pharmacodynamics Flashcards
1
Q
- the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response
- the central focus of investigation of drug effects and their mechanisms of action
A
RECEPTORS/DRUG TARGETS
2
Q
mediate the actions (affinity and efficacy) of
pharmacologic agonists and antagonists.
A
receptors
3
Q
largely determine the quantitative relations
between dose or concentration (potency) of drug and pharmacologic effects.
A
receptors
4
Q
are responsible for selectivity (specificity) of
drug action.
A
receptors
5
Q
ability to bind to receptors
A
affinity
6
Q
ability to activate receptors & generate a response
A
efficacy / intrinsic activity
7
Q
the amount of drug needed to produce an effect, affected by both affinity and efficacy
A
potency
8
Q
ability to distinguish between receptors
A
specificity
9
Q
determines affinity, efficacy, and specificity of drugs.
A
structure
10
Q
- by Clark and Gadum
- Tissue response is proportional to number receptors occupied (Affinity)
A
OCCUPANCY THEORY
11
Q
- by Ariens and Stephenson
- Retains the assumption that tissue response is proportional to number of receptors occupied
- Drug-receptor interaction occurs in 2 steps
- Combination of drug and receptor (Affinity)
- Production of effect (Efficacy/Intrinsic Activity)
A
MODIFIED OCCUPANCY THEORY
12
Q
- same efficacies, different affinities
A
MODIFIED OCCUPANCY THEORY
13
Q
- by Croxatto and Paton
- Drug-receptor interaction effect is proportional to the rate of drug-receptor combination
A
RATE THEORY
14
Q
high rate of association and dissociation
A
agonist
15
Q
high rate of association, low rate of dissociation
A
antagonist
16
Q
- by Koshland
- Combination of ligand and receptor produces a change in conformation of the receptor leading to an enzymatically active orientation of groups
- Receptor is partially flexible as compared to lock & key where receptor is rigid
A
induced-fit theory
17
Q
- by Belleau
- Interaction of small molecules (drug) + macromolecule (receptor) results in
- SCP – specific conformational perturbation (agonist effect)
- NSCP – nonspecific conformational perturbation (antagonist effect)
A
MACROMOLECULAR PERTURBATION THEORY
18
Q
- by Black and Leff
- Describes the reaction between a ligand, receptor and active receptor
- Proposes that when a ligand binds, this results in a change in receptor state from inactive to active based on receptor
conformation - A receptor in its active state will elicit a biological response
A
TWO-STATE RECEPTOR THEORY
19
Q
- by De Lean, et al
- Describes ligand, receptor, and G-protein interactions
- Uses equilibrium dissociation constants for the interactions between the receptor and each ligand (Ka for ligand A; Kb for
ligand B), as well as a cooperativity factor (α) that denotes the mutual effect of the two ligands on each other’s affinity for the
receptor - Describes a receptor, when activated by an agonist, moves laterally in the cell membrane to physically couple to a G-protein
A
TERNARY COMPLEX MODEL
20
Q
- Active (Ra) and Inactive (Ri)
- In equilibrium, usually favoring the inactive state without the drug
A
receptor states
21
Q
production of physiologic effect
without the drug
A
Constitutive activity
22
Q
1 intrinsic activty
maximal shift to Ra
A
agonist
23
Q
> 0 & <1 intrinsic activity
partial shift to Ra
A
partial agonist
24
Q
0 intrinsic activity
A
antagonist
25
<0 intrinsic activity
shift to R1
inverse agonist
26
prevents activation of receptor by
agonist
* Competitive
* Noncompetitive
receptor antagonist
27
opposes effects of agonist through a
different receptor
* e.g. vasoconstriction by epinephrine vs vasodilation by histamine
physiologic antagonist
28
renders a substance inactive by binding
to it
* e.g. protamine sulfate for heparin, NaHCO3
for gastric acid
chemical antagonist
29
* Structurally similar to agonist
* Binds reversibly to the same site of agonist
* Can be overcome by increasing agonist concentration
Competitive antagonist
30
Noncompetitive antagonist
* 2 types
Irreversible antagonist
Allosteric inhibitor
* Cannot be overcome by increasing agonist concentration
31
binds irreversibly (covalently) to the same site of agonist
Irreversible antagonist
32
binds to a different site (allosteric site) from the site of the agonist
Allosteric inhibitor
33
* binding of drug to receptor
* generation of a response (signal
transduction)
drug receptor interaction
34
has altered physical and chemical properties, which leads to interaction with cellular molecules to cause a biologic response
receptor with bound ligand
35
* the conversion of a signal carried by a chemical messenger into an intracellular response
SIGNAL TRANSDUCTION
36
signal
chemical messenger: ligand (drug)
response
increased/decreased protein synthesis/ activity, cell growth, replication
37
* Allow passive diffusion of ions down electrochemical gradients across the cell membrane
* Gating of ion channels
* Voltage-Gated Channels
* Ligand-Gated Channels
ION CHANNELS
38
action potential across the cell membrane causes conformational change in the channel that opens or closes the gate
Voltage-Gated Channels
39
binding of a chemical substance (a ligand) with the channel causes conformational in the channel that opens or closes the gate
Ligand-Gated Channels
40
depolarization
open
41
hyperpolarization
closed
42
* Works through 2° messengers (non-
protein compounds)
* Largest and most diverse group of
receptors
G PROTEIN-COUPLED RECEPTOR (GPCR)
43
G PROTEIN-COUPLED RECEPTOR (GPCR)
3 Components:
* Heptahelical receptor: 7 membrane
spanning α-helices
* G protein
* Effector enzyme
44
