Pharmacodynamics

Pharmacodynamics - study of the

physiological effects of drugs on the body or
on microorganisms or parasites within
- and the mechanisms of drug action and the
relationship between drug concentration and
effect.
L +R = L.R
where L=ligand (drug), R=receptor (attachment
site)
 PK PD analysis
Pharmacodynamics is often summarized as the
study of what a drug does to the body,
whereas pharmacokinetics is the study of
what the body does to a drug.
Pharmacodynamics is abbreviated as "PD",
and when referred to in conjunction with
pharmacokinetics can be referred to as
"PKPD"
Effects on the body
The majority of drugs either
(a) mimic or inhibit normal physiological/biochemical
processes or inhibit pathological processes in animals
(b) inhibit vital processes of endo or ectoparasites and
microbial organisms.
There are 5 main drug actions:
• Depressing
• Stimulating
• Destroying cells (cytotoxicity)
• Irritation
• Replacing substances
Desired activity
The desired activity of a drug is mainly due to one
of the following:
• Cellular membrane disruption (of the pathogen)
• Chemical reaction
• Interaction with enzyme proteins
• Interaction with structural proteins
• Interaction with carrier proteins
• Interaction with ion channels
• Ligand binding to receptors
– Hormone receptors
– Neuromodulator receptors
– Neurotransmitter receptors
 Few of them – their mode of action
• General anesthetics - work by disordering the neural
membranes, thereby altering the Na+ influx.
• Antacids and chelating agents combine chemically in
the body.
Ex. Enzyme-substrate binding is a way to alter the
production or metabolism of key endogenous
chemicals, for example aspirin irreversibly inhibits the
enzyme prostaglandin synthetase (cyclooxygenase)
thereby preventing inflammatory response.
• Colchicine, a drug for gout, interferes with the function
of the structural protein tubulin.
• Digitalis, a drug still used in heart failure, inhibits the
activity of the carrier molecule, Na-K-ATPase pump
 NEED LESS TO SAY
The widest class of drugs act as ligands
which bind to receptors which determine
cellular effects.
Upon drug binding, receptors can elicit their
normal action (agonist), blocked action
(antagonist), or even action opposite to
normal (inverse agonist).
 Undesirable effects
(Unwanted effects or side effects)
Undesirable effects of a drug include:
• Increased probability of cell mutation
(carcinogenic activity)
• A multitude of simultaneous assorted actions
which may be deleterious
• Interaction (additive, multiplicative, or metabolic)
• Induced physiological damage, or abnormal
chronic conditions
 Therapeutic Window
The therapeutic window is the amount of a
medication between the amount that gives an
effect (effective dose) and the amount that gives
more of adverse effects than desired effects.
For instance, medication with a small therapeutic
window must be administered with care and
control, e.g. by frequently measuring blood
concentration of the drug, since it easily loses
effects or gives adverse effects
 The therapeutic index (also known as therapeutic ratio), is a
comparison of the amount of a therapeutic agent that causes
the therapeutic effect to the amount that causes death.
A therapeutic index is the lethal dose of a drug for 50% of the
population (LD50) divided by the minimum effective dose for
50% of the population (ED50).

A high therapeutic index is preferable to a low one: this

corresponds to a situation in which one would have to take a
much higher dose of a drug to reach the lethal threshold than
the dose taken to elicit the therapeutic effect.
 One of the more commonly used measures of
toxicity is the LD50.
The LD50 (the lethal dose for 50 percent of the
animals tested) of a poison is usually expressed
in milligrams of chemical per kilogram of body
weight (mg/kg). A chemical with a small LD50
(like 5 mg/kg) is very highly toxic. A chemical
with a large LD50 (1,000 to 5,000 mg/kg) is
practically non-toxic.
 DOSE RESPONSE RELATIONSHIP
The characteristics of exposure to a chemical and the
spectrum of effects caused by the chemical come
together in a correlative relationship that toxicologists
call the dose-response relationship. This relationship is
the most fundamental and pervasive concept in
toxicology. To understand the potential hazard of a
specific chemical, toxicologists must know both the
type of effect it produces and the amount, or dose,
required to produce that effect.
 DOSE RESPONSE RELATIONSHIP
The dose-response relationship, or exposure-response
relationship, describes the change in effect on
an organism caused by differing levels of exposure
(or doses) to a stressor (usually a chemical) after a
certain exposure time . This may apply to individuals
(e.g.: a small amount has no significant effect, a large
amount is fatal), or to populations (e.g.: how many
people or organisms are affected at different levels of
exposure).
DOSE RESPONSE RELATIONSHIP

A dose-response curve is a simple X-Y graph relating the magnitude of a

stressor (e.g. concentration of a pollutant, amount of a drug, temperature,
intensity of radiation) to the response of the receptor (e.g. organism under
study). The response may be a physiological or biochemical response, or
even death (mortality), and thus can be counts (or proportion, e.g.,
mortality rate), ordered descriptive categories (e.g., severity of a lesion), or
continuous measurements (e.g., blood pressure). A number of effects
(or endpoints) can be studied, often at different organizational levels (e.g.,
population, whole animal, tissue, cell).
The measured dose (usually in milligrams, micrograms,
or grams per kilogram of body-weight for oral
exposures or milligrams per cubic meter of ambient air
for inhalation exposures) is generally plotted on the X
axis and the response is plotted on the Y axis. Other
dose units include moles per body-weight, moles per
animal, and for dermal exposure, moles per square
centimeter. In some cases, it is the logarithm of the
dose that is plotted on the X axis, and in such cases the
curve is typically sigmoidal, with the steepest portion in
the middle. 
BIOCHEMICAL BASIS OF
TOXICITY
 DETOXIFICATION
OR
BIOTRANSFORMATION
OR
METABOLISM OF XENOBIOTICS
 BIOTRANSFORMATION
Process that converts the parent compound
into metabolites and then forms conjugates

Can happen in 2 phases

Phase I Phase II
 BIOTRANSFORMATION
Considered as the mechanism of
detoxification by host organisms

