YR1 Lecture 1H - Introduction to Pharmacodynamics 1 - Prof Gerald Muench 2019 (1).pdf

Introduction to Pharmacodynamics (Pharmacodynamics I) Yr 1 Prof Gerald Muench School of Medicine University of Western Sydney LEARNING OBJECTIVES Define the term pharmacodynamics Describe the concept of receptors and their significance Discuss the mechanisms of action of the four different receptor...

Introduction to Pharmacodynamics (Pharmacodynamics I) Yr 1 Prof Gerald Muench School of Medicine University of Western Sydney LEARNING OBJECTIVES Define the term pharmacodynamics Describe the concept of receptors and their significance Discuss the mechanisms of action of the four different receptor types Define and compare affinity, efficacy and potency Discuss the measurement of risk of drugs Pre-prep before the lecture Video: https://www.youtube.com/watch?v=9V8T8X ZsrcU Reading: https://www.nps.org.au/australianprescriber/articles/pharmacokineticsmade-easy-10-pharmacodynamics-theconcentration-effect-relationship#1-whatis-pharmacodynamics Pharmacodynamics Definition: study of the mechanism of drug action on living tissue, i.e., the response of tissues to specific chemical agents at various sites in the body “What the drug does to the body” Mechanism of action of drugs – Drugs that work by interacting with a protein - Receptors  Carrier molecules  Ion channels  Enzymes – Drugs that work by chemical action – Drugs that work by physical action What are the drug targets? Four major protein targets for drugs  Receptors  Carrier molecules (Transporters)  Ion channels  Enzymes Receptors Receptors Definition: Receptors are complex macromolecules to which endogenous mediators (eg. hormones, neurotransmitters) bind and initiate changes in cellular function Most receptors are embedded in cell membranes (and only a few are found inside the cell) To reach intracellular receptors drugs must be lipid soluble to pass through the cell membrane All receptors that exist in the organism have physiologic roles, and no receptor has been specifically ‘allocated’ for drugs Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-6, Pg 8 Receptors Definition: Receptors are complex macromolecules to which endogenous mediators (eg. hormones, neurotransmitters) bind and initiate changes in cellular function Most receptors are embedded in cell membranes (and only a few are found inside the cell) To reach intracellular receptors drugs must be lipid soluble to pass through the cell membrane All receptors that exist in the organism have physiologic roles, and no receptor has been specifically ‘allocated’ for drugs Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-6, Pg 8 Main Types of Receptors Ligand-gated ion channels G-protein-coupled receptors Tyrosine kinase-linked receptors Nuclear receptors (Nitric oxide receptors. e.g. soluble guanylyl cyclase (sGC)) Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-13, Pg 15 Ligand-gated ion channels Ligand-gated ion channels are coupled directly to ion channels (ligand-gated ion channels) and their activation leads to ion channel gate) opening and movement of certain ions through the cell membrane This ionic movement causes changes in resting membrane potential These receptors are very fast; important examples are - nicotinic acetylcholine receptor (muscle contraction) - GABAA receptor (inhibitory NT – target for alkohol, benzodiazpines) Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-13, Pg 15 Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-13, Pg 15 G-protein coupled receptors G-protein coupled receptors are coupled to various second messengers such as cyclic adenosine monophosphate (cAMP) via membrane bound G-proteins (there is a family of different G-proteins) Second messengers may produce several intracellular changes  Ion channel modulation  effect on resting membrane potential or muscle contractility (via regulating Ca2+ entry)  Activation of certain enzymes  Release of Ca2+ from intracellular stores; Ca2+ appears to control many important intracellular processes Examples are muscarinic receptors for acetylcholine and adrenergic receptors for adrenaline Signal Amplification and Termination in Gprotein signalling Amplification: Effect of G-protein coupled receptors does not occur in linear fashion; instead it is significantly amplified: – Single drug molecule binds to receptor; this activates up to 100 G-proteins – Each G-protein activates one adenylyl cyclase molecule which then produces up to 1,000 cAMP molecules from ATP – Each cAMP activates one protein kinase, which may act upon 1,000’s of substrate molecules (other enzymes) Termination: – cAMP is quickly broken down by phosphodiesterase Tyrosine Kinase Receptors Tyrosine Kinase Receptors are directly linked to kinases which cause phosphorylation and activation of certain intracellular proteins (eg. enzymes and regulatory proteins) and thus cellular effects Tyrosine kinase is the most common receptor/enzyme complex which, when activated by an agonist, produces phosphorylation of tyrosine residues in intracellular regulatory proteins Examples for type 3 receptors