Procaine Action Site Mechanism Effect Local Anesthetic Sodium Channels Nerve Cells Blocks Nerve Cell Conductance Reduced Pain
Lipid-soluble drug cross membrane and interacts with receptor. Receptor may be enzyme(activated) or gene regulator. Gene regulator enters nucleus and increases protein synthesis Results in increased enzyme activity.
Hormones, Steroids, Vitamins and Neurotransmitters alter cell functions by interacting with cellular receptors. Four specific examples of receptor-mediated transmembrane signaling processes.
Inside cell
Membrane
Receptor
Nucleus
Signal Transduction II
Ca Na
Drugs bind to sodium and calcium channels allowing the influx of sodium and calcium. Increase in cellular sodium and calcium alters cell functions.
TK
Y ~P
Ca
Na
Signal Transduction IV
Agonist
Rec
AC PLC
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.
ATP
cAMP PDE
5'-AMP
GC
Response
Agonist
Calcium/Phosphoinositide pathway
G PLC PIP 2 DAG
IP 3
ER
Ca 2+
CaM
CaM-E*
Response
Affinity
k1 k2 DR
Efficacy
k3 effect 25% 50% 75%
-OH C
+
CH3
CH3
100%
Terminology of Antagonists
Competitive: competes with agonist for receptor, Ic effect Competitive is reduced by increasing dose of agonist. Non-Competitive: reduces number of active receptors, Inc effect is not reduced by increasing dose of agonist. Reversible Antagonist: I and R have weak chemical bonds. Irreversible Antagonist: I and R have strong chemical bonds.
DOSE
100
% OF MAXIMAL EFFECT
% OF MAXIMAL EFFECT
A AGONIST +IC
100
AGONIST Emax
50 KD
DOSE
50 KD
DOSE
+INC
Competitive Inhibitor
Non-competitive Inhibitor
100
B AGONIST Emax
50 KD 0
LOG DOSE
-1/K D
Competitive Inhibitor
+IC 1/E -1/KD 1/EMAX
1/DOSE AGONIST
Non-competitive Inhibitor
% OF MAXIMAL EFFECT +INC
AGONIST
% OF MAXIMAL EFFECT
100
B AGONIST +IC KD
100
B AGONIST
Emax +INC
50
50 KD 0
LOG DOSE
LOG DOSE
Drug concentration that produces 50% of maximal response (EC50) is not equal to KD (saturation of 50% of receptors). EC50 is not equal to KD when tissues have spare receptors. 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 D
+97 I E
EC50 (A) EC50 (B) EC50 (C) EC50 (D,E) = KD