You are on page 1of 280


BY; Laychiluh Bantie

4/30/2018 1
Chapter objectives

 After the completion of this chapter the students

are expected to;-
 Define pharmacology
 Identify the different branches of pharmacology
 Identify sources and names of drugs
 Describe drug development stages
 Classify dosage forms and routes of administration
 Discuss the different pharmacokinetic parameters of a
 Understand concept of pharmaco dynamics
 Identify the different types of drug interactions and
their clinical implication
 Understand adverse drug reactions of drugs
4/30/2018 2
 Pharmacology
 Blend of two Greek words, “Pharmakon” drug or medicine,
and “Logos” study
 Pharmacology is the science of drugs
 Is the study of how drugs exert their effects on living
 In a broad sense, it deals with interaction of
exogenously administered chemical molecules (drugs)
with living systems.

4/30/2018 3
Introduction cont…

 In general, Pharmacology can be defined as the

study of substances that interact with living systems
through chemical processes, especially by binding to
regulatory molecules.

 The interaction is either

 Activating or

 Inhibiting normal body processes.

4/30/2018 4
Introduction cont…

 These substances may be chemicals administered to

achieve a beneficial therapeutic effect on some process
within the patient or for their toxic effects on
regulatory processes in parasites infecting the patient.
 These chemicals are
 Drugs
 Medicines

4/30/2018 5
Definition of terms
Drug (Drouge – a dry herb)
 It is the single active chemical entity or combination of
active ingredient present in a medicine that is used for
diagnosis, prevention, treatment or mitigation of diseases.
 It can also be defined as a substance or mixture of
substances that can alter the function of the body such as
breathing, digestion, blood circulation, metabolism etc.
 Drug=active pharmaceutical ingredient

4/30/2018 6
Definition cont…

• The WHO (1966) has given a more

comprehensive definition-
• "Drug is any substance or product that is used
or is intended to be used to modify or
explore physiological systems or pathological
states for the benefit of the recipient."

• NB: Drugs can not impart (give) new functions

to organs or physiological systems but only
modify them.

4/30/2018 7
Definition cont…
Medicine = (API+IPG)
 Is a drug along with other substances in a proper,
stable dosage form, acceptable to the patient and fit
for administration.
 Medicine= API+IPG
 API=active pharmaceutical ingredient
 IPG=inactive pharmaceutical ingredient =additive

4/30/2018 8
History of Pharmacology
• For thousands of years most drugs were crude
natural products of unknown composition and
limited efficacy.
• Pharmacology as an experimental science was
guided by Rudolf Buchheim who founded the first
institute of pharmacology in 1847 in Germany.
• In the late 18th and early 19th centuries, François
Magendie and later his student Claude Bernard
began to develop the methods of experimental
animal physiology and pharmacology.

4/30/2018 9
- The three important figures in the early history of pharmacology
are (left to right) Rudolf Bucheim, Oswald Schmiedeberg, and John
Jacob Abel.
- They not only created new laboratories devoted to the laboratory
investigation of drugs but also firmly established the new discipline
through the training of future faculty, the writing of textbooks, and
the founding of scientific journals and societies.

4/30/2018 10
• Advances in chemistry and the further
development of physiology in the 18th, 19th,
and early 20th centuries laid the foundation
needed for understanding how drugs work at
the organ and tissue levels.

• In the later part of the 19th century,

Oswald Schmiedeberg, regarded as the
'father of pharmacology', together with his
many disciples propounded some of the
fundamental concepts in pharmacology.

4/30/2018 11
• The last 3 decades have seen an even more
rapid growth of information and
understanding of the molecular basis for drug

• The molecular mechanisms of action of many

drugs have now been identified, and
numerous receptors have been isolated,
structurally characterized, and cloned.

4/30/2018 12
Pharmacology today with its various subdivisions.

4/30/2018 13
Source of Drugs

 Sources of drugs may be :

I. Synthetic sources

II. Natural sources

III. Semi synthetic

4/30/2018 14
I-Synthetic Sources
 At present majority of drugs used in clinical practice are
prepared synthetically.
 Examples: Aspirin, chloroquine, sulphonamides, etc …

Advantages of synthetic drugs

 They are chemically pure
 The process of preparing them is easier & cheaper
 Control on the quality of the drug is excellent
 Modification of molecules is possible

4/30/2018 15
II-Natural Sources
Drugs are obtained from the following natural sources
E.g. Alkaloids –atropine,quinine.morphine, nicotine
Glycosides E.g. Digitoxin, Digoxin, etc.
Oils- Clove oil, peppermint oil
2)Animal Sources Examples: -
 Insulin from pork & beef pancreas for diabetes, Vaccines
3)Microbiological Sources
• Many life-saving drugs are obtained from microorganisms such as
fungi, moulds and bacteria.
Example - Penicillin ,Chloramphenicol
4)Mineral Sources
 Minerals or their salts are useful pharmaco therapeutic agents. For
examples : Ferrous sulfate is used in iron deficiency anemia
4/30/2018 16
III. Semi Synthetic Sources
 Sometimes semi-synthetic processes are used
to prepare drugs.
 Semi synthetic sources are used when
 Synthesis of drugs is – Difficult
– Expensive and
 Natural sources yield impure compounds
Examples: Ampicillin, Amoxicillin
4/30/2018 17
Nomenclature of drugs
Drug names
1. Generic name: e.g. Ibuprofen
 Non proprietary name, Only one generic name for a drug
 Accepted internationally & most commonly used in
2. Brand name: e.g. Advil, Motrin, Nuprin, Brufen
 By manufacturer company, Several name for single
drug may occur
 Have letter ® with its name, expensive cost
3. Chemical name: e.g. 2-(4-isobutylphenyl) Propionic
 Interest of chemists, only one chemical name for a
4/30/2018 18
Drug Development
With the development of the pharmaceutical
industry towards the end of the 19th century, drug
discovery became a highly focused and managed
Today, the bulk of modern therapeutics, and of
modern pharmacology, is based on drugs that came
from the laboratories of pharmaceutical companies.
4/30/2018 19
The main stages of the process, namely
The discovery phase:- the identification of a new
chemical entity as a potential therapeutic agent.
The development phase:- during which the compound is
tested for safety and efficacy in one or more clinical
indications, and suitable formulations and dosage forms
The aim is to achieve registration by one or more
regulatory authorities, to allow the drug to be marketed
legally as a medicine for human use.

4/30/2018 20
 Broadly, the process can be divided into three main
components, namely:
Drug discovery, during which candidate molecules are
chosen on the basis of their pharmacological properties .
Preclinical development, during which a wide range of
non-human studies (e.g. toxicity testing, pharmacokinetic
analysis and formulation) are performed.
Clinical development, during which the selected
compound is tested for efficacy, side effects and potential
dangers in volunteers and patients.

4/30/2018 21

• After synthesizing/identifying a prospective compound/

series of compounds, it is tested on animals to expose the
whole pharmacological profile.

• Experiments are generally performed on a rodent (mouse, rat,

guinea pig, rabbit) and then on a larger animal (cat, dog,

• As the evaluation progresses unfavorable compounds get

rejected at each step, so that only a few out of thousands
reach the stage when administration to man is considered.

4/30/2018 22
Preclinical cont…

The aim of preclinical development is to satisfy all the

requirements that have to be met before a new compound is
deemed ready to be tested for the first time in humans.

Pharmacological testing to check that the drug does not

produce any obviously hazardous acute effects, such as
broncho constriction, cardiac dysrhythmias, blood pressure
changes and ataxia.
This is termed Safety Pharmacology.

4/30/2018 23
Preclinical cont…

 Preliminary toxicological testing to eliminate genotoxicity

and to determine the maximum non-toxic dose of the drug
(usually when given daily for 28 days, and tested in two

 As well as being checked regularly for weight loss and

other gross changes, at the end of the experiment to look for
histological and biochemical evidence of tissue damage.

4/30/2018 24
Preclinical cont…
 Pharmacokinetic testing, including studies on the
absorption, metabolism, distribution and
elimination (ADME studies) in laboratory animals.
 Chemical and pharmaceutical development to assess
 The feasibility of large-scale synthesis and
 To assess the stability of the compound
under various conditions, and
 To develop a formulation suitable for clinical

4/30/2018 25
Preclinical cont…

Roughly half the compounds identified as drug

candidates fail during the preclinical development
For the rest, a detailed dossier is prepared for
submission to the regulatory authority such as the
European Medicines Evaluation Agency or the US
Food and Drugs Administration, whose permission
is required to proceed with studies in humans.
4/30/2018 26
Preclinical cont…

Non-clinical development work continues throughout the

clinical trials period, when much more data, particularly in
relation to long-term toxicity in animals, has to be generated.

If a drug is intended for long-term use in the clinic, the

toxicology studies may have to be extended for up to 2 years,
and may include time-consuming studies for possible effects
on fertility and fetal development.

4/30/2018 27

• Experiments conducted on animals are

essential to the development of new
chemicals for the management of disease.

• The safety and efficacy of new drugs,

however, can be established only by
adequate and well-controlled studies on
human subjects.

4/30/2018 28

• Since findings in animals do not always

accurately predict the human response to
drugs, subjects who participate in clinical
trials are put at some degree of risk.

