Course title: toxicology

Course code: Phar 3103

Lecture: 32 hours
Instructor: Getnet M(Bpharm, Msc, Assi.
Professor of Pharmacology)

Chapter 1 – Introduction

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 Learning Objectives: ch-I

@ the end of this session students will be able to:

 Define toxicology & different terms used in toxicology

 Identify branches of toxicology

 Discuss scope and application of toxicology

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 Definition
 Toxicology - the branch of science that deals with

 It is “the study of the detection, occurrence, properties, effects, and

regulation of toxic substances.”

 A poison - any substance that causes a harmful effect when

administered, either by accident or design, to a living organism.

 Poison is a concept, almost any substance being

harmful at some doses but, at the same time, being without harmful
effect at some lower dose.

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 may be taken as an example

 It is a potent hepatotoxicant at high doses

 a carcinogen with a long latent period at lower doses

 apparently without effect at very low doses

Clinical drugs

therapeutic and highly beneficial at some doses

may be lethal at higher doses.

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 A poison also involves a biological aspect
 a compound, toxic to one species or genetic strain, may

be relatively harmless to another

E.g. CCl4, a potent hepatotoxicant in many species, is
relatively harmless to the chicken
 Compounds may be toxic under some circumstances

but not others or, perhaps, toxic in combination with

another compound but nontoxic alone.

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 Terms
 Poisons can be either or toxicants

 Toxins -natural poisons produced by plants (Phytotoxins) , animals

(Zootoxins), or bacteria (Bacteriotoxins

 Toxicant - the specific poisonous chemical

 Xenobiotic - any foreign substance not normally found in the body.

 Toxic: having the characteristic of producing an undesirable or

adverse health effect

 Toxicity: any toxic (adverse) effect that a chemical, biological or

physical agent might produce within a living organism.

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 Selective Toxicity: means that a chemical will produce injury

to one kind of living matter without harming another form of

life, even though the two may exist close together.

 Hazard: is the likelihood that injury will occur in a given

situation or setting, the conditions of use and exposure are

primary considerations.

 Risk: is defined as the expected frequency of the occurrence

of an undesirable effect arising from exposure to a chemical,

biological or physical agent.
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Historical aspects of Toxicology
 It is only recently that the study of poisons becomes

truly scientific & in the past it was mainly a practical art

utilized by murderers & assassins.

 Poison has played an important part in human history.

 In Ancient time (1500 BC) earliest collection of medical

records contains many references and recipes for

poisons.

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 Dioscorides (50 AD) a Greek physician, classify poisons as
animal, plant or mineral origin & recognized the value of
emetics.
 Maimmonides (1135-1204 AD), wrote about poisons and
their antidote.
 Paracelsus (1493 AD), viewed a poison in the body would
be cured by a similar poison but the dosage is very
important.
“All substances are poisons; there is none that is not a
poison. The right dose differentiates a poison from a

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remedy”. 3/23/2023
 Orfila (1787-1853 AD), Spanish physician who contributed to

forensic toxicology by devising means of detecting poisonous

substances.

 From then on toxicology began in a more scientific manner & began

to include the study of the MOA of poisons.

 In the 20th century toxicology become much more than the use of

poisons.

 There are marked improvements in toxicological diagnosis (that

ranges from screening to confirmatory tests), & management

(production of antidote for them).

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 Classification of Toxicology
I. Based on research methodology
A. Descriptive toxicology

 Concerned directly with toxicity testing, which provides

information for safety evaluation and regulatory requirements.
 Toxicity in experimental animals are designed to yield information

that can be used to evaluate the risks posed to humans and the
environment by exposure to specific chemicals.

 Is abridge between the public and the field of toxicology.

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B. Mechanistic toxicology
 Deals with the MOA (cellular, biochemical, molecular mechanisms)
& toxic effects of chemicals on living organisms.
 This is important for,

 Rational treatment of the manifestations of toxicity.

 Design of antidotes.

E.g. organophosphate poisoning reversed by oximes.

 Prediction of risks

E.g. OP poisoning →leads to accumulation of Ach→activate

muscarinic and nicotinic receptors→ respiratory failure.
 Facilitation of search for safer drugs

e.g. use of reversible in stead of irreversible ChEIs

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C. Regulatory toxicology

 Studies whether the chemical substances has low risk to be used in

living systems.

 Has the responsibility for deciding, on the basis of data provided by

descriptive and mechanistic toxicologists, whether a drug or

another chemical poses a sufficiently low risk to be marketed for a
stated purpose.

 Regulatory toxicologists also are involved in the establishment of

standards for the amounts of chemicals permitted in ambient air,

industrial atmospheres, and drinking water.
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 Examples of regulatory agencies;

− FDA – regulates drugs, food, cosmetics, medical devices &

supplies.
− EPA – regulates pesticides, toxic chemicals, hazardous wastes and

toxic pollutants.
− OSHA – regulates the safe conditions for employees.

 FMHACA (EFDA) –regulates drugs, cosmetics and medical

devices & supplies in Ethiopia.

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D. Predictive toxicology

 Studies about the potential and actual risks of chemicals

/drugs.

This is important for licensing a new drug/chemical for

use.

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II. Based on specific socio-medical issues

A. Occupational toxicology

 Deals with chemical found in the workplace.

• Industrial workers may be exposed to these agents

during the synthesis, manufacturing or packaging of

substances.
• Agricultural workers may be exposed to harmful

amounts of pesticides during the application in the field.

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B. Environmental toxicology

 Deals with the potentially deleterious impact of

chemicals, present as pollutants of the environment, to
living organisms.

C. Clinical toxicology

 Deals with diagnosis and treatment of human poisoning.

 Understanding the toxic effects of medicines (mechanism

of intoxication and methods of toxicity evaluations).

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D. Forensic toxicology

 It is closely related to clinical toxicology, deals with the

medical and legal aspects of the harmful effects of chemicals

on man, often in post mortem material, for instance,
where there is a suspicion of murder, attempted murder or
suicide by poisoning.

 Establish the cause of death or identify clues that can solve a

crime.

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E. Developmental toxicology

 is the study of adverse effects on the developing organism

that occur any time during the life span of an organism that

may result from exposure to chemical or physical agents

before conception (either parent), during prenatal

development, or postnatally until the time of puberty.

 Teratology is the study of defects induced during

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development between conception & birth. 3/23/2023
F. Reproductive toxicology

 is the study of the occurrence of adverse effects on the male or

female reproductive system that may result from exposure to

chemical or physical agents.

The various sub disciplines of toxicology are not

mutually exclusive and are frequently interdependent.

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III. Based on the organ/system effect

Cardiovascular toxicology

Renal toxicology

Central nervous system toxicology

Gastrointestinal toxicology

Respiratory toxicology etc.

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Classification of Poison
 Toxic agents can be classified in accordance with the

interests and needs of the classifier.

