Problem 3_Pharmacology 2024.pdf

1 Pharmacodynamics Prof. Kannan Sridharan Department of Pharmacology & Therapeutics CMMS, AGU. Power of drug in the body 2 ...

1 Pharmacodynamics Prof. Kannan Sridharan Department of Pharmacology & Therapeutics CMMS, AGU. Power of drug in the body 2  What happens to the drug once it is in tissues? Once the drug is inside the cells, it may interact or may not. If it doesn’t interact, it is just temporarily stored in the target organ. If it interacts, it produces the changes that lead to the observed effect of the drug. in the body Drug either L I interacts not interact stored produce changes temporarily - - that lead to the in target organ observed effect In the body 3  Drugs do not impart new functions to any system, organ or cell; they only alter the pace of ongoing activity. Gene Therapy Drugs (except those gene based) do not impart new functions to any system, organ or cell; they only alter the pace of ongoing activity. not add new functions to drugs do any system or. organ They only alter the pace of ongoing activity based the only exception : gene 4  Ways of altering the physiological functions. Adrenaline in heart Stimulation Orlistat inhibits intestinal Inhibition lipase Insulin in diabetes Replacement mellitus Cytotoxicity Anticancer drugs The most common ways of altering the physiological functions include stimulating it’s function, inhibiting the function, replacing some molecules that are lost or synthesized less, or kill the cells. of altering ways ↓ Stimulatonfasteningthe functioa the function. Inhibition 2 intestinal lipase orlistat inhibits. replacement 3 thats absent molecule replacing a to diabetic Insulinadministered Patients with low Insulin. cell) cytotoxic (killing 4· the patient this is needed when treating a with cancer 5 Most common way of drug interaction with target cells. - The most common mechanism by which drugs interact with the target cells and produce effect include receptors followed by interactions with enzymes and ion channels. Receptors are the most common a acts. way a drug orlistat doesn't bind to a receptor It binds to an enzyme (intestinal lipase) to channels drugs bind lon , they interact , produce changes to target molecule, relay information to cell , to either Stimulate, inhibit or kill. 6  Other mechanisms by which drugs act.. Activated charcoal – to adsorb ingested drugs/poisons Ispaghula husk – laxatives in treating constipation Antacids – to neutralize gastric acid in peptic ulcer disease The other ways include chemical, physical and enzymatic actions. There are other ways of observing drug effects not binded to any receptors, but because of their attribute physical 1. charcao given to patients who have taken oral poison 2. antacid vicer given to gastric 3. Isaghula constipation to treat given 7 Most common ways of drug interaction with target cells. The largest number of drugs bind through specific regulatory macromolecules the sites which are called ‘receptors’. macromolecules receptors are large memberance cell (mostly protein) located In 8  Receptors Receptors are protein macromolecules mostly located on the cell membranes but in exceptional cases, they may also be located intracellularly in the cytoplasm. The receptors are there because there are endogenous chemical molecules binding to them and produce some effect. 9 After the messenger binds to the receptor, only the message is transferred without allowing the messenger into the cell. After the messenger binds to the receptor, only the message is transferred without allowing the messenger into the cell. There is a confirmational change in the receptor structure that sends the message. 10 Signal transduction 11 After the drug leaves, the receptor goes back to the normal shape. A receptor serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function. There are two domains for a receptor: Ligand-binding domain where the chemical messenger binds to the receptor and the effector domain where the effect of binding is observed. for receptor Two ways I ligand-binding effector effect of domain binding - chemical messenger is observed binds to the domain 12  Receptors are selective in binding to the drugs. Each active site of the receptor allows only certain types of messenger to bind as they are highly selective, and the sites have different size, shape and structure. Hence, only molecules with best fit will be allowed to bind to the receptors. receptors are highly selective : think Plug and socket 13  Affinity & Intrinsic activity These are independent properties. The ability to bind with the receptor is called affinity, and the capacity to induce a functional change in the receptor designated is called intrinsic activity. These two are independent processes. Affinity : ability of with receptor drug to bind Intrinsic activity : Capacity to induce a functional In the receptor change 14  Agonist or Full agonist Has affinity and maximum intrinsic activity. Agonists have both affinity and maximal intrinsic activity agonist Partial agonist antagonist affinity affinity affinity no Intrinsic activity