Pharmacology study of drugs

Drug any substance that, when

administered to living organisms,
produces a change in function
Pharmacodynamics study of the action of the
drug on living tissue
Pharmacokinetics study of the processes of
drug absorption, distribution, metabolism &
excretion
Pharmacotherapeutics study of the use of drugs
in treating disease
Pharmacy science of preparing and dispensing
medicines
Posology study of the amount of drug that is
required to produce therapeutic effects
Toxicology study of the harmful effects of drugs
on living tissue
- In the early days it came from
plants or animal sources containing
active substances that can be
isolated, purified, and formulated
into effective drug preparations
- The main source of new drugs today
is from chemical synthesis
Adverse Effect: general term for
undesirable and potentially harmful
drug effects.
Agonist: drugs that binds to its
receptor and produces a drug action.
Antagonist: drug that binds to its
receptors and prevents other drugs or
substances from producing an effect.
Chemical name: name that defines the
chemical composition of the drug.
Contraindications: situations or conditions
when a certain drug should not be
administered.
Controlled substance: drug that has the
potential for abuse and thus is regulated by
law.
Dose: exact amount of a drug that is
administered in order to produce a specific
effect
Drug indications: intended or indicated
uses for any drug.

ED50: effective dose 50, or dose
that will produce an effect that is
half of the maximal response.
Generic name: nonproprietary, or
common, name of a drug.
LD50: lethal dose 50, or dose that
will kill 50 percent of the animals
tested.
Mechanism of Action: explanation
of how a drug produces its effects.

Nonprescription, over-the-counter
(OTC) drug: drug that can be purchased
without the services of the physician.
Potency: measure of the strength, or
concentration of a drug required to
produce a specific effect.
Prescription drug: drug for which
dispensing requires a written or phone
order that can only be issued by or
under the direction of a licensed
physician.
Receptor: specific location on a cell
membrane or within the cell where
a drug attaches to producing its
effect.
Side effect: drug effect other than
the therapeutic effect that is usually
undesirable but not harmful.
Site of action: location within the
body where a drug exerts its
therapeutic effect, often a type of
specific receptor.
Therapeutic effect: desired drug
effect to alleviate some condition or
symptom of disease.
Therapeutic index (TI): ratio of the
LD50 to the ED50.
Toxic effect: undesirable drug effect
that implies drug poisoning; can be
very harmful or life-threatening.
Trade name: patented proprietary
name of drug sold by a specific drug
manufacturer.
SITE OF ACTION
Defined as the location within the
body where the drug exerts its
therapeutic effect.
The site of action of some drugs is
not known; however, the site of
action for most drugs has been
determined (e.g. Aspirins effect on
the hypothalamus)
MECHANISM OF ACTION
Explains how a drug produces its
effect.
e.g. Local anesthetic produce a loss
of pain sensation by interrupting
nerve conduction in sensory nerves
by attaching to nerve membrane
and preventing passage of sodium
ions.
RECEPTOR SITE
Drug action is usually thought to
begin after a drug has attached
itself to some cell membrane.
For some drugs and normal body
substances, there seems to be a
specific location on certain cells
(RECEPTOR site).
RECEPTOR SITE
e.g. Morphine receptors are
found in the brain. When
morphine binds to its receptors,
it produces cell changes that
reduce the perception of pain.
AGONISTS AND ANTAGONISTS
Drugs that bind to specific receptors
and produce a drug action are called
agonists.
Drugs that bind to specific receptors
but do not produce any drug action
are called antagonists. They are also
called blocking agents.
AGONISTS AND ANTAGONISTS
e.g. Morphine is an agonist. But
in cases of Morphine overdose,
Naloxone, which is an antagonist
of morphine, binds to the
morphine receptors thus
preventing morphine to exert its
action.
AGONISTS AND ANTAGONISTS
When both agonists and antagonists
are administered together, they
compete with each other for the
same receptor site.
This effect is known as competitive
antagonism. The amount of drug
action is dependent on which drug
occupies the greatest number of
receptors.

Agonist
Antagonist
Receptor
COMPETITIVE ANTAGONISM
These are our
receptors!!!
Sorry pal!
We got here first!
DOSE-RESPONSE CURVE
A fundamental principle in
pharmacology is that the response to
any drug depends on the amount of
drug given (dose-response relationship).
A dose is the exact amount of a drug
that is administered in order to produce
a specific effect. The effect is referred
to as the response.
A Typical Dose-Response Curve
Drug response is
proportional to the
dose. Eventually, a
maximal response is
usually attained and
that further increases
in dose does not
produce any greater
effect. Doses above
those needed to
produce the ceiling
effect
100
50
5 10 15 20 25
%

R
e
s
p
o
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s
e

Dosage of Drug (mg/kg)
ED 50
ED 50
Ceiling effect
Dose-Response Curve
Drugs within a drug class that are more
potent than other drugs in the same
class will produce the ceiling effect at a
lower dosage, but they will not raise
the ceiling.
Drugs that continue to cause an
increased effect as long as the dose is
increased do not have a ceiling effect.
Graded Dose-Response Curve
Can be used to evaluate drug
response among different drugs.
The increases in drug dosage are
plotted against the increases in
drug response (compare potency
of similar drugs).
Graded Dose-Response Curve
Potency is a measure of the strength, or
concentration, of a drug required to
produce a specific effect.
The dose that will produce an effect
that is half of the maximal response is
referred to as the effective dose 50 or
ED50. This can be used to compare the
potency of drugs that produce the same
response
A Typical Dose-Response Curve
The ED50 of Drug A is
at 10mg while the
ED50 of Drug B is at
20mg.
Which
means____________?
100
50
5 10 15 20 25
%

