International Post-Baccalaureate

PharmD. Program (IPBP)

Internal Assessment (IA) Exam

STUDY GUIDE

PHARMACOLOGY- III

© 2006

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 INTRODUCTION TO TOXICOLOGY

IPBP – October 2006

Learning Objectives

After going through this material, the candidate should be able to:

• Interpret basic toxicological terminology

• Explain the basic principles of toxicodynamics and toxicokinetics

• Assess the relative safety of a drug from their pharmacodynamic and

pharmacokinetic parameters.

• Explain the concept of selective toxicity and its application in pharmacy

• Recall the mechanisms of cell-level toxicity, organ-specific toxicity, mutagenesis,

carcinogenesis and teratogenesis.

• Outline the basic principles and methods of assessing toxicity in animals and
humans

Toxicology

Toxicology is the study of deleterious effects of chemical, physical or biological agents

on living systems.

Why pharmacy students should learn toxicology?

• Most toxic exposures reported by poison centers are caused by clinically used
drugs
• Majority of the adverse effects of drugs in the US are reported by pharmacists.
• For personal enrichment
Children under 6 years are more prone to toxic exposures

American Association of Poison Control Centers: 2004 Annual Report

According to this report, pharmaceuticals are involved in the majority of human toxic
exposures, the major group being ANALGESICS in 2004.
Also, the category which caused largest number of DEATHS in the US among all toxic
categories was ANALGESICS in 2004.
History of Toxicology

• Dates back to time immemorial!

• Recorded: c.a. 1500 BC – book named Ebers papyrus contains information on:

• Hemlock
• Opium
• Aconite
• Lead
• Antimony

• Hippocrates – c.a. 400 BC

• Theophrastus (370-286 BC)

• Dioscorides – 1st century AD

• Sulla – c.a. 82 BC
 • Moses ben Maimon – 1135 -1204 AD

• Paracelsus – 1493-1541

Modern Toxicology

• Started with the invention of anesthetics, disinfectants

• 1890s and early 1900s : toxicity testing in animals

• Wiley Bill -1906: First of many US food and drug laws

• 1930: first journal in toxicology: Archiv für toxikologie

• 1930: NIH established

• 1938: acute kidney damage due to sulfanilamide in

glycol solution –Copeland Bill led to formation of FDA

• 1947: first US pesticide act

• 1958: Delaney clause: carcinogens not permitted in food

• 1958: Toxicology and Applied Pharmacology

• 1960s: THALIDOMIDE disaster

• Currently TOXICOLOGY is a big discipline with > 120 journals

Thalidomide Disaster: A turning point in drug-safety studies

• Morning sickness drug

• Occurred in Europe, 1960s

• Manufacturer: Chemie Grünenthal

• 10,000 children born with deformed limbs: Teratogenicity - Phocomelia

• Teratogenicity was not tested in pregnant animals

• Watch out! Thalidomide is back in pharmacy for different indications

Terminology

Toxicant/ Toxic substance/ Toxic material: That produces adverse biological effects of
any nature.

Toxic chemical (organic or inorganic): Specific chemical substance that is toxic; has a
definite chemical identity

Toxic agent: That can produce adverse biological effect; includes physical, chemical or
biological agents.

Poison: That cause immediate death or illness when taken in small quantities

Toxin (Toxinology): Specific toxic substances, mostly proteins, produced by living

organisms

Toxoid: Detoxified exotoxins (usually with formalin)

Xenobiotic: General term used for any foreign substance introduced into the body

Toxicity: Deleterious effect(s) occurring after being exposed to toxicants

Intoxication: The process of acquiring toxicity

Detoxification: Process of removing toxic agents from the living organism

Toxicodynamics: Mechanism of action of toxicants and the mechanisms behind

management of toxicity

Toxicokinetics: ADME of toxicants

Hazard: Ability of toxic agents to cause injury in a given situation or setting

Exposure: Acute and chronic

Risk: Expected frequency of the occurrence of an undesirable effect arising from

exposure to a hazardous agent

Risk = Exposure + Hazard

Bioaccumulation: Accumulation of toxic substance or its metabolites in the body, when

removal rate is slower than intake.