 In terms of their target organ effects, source;

 In terms of their physical state, chemical stability or

reactivity, general chemical structure, or poisoning

potential.

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 Classification of Poison….
 According to the organs affected:

 The poison may be:

 Hepatotoxic: phosphorus, CCl4, arsenic…,
 Cardiotoxic: digitalis…,
 Nephrotoxic: mercury…,
 Neurotoxic: alcohol…. etc.
 According to the chemical nature:

 Acids: H2SO4, HCl, HNO3...

 Alkalies: NaOH, KOH, NH4(OH)2…
 According to their source:

 Natural
 Synthetic
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 Scope and application of Toxicology
 Scope of toxicology is broad, encompassing hazardous effects of

 Chemicals:

Industrial/synthetic (drugs, pesticides, food additives, solvents,

dyes, petroleum….).

 Biological agents/toxins:

Poisonous plants and venomous animals.

 Physical agents:

Radiation, noise.

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 The science of toxicology aids the society
 Protect humans and other organisms from deleterious

effects of toxicants.

 To facilitate the development of more selective toxicants

such as anticancer and other clinical drugs and pesticides.

 Frequently, the perturbation of normal life processes by

toxic chemicals enables us to learn more about the life

processes themselves.

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 Chapter II:
Principles of Toxicology
 Principles of Toxicology
1. What are principles of toxicology?

2. What is toxicokinetics?

3. What is toxicodynamics?

4. What are factors that affect the toxicity of a substance?

5. What are sources of toxic substances?

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Toxicokinetics
 The first general principle related to understanding relationships

between external exposure and internal dose.

 Exposure: the concentrations or amount of a substance presented

to individuals or populations; amounts found in specific volumes of

air or water, or in masses of soil.

 Dose: the concentration or amount of a substance inside an

exposed person or organism.

 The intensity of a toxic effect depends on the concentration and

persistence of the ultimate toxicant at its site of action.

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  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.

 Toxicokinetics deals with the ADME of toxic substances.

 The passage through the body of a toxic agent or its metabolites,

usually in an action similar to that of pharmacokinetics.

 Factors that determine the relationships among exposure, dose

and response are those related to uptake, absorption, distribution,

metabolism & excretion.

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Absorption
 Is the transfer of a chemical from the site of exposure, usually an

external or internal body surface, into the systemic circulation.

 Several factors influence absorption;

 concentration

 surface area of exposure

 characteristics of the epithelial layer through which the toxicant

is being absorbed
 lipid solubility (usually the most important factor)

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Common sites of absorption (routes of exposure)
 Oral route: the GIT is the most important route of absorption,

as most acute poisonings involve ingestions.

 Dermal route: lipid solubility of a substance is an important

factor affecting the degree of absorption through the skin.

 Inhalational route: toxic fumes, particulate and noxious gases

may be absorbed through the lungs.

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Routes of Exposure ….

 The major routes by which toxic agents gain access to the

body are; Ingestion (GIT), Inhalation (lungs), Topical

/percutaneous (skin), and other parenteral routes.

 Toxicity may vary as much as tenfold with the route of

administration.

 Question

 Put in descending order of effectiveness routes of exposure

for toxic effects (PO, IV, inhalation, IP, IM, topical)? 3/23/2023
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Types of exposure
 Acute - < 24hr usually 1 exposure.

 Subacute - 1 month, repeated doses.

 Sub-chronic - 1-3months, repeated doses.

 Chronic - > 3months, repeated doses.

Over time, the amount of chemical in the body can build

up, it can redistribute, or it can overcome repair and

removal mechanisms.

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 Assume that you conduct oral toxicity test for 80% methanol

extract of Ruta chalepensis L. (Tena adam) leaves. For this, five

female mice were given 2,000 mg/kg of the extract as a single dose
by oral gavage daily. The animals were observed continuously for 4
hr with 30 min interval and then for 14 consecutive days with an
interval of 24 hr for the general signs and symptoms of toxicity.
This indicate:
A. Acute oral toxicity test
B. Subacute oral toxicity test
C. Subchronic oral toxicity test
D. Chronic oral toxicity test
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Distribution
 Toxicants exit the blood during this phase.

 Blood carries the agent to and from site of action, storage depots,

organs of transformation, and organs of elimination.

 Rate of distribution dependent on:

 Blood flow

 Presence of barriers (BBB, cell membrane…),

 Concentration in blood

 Characteristics of toxicant (affinity for the tissue, plasma protein

binding etc).

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Vd=dose/ plasma concentration(Cp) 3/23/2023
Example:
 A 60Kg epileptic victim attempted suicide by ingesting

Phenytoin tablets. Vd listed is 0.6 L/Kg. Peak blood

concentration measured by the laboratory is 50mg/ L.
What is the dose of the drug that was taken by the
victim?

Dose = plasma concentration x Vd

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Factors affecting distribution of chemicals
 Protein binding: chemicals highly bound to protein have low Vd

 Plasma concentration: when the Vd of chemicals is low, most of the

chemicals remain in the plasma.

 Physiological barriers: chemicals will not uniformly distributed to the

body due to specialized barriers. E.g., BBB, BPB, cell membranes.

 Affinity of chemicals to certain tissues: the concentration of a

chemical in certain tissues after a single dose may persist even when its
plasma concentration is reduced. Examples:
 Calcium, Fluoride, Lead, Strontium concentrate in bone tissue.

 Highly lipophilic compounds (DDT) Stored in adipose tissue.

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Biotransformation
 Can occur at any point during the compound’s journey from absorption
to excretion.
 Why metabolism?

 To facilitate excretion of toxicants by converting lipophilic xenobiotics

to more hydrophilic or polar metabolites.
 Out come of metabolism:

 Less toxic detoxication.

 More toxic toxication/metabolic activation.
E.g. Parathion Parathoxon(toxic metabolite).
APAP NAPQI
 Including activation of protoxicants.
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Biotransformation…
 Key organs in biotransformation;

 Liver (high),

 Lung, Kidney, Intestine (medium), Others (low)

 Biotransformation pathways:

Phase – I (non synthesis):

 Oxidation, reduction & hydrolysis.

 Make the toxicant more water soluble

Phase – II (synthesis):

 Links with a soluble endogenous agent (conjugation,

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methylation, sulfation, acetylation…). 3/23/2023
 Excretion
 The ultimate clearance (Cl) of the substance from the body.

 Routes:

 Urinary excretion

 Exhalation: Volatile cpds, alcohol...

 Biliary excretion via fecal excretion

̶ Cpds can be extracted by the liver and excreted into the bile.

̶ The bile drains into the small intestine and is eliminated in the

feces.
 Others: via milk, sweat, saliva.

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Toxicodynamics
 Studies about the mechanism of action of toxic chemicals & their

adverse effects that can occur at the level of the molecule, cell,
organ, or organism.