R
e
s
p
o
n
s
e

Dosage of Drug (mg/kg)
ED 50
ED 50
Ceiling effect
Time-Response Curve
The relationship of the drug
response and time (duration of
action) is known as the time-
response relationship.
Duration of action is the length of
time that a drug continues to
produce effect.
A Typical Time-Response Curve
1 2 3 4
P
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(
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/
m
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Time in hours
Onset of
Action
Termination
of Action
Minimal effective concentration
required to observe drug effect
Duration
of Action
DRUG SAFETY
Every drug must fulfill two major requirements
before it can be approved for use in humans:
efficacy (proof of effectiveness) and safety.
The drug must be effective in the disease state
for which it has been approved.
Approved drugs must satisfy specific safety
criteria as determined by animal testing and
controlled human testing. One of the first tests
that is performed is the lethal dose 50 or LD50
(dose that will kill 50% of the animals tested).
Note: All drugs will act as poison if taken in
excess.
Therapeutic Index (TI)
Is a ratio of the LD50 to the ED50 of a
drug expressed as
TI = LD50/ED50
e.g. TI = 1000mg/10mg = 100
In this example this index indicates that
one hundred times as much drug is
needed to produce a lethal effect in
50% of animals.
The goal of drug therapy is to achieve
therapeutic effects in all individuals
without producing any harmful effects.
Adverse Effects
Most are dose dependent, which means the
higher the dose, the greater the chances for
producing an adverse effect.
Certain tissues are more frequently than others
(liver, kidneys, brain and cardiovascular system)
because of their exposure to the highest
concentrations of the drug.
Drugs that produce birth defects are called
teratogens.
Drugs that promote the growth of cancerous
tumors are called carcinogens.
Adverse Effects (cont.)
A few adverse effects are not dose
dependent. These effects, such as
idiosyncrasy and drug allergy, are
determined by individual variation (i.e.
certain enzymes and body proteins).
An individual reaction to a drug with an
unusual or unexpected response is
known as Idiosyncrasy.
Adverse Effects (cont.)
Drug allergy occurs when an individual
becomes sensitized to a particular drug and
produces antibodies against the drug
(antigens). Subsequent administration of
the drug leads to an antigen-antibody
reaction causing the release of histamine
(causes rashes, hives, itching, nasal
secretion, hypotension and
bronchoconstriction and even
anaphylaxis.).
DRUG NOMENCLATURE
Chemical name:
5,5,-Phenylethylbarbituric acid
Nonproprietary name:
Phenobarbital
Proprietary name:
Solfoton
DRUG NOMENCLATURE (cont.)
Controlled Substances Act
Federal Comprehensive Drug
Abuse Prevention and Control Act
of 1970 is designed to regulate the
dispensing of certain drugs that
have the potential for abuse
Schedule Definition Controlled Drugs
Schedule I Drugs with high abuse
potential and no accepted
medical use
Heroin, hallucinogens,
marijuana; these drugs are
not to be prescribed
Schedule II Drugs with high abuse
potential and accepted
medical use
Narcotics (morphine and
pure codeine), cocaine,
amphetamines, short-
acting barbiturates; no
refills without a new
written prescription from
the physician
Schedule III Drugs with moderate
abuse potential and
accepted medical use
Moderate- and
intermediate-acting
barbiturates, glutethimide,
preparations containing
codeine plus another drug;
prescription required, may
be refilled five times in six
months when authorized
by the physician
Schedule Definition Controlled Drugs
Schedule IV Drugs with low abuse
potential and accepted
medical use
Phenobarbital, chloral
hydrate, antianxiety drugs
(Librium, Valium);
prescription required, may
be refillable five times in 6
months when authorized
by the physician
Schedule V Drugs with limited abuse
potential and accepted
medical use
Narcotic drugs used in
limited quantities for
antitussive and
antidiarrheal purposes;
drugs can be sold only by a
registered pharmacist;
buyer must be 18 years old
and show identification
REVIEW OF PHARMACOKINETIC
PRINCIPLES

The familiar saying no two people
are exactly alike applies well to the
effects produced by drugs.

An identical drug and dose may
produce an intense response in one
individual and no observable effect in
another (Individual variation).


DRUG FORMS
Drugs are prepared in various forms for
administration
The physical and chemical properties of a
drug usually determine which form will be
most effective.
In addition, most drug products contain
other ingredients that facilitate the
administration and absorption of the drug.
Drug preparations should always be taken
exactly as prescribed.


DRUG FORMS (cont.)
Aqueous Preparations
e.g. Syrup solution of water and sugar
to which the drug is added. Flavoring may be
added to eliminate the bitter taste of the
drug.
Alcoholic Preparations
e.g. elixirs, spirits, tinctures and fluid
extracts are dissolved in alcohol, usually in
the range of 5 to 20%


DRUG FORMS (cont.)
Solid and Semisolid Preparations
Powders are drugs or drug extracts that
are dried and ground into fine particles.
Tablets drug powders that have been
compressed into a convenient form for
swallowing. They usually disintegrate in
the stomach more rapidly than most
other solid preparations.
Troches and Lozenges flattened tablets
that are allowed to dissolve in the
mouth. They are commonly used for
colds and sore throat.

DRUG FORMS (cont.)
Capsules Gelatin capsules are used to
administer drug powders or liquids and
dissolve in the stomach, thereby
releasing the drug.
Delayed-Release Products are usually
tablets or capsules that are treated with
special coatings so that various portions
of the drug will dissolve at different
rates. They usually contain the
equivalent of two or three single-dose
unit and are designed to produce drug
effects over an extended time.

DRUG FORMS (cont.)
Enteric-Coated Products used for drugs
that are irritating to the stomach or that
are inactivated by gastric juices. The
drug tablet or capsule is coated with an
acid-resistant substance that will dissolve
only in the less acidic environment of the
intestines. They should taken on an
empty stomach with water, either 1 hour
before or 2 hours after meals.
Suppositories these are drugs mixed
with a substance (cacao butter) that will
melt at body temperature.

DRUG FORMS (cont.)
Ointments or salves are soft, oily
substances (petrolatum or lanolin)
containing a drug that is applied to the
skin, or in the case of ophthalmic
ointments, to the eye.
Transdermal Products administered
through a bandage or patch system
where the drug is released and is then
absorbed through the skin into the
systemic circulation. This provides a
continuous source of the drug over 24
hours or more.