Bioactivation (in toxicology): Conversion of nontoxic to toxic substance by

living system

Biomagnification: Higher organisms in food chain accumulate higher concentrations of

toxicants, as shown in the table below.

Forensic toxicology: Concerned with law enforcement. Used frequently by Federal

Bureau of Investigation (FBI).

Regulatory toxicology: Concerned with setting regulations to protect general public from
exposure to toxicants. Environmental Protection Agency (EPA) sets acceptable limits for
exposure to environmental toxic agents.
 TOXICODYNAMICS

Dynamics and mechanism of action of toxicants and the mechanisms behind management
of toxicity (Toxicodynamics is what the toxic substances do to the body).

Units
Toxic exposure : mg/m3 (e.g. air); mg/g (e.g. food); mg/L (e.g. water)

ppm (part per million)

1 per 1,000,000 ≡ 1 mg in 1 kg ≡ 0.5 mg in 500 g ≡ 1 cent in $10,000

ppb (parts per billion)

1 per 1000,000,000 ≡ 1 mg in 1000 kg

ppt (parts per trillion)

1 per 1000,000,000,000 ≡ 1 mg in 1000, 000 kg

Response = In toxicodynamics, response will be toxicity

Graded response: response proportional to dose
Quantal response: all or none response (e.g. death as endpoint in LD50 tests)

Toxicity Threshold Value: The minimum dose at which toxicity occurs

Importance of Threshold Value
• Body’s ability to detoxify toxicants compromises at this point

• Therapeutic drug dose should be below the threshold for toxicity

Variability in Response
In a bigger population, response to a toxic agent will follow normal distribution. Majority
of the people will respond to the same dose. Fewer numbers will show either no response
(resistant group) or augmented effect (sensitive group).

Factors Affecting Threshold

• Species
• Gender
• Genetic strain
• Age
• Route of administration
• Environmental conditions
• Nutritional status

Measures of Toxicity
LD50: Dose which is lethal to 50% of the organisms exposed. This is usually determined
in experimental animals such as mice by administering increasing doses of the test
substance and finding out graphically the dose required to kill 50% of the animals tested.
When LD50 of substance ‘A’ is higher (let us say 100 mg/kg) than another substance ‘B’
(10 mg/kg), then substance ‘A’ will be less toxic than substance ‘B’. You have to
remember that LD50 is a measure of ACUTE TOXICITY, not chronic toxicity.
Other Measures of Toxicity
LD0, LD1, LD10 , LD70 , LD90, LC50, TD50

Measures of Safety
Therapeutic Index (TI): Ratio of Lethal Dose 50 to Effective Dose 50, as shown in the
graph below. TI = LD50/ ED50. If the LD50 values are much higher than ED50 values, i.e.
TI is higher, then the drug will be relatively more safe.
Margin of Safety (MOS)
This is another measure of safety and calculated as a ratio of undesired effect dose (LD1)
to desired effect dose (ED99)

NOAEL : No Observed Adverse Effect Level

Highest dose of a chemical that causes no observable effect in test animals, in a given
toxicity test

LOAEL : Lowest Observed Adverse Effect Level

Lowest dose of a chemical that, in a given toxicity test, does cause an observable effect in
test animals

Therapeutic Window
Practically, therapeutic window is the range of dose of a drug which is clinically effective
without causing toxicity. Ideally it may be taken as the dose range from ED50 to TD0
(dose which causes no toxicity).

Duration of Exposure

• Acute : short-term < 24 hours

• Subacute : up to 1 month

• Subchronic : 1-3 months

• Chronic : long-term > 3 months

Toxicity due to Interactions

Interaction between two normally nontoxic substances can produce toxicity.