• The risk comes not only from the potential

toxicity of the new drug but also from
possible lack of efficacy, with the result that
the condition under treatment becomes

4/30/2018 29

• The clinical development of new drugs usually

takes place in steps or phases conventionally
described as;-
– clinical pharmacology (phase I),
– clinical investigation (phase II),
– clinical trials (phase III), and
– post marketing studies (phase IV).
4/30/2018 30
Phase I (Human pharmacology and safety)
• The first human administration of the drug
is carried out by qualified clinical
pharmacologists / trained physicians in a
setting where all vital functions are
monitored and emergency resuscitative
facilities are available.
• When a drug is administered to humans for
the first time, the studies generally have been
conducted in healthy men between 18 and 45
years of age.
4/30/2018 31
Phase I cont…
• For certain types of drugs, such as
antineoplastic agents, it is not appropriate
to use healthy subjects because the risk of
injury is too high.
• The purpose of phase I studies is to
establish the dose level at which signs of
toxicity first appear.
• The emphasis is on safety and tolerability,
while the purpose is to observe the
pharmaco dynamic effects in man, and to
characterize absorption, distribution,
metabolism and excretion.
4/30/2018 32
Phase I cont…

• The initial studies consist of administering a

single dose of the test drug and closely
observing the subject in a hospital or clinical
pharmacology unit with emergency facilities.

• If no adverse reactions occur, the dose is

increased progressively until a predetermined
dose or serum level is reached or toxicity

4/30/2018 33
Phase I cont…

• Phase I studies are usually confined to a group

of 20 to 80 subjects.

• If no untoward effects result from single

doses, short-term multiple-dose studies are

4/30/2018 34
Phase II Therapeutic exploration and dose
• If the results of phase I studies show that it is
reasonably safe to continue, the new drug is
administered to patients for the first time.
• Ideally, these individuals should have no
medical problems other than the condition for
which the new drug is intended.
• Efforts are concentrated on evaluating
efficacy and on establishing an optimal dose

4/30/2018 35
Phase II cont…
• Therefore, dose–response studies are a
critical part of phase II studies.

• Monitoring subjects for adverse effects is also

an integral part of phase II trials.

• The number of subjects in phase II studies is

usually between 80 and 100.

4/30/2018 36
Phase III Therapeutic
• When an effective dose range has been
established and no serious adverse reactions
have occurred, large numbers of subjects can
be exposed to the drug.

• In phase III studies the number of subjects

may range from several hundred to several
thousand, depending on the drug.

4/30/2018 37
Phase III cont…

• The purpose of phase III studies is to verify the

efficacy of the drug and to detect effects that
may not have surfaced in the phase I and II
trials, during which exposure to the drug was

• A new drug application is submitted at the

end of phase III.

4/30/2018 38
Phase IV Post marketing
• After the drug has been marketed for general
use, practicing physicians are identified
through whom data are collected about the
efficacy, acceptability and adverse effects of the
drug (similar to prescription event monitoring).

• Controlled and uncontrolled studies often are

conducted after a drug is approved and

4/30/2018 39
Phase IV cont…

• Such studies are intended to broaden the

experience with the drug and compare it with
other drugs.

• Further therapeutic trials involving special

groups like children, elderly,
pregnant/lactating women, patients with
renal/hepatic disease, etc. (which are
generally excluded during clinical trials) may
be undertaken at this stage
4/30/2018 40
Phase IV cont…

• Modified release dosage forms, additional

routes of administration, fixed dose drug
combinations, etc. may be explored.

• As such, many drugs continue their

development even after marketing.

4/30/2018 41
Pharmaceutical dosage forms

• Are different preparations of a drug which

help to facilitate drug administration &

• Any dosage form has two important contents

–The active ingredient
–The additive /excipients /adjuvant

4/30/2018 42
Pharmaceutical dosage forms

• 4 types of dosage forms exist

–Solid dosage forms

–Semisolid dosage forms
–Liquid dosage forms
–Gaseous dosage forms

4/30/2018 43
A. Gaseous pharmaceutical DFs
• Medicinal gases, inhalation/volatile anesthetics
• Aero-dispersions of solid particles or liquid
particles in gases,
1. Sprays - are composed of various bases such
as alcohol or water in a pump-type dispenser
2. Inhalants and Aerosols - variety of forms;
devices – nebulizers and humidifiers

4/30/2018 44
Medical gases
 Preparations for
 Inhaled through
breathing apparatus
 The active
ingredient is found as
gas or volatile liquid

4/30/2018 45
 Are another gaseous dosage
 Contain an active drug
suspended in a gaseous
 They are dispersions of solid
particles or liquid droplets
in a gaseous vehicle
 Do not need breathing
 They have their own
administration mechanisms

4/30/2018 46
Liquid pharmaceutical DFs
I. Solutions
• Homogenous phase
• Prepared by dissolving one or more solutes
in a solvent or composed of various
solutions like aqueous, oils, etc
• Dosage forms which can be administered by
all routes.
Examples of pharmaceutical solutions
Syrups, elixirs, tinctures
4/30/2018 47
I. Elixirs
 Clear solutions w/h contain alcohol & water as solvent
 Also contain flavoring agents, are mainly used for
pediatric use

II. Syrups
 Clear solutions w/h contain water, sugar & flavoring agent
 They don’t contain alcohol
 E.g. multivitamin syrup

4/30/2018 48
III. Tinctures
 Are clear solutions w/h contain both water &
alcohol as solvent
 But, unlike elixirs, they are used for external
use and don’t contain flavoring agent
 E.g. iodine tincture
IV. Miscellaneous solutions
 Includes: injectable clear solutions, large volume
 E.g. gentamicin injection, glucose preparations

4/30/2018 49
II. Dispersed liquids
A. Emulsions (o/w or w/o)
• A dispersion system consisting of two
immiscible liquids used with an emulsifier that
binds the two together
B. Suspensions
• A dispersion system where solid particles are
dispersed in liquid phase
• Not intended for systemic administration of
• “shake well” sticker

4/30/2018 50
III. Semisolid Dosage Forms
• Creams - semisolid emulsion systems (o/w,
w/o) containing more than 10% of water
• Ointments - semisolid systems with the
oleaginous , water-soluble or emulsifying
• Pastes - semisolid dispersion system, where a
solid particles (> 25%) are dispersed in
• Gels
4/30/2018 51
Semi solid cont…

Shaped Semi Solids

Suppositories (for rectal administration)
• solid dosage form under room temperature
• melting at body temperature
Pessaries (vaginal suppositories)
• PEGs or glycerinated gelatin base
• mainly to treat vaginal infections

4/30/2018 52
IV. Solid Dosage Forms

Unshaped - Powders for external/internal use

Shaped - tablets, capsules, implants,
trans dermal patches, lozenges and
- Capsules- made of soft and hard gelatin

4/30/2018 53
 Types are:
 Most common forms of
 Scored tablet,
solid dosage forms
 Effervescent tablet,
 Written as tab or tabs on  Enteric-coated tablet,
 Slow-release tablet,
 Several kinds of tablets  Caplet, and
are available  Lozenges

4/30/2018 54
Scored tablet
• Has an indented line
running across it
• It can be easily broken
into equal pieces to
produce an accurate,
but reduced, dose
• See figure below

4/30/2018 55
• Effervescent tablet
• Caplets: are oval
 is one that is dissolved
shaped tablets
in a glass of water before
being swallowed.
• Enteric coated tablets:
 have special coating
• Slow release tablets:
 designed to provide
sustained release of the

4/30/2018 56
 Sweet tablets containing
sugar, water & flavoring
 Are to be chewed/held
in the mouth
 Are not swallowed
 Prepared as sheets or
beads for sustained
release e.g. Norplant

4/30/2018 57
 Written as cap or caps on
 Prepared in two forms
1. Soft capsules: are made of
soft gelatin
 Contain liquid inside &
are sealed
 E.g. Vitamin A & E
 Hard capsules: are made
of hard gelatin
 Contain two separable
pieces or cups
 Contain powder or
granules inside
 E.g. Amoxicillin,
tetracycline capsules
4/30/2018 58
Systems of Measurement
• Metric
• Apothecary
• Household

Metric Apothecary Household

1ml 15minims 15drops

4.5ml 1fluid dam 1tea spoon full

15ml 4fluid drams 1 table spoon full

30ml 1fluid ounce 2 table spoon full

4/30/2018 59
• Objectives

• At the end of this session the students be able to :

List the different type of route of drug

Describe advantages and disadvantages of each

routes of drug administration

4/30/2018 60
Routes of Drug Administration

 In pharmacology, a route of administration is the

path by which a drug is brought into contact with
the body.
 Most drugs can be administered by a variety of
 The appropriate choice depends both on drug
and patient related factors.
4/30/2018 61
Classification of route of drug
 Broadly seen in two ways
I. Enteral: drugs placed in the GIT
• Oral
• Sublingual
• Rectal
II. Parentral: drugs delivered to the systemic circulation
without crossing intestinal mucosa
• Intravenous Transdermal
• Intramuscular Inhalational
• Subcutaneous Intraperitonial
• Intrathecal Intra-arterial

