1. SOD(superoxidedismutase)convertsO
2
to
hydrogenperoxide
2. CatalaseconvertsH
2
O
2
towaterandO
2
59
Oxygen Free Radicals:
Theory of Aging
Defensemechanismsmaybecompromised:
1. H
2
O
2
movestothenucleusofthecell
2. H
2
O
2
reactswithFe
2+
toproducehydroxylradical
3. HydroxylradicalsdamageDNAandother
cellularcomponents
Hydroxylradicalcausesthemostdamage
4. Fe
3+
canoxidizesuperoxideradicalsbacktoO
2
60
Oxygen Free Radicals:
Theory of Aging
61
Parkinsons Disease and
Neuronal Degeneration
Model for ROS and RNOS in
neuronal degradation in
Parkinsons disease:
Dopamine is reduced due to
degeneration of dopaminergic
neurons
Dopamine metabolism by MAO
(monoamine oxidase) generates H
2
O
2
Damaged mitochondria leak Fe
2+
allowing the generation of OH
Superoxide radical (O
2
-
) generated
by the mitochondria
NO and O
2
-
forms RNOS
Leads to oxidative damage
62
Cellular Defenses
Cells have defenses against oxygen toxicity:
Antioxidant scavenging enzymes (red)
Nonenzymatic antioxidants (free radical scavengers)
Compartmentalization and metal sequestration
Repair of damaged components
SOD = superoxide
dismutase
GSH = glutathione
63
Antioxidant
Scavenging Enzymes
Antioxidant scavenging enzymes:
Superoxide dismutase (SOD)
Converts O
2
- to H
2
O
2
3 isoforms:
Cytosol, mitochondria, extracellular
Catalase
Reduces H
2
O
2
to H
2
O
Prevents OH formation
mostly peroxisome
64
Antioxidant Enzymes
Glutathione peroxidase, glutathione reductase:
GSH = glutathione (-glu-cys-gly)
Cytosolic and Mitochondrial Glutathione Peroxidase
reduces H
2
O
2
, oxidizing two GSH groups GSSG
Reductase recycles the glutathione, with NADPH
65
Nonenzymatic Antioxidants
Vitamin E (-tocopherol) is antioxidant:
Lipid-soluble, protects against lipid peroxidation in membranes
Nonenzymatic terminator of free-radical chain reaction
Vitamin C (ascorbate) is antioxidant:
Can donate e- to vitamin E to regenerate Vitamin E
Water-soluble, circulates blood and fluids to access membranes
Vitamin C is also redox coenzyme for collagen synthesis & other reactions
Carotenoids (-carotene, precursor of vitamin A):
Antioxidants found in fruits and vegetables
May slow cancer, atherosclerosis and protect against macular degeneration
Flavonoids are antioxidants:
May inhibit enzymes responsible for ROS
May chelate Fe and Cu; free-radical scavengers
Endogenous antioxidants: melatonin and uric acid
66
Shock due to hemorrhage or internal
bleeding
Hypovolemia due to vomiting, diarrhea or
vascular collapse
Hypothermia worsened by i.v. fluids
administered rapidly at room temperature
Cellular hypoxia in spite of adequate
ventilation and O
2
admin. due to CN, CO or
H
2
S poisoning
Common Causes of Death in the
Acutely Poisoned Patient
67
Process for Treating Poisoned Patients
Approach to Treatment:
History and Physical Examination
Recognition that poisoning has occurred, identification of
agents involved, & assessment of severity of toxicity
Initial Management
Remove the patient from the toxic environment.
Protect rescuer safety.
Supportive care if necessary (ABC)
Alter absorption or metabolism, or increase
elimination
Decontamination
Emesis, orogastric lavage, charcoal, or whole bowel irrigation
Diuresis, Dialysis and Hemoperfusion
Antidotes
68
Supportive Care (ABCs)
Immediate concern is to keep the patient alive!!
Ensure vital functions are stable and recorded frequently
Airway endotracheal tube if needed, watch for fluid
accumulation in airway (e.g. aspiration of vomit)
Breathing Supplemental oxygen, bag valve mask (BVM)
and respirator.
Circulation Monitor HR, BP, and ECG; watch for
arrhythmias, cardiac arrest and shock
After stabilization, determine identification of the drug,
overdose, poison, or toxin.
Take appropriate measures to manage specific toxin
69
HISTORY
If Available
Name and amount of agent(s)
Type of agent (immediate release, sustained
release)
Time and route of ingestion/exposure
Any co-ingestants (including prescription, OTCs,
recreational drugs, herbals, chemicals, metals)
Reason for ingestion/exposure (e.g. accident,
suicide attempt, therapeutic misuse, occupational)
Search exposure environment for pill bottles, drug
paraphernalia, suicide note, chemical containers
70
PHYSICAL EXAM & VITAL SIGNS
Assess Patient for Possible Toxidromes:
Respiratory rate
Tachypnea: Salicylates
Bradypnea: Opioids
Respiratory depth
Hyperpnea: Salicylates
Shallow respirations: Opioids
Temperature
Hyperthermia: Serotonin syndrome, NMS, malignant
hyperthermia, anti-cholinergic toxidrome, salicylates
Hypothermia: Narcotic or sedative-hypnotic agents
71
PHYSICAL EXAM
PUPIL Size:
Large: Anticholinergic or sympathomimetic toxidrome
Small: Cholinergic toxidrome
Pinpoint: Opioid toxidrome
Nystagmus: Check for horizontal, vertical, or rotatory
(ethanol, phenytoin, ketamine, PCP)
SKIN:
Temperature
Hyperpyrexia: Anticholinergic or sympathomimetic
toxidrome, salicylates
Moisture:
Dry: Anticholinergic toxidrome
Moist: Cholinergic, sympathomimetic
Color: Cyanosis, pallor, erythema
72
PHYSICAL EXAM
OVERALL EXAM
Physiologic stimulation:
Everything is up: Elevated temperature, HR, BP,
RR, agitated mental status: Sympathomimetics,
anticholinergics, central hallucinogens, some
drug withdrawal states
Physiologic depression:
Everything is down: Depressed temperature, HR,
BP, RR, lethargy/coma: Sympatholytics,
cholinergics, opioids, sedative-hypnotics
Mixed effects:
Polysubstance overdose, metabolic poisons: toxic
alcohols, salicylates, hypoglycemic agents
73
TOXIDROMES
Anticholinergic
Cholinergic
Opioid
Sympathomimetic
Sympatholytic
Serotonin syndrome
Sedative-hypnotic
All of these toxidromes
will be covered in detail
when we cover these
drug agents during the
course. It is imperative
that as a pharmacist
you recognize possible
overdose of these
various agents
74
Poison and the Suicidal Patient
Estimated that there are 25 attempted
suicides for every one suicide
Poisoning was the leading mechanism of
self-inflicted injury for both males (69%) and
females (84%).
Leading mechanisms of successful suicide:
Males: firearms (63.5%), suffocation (19.0%),
and poisoning (11.6%).
Females: poisoning (38.8%), firearms (36.1%),
and suffocation (17.2%).