But some times the metabolites are more toxic

than the parent compound

Bioactivation
 BIOTRANSFORMATION
Phase I – involves oxidation, reduction and hydrolysis
(may be considered as degradation reactions)
Phase II – involves the production of compound
(a conjugate) that is biosynthesized
from the toxicant or its metabolite
Example : Benzene Phase I Phenol

Phase II
conjugates with sulfate
 Drug Metabolism

Extrahepatic microsomal enzymes

(oxidation, conjugation)

Hepatic microsomal enzymes

(oxidation, conjugation)

Hepatic non-microsomal enzymes

(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
 Phase I vs Phase II
Enzyme Phase I Phase II
Types of reactions Hydrolysis Conjugations
Oxidation
Reduction
Increase in Small Large
hydrophilicity
General mechanism Exposes functional Polar compound added
group to functional group

Consquences May result in Facilitates excretion

metabolic activation
 The Phase I System
The Phase I detoxification system, composed
mainly of the cytochrome P450 supergene
family of enzymes, is generally the first
enzymatic defense against foreign
compounds.
Most pharmaceuticals are metabolized
through Phase I biotransformation
 The Phase I System
In a typical Phase I reaction, a cytochrome P450 enzyme (CypP450)
uses oxygen and NADH as a cofactor, to add a reactive group,
such as a hydroxyl radical.

reactive molecules
which may be more toxic than the parent molecule
If these reactive molecules are not further metabolized by Phase II
conjugation, they may cause damage to proteins, RNA, and DNA
within the cell.
 The Phase I System
Several studies have shown evidence of
associations between induced Phase I and/or
decreased Phase II activities and an increased
risk of disease, such as cancer, SLE , and
Parkinson’s disease
Compromised Phase I and/or Phase II activity
has also been implicated in adverse drug
responses
 CYP P 450
Cytochrome P450 (abbreviated CYP, P450, infrequently
CYP450) is a very large and diverse superfamily of
hemoproteins found in all domains of life.
Cytochromes P450 use a plethora of both exogenous and
endogenous compounds as substrates in enzymatic
reactions.
Usually they form part of multi-component electron
transfer chains, called P450-containing systems.
The most common reaction catalysed by cytochrome
P450 is a monooxygenase reaction, e.g. insertion of
one atom of oxygen into an organic substrate (RH)
while the other oxygen atom is reduced to water:
RH + O2 + 2H+ + 2e– → ROH + H2O
 CYP P 450
• CYP enzymes have been identified from all lineages
of life, including mammals, birds, fish, insects,
worms, sea squirts, sea urchins, plants, fungi, slime
molds, bacteria and archaea.
• More than 11500 distinct CYP sequences are
known and named .
• The name cytochrome P450 is derived from the
fact that these are colored ('chrome') cellular
('cyto') proteins, with a "pigment at 450 nm", so
named for the characteristic Soret peak formed by
absorbance of light at wavelengths near 450 nm
when the heme iron is reduced (often with sodium
dithionite) and complexed to carbon monoxide.
NADP+ Drug
CYP Fe+3
CYP e -

R-Ase PC Drug Drug OH

NADPH

CO CYP Fe+3
CO
CYP-Fe+2 CYP Fe+2 Drug OH
Drug h
Drug
e-
O2
CYP Fe+2 H2O
O2 Drug
2H+

Electron flow in microsomal drug oxidizing system

 Cytochrome P450 Isoforms (CYPs) - An Overview

• NADPH + H+ + O2 + DrugNADP+ + H2O + Oxidized Drug

• Carbon monoxide binds to the reduced Fe(II) heme and
absorbs at 450 nm (origin of enzyme family name)
• CYP monooxygenase enzyme family is major catalyst of
drug and endogenous compound oxidations in liver,
kidney, G.I. tract, skin, lungs
• Oxidative reactions require the CYP heme protein, the
reductase, NADPH, phosphatidylcholine and molecular
oxygen
• CYPs are in smooth endoplasmic reticulum in close
association with NADPH-CYP reductase in 10/1 ratio
• The reductase serves as the electron source for the
oxidative reaction cycle
 Phase I - Hydrolysis
• Carboxyesterases & peptidases
– hydrolysis of esters, eg: valacyclovir, midodrine
– hydrolysis of peptide bonds, eg: insulin (peptide)
• Epoxide hydrolase
– H2O added to epoxides, eg: carbamazepine
 Phase I - Reduction
• Azo reduction
– N=N to 2 -NH2 groups
– eg: prontosil to sulfanilamide
• Nitro reduction
– N=O to one -NH2 group
– eg: 2,6-dinitrotoluene activation
• N-glucuronide conjugate hydrolyzed by gut microflora
• Hepatotoxic compound reabsorbed
• Carbonyl reduction
– Alcohol dehydrogenase (ADH)
• Chloral hydrate is reduced to trichlorothanol
• Disulfide reduction
– First step in disulfiram metabolism
• Sulfoxide reduction
– NSAID prodrug Sulindac converted to active sulfide moiety
 Phase I - Reduction
• Quinone reduction
– Cytosolic flavoprotein NAD(P)H quinone oxidoreductase
• two-electron reduction, no oxidative stress
• high in tumor cells; activates diaziquone to more potent form
– Flavoprotein P450-reductase
• one-electron reduction, produces superoxide ions
• metabolic activation of paraquat, doxorubicin
• Dehalogenation
– Reductive (H replaces X)
• Enhances CCl4 toxicity by forming free radicals
– Oxidative (X and H replaced with =O)
• Causes halothane hepatitis via reactive acylhalide intermediates
– Dehydrodechlorination (2 X’s removed, form C=C)
• DDT to DDE
 Phase I: Oxidation-Reduction
• Alcohol dehydrogenase
– Alcohols to aldehydes (Genetic polymorphism-
Asians metabolize alcohol rapidly)
– Inhibited by ranitidine, cimetidine, aspirin
• Aldehyde dehydrogenase
– Aldehydes to carboxylic acids
– Inhibited by disulfiram
 Phase I: Monooxygenases
• Flavin-containing mono-oxygenases
– Generally results in detoxification
– Microsomal enzymes
– Substrates: nicotine, cimetidine, chlopromazine,
imipramine
– Repressed rather than induced by phenobarbital,
3-methylcholanthrene
 Phase I: Monooxygenases
• Monoamine oxidase
– Primaquine, haloperidol, tryptophan are substrates
– Activates 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
(MPTP) to neurotoxic toxic metabolite in nerve tissue,
resulting in Parkinsonian-like symptoms
• Peroxidases couple oxidation to reduction of H2O2 &
lipid hydroperoxidase
– Prostaglandin H synthetase (prostaglandin metabolism)
• Causes nephrotoxicity by activating aflatoxin B1, acetaminophen
to DNA-binding compounds
– Lactoperoxidase (mammary gland)
– Myleoperoxidase (bone marrow)
• Causes bone marrow suppression by activating benzene to DNA-
reactive compound
 Phase I Effects
Biotransformation by liver or gut enzymes
before compound reaches systemic circulation
&
Results in lower systemic bioavailbility of parent
compound
 The Phase II System
Phase II conjugation reactions generally follow
Phase I activation, resulting in a xenobiotic
that has been transformed into a water-
soluble compound that can be excreted
through urine or bile.
Several types of conjugation reactions are seen
in PII - glucuronidation, sulfation, and
glutathione and amino acid conjugation
 The Phase II System
In phase II reactions, the activated xenobiotic
metabolites are conjugated with charged
species such as glutathione (G-SH), sulfate,
glycine, or glucuronic acid. These reactions are
catalysed by a large group of broad-specificity
transferases, which in combination can
metabolise almost any hydrophobic
compound that contains nucleophilic or
electrophilic groups.
 The Phase II System
One of the most important of these groups are
the glutathione S-transferases (GSTs). The
addition of large anionic groups (such as G-SH)
detoxifies reactive electrophiles and produces
more polar metabolites that cannot diffuse
across membranes, and may, therefore, be
actively transported.
 The Phase II System