maximal intrinsic submaximal Intrinsic activity activity 15  Partial agonist Has affinity and sub- maximal intrinsic activity. Partial agonists have affinity and sub-maximal intrinsic activity 16  Antagonist Has affinity and no intrinsic activity. Antagonists have only affinity but no intrinsic activity 17 Receptor 100 Full agonist maximum effect response 75 (%) Partial 50 agonist 25 0 Antagonist binds but no effect on Drug concentration receptor 18  Types of receptors Ligand-gated ion channel Cell-surface Enzyme-linked GPCR Intracellular Intracellular Broadly, receptors can be classified into cell surface (located on the cell membranes) and intracellular receptors (located inside the cells usually in the cytoplasm). There are 3 types of cell-surface receptors. we classify receptors based on their location L I cell surface intracellular cell memberane I ligand gated lon channels. entyme 2 linked 3 GPCR. 19  Ligand-gated ion channel Ligand-gated ion channels remain closed in the absence of drug and when the drug binds to the channel, it opens and allows either influx of an ion or efflux of ion. This results in the change in the membrane potential of the cells resulting in either stimulation or inhibition of the cells. ligand gated ion channels, enclose ion selective channels (for Na+, K+, Ca2+ or Cl¯) within their molecules. Agonist binding opens the channel and causes depolarization/hyperpolarization/changes in cytosolic ionic composition, depending on the ion that flows through. Potassium Sodium to Intracellular extracellular extracellular to intracellular calcium chloride extracellular to intracellular 20 Enzyme-linked receptors This class of receptors are utilized primarily by peptide hormones, and are made up of a large extracellular ligand binding domain connected through a single transmembrane helical peptide chain to an intracellular subunit having enzymatic property. On binding the peptide hormone to the extracellular domains, the monomeric receptors move laterally in the membrane and form dimers. Dimerization activates tyrosine-kinase (RTK) activity of the intracellular domains so that they phosphorylate tyrosine (t) residues on each other, as well as on 21 several SH2 domain substrate proteins (SH2-Pr). The phosphorylated substrate proteins then perform downstream signaling function. 21  attached/joined of receptors G-protein coupled receptors (GPCR) belong body 90 % 3. to this type The receptor consists of 7 membrane spanning helical segments of hydrophobic amino acids. The amino terminus of the chain lies on the extracellular face, while the carboxy terminus is on the cytosolic side. GPCRs interact with G proteins in the plasma membrane. When an external signaling molecule binds to a GPCR, it causes a conformational change in the GPCR. This change then triggers the interaction between the GPCR and a nearby G protein. In unstimulated cells, the state of G alpha (orange circles) is defined by its interaction with GDP, G beta-gamma (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Upon receptor stimulation by a ligand called an agonist, the state of the receptor changes. G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. when no molecule is At phase resting , all subunits binded to extracellular segment , beta gamma) and It are together (Alpha , , to has gap But. when autogonist bind extracellular surface , there are changes separated by happening. Alpha gets to beta 3 and GDP converts gamma , it can more active so atp becomes (next slide - do one of the 4 functions 22  Gs – Increase cAMP Gi – Decrease cAMP/Open potassium channel Gq – Increase Calcium channel Three types ofG protein increase calcium Gq- as > - Increase camp Gi decrease camp Two ways: channels I opening potassium and they move out. in selected tissues 2 , receptors also cause gi a fall in camp levels 23  Intracellular receptors usually in cytoplasm In contrast to the above 3 classes of receptors, these are intracellular (cytoplasmic or nuclear) soluble proteins which respond to lipid soluble chemical messengers that penetrate the cell. The receptor protein (specific for each hormone/regulator) is inherently capable of binding to specific genes and either increase or decrease their expression. Because it involves changing the genetic expression, it takes some time for this action to be mediated unlike the previous three receptors. for this type , for the drug to bind It has to have the ability to cross cell membrane. So the drug has to small and have lipophilicity. then nucleus and change go to the some genes are doing ways time their jop- they take a longer bind to the gene because they and alter their expression 24  Receptor desensitization & downregulation Drug holidays A process that results in a cell or tissue being less responsive to further stimulation after a cell or tissue has been exposed to an agonist. Multiple mechanisms of desensitization exist depending on the cell, tissue, receptor, and ligand type. Desensitization can result in transcriptional and translational changes that alter receptor levels and expression and may take