• Chemical/ drug x food

• Wine (containing tyramine) and monoamine oxidase (MAO)
inhibitors

• Chemical/ Drug x Chemical/ Drug

• morphine and cocaine

Modulation of Toxicity caused by Interaction (similar concept as modulation of drug

response in pharmacodynamics)

• Additive effect
• Two toxicants produce combined effect which is equal to the sum of the
effects produced by the individual components.
• Analogy: 1+1 = 2
 • Potentiation
• A nontoxic substance enhances the toxicity of a toxicant.
• Analogy: 0+1 = 3

• Synergism
• Two toxicants produce combined effect which is considerably greater than
the sum of the effects produced by the individual components.
• Analogy: 1+1 = 5

• Antagonism
• A nontoxic substance (antagonist) reduces the toxicity of a toxicant.
• Analogy: 1+0= 0

Toxicity - Species Differences (selective toxicity)

Response to same toxicant might vary in different species due to the differences in the
metabolism and enzyme system. Therefore interpretation of animal toxicity data has to be
done with caution when extrapolating to humans. E.g. Atropine does not produce toxicity
in rabbits even at higher doses, whereas it can be toxic in humans at higher doses.

Prediction of Toxicity
While testing a new drug in animals, dog is a better predictor of human toxicities than
rodents and primates.

Nature Reviews, 2004, 3:226-236

Cellular Differences & Selective Toxicity
Differences in cellular structure or biochemical processes of microorganisms compared to
human cells are utilized to selectively cause toxicity (inhibit growth or kill) to
microorganisms.

• Human
– eukaryotic

• Fungal
– eukaryotic

• Bacterial
– prokaryotic

• Viral
– lives and multiplies in the host cell

Selective Toxicity – Importance in pharmacy

The concept of selective toxicity is utilized in therapeutics for treating certain diseases
caused by bacteria, fungus and virus. The following targets in bacterial, fungal and viral
structure shows differences from human cells. Hence these structures or biochemical
processes can be specifically targeted to inhibit the growth or kill these organisms.

• Antibacterials
• Target cell wall/ membrane
• Target cytoplasmic components

• Antifungals
• Target cell membrane/ wall
• Target cytoplasmic components

• Antivirals
• Target viral release mechanisms
• Target viral enzyme-directed nucleic acid synthesis
Antibacterials : Target structures & drugs
The targets shown in the cartoon have differences from human cells. Hence these drugs
can be relatively safe in humans.

Antifungals: target structures and drugs

Although fungal cells have differences from human cells, the level of difference is lower
than that between bacterial cells and human cells. Both fungal cells and human cells are
eukaryotic. The following diagram shows some of the targets in fungal cells which are
different from human cells. However, because of the greater similarity between human
cells and fungal cells, antifungal cells show higher toxicity compared to antibacterial
drugs in humans.
Antivirals: targets and drugs
Unlike bacteria and fungi, virus live in host cells (e.g. humans cells) and use the host cell
processes to survive and multiply. Hence it is extremely difficult to find viral targets to
destroy them selectively without causing toxicity to human cells. However, as shown in
the following diagram, there are a few targets to inhibit viral processes in the human
cells, which are common to human cell processes. Therefore, antiviral drugs are even
more toxic compared to antibacterials and antifungals.
 TOXICOKINETICS

Toxicokinetics deals with the processes by which toxic substances are absorbed,
distributed, metabolized and excreted by the body. Basically toxicokinetics describes
what the body does to toxic substances (Toxicodynamics tells you what toxic substances
do to the body). Concepts are similar to pharmacokinetics.

Absorption
• Routes of exposure (for toxicants, see pie chart below)
• Enteral/ ingestion (major route for toxic exposure)
• Topical (dermal)
• Inhalation
• Ocular (eye)

• Routes of administration (for drugs)

• Enteral
• Parenteral
• Topical
• Inhalation

Similar to drug absorption, absorption of toxicants are influenced by the physicochemical

properties of the toxicants such as lipophilicity, size of the molecule, degree of ionization
etc. The nature of absorbing environment like pH, and membrane properties will also
influence absorption.

