BIOS101 W12 - Introduction to Pharmacology and Pharmacodynamics PDF

INTRO ON PHARMACOLOGY AND PHARMOCODYNAMICS - Introduction to Drug Discovery, Drug Action, Drug Targets, Drug Development, - Difference between DRUG and MEDICINE - Pharmacokinetics and Pharmacodynamics - Describe the four main drug targets and where drugs come from - The study of t...

INTRO ON PHARMACOLOGY AND PHARMOCODYNAMICS - Introduction to Drug Discovery, Drug Action, Drug Targets, Drug Development, - Difference between DRUG and MEDICINE - Pharmacokinetics and Pharmacodynamics - Describe the four main drug targets and where drugs come from - The study of the effect of DRUGS on the function of living systems -- anything including humans, animals, microbes... - Our focus in therapeutic drugs for humans - Pharmacology is: - The discovery and development of new medicinal products to treat diseases - Improve drug effectiveness and reduce unwanted side effects - Understanding individual variation in drug response -- personalized medicine - Understand why some drugs cause tolerance and addiction Physiology of How Diseases Come About - By understanding the mechanisms, we design drugs and drug targets - We are all multicellular with a system of chemical communication we use to coordinate our cells and organs -- without them we wouldn't be able to function at all - Endogenous chemical molecules have evolved to fine-tune the control of cells and physiological functions -- neurotransmitters and hormones - It's not just the stimulus, but also the preventative side as well -- if you want to contract something, you have to be able to relax it - Contract and relax -- muscles - Stimulate and inhibit -- mood - Reduce and increase -- heartbeat, it can't be going fast all the time, nor too slow - Drugs/medicines hijack these control steps to treat sickness and disease, but we MUST know the mechanisms behind them What is a Drug? - A drug is a substance that when introduced to the body, produces a biological effect for an intended purpose - Therapeutic -- treat, cure, diagnose or prevent disease - Lifestyle -- caffeine in coffee, street drugs, performance improvement (doping, magnesium...), drugs and medicines taken for non-medical reasons - A medicine is a substance preparation that contains one or more drugs, administered with the intention of producing a therapeutic effect - Medicines contain other substances (stabilizers, solvents, etc.) to make them more convenient for use - A tablet isn't just made from drugs, it's made up of many other substances that allow it to be able to get ingested Can a Drug be a Poison? - Poison -- intended to have harmful effects on the body. If the drug has such effects, then it can be considered a poison. Drugs can be poisons - Botulinum toxin -- the most lethal poisonous drug - 2 kg of Botulinum can wipe out ALL people - All drugs are actually poisons. The dose determines whether a drug is therapy or poison - At therapeutic levels drugs are safe and effective -- Botox - Smooths out wrinkles - Botox -- shortened for botulinum toxin Where Drugs Come From? - From natural products -- plants, microbes, animals - By changing the structure of an existing molecule - Serendipity -- by accident, we might be testing a drug for a certain indication, but its actual effect is surprising on something else - Rational/informed drug design -- by studying disease processes, understanding physiological pathways behind diseases and then identify drug targets - Adapting an existing drug to a new therapy - repurposing From Natural Products - Poppy seed can produce anti-pain effects - It produces Morphine -- painkiller - Morphine is super addictive - Willow tree and coal tar can produce salicylic acid - painkiller - However, salicylic acid is very bitter and non-compliable - Back in the 19^th^ century, the main energy source was coal, main waste product was coal tar - Coal tar was packed with chemicals - These chemical were used in the dye industry - Most of the current pharmaceutical industry were once dye industries - They wanted to come up with other ways to use these chemicals, not just for dyes - So, Bayer used the already known chemicals to see whether they can make morphine less addictive and salicylic acid less bitter - Within a 2-week period, he created these 2 drugs: - Heroin -- derived from morphine - Aspirin -- derived from salicylic acid - Drugs coming from plants, we've taken a chemical structure, and we've adapted it to make it a better molecule Serendipity -- By Accident - Sildenafil -- developed as an anti-angina drug - In search to lower the blood pressure, side effects were obtained - The side effects were reported by male Welsh miners during clinical trials - They saw the beneficial side effects of sildenafil - Best known now as VIAGRA - Billion-dollar Blockbuster drug for Pfizer - Pfizer in 1950 were the first company to produce penicillin, which was a massive breakthrough for the Allied Forces in WW2, to be able to get soldiers back the frontline, when they got sick Modern Day Pharmacology -- How Are Drugs Made? - We select the disease indication - Identify the target -- DNA, protein, etc. - We synthesize selective ligands that will bind to the targets - Asses the functions - The whole thing is called "from molecule to man" How Drugs Work? - How does a small tablet or capsule often containing only milligram of quantities of drug in an injection of less than 1ml have such profound effects on the body? - Molecules in an organism vastly outnumber drug molecules - Random drug distribution throughout the body -- NO pharmacological effect - What should we do? - Paul Ehrlich -- found out that certain dyes will dye-out certain microbes - He worked in the dye industry - He was trying different dyes out on a combination of cells and microbes in the same well - He found out that certain dyes will dye the microbes, they would come out blue under a microscope - He thought that if you selectively target the microbes, you can produce toxicity only selective to microbes and not to the rest of the cells - Ehrlich designed the very first cure of syphilis - Non-uniform drug distribution -- drugs need to interact with a cellular molecule, only expressed in specific tissues of interest (liver will express a certain receptor and the drug will only bind to that receptor, nowhere else in the body) Branches of Pharmacology -- What is Pharmacology? - Pharmacokinetics -- the effect of the body on the drug - How the drug is metabolized, how it is distributed and excreted... - Understanding drug exposure over time - How much free drug is systemically free to bind to the targets over the time the drug is active? - Pharmacodynamics -- what we are talking about now - The effect of the drug ON the body - The overall importance is to understand drug response over time - The mix of drug exposure and drug response can be combined, allows us to predict what does to use and create a safe and efficient drug Pharmacodynamics - Understand of the effect of the drug on the body - Investigates the mechanisms of drug action, including the molecular (receptor and drug binding onto the receptor), cellular (transduction of the signal through the cell) and physiological (response on the cellular/tissue/systemic level) effects of the drug - Investigates the relationship between drug concentration and the effect -- if you increase drug concentration, you expect to increase the effect - The purpose of pharmacodynamics is to develop safe and effective medicines by: - Confirming drug efficacy -- does the drug work? - Confirming drug safety - Minimizing potential adverse effects - Optimizing dose and dose regimen -- Pharmacokinetic and pharmacodynamic relationships What Happens When You Take a Drug? - The physiological Exposure -- enters the bloodstream, the amount of free drug that manages to bind to the drug targets (Pharmacodynamics) - Physical exposure to the local free drug, running around our bodies, will lead to binding to a drug target - Drug targets are molecules, the function of which can be modulated by a drug to produce a biological effect, they are specific on different tissues, depending on what you want to target - Physiological Clearance -- detoxified and excreted (Pharmacokinetics) A diagram of a drug Description automatically generated - Each red box is a core concept we'll cover Drug Targets - 4 main drug targets for the drugs that are currently on the market: - Receptors - Ion channels - Transporters - Enzymes - These are mainly found embedded in the cellular membrane, some are found intracellularly - Exceptions: - Biologics -- antibodies (secreted proteins) and