Pharmacodynamics Collected and Prepared By S Bohlooli Ph

Pharmacodynamics Collected and Prepared By S. Bohlooli, Ph. D

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

Molecular pharmacology : n Molecular pharmacology is concerned with studies of basic mechanisms of drug actions on biological systems. n The idea that drugs act upon specific sites (receptive substance) began with John New Port Langley (18521926) of Cambridge. n However the word ‘receptor’ is given by Paul Ehrlich (1854 - 19 15). n 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 (1885 -1941), a professor of pharmacology at Kings College London.

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

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

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

Quantitative aspects of drug-receptor interaction

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

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

When [D] = KD [DR] = 0. 5 RT 1. 00 [DR]/Rt 0. 75 0. 50 0. 25 0. 00 0 5 KD 10 [D] 15 20

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

Relation between drug dose & clinical response

Drugs are described based on the magnitude of two properties: 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.

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

Receptor ligand types

% Max Response Full Agonists (i. e. , equal efficacies) that Differ In Potency: A B C Compare the EC 50 s Drug Concentration (log scale)

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

Full and partial agonist occupancy and response relationship 100 Response(%) Response (full agonist) Occupancy (both) 50 Response (partial Agonist) 0. 01 0. 1 Concentration (umol/l) 1. 0 10. 0

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

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

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

Spare receptor 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 Agonist with Agonist full complement of availablenoncompetitive receptors noncompetitive alone Respones(%) Emax Receptors antagonist in presence of spare receptor Log Concentration antagonist in absence of spare receptor

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

Desensitization and Tachyphylaxis ØDesensitization ØTolerance ØRefractoriness ØDrug resistance ØChanges in receptor ØLoss of receptor How? ØExhaustion of mediators ØIncreased metabolic degradation ØPhysiological adaptation ØActive extrusion of drug from cells

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

Signaling mechanism & drug action

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

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

Ligand gated ion channel (iontropic receptors) ions R Hyper polarization or depolarization Cellular effects

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

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

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

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

Nuclear receptors Nucleus R Gene transcription Protein synthesis Cellular effects

Well Established Second Messengers n Cyclic Adenosine Monophosphate (c. AMP) n Calcium and Phosphoinositides n Cyclic Guanosine Monophosphate (c. GMP)

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