IN THE NAME OF GOD

Principles of pharmacodynamics Introduction What is pharmacology Principles of pharmacodynamics Mechanism of Drug Actions Drug-Receptor Interaction Classification of Drugs Dose-Response Relationships

The science that deals with: What is Pharmacology? Pharmakon = a drug or poison Logos = discourse or study The science that deals with: The fate of drugs in the body Pharmacokinetics The actions of drugs on the body Pharmacodynamics

Pharmacotherapeutics Pharmacy The science of preparation of drugs Pharmacotherapeutics The treatment of diseases by drugs

Textbooks Basic & Clinical Pharmacology, 2004 Bertram G. Katzung Goodman and Gilman’s The pharmacological basis of therapeutics, 2001 (J.G. Hardman and L.E. Limbard, eds.) New York: McGraw-Hill (first published in 1941)

Principles of Pharmacodynamics

Why to study Pharmacodynamics? Mechanisms of drug action & the relationship between drug concentration and effect Why to study Pharmacodynamics? Scientific basis for the selection & use of drugs

Mechanism of Drug Action Basic Concept Interaction of a drug with its target tissue involves specific binding sites Receptor A macromolecular component of the cell to which the drug binds and leads to an effect on the cell Nonspecific binding site A biological component to which the drug binds but does not lead to any effect

Nature of Drug Receptors Proteins Transmembrane proteins Receptors for neurotransmitters Transport proteins Na+/K+ ATPase digitalis glycosides Ion channels benzodiazepines Structural proteins Tubulin colchicine Enzymes Cycloxygenase acetylsalicylic acid ACE Captopril

Non-protein drug receptors Lipids Anesthetics Nystatin, Amphotericin Nucleotides Antineoplastic drugs Cyclophosphamide

Other Sites of Drug Action Water Osmotic Diuretics & Laxatives Ions Antacids Changing urine pH Chelators Dimercaprol Hg+2 , As+2 Penicillamine Cu+2 EDTA Pb2

Drug-Receptor Interaction

Drug-Receptor Interaction K1 R + D R-D Effect Affinity The tendency of a drug to combine with its receptor Kd The concentration of drug that binds to 50% of the receptors Affinity= the reciprocal of the Kd K2

Drug-Receptor Interaction K1 R + D R-D Effect Intrinsic Activity The ability of a drug to initiate a cellular effect K2

Receptor-Effector Coupling Receptor conformational change Coupling Efficiency

Drug-Receptor Binding

Concentration-Effect Relationship

Classification of drugs Agonist Full agonist Partial agonist Antagonist Competitive antagonist Non-competitive antagonist

Other Drug Antagonism Chemical antagonists Physiologic antagonism Heparin & protamine Physiologic antagonism Glucocorticoids & Insulin

Dose-Response Relationship Graded dose-response Quantal dose-response

Graded Dose-Response Relationship

Sigmoidal D-R Curve

Graded Dose-Response Relations Potency Efficacy

Relative potency

Relative Efficacy

Agonists with different potency

Agonists with different efficacy

Competitive Antagonism

D-R Curve for Competitive Antagonists

Non-Competitive Antagonism

Quantal D-R Curve

Quantal D-R Curve

Quantal D-R Curve

Quantal-Dose Response Median Effective Dose (ED50) Median Toxic Dose (TD50) Median Lethal Dose (LD50) Therapeutic index LD50/ED50 or TD50/ED50

Signaling Mechanisms & Drug Action

Transmembrane Signaling Intracellular receptors Enzyme-linked receptors Ligand-gated ion channels G-protein-coupled receptors

Intracellular Receptors Steroid Receptor Superfamily Glucocorticoids Mineralocorticoids Sex hormones Vitamin D Thyroid hormone Retinoic Acid

Therapeutically important consequences Slow onset of action Persistence of effect following withdrawal of the drug

Enzyme-Linked Receptors Receptor Tyrosine Kinases Insulin Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF)

Receptor Tyrosine Kinases

Enzyme-Linked Receptors Receptor Guanylyl Cyclase Atrial natriuretic factor (ANF) cGMP (Natriuresis; Vasodilation) Receptor Serine Kinase Transforming growth factor-beta (TGF-b) Cytokine Receptors

Cytokine Receptor

Ligand-gated Ion Channels Acetylcholine nicotinic receptors Neuromuscular blocking drugs (tubucurarine) Ganglion blockers (Mecamylamine) GABAA Benzodiazepines (sedative-hypnotic) Glutamate Topiramate (anticonvulsant)

Ligand-gated Ion Channels

G Protein-Coupled Receptors