These reactions require

cofactors which must be replenished through
dietary sources.
 Phase II - Glucuronidation
Major Phase II pathway in mammals
UDP-glucuronyltransferase forms O-, N-, S-, C-
glucuronides; six forms in human liver
Cofactor: UDP-glucuronic acid
Inducers: Phenobarbital, indoles,
3-methylcholanthrene, cigarette smoking
Substrates : dextrophan, methadone, morphine,
p-nitrophenol, valproic acid, NSAIDS, bilirubin,
steroid hormones
 Conjugation Reactions
Glucuronidation
+ CO2H
CO2H ROH OO R
O OH
O or
OH HO O R 3N OH
OH O P O P O CH 2 NH OH
OH O OH ON
O-glucuronide
O UGT

CO2H R
UDP- -D-glucuronic acid N +R
O R
OH
OH
OH

N+-glucuronide

Liver has several soluble UDP-Gluc-transferases

 Phase II – Sulfation

- Sulfotransferases are widely-distributed enzymes

- Cofactor is 3’-phosphoadenosine-5’-phosphosulfate
(PAPS)
- Produce highly water-soluble sulfate esters,
eliminated in urine, bile
- Xenobiotics & endogenous compounds are sulfated
(phenols, catechols, amines, hydroxylamines)
 Conjugation Reactions
Sulfation

O
R OH
R O S OH
NH2
+ O
N N

N N
OH O
OH
H O H O P O S (PAPS, 3’-phosphoadenosine-
O O 5’-phosphosulfate)
H H
HO OH

Examples: ethanol, p-hydroxyacetanilide, 3-hydroxycoumarin

 Phase II – Acetylation

- Major route of biotransformation for aromatic

amines, hydrazines

- Generally decreases water solubility

N-acetyltransferase (NAT)

- Cofactor is AcetylCoenzyme A

- Humans express two forms

Substrates include sulfanilamide, isoniazid, dapsone
 Conjugation Reactions
Acetylation

O O
Ar NH2 O Ar N R O
CoA S CH3 CH3
H
R NH2
+ O O
R OH
Acetyl transferase R N R S
CH3 CH3
R SH H

Examples: Procainamide, isoniazid, sulfanilimide, histamine

NAT enzyme is found in many tissues, including liver

 METHYLATION

- Common, minor pathway which generally

decreases water solubility
- Enzyme involved is Methyltransferases
- Cofactor: S-adenosylmethionine (SAM)
- Reaction (-CH3 ) transfer to O, N, S, C
- Substrates include phenols, catechols, amines,
heavy metals (Hg, As, Se)
 AMINO ACID CONJUGATION

- Alternative to glucuronidation
Two principle pathways
- COOH group of substrate conjugated with -NH2 of
glycine, serine, glutamine, requiring CoA activation
(e.g: conjugation of benzoic acid with glycine to form
hippuric acid)
(or)
- Aromatic -NH2 or NHOH conjugated with -COOH of
serine, proline, requiring ATP activation
 AMINO ACID CONJUGATION

- Substrates: bile acids, NSAIDs

- Species specificity in amino acid acceptors
mammals: glycine (benzoic acid)
birds: ornithine (benzoic acid)
dogs, cats: taurine (bile acids)
nonhuman primates: glutamine
- Metabolic activation
(Serine or proline N-esters of hydroxylamines are
unstable & degrade to reactive electrophiles)
 GLUTATHIONE CONJUGATION

- Enormous array of substrates

- Glutathione-S-transferase catalyzes
conjugation with glutathione
- Glutathione is a tripeptide of glycine, cysteine,
glutamic acid
-Formed by -glutamylcysteine synthetase,
glutathione synthetase
- Buthione-S-sulfoxine is inhibitor
GLUTATHIONE CONJUGATION

- Two types of reactions with glutathione

1. Displacement of halogen,
sulfate, sulfonate, phospho, nitro
group
2. Glutathione added to activated
double bond or strained ring system
- Glutathione substrates are hydrophobic,
containing electrophilic atom
- Can react with glutathione nonenzymatically
 GLUTATHIONE CONJUGATION

