Pharmacokinetics ,Pharmacodyn

amics ( fate of drug and

drug action in the body), Drug
interaction and Toxicology
Dr. Joseph
 Definitions
• Pharmacokinetics
– The process by which a drug is absorbed,
distributed, metabolized and excreted
by the body
– Is a study of what the body does to a
drug
-In Pharmacokinetics an attempt is made to
quantify the various dispositional
parameters regarding;
• Absorption
• Distribution ADME
• Metabolism
• Excretion
 ABSORPTION
• In general, for a drug to reach its intended target, the
drug must be present in the bloodstream (an
exception is application of drug for local effects such
as local anesthesia).
• Thus, absorption of drugs refers to the process
where by an amount of a drug reaches the general
circulation from its site of administration.
• The fraction of unchanged drug reaching the
systemic circulation is expressed as the
bioavailability.
Figure 2-3 Factors affecting bioavailability of drugs.
 Routes of Administration
• Routes of administration greatly affect bioavailability
by changing the number of biologic barriers a drug
must cross or by changing the exposure of drug to
pumping and metabolic mechanisms.
• Enteral administration involves absorption of the drug
via the GI tract and includes oral, gastric or duodenal
(e.g., feeding tube), and rectal administration
• Parenteral administration refers to any routes of
administration that do not involve drug absorption via
the GI tract (par = around, enteral = gastrointestinal),
including the IV, intramuscular (IM), subcutaneous (SC
or SQ), and transdermal routes.
Figure 1-2 Drugs administered sublingually and rectally avoid
"first-pass metabolism" in the liver.
• The first-pass effect(first- pass metabolism or
pre systemic metabolism) is a phenomenon of
drug metabolism whereby the concentration
of a drug is greatly reduced before it reaches
the systemic circulation.
 DISTRIBUTION
• After absorption into the bloodstream, drugs
are distributed to the tissues via blood flow
and diffusion and/or filtration across the
capillary membranes of various tissues.
• Initial distribution is determined by cardiac
output and regional blood flow.
– ▴ Drugs are initially distributed to tissues with the
highest blood flow (e.g., brain, lungs, kidney, and
liver).
– ▴ Tissues with lower blood flow (e.g., fat) receive
drugs later.
• Distribution to some tissue compartments is
restricted by barriers.
– ▴ The blood-brain barrier restricts distribution of
hydrophilic drugs into the brain.
Drug Redistribution
• After the initial distribution to high-blood flow
tissues, drugs redistribute to those tissues for
which they have affinity.
• Drugs may sequester in tissues for which they have
affinity.
• These tissues may then act as a sink for the drug
and increase its apparent volume of distribution
(see later).
• In addition, as plasma concentrations of drug fall,
the tissue releases drug back into the circulation,
thus prolonging the duration of action of the drug.
• In addition to specific molecular targets, drugs
show varying degrees of binding to different
components in body compartments.
• This type of binding can play an important role
in a drug's pharmacokinetic profile and in drug
interactions.
 Plasma Protein Binding
• Plasma proteins, such as albumin, α-
glycoprotein, and steroid hormone binding
globulins, exhibit affinity for a number of
drugs.
• Binding to plasma protein is generally
reversible
• Plasma protein binding greatly reduces the
amount of drug free in the plasma.
• Only free drug in the plasma is able to diffuse
to its molecular site of action.
• Thus plasma protein binding can greatly
reduce the concentration of drug at the sites
of action and necessitate larger doses.
• For highly protein-bound drugs, a small change in
plasma protein binding can lead to a large change
in the proportion of free drug in the plasma and
may lead to toxicity.
– ▴ For a drug that is 99% bound to plasma protein, only
1% is free in the plasma. Reduction of plasma protein
binding to 98% results in a doubling of free drug and
drug effect.
• Changes in plasma protein binding can occur as a
result of:
– ▴ Disease
– ▴ Competition between drugs for the same binding site
– ▴ Saturation of binding sites
 Tissue Binding
• Similarly to binding to plasma proteins, drugs
may also bind to individual components of
tissues.
• Binding to tissues results in sequestration of
drug in the tissue.
 ELIMINATION
• Drugs are eliminated from the body via two
basic mechanisms: biotransformation
(metabolism) and excretion.
• These processes are initiated as soon as the
drug reaches the systemic circulation.
 METABOLISM
• Many drugs are lipophilic molecules that
resist excretion via the kidney or gut because
they can readily diffuse back into the
circulation.
Figure 2-6 Renal mechanisms in drug excretion .
• Biotransformation is an essential step in
eliminating these drugs by converting them to
more polar water-soluble compounds.
• There are several different biotransformation
pathways that drug molecules may follow
Figure 2-5 Drug biotransformation pathways.
 Biotransformation:

• May convert drugs to inactive metabolites, thus

terminating their actions
• May convert drugs to active metabolites that may have the
same or different beneficial actions as the parent drug
• May convert inactive drug molecules (prodrugs) to active
drugs
• May convert drugs to reactive intermediates that exert
toxic effects
• Occurs in many tissues including the kidney, gut, and lungs,
but for most drugs the liver is the major site of
biotransformation
• Two major processes contribute to
biotransformation of drugs.
– Phase I Reactions
– Phase II Reactions
 Phase I Reactions
• Phase I reactions are also called oxidation-
reduction reactions or handle reactions.
• These reactions uncover or add a reactive
group to the drug molecule through oxidation,
reduction, or hydrolysis.
• They make the drug molecule more polar and
more reactive, which facilitates excretion or
further biotransformation of the drug through
phase II reactions.
• Oxidation accounts for a large proportion of
drug metabolism.
• It is mediated primarily by mixed function
oxygenases (monooxygenases; microsomal
mixed function oxidases) located in
endoplasmic reticulum, which include the
following:
– ▴ Cytochrome P-450 (CYP) family of enzymes
– ▴ Flavin monooxygenase family of enzymes
– ▴ Hydrolytic enzymes (e.g., epoxide hydrolase)
 Phase II Reactions
• Phase II reactions are also called conjugation
reactions.
– These reactions add a polar group, such as
glucuronide, glutathione, acetate, or sulfate, to the
drug molecule.
– They increase the water solubility of compounds to
facilitate excretion.
– Generally they inactivate the drug but in some cases
can produce active metabolites (e.g., conversion of
procainamide to N-acetylprocainamide).
• Conjugation reactions can occur:
– ▴ Directly with the parent drug molecule or
– ▴ With a reactive intermediate generated by phase
I reactions.
 Drug Excretion
• Drug excretion refers to the removal of drug from
the body.
• Generally, only hydrophilic molecules are
excreted effectively.
• Accordingly, drugs may be excreted as
unchanged parent molecules if they are
sufficiently hydrophilic.
• Lipophilic drugs must be biotransformed to
hydrophilic drug metabolites to be excreted.
• Drug may be excreted via a number of routes,
such as the kidney or in bile, sweat, and breast
milk.
• The lungs are an excretion route by which
volatile lipophilic substances (e.g., inhaled
general anesthetics) can be excreted.
• Changes in excretion rates will affect the
plasma concentration of drugs and their
metabolites and thus play an important role in
the design of drug regimens.
 RENAL EXCRETION
• Renal excretion is quantitatively the most
important route of excretion for most drugs
and drug metabolites.
• Renal excretion involves three processes:
glomerular filtration, tubular secretion,
and/or tubular reabsorption.
• The sum of these processes determines the
extent of net renal drug excretion.
Figure 2-6 Renal mechanisms in drug excretion .
 DRUG ACTION IN THE BODY
• Pharmacodynamics
– The interactions of a drug and the receptors
responsible for its action in the body
– Is a study of what the drug does to the body
• Drug molecules must be ‘bound’ to
particular constituents of cells and tissues
inorder to produce an effect
• The sites where drug molecules are bound
are called drug targets
• Most drug targets are protein molecules
• Other targets include DNA (antimicrobial
and antitumour drugs) and calcium salts
(biphosphonates)
 Protein targets for drug binding
• Four main kinds of regulatory protein
commonly involved as primary drug targets
– Receptors
– Enzymes
– Carrier molecules (transporters)
– Ion channels
 Drug receptors
• Definition in pharmacology: target molecule
through which soluble physiological mediators
(hormones, neurotransmitters, inflammatory
mediators, e.c.t) produce their effects.
• Other macromolecules with which drugs
interact to produce their effects are known as
drug targets
 Drug specificity

• To be useful as either a therapeutic or scientific tool,

a drug must act selectively on particular cells and
tissues (show high degree of binding site specificity)
• Proteins that function as drug targets generally show
a high degree of ligand specificity – will ignore
closely related molecules
• Example: angiotensin acts strongly on vascular
smooth muscle and kidney tubules but very little
effect on other kinds of smooth muscle or intenstinal
epithellium
• However, no drug acts with complete specificity
• In general, the lower the potency of a drug, and the
higher the dose needed, the more likely is that sites
of action other than the primary one will assume
significance
 Drug receptor interactions
• When drug molecule occupies a receptor, the
receptor may or may not be activated
• Receptor activation: the bound drug molecule
influences the receptor to elicit a tissue
response
• Binding and activation are two distinct steps of
the receptor-mediated tissue response
 Concepts used to characterise drug
effects
• Receptor agonist: a drug which upon binding to
a receptor causes its activation
• Receptor antagonist: a drug which binds to a
receptor without causing activation thereby
preventing the agonist from binding
• Affinity of a drug: something which governs the
tendency of the drug to bind to the receptors
• Efficacy of a drug: something governing the tendency
to for the drug, once bound, to activate the receptor
• Drugs of high potency: generally have high affinity to
the receptors occupying a significant proportion of the
receptors even at low concentration
• Agonists possess high efficacy
• Antagonists have, in the simplest case, zero efficacy
• Partial agonists: drugs with intermediate level of
efficacy, even at 100 % receptor occupancy the tissue
response is submaximal
• Full agonists: drugs with sufficient efficacy that they
can elicit a maximal tissue response
• Full agonists: can produce a maximal response
(the largest response that the tissue is capable
of giving)
• Partial agonists: can produce only a
submaximal response
• The difference between full and partial agonists
lies in the relationship between receptor
occupancy and response
• The response at any given occupancy is much
smaller for the partial agonist (cannot produce
maximal response even at 100 % occupancy)
 Measurement of drug effects
• Biological response measured by varying drug
concentration and observing tissue response
in an organ or tisssue bath
• This is often plotted as a concentration-effect
or dose-response curve
 Uses of the dose-response curve