75
General Treatment
ED and the suicidal patient
Know local procedures and laws
Laws for protective custody vary widely
Evaluation by a qualified mental health
professional
Constant staff observation & security
Discharge plan
20 percent of those who attempted suicide in the
past will try again in the future
Restriction Education
76
GI Tract Decontamination
Syrup of Ipecac (not used any more)
Gastric lavage only within 1
st
hour
Activated charcoal
Inert
Reduces bioavailability of drug
Not used w/ hydrocarbons or corrosives
Cathartics decrease transit time
WBI (whole bowel irrigation)till clear
77
Prevention of Toxin Absorption
Emesis: Previously indicated after oral
ingestion of some chemicals
Must consider time since chemical ingested
Must consider the type of chemical ingested
Contraindications:
Ingestion of corrosives such as strong acid or
alkali (risk of ruptures)
If patient has ingested a petroleum distillate
If patient is comatose, delirious, or convulsing
78
Emesis: Syrup of Ipecac
Non-prescription drug of choice for
poisoning in US for 50 years
Root of the Ipecacuanha plant
Stimulates chemoreceptor trigger zone by interacting with
GI mucosa
Limited evidence to its clinical effectiveness
Research failed to show benefits to children treated with
Syrup of Ipecac
Emesis in general is not considered a viable option
More harm than good
Discontinued in the US
79
Gastric lavage:
Insert tube into stomach and washout stomach with
saline to remove unabsorbed poison
Only for patients who have ingested a toxic agent within
the previous hour
There are significant downsides to gastric lavage:
Aspiration, enhancement of drug absorption, and
physical trauma to the GI tract.
Contraindications
Corrosives such as strong acid or alkali,
hydrocarbons or petroleum distillates
If patient is comatose or convulsing
Generally not attempted with very young children
80
Activated Charcoal
Decreases toxin absorption
Activated charcoal will adsorb many poisons
The activated charcoal has a fine particle size.
Increases the overall surface area and
adsorptive capacity of the charcoal
Because charcoal is not absorbed, stays
inside the GI tract and eliminates the toxin
when the person has a bowel movement
Purported to be superior to gastric lavage, but
overall effectiveness is questionable
Does not help once toxin is absorbed.
81
Limitations of Activated Charcoal
Important: the chemical or drug CAN NOT
already be absorbed by the GI tract
Generally not a substitute for more aggressive systemic
decontamination therapies (hemodialysis, hemoperfusion, antidotes)
NOT Useful for:
Lithium, heavy metals, strong acids and bases
Alcohols such as ethanol, methanol, isopropyl alcohol
Hydrocarbons (such as petroleum distillates)
Activated charcoal is often combined with cathartics (sorbitol
or magnesium citrate) to shorten the amount of time toxin has
to move through the system
Based on available data, routine use of a cathartic in combination
with activated charcoal is not endorsed. If used, it should be limited
to a single dose to minimize adverse effects.
82
Whole Bowel Irrigation (WBI)
Flush the entire GI tract to reduce transit time and limit
opportunity for toxins to be absorbed into blood stream
Whole bowel irrigation (WBI) cleanses the bowel by the
enteral administration of large amounts of an osmotically
balanced polyethylene glycol (PEG) electrolyte solution to
induce a liquid stool
Routinely administered through an NG tube
PEG will produce a voluminous diarrhea within a few hours.
PEG is an innocuous substance that doesn't cause fluid overload
or electrolyte abnormalities.
Potential to reduce drug absorption by decontaminating
the entire gastrointestinal tract
Elimination of packets of smuggled cocaine or heroin
Ingestion of a sustained-released drug
83
Whole Bowel Irrigation (WBI)
GoLYTELY, NuLYTELY, Colyte, TriLyte:
Polyethylene glycol (PEG) and electrolyte
solution
Generally administered by nasogastric tube
Quickly causes GI clearance
Continue until evacuate is clear
Effective for enteric-coated drugs and packets of
smuggled cocaine or heroin
Heavy metals (iron)
Other toxins which are not absorbed well by charcoal
84
Enhancement of Toxin Elimination
Enhanced Elimination: Urine
acidification or alkalinization
(Ion Trapping)
Alkalinization effective for elimination
of weak acids such as salicylates,
TCAs, barbiturates, and methotrexate
Conversely, weak bases, such as amphetamines and
PCP, can be ionized by acidification of the urine with citric
acid or ammonium chloride
Not widely used due to risk of acidosis and
rhabdomyolysis
85
Enhanced Elimination in Urine
Alkalinization or Acidification of urine
Use of an acid or base to alter the urinary pH
If a toxin has a pKa near the pH of the blood, this
manipulation can be used to change the charge status
of the toxin and possibly enhance its secretion and
elimination in urine
In an acidic medium (which urine normally is), basic
drugs are more charged and likely to be excreted,
whereas acidic drugs are less charged and more
likely to be reabsorbed.
Acidic Drugs: A-COOH H
+
+ A-COO
-
Low pH (high [H+])
High pH (low [H+])
86
Example: Urine Alkalinization
If urine is rendered alkaline, the proportion of the ionized
weak acid increases in the renal tubule, making the
drug/toxin prone to be retained in the renal filtrate and
excreted, not reabsorbed
For an acidic drug, there is a greater degree of
ionization at pH 8 than pH 7.4. Thus, elimination of a
weak acid by the kidneys is increased in alkaline urine.
Titrate NaHCO3 to maintain urinary pH of 7.5-8.0.
Since pKa is a logarithmic function then, a small change
in urine pH could have a larger effect on clearance
87
Ion Trapping
Consider a barbiturate (weak acidic drug) overdose.
Urine Blood
pH 5.3 pH 7.4
Non-ionized weak acid drug
Ionized
Urine
Under normal physiological conditions, most of acidic
drug will be converted to the unionized form in the urine
and be reabsorbed back into blood.
88
Ion Trapping
Urine Blood
pH 8.0 pH 7.4
Less Non-ionized weak acid drug
More Ionized
Urine
In presence of sodium bicarbonate, the urine is
rendered alkaline and the acidic drug will be ionized (via
removal of the acidic H
+
) and eliminated into urine
89
Select the statement that BEST explains the effect of
urinary pH on the urinary excretion of indobufen, whose
structure is shown above (weak acid, pKa=5.2):
1. Raising the pH shifts the ionization equilibrium towards
the ionized form, which facilitates reabsorption.
2. Lower [H
+
] leads to a higher level of unionized drug,
which facilitates excretion.
the ionized form, which facilitates excretion.
4. Higher [H
+
] leads to a higher level of ionized drug, which
facilitates excretion.
90
Select the statement that BEST explains the effect of urinary
pH on the urinary excretion of salicylic acid, whose structure
is shown above (weak acid, pKa = 3.0):
the ionized form, which facilitates reabsorption.
2. Lower [H
+
which facilitates excretion.
3. Lowering the pH shifts the ionization equilibrium towards
the ionized form, which facilitates excretion.
4. Higher [H
+
which facilitates reabsorption.
91
Select the statements that explain the effect of pH on the
absorption or urinary excretion of pilocarpine, whose structure
is shown above. Pilocarpine is a weak base of pKa 6.9.
A. After parenteral administration, the concentration of pilocarpine in the
aqueous humor(pH-7.8) will be lower than the concentration in the
duodenum(pH-5.5)
B. When administered as eye drop, absorption into the eye will be faster
if the drops are alkaline (pH-8.0) than if they are acidic (pH-5.5)
C. Excretion in the urine will be faster if urine pH is alkaline (pH-8.0)
than if the urine pH is acidic (pH-5.8)
D. The proportion of pilocarpine in the protonated form will be
approximately 90% at pH-5.9
E. The proportion of pilocarpine in the more lipid soluble form will be
approximately 99% at pH-8.9
Pilocarpine
92
Enhancement of
Toxin Elimination:
Hemodialysis
Blood is circulated through a
dialyzer in which a
semipermeable membrane
separates the components of
the blood from the constituents
of the dialysis fluid.
