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General Principles of Toxicology General Principles of
Toxicology
Dr. Charles BreeseOffice: 204 McGlothlin Hall
DEPARTMENT OF PHARMACEUTICAL SCIENCES
[email protected]
Dr. Charles BreeseOffice: 204 McGlothlin Hall
DEPARTMENT OF PHARMACEUTICAL SCIENCES
[email protected]
ResourcesRequired 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 LWW
Health Library
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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
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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
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DEFINITIONSTOXICOLOGY: 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)
Every known chemical has the potential to be a toxicant if
present in a sufficient amount.
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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.
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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
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Examples of Environmental and Toxicological Health Hazards
Chemical
Pesticides, industrial discharges, household cleaners,
cosmetics, drugs
Physical Fire, explosions, injuries
Biological Microbes, poisonous plants and animals
Nuclear/Radioactive Nuclear weapons and power plants, radon
gas
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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
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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
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Risk AssessmentA hazard can not constitute a
risk unless there is exposure1. 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
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Fundamental Rules of Toxicology
Exposure must first occur for the chemical to present a
risk.
Hazard + Exposure = RiskThe 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
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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.
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(ADME)
ReabsorbtionBioactivation &
Active metabolites
Detoxification & Elimination
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Introduction to Toxicology:Routes of Exposure
Rapidity of Response Will TypicallyDepend 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?
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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)
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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
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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
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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
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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.
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Special Aspects of ToxicokineticsVolume 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 (
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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.
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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
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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++)
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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
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Metabolic BiotransformationsDrug / 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
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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
H2OCYP
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Metabolic BiotransformationsPhase 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.
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Metabolic BiotransformationsCytochrome P450s Currently 50 known
human P450s Subdivided into families of similar gene sequencesFor
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 CYP3A4CYP2D6 CYP2E1
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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
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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
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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
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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
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Measures of Acute Toxicity:The Median Lethal Dose or
Concentration (LD50 and LC50)
LD50The 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
LC50The 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 LD50 and LC50
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Measures of Toxicity: The Median Lethal Dose / Concentration
(LD50)
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 LD50 of 25 mg/kg is more
toxic than is
an LD50 of 6,000 mg/kg
HIGHER LD50 = Lower the Toxicity
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APPROXIMATE ACUTE LD50 (mg/Kg) of Representative Chemical
Agents
Water 80,000Sodium Chloride 4,000Household bleach 2,000Aspirin
1,700Morphine Sulfate 900Phenobarbital Sodium 150Picrotoxin
5Strychnine Sulfate 2Nicotine 1d-tubocurarine 0.5Tetrodotoxin
0.10Dioxin 0.001Botulinum toxin 0.00001
Not verytoxic
Highlytoxic
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Dose-Effect Curves:Quantal ResponsesDose-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 frequencywith 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 frequencywith which an effect
occurs in a population
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Cumulative Frequency Distribution For Quantal (all-or-none)
Effects
QuantalResponses
CumulativePercent
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 TD50defines the
median lethal dose (LD50).
Shows variation in the minimum or threshold dose for individuals
in a population.
ED50 TD50LD50
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Measures of Toxicity:Usage of an LD50 value
Effective dose (ED50)
Toxic Dose (TD50)
Lethal Dose (LD50)
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Therapeutic IndexThe 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
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LD50 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 / ED50TI = 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
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Cummulative Percent Dead at each DosePercent requiring a
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DosePercent requiring a Specific Dose for Inducing Sleep
QuantalResponses
ED50 TD50LD50
What happens to the TI if the LD50 or TD50 curve shifts to the
right? or Left?
CumulativePercent
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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 LC50 is
often a measure of acute (short-term) toxicity.
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Exposure: DurationAcute < 24hr usually 1 exposureSubacute 14
d-1mo repeated dosesSubchronic 1-3mo repeated dosesChronic > 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
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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
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ScenarioA 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.
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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
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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. -
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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 (O2-) Hydrogen peroxide
(H2O2), Hydroxyl radical (OH)
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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).
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Oxygen Radicals Hydroxyl radical (OH.)
Most reactive of biologically important radicals and can readily
oxidize cellular macromolecules
Generated by ionizing radiation H2O 2 OH + H
Generated from hypochlorous acid (HOCl) reacting with O2- HOCl +
O2- O2 + Cl- + OH Produced from H2O2 by neutrophils to destroy
invading organisms
Generated by reactions with transitional metals such as Fe and
Fe containing proteins
Superoxide radical (O2-) 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 H2O2 (Haber-Weiss and Fenton reactions)
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Formation of the reactive oxygen species OH H2O2 (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
H2O2 diffuses freely into and through cell membrane
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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 O2- to form the strong oxidant peroxynitrite
(ONOO-)
NO + O2- ONOO-
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Nitrogen Containing Radicals (RNOS)Peroxynitrite (ONOO-) ONOO-
is thought to form
through NO reaction with O2- ONOO- produces damage by
decomposing at physiological pH to reactive species with
reactivity similar to OH and NO2.