• Estimation of the maximal response that the

drug can produce (Emax)
• Estimation of the concentration or dose needed
to produce 50 % of maximal response (EC50 or
ED50)
• These parameters are useful in comparing
potencies of different drugs that produce
qualitatively similar effect
Figure 2-3 Experimentally observed concentration-effect curves. Although the lines, drawn according to the binding equation 2.5, fit the points well, such curves do not give correct
estimates of the affinity of drugs for receptors. This is because the relationship between receptor occupancy and response is usually non-linear.
 DRUG ANTAGONISM
• Drugs interfere each other’s action
• Frequently, the effect of one drug is diminished or
completely abolished in the presence of another
• The mechanisms through which drugs do this may be
classified as follows
– Chemical antagonism
– Pharmacokinetic antagonism
– Antagonism by receptor block
– Non-competitive antagonism (block of receptor-effector
linkage)
– Physiological antagonism
Antagonism by receptor block
Physiological antagonism
 Desensitisation and Tachyphylaxis
• Synonymous terms used to describe the
phenomenon whereby the effect of a drug
diminishes when it is given continously or
repeatedly.
• Desensitisation often develops within few
minutes
• Tolerance, conventionally describe a more
gradual decrease in responsiveness taking
days or weeks to develop
• Drug resistance, describe the loss of
effectiveness of antimicrobial or antitumour
drugs
• Mechanisms through which desensitasation
develops include
– Change in receptors
– Loss of receptors
– Exhaustion of mediators
– Increased metabolic degradation of the drug
– Physiological adaptation
– Active extrusion of drug from cells (mainly
relevant in cancer chemotherapy
DRUG INTERACTION
 Definition
• Drug interaction is a situation in which a
substance affect the activity of a drug, that is
the effects are increased or decreased or they
produce a new effect that neither produce on
its own
• Drug-drug interactions, Drug-food
interactions, Drug-nutrient interaction, Drug-
disease interactions.
• Drug- drug interaction is the modifications of
the effects of one drug by another drug
(Polypharmacy).
• Drug interaction can result in
Increased effect
i. Increased therapeutic effect Good
ii. Increased toxic or adverse effect Bad
 Decreased effect
i. Decreased therapeutic effect Bad
ii. Decreased toxic effect Good
 Mechanisms of Drug Interaction
• Pharmacokinetics involve the effect of a
drug on another from the point of view that
includes absorption ,distribution ,metabolism
and excretion.
• Pharmacodynamics are related to the
pharmacological activity of the interacting
drugs.
 PD Interactions
• Drug synergism
• Drug antagonism
• Synergism occurs if two drugs with the same
effect, when given together, produce an
effect that is greater in magnitude than the
sum of the effects when the drugs are given
individually.
• EAB > EA + EB 1 + 1 >2
• when the therapeutic or toxic effects of two
drugs are greater than the effect of individual
drug
• Drug synergism is of two types
• Additive effect
• Potentiation
• Additive drug effects occur if two drugs with the
same effect when given together, produce an
effect that is equal in magnitude to the sum of
the effects when the drugs are given individually.
EAB = EA + EB 1+ 1 = 2

• E.g. the combination of a thiazide diuretic and a

beta adrenergic blocking drug in the treatment of
hypertension
Potentiation occurs if a drug lacking an effect of its
own increases the effect of a second, active
drug
EAB > EA + EB 0 + 1 >1
• Potentiation: when the net effect of two drugs
used together is greater than the sum of the
individual drug effect
• E. g. the combination of amoxicillin and
clavulanic acid
• Antagonism: the effects of one drug can be
reduced or abolished by the presence of
another drug.
 Summary PD interactions

Synergistic effect : 1+1>2

Additive effect : 1+1=2
Potentiation effect : 1 + 0 = 2

Antagonism : 1 - 1 = 0 or 0.5
 PK interactions.
1. Altered GIT absorption.
Altered pH, Altered bacterial flora,
formation of drug chelates or complexes,
drug induced mucosal damage and altered
GIT motility.
a) Altered pH;
The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT
than the ionized form does.
b)Altered intestinal bacterial flora ;
• EX., In 10% 0f patients receive digoxin…..40%
or more of the administered dose is
metabolized by the intestinal flora
c) Complexation or chelation;
• EX1., Tetracycline interacts with Milk (Ca2+ )
• Unabsorbable complex
 d)Drug-induced mucosal damage.
Antineoplastic agents e.g., cyclophosphamide
vincristine
procarbazine
Inhibit absorption
of several drugs
eg., digoxin
e) Altered motility
Metoclopramide (antiemitic)

Increase the toxicity Increase absorption of cyclosporine

of cyclosporine due to the increase of stomach
emptying time
2. Altered distribution
Competition for protein binding, displacement
from tissue binding sites, alterations in local
tissue barriers
Displaced protein binding
• It depends on the affinity of the drug to
plasma protein.
• The most likely bound drugs is capable to
displace others.
• The free drug is increased by displacement by
another drug with higher affinity.
Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)

Drugs that displace these agents are Aspirin

Sulfonamides
phenylbutazone
 3. Altered metabolism
• The effect of one drug on the metabolism of the
other is well documented. The liver is the major
site of drug metabolism.

• CYP450 family is the major metabolizing enzyme

in phase I (oxidation process).

•Therefore, the effect of drugs on the rate of

metabolism of others can involve the following
examples.
EX1., Enzyme induction
A drug may induce the enzyme that is responsible
for the metabolism of another drug or even itself e.g

Carbamazepine (antiepileptic drug ) increases its own

metabolism

Phenytoin increases hepatic metabolism of

Theophylline Leading to decrease its level

N.B enzyme induction involves protein synthesis .Therefore,

it needs time up to 3 weeks to reach a maximal effect
EX2., Enzyme inhibition;
•It is the decrease of the rate of metabolism of a
drug by another one.
•This will lead to the increase of the concentration
of the target drug and leading to the increase of its
toxicity .
• Inhibition of the enzyme may be due to the
competition on its binding sites , so the onset
of action is short may be within 24h.
N.B; When an enzyme inducer
(e.g.carbamazepine) is administered with an
inhibitor (verapamil)

The effect of the inhibitor

will be predominant
4. Renal excretion
Active tubular secretion, Passive tubular
reabsorption
a)Active tubular secretion;
• It occurs in the proximal tubules.
•The drug combines with a specific protein to pass
through the proximal tubules.
•When a drug has a competitive reactivity to the
protein that is responsible for active transport of
another drug .
•This will reduce such a drug excretion increasing
its con. and hence its toxicity.
• EX., Probenecid …..
decreases tubular secretion of penicillin
 b)Passive tubular reabsorption;
Excretion and reabsorption of drugs occur in the
tubules by passive diffusion which is regulated by
concentration and lipid solubility.

