Pharmacology

MASUM SHAHRIAR

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Professor
Department of Pharmacy
Jahangirnagar University

REQUIRED READING

Goodman and Gilman's The Pharmacological Basis

of Therapeutics, Twelfth Edition 12th Edition
by Laurence Brunton (Author), Bruce Chabner (Author),
Bjorn Knollman (Author)

Basic and Clinical Pharmacology 13th Edition

by Bertram Katzung (Author), Anthony Trevor (Author)

Rang & Dale's Pharmacology, 8th Edition

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by Humphrey P. Rang MB BS MA DPhil Hon FBPharmacolS

FMedSci FRS (Author), James M. Ritter DPhil FRCP

One of the features which is thought to

distinguish man from other animals is his
desire to take medicines

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(Sir William Osler, 1849-1919)

What is Pharmacology?
In general terms, pharmacology is the
science of drug action on biological
systems.
The term pharmacology comes from the Greek words:

pharmakon - drug or medicine

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logos - the truth about or a rational discussion

Pharmacology embraces knowledge of the sources,
Pharmacology is the science of drugs.
chemical
properties,
biological
effects
and
therapeutic uses of drugs.

Pharmacology studies the effects of drugs and how

they exert their effects:
Paracetamol can reduce body temperature in case
of

fever

by

inhibiting

an

enzyme

known

as

cyclooxygenase in CNS, which is responsible for the

synthesis of a number of inflammatory mediators.
Penicillin cures certain bacterial infections by
disrupting the synthesis of bacterial cell walls by

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inhibiting a key enzyme.

A synthesis of several biomedical sciences.

Ph
ys
io
lo
gy

m
e
h
c
o
Bi

ry
t
is

Pharmacology

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Ch

ry
t
is
m
e

Me
di
ci

ne

but unique in its own right

Pharmacology: Its Scope

Three important and interrelated areas:
Pharmacokinetics
Pharmacodynamics

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Pharmacogenetics

Pharmacokinetics
Pharmacokinetics is the description of the time course of
a drug in the body, encompassing
Liberation
Absorption
Distribution
Metabolism
Elimination
In simplest terms it can be describe what the body does
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to the drug.

Pharmacodynamics
Is what the drug does to the body.
Interaction of drugs with cellular proteins, such
as receptors or enzymes, to control changes in
physiological function of particular organs.
Drug-Receptor Interactions
Binding

Dose-Response
Effect

Signal Transduction
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Mechanism of action, Pathways

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Pharmacogenetics
Area of pharmacology concerned with unusual
responses to drugs caused by genetic
differences between individuals.
Responses that are not found in the general
population, such as general toxic effects,
allergies, or side effects, but due to an inherited
trait that produces a diminished or enhanced
response to a drug.

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Differences in Enzyme Activity

Acetylation polymorphism
Butylcholinesterase alterations
Cytochrome P450 aberration

Subdivisions of Pharmacology
Neuropharmacology: study of the effect of drugs
on components of the nervous system (brain, spinal
cord, nerves)
Example: treatment of Alzheimer's

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Cardiovascular Pharmacology: study of the

effects of drugs on heart, vasculature, kidney,
nervous
and
endocrine
systems
that
participate in cardiovascular function.
Example: treatment of high blood pressure
(hypertension)

Subdivisions of Pharmacology
Molecular Pharmacology: study of the biochemical and
biophysical characteristics of interactions between
drug molecules and those of the cell
Example: Drug-Receptor Interaction

Biochemical Pharmacology: study of how drugs act

with and influence the chemical machinery of the
organism

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Example: signal transduction through G proteins

Subdivisions of Pharmacology
Behavioral Pharmacology:
drugs on behavior

study of the effects of

Example: treatment of Attention Deficit Disorders

Endocrine Pharmacology: study of drugs that are

hormones or hormone derivatives

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Example: creation of The Pill

Subdivisions of Pharmacology

Clinical
Pharmacology:
application
of
pharmacodynamics and pharmacokinetics to patients
with disease.
Example: use of pharmacogenomics to tailor individual
medical treatment
Chemotherapy: study of drugs used for treatment of
microbial/viral infection and malignancies

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Example: treatment of cancer through anti-angiogenic

agents such as bevacizumab. ANTIBODY THERAPY

Subdivisions of Pharmacology
Systems and Integrated Pharmacology: study of the
use of whole animal approaches to best predict the
efficacy of new treatments in the human.

Veterinary Pharmacology: study of the use of drugs

for disease and health problems unique to animals.

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Example: treatment of feline leukemia (Viral) with emannan

Drugs
Drugs can be defined as chemical agents that
uniquely interact with specific target
molecules in the body, thereby producing a
biological effect.