G PROTEIN-COUPLED RECEPTOR (GPCR)
first messenger
hormone
45
G PROTEIN-COUPLED RECEPTOR (GPCR)
2nd messenger
cAMP
DAG
IP3
results n cellular response
46
* Guanosine-nucleotide binding protein
* Different receptors bind different G proteins and different G proteins exert different effects
* 3 subunits (heterotrimer)
* are classified according to the type of α subunit
G PROTEIN
47
* α – contains guanosine nucleotide binding site and GTPase activity (for
regulation)
* β
* γ
3 subunits (heterotrimer)
48
converts ATP to cAMP
Adenyl cyclase
49
hydrolyzes PIP2 to DAG and IP3
Phospholipase C
50
* cAMP (3’,5’-cyclic AMP)
* DAG (diacylglycerol) – lipid soluble
* IP3 (1,4,5-inositol triphosphate) – water-soluble
* Ca2+
2° MESSENGERS
51
ENZYME-LINKED RECEPTORS
* Extracellular domain: Ligand binding site
* Intracellular domain
* Receptor protein kinases – phosphorylates proteins
* Receptor tyrosine kinase
* Receptor serine/threonine kinase
* Receptor bind protein kinases – binds kinases which can
phosphorylate proteins
* Cytokine receptor (JAK-STAT receptor)
52
Ligand binding site
Extracellular domain
53
(JAK-STAT receptor)
Cytokine receptor
54
binds kinases which can phosphorylate proteins
Receptor bind protein kinases
55
* Receptor tyrosine kinase
* Receptor serine/threonine kinase
Receptor protein kinases
56
Signal transducer protein:
Grb2
57
is a guanine nucleotide exchange factor (GEF) for Ras, a monomeric G protein located in the plasma membrane
SOS
58
activates exchange of GTP for guanosine diphosphate on Ras, causing a conformational change in Ras that
promotes binding of the protein Raf
SOS
59
is a serine protein kinase that is also called MAPKKK (mitogen activated protein kinase kinase kinase)
Raf
60
monomer
tethered to plasma membrane
exchange GDP with GTP
SOS activator
has GTPase activity
RAS
61
heterotrimer
tethered to plasma membrane
exchange GDP with GTP
ligand-GPCR complex activator
has GTPase activity
G protein
62
allows exchange of GDP for GTP; activation
GEF (guanine nucleotide exchange factor)
63
increases GTPase activity of G proteins or Ras; inactivation
GAP (GTPase activating proteins)
64
* Intrinsic serine/threonine kinase activity
* Signal transducer protein: ???
* eg transforming growth factor β (TGF-
β), bone morphogenetic proteins
(BMP)
Smad
65
* aka JAK-STAT receptor
* Binds (associates with) the tyrosine
kinase, JAK (janus kinase)
* Signal transducer protein: STAT
(signal transducer and activator of
transcription)
* eg cytokines of the immune system
cytokine receptor
66
JAK-STAT / cytokine receptor
signal transducer protein???
STAT
(signal transducer and activator of
transcription)
67
* has intrinsic guanylyl cyclase activity
* 2 kinds:
* Membrane-bound
* Soluble
* 2° messenger: cGMP
* Signal cascade: PKG
* eg NO, ANP, BNP
RECEPTOR GUANYLYL CYCLASE
68
* For hydrophobic drugs
* 2 kinds:
* Cytosolic
* Nuclear
* Signal cascade: response element
INTRACELLULAR RECEPTORS
69
the drug receptor complex binds to ___, activating the transcription of specific genes
chromatin
70
* Ability of receptors to amplify signal duration and intensity
SIGNAL AMPLIFICATION
71
SIGNAL AMPLIFICATION
2 mechanisms
* a single ligand–receptor complex can interact with many transducer proteins, thereby multiplying the original signal
intensity
* transducer proteins persist for a longer duration than the original ligand–receptor complex
72
* e.g. ion influx/efflux, alteration of protein activity
* usually immediate and brief
non genomic response
73
* e.g. gene expression
* usually delayed and prolonged
genomic response
74
Decrease in response to a drug due to continued stimulation of receptors with agonists
DESENSITIZATION
75
rapid desensitization
Tachyphylaxis
76
DESENSITIZATION
Can be caused by:
* Downregulation
* Decrease in receptor synthesis
* Phosphorylation (inactivation) of receptors
77
– endocytosis of receptors and sequestration
inside cells
Downregulation
78
* magnitude of the drug effect depends on receptor sensitivity and the drug concentration at the receptor site,
which, in turn, is determined by both the dose of drug administered and by the drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and
elimination
DOSE-RESPONSE RELATIONSHIPS
79
* Plot of the degree of a given response against the plasma concentration/dose of the drug
* Graded effect
GRADED-DOSE RESPONSE CURVE
80
* measure of the amount of drug necessary to produce an effect
* determined by EC50/ED50 – concentration/dose of a drug required to
produce 50% of maximal effect
potency
81
* maximum effect
* ability of a drug to elicit a response when it interacts with a receptor
* dependent on the number of drug–receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses
Efficacy
82
* Plot of the proportion of the population that produces a response against the dose of the drug
* Quantal effect – either-or effect
QUANTAL DOSE RESPONSE CURVE
83
* the dose at which 50% of individuals exhibit the specified quantal therapeutic effect
Median Effective Dose (ED50)
84
* the dose at which 50% of individuals exhibit the specified quantal toxic effect
* Median Lethal Dose (TD50) – if the toxic effect is death
Median Toxic Dose (TD50)
85
range between the minimum toxic dose and
the minimum therapeutic dose
Therapeutic Window
86
ratio of the dose that produces toxic effect in half the population (TD50) to the dose that produces therapeutic effect (ED50) in half the population
TI=TD50/ED50
Therapeutic Index
87
ratio of the dose that produces toxic effect in 1% the population (TD1) to the dose that produces therapeutic effect (ED99) in 99% the population
Margin of Safety