ROUTES OF ADMINISTRATION
ORAL ADMINISTRATION
Safest, most convenient and most common
method
Requires 30 to 60 minutes before
significant absorption from the GI tract
occurs (onset of action is delayed)
Affected by the presence of food in the
stomach delay absorption
Can be removed within the first few hours
by lavage or inducing vomiting

ROUTES OF ADMINISTRATION
PARENTERAL ADMINISTRATION
Intramuscular injection, Intravenous
injection, intradermal injection,
subcutaneous injection, inhalation and
topical application
Drugs are prepared in various forms for
administration


Pharmaceutic

Disintegration and dissolution
Rate limiting
Pharmaceutics
Disintegration and dissolution
Rate limiting

DRUG ABSORPTION
Refers to the entrance of the drug into the
bloodstream.
In order for the drug to be absorbed, it
must be dissolved in body fluids and pass
through membranes of the GI lining and
blood vessels before they gain access to the
blood with the exception of IV or IA
administration.
DRUG ABSORPTION
DRUG ABSORPTION
Cells have special transport mechanisms
that allow various substances to pass
through the cell membrane.
These mechanisms include filtration,
passive transport, and active transport.
Most drugs move by passive transport by
law of diffusion.
The speed or rate of drug absorption also
depend on the chemical properties of the
drug (lipid solubility and degree of drug
ionization) and the site of administration.

DRUG ABSORPTION
DRUG ABSORPTION

DRUG ABSORPTION (cont.)
Lipid Solubility
Most drugs are primarily water-soluble
with the exception of general anesthetics
which are highly lipid-soluble.
Many water-soluble drugs are weak acids
or bases that can form charged particles
or ions (ionization) when dissolved in
body fluids.

DRUG ABSORPTION (cont.)
Drug Ionization
Most drugs exist in two forms, ionized
and un-ionized.
Ionized drugs are charged molecules
because their atomic structure has
lost or gained electrons and do not
readily cross the cell membrane.
Un-ionized drugs readily pass through
the cell membrane.

DRUG ABSORPTION (cont.)
Drug Ionization (cont.)
Generalizations:
1. Acid drugs (e.g. aspirin) are mostly un-ionized
when they are in an acidic fluid (e.g. gastric juice)
so that drug absorption is favored. If acid drugs
are in alkaline environment, they are ionized,
hence slowly absorbed and to a lesser extent.
2. Basic drugs (e.g. streptomycin, morphine) are
mostly un-ionized when they are in alkaline
medium (e.g. lower GI tract). If they are in acidic
medium (e.g. upper GI tract), they are ionized.
This the reason why morphine is usually
administered parenterally.

DRUG ABSORPTION (cont.)
Drug Ionization (cont.)
The acid and base nature of drugs may
be useful in treating drug toxicity
(overdose).
Drugs are generally excreted by the
kidneys in an ionized form. To increase
drug excretion, the pH of urine can be
altered (e.g. to increase the renal
excretion of an acid drug, the urine is
alkalinized and the same principle is
applied to alkaline drugs).

Drug Formulation
Liquid medications are generally
absorbed faster than solid forms.
Drug particles can be formulated into
different sizes, such as crystals,
micronized particles, or ultramicronized
particles. The smaller the size of the
drug particle, the faster the rate of
dissolution and absorption.

DRUG DISTRIBUTION
After the drug gains access to the blood, it
is distributed to the various tissues and
organs of the body.
Several factors determine how much drug
reaches any one organ or area of the body:
1. Plasma protein binding
2. Blood flow
3. Presence of specific tissue barriers

DRUG DISTRIBUTION (cont.)
Plasma Protein Binding
Several different proteins (albumin and
globulins) are in plasma and form a circulating
protein pool. The help regulate osmotic
pressure in the blood and transport many
hormones and vitamins.
Many drugs are attracted to the plasma
proteins especially to albumin. Only the free
(unbound) drugs can exert a pharmacological
effect.
Occasionally, there is competition between
drugs or other plasma substances for the same
protein binding site.

DRUG DISTRIBUTION (cont.)
Blood Flow
Organs such as the liver, kidneys and the brain
have the largest blood supply hence exposing
them to the largest amount of drug.
Other tissues such as adipose tissue receive a
relatively poor blood supply and do not
accumulate large amounts of drug (except for
highly lipid-soluble drugs).
Blood-Brain Barrier
This is an additional lipid barrier that protects
the brain by restricting the passage of
electrolytes and other water-soluble
substances.


DRUG METABOLISM
(Biotransformation)
Whenever a drug or other foreign
substance is taken into the body, the body
attempts to eliminate it.
Some drugs can be excreted in the same
chemical form in which they were
administered. Other drugs, however, must
be chemically altered before they can be
excreted by the kidneys.

DRUG METABOLISM (cont.)
The liver is the main organ involved in drug
metabolism.
Within its cells are a group of enzymes that
specifically function to metabolize foreign (drug)
substances. These enzymes are referred to as
drug microsomal metabolizing system (DMMS)
whose main function is to take lipid-soluble drugs
and chemically alter them so that they become
water-soluble compounds.
Although most drugs are inactivated by
metabolism, a few are initially converted into
pharmacologically active metabolites.

DRUG METABOLISM (cont.)
An interesting phenomenon occurs with some
drugs (especially barbiturates and other sedative-
hypnotic drugs). When taken repeatedly, they
stimulate the DMMS. The drug actually increases
the amount of enzymes in the system (enzyme
induction). Consequently, the duration of the
drug action is decreased for all drugs metabolized
by the microsomal enzymes.
On the other hand, other drugs can inhibit the
DMMS to cause enzyme inhibition. This will
increase the duration and intensity of the drug.
Enzyme induction and enzyme inhibition are
common causes of adverse drug reactions.

DRUG METABOLISM (cont.)
After oral administration , all drugs are absorbed
into the portal circulation, which transports the
drug to the liver before they are distributed
throughout the body.
Some drugs are metabolized significantly as they
pass through the liver this first time. This effect is
called first-pass effect/metabolism. It can
significantly reduce the amount of active drug that
reaches the general circulation.

DRUG EXCRETION
The common pathways of drug excretion are
renal, GI, and respiratory.
The kidneys are the most important organs for
drug excretion.
RENAL EXCRETION
In order for drug excretion to occur, the drug or
drug metabolite must be water soluble and
preferably in an ionized form.
GI EXCRETION
A small amount of drug that is unabsorbed and
excreted in the feces.
Another pathway involving the intestinal tract
is the enterohepatic pathway.