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Drugs can be stimulatory or inhibitory

A medicine is a chemical
preparation, which usually but not
necessarily contains one or more
drugs, administered with the
intention of producing a therapeutic
effect.

Drug Nomenclature
Brand Name
Prevacid, Zoton

(New Zealand),

Keval

(Mexico),

(France), etc.

Generic Name
Lansoprazole

Chemical Name

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2-[[[3-methyl-4-(2,2,2-trifluroethoxy)-2pyridyl]methyl]sulfinyl]-benzimidazole

Lanzor

Properties of Ideal Drug

Effectiveness:
A drug that elicits the response it was meant to. It is the most
important property. No effect=no justification of use (FDA
approved with appropriate experiments).

Safety:
Safe even at high concentrations and for long periods of
administration (no

such thing as a safe drug)

Reduced by proper administration (iv, ip, im, sc, etc)

No habit forming aspects

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No side effects ( excessive dosage of opioid analgesics

carries a risk of respiratory failure, cancer drugs increase
infections, aspirin causes gastric ulcer etc)

Properties of Ideal Drug

Selectivity:
One that elicits only the response for which it is given
Selective for specific reaction with no side effects (there
is no such thing)

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Drowsiness can be caused by antihistamines

Morning sickness, cramps, and depression can be caused by oral
contraceptives
Constipation, urinary hesitance, and respiratory depression can be
caused by morphine.

Additional Properties of Ideal Drug (no drug is ideal!)

Reversible action
Effects be reversible, i.e., removal/subside w/i specific
time (1/2 life is short but potent during that time)
Example: General Anesthetic; Contraceptives

1.

2. Predictability
Know how patient will respond

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3. Ease of Administration
Number of doses should be low and easy to administer
1. increase compliance &
2. decrease errors
Diabetic patient: Multiple daily injection of insulin
Intravenous infusion

Additional Properties of Ideal Drug (Continued)

4. Freedom

from drug interactions

Should not augment or decrease action of other drugs or
have adverse combined effects
Respiratory depression caused by diazepam (valium), which is normally
minimal, can greatly be intensified by alcohol.
Antibacterial effects of Tetracycline can be greatly reduced by taking
iron or calcium supplements

5. Low Cost
Easy to afford (especially with chronic illness)

Growth hormone (somatrem) costs between $10,000 and $20,000

Lifelong medication: hypertension, arthritis, diabetes

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6. Chemical Stability
No lose of effectiveness with storage

Orphan Drug
These are the drug or biological products for diagnosis,
prevention and treatment of a rare or a more common
disease(ebdemic only in poor country) for which there is
no reasonable exception that the cost of developing and
marketing will be recovered from the from the sale of

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these medicine.

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Pharmacology, Definitions

Prophylactic refers to a drug or procedure aimed to prevent disease

Palliative refers to a drug or procedure aimed to relieve symptoms

Therapeutic refers to a drug or procedure aimed to cure disease

Tolerance is the increased resistance to the usual effects of an established

dose of a particular drug

Effective dose (ED50) is the concentration at which 50% of the subject show
a predefined response

Efficacy refers to the inherent capability of a drug to produce a desired effect

Potency compares the relative effectiveness of drugs to produce a desired

effect

Pharmacology, Definitions
Effects (therapeutic effects)
The desired results of
administration of a medication
Side Effects (adverse effects)
Effects that are harmful and
undesired, and that occur in
addition
to
the
desired
therapeutic effects
Indications
The reasons for administering a
medication or performing a
treatment

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Contra-indications
Factors that prevent the use of a medication or treatment (e.g., Allergies)

Pharmacology, Definitions
Pharmacologic Profile
- A description of all of the pharmacologic effects of a drug (e.g.,
effects on blood pressure, respiration, renal function, endocrine
function, the central nervous system, etc.).

"Therapeutic Window" or "Therapeutic Concentration

Range: " is the range of concentration over which the probability
for therapeutic success is very high at only limited toxicity.
Mechanism of Action

How the drug exerts its action

Dose

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The amount of a drug to be administered at one time

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Plasma Concentration

Plasma concentration vs. time profile of a single

dose of a drug ingested orally

MTC
Therapeutic
Window

MEC

Onset

Time

Termination

i.v. & inhalation

Blood
Level
im, sc, ip
p.o.
sec

min

hr

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Time

hrs

New Drug Discovery

Extremely high cost of new drug development in general
restricts it to the province of large pharmaceutical companies
Cost of new drug development is in the $100 to $800 million
range
Cost of initial marketing is also very high