- Excretion of glutathione conjugates - Excreted

intact in bile - Converted to mercapturic acids in
kidney and excreted in urine

- Enzymes involved are -

glutamyltranspeptidase, aminopeptidase
Environmental
Toxicology
“What is there that is not
poison?
All things are poison and
nothing is without
poison.
Solely the dose
determines that a thing is
not a poison.”
In other words, “the dose
makes the poison”
Paracelsus
 Terms
• Toxicology – study of exposure to and adverse
effects of chemicals in living organisms
• Toxicant – A toxic chemical of human origin
• Toxin – A natural toxic chemical usually a protein
• Exposure – Chemicals come in contact with, and
are absorbed into organisms
• Effect – Absorbed chemicals interact with a
molecular target and cause a (generally adverse)
change
 Major Routes of Chemical Entry
• Ingestion – via the gastro-intestinal [GI] tract
• Inhalation – via the lungs
• Dermal – via the skin

Exposure Duration
• Acute – Less than 24 hours – generally a single dose
• Repeated Exposures – usually dietary
• Subacute – Repeated exposure for 1 month or less
• Subchronic – Repeated exposure for 1 to 3 months
• Chronic – Repeated exposure for greater than 3
months
 Acute and Chronic Exposures
Can Lead to Very Different Outcomes
Benzene
• Acute exposure – Central nervous system narcosis
• Chronic exposure – bone marrow damage and
leukemia
Cigarette Smoke
• Acute exposure – Nervous system stimulation,
calming (nicotine)
• Chronic exposure – Cancer of mouth, pharynx,
larynx, lung, esophagus, pancreas and bladder;
emphysema
Inorganic
Metals
Pharmaceuticals
Toxic metals Drug overdoses
• Lead · Mercury· Cadmium · Silver · Thallium ·
Tin · Beryllium · Cobalt On nervous system
Dietary minerals
• Manganese · Copper · Iron · Chromium · Zinc· • Salicylate · Paracetamol ·
Selenium
Opioids · Benzodiazepines ·
Metalloids
• Arsenic TCAs · Anticholinesterase
Nonmetals/halogen compounds
• Fluoride · Chlorine
On cardiovascular system
Other • Digoxin toxicity
• Radiation poisoning
Organic • Dipyridamole
 Phosphorus
• Pesticides: Organophosphates
Vitamins
Nitrogen • Vitamin A
• Cyanide
CHO • Vitamin D
• alcohol (Ethanol, Methanol, Ethylene glycol)
Carbon monoxide · Oxygen toxicity • Vitamin E
Biological
(including venom, toxin, food poisoning)
Fish/seafood
• Shellfis poisoning (Paralytic shellfish poisoning, Diarrheal shellfish
poisoning, Amnesic shellfish poisoning, Neurotoxic shellfish
poisoning) · Ciguatera · Ichthyoallyeinotoxism· Scombroid · Haff
disease
Other vertebrates
• snake venom(Alpha-Bungarotoxin, Ancrod, Batroxobin) amphibian
venom: Batrachotoxin · Bombesin · Bufotenin · Physalaemin
birds/quail: Coturnism
Arthropods
• arthropod venom: Bee sting/bee venom (Apamin, Melittin) · spider
venom (Latrotoxin/Latrodectism) · scorpion venom (Charybdotoxin)
Tick paralysis
Poisonous plants/ derivatives
• Mushroom poisoning · Lathyrism · Ergotism · Strychnine poisoning ·
Cinchonism  · Locoism (Pea struck)
 Toxicity
• Tissue specific toxicity (Hepatotoxicity)
• Genotoxicity
• Pesticide toxicity
• Food toxicity
• Occupational toxicity
• Environmental toxicity
 Hepatotoxicity
Implies chemical-driven liver damage. The liver
plays a central role in transforming and clearing
chemicals and is susceptible to the toxicity from
these agents. Certain medicinal agents when
taken in overdoses and sometimes even when
introduced within therapeutic ranges may injure
the organ. Other chemical agents such as those
used in laboratories and industries, natural
chemicals (e.g. microcystins- non ribosomal
peptides produced by cyanobacteria) and herbal
remedies can also induce hepatotoxicity.
Chemicals that cause liver injury are called
hepatotoxins.
 Hepatotoxicity
More than 900 drugs have been implicated in
causing liver injury and it is the most common
reason for a drug to be withdrawn from the
market. Chemicals often cause subclinical
injury to liver which manifests only as
abnormal liver enzyme tests. Drug induced
liver injury is responsible for 5% of all hospital
admissions and 50% of all acute liver failures.
Drug metabolism in liver