4/30/2018 62
Drug Administration

Topical/Local Systemic
Administration Administration

Mucus Enteral Parenteral

Skin Inhalation

4/30/2018 63
Oral Route
 Most commonly employed
 Drugs are administered for local and systemic effect
 If possible drugs are preferably given by oral route
Advantages of oral route
 Most convenient, safe and economical
 Self administration is possible
 Drugs need not be highly purified
 Higher concentration can be achieved for local effect in the gut.
 Untoward effect, if any appears slowly.
 It is possible to limit the absorption of drugs if wrongly taken
(Reverse of dose management is easily done)
4/30/2018 64
Disadvantage of oral route
 Irritation to GI
 High first pass effect
 Some drugs are destructed by GI flora (digoxin),
enzyme(insulin), pH (penicillin)
 Liver metabolism( by liver enzymes)
 The loss of drug activity through its first passage in
the liver is described as a first pass effect
 Not given for unconscious, uncooperative, vomiting
 Slow onset of action
 Irregular absorption (drug- food interaction)
 E.g. fatty meals delay absorption of many drugs

4/30/2018 65
 Sublingual route
• Placing drugs under the tongue (Nitroglycerin)
• Rapid absorption, almost avoids first pass effect???
• Advantages:
Rapid absorption takes place.
Drug is dissolved easily
Drug enters the blood directly
• Disadvantages:
This method is inconvenient.
Irritation of the mucous membrane might occur
Person may swallow the drug

4/30/2018 66
 Rectal route
 Drugs placed in the rectum
 Drugs are called suppositories
 Merits
• For unconscious & children patients , For nauseas or
vomiting patients
• Easy to terminate action, can reduce first pass effect
by 50%
• Good for emesis inducing drugs
 Demerits
• Inconvenient (embarrassing), erratic absorption

4/30/2018 67
Parentral route

The major routes are:

Intra muscular(IM)
Intra venous(IV)
Subcutaneous route

4/30/2018 68
 Administration of drug in to fatty tissue below the skin
arm, forearm and thigh.
 Insoluble suspensions and solids might be applied.
• Advantages:
 Absorption is slow and constant
 Can be self administered
• Disadvantages:
 It might lead to abscess formation
 Absorption is limited by blood flow

4/30/2018 69
• Intramuscular route:
 Administration of drug in to muscle.
 Upper arm, buttock or thigh.
• Advantages:
 Absorption is rapid than subcutaneous route.
 Oily preparations can be used.
 Irritative substances might be given
 Slow releasing drugs can be given by this route.
• Disadvantages
 Using this route might cause nerve or vein damage.

4/30/2018 70
• Intravenous injections
 Liquid forms are injected directly into the blood stream via a vein
• Advantages:
 Immediate action takes place
 preferred in emergency situations and
 for unconscious patients.
 Large volume of fluids might be injected
 Diluted irritant might be injected
 Absorption is not required
 No first pass effect takes place.
 There is no retreat
 This method is more risky
 This method is not suitable for oily and insoluble preparations

4/30/2018 71
• Inhalation:
Via inhaler
Via nebulizer
Medication directly to the respiratory system
 Rapid absorption takes place.
 Rapid onset of action takes place.
 This route has minimum side effects.
 No first pass effect takes place.
 This method is easy.
 Both for local and systemic use
4/30/2018 72
• Disadvantages:
Special apparatus is required.

Irritation of the respiratory tract may take place.

Cooperation of the patient is required.

4/30/2018 73
Topical Application

Drugs are applied to the mucous

membranes of the conjunctiva,
nasopharynx, oropharynx, vagina,
colon, urethra, and urinary bladder
primarily for their local effects.
Ointment, cream, drops, jelly, powder,
tablet, suppository, pessary, sprays,
4/30/2018 74
• Topical Application- Skin
 Absorption depends on surface area of application, lipid
 Few drugs readily penetrate skin
 Burned, denuded, abraded, inflammation increase
systemic absorption

• Advantages:
Absorption rapid
Only local effect

• Disadvantages:
 Toxicity by highly lipid soluble substances
4/30/2018 75
4/30/2018 76
Other routes include:

 Intra arterial: into an artery

 Intra cardiac: into the heart
 Intra dermal: into the skin itself
 Intra thecal: into the spinal canal
 Intra peritoneal: into the peritoneum etc…
 Anti-rabbis vaccination

4/30/2018 77
Basic principles of pharmacology
– Most drugs after administered to the body they
undergo 2 major process

1. Pharmacokinetics process:- process that

involve absorption, distribution, metabolism &
excretion of drugs
• Describes the time course of the drug in the
• What the body does to the drug

2. Pharmacodynamics process:-

Deals with the study of the biochemical and

physiological effects of drugs and their

mechanisms of action.

•Process that involve receptor-drug interaction.

•What the drug does to the body


4/30/2018 80
• Pharmacokinetics is the quantitative study
of drug movement in, through and out of the
• Pharmacokinetic considerations, therefore,
determine the route(s) of administration,
dose, latency of onset, time of peak action,
duration of action and frequency of
administration of a drug.
• All pharmacokinetic processes involve
transport of the drug across biological
4/30/2018 81
Factors affecting the transfer of drugs
across the membranes

• The ADME of a drug all involve its passage

across cell membranes.
• The transfer of the drug across the
membrane depends on:-
• Mechanisms by which drugs cross
membranes and
• The physicochemical properties of
molecules and
• Membranes that influence this transfer.
Cell Membranes
• In most cases, a drug must cross the plasma
membranes of many cells to reach its site of action.

• The plasma membrane represents the common barrier

to drug distribution.
• The plasma membrane consists of a bilayer of
amphipathic lipids.
• Hydrocarbon chains oriented inward to form a
continuous hydrophobic phase and their hydrophilic
heads oriented outward.
Membranes cont…

• Cell membrane made of phospholipids,

cholesterol, and proteins.

• Phospholipids permit lipid-soluble materials to

easily enter or leave the cell by diffusion
through the cell membrane.

4/30/2018 85
Cell membrane

• Membrane proteins embedded in
the bilayer serve as:
• Receptors,

• Ion channels, or

• Transporters to transduce electrical or

chemical signaling pathways and

• Cell membranes are relatively permeable to
• Therefore, bulk flow of water can carry with it
drug molecules.
• However, proteins with drug molecules bound
to them are too large and polar for this type of
transport to occur;
• Thus, trans membrane movement generally
is limited to unbound drug.
• Bulk flow of water can carry with it small
water-soluble substances.
• Accordingly, most large lipophilic drugs must
pass through the cell membrane itself.
• Drugs, like most organic electrolytes, generally do not
completely dissociate (i.e., form ions) in aqueous
• Drugs in solution exist in both the non ionized and
ionized species.
• Only a certain proportion of an organic drug molecule
will ionize at a given pH.
• The smaller the fraction of total drug molecules
ionized, the weaker the electrolyte.
• Since most drugs are either weak organic acids or
bases (i.e., weak electrolytes), their degree of
ionization will influence
Their lipid–water partition coefficient
Hence their ability to diffuse through
• The ability of a drug to diffuse across
membranes is frequently expressed in terms
of its lipid–water partition coefficient rather
than its lipid solubility per sec.

• The partition coefficient is a measure of the

relative affinity of a drug for the lipid and
aqueous phases.
• Increasing the polarity of a drug, decreases
the lipid–water partition coefficient.
• Alternatively, reducing drug polarity results in
an increase in the lipid–water partition

4/30/2018 90
– The characteristics of a drug that predict its
movement and availability at sites of action are

Its molecular size and shape,

Degree of ionization,

Relative lipid solubility of its ionized and non

ionized forms, and

Its binding to serum and tissue proteins.

4/30/2018 91

• Except for intravenous administration, all routes of

drug administration require that the drug be
transported from the site of administration into the
systemic circulation.
• A drug is said to be absorbed only when it has
entered the blood or lymph capillaries.
• Drugs cross membranes either by
 Passive processes or
 Mechanisms involving the active
participation of components of the
1. Passive transport

• The drug diffuses across the membrane in

the direction of its concentration gradient,
the membrane playing no active role in the
• This is the most important mechanism for
majority of drugs; drugs are foreign
substances (xenobiotics), and specialized
mechanisms are developed by the body
primarily for normal metabolites.

• Lipid soluble drugs diffuse by dissolving in the
lipoidal matrix of the membrane , the rate of
transport being proportional to the lipid :
water partition coefficient of the drug.
• A more lipid-soluble drug attains higher
concentration in the membrane and
diffuses quickly.
• Also, greater the difference in the
concentration of the drug on the two sides of
the membrane, faster is its diffusion.

4/30/2018 94
Therefore, Passive transport is

– Major means of drug transportation

– Down their concentration gradient of the
unionized moiety.
– The rate of diffusion depends mainly on the
lipid–water partition coefficient.

