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Chapter objectives
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Introduction cont…
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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
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Definition cont…
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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
=adjuvant
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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.
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- 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.
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• 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.
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• The last 3 decades have seen an even more
rapid growth of information and
understanding of the molecular basis for drug
action.
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Pharmacology today with its various subdivisions.
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Source of Drugs
I. Synthetic sources
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I-Synthetic Sources
At present majority of drugs used in clinical practice are
prepared synthetically.
Examples: Aspirin, chloroquine, sulphonamides, etc …
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II-Natural Sources
Drugs are obtained from the following natural sources
1)Plants
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
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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
uneconomical
Natural sources yield impure compounds
Examples: Ampicillin, Amoxicillin
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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
prescriptions
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
acid
Interest of chemists, only one chemical name for a
drug
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Drug Development
Introduction
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.
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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
devised.
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.
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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.
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PRECLINICAL DEVELOPMENT
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Preclinical cont…
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Preclinical cont…
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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
purification,
To assess the stability of the compound
under various conditions, and
To develop a formulation suitable for clinical
studies.
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Preclinical cont…
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CLINICAL TESTING OF DRUGS
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CLINICAL TESTING OF DRUGS
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PHASES OF CLINICAL INVESTIGATION
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Phase I cont…
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Phase II Therapeutic exploration and dose
ranging
• 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
range.
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Phase II cont…
• Therefore, dose–response studies are a
critical part of phase II studies.
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Phase III Therapeutic
confirmation/comparison
• 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.
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Phase III cont…
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Phase IV Post marketing
surveillance/studies
• 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).
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Phase IV cont…
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Pharmaceutical dosage forms
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Pharmaceutical dosage forms
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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
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Medical gases
Preparations for
intrapulmonary
administration
Inhaled through
breathing apparatus
The active
pharmaceutical
ingredient is found as
gas or volatile liquid
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Aerosols
Are another gaseous dosage
forms
Contain an active drug
suspended in a gaseous
vehicle
They are dispersions of solid
particles or liquid droplets
in a gaseous vehicle
Do not need breathing
apparatus
They have their own
administration mechanisms
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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
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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
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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
preparations
E.g. gentamicin injection, glucose preparations
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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
drugs
• “shake well” sticker
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III. Semisolid Dosage Forms
Unshaped
• Creams - semisolid emulsion systems (o/w,
w/o) containing more than 10% of water
• Ointments - semisolid systems with the
oleaginous , water-soluble or emulsifying
base
• Pastes - semisolid dispersion system, where a
solid particles (> 25%) are dispersed in
ointments
• Gels
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Semi solid cont…
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IV. Solid Dosage Forms
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Tablets
Types are:
Most common forms of
Scored tablet,
solid dosage forms
Effervescent tablet,
Written as tab or tabs on Enteric-coated tablet,
prescriptions
Slow-release tablet,
Several kinds of tablets Caplet, and
are available Lozenges
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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
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• 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
material.
• Slow release tablets:
designed to provide
sustained release of the
drugs
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Lozenges
Sweet tablets containing
sugar, water & flavoring
agents
Are to be chewed/held
in the mouth
Are not swallowed
Pellets/beads
Prepared as sheets or
beads for sustained
release e.g. Norplant
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Capsules
Written as cap or caps on
prescriptions
Prepared in two forms
1. Soft capsules: are made of
soft gelatin
Contain liquid inside &
are sealed
E.g. Vitamin A & E
capsules
Hard capsules: are made
of hard gelatin
Contain two separable
pieces or cups
Contain powder or
granules inside
E.g. Amoxicillin,
tetracycline capsules
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Systems of Measurement
• Metric
• Apothecary
• Household
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Routes of Drug Administration
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Drug Administration
Topical/Local Systemic
Administration Administration
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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)
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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
(metabolism)
Not given for unconscious, uncooperative, vomiting
patients
Slow onset of action
Irregular absorption (drug- food interaction)
E.g. fatty meals delay absorption of many drugs
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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
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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
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Parentral route
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Subcutaneous:
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
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• 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.
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• 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.
Disadvantages:
There is no retreat
This method is more risky
This method is not suitable for oily and insoluble preparations
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• Inhalation:
Via inhaler
Via nebulizer
Medication directly to the respiratory system
Advantages:
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
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• Disadvantages:
Special apparatus is required.