recombinant proteins. Type I diabetes, you don't produce enough insulin, you get injected with a recombinant protein - Specific antimicrobial and antitumoral small molecule drugs interact with nucleic acids. Chemotherapeutics interact with the nucleic acids within the nucleus - Concentrating on the 4 main targets Drug-Target Interaction - Drug-target interaction describes the different ways the drug interacts with the target to produce the biological effects - Determined by intermolecular forces, steric match, and the types of bonds formed - Generally, small molecule drug binding sites are a defined pocket/cavity In the structure of the drug target - Drug-target interactions may occur at the active or orthostatic site or allosteric site elsewhere on the drug target - Drugs can bind to their targets reversibly or irreversibly, depending on the type of bonds formed - Structure-activity relationship -- the unique relationship between the structural characteristics of a drug (all different side chains, groups...) and specific amino acids in a target protein binding site, and the resultant biological effect - This is the basis of rational drug design - It's manipulated during drug development processes to alter therapeutic and adverse effects - Generally, small molecule drug binding sites are a define pocket/cavity in the structure of the drug target - The protein can be absolutely enormous, but the small cavity that embeds within the protein that a chemical can bind to, has a profound effect on the protein itself, which will produce the biological effect - Drug-Target interactions may occur at the active or orthostatic site (endogenous interactions occur) or allosteric site elsewhere on the drug target - If you have a neurotransmitter that binds into its active sites, this is the endogenous interaction - Drug competes at binding sites, where we have an endogenous interaction - Allosteric sites -- elsewhere on the protein, can directly affect the endogenous effect - Drugs can bind to their targets reversibly or irreversibly, depending on the type of bonds formed - Most drugs bind reversibly - Important when interpreting drug concentration/effect curves Affinity and Efficacy - The binding of the drug to the targets determines the affinity -- how strong the drug binds to the target - Affinity: binding strength of a drug to the target, how strong the drug binds to the target - Efficacy: ability to elicit a response once the drug is bound to a target - You get a response, or you don't get a response. You may have affinity for the receptor, but there could be no effect on the receptor - Structure-activity relationship comes in because if you change certain side chains of the drug, you can enhance the efficacy, or you can lose it - Agonists: If you get a response. Endogenous or exogenous molecules that have BOTH affinity and efficacy at a receptor to elicit a biological response - Antagonists: Molecules that have affinity for a receptor to limit the effect of agonists, but lack intrinsic efficacy  - There is a drug and a free receptor. The affinity is where the drug binds to that receptor, if you have efficacy, the drug-receptor interaction will cause a conformational change in the receptor, and this will get a biological response A diagram of a drug Description automatically generated Drug Selectivity - The drug's ability to discriminate between different drug targets - Determined by the affinity and efficacy for one target vs another - You can have multiple receptor for the same drug, but the drug might have a stronger efficacy for a certain target - Each drug target recognizes only a small number of molecules, all of which will have some structural similarity - Example -- histamine receptors and Sir James Black - A pharmacologist, looking at responses of histamine receptors - He knew that the histamine receptor was causing immunological allergic responses - He noticed that histamine was also causing an increase in gastric acid secretions - He thought "Oh, histamine is having an effect on receptors other than the ones that were causing the allergic reaction" - So, he started to change the structure of the histamine chemical, modifying the structure-activity relationship, and he could find that by changing the structure of histamine, he could be more selective to specific histamine receptors - This idea is the basis of the structure-activity relationship in terms of design and development - Different receptors for the same endogenous agonist are called subtypes. Some drugs exhibit selective activity towards different subtypes - Example: - Histamine has 4 receptors; we'll focus on 2 of them H1 and H2 - If histamine binds to H1, it causes smooth muscle vasodilation -- allows blood flow to go slower. During an immune reaction you want the blood to go slower because this allows the immune cells to get out of the blood vessels and go to the tissues, where the inflammation is. Allow vascular permeability, immune cells can migrate to the areas of inflammation - When you have an allergic reaction, you don't want that to happen, you want to prevent that - Histamine will also bind to the H2 receptor at the gastric parietal cell, causing acid secretion -- good when we have lunch or dinner, allows for acid digestion and breakdown of the food we consume. If we continuously have acid secretion, it causes stomach issues, acid reflux - In terms of pharmacological responses, we've managed to develop specific drugs that will specifically target the H1 receptor and the H2 receptor - Cetirizine is a H1 receptor antagonist, it blocks the effect of histamine on the target, alleviates the symptoms of allergic reactions, without changing the acid production in the gastrointestinal tract. We take it commonly during summer months - Cimetidine selectively targets the H2 receptor, it is a H2 receptor antagonist, prevents acid secretion and prevent production of gastric acid, helps stop reflux,  A screenshot of a cell phone Description automatically generated  Potency - The amount of a drug, expressed as the concentration or dose, needed to produce a defined effect - If you have an extremely potent compound, you need a little dose of it, a very small concentration to get the biological effect - If the compound is less potent, you need more concentration of the drug Mechanisms of Drug Action - The process, by which drugs produce a biological effect - Can be observed on multiple layers: - Molecular -- where the drug binds to the target - Cellular -- transduction of the signal - Physiological -- what happens to the cell, organ or system? - Targeted cells/tissues have specialized physiological function - The mechanism of drug action may involve blocking, limiting, activating, or enhancing a physiological process - Drugs aren't evenly distributed around the body, they tend to be bound to specific targets (4 main targets -- receptors, ion channels, enzymes, transporters) PROPERTIES OF DRUG TARGETS AND MECHANISM OF DRUG ACTION Session 1 -- Lecture 2 Drug Targets - Molecules (usually proteins), which play a pivotal role in existing physiological or biochemical processes, the function of which can be modulated by a drug to produce a biological effect - Majority of drugs have the following targets -- receptors, ion channels, transporters, ion channels RECEPTORS - Most are embedded in the lipid bilayers of the cell membrane - Proteins, whose function is to recognize and respond to endogenous chemical signals - Nuclear receptors can sometimes be in the nucleus or in the cytoplasm -- don't get confused by the name - 4 types: - Ligand-gated ion channels - G-protein coupled receptors - Kinase-linked receptors - Nuclear receptors - As proteins they have a well-defined 3D structure, which is critical for their actions sites -- allosteric sites, little cavities, where drugs can bind - Each receptor recognizes only a small number of molecules, all of which will have some sort of structural similarity - Each receptor is really specific to the types of molecules that can bind to it. If they can bind to a molecule, they are very very very similar in terms of structure - Agonists -- endogenous or exogenous molecules that elicit a biological response - Endogenous -- neurotransmitters - Exogenous -- the drug itself - Antagonists -- Molecules which limit the effect of antagonists, limit the biological response - These words only apply to receptors, NOT THE OTHER 3 TYPES OF DRUG TARGETS Receptor Types and Signal Transduction - How does binding of a drug to a receptor on the cell surface evoke responses inside the cell? - You need a signal transduction inside the cell to