Simple passive diffusion
Not need energy

Not need carrier protein, not saturable, no


Occurs along concentration gradient of the


Dependant on concentration of drugs

• Such transfer is directly proportional to
the magnitude of:

The concentration gradient across the

The lipid-water partition coefficient of
the drug, and
 The membrane surface area exposed
to the drug.
• After a steady state is attained, the
concentration of the unbound drug is the
same on both sides of the membrane if the
drug is a non electrolyte.
Passive diffusion and filtration across
the lipoidal biological membrane with aqueous pores

• The rate of filtration depends both on the
existence of a pressure gradient as a driving
force and on the size of the compound relative
to the size of the pore through which it is to
be filtered.
• In biological systems, the passage of many
small water-soluble solutes through aqueous
channels in the membrane is accomplished by

4/30/2018 99
Carrier-Mediated Membrane Transport

• Special carrier molecules exist for certain

substances that are important for cell
• Too large or too insoluble in lipid to diffuse
passively through membranes, e.g.,
peptides, amino acids, glucose.
• unlike passive diffusion, are saturable and
• These carriers bring about movement by
active transport or facilitated diffusion

Active transport

• The energy-dependent movement of compounds

across membranes, most often against their
concentration gradient, is referred to as active

• In general, drugs will not be actively transported

unless they sufficiently resemble the endogenous
substances (such as sugars, amino acids, nucleic acid
precursors) that are the normal substrates for the
particular carrier system.
• Against electrochemical gradient

 Substances are transported from smaller

concentrations to higher concentrations

 Carrier mediated

 Saturable, competition is possible

• Compounds or conditions that inhibit energy

production will impair active transport.

• Structural similarity can also inhibit the transport


Facilitated diffusion
• It differs from active transport, however, in
that no energy input is required beyond that
necessary to maintain normal cellular
• In facilitated transport the movement of the
transported molecule is from regions of higher
to regions of lower concentrations, so the
driving force for facilitated transport is the
concentration gradient.
• Carrier mediated, saturable, competition

• Endocytosis involves the cellular uptake of exogenous
molecules or complexes inside plasma membrane
derived vesicles.
• This process can be divided into two major categories:
• (1) adsorptive or phagocytic uptake of particles that
have been bound to the membrane surface and
• (2) fluid or pinocytotic uptake, in which the particle
enters the cell as part of the fluid phase.
• The solute within the vesicle is released intracellularly,
possibly through lysosomal digestion of the vesicle
membrane or by intermembrane fusion.

4/30/2018 104
• The reverse process (exocytosis) is
responsible for the secretion of many
substances from cells.

• For example, neurotransmitter release

from their vesicles.

At the end of the session students will be able to:

• Define drug absorption

• Describe the factors that affect drug absorption at

different routs

• Refers to the passage of drugs from the site of
administration to systemic circulation
– Drugs can be absorbed from
• GI tract (oral, sublingual or rectal routes)
• Mucous membranes (nasal, buccal, eye,
vaginal routes)
• Skin
• Lungs
• Muscle & subcutaneous tissues
• In order for a drug to be absorbed, it must pass
through cell membranes

• Drugs can be absorbed by one or combination

of the following transport systems

Passive transport

Active transport

Bulk transport
The presence of a drug in the blood, does not
lead to a pharmacological response.
To be effective, the drug must leave the
vascular space and enter the tissues.
The rate at which a drug reaches its site of
action depends on two rates:
Absorption and
• Distribution is the delivery of the drug to the
• Since most drugs are weak acid or weak base the
concentration of ionized and unionized state
depends on
• PH of media
• PKa of the drug HA ←→ H + + A-
More lipid soluble- Usually unable to penetrate
diffuse readily across the lipid membranes

Q1.Where does diffusion of weakly acidic drugs

across cell membrane better: in stomach or small

1. Oral Cavity and Sublingual Absorption

• Drugs absorbed from the oral cavity enter the

general circulation directly.

• Although the surface area of the oral cavity is

small, absorption can be rapid if the drug has
a high lipid–water partition coefficient
• In addition, oral mucosa is highly vascularized and its
epithelial lining is quite thin facilitates rapid drug

• Compare the absoption of weak base nicotine (pKa 8.5);

from the mouth (pH 6), and from the gastrointestinaltract

(pH 1–5)???

• Answer- The weak base nicotine (pKa 8.5) reaches peak blood

levels faster when absorbed from the mouth (pH 6) than from the

GIT (pH 1–5), where the drug exists mainly in its ionized

(protonated) form
Absorption from the Stomach

• The rich blood supply and the contact of its contents

with the epithelial lining of the gastric mucosa
provide a potential site for drug absorption.
• However, since stomach emptying time can be
altered by many variables
 Volume of ingested material,
 Type and viscosity of the ingested meal,
 Psychological state, e.t.c.
• Therefore, the extent of gastric absorption will
vary from patient to patient as well as at
different times within a single individual.

• The low pH of the gastric contents (pH 1–2)

may have consequences for absorption
Absorption from the Small Intestine

• The epithelial lining of the small intestine is

composed of a single layer of cells called

• It consists of many villi and microvilli and has a

complex supply of blood and lymphatic vessels into
which digested food and drugs are absorbed.
• The small intestine, with its large surface area
and high blood perfusion rate.

• Therfore, it has a greater capacity for

absorption than does the stomach.

• Most drug absorption occurs in the proximal

• Diffusion is the predominant process for the transfer
of most drugs across the intestinal wall .

• Thus, the pKa of the drug and the pH of the

intestinal fluid (pH 5) will strongly influence the rate
of drug absorption.

• Conditions that shorten intestinal transit time

(e.g.arrhea) decrease intestinal drug absorption.

• While increases in transit time will enhance

intestinal absorption by permitting drugs to remain
in contact with the intestinal mucosa longer.
• Although delays in gastric emptying time will
increase gastric drug absorption.

• In general, total drug absorption may actually


• Since material will not be transferred to the

large absorptive surface of the small intestine
Absorption from the Large Intestine
• The large intestine has a considerably smaller
absorptive surface area than the small

• But it may still serve as a site of drug

absorption, especially for compounds that
have not been completely absorbed from the
small intestine.
Large Intestine cont…
• However, little absorption occurs from this

• Because the relatively solid nature of the

intestinal contents impedes diffusion of the
drug from the contents to the mucosa
Rectal absorption
• Although the surface area is not large for
absorption. But, absorption can still occur due to
the extensive vascularity of the rectal mucosa.

• Drugs absorbed from the rectum largely escape

the biotransformation to which orally
administered drugs are subject.

• Because a portion of the blood that perfuses the

rectum is not delivered directly to the liver, less
first pass effect
1. lipid–water partition coefficient of drugs
2. local blood flow and
3. Surface area and others
4. Gastric empting time
5.Intestinal motility
6. Food
7. Formulation factors and
8. Metabolism
Gastric Emptying Time
• Factors that accelerate gastric emptying time,
will increase drug absorption.

• By permitting drugs to reach the large

absorptive surface of the small intestine
Intestinal Motility
• Increased GI motility may facilitate drug
absorption by thoroughly mixing intestinal
contents and thereby bringing the drug into more
intimate contact with the mucosal surface.

• However, the opposite may also occur in that an

increase in motility may reduce contact time in
the upper portion of the intestine where most of
drug absorption occurs.
Formulation Factors

• The ability of solid drug forms to dissolve and

• The solubility of the individual drug in the

highly acidic gastric juice must be considered.

• Drugs administered in aqueous solution are

absorbed faster and more completely than
tablet or suspension forms.
• Drugs may be inactivated in the GIT before
they are absorbed.

• The gut microflora and drug metabolizing

enzymes, such as the cytochrome P450
enzymes, play a major role in determining the
extent of drug absorption of some drugs.
• Absorption of agents from the lung is
facilitated by;
 The large surface area of the pulmonary
alveolar membranes.
The limited thickness of these
membranes and
The high blood flow to the alveolar
• The diffusion rate of a drug through the skin is
largely determined by the compound’s lipid–
water partition coefficient.

• However, the stratum corneum, or outer layer

of the epidermis, forms a barrier against the
rapid Penetration of most drugs.
Absorption through the skin cont…

• This is due in large part to the relatively close-

packed cellular arrangement and decreased
amount of lipid in these cells.

• Thus, even highly lipid-soluble compounds

will be absorbed much more slowly through
the skin than from other sites.

• The dermis, on the other hand, is well
supplied with blood and lymph capillaries and
therefore is permeable to both lipid-soluble
and water-soluble compounds.

• If penetration of the skin by lipid-insoluble

compounds does occur, it is probably
accomplished by diffusion through the hair
follicles, sweat glands, or sebaceous glands

Intramuscular and Subcutaneous


• Because of the high tissue blood flow drug

absorption is more rapid after intramuscular
than after subcutaneous injection.
Factors affecting drug absorption
 Route of administration
 Physicochemical properties of the drug
 Dosage forms
 Circulation at the site of absorption
 Concentration of the drug
 Surface area of absorption site
 Contact time at site of absorption
 Presence & type of food

• Refers to the fraction of the intact/unchanged

drug absorbed into the systemic circulation.

– Varies with different routes of administration

• For intravenous administration the
bioavailability may be 100%.
• For other routes of administration, the
bioavailability is less than 100%.
• This is mainly due to
 Incomplete absorption
 Destruction by gastric juice
 First-pass effect etc
• Factors affecting Bioavailability :-
• Dose
• Route of administration
• Pharmacokinetic factors extent of

First-pass effect (Metabolism)

• This is a condition in which a drug after

absorption across the wall of the GIT is
delivered to the liver by portal vein before it
enters the general circulation.

• Certain proportion of the drug may be

metabolized in the liver or excreted through
the liver.

