Adobe Systems PHARMACODYNAMICS [USEMAP] Adobe Systems Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slidesis against the law. Pharmacokinetics (PK) Pharmacodynamics (PD) Deals with the fate of the drug in the body – processes of Absorption, Distribution Metabolism Excretion …“ADME“ deals with the mechanism of action (e.g. receptor sites, molecular level of action..) „What the body makes with the drug“ „How does it work“ PHARMACOLOGY [USEMAP] Adobe Systems Pharmacodynamics (how drugs work on the body) ̶The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action ̶ ̶Main targets – cellular, molecular, genetic level… •Therapeutic effects •Adverse effects ̶ ̶ ̶ [USEMAP] Adobe Systems Mechanism of drug actions non-specific specific Receptor non-receptor [USEMAP] Adobe Systems I. Non-specific drug effects …through by the general physical-chemical properties of substances - no specific chemical and structural configuration of drugs is needed - influencing pH - oxidating and reducing agents - protein precipitation - adsorbents / detergents - chelating agents [USEMAP] Adobe Systems a. based on osmotic properties §e.g. salinic laxatives (magnesium sulphate, lactulosa) §osmotic diuretics (mannitol) [USEMAP] Adobe Systems b. influencing acid-base balance §Antacids ̶aluminium hydroxide ̶magnesium carbonate ̶calcium carbonate ̶sodium bicarbonate - §pH modifiers (blood, urine) -sodium bicarbonate, ammonium chloride - [USEMAP] Adobe Systems c. based on oxido – reducing properties §e.g. 3% hydrogen peroxide, boric acid, fenols § chlorhexidine act as antiseptics Ø [USEMAP] Adobe Systems d. chelates (chelating agents) §ethylenediaminetetraacetic acid (EDTA) is a chelating agent, it can form bonds with a metal ion §dexrazoxane - a cyclic analog of EDTA administered with anthracyclines to prevent cardiotoxicity → Fe2 + ions Ø [USEMAP] Adobe Systems II. Specific drug effects effect depends on the specific molecules configuration Ø most drugs act (bind) on receptors Ø in or on cells Ø form tight bonds with the ligand Ø….on ion channels or carriers [USEMAP] Adobe Systems Specific drug effects Ømany drugs inhibit enzymes ̶A very common mode of action of many drugs Ø in the patient (ACE inhibitors) Ø in microbes (sulfas, penicillins) Ø in cancer cells (5-FU, 6-MP) Ø some drugs bind to: Ø proteins (in patient, or microbes) Ø DNA (cyclophosphamide) Ø microtubules (vincristine) ̶ [USEMAP] drug reaction A. RECEPTORS B. ION CHANNELS C. ENZYMES D. CARRIERS Agonist Antagonist Direct Signal Transduction No effect Endogenous mediator blocked Ion channels Open/closed Enzymes Activation/inhibition n channel modulation DNA transcription Blockers Modulators Flow is blocked Increasing or decreasing probability of opening Inhibitor False substrate Prodrug Reaction is inhibited Abnormal metabolites Active substance normal transport Inhibitor Transport is blocked Rang and Dale Pharmacology, 2017 [USEMAP] Adobe Systems A. Receptor – effector system = complex of processes extracelullar signal -------------> intracell. signal cascade---------> effector (own effect) • üreceptor = protein, which interacts ligands –involved in signal transduction üeffector = enzyme, ionic channel etc. change in the activity leads to the effect of drug üligand (signal molecule) = molecule able to bind to specific receptor –endogenous - neurotransmitters, hormones –exogenous - xenobiotics, drugs ̶ [USEMAP] Adobe Systems Receptor classification [USEMAP] Adobe Systems Receptor classification [USEMAP] Type 1 Receptors connected with ion channels Type 2 G-protein coupled receptor Type 3 Receptor tyrosin kinases Type 4 Intracellular (nuclear) receptors Place Membrane Membrane Membrane Intracellular Efector Ion channel Channel or enzyme Enzyme Gene transcription Binding direct G-protein direct DNA mediated Examples Nicotin-cholinergic receptor, GABA receptor Muscarin-cholinergic adrenoreceptors Inzulin, growth factor, cytokin receptor