N.B., Ionized drugs are reabsorbed lower than

non-ionized ones
 Increases salicylates
Ex2., Antacids
clearance and
decreases its action
 Onset of drug interaction

• It may be seconds up to weeks

• for example in case of enzyme induction, it
needs weeks for protein synthesis
• while enzyme inhibition occurs rapidly.
 Laboratory workup
• Blood(metabolite or unchanged drug)
• Urine(metabolite or unchanged drug)
• Hormone levels or their metabolites
• Serum electrolytes
• Laboratory indices e.g. INR
General Principles of Toxicology
 Background
• The field of toxicology is a broad-based
multidisciplinary science that examines the
harmful effects of substances on living
organisms, including humans.

• There are several major subdivisions of

toxicology.
• Descriptive toxicology
– focuses on toxicity testing with the intent of
defining the degree of risk associated with
substances.
• Environmental toxicology
– involves the detection and understanding of
environmental pollutants and their effects on
humans and other organisms.
• Forensic toxicology
– is primarily concerned with detection and
quantification of toxic substances for legal
purposes.

• Mechanistic toxicology
– is focused on determining the mechanisms by
which substances exert toxic effects
• Regulatory toxicology
– uses toxicologic data to establish policies
regarding exposure limits for toxic substances.

• Medical or clinical toxicology
– focuses on the diagnosis and treatment of toxic
effects in humans.
 Objective of this Discussion
• The understanding of the concepts of medical
toxicology
• In principle, these concepts are similar in to
those of pharmacodynamics and
pharmacokinetics.
• This is not surprising, because any substance
can be toxic under the appropriate
conditions.
 Objective continued
• Indeed, Paracelsus, an early toxicologist, stated,
“All things are poison and nothing is without
poison, only the dose permits something not
to be poisonous.”
• In fact, even water in excess can exert toxic
effects (water intoxication) by disrupting
electrolyte balance.
• Thus toxicity may be associated with
therapeutic agents and nontherapeutic agents
alike.
 Terminology
Some useful definitions in toxicology include:
• Poison 
• is any substance that may disrupt biologic function and
potentially kill an organism.

• Toxin, by strict definition,

• is a poison of biologic origin that does not have the ability
to replicate. However, the term toxin has been used more
loosely. For example, environmental toxin has been used
to describe toxic substances of nonbiologic origin.
• Venom 
– is a toxin that is injected into the victim by some
means (e.g., bee sting, snake bite).

• Toxicant 
– is a general term that refers to any harmful 
substance and is generally interchangeable
with poison.
• Toxicodynamics 
• refers to the general concepts of
pharmacodynamics (interaction with molecular
targets and mechanisms of effects) as applied to
interactions and mechanisms that generate toxic
effects

• Toxicokinetics 
• refers to the general concepts of pharmacokinetics
(absorption, distribution, biotransformation, and
elimination) as applied to toxic substances
 General Mechanisms of Toxicity
• Toxicity can be caused by both therapeutic
and nontherapeutic substances.
• In terms of therapeutic drugs, toxicity may
arise from a direct extension of the drug’s
primary action. For example, central nervous
system (CNS) depression or coma may occur
with excessive doses of barbiturates used in
the treatment of epilepsy.
• The toxic effect may also be unrelated to the
primary therapeutic effect but related to the
general pharmacology of the drug
(nonsteroidal antiinflammatory agents may
increase edema in heart failure patients).

• The toxic effect may also have no relationship

to the therapeutic action of the
drug(ototoxicity induced by aminoglycoside
antibiotics).
• There are several general mechanisms by
which toxic effects occur. These mechanisms
can be classified as follows:
• Physical
– The physical presence of the toxicant triggers
reactions that are harmful (e.g., asbestos fibers in
the lung).
• Chemical
– Toxicants react chemically with the tissues or body
fluids such as blood to produce harmful effects
(e.g., strong acids or bases cause burns).
• Pharmacologic
• Toxicants interact with endogenous pharmacologic
pathways, resulting in inhibition or
overstimulation (e.g., botulinum toxin inhibits
release of acetylcholine to cause paralysis).
• Biochemical
• Toxicant reacts biochemically with cellular
constituents to produce cellular damage (e.g.,
venom of many snakes contains phospholipases
that destroy cell membranes).
• Genomic (genotoxic)
• Toxicant alters the genetic material of the cell,
resulting in disruption of function.
• Genotoxic substances may be mutagenic or
carcinogenic.

• Mutagenic (carcinogenic)
• Toxicants alter DNA structure or function
sufficiently to cause mutations (benzene) or
initiate and promote the development of cancers
(polycyclic aromatic hydrocarbons such as
benzo[a]pyrene, found in cigarette smoke).
• Immunologic
• Toxicant may trigger an immune response that
leads to cellular damage (e.g., penicillin-induced
hemolytic anemia) or conversely suppresses the
immune system, causing an increased
susceptibility to infection (e.g., procainamide-
induced agranulocytosis).
• Teratogenic
• Toxicant alters fetal development, resulting in
birth defects (e.g., phenytoin is associated with
development of cleft lip)
 Target Organs
• Toxicity may be systemic, affecting the whole
body, or it may be largely confined to select
target organs, the so-called toxic
effect organs.