Distribution
• Compartment models
• 1 compartment model
• 2 compartment model
 • Multi-compartment models

• Apparent Volume of Distribution

Vd = exposed total dose/ plasma concentration
Relevance in toxicology: If the Vd values are higher than blood/ plasma volume, it means
that the toxic substance has been distributed to tissues outside the blood compartment, or
has been eliminated.

• Bioavailability
Fraction of the total toxic substance available in the systemic circulation.

• Half life
This is the time period required for the concentration or amount of a toxic
substance in the body to be reduced by one-half. Usually measured in relation
to plasma concentration of the substance.

Factors Affecting Absorption/ Distribution

• Route
• Physicochemical nature
• Blood Brain Barrier (BBB)
• Placental barrier

Accumulation of Toxicants – mainly depends on the physicochemical properties of the

substance.

• Arsenic
• Liver, Kidney, skin, hair, nails

• Lead
• Soft tissues, redistributed to skeleton

• Mercury
• Kidney, CNS

• DDT
• Adipose tissue

• Drugs
• Plasma proteins, adipose tissue

Metabolism (Biotransformation)
Happens mainly in the liver in two phases, Phase I and Phase II

Phase I (makes the molecule ready for phase II)

 • Hydrolysis
• Esters, amides

• Reduction
• Aldehyde, ketone

• Oxidation
• Alcohol

Phase II (makes the molecule more hydrophilic or water-soluble)

• Glucuronidation
• Alcohol, phenols, amines

• Acetylation
• Aromatic amines

• Sulfonation
• Alcohol, phenols, amines
Factors Affecting Biotransformation
• Age

• Genetic factors

• Enzyme induction-inhibition (CYP series enzymes)

• Nutrition

• Dose

Excretion
• Urinary (water soluble substances or metabolites)

• Lung (volatile substances)

 • Milk (mainly lipohilic substances)

• Body fluids (saliva, sweat, semen etc.)

• Bile-Fecal

Urinary Excretion

Has three main components: glomerular filtration which happens in the glomerulus;
tubular secretion and tubular reabsorption which happen in the renal tubules.

The toxic substances or their metabolites remain ionized or unionized in the urine
depending on the chemical nature of the molecules and the urine pH. Unionized
molecules get reabsorbed from the urine and get back to the body through systemic
circulation. Changing urine pH can modulate tubular reabsorption depending on the
chemical nature of the toxicant. If the toxicant is acidic, alkalinizing the urine will help
to excrete the toxicant in urine and vice versa. This is because an acidic substance will
remain ionized in alkaline medium, and a basic substance will be ionized in acidic
medium. Ionized molecules will not get reabsorbed and will be excreted in the urine.
Ammonium chloride is sometimes used to acidify urine and sodium bicarbonate to make
it alkaline.
Excretion by Lung
Usually volatile substances such as ethanol will be excreted by this route. This is why the
blood alcohol content can be measured (indirectly) using breath analyzers (used by police
to detect DUI).

Excreted in Milk
Usually lipohilic substances get excreted in milk. A pesticide, dieldrin, used to be present
in human milk when this pesticide was in use in the US. When this pesticide was banned
in 1970s, its presence in milk started to diminish.
J.S. LaKind et al. / Toxicology and Applied Pharmacology 198 (2004) 184–208
Hepatobiliary Excretion & Enterohepatic Recirculation
Drugs and toxicants are excreted from the liver into the small intestine through bile.
Depending on the physicochemical nature of the substance, part of it may be reabsorbed
by the portal vein back to the liver, and part of it may be excreted in the feces. Once the
substance reaches the liver, it will be recirculated again. This is known as enterohepatic
recirculation.
 DIFFERENT TYPES OF TOXICITY