Steroids, thyroid hormon receptors Structure Oligomer composed by subunits surrounding center of the channel Monomer (or dimer) containing 7 transmembrane helical domains. Single transmembrane helical domain interconencted with extracelular kinase Monomer structure with separate receptor and DNA binding domain 4 main type of receptors Rang and Dale Pharmacology, 2012 [USEMAP] Adobe Systems Receptor – effector system ̶Affinity üthe ability of the ligand to bind to the receptor § ̶ Instrinsic activity ü ability to evoke an effect after binding to receptor § ̶!!!the presence of sufficient number of receptor for the induction of pharmacological effect is essential as well as sufficient amounts of receptor ligand!!! ̶ [USEMAP] Adobe Systems Receptor – effector system lock and key image [USEMAP] Adobe Systems Ligand classification (intrinsic activity) AGONISTS [USEMAP] Adobe Systems Ligand classification Antagonists üIA = 0 üBlocks agonist binding to receptor Inverse agonist üIA = -1 üStabilizes the receptor in the constitutive activity Image44 [USEMAP] Adobe Systems Relation between dose and effect Receptor-effector system [USEMAP] Spectrum of ligands Image48 [USEMAP] Adobe Systems Antagonism ̶ competitive reversible non-competitive irreversible ̶ • at the receptor level at the function level [USEMAP] Adobe Systems Antagonism Competitive üligands compete for the same binding site ü c of antagonist decreases agonist effect and inversely üthe presence of antagonist incerases the amounts of agonist needed to evoke the effect ü Non-competitive üallosteric antagonism üirreverzible bounds ü c of agonist does not interrupt the effect of antagonist [USEMAP] Adobe Systems Regulation of receptor function [USEMAP] Adobe Systems Receptor desensitization ̶reducing the sensitivity of the receptors after repeated agonist exposure ̶ ̶Tachyphylaxis – acute drug „tolerance“ ̶reduced sensitivity to the active substance evolving quickly (minutes) → distortion of the signal cascade ̶the reactivity of the organism returns to the original intensity after the elimination of the substance ̶Ex. of tachyphylaxis – nitrates administration, ephedrine ̶ ̶Tolerance – reduced sensitivity to the active substance, arising from the repeated administration of the drug (days – weeks) → down-regulation, internalization of the receptors ̶to achieve the original effect required increasingly higher doses of drug ̶the original reactivity of the organism returns to a certain period of time after discontinuation of the drug ̶Ex. of tolerance – opioids administration Regulation of receptor sensitivity and counts [USEMAP] Adobe Systems Hypersensitivity üincerase of receptor sensitivity/counts after chronic anatagonist exposure Rebound phenomenom after discontinuation of long-term administered drugs return to its original state or ↑ intensity of the original condition (hypersensitivity of receptors to endogenous ligands → up-regulation) Example: chronic administration of β blockers ü Regulation of receptor sensitivity and counts [USEMAP] Adobe Systems B. Non-receptor mechanism of action Interaction with „non-receptor“ proteins ̶1. enzyme inhibition ̶2. block of ion channels ̶3. block of transporters „non-proteins“ ̶binding to cellular components (ATB-ribosomes, hydroxyapatit, tubulin etc.) ̶ [USEMAP] Adobe Systems 1. Enzyme inhibition Competitive or non-competitive enzyme inhibitors ̶ §reversible §acetylcholinesteraze– physostigmine §phosphodiesteraze – methylxantine § §irreversible: §Cyklooxygenaze – ASA (aspirin) §MAO-B – selegilin §aldehyddehydrogenaze– disulfiram [USEMAP] Adobe Systems 2. Ion channels §Calcium channel blockers (nifedipin, isradipin…) § §Potassium channel blockers (flupirtin – selective neuronal potassium channel modulator, oral antidiabetics…) § §Natrium channel blockers – local anesthetics ̶ [USEMAP] Adobe Systems 3. “Carriers“ §Proton pump inhibitors (PPIs) – omeprazol §Na+/K+ ATPasa inhibitors – digoxin ̶ [USEMAP]