 “How & what chemicals do to the body”

 Molecularly:

 Chemical can interact with proteins, lipids, DNA and RNA

 Cellularly:

 Interfere with receptor ligand binding

 Interfere with membrane function

 Interfere with cellular energy production

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 Dose response relationships
 There are three types of dose response r/ships.

1. The Graded dose response r/ship

 Describes the response of an individual organism to
varying doses of a chemical.
 Often referred to as a "graded" response because the
measured effect is continuous over a range of doses.

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2. Quantal dose response r/ships(“All or None”)
 Characterizes the distribution of responses to different doses in a

population of individual organisms.

 An individual in the population is classified as either a "responder"

or a "nonresponder."

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3. Hormesis

 Refers a theoretical phenomenon of dose response r/ship in which

something (as a heavy metal) that produces harmful biological effects at

moderate to high doses may produce beneficial effects at low doses.

 This concept of "hormesis“ result in a U shaped dose response curve.

 For example, chronic alcohol consumption is well recognized to increase the

risk of esophageal cancer, liver cancer, and cirrhosis of the liver at relatively high
doses, and this response is dose related.

 However, there is substantial clinical and epidemiologic evidence that low to

moderate consumption of alcohol reduces the incidence of coronary heart

disease and stroke.

 Thus, when all responses are plotted a U shaped curve is obtained.

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Dose-response r/ship for representative essential substances
trace elements (e.g., Cr, Co, Se…).

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 Therapeutic Index

 Median lethal dose (LD50): is the dose which is expected to kill 50% of the

population in the particular group.

 Median effective dose (ED50): is the dose that produces a desired response in

50% of the test population when pharmacological effects are plotted against
dose.

 Median toxic dose (TD50): is the dose which is expected to bring toxic effect in

50% of the population in the particular group.

 TI=the ratio of the dose required to produce a toxic effect and the dose needed

to elicit the desired therapeutic response. TI=TD50/ED50.

 Margin of safety=LD1/ED99.

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Potential sources of Poison
 Therapeutic agents: drug toxicity can be due to over doses,
unusual adverse effects, frequent administrations of therapeutic
doses & drug interactions.
 Industrial chemicals: chemicals may contribute to environmental
pollution & they may be a direct hazard in the work place they are
used.
 House hold chemicals: like cleaning agents, cosmetics & personal
products .
 Environmental contaminants: like industrial processes,
pesticides & smokes from factories & vehicles.
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Potential sources cont’d
 Natural toxicants: many plants & animals produce toxic
substances.
 Food additives.

 Traditional medicines(Botanicals).

 Drugs of abuse: excessive or improper use of drugs or other

substances for non-medical purposes, usually for altering
consciousness but also for body building is known as abuse of
drug.
 There are a lot of drugs of abuse with high potential of
dependence & tolerance (e.g. alcohol, pethidine, nicotine…).
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Spectrum of undesired effects
The spectrum of undesired effects of chemicals is broad.

 Includes;

Allergic reactions
Idiosyncratic reactions
Immediate Vs delayed toxicities
Reversible Vs irreversible toxic effects
Local Vs systemic toxicities…..

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Factors affecting toxicity
1. Quantity/Dose 8. State of body health
2. Physical form/State 9. Presence of disease.
3. Chemical form 10. Intoxication arid poisoning
4. Concentration states.
5. Condition of the stomach 11. Sleep
6. Route of administration 12. Exercise
7. Age 13. Tolerance
14. Idiosyncrasy
15. Cumulation....

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 Interaction of chemicals

 Can occur through various mczs, such as alterations in

absorption, protein binding, and the biotransformation

and excretion of one or both of the interacting toxicants
(interaction at toxicokinetics level).

 In addition to these modes of interaction, the response

of the organism to combinations of toxicants may be

increased or decreased because of toxicologic responses
at the site of action (interaction at toxicodynamics level).
3/23/2023
26
.
 Pharmacokinetic/Dispositional antagonism

 The antagonist reduces free concentration of drug at target either

by reducing drug absorption or increasing elimination.

Examples:
 Prevention of absorption of a poison by ipecac or charcoal.

 Warfarin and NSAIDs.

 Phenobarbitone and Warfarin.

 Increased excretion of a chemical.

 Use of diuretics,

 Aspirin and Probenecid.

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 Additive effect
 Occurs when the combined effect of two chemicals is equal to the
sum of the effects of each agent given alone.(1+1=2).
 Is the most common.
 Synergistic effect
 Occurs when the combined effects of two chemicals are much
greater than the sum of the effects of each agent given
alone.(1+1>2).
Examples:
 Both CCl4 and ethanol are hepatotoxic compounds, but together
they produce much more liver injury than the mathematical sum of
their individual effects suggest.
 Alcohol and barbiturate.

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 Potentiation:

 Occurs when one substance does not have a toxic effect on a

certain organ or system but when added to another chemical

makes that chemical much more toxic.(1+0>1)

Example:

 Isopropanol is not hepatotoxic, but when it is administered in

addition to CCl4, the hepatotoxicity of CCl4 is much greater

than is the case when it is given alone.

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 Antagonism: it occurs when the effect of one drug is diminished
by another drug.(1+1<1).
 Chemical antagonism or inactivation:

 Is simply a chemical reaction between two compounds that

produces a less toxic product.
 Chemical antagonist combines with drug to produce insoluble,
inactive complex.
Examples:
 Tannin and alkaloid form chemical bond,

 Chelators of metal ions decrease metal toxicity and

 Antitoxins antagonize the action of various animal toxins.

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 Physiological (functional) antagonism

 The “antagonist” has the opposite biological action by its action on

a different receptor.

Examples:

 Insulin and glucagon,

 Histamine and omeprazole,

 Phenobarbitone and amphetamine.

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 Pharmacologic or Receptor antagonism:

 Blockade of the action of the drug at receptor level.

 Occurs when two chemicals that bind to the same receptor

produce less of an effect when given together than the addition of

their separate effects, (E.g., 4 + 6 = 8) or when one chemical
antagonizes the effect of the second chemical, (example: 0 + 4 =
1), (4 + (–4) = 0).

 Receptor antagonists often are termed blockers.

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 Poison prevention & control strategies

 Keep all household poisons separate from food.

 Keep all products in their original containers

 Always read all labels carefully before using the product

 Never give or take any medication in the dark

 Dispose all products in a safe and proper manner

 Encourage periodic home hunts and dispose of old medicine

 Teach children never to take medication unless given by an adult they

know and trust
 Teach children not eat plants or berries

 Store all drugs or potentially toxic substances out of sight and out of

33 reach of children: use cabinet locks. 3/23/2023

 Summary
 Toxicokinetics
 Absorption
 Factors affecting absorption
 Common routes of absorption
 Distribution
 Factors affecting distribution
 Metabolism
 Phases
 Excretion
 Routes

 Toxicodynamics
 Dose response r/ship
 Sources of poisons
 Spectrum of undesired effects
 Factors affecting toxicity.
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35
Getnet M. (MSc, Assi. Professor of
Pharmacology)
Clinical toxicology

Clinical toxicology encompasses the expertise in the specialties

of medical toxicology, applied toxicology, and clinical poison

information.

