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Flashcards in pharmacodynamics Deck (85):
1

Actions/effects of the drug on the body
Determines the group in which the drug is
classified and plays a major role in deciding
whether a group is appropriate therapy for
particular symptom or disease

pharmacodynamics

2


Specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system

RECEPTORS

3


Determine the quantitative relations between
dose or concentration of drug and
pharmacologic effects

RECEPTORS

4


Selective in choosing a drug molecule to bind
to avoid constant activation by promiscuous
binding of many different molecules

RECEPTORS

5

Changes its function upon binding in such a
way that the function of the biologic system
is altered in order to have pharmacologic
effect

RECEPTORS

6


Selective in ligand-binding characteristics
(respond to proper chemical signals and
not to meaningless ones)
Mediate the actions of both pharmacologic
agonists and antagonists

RECEPTORS

7

Majority are proteins which provide the
necessary diversity and specificity of
shape and electrical charge

RECEPTORS

8

Specific binding region of the macromolecule
High and selective affinity to the drug molecule

RECEPTOR SITE/RECOGNITION SITE

9


is the fundamental event that initiates the action
of the drug

Interaction between the drug and the receptor

10

CLASSIFICATION OF RECEPTORS

Best characterized drug receptors
Mediates the action of endogenous chemical
signals like neurotransmitters, autacoids and
hormones
Mediates the effects of the most useful
therapeutic agents

REGULATORY PROTEIN

11

CLASSIFICATION OF RECEPTORS

Inhibited (or less commonly, activated) by
binding a drug
Eg, dihydrofolate reductase, the receptor for
methotrexate

ENZYMES

12

CLASSIFICATION OF RECEPTORS

Eg, Na+/K+ ATPase, the membrane receptor
for digitali

TRANSPORT PROTEINS

13

CLASSIFICATION OF RECEPTORS

Eg, tubulin, the receptor for colchicine,
an anti-inflammatory drug

STRUCTURAL PROTEINS

14


Molecules that translate the drug-receptor
interaction into a change in cellular activity
Eg, adenyl cyclase

EFFECTORS

15


Response of a particular receptor-effector
system is measured against increasing
concentration of a drug
Graph of the response versus the drug
dose

GRADED DOSE-RESPONSE CURVE

16


Sigmoid curve
Efficacy (Emax) and potency (EC50) are
derived from this curve
The smaller the EC
50, the greater the
potency of the drug

GRADED DOSE-RESPONSE CURVE

17

Maximal response that can be produced
by a drug
All receptors are occupied
No response even if the dose is increased

Emax

18


Concentration of drug that produces
50% of maximal effect
Smaller EC
50–more potent

EC50

19

Total number of receptor sites
All receptors have been occupied

Bmax

20

Equilibrium dissociation constant
Concentration of drug required to
bind 50% of the receptors

KD

21

Measure of the affinity of a drug
for its binding site on the receptor

KD

22

Smaller KD

–greater affinity of drug to receptor

23

Transduction process between the occupancy
of receptors and production of specific effect
Highly efficient coupling can be elicited by a
full agonist and spare receptors

COUPLING

24


Maximal drug response is obtained at less
than maximal occupation of the receptors
Not qualitatively different from nonspare
receptors, not hidden or unavailable

SPARE RECEPTORS

25

Temporal in character, when occupied, they
can be coupled to respond, there is still effect
Drugs with low binding affinity for receptors
will be able to produce full response even at
low concentration

SPARE RECEPTORS

26


Compare concentration for 50% of maximal
effect (EC50) with concentration for 50%
maximal binding (KD)
KD > EC50 with spare receptors

SPARE RECEPTORS

27


Effect of the drug-receptor interaction may
persist for a longer time than the interaction
itself
Actual number of receptors may exceed the
number of effectors available

SPARE RECEPTORS

28


Non-regulatory molecules of the body
Binding with these molecules will result
to no detectable change in the function
of the biologic system

INERT BINDING SITES

29


Buffers the concentration of the drug
Bound drugs do not contribute directly
to the concentration gradient that drives
diffusion
Eg, albumin

INERT BINDING SITES

30

Binds to the receptor and directly or
indirectly bring about an effect
Full activation of the effector system

AGONIST

31


Produces less than the full effect, even
when it has saturated the receptors
Acts as an inhibitor in the presence of
a full agonist