are insulin receptor, receptors for cytokines, and receptors for various growth factors Important targets for cancer therapy Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-13, Pg 15 Nuclear Receptors Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-13, Pg 15 Nuclear Receptors are the only receptors located inside the cell (cytoplasm or cell nucleus) After formation drug-receptor complex interacts with DNA and cellular effects are produced as a result of gene activation and subsequent protein synthesis This is a slow process compared to other types of receptors and often takes hours or more to produce the effect All steroid hormones and drugs (very lipid soluble compounds) act on such receptors, as well as thyroid hormones and vitamin D Concepts in Pharmacodynamics Drug Specificity Modern drugs are made to interact with a specific binding-site in order to be clinically useful (selectivity) Targets of drugs generally also show a high degree of physiological ligand specificity THEREFORE: Drugs are often similar to the physiological (natural) ligands Complete selectivity, however, is difficult to achieve because: – the same target protein can have different functions in different locations – many functionally different target proteins are structurally similar (evolution uses the protein motive for different functions) Lack of specificity is one of the major causes of side effects Drug-Receptor Binding Most drugs produce their effects by non-covalent binding to target molecules Such bond is almost always reversible and occurs via – electrostatic forces such as ionic bonds (opposite charges) and hydrogen bonds – weak electrostatic van der Waals forces Strength and duration of the bonding depends on number of such bonds, which in turn depends on how complementary in shape the drug and the target are Only rarely the bond is irreversible via strong covalent bonds Receptor Occupancy In general, pharmacological response is directly proportional to receptor occupancy (number/fraction of receptors to which drug molecules have adhered to) Receptor occupancy depends on: – drug concentration (depends on dose) – drug affinity Drug with high affinity will achieve a large degree of receptor saturation at low concentrations Dissociation Constant, KD, for Drugreceptor Interactions k+1 L+R k-1 L-R Complex (C) Kd (the dissociation constant) is the ratio of the backward and forward reaction constants  Kd is equal to the concentration of drug required to occupy 50% of the receptor sites  Lower Kd reflects higher receptor affinity – less drug is required to bind the same percentage of receptors and activate signallinh Rang et al. 1999. Pharmacology (4th ed.). Fig 1.1, Pg6 Dose-response Curve Dose-response relationship - drug concentration plotted on the x-axis and the effect on the y-axis; its shape is a hyperbola Drug effect reaches a plateau (maximum) because there is a finite number of receptors The log of the drug concentration is plotted versus the effect; such plot is a sigmoid curve Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-19, Pg 21 Affinity, Efficacy and Potency Affinity is of a drug is its ability to bind to its biological target (receptor, transport system) – readout: EC(50), measured in mol/l Potency is relative amount or concentration of drug that has to be present to produce a desired physiological effect – readout: EC(50), measured in mol/l Efficacy is its maximum ability to activate receptors after binding and elicit a desired physiological effect – readout: effect measured in % of maximum Affinity is of a drug is its ability to bind to its biological target (receptor, transport system) Potency is relative concentration of drug that has to be present to produce a desired effect Efficacy is its maximum ability to activate receptors after binding and elicit a response Parameters of Benefit and Risk EC50 / ED50: median effective concentration / dose which refer to the dose required to produce a related drug effect in 50% of the subjects TD50 (median toxic dose): dose required to produce a toxic effect in 50% of the subjects LD50: In animal studies, toxicity may be measured by death. LD50 is the dose required to produce death in 50% of the tested animals Therapeutic Index (TI) TI=LD50/ED50 Parameters of Benefit and Risk - the Therapeutic Index (TI) The therapeutic index (TI; also known as therapeutic ratio) is a ratio that compares the blood concentration at which a drug causes a therapeutic effect (EC50) to the amount that causes - death (in animal studies) – LD50 - toxicity (in human studies) – TD50 Eur J Clin Pharmacol. 2015; 71(5): 549–567. Published online 2015 Apr 15. doi: 10.1007/s00228-015-1832-0 Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide Therapeutic Index (TI) TI=LD50/ED50 Groupwork question: Some drugs form irreversible covalent bonds with their target proteins. Discuss advantages and disadvantages of these type of drugs. MCQ Which drug target changes the structure of the compound it interacts with? 1. Acetylcholine receptor 2. Glucose transporter 3. Co-enzyme P450 4. Sodium Channel 5. Estrogen receptor