Transcript Document 7510444

Principles of
pharmacodynamics
Anton Kohút
How drugs act?
 Indirectly
only a few drug (osmotic
diuretics, general anesthetics)
act on the base their
physicochemical properties
 they need no specific
binding site

Directly
drugs interact with specific
protein macromolecule
 special regulatory proteins:
1. enzymes
2. ion channels
3. carrier molecules
4. receptors
Targets - regulatory proteins
1.
2.
. Receptors
Enzymes
3 . Ion channels
Ca, Na, K
aspirin  COX
neostigmine  AChE
methotrexate DH-folate
reductase
digoxin  Na+-K+-ase
allopurinol  xanthine oxidase
omeprazole  H+/K+- ATPase
4. Carrier molecules
 transport of glucose, amino
acids
 transport in renal tubules
 re-uptake of neurotransmiters
(NA, 5-HT)
No drugs are completely specific in
their actions. In many cases,
increasing the dose of a drug will cause
it to affect targets other than the
principal one, and this can lead to sideeffects.

Receptors
Regulatory proteins – receptors
drugs act on receptors as agonists or antagonists
1. Agonists
bind to receptors and produce a responseeffects of various types
2. Antagonists
bind to receptors without producing a response and
by occupying the receptors they prevent action of
agonists.
1. Agonists
 agonist I - the drug binds to the same site as the
endogenous compounds and produce the same type
of action
 agonist II - the drug binds to a different site than
does agonist I - allosteric action
 inverse agonist – produces inactivation of
active receptor
1. Agonists (cont.)

Affinity - tendency to bind to the receptors
(attraction between receptor and drug)

Efficacy - ability once bound, to initiate changes,
which lead to effect (is the capacity of drug to
activate a receptor)
Full agonists - can produce maximal effect when
all receptors are occupied (high efficacy)
 Partial agonists - can produce only submaximal
effects even when all receptors are occupied
2. Antagonists

competitive antagonism
 antagonists are able to displace the agonists from
the receptors (one drug can be displaced by another
drug),
 may be abolished by adding an excess of agonist.
a. reversible
b. ireversible
antagonist dissociates very slowly or not
2. Antagonists (cont.)
non-competitive antagonism
a. form bonds with the receptors usually at sites other
than the endogenous agent.
b. in some cases binding may be covalent and
ireversible
c. cannot be overcom by higher concentration of
agonist
Receptors –types of receptors
A. for fast neurotransmitters - coupled directly to
an ion channel, e.g the nicotinic ACh receptor,
GABA, glutamate, 5-HT3
B. coupled to G-protein - for many hormones and
slow transmitters (neurohormonal receptors),
muscarinic ACh receptors, adrenergic
receptors
C. coupled to tyrosine kinase - for insulin and
various growth factors,
D. cytosolic receptors - for steroids (are usually
slow)
Adrenergic beta receptor
Transduction system






