GENERAL PHARMACOLOGY

Introduction
Mechanisms of drugs action
MAIN DEFINITIONS
PHARMACOLOGY
the study of the interactions of chemicals with living
systems
the study of the effects of drugs on the function
of living systems
the science concerned with drugs, their sources,
appearance, chemistry, actions, and uses
TOXICOLOGY
the study of undesirable effects of chemical agent
on living systems
an area of pharmacology
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MAIN DEFINITIONS
DRUG
substances that act on living systems at the chemical
(molecular) level
chemical substance of known structure, which, when
administered to a living organism, produces a
biological effect
therapeutic agent; any substance, other than food,
used in prevention, diagnosis, alleviation, treatment
or cure of disease
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MAIN DEFINITIONS

PHARMACODYNAMICS
the actions of drug on the body, including receptors
interactions, dose-response phenomena,
and mechanisms of therapeutic and toxic action
the study of uptake, movement, binding, and
interactions of pharmacologically active molecules
at their tissue site(s) of action
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MAIN DEFINITIONS

PHARMACOKINETICS
the actions of the body on the drug, including
absorption, distribution, metabolism, and excretion
movements of drugs within biologic systems,
as affected by uptake, distribution, binding,
elimination and biotransformation; particularly
the rates of such movements
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RECEPTORS
Receptors specific molecules (protein) in a biologic
system with which endogenous substance (or drug)
interacts to produce changes in the function of the
system
receptors recognize substances and response to stimuli
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AGONIST
Ion channel modulation
Enzyme activation/inhibition
Ion channel opening/closing
DNA trancription
Transduction
mechanisms
Direct
ANTAGONIST No effect
Endogenous mediators
blocked
down-regulation phenomenon
the process of decreasing the
number and/or sensitivity of
the receptors during the
treatment with agonist
sometimes also blind
receptors are synthesized
up-regulation phenomenon
the process of increasing the
number and/or sensitivity of
the receptors during the
administration of antagonist

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DRUG INTERACTION WITH RECEPTORS
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[R] + [DAg]
k
+1

[RDAg]
[RDAg*]
EFFECT
k
-1

[R] receptor
[DAg] drug-agonist
[DAn] drug-antagonist
[RDAg] or [RDAn] drug-receptor complex
[RDAg*] activated form of occupied receptor
k
+1
binding constant
k
-1
dissociation constant
/ equilibrium constant


[R] + [DAn]
k
+1

[RDAn]
k
-1

NO EFFECT
DRUG INTERACTION WITH RECEPTORS
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allosteric activator
allosteric inhibitor
A
B
C
D
DRUG
agonist
antagonist/
competitive inhibitor
RECEPTOR EFFECTS
R
e
s
p
o
n
s
e

Log dose
A + C
A
A + B
A + D
+
-
+
-
EFFECT
B
DRUG INTERACTION WITH RECEPTORS
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EFFECT
dose log
0%

50%

100%
full agonist activates fully
its receptor (high efficacy)
partial agonist produces
a smaller effect at full dosage than
a full agonist (intermediate efficacy)
antagonist binds to its receptor
without activating it (efficacy = 0)
inverse agonist binds to the
receptor and decreases the rate of
signal transduction
DRUG INTERACTION WITH RECEPTORS
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TWO-STATE MODEL
R R*
receptor
in resting state
receptor
in activated state
EFFECT
INVERSE
AGONIST
AGONIST
ANTAGONIST
DRUG INTERACTION WITH RECEPTORS
antagonist: / = 0
agonist: / > 0
different for different drugs
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/ small only small proportion
of occupied receptors are activated
even when occupancy approaches 100%
/ large most of the
occupied receptors are activated
/ a measure of EFFICACY
DRUG INTERACTION WITH RECEPTORS
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Bond type Characteristics
van der Waals
weak polar;
very important in pharmacology
hydrogen
weak polar;
between hydrogen donors and acceptors
ionic (electrostatic)
electrostatic bond;
between cations and anions, pH dependent;
very important in pharmacology
covalent (esther, ether,
tioether, amid type etc.)
strong;
between pairs of electrons
chelate
a kind of covalent bond;
metal atom is bond between a few groups of atoms
change in heart rate
(beats/min)
E
max

drug dose (mg)
100
50
EC
50

5 10 20 15 500
DOSE-RESPONSE CURVE
drug effect against increasing concentration of a drug
to determine the particular drug action
(pharmacodynamic properties)
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DOSE-RESPONSE AND DOSE-BINDING CURVES
the same data on semilogarithmic axes
one division means ten time higher dose
a sigmoid curve
simplifies the mathematical manipulation of the dose-response data
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100
0,5 5 500 50
50
c
h
a
n
g
e

i
n

h
e
a
r
t

r
a
t
e

(
b
e
a
t
s
/
m
i
n
)