cause the response - Picking up something requires a hell lot of muscle signals and transduction -- that's why they need to be really really fast, you need a rapid response from the muscles - We have systems, designed for rapid responses, such as muscle contraction, heartbeat - Other types of processes don't need to be rapid, they can take minutes or hours - Such processes involve usually gene transcription and protein synthesis because these things take a lot of time - Other examples are the adaptive immune system -- you don't want your immune system to go absolutely mental because it will just destroy us, it needs to be well-controlled, that's why it takes a while to kick in - For the lecture, we'll concentrate on the rapidly producing receptors, which include ligand-gated ion channels and G protein-coupled receptors Regulation of Ions - Ion channels are super popular drug targets - Controlling the balance of intracellular ions (Ca 2+, Na+, K+, Cl-) is critical for controlling cell function and several other physiological responses, such as: - Contraction - muscles - Electrical excitations -- stimulus in our brains - Secretion signaling - These are the fast reactions ION CHANNELS - Can be formed from multiple 3-5 subunits (Complex protein complexes, not just 1 protein) - Subunits = proteins - Ligands (drugs in our case) bind to an extracellular domain -- when they bind, a channel opens, allowing ions to flow either from the extracellular space or the intracellular space - When the ligand is NOT bound, the channel is closed, no ions go in or out - The pore domain (parts of each subunit) forms a hydrophilic (water-filled) channel to selectively allow ions to flow through the membrane - The pore domain is the important structural element of ion channels - VERY SELECTIVE ions channels -- won't let just any ions to flow through - Two very popular types of ions channels for pharmacologists - Ligand-gated ion channels - Voltage-gated ion channels - Opens and closes, depending on the membrane potential -- the voltages between the intracellular and extracellular membranes - When they are not in equilibrium, the pores open and starts ions to flow in or out of the cell - BOTH OF THEM ARE RAPID!!!!! - Voltage-gated ion channels: - An action potential runs through the post-synaptic cell, causing the opening of the voltage-gated Calcium channel, allowing Calcium to flow into the pre-synaptic cell, the influx of Ca causes the synaptic vesicles, holding acetylcholine (neurotransmitter) to fuse to the extracellular membrane and release the acetylcholine into the synaptic cleft - Once it is released, it can bind to the nicotinic acetylcholine receptor, which is a ligand-gated ion channel, causing Na influx into the cell because the ion channel is now open, it depolarizes the membrane, eventually leading to skeletal muscle contraction - The two ion channels work in sync A diagram of a structure Description automatically generated Drug Action on Ion Channels - How do the drugs act on the channels? - By blocking the ion channels -- blocking any ions from running through - By modulating the ion channel -- increase or decrease the amount of ions going through, depending on what the modulator is - Most ion channel drugs used are ion channel blockers Ion Channels: Blockers - Voltage-Gated Calcium Channel Blocker - Ca2+ currents drive signaling in vascular smooth muscle and some cardiac cells -- increases the rate of contraction of cardiac cells - Ca2+ channel blockers are used to treat cardiac disorders, when the heart is beating in an unusual rate - Example -- Verapamil - Vascular smooth muscle cells -- we want to cause a contraction of the vascular smooth muscle - Action potential comes down - Voltage-gated Ca2+ channel opens - Synaptic vesicles fuse - Acetylcholine is released into the space - This time, we've got a muscarinic acetylcholine receptor, which is a G protein-coupled receptor - Acetylcholine binds to the G protein-coupled receptor, which causes enzyme activation by the G protein, leads to muscle contraction - However, we still have the action potential, we block the channel -- prevents the synaptic vesicles fusion and the cells activating, we don't get a contraction, the muscle relaxes G-PROTEIN COUPLED RECEPTORS - A single protein polypeptide -- made from a single protein, not a complex of multiple proteins, has 7 transmembrane domains - complicated - Ligands can bind either to the extracellular domain or within a transmembrane domain (in the lipid bilayer), depending on type - G protein is a guanine-nucleotide binding protein - Made up of 3 subunits -- alpha, beta and gamma - When the receptor is bound to its ligand, GDP (Guanina DiPhosphate) binds to the a subunit and causes the alpha complex to dissociate - A subunit is now free to bind to an ion channel or an enzyme - NOT ALWAYS A POSITIVE RESPONSE, IT DEPENDS ON THE G PROTEIN ITSELF -- IT CAN BE A NEGATIVE RESPONSE, BUT IT ALLOWS US TO BALANCE OUT PHYSIOLOGICAL RESPONSES - Responses can be both positive and negative, G proteins can always do the reverse TRANSPORTERS - Move ions and chemicals against their concentration gradient, NOT ion channels - Active transport -- needs energy to move ions against their concentration gradients - Energy is provided by ATP hydrolysis - 2 types of active transport - Primary -- direct, transporter directly uses ATP to fuel the ions that move against their concentration gradient - The secondary active transport: - Does not directly rely on a chemical source of energy, such as ATP, no ATP attached to the transporter - Uses an electrochemical gradient, generated by primary active transport to bring a substance back across to the other side of the membrane - Some drugs block these transporters: - Drug transporters act as anti-depressants - A decrease in neurotransmitters - serotonin, norepinephrine, dopamine has a role in modulating mood, emotion, sleep, cognition, cause symptoms of sadness - Serotonin regulates mood and emotions - Antidepressants aim to increase the amount of serotonin at the receptor - 3 ways to do this: - Block the enzyme clearance of serotonin -- when it is in the synaptic cleft and binding to our receptor, it causes our mood to be happy, we need to get rid of it at some point, there is an enzyme that will break up the serotonin - Increase the amount of serotonin in the brain -- use a drug that will repopulate serotonin in the brain and increase our mood - Boost the effects of serotonin by blocking the transporter re-uptake -- In our postsynaptic cell, we can transmit these signals through G protein coupled receptors and ligand-gated ion channels, depending on which area of the brain we are trying to stimulate. We have our voltage-gated Ca2+ channel open, this time serotonin is the neurotransmitter, released in the synaptic cleft, combined with the G protein coupled receptors causes improvement in mood. However, we need to get rid of the serotonin so that we can recycle it back to the vesicles, so that we aren't feeling this continuous elevation of mood. To do this, one of the ways is to transport it back to the vesicles (secondary active transport). This is done using serotonin re-uptake transporter. You create the ion gradients, based on ATP-generated ion transport. When Na binds to the transporter, it also binds serotonin, following this, Cl also binds, causing the transporter to flip and open on the other side of the membrane, releasing the serotonin and ions back into the cleft side of the channel. Serotonin can then fuse back into the vesicles and be recycled and used for the next stimulus. - Prozac is the medicine name with the drug fluoxetine that blocks the serotonin re-uptake transporter. Prozac is a selective serotonin reuptake inhibitor. It inhibits the transporter, maintaining the amount of serotonin in the synaptic cleft. This increases the amount of serotonin binding to its receptors and elevating the mood and reducing the symptoms of depression.  