1. Principles of pharmacodynamics
Anton Kohút

2. How drugs act? Indirectly Directly drugs interact with specific
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

3. Targets - regulatory proteins
. Receptors
Enzymes
aspirin  COX
neostigmine  AChE
methotrexate DH-folate reductase
digoxin  Na+-K+-ase
allopurinol  xanthine oxidase
omeprazole  H+/K+- ATPase
3 . Ion channels
Ca, Na, K
4. Carrier molecules
 transport of glucose, amino acids
 transport in renal tubules
 re-uptake of neurotransmiters (NA, 5-HT)

4. 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 side-effects.

6. Receptors

9. Regulatory proteins – receptors drugs act on receptors as agonists or antagonists
bind to receptors and produce a response-
effects of various types
2. Antagonists
bind to receptors without producing a response and by occupying the receptors they prevent action of agonists.

10. 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

13. 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

15. 2. Antagonists competitive antagonism a. reversible b. ireversible
 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

16. 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

18. 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)

20. Adrenergic beta receptor
Transduction system
Agonist (noradrenaline)
Receptor (1-2)
G-protein (Gs, Gi)
Effector enzyme (adenylcyclase, AC)
Second messenger (cAMP)
Drug action

21. Adrenergic beta receptor

22. Cholinergic receptor

26. Receptors - localization

28. of intracellular receptors
A lipid-soluble drug diffuses across cell membrane and moves to the nucleus of the cell
Mechanism of action
of intracellular receptors
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

29. 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).

30. - effect of the dose on the magnitude of pharmacologic response. 100
Semilogaritmic
- effect of the dose on the magnitude of pharmacologic response.
100
Drug A
Drug B 50
Percentage of maximum effect
EC50
log [Drug]
The potency of drug can be compared using the EC50, the smaller the EC50 the more potent the drug.
(according to Lippincott´s
Pharmacology, 2006)

31. Log-concentration-effect curve
10-8
10-7
10-6
10-5
10-4
potency (affinity)
efficacy
50%
EC50
slope of the curve

32. EC50 for Drug A EC50 for Drug B EC50 for Drug 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.
100
Drug A
Biologic effect 50
Drug B
Drug C
Log drug concentration
EC50
for
Drug A
EC50
for
Drug B
EC50
for
Drug C
(according to Lippincott´s
Pharmacology, 2006)

33. 3. Antagonism by receptor block
Antagonists in this sense are the drugs that bind to receptors but do not
activate them.
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

35. Drug with competitive antagonist Drug with non- competitive antagonist
Effects of drug antagonists
Drug with
competitive
antagonist
Drug with non-
competitive
antagonist
Drug
alone
Biologic effect
Drug concentration
EC50
or drug alone or in presence of a noncompetitive antagonist
EC50
for drug in the presence of a competitive antagonist
(according to Lippincott´s
Pharmacology, 2006)

37. 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).

38. 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

39. 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."

40. Desensitization of receptors
tachyphylaxis
Repeated administration of an agonist (such as epinephrine) over a short time period, results in diminished response of the cell.
Response
Time 50 10 50 10 50 10 40 20 40 20 40 20 30 30 30
Repeated injection of drug
Following a period of rest, administration of the drug results in a response of the original magnitude.
(according to Lippincott´s
Pharmacology, 2006)

41. Tachyphylaxis after repeated administration of ephedrine
(decrease in its effect on blood pressure)
E = administration of ephedrine

42. Log concentration of drug in plasma
Cumulative percentage of patients responding to plasma levels of a drug
B: Penicillin: Large therapeutic index
Therapeutic window
100
Percentage of patients 50
Desired
therapeutic
effect
Unwanted
adverse
effect
Log concentration of drug in plasma
(arbitrary units)
(according to Lippincott´s
Pharmacology, 2006)

43. QUANTAL DOSE-RESPONSE CURVES
TI = -----
Therapeutic range = TD50 - ED50
ED50

44. 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.