DRUG EXCRETION (cont.)
Certain drugs (fat-soluble) can enter the
intestines via the biliary tract. After the drug is
released into the intestines (in the bile) it may
be absorbed in the blood again (enterohepatic
cycle) thereby prolonging the duration of
action of the drug.
RESPIRATORY EXCRETION
Some drugs are metabolized to products that
can be exchanged from the blood into the
respiratory tract i.e. general anesthetic gases.
MISCELLANEOUS
Some drugs and its metabolites may be
detected in sweat, saliva, and milk.


HALF-LIFE
Is the time required for the blood plasma
concentration of the drug to fall to half of its
original level.
It is important in determining the frequency of
drug administration.
The major factors that determine half-life are the
rates of drug metabolism and excretion. It can be
prolonged when liver and kidney disease is
present.

BLOOD DRUG LEVELS
The intensity of drug effect is mainly determined
by the concentration of drug in the blood or
plasma (determined by pharmacokinetics).
Drug monitoring, the periodic measurement of
blood drug levels, is performed to ensure that the
level of the drug in the blood is within the
therapeutic range.
Drug levels below the therapeutic range will not
produce the desired effect, while levels above the
therapeutic range cause increased side effects and
toxicity.

BLOOD DRUG LEVELS (cont.)

1 2 3 4
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Time in hours
Onset of
Action
Termination
of Action
Minimal effective concentration
required to observe drug effect
Duration
of Action
T
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Maximal therapeutic concentration

BLOOD DRUG LEVELS (cont.)
There are some drugs that require several dosages
or several days or weeks to reach the desired drug
effect.
In some clinical situations it may be necessary to
reach therapeutic drug levels as rapidly as
possible. In these cases, a loading dose (an initial
higher dose of drug to rapidly attain the
therapeutic drug level and drug effects) may be
administered.
Loading doses are often followed by maintenance
doses (smaller and calculated doses to maintain
the drug level within the therapeutic range).

BIOAVAILABILITY
Is the percentage of the dose of a drug that
is actually absorb into the bloodstream.
Differences in drug formulation, route of
administration, and factors that affect GI
absorption can influence bioavailability.
The type of the drug may be the same but
the product may be different because of
particle size, binders, fillers, and tablet
coating. These differences may alter
bioavailability.

DRUG RECEPTORS &
PHARMACODYNAMICS

Therapeutic and toxic effects of drugs result
from their interactions with molecules in
the patient.
Most drugs act by associating with specific
macromolecules in ways that alter the
macromolecules biochemical or biophysical
activities.
Receptors have become the central focus of
investigation of investigation of drug effects
and their mechanisms of action
(pharmacodynamics). The receptor concept
has proved essential for explaining many
aspects of biologic regulation.


The receptor concept has important practical
consequences for the development of drugs and for
arriving at therapeutic decisions in clinical practice.
1. Receptors largely determine the quantitative
relations between dose or concentration of drug
and pharmacologic effects.
2. Receptors are responsible for selectivity of drug
action.
3. Receptors mediate the actions of pharmacologic
agonists and antagonists. (Some drugs, and many
natural ligands [an ion or molecule that binds to a
central metal atom to form a coordination complex],
regulate the function of receptor molecules as
agonists; this means that they activate the receptor
to signal as a direct result of binding to it.)


MACROMOLECULAR NATURE OF
DRUG RECEPTORS
Most receptors are proteins (structures of
polypeptides provide both the necessary
diversity and the necessary specificity of
shape and electrical charge).
Other than those receptors discovered by
predicted structure or sequence homology
to other (known) receptors and drugs that
bind to them, there are also orphan
receptors (ligands presently unknown) that
have been identified which can be useful
targets for the development of new drugs.

MACROMOLECULAR NATURE OF
DRUG RECEPTORS (cont.)
The best characterized drug receptors are
regulatory proteins, which mediate the actions of
endogenous chemical signals such as
neurotransmitters, autacoids (biologically active
amines), and hormones.
Other classes of proteins that have been clearly
identified as drug receptors include enzymes,
which may be inhibited (or less commonly,
activated) by binding a drug; transport proteins
(e.g. Na
+
, K
+
ATPase, the membrane receptor for
digitalis); and structural proteins (e.g. tubulin
which is a receptor for colchicine).

MACROMOLECULAR NATURE OF
DRUG RECEPTORS (cont.)
Three aspects of drug receptor function:
1. Receptors as determinant of the quantitative
relation between the concentration of a drug
and the pharmacologic response;
2. Receptors as regulatory proteins and
components of chemical signaling
mechanisms that provide targets for
important drugs; and
3. Receptors as key determinants of the
therapeutic and toxic effects of drugs in
patients.

RELATION BETWEEN DRUG
CONCENTRATION & RESPONSE

Concentration-Effect Curves &
Receptor Binding of Agonists
Responses to low doses of a drug usually increase
in direct proportion to dose.
As doses increase, however, the response
increment diminishes; finally dose may be reached
at which no further increase in response can be
achieved.
This relation resembles the mass action law, which
describes association between two molecules of a
given affinity. This suggests that drug agonists act
by binding to (occupying Occupancy Theory) a
distinct class of biologic molecules with a
characteristic affinity for the drug receptor.

CONCENTRATION-EFFECT CURVES

Receptor-Effector Coupling & Spare
Receptors
When a receptor is occupied by an agonist, the
resulting conformational change is only the first of
many steps usually required to produce a
pharmacologic response.
The transduction process that links occupancy of
receptors and pharmacologic response is termed
coupling. The relative efficiency of occupancy-
response coupling is partially determined by the
initial conformational change in the receptor; thus
the effect of full agonists can be considered more
efficiently coupled to receptor occupancy than can
the effects of partial agonists.


Receptor-Effector Coupling & Spare
Receptors (cont.)
Another factor that can contribute to occupancy-
response coupling is the concept of spare
receptors. They are said to be spare for a given
pharmacologic response if it is possible to elicit a
maximal biologic response at a concentration of
agonist that does not result in occupancy of the
full complement of available receptors.