A diagram of a human body Description automatically generated DRUGS ACTING ON ENZYMES - Enzymes catalyze the conversion of a substrate into a product - Drugs are often enzyme inhibitors, NOT antagonists - We are not talking about receptors, we are talking about enzymes - Drugs can also increase enzyme activity -- positive or detrimental - Drugs can also be converted from their inactive form to their active form -- pro drugs - Targeted drugs for specific areas, for specific tissues, which produce specific enzymes if you have a place, which produces an enzyme, which isn't expressed anywhere else, the drug gets in there, it's cleaved to the active form in the site, when needed to work - Example of drugs being enzyme inhibitors: Acetylcholines as anesthesias - In general anesthesia, the action of nicotinic ACh is blocked to stop movements, ACh causes muscle contraction, and by blocking ACh, it makes muscles relaxed during surgery - After surgery, we need our muscles being able to contract back again - At the end of surgery, the effect of these neuromuscular blockers is reversed by anti-cholinesterases - Neostigmine -- inhibits cholinesterases, preventing ACh breakdown, therefore, increasing ACh concentration within the synaptic cleft, this displaces the receptor blocker (the anesthetic) from the receptor, reversing its effect - Uses an enzyme to break down the ACh, ACh will bind to the enzyme, where it can't function -- anesthesia - If you want to reverse the effects of anesthesia, you need to block acetylcholinesterase, which inhibits ACh to bind to its ion channels. It can be done using the inhibitor neostigmine. If you block the enzyme, you cause an increase in ACh on a prolonged effect, increases the possibility of ACh binding to its ion channel receptor and then you can start muscle contraction again after surgery QUONTITATIVE PHARMACODYNAMICS Session 2 11/12/2024 Questions from last Session: - Levodopa is used to treat Parkinson's disease - Usually Parkinson's is a result from the lack of dopamine produced in the brain - Symptoms are tremors, balance problems, speech problems... - We need to try to restore the levels of dopamine in the areas of the brain, where it lacks - It can't be treated with dopamine itself because dopamine doesn't cross the blood brain barrier, which is the target tissue you need to get to - Dopamine is poorly soluble, brain lacks the transports to transport dopamine into the brain - L-DOPA is the immediate precursor to dopamine in the biosynthetic pathway - L-DOPA can cross the blood brain barrier because it mimics amino acids, the transporter is tricked into thinking L-DOPA is an amino acid and it will take it across the blood brain barrier, where L-DOPA decarboxylase is expressed and the mask is taken off, dopamine levels are increased - Carbidopa is an inhibitor of L-DOPA decarboxylase -- why use it in combination of L-DOPA? - L-DOPA decarboxylase is also expressed in the blood system and not just the brain - Usually, L-DOPA will be decarboxylased in the system as well, so Carbidopa will hold L-DOPA in place in an area, where you don't want it activated. Carbidopa can't cross the blood brain barrier and won't block L-DOPA inside. It will block it in the body system, but not in the brain What is a Pro Drug? - An active drug that has been masked, often metabolized by an enzyme, removing its mask, allowing its action on a specific site - The mask lets it reach the target site and not get metabolized by the body - A prodrug must undergo chemical conversion within the body before becoming an active pharmacological agent - Why do we have prodrugs? - To enable a drug to be formulated - To enhance solubility of the drug - To minimize excretion from the body - To enhance the stability of the chemical - To target the drug to a specific area -- specific for pharmacodynamics - If you want to target the drug to the lung, the enzyme that metabolizes the drug and unveils the active form is only present in the lung, that way the active form of the drug will be at the correct tissue you want it to be in Background - No equations in year 1 - When a new molecule with a potential to have a therapeutic effect is discovered, the biological response needs to be studied and understood - Is there such a biological effect, and if yes, what concentration of the drug is needed to induce that response? - We expect a biological response, but we are not sure - Pharmacologists need to understand the relationship between drug concentration and drug effect - Pharmacologists will develop bioassays and biomarkers that are linked to the action of the target and test drug effect experimentally to create dose/response curves - Dose response curves allow pharmacologists to quantitatively measure and compare drug efficacy and potency, which is vital for: - Drug discovery programs -- allows to explore a number of different compounds and see their efficacy and potency. We select the ones we want to take forward to progress the drug discovery programs - Predict safe therapeutic doses - Mnimise side effects/adverse effects - There is NO SUCH A THING AS A SAFE MEDICINE - Anything we do to ourselves chemically over long periods of time, will change us physiologically and increase the risk of a side effect, and also change our physiology - Even medicines taken without prescription such as paracetamol has a strict limit to the amount you can take - Max dose of paracetamol a day is 4g in 24 hours - If you take more, you develop toxicity - Paracetamol has a narrow therapeutic window -- the barrier between causing a therapeutic effect and causing harm to the body - There are lots of accidental and deliberate overdoses - Nowadays, the pharmaceutical industry is the MOST highly regulated industry in the world - The dose of the medicine we take, why we take it at that dose, and understanding how we quantify biological effect of different molecules on receptors is what we are trying to take away from this lecture Pharmacodynamics - The study of the biochemical and physiological effects of drug on the body, the mechanism of drug action and the relationship between drug concentration and effect - Pharmacodynamics is often summarized as a study of what the drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug - Pharmacodynamics -- PD, when referred to in conjunction with pharmacokinetics, it can be referred to as PKPD RECEPTORS -- AGONISTS - Affinity: Ability to bind to receptors - Efficacy: Ability to switch receptor to its active form and produce a response, the activation step. Once the drug is bound to the receptor, it needs to switch it on and elicit a biological response, an activates drug-receptor complex - Agonists: Endogenous or exogenous molecules that have an affinity for and efficacy at a receptor to elicit a biological response - Endogenous -- neurotransmitters Dose-Response Curves - The size of a response to an agonist depends on how much of the drug is administered - It could be either an endogenous agonist or a drug agonist - Increase the dose, increase the response -- dose-response relationships between drugs - Suitable doses of the drug should be given so that the desired response is produced without unwanted side-effects - If you administer much higher doses than the safe therapeutic ones, you'll get unwanted side effects - Dose-Response curve for an agonist: - Y axis -- response, going up to 100%, anything from a bioassay to a biomarker - X axis -- concentration of the agonist - This forms a hyperbolic curve with a really sharp increase, flowed by a plateau at the top. You can get the maximum response, but at one point, even if you add more drug, you get no change in response, once you've reached the maximum - However, you can't measure the EC50 (Effective Concentration 50), it's really close to the x axis with the numbers being very close to each other and not very accurate -- not very useful - So, the x axis is a logarithmic axis - Using a log concentration makes a sigmoidal curve -- useful because it makes a straight line, which can make an equation to calculate the EC50 - The middle part is a rapid increase in response -- high change in response over a lower change in drug concentration - The plateau means that even if not all the receptors are occupied, no matter how much more receptors you occupy, you are not going to increase the maximal effect - Cmax Why Using Log Plots? - The central portion (20-80%) is a straight line -- allows for calculating EC50 - A small change in concentration produces a relatively large change in response -easier to display on a log plot - Easy to compare relative potency of agonists - Chemicals that are better at lower concentrations can be identified -- if you have multiple chemicals targeting the same target, if you got this biological system that will allow you to work out the potency of the chemicals, if you have 100 compounds, you can identify the least and most potent ones - Measure EC50 -- concentration giving a 50% response - Gives the idea of the structure -- activity relationship -- you change the side chains of the chemical, this can affect the potency and you can see this visually using the logarithmic dose-response curve Measuring EC50 - The concentration of the drug needed to give 50% response - Can be measured directly