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Incentives are very high with important new drugs having

greater than $1 Billion in yearly sales

Patent Protection of new Drugs

Patent life in the US is 20 years
Drug is frequently patented five years or more before
marketing begins
After patents expire, other manufacturers may
produce and sell bioequivalent generic products

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(usually much cheaper, as these companies had very little development cost)

Drug Development Process

Preclinical studies
Clinical Studies
Phase I clinical studies
Phase II clinical studies
Phase III clinical studies

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Phase IV post-marketing
surveillance

Preclinical Studies
Pharmacological effects or pharmacological profile
In-vitro effects using isolated cells/organs
Receptor-binding characteristics
in-vivo effects in animals/animal models of human
disease
Drugs are lacking where a good animal model of a
human disease does not exist

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Prediction of potential therapeutic use

Preclinical Studies
Pharmacokinetics
Identification of metabolites (since these
may be the active form of the compound)
Evidence of bioavailability (to assist in
design of clinical trials and assess toxicity)
Establishment

of

principal

route

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administration and rate of elimination

of

Preclinical Studies
Toxicological effects

In vitro and in vivo batteries of tests to identify toxic

compounds and metabolites prior to extensive
exposure of animals and subsequently humans

Toxicity testing has two primary goals:

Recognition of hazards
Prediction of that hazard occurring in humans at
therapeutic doses
A wide range of doses is tested

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High doses to detect acute toxicity

Low doses to predict risk at long-term therapeutic doses

Toxicity Testing
Animal Studies:
Remain an important part of toxicological testing
Essential to investigate both interference with integrative
function and complex homeostatic mechanisms
Necessary to prevent extensive toxicity in subsequent human
trials

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Extensive research underway to reduce the need for animal

studies by using in vitro methodology

Toxicity Testing
Acute Toxicity

Animal model - single dose given by proposed route for humans

Defines dose range associated with toxicity
Defines dose range for initial human trials

Subacute Toxicity

Repeated doses given for 14 or 28 days

Reveals target for toxic effects
Comparison with single-dose studies indicate potential for
accumulation

Chronic Toxicity

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Repeated doses given up to six months

Reveals target(s) for toxicity (except cancer)
Aim is to define doses associated with adverse effects and no
observed adverse effect level associated with safe dose

Toxicity Testing
Mutagenicity

A variety of in vitro tests using bacteria and mammalian cell

lines are employed at an early stage to define any potential
effect on DNA that may be linked to carcinogenicity or
teratogenicity

Carcinogenicity

Repeated doses given throughout lifetime of an animal

(usually two year rodent assay)
Especially important in drugs intended for
administration (greater than one year)

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Reproductive toxicity

chronic

Repeated doses given prior to mating and throughout gestation

Assesses effect on fertility, implantation, fetal growth, production
of fetal abnormalities and neonatal growth

Premarketing Clinical Studies: Phase I-III Trials

Notice of Claimed Investigational New Drug (IND) is

filed with the regulatory authority
Information on composition and source of drug
Manufacturing information
Data from animal studies
Clinical plans and protocols

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Names and credentials of physicians conducting the trials

Phase I Studies
Studies carried out in healthy volunteers.
Carried out by pharmaceutical companies or major
hospitals
In some cases patients with the disease in question may
be enrolled (cancer chemotherapy)
Initially small doses (as little as one fiftieth of intended
dose)

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Toxicity evaluated with routine hematology

biochemical monitoring of liver and renal function

and

Dose is escalated until pharmacologic effect is observed

or toxicity occurs

Phase I Studies
Used to study the disposition, metabolism and
main pathways of elimination of the new drug in
humans
Identify the most suitable dose and route of
administration for further clinical studies
Use of isotope-labeled (usually beta-emitting)
compounds to investigate pharmacokinetics and
metabolism
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1 year in Phase I trials

Phase II Studies
Pharmacology of the new drug is determined in patients with the
intended clinical condition
Principal aim is to define relationship between dose and
pharmacological and/or therapeutic response in humans
During phase II some evidence of beneficial effect may emerge
Address subjective element in human illness (placebo effect)
Additional studies:
Special populations (elderly, etc.)
Tests for potential interactions with other drugs
Optimum dosage established for use in phase III trials

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2-3 years in Phase II trials

Phase III Studies

Main clinical trial
Drug is compared to placebo, or if this would be
unethical (effective treatment for the disease in question
already exists), an established drug in use for this
disease
Comparison to other established treatments
Addition to established treatment with placebo control

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Measurements of adverse effects and possible benefit

made at regular intervals

Phase IV studies:
Postmarketing Surveillance
Ongoing monitoring of drug safety under actual conditions
of use in large numbers of patients. (Pharmacovigilance)
Physician and pharmacist reporting of adverse drug events
No fixed duration