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
NO2 (nitrogen dioxide), which is a radical
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Phagocytes use free radicalsPhagocytic cells of the immune
system release reactive oxygen species as part of antimicrobial
defense:
NADPH oxidase forms O2- H2O2 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.
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Cellular Consequences of ROS/RNOS
Oxygen radicals react with cell components: Lipid peroxidation
of
membranes Increase Ca2+ permeability mitochondrial damage
Cys SH and other amino acids of proteins are oxidized and
degraded
DNA oxidized breakage
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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 O2
C.Lipid peroxy radical propagates, lipid peroxide degrades
Major contributor to ROS-induced injury
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ROS attack proteins, peptides, DNAProteins 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
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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
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Oxygen Free Radicals E.T.C.producesSuperoxideRadical,O2
10,000percellperday! DamagesDNAandmembranesofmitochondria
Normallythesuperoxideradicalisdeactivated:1.
SOD(superoxidedismutase)convertsO2 to
hydrogenperoxide
2. CatalaseconvertsH2O2 towaterandO2
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Oxygen Free Radicals: Theory of Aging
Defensemechanismsmaybecompromised:1. H2O2
movestothenucleusofthecell2. H2O2 reactswithFe2+
toproducehydroxylradical
3. HydroxylradicalsdamageDNAandothercellularcomponents
Hydroxylradicalcausesthemostdamage
4. Fe3+ canoxidizesuperoxideradicalsbacktoO2
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Oxygen Free Radicals: Theory of Aging
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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
H2O2
Damaged mitochondria leak Fe2+ allowing the generation of OH
Superoxide radical (O2-) generated by the mitochondria
NO and O2- forms RNOSLeads to oxidative damage
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Cellular DefensesCells have defenses against oxygen toxicity:
Antioxidant scavenging enzymes (red) Nonenzymatic antioxidants
(free radical scavengers) Compartmentalization and metal
sequestration Repair of damaged components
SOD = superoxidedismutase
GSH = glutathione
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Antioxidant Scavenging EnzymesAntioxidant scavenging enzymes:
Superoxide dismutase (SOD)
Converts O2- to H2O2 3 isoforms: Cytosol, mitochondria,
extracellular
Catalase Reduces H2O2 to H2O Prevents OH formation mostly
peroxisome
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Antioxidant Enzymes Glutathione peroxidase, glutathione
reductase:
GSH = glutathione (-glu-cys-gly) Cytosolic and Mitochondrial
Glutathione Peroxidase
reduces H2O2, oxidizing two GSH groups GSSG Reductase recycles
the glutathione, with NADPH
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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
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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 O2 admin.
due to CN, CO or H2S poisoning
Common Causes of Death in the Acutely Poisoned Patient
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Process for Treating Poisoned PatientsApproach 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
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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
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HISTORYIf 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
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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
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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
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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
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TOXIDROMES
Anticholinergic Cholinergic Opioid Sympathomimetic Sympatholytic
Serotonin syndrome Sedative-hypnotic
All of these toxidromeswill 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
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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%).
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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
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GI Tract Decontamination Syrup of Ipecac (not used any more)
Gastric lavage only within 1st hour Activated charcoal
Inert Reduces bioavailability of drug Not used w/ hydrocarbons
or corrosives
Cathartics decrease transit time WBI (whole bowel
irrigation)till clear
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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
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Prevention of Toxin Absorption
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
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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
Prevention of Toxin Absorption
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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.
Prevention of Toxin Absorption
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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.
Prevention of Toxin Absorption
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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
Prevention of Toxin Absorption
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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
Prevention of Toxin Absorption
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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
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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+])
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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
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Ion TrappingConsider a barbiturate (weak acidic drug)
overdose.
Urine BloodpH 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.
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Ion Trapping
Urine BloodpH 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
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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.
3. Raising the pH shifts the ionization equilibrium towards the
ionized form, which facilitates excretion.
4. Higher [H+] leads to a higher level of ionized drug, which
facilitates excretion.
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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):
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.
3. Lowering the pH shifts the ionization equilibrium towards the
ionized form, which facilitates excretion.
4. Higher [H+] leads to a higher level of unionized drug, which
facilitates reabsorption.
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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
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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
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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!
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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
ARTERYor
VEINVEIN
Return to
patient
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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
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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
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Antagonism of the Absorbed PoisonTypes 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
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Important Antidotes
Antidote Poison(s)N-Acetylcysteine* Acetaminophen; best given
within 810 h of overdoseAtropine Cholinesterase inhibitors
Bicarbonate Membrane-depressant cardiotoxic drugs (e.g.,
quinidine, TCAs)Calcium Fluoride; calcium channel
blockersDeferoxamine Iron salts
Digoxin antibodies Digoxin and related cardiac glycoside Ethanol
Methanol, ethylene glycolFlumazenil Benzodiazepines, zolpidem
Fomepizole Methanol, ethylene glycolGlucagon Beta adrenoceptor
blockersGlucose HypoglycemicsHydroxocobalamin CyanideNaloxone
Opioid analgesicsOxygen Carbon monoxidePhysostigmine muscarinic
receptor blockers
Pralidoxime Organophosphate cholinesterase inhibitors
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Limitations of Antidotes
Must know the identification of the poison or toxin
Must be given in a timely fashionNo 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.