from a log-concentration response curve - It can also be calculated with the equation, but for now we will use graphs - In terms of potency, you want to have the lowest concentration possible to see which one is more potent - 10\^-5 is less concentration than 10\^-4 giving 50% response the first drug is more potent - If you shifted it to the right, it's a slightly higher concentration - Histamine has the higher potency Affinity and Efficacy - Agonists have BOTH affinity and efficacy - Affinity -- ability to bind to receptors - Efficacy -- ability to produce a response - Full agonists are drugs whose maximum response is the largest a tissue or cell is capable of giving - Always based on the endogenous agonist (neurotransmitters, for example) - They reach the maximum response - Less potent full agonists also reaches the max response, but needs more time - They have VERY HIGH EFFICACY - Partial agonists are drugs whose maximum response is lower than the maximum response a tissue or a cell is capable of giving - Partial agonists is causing a response, but it never reaches the max response (Cmax) - It may bind to the receptor as strongly as the endogenous agonist, but it may not have as potent biological response - The more to the left the dose-response curve is, the more potent the drug - The more up the curve is, the higher the efficacy  A graph of a high efficiency Description automatically generated - High potency -- you need a low concentration for it to have its maximum effect, but its efficacy is low -- it is a partial agonist, doesn't reach the full tissue response - Low potency -- takes more concentration to elicit the response, but the response is higher, reaches the maximum -- has higher efficacy RECEPTORS - ANTAGONISTS - There are 2 distinct steps - Generate no receptor-mediated response - The drug is still binding to the receptors, still driven by the affinity, but lacks efficacy, receptor remains in inactive conformation, elicits no response - Antagonists have affinity for a receptors to limit the effect of agonists, but lack intrinsic efficacy - Antagonists bind to the receptors and block the activity of agonists - Agonists have to be able to dissociate from this drug-receptor complex because if they didn't the complex will be locked in place all the time. It would be a case of you producing more of the target receptor so that the agonist can bind - However, the agonists need to have a way to be removed -- if the drug binds so strong to the target that it couldn't be removed, then it is pointless - ALL endogenous agonists are reversible - Antagonists are also reversible - Agonists are binding to its receptor and dissociates, after it has activated the receptors - Bind, activate, dissociate (free the space for binding) - If you start with an antagonist, it will compete for access to the binding site, stops the agonist to bind to the receptor and causes its antagonistic response - Antagonists stop agonists from binding to the receptor, and doesn't allow for any biological response from happening Reverse Drug Binding - Almost all agonists bind reversibly to the receptor - Weak chemical bonds between drug and receptor - Agonist dissociates readily from the receptor -- binding on and binding out - Antagonists also bind reversibly, therefore blocking the effect of the agonist on the receptor - If the agonist concentration is increased, it will displace an antagonist from the receptors creates a competitive action Competitive Antagonists - HIGH AFFINITY, BUT NO EFFICACY - In the presence of increasing antagonist concentrations, the log-concentration response curve for an agonist will be shifted to the right - For competitive antagonists, the shift will be parallel - Competitive antagonists -- antagonists that bind reversibly to the receptor - The dose-response curves that reach Cmax will be shifted to the right the more antagonists you add - A competitive antagonist can be displaced from the receptor by increasing the concentration of the agonist - Atropine is a competitive antagonist -- it blocks the binding of acetylcholine (Ach) to muscarinic Ach receptors - Acetylcholine is an endogenous agonist - If you add a fixed amount of competitive antagonists (atropine), you get a parallel shift to the right - So, you need to increase the concentration of acetylcholine in order to elicit the same maximal response - As you increase the fixed dose of atropine, the curve gets shifted even more to the right - Atropine is used as a medication against nerve gas poisoning  A graph of a patient\'s reaction Description automatically generated with medium confidence Other Actions at ACH Receptors - Propiverine is a non-competitive antagonist of the actions of Ach at muscarinic receptors -- binds to a target, different than the active site - Propiverine acts at another site to prevent the effects of stimulation of the muscarinic receptors by Ach - If you have Ach by itself, it reaches the top of the sigmoidal curve, a competitive antagonist will shift the curve parallel to the right you need to increase the concentration of Ach to elicit the same response - With propiverine, which is a non-competitive antagonist, it doesn't just shift the curve to the right, but it also decreases the Cmax because it's non-competitive Competitive and Non-Competetuve Antagonists - ALL antagonists shift the dose-response curve of an agonist to the right - For a competitive antagonist (atropine) the maximal response remains THE SAME, and the response curves are shifted in a parallel manner - Competitive antagonists bind at the same site as agonists, and can be displaced by an agonist - For a non-competitive antagonist (propiverine), the maximal response to the agonist is REDUCED, the curve is not shifted parallel to the agonist alone. There is a new maximal effect and the EC50 doesn't change, but the maximal effect is reduced - Non-competitive antagonists bind at another site (not the site to which the agonist binds) Classical Drug Discovery - Study molecules, examine effects on disease Isolate active components Determine the structure and re-synthesize them Prove the biological activity of the active "Principle" Chemically modify the structure - Back in the day, people were using extracts of plants and try to understand that these extracts were helping to alleviate diseases. As the world advanced, we got able to isolate these active components and resynthesize their structure and develop the drugs - The method doesn't require knowledge of the target in cellular or molecular terms - Majority of the lecture is about small molecules Modern Day Drug Discovery - Understand the biology of the disease Identify molecular target to alter the biology Develop drug that acts on the target and elicit the wanted therapeutic effects Test the hypothesis that drug will have clinical efficiency - Understand the physiology of the body normally and then the physiology with the disease - Testing requires a deep knowledge of the target in cellular terms - It is an expensive and high-risk business - Average cost to the point of marketing approval including compound abandoned during development is approx. \$2.5 billion - All work projects going on -- research, resources, all the processes, trials, testing... - Drugs takes a long time to develop -- 10-15 years for full marketing approval, with patents for 20 years - When do you submit your patents? - Every minute you waste after you submit the patents, you lose money on the back end - When you lose your patents, other companies are allowed to make your product, competition goes up - High attrition rate - 1 in 10 drugs that start the clinical phases will make it to market - 90% will fail!! - Because of: - Lack of clinical efficacy -- it may work in test subjects, but not in humans (40%-50%) - Unmanageable toxicity -- when you do preclinical testing you look for signs for potential toxicity and how it can be managed in a clinic, but a lot of drugs in the clinic have unmanageable toxicity (30%) - Poor drug-like properties -- drug doesn't reach the target (10-15%) - Lack of commercial needs -- multiple competitors for the same effect of the compound - Poor strategic planning -- combined with the above (10%) Drug Discovery and Development - Every single drug has to go through regulation -- you have to prove your drug is safe and efficacious, and of best quality - Efficacy must be proven across ethnicities as well as across different age groups, depending on the target population - All clinical trials will generally be held on adults - Each drug must pass regulatory review by the specific governing body from each individual