• Some organs, such as the liver, brain, lungs,

heart, and kidney, play a central role in
poisonings
• A number of factors interact to determine the
susceptibility of organs to toxic effects.
• These include :
– the organ’s anatomic location
– blood flow
– metabolic processes and activity
– affinity for the toxicant
– capacity for self-repair.
• Major toxic effect organs include the
following:
• Liver
– The liver is exposed to a high concentration of
toxic substances

– Orally absorbed toxicants are presented first to

the liver via the portal circulation.

– The liver also receives a large proportion of

systemic blood flow.
• Liver continued
– Enterohepatic cycling extends exposure to
toxicants excreted through the bile.

– The high metabolic activity of the liver also results

in the generation of reactive intermediates that
may have toxic actions
• Kidney 
– The kidney receives a high proportion of the
cardiac output. Many toxic substances
are excreted by the kidney

– These toxicants are concentrated in the urine as

fluid is reabsorbed from the renal tubule
• Heart
– The total blood volume passes through the heart.
Thus it is exposed to all blood-borne toxicants.
• Lungs
– The lungs represent an extremely large surface
area for interaction with toxicants, particularly
those that are airborne.

– The total cardiac output passes through the lungs,

so blood-borne toxicants are also distributed
extensively to the lungs.
• Brain
– The brain is a critical target organ because of its
central role in homeostasis
– Thus toxicants that affect the brain may influence
multiple systems and result in widespread
systemic toxicity.
 Liver
•Exposed to high concentrations of toxicants absorbed from GI
tract
•Repeated exposure via entero hepatic recycling
•High blood flow
•High biotransformation activity

Brain
•Central homeostatic
regulator
Major target organs

Heart
•High blood flow Lungs
•Large surface area
Kidneys •High blood flow
•High blood flow •Exposed to atmospheric
•Toxicants concentrated in urine toxicants
 Risk Assessment
• Poisoning remains a significant public health
issue that affects up to approximately 5% of
the population per year in industrialized
countries.
• Many countries have established national
poison control centers that can serve as
valuable sources of information.
• The World Health Organization maintains a
directory of these centers (see Websites).
• Because virtually all substances are potentially
toxic, key questions in toxicology are:
–  how much risk is associated with a particular
substance and under what conditions does this
risk become apparent?

– In addition, the level of acceptable risk will vary.

– In some circumstances, very toxic substances (e.g.,

anticancer drugs) are used therapeutically despite
their known toxic effects because the benefits of
such treatments outweigh the risks.
• Accordingly, risk assessment is a primary
consideration in the management of toxic
events
• Key factors contributing to risk assessment
include the following:
• Hazard identification 
– What substances are involved and what are the
adverse effects of each substance?
– Knowledge of the physicochemical properties,
toxicokinetics, and toxicodynamics of the
suspected toxicant(s) is invaluable in designing
treatment strategies.
• Dose response
– Is there a known dose response relationship for
the toxic effects of the toxicant?
– Do toxic effects mirror plasma concentrations?
– At what dose (concentration) do toxic effects
appear?
• Exposure assessment
– Exposure assessment is a key process in
determining the urgency and strategy for
treatment of toxic events.
• Exposure assessment includes estimation of
the following:
• Degree of exposure 
– An estimate of the degree of exposure is essential

– This may be the dose of drug ingested, the

concentration of chemical to which a patient was
exposed, or some other measure (e.g., parts per
million) of the amount of toxicant.

– Included in this assessment is whether the

exposure was acute or chronic.
• Route of exposure
– The route of exposure is an important
determinant of both the extent and rate of
absorption of the toxicant.

– For example, dermal exposure is generally

associated with reduced rates and extent of
absorption compared with oral ingestion or
inhalation.
• Time since exposure
• An estimate of the time since the exposure
will be helpful in estimating the following:
– Degree of absorption at presentation.
– Usefulness of blood sampling
• Blood sampling is useful for toxicants that exhibit a
relationship between the plasma concentration and
toxic effect(s).
• However, if the time of exposure has been long, it is
most likely that plasma concentrations have reached a
maximum value and are of lesser benefit compared
with symptomatology in determining course of
treatment.
• Time since exposure continued
– Value of certain therapies
• The time since exposure will dictate to a certain extent
the appropriateness of treatment approaches.

• For example, if the time since initial exposure has been

very long, then therapies aimed at inhibiting
absorption may have only a minor influence on the
course of poisoning.
• Clinical Status
– In many cases, information about the degree and
time of exposure may be lacking

– In such cases, careful determination of the clinical

status of the patient coupled with knowledge of
potential hazards can assist in determining the
type of toxicant, the suspected time course, and
the treatment protocol.

– In addition, recognition of compromised airway,

circulatory, or neural function requires immediate
supportive measures.
• Patient Characteristics
– The specific characteristics such as
anthropomorphic characteristics, genetic
background, and preexisting conditions of each
patient also factor into risk assessment

– Some (e.g., weight) may affect the course of

poisoning indirectly, whereas others may have a
more direct effect (e.g., alcoholism) by influencing
the production or elimination of toxic substances.