Toxins diffuse across
membrane
The [toxin] is less in dialysis
buffer than blood, so toxin diffuses
across membrane into dialysate
Poor candidates include:
High MW toxins
Toxins with high protein binding
Toxins with high volume of
distribution (Vd)
Lipophilic compounds
High tissue distribution
93
Enhancement of Toxin Elimination:
Hemodialysis
Hemodialysis is ineffective
or not very useful for:
Amphetamines
Antidepressants
Antipsychotic drugs
Benzodiazepines
Calcium channel blockers
Digoxin
Metoprolol and propranolol
Opioids
Hemodialysis is somewhat
effective for:
Lithium (not a good charcoal
binding substance)
Methanol
Ethylene glycol
Isopropanol
Salicylates
Carbamazepine
Metformin
Phenobarbital
Theophylline
Valproic acid
Please do not memorize this list!
94
Hemoperfusion
Uses hemodialysis machine - but runs blood directly
through a charcoal or absorbent-containing filter
An advantage of hemoperfusion over hemodialysis is
that the total surface area of the dialyzing membrane
is much greater with the hemoperfusion cartridges.
Blood
from
patient
ARTERY
or
VEIN
VEIN
Return
to
patient
95
Enhancement of Toxin Elimination:
Hemoperfusion
Process by which blood is
pumped through an external
cartridge
Cartridge may contain charcoal
or other absorbant
Advantageous
Faster than dialysis
Rapidly expose toxins to filtering device
Good for higher MW toxins
which may be difficult to dialyze
Good for toxins with high
protein binding levels
Poor candidates include:
Drugs with large Vd
96
What can be done if the toxin has
already reached the tissue?
Once toxin has reached site of action
(absorbed and distributed)
Supportive care may be all that can be done
ABC
Antidotes may be utilized if available
Medicinal intervention that is specific to a toxin and
is effective only for that toxin
Any substance which effectively raises the lethal
dose of a toxin
Concerns about the toxicity antidotes
97
Antagonism of the Absorbed Poison
Types of Antidotes:
Reacts with poison forming a compound with
lesser toxicity
Metal chelators
Deferoxamine for Fe poisoning
Calcium disodium edetate (EDTA)
Competes with a poison by binding to receptors
or other toxin binding sites
Naloxone for opiate overdose
Flumazenil for Benzodiazepines
Anticholinergics for organophosphate ingestion
Reduces the amount of toxin available to the
tissue (altering ADME components)
N-acetylcysteine for acetaminophen poisoning
98
Important
Antidotes
Antidote Poison(s)
N-Acetylcysteine*
Acetaminophen; best given within
810 h of overdose
Atropine Cholinesterase inhibitors
Bicarbonate
Membrane-depressant cardiotoxic
drugs (e.g., quinidine, TCAs)
Calcium Fluoride; calcium channel blockers
Deferoxamine Iron salts
Digoxin antibodies
Digoxin and related cardiac
glycoside
Ethanol Methanol, ethylene glycol
Flumazenil Benzodiazepines, zolpidem
Fomepizole Methanol, ethylene glycol
Glucagon Beta adrenoceptor blockers
Glucose Hypoglycemics
Hydroxocobalamin Cyanide
Naloxone Opioid analgesics
Oxygen Carbon monoxide
Physostigmine muscarinic receptor blockers
Pralidoxime
Organophosphate cholinesterase
inhibitors
99
Limitations of Antidotes
Must know the identification
of the poison or toxin
Must be given in a timely fashion
No antidote is completely without
side effects of its own
Often times given infrequently
American Association of Poison Control
Centers says antidotes are employed in only
0.9 to 1.3% of poisoning incidents.
100
Pharmacists can play a key role
Pharmacists can help reduce morbidity and
mortality due to poisonings and overdoses by:
1. Recognizing the signs and symptoms of various
types of toxic exposure (toxidrome)
2. Guiding emergency room staff on the appropriate
use of antidotes and supportive therapies
3. Helping to ensure appropriate monitoring of patients
for antidote response and adverse effects
4. Managing the procurement and stocking of antidotes
to ensure their timely availability
Marraffa JM, Cohen V, Howland MA, Antidotes for toxicological emergencies:
a practical review. Am J Health Syst Pharm. 2012 Feb 1;69(3):199-212.
101
Ethanol
Epidemiology:
The toxic effects are generally less important than
injuries resulting from psychomotor impairment.
5-10% of all drinkers of ethanol in the U.S. are
alcohol dependent
> 200,000 people in the U.S. die from alcoholism
In the 15-45 age group alcohol is associated with:
50% of traffic fatalities
Driving under the influence of alcohol is the major cause
of fatal auto accidents.
50% of deaths by fire
67% of drownings and homicides
35% of suicides
102
Ethanol
Intoxicating effects of alcohol are due in
part to enhancement of GABA at GABA
A
receptors, and blockade of the NMDA and
AMPA subtype of glutamate receptors
Chronic alcohol use results in down-
regulation of GABA
A
receptors (inhibitory)
and up-regulation of NMDA receptors
(excitatory)
Increased glutamatergic activity may
account for hyperexcitable state seen with
abrupt alcohol withdrawal
103
Blood Alcohol Concentration
Blood alcohol concentration (BAC) is a measure of the
amount of alcohol in a person's bloodstream.
BAC is commonly expressed in percentage terms (mg%) or in mg/dL:
A BAC of 0.08 % or 80mg/dL means that a person has eight parts
alcohol per 10,000 parts blood in the body
Blood alcohol level and the time necessary to achieve it are
controlled largely by the rapidity and extent of ethanol
consumption and rate of gastric emptying .
Ethanol is distributed in body water and adipose tissue.
Alcohol eliminated by urinary excretion, exhalation, and metabolism.
Blood levels in an average adult decrease by ~15 to 20
mg/dL per hour. Thus, a person with a blood alcohol level
of 120 mg/dL (0.12 %) would require 6 to 8 h to reach
negligible levels.
Blood Alcohol Concentration Estimator: http://www.indiana.edu/~iupd/drunkdriving.htm#cal
104
Blood Alcohol Concentration
Blood Alcohol Level (BAC mg%): Effects On the Body
0.02 Slight mood changes
0.06 Lowered behavioral inhibition and impaired
judgement
0.08 Level of legal intoxication, deterioration of
reaction time and control.
0.15 Impaired motor functions: balance, movement, &
coordination. Difficulty standing, walking, talking.