hours or days. More rapid desensitization can also occur as a result of conformational changes at individual receptors or changes in receptor localization. Desensitization can result in decreased therapeutic efficacy by limiting the drug response over time. Clinically, this can impact dosing requiring larger doses, drug holidays, or a combination of drug targets to achieve the desired therapeutic response over longer periods of time. 25 Dose and effect Respon se As we increase the close , effect increase 26  Dose-effect curve or Dose-response curve Therapeutic index (in animals) = lethal effective LD50/ED50 Therapeutic index (in humans) = to XIC effect TD50/ED50 no lethal dose in humans ED = Effective dose TD = Toxic dose LD = Lethal dose The therapeutic index is a ratio [LD50/ED50] of the dose at which 50% of animals experience the toxic effect to the dose at which 50% of animals experience the therapeutic effect. In humans, the therapeutic index is a ratio [TD50/ED50] of the dose at which 50% of subjects experience the toxic effect to the dose at which 50% of patients experience the therapeutic effect. of effect Three type > effective effect ED- > toxic TD - effect (side effects) LD > lethal effect (dose that kill animals) 27  Clinical relevance of Therapeutic index A Wide therapeutic index Narrow therapeutic B index Narrow therapeutic index (NTI) drugs are drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. Drugs with wide therapeutic index are preferred. IndeX Therapeutic I h narrow wide of index small difference this type - - lead Is preffered in dose may to therapeutic failure 28  gives idea how safe drug is Clinical relevance of Therapeutic index LD50 = 300 mg Drug A -3 ED50 = 100 mg LD50 = 300 mg Drug B = 0. 5 ED50 = 600 mg 29  Clinical relevance of Therapeutic index Drug A Drug B ED50 5 mg/kg 6 mg/kg P LD50 50 mg/kg 12 mg/kg When more than one drug is available for treating a particular disease, better to choose the drug with higher therapeutic index. A 50 B B. = 10. = 2 S better therapeutic effect drug A the - the larger , 30  A different B same safer than B So A seems drug 31 We use only those compounds with therapeutic index above 1 as drugs in clinical practice. 32  X axis YaXIS Drug potency & efficacy efficacy : maximum effect seen in the drug Potency : dose that produce 50% of Maximum activity 33  Drug potency & Efficacy t potency Potency refers to the amount/concentration producing a defined response usually we refer to the 50% of maximum effect. Efficacy refers to the maximum effect observed with a drug. 34  first see efficacy efficacy : all are same Potency : A most Potent A : more efficacy A Is preffered So drug A is chosen drug eff Same A Best with efficacy first we go and choose It. But if more same efficacy, than one drug has go for we most potent 35 Combination effect of drugs combining drugs when treating patients most likely to use more than a drug 36 ased Drug A Drug B Additive effect Orlistat (Alone = 5 kg) + Liraglutide (Alone = 5 kg) = Orlistat + Liraglutide (together = 10 kg) Synergistic Drug A Drug B effect Orlistat (Alone = 5 kg) + Liraglutide (Alone = 5 kg) = Orlistat + Liraglutide (together = 15 kg) Additive effects: The effect of the two drugs is in the same direction and simply adds up: effect of drugs A + B = effect of drug A + effect of drug B. Synergistic effects: The effect of combination is greater than the individual effects of the components: effect of drug A + B > effect of drug A + effect of drug B 37  Antagonist drugs reduction Antagonistic Drug A Drug B effect Orlistat (Alone = 5 kg) + Drug X (Alone = 5 kg) = Orlistat + Drug X (together = 3 kg) All the drug combinations in the last two slides are just for your understanding based only on the drug class taught to you as of now. They are not real-time examples (not true). additive : 5 + 5 = 10 Synergetic : 5 +5 = 15 5 +5 3 antagonist : = 38 Receptor antagonist Higher agonist concentrations can displace the competitive antagonist Higher agonist concentrations cannot displace the non- competitive antagonist Competitive antagonist: The antagonist is chemically similar to the agonist, competes with it and binds to the same site to the exclusion of the agonist molecules. Antagonist ↓ & competitive non-competitive - happens between - doesn't have the same structure as two drug - chemically similar agonist , so cannot bind to. it Structure agonist to - binds to different site - competes and bind but non competitive to the same site of antagonist inhibits agonist the receptor 39  Drug action Vs. Drug effect mechanism of action orlistat action : Inhibiting lipase effect : reduced body weight 40  Summary Mechanisms of drug action: Receptor & Non-receptor mediated. Types of receptors Agonist, Partial agonist, & Antagonists LD50, ED50, TD50, & Therapeutic index Drug potency & Efficacy Additive, Synergistic & Antagonistic effects Receptor antagonism: Competitive & Non-competitive Drug action vs. Drug effect 41 Questions/Clarifications: Office @ 2-063; Student office hours: Thursdays 8-10 AM. Email: [email protected] Telephone: 17239794 42