Drugs are biologically active molecules used in the treatment,

prevention & diagnosis of disease.

Drugs have made & will continue to make a major contribution

to human health but there are risks attached to these benefit.

2
Clinical toxicology ….

Mechanisms for the toxicities arising from drugs include:

• Direct & predictable toxic effects due to over doses

• Toxic effects occurring after repeated therapeutic doses

• Direct but unpredictable toxic effects occurring after single

therapeutic doses (Idiosyncratic response)

• Toxic effects due to drug interaction

• Important components of the initial clinical encounter
with a poisoned patient include

1. Stabilization of the patient

2. Clinical evaluation (history, physical, laboratory, radiology)

3. Prevention of further toxin absorption

4. Enhancement of toxin elimination

5. Administration of antidote

6. Supportive care and clinical follow-up

• The first priority in the treatment of the poisoned patient is
clinical stabilization. This is the so-called ABCs (Airway,
Breathing, Circulation) of initial emergency treatment.

• Assessment of the vital signs and the effectiveness of

respiration and circulation are the primary objectives of this
initial encounter

• Early in the course of some poisonings there is a varying

range of severity of demonstrated toxic effects by patients
poisoned with even lethal dosages of toxins.
• Some chemicals, such as a benzodiazepine can cause
pronounced clinical effects early such as sedation but can
have a comparatively mild clinical course; while other
chemicals, such as camphor, show little clinical effects
initially but can produce a fatal outcome.

• Some chemicals can cause seizures early in the course of their

presentation.

• Control of chemical-induced seizures can be an important

component of the initial stabilization of the poisoned patient.
• The primary goal of taking a medical history in poisoned
patients is to determine

What substance the poisoned patient has been exposed

the extent and time of exposure

• Can be assessed through

Physical Examination

Laboratory Evaluation

Radiographic Examination
 Physical Examination
• is one of the most important aspects of the initial clinical
encounter in the treatment of the poisoned patient

• A thorough examination of the patient is required to

assess the patient’s condition

categorize the patient’s mental status (normal & altered)

if altered, determine possible additional explanations for

the abnormal mental status such as trauma or CNS
 Physical Examination …

 The patient’s physical examination parameters are categorize

into broad classes of symptoms referred to as toxic

syndromes (toxidromes).

 A toxidrome is a group of clinical signs and symptoms that,

when taken together, are likely associated with exposure from

certain toxicologic classes of chemicals.

• Categorization of the patient presentation into toxic

syndromes allows for the initiation of rationale treatment

based on the most likely category of toxin responsible.

 Physical Examination …

 The major toxic syndromes include Narcotic, Cholinergic,

Sympathomimetic, and anticholinergic toxidromes

• Occasionally a characteristic odor can be detected on the
poisoned patient’s breath or clothing which may point toward
exposure or poisoning by a specific agent.
 Physical Examination …

• Periodic reexamination of the patient is a very important

aspect of clinical toxicology treatment procedures.

• Follow-up clinical examinations can help gauge the

progression of the clinical course of poisoning as well as
determine the effectiveness of treatment interventions and
gauge the need for additional treatment procedures.
 Laboratory Evaluation

• In some cases, measurement of an indicator of the biologic

effect of a poison provides sufficient information to render
definitive treatment to the patient.

• For instance measurement of methemoglobin concentration

is sufficient to initiate treatment for methemoglobinemia
without identification of the specific toxin that caused the
condition
List o tests that are commonly measured in a
hospital setting on a stat basis
Laboratory Evaluation ….
• Because of the limited clinical availability of “diagnostic”

laboratory tests for poisons, toxicologists utilize specific,

routinely obtained clinical laboratory data

• especially the anion gap and the osmol gap

• to determine what poisons may have been ingested.

• An abnormal anion or osmol gap suggests a differential

diagnosis for significant exposure.

Laboratory Evaluation …

Anion gap

• is the difference between the serum Na ion concentration and

the sum of the serum Cl and HCO3 ion concentrations.

• A normal anion gap is < 12

• When there is laboratory evidence of metabolic acidosis, the

finding of an elevated anion gap would suggest systemic

toxicity from a relatively limited number of agents

Differential diagnosis of metabolic acidosis with
elevated anion gap: “AT MUD PILES”
Laboratory Evaluation …
osmol gap

• is the numerical difference between the measured serum

osmolarity and the serum osmolarity calculated from the
clinical chemistry measurements of the serum sodium ion,
glucose, and blood urea nitrogen (BUN) concentrations.

• The normal osmol gap is < 10 mOsm.

• An elevated osmol gap suggests the presence of an

osmotically active substance (methanol , ethanol , ethylene
glycol, and isopropanol) in the plasma that is not accounted
for by the sodium ion, glucose, or BUN concentrations
 Radiographic Examination

• The most useful radiographs ordered in an overdose or

poisoned patient include the chest and abdominal radiographs

and the computed head tomography study.

• The abdominal radiograph has been used to detect

recent lead paint ingestion in children

a halogenated hydrocarbon such as CCl4 or chloroform.

these organic solvents will be visualized as a radiopaque liquid

in the gut lumen on the abdominal film relatively recently after
ingestion
• During the early phases of poison treatment or intervention for
a toxic exposure via the oral, inhalation or the topical route the
treatment team may have an opportunity to prevent further
absorption of the poison to minimize the total amount that
reaches the systemic circulation

• For toxins presented by the inhalational route

• removing the patient from the env’t where the toxin is found
• providing adequate ventilation and oxygenation

• For topical exposures

• clothing containing the toxin must be removed
• the skin washed with water and mild soap
• Poison absorption from oral route can be minimized by

• Inducing vomiting (Emetics such as ipecac Syrup,

apomorphine)

• Gastric Lavage

• Activated Charcoal

• Whole-Bowel Irrigation

• Cathartics
 Inducing vomiting (Emetics)

 Contraindications to any form of induced emesis include

If the patient is without a gag reflex; is lethargic, comatose, or

convulsing; or is expected to become unresponsive within the

next 30 minutes

If a fruitful emesis has occurred spontaneously shortly after

ingestion

Ingestions of caustics, corrosives, ammonia, and bleach

Ingestion of aliphatic hydrocarbons (e.g., gasoline, kerosene)

 Contraindications to induced emesis include

• When the agent is definitely known to be nontoxic

• The rapid onset of coma or seizures or the potential to

exaggerate the toxic effects of the poison

• Some examples include poisonings with diphenoxylate,

propoxyphene, clonidine, TCA, hypoglycemic agents, nicotine,

strychnine, β-blocking agents, and calcium channel blockers.