0.20 Decreased pain and sensation (serious intoxication)
0.30 Diminished reflexes. Semi-conscious state
(Potentially fatal)
0.40 Loss of consciousness. Anesthetic effects
(Potentially fatal)
0.50 Death
Source: NIAAA
105
Ethanol Metabolism
Ethanol is small molecule which is both
lipid and water soluble and readily
absorbed:
Majority is absorbed from small intestine
(about 80%)
85% of absorbed ethanol is metabolized in
the liver
Major route of metabolic conversion is cytosolic ADH and ALDH
Acetaldehyde is converted to acetate in the mitochondria and
primarily enters the blood stream to be taken up by other cells
Acetate is converted to acetyl CoA to participate in other
reactions, but in large volumes, contributes to metabolic
disruptions related to acute and chronic alcohol use and
toxicity
106
ETOH metabolism
occurs primarily
through 3 pathways:
1. MAJOR: Ethanol conversion
to acetaldehyde by Alcohol
Dehydrogenase (ADH)
Also generates NADH
2. Ethanol conversion to
acetaldehyde via CYP2E1
In ER complex, inducible and
active at high BACs
3. Ethanol conversion to
acetaldehyde via catalase
Peroxisomal catalase
Ethanol
Metabolism
3
1
2
107
Alcohol Dehydrogenase (ADH)
Major pathway of oxidative metabolism
of ETOH
Occurs in the cytosol and primarily in the liver
Many different variants or isozymes
Produces acetaldehyde and NADH
Highly toxic compound
Correlated with decreased use of alcohol
Increases NADH/NAD+ ratio
5 classes of ADH based on structural and kinetic
properties
108
Acetaldehyde is generated
along with NADH by ADH
80% of acetaldehyde is
converted to acetate by
mitochondrial aldehyde
Dehydrogenase (ALDH2)
Also generates NADH
Approximately 40% of
Asians and 80% of
Native Americans have
inactive ALDH2 enzyme
(Genotype: ALDH2*2)
Ethanol
Metabolism
109
Acidosis can occur due to
increased NADH/ NAD
+
Ratio
Alcohol Induced
Ketoacidosis:
High levels of NADH
inhibits TCA cycle by
preventing reaction of
malate to oxaloacetate
from occurring
Shunts Acetyl-CoA into ketone body production
NADH is oxidized in ETC in mitochondria
110
Acidosis due to increased
NADH/NAD
+
Ratio
Alcohol Induced Lactic
acidosis
High levels of
NADH/NAD+ shifts
conversion of pyruvate
to lactate
Results in high levels
of blood lactate
111
Ethanol Methanol
Ethylene
Glycol
Acetaldehyde
(hangover, flushing)
Formaldehyde
(blindness,
cerebral oedema)
Glycoaldehyde
(CNS effects)
Acetic acid
Formic acid
(metabolic acidosis)
Glycolic acid
(metabolic acidosis)
CO
2
+ H
2
O Glyoxylate
(lactic acidosis)
Oxalate
(cerebral and renal
damage, hypocalcaemia)
LDH or glycolic
acid oxidase
LDH or aldehyde
oxidase
ALDH
ADH
112
Methanol Poisoning
Sources: automobile windshield washer
solvent, gas line antifreeze, copy machine
fluid, fuel for small stoves, paint strippers,
solvents
Clear, colorless and sweeter than ethanol
Peak levels- 30-60 min with toxic effects
taking place over the next 12-24 hours
>80% is metabolized to formaldehyde
and formic acid
3-5% excreted unchanged in the urine and
12% excreted unchanged by the lung
113
Ocular Effects of Methanol
Toxicity
Formaldehyde and Formic Acid
accumulation in eyes leads to dim or
blurred vision (snowstorm blindness)
Edema of the optic disk/nerve
Abnormal pupillary light reflexes
(dilated pupil) and sluggish response
114
Ethylene Glycol
Ethylene glycol is a synthetic odorless liquid
that absorbs water and has a sweet taste
Antifreeze and de-icing solutions
Peak levels: ~1-4 hours post ingestion
Metabolized by the liver (~80%) to:
Glycoaldehyde and glycolic acid (acidosis)
In 2009, there were 5282 exposure cases with
10 deaths*
Main mechanisms of toxicity:
Acidosis
Calcium oxalate crystal accumulation
*American Association of Poison Control Centers' National Poison Data System (NPDS)
115
Ethylene Glycol
Metabolic Acidosis
Ethylene glycol itself has low toxicity, but is
metabolized in liver to a variety of toxic
metabolites
Glycolaldehyde (via ADH)
Glycolic acid (via ALDH)
Glyoxylate
Oxalate
Accumulation of glycolic acid results in
metabolic acidosis
If untreated, ingestion of only 30-60 ml may
be sufficient to cause permanent organ
damage or death
116
Ethylene Glycol
Nephrotoxicity and neurotoxicity occurs
through the production of insoluble
calcium oxalate monohydrate crystals
Oxalate crystal formation leads to
hypocalcemia and imbalance of serum divalent
ion concentrations
Glycolic acid accumulation and metabolic
acidosis do not contribute to renal toxicity,
which is solely caused by oxalate crystal
accumulation
117
Isopropanol
A secondary, low molecular weight
hydrocarbon commonly found as a solvent
and disinfectant
Isopropanol is in many mouthwashes, skin
lotions, and rubbing alcohol. Because of its
widespread availability, lack of purchasing
restrictions, and profound intoxicating
properties, it is commonly used as an
ethanol substitute.
It is the parent compound that is toxic, not
the metabolites
118
Isopropanol
Isopropanol is rapidly absorbed across the gastric
mucosa and reaches peak blood concentration in
approximately 30-120 minutes after ingestion.
Thought to be about twice as potent as ethanol
Isopropanol is primarily metabolized via
ADH to acetone
A small portion of isopropanol is excreted unchanged in
the urine.
Fruity odor on the patient's breath is due to acetone
Acetone cannot be further oxidized to a carboxylic
acid and shows only limited acidemia and toxicity
Fatalities from isolated isopropyl alcohol toxicity
are rare.
Isopropyl alcohol does NOT cause an elevated anion gap
acidosis, retinal toxicity (as does methanol), or renal
failure (as does ethylene glycol).
119
Behavioral Effects of Ethanol Overdose
Toxidrome for Acute Ethanol poisoning
Range of symptoms (BAC > 0.1%):
Parietal lobe deficiencies become more pronounced
Motor skills increasingly deficient
Sensory systems and perception altered further
Increased irritability and abusive behavior
BAC > 0.3%:
Depressed Cardiovascular function
Depressed respiratory function (depression)
Coma
Death
120
Ethanol Management
Diagnosis
Clinical presentation
Confirm alcohol content and presence of other
drugs or sedatives
Anion and Osmolar gaps
Management
Supportive Care
IV fluids
Thiamine (for deficiencies; Wernicke-Korsakoff)
Gastric lavage employed for recent ingestion (< 1 hr)
Activated charcoal usually reserved for co-ingestion
Endotracheal intubation for respiratory depression
Management of alcohol dependence
121
Methanol Intoxication
Clinical Course
Intoxication with severe effects occurring
within 12-24 hrs without treatment
CNS early stages: inebriation
CNS late stages: coma, stupor, seizures and
bilateral basal ganglia infarcts
Metabolic acidosis
Characteristic visual dysfunctions include
pupillary dilation and loss of pupillary reflex
and difficulty with vision
122
Ethylene Glycol Intoxication
Tri-phasic Presentation
3 Stages
Neurological (30 minutes to 12 hrs)
Euphoria/inebriation/nausea/vomiting
Mild acidosis with CNS depression
Cardiopulmonary (12-24 hrs)
Tachycardia
Mild hypertension
Metabolic acidosis and hyperventilation
Highest death rate
Renal (24-72 hrs)
Renal failure may occur if reach this stage
123
Diagnosis: Serum Anion Gap
Estimation of serum anions and cations for
determining acidosis from methanol and
ethylene glycol exposure
Anion gap = cations anions = 8-12mEq/L
Na
+
, Cl
-
and HCO
3
-
are used clinically for
calculation of the anion gap:
Anion gap= ([Na
+
] - [Cl
-
+ HCO
3
-
])
A high anion gap indicates that there is loss of
HCO
3
-
without a concurrent increase in Cl
-
to
compensate for increased metabolic acidosis
124
Diagnosis: Osmol Gap
The classic profile of ethylene glycol ingestion is an early
osmolar gap (the EG serves as an unmeasured osmole) that
transitions to an anion gap metabolic acidosis as the EG is
converted into acidic derivatives.
Normal Osmol gap = 0 5-10 mOsm/L
(Measured osmol - Calculated osmol*)
Calculated Osmolarity = [2(Na) + BUN/2.8 + Glucose/18]
An Osmol gap greater than 15 has traditionally
been considered a critical value or cutoff.
