Pharmacodynamics I (2024-2025) PDF

Block 1.1 lectures 2024-2025 lecture Highlighter key Writer Doctor explanation Abbreviation Key information Book...

Block 1.1 lectures 2024-2025 lecture Highlighter key Writer Doctor explanation Abbreviation Key information Book Reviser >> >> Amira Alhassan Abdulaziz Alessa 221-222-223 notes References Student explaintion Deleted  By Dr. ShereenRefaie 10 November 2021 Dr ShereenRefaie  By the end of this lecture, you should: 1.Define pharmacodynamics. 2.Know different targets for drug action 3.Explain different types of drug receptor interactions 4.Know what is drug specificity 5.Interpret dose response curve 6.Identify types of agonists 7.Differentiate between competitive and irreversible competitive antagonists 10 November 2021 Dr Shereen Refaie  What is pharmacodynamics Pharmacodynamics is the studyof what a drugdoes tothe body. The pharmacodynamics process describes all those issues concerned with the pharmacological actions of a drug. Effect of drug on human is pharmacodynamics The effect of human body on the drug is known as pharmacokinetics. For example: the reactions that are triggered For example: how we absorb the drug , how we metabolise it , by this drug , the side effects of drugs , etc... how we take the drug whether orally or through injections etc... : ‫مصطلحات ( معلومة اضافية ) من الدكتورة‬ indications : ‫دواعي استعمال الدواء‬ contraindications : ‫موانع استعمال الدواء‬ 10 November 2021 Dr Shereen Refaie  Drugs just modify(affect) an existing function ,may increase it or decrease In order for most drugs to work, they must be targeted to a specific site in the cell. 10 November 2021 Dr Shereen Refaie  DRUG SPECIFICITY For a drug to be useful as either a therapeutic or a scientific tool, it must act selectively on particular cells and tissues. Every time the same drug enters the it needs to target specific cells or tissues, body it tagets the same cell and the minimizing effects on other parts to reduce side same part of that cell effects and increase effectiveness. On the other hand, proteins that function as drug targets generally show a high degree of ligand specificity; they bind only molecules of a certain precise type. Ligand specificity means that proteins selectively bind only For example: Puzzle parts have to be complementary to with specific molecules each other in order to fit properly or they wont fit. So (ligands), like a “lock and are the drugs, they bind to specific targets expressed by key.” specific cells that's why we call it (drug specificity) 10 November 2021 Dr Shereen Refaie  DRUG SPECIFICITY No drugs are completely specific in their actions. In many cases, increasing the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side effects As we know that the drug will target a specific protein but No drugs are completely specific so a small part of the drug will target another protein - and this is what we name THE SIDE EFFECT 💢all adverse effects are side effects, but not all side effects are adverse. THE SIDE EFFECT are Unavoidable even with Therapeutic doses , and the more the dose is the more side effects are there 10 November 2021 Dr Shereen Refaie  Targets for drug action Enzymes All of them are proteins Carrier proteins Ion channels. 💡 : Always remember that drugs target proteins in the Receptors first place 10 November 2021 Dr Shereen Refaie  1. Enzymes Drug is substrate analog, it may act as: Reversible Attaches to the enzyme for a certain period of time and then Antagonists or inhibitors oCompetitive inhibitor detaches without causing any damage or structural changes are divided into two types : oIrreversible non-competitive inhibitor Drug attaches to the enzyme and changes its shape, so the enzyme gets damaged which is irreversible Drugs are divided into two categories: 1- antagonists or inhibitors:Blocker of the receptor 2- agonists:Activator of the receptor 10 November 2021 Dr Shereen Refaie  2. Carriers molecules Some kinds of drugs target carrier proteins in two ways: 1- Stimulate the carrier proteins to allow the entry of some molecules, eg: Diabetes drugs stimulate carrier proteins to allow entry of glucose into cells 2- Inhibit these proteins to stop the inside entry or leaving of specific molecules 10 November 2021 Dr Shereen Refaie  Here it describes carrier molecules and their role in molecule transport across cell membranes, so Here’s a summary of the transport methods: 1. Facilitated Diffusion: Passive 2. Active Transport: Uses