EC
50

E
max

dose (log scale)
100
0,5 5 500 50
50
P
e
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n
t

o
f

r
e
c
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p
t
o
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s

b
o
u
n
d

K
d

B
max

dose (log scale)
SPARE RECEPTORS
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100
0,5 5 500 50
50
P
e
r
c
e
n
t

o
f

m
a
x
i
m
u
m

EC
50

Drug
effect
dose (log scale)
K
d

Drug
binding
SPARE RECEPTORS
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duration
of receptors
activation
duration
of drug-receptor
interaction
actual number
of receptors
number of available
effector molecules
or second messanger system
>
>
FEATURES OF RECEPTORS
protein, lipoprotein, glycoprotein; one or more subunits
different tissue distributions
drug binding is usually reversible and stereoselective
specificity of binding not absolute; nonspecific effects
saturable (limited number)
agonist activation results in signal transduction
may require more than one drug molecule to be activated
magnitude of signal depends on degree of binding
signal can be amplified by intracellular mechanisms
drugs can enhance, diminish, or block signal generation or
transmission
can be up regulated or down regulated

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25
20
15
10
5
1 4 16 64 256
Percent
individuals
responding
Dose (log scale)
[mg]
[%]
QUANTAL DOSE-RESPONSE
is defined, when the minimum dose required
to produced a specified response is determined
in each member of a population.
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100
50
1,25 10 2,5 5 20 40 80 160 320 640 1280
Percent
individuals
responding
Cumulative percent
exhibiting
therapeutic effect
Cumulative
percent dead at
each dose
Percent requiring
dose for a lethal
effect
Percent
requiring dose
to achieve
desired effect
ED
50
LD
50

Dose (mg)
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DOSES
pharmacological effect of drug depends on a dose

subtherapeutical doses do not exert any effect
the lowest dose exerting the desired effects is called
minimal dose
with increasing dose also therapeutic effect
increases up to maximal tolerated dose/minimal
toxic dose
in this range are effective doses (ED)
over minimal toxic dose are the range of toxic doses
(TD) up to lethal dose (LD)
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DOSES
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effect
dose or concentration (log scale)
E
max
subtherapeutic
therapeutic window
toxic
lethal
minimal
therapeutic
maximal
therapeutic

minimal
toxic
maximal
toxic

minimal
lethal
AFFINITY, EFFICACY, POTENCY
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K
d
= 5.0
B
max

100 %
50 %
B
max

RD

RD

C

0 5 10
0,5 5 500 50
20
50 %
100 %
K
d
= 5.0
C (log scale)

30
Kd the concentration of drug resulting in 50% receptors binding
AFFINITY, INTRINSIC ACTIVITY
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AFFINITY
tendency of a drug
to bind to the receptors
INTRINSIC
ACTIVITY
ability of a drug
to activate the receptors
AFFINITY
high affinity = low Kd
low affinity = high Kd
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0 5 10
50 %
100 %
20
C

RD

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affinity:
> >
EFFICACY, POTENCY
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the amount of a drug
needed to produce given
effect (usually 50% of the
maximal effect EC
50
)
EFFICACY POTENCY
maximal effect (E
max
)
an agonist can produce
if the dose is taken
to very high levels
determined by
intrinsic activity
determined by
the affinity for the receptor
EFFICACY AND POTENCY
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effect
log of dose
drug A drug B
drug C
drug D
AFFINITY AND POTENCY
Drugs of high potency will generally have a high affinity
for the receptors and thus occupy a significant
proportion of the receptors even at low concentrations.


Affinity herself doesnt tell anything about drugs effect.
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RECEPTORS VS. DRUG TARGETS
Drug targets any target molecule with which
a drug molecule has to combine in order to elicit
its specific effect
receptors
enzymes
ion channels
carrier molecules (transporters)
others (e.g. tubuline)

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ENZYMES
drug molecule is a substrate analogue
acts as a competitive inhibitor of the enzyme
binding may be also irreversible and non-competitive
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Pro-drug
False
substrate
Inhibitor
Abnormal metabolite
produced
Active drug produced
Normal reaction inhibited
ION CHANNELS
also known as ligand-gated ion channels or ionotropic
receptors
open when their receptor is occupied by an agonist
drugs can also affect ion channel directly
drug binds to the channel protein and alters its function
the action of local anaesthetics on the voltage-gated
sodium channel
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Blockers
Modulators
Permeation blocked
Increased or decreased
opening probability
CARRIER MOLECULES
transport of ions and small organic molecules across
cell membranes generally requires a carrier protein
some drugs act through changes in carrier
molecules activity
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Normal
transport
Inhibitor
or
Transport
blocked
False substrate
Abnormal
compound
accumulated
RECEPTORS TRANSDUCTION
signal have to be translated into cellular effects
by transduction mechanisms
some of this effect can be very rapid
e.g. cell membrane depolarization
some could last for days
e.g. protein synthesis
according to structure and transduction mechanism four
receptors superfamilies may be distinguished
ionotropic receptors
G-protein-coupled receptors (metabotropic receptors)
kinase-linked and related receptors
nuclear receptors
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Type 1
ligand-gated ion
channels
Type 2
G-protein-
coupled
receptors
Type 3
receptor kinases
Type 4
nuclear
receptors
Location Membrane Membrane Membrane Intracellular
Effector Ion channel
Channel
or enzyme
Protein kinases
Gene
transcription
Coupling direct G-protein direct via DNA
Examples
nicotinic
acetylcholine
receptor, GABA
A