* Major causes of high osmolar gap are ethylene
Glycol, methanol, ethanol, and isopropanol
alcohols
125
Ethanol Therapy for Methanol
and Ethylene Glycol
ETOH Competition of ADH allows for the excretion or
removal of the parent compound without formation of
their toxic metabolites by ADH and ALDH
Prolongs methanol half-life from 8 to 30 hours
Prolongs ethylene glycol half-life from 2-4 to 17 hours
Ethanols affinity for alcohol dehydrogenase (ADH):
20 times more than methanol
100 times more than EG
Effective ethanol level >100 mg/dL to completely
saturate the enzyme
Hospitalization in ICU may be necessary during treatment
Use of dialysis to remove these alcohols and their
metabolites are the cornerstones of therapy
Bicarbonate infusion may improve metabolic acidosis
126
Fomepizole (4-methylpyrazole)
Only antidote approved for ethylene
glycol and methanol toxicity:
Elevated osmol gap or anion gap acidosis
Oxalate crystals in urine
Fomepizole is a competitive inhibitor of alcohol
dehydrogenase (ADH)
1000x times greater affinity for ADH than ethanol
Compared to ethanol it is easier to dose and
causes less CNS side effects
It is more expensive (approximately $5000 per 48 hr
course of therapy), and as a result is often not stocked
Effective in adults and children
May prevent the need for hemodialysis for EG
127
Isopropanol Intoxication Clinical
Course and Treatment
As little as 20 mL can induce symptoms, with 150 to 240
mL often representing a lethal dose due to central
nervous system and myocardial depression (leading to
hypotension or shock in severe cases).
A plasma concentration of 400 mg/dL or higher is
considered life-threatening
Fatality from isolated isopropyl alcohol toxicity is rare,
but can result from injury due to inebriant effects, or
untreated coma with airway compromise, or more rarely,
cardiovascular depression and shock following massive
ingestion.
Supportive care can avert most
morbidity and mortality
128
Isopropanol Intoxication Clinical
Course and Treatment
Sweet-smelling breath and absence of an elevated
anion gap or metabolic acidosis suggests isopropanol
overdose
A serum isopropanol level confirms the diagnosis
Provide supportive care
The rapid absorption of isopropanol often limits the
utility of gastric lavage
Indications for hemodialysis include when lethal
doses have been ingested, hypotension, plasma levels
above 400 mg/dL, prolonged coma, or underlying
renal or hepatic insufficiency that will limit the
metabolism and excretion of isopropanol
Hemodialysis removes both isopropanol and acetone.
129
Sedatives-Hypnotics
Barbiturates:
Advent in early 1900s
phenobarbital: 1912
Dominated market for >60 years
Benzodiazepines: Developed to provide
more selective effects on CNS
Selected based on potency of anxiolytic
activity vs. CNS depressant effects
Most retain selective sedative / hypnotic
effects, some have amnesic effects
Generally safer and less toxic
Which agent would have the higher TI?
Have clinically replaced barbiturates
130
Sedative-Hypnotics
Enhances function of GABA system:
Inhibitory neurotransmitter in the CNS
Barbiturates:
Increases duration of the chloride channel opening
Very narrow therapeutic range
Does not require endogenous GABA to operate and
increase the efficacy of the GABA receptor
Benzodiazepines:
Allosteric modulator of GABA-A chloride channels
Modulates GABA binding and increases affinity of GABA
for the GABA-A receptor
Increases the frequency of bursts of the chloride
channel opening
131
Activation of the GABA
A
receptor results in an
increase in Cl
-
ion
conductance via the
receptor-gated ion
channel. Associated
with fast GABA
neurotransmission.
GABA
A
Receptors
Cl
-
132
Benzos vs. Barbs
Death
Coma
Anesthesia
Hypnosis
Sedation
Dose
Barbiturates
Benzodiazepines
Depression of the medullary
respiratory centers is the
usual cause of death of
barbiturate overdose.
What does the leftward shift in
the dose-response curve mean?
133
Sedative-Hypnotics
Signs and Symptoms of Acute Toxicity
Directly related to CNS and CV depression
Reactions are dose-dependant
Mild sedation to coma and paralysis
Widespread use makes benzodiazepines a
more likely candidate for overdose
Determined by urine toxicology screen
Always consider that there may be other
drugs on board along with B and Bs
Especially alcohol
Alcohol makes Benzos more toxic!
134
Sedative-Hypnotics
Clinical presentation:
Slurred speech
Ataxia / drowsiness
Incoordination / Stupor
Respiratory depression
Comatose
Hypotension (esp. barbiturates)
Hypovolemia (esp. barbiturates)
Cardiovascular depression and collapse is a
major concern (esp. barbiturates)
135
Sedative-Hypnotics
Clinical Management of Acute Overdose
Barbiturates
ABC management
Ventilation
Vital function support
Volume expanders to maintain blood pressure
After ingestion:
Gastric lavage (if <1 hour); Activated charcoal (if >1 hr)
Urine alkalinization to pH 7.5-8 to enhance excretion of
phenobarbital (of limited use for other barbiturates)
Charcoal based hemoperfusion MAY be useful if in
prolonged coma or refractory
136
Sedative-Hypnotics
Clinical Management of Acute Overdose
Benzodiazepines
ABC management
Ventilation
Vital function support
Volume expanders to maintain blood pressure
After ingestion:
Gastric lavage (if <1 hour)
Activated charcoal (if >1 hr)
Flumazenil (benzodiazepine antagonist)
NO ROLE for hemodialysis or hemoperfusion
137
Sedative-Hypnotics
Pharmacological Treatment
Antidote: Flumazenil for Benzodiazepines
A competitive benzodiazepine antagonist
No role in mixed overdoses due to risk of seizures
and dysrhythmias
Potential to cause withdrawal symptoms in patients
who are benzodiazepine dependent
Reverses CNS effects but not the respiratory
depression
Flumazenil is only available for IV dosing and has a
shorter duration of action than most benzos
138
Sedative-Hypnotics
A Word Regarding Dependence &
Withdrawal
Dependence due to plasticity of receptors
More on that later
Approximately 30% of chronic benzo
users will experience withdrawal
Withdrawal from benzodiazepine and
barbiturates can be as life-threatening
as an overdose and must be considered
139
Acetaminophen
Acetaminophen is a generally safe alternative for
analgesic and anti-pyretic effects of aspirin (ASA)
The MOST commonly reported overdose from poison
control centers (>17% of all overdoses)
Rapidly absorbed from GI tract
Undergoes hepatic metabolism; dose-dependent
Adverse Effects:
Few at therapeutic doses
Large doses deplete cellular glutathione stores
Hepatotoxicity is a serious consequence of
Acetaminophen overdose
Avoid in patients with hepatic impairment
Avoid when taking with ethanol
140
Toxicity of Acetaminophen
In overdose situations, liver enzymes become
saturated, glutathione is depleted and
N-acetyl-p-benzoquinoneimine (NAPQI)
accumulates, leading to hepatic necrosis
Hepatotoxicity can occur in chronic overuse or
acute overdose
Severe irreversible damage to liver hepatocytes
Centrolobular necrosis -- liver cell death (may
require liver transplant)
Possible kidney toxicity
Oral ingestion--> stomach-GI tract --> first-
pass metabolism in liver by P-450 enzymes
141
Toxicity of Acetaminophen
Acetaminophen Metabolism:
Phase 2 sulfation (52%)
Most important in children
Phase 2 glucuronidation (42%)
More important in adults
Cytochrome P450 System
CYP 2A6 pathway
Produces non-toxic metabolites
Major metabolite 3-hydroxyl-APAP
CYP 2E1 pathway
Produces toxic metabolites
Major metabolite is N-acetyl
benzoquinoneimine (NABQI)
NABQI reacts with target and
non-target nucleophiles
142
Hepatic Metabolism of Acetaminophen
Acetaminophen is metabolized based on dosage
At higher doses, the cellular reducing agent
glutathione converts NAPQI to a non-toxic
metabolite
At continued high levels of NAPQI, glutathione
stores are depleted and the cell can no longer
convert NAPQI
NAPQI accumulates and is capable of producing
severe cellular damage
ETOH, as an inducer of CYP2E1, lowers the
threshold of NAPQI generation and can
contribute to glutathione depletion
143
Toxic Dose: 200 mg/kg children and > 4 g in adults
Alcoholics and those taking drugs which are
inducers of CYP2E1 are also at risk
Four phases of acetaminophen toxicity
Phase I: Common in the first 24 h
Anorexia, malaise, pallor, diaphoresis, nausea and
vomiting
Phase 2: occurs 24 to 48 h after overdose
Right upper quadrant pain
Abnormal liver function test results, which occur
even while signs and symptoms of phase 1 improve
Clinical Toxicology of Acetaminophen
144
Phase 3: 48 to 96 hours
symptoms of severe hepatotoxicity including
encephalopathy, coagulopathy, and hypoglycemia
Elevated liver enzyme tests
Approaching limits of effectiveness of therapy
Renal failure / nephrotoxicity
Phase 4: Post-4 days ingestion
Death
Necessity for liver transplant
Recovery with limited liver damage (usually 5-7
days post ingestion if occurs)
145
Diagnosis and Treatment:
Serum levels of acetaminophen
4- 24 hrs post ingestion are
evaluated according to the
Rumack-Matthew nomogram for
determining risk of hepatotoxicity
Relationship between acetaminophen
level and time after ingestion
150 mg/dl at 4 hours is possibly toxic
N-acetylcysteine is indicated for
acetaminophen levels above the lower line
N-acetylcysteine is also indicated if serum
acetaminophen level is >5 g/mL after an
unknown time of ingestion (but <24 h) or if
serum acetaminophen levels are not available
Low Risk
Probable
Risk
146
Limits of Rumack-Matthew Nomogram
Only used in relation to a single acute ingestion
Serum acetaminophen levels obtained prior to 4 hr
post-ingestion are not interpretable because of
ongoing drug absorption and distribution
For chronic ingestion or an overdose with an extended-
release preparation, the nomogram is less predictive of
toxicity
For extended-release preparation, acetaminophen levels
should be drawn every 4 to 6 h postingestion and plotted on
the Rumack-Matthew nomogram. If any point is above the
lower line, or there are any signs of hepatotoxicity an entire
course of N-acetylcysteine is indicated.