• Debilitated, pregnant, and elderly patients may be further

compromised by induction of emesis.

 Gastric lavage
 involves the placement of an orogastric tube and washing out
of the gastric contents through repetitive instillation and
withdrawal of fluid.

 may be considered only if a potentially toxic agent has been

ingested within the past hour for most patients.

 If the patient is comatose or lacks a gag reflex, gastric lavage

should be performed only after intubation with a cuffed or
well-fitting endotracheal tube.
 Gastric lavage …

 The largest orogastric tube that can be passed (external

diameter at least 12 mm in adults and 8 mm in children)
should be used to ensure adequate evacuation, especially of
undissolved tablets.

 Lavage should be performed with warm (37°C to 38°C)

normal saline or tap water until the gastric return is clear; this
usually requires 2 to 4 L or more of fluid.
Gastric lavage …
 Gastric lavage …

• Relative contraindications for gastric lavage include ingestion

of a corrosive or hydrocarbon agent.

• Complications of gastric lavage include aspiration pneumonitis,

laryngospasm, mechanical injury to the esophagus and

stomach, hypothermia, and fluid and electrolyte imbalance

 Activated Charcoal

• Used to reduce toxin absorption

• It is a highly purified, adsorbent form of carbon that prevent

gastrointestinal absorption of a drug by binding (adsorbing)

the drug to the charcoal surface.

• It is not indicated for aliphatic hydrocarbons because of the

increased risk for emesis and pulmonary aspiration.

• Activated charcoal is most effective when given within the first

few hours after ingestion, ideally within the first hour.

 Activated Charcoal

 is mixed with water to make a slurry, shaken vigorously, and

administered orally or via a nasogastric tube.

 Activated Charcoal …

 is contraindicated when the gastrointestinal tract is not intact.

 is relatively nontoxic, but two identified risks are

emesis following administration and

pulmonary aspiration of charcoal and gastric contents

leading to pneumonitis in patients with an unprotected

airway or absent gag reflex

Whole-Bowel Irrigation

• is performed by administration of large quantities of polyethylene

glycol and electrolyte solution(1-2l/hr for an adult), often via a
nasogastric tube until the rectal effluent is clear

• is occasionally indicated to enhance the elimination of ingested

packets or slow release tablets that are not absorbed by activated
charcoal (e.g. iron, lithium)

• may be indicated for certain patients in whom the ingestion

occurred several hours prior to hospitalization and the drug still is

suspected to be in the gastrointestinal tract, such as drug

smugglers who swallow condoms filled with cocaine

 Whole-Bowel Irrigation …

• Contraindication include inadequate airway protection,

hemodynamic instability, GI hemorrhage, obstruction or ileus

• Doesn’t cause osmotic changes but may precipitate N & V,

abdominal pain and electrolyte disturbances

 Cathartics

• Cathartics, such as magnesium citrate and sorbitol, were

thought to decrease the rate of absorption by increasing

gastrointestinal elimination of the poison and the poison-

activated charcoal complex.

4. Enhancement of Poison Elimination

• There are several methods available to enhance the

elimination of specific poisons or drugs once they have been

absorbed into the systemic circulation.

• The primary methods employed for this use include:

alkalinization of the urine, hemodialysis, hemoperfusion,

hemofiltration, plasma exchange or exchange transfusion,

and serial oral activated charcoal.

 Renal elimination
• The use of urinary alkalinization results in the enhancement of
the renal clearance of certain weak acids.

• The basic principle is to increase urinary filtrate pH to a level

sufficient to ionize the weak acid and prevent renal tubule
reabsorption of the molecule (referred to as ion trapping).

• The ion-trapping phenomenon occurs when the pKa of the

agent is such that after glomerular filtration into the renal
tubules, alteration of the pH of the urinary filtrate can ionize
and “trap” the agent in the urinary filtrate.

• Once the toxin is ionized, reabsorption from the renal tubules is

impaired and excreted in the urine
 Renal elimination …

• Clinical use of this alkalinization procedure requires adequate

urine flow and close clinical monitoring including that of the pH
of the urine.

• The procedure is accomplished by adding sterile NaHCO3 to

sterile water with 5% dextrose for iv infusion and titrating the
urine pH to 7.5 to 8.5.

• The drugs for which this procedure has been shown clinically
efficacious include salicylate compounds and phenobarbital
which have pKa’s of 3.2 and 7.4, respectively
 Renal elimination …

 Theoretically there are similar advantages to be gained from

acidification of the urine regarding enhancement of clearance
of drugs such as amphetamine and phencyclidine

 However there are significant adverse events associated with

acidification such as acute renal failure and acid-base and
electrolyte disturbances.

 For this reason, acidification of the urine is not recommended

as a therapeutic intervention in the treatment of poisoning.
 The dialysis technique

• The dialysis technique, either hemodialysis or peritoneal

dialysis, relies on passage of the toxic agent through a

semipermeable dialysis membrane (or the peritoneal

membrane) so that it can equilibrate with the dialysate and

subsequently be removed
 Hemodialysis
• Hemodialysis incorporates a blood pump to pass blood next
to a dialysis membrane to allow agents permeable to the
membrane to pass through and reach equilibrium.

• In order for this method to be clinically beneficial the

chemcial must have a relatively low volume of distribution,
low protein binding, a relatively high degree of water
solubility and low molecular weight.

• But drugs with a high volume of distribution, such as digoxin,

would not be clinically beneficial from hemodialysis
Chemicals for which hemodialysis has been shown effective
as a treatment modality for poisoning.
 Hemoperfusion
• The technique of hemoperfusion is similar to hemodialysis

except there is no dialysis membrane or dialysate involved in

the procedure.

• The patient’s blood is pumped through a perfusion cartridge

where it is in direct contact with adsorptive material (usually

activated charcoal) that has a coating of material such as

cellulose or a heparin-containing gel to prevent the adsorptive

material from being carried back to the patient’s circulation.

 Hemoperfusion …
 The principle characteristics for a drug/ toxin to be successfully
removed by this technique are

Low volume of distribution

Adsorption by activated charcoal

Lipid soluble compounds and with higher molecular weight

compounds than for hemodialysis

 Protein binding does not significantly interfere with removal by

hemoperfusion.
 Hemoperfusion …

• The medical risks of this procedure include thrombocytopenia,

hypocalcemia and leukopenia.

• This technique is primarily used for the treatment of serious

theophylline overdose, and possibly amanita toxin exposure,

paraquat and meprobamate poisoning.

• Serial oral administration of activated charcoal, also referred to as
MDAC, has been shown to increase the systemic clearance of
various drug substances.

• The mechanism for the observed augmentation of non-renal

clearance caused by repeated doses of oral charcoal is thought to
be translumenal efflux of drug from blood to be adsorbed to the
charcoal passing through the gastrointestinal tract

• In addition, MDAC is thought to produce its beneficial effect by

interrupting the enteroenteric-enterohepatic circulation of drugs.
 After systemic absorption, a drug may reenter the gut lumen
by passive diffusion if the intraluminal drug concentration is
lower than that in blood.