• Cell-level toxicity
• Mutagenicity
• Carcinogenicity
• Teratogenicity
• Organ-specific toxicity
• Immunotoxicity
• Systemic toxicity

Cellular Toxicity: mechanisms

• Dysregulation of gene expression

• Interference with receptor-ligand interaction

• Botulinum toxin, organophosphate compounds

• Interference with membrane function

• Tetradotoxin, organic solvents

• Interference with energy production

• HCN, CO

• Covalent binding to biomolecules

• Acetaminophen, mutagens

• Interference with calcium homeostasis

• Arsenic, Cobalt

• Oxidative damage to macromolecules

Mutagenicity
Heritable change in DNA sequence

Mechanisms
• Addition or deletion of base pairs
• Substitution of wrong base pair in the DNA

• Mutation is usually caused by:

• Chemical agents
• Physical agents
• Spontaneous occurrence

• Common Mutagenic agents

• Free radicals
• Radiation
Mutation
Note the normal and mutated DNA sequences.

Carcinogenicity
The ability of a substance to produce malignant tumors.

Mechanisms
• Mutation
• Failure of DNA repair
• Apoptosis inhibition
• Failure to terminate proliferation
Epidemiology of Carcinogens
Major carcinogenic factors in humans are diet and tobacco.

Common Carcinogenic Drugs

Teratogenicity
Production of congenital (at birth) defects

Mechanisms
• Interference with nucleic acids
• Deficiency of energy supply
• Inhibition of enzymes
• Oxidative stress

Teratogenicity in cattle caused by feeding on a plant (Lupin)

Chronology of Fetal Development

Major organogenesis in human fetus occurs in the first trimester of pregnancy (see the
table for other species). Hence exposure to drugs and chemicals should be avoided in the
mother during this period.
Teratogenic Agents
• Chemicals, drugs, plants

• Radiation

• Metabolic imbalances

• Infections

Teratogenic Drugs and the specific defect they cause in offsprings

• Thalidomide – phocomelia, amelia
• DES – vaginal cancer
• ACE inhibitors – renal damage
• Alcohol – fetal alcohol syndrome
• Phenytoin – fetal hydantoin syndrome
• Carbamazepine – cleft palate, lip
• Cocaine – abnormal fetal development
• Tetracycline – teeth malformation & discoloration
Organ-specific Toxicity
• Hepatotoxicity (liver)
• Nephrotoxicity (kidney)
• Cardiotoxicity (heart)
• Neurotoxicity (nerve tissue)
• Respiratory toxicity
• Blood toxicity
• Ototoxicity (ear, hearing)
• Dermal toxicity (skin)
• Ocular toxicity (eye)

Hepatotoxicity
Mechanisms
• Disruption of cytoskeleton
• Cholestasis
• Mitochondrial damage
• Depletion of GSH >>>> Apoptosis/ Necrosis

Hepatic Toxicity Mechanisms of Acetaminophen (paracetamol)

• At normal clinical doses, acetaminophen gets converted to N-acetyl p-

benzoquinoneimine (NAPQI).
• NAPQI is then conjugated and detoxified by glutathione

• At overdoses, higher amount of NAPQI will be produced and glutathione

depletes. NAPQI then binds covalently to macromolecules in liver cells >>
toxicity>> cell death
Acetaminophen Poisoning - Treatment
• N-acetylcysteine (NAC) is the antidote – p.o. usually given intravenously or
orally (in cola drinks to mask bad taste).

• Major mechanism: NAC directly conjugates with NAPQI and prevents cellular
damage

• NAC is a glutathione precursor >> repletes glutathione storage >> conjugate

NAPQI

• NAC has some non-specific cellular protective effects, anti-oxidant effects?