Nomogram does not account for at-risk populations:
Whereas 7.5 to 10 g of acetaminophen are toxic in healthy
adults, 4 to 6 g may be enough in chronic alcohol users
Malnourished individuals or conditions with loss of glutathione
147
N-acetylcysteine substitutes for glutathione, combining
directly with NAPQI and detoxifying NAPQI
May supply inorganic sulfur to enhance sulfate conjugation of
acetaminophen
NAC is virtually 100% effective when administered
within the first 8 to 10 hours:
Benefits may be seen up to 24 h after ingestion and even after
the onset of fulminant hepatic failure
Oral 72 hour protocol:
Loading dose is 140 mg/kg
Maintenance dose of 70 mg/kg, given every 4 hours x 17 doses
If NAC is indicated, full regimen should be followed. Do not stop
NAC early if nomogram indicates possible toxicity
Benefits include lower incidence of hepatic encephalopathy
Treatment options:
N-acetylcysteine
148
Activated charcoal is GI
decontamination method of choice
Can be effective in reducing toxic levels of up
to 10 grams of ingested acetaminophen
Reduces requirement of N-acetylcysteine and
reduces treatment paradigm and hospital stay
Unlikely to reduce efficacy of N-acetylcysteine
Gastric lavage can also be employed but not
recommended if other options available
Hemodialysis, Hemoperfusion, and Peritoneal
dialysis are of limited to no benefit
Clinical Toxicology
Treatment options: GI Decontamination
149
Salicylate Metabolism
Once ingested, acetylsalicylic acid or aspirin is rapidly
converted to salicylic acid, its active metabolite
Salicylic acid is readily absorbed from the stomach
and small intestine
At therapeutic doses, salicylic acid is metabolized by
the liver and eliminated in 2 to 3 hrs.
Therapeutic serum levels are 10 to 30 mg/dL
Signs and symptoms of toxicity begin to appear at levels
higher than 30 mg/dL
A 6-hour salicylate level higher than 100 mg/dL is potentially
lethal and is an indication for hemodialysis
Chronic ingestion can increase the half-life to >20 hrs
150
Salicylate Toxicity
Salicylate poisoning:
Metabolic acidosis
The major feature of poisoning is a metabolic acidosis
This is due to "uncoupling of oxidative phosphorylation"
which leads to an increase in metabolic rate
Increased oxygen consumption
Increased CO2 formation
Increased heat production
Increased glucose utilization and hypoglycemia
Hypoglycemia
Increased peripheral glucose demand
Increased rate of tissue glycolysis
Impaired rate of glucose synthesis
151
Salicylate Toxicity
Salicylate poisoning:
Respiratory alkalosis
Salicylates directly stimulate the respiratory
center leading to hyperventilation and a respiratory
alkalosis.
This leads to compensatory increased renal
excretion of bicarbonate which contributes to the
metabolic acidosis which may coexist or develop
subsequently
Tinnitus:
Perception of sound within the human ear in the
absence of corresponding external sound
152
Salicylate Toxicity Management
Accounts for 10% of all analgesic-related deaths
Activated charcoal and hemodialysis (severe cases)
Alkalinization (Sodium Bicarbonate)
Alkalinization with sodium bicarbonate results in
enhanced excretion of ionized acid form of salicylate
Decreases the tissue half-life from 20 to 6 hours
Urine pH must be maintained at 7.5-8.0 and
hypokalemia must be corrected
Hypokalemia is a common complication due to movement of
potassium into cells in exchange for hydrogen ions to
compensate for the alkalemia
Calcium should also be measured as decreases are a
complication of bicarbonate therapy
153
Salicylates Summary
Initial assessment of ASA toxicity is important in
the elderly, as the clinical manifestations can mimic
other common medical complaints in that age group
Knowledge of drug combinations that include ASA in
their formulation is important, as patients may not
be aware of its presence
Prompt response to a case of ASA toxicity with
alkalinization of the urine is important and can
reverse the levels of salicylates rapidly
Activated charcoal may be effective
Hemodialysis is indicated in severe poisonings or impaired
renal function
154
Sources of Cyanide poisoning
Global consumption approximates 150 million
tons of cyanide annually
Chemical Manufacturing:
Mineral extraction and electroplating
Bulk of consumption is for plexiglas and nylon
Animal feed industry to synthesize amino acids
Vermin extermination with HCN
Smoke from household fires (most common cause in US)
Cyanide salts
Nitroprusside can be cyanogenic (it is 44% cyanide by weight)
Natural sources of cyanide and amygdalin
Cherry laurel, seeds/pits of apricot, cherry, and almond seeds
Amygdalin is converted to HCN upon ingestion
Hydrogen cyanide gas is released when cyanide salts are
mixed with acids
155
Cyanide Poisoning
Chemical asphyxiant
Principal toxicity occurs as a result of the
inactivation of the mitochondrial enzyme
cytochrome oxidase (cytochrome a3),
leading to the inhibition of cellular
respiration.
