PHA 0154 Toxicology Color 2014

PHA154:ANS/CNS Spring2014

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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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Cummulative Percent Dead at each DosePercent requiring a specific dose for deathCummulative Percent Sleeping at each DosePercent requiring a Specific Dose for Inducing Sleep

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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QuantalResponses

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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


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 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


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 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


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 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.


88

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


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.

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.


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):

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.


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

ARTERYor

VEINVEIN

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 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


98

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


99

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.


100

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.


101

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


102

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


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 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


105

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


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

12


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 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


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 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


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 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


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 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


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-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


130

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


131

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-


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 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!


134

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)


135

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


136

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


137

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


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 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


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 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

PHA 0154 Toxicology Color 2014

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