 The rate of this passive diffusion depends on the concentration

gradient and the intestinal surface area, permeability, and
blood flow.

 The activated charcoal in the gut lumen serves as a “sink” for

toxin.
• A concentration gradient is maintained and the toxin
passes continuously into the gut lumen, where it is
adsorbed to charcoal.

• Agents for which activated charcoal has been shown as

an effective means of enhanced body clearance include
carbamazepine, dapsone, digoxin, digitoxin, nadolol,
phenobarbital, salicylates, theophylline
 5. Use of Antidotes in Poisoning
• An antidote is a substance which can counteract a form of

poisoning (from the Greek antididonai, "given against“).

• The antidotes for some particular toxins are manufactured by

injecting the toxin into an animal in small doses and extracting

the resulting antibodies from the host animals' blood.

• This results in an antivenom that can be used to counteract

poison produced by certain species of snakes, spiders, and

other venomous animals.

 Mechanism action of Antidotes

• Physically binding the toxin, preventing the toxin from

exerting a deleterious effect in vivo & facilitating clearance
a chelating agent or Fab fragments specific to digoxin

• Pharmacologically antagonize the effects of the toxin.

 Atropine antagonizes the effects of organophosphate insecticides

• Chemically reacting with biologic systems to increase

detoxifying capacity for the toxin.
 sodium nitrite is given to patients poisoned with cyanide to cause
formation of methemoglobin, which serves as an a alternative binding
site for the cyanide ion
 Specific antidotes
Agent (antidotes) Indication (poisons)
100% oxygen or hyperbaric oxygen carbon monoxide poisoning and cyanide
therapy (HBOT) poisoning
Theophylline antidote for adenosine poisoning
Atropine organophosphate and carbamate insecticides,
nerve agents, some mushrooms
Beta blocker theophylline
Calcium chloride CCB, black widow spider bites
Calcium gluconate hydrofluoric acid
Chelators (EDTA, dimercaprol heavy metal poisoning
(BAL), penicillamine, and DMSA)
amyl or Na nitrite or thiosulfate) cyanide poisoning
Cyproheptadine serotonin syndrome
Deferoxamine mesylate Iron poisoning
Digoxin Immune Fab antibody Digoxin poisoning
(Digibind and Digifab)
Diphenhydramine hydrochloride and Extrapyramidal reactions associated with
benztropine mesylate antipsychotic
Ethanolor fomepizole ethylene glycol poisoning and methanol
poisoning
Flumazenil benzodiazepine poisoning
Glucagon beta blocker poisoning and calcium
channel blocker poisoning

Leucovorin Methotrexate and trimethoprim

Methylene blue treatment of conditions that cause
methemoglobinemia

N-acetylcysteine Paracetamol (acetaminophen) poisoning

Naloxone hydrochloride opioid poisoning
Octreotide oral hypoglycemic agents
Physostigmine sulfate Anticholinergic poisoning
Phytomenadione (vitamin K) and Warfarin poisoning and
fresh frozen plasma indanedione
Pralidoxime chloride (2-PAM) organophosphate insecticides,
followed after atropine
Protamine sulfate Heparin poisoning
Prussian blue Thallium poisoning
Pyridoxine Isoniazid poisoning, ethylene
glycol
Sodium bicarbonate ASA, TCAs with a wide QRS
 6. Supportive Care of the Poisoned Patient

• Supportive and symptomatic care is the mainstay of

treatment of a poisoned patient.

• In the search for specific antidotes and methods to

increase excretion of the drug, attention to vital signs and
organ functions should not be neglected.

• Establishment of adequate oxygenation and maintenance

of adequate circulation are the highest priorities.
 Supportive Care …

• Other components of the acute supportive care plan include

the management of seizures, arrhythmias, hypotension, acid–

base balance, fluid status, electrolyte balance, and

hypoglycemia.

• Placement of intravenous and urinary catheters is typical to

ensure delivery of fluids and drugs when necessary and to

monitor urine production, respectively.

• is one of the drugs commonly involved in suicide attempts and
accidental poisonings, both as the sole agent and in
combination with other drugs.

• Acute acetaminophen poisoning characteristically results in

Hepatotoxicity.

• Toxicity is likely with single ingestions greater than 250 mg/kg

or those greater than 12 g over a 24-hour period

• Virtually all patients who ingest doses in excess of 350 mg/kg

develop severe liver toxicity unless appropriately treated
 Mechanism of Toxicity
• Acetaminophen is metabolized in the liver primarily to

glucuronide or sulfate conjugates, which are excreted into the

urine with small amounts (<5%) of unchanged drug.

• Approximately 5% of a therapeutic dose is metabolized by the

cytochrome P450 mixed-function oxygenase system, primarily

CYP2E1, to a reactive metabolite, Nacetyl- p-benzo-

quinoneimine (

• NAPQI is conjugated with glutathione, a sulfhydryl-containing

compound, in the hepatocyte and excreted in the urine as a

 Mechanism of Toxicity

• In therapeutic acetaminophen ingestions, the liver generates

glutathione, which detoxifies NAPQI.

• However, in overdose, the glutathione is depleted, leaving

the metabolite to produce toxicity.

• Conditions of CYP induction (e.g., heavy alcohol

consumption) or GSH depletion (e.g., fasting or malnutrition)

increase the susceptibility to hepatic injury

Pathway of acetaminophen metabolism
 Factors influencing toxicity
• Dose ingested
• Excessive cytochrome P450 activity due to induction by
chronic alcohol or other drug use
• e.g. carbamazepine, phenytoin, isoniazid, rifampin
• Decreased capacity for glucuronidation or sulfation
• Depletion of glutathione stores due to malnutrition or chronic
alcohol ingestion
• Acute alcohol ingestion is not a risk factor for hepatotoxicity
and may even be protective by competing with acetaminophen
for CYP2E1
 Clinical features
• There are four phases typically describing acetaminophen
toxicity

Phase 1 (0 to 24 hours): loss of appetite, nausea, vomiting,

general malaise

Phase 2 (24 to 72 hours): abdominal pain, increased liver

enzymes

Phase 3 (72 to 96 hours): liver necrosis, jaundice,

encephalopathy, renal failure, death

Phase 4 (>4 days to 2 weeks): complete resolution of

symptoms and organ failure
 Paracetamol overdose treatment
• Activated charcoal within four hours of ingestion
May reduce absorption by 50 to 90 %
Single oral dose of one gram per Kg
Inhibits absorption of oral methionine

• N-acetylcysteine
• Antidote (a glutathione precursor)
• Limits the formation and accumulation of NAPQI
• Powerful anti-inflammatory and antioxidant effects
• IV infusion or oral tablets (also oral methionine)
• 150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg
over next 16 hrs up to 36hrs
• Beyond 8 hours, NAC efficacy progressively decreases
 Paracetamol overdose treatment …

• At the end of NAC infusion, a blood sample should be taken for

determination of the plasma creatinine and ALT.