market territory - MHRA (UK), EMA (EU), FDA (USA) - Put the drug submission into each governing regulatory body to be passed through their own territory and then to the rest of the world - Approved drugs must appeal to global markets across different healthcare systems and distribution systems - You don't have to get it past just the governing body, but all healthcare bodies as well Pharmacological Drug Discovery - How this 10--15-year period of drug discovery and appearance is laid out? - Development of a new small molecule drug are divided into 3 main stages: 1. Drug Discovery -- lasts between 2-5 years 2. Preclinical development -- lasts 1.5 years 3. Clinical development -- done over 4 phases - Includes Phase I-III (5-7 years), regulatory approval and Pharmacovigilance (Phase IV, 1-2 years) - Once you've performed all the clinical studies, it can take 2 years for the regulators to approve the drug - Then you have Pharmacovigilance -- once the drug is approved, how the drug performs at the market -- you need to keep an eye on what is the efficacy to the millions of people and whether there are any red flags (toxicities) Drug Discovery  - New technologies for innovation in drug development is reliant on the integrative collaboration between experts from multiple disciplines under the umbrella of Biosciences - For example, - Selecting drug candidates is an iterative process between chemistry, biology and pharmacology - Refining the properties of the molecule until you hit the sweet spot compound, which is developed to advance to pre-clinical development and first in human studies - You need the relationships between the different discipline to design drugs - It is important to select therapeutic areas to invest in. This is driven by: - Therapeutic need -- is the drug needed, are there competitors in the market? - Prevalence of disease -- if there are more affected people, more demand of the drug will be present - Likelihood of success -- success rate varies between therapeutic areas, central nervous system drugs have the lowest success rate - Additional considerations - Technical feasibility -- big needs give big ideas for creating a drug. The problem with penicillin -- Fleming discovered the fungus that could kill a specific type of bacteria on a petri dish. He laid a lot of petri dishes, went on a holiday and some fungus from the lab next door landed on one of these plates. He noticed that there is a huge amount of space between the fungus and the bacteria. He came up with the assumption that the fungus was producing something that was killing the bacteria off (later it was discovered that this was penicillin) - In WW2, there was a big demand for doses of drugs that help fight infections in soldiers, which was a problem because the fungus only grows on the top of media -- you can only get a certain amount of it. There was such a need for a drug, so scientists had to think very big and deep to create a drug. They managed to allow the fungus to grow within the media itself, so that they could produce a shit ton load of penicillin. - If you can't create enough of the molecule, it's never going to be commercially successive. - Research and development costs -- cost a lot of money - Commercial considerations -- market share, competition - ONLY high priority projects within budget will be selected for progression - Annual review on all ongoing for projects - First step in modern day drug discovery is target identification - A substantial body of fundamental research occurs in both academia and industry -- this trend is starting to go up in counts because of the price of developing drugs. It is so expensive to the industry that they look for academic spinouts that have really exciting compounds in their portfolio and buy their academic spinoff compounds - Three cornerstones for target selection: 1. Link to human disease 2. Link to a pathway and mechanism of action 3. Link to a chemical modality - Requires extensive knowledge of the fundamental biological mechanisms giving the disease progression - We know the disease we want to target, we know the actual target, we need to get a chemical that can bind to the target - Screening and lead identification - Once identified the target, you need to search for chemicals, which can interact with the target and have the desirable biological effect - Early chemical starting points are: 1. Naturally occurring -- plants, humans, animals. This still goes on all the time 2. Targeted chemical synthesis -- compound libraries. Each company will have millions of compounds in libraries that they can use and put in their bioassays and see if any of the compounds has efficacy and a biological response - One way of screening for compounds is through high throughput screening (HTS) -- screening of the entire chemical compound library against the drug target (usually over 100k). You have your biological system, linked to the target receptor to produce a response and that response can be measured -- bioassay. The company will develop these bioassays and throw their entire compound library on the bioassay to try and identify some hits (usually 0.1% hits out of a 100 000) - Another way is in-silico virtual screening -- selecting from the chemical compound library, smaller subsets of chemicals with potential activity at the target protein in a computational model. You know your target and you know the dynamics of the active sites; you can program your computer to take up to a million molecules and see how they bind. - In reality, it is a mix between the two - Once you go through your screening, you get a number of "hits" - "Hits" chemicals that need to be characterized to confirm they are biologically active and not false positives. To confirm they are biologically active, you will do dose-response curves, proving that the hit isn't just a false readout - You take the tested "hits", which are now called "Active leads", optimize them chemically, improve the structures, throw them into another round of bioassays to see which ones are the most efficient and potent to see which ones you want to take forward) to improve safety, efficacy and purpose Drug Discovery Preclinical Development A screenshot of a computer screen Description automatically generated - Build a profile of the efficacy and safety of a drug candidate and potential safety liabilities that can be monitored in the clinic - The portfolio/profile will inform the regulatory bodies to decide whether the drug will progress to First-in-Human trials (FIH trials) - Build a picture of your chemical, you want to know if it is safe and efficient, there are a number of assays to do that - A combination of PK and PD testing (PKPD) to get the dose-range you need to predict to go into the FIH trials - Includes a lot of toxicology testing to inform clinicians and volunteers about the safety profile of the lead compound - We still use animal studies always to predict the safety and toxicology because our systems aren't good enough Clinical Development  - The whole point of preclinical development is to build up to the clinical development - Try to accurately translate the data into humans - PHASE 1: - Clinical trials are performed always in small amounts in healthy volunteers - Very low starting dose, slowly do increases over the course of the phases -- we don't want to cause any toxicities in healthy individuals - We are looking at the PKPD relationships, safety, tolerability and the dose ranges - When would you not use healthy volunteers? -- if the patient is going to die anyway, or if that drug is going to cause harm to the individual -- you are not giving chemotherapy or gene therapy to a healthy volunteer - Treat someone with an expected therapeutic dose - Such trials are performed in specialized units in hospitals, equipped with specialized medical teams ready to adverse any adverse reactions immediately - PHASE 2: - Moving from healthy people to the first patient cohort - We are trying to establish efficacy of the drug -- whether the drug is having its therapeutic effect in the patients - Understand the dose-response relationship in order to nail down the specific dose regimens for the final pivotal study in phase III - Further establish the safety of the drug - Cohort of patients with target disease - PHASE 3: - We call the studies in phase III "pivotal studies" - Large cohort of patients (300-3000, spread all over the world in different clinical study sites) with target disease -- recruit them from all parts of the world -- not exclusive - If you have a number of competitors looking at the same disease, you are losing the pool of patients