Download Lamb Mechanisms Drug Action

Mechanisms of Drug Action
Mechanisms of Drug Action
Dr. Robert G. Lamb
Professor
Pharmacology & Toxicology
Direct Effect: antacid (base) neutralizes
excess acid in stomach
Indirect Effect: drug interacts with cell
receptor and initiates a sequence of
cellular events.
Procaine’s Mechanism of Action
Drug Action (mechanism)
Drug Action Sites
Drugs influence normal cellular processes.
Drug Effect (therapeutic effect)
Drugs do not produce new cell functions.
Procaine ⇒ Action Site ⇒ Mechanism ⇒ Effect
Local
Anesthetic
Sodium
Channels
Nerve Cells
Blocks
Nerve Cell
Conductance
Reduced
Pain
Extracellular Sites of Drug Action
Stomach: neutralize acid with base (antacids)
Cellular Sites of Drug Action
Antibiotics inhibit bacterial but not host functions.
Blood: bind metals (chelation) like lead with EDTA
GI Tract: bind drugs (adsorption) with Cholestyramine.
GI Tract: increase water by osmotic effects (laxatives)
Kidney: increase water elimination (diuretics)
Penicillin inhibits cell wall formation.
Tetracycline inhibits protein synthesis.
Erythromycin inhibits protein synthesis.
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Signal Transduction I
Cellular Sites of Drug Action
Lipid-soluble drug
cross membrane and
interacts with receptor.
Drug
Outside
Hormones, Steroids, Vitamins and Neurotransmitters
alter cell functions by interacting with cellular receptors.
Membrane
Receptor may be
enzyme(activated) or
gene regulator.
Inside
cell
Receptor
Gene regulator enters
nucleus and increases
protein synthesis
Four specific examples of receptor-mediated
Nucleus
transmembrane signaling processes.
Signal Transduction II
Ca
Na
Signal Transduction III
Drug binds to extracellular
domain of transmembrane
protein and activates
intracellular proteins such as
Tyrosine Kinase (TK).
Drugs bind to sodium and
calcium channels allowing the
influx of sodium and calcium.
Increase in cellular sodium and
calcium alters cell functions.
Ca
TK
Y
AC
PLC
GC
X
Y
Drugs bind to receptor linked to
effector enzymes (AC, GC, PLC)
by a G protein.
Activated effector enzyme
generates second messengers
(cAMP, cGMP, IP3 and DG)
that alter cell functions.
cAMP second messenger pathway
Agonist
Rec
G
Activated TK alters enzyme
activity as a result of protein
phosphorylation.
Y ~P
Na
Signal Transduction IV
R
Results in increased
enzyme activity.
Gs
ATP
AC
cAMP
5'-AMP
PDE
R2 • cAMP
R2C2
2C*
ATP
ADP
S
S~P
Pi
P'ase
Response
2
Calcium/Phosphoinositide pathway
Agonist
R
G
PIP 2
PLC
Cellular Enzymes (altered activity)
IP 3
ER
PK-C
ATP
Ca 2+
Examples of Cell Receptors
DAG
CaM
Transmembrane Signaling Processes
ADP
S-P
S
Cellular Macromolecules (DNA, RNA, etc.)
Pi
E
CaM-E*
Response
Drug Receptor Complex
D+R
Drug-Dependent Dose Response
DR
RECEPTOR THEORY
Possible
H-bond site
Cavity
CH3
+
N
Anionic group
Cavity
Flat region
CH3
CH2
CH3
CH2
VDW
O
-OH
Affinity
MASS ACTION LAW
R
+
Efficacy
k1
D
DR
k2
k3
effect
25%
Possible
electron
donor group
50%
75%
+
C
CH3
100%
5Å
ACETYLCHOLINE
Michaelis-Menten Dose Response Curves
100
Competitive:
Competitive competes with agonist for receptor, Ic effect
is reduced by increasing dose of agonist.
Reversible Antagonist: I and R have weak chemical bonds.
Irreversible Antagonist: I and R have strong chemical bonds.
100
% OF MAXIMAL
EFFECT
Non-Competitive: reduces number of active receptors, Inc
effect is not reduced by increasing dose
of agonist.
AGONIST
Emax
50
KD
0
= EC50
DOSE
100
A AGONIST
+IC
50
0
A
KD
DOSE
Competitive Inhibitor
% OF MAXIMAL
EFFECT
% OF MAXIMAL
EFFECT
Terminology of Antagonists
A
AGONIST
Emax
50
0
+INC
KD
DOSE
Non-competitive Inhibitor
3
K D / MAX
EFFECT
1 / MAX EFFECT
1/DOSE
AGONIST
AGONIST
1/E
-1/KD
1/E
1/EMAX
1/DOSE
Emax
50
KD
LOG DOSE
Non-competitive Inhibitor
+INC
+IC
B
AGONIST
0
-1/KD
1/EMAX
1/DOSE
% OF MAXIMAL
EFFECT
Competitive Inhibitor
100
100
B
AGONIST
+IC
50
KD
0
Lineweaver-Burke Dose Response Curves
Summary of Antagonist Effects
% OF MAXIMAL
EFFECT
-1/K D
AGONIST
% OF MAXIMAL
EFFECT
1/EFFECT
Log Dose Response Curves
C
100
B
AGONIST
+INC
KD
0
LOG DOSE
Emax
50
LOG DOSE
Occupancy Theory of Drug Action
K1
K3
D (Drug) + R (Receptor) ↔ DR → Response
K2
2. Reversible drug-receptor interaction
Competitive: same Emax (efficacy)
higher KD (lower affinity and potency)
3. Response is proportional to number of receptors occupied.
Non-Competitive: same KD (affinity and potency)
4. Maximum response when all receptors are occupied.
lower Emax (efficacy)
4. Agonist (high Kl, K2 and K3)
5. Antagonist (high Kl, little or no K2 and K3).
Effect of Spare Receptors on Dose Response
-I
+45 I
+90 I
Modifications of Occupancy Theory
EC50 is not equal to KD when tissues have spare receptors.
A
Agonist effect
Drug concentration that produces 50% of maximal response
(EC50) is not equal to KD (saturation of 50% of receptors).
B
C
D
Heart tissue has spare receptors (90%) which means that only 10
of 100 receptors have to be occupied to obtain maximal response.
Under these conditions EC50 is equal to 5 (50% of 10 receptors) and
KD is equal to 50 (50% of 100 receptors).
+94 I
+97 I
E
EC50 (A)
EC50 (B)
EC50 (C)
EC50 (D,E) = KD
Agonist concentration (C) (log scale)
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