– Genetic polymorphisms may affect absorption,

biotransformation, or elimination of toxicants
Hazard Identification Exposure
•What toxicant(s) are involved •What was the extent of exposure
•What are the physicochemical •What was the route of exposure
properties of each •Time since exposure
•What are the toxicokinetic and
toxicodynamic properties of each
toxicant

Dose Response
•Do toxic effects exhibit a dose Risk
dependent response relationship Assessment
•What are the critical plasma
concentrations

Clinical Status Patient Characteristics

•May suggest identity of toxicant •Genetic background
•May suggest extent and time of •Pre existing conditions
exposure •Anthropometric characteristics
•May suggest treatment strategy (e. g. weight)

Risk assessment during management of toxic events

GENERAL FACTS ABOUT POISONS,
CORROSIVES,
IRRITANTS,ANALGESICS,
HYPNOTICS, TRANQUILLIZERS,
NARCOTIC POISONS
 POISONS
• Poison is a substance ( solid/ liquid or gaseous ),
which if introduced in the living body, or brought into
contact with any part of the body, will produce ill
health or death, by its constitutional or local effects
or both.

poison vs toxin
Poison is a chemical substance(industrial made-
synthetic)
Toxin is biological in origin
 Examples of poisons
Household poisons/ chemicals
– Hair relaxer – Kerosene
– Hair removal products – Cigarettes
– Toilet bowl cleaners – Antifreeze
– Oven cleaners – Turpentine
– Lamp oil – Paint thinner
– Plants
– Pesticides
– Furniture polish
Medications
Poisons are not beneficial, they give harmful effect predominantly
Medicines are primarily beneficial except in overdosage, turns to be
poisons
Prescription pharmaceuticals
Over-the-counter

Alcohols

Gases and Fumes

Carbon monoxide
 Classification of poisons
• Poisons can be classified by
1. Origin
2. Physical form
3. Chemical nature
4. Chemical activity
5. Target site or
6. Use.
 Classification based on origin
1. Microbial
microscopic organism (e.g bacteria and fungi)
clostridium botulinum (botulinus toxin)
2. Plants
plant toxins (e.g belladonna alkaloid m
hyoscyamine found in belladonna (Atropa
belladonna) and jimsonweed (Datura
stramonium)
3. Animal
animal poisons transferred through bites and
stings of venomous terrestrial or marine
animals
terrestrial animals – poisonous snakes,
scorpions, spiders, and ants
marine animals – sea snakes, stingrays and
jellyfish.
4. Synthetic – chemicals manufactured by
chemist in the laboratory
e.g drugs and pesticides
chemicals purified from natural sources e.g
metals from ores and solvents from petroleum
synthetic poisons – pesticides, household
cleaners, cosmetics, pharmaceuticals and
hydrocarbons.
 Classification based on physical form

Physical form of a chemical influences the

exposure and absorbability.
1. Solid
granules of lead vs lead sulfate (solubility)
arsenic trioxide (small vs large granules)
2. Liquid
can be absorbed by ingestion, inhalation, and
through the skin.
 organic vapour vs inorganic vapour
(inhalation)
3.Aerosols
solid or liquid particles small enough to
remain suspended in air for few minutes e.g
fibre (asbestos) and dust are solid aerosols
through skin or inhalation.
aerosol toxicity (lungs>>>skin)
Classification based on chemical nature
• Metallic vs non metallic
Toxicity metallic >>> non metallic (slow
elimination) – chronic exposure
• Organic vs inorganic
toxicity organic>>> inorganic –solubility lipids
membrane
• Acidic vs alkaline
both corrosives
Toxicity alkaline>> acids – penetrate deep in tissues
Classification based on chemical activity

• Electrophilic chemicals attack nucleophilic

site of the cells macromolecules e.g DNA
producing mutations , cancers and
malformations
Classification based on the mode of action

1. corrosives poisons
mainly produce ulceration of tissue
2. Irritant poisons
these produce symptoms of pain in the abdomen,
vomiting and purging.
A. inorganic poisons – metallic (arsenic, mercury, lead
and copper) non metallic (phosphorus, chlorine,
bromine and iodine)
B. organic poisons – vegetable (castor oil) animal
(snakes, scorpion and spiders)
C. Mechanical poisons- powder glass, diamond dust
3. Neurotic poisons – these chiefly act on the
CNS
headache, drowsiness, giddiness, delirium,
stupor, coma and convulsions
A. cerebral poisons – opium, alcohol
sedatives, hypnotics anaesthetics
B. spinal poisons – strychnine
C. peripheral - curare
4. Cardiac poisons
digitalis, tobacco
5. Asphyxiants
coal gas, CO, CO2 and war gases
6. Miscellaneous
analgesics, antipyretic, tranquillizers, anti
depressants
 Other classifications
Target site Uses
• Nervous system • Pesticides
• Cardiovascular system • Household products
• Reproductive system • Pharmaceuticals
• Immune system • Organic solvents
• Lungs • Drugs of abuse
• Liver • Industrial chemicals
• kidneys
Symbol for poisons
 CORROSIVES
• A corrosive substance is one that will destroy
and damage other substances with which it
comes into contact.

• Other substances may be metals, various

organic compound but more concern on living
tissue where it causes chemical burns on
contact.
• Examples of corrosives
– Strong acids
– Strong bases
– Concentrated solutions of certain weak acids or
bases
• Corrosives can exist as any state of matter
example solid , liquid , gases, mists or
vapours.
• Colloquially, corrosives may be called poisons
but these term are different
• There are substances that are both corrosives
and poisons.
– All corrosives are poisons
– Not all poisons are corrosives.
Symbol for corrosives
 IRRITANTS
• agents that set up an inflammatory
process at the site of application or
contact.
– They do not destroy body tissues
 The most common signs and symptoms of
irritant and poisons are due to their local action
on the mucosa of the GIT, causing
inflammatory changes and partial desquamation
of the intestinal mucosa
This leads to burning pain, vomiting and
diarrhea with bloody stools
Symbol for irritants
 ANALGESICS
• Agents used for pain relief
• If overdosed ---toxicity/poisoning
• Most commonly encountered poisoning
– Salicylates poisoning
– Paracetamol poisoning
– Opioid poisoning
 HYPNOTICS
• Class of psychoactive drugs whose primary
function is to induce sleep and to be used in the
treatment of insomnia or surgical anesthesia.
• Related to a very similar group of drugs called
sedatives.
• Whereas the term sedatives describes drugs that
serve to calm or relieve anxiety
• Hypnotics generally describes drugs whose main
purpose is to initiate, sustain or lengthen sleep.
• Most hypnotics prescribed are:
– Benzodiazepines e.g diazepam
• Likelihood of toxicity is more for children and
elderly
• For childrenmultiple convulsions need
multiple doses  overdose/toxicity
• In elderly handling (metabolism) of diazepam is
reduced (prone to toxicity)
 TRANQUILIZERS
• are drug that induces tranquility in an
individual.
– Minor tranquilizer - anxiolytics e.g diazepam
– Major tranquilizer  antipsychotics
 NARCOTICS
• Are group of drugs whose analgesic effect(strong analgesia) is
coupled with euphoria and somnolence
• Side effects –euphoria, somnolence
• They are potential for addiction
• They are respiratory depressants- overdosedeath
• Most frequently prescribed in clinical medicine(moderate to
severe acute/chronic pain) are:
– Morphine
– Codeine
– Methadone
• Most abused heroin which is not prescribed in clinical medicine.
 Poisoning
• The development of dose related adverse
effects following exposure to chemicals,
drugs or other xenobiotics
 Types of poisoning
1. Acute poisoning – excessive single
dose, or several smaller doses of a poison
taken over a short interval of time.