Binds to ferric iron in cytochrome oxidase
Blocks aerobic utilization of oxygen in tissues
Oxygen level will be high but it is not utilized
Metabolism shifts to anaerobic glycolysis
Lactate and an anion gap metabolic acidosis is
the primary outcome of anaerobic metabolism
156
Cyanide Toxicity
Poisoning can occur through ingestion,
skin absorption, and inhalation
Poisoning symptoms appear after inhalation (5 min),
ingestion (20 min), dermal (varies)
Toxicity depends on the form (salt or gas),
duration, and route of exposure
Toxic oral dose of KCN is 200 mg (LD
50
: 140-250mg)
Inhalation of 270 ppm of HCN is fatal
Degree of symptoms depends on severity
of exposure
242 cases in 2007; 148 deemed accidental exposures
Predominantly > age 19
8 major outcomes with 5 deaths
157
Signs and Symptoms of
Cyanide poisoning
Based on history of exposure
At risk populations
Severe lactic acidosis
Increased venous oxygen saturation will
be elevated
Dyspnea and confusion
Syncope, seizures, coma
May have profound cardiovascular effects
Palpitations, ventricular arrhythmias, cardiac arrest
Bitter almond odor may or may not be
present
158
Cyanide Poisoning
Metabolism:
2 routes of elimination
Major: converted to thiocyanate by
thiotransferase enzyme Rhodanese and
renally eliminated
Minor ( 15%): Cyanide binds with high
affinity to cobalt
Cyanide is combined with hydroxycobalamin to
cyanocobalamin (Vitamin B12 ).
159
Treatment of Cyanide Poisoning
Decontamination
Vital life support: ABC
Antidotes: Several Approaches
Direct binding agents
Cobalt chemistry
Methemoglobin generators
Preferential binding of CN to Fe3+
Sulfur donors
Takes advantage of metabolic clearance
to form thiocyanate
160
Cyanide Antidote Kits
The cyanide antidote kit
Used in the United States for decades
Kit consists of 3 medications given
together for their synergistic effects:
amyl nitrite, sodium nitrite, and sodium
thiosulfate
Hydroxocobalamin (Cyanokit)
Approved by the FDA in December 2006
Low incidence of adverse events
161
The cyanide antidote kit
Methemoglobin generators and sulfur donors
Treated with a Cyanide Antidote Kit containing amyl
nitrite and/or sodium nitrite and sodium thiosulfate
Step 1: Develop competing substrate for CN
instead of Cytochrome Oxidase
The nitrites (amyl nitrite, sodium nitrite) act by oxidizing
hemoglobin to methemoglobin to provide a substrate that can
compete with cytochrome c oxidase for cyanide molecules
Step 2: Enhance metabolism of CN by providing
sulfur source
The addition of thiosulfate provides a ready source of sulfur for
the detoxification reaction and enhances cyanide metabolism and
renal elimination.
162
Cyanide Antidote Kit
Nitrites
Therapeutic induction of
methemoglobinemia
Nitrites oxidize Fe
2+
in hemoglobin to form methemoglobin
NO
2
+ Hb (Fe
2+
) = MHb (Fe
3+
)
Methemoglobin binds CN
-
and removes from tissues
CN
-
+ MHB = cyanomethemoglobin
Cyanomethemoglobin relatively non-toxic
Sodium Thiosulfate
Sodium thiosulfate donates sulfur to rhodanese which
catalyzes metabolic inactivation of cyanide to thiocyanate
Na
2
S
2
O
3
+ HCN + O = HSCN
Thiocyanate is eliminated renally
163
Cyanokit:
Hydroxocobalamin
Hydroxocobalamin
Vitamin B
12
precursor with Cobalt-containing group
Freely exchanges its hydroxyl group for circulating and
cellular cyanide to form cyanocobalamin (Vitamin B
12
)
Cyanide has greater affinity for hydroxocobalamin than for
the cytochrome oxidase
Cyanocobalamin is nontoxic and is eliminated renally.
Each kit contains two 250-mL glass vials, containing 2.5 g of lyophilized
hydroxocobalamin. The kit also contains a sterile intravenous infusion set.
Dose: The standard dose is 5 gm IV infused over 15 minutes. A second
5 gm dose can be given in patients with severe toxicity.
Adverse reactions: minimal toxicity. Is safe enough to be given to smoke
inhalation victims at the scene of a fire
164
Carbon Monoxide Poisoning
Colorless, odorless, tasteless gas
40,000 Emergency room visits a year
Produced by incomplete combustion of carbon-
containing material
Smoke inhalation and auto exhaust, charcoal, kerosene
or gas stoves, particularly in enclosed environments
Cigarette smoke
CO binds hemoglobin with high affinity (<250x)
Causes cellular hypoxia and ischemia
Reduces O
2
carrying capacity and oxygen delivery
Cytochrome oxidase and myoglobin O
2
as well
The CO-Hgb t
1/2
= 200 min at room air and
20 minutes at hyperbaric oxygen
165
Carbon Monoxide
Poisoning
Carboxyhemoglobin concentrations
up to 5% are generally tolerated
5-10% carboxyhemoglobin may result in
headache and mild dyspnea
Heavy smokers and commuters on polluted roads
10% and 30% carboxyhemoglobin: headache,
dizziness, weakness, irritability, nausea, and
vomiting
50% carboxyhemoglobin : coma, seizures,
cardiovascular collapse, and death
166
Treatment of CO poisoning
Antidote: supplemental oxygen
100% O
2
will enhance elimination of CO
from 6 hours to approximately one hour
Hyperbaric oxygen (2.8 atmospheres
within 6 h of exposure) decreases
the half-life to 15 to 30 min
Debate on effectiveness of hyperbaric O
2
Decontamination
Remove from the contamination source
167
Iron Absorption and Storage
Iron deficiency is a common problem,
usually as a result of menstruation or
bleeding (GI)
Iron overload can affect about 10% of
the population- a condition known as
hemochromatosis
Iron is found primarily in O
2
transport
proteins (hemoglobin), O
2
storage
proteins (myoglobin) and plays a role in
the electron transport chain as part of
cytochromes
Iron in high amounts is very toxic, so
cells and organisms TIGHTLY regulate
the amount of iron
168
Iron
Absorption
and Storage
Iron absorption is very poor; only about 10% is absorbed
Iron as Fe
2+
is absorbed via facilitated transport (Divalent
metal transporter (DMT-1)) and stored bound to an
intracellular iron binding protein called ferritin
Fe
2+
enters the blood stream from intestinal epithelial cells via
the basolateral iron transporter (Ferroportin/hepcidin)
In the blood stream, Fe
2+
is converted to Fe
3+
and binds to the
plasma protein transferrin which circulates iron to tissues
Transferrin/Fe
3+
is taken up by cells using receptor mediated
endocytosis (transferrin receptor)
169
Iron Toxicity
Corrosive toxicity:
Iron is extremely corrosive to the GI tract. Acts on
mucosal tissues and can manifest with nausea,
vomiting, abdominal pain, hematemesis, and diarrhea.
Patients may become hypovolemic because of fluid and blood loss.
Cellular toxicity:
Severe overdose causes impaired oxidative phosphorylation and
mitochondrial dysfunction. The liver is one of the organs most
affected by iron toxicity, but other organs such as the heart,
kidneys, lungs, and the hematologic systems may also be impaired.
Result of corrosive and cellular toxicity is a metabolic
acidosis due to inhibition of oxidative phosphorylation and
anaerobic metabolism resulting in lactic acidosis.
170
Iron: Hepatocyte Mechanism
of Toxicity
Hepatotoxicity is a major end target organ
Hepatocellular iron uptake is especially efficient
High number of transferrin receptors on hepatic cells
Normal physiological response:
Liver synthesizes and releases hepcidin
Hepcidin increases iron storage by reticuloendothelial
macrophages
Decreases iron absorption by enterocytes by down regulating
ferroportin transporters
When liver iron storage reaches critical levels,
non-transferrin-bound iron (free iron) is
released intracellularly
171
Iron: Hepatocyte Free Iron
From previous discussion on ROS and RNOS,
anything that increases the levels of free iron
in the cells promotes ROS generation and
oxidative stress
As free [Fe] increases, it is available to
produce free radicals (H
2
O
2
, OH
-
, O
2-
)
These are highly reactive species with the
potential to damage cellular proteins, lipids,
nucleic acids and, ultimately, organ systems
Oxidative damage to cellular organelles such as
mitochondria, leading to cellular dysfunction and death
172
Acute Iron Overdose
Acute overdose occurs when bodys storage capacity
is exceeded:
Primary Source of iron:
Iron preparations & Vitamin supplements
Signs of GI toxicity may be seen after ingestion of
20 mg/kg. Moderate intoxication occurs when ingestion
exceeds 40 mg/kg. Ingestions >60 mg/kg can cause severe
toxicity and may be lethal.