from competition - Large scale safety and efficacy conformation studies - 1 in 10 drugs that start the clinical phase, will not make it to the market Regulatory Approval A screenshot of a computer screen Description automatically generated - Benefits must outweigh the risks - Example: If you have an adult with stage 4 cancer and you have developed a drug doxorubicin. You treat the patient with doxorubicin. With the toxicity profile of doxorubicin, it's likely that they are going to have cardiovascular effects and disease 10-15 years after a doxorubicin cycle. Would you treat the patient with doxorubicin? Do the risks outweigh the risks? - Each drug must demonstrate safety and efficacy in the intended patient population - Strict regulatory standards govern the conduct of all parts of drug development: - Pre-clinical development - Clinical trials - Manufacturing - Post marketing safety (Phase IV - Pharmacovigilance) studies the long term risks by monitoring adverse events in the wider population - Once the drug has been approved onto the market Drug Life Cycle Management - Pharmaceutical companies will design a life cycle for the drug from the very start of the drug design phase - When the patents are announced, they are always thinking of different ways of marketing the drugs, so drugs can be delivered using different delivery systems - You can combine a drug with other drugs to improve marketing efficacy - Every time you go to market approval, the market approval is for a specific indication. If you discover your drug is beneficial for another indication, you can repurpose it to that indication -- adapting an existing drug for a new therapy - You go straight into phase II and phase III because you know that this drug is safe for humans from phase I -- it's already on the market, it exists. Emerging Technologies - AI - Potential to improve speed, efficiency and cost - Can analyses and process enormous amounts of Data - It relies on sufficient quality and volume of data to train the system -- if the data you put in is rubbish, then the information you get out of it is going to be unreliable and inaccurate. A lot of data out on the internet is absolute rubbish!!! We need to come up with ways to refine what is going inside the AI systems - New Modalities - Of the 667 FDA approved drugs targeting human proteins: - 82.3% are small molecules -- all our lectures have been focused on such - 17.7% are biologics/biopharmaceuticals -- a growing field, estimated to be worth \$326 billion by 2026 - Human genome project, human protein atlas show there are many thousands of potentially druggable human proteins -- we think of druggable proteins as proteins with active sites, but not all druggable proteins have active sites. We need to figure out ways to target flat proteins (no active sites) to be able to use them therapeutically -- this is where the new modalities come in - There are approximately 6500 rare diseases, with only 250 treatments available -- when you target these rare diseases it is easier for a drug to go into the market, but it is also challenging to develop a drug to a disease, which hasn't been studied as much as other diseases - Regulatory bodies really try to push pharmaceutical companies to the market for rare disease drugs - Huge investments have been made to drive the innovation of new modalities to treat these indications - There is still a HUGE role for traditional small molecule drugs - Examples: - Small molecules: Protacs. If we have cancer and also kinase cascades, we identify a protein in the kinase cascade that is causing the proliferation of cancer cells (drive them to grow) -- we want to target that specific protein and get rid of it. The idea of Protacs is to hijack the body's own dumping system. We have a chemical that binds to two proteins, the first protein is E3 ligase and the second is the target protein. The chemical brings the two proteins in line, allowing the ubiquitination of the target protein, which then goes to the protein degradation system -- a clever way to get rid of a protein in a cascade of systems that is causing a problem in cancer - Biologics: Recombinant proteins. If we have a disease, such as type I diabetes, where the islet cells of the pancreas are destroyed and don't produce any insulin anymore, we can make recombinant insulin and inject it into ourselves at the correct times. Recombinant proteins is a treatment for breast cancer -- Herceptin. A personalized medicine -- they take a biopsy of the tumor, and they look to see if it expresses the HER2 molecule (a receptor, when bound can help the breast cancer to proliferate (grow) and attract in blood vessels -- we don't want that). There is a personalized test, which says whether the woman is HER2 positive. If the woman is positive, she can have Herceptin, which is a monoclonal antibody that will bind to the HER2 receptor and block the negative effects of HER2 molecule binding. - Gene therapies: There are lots of monogenic diseases and a lot of them are in children. Monogenic -- the disease is caused by single mutations in a single protein. We do genetic testing on these children, identify they have such mutations, then we ca use gene therapy. It is about delivering genes to the patients. One of the ways is using viruses to deliver the RNA that replaces the defective gene. Used in Spinal Muscular Atrophy therapy (therapy name - Zolgensma) CHEMISTRY BEHIND PHARMACOLOGY Session 5, 6, (Anil) - Every drug should bind to its specific target to elicit a biological response!!! - Targets are receptors, ion channels, transporters or enzymes - A drug molecule binds to the specific target to elicit a biological response - 2 very important terms - POTENCY: The strength of a drug, indicating the concentration/dose required to elicit a specific biological effect. A more potent drug achieves its effect at a lower concentration - SELECTIVITY: The drug stability to target specific receptors or other biological pathways, while minimizing the interaction with other targets. Reducing off-target effects - A drug won't work unless it's bound - Several drug targets with different types - Every drug molecule should bind to one of these - ALL THE TARGETS ARE COMPOSED OF PROTEINS!!! The Proteins: - All proteins are produced by chains of amino acids - Understanding the chemistry of proteins is important for drug design - In humans, we have a set of 20 amino acids - They have the same base body, but differ in the R (side chain) - They all have an amine side chain, a carboxyl group and an R group  - Generally, substitution in the R group makes a different amino acid with different behaviours -- changing the functional R position makes a new amino acid - Depending on the structure, amino acids are defined into 2 types: - Hydrophobic -- dislikes water, doesn't dissolve in water, also lipophilic -- likes fat, no ionizable side chains (non-polar functional groups) - Hydrophobic molecules repel water and associate with other hydrophobic molecules in an aqueous environment. Such interactions play a pivotal role in biological systems -- lipid bilayer, protein folding. - Glycine, Alanine, Valine, Leucine - Hydrophilic -- likes water, also lipophobic, polar, have ionizable side chains - Hydrophilic molecules can interact favorably with water molecules, have charged molecules in the side chains (Phosphate group, hydroxyl group...) - Dissolve in water through H bonding and hydrophilic interactions -- crucial in systems, such as formation of H bonds in DNA, increasing solubility - Serine, Lysine, Histidine, Glutamic acid Some Amino Acids Can Form Cross-Links - Cystine can cross-link to another cystine by an interaction between the SH group - Important for protein folding A diagram of a structure Description automatically generated - Polar amino acids are hydrophilic and are mainly surface-binding amino acids - Non-polar amino acids are hydrophobic and are mainly present in the membrane and receptor binding between hydrophilic and hydrophobic amino acids - A drug molecule is a small chemical, which binds to the various target molecules (proteins), there is a chemical interaction within the receptor between eliciting the response - Mainly driven by AFFINITY and SPECIFICITY Drugs Are: - Usually organic -- primarily composed of C compounds, bound with O, N, P and other elements - Frequently cyclic -- aromatic rings, which mainly contributes to their stability and specificity for biological interactions - Cyclic nature is mainly responsible for the binding to the specific targets  - The chemical interaction between 2 molecules - If you look at the structure of paracetamol, the functional groups should be at the para position in order to elicit antipyretic activity - If you change the positions of the functional groups, it reduces the effect - If OH- group is removed, the remaining structure will become less-effective and toxic - If the acetyl group leads to paraminophenol, which is also very toxic in the body - Every paracetamol has specific positions for the side chains for its main action - Every functional group is important for the activity of the drug!!! A diagram of a chemical structure Description automatically generated - Reducing the COOH group to either amine side chains leads to salicylamide, makes the compound lose its anti-inflammatory activity - Substitution of a Halogen atom in the aromatic ring increases the potency and toxicity of the drug - Aspirin has an optimized structure with minimized side effects and maximized anti-inflammatory activity - STRUCTURE-ACTIVITY RELATIONSHIP!!!  - There are various chemical bonds, involved in the drug action - Affinity and Selectivity depends on the overall strength of the molecule, interaction - Several types of bonds may act simultaneously - Rarely covalent, usually reversible - Structure-Relationship studies aim to optimize BOTH Affinity and Selectivity/Specificity - Drug treatments for AIDS - Acquired ImmunoDefficiency Syndrome -- acquired suppression of the immune system - The causative agent for AIDS is an RNA retrovirus, HIV - There are various important components in the virus (reverse RNA transcriptase, protease, RNA) for the virus replication - Researchers identified these as a target in order to synthesize small drug molecules - By identifying the target, we can easily create a drug molecule for the treatment for AIDS - Protease inhibitors: - Protease enzyme is crucial for the HIV virus replication -- by inhibiting it, we can treat the diseases, caused by the virus - Drugs are designed to bind the catalytic side of proteases and destroy it A screenshot of a cell phone Description automatically generated Structure-Activity Relationships (SAR) - SAR is the relationship between the chemical structure of a molecule (drug) and its biological effects - Pharmacophore -- functional groups, which are ESSENTHIAL for pharmacological activity Penicillin -- Mechanism of Action  A diagram of a cell membrane Description automatically generated - Bacterial cell walls contain peptidoglycans in this case, which contains amino acid chains (green and blue), which are cross-linked to other amino acid chains by transpeptidase enzymes - When penicillin enter the bacteria through the pores, binds to the penicillin binding proteins (the red). Activated penicillin binding proteins inactivate the transpeptidase enzyme, disturbing the amino acid architecture - Penicillin binds to the PBP, leading to the inactivation of the transpeptidase cross-link, which breaks down the amino acid architecture in the bacterial cell wall. - Inhibits bacterial growth - Penicillin is a bactericidal drug (kills bacteria) by inhibiting bacterial cell wall synthesis - By changing the penicillin ring structure at R position to become a different penicillin can change its properties - Could treat different diseases for different bacteria (Gram-positive and Gram-negative) Chemical and Neurotransmission in the Nervous System  - NO somatic nervous system -- we focus on the autonomic Sympathetic Nervous System - Has many various effects on blood vessels, sweat glands, saliva glands, heart... - Responsible for the fight or flight response Parasympathetic Nervous System - Has regulatory body activities - Has impact on pupils, salivary glands, heart, reproductive system... BOTH - Completely different, will regulate heart rate, blood vessel contraction, smooth muscle contraction How Chemical Transmission Occurs in those 2 nervous systems? - There is an electrical impulse, there are chemicals (various neurotransmitters, synthesized within the ganglia) are released to the presynaptic or postsynaptic cleft, which elicit the pharmacological response - The released chemical binds to the receptor, the receptor gets activated and elicits the biological response - A chain: a chemical is released to the postganglionic fiber/synaptic region, due to the electrical impulse, the released chemical binds to the receptor on the postganglionic fiber, which sends the chemical into another receptor - There are 2 different neurotransmitters, presenting 2 different systems - Parasympathetic has acetylcholine - Sympathetic has noradrenaline Acetylcholine - Parasympathetic A chemical formula of acetylcholine Description automatically generated - Acetyl group, attached to the choline molecule - Ach is synthesized within the neuron - Synthesized Ach is stored within vesicles, unless there is an electrical impulse (depolarization) - Such impulse opens ion channels, increasing ion concentration within the cell, activation of secondary messengers, leading to smooth muscle contraction ultimately - Ach released from the synaptic cleft binds to various receptors to elicit pharmacological action - A N+ atoms with methyl groups in all direction -- quaternary ammonium ion - 3 methyl groups and 1 ethyl -- ethylene bridge - Ach has 3 different structural components -- ammonium group, ethylene bridge, acetyl group - Quaternary ammonium groups are very active, compared to other groups. It is also important for the activity because of the + charge - Methyl groups on the side chain -- if you change the methyl to further groups, it becomes more toxic and more reactive - Numbering of C atoms starts to the closest one to the N - The ethylene bridge -- if you add methyl groups to one of the Cs there, it becomes highly toxic. - Acetylcholine has 2 types of receptors -- nicotinic and muscarinic - If you put methyl group at alpha position (1^st^ C), there are more nicotinic receptors to recognize the molecule, whereas if put methyl group at the beta positions (2^nd^ Carbon), it makes it more selective to muscarinic receptors - If you modify the alpha C, it has higher selectivity for nicotinic receptors, kif you modify the beta C, is has higher selectivity for muscarinic receptors -- modify with methyl - Acetyl group -- if you change it in any way, it has reduced therapeutic activity and higher toxicity Noradrenaline  - 3 Hydroxyl molecules -- important for the function - Ach transmits the signal to the postganglionic fiber, when there is an electrical impulse - Ach is released to the synaptic cleft and transmitted to the postganglionic fiber - Then, it binds to the receptors -- nicotinic or muscarinic - When Ach binds to the receptors: - Nicotinic receptors are ligand-gated ion channels -- opening of channels, entry of ions, depending on what type of ion the channel is, then it stimulates the secondary messengers, activating phosphorylated myosin-kinase, which activates actin-myosin filaments on the smooth muscle, leading to contraction - Muscarinic receptors are G protein-coupled receptors -- divided into subunits. Binding/Activation leads to dissociation of the alpha group, which binds to alpha receptors, eliciting biological responses Transmission in the SYMPATHETIC Nervous System - The neurotransmitter at ALL ganglia is ACETYLCHOLINE - The neurotransmitter at ALL sympathetic neuroeffector junctions is NORADRENALINE - The initial neurotransmitter is acetylcholine, which stimulates the release of noradrenaline in the postganglionic fiber in the sympathetic nervous system - Noradrenaline is synthesized and stored in the synaptic vesicles - Sympathetic nervous system increases heart rate, while parasympathetic decreases heart rate -- ALWAYS A BALANCE, Opposing effects - The neurotransmitters are released balanced -- if you have too much noradrenaline, heart rate becomes crazy, high force contraction hypothalamus in the brain stimulates the parasympathetic nervous system to release acetylcholine and balance the heart rate out 2 Types of Receptors Diagram of a diagram of a heart and bronchial flow Description automatically generated - Each ahs a unique role in the body - Alpha receptors: Noradrenaline \> Adrenaline - Beta receptors: Adrenaline \> Noradrenaline - Contraction of these receptors stimulates smooth muscle and the heart to induce various effects - SELECTIVITY IS VERY IMPORTANT - If we need to increase the heart rate -- beta receptors are the ones that get activated in order to improve heart rate - ALPHA receptors -- present on blood vessels, mainly regulate blood pressure - No activity -- no specificity to any receptor - Dopamine is initially inactive, it becomes active after it is converted to levodopa  -