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Picks up adverse events occurring in less than one in 1000

subjects

Drug to Market Timeline

Preclinical testing 4 years
Phase I clinical trials 1 year
Phase II clinical trials2 years
Phase III clinical trials
FDA review

2 years

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Total time 12 years

3 years

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Innovator Development Costs

Routes of Drug Delivery

Parenteral
(IV)

Inhaled
Oral

Transdermal

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Topical

Parenteral
(SC, IM)
Rectal

Routes of Drug Administration

The route of administration (ROA) that is
chosen may have a profound effect upon the
speed and efficiency with which the drug
acts.
The possible routes of drug entry into the
body may be divided into three classes:
Enteral

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Parenteral
Topical

Enteral Routes
drug placed directly in the GI tract:

sublingual - placed under the tongue

oral - swallowing (p.o., per os)

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rectum - Absorption through the rectum

Sublingual/Buccal

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Some drugs are taken as smaller tablets which are

held in the mouth or under the tongue.

Sublingual/Buccal
Advantages

rapid absorption
drug stability
avoid first-pass effect

Disadvantages

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inconvenient
Only lipid soluble drugs
small doses
unpleasant taste of some drugs

Oral
Advantages
Convenient - can be self- administered, pain free, easy
to take
Cheap - compared to most other parenteral routes

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Disadvantages
Sometimes inefficient - only part of the drug may be
absorbed
irritation to gastric mucosa - nausea and vomiting
destruction of drugs by gastric acid and digestive
juices
effect too slow for emergencies
unpleasant taste of some drugs
unable to use in unconscious patient

Rectal

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1. unconscious patients and children

2. if patient is nauseous or vomiting
3. easy to terminate exposure
4. absorption may be variable
5. good for drugs affecting the bowel such
as laxatives
6. irritating drugs contraindicated

PARENTERAL DRUG DELIVERY

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What are Parenterals?

The term parenteral has its derivation from Greek words para (besides)
enteron (intestine), meaning outside of intestine, and denotes routes of
administration other than the oral route.
Typically, formulations intended for parenteral administration are sterile,
pyrogen free preparations, called injections.
Advantages
Emergency situations, when a rapid drug action is required,
uncooperative or unconscious patient or unable to accept or tolerate
oral medications
Unreliable absorption from GI tract, for example heparin.
Inactivation or destruction from GI tract, for example insulin
It is possible to titrate the dose of a drug to obtain a desired
response
Disadvantages
Difficult to withdraw
Invasive
Difficult to manufacture
Sterility Requirements

PARENTERAL ROUTES OF DRUG

ADMINISTRATION
The three most common
administrations are:
Subcutaneous
Intramuscular
Intravenous

Less common routes are

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Intrathecal
Intracisternal
Intraarterial
Intraspinal
Intraepidural
Intraocular

parenteral routes of

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Intravascular
Absorption phase is bypassed
(100% bioavailability)
1. precise, accurate and almost immediate onset of
action,
2. large quantities can be given, fairly pain free

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3. greater risk of adverse effects

a. high concentration attained rapidly
b. risk of embolism

Intramuscular

1. very rapid absorption of drugs in aqueous

solution
2. repository and slow release preparations

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3. pain at injection sites for certain drugs

Subcutaneous

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1. slow and constant absorption

2. absorption is limited by blood flow,
affected if circulatory problems exist
3. concurrent administration of
vasoconstrictor will slow absorption

Inhalation
Gaseous and volatile agents and aerosols

ADVANTAGES
Extensive absorbing surface
Extensive blood supply
Particles < 2 um penetrate deep
into lungs
Rapid, local effects

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DISADVANTAGES
Administration requires GOOD
TECHNIQUE and special
equipment
Amount reaching alveoli is
variable
Many physiologic variables affect
absorption cilia, mucus, size of
particle
Possible systemic side effects
Thrush

Topical

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Mucosal membranes (eye drops, antiseptic,

sunscreen, callous removal, nasal, etc.)
Skin
a. Dermal - rubbing in of oil or ointment
(local action)
b. Transdermal - absorption of drug through
skin (systemic action)
i. stable blood levels
ii. no first pass metabolism
iii. drug must be potent or patch becomes to
large

Route for administration

-Time until effect-

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intravenous 30-60 seconds

endotracheal 2-3 minutes
inhalation 2-3 minutes
sublingual 3-5 minutes
intramuscular 10-20 minutes
subcutaneous 15-30 minutes
rectal 5-30 minutes
ingestion 30-90 minutes
transdermal (topical) variable (minutes to hours)

t
n
a
t
r
o
p
m
I
y
r
e
!
o
V
f
n
I

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No single method of drug

administration is ideal for all
drugs in all circumstances