Drug metabolism in liver: transferases

are : glutathione, sulfate, acetate,
glucoronic acid. P-450 is cytochrome P-
450 enzymes. 3 different pathways are
depicted for Drugs A, B and C
 Hepatotoxicity
• The human body identifies almost all drugs as foreign
substances (i.e. xenobiotics) and subjects them to various
chemical processes (i.e. metabolism) to make them suitable
for elimination.
• This involves chemical transformations to
(a) reduce fat solubility
(b) to change biological activity.
Although almost all tissue in the body have some ability to
metabolize chemicals, smooth endoplasmic reticulum in
liver is the principal "metabolic clearing house" for both
endogenous chemicals (e.g., cholesterol, steroid hormones,
fatty acids, and proteins), and exogenous substances (e.g.
drugs).The central role played by liver in the clearance and
transformation of chemicals also makes it susceptible to
drug induced injury.
 Hepatotoxicity
Factors influencing drug induced hepatotoxicity
• Age
• Ethnicity and race
• Gender
• Nutritional status
• underlying liver disease
• Renal function
• Pregnancy
• Duration and dosage of drug
• Enzyme induction
• Drug- drug interaction
 Hepatotoxicity
• Drugs continue to be taken off the market due
to late discovery of hepatotoxicity. Due to its
unique feature and close relationship with the
gastrointestinal tract, the liver is susceptible
to injury from drugs and other substances.
75% of blood coming to the liver arrives
directly from gastrointestinal organs and then
spleen via portal veins which bring drugs and
xenobiotics in concentrated form. Several
mechanisms are responsible for either
inducing hepatic injury or worsening the
damage process.
 Hepatotoxicity
• Many chemicals damage mitochondria, an
intracellular organelle that produce energy. Its
dysfunction releases excessive amount of
oxidants which in turn injures hepatic cells.
Activation of some enzymes in the cytochrome P-
450 system such as CYP2E1 also lead to oxidative
stress.Injury to hepatocyte and bile duct cells lead
to accumulation of bile acid inside liver. This
promotes further liver damage. Non-parenchymal
cells such as Kupffer cells, fat storing stellate cells
and leukocytes (i.e. neutrophil and monocyte)
also have role in the mechanism.
 Hepatotoxicity
Specific histo-pathological patterns of liver
injury from drug induced damage are
discussed below.
Zonal Necrosis - This is the most common type
of drug induced liver cell necrosis where the
injury is largely confined to a particular zone
of the liver lobule. It may manifest as very
high level of ALT and severe disturbance of
liver function leading to acute liver failure.
Causes include:
• Paracetamol, carbon tetrachloride
 Hepatotoxicity
Hepatitis In this pattern hepatocellular necrosis is
associated with infiltration of inflammatory cells. There
can be three types of drug induced hepatitis.
(A) viral hepatitis - is the commonest, where
histological features are similar to acute viral hepatitis.
(B) Focal hepatitis - lymphocytic infiltrate.
(C) chronic hepatitis - is very similar to autoimmune
hepatitis clinically, serologically as well as
histologically.
Causes:
(a) Viral hepatitis like: Halothane, isoniazid, phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac
 Hepatotoxicity
Cholestasis Liver injury leads to impairment of bile flow
and clinical picture is predominated by itching and
jaundice. Histology may show inflammation
(cholestatic hepatitis) or it can be bland without any
parenchymal inflammation. In rare occasions it can
produce features similar to primary biliary cirrhosis
due to progressive destruction of small bile ducts
(Vanishing duct syndrome).
Causes:
(a) Bland: Oral contraceptive pills, anabolic steroid,
androgens
(b) Inflammatory: Allopurinol, co-amoxiclav,
carbamazepine
(c) Ductal: Chlorpromazine, flucloxacillin
 Hepatotoxicity
Steatosis Hepatotoxicity may manifest as triglyceride
accumulation which leads to either small droplet
(microvesicular) or large droplet (macrovesicular) fatty
liver. There is a separate type of steatosis where
phospholipid accumulation leads to a pattern similar to
the diseases with inherited phospholipid metabolism
defects (e.g. Tay-Sachs disease)
Granuloma Drug induced hepatic granulomas are
usually associated with granulomas in other tissues
and patients typically have features of systemic
vasculitis and hypersensitivity. More than 50 drugs
have been implicated.
Causes:
• Allopurinol, phenytoin, isoniazid, quinine, penicillin,
quinidine
 Hepatotoxicity
Vascular lesions
• They result from injury to the vascular endothelium.
Causes:
Venoocclusive disease: Chemotherapeutic agents, bush tea
Peliosis hepatis: anabolic steroid
Hepatic vein thrombosis: Oral contraceptives
Neoplasm
Neoplasms have been described with prolonged exposure to
some medications or toxins. Hepatocellular carcinoma,
angiosarcoma and liver adenomas are the ones usually
reported.
Causes:
Vinyl chloride, combined oral contraceptive pill, anabolic
steroid, arsenic, thorotrast
 Genotoxicity

Genotoxicity describes a deleterious action on

a cell's genetic material affecting its integrity.
Genotoxic substances are known to be
potentially mutagenic or carcinogenic,
specifically those capable of causing genetic
mutation and of contributing to the
development of tumors. This includes both
certain chemical compounds and certain types
of radiation.
 Genotoxicity

Typical genotoxins like aromatic amines are

believed to cause mutations because they are
nucleophilic and form strong covalent bonds
with DNA resulting with the formation of
Aromatic Amine-DNA Adducts, preventing
accurate replication.
• Genotoxins affecting sperm and eggs can
pass genetic changes down to descendants
who have never been exposed to the
genotoxin.
 PESTICIDE TOXICITY
Pesticide is a collective term for natural or
synthetic substances, which inhibit or kill insects
(insecticides), nematodes (nematicides), snails
(molluscicides), bacteria (bactericides), fungi
(fungicides) and weeds (herbicides). 
• Nevertheless, most often the term is used as
synonymous with insecticides.   While there are
several insecticides of biological origin, such as
the products of the bacterium Bacillus
thuringiensis, the neem tree and others, control
of crop insect pests has been dominated by
synthetic insecticides for over half a century.
Some insecticides may also be bactericidal or
fungicidal
 PESTICIDE TOXICITY
There are more than 1100 officially recognized
synthetic organic (that contain carbon)
insecticides, which belong to a vast array of
chemical groups, the more important being
a) Organophosphates (OPs), with subgroups like
organothiophosphates, derived from phosphoric
acid
b)Organochlorines (OCs), derived from chlorine.  
c) Carbamates and Pyrethroids are some of the
other groups.
Insecticides are referred by their common names,
derived from the cumbersome scientific names
 PESTICIDE TOXICITY
• Insecticides are not just crop pest specific. 
They pose a serious risk to farm labour and
farm animals, and most other animals in the
environment that feed on insecticide sprayed
crops, all of which suffer from insecticide
poisoning, by dermal contact, inhalation or
ingestion.  
• The lack of target specificity and an
indiscriminate and excessive insecticide
application has disturbed large components of
biodiversity of agricultural lands.  
 PESTICIDE TOXICITY
• Most insecticides are not completely
degraded and so leave residues in the food,
feed, other agricultural produce, soil and
water.   Insecticide (pesticide) residues are
poisonous, when the food or feed from
insecticide sprayed crops was consumed,
without proper cleaning.  Insecticides and
their residues also contaminate soil and
water.   In the process the natural food chain
gets contaminated.
 PESTICIDE TOXICITY
The nature and intensity of insecticidal toxicity
depends upon the
• chemical structure of the insecticide
• the mode of its action and not on whether it is
natural or synthetic. 
The level of exposure and the concentration
of the insecticide or its residue in the body are
critical factors.
 PESTICIDE TOXICITY
There are two states of insecticide poisoning, both of
which are equally dangerous:
1. Acute State is when a single very high dose that may
be lethal was administered
2. Chronic State is one in which several sub-lethal doses
were consumed over a long period of time, resulting in
high concentrations in the body. 
Some insecticides may accumulate in the body and
cumulatively reach hazardous concentrations. 
Chronic situations have indicated that about 60 per
cent of the synthetic insecticides may cause cancer or
Parkinson’s disease. 
 PESTICIDE TOXICITY
OPs and carbamates are very potent neurotoxins that inhibit
the enzyme choline esterase, leading to the loss of control of
acetylcholine, the most important neurotransmitter.  The OPs
are degraded rapidly on exposure to light, air, soil and water.