PARTIAL AGONIST

32


Binds but do not activate the receptors
Blocks or competes with agonist

ANTAGONIST

33

CLASSIFICATION

Competes with agonist receptor
Binds to the receptor reversibly without
activating the effector system

COMPETITIVE ANTAGONIST

34

CLASSIFICATION

Antagonist increases the agonist concentration
needed for a given degree of response
Concentration-effect curve is shifted to higher
doses (ie, horizontally to the right of the dose
axis)
Same maximal effect is reached

COMPETITIVE ANTAGONIST

35

CLASSIFICATION

Effects are overcomed by adding more agonist
Increases the median effective dose
(ED50)

COMPETITIVE ANTAGONIST

36

2 THERAPEUTIC IMPLICATIONS
produced by the competitive antagonist depends on the

(1) Degree of inhibition

37

2 THERAPEUTIC IMPLICATIONS
concentration of antagonist (eg, propranolol)
depends on the concentration of agonist that
is competing for binding to the receptor

(2) Clinical response to a competitive antagonist

38

CLASSIFICATION

Binds with the receptor via covalent bonds
Antagonist’s affinity to the receptor maybe so high
Receptor is not available to bind the agonist

IRREVERSIBLE ANTAGONIST

39

CLASSIFICATION

Concentration-effect curve moves downward
No shift of the curve in the dose axis
Emax is not reached
No increase in median effective dose (ED50)
unless there are spare receptors

IRREVERSIBLE ANTAGONIST

40

CLASSIFICATION

Duration of action is relatively independent
of its own rate of elimination
More dependent on the rate of turnover of
receptors
Eg, phenoxybenzamine binding with alpha
receptors

IRREVERSIBLE ANTAGONIST

41

Does not depend on interaction with the
agonist’s receptor
Drug that interacts directly with the drug
being antagonized to remove it or to
prevent it from reaching its target

CHEMICAL ANTAGONISM

42

Eg, protamine used to counteract the
effect of heparin making it unavailable
for interaction with proteins involved in
the formation of blood

CHEMICAL ANTAGONISM

43


Makes use of the regulatory pathway
Effects that are less specific and less
easy to control
Binds to a different receptor producing
an effect opposite to that produced by
the drug it is antagonizing

PHYSIOLOGIC ANTAGONISM

44

5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
crossing the plasma membrane and acts on intracellular
receptor (eg, steroids)

(1) Lipid soluble drug

45

5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS

intracellular enzymatic activity is
regulated by a ligand that binds to
the protein’s extracellular domain

(2) Transmembrane receptor protein

46

5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
that binds and stimulates a protein tyrosine
kinase (eg, insulin)

(3) Transmembrane receptor

47

5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
which regulates the opening
of the ion channel (eg, GABA, excitatory
acetylcholine)

(4) Ligand-gated transmembrane ion
channel

48

5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
is coupled with an effector enzyme by G protein
which modulates production of an intracellular second messenger
[eg, cathecolamine (epinephrine)]

(5) Transmembrane receptor

49

INTRACELLULAR 2ND MESSENGERS

Mediates hormonal responses
Mobilization of stored energy
(breakdown of carbohydrates in the liver stimulated by cathecolamines
Conservation of water by the kidneys
mediated by vasopressin

A. cAMP

50

INTRACELLULAR 2ND MESSENGERS

Bind to receptors linked to G proteins while others bind to receptor tyrosine kinases

B. CALCIUM AND PHOSPHOINOSITIDES

51

INTRACELLULAR 2ND MESSENGERS

Crucial step is the stimulation of membrane enzyme phospholipase C

B. CALCIUM AND PHOSPHOINOSITIDES

52

INTRACELLULAR 2ND MESSENGERS

Few signaling roles in a few cell types like the intestinal mucosa and vascular smooth muscle cells

C. cGMP

53

INTRACELLULAR 2ND MESSENGERS

Causes relaxation of vascular smooth
muscles by a kinase-mediated mechanism

C. cGMP

54


Response gradually diminishes even if the
drug is still there (after reaching an initial
high level of response)
Reason is not known

RECEPTOR DESENSITIZATION

55

STRUCTURE ACTIVITY RELATIONSHIP

Cells use more than one signaling mechanism
to respond to the drug

56


Graph of the fraction of a population that
shows a specified response to increasing
doses of a drug

QUANTAL DOSE-RESPONSE CURVE

57


Minimum dose required to produce a specific
response is determined in each member of
the population
Sigmoid curve