• If any is abnormal or the patient is symptomatic, further

monitoring is required

• Patients with normal plasma creatinine and ALT and who are
asymptomatic may be discharged from medical care.

• They should be advised to return to hospital if vomiting or

abdominal pain develop or recur
 Paracetamol overdose treatment …
Indications for liver transplantation

• Liver transplantation is life-saving for fulminant hepatic

necrosis

• The indications for liver transplantation are: acidosis (pH <

7.3), PT > 100 sec, creatinine > 300 mcg/l, Grade 3
encephalopathy (or worse)

• It is better to contact the local liver transplant centre earlier

than this.

• Grossly abnormal prothrombin time should trigger referral:

• PT > 20 sec at 24 hr and PT > 40 sec at 48 hr
• Aspirin (acetylsalicylic acid) is most common

- Still accounts for numerous suicidal and accidental poisonings

- Also result from chronic over medication in elderly

- Salicylic acid is metabolized by conjugation

- Conjugation steps are saturable so the half life of aspirin

increases significantly with only small increase in the number
of tablets
 Salicylate overdose & signs
• Inhibition of cyclooxygenase results in decreased synthesis of

prostaglandins, prostacyclin, and thromboxanes

• Stimulation of the CTZ in the medulla causes nausea and vomiting

• Direct toxicity in the CNS, cerebral edema, and neuroglycopenia

• Activation of the respiratory center of the medulla results in

tachypnea, hyperventilation, respiratory alkalosis

• Uncoupled oxidative phosphorylation in the mitochondria generates

heat and may increase body temperature

Salicylate overdose & signs …

• Acute ingestion of more than 200 mg/kg is likely to produce

intoxication

- The first sign of salicylate toxicity is often hyperventilation and

respiratory alkalosis due to medullary stimulation

- Metabolic acidosis follows from accumulation of lactate as well

as excretion of bicarbonate by the kidney to compensate for
respiratory alkalosis

66
 Salicylate overdose & signs ….
- Absorption of salicylate and signs of toxicity may be delayed after
very large overdoses or ingestion of enteric coated tablets

- Tinnitus may be a reliable index for toxicity (200 to 450 mg/ml).

- Tinnitus generally resolves within 2 or 3 days after withdrawal of the

drug
- Reye's syndrome
A potentially fatal disease that causes numerous detrimental
effects to many organs, especially the brain and liver
Disease causes hepatitis with jaundice and
encephalopathy
- Hematologic: decreased platelet aggregation; prolonged bleeding
time
67
Treatment of Aspirin poisoning
- General supportive care is essential

- After massive aspirin ingestions (eg, more than 100 tablets),

aggressive gut decontamination is advisable, including

- gastric lavage

- repeated doses of activated charcoal

- and consideration of whole bowel irrigation

- Intravenous fluids are used to replace fluid losses caused by

tachypnea, vomiting, and fever.

68
 Treatment of Aspirin poisoning …

 For moderate intoxications, IV sodium bicarbonate is given to

alkalinize the urine and promote salicylate excretion by
trapping the salicylate in its ionized, polar form.

 For severe poisoning (eg, patients with severe acidosis, coma,

and serum salicylate level > 100 mg/dL), emergency
hemodialysis is performed to remove the salicylate more
quickly and restore acid-base balance and fluid status

69
 Barbiturates and Benzodiazepines poisoning

- Are sedative hypnotics

Drug A Barbiturates
Coma

Anesthesia
CNS Drug B Benzodiazepines
effect
Hypnosis

Sedation

Increasing dose

Fig. Dose - response curve for two hypothetical sedative - hypnotics.

70
 Barbiturate poisoning

- 10x the hypnotic dose causes the poisoning

 Respiratory depression, decrease BP - collapse in CVs

 Acute renal failure

- Oliguria (diminished urine production)

- Anuria (absence of urine)

 Severe intoxication causes coma

71
 Barbiturate Poisoning

- The incidence of barbiturate poisoning has declined markedly,

largely as a result of their decreased use as sedative-hypnotic
agents.

- Most of the cases are the result of deliberate attempts at

suicide, but some are from accidental poisonings in children
or in drug abusers.

- If alcohol or other depressant drugs also are present, the

concentrations that can cause death are lower

72
 Treatment of barbiturate toxicity
- General supportive care should be provided

- With careful attention to protecting the airway (including

endotracheal intubation) and assisting ventilation, most
patients recover as the drug effects wear off

- Hypotension usually responds to intravenous fluids, body

warming if cold, and, if needed, dopamine
 Dopamine injection- vasopressor & increase RBF (renal
blood flow)

73
 Benzodiazepines
o Have wider safety margin between therapeutic & toxic doses
o Rarely lethal in overdose unless combined with another CNS
depressant drug such as alcohol

Flumazenil
- Specific benzodiazepine antagonist
- Binds with high affinity to specific sites on the GABAA
receptor
- Available only for intravenous administration
- Flumazenil is not effective in single-drug overdoses with
either barbiturates or tricyclic antidepressants.
74
 ANTIDEPRESSANTS

- Tricyclic antidepressants (eg, amitriptyline, desipramine,

doxepin, many others) are among the most common

prescription drugs involved in life-threatening drug overdose.

- Ingestion of more than 1 g of a tricyclic (or about 15–20

mg/kg) is considered potentially lethal.

75
 Antidepressants …

Adverse effects:

- Antimuscarnic: blurred vision, xerostomia (dry mouth),

urinary retention, sinus tachycardia, constipation, and
aggravation of narrow-angle glaucoma

- Block α-adrenergic receptors: orthostatic hypotension,

dizziness, and reflex tachycardia

- Block histamine H1 receptors: sedation, weight gain

- Erectile dysfunction in men and anorgasmia in women

76
 Antidepressants …

- Most important is the fact that tricyclics have quinidine-like

cardiac depressant effects on the sodium channel that

cause slowed conduction with a wide QRS interval and

depressed cardiac contractility.

- This cardiac toxicity may result in serious arrhythmias,

including ventricular conduction block and ventricular

tachycardia.

77
 Treatment of tricyclic antidepressant overdose
• Endotracheal intubation and assisted ventilation may be
needed

• Intravenous fluids are given for hypotension, and dopamine

or norepinephrine is added if necessary.

• The antidote for quinidine-like cardiac toxicity (manifested by

a wide QRS complex) is sodium bicarbonate: a bolus of 50–
100 mEq (or 1–2 mEq/kg) provides a rapid increase in
extracellular sodium that helps overcome sodium channel
blockade.