energy to transport down a concentration move molecules against the gradient (no energy needed), concentration gradient, essential for allowing molecules like glucose concentrating substances in or out into cells. of cells. Lipid solubility, concentration gradient, and molecule size determine if a molecule can passively cross the cell membrane 10 November 2021 Dr Shereen Refaie  3. Ion channels are two types: Gateways in the cell membrane which selectively allow the passage of particular ions Any substance that Ligand-gated the ions start going in or out depending on the concentration. activate the channel the name of the channel is based on the ion that is passing through it. beta delta outside: drugs inside: enzyme , hormones or nurotransmiters....etc Ligand-gated ion channels: Open when a ligand (such as a 5 protein subunits alpha hormone, neurotransmitter, or drug) binds to the receptor, allowing ions to pass through. The alpha subunits are typically where the ligand gamma binds, which initiates the opening of the channel. ( Channel Conductor ) 10 November 2021 Dr ShereenRefaie  3. Ion channels Gateways in the cell membrane which selectively allow the passage of particular ions Voltage-gated Change in Electric Charge Voltage-gated ion channels: Open in response to changes in stimulation by membrane potential, allowing ions action potential to flow according to their concentration gradients. Drugs that block these channels, such as calcium channel blockers, can inhibit calcium This process is entry and reduce functions very fast dependent on calcium, like muscle contraction and secretion. 10 November 2021 Dr ShereenRefaie  ( Most comman ) Sensing elements in the system of chemical communications that coordinates the function of all different cells in the body. The receptor can be present: Drugs may be agonist (full or partial) or antagonists 1. On the surface of the cell membrane 2. In the cytoplasm 3. In the nucleus the drug (ligand) and receptor need to be complementary to each other. Receptor Ligand Ligand 10 November 2021 Dr Shereen Refaie  Drug-Receptor (D/R) Interaction Affinity:is the ability of the drug to bind the receptor forming D/R complex. Either drug binds to the receptor on a cell and makes D/R complex and stops (blocker or antagonist) Or The drug continues in making changes in the cell (agonist effect) D/R complex = Drug receptor complex Kd: measures how Ka: measures how long the drug kept Ka Kd fast the drug was able to leave the receptor on being linked to the receptor factors that determine the affinity of a drug: 1- Drug Association (Ka): their binding to the receptor 2- Drug Dissociation(Kd): their detachment from the receptor 10 November 2021 Dr Shereen Refaie  Which pair has higher affinity? -The higher the drug association(Ka) = the higher the affinity of the drug -The higher the drug dissociation(Kd) = the lower the affinity of the drug When a drug binds When a drug to a receptor and associates with a then rapidly receptor for a long disassociates, it has period of time then low affinity. we can say it has high affinity Affinity = Ka/Kd Dr Shereen Refaie 10 November 2021  Drug-Receptor (D/R) Interaction Efficacy (Intrinsicactivity):is the ability of the D/R- complex to produce cellular response. initiate / stimulate Having high ability to bind (high affinity) doesn’t mean you will have high ability to produce cellular response (high efficacy). For example: blockers have high affinity but have zero efficacy. 10 November 2021 Dr Shereen Refaie 💡 When we are studying a drug, we need Maximal to make a dose response curve When efficacy Efficacy = reach its maximum Full level , there is no saturation benefit of A dose-response curve defines the relationship increasing the doses because the result will be the between dose and response based on the same following assumptions: y-axis : ‫ من الدكتورة‬Clinical ‫نقطة‬ Maximal ‫مو شرط المريض يوصل للـ‬ (vertical ) ‫ انما مهم للطبيب‬, ‫ عشان يشفى‬Efficacy 1) Response increases as dose increases = the ‫ان يضع سلامة المريض نصب عينه في‬ ↑Drug dose = ↑ response Until response 👩‍⚕️👨‍⚕️‫المقام الاول‬ the maximal efficacy is reached 2) There is a threshold dose(i.e., a dose below which there is no effect. if you gave a patient a dose below the threshold dose, the drug will have no effect. In this area, there is no response although doses are given. At a x-axis (horizontal) = the dose specific dose, the action starts, this is the threshold dose. 10 November 2021  