At the end of these session the students should
be able to :

Define drug distribution

Identify factors that affect drug distribution
Define volume of drug distribution

B. Distribution
– Is the delivery of drugs from systemic
circulation to different tissues of the body.
– The transportation of the drug to the target
site of action.
– The organs that have greatest blood supply
receive the medication faster.
– Lipid soluble drugs distribute well and remain
in the body long.
Factors that affect Drug Distribution

• The concentration of drugs in different tissues

differs due to different factors which affect
 Tissue perfusion
 Plasma protein binding
 Physiological barriers
 Tissue uptake (affinity of drugs to tissue)

I. Tissue perfusion

– Different tissues have different rate and

amount of blood flow.

– Organs that are highly vascular such as the

heart, liver and kidney will rapidly acquire a

Based on the amount of blood they receive,
body tissues can be grouped into two:

• Highly perfused tissues:- receive high

blood flow heart, lung, brain, liver, kidney
• Intermediately perfused tissues:-
moderate blood flow skeletal muscle
• Poorly perfused tissues:- minimal blood
provision skin, bone, nail, fat tissue

II. Plasma protein binding

– Drug in systemic circulation exists as bound

and unbound form with plasma proteins.

– Drugs ordinarily bind with plasma proteins in

reversible fashion

D + PP →[DPP] → D + PP

– As free drugs leave the systemic circulation

the bound drug dissociates.
Factors affecting drug plasma protein binding

 Drug affinity for binding site

 Number of binding sites of the plasma
• Since drug binding is saturable process -
-- ↑ in site of binding --- ↑ binding

• The extent of this binding will influence the drug’s
distribution and rate of elimination .

• Only the unbound drug can

• Diffuse through capillary and cell membrane

• Produce pharmacological effect

• Produce toxic effect

• Be metabolized

• Be excreted
The major binding plasma proteins are
α1 –acid glycoprotein
– Most common drug binding glycoprotein
– Mainly acidic and hydrophobic drugs
bind to albumin

α1 –acid glycoprotein
 Binding site mainly for basic drugs such as
imipramine, amitriptillin
 Plasma level ↑ in situation such as
Stress, injury, trauma, Rheumatoid arthritis,
Others plasma proteins
 Lipoprotein , Globulin, Hormone-binding factor,
sex hormone binding proteins 146
III. Physiological barriers
 Blood brain barrier (BBB)
 Transfer of drug to brain is regulated by BBB

• Not pass BBB Cross BBB

• -- ionized drugs --unionized drugs
• -- hydrophilic drugs
• -- Bound drug -- small size drugs
• --larger size drugs -- unbound drugs

 Inflammation such as due to meningitis or
encephalitis increase the permeability of BBB
so permeating the passage of ionized , lipid
insoluble drugs.

 Eg:- penicillin and ampicillin – not cross

BBB ( highly polar) but inflammation– they
can pass BBB --used for antibiotic effect

Placental blood barrier
– Blood vessel of mother and fetus separated
by PBB

– Highly polar and ionized drugs do not cross

placenta readily

– Drugs with high lipid solubility shouldn't be
given to pregnant mothers

• E.g. TTC –accumulate in bone and teeth of

neonate—↓development of bone and
– Drugs which cross PBB and cause fetal
abnormalities called teratogenic drugs
• These drugs shouldn’t be used during
IV. Tissue uptake
 Drugs will not always be uniformly distributed to
and retained by body tissues

 Some drugs will be either considerably higher or

considerably lower in particular tissues

 Due to difference in tissue affinity for the drug.

o Adipose tissues: accumulate drugs with high
 May result :–
 Decrease therapeutic activity
 Prolonged activity (e.g. fat depot
 Toxicity
o Kidney : contains proteins, methallothionein,
that has high affinity for metals
 Cadmium, pb, Hg accumulation -----toxicity
oEye – drugs which have affinity for retinal
pigment, melanin, accumulate in the eye
 Chlorpromazine (other phenothiazine) and
chloroquine---accumulate in eye
oBone- TTC, Lead
 TTC accumulation may cause dysplasia, poor
bone development.
 Lead accumulation result bone brittleness
(displace Ca2+ ).
o Teeth –TTC accumulation result yellow- brown
discoloration of teeth
o Liver – Chloroquine
Generally tissue accumulation of drugs may have
Advantageous effect ---( target tissue therapy eg
Chloroquine, : sustained release effect, eg fat depot)
Disadvantageous effect---mainly toxicity
• Heavy metals accumulation in the kidney, TTC
accumulation on bone
Volume distribution (Vd)

• Generally the distribution of drugs to body

compartment is determine by volume of
distribution (Vd).
 Vd is the apparent volume to which the drug is
 Relates drug concentration in the plasma to
total drug in the body
 Gives rough estimation of overall distribution of
a drug in the body
 Total body fluid is approximately 42L
(plasma=3L, ISF=12L & ICF =27L)
 Vd = amount of drug in body
amount of drug in blood
 Is apparent/ideal
 Its value can be greater than TBW
 Drugs with very high volumes of distribution
have much higher concentrations in extra
vascular tissue than in the vascular

• Drugs that are completely retained within the
vascular compartment, have a minimum
possible volume of distribution equal to the
blood component in which they are distributed,
eg, 3 L/70 kg for a drug that is restricted to the
plasma compartment.

• Vd have inverse relationship with PPB

 ↑PPB ----- ↓VD (mainly found in plasma)

 Vd can roughly indicate where the drug is
 Drug having high PPB and/or large molecular
weight----mainly found in plasma ( Vd in
 Highly large molecular weight and water
soluble drug have Vd at extracellular water
E.g. Gentamicin

 Highly water soluble & smaller size drug has Vd
of total body water
E.g. ethanol

 Highly lipophilic drug have Vd of greater than

total body water
 Example: for digoxin, if 500μg dose is given to 70kg
adult, plasma concentration is 0.75ng/ml, so Vd
will be
 500μg/0.75ng/ml=667L = 9.5 L/Kg

Compartment and
. Volume of water

 Total body water (0.6 L/kg)

Small water-soluble molecules: eg, ethanol.
• Extracellular water (0.2 L/kg)
Larger water-soluble molecules: eg, gentamicin.
• Blood (0.08 L/kg); plasma (0.04 L/kg)
Strongly plasma protein-bound molecules and very large
molecules: eg, heparin.
• Fat (0.2–0.35 L/kg)
Highly lipid-soluble molecules: eg, DDT.
• Bone (0.07 L/kg)
 Certain ions: eg, lead, fluoride.

At the end of these session the student be able
to :
– Define drug metabolism/ biotransformation
– Identify mechanism of drug metabolism
– To describe factors affecting drug

III. Metabolism/Biotransformation

 What is biotransformation?
 The process of modifying or altering the
chemical composition of the drug.
• A chemical change (transformation) of drugs
by body enzymes to metabolite(s)

 Why biotransformation is needed?
• To make drugs more hydrophilic so as to
facilitate their excretion
• Lipophilic drug → more hydrophilic
metabolites → easy excretion of drug
 The pharmacological activity of the drug is
usually removed but not always.

Sites of biotransformation
 Metabolism of drugs occur in most of the body
 Liver, Lung, GI, Kidney, Blood…
 But mainly it takes place in liver
B/s liver contains large amount of metabolizing
Mechanisms of biotransformation
 Metabolism in liver involves 2 steps
Phase I - functionalization
Phase II - biosynthetic (conjugation)

Phase I reactions
 Are called functionalizing reactions
since these reactions mediate addition
or exposure of functional group
 Produce more reactive and more
hydrophilic metabolites

 Oxidation: addition of O2 molecule or removal
of H2 molecule from a compound
 Reduction: addition of H2 molecule to a
 Hydrolysis: breaking down a compound with the
addition of a molecule of water

Consequence of phase -I reaction
• Loss of pharmacological activity

• Retention or enhancement of activity.

• In rare instances, it is associated with an

altered pharmacological activity E.g. prodrugs.

• Formation of toxic metabolites E.g.


• Most phase I reactions utilize CYP450
enzymes; not necessarily for all.
 CYP450 enzymes have different families and
sub families
 Most common are:
 CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2,
 CYP3A4 is responsible for metabolism of
most of currently useful drugs

Enzyme inducers:-
↑ synthesis of microsomal enzymes --
-- ↑ metabolism of drugs ----
↑excretion… ↓efficacy of drugs
E.g. rifampin, rifabutin, carbamazepin,
phenytoin, NVP, EFV, phenobarbital,
griseofulvin etc
Enzyme inhibitors:-
↓liver enzyme synthesis ---
↓metabolism of drugs --- ↓excretion--
Cimetidine, ketoconazole, ritonavir,
omeprazole, CAF, erythromycin, etc 170
• If not excreted rapidly into the urine Phase I
metabolites react with endogenous
compounds to form a highly water-soluble
conjugate → goes to Phase II.

