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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. 1 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) 4