• Benzodiazepines for seizures 78

 Do not use physostigmine

- Although this agent does effectively reverse anticholinergic

symptoms, it can aggravate depression of cardiac conduction

and cause seizures

79
 Digitalis toxicity (digoxin, digitoxin)
- Digitalis has a narrow therapeutic index
a. cardiac arrhythmia due to
1. Disturbed impulse formation
2. Disturbed impulse conduction
3. Both
b. GIT – N/V
c. Skin rashes, gynaecomastia, neuralgic pain in face and
extremities, vertigo

80
 Treatment of digitalis toxicity

- Stop digitalis therapy

- Stop diuretic therapy (most diuretic produce hypokalemia)

- Treat bradycardia with atropine

- Mild toxicity can be treated with K+

- Supraventricular tachycardia can be treated with anti-

arrhythemic drug

- Digibind

81
 Opiates
Toxic effects

• Behavioral restlessness, tremulousness, hyperactivity (in

dysphoric reactions)

• Respiratory depression

• Nausea and vomiting

• Increased intracranial pressure

• Postural hypotension accentuated by hypovolemia

• Constipation and Urinary retention

• Itching around nose, urticaria (more frequent with parenteral

and spinal administration) 82
NARCOTIC (OPIOID) ANTAGONISTS
• Are drugs that reverse the depressants effects
• Act by displacing the agonists from their receptor sites.
• When an opiate (narcotic drug) cannot bind to receptors, it is
neutralized and cannot exert its depressant effects on body cells
CLINICAL USE
• Relieve the severe CNS and respiratory depression that occurs with
narcotic overdose.
NALOXONE
• is the drug of choice
• its effect starts within minutes of injection and lasts 1 to 2 hrs
• It produces few adverse effects hence repeated injections can be
given safely 83
Clinical Presentation

 The clinical manifestations of AChE insecticides poisoning include:

pinpoint pupils, excessive lacrimation, excessive salivation,

bronchorrhea, bronchospasm and expiratory wheezes,
hyperperistalsis producing abdominal cramps and diarrhea,
bradycardia, excessive sweating, fasciculations and weakness of
skeletal muscles, paralysis of skeletal muscles, convulsions, and
coma.

 The time of onset and severity of symptoms depend on the route

of exposure, potency of the agent, and total dose received

Mechanism of Toxicity

• It phosphorylate the active site of cholinesterase and leads to

accumulation of acetylcholine at affected receptors and results

in widespread toxicity.
Causative Agents

• include organophosphate and carbamate insecticides.

• These insecticides are currently in widespread use throughout

the world for eradication of insects in dwellings and crops.

• Carbamates typically are less potent and inactivate

cholinesterase in a more reversible fashion through
carbamylation compared with organophosphates
Risk Assessment

• The triad of miosis, bronchial secretions, and muscle

fasciculations should suggest the possibility of
anticholinesterase insecticide poisoning

• In cases of low-level exposure, failure to develop signs within

6 hours indicates a low likelihood of subsequent toxicity
Management of Toxicity

• If the poison has been ingested within the hour, gastric

lavage should be considered and followed by the
administration of activated charcoal.

• For the patient with skin contamination, contaminated

clothing should be removed and the patient washed with
copious amounts of soap and water before he or she is
admitted to the emergency department or other patient care
area.
 Management of Toxicity
• Pharmacologic management of organophosphate intoxication relies on the
administration of atropine and pralidoxime

Atropine

 competitively blocks the actions of acetylcholine

 alleviates bronchospasm and reduces bronchial secretions.

 is indicated in all symptomatic patients

 can be used as a diagnostic aid

 should be given IV (0.05 to 0.1 mg/kg in children younger than 12 years

and 2 to 5 mg in adolescents and young adults).

 should be repeated at 5- to 10-minute intervals until bronchial secretions

and pulmonary rales resolve
Management of Toxicity

• Restoration of enzyme activity is necessary for severe

poisoning, characterized by a reduction of cholinesterase
activity to <20% of normal, profound weakness, and
respiratory distress.

• Pralidoxime (2-PAM) breaks the covalent bond between the

cholinesterase and organophosphate and regenerates
enzyme activity.

• The drug should be given at a dose of 25 to 50 mg/kg up to

1g intravenously over 5 to 20 minutes
 Management of Toxicity …
 Organophosphate cholinesterase binding is reversible initially,

but it gradually becomes irreversible. Therefore, therapy with

pralidoxime should be initiated as soon as possible, preferably

within 36 to 72 hours of exposure.

 Both atropine and pralidoxime should be given

together because they have complementary actions.

 Carbamate insecticide poisonings typically do not require the

administration of pralidoxime
• Cyanide combines with the cytochrome oxidase Fe3+, paralysing
cellular respiration.

• In adults the lethal dose of hydrocyanic acid is 50 mg, while

that of an ingested cyanide salt is 250 mg, both of which may
be associated with blood cyanide levels of 0.25 - 0.30 mg/100 mL
(96 - 115 μmol/L)

• Cyanide poisoning may also occur in patients with amygdalin

toxicity (a cyanogenic glycoside found in the kernels of apricots,
peaches and plums).

• When amygdalin is taken by mouth it can be hydrolysed to

benzaldehyde and cyanide by beta-glucosidases.
 Clinical features

• The patient often has a characteristic smell of bitter

almonds.

• With moderate doses, death usually occurs within 4 hr.

• The body’s natural detoxification mechanisms will normally

inactivate 50% of absorbed cyanide within 1 hr; thus if there
are no signs of cyanide toxicity within the first 1 - 3 hr of
exposure to cyanide, it is unlikely that cyanide toxicity will
occur.
 Treatment
Chelating agents

• Dicobalt edetate has a higher affinity for cyanide ions than

cytochrome oxidase, and will form cobalt cyanide complexes that
are stable and nontoxic.

• Approximately 300 mg is infused slowly intravenously followed by

50 mL of 50% dextrose

• Hydroxocobalamin is also a specific cyanide antidote acting by

combining with the cyanide ion on a molar basis to form the
nontoxic cyanocobalamin

• While hydroxocobalamin is nontoxic and believed to be a more

effective agent for cyanide toxicity than dicobalt edetate
Methaemoglobin forming agents and thiosulphate

 Sodium or amyl nitrite can produce methaemoglobin (i.e.

change Fe2+ to Fe3+) which has the capacity to provide an
alternative sink for the cyanide ion.

 The methaemoglobin level aimed for in treatment of cyanide

toxicity is 25%, which may be achieved by

NaNO2 0.3 g intravenously over 20 min and sodium

thiosulphate 12.5 g intravenously over 10 min.

The latter is administered to provide sulphur for the

formation of the nontoxic thio-cyanate.
• Amyl nitrite inhalation for 5 min (which may require 2 - 3
amyl nitrate ampoules) has also been recommended.

• However, it is now not used as it does not achieve adequate

levels of methaemoglobin