Acute iron poisoning limited to 2 main populations:
Accidental ingestions by young children
Most common form of accidental ingestions in young
children (61% of accidental overdoses <6 YO*)
Intentional ingestions as suicide attempts in
adolescents and adults
*2008: American Association of Poison Control Centers
173
Signs of Acute Iron Overdose
Symptoms depend on time since ingestion:
Within 6 hours: Mostly gastrointestinal effects
Abdominal tenderness in the epigastric region
Increased bowel sounds and frequent loose stools
Emesis containing brownish fluid, blood, or pill fragments may be seen
Fatality most likely to occur during this phase
Once a leading cause of mortality (pre-1995), fatalities very rare today
6-8 hours - up to 2 days: metabolic/cardiovascular effects
Hypotension and potential for cardiovascular collapse
Hyperventilation from metabolic acidosis
Coagulopathy
This phase is also characteristic of CNS symptoms, stupor and coma
Later and delayed effects:
Elevated liver enzymes and bilirubin levels observed with
coagulopathy, indicative of hepatic dysfunction.
Hypoglycemia may accompany liver dysfunction.
Scarring of the GI tract, resulting in gastric or intestinal obstruction
174
Treatment of Iron Toxicity
ABC management
Activated charcoal and hemodialysis is
not effective for oral iron overdose
Gastric lavage for ingested liquids only
Whole Bowel irrigation may be effective
Chelating therapy
Deferoxamine
175
Deferoxamine
(Desferal)
Polydentate chelating agent with high selectivity
and affinity for iron
Chelating agent used only for shock, severe acidosis
and or serum iron overdose (>500-600 ug/dL)
Deferoxamine is used in addition to supportive
measures
Administered parentally
Chelates iron from ferritin but generally not from
transferrin and cytochrome coordinated complexes
or hemoglobin
176
Other Heavy Metals: Lead
Lead History
100 BC. - Greek physicians give clinical description
of lead poisoning.
1904 - Child lead poisoning linked to lead-based
paints.
1923 - Leaded gasoline goes on sale in selected
markets
1971- U.S. Lead-Based Paint Poisoning Prevention
Act passed
1923 - Leaded gasoline goes on sale in selected
markets
1986 - Primary phase out of leaded gas in US
completed
177
Lead Poisoning
Manufacturing sources
Pipes, weights, radiation shields,
batteries, solder, electrical devices
House paint
Curtailed since the 1970s
Common source of poisoning in children
Lead glazed ceramics
Gasoline
Organic lead poisoning
Tetraethyl lead
Readily absorbed through skin and
lungs
CNS effects: seizures, convulsions
178
Lead Poisoning
Chronic exposure is primary source of toxicity:
Acute exposures are rare
Children vulnerable than adults:
Orally consumed lead absorbed in place of calcium
Children absorb 30-50% of an oral lead dose:
Decreased intelligence (lower grades)
Hyperactivity (higher school dropout rate)
Growth retardation
Effects at blood lead levels of 10 q/dl
Adults absorb 5-10% of oral lead
Increased absorption during pregnancy
Multi-system mechanism of toxicity
Binds to proteins containing phosphates, sulfhydryl
and carboxyl-groups
Heme synthesis
Neurotransmitter synthesis
179
Lead Poisoning
Chelation: Succimer (Chemet)
Used for oral treatment of lead toxicity
Water-soluble bidentate congener of
dimercaprol
Weight based-dosing
Oral 100 mg capsules
100-500 mg doses (8 - >45 kg)
NOT approved for children < 1 YO
Also effective for Arsenic and Mercury
poisoning if given within a few hours of
exposure
180
Lead Poisoning
Chelation: Calcium EDTA
Also indicated for lead overdose
ONLY use Calcium disodium salt
Non-calcium form (Endrate) is not interchangeable
Prevents hypocalcemia
1000 mg/m2/day IM or over 12 hours IV for 5 days
Cease treatment for 2-4 days and repeat
Two courses usually necessary to fully treat
Warning: Beware of lead-induced encephalopathy
181
Mercury
Elemental mercury vapor
Mainly occupational exposure
Mercury vapor can be released from dental amalgams but rarely
at toxic levels
Ingested elemental mercury poorly absorbed and is not toxic
Mercury vapor constitutes majority of toxic exposure eliciting
highly toxic neurological events
Mercury salts
Monovalent (mercurous) and divalent (mercuric) salts
Mercuric salts are more irritating (severe acute toxicity to
mucosal tissue)
Mercuric nitrate commonly used in felt-hat industry
Mercuric chloride: life threatening hemorrhagic gastroenteritis
Mad as a hatter depicted the acute neurotoxicological-
associated behavior upon exposure to these compounds
182
Mercury
Organomercury (Methylmercury)
Methylmercury has a high affinity for sulfhydryl groups, which
attributes to its high protein binding and effect on enzyme
dysfunction
Methylmercury accumulates in fish, which are consumed by
humans (primary route of exposure in humans).
Freely crosses blood-brain barrier and the placenta
In children, methylmercury exposure during pregnancy (in
utero) has been associated with delays in reaching
developmental milestones and decreased intelligence
At high doses of methylmercury exposure, children may
experience mental retardation, reduced muscle coordination,
blindness, seizures, muscle weakness, and an inability to speak
Can pass to neonates via breast milk
183
Mercury
Treatment: Chelating agents
Dimercaprol (BAL in oil)
Effective for lead, mercury, arsenic
and gold overdose
Consult poison control center for
specialized dosing related to which
agent exposed
Mercury: best for elemental and
inorganic salts
Not indicated for children
Dimercaprol should NOT be used in iron,
poisoning because the dimercaprol-metal
complexes are more toxic than the iron
184
Other Heavy Metals: Mercury
Treatment: Chelating agents
Penicillamine (Cuprimine):
Bidentate chelator
Derivative of Penicillin
Water soluble
Well absorbed
Side effects:
Nephrotoxicity
Autoimmune disorders
Lupus
185
Arsenic
Arsenic Poisoning is relatively rare
Industrial pollutant
Environmental toxin
Coal burning
Trivalent form is most toxic
Acute:
Severe GI distress
Sweet garlicky odor on breath
Chronic:
Skin lesions, hair loss, anemia
Hyperkeratosis (skin bumps that
resemble corns or warts)
Treatment:
Supportive therapy (ABC)
Chelating agents: Dimercaprol,
Penicillamine, Succimer
Hyperkeratosis
186
Heavy Metals: Summary
Metal Form Route Target organs Treatment
Lead Inorganic GI, Respiratory Hemap., CNS,
Kidneys
Dimercaprol,
EDTA,
Succimer
Tetraethyl lead Skin, GI CNS Supportive
Arsenic Inorganic
(trivalent)
Mucosal
surfaces
GI tract,
hemap.
Dimercaprol,
Penicillamine,
Succimer
Mercury Elemental Inhalation CNS, Kidneys Dimercaprol
Inorganic GI Kidneys, GI Penicillamine,
Dimercaprol
Organic GI CNS Supportive
Iron Ferrous Sulfate GI GI, CNS, Liver Deferoxamine

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