Doctor’s examples to explain the dose response curve more: Theoretically, because the drug stimulate the receptor, when the dose More explanation: The drug response is just increases, the response should increase. UNTIL! the maximal efficacy is like when you try to pull an all nighter reached. Maximal efficacy = the drug made the maximum stimulation of before an exam to study everything, you’ll the receptor. If the maximal efficacy is reached and you increased the start by understanding then you’ll reach a dose the following could happen: 1) the response will not increase or level where you cant study anymore, decrease(it will keep giving the same effect) 2) It could cause side because you reached your maximum (so effects then toxicity 3) the effect will start decreasing because the cells dont do that!) are exhausted and saturated. A RULE IN PHARMA: All Drugs are Poisons in Large Doses. FOR EXAMPLE: Drugs have ranges of doses that can be given. if a drug has a range of 100mg200mg. You cannot give a patient a dose less than which means any drugs even safe ones, if 100 mg, it will have no effect because 100mg is the threshold, and you they are given in large doses cannot give a patient a dose more than 200mg it will cause side effects (supratherapeutic dose) they will turn and toxicity because 200mg is the maximal efficacy. into poison= side effects will happen then toxicity which could lead to death  E-max Allows to estimate : ✅ The maximal response that the drug can produce y-axis (vertical ) (E-max). ✅ The concentration or dose needed to produce a 50% maximal response = Effective dose 50 (ED50). These two parameters are useful for comparing the potencies of different drugs that produce qualitatively similar effects Which dose should you give the patient as a start? ( ‫) خير الأمور اوسطها‬ Give the patient the ED50(effective dose 50) which is in the middle (not the x-axis (horizontal) minimal or maximal dose.) ED50 = the dose that give 50% of the response in patients 10 November 2021 Dr Shereen Refaie  E-max if you gave a patient the ED50 and… 1- the patient was responding to the drug step 1 more than needed -> give a lower dose. step 2 2- If the patient wasn’t responding -> give a higher dose till the maximal efficacy is reached. If the patient still didn’t respond to the drug after reaching the E-max, then change the drug. 10 November 2021 Dr Shereen Refaie  Drug A and B in this figure more efficacy affect the same receptor. to see the efficacy of the drug, look at how high the curve is. Higher curve = more efficacious. Lower curve = less efficacious. 10 November 2021 Dr Shereen Refaie  To compare the potent of drugs. Look at which drug reaches a specific fixed point with a smaller dose. *ED50 was chosen as a fixed point for comparison. ↓Dose to reach a specific point = ↑Strength step 1 ED50 step 2 1- Draw a horizontal line from the y-axis to the middle of the 1. step 3 curves. 2. find ED50 of Drug A 2- 3- 3. find ED50 of Drug B the drug that needs a lower dose to reach a fixed point (ED50 in this example) is more potent. Drug A is stronger than Drug B: Drug A and B in this figure since Drug A needed a dose less than 1 to reach ED50 while affect the same receptor, and Drug B needed a dose more than 10 to reach ED50. they have the same efficacy. 10 November 2021 Dr Shereen Refaie  Therapeutic index= the relation between Therapeutic index The lethal dose and the effective dose Before the drug is sent to the market, two things should be made: 1- dose response curve (explained before) 2- therapeutic index Imagine the curves like they are a window the wider they get —> far away —> safer the narrower they get —> close to each other—> more toxic ✖️➕➖➗ ‫ اكبر ( البسط ) بيكون‬LD ‫اذا كان الـ‬ Safe = 1 ‫الناتج اكبر من‬ ‫ اكبر ( المقام ) بيكون الناتج‬ED ‫اذا كان الـ‬ LD50 (lethal dose 50)= the dose that killed Not safe = 1 ‫اقل من‬ LD 50 50% of the animals that were tested. Example in the next slide 👇 Therapeutic index = ED 50 ED50 (effective dose 50) = the dose that gave effects in 50% of the patients 10 November 2021 Dr Shereen Refaie  Therapeutic index This is the doctor’s example to explain the therapeutic index: For example, if you have Drug 1 and Drug 2 with the same ED50 but different LD50 Drug 1: Drug 2: LD50 = 200 LD50 = 40 ED50 = 20 ED50 = 20 Therapeutic index = 200/20 =10. therapeutic index = 40/20 = 2. the LD 50 The person will need a drug 10 times person will need a drug only 2 times Therapeutic index = more than the