receptor
muscarinic
acetylcholine
receptor,
adrenoceptors
insulin, growth
factors, cytokine
receptors
steroid receptors
Structure
oligomeric
subunits
surrounding
central pore
monomeric
dimericor with
seven
transmembrane
helices
single
transmembrane
helix
monomeric
structure;
receptor- and
DNA-binding
domains
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R
Ions
Hyperpolarisation
or
depolarisation
Cellular effects
R E
R/E
Ions
Change in
excitability
G
+ or- or- +
G
Second messengers
Ca
2+

release
Protein
phosophorylation
Cellular effects
Protein
phosphorylation
R
Gene
transcrpition
Protein
synthesis
Ligand-gated ion
channels
(ionotropic receptors)
G-protein-coupled
receptors
(metabotropic)
Kinase-linked
receptors
Nuclear receptors
Nucleus
other
Cellular effects Cellular effects
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DRUG-DRUG INTERACTIONS
INTERACTION influence of one drug on another one

in modern pharmacology very common
is administrations of more than one drug
moreover, patient takes a lot of OTC drugs
possible are also interactions between drugs
and environmental factors (e.g. heavy metals)
may be changed both: the effect of drug or the
durations of action
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POSITIVE NEGATIVE
DRUG-DRUG
INTERACTIONS
PHARMACEUTIC
PHARMACODYNAMIC
PHARMACOKINETIC
chemical
or physicochemical
incompatibilities
changes of the
effects or duration
of action
impact of one drug on
the movement of other
drug in the organism
SYNERGISM ANTAGONISM
on the level of: absorption,
protein binding, distribution,
biotransformation, excretion
PHARMACODYMAMIC INTERACTIONS
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Dose of drug A
D
o
s
e

o
f

d
r
u
g

B

antagonism
synergism
additive
hyperadditive
relative
absolute
SYNERGISM
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ADDITIVE
HYPERADDITIVE
(potentialization*)
action of two drugs together
is equal to the action
of each drug alone
the same binding site various binding sites
action of two drugs together
is better than the action
of each drug alone
CLINICALLY
IMPORTNANT
CLINICALLY
UNIMPORTNANT
ANTAGONISM
the effect of one drug is diminished or completely
abolished in the presence of another
competitive
equilibrium (reversible)
non-equilibrium (irreversible)
non-competitive
functional antagonism (physiologic)
chemical antagonism

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COMPETITIVE ANTAGONISM
reversible (or equilibrium) competitive antagonism
is the most common and most important type of
antagonism
the drug in higher concentration or with higher
affinity may displace onother drug
a drug binds selectively to a particular type of
receptor without activating it, but in such a way as
to prevent the binding of the agonist
two substances competee for the same receptor site
examples
acetylcholine and atropine
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COMPETITIVE ANTAGONISM
irreversible (non-equilibrium), competitive
antagonism takes place when:
the antagonist dissociates very slowly, or not at all,
from the receptors no change in the antagonist
occupancy takes place when the agonist is applied
when the amount of antagonist is adequate high NO
AMOUNT of agonist can produce any response
example:
phenoxybenzamine (-receptor antagonist) and
norepinephrine
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effect
dose log
agonist
agonist + reversible
antagonist
agonist +
irreversible
antagonist

or non-
competitive
COMPETITIVE ANTAGONISM
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NONCOMPETITIVE ANTAGONISM
antagonist blocks at some point the chain of events
that leads to the production of a response by the
agonist
act at a site beyond the receptor for agonist
as a rule, the effect will reduce the slope and E
max