COMPETITIVE & IRREVERSIBLE
ANTAGONISTS
Receptor antagonists bind to receptors but do not
activate them.
The primary action of antagonists is to prevent
agonists from activating receptors.
Some antagonists (inverse agonists) also reduce
receptor activity below basal levels observed in
the absence of bound ligand.
Antagonists are divided into two classes
depending on whether or not they reversibly
compete with agonists for binding to receptors.

In the presence of a fixed concentration of agonist,
increasing concentrations of a reversible competitive
antagonist progressively inhibit the agonist response;
high antagonist concentration prevent response
completely.
Conversely, sufficient high concentrations of agonist
can surmount the effect of a given concentration of
the antagonist.
Because of the competitive antagonism, the presence
of antagonist increases the agonist concentration
required for a given degree of response, and so the
agonist concentration-effect curve is shifted to the
right.
COMPETITIVE & IRREVERSIBLE
ANTAGONISTS


COMPETITIVE & IRREVERSIBLE
ANTAGONISTS (cont.)
This relationship has two therapeutic implications:
1. The degree of inhibition produced by a
competitive antagonist depends on the
concentration of antagonist.
2. Clinical response to a competitive antagonist
depends on the concentration of agonist that
is competing for binding to receptors.

COMPETITIVE & IRREVERSIBLE
ANTAGONISTS (cont.)
Some receptor antagonists bind to the receptor in
an irreversible or nearly irreversible fashion, either
by forming a covalent bond with the receptor or
by binding so tightly that the receptor is
unavailable for binding of agonist.
After occupancy of some proportion of receptors
by such an antagonist, the number of remaining
unoccupied receptors may be too low for the
agonist (even at high concentrations) to elicit a
maximal response.

MACROMOLECULAR NATURE OF
DRUG RECEPTORS (cont.)
The best characterized drug receptors are
regulatory proteins, which mediate the actions of
endogenous chemical signals such as
neurotransmitters, autacoids (biologically active
amines), and hormones.
Other classes of proteins that have been clearly
identified as drug receptors include enzymes,
which may be inhibited (or less commonly,
activated) by binding a drug; transport proteins
(e.g. Na
+
, K
+
ATPase, the membrane receptor for
digitalis); and structural proteins (e.g. tubulin
which is a receptor for colchicine).

MACROMOLECULAR NATURE OF
DRUG RECEPTORS (cont.)
The best characterized drug receptors are
regulatory proteins, which mediate the actions of
endogenous chemical signals such as
neurotransmitters, autacoids (biologically active
amines), and hormones.
Other classes of proteins that have been clearly
identified as drug receptors include enzymes,
which may be inhibited (or less commonly,
activated) by binding a drug; transport proteins
(e.g. Na
+
, K
+
ATPase, the membrane receptor for
digitalis); and structural proteins (e.g. tubulin
which is a receptor for colchicine).
COMPETITIVE & IRREVERSIBLE
ANTAGONISTS (cont.)
Antagonists can function noncompetitively in a
different way by binding a site on the receptor
protein separate from the agonist binding site and
thereby preventing receptor activation without
blocking agonist binding. Although these drugs
act noncompetitively, their actions are reversible if
they do not bind covalently.
Some drugs called allosteric modulators bind to a
separate site on the receptor protein and alter
receptor function without inactivating the
receptor.

PARTIAL AGONISTS
Based on the maximal pharmacologic
response that occurs when all receptors are
occupied, agonists can be divided in two
classes: partial agonists produce a lower
response, at full receptor occupancy, than
do full agonists.
It is important to emphasize that the failure
of partial agonists to produce a maximal
response is not due to decreased affinity for
binding to receptors. Rather, they
competitively inhibit the responses
produced by full agonists.



OTHER MECHANISMS OF DRUG
ANTAGONISM
Not all mechanisms of antagonism involve
interactions of drugs or endogenous ligands at a
single type of receptor, and some types of
antagonism do not involve a receptor at all.
A drug may act as chemical antagonist of the
other simply by ionic binding that makes the other
drug unavailable for interactions. (e.g. protamine
that is positively charges at physiologic pH can be
used to counteract the effects of heparin that is
negatively)


OTHER MECHANISMS OF DRUG
ANTAGONISM (cont.)
Another is physiologic antagonism between
endogenous regulatory pathways mediated by
different receptors (e.g. glucocorticoids may
increase blood sugar levels can be treated with
the use of insulin).
In general, use of a drug as a physiologic
antagonist produce effects that are less specific
and less easy to control than are the effects of a
receptor-specific antagonist.

SIGNALING MECHANISMS & DRUG ACTION
Why do some drugs produce effects that persist
for minutes, hours, or even days after the drug is
no longer present?
Why do responses to other drugs diminish rapidly
with prolonged or repeated administration?
How do cellular mechanisms for amplifying
external chemical signals explain the phenomenon
of spare receptors?
Why do chemically similar drugs often exhibit
extraordinary selectivity in their actions?
Do these mechanisms provide targets for
developing new drugs?

SIGNALING MECHANISMS & DRUG
ACTION (cont.)
Five basic mechanisms of transmembrane signaling
are well understood. Each uses a different strategy
to circumvent the barrier posed by the lipid bilayer
of the plasma membrane.
1. a lipid-soluble ligand that crosses the
membrane and acts on an intracellular
receptor;
2. A transmembrane receptor protein whose
intracellular enzymatic activity is allosterically
regulated by a ligand that binds to a site on
the proteins extracellular domain;
3. A transmembrane receptor that binds and
stimulates a tyrosine kinase;

SIGNALING MECHANISMS & DRUG
ACTION (cont.)
4. a ligand-gated transmembrane ion channel
that can be induced to open or close by the
binding of a ligand; or
5. a transmembrane receptor protein that
stimulated a GTP-binding signal transducer
protein (G protein), which in turn modulates
production of an intracellular second
messenger.