Types of Hepatic Injury & Causative Agents

Nephrotoxicity

Mechanisms
• Interaction with receptors
• Inhibition of oxidative phosphorylation
• Disturbance of Ca homeostasis
• Structural damage
• Lysosome rupture
• Mitochondrial damage
>>necrosis of epithelial cells
Nephrotoxic Agents and Sites of Action

Examples of Nephrotoxic Agents

• Antibiotics : aminoglycosides
• Antiviral agents: acyclovir
• Immunosuppressants: CsA
• Chemotherapeutic agents: cisplatin
• NSAIDs: ibuprofen
• ACE inhibitors: captopril
• Radiocontrast dye: iothalamate
• Heavy metals : Hg, Pb
• Solvents : ethylene glycol
• Plants: Aristolochia spp
Cardiotoxicity
Toxicity caused to the heart tissues, esp. myocardium, coronary artery or valves.

• Structural damage
• Cardiomyopathy – Cobalt, adriamycin
» Reduce O2 uptake, increase Ca influx
• Atrophy – anthracyclines
» Inhibit RNA > protein synthesis

• Functional abnormalities
• Arrhythmia – cocaine, digoxin
» Interference with Na-K ATPase - digoxin
» Na channel blocker- tetradotoxin
» Prolongation of QT interval - terfenadine
• Reduced contractility
» Ca channel blocker -verapamil

QT prolongation - Torsade de pointes

QT prolongation produced by certain drugs can lead to lethal ventricular arrhythmias. All
new drugs are now routinely screened for QT-prolongation potential. Several drugs have
been removed from the market because of its prolongation effect on QT interval.

Normal ECG recording

P wave corresponds to atrial depolarization
QRS complex represents ventricular depolarization
T wave corresponds to ventricular Repolarization
Atrial Repolarization is masked by QRS complex.

When the ventricular Repolarization is delayed, QT interval is prolonged. This can

happen due to several reasons, and drug-induced prolongation is common.

QT Prolongation - Drugs and Risk Factors

Antiarrhythmic drugs
Amiodarone, sotalol, quinidine, disopyramide

Antihistamines
Terfenadine, astemizole (NOT IN USE)

Anti-infectives
Erythromycin, chloroquine, pentamidine

Psychiatric drugs
Tricyclic antidepressants, Chlorpromazine, haloperidol, sertindole, lithium, thioridazine,
pimozide

Others
Cisapride, tacrolimus, probucol, terodiline
Cardiotoxic Agents
• Heavy metals – Cd, Co, Pb
• Solvents – acetone, toluene, CCl4
• Drugs – disopyramide, digoxin, doxorubicin
• Plants – Digitalis spp., Aconitum spp.
• Toxins - bufadienolide

Neurotoxicity

Toxic effects caused to neuronal tissues or the myelin sheath.

Common forms of neurotoxicity
• Neuronopathy – doxorubicin, methyl mercury
• Axonopathy – organophosphate pesticides, CS2
• Myelinopathy – lead, hexachlorophene
• Neurotransmitter related – organophosphate pesticides, nicotine, botulinum toxin
• BBB disturbances – e.g. inflammation can compromise the efficiency of BBB and
toxicants can easily pass to the CNS.

Botulinum toxin: inhibits the release of acetylcholine from the nerve terminal in the
neuromuscular junction and causes paralysis of skeletal muscles.

Cholinesterase Inhibitor (ChEI) Toxicity

Cholinesterase inhibitor compounds such as organophosphate pesticides, carbamates, and
nerve agents such as sarin gas, inhibit cholinesterase enzymes. (ChEIs). These enzymes
are responsible for the degradation of acetylcholine in the neuromuscular junctions and
synapses. When these enzymes are inhibited, there will be an excess of ACh and this will
lead to CHOLINERGIC CRISIS with symptoms such as miosis, excessive lacrimation,
salivation, urination, diarrhea, bradycardia etc. (more details can be seen in text books of
pharmacology).

