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