Phase II reactions
 Are called conjugation/synthesis reactions
 Involve conjugation of more polar molecules to
↑ water solubility
 Drug + endogenous polar compound

 Examples
• Glucuronide conjugation
• Acetylation reactions
• Glutathione conjugation
• Sulfate conjugation
• Methyl conjugation
Factors affecting biotransformation of drugs
1. Genetic make up
• N-acetyl transferase Vs isoniazide
– Acetylation of isoniazide
Slow acetylators
–↓enzyme level---- ↓ Acetylation -----↓
excretion ------↑ plasma level of INH ------
toxicity ( peripheral neuropathy)
Fast acetylators
–Excessive enzyme----↑ acetylation-----↑
excretion--- ↓ plasma level of INH-----
↓outcome of therapy
2. Diet: grape fruit juice ( inhibit cyp3A4)
3. Age: children & older patients metabolize
drugs in slow rates
4. Sex: alcohol Vs alcohol dehydrogenase
5. Disease state: liver damage
6. Physiologic variation
–Pregnancy (reduced plasma level of
albumin) 175
Consequence of biotransformation

• Inactivation of parent drug:

E.g. Procain→PABA
• Conversion of inactive drug (prodrug) to more
active drug: e.g. levodopa → Dopamin
• Conversion to more hydrophilic metabolite
• Metabolite retaining similar activity formation
E.g.Imipramine → desipramine (anti

• At the end of these session the students be

able to ;

 Define drug excretion

Ways of drug excretion

IV. Excretion

• The drug (the parent drug / its metabolite)

discarded from the body.

• Drug transfer from the internal to the external


• Where does excretion take place?

– Kidney, biliary system, sweat, saliva, milk, lung

o 178
Renal excretion
– Principal organ for most drug removal
especially for
water soluble and
non volatile drugs
– Excretion of drugs through kidney involves
3 steps
• Glomerular filtration
• Tubular secretion
• Tubular reabsorption
 The amount of drug entering the tubular
lumen by filtration depends on ;

the glomerular filtration rate and

the extent of plasma binding of the drug

Small drug or metabolite molecules may be

transported by glomerular filtration into the

• In the proximal renal tubule;

An active &carrier-mediated tubular

secretion also may add drug to the
tubular fluid.

This process however, requires

membrane carriers and energy.

• Membrane transporters, mainly located in
the distal renal tubule;

 Are responsible for any active

reabsorption of drug from the tubular
lumen back into the systemic circulation.

 However, most of such reabsorption

occurs by nonionic diffusion.
• The concentration gradient for back-diffusion is
created by the reabsorption of water with Na+
and other inorganic ions.

• Since the tubular cells are less permeable to

the ionized forms of weak electrolytes,;
Passive reabsorption of these substances
depends on the pH.

• Tubular urine → alkaline, weak acids are
largely ionized → excreted more rapidly and
to a greater extent.

• Tubular urine → acidic, the fraction of drug

ionized is reduced →excretion is likewise

• In the treatment of drug poisoning:

 the excretion of some drugs can be

hastened by appropriate alkalinization
or acidification of the urine how???

• The rate of urinary drug excretion will depend
Presence of kidney disease E.g. Renal failure
Glomerular filtration rate
 Altered renal blood flow
PH of urine(Tubular fluid PH)
Concentration of the drug in plasma
 Molecular weight of the drug
Extent of plasma binding of the drug
Extent of back-diffusion of unionized form
Extent of active tubular secretion of the

Biliary and fecal excretion

 Ultimately, drugs and metabolites present
in bile are released into the GI tract during
the digestive process through:
 via the common bile duct

 direct secretion from the systemic

circulation by secretory transporters
which is found on the apical membrane
of enterocytes
Generally conclude that;
 Excretory route mainly for conjugated
 Enterohepathic recirculation is common
feature of this route
Highly conjugated drug excreted in the
bile ---- go to GIT --- GI flora and
enzymes hydrolyze the conjugated
metabolite ----- free drug reabsorbed

• Such enterohepatic recycling, if extensive, may
prolong significantly the presence of a drug
(or toxin).
• For this reason, drugs may be given orally to
bind substances excreted in the bile.

E.g. Mercury poisoning, a resin can be

administered orally that binds with
dimethylmercury excreted in the bile, thus
preventing reabsorption and further toxicity.

`` `
• Enterohepatic recycling also can be an
advantage in the design of drugs.
E.g. Ezetimibe - reduces the intestinal
absorption of cholesterol.

• This drug is absorbed rapidly and

glucuronidated in the intestinal cell
before secretion into the blood.

• And avidly taken up by the liver from
the portal blood and excreted into the
bile, resulting in low peripheral blood
• The glucuronide conjugate is
hydrolyzed and absorbed and is
equally effective in inhibiting sterol
• Some drugs will be reabsorbed back into
the blood stream and return to the liver
by the enterohepatic circulation.
• The drug then undergoes further
metabolism or is secreted back into bile.

• Drugs secreted into bile, will ultimately

pass through the large intestine and be
excreted in faeces.

oPulmonary excretion
 Main excretory route for drugs that are
volatile liquids and gases
 E.g. ethanol, inhalational anesthetics
oOther excretion routes
 Drugs & their metabolites can also be
excreted through breast milk, sweat,
 Contribute only to minimal excretion of a
• Elimination by these routes depends mainly
 Diffusion of the non ionized drug
• Milk is more acidic than plasma, basic
compounds may be slightly concentrated in
this fluid→→Excretion???

• Non electrolytes, readily enter breast milk and
reach the same concentration as in plasma,
independent of the pH of the milk

– Define pharmaco dynamics
– Define receptor
– Identify types of drug receptor interactions
– Define terms used in drug receptor

 Branch of pharmacology which studies the
action of drugs to the body
• Mechanism of action of drugs & their effects
on the body
• The relationship of the plasma concentration
of the drug with its response and the duration
of action.
 Mainly concerned on interaction of drugs with
• What the drug does to the body
The action of drugs produc through :
Reaction via recptor.
With out receptor.

4/30/2018 199
What are receptors?

 Are macromolecules whose main function

is to recognize and respond to
endogenous chemicals and xenobiotics
 Are sites where drugs interact to produce
their effect
 There are drugs which don’t need
receptors to produce an action
E.g. antacids, osmotic diuretics

Classification Of Drug
 Based on their location on the cells, receptors
could be
 Intracellular receptors
• Found inside the cells in the cytosol or on the
nuclear membrane
• E.g. estrogen receptors, progestin receptors
 Cell surface receptors
• Found on the external surface of the cell
• E.g. muscarinic, nicotinic, alpha, beta receptors
• Based on their constituent molecules, receptors
could be
Lipids (less common)
Pure proteins
Nucleic acids

• Generally, Cell surface receptors are classified into
4 classes
– Based on structure & signal transduction mechanism
a) G-protein coupled receptors (GPCRs)
b) Ligand gated ion channels
c) Tyrosine kinase linked receptors
d) Receptors with intrinsic enzymatic activity

Figure Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain
of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is
coupled to a G protein.C. Ligand binds to the extracellular domain of a receptor that
activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact
with its intracellular receptor.
4/30/2018 204
Chemistry of drug receptor interaction

 To permit the initiation signal transduction & biological

response, the force that attract the drug to its receptor
must be
 Strong enough to hold the drug with its receptor
 Specific enough to select for the correct ligand
 The different electrochemical forces involved in drug
interaction includes
 Covalent bonds
 Ionic bonds
 H-bonds
 Van Der Waals forces 205
• The interactions between a drug and the body are
conveniently divided into two classes.
 Pharmacokinetic:ADME
 Pharmacodynamic Principles:
• Most drugs must bind to a receptor to bring about an
• However, at the cellular level, drug binding is only the
first in what is often a complex sequence of steps:
Drug (D) + receptor-effector (R) → drug-receptor-effector
complex → effect

4/30/2018 206
4/30/2018 207
Receptor states
 Receptors exist in at least two states:
 Inactive (R)
 Active (R*),
 that are in reversible equilibrium with one another,
usually favoring the inactive state.
 Binding of agonists causes the equilibrium to shift from
R to R* to produce a biologic effect.
 Antagonists occupy the receptor but do not increase
the fraction of R* and may stabilize the receptor in the
inactive state.
 Some drugs (partial agonists) cause similar shifts in
equilibrium from R to R*, but the fraction of R* is less
than that caused by an agonist (but still more than that
caused by an antagonist).

4/30/2018 208
 Agonists are those drugs that have a much higher
affinity for the (R*), configuration and stabilize it,
 so that a large percentage of the total pool resides in
the R* –D fraction and a large effect is produced.
 The recognition of constitutive activity may depend on:
 the receptor density
 The concentration of coupling molecules (if a coupled
 the number of effectors in the system.

4/30/2018 209
• When agonist drugs administered at
concentrations sufficient to saturate the
receptor pool, can activate their receptor-
effector systems to the maximum extent that
capable to cause a shift of almost all of the
receptor pool to the R* –D pool.
• Such drugs are termed full agonists.
• affinity and intrinsic activity

4/30/2018 210
Partial agonist:-
 Partial agonists have intrinsic activities greater than
zero but less than one.
 Even if all the receptors are occupied, partial agonists
cannot produce the same Emax as a full agonist.
act as
 antagonists : if a full agonist is present
 agonists: if a full agonist isn't presnt.

4/30/2018 211
The fractions of drug-bound R i and R a in the
same relative amounts as in the absence of any
 No change will be observed, so the drug will
appear to be without effect.
 The presence of the antagonist at the receptor
site will block access of agonists to the receptor
and prevent the usual agonist effect.
They have affinity but not intrinsic activity
4/30/2018 212
Inverse agonists
The drug has a much stronger affinity for the R i than
for the R a state and stabilizes a large fraction in the
R i –D pool.
the drug would reduce any constitutive activity,
thus resulting in effects that are the opposite of the
effects produced by conventional agonists at that

4/30/2018 213
The γ-aminobutyric acid (GABA A ) receptor-effector
(a chloride channel) in the nervous system.
This receptor is activated by the endogenous
transmitter GABA and causes inhibition of
postsynaptic cells.
Conventional exogenous agonists such as
benzodiazepines also facilitate the receptor-effector
system and cause GABA-like inhibition with sedation
as the therapeutic result.