QUANTAL DOSE-RESPONSE CURVE

58


Median effective dose
50% of the individuals manifested
the desired therapeutic effect

ED50

59

Median toxic dose
50% of the individuals manifested the toxic effects

TD50

60

Median lethal dose

LD50

61


Ratio of the TD
50 (or LD50 ) to the ED50 determined from the quantal dose-response curves
Increased therapeutic index-wide margin of
safety

THERAPEUTIC INDEX

62

Represents an estimate of the safety of the
drug
A very safe drug might be expected to have
a very large toxic dose and a much smaller
effective dose
Eg, ED50 of 3mg and the LD50 is 150 mg
Therapeutic index is 50 (150/3)

THERAPEUTIC INDEX

63


Dosage range between the minimum
effective therapeutic concentration or
dose (MEC) and the minimum toxic
concentration or dose (MTC)
More clinically relevant index of safety

THERAPEUTIC WINDOW

64

normal value MEC

7-10 mg/L (average of 8 mg/L)

65

normal value Therapeutic window

8-18 mg/L

66

normal value MTC

15-20 mg/L (average of 18 mg/L)

67

ex of therapeutic window

theophylline

68


Maximal effect (Emax) an agonist can
produce if the dose is taken to very high
levels
Determined mainly by the nature of
receptors and its associated effectors

MAXIMAL EFFICACY

69

Measured with a graded dose-response
curve but not with quantal dose-response
curve

MAXIMAL EFFICACY

70

Amount of drug needed to produce a given
effect
In the graded dose-response curve, the effect
chosen is the 50% of the maximal effect and
the dose is (EC50)

POTENCY

71

In the quantal dose-response curve, ED50,
TD50, and LD50 are variables in 50% of the
population

POTENCY

72

VARIATION OF RESPONSES IN INDIVIDUALS

Caused by differences in metabolism (genetic)
or immunologic mechanisms
Response to the drug is unknown or unusual

IDIOSYNCRATIC RESPONSE

73

VARIATION OF RESPONSES IN INDIVIDUALS

Intensity of the drug is decreased
Large dose of the drug is needed to have
an effect

HYPOREACTIVE RESPONSE

74

VARIATION OF RESPONSES IN INDIVIDUALS

Intensity of the drug is increased or exaggerated

HYPEREACTIVE RESPONSE

75

VARIATION OF RESPONSES IN INDIVIDUALS

Decreased sensitivity acquired as a result of
exposure to the drug

TOLERANCE

76

VARIATION OF RESPONSES IN INDIVIDUALS

Tolerance develops after a few doses

TACHYPHYLAXIS

77

VARIATIONS IN DRUG RESPONSIVENESS

that reaches the receptor due to absorption,
distribution and elimination differences

1. Alteration on the concentration of the drugq
2. Variation in the concentration of the endogenous
3. Alterations in number/function of receptors
4. Changes in 2nd messengers
5. Clinical selectivity

78

VARIATIONS IN DRUG RESPONSIVENESS

Drug has been taken for a long time, then
abruptly discontinued
Eg, propranolol (beta-blocker)
Gradual decrease of taking the drug by
decreasing/tapering the dose

OVERSHOOT PHENOMENON/
REBOUND HYPERTENSION

79

VARIATIONS IN DRUG RESPONSIVENESS
3. Alterations in number/function of receptors

Decrease in # of receptors

DOWN REGULATION

80

VARIATIONS IN DRUG RESPONSIVENESS
3. Alterations in number/function of receptors

Increase in the # of receptors

UP REGULATION

81

WHAT TO DO TO AVOID/CIRCUMVENT
TOXIC EFFECTS

Give low doses
Carefully monitor the patient
Employ ancillary procedures

82

VARIATIONS IN DRUG RESPONSIVENESS
Beneficial and toxic effects may be mediated
by the same receptor-effector mechanism
D + R DR X (beneficial/toxic)

5. Clinical selectivity

83

WHAT TO DO TO AVOID/CIRCUMVENT
TOXIC EFFECTS

Use a safer drug if possible
Beneficial and toxic effects are mediated
by identical receptors but in different ways

84


Low doses for prevention of blood clots
Very high doses causes internal bleeding
Monitor PT, PTT and bleeding parameters

HEPARIN

85


Give lowest dose possible
Give adjunctive drugs
Anatomic selectivity (lungs-by inhalation)

STEROIDS

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