Agonist (noradrenaline)
Receptor (1-2)
G-protein (Gs, Gi)
Effector enzyme
(adenylcyclase, AC)
Second messenger
(cAMP)
Drug action
Adrenergic beta receptor
Cholinergic receptor
Receptors - localization
Mechanism of action
of intracellular receptors
A lipid-soluble drug diffuses
across cell membrane and moves
to the nucleus of the cell
Drug
Drug
TARGET
CELL
CYTOSOL
Drug
Inactive
receptor
NUCLEUS
Activated
receptor
complex
The drug binds to an
intracellular receptor.
Gene
The drug-receptor complex binds to
chromatin, activating the
transcription of specific genes.
mRNA
mRNA
Specific proteins
according to Lippincott´s
Pharmacology, 2006)
Biologic effects
DOSE-RESPONSE RELATIONSHIPS
A agent that can bind to a receptor and elicit a response.
magnitude of the drug effect depends on its concentration at the receptor
site, which in turn is determined by the dose of drug and by factors
characteristic of the drug (e.g. rate of absorption, distribution,
metabolism).
(according to Lippincott´s
Pharmacology, 2006)
100
Percentage of maximum effect
Semilogaritmic
- effect of the dose on the
magnitude of
pharmacologic response.
Drug A
Drug B
50
EC50
0
log [Drug]
The potency of drug can be
compared using the EC50, the
smaller the EC50 the more potent the
drug.
Log-concentration-effect curve
potency (affinity)
efficacy
slope of the curve
50%
EC50
10-8
10-7
10-6
10-5
10-4
c
Typical dose-response
curve for drug showing
differences in potency
and efficacy.
(EC50 = drug dose that
shows fifty percent of
maximal response.)
Drug A is more potent
than Drug B, but both
show the same efficacy.
Drug C shows lower
potency and lower
efficacy than Drugs A
and B.
Biologic effect
100
50
Drug A
Drug B
Drug C
0
Log drug concentration
(according to Lippincott´s
Pharmacology, 2006)
EC50
for
Drug A
EC50
EC50
for
for
Drug B Drug C
3. Antagonism by receptor block
Antagonists in this sense are the drugs that bind to receptors but do not
activate them.
a) Reversible competitive antagonism:
competitive antagonists bind reversibly with receptors at the same site
as the agonist.
The response can be returned to normal by increasing the dose of agonist.
! Competitive antagonist has no intrinsic efficacy !
Reversible competitive antagonism is the commonest and most
important type of antagonism;
Two main characteristics:
― in the presence of the antagonist, the agonist log DRC is shifted to
the right without change in slope or maximum, the extent of the shift
being a measure of the dose ratio
― the dose ratio increases linearly with antagonist concentration
Effects of drug antagonists
Drug with
competitive
antagonist
Biologic effect
Drug
alone
Drug with noncompetitive
antagonist
Drug concentration
EC50
EC50
or drug alone or in presence for drug in the presence
of a competitive
of a noncompetitive
(according to Lippincott´s
antagonist
antagonist
Pharmacology, 2006)
Variation in receptor numbers
Continued stimulation or inhibition of living systems tends to induce
compensatory processes.
Thus individuals continually exposed to an agonist - predictably
require larger doses to achieve a given effect than would a naive
subject. This tolerance is thought to results from a decrease in
reception numbers - down-regulation.
(
The opposite may also occur: in patients on long-term beta-blocker
therapy, it is thought that catecholamine receptor numbers are
increased - up-regulation  the tendency to a marked rise in blood
pressure if the drug is stopped suddendly (rebound hypertension).
Desensitisation (tachyphylaxis) and tolerance
The loss of a drug’s effect, commonly seen when it is given repeatedly or
continuously.
 The onset and recovery :
varies from seconds to minutes (called TACHYPHYLAXIS)
 to days or weeks (called TOLERANCE)
Many mechanisms:
― changes in receptors
― loss of receptors (down regulation)
― exhaustion of mediators
― enhanced drug metabolism
― active efflux of drugs
― compensatory physiological mechanisms
Desensitization of receptors
- -- down-regulation - types of desensitization - when receptors are (they
undergoe endocytosis – they are not available for further agonist action).
These receptors may be recycled to the cell surface, restoring sensitivity,
or may be further degraded, decreasing the total number of receptors
available.
Some receptors (particularly voltage-gated channels) - they require a rest
period following stimulation before they can be activated again. During this
recovery phase they are said to be "refractory" or "unresponsive."
Desensitization of receptors
Repeated administration of an
agonist (such as epinephrine) over
a short time period, results in
diminished response of the cell.
Response
tachyphylaxis
Time
0
0
0
50
10
50
10
50
10
40
20
40
20
40
20
30
30
30
Repeated injection of drug
(according to Lippincott´s
Pharmacology, 2006)
Following a period of rest,
administration of the drug
results in a response of the
original magnitude.
Tachyphylaxis after repeated administration of ephedrine
(decrease in its effect on blood pressure)
E = administration of ephedrine
Cumulative percentage of patients responding to plasma levels of a drug
B: Penicillin: Large therapeutic index
Therapeutic window
Percentage of patients
100
50
0
(according to Lippincott´s
Pharmacology, 2006)
Desired
therapeutic
effect
Log concentration of drug in plasma
(arbitrary units)
Unwanted
adverse
effect
QUANTAL DOSE-RESPONSE CURVES
LD50
TI = ----ED50
Therapeutic range = TD50 - ED50
Therapeutic index
The ratio of the dose that produces toxicity to the dose that produces a
clinically desired or effective response in a population of individuals:
Therapeutic index = LD50/ED50
or TD50/ED50
TD50 = the dose that produces a toxic effect in half the population,
LD50 = the dose that produces a death in half the population
ED50 = the dose that produces a therapeutic or desired response in half the
population.
The therapeutic index = a measure of a drug's safety –
a large value = there is a wide margin between doses that are effective and
toxic.