normal dose to cause more than the normal dose to cause toxicity/death. toxicity/death. ED 50 Which ones is safer?? Drug 1 (LD is way higher than ED, and therapeutic index of Drug 1 is larger than drug 2 = it’s safer) 10 November 2021 Dr Shereen Refaie  Therapeutic index This pharmacodynamicparameter is relevant to clinical practice because it determines how safe (or toxic) a drug is. Drug A Drug B 💡 Remember: when the curves are far away from each other, the drug is safer. drug B is safer than drug A 10 November 2021 Dr ShereenRefaie  Types of drug -receptor interactions 1. Agonists: drugs that bind and activate the receptors in some fashion which directlyor indirectlybringabouttheeffect. Agonists have both affinity as well as efficacy  Types of agonists 1- Full agonist = stimulate the receptor and reach the maximal efficacy. 2- Partial agonist = stimulate the receptor but can’t reach maximal efficacy. It has submaximal efficacy or moderate efficacy but not maximal efficacy. 10 November 2021 Dr Shereen Refaie  Has affinity but no efficacy 2-Antagonists (blockers): have affinity for the receptor but NO intrinsic activity at the receptor. An antagonist can bind the receptor but does not produce a response. Zero Efficacy Effect 0 Log Dose 10 November 2021 Dr Shereen Refaie  Yes, their effect is that they block the natural agonist from binding to its receptor 10 November 2021 Dr Shereen Refaie  Antagonists prevent binding of agonists to the receptor and so prevent the response of tissue to the agonist Antagonist Receptor Agonist Example: In the sympathetic nervous system: Like when a person gets scared Norepinephrine (natural agonist) bind to the beta receptor found in the heart, which increases the heart rate (tachycardia). Beta blocker (antagonist) bind to the receptor and block norepinephrine, which decrease the heart rate. 10 November 2021 Dr Shereen Refaie  Yes! 10 November 2021 Dr Shereen Refaie  Effect It can not be measured It can be measured for example:you can only see the person for example:the opening the book;you result of the test can not know if he is actually studying 10 November 2021 Dr Shereen Refaie  Drug action= binding to the receptor and  Drugactions:Theinitialconsequencesthatfollowthedrugbindingtoitsreceptorasactivation activating or of certain enzyme, formation of intracellular second messenger, opening of ion channel. The stimulating it. drug actions can not be observed or measured. Drug effect= the result of binding or blocking.  Drugeffects:Theeventsthatfollowdrugactionappearingasphysiologicalandbiochemical changes in cell function as lowering of blood pressure, lowering of blood glucose, decrease in heart rate. The drug effects can be observed and measured.  Adverse drug effects ( side effects): unintended (may be harmful) response that occurs at normal doses of the drug (e.g., sedation with antihistamines) Beta blockers don’t have actions (they just bind without activating/stimulating the receptor) they have an effect: the result of blocking the agonist. 10 November 2021 Dr Shereen Refaie  Competitive antagonism -It shifts the dose-response curve of the agonist parallel to the right without decreasing its maximal response. When the antagonist and agonist both compete for the same binding site of the receptor. It’s called competitive because the agonist can displace the antagonist if the concentration of the agonist increased (it got stronger) 10 November 2021 Dr Shereen Refaie  Irreversible Competitive Antagonism -It shifts the dose-response curve of the agonist downwards to the right and decreases its maximal response. The antagonist binds to another binding site beside the the binding site of the agonist, but it changes the shape of the receptor which prevents the agonist from binding to it. It’s called irreversible because the receptor is no longer functioning. The agonist will recognize the receptor only after the cell replaces it with a new functioning one. 10 November 2021 Dr Shereen Refaie  [email protected] Ext: 7874 10 November 2021 Dr Shereen Refaie We have a drug that has 140 Association constant (Ka) How many α are there in Ligand-Gated ion and 2 Disassociation constant (Kd) channel ? Count this drug Affinity : A) 1 A) 70 B) 2 B) 80 C) 3 C) 90 We have a drug that has 140 Association constant (Ka) How many α are there in Ligand-Gated ion and 2 Disassociation constant (Kd) channel ? Count this drug Affinity : A) 1 A) 70 ✅ B) 2 ✅ B) 80 C) 3 C) 90 SLIDE 16 SLIDE 12  team Wishes you the best