SIGNALING MECHANISMS & DRUG ACTION (cont.)
Intracellular Receptors for Lipid-Soluble Agents
Several biologic ligands (steroids and thyroid hormone)
are sufficiently lipid-soluble to cross the plasma
membrane and act on intracellular receptors that
stimulate the transcription of genes by binding to
specific DNA sequences (response elements) near the
gene whose expression is to be regulated.
The mechanism used by hormones that act on gene
expression has two therapeutically important
consequences:
1. All of these hormones produce their effects after a
characteristic lag period of 30 minutes to several hours
the time required for synthesis of new proteins.
2. The effect of these agents can persist for hours or days
after the agonist concentration has been reduced to zero
and is primarily due to the relatively slow turnover of most
enzymes and proteins, which can remain active in cells for
hours or days after they have been synthesized.

SIGNALING MECHANISMS & DRUG ACTION
Why do some drugs produce effects that persist
for minutes, hours, or even days after the drug is
no longer present?
Why do responses to other drugs diminish rapidly
with prolonged or repeated administration?
How do cellular mechanisms for amplifying
external chemical signals explain the phenomenon
of spare receptors?
Why do chemically similar drugs often exhibit
extraordinary selectivity in their actions?
Do these mechanisms provide targets for
developing new drugs?
SIGNALING MECHANISMS & DRUG ACTION (cont.)
Ligand-Regulating Transmembrane Enzymes
including Receptor Tyrosine Kinases
This class of receptor molecules mediates the first step in
signaling by insulin, epidermal growth factor, platelet
derived growth factor, atrial natriuretic peptide,
transforming growth factor-B, and other tropic hormones.
These receptors are polypeptides consisting of extracellular
hormone-binding domain and cytoplasmic enzyme domain,
which may be a protein tyrosine kinase, serine kinase, or a
guanylyl cyclase.
In all these receptors, the two domains are connected by a
hydrophobic segment of polypeptide that crosses the lipid
bilayer of the plasma membrane. The receptors convert
from its monomeric form to a dimeric form. The
cytoplasmic domains become phosphorylated on specific
tyrosine residue and their enzymatic activities are activated,
catalyzing phosphorylation of substrate protein.


SIGNALING MECHANISMS & DRUG ACTION
Why do some drugs produce effects that persist
for minutes, hours, or even days after the drug is
no longer present?
Why do responses to other drugs diminish rapidly
with prolonged or repeated administration?
How do cellular mechanisms for amplifying
external chemical signals explain the phenomenon
of spare receptors?
Why do chemically similar drugs often exhibit
extraordinary selectivity in their actions?
Do these mechanisms provide targets for
developing new drugs?
The intensity and duration of action of EGF,
PDGF and other agents that act via receptor
tyrosine kinases are limited by a process called
receptor down-regulation. Ligand binding
often induces accelerated endocytosis of
receptors from the cell surface, followed by
the degradation of those receptors (and their
bound ligands) thus leading to reduced cell-
surface receptors (down-regulated), and the
cells responsiveness to ligand is
correspondingly diminished.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Cytokine Receptors
Respond to a heterogenous group of peptide ligands,
which include growth hormone, erythropoietin, several
kinds of interferon, and other regulators for growth
and differentiation.
These receptors use a mechanism resembling that of
receptor tyrosine kinase except that the protein
tyrosine kinase activity is not intrinsic to the receptor
molecule. Instead, a separate protein tyrosine kinase,
from the Janus-Kinase (JAK) family, binds noncovalently
to the receptor.

Cytokine receptors dimerize after binding the activating ligand,
allowing the bound JAKs to become activated and to
phosphorylate tyrosine residues on the receptors cytoplasmic
surface, then set in motion a complex signaling dance by binding
another set of proteins, called STATs (signal transducers and
activators of transcription). The bound STATs are themselves
phosphorylated by the JAKs, two STAT molecules dimerize, and
finally the dimer dissociates from the receptor and travels to the
nucleus, where it regulates transcription of specific genes.


SIGNALING MECHANISMS & DRUG ACTION (cont.)
Ligand- and Voltage-Gated Channels
Many of the most useful drugs in clinical medicine act
by mimicking or blocking the actions of endogenous
ligands that regulate the flow of ions through plasma
membrane channels.
The natural ligands are acetylcholine, serotonin, GABA,
and glutamate. All of these agents are synaptic
neurotransmitters.
Each of their receptors transmits its signal across
plasma membrane by increasing transmembrane
conductance of the relevant ion and thereby altering
the electrical potential across the membrane.
The time elapsed between the binding of the agonist
to a ligand-gated channel and the cellular response can
often be measured in milliseconds.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Ligand- and Voltage-Gated Channels (cont.)
The rapidity of this signaling mechanism is crucially
important for moment-to-moment transfer of
information across synapses.
Ligand-Gated ion channels can be regulated by
multiple mechanisms including phosphorylation and
endocytosis. In the nervous system, these mechanisms
contribute to synaptic plasticity involved in learning
and memory.
Voltage-Gated ion channels do not bind
neurotransmitters directly but are controlled by
membrane potential; such channels are also important
drug targets.



SIGNALING MECHANISMS & DRUG ACTION (cont.)
G Proteins & Second Messengers
Many extracellular ligands act by increasing the
intracellular concentrations of second messengers such
as cAMP, calcium ions, or the phosphoinositides.
In most cases, they use a transmembrane signaling
system and detects an extracellular ligand by a cell-
surface receptor which in turn activates a G protein
(guanine nucleotide-binding proteins which are a
family of involved in transmitting chemical signals
outside the cell, and causing changes inside the cell).
The G protein then changes the activity of an effector
element, usually an enzyme or ion channel, which in
turn changes the concentration of intracellular second
messenger (are molecules that relay signals from
receptors on the cell surface to target molecules inside
the cell, in the cytoplasm or nucleus).

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Receptor Regulation
G protein-mediated responses to drugs and hormonal
agonists often attenuate with time. After reaching an
initial high level, the response diminishes over seconds
or minutes, even in the continued presence of the
agonist. This desensitization is often rapidly
reversible; second exposure to agonist, if provided a
few minutes after termination of the first exposure,
results in a response similar to the initial response.