2. Chronic poisoning – smaller doses over

a period of time, resulting in gradual
worsening eg. Arsenic , Phosphorus ,
Antimony etc.
 Nature of poisoning
1. Homicidal – killing of a human being by another
human being by administering poisonous substance
deliberately.
2. Suicidal – when a person administer poison himself
to end his/ her life.
3. Accidental – Eg. Household poisons- nail polish
remover , acetone .
Depilatories- Barium sulphide

4. Occupational – in professional workers. Eg.

insecticides, noxious fumes.
 Routes of Chemical/poison Entry
1. Inhalational
volatile gas, chemical dust, smoke, aerosol.
2. Injectable
a) Intra venous – Benzodiazepines, barbiturates,
tricyclic antidepressants etc.
b) Intramuscular – Benzodiazepines, opioids etc
c) Subcutaneous – Botulinum toxin
d) Intra- dermal – Local anaesthetics,
organophosphates
3. Oral – Corrosives, organophosphorus
4. Through natural orifices- rectum/
vagina/ urethra
Abrus precatorius, croton, calotropis
5. Through unbroken skin –
organophosphorus, Mercury, Lead
Routes of Chemical/poison Entry

Ingestion
mouth
Inhalation
lungs

Injection
Absorption puncture
skin wound
 Diagnosis of poisoning
History – patient
witness
Circumstantional evidence
 suicide note
 containers & potential toxins at scene of
discovery
Physical examination
Investigations
-Biochemical investigations
-ECG abnormalities
-Radiology
-Toxicologic screening
• Patient
 If person is conscious , & immediately brought to the ED,
history may be relevant
Mostly patient estimates of drug/ nature of substance ingested
are inaccurate.

• Witness
 What substance/ substances ?
 What route/ routes ?
 What dose/ doses ?
 When and for how long?
 H /O psychiatric illness?
 Circumstantial evidence

• Unconscious adults • Tablet particles staining

• Empty drug containers/ mouth / clothing
wrappers /tablet neraby • Suicide note
↓ ↓
some sort of poisoning Assumption of
poisoning
Following conditions should arouse
suspicion of poisoning:
 Sudden appearance of symptoms after
food or drink in an otherwise healthy
person
 Symptoms – uniform in character, rapidity
 Sudden onset delirium, paralysis,
cyanosis, collapse etc.
 Physical examination
General appearance

Neurological status- conscious, confused, comatose.

Glasgow coma scale

Pupillary examination
Normal – Celphos poisoning
Miosis – Opioids, OP poisoning
Mydriasis – TCA, Theophylline, Dhatura, Methanol

Convulsions - Ethylene glycol, Lithium, SSRI

Muscular fasciculations – OP poisoning

Vital parameters –
Cardiorespiratory system -
PR, BP, RR, Temp

Hypotension with bradycardia :-

 Beta blockers, Cyanide, Benzodiazepines,
Barbiturates, Opioids, Alchohol , OP insecticides
Hypotension with tachycardia :-
 Beta -2 stimulants, Caffeine ,Theophylline,
Amatoxin containing mushroom
Hypertension with tachycardia :-
 Sympathomimetics, Ergot alkaloids, Anticholinergics,
Alcohol withdrawal

Respiratory depression with failure:-

 Barbiturates, Benzodiazepines, Opiates, Sedative-
hypnotics, Snake venom

Hyperventilation :-
 Amphetamines , Salicylates, Hallucinogens, Cyanide, CO,
H2S
Body tempearture

• Hypothermia :-
 Barbiturates, Benzodiazepines, Ethanol,
Opiates, Cyclic antidepressants

• Hyperthermia :-
 Amphetamines, Alcohol withdrawal, MAO
inhibitors, Anticholinergic agents, Salicylates
Examination of Skin colour and lesions

Colour Toxin/ poison

1. Pink Cyanide
2. Yellow ( jaundice)Phosphorus ,hepatotoxins
(Acetaminophen, mushroom )
3. Red Rifampicin
4. Blue (cyanosis) Aniline, Nitrites, . .
Methemoglobinemia

 Diaphoresis –
 Salicylate, OP poisoning
 Sympathomimetics, serotonin syndrome
 Phencyclidine, alcohol or sedative withdrawal
Bruising Needle tracks