The symptoms of OP poisoning are running nose, chest

tightness, shortness of breath, sweating, nausea, vomiting,
stomach cramps, muscle twitching, confusion, seizers,
paralysis, and coma, which lead to death.  OPs can also cause
the Mad Cow Disease.
The symptoms of OC poisoning are tremors, headache,
dermal irritation, respiratory problems, dizziness, nausea, and
seizures.  They may also cause neurological and respiratory
illnesses and are implicated in cancer.  The OCs are more
persistent in nature, but are relatively less toxic than the OPs.
 PESTICIDE TOXICITY
Studies on the safety of chemicals are conducted on
rats since human subjects cannot be used.
The critical concentrations are estimated as milligrams
per kg of body weight, that would kill 50 per cent of
the rats in the study group, a factor called LD50 (Lethal
Dose Fifty) with an alternative measure LC50 (Lethal
Concentration Fifty). 
• Chemicals with LD50 of less than five mg/kg are super
toxic
• Chemicals that have values above 15,000 are
practically non-toxic. 
• For insecticides the LD50 values range from 13 mg/kg
(parathion) to 1375 mg/kg (malathion), which means
that the former is extremely toxic and the latter is
mildly toxic. 
 PESTICIDE TOXICITY
• The LD50 values depend upon so many factors and so there is
actually no standard.
• Though such results cannot be directly extrapolated to humans,
they are the only means of evaluating toxicity potential.   In
general, children and small-bodied people (and animals) are at a
greater risk.     
The farm workers and farm animals that are in direct contact with
insecticides should be periodically tested for toxic concentrations.
Farm animals should not be allowed to graze on crop stubble that
was exposed to extensive pesticide application.  The local medical,
veterinary and agricultural professionals are expected to be
familiar with the safe use insecticides and treatment of people
and animals that were affected, but more often than not, no such
professional support is available.  The levels of awareness among
consumers are poor and illness from toxicity of insecticides and
their residues often goes unrecognized. 
 FOOD TOXICITY
• Any substance in food may have a degree of toxicity or
'poisonousness', whether it is natural, deliberately
added, or a contaminant. There is nothing special
about natural chemicals in food and no distinction
should be made between natural and other substances
when deciding if a food is likely to be hazardous.
• For example, a potato contains a number of
poisonous substances such as nitrate, arsenic and
solanine but in the amounts in which potatoes are
normally eaten these natural substances are not
hazardous. For this reason it is important not to
consume large amounts of a small number of foods ,
but to consume a wide variety of foods. This not only
minimizes the amount of a particular potentially
hazardous substance but also ensures that a range of
essential nutrients are consumed.
 FOOD TOXICITY
Aflatoxin
• Peanuts, peanut products, corn, wheat, rice, that
are grown or stored under conditions that favour
mould growth
- Liver damage, possibility of liver cancer
Allergens
• Cereals (rice, wheat, barley, etc.), peanuts, peas,
lentils, soya beans, strawberries, bananas,
mangoes, pineapples, sesame, poppy and
caraway seeds, tea, chocolate, coffee, yeasts,
alcoholic beverages, honev and other foods likely
to contain pollen
- Eczema, hives, hay fever, asthma, headaches,
abdominal distress, behavioural abnormalities
 FOOD TOXICITY
Caffeine
• Tea, coffee, cola-type soft drinks
- Increased urination, nervousness, upset stomach,
tremors, irritability, possibility of birth defects,
possibility of behavioural change
Cyanide
• Apricot kernels, peach kernels, apple seeds,
young bamboo shoots, bitter almonds, coloured
varieties of lima beans
- Abdominal pain, vomiting, mental confusion,
sensory loss, respiratory distress, spastic
weakness
 FOOD TOXICITY
Favism
• Broad beans
• Anaemia due to an inborn error of metabolism; the disease has an
ethnic distribution around the Mediterranean and some other
areas
Goitrogens
• Cabbage, Brussels sprouts, broccoli, kale, turnips, mustard seeds,
horseradish
• Goitre, particularly in areas where the iodine content of food is low
Haemagglutinins
• Uncooked legumes (castor beans, kidney beans, lima beans, soya
beans, lentils, peas)
• Retarded growth, diarrhoea
Lathyrogens
• Chickpeas
• Paralysis of the legs, skeletal abnormalities
 FOOD TOXICITY
Mycotoxins:
• Ergotism, Alimentary toxic aleukia
• Mouldy rice, mouldy grain
• Vomiting, damage to bone marrow, convulsions,
psychotic behaviour
Oxalic acid
• Spinach, rhubarb
• Fatal poisoning is probably mythical; there is little
danger from eating normal amounts of oxalic-acid
containing plants
Nitrates and nitrites
• Celery, lettuce, spinach, cabbage, cured meats
• Decreased oxygen-carrying ability of blood in infants
with gastro-enteritis; possible risk of gastric cancer
 FOOD TOXICITY
Pyrrolizidine alkaloids
• Comfrey, some 'herbal' teas
• Possibility of liver disease and liver cancer
Solanine
• Sprouted and 'greening' potatoes
• Vomiting, diarrhoea, abdominal pain,
headache, throat irritation
 FOOD TOXICITY
• Usually these effects have occurred only when
excessive amounts of a food containing these
substances have been eaten. In fact, for most of us
there is little hazard from these foods. The
concentration of these poisonous substances is so
low in the food we eat that we would have to
consume huge amounts over a long time for the toxic
effect to show up. Nevertheless, it is import to realize
that there are many potentially hazardous substances
in our diet without any obvious effects on our health,
and that this applies equally to 'natural' and
processed foods. Natural foods can be harmful if they
are contaminated with excessive amounts of
environmental contaminants, or aflatoxin or other
mycotoxins produced by some moulds.
 OCCUPATIONAL TOXICITY
What is Occupational Toxicology?

