Mechanisms of Drug Action

Dr. Robert G. Lamb Professor Pharmacology & Toxicology

Mechanisms of Drug Action

Direct Effect: antacid (base) neutralizes
excess acid in stomach

Indirect Effect: drug interacts with cell

receptor and initiates a sequence of cellular events.

Procaines Mechanism of Action

Drug Action (mechanism) Drug Effect (therapeutic effect)

Drug Action Sites

Drugs influence normal cellular processes. 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) 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)

Cellular Sites of Drug Action

Antibiotics inhibit bacterial but not host functions. Penicillin inhibits cell wall formation. Tetracycline inhibits protein synthesis. Erythromycin inhibits protein synthesis.

Signal Transduction I Cellular Sites of Drug Action

Drug Outside

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

Signal Transduction III

Drug binds to extracellular domain of transmembrane protein and activates intracellular proteins such as Tyrosine Kinase (TK).

Y ~P

Ca

Na

Activated TK alters enzyme activity as a result of protein phosphorylation.

Signal Transduction IV

Agonist

cAMP second messenger pathway

Gs AC

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

R2 cAMP R2C2 2C* ATP S Pi P'ase ADP S~P

Response

Agonist

Calcium/Phosphoinositide pathway
G PLC PIP 2 DAG

Examples of Cell Receptors

Cellular Enzymes (altered activity)

IP 3

PK-C ATP ADP S-P Pi

ER

Ca 2+

Transmembrane Signaling Processes Cellular Macromolecules (DNA, RNA, etc.)

CaM

CaM-E*

Response

Drug Receptor Complex

D+R DR
Possible H-bond site Cavity CH3 + N Anionic group Cavity Flat region CH3 CH2 CH2 VDW 5 ACETYLCHOLINE O Possible electron donor group

Drug-Dependent Dose Response

RECEPTOR THEORY MASS ACTION LAW R + D

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.

Michaelis-Menten Dose Response Curves

% OF MAXIMAL EFFECT 100 A AGONIST Emax 50 KD 0 = EC50

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

Log Dose Response Curves

% OF MAXIMAL EFFECT
1/EFFECT C AGONIST
K D / MAX
EFFECT

100

B AGONIST Emax

50 KD 0
LOG DOSE

-1/K D

1 / MAX EFFECT 1/DOSE

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

1/E -1/KD 1/EMAX

1/DOSE

Emax +INC

50

50 KD 0
LOG DOSE

Lineweaver-Burke Dose Response Curves

LOG DOSE

Summary of Antagonist Effects

Competitive: same Emax (efficacy) higher KD (lower affinity and potency) Non-Competitive: same KD (affinity and potency) lower Emax (efficacy)

Occupancy Theory of Drug Action

K1 K3 D (Drug) + R (Receptor) DR Response K2 2. Reversible drug-receptor interaction 3. Response is proportional to number of receptors occupied. 4. Maximum response when all receptors are occupied. 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

Agonist effect

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

Agonist concentration (C) (log scale)