 Diffuse ecchymosis:-  I/V abuse :-

 Anticoagulant poisoning  Opiates
 Rodenticides  Amphetamines
 Cocaine

 May be hidden in groin or

interdigital spaces
Hair
 Hair loss – Chemotherapeutic agents
Thallium

Nails
 Mee’s lines – Arsenic poisoning
Thallium
 Urine colour
Colour Drug/ toxin
1. Brown Myoglobin, CCL4 ,
Aniline , Methydopa
2. Black Naphthalene, Phenols ,
Cresols
3. Red Rifampicin, Phenytoin,
Phenolphthalein,
Desferoxamine
4. Smoky Phenols
5. Green / blue Copper sulphate,
Methylene blue
6. Green Propofol, Indomethacin
 Biochemical investigations
• Hematologic
• CBC, Platelet count, Coagulation profile
– Hemolytic anemia- lead, NSAIDS, Quinidine
– Thrombocytopenia- Aspirin, Phenytoin, Procanamide
– Coagulopathy- snake venoms, warfarin

• Liver function tests

• S. bilirubin , enzymes – AST,ALT , ALP, coagulation profile
– Acetaminophen, sulfonamides, rifampicin, TCA, INH,

• Renal functions tests

– Aspirin, lead, barbiturates, alcohol, amphetamines, copper sulphate
 Other laboratory abnormalities
Hyperkalemia
 Digoxin, Cardiac glycosides, Rhabdomyolysis, K + sparing
diuretics
Hypokalemia
 Theophylline, Amphetamines, Sympathomimetics
Hypernatremia
 Uncommon in clinical toxicology
 Large dose of NaHCO3 for TCA overdose
 Correction of life threatening metabolic acidosis
Hyponatremia
 Rare
Metabolic acidosis
 Acetaminophen, Ethanol, Methyl alcohol, Toulene

Metabolic alkalosis
 Calcium carbonate, Furosemide, Laxative

Anion Gap
 Anion Gap = [ Na+ ] – { [ Cl] +[ HCO3 ] }
 Normal – 8- 12 mmol/ l
Increased anion gap :-
• Ethylene glycol
• Methanol
• Salicylate poisoning
 ECG abnormalities
• Usually non specific
ECG abnormality Drugs/ toxins

1. Bradycardia & AV Block Barbiturates, ß- blockers,

Antiarrhythmics
2. Ventricular Cardiac glycosides, Fluorides,
tachyarrhythmias Membrane active agents,
Sympathomimetics
3. QRS prolongation Amantidine , Hyperkalemia
4. QT prolongation Amantadine, Amiodarone,
Thallium
 Radiological studies
Not particularly helpful in diagnosis.
 May be useful in confirming :-
Ingestion of metallic objects.
Packets of heroin / cocaine ( body
packing)
Serial chest X-ray - Aspiration
pneumonitis, ARDS
 Bio assays of drugs
• Bioassay is the estimation of the
concentration or potency of a substance by
measurement of the biological response that
it produces.
• Qualitative information- present/ absent,
detectable/not detectable
• Quantitative information- how much is
present.
 Bio assays of drugs

• Monitoring of drug/poison concentration

gives information on the amount of that
substance present in the plasma at that
specific time.
• But not all the time plasma concentration of a
drug/poison correlate with the actual amount
present in the body ( protein and tissue
binding)
Bio assays of drugs
 Acetaminophen
 Acetone
 Ethylene glycol
 Methanol
 Salicylate
 Phenobarbital
 Theophylline
 Lithium
Toxicologic analysis
 Urine , blood, gastric contents – confirm or rule out
suspected poisoning.

 Interpretation requires various methods:-

 Thin layer chromatography – Acetaminophen
 Gas liquid chromatography – BZD, Amphetamines
 HPLC- BZD
 Mass spectrometry- Anticonvulsant

 Enzyme assays
 RBC cholinestrase , serum cholinestrase – OP poisoning
 Pseudocholinestrase levels – OP poisoning
Fundamentals of poisoning management

1. Initial resuscitation and stabilization

2. Removal of toxin from the body
3. Prevention of further poison absorption
4. Enhancement of poison elimination
5. Administration of antidote
6. Supportive treatment
7. Prevention of re - exposure
 Administration of Antidotes
• Not all poisons have antidotes.
Poison Antidote Dose
Acetaaminophen N - acetylcysteine 140mg/kg. then 70 mg/kg every 4
hrs to total of 18 doses over 72
hrs
Benzodiazepine Flumazenil 0.1mg/min infusion to a total of
1mg
Anticholinergics Physostigmine 1gm I/M or I/V
Opioid Naloxone 2 mg I/V , repeated every half to
one min to a total of 20 mg I/V
Cyanide Thiosulphate , 0.3 g sodium nitrite in 10 ml
nitrite sterile water iv. 25 g sodium
thiosulphate iv slow
Iron Desferrioxamine 2g im 12 hrly or 10- 15 mg/kg/hr
not to exceed 80 mg /kg /24 hrs
 Administration of antidotes….
Poison Antidote Dose
OP Poisoning Atropine , Oximes Atropine : Loading dose - 2 , 4 ,
6 every 5 mins .
Maintenance – infusion <
3mg/hr
PAM – 15-30 mg/kg IV to be
repeated 6-12 hourly
Infusion – 20- 40 mg/kg f/b 5-
10mg /kg/h

Methanol Ethanol , Ethanol 50% 1 ml/kg every 2 hr

Fomepizole for 5 days
Fomepizole 15 mg/kg loading
dose f/b 10 mg/k every 12 h for
4 days
Toxicologic analysis
 Urine , blood, gastric contents – confirm or rule out
suspected poisoning.

Interpretation requires various methods:-

 Thin layer chromatography – Acetaminophen
 Gas liquid chromatography – BZD, Amphetamines
 HPLC- BZD
 Mass spectrometry- Anticonvulsant
Thank you