ASSESSMENT OF TOXICITY

• Acute Toxicity

• Subacute Toxicity

• Subchronic Toxicity

• Chronic Toxicity

Acute Toxicity Testing

• Determine acute or short-term effects (usually single

administration for 1 day)
 • Determine LD50 in animals
• LD50 in shrimp
• Behavioral toxicity
» Carry out a battery of tests
• Topical toxicity: usually in skin and eye (Draize test)

LD50 Determination
• Animal: usually mice, and occasionally brine shrimp is used
• Test substance administered -p.o. or i.p. at different doses
• Observed for 14 days for lethal effect
• Determine lethality
• Graph the data
• Calculate LD50 from the graph
• Alternate procedure: Up and Down Procedure; limited dose procedure

Effect of Route on LD50

LD50 values can change depending on the route of administration used in the test. This is
attributed to different metabolic processes such as first-pass metabolism.
LD50 Values - Comparison

Topical/ Ocular Toxicity Testing

• Animal used: Rabbit
• Skin – Draize test, applied to shaved skin
• Eye – Instilled in the eye
 • Alternative tests without using live animals
• Test in vitro on
• Epidermal keratinocyte culture (skin)
• Corneal epithelial culture (eye)

Subacute Toxicity Testing

• Usually administered for 14 days
• Aim is to determine doses for subchronic study

Subchronic Toxicity Testing

• Usually administered for 90 days
• Conducted in at least 2 species
• At least 3 doses used

Chronic Toxicity Testing

• 6 months to 2 years
• Assess cumulative toxicity and carcinogenicity
• Gross and microscopic pathological study
• Maximum Tolerable Dose (MTD) found from subchronic study
• Doses used: MTD, half MTD, quarter MTD and control group

Organ Toxicity Testing

• Histopathology of different organs

• Enzyme levels in plasma (e.g. AST, ALT for liver)

• Renal Clearance (kidney)

• Protein level in urine (kidney)

• Blood microscopy for blood toxicity

Mutagenicity & Teratogenicity

• Mutagenicity
• Ames Test
– Salmonella typhimurium

• Teratogenicity
• Rodents
– Drug administered to pregnant animals
– Fetus examined before delivery
Factors affecting Toxicity Data
• Species
• Gender
• Genetic strain
• Age
• Route of administration
• Environmental conditions
• Nutritional status

Assessment of Toxicity in Humans

Epidemiological Studies
• Prospective
• Retrospective

Safety Evaluation of New Drugs

• FDA requires proof of safety and efficacy for all new drugs
• Preclinical Safety Evaluation (animals)
• Clinical Safety Evaluation (humans)

• Phase I
• Limited number of healthy human volunteers. Intention is
to study the safety and pharmacokinetic parameters of a
new drug in healthy human beings.

• Phase II
• Limited number of target population (patients). Major goal
is to prove efficacy and safety in target patient population

• Phase III
• Larger number of patients, usually carried out as a multi-
center study. Aim is to confirm efficacy and safety in a
larger population.

• Phase IV
• Post-marketing surveillance. A large volume of data on
adverse effects and chronic toxicity on the drug is collected
during this phase. Pharmacists play an important role in
collecting and reporting adverse effects events. Drugs that
show serious adverse effects / toxicity are withdrawn from
the market based on Phase IV data (recent e.g. VIOXX®).
References
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition,
2006. McGraw-Hill.
•
• Katzung BG, Basic and Clinical Pharmacology, 9th Edition, 2004. Appleton and
Lange.
•
• Klaassen, Curtis D. Watkins, John B. Casarett & Doull's Essentials of Toxicology.
2003. McGraw-Hill Professional.
•
• Galichet (Ed). Clarke’s analysis of drugs and poisons, 2004, Pharmaceutical
Press.
•
• Miller and Murray (Eds). Herbal Medicinals, A Clinician’s Guide. 1998.
Pharmaceutical Products Press.
• Toxicology Tutor, National Library of Medicine.
http://sis.nlm.nih.gov/Tox/ToxTutor.html