Pharmacodynamics Collected and Prepared By S.Bohlooli, PhD

BoundFree Bound LOCUS OF ACTION “RECEPTORS ” TISSUE RESERVOIRS SYSTEMIC CIRCULATION Free Drug Bound Drug ABSORPTION EXCRETION BIOTRANSFORMATION

Molecular pharmacology : Molecular pharmacology is concerned with studies of basic mechanisms of drug actions on biological systems. The idea that drugs act upon specific sites (receptive substance) began with John New Port Langley ( ) of Cambridge. However the word ‘receptor’ is given by Paul Ehrlich ( ). The receptor concept which forms a key note in the development of molecular pharmacology became firmly established by the quantitative work of Alfred Joseph Clark ( ), a professor of pharmacology at Kings College London.

Receptor (key element) In addition to its usefulness for explaining biology, the receptor concept has important practical consequence for  The development of drugs  Arriving at therapeutic decisions in clinical practice.

Receptors:  Largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects  Are responsible for selectivity of drug action  Mediate the actions of pharmacologic antagonists

Macromolecular nature of drug receptors Regulatory proteins Enzymes Transport proteins Structural proteins

Quantitative aspects of drug-receptor interaction

Drug-Receptor Interactions Obey the Law Of Mass Action By law of mass action: At equilibrium Therefore:

Total number of receptors: R t = [R] + [DR] [R] = R t – [DR] After rearrangement:

KDKD When [D] = K D [DR] R T = 0.5 [D] [DR]/R t

Receptor Binding The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996). % Bound Concentration of Ligand KDKD

Relation between drug dose & clinical response

1. Affinity for the receptor. Affinity is related to potency. 2. Efficacy once bound to the receptor. Efficacy refers to the maximal effect the drug can elicit. Drugs are described based on the magnitude of two properties:

AGONIST - Has affinity for receptor and efficacy. AGONIST - Has affinity for receptor and efficacy. ANTAGONIST - Has affinity but no efficacy. ANTAGONIST - Has affinity but no efficacy.  Competitive Antagonist Noncompetitive Antagonist Noncompetitive Antagonist Partial Agonist or Partial Antagonist – Partial Agonist or Partial Antagonist – Has affinity but lower efficacy than full agonist. Has affinity but lower efficacy than full agonist. Agonists and Antagonists

Receptor ligand types

Full Agonists (i.e., equal efficacies) that Differ In Potency: Drug Concentration (log scale) % Max Response A B C Compare the EC50s

Agonists That Differ in Efficacy A B C Log Drug Concentration % Max response

Full and partial agonist occupancy and response relationship Response(%) Response (full agonist) Occupancy (both) Response (partial Agonist) Concentration (umol/l)

Inverse agonist Inverse agonist can exist where an appreciable level of activation may exist even when no ligand is present For example: receptors for benzodiazepines, cannabinoids and dopamine Under such condition it may be possible for a ligand to reduce the level of activation. such drugs are known as inverse agonist

Competitive Antagonism Shifts The Agonist D-R Curve (Potency) Drug Concentration (log scale) % Max Response AG + ANT AG alone EC 50

Noncompetitive Antagonism Decreases Agonist Efficacy Log Drug Concentration % Max response AG alone AG + NC ANT AG + higher dose NC ANT

Receptors are said to be ‘spare’ for a given pharmacological response when the maximal response can be elicited by an agonist at a concentration that not result in occupancy of the full complement of available receptors Spare receptor Emax Log Concentration Respones(%) Agonist alone Agonist with noncompetitive antagonist in presence of spare receptor Agonist with noncompetitive antagonist in absence of spare receptor

R R’ LR LR’ L L Effect No effect Possible mechanism for the partial agonist phenomenon. Agonist like to bind to receptor in R’ state and shifts the equilibrium toward more LR’ and makes effect Antagonist like to bind to receptor in R and R” state without any preference and makes no shifts in net equilibrium Partial agonist has a little more affinity for receptor in R’ states than R state and makes partial effect Inverse agonist has more affinity to receptor in R state and shifts the equilibrium toward more LR and make negative response than resting state.

Desensitization and Tachyphylaxis  Desensitization  Tolerance  Refractoriness  Drug resistance  Changes in receptor  Loss of receptor  Exhaustion of mediators  Increased metabolic degradation  Physiological adaptation  Active extrusion of drug from cells How?

Drug Antagonism Pharmacologic Chemical Pharmacokinetic Physiologic Dimercaprol & heavy metals Propranolol & norepinephrine Phenobarbital & warfarine Epinephrine & histamine

Signaling mechanism & drug action

Type of receptors  Ligand gated ion channels  G protein coupled receptors  Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases  Cytokine Receptors  Intracellular receptors

 -amino butyric acid (GABA) Glycine Aspartate Glutamate Acethylcholine Serotonin Ligand gated ion channel (iontropic receptors)

R ions Hyper polarization or depolarization Cellular effects

Adernocorticotropic hormone Acetylcholine Angiotensin Catecholamines Chrionic gonadotropin Follicle stimulating hormone Glucagon Histamine Luteinizing Hormone Seretonin Vasopressin G protein coupled receptors

R + E GG - +- Ions Second messengers Change in excitability Ca 2+ release Protein phosphorylation other Cell effects G protein coupled receptors

Ligand -regulated transmembrane enzyme including receptor tyrosine kinases Insulin Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) Arterial natriuretic factor (ANF) Transforming growth factor  (TGF-  ) Cytokine receptors Growth hormone Erythropoietin Interferones Kinase linked receptors

R/E Protein phosphorylation Gene transcription Protein synthesis Cellular effects Kinase linked receptors

R Nucleus Gene transcription Protein synthesis Cellular effects Nuclear receptors

Well Established Second Messengers Cyclic Adenosine Monophosphate (cAMP) Calcium and Phosphoinositides Cyclic Guanosine Monophosphate (cGMP)

Good Luck