• The discipline which Identifies chemical,

physical or biological hazards, encountered in
the work environment.
• Recognizes adverse health effects that arise
out of workers’ exposures to these toxicants
• Establishes control measures to prevent or
minimize exposures
 OCCUPATIONAL TOXICITY
Work history (present and past)
Type of work
a) Physical demand (increased metabolism
and increase inhalation and thus absorption)
b) Shift system (exposure duration &
frequency)
c) Working practices such as eating, drinking
in the work place (other route of exposure)
d) Workplace conditions (dust, mold…)
 OCCUPATIONAL TOXICITY
Work history (present and past)
Exposures
a) Physical (noise, cold, heat, radiation)
b) Biological (viruses, bacteria, fungus..)
c) Chemical (dust, vapors, fumes, …)
 Environmental toxicology (EnTox)
EnTox is a young (1965) and interdisciplinary
science that uses both basic and applied scientific
knowledge to understand natural and
anthropogenic pollutants life cycle and their
impacts upon structure and functions of
biological and ecological systems. Research in
EnTox includes both laboratory experiments and
field studies. EnTox wants to answer two main
questions
(1) How the released pollutant causes harmful
effects?
(2) What can we do to prevent or minimize risk to
biological and ecological system?
 Environmental toxicology
EnTox objective is divided into a 5-steps
• Release of pollutant into the environment
• Transport and fate into biota (with/out
chemical transformation)
• Exposure to biological and ecological system
• Understanding responses and/or effects
(molecular to ecological systems)
• Design remediation, minimization,
conservation, and risk assessment plans to
eliminate, prevent or predict environmental
and human health pollutions situations.
 Diagnosis of toxic effects in liver
This remains a major challenge in clinical practice due
to lack of reliable markers. Many other conditions
lead to similar clinical as well as pathological picture.
To diagnose hepatotoxicity, a causal relationship
between the use of the toxin or drug and subsequent
liver damage has to be established, but might be
difficult, especially when idiosyncratic reaction is
suspected.
Simultaneous use of multiple drugs may add to the
complexity
 Diagnosis of toxic effects in liver
An initial step in detecting liver damage is a
simple blood test to determine the presence
of certain liver enzymes in the blood. Under
normal circumstances, these enzymes reside
within the cells of the liver. But when the liver
is injured for any reason, these enzymes are
spilled into the blood stream.
Enzymes are proteins that are present
throughout the body, each with a unique
function.
 Diagnosis of toxic effects in liver
Among the most sensitive and widely used of
these liver enzymes are the
aminotransferases. They include aspartate
aminotransferase (AST or SGOT) and alanine
aminotransferase (ALT or SGPT). These
enzymes are normally contained within liver
cells. If the liver is injured, the liver cells spill
the enzymes into blood, raising the enzyme
levels in the blood and signaling the liver
damage.
 Diagnosis of toxic effects in liver
• AST (SGOT) is normally found in a diversity of tissues
including liver, heart, muscle, kidney, and brain. It is
released into serum when any one of these tissues is
damaged. For example, its level in serum rises with heart
attacks and with muscle disorders. It is therefore, not a
highly specific indicator of liver injury.
• ALT (SGPT) is, by contrast, normally found largely in the
liver. This is not to say that it is exclusively located in liver,
but that is where it is most concentrated. It is released into
the bloodstream as the result of liver injury. It therefore
serves as a fairly specific indicator of liver status.