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Topical Application
• Advantages:
Absorption rapid
Only local effect
• Disadvantages:
Toxicity by highly lipid soluble substances
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Other routes include:
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Basic principles of pharmacology
– Most drugs after administered to the body they
undergo 2 major process
78
2. Pharmacodynamics process:-
mechanisms of action.
79
Pharmacokinetics
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• Pharmacokinetics is the quantitative study
of drug movement in, through and out of the
body.
• 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
membranes.
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82
Factors affecting the transfer of drugs
across the membranes
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Cell membrane
86
• Membrane proteins embedded in
the bilayer serve as:
• Receptors,
• Ion channels, or
87
• Cell membranes are relatively permeable to
water.
• 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.
88
• Drugs, like most organic electrolytes, generally do not
completely dissociate (i.e., form ions) in aqueous
solution.
• 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
membranes.
89
• 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.
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– The characteristics of a drug that predict its
movement and availability at sites of action are
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MECHANISMS OF SOLUTE TRANSPORT
ACROSS MEMBRANES
93
• 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.
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Therefore, Passive transport is
95
Simple passive diffusion
Not need energy
96
• Such transfer is directly proportional to
the magnitude of:
98
Filtration
• 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
filtration.
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Carrier-Mediated Membrane Transport
100
Active transport
Carrier mediated
102
Facilitated diffusion
• It differs from active transport, however, in
that no energy input is required beyond that
necessary to maintain normal cellular
function.
• 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
possible
103
Endocytosis
• 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.
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• The reverse process (exocytosis) is
responsible for the secretion of many
substances from cells.
105
Objectives
At the end of the session students will be able to:
106
Absorption
• 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
107
• In order for a drug to be absorbed, it must pass
through cell membranes
Passive transport
Active transport
Bulk transport
108
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
• Distribution is the delivery of the drug to the
tissues.
109
• 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
membranes
(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
129
• 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.
133
• 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
134
• Factors affecting Bioavailability :-
• Dose
• Route of administration
• Pharmacokinetic factors extent of
absorption
135
First-pass effect (Metabolism)
136
Objective
At the end of these session the students should
be able to :
137
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.
138
Factors that affect Drug Distribution
139
I. Tissue perfusion
140
Based on the amount of blood they receive,
body tissues can be grouped into two:
141
II. Plasma protein binding
D + PP →[DPP] → D + PP
143
• The extent of this binding will influence the drug’s
distribution and rate of elimination .
• Be metabolized
• Be excreted
144
The major binding plasma proteins are
Albumin
α1 –acid glycoprotein
Albumin
– Most common drug binding glycoprotein
– Mainly acidic and hydrophobic drugs
bind to albumin
145
α1 –acid glycoprotein
Binding site mainly for basic drugs such as
imipramine, amitriptillin
Plasma level ↑ in situation such as
Stress, injury, trauma, Rheumatoid arthritis,
Surgery
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
147
Inflammation such as due to meningitis or
encephalitis increase the permeability of BBB
so permeating the passage of ionized , lipid
insoluble drugs.
148
Placental blood barrier
– Blood vessel of mother and fetus separated
by PBB
149
– Drugs with high lipid solubility shouldn't be
given to pregnant mothers
151
o Adipose tissues: accumulate drugs with high
lipophilicity
May result :–
Decrease therapeutic activity
Prolonged activity (e.g. fat depot
preparation)
Toxicity
152
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+ ).
153
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
154
Volume distribution (Vd)
156
• 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.
157
Vd can roughly indicate where the drug is
distributed
Drug having high PPB and/or large molecular
weight----mainly found in plasma ( Vd in
plasma)
Highly large molecular weight and water
soluble drug have Vd at extracellular water
E.g. Gentamicin
158
Highly water soluble & smaller size drug has Vd
of total body water
E.g. ethanol
159
Compartment and
. Volume of water
160
Objectives
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
metabolism
161
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)
162
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.