SIGNALING MECHANISMS & DRUG ACTION (cont.)
Well-Established Second Messengers
A. Cyclic Adenosine Monophosphate
Mediates such hormonal responses as the
mobilization of stored energy, conservation of
water by the kidney, Calcium homeostasis, and
increased rate and contractile force of hear
muscle.
It also regulates the production of adrenal and
sex steroids, relaxation of smooth muscle and
many other endocrine and neural processes.
It exerts most of its effects by stimulating
cAMP-dependent protein kinases to release
active catalytic chains that diffuse through the
cytoplasm and nucleus where they transfer
phosphate from ATP to appropriate substrate
proteins, often enzymes.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Well-Established Second Messengers (cont.)
A. Cyclic Adenosine Monophosphate (cont.)
When the hormonal stimulus stops, the
intracellular actions of cAMP are terminated by
elaborate series of enzymes.
cAMP-stimulated phosphorylation of enzyme
substrates is rapidly reversed by a diverse group
of specific and nonspecific phosphatases.
cAMP is degraded to 5-AMP by several
nucleotide phosphodiesterases.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Well-Established Second Messengers
B. Calcium and Phosphoinositides
Some of the hormones, neurotransmitters, and
growth factors that trigger phosphoinositide
hydrolysis bind to receptors linked to G
proteins, whereas others bind to receptor
tyrosine kinases.
In all cases, the crucial step is stimulation of a
membrane enzyme, phospholipase C (PLC),
which splits a minor phospholipid component
of the plasma membrane, phosphatidylinositol-
4,5-biphosphate (PIP
2
), into two second
messengers, diacylglycerol (DAG) and inositol-
1,4,5-triphosphate (IP
3
or InsP
3
).

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Well-Established Second Messengers (cont.)
B. Calcium and Phosphoinositides (cont.)
DAG is confined to the membrane where it
activates a phospholipid- and calcium-sensitive
protein kinase called protein kinase C.
IP
3
is water-soluble and diffuses through the
cytoplasm to trigger release of Ca
2+
by binding
to ligand-gated

calcium channels in the limiting
membranes of internal storage vesicles.
Elevated cytoplasmic Ca
2+
concentration
resulting from IP
3
promoted opening of these
channels promotes the binding of Ca
2+
to the
calcium-binding protein calmodulin, which
regulates activities of other enzymes, including
calcium-dependent protein kinases.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Well-Established Second Messengers (cont.)
C. Cyclic Guanosine Monophosphate (cGMP)
Has established signaling roles in only a few cell
types. In intestinal mucosa and vascular
smooth muscle, the cGMP-based signal
transduction mechanism closely parallels the
cAMP-mediated signaling mechanism. Ligands
detected by cell-surface receptors stimulate
membrane-bound guanylyl cyclase to produce
cGMP, and cGMP acts by stimulating cGMP-
dependent protein kinase. The actions of
cGMP in these cells are terminated by
enzymatic degradation of the cyclic nucleotide
and by dephosphorylation of kinase substrates.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Interplay among Signaling Mechanisms
The calcium-phosphoinositide and cAMP
signaling pathways oppose one another in
some cells and are complementary to others.
e.g. vasopressor agents that contract smooth
muscle act by IP
3
-mediated mobilization of
Ca
2+
, wheras agents that relax smooth muscle
often act by elevation of cAMP. In contrast
cAMP and phosphoinositide second
messengers act together to stimulate glucose
release from the liver.

SIGNALING MECHANISMS & DRUG ACTION (cont.)
Phosphorylation
Almost all second messenger signaling involves reversible
phosphorylation, which performs two principal functions in
signaling: amplification and flexible regulation.
Amplification
The initial regulatory is powerfully amplified by
recording a molecular memory that the pathway has
activated; dephosphorylation erases the memory.
Flexible regulation
Differing substrate specificities of the multiple protein
kinases regulated by second messengers provide
branch points in signaling pathways that may be
independently regulated. In this way, other second
messengers can use the presence or absence of
particular kinases or kinase substrates to produce
different effects in different cell types.

RECEPTOR CLASSES & DRUG
DEVELOPMENT

The existence of a specific drug receptor is usually inferred from
studying the structure-activity relationship of a group of
structurally similar congeners of the drug that mimic or
antagonize its effects.
Thus, if a series of related agonists exhibits identical relative
potencies in producing two distinct effects, it is likely that the
two effects are mediated by similar or identical receptor
molecules.
In addition, if identical receptors mediate both effects, a
competitive antagonist will inhibit both responses with the
same dissociation constant; a second competitive antagonist will
inhibit both responses with its own characteristic dissociation
constant.
Thus, studies of the relation between structure and activity of a
series of agonists and antagonists can identify a species of
receptor that mediates a set of pharmacologic responses.


Exactly the same experimental procedure can show that
observed effects of a drug are mediated by different receptors.
In this case, effects mediated by different receptors may exhibit
different orders of potency among agonists and different
dissociation constant values for each competitive antagonist.

New drug development is not confined to agents that act on
receptors for extracellular chemicals. Pharmaceutical chemists
are now determining whether elements of signaling pathways
distal to the receptors may also serve as targets of selective and
useful drugs. For example, clinically useful agents might be
developed that act selectively on specific G proteins, kinases,
phosphatases, or the enzyme that degrade second messengers.

RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE
When faced with a patient who needs treatment, the
prescriber must make a choice among a variety of
possible drugs and device a dosage regimen that is
likely to produce maximal benefit and minimal
toxicity.
To make rational therapeutic decisions, the prescriber
must understand how drug-receptor interactions
underlie the relations between dose and response in
patients, the nature and cause of variation in
pharmacologic responsiveness, and the clinical
implications of selectivity of drug action.

RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Dose & Response in patients
A. Graded Dose-Response Relations
To choose among drugs and to determine appropriate
doses of a drug, the prescriber must know the relative
pharmacologic potency and maximal efficacy of the drugs
in relation to the desired therapeutic effect.


RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Dose & Response in patients (cont.)
B. Shape of Dose-Response Curves
Although the responses depicted in curves A, B and C
represent the drugs potency and efficacy, some clinical
responses do not. Extremely steep dose-response
curves (e.g. curve D) may have important clinical
consequences if the upper portion represents an
undesirable extent of response (e.g. coma caused by
sedative-hypnotic).
Steep dose-response curves in patients can result from
cooperative interactions of several different actions of a
drug (e.g. effects on brain, heart, and peripheral
vessels, all contributing to lowering of blood pressure).



RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Dose & Response in patients (cont.)
B. Shape of Dose-Response Curves (cont.)


RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
Dose & Response in patients (cont.)
C. Quantal Dose-Effect Curves
Determining the dose of drug required to produce a
specified magnitude of effect in a large number of individual
patients and plotting the cumulative frequency distribution
of responders versus the log dose aids in clinical decision
making rather than the Graded Dose-Response Relations.
The specified quantal effect may be chosen on the basis of
clinical relevance (e.g. relief of headache) or for preservation
of safety of experimental subjects (e.g. using low dose of
cardiac stimulant and specifying an increase in heart rate of
20bpm as the quantal effect), or it may be an inherently
quantal event (e.g. death of an experimental animal). In
addition to potency, selectivity and maximal efficacy, this
curve indicates the potential variability of responsiveness
among individuals.

RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
Dose & Response in patients (cont.)
C. Quantal Dose-Effect Curves



RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Variation in Drug Responsiveness
A single individual may respond differently to the
same drug at different times during the course of
treatment.
Occasionally, individuals exhibit an unusual or
idiosyncratic drug response, one that is
infrequently observed in most patients. They are
usually caused by genetic differences in
metabolism of the drug or by immunologic
mechanisms, including allergic reactions.

RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Variation in Drug Responsiveness (cont.)
Quantitative variations in drug response are in general
more common and more clinically important. An
individual patient is hyporeactive or hyperreactive to a
drug in that the intensity of effect of a given dose of
drug is diminished or increased compared with the
effect seen in most individuals.
With some drugs, the intensity of response to a given
dose may change during the course of therapy; in
these cases, responsiveness usually decreases as a
consequence of continued administration, producing a
state of tolerance to the drugs effect.

RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Variation in Drug Responsiveness (cont.)
When responsiveness diminishes rapidly after
administration of a drug, the response is subject to
tachyphylaxis.
Even before administering the first dose of a drug, the
prescriber should consider factors that may help in
predicting the direction and extent of possible
variations in responsiveness. These include the
propensity of a drug to produce tolerance or
tachyphylaxis as well as the effects of age, sex, body
size, disease state, genetic factors, and simultaneous
administration of other drugs.

RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE (cont.)
Variation in Drug Responsiveness (cont.)
Four general mechanisms may contribute to variation
in drug responsiveness among patients or within an
individual patient at different times.
A. Alteration in Concentration of Drug that reaches the
Receptor
B. Variation in Concentration of an Endogenous
Receptor Ligand
C. Alterations in number or function of Receptors
D. Changes in Components of Response distal to the
Receptor

RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
(cont.)
Variation in Drug Responsiveness (cont.)
A. Alteration in Concentration of Drug That Reaches the
Receptor
Patients may differ in the rate of absorption, distribution
and excretion. By altering the concentration of drug that
reaches relevant receptors, these differences may alter the
clinical response. Some differences can be predicted on the
basis of age, sex, weight, disease state, and liver and kidney
function, and by testing specifically for genetic differences
that may result from inheritance of a functionally distinctive
complement of drug-metabolizing enzymes.
Another important mechanism is the active transport of
drug from the cytoplasm, mediated by a family of
membrane transporters encoded by the so-called multi drug
resistance (MDR) genes.


RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
(cont.)
Variation in Drug Responsiveness (cont.)
B. Variation in Concentration of an Endogenous Receptor Ligand
e.g. Saralasin, a weak partial agonist at angiotensin II receptors, lowers
blood pressure in patients with hypertension caused by increased
angiotensin II production and raised blood pressure in patients who
produce normal amounts of angiotensin.
C. Alterations in Number or Function of Receptors
Increase or decrease in the number of receptor sites or alteration in the
efficiency of coupling of receptors to distal effector mechanisms changes
the drug response.
In some cases, the change in receptor number is caused by other
hormones or the agonist ligand itself induces a decrease in the number
or coupling efficiency of the receptors. These mechanisms contribute to
two clinically important phenomena: first, tachyphylaxis or tolerance to
the effects of some drugs, and second, the overshoot phenomena (a
signal or function exceeds the steady state value) that follows
withdrawal of certain drugs.

RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
(cont.)
Variation in Drug Responsiveness (cont.)
C. Alterations in Number or Function of Receptors (cont.)
Genetic factors also play a role in altering the number or
function of specific receptors. The identification of these
factors holds promise for clinical diagnosis and may help the
physician design the most appropriate pharmacologic therapy
for individual patients.
D. Changes in Components of Response Distal to the Receptor
The response observed in patients depend on the functional integrity of
biochemical processes in the responding cell and physiologic regulation
by interacting organ systems.
Clinically, changes in these postreceptor processes represent the largest
and most important class of mechanisms that cause variation in
responsiveness to drug therapy.

RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE
(cont.)
Variation in Drug Responsiveness (cont.)
D. Changes in Components of Response Distal to the Receptor
(cont.)
Before initiating therapy with a drug, the prescriber should be aware of
patient characteristics that may limit the clinical response which include
the age and general health of the patient, and most importantly the
severity and pathophysiologic mechanism of the disease.
A wrong or incomplete diagnosis are important potentials for failure.
Drug therapy is always most successful when it is accurately directed at
the pathophysiologic mechanism responsible for the disease.
When the diagnosis is correct and the drug is appropriate, an
unsatisfactory therapeutic response can often be traced to compensatory
mechanisms in the patient that respond to and oppose the beneficial
effects of the drug (e.g. increased sympathetic nervous tone and fluid
retention by the kidneys contribute to tolerance the antihypertensive
effect of vasodilators). In such cases, additional drugs may be required.

CLINICAL SELECTIVITY: BENEFICIAL VS. TOXIC
EFFECTS OF DRUGS
No drug causes only a single, specific effect. It is
unlikely that any kind of drug molecule will bind to
only a single type of receptor molecule because the
number of receptors are astronomically large.
Drugs are only selective because they bind to one or a
few types of receptor more tightly than to others and
because these receptors control discrete processes
that result in distinct effects.