• The normal range of values for AST (SGOT) is from 5 to 40

units per liter of serum (the liquid part of the blood).
• The normal range of values for ALT (SGPT) is from 7 to 56
units per liter of serum.
 Diagnosis of toxic effects in liver
• AST (SGOT) and ALT (SGPT) are sensitive indicators of liver damage
or injury from different types of disease. But it must be emphasized
that higher-than-normal levels of these liver enzymes should not be
automatically equated with liver disease. They may mean liver
problems or they may not. For example, elevations of these
enzymes can occur with muscle damage. The interpretation of
elevated AST and ALT levels depends upon the entire clinical
evaluation of a patient, and so it is best done by doctors
experienced in evaluating liver disease.
• The precise levels of these enzymes do not correlate well with the
extent of liver damage or the prognosis (outlook). Thus, the exact
levels of AST (SGOT) and ALT (SGPT) cannot be used to determine
the degree of liver disease or predict the future. For example,
patients with acute viral hepatitis A may develop very high AST and
ALT levels (sometimes in the thousands of units/liter range). But
most patients with acute viral hepatitis A recover fully without
residual liver disease. For a contrasting example, patients with
chronic hepatitis C infection typically have only a little elevation in
their AST and ALT levels. Some of these patients may have quietly
developed chronic liver disease such as chronic hepatitis and
cirrhosis (advanced scarring of the liver).
 Diagnosis of toxic effects in kidney
• Creatinine is a chemical waste molecule that is
generated from muscle metabolism. Creatinine is
produced from creatine, a molecule of major
importance for energy production in muscles.
Approximately 2% of the body's creatine is
converted to creatinine every day. Creatinine is
transported through the bloodstream to the
kidneys. The kidneys filter out most of the
creatinine and dispose of it in the urine.
• Because the muscle mass in the body is relatively
constant from day to day, the creatinine level in
the blood normally remains essentially
unchanged on a daily basis.
 Diagnosis of toxic effects in kidney
• The kidneys maintain the blood creatinine in a
normal range. Creatinine has been found to be a
fairly reliable indicator of kidney function.
• As the kidneys become impaired for any reason,
the creatinine level in the blood will rise due to
poor clearance by the kidneys. Abnormally high
levels of creatinine thus warn of possible
malfunction or failure of the kidneys. It is for this
reason that standard blood tests routinely check
the amount of creatinine in the blood. A more
precise measure of the kidney function can be
estimated by calculating how much creatinine is
cleared from the body by the kidneys and it is
referred to creatinine clearance
 Diagnosis of toxic effects in kidney
Normal levels of creatinine in the blood are
approximately 0.6 to 1.2 milligrams (mg) per
deciliter (dl) in adult males and 0.5 to 1.1
milligrams per deciliter in adult females. (In
the metric system, a milligram is a unit of
weight equal to one-thousandth of a gram,
and a deciliter is a unit of volume equal to
one-tenth of a liter.)
 Diagnosis of toxic effects in kidney
• Muscular young or middle-aged adults may have more
creatinine in their blood than the norm for the general
population. Elderly persons, on the other hand, may
have less creatinine in their blood than the norm.
Infants have normal levels of about 0.2 or more,
depending on their muscle development. In people
with malnutrition, severe weight loss, and long
standing illnesses the muscle mass tends to diminish
over time and, therefore, their creatinine level may be
lower than expected for their age.
• A person with only one kidney may have a normal level
of about 1.8 or 1.9. Creatinine levels that reach 2.0 or
more in babies and 10.0 or more in adults may indicate
severe kidney impairment and the need for a dialysis
machine to remove wastes from the blood.
 Diagnosis of toxic effects in kidney
• Any condition that impairs the function of the
kidneys will probably raise the creatinine level in
the blood. It is important to recognize whether
the process leading to kidney dysfunction (kidney
failure, azotemia) is longstanding or recent.
• The most common causes of longstanding kidney
disease in adults are high blood pressure and
diabetes mellitus. Certain drugs can sometimes
cause abnormally elevated creatinine levels.
Serum creatinine can also transiently rise after
ingestion of large amount of dietary meat.
 Bioremediation
Bioremediation can be defined as any process
that uses microorganisms, fungi, green plants or
their enzymes to return the natural environment
altered by contaminants to its original condition.
Bioremediation may be employed to attack
specific soil contaminants, such as degradation of
chlorinated hydrocarbons by bacteria.
An example of a more general approach is the
cleanup of oil spills by the addition of nitrate
and/or sulfate fertilisers to facilitate the
decomposition of crude oil by indigenous or
exogenous bacteria.
 Bioremediation
Bioremediation technologies can be generally
classified as in situ or ex situ.
In situ bioremediation involves treating the
contaminated material at the site
ex situ involves the removal of the
contaminated material to be treated
elsewhere.
Some examples of bioremediation technologies
are landfarming, bioreactor, composting,
bioaugmentation, rhizofiltration, and
biostimulation.
 Bioremediation
Landfarming - performed in the upper soil zone or in
biotreatment cells. Contaminated soils, sediments, or
sludges are incorporated into the soil surface and
periodically turned over (tilled) to aerate the mixture
Bioreactor - bioreactor is a vessel in which is carried out a
chemical process which involves organisms or
biochemically active substances derived from such
organisms. This process can either be aerobic or
anaerobic . Bioreactors are designed to treat sewage and
waste water
Composting - Composting is the purposeful biodegradation
of organic matter, such as yard and food waste. The
decomposition is performed by micro-organisms, mostly
bacteria, but also yeasts and fungi
 Bioremediation
Bioaugmentation is the introduction of a group of
natural microbial strains or a genetically engineered
variant to treat contaminated soil or water.
Phytoremediation describes the treatment of
environmental problems (bioremediation) through the
use of plants which mitigate the environmental
problem without the need to excavate the
contaminant material and dispose of it elsewhere.

Biostimulation involves the modification of the

environment to stimulate existing bacteria capable of
bioremediation. This can be done by addition of
various forms of rate limiting nutrients and electron
acceptors, such as phosphorus, nitrogen, oxygen, or
carbon (e.g. in the form of molasses).
 Bioremediation
The elimination of a wide range of pollutants
and wastes from the environment requires
increasing our understanding of the relative
importance of different pathways and
regulatory networks to carbon flux in
particular environments and for particular
compounds and they will certainly accelerate
the development of bioremediation
technologies and biotransformation processes
ITS ALL IN OUR HANDS TO UNDERSTAND OUR SYSTEM
AND ITS LIMITATIONS – DOSE MATTERS
 Review
Toxicology is the science that studies the harmful effects of
overexposure to drugs, environmental contaminants, and
naturally occurring substances found in food, water, air, and
soil.
– Main objectives are to establish safe doses and
determine mechanisms of biologic action of chemical
substances.

A career in toxicology involves evaluating the harmful effects

and mechanisms of action of chemicals in people, other
animals, and all other living things in the environment.
– This work may be carried out in government, private
industry and consulting firms, or universities and other
research settings.

Toxicologists routinely use many sophisticated tools to

determine how chemicals are harmful.
(e.g.) computer simulations, computer chips, molecular
biology, cultured cells, and genetically-engineered
laboratory animals .
Animals in
Research
“Virtually every medical
achievement of the last
century has depended
directly or indirectly on
research in animals.”
U.S. Public Health
Service
 Summary
Toxicology is a fascinating science that
makes biology and chemistry interesting
and relevant.

Understanding HOW (i.e. mechanism)

something produces a toxic effect can lead to new ways of
preventing or treating chemically-related diseases. Animal
use in research is essential for medical progress.

Many diseases are the result of an interaction between our

genetics (individual variability) and chemicals in our
environment.

Toxicology provides an interesting and exciting way to apply

science to important problems of social, environmental,
and public health significance.
TOXICOLOGY / ENV HEALTH SCIENCE – A
HOOK FOR US TO THINK ABOUT
 YOUR ROLE
The responsibility to help educate the next generation of
citizens to better understand the world around them, and
especially to understand how chemicals – man-made or
natural – present both risks and benefits to society.

Of course, everything we eat, drink, breathe, touch, or use

is made of chemicals, so the task is LARGE!

We hope to make the science of toxicology ‘less obscure’

to the public.
REUSE RESTORE

RECYCLE RETHINK