of the agonist log concentration-response curve
(similar to competitive irreversible antagonism)
the difference is in SPECIFICITY
noncompetitive more than one receptor systems
nonequilibrium-competitive only one receptor system
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CHEMICAL ANTAGONISM
chemical antagonism refers to the uncommon
situation where the two substances interact before
reaching the target
as a result, the effect of the active drug is lost
(inactivation)
if such situation is outside the body = incompatibility
examples:
the use of dimercaprol that bind to heavy metals
and thus reduce their toxicity
the use of neutralizing antibodies against proteins
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FUNCTIONAL = OR PHYSIOLOGICAL ANTAGONISM
two drugs exert an opposite action on two different
receptors in the same organ (functional) or even in
two different organs (physiological)
example:
histamine acts on receptors of the parietal cells of the
gastric mucosa to stimulate acid secretion, while
omeprazole blocks this effect by inhibiting the
proton pump
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PHARMACOKINETIC ANTAGONISM =
PHARMACOKINETIC INTERACTION
the antagonist effectively reduces the concentration
of the active drug at its site of action
this can happen in various ways by affecting
pharmacokinetic processes such as absorption,
protein binding, distribution, metabolism, excretion
example
phenobarbital is a potent microsomal enzymes
activator and thus it can accelerate hepatic
metabolism of many drugs
salicylates may displace many drugs from their
binding with albumins
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PHARMACOKINETIC INTERACTIONS
on the level of drug absorption
absorbance of drug on the surface
formation of nonabsorbable complexes
changes in surface tension
changes in pH of gastrointestinal fluids
competition for the same transporters
changes in gastrointestinal motility
influence on OATP systems or P-glycoprotein activity
changes in blood vessels dilation
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PHARMACOKINETIC INTERACTIONS
on the level of protein binding
displacement of drugs from binding sites on albumins
or more specific proteins
changes in sorpitve properties of proteins
mainly by changes in blood pH
on the level of membrane transport (distribution)
impact on passive diffusion
pH changes
changes in membranes permeability
impact on active transport
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PHARMACOKINETIC INTERACTIONS
on the level of biotransformation
enzymatic inducers
enzymatic inhibitors
on the level of excretion
changes in pH of urine
less important impact on GFR
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THERAPEUTIC INDEX (TI)
is the ratio of the TD
50
(or LD
50
) to the ED
50
,
determined from quantal dose-response curves



therapeutic index is intended to indicate the margin
of safety in use of a drug

better are:
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TI =
ED
50

TD
50
or LD
50

TI =
ED
75

LD
25

TI =
ED
99

LD
1

LD
1
the lowest dose producing toxicity (lethal)
ED
99
the highest dose producing maximal therapeutic response
or
THERAPEUTIC INDEX (TI)
some other definition:
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TI =
minimum effective dose
maximum non-toxic dose
variability between individuals are not taken under
the consideration
it is better to evaluate risk-benefit ratio
(simply the risk of the treatment shouldnt be greater
than the risk of the disease)
evaluation of NNT (number needed to treat)
lethal effect

100%
50%
100%
50%
Drug A Drug B
ED
50

LD
50
TD
50
ED
50
LD
50
TD
50

therapeutic effect toxic effect

DRUG SAFETY
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PROTECTIVE INDEX

undesirable side effects occur in lower doses than
lethal

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Protective index =
ED
50
(desired effect)
ED
50
(undesired effect)
TACHYPHYLAXIS AND TOLERANCE
the effect of a drug may gradually diminish when it
is given continuously or repeatedly
tachyphylaxis (desensitization) when this effect
develops in the course of a few minutes.
tolerance is conventionally used to describe a more
gradual decrease in responsiveness to a drug, taking
days or weeks to develop
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TACHYPHYLAXIS AND TOLERANCE - MECHANISMS
changes in receptors
receptors directly coupled to ion channels,
desensitization is often rapid and pronounced
e.g. at the neuromuscular junction the desensitized state is
caused by a conformational change in the receptor, resulting
in tight binding of the agonist molecule without the opening
of the ionic channel
loss of receptors
prolonged exposure to agonists often results in a
gradual decrease in the number of receptors
expressed on the cell surface, as a result of
internalization of the receptors.
e.g. -adrenoceptors (slower process than the uncoupling)
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TACHYPHYLAXIS AND TOLERANCE - MECHANISMS

exhaution of mediators
depletion of an essential intermediate substance
e.g. ephedrine
altered drug metabolism
because of increased metabolic degradation
e.g. barbiturates and ethanol
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TACHYPHYLAXIS AND TOLERANCE - MECHANISMS

physiological adaptation
decreased drug effect occurs because it is nullified by
a homeostatic response
e.g limited effect of thiazide diuretics because of a gradual
activation of the renin-angiotensin system
other
anatomical changes
e.g. in gastrointestinal tract or respitatory tract after
exposure to some toxins or irritants
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Modern Pharmacology with Clinical Applications, LWW,
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Podstawy farmakologii dla lekarzy, farmaceutw i studentw
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Basic and Clinical Pharmacology, McGraw Hill, Lange,
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Stedmans Medical Dictionary, LWW, 28th Ed, 2006
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3

59
REFERENCES