4/30/2018 214
4/30/2018 215
Antagonist like to bind to Agonist like to bind to receptor in R’
state and shifts the equilibrium toward
receptor in R and R” state
more LR’ and makes effect
without any preference and
makes no shifts in
R R’
L L Effect
No effect

Inverse agonist has more affinity
to receptor in R state and shifts Partial agonist has a little
the equilibrium toward more LR more affinity for receptor in R’
and make negative response than states than R state and makes
resting state. partial effect

• To understand drug–receptor interactions, it is

necessary to quantify the relationship between
the drug and the biological effect it produces.
• Since the degree of effect produced by a drug is
generally a function of the amount administered,
we can express this relationship in terms of a
dose–response curve.

4/30/2018 217
Dose–response curve cont…
Concentration of drug in plasma ~ drug administered

Concentration of drug in receptors ~ concentration of

drug in plasma

So, response ~ drug administered

Expressed in dose-response curve

4/30/2018 218
 Two types of dose-response curve
1. Graded dose-response curves
2. Quantal-dose response curves.

A. Graded dose response curve
 The relationship between dose and response is a
 The response continuously increase as the administered
dose is increased


Phenobarbital Dose

When a graded dose–response relationship exists, the

response to the drug is directly related to the number of
receptors with which the drug effectively interacts.
 More common than quantal dose response, since
involve single patient/animal.
 Graph is done by giving d/f doses of a drug to single
individual & recording response.
 The entire dose response relationship is deter- mined
from one animal, the curve cannot tell us about the
degree of biological variation inherent in a population
of animals.

Graded cont…
It is impossible to construct grade dose reponse
curve if the pharmacologic response is an either-or
(quantal) event.
Two important properties of drugs can be
determined by graded dose response curves are:
 Potency
 Maximal efficacy of the drugs

4/30/2018 222
• Potency refers to the concentration (EC50) or
dose (ED50) of a drug required to produce 50%
of that drug's maximal effect.

• Potency of a drug depends on:

 The affinity of receptors for binding the drug
The efficiency with which drug-receptor
interaction is coupled to response.
Pharmacologic potency can largely determine
the administered dose of the chosen drug.
4/30/2018 224
• The clinical effectiveness of a drug depends
its maximal efficacy
 its ability to reach the relevant
But not on its potency (EC50)

4/30/2018 225
Quantal Relationships
 The relationship between dose and some specified
quantity of response among all individuals taking that
 data are obtained from many individuals to construct
the curv.
 The patient (or animal) will or will not respond to a
given dose.
 a comparison of individuals within a population show
that the population are not identical in their ability to
respond to a particular dose.
 useful for determining doses to which most of the
population responds.

4/30/2018 226
 Show the effect of d/t dose on response among all (
many) individuals taking the drug.
 Show individual variation in response for a given dose
 Follow none or all response for dose administered
 Is actually a cumulative plot of the normal frequency
 Usually done on animals than humans.
 used to generate information regarding the:
 margin of safety,LD50,TD50,ED50

4/30/2018 227
Ma Maximum effect

ED 50:- the dose that

produces response in
50% of the individuals

LD 50:- the dose

that cause death in
50% of the animal

4/30/2018 228
• As Figure A shows, the lowest dose protected
none of the 10 rats to which it was given.

• Whereas 10mg/kg protected 10 of 10.

• With the intermediate doses, some rats were

protected and some were not.

• This indicates that the rats differ in their

sensitivity to phenobarbital.

4/30/2018 229
Lethal Dose
• Another important characteristic of a drug’s
activity is its toxic effect.

• Obviously, the ultimate toxic effect is death.

• A curve similar to that already discussed can

be constructed by plotting percent of animals
killed by phenobarbital against dose (Fig.
4/30/2018 230
Lethal Dose cont..

From this curve, one can calculate the LD50 (lethal

dose, 50%).
Since the degree of safety associated with drug
administration depends on an adequate separation
between doses producing a therapeutic effect (e.g.,
ED50) and doses producing toxic effects (e.g., LD50),
One can use a comparison of these two doses to
estimate drug safety.

4/30/2018 231
Therapeutic Index (TI)
• An estimate of a drugs
margin of safety.
• range of the drug
concentration b/n the
MEC and MTC.
• Mathematically: MEC

• A more realistic estimate of drug safety would include a

comparison of the lowest dose that produces toxicity (LD1)
and the highest dose that produces maximal therapeutic
response (ED99)
Cont’d …
Several parameters can be obtained from this curve.
• Minimum Effective Concentration (MEC)- minimum
concentration that must be reached in plasma to
obtain the desired therapeutic effect.
• Minimum Toxic Concentration (MTC)- the
concentration above which toxic effect may occur
• The onset- the time required to achieve MEC
following administration
• Duration- the period in which the concentration of
plasma remains above the MEC
• Peak concentration- is highest concentration of drug
achieved in plasma, Cpmax

• Thus, one estimate of a drug’s margin of
safety is the ratio LD50/ED50; this is the
therapeutic index.

• The therapeutic index for phenobarbital used

as an anticonvulsant is approximately 40/4, or

4/30/2018 234
• A ratio less than unity would indicate that a
dose effective in 99% of the population will be
lethal in more than 1% of the individuals
taking that dose.

• TW=LD1/ED99

4/30/2018 235
• Factors Altering Drug Responses
• Drug elimination is less efficient in newborns & old people
– Lesser renal & hepatic functions
– Body composition changes (in oldies)
– Greater risk of drug interactions (in oldies)
• Big patients “spread” drug over larger volume
• Difference in sizes, difference in fat/water distribution
• Chinese are more sensitive to CVS effects of β-blockers than Whites
• Afro-Caribbeans are less sensitive to CVS effects of β-blockers
• Genetic & environmental differences may account for the
perceived differences
4/30/2018 236
• Renal or hepatic diseases may produce toxicity
• Increased drug concentration following standard dose
• Gastric stasis
• Caused by migraine, diabetic neuropathy
• May slow drug absorption
• Hypothermia
• Common in elderly, markedly reduces drug metabolism
Genetic effects
• Polymorphism in metabolizing enzymes
• Reduced/increased metabolism of drugs
• Increased cardiac output, reduced plasma albumin
• Affects drug disposition in both the mother & fetus
4/30/2018 237
 Pediatric Patients: drug response may be affected
due to
• Higher proportion of water
• Lower plasma protein levels
 More available drug
• Immature liver/kidneys
 Liver often metabolizes more slowly
 Kidneys may excrete more slowly
 Geriatric patients: drug response may be affected
due to
 Chronic disease states
 Decreased plasma protein binding
 Slower metabolism
 Slower excretion
 Dietary deficiencies
 Lack of drug compliance
4/30/2018 238
Drug interactions
– Drug could have an interaction with other agents that are
administered to body concomitantly .
– A drug interaction may result in beneficial or
harmful effects.
• Other drugs
– Drug-drug interactions
• Foods taken
– Drug-food interactions
• Beverages
– Drug-beverage interactions
• Herbs
– Drug-herb interactions
– Drug interaction could be significantly important or
• Type of interaction: based on type of agents that
Drug –drug interaction
•Antacid Vs ketoconazole
•Floroquinolons Vs iron preparations
•Cimetidine Vs warfarin
• Probenecid Vs penicillin

Drug-food interaction
oGrape fruit juice Vs phenytoin
oGrape fruit juice Vs protease inhibitors
(Grape fruit juice is inhibitor of CYP3A4
Drug – beverage interaction

•Benzodiazepine Vs Alcohol
•MAOI Vs wine
•Metronidazole Vs alcohol
•Paracetamol Vs chronic alcoholism

Drug-herbal interaction
Saint John's herb Vs Phenytoin
Saint John's herb Vs Protease inhibitors
(Saint John's is liver microsomal enzyme
 Based on level of interaction: drug- interactions
classified as:-
 Direct chemical or physical interaction
 Pharmaceutical interaction – mixing drugs
before and during administration of drugs
 Eg. diazepam if added to infusion fluid there will be
a precipitate formation →loss of therapeutic effect.
 protamine,(+ve charge) counteract the
effects of heparin(-ve charge) by form
achemical intraction.

 Based on level of interaction: drug- interactions classified
A. Pharmacokinetic level interaction
 Absorption level drug interactions
 Ergotamine + caffeine : ergotamine better absorbed from small
intestine hence caffeine ↑motility --- ↓emptying time ---
facilitate absorption of ergotamine from small intestine ( high
surface area and alkaline media favor absorption)
 Cholestyramine + FeSO4: Cholestyramine is large
macromolecule which have potential to adsorb other agents --
-so FeSO4 adsorbed to Cholestyramine ---- ↓absorption
 Tetracycline + antacids : interaction in 3 ways
 TTC needs an acidic env’t for better absorption since antacids are
alkaline --alkaline media----absorption of TTC ↓ (neutralization)
 Antacids contain heavy metals like Ca2+, Mg2+, Al+ --- TTC can bind
with these metals ----form complex ----- ↓ absorption (complexetion)
 Since most antacids are gely and massy adsorption may take place b/n
antacid and TTC ---↓ absorption (adsorption)
Distribution level interaction
 Main factor for this interaction is:
 high plasma protein binding capacity
 So displacement of these drugs by other highly
plasma protein binding drug ---- ↑plasma level of
unbound drug-----toxicity

Eg: Warfarin + phenylbutazone -------both are highly plasma protein

binding, so taking of phenylbutazone while in Warfarin therapy-------
Warfarin displaced from albumin by phenylbutazone-----↑Warfarin in

Biotransformation level interaction
 A drug administered may induce or inhibit the
liver microsomal enzymes
 As a result there may be drug interaction in
concomitant use of 2 or more drugs

 Commonly they are:
Enzyme inhibitors
Enzyme inducers Cimetidine
•Phenobarbital Ketoconazole
•Carbamazepine Erythromycin
•Phenytoin Isoniazide
•Rifampin CAF
•NVP &EFV Omeprazole
•Gresofulvin Grape fruit

 Eg : Cimetidine + Warfarin ----- bleeding …??

Phenobarbital + OCT-----pregnancy….??
Excretion level interaction:
Filtration:decreased reduce cardiac output
 Reabsorption:
Active secretion
• Competition between two drugs for active tubular
secretion can decrease the renal excretion of both
agents :- since there is carrier protein
 E.g. Probenecid + pencillin : since pencillin have short
duration of action ---- ↑duration ---by ↓excretion

 Tubular reabsorption: since there is PH based
ionization of drug and further degree of
 Aspirin Vs Sodium bicarbonate
 Ammonium chloride Vs Amphetamines

B. Pharmacodynamic drug interactions
I. Agonizing interactions
II. Antagonizing interactions
I. Agonizing interactions
 It occurs by modification of pharmacological
response of one drug by another without altering the
concentration of the drug in the tissue or tissue fluid.

1. Additive interactions:– Occurs when the combined effect of
two drugs is equal to the sum of the effects of each agent
given alone.
• The effect of the two drugs is in the same direction and
simply adds up.
• Mathematically expressed as: 2 + 2 = 4
E.g. H1antagonist + CNS depressant
Aspirin + paracetamol as analgesic/ antipyretic
Glibenclamide .:+ metfottnip. as hypoglycaemic

2. Potentiation:- occurs when one drug enhances the action
of another drug without having an effect by itself.
• This is always the case when one component is inactive
as such.
Mathematically expressed as: 0 + 1 > 1
E.g. Augmentin – Amoxicillin– Clavunic acid

Acetylcholine and Physiostigmin ( inhibition of break


3. Synergism:- occurs when the combined
effects of two drugs are much greater than
the sum of the effects of each agent given

Mathematically expressed as: 1 + 1 >>> 2

E.g. NE + Digoxine

B. Antagonizing interaction: reduced/opposite
effects are produced
Three types
a. Chemical antagonism
 Involve direct chemical interaction b/n agonist
and antagonist
 E.g. chelating agent (dimercaprol) + heavy
metals(Hg, Pb…)

b. Functional (physiologic) antagonism
 Involves interaction of two agonists that
act independently of each other but
happen to cause opposite effect
 E.g. acetylcholine + epinephrine
– Glucagon and insulin on blood sugar level.

c. Receptor or pharmacologic antagonism
 Competitive antagonism
 Reversible competitive antagonism
 Irreversible competitive antagonism
 Noncompetitive antagonism

Competitive antagonism
Depending on the type of bond formed b/n antagonist
and receptor competitive antagonism can be classified:

 Reversible competitive antagonism

 Irreversible competitive antagonism

Competitive antagonism

Antagonist Receptor

4/30/2018 257
Reversible ( equilibrium) competitive
 If bond is loose (non-covalent)
 Antagonism↑ as concentration of
antagonist↑ and inversely if ↑agonist
concentration----antagonism ↓

4/30/2018 258
Competitive antagonism cont…

 Characterized by a parallel shift

to right in dose response curve
 E-max is not changed A B C

 ED50 is increased

Dose of the agonist

 Irreversible (not equilibrium) competitive antagonism
 If bond is covalent
 As the concentration of antagonist increases
o The slope of the agonist curve ↓
o The maximum response (E-max)↓i
o There is no parallel shift to the right
o No change of ED50
o When the amount of antagonist is adequate
no amount of agonist can produce any response


Dose of the agonist 260


4/30/2018 261
Non-competitive antagonism
 Involves 2 binding sites in the receptor for
antagonist and agonist
• Active site --- binding site of the agonist
• Allosteric site --- binding site of the antagonist

 The binding of the antagonist to the allosteric
site produces a conformational change on the
active site
• Prevents binding of the agonist to the active
It influence transduction pathway of the
 Similar dose response curves for agonist with
irreversible competitive antagonist
ED50 not affected
E-max is reduced
Non-competitive antagonism

Non-competitive Antagonist

Agonist Receptor

4/30/2018 DENIED! 264

Importance of Drug antagonism
i. correcting adverse effects of drugs.
ii. Treating drug poisoning. e.g. - Morphine with
iii. Predicting drug combinations which would reduce
drug efficacy.


Definition: ADR -Noxious and unintended effect

of drug, occurring at normal dose.

• Assumed drug dosage is within therapeutic


1. Reactions that may occur in anyone
 Drug side effect
 Undesirable,
 inseparable and unavoidable,
 extension of the pharmacological effect of the
Drug interaction
co-administration of another drug, food,
beverage or diseases.

2. Reactions that occur only in susceptible
• Drug Idiosyncrasy
 A genetically determined
 Abnormal to a drug related to a metabolic
or enzyme deficiency.
• Drug Allergy (hypersensitivity)
 An immunologically mediated reaction

Risk Factors for ADR
• Receives new drug
• Undergoing treatment by two or more
• physician.
• Takes several prescription drugs
• Extremes of age
• History previous adverse reactions

Drug Discovery and Development
• With the development of the pharmaceutical industry towards the
end of the 19th century, drug discovery became a highly focused
and managed process.
• Today, the bulk of modern therapeutics, and of modern
pharmacology, is based on drugs that came from the laboratories
of pharmaceutical companies
• The two main stages of the process, are:
• (i) the discovery phase, i.e. the identification of a new chemical
entity as a potential therapeutic agent;
• (ii) the development phase, during which the compound is tested
for safety and efficacy in one or more clinical indications, and
suitable formulations and dosage forms devised.

• Given the task of planning a project to discover a new drug to
treat,where does one start? choose a new molecular target.
• Molecular target: as you know in the earlier chapters, drug
targets are, with few exceptions, functional proteins (e.g.
receptors, enzymes, transport proteins).
• When the biochemical target has been decided and the
feasibility of the project has been assessed, the next step is to
find lead compounds
• LEAD FINDING :Large companies will typically maintain a
growing collection of a million or more synthetic compounds,
which will be routinely screened whenever a new assay is set up.

The Development Phase
preclinical and clinical development
• The testing of new drugs has two principal steps:
• preclinical testing and clinical testing.
• Preclinical tests are performed in animals.
• Clinical tests are done in humans.

Preclinical Testing
Preclinical testing is required before a new drug
may be tested in humans.
During preclinical testing, drugs are evaluated for
toxicities, pharmacokinetic properties, and
potentially useful biologic effects.
Preclinical tests may take 1 to 5 years.
When sufficient preclinical data have been
gathered, the drug developer may apply to the
FDA for permission to begin testing in humans.
If the application is approved, the drug is awarded
Investigational New Drug status and clinical trials
may begin.

4/30/2018 273
4/30/2018 274
Clinical Testing

 Clinical trials occur in four phases and may take 2 to

10 years to complete.
1. Clinical pharmacology (phase I)
2. Clinical investigation (phase II)
3. Clinical trials (phase III)
4. Postmarketing studies (phase IV).
• The first three phases are done before a new drug is
• The fourth is done after marketing has begun.
4/30/2018 275
Phase I
• When a drug is administered to humans for the first
• Phase I studies are usually confined to a group of 20 to 80

• For certain types of drugs, such as antineoplastic

agents, it is not appropriate to use healthy subjects
because the risk of injury is too high.
• The purpose of phase I studies is to establish :
• the dose level at which signs of toxicity first appear.
• check for safety, tolerability and pharmacokinetic
4/30/2018 276
Clinical investigation (phase II)

 the new drug is administered to patients for the first time.

 Ideally, these individuals should have no medical problems
other than the condition for which the new drug is intended.
 Efforts are concentrated on evaluating efficacy and on
establishing an optimal dose rang.
 The number of subjects in phase II studies is usually
between 80 and 100.

4/30/2018 277
Phase III Therapeutic confirmation/comparison

• Phase III When an effective dose range has been

established and no serious adverse reactions have
occurred, large numbers of subjects can be exposed to
the drug.
• In phase III studies the number of subjects may range
from several hundred to several thousand, depending
on the drug.
• The purpose of phase III studies is to verify the efficacy
• of the drug and to detect effects that may not have
surfaced in the phase I and II trials, during which
exposure to the drug was limited.

4/30/2018 278
Phase IV Post marketing

 After the drug has been marketed for general

use, practicing physicians are identified
through whom data are collected about the
efficacy, acceptability and adverse effects of
the drug.
 Controlled and uncontrolled studies often are
conducted after a drug is approved and
4/30/2018 280