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Pharmacists can play a key rolePharmacists 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.
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EthanolEpidemiology: 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
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Ethanol Intoxicating effects of alcohol are due in
part to enhancement of GABA at GABAAreceptors, and blockade of
the NMDA and AMPA subtype of glutamate receptors
Chronic alcohol use results in down-regulation of GABAA
receptors (inhibitory) and up-regulation of NMDA receptors
(excitatory)
Increased glutamatergic activity may account for hyperexcitable
state seen with abrupt alcohol withdrawal
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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
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Blood Alcohol ConcentrationBlood Alcohol Level (BAC mg%):
Effects On the Body0.02 Slight mood changes 0.06 Lowered behavioral
inhibition and impaired
judgement0.08 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
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Ethanol MetabolismEthanol 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
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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
12
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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
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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
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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
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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
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Ethanol MethanolEthylene Glycol
Acetaldehyde(hangover, flushing)
Formaldehyde(blindness,
cerebral oedema)
Glycoaldehyde(CNS effects)
Acetic acid Formic acid(metabolic acidosis)Glycolic acid
(metabolic acidosis)
CO2 + H2O Glyoxylate(lactic acidosis)
Oxalate(cerebral and renal
damage, hypocalcaemia)
LDH or glycolic acid oxidase
LDH or aldehyde oxidase
ALDH
ADH
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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
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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
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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)
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Ethylene GlycolMetabolic 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
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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
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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
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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).
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Behavioral Effects of Ethanol Overdose
Toxidrome for Acute Ethanol poisoningRange 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
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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
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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
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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
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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 HCO3- are
used clinically for
calculation of the anion gap:
Anion gap= ([Na+] - [Cl- + HCO3-]) A high anion gap indicates
that there is loss of
HCO3- without a concurrent increase in Cl- to compensate for
increased metabolic acidosis
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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
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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
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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
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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
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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.
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Sedatives-HypnoticsBarbiturates: Advent in early 1900s
phenobarbital: 1912Dominated market for >60 years
Benzodiazepines: Developed to provide more selective effects on
CNSSelected based on potency of anxiolytic
activity vs. CNS depressant effectsMost retain selective
sedative / hypnotic
effects, some have amnesic effectsGenerally safer and less
toxic
Which agent would have the higher TI?
Have clinically replaced barbiturates
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Sedative-HypnoticsEnhances function of GABA system: Inhibitory
neurotransmitter in the CNSBarbiturates: Increases duration of the
chloride channel openingVery 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
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Activation of the GABAAreceptor results in an increase in Cl-
ion conductance via the receptor-gated ion channel. Associated with
fast GABA neurotransmission.
GABAA Receptors
Cl-
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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?
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Sedative-Hypnotics Signs and Symptoms of Acute ToxicityDirectly
related to CNS and CV depressionReactions are dose-dependantMild
sedation to coma and paralysis
Widespread use makes benzodiazepines a more likely candidate for
overdoseDetermined by urine toxicology screenAlways consider that
there may be other drugs on board along with B and Bs Especially
alcohol
Alcohol makes Benzos more toxic!
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Sedative-HypnoticsClinical 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)
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Sedative-Hypnotics Clinical Management of Acute
OverdoseBarbiturates
ABC managementVentilationVital function supportVolume expanders
to maintain blood pressure
After ingestion:Gastric lavage (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
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Sedative-Hypnotics Clinical Management of Acute
OverdoseBenzodiazepines
ABC managementVentilationVital function supportVolume expanders
to maintain blood pressure
After ingestion:Gastric lavage (if 1 hr)Flumazenil
(benzodiazepine antagonist)NO ROLE for hemodialysis or
hemoperfusion
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Sedative-HypnoticsPharmacological TreatmentAntidote: 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
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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
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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
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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
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Toxicity of AcetaminophenAcetaminophen 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
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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
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Toxic Dose: 200 mg/kg children and > 4 g in adultsAlcoholics
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
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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)
Clinical Toxicology of Acetaminophen
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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
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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
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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
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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 ToxicologyTreatment options: GI Decontamination
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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
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Salicylate ToxicitySalicylate 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
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Salicylate ToxicitySalicylate 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
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Salicylate Toxicity Management Accounts for 10% of all
analgesic-related deaths Supportive Care (ABCs) 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
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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
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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
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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
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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
(LD50: 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
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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
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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 ).
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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
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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
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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.
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Cyanide Antidote Kit
Nitrites Therapeutic induction of
methemoglobinemia Nitrites oxidize Fe2+ in hemoglobin to form
methemoglobin
NO2 + Hb (Fe2+) = MHb (Fe3+) 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
thiocyanateNa2S2O3 + HCN + O = HSCN
Thiocyanate is eliminated renally
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Cyanokit:Hydroxocobalamin
Hydroxocobalamin Vitamin B12 precursor with Cobalt-containing
group Freely exchanges its hydroxyl group for circulating and
cellular cyanide to form cyanocobalamin (Vitamin B12) 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
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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, par