163
Sites of biotransformation
Metabolism of drugs occur in most of the body
parts
Liver, Lung, GI, Kidney, Blood…
But mainly it takes place in liver
B/s liver contains large amount of metabolizing
enzymes
164
Mechanisms of biotransformation
Metabolism in liver involves 2 steps
Phase I - functionalization
Phase II - biosynthetic (conjugation)
reactions
165
Phase I reactions
Are called functionalizing reactions
since these reactions mediate addition
or exposure of functional group
Produce more reactive and more
hydrophilic metabolites
166
Includes
Oxidation: addition of O2 molecule or removal
of H2 molecule from a compound
Reduction: addition of H2 molecule to a
compound
Hydrolysis: breaking down a compound with the
addition of a molecule of water
167
Consequence of phase -I reaction
• Loss of pharmacological activity
168
• 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,
CYP2A6, CYP 2E1
CYP3A4 is responsible for metabolism of
most of currently useful drugs
169
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--
--toxicity
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.
171
Phase II reactions
Are called conjugation/synthesis reactions
Involve conjugation of more polar molecules to
↑ water solubility
Drug + endogenous polar compound
172
Examples
• Glucuronide conjugation
• Acetylation reactions
• Glutathione conjugation
• Sulfate conjugation
• Methyl conjugation
173
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
174
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
177
IV. Excretion
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
179
The amount of drug entering the tubular
lumen by filtration depends on ;
180
• In the proximal renal tubule;
181
• Membrane transporters, mainly located in
the distal renal tubule;
183
• Tubular urine → alkaline, weak acids are
largely ionized → excreted more rapidly and
to a greater extent.
184
• In the treatment of drug poisoning:
185
• The rate of urinary drug excretion will depend
on:
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
drug
186
Biliary and fecal excretion
187
Ultimately, drugs and metabolites present
in bile are released into the GI tract during
the digestive process through:
via the common bile duct
189
• 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.
190
`` `
• Enterohepatic recycling also can be an
advantage in the design of drugs.
E.g. Ezetimibe - reduces the intestinal
absorption of cholesterol.
`
191
• And avidly taken up by the liver from
the portal blood and excreted into the
bile, resulting in low peripheral blood
concentrations.
• The glucuronide conjugate is
hydrolyzed and absorbed and is
equally effective in inhibiting sterol
absorption.
192
• 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.
193
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,
saliva
Contribute only to minimal excretion of a
drug
194
• Elimination by these routes depends mainly
on;
Diffusion of the non ionized drug
pH
• Milk is more acidic than plasma, basic
compounds may be slightly concentrated in
this fluid→→Excretion???
195
• Non electrolytes, readily enter breast milk and
reach the same concentration as in plasma,
independent of the pH of the milk
196
Objectives
– Define pharmaco dynamics
– Define receptor
– Identify types of drug receptor interactions
– Define terms used in drug receptor
interaction
197
Pharmacodynamics
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
receptors
• What the drug does to the body
198
The action of drugs produc through :
Reaction via recptor.
With out receptor.
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What are receptors?
200
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
membrane
• E.g. muscarinic, nicotinic, alpha, beta receptors
201
• Based on their constituent molecules, receptors
could be
Lipoproteins/glycoproteins
Lipids (less common)
Pure proteins
Nucleic acids
202
• 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
203
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.
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Chemistry of drug receptor interaction
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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).
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Agonist
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
system).
the number of effectors in the system.
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• 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
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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.
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Antagonist
The fractions of drug-bound R i and R a in the
same relative amounts as in the absence of any
drug.
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
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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
receptor.
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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.
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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
netequilibrium
R R’
L L Effect
No effect
LR LR’
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
DOSE–RESPONSE RELATIONSHIP
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Dose–response curve cont…
Concentration of drug in plasma ~ drug administered
4/30/2018 218
Two types of dose-response curve
1. Graded dose-response curves
2. Quantal-dose response curves.
219
A. Graded dose response curve
The relationship between dose and response is a
continuous.
The response continuously increase as the administered
dose is increased
Death
Response
Coma
Anesthesia
Hypnosis
Sedation
Phenobarbital Dose
221
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
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• Potency refers to the concentration (EC50) or
dose (ED50) of a drug required to produce 50%
of that drug's maximal effect.
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Quantal Relationships
The relationship between dose and some specified
quantity of response among all individuals taking that
drug.
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.
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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
distribution
Usually done on animals than humans.
used to generate information regarding the:
margin of safety,LD50,TD50,ED50
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Ma Maximum effect
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• As Figure A shows, the lowest dose protected
none of the 10 rats to which it was given.
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Lethal Dose
• Another important characteristic of a drug’s
activity is its toxic effect.
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Therapeutic Index (TI)
• An estimate of a drugs
MTC
margin of safety.
Cpmax
• range of the drug
concentration b/n the
MEC and MTC.
TI
• Mathematically: MEC
233
• Thus, one estimate of a drug’s margin of
safety is the ratio LD50/ED50; this is the
therapeutic index.
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• 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
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• Factors Altering Drug Responses
Age
• 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)
Weight
• Big patients “spread” drug over larger volume
Gender
• Difference in sizes, difference in fat/water distribution
Race
• 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
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Pathology
• 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
Pregnancy
• Increased cardiac output, reduced plasma albumin
• Affects drug disposition in both the mother & fetus
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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
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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
harmful
239
• Type of interaction: based on type of agents that
interact
Drug –drug interaction
Examples
•Antacid Vs ketoconazole
•Floroquinolons Vs iron preparations
•Cimetidine Vs warfarin
• Probenecid Vs penicillin
Examples
Drug-food interaction
oGrape fruit juice Vs phenytoin
oGrape fruit juice Vs protease inhibitors
(Grape fruit juice is inhibitor of CYP3A4
enzyme)
240
Drug – beverage interaction
Examples
•Benzodiazepine Vs Alcohol
•MAOI Vs wine
•Metronidazole Vs alcohol
•Paracetamol Vs chronic alcoholism
Drug-herbal interaction
Examples
Saint John's herb Vs Phenytoin
Saint John's herb Vs Protease inhibitors
(Saint John's is liver microsomal enzyme
inducer)
241
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.
242
Based on level of interaction: drug- interactions classified
as:-
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)
243
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
244
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
245
Commonly they are:
Enzyme inhibitors
Enzyme inducers Cimetidine
•Phenobarbital Ketoconazole
•Carbamazepine Erythromycin
•Phenytoin Isoniazide
•Rifampin CAF
•NVP &EFV Omeprazole
•Gresofulvin Grape fruit
juice
247
Tubular reabsorption: since there is PH based
ionization of drug and further degree of
reabsorption
Aspirin Vs Sodium bicarbonate
Ammonium chloride Vs Amphetamines
248
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.
249
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
250
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
251
3. Synergism:- occurs when the combined
effects of two drugs are much greater than
the sum of the effects of each agent given
alone
E.g. NE + Digoxine
252
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…)
253
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.
254
c. Receptor or pharmacologic antagonism
Competitive antagonism
Reversible competitive antagonism
Irreversible competitive antagonism
Noncompetitive antagonism
255
Competitive antagonism
Depending on the type of bond formed b/n antagonist
and receptor competitive antagonism can be classified:
256
Competitive antagonism
Competitive
Inhibition
Antagonist Receptor
Antagonist-Receptor
DENIED!
Complex
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Reversible ( equilibrium) competitive
antagonism
If bond is loose (non-covalent)
Antagonism↑ as concentration of
antagonist↑ and inversely if ↑agonist
concentration----antagonism ↓
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Competitive antagonism cont…
Response
ED50 is increased
259
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
Response
A
B
C
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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
262
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
site
It influence transduction pathway of the
agonist
Similar dose response curves for agonist with
irreversible competitive antagonist
ED50 not affected
E-max is reduced
263
Non-competitive antagonism
Non-competitive Antagonist
Inhibition
Agonist Receptor
265
ADVERSE DRUG REACTIONS (ADR)
266
Classification
1. Reactions that may occur in anyone
Drug side effect
Undesirable,
inseparable and unavoidable,
extension of the pharmacological effect of the
drug.
Drug interaction
co-administration of another drug, food,
beverage or diseases.
267
2. Reactions that occur only in susceptible
subjects
• Drug Idiosyncrasy
A genetically determined
Abnormal to a drug related to a metabolic
or enzyme deficiency.
• Drug Allergy (hypersensitivity)
An immunologically mediated reaction
268
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
269
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.
270
THE DRUG DISCOVERY PHASE
• 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.
271
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.
272
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.
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Clinical Testing
4/30/2018 277
Phase III Therapeutic confirmation/